Management of Menopause-Related Symptoms - AHRQ Archive ...

Evidence Report/Technology AssessmentNumber 120Management of Menopause-Related SymptomsPrepared for:Agency of Healthcare Research and QualityU.S. Department of Health and Human Services540 Gaither RoadRockville, MD 20850www.ahrq.govContract No. 290-02-0024Prepared by:Oregon Evidence-based Practice CenterOregon Health & Science UniversityPortland, OregonInvestigatorsHeidi D. Nelson, MD, MPHElizabeth Haney, MDLinda Humphrey, MD, MPHJill Miller, MDAnne Nedrow, MDChristina Nicolaidis, MD, MPHKimberly Vesco, MDMiranda Walker, BAChristina Bougatsos, BSPeggy Nygren, MAAHRQ Publication No. 05-E016-2March 2005

This document is in the public domain and may be used and reprinted without permission exceptthose copyrighted materials noted for which further reproduction is prohibited without thespecific permission of copyright holders.Suggested citation:Nelson HD, Haney E, Humphrey L, Miller J, Nedrow A, Nicolaidis C, Vesco K, Walker M,Bougatsos C, Nygren P. Management of Menopause-Related Symptoms. EvidenceReport/Technology Assessment No. 120. (Prepared by the Oregon Evidence-based PracticeCenter, under Contract No. 290-02-0024.) AHRQ Publication No. 05-E016-2. Rockville, MD:Agency for Healthcare Research and Quality. March 2005.ii

PrefaceThe Agency for Healthcare Research and Quality (AHRQ), through its Evidence-BasedPractice Centers (EPCs), sponsors the development of evidence reports and technologyassessments to assist public- and private-sector organizations in their efforts to improve thequality of health care in the United States. The Office of Medical Applications of Research,National Institutes of Health, requested and provided funding for this report. The reports andassessments provide organizations with comprehensive, science-based information on common,costly medical conditions and new health care technologies. The EPCs systematically review therelevant scientific literature on topics assigned to them by AHRQ and conduct additionalanalyses when appropriate prior to developing their reports and assessments.To bring the broadest range of experts into the development of evidence reports and healthtechnology assessments, AHRQ encourages the EPCs to form partnerships and enter intocollaborations with other medical and research organizations. The EPCs work with these partnerorganizations to ensure that the evidence reports and technology assessments they produce willbecome building blocks for health care quality improvement projects throughout the Nation. Thereports undergo peer review prior to their release.AHRQ expects that the EPC evidence reports and technology assessments will informindividual health plans, providers, and purchasers as well as the health care system as a whole byproviding important information to help improve health care quality.We welcome comments on this evidence report. They may be sent by mail to the Task OrderOfficer named below at: Agency for Healthcare Research and Quality, 540 Gaither Road,Rockville, MD 20850, or by e-mail to epc@ahrq.gov.Carolyn M. Clancy, M.D.DirectorAgency for Healthcare Research and QualityBarnett S. Kramer, M.D., M.P.H.DirectorOffice of Medical Applicationsof ResearchNational Institutes of HealthJean Slutsky, P.A., M.S.P.H.Director, Center for Outcomes and EvidenceAgency for Healthcare Research and QualityKenneth S. Fink, M.D., M.G.A., M.P.H.Director, EPC ProgramAgency for Healthcare Research and QualityCarmen Kelly, PharmDEPC Program Task Order OfficerAgency for Healthcare Research and QualityThe authors of this report are responsible for its content. Statements in the reportshould not be construed as endorsement by the Agency for Healthcare Research andQuality or the U.S. Department of Health and Human Services of a particular drug,device, test, treatment, or other clinical service.iii

AcknowledgmentsThis systematic evidence review was developed for the National Institutes of Health State-of-the-Science Conference on Management of Menopause-Related Symptoms. It was supported by theOffice of Medical Applications of Research (OMAR) at the National Institutes of Health and theAgency for Healthcare Research and Quality (AHRQ), and the investigators acknowledge thecontributions of Carmen Kelly, PharmD, Task Order Officer, AHRQ, Lata Nerurka, PhD,OMAR, and Carol Mangione, MD, MSPH, Chair of the State-of-the-Science Conference Panel.The Women’s Health Fellowship at the Portland Veterans Administration Medical Centerprovided support for Kimberly Vesco, MD. Investigators thank the Technical Expert Panelmembers providing guidance for the project, expert reviewers commenting on the draft version,Andrew Hamilton, MLS, MS for conducting the literature searches, and Laurie Huffman, MS,and Korene Maceo, BS, for assisting with the project.iv

Structured AbstractContext: Although many symptoms have been attributed to the menopausal transition, it isunclear which symptoms are actually associated and how to effectively manage them.Objective: To describe the evidence about symptoms associated with menopause, factors thatinfluence them, benefits and adverse effects of therapies, factors that influence therapies, andfuture research needs.Data Sources: Relevant studies were identified from multiple searches of MEDLINE ® ,PsycINFO, DARE, the Cochrane database, MANTIS, and AMED (1953 to November 2004);and from recent systematic reviews, reference lists, reviews, editorials, websites, and experts.Study Selection: Specific inclusion and exclusion criteria were developed to determine studyeligibility. The target population includes adult women in the U.S. undergoing the menopausaltransition.Data Extraction: All eligible studies were reviewed and relevant data were extracted, enteredinto evidence tables, and summarized by descriptive methods. Two reviewers independentlyrated the quality of studies using predefined criteria.Data Synthesis: Forty-eight studies conducted among 14 cohorts and 22 studies from otherpopulations provide data about symptoms. Vasomotor symptoms and vaginal dryness are mostconsistently associated with menopause; sleep disturbance, somatic complaints, urinarycomplaints, sexual dysfunction, mood, and quality of life are inconsistently associated. Nostudies provide data on cognition and uterine bleeding problems, duration and severity ofspecific symptoms, or conclusive data on the influence of race/ethnicity, age of onset ofmenopause, body mass index, oophorectomy status, depression, or smoking. Results of 192randomized controlled trials of therapies indicate that for vasomotor symptoms, estrogen iseffective; tibolone demonstrates benefit, but most studies are poor-quality; paroxetine,veralipride, gabapentin, soy isoflavones, and other phytoestrogens report benefit in some trials.Results for other symptoms are mixed, adverse effects are inadequately reported, and placeboeffects are large. No trials describe the influence of bilateral oophorectomy, premature ovarianfailure, use of potentially interacting agents, lifestyle and behavioral factors, recentdiscontinuation of hormones, or body mass index. For women with breast cancer, clonidine,venlafaxine, and megestrol acetate improve vasomotor symptoms, and results for othersymptoms are mixed.Conclusions: Vasomotor symptoms and vaginal dryness are most consistently associated withthe menopausal transition. Results of treatment trials are consistent and conclusive only forestrogen. For other agents, the evidence base is limited by lack of studies demonstratingeffectiveness, poor quality of existing studies, and incomplete information on adverse effects.Keywords: Menopause, menopause transition, menopause symptoms, treatment of menopausesymptomsv

FiguresFigure 1. Normal Reproductive Aging in Women.........................................................................82Figure 2. Analytic Framework.......................................................................................................83Figure 3. Quality Rating Criteria ...................................................................................................84TablesTable 1. Measures of Menopause-Related Symptoms...................................................................86Table 2. Descriptions of Cohort Studies........................................................................................89Table 3. Results of Cohort Studies of Menopause-Related Symptoms.........................................91Table 4. Results of Cross-Sectional Studies of Menopause-Related Symptoms.........................105Table 5. Trials of Estrogen for Depression..................................................................................107Table 6. Trials of Progestins ........................................................................................................110Table 7. Trials of Androgens .......................................................................................................111Table 8. Trials of Tibolone ..........................................................................................................114Table 9. Trials of Antidepressant Drugs......................................................................................119Table 10. Trials of Clonidine......................................................................................................121Table 11. Trials of Methyldopa, Bellergal, and Gabapentin........................................................124Table 12. Trials of Phytoestrogens and Isoflavones ....................................................................125Table 13. Trials of Complementary and Alternative Therapies ..................................................130Table 14. Trials of Behavioral Interventions ...............................................................................137Table 15. Summary of Benefits of Therapies ..............................................................................139Table 16. Trials in Women with Breast Cancer...........................................................................141AppendixesAppendix A. Technical Expert Panel MembersAppendix B. Expert ReviewersAppendix C. Literature Search StrategiesAppendix D. Inclusion and Exclusion CriteriaAppendix E. Literature Search TreeAppendix F. Evidence TablesNote: Appendixes and Evidence Tables are provided electronically athttp://www.ahrq.gov/clinic/tp/menopstp.htmviii

Agency for Healthcare Research and QualityEvidence Report/Technology AssessmentNumber 120Management of Menopause-Related SymptomsSummaryAuthors: Nelson HD, Haney E, Humphrey L, Miller J, Nedrow A, Nicolaidis C, Vesco K,Walker M, Bougatsos C, Nygren PIntroductionMenopause is defined as the permanentcessation of menses resulting from reducedovarian hormone secretion that occurs naturallyor is induced by surgery, chemotherapy, orradiation. Natural menopause is recognized after12 months of amenorrhea that is not associatedwith a pathologic cause. The average age ofmenopause in the United States is 51 years, andcan vary normally between 40 and 58 years. 1 Themenopausal transition can span over several years,and often begins with variations in menstrualcycle length in response to rising levels of folliclestimulating hormone (FSH). The mean age ofonset of the menopausal transition is 47.5 yearsand commonly lasts approximately 4 to 5 years. 1Stages and nomenclature of the menopausaltransition were defined by experts in 2001 at theStages of Reproductive Aging Workshop(STRAW). 2 The group recognized seven stages ofthe reproductive aging continuum, andacknowledged that most women do not progressprecisely through each stage. These stages are alsodescribed by the following terms:• Premenopause: the time up to the beginningof the perimenopause, but is also used todefine the time up to the last menstrualperiod.• Perimenopause: the time around menopauseduring which menstrual cycle and endocrinechanges are occurring but 12 months ofamenorrhea has not yet occurred.• Postmenopause: begins at the time of the lastmenstrual period, although not recognizeduntil after 12 months of amenorrhea.A hot flash or flush refers to the spontaneoussensation of warmth, often associated withperspiration, resulting from a vasomotor responseto declining estrogen levels. Nightsweats are hotflashes or flushes occurring at night, often whilesleeping. Other symptoms, such as vaginaldryness, sleep disturbance, mood symptoms,cognitive disturbances, somatic complaints,urinary complaints, uterine bleeding problems,sexual dysfunction, and reduced quality of life arealso attributed to the menopausal transition.Although many measures have been developedto assess menopausal symptoms, few demonstratestandardization, validity, or reliability. Somemeasures are based on self-reports of the presence,severity, and frequency of individual symptoms,such as hot flashes. Others utilize cumulative orglobal scores based on lists or scales of symptomsattributed to menopause, such as mood,cognition, quality of life, sexual function, andsomatic symptoms. Many studies base theirmeasures on study-specific checklists,questionnaires, or scales. Ninety-two measures ofmenopausal symptoms were reported by studiesincluded in this evidence review.PurposeThis systematic evidence review focuses on fiveKey Questions relating to symptoms ofmenopause and their management, as specified bythe Planning Committee for the NationalInstitutes of Health State-of-the-ScienceAgency for Healthcare Research and QualityAdvancing Excellence in Health Care • www.ahrq.govEvidence-BasedPractice

Conference on Management of Menopause-Related Symptoms.The target population includes adult women in the UnitedStates undergoing the menopausal transition.1. What is the evidence that the symptoms more frequentlyreported by middle-aged women are attributable toovarian aging and senescence? These include vasomotorsymptoms, vaginal dryness, sleep disturbance, moodsymptoms, cognitive disturbances, somatic complaints,urinary complaints, uterine bleeding problems, sexualdysfunction, and reduced quality of life.2. When do the menopausal symptoms appear, how long dothey persist and with what frequency and severity, andwhat is known about the factors that influence them?Factors include race and ethnicity, age at onset of themenopause transition, body mass index (BMI), surgicalversus natural menopause, depression, and smoking.3. What is the evidence for the benefits and harms ofcommonly used interventions for relief of menopauserelatedsymptoms? Interventions include estrogens,progestins, androgens, tibolone, antidepressants, otherdrugs, phytoestrogens, complementary and alternativemedicine, and behavioral interventions.4. What are the important considerations in managingmenopause-related symptoms in women with clinicalcharacteristics or circumstances that may complicatedecision-making? These include bilateral oophorectomy,premature ovarian failure, breast cancer, concurrent use ofselective estrogen receptor modulators (SERMs) and otherinteracting therapeutic agents, lifestyle and behavioralfactors, recent discontinuation of menopausal hormonetherapy, and very low or very high BMI.5. What are the future research directions for treatment ofmenopause-related symptoms and conditions?MethodsA Technical Expert Panel was assembled to provide inputfrom experts and clinicians in the field to ensure that the scopeof the project addressed important clinical questions and issues.The panel included obstetrician/gynecologists, internists,naturopathic physicians, behavioral experts, and researchers.The panel was convened for periodic conference calls duringthe course of the project. Expert reviewers, including severalpanel members, provided comments on the draft evidencereport.Literature Search and StrategyRelevant studies were identified from multiple searches ofMEDLINE ® , PsycINFO, DARE, the Cochrane database ofsystematic reviews and controlled trials, MANTIS, and AMED(1953 to November 2004); and from recent systematic reviews,reference lists, reviews, editorials, websites, and experts.Retrieved abstracts were entered into an electronic database(EndNote ® ).Inclusion and Exclusion CriteriaFull text cohort studies with data on women experiencingmenopause and at least one of the symptoms listed in KeyQuestion 1 were initially reviewed and subsequently included ifthe study enrolled 100 or more subjects, subjects representedthe target population, and data on symptoms associated withmenopause were provided. Exclusions included studies ofwomen not undergoing the menopausal transition andexperiencing menopause related symptoms, studies of agingand its effects, and biologically based studies that did not reportepidemiological data relating to symptoms (e.g., studies ofhormone levels). Non-English language papers and studies ofanimals or cadavers were also excluded. Cross-sectional studiesmeeting similar inclusion/exclusion criteria were examined forcontributory data and included if they reported relevant dataabout symptoms by menopausal stage, such as prevalence rates.Full text randomized controlled trials and meta-analyses ofrandomized controlled trials providing data on treatment ofmenopausal symptoms, using one or more of the interventionslisted in Key Question 3, were included. Trials enrollingwomen with breast cancer were considered separately fromthose enrolling women without breast cancer. Exclusionsincluded studies of women not undergoing menopause andexperiencing menopause related symptoms during the course ofthe study, studies of animals, and non-English language papers.Data Extraction and SynthesisAll eligible studies were reviewed and a “best evidence”approach was applied, in which studies with the highest qualityand most rigorous design are emphasized. 3 Data were extractedfrom each study, entered directly into evidence tables, andsummarized descriptively. Benefits and adverse effects oftherapies were considered equally important and both types ofoutcomes were abstracted. Trials of alternative andcomplementary therapies were grouped according to theNational Center for Complementary and Alternative Medicinecategories 4 most closely related to included topics. Results of2

ecently published meta-analyses on estrogens 5-7 and isoflavones 8are included in this report. No new meta-analyses wereconducted because of heterogeneity of trials of other therapies.Two reviewers independently rated the quality ofrandomized controlled trials and cohort studies using criteriaspecific to different study designs developed by the UnitedStates Preventive Services Task Force. 9 Similar criteria for crosssectionalstudies are not available. The overall rating is acombination of internal and external validity scores. Whenreviewers disagreed, a final rating was reached throughconsensus. Studies reporting several different outcomes mayhave different quality ratings for each outcome depending onhow completely it controlled for key confounders in multivariablemodels.Size of LiteratureA total of 10,059 unique citations were reviewed, including6,342 about symptoms and factors influencing them (KeyQuestions 1 and 2); 4,078 about therapies (Key Question 3);and 806 about specific characteristics that may influence theeffects of therapies (Key Question 4).ResultsTo address Key Questions 1 and 2, the review focused onprospective studies of cohorts of midlife women transitioningthrough the stages of menopause. Forty-eight studiesconducted among 14 cohorts met inclusion criteria. Sevencohorts were based in the United States (MassachusettsWomen’s Health Study, Seattle Midlife Women’s Health Study,Ohio Midlife Women’s Study, National Health ExaminationFollow-up Study [NHANES], Study of Women’s Health Acrossthe Nation [SWAN], University of Minnesota/Tremin TrustLongitudinal Study, and Pennsylvania Ovarian Aging Study).Seven cohorts were based outside the United States(Gothenburg, Sweden, Australian Longitudinal Study onWomen’s Health, Medical Research Council [MRC], U.K.,Melbourne Women’s Midlife Health Project, Australia,Manitoba Project on Women and Their Health in the MiddleYears, Canada, Copenhagen, Denmark, and Eindhoven,Netherlands). An additional 22 cross-sectional studies fromother populations meeting similar inclusion criteria wereobtained to provide additional prevalence data.Major limitations of studies include dissimilar methods forevaluating and reporting symptoms and for assessingmenopausal change. Some cohort studies based results oncross-sectional data reported at serial time points rather thanindividual tracking of women over time. Some studies failedto adjust or stratify for potentially important variables such asage, race, BMI, life events, or history of depression whenattempting to attribute symptoms to change in menopausalstage. Although most included studies were population-based,in many cases, enrolled women were additionally selected fromthe initial recruited cohort and may have been lessrepresentative of the general population. Also, many studieswere based on cohorts recruited from community populationsand are more representative of volunteers than entirecommunities.Key Question 1. What is the evidence that the symptomsmore frequently reported by middle-aged women areattributable to ovarian aging and senescence?• Vasomotor symptoms: Evidence from population-basedcohort and cross-sectional studies supports the associationbetween vasomotor symptoms and menopausal stage.Studies are consistent in reporting increasing prevalencerates of vasomotor symptoms as women transition frompremenopause to either perimenopause or postmenopause,affecting 50 percent or more of women. Studies suggestthat vasomotor symptoms persist for several years aftermenopause for some women.• Vaginal dryness: Vaginal dryness is associated withmenopause and prevalence rates increase as womentransition through the menopausal stages. Estimatesindicate that up to one third of perimenopausal andpostmenopausal women experience vaginal dryness.• Sleep disturbance: Although results of studies are mixed,two good-quality cohort studies indicate that women havemore difficulty sleeping as they transition throughmenopausal stages, and this may be due to vasomotorsymptoms. Up to 40 percent to 60 percent ofperimenopausal and postmenopausal women experiencesleep disturbance, a slight increase from prevalence rates ofpremenopausal women.• Mood symptoms: The majority of studies from a largeliterature report no associations between menopausal stageand mood symptoms, development of a mental disorder,or general mental health. Studies of prevalence ratesreport wide ranges that are similar across menopausalstages.• Cognitive disturbances: No cohort studies are available.Cross-sectional studies indicate no difference inforgetfulness, memory, or concentration.• Somatic complaints: Most studies report no association ofsomatic symptoms with menopause, although somaticsymptoms were increased among perimenopausal women3

compared with premenopausal women in one cohort andtwo cross-sectional studies.• Urinary complaints: Urinary leakage increased amongperimenopausal women compared with premenopausalwomen in one study, and another reported noassociations. Studies of prevalence rates report wideranges that are similar across menopausal stages.• Uterine bleeding problems: No studies meeting inclusioncriteria addressed uterine bleeding problems, most likelybecause currently accepted definitions of menopause relyhistorically on changes in uterine bleeding.• Sexual dysfunction: Women from one study cohortreported declines in some or all of the measured sexualparameters as they transitioned through menopausalstages. Results of cross-sectional studies are mixed.• Reduced quality of life: Results of available cohort andcross-sectional studies are conflicting.Key Question 2. When do the menopausal symptomsappear, how long do they persist and with what frequency andseverity, and what is known about the factors that influencethem?• Included studies do not provide adequate details tocharacterize the onset, severity, and duration of specificsymptoms. Frequency is described by prevalence data inKey Question 1.• Race and ethnicity: The influence of race and ethnicity onmenopausal symptoms has not been extensively studied.Prevalence rates of vasomotor and mood symptoms varyamong race and ethnic groups in the large SWAN cohort.• Age at onset of menopausal transition: Available studies areinconclusive.• Body mass index: Available studies are inconclusive.• Surgical versus natural menopause: Studies present mixedresults regarding the impact of surgical menopause onvasomotor symptoms, vaginal dryness, and mood.Adjustment for confounders is necessary because womenundergoing hysterectomy differ from women with naturalmenopause in ways that may also influence theirmenopause related symptoms.• Depression: One cross-sectional study reported that prioranxiety or depression did not predict menopausalsymptoms. Cohort studies show that a history ofdepression predicts depression in the menopausaltransition. No studies evaluated depression in associatonwith other menopausal symptoms.• Smoking: Available studies are inconclusive.Key Question 3. What is the evidence for the benefits andharms of commonly used interventions for relief of menopauserelatedsymptoms?• A total of 192 randomized controlled trials of therapies formanaging menopause-related symptoms were evaluated,including trials of estrogens, progestins, androgens(testosterone and DHEA [dehydroepiandrosterone]),tibolone, antidepressants (selective serotonin reuptakeinhibitors, moclobemide, veralipride), other drugs(clonidine, methyldopa, gabapentin, Bellergal),phytoestrogens (dietary and extract forms of soyisoflavones, other forms of phytoestrogen, combinations),complementary and alternative medicine (acupuncture,Chinese herbs, red clover, black cohosh, combinations,other types of supplements, manual therapies, energytherapies), and behavioral interventions (exercise and othertypes of interventions).• Estrogen, in either opposed or unopposed regimens, is themost consistently effective therapy for vasomotorsymptoms, and demonstrates benefit in most trialsevaluating urogenital symptoms. Some, but not all, trialsevaluating sleep, mood and depression, sexual function,and quality of life outcomes also report benefit withestrogen compared to placebo.• Breast tenderness and uterine bleeding are the mostcommonly reported adverse outcomes in estrogen trials;others include nausea and vomiting, headache, weightchange, dizziness, venous thromboembolic events,cardiovascular events, rash and pruritus, cholecystitis, andliver effects.• Trials of progestin indicate mixed results for treatment ofvasomotor symptoms.• Few trials of testosterone are available; one trial indicatedno differences between testosterone/estrogen and estrogenalone for hot flash severity, vaginal dryness, or sleepproblems. Sexual symptoms were improved withtestosterone/estrogen compared to estrogen alone orplacebo in two other trials.• For women using testosterone combined with estrogen,acne and hirsutism occur significantly more often than forwomen using estrogen alone.• Based on only a few fair or good-quality trials, tibolonedemonstrated benefit for vasomotor symptoms, sleep, andsomatic complaints compared to placebo, and was similarto estrogen for some, but not all, symptoms.• Uterine bleeding, body pain, weight gain, and headachewere more common in tibolone vs. placebo groups.4

• Several agents demonstrate benefits in managingvasomotor symptoms in some, but not all trials, or in onlya few available trials, including paroxetine, veralipride,gabapentin, soy isoflavones, and other phytoestrogens.• Trials of soy isoflavones and other complementary andalternative medicine therapies report benefits in improvingnonvasomotor symptoms, although results vary widely,methods are lacking, and studies are typically small andnot generalizable.• Placebo effects in trials are large reflecting underlyingfluctuations of symptoms.• Although benefits and adverse effects of therapies wereequally important in this review, most trials did not reportadverse effects or reported them incompletely.Key Question 4. What are the important considerations inmanaging menopause-related symptoms in women with clinicalcharacteristics or circumstances that may complicate decisionmaking?• Evidence is not available to determine if the effectivenessof therapy for menopause related symptoms or adverseeffects differ for women with bilateral oophorectomy,premature ovarian failure, concurrent use of SERMs orother potentially interacting agents, lifestyle andbehavioral factors, recent discontinuation of menopausalhormone therapy, or very low or very high BMI.• For women with breast cancer, results of 15 randomizedcontrolled trials indicate that clonidine, venlafaxine, andmegestrol acetate are associated with significantlyimproved measures of hot flashes, and vitamin E, blackcohosh, isoflavones, magnets, and fluoxetine are not.Results for nonvasomotor outcomes are mixed.Key Question 5. What are the future research directions fortreatment of menopause-related symptoms and conditions?In order to fill evidence gaps, future research could focus on:• Determination of optimally effective doses, combinationregimens, durations of use, and timing of therapy.• Evaluation of approaches to identify optimal candidatesfor specific therapies (e.g., identification ofthrombophilias).• Head-to-head and placebo comparisons of estrogen aloneand combined with other types of therapies including nondrug interventions.• Trials demonstrating how to discontinue estrogen whensymptoms subside, including the effectiveness of taperingdoses and/or replacing with other therapies including nondrug interventions.• Better reporting of adverse effects in trials and use ofstandardized categories of adverse effects so data can becombined across trials.• Improved analysis of results including analysis byhysterectomy and oophorectomy status, stage ofmenopause, age, concurrent conditions and medications,and other factors.• More comprehensive trials to determine the role of regularexercise, sleep management, optimal nutrition, healthyrelationships, social support, and relaxation; effects ofmind-body techniques such as biofeedback and breathing;effects of a whole system approach with Chinese medicine.• Additional, well-designed and controlled trials ofphytoestrogens, botanicals, and bio-identical hormones,especially estriol, estradiol, and progesterone. Furtherstudy of antidepressants for vasomotor symptoms wouldbe justified based on evidence of currently available trials.• Enrollment of women with specific characteristics whohave not previously been evaluated such as nonwhitewomen, women with premature ovarian failure, thoseusing SERMs and other agents influencing symptomsconcurrently, women with very high or low BMI, andthose with lifestyle and behavioral factors influencingsymptoms. Trials should report data specific to thesegroups in order to interpret their influence on therapy.• Use of standard definitions, measures, outcomes, andstatistical methods for longitudinal data so results can becompared across trials and population cohorts.• Prevalence data in U.S. women.• Details about onset, timing, and duration of symptoms inrelation to menopausal stage.• Studies of symptoms after surgical menopause with andwithout hormonal therapy.ConclusionsBased on review of currently available cohort and crosssectionalpopulation studies, vasomotor symptoms and vaginaldryness are symptoms most consistently associated with themenopausal transition. Sleep disturbance, somatic complaints,urinary complaints, sexual dysfunction, mood, and quality oflife are inconsistently associated. No cohort studies providedata on cognition, but cross-sectional studies suggest noassociation. There are no studies about uterine bleedingproblems, onset, duration, and severity of specific symptoms, orconclusive data on the influence of race/ethnicity, age of onsetof menopause, BMI, oophorectomy status, presence of5

depression, or smoking status. The literature is limited bydifferences in how symptoms are defined and measured,variability of study populations, and incompatibility of datapreventing direct comparisons between studies or pooling ofresults. Future research using standard and validated measuresand uniform definitions for a more comprehensive array ofsymptoms would improve knowledge of these associations.Trials of therapy are conclusive only for estrogen and its usein treating vasomotor and urogenital symptoms, although othertherapies may prove effective if further studied. Undertakingtrials to treat symptoms that are not clearly associated with themenopausal transition would not be useful. Trials are limited inmany ways including use of highly selected small samples ofwomen; short durations; inadequate reporting of loss to followup, maintenance of comparable groups, contamination,methods of analysis, and adverse events; use of dissimilarmeasures and outcomes that are often not standardized orvalidated; unclear inclusion and exclusion criteria; and industrysponsorship. Future research addressing these deficiencies, asoutlined in Key Question 5, would guide patient and cliniciandecision making when managing menopause related symptoms.The evidence review is limited in several ways. For KeyQuestions 1 and 2, literature searches focused on populationstudies of women undergoing the menopausal transitionreporting symptoms, and did not include epidemiologic orbiologically-based etiologic studies. In addition, studies thatmay not have been identified by searches include those inwhich menopause was not a primary focus of the study, but apredictor variable included in a multivariable model evaluatingthe outcome or symptom of interest. Studies potentially notidentified would be those that identified no association betweenmenopausal stage and the outcome of interest. Studies with apositive association would probably have reported it in theabstract and be identified by the searches. Also, the review waslimited to English-language randomized controlled trials oftherapies. Exploratory studies of agents may providecontributory data that were not included in this report.Availability of the Full ReportThe full evidence report from which this summary was takenwas prepared for the Agency for Healthcare Research andQuality (AHRQ) by the Oregon Evidence-Based PracticeCenter, under Contract No. 290-02-0024. It is expected to beavailable in March 2005. At that time, printed copies may beobtained free of charge from the AHRQ PublicationsClearinghouse by calling 800-358-9295. Requesters should askfor Evidence Report/Technology Assessment No. 120,Management of Menopause-Related Symptoms. In addition,Internet users will be able to access the report and summaryonline through AHRQ’s Web site at www.ahrq.gov.Suggested CitationNelson HD, Haney E, Humphrey L, Miller J, Nedrow A,Nicolaidis C, Vesco K, Walker M, Bougatsos C, Nygren P.Management of Menopause-Related Symptoms. Summary,Evidence Report/Technology Assessment No. 120. (Prepared bythe Oregon Evidence-based Practice Center, under ContractNo. 290-02-0024.) AHRQ Publication No. 05-E016-1.Rockville, MD: Agency for Healthcare Research and Quality.March 2005.References1. North American Menopause Society. Available at:www.menopause.org. Accessed 13 Dec, 2004.2. Soules MR, Sherman S, Parrott E, al. e. Executive summary: stages ofreproductive aging workshop (STRAW) Park City, Utah, July 2001.Menopause. 2001;8:402-407.3. Slavin RE. Best practice synthesis: An alternative to meta-analytic andtraditional reviews. Education Research. 1986;15:5-11.4. National Center for Complementary and Alternative Medicine.http://nccam.nih.gov/health/whatiscam/. Accessed 10 Jan. 20055. Nelson HD. Commonly used types of postmenopausal estrogen fortreatment of hot flashes: scientific review. JAMA. 2004;291(13):1610-1620.6. MacLennan AH, Broadbent JL, Lester S, Moore V. Oral oestrogenand combined oestrogen/progestogen therapy versus placebo for hotflushes. Cochrane Database Syst Rev. 2004.7. Nelson HD, Nygren P, Freeman M, Benjamin K. Drug Class Reviewon Estrogens. Final report. http://www.ohsu.edu/drugeffectiveness/reports/documents/Estrogens%20Final%20Report%20u2pdf.2004.Accessed 10 Jan. 20058. Krebs EE, Ensrud KE, MacDonald R, Wilt TJ. Phytoestrogens fortreatment of menopausal symptoms: A systematic review. ObstetGynecol. 2004;104(4):824-836.9. Harris RP, Helfand M, Woolf SH, et al. Current methods of the thirdU.S. Preventive Services Task Force. Am J Prev Med. 2001;20(3S):21-35.6www.ahrq.govAHRQ Pub. No. 05-E016-1March 2005ISSN 1530-440X

Evidence Report

Chapter 1. IntroductionPurposeThis systematic evidence review focuses on five Key Questions relating to symptoms ofmenopause and their management, as specified by the Planning Committee for the NationalInstitutes of Health State-of-the-Science Conference on Management of Menopause-RelatedSymptoms:1. What is the evidence that the symptoms more frequently reported by middle-aged womenare attributable to ovarian aging and senescence? These include vasomotor symptoms,vaginal dryness, sleep disturbance, mood symptoms, cognitive disturbances, somaticcomplaints, urinary complaints, uterine bleeding problems, sexual dysfunction, andreduced quality of life.2. When do the menopausal symptoms appear, how long do they persist and with whatfrequency and severity, and what is known about the factors that influence them? Factorsinclude race and ethnicity, age at onset of the menopause transition, body mass index(BMI), surgical versus natural menopause, depression, and smoking.3. What is the evidence for the benefits and harms of commonly used interventions forrelief of menopause-related symptoms? Interventions include estrogens, progestins,androgens, tibolone, antidepressants, other drugs, phytoestrogens, complementary andalternative medicine, and behavioral interventions.4. What are the important considerations in managing menopause-related symptoms inwomen with clinical characteristics or circumstances that may complicate decisionmaking?These include bilateral oophorectomy, premature ovarian failure, breast cancer,concurrent use of selective estrogen receptor modulators (SERMs) and other interactingtherapeutic agents, lifestyle and behavioral factors, recent discontinuation of menopausalhormone therapy, and very low or very high BMI.5. What are the future research directions for treatment of menopause-related symptoms andconditions?The target population includes adult women in the U.S. undergoing menopause. Theevidence review emphasizes the patient’s perspective in assessment of symptoms, the choice ofinterventions, outcome measures, and potential adverse effects, and focuses on those that areapplicable to clinical practice. It also considers the generalizability of efficacy studies performedin controlled settings. Although the evidence review attempts to assess research findings fromthe perspectives of clinicians and patients, it is not intended to propose practicerecommendations.3

Menopausal TransitionMenopause is defined as the permanent cessation of menses resulting from reduced ovarianhormone secretion that occurs naturally or is induced by surgery, chemotherapy, or radiation.Natural menopause is recognized after 12 months of amenorrhea that is not associated with apathologic cause. The average age of menopause in the U.S. is 51 years, and can vary normallybetween 40 and 58 years. 1 The menopausal transition can span over several years, and oftenbegins with variations in menstrual cycle length in response to rising levels of follicle stimulatinghormone (FSH). The mean age of onset of the menopausal transition is 47.5 years andcommonly lasts approximately 4 to 5 years. 1Stages and nomenclature of the menopausal transition were defined by experts in 2001 at theStages of Reproductive Aging Workshop (STRAW), sponsored by the American Society forReproductive Medicine, the National Institute on Aging, the National Institute of Child Healthand Human Development, and the North American Menopause Society. 2 The group recognizedseven stages of the reproductive aging continuum, and acknowledged that most women do notprogress precisely through each stage (Figure 1). These stages are also described by thefollowing terms:• Premenopause: the time up to the beginning of the perimenopause, but is also used todefine the time up to the last menstrual period.• Perimenopause: the time around menopause during which menstrual cycle and endocrinechanges are occurring but 12 months of amenorrhea has not yet occurred.• Postmenopause: begins at the time of the last menstrual period, although not recognizeduntil after 12 months of amenorrhea.Menopausal SymptomsA hot flash or flush refers to the spontaneous sensation of warmth, often associated withperspiration, resulting from a vasomotor response to declining estrogen levels. Although theterm “flash” indicates a prodromal phase and “flush” the vasomotor dilation phase, they arecombined in this report because they are reported inconsistently in studies. Nightsweats are hotflashes or flushes occurring at night, often while sleeping. Other symptoms, such as vaginaldryness, sleep disturbance, mood symptoms, cognitive disturbances, somatic complaints, urinarycomplaints, uterine bleeding problems, sexual dysfunction, and reduced quality of life are alsoattributed to the menopausal transition.4

Measures of Menopausal SymptomsAlthough many measures have been developed to assess menopausal symptoms, fewdemonstrate standardization, validity, or reliability. Some measures are based on self-reports ofthe presence, severity, and frequency of individual symptoms, such as hot flashes. Others utilizecumulative or global scores based on lists or scales of symptoms attributed to menopause, suchas mood, cognition, quality of life, sexual function, and somatic symptoms. Many studies basetheir measures on study-specific checklists, questionnaires, or scales. Ninety-two measures ofmenopausal symptoms were reported by studies included in this evidence review (Table 1). Themost common measures are described below.The Kupperman Index, or Kupperman Blatt Index, assesses overall menopause symptoms,and is frequently used to determine severity of hot flashes. The Kupperman Index grades theself-reported severity of 11 symptoms (hot flashes, paresthesias, insomnia, nervousness,melancholia, vertigo, weakness, arthralgia or myalgia, headache, palpitations, and formication)on a scale from 0 to 3. Item scores are weighted to create a composite score. This measure hasbeen validated and is responsive to change, however, it lacks statistical justification for weights. 3The Greene Climacteric Scale assesses the severity of 21 self-reported symptoms on a 4-pointscale. 4 Psychological, somatic, and vasomotor symptoms are assessed, along with one questionon sexual dysfunction. The Women’s Health Questionnaire was developed for use primarily as aquality of life instrument, although it is also used to measure overall symptoms. It includes 36items with 4-point self-report response categories. It has demonstrated reliability, has undergonepsychometric evaluation, and allows for cross-cultural comparisons. 3The Beck Depression Inventory and Hamilton Depression Rating Scale are widely-used andvalidated measures of depression that are highly correlated. 5,6 The Hamilton Depression RatingScale is the usual standard against which other depression rating scales are validated. ThePsychological General Well-Being Index is less commonly used, and has demonstrated validityin assessing general psychological well-being. 7The Brief Index of Sexual Functioning for Women is a 22-item validated self-reportinstrument measuring current levels of female sexual functioning and satisfaction, assessing bothquantitative and qualitative aspects. 8 The McCoy Sex Scale assesses sexual experience andresponsiveness in the 30 days prior to testing utilizing 14 items on a 7-point scale. 9The Menopause Specific Quality of Life Questionnaire is a validated instrument that assessesphysical, vasomotor, psychosexual, and sexual domains of life quality using a 7-point scale. Adifference in one point on a domain score represents a 15 percent change. 10 The NottinghamHealth Profile includes 38 yes/no questions in six subsections (physical mobility, pain, sleep,energy, social isolation, and emotional reactions). 11 The Short-Form 36 Health Survey measureseight health concepts and has been extensively tested and validated. 125

Chapter 2. MethodsAnalytic Framework and Key QuestionsThe Key Questions for this evidence review were determined by the Planning Committee forthe National Institutes of Health State-of-the-Science Conference on Management ofMenopause-Related Symptoms. Key Questions examine a chain of evidence about symptomscommonly associated with menopause, factors that may influence the frequency, severity, orpersistence of these symptoms, the effectiveness, benefits, and adverse effects of interventionsfor managing menopausal symptoms, and how the effects of interventions may differ for womenwith specific characteristics. The analytic framework (Figure 2) outlines the organization of keyquestions by identifying the target population, treatment interventions, health outcomes, and theirrelationships.Technical Expert Panel (TEP) and Expert ReviewersA Technical Expert Panel (Appendix 1) was assembled to provide input from experts andclinicians in the field to ensure that the scope of the project addressed important clinicalquestions and issues. The panel included obstetrician/gynecologists, internists, naturopathicphysicians, behavioral experts, and researchers. The panel was convened for periodic conferencecalls during the course of the project. Expert reviewers, including several panel members,provided comments on the draft evidence report (Appendix 2).Literature Search and StrategyRelevant studies were identified from multiple searches of MEDLINE, PsycINFO, DARE,the Cochrane database of systematic reviews and controlled trials, MANTIS, and AMED (1953to November 2004) (Appendix 3). Additional articles were obtained from recent systematicreviews, reference lists, reviews, editorials, websites, and by consulting experts. Retrievedabstracts were entered into an electronic database (EndNote®).7

Inclusion and Exclusion CriteriaKey Questions 1 and 2Full text cohort studies with data on women experiencing menopause and at least one of thesymptoms listed in Key Question 1 were initially reviewed and subsequently included if thestudy enrolled 100 or more subjects, subjects represented the target population, and data onsymptoms associated with menopause were provided. Exclusions included studies of women notundergoing the menopausal transition and experiencing menopause related symptoms, studies ofaging and its effects, and biologically based studies that did not report epidemiological datarelating to symptoms (e.g., studies of hormone levels) (Appendix 4). Non-English languagepapers and studies of animals or cadavers were also excluded. Cross-sectional studies meetingsimilar inclusion/exclusion criteria were examined for contributory data and included if theyreported relevant data about symptoms by menopausal stage, such as prevalence rates.Key Questions 3 and 4Full text randomized controlled trials and meta-analyses of randomized controlled trialsproviding data on treatment of menopausal symptoms, using one or more of the interventionslisted in Key Question 3, were included. Trials enrolling women with breast cancer wereconsidered separately from those enrolling women without breast cancer. Exclusions includedstudies of women not undergoing menopause and experiencing menopause related symptomsduring the course of the study, studies of animals, and non-English language papers (Appendix4). For this report, abstracts of unpublished trials are included in evidence tables, but not insummary tables and text.Data Extraction and SynthesisAll eligible studies were reviewed and a “best evidence” approach was applied, in whichstudies with the highest quality and most rigorous design are emphasized. 13 Data were extractedfrom each study, entered directly into evidence tables, and summarized descriptively. Benefitsand adverse effects of therapies were considered equally important and both types of outcomeswere abstracted. Trials of alternative and complementary therapies were grouped according tothe National Center for Complementary and Alternative Medicine categories 14 most closelyrelated to included topics. For this report, acupuncture and Chinese herbal treatments werecategorized in the alternative healthcare systems category, and lifestyle modifications, such asexercise, counseling and education, were placed within the mind-body category. Additionalcategories include biologically based therapies (e.g., red clover), manual medicine (e.g.,osteopathic manipulations), and energy therapies (e.g., reflexology).Results of recently published meta-analyses on estrogens 15-17 and isoflavones 18 are includedin this report. No new meta-analyses were conducted because of heterogeneity of trials of othertherapies.8

Two reviewers independently rated the quality of randomized controlled trials and cohortstudies using criteria specific to different study designs developed by the U.S. PreventiveServices Task Force (Figure 3). 19 Similar criteria for cross-sectional studies are not available.The overall rating is a combination of internal and external validity scores. When reviewersdisagreed, a final rating was reached through consensus. Studies reporting several differentoutcomes may have different quality ratings for each outcome depending on how well itmeasured the symptom and how completely it controlled for key confounders in multi-variablemodels.Size of LiteratureA total of 10,059 unique citations were reviewed, including 6,342 about symptoms andfactors influencing them (Key Questions 1 and 2); 4,078 about interventions (Key Question 3);and 806 about specific characteristics that may influence the effects of interventions (KeyQuestion 4) (Appendix 5).9

Chapter 3. ResultsTo address Key Questions 1 and 2, 6,342 abstracts were reviewed to identify relevant studiesevaluating menopause related symptoms and their associations with the menopausal transition.The review focused on prospective studies of cohorts of midlife women transitioning through thestages of menopause. Forty-nine studies conducted among 14 cohorts met inclusion criteria.Seven cohorts were based in the U.S. (Massachusetts Women’s Health Study, 20-25 SeattleMidlife Women’s Health Study, 26-28 Ohio Midlife Women’s Study, 29 National HealthExamination Follow-up Study [NHANES], 30 Study of Women’s Health Across the Nation[SWAN], 31-39 University of Minnesota/Tremin Trust Longitudinal Study [includes a smallsubset from other countries], 40 and Pennsylvania Ovarian Aging Study 41,42 ). Seven cohorts werebased outside the U.S. (Gothenburg, Sweden, 43-45 Australian Longitudinal Study on Women’sHealth, 46,47 Medical Research Council [MRC], U.K., 48-51 Melbourne Women’s Midlife HealthProject, Australia, 52-62 Manitoba Project on Women and Their Health in the Middle Years,Canada, 63 Copenhagen, Denmark, 64-66 and Eindhoven, Netherlands. 67,68 ). Cohorts are describedin Table 2, results are listed by symptoms in Table 3, and full details are provided in Appendix 6-1.Major limitations of cohort studies include dissimilar methods for evaluating and reportingsymptoms and for assessing menopausal change. Some studies based results on cross-sectionaldata reported at serial time points rather than individual tracking of women over time. Somestudies failed to adjust or stratify for potentially important variables such as age, race, BMI, lifeevents, or history of depression when attempting to attribute symptoms to change in menopausalstage. Although most included studies were population-based, in many cases, enrolled womenwere additionally selected from the initial recruited cohort and may have been less representativeof the general population. 44,52,53,55,57-59 Also, many studies were based on cohorts recruited fromcommunity populations and are more representative of volunteers than entire communities.A total of 51 cross-sectional studies meeting similar inclusion criteria were obtained toprovide additional prevalence data including 29 studies from the 14 study cohorts 21-25,27,30,33-40,42,45,48-50,56,60-66,69 and 22 studies from other populations. 70-91 Results of cross-sectional studiesare summarized in Table 4.Key Question 1. Symptoms Associated with MenopauseWhat is the evidence that the symptoms more frequently reported bymiddle-aged women are attributable to ovarian aging andsenescence?Vasomotor SymptomsFour studies from four population-based cohorts evaluated the association betweenvasomotor symptoms and menopausal stage, including three rated good-quality 46,51,53 and one11

fair. 26 Women transitioning from premenopause to either perimenopause or postmenopause hadincreased vasomotor symptoms in the three good-quality studies. 46,51,53The prevalence of hot flashes was reported in 33 cross-sectional studies. 25,27,33,35-37,40,48,60,62,64,66-67,69-76,78-85,87-90 Prevalence rates ranged from 14 percent to 51 percent for premenopausalwomen, were approximately 50 percent for perimenopausal women, and between 30 percent to80 percent for postmenopausal women, depending on the age and population studied. In onestudy, approximately 29 percent of women age 60 years reported hot flashes, suggesting only amodest decline in frequency with increasing time from menopause. 66Vaginal DrynessVaginal dryness was associated with menopause, and became more common with thetransition from premenopause to postmenopause, in the one good-quality cohort study examiningthis relationship. 53 Thirteen cross-sectional studies 37,40,48,69,71,72,74-76,80,83-85 reported prevalencerates ranging from 4 percent to 22 percent for premenopausal women, 7 percent to 39 percent forperimenopausal women, and 17 percent to 30 percent for early postmenopausal women. Twocross-sectional studies showed either no association, 84 or a weak association, 83 between vaginaldryness and menopausal stage.Sleep DisturbanceThree cohort studies evaluated the impact of menopausal status on sleep; two were ratedgood-quality 46,53 and one fair. 26 In the good-quality studies, women had more difficulty sleepingas they progressed through the menopausal stages, 46,53 and sleeping difficulty was associatedwith the presence of hot flashes. 53 The fair-quality study reported no association. 26Eighteen cross-sectional studies evaluated the prevalence of sleep disturbance at differentmenopausal stages. 25,35-38,48,60,69,78-82,84,85,87,90,92 Of these, eight reported prevalence rates rangingfrom 16 percent to 42 percent for premenopausal women, 39 percent to 47 percent forperimenopausal women, and 35 percent to 60 percent for postmenopausal women (includingwomen with either surgical or natural menopause and hormone therapy users). 37,60,78,80-82,85,90Some studies, 79,82,87 but not others, 38,90 reported an association between hot flashes and sleepdisturbance. When hot flashes/night sweats and insomnia were considered together in one study,27 percent of premenopausal women, 46 percent of perimenopausal women, and 38 percent ofpostmenopausal women reported disturbances. 25Four cross-sectional studies reported increased adjusted odds ratios for difficulty sleeping formenopausal women compared to premenopausal women 37,48,69,92 In one study, an age-adjustedsignificant correlation between sleep problems and menopausal status was reported, but increasesamong perimenopausal and postmenopausal women were small, and social class was a strongerpredictor. 69 A factor analysis of sleep-related problems found sleep was not associated withmenopausal status. 84 In another study, sleep disordered breathing increased across themenopausal stages after multivariate adjustment and stratification by BMI and age. 92Mood SymptomsFourteen studies from 11 cohorts evaluated the impact of menopausal stage onmood. 20,24,26,28-30,41,44,47,51,54,55,63,68 Of these, seven were rated good-quality, 29,41,47,51,54,55,68 four12

fair, 20,26,28,63 and three poor. 24,30,44 Symptoms included anxiety, 29 depression, 20,24,28-30,41,63,68dysphoric or negative mood, 26,54 and positive mood. 55 Development of a mental disorder, 44psychological symptom reporting, 51 and general mental health 47 were also assessed.Twelve of the 14 studies, including five good-quality, four fair, and three poor, found noinfluence of menopausal stage on mood symptoms, development of a mental disorder, or generalmental health. 20,24,26,28-30,44,47,51,54,55,63 Two good-quality studies demonstrated a change in moodsymptoms with the menopausal transition. 41,68 A well-designed, nested case-control study ofage-matched menopausal and premenopausal women from the Pittsburgh cohort found nodifferences between the groups in depression, anger, anxiety, or stress symptoms. 93Twenty-four cross-sectional studies reported relevant data. 22-24,33,35,36,48,50,60,63,64,66,67,69,70,72,76,80-85,90 The prevalence of depressed mood ranged from 8 percent to 37 percent forpremenopausal women, 11 percent to 46 percent for perimenopausal women, 8 percent to 47percent for women with natural menopause, and 8 percent to 38 percent for women with surgicalmenopause. 23,66,67,80,85Cognitive DisturbancesNo cohort studies longitudinally assessed cognitive symptoms. Eight cross-sectional studiesshowed no differences in the prevalence rates of memory or concentration problems bymenopausal stage. 37,48,67,69,80,81,84,85Somatic ComplaintsSomatic complaints were evaluated in four studies conducted among three cohorts ratedgood-quality 46,47,53 or fair-quality. 26 Perimenopausal women had increased somatic symptomscompared to premenopausal women in one cohort. 46,47 Symptoms included back pain, severetiredness, stiff or painful joints, bodily pain, and worse general health. Other studies reportedreduced breast tenderness, 53 or no association with somatic or neuromuscular symptoms. 26Fourteen of 18 cross-sectional studies evaluating changes in somatic symptoms showed nosignificant increases as women transitioned from premenopause to postmenopause in adjustedanalytic models. 36,37,48,64,66,67,69,71,72,81-85,87 Three studies showed slight increases in somaticsymptoms during perimenopause that decreased during postmenopause, 78,89 or remained stable. 67Another study showed significantly fewer somatic symptoms for women at menopausecompared with those at premenopause. 90Urinary ComplaintsThree good-quality cohort studies evaluated the impact of menopausal stage on urinarysymptoms. 46,53,56 In one study, women who were perimenopausal at baseline were more likely toreport leakage of urine two years later than women who remained premenopausal. 46 Two studiesfrom the Melbourne cohort found no association of menopausal status with urinarysymptoms. 53,56Fourteen cross-sectional studies 37,45,48,49,56,60,67,71,75,77,84-87 provided relevant data. Prevalencerates of urinary incontinence or leakage ranged from 10 percent to 36 percent for premenopausalwomen, 17 percent to 39 percent for perimenopausal women, 14 percent to 36 percent for13

women undergoing natural menopause, and 18 percent to 36 percent for women undergoingsurgical menopause. 37,46,56,67,86Uterine Bleeding ProblemsNo studies meeting inclusion criteria addressed uterine bleeding problems, most likelybecause currently accepted definitions of menopause rely historically on changes in uterinebleeding.Sexual DysfunctionSexual dysfunction was evaluated in two fair-quality studies from the Melbourne cohort. 57,58Sexual function was variably measured and included decreased responsivity, decreased libido,and/or decreased frequency of sexual activity. In that cohort, women demonstrated decreases insome or all of the sexual parameters as they transitioned from early to late perimenopause orpostmenopause. 57,58Thirteen cross-sectional studies, including one from the Melbourne cohort, also evaluatedsexual function. 22,40,42,48,61,65,66,69,83,84,86,89 Five studies showed the prevalence of sexualdisinterest, dysfunction, or discomfort to increase from premenopause to perimenopause topostmenopause, 48,61,67,69,86 and four showed no change. 40,65,84,89Reduced Quality of LifeFour cohort studies addressed the impact of menopausal stage on quality of life, three ratedgood-quality 47,52,59 and one poor. 30 Two studies from the Melbourne cohort had conflictingresults. 52,59 One study showed declines in well-being across progressive menopausal stages(lowest for the one to two years postmenopause) that improved when women were more thantwo years postmenopause. 52 A second study showed increased well-being from early to lateperimenopause and postmenopause. 59 In another good-quality study, women who remainedperimenopausal over a two year follow-up period reported significant decreases in quality of lifecompared to women who remained premenopausal, although significant decreases were notreported by women in other stages. 47 A poor-quality cohort study found that well-being was notassociated with change in menopausal status. 30Three cross sectional studies also evaluated quality of life. 22,34,74 Satisfaction with life, 22 andimpaired functioning 34 did not vary with menopausal stage in multivariate regression modelingof data from the Massachusetts Women’s Health Study. In another study, various aspects ofgeneral well-being were lower among postmenopausal women compared to premenopausalwomen. 74Summary• Vasomotor symptoms: Evidence from population-based cohort and cross-sectionalstudies supports the association between vasomotor symptoms and menopausal stage.Studies are consistent in reporting increasing prevalence rates of vasomotor symptoms aswomen transition from premenopause to either perimenopause or postmenopause,14

affecting 50 percent or more of women. Studies suggest that vasomotor symptomspersist for several years after menopause for some women.• Vaginal dryness: Vaginal dryness is associated with menopause and prevalence ratesincrease as women transition through the menopausal stages. Estimates indicate that upto one third of perimenopausal and postmenopausal women experience vaginal dryness.• Sleep disturbance: Although results of studies are mixed, two good-quality cohortstudies indicate that women have more difficulty sleeping as they transition throughmenopausal stages, and this may be due to vasomotor symptoms. Up to 40 percent to 60percent of perimenopausal and postmenopausal women experience sleep disturbance, aslight increase from prevalence rates of premenopausal women.• Mood symptoms: The majority of studies from a large literature report no associationsbetween menopausal stage and mood symptoms, development of a mental disorder, orgeneral mental health. Studies of prevalence rates report wide ranges that are similaracross menopausal stages.• Cognitive disturbances: The few studies evaluating cognitive disturbances in menopausehave inadequate measures.• Somatic complaints: Most studies report no association of somatic symptoms withmenopause, although somatic symptoms were increased among perimenopausal womencompared with premenopausal women in one cohort and two cross-sectional studies.• Urinary complaints: Urinary leakage increased among perimenopausal women comparedwith premenopausal women in one study, and another reported no associations. Studiesof prevalence rates report wide ranges that are similar across menopausal stages.• Uterine bleeding problems: No studies meeting inclusion criteria addressed uterinebleeding problems, most likely because currently accepted definitions of menopause relyhistorically on changes in uterine bleeding.• Sexual dysfunction: Women from two study cohorts reported declines in some or all ofthe measured sexual parameters as they transitioned through menopausal stages. Resultsof cross-sectional studies are mixed.• Reduced quality of life: Results of available cohort and cross-sectional studies areconflicting.15

Key Question 2. Factors Influencing SymptomsWhen do the menopausal symptoms appear, how long do they persistand with what frequency and severity, and what is known about thefactors that influence them?Included studies do not characterize the severity and duration of specific symptoms, andfrequency is described by prevalence data in Key Question 1.Race and EthnicityTwo cohort studies 38,41 addressed the influence of race and ethnicity on menopausalsymptoms, while many adjusted for it in multivariable models. Depression was reported moreoften among African American women compared to Caucasian women, 41 and sleep difficultieswere reported more often among Caucasian and Hispanic women and less often among AfricanAmerican, Chinese, and Japanese women. 38Seven cross-sectional studies conducted in the large SWAN cohort also evaluated symptomsby race or ethnicity. 33-37,39,70 In SWAN, vasomotor symptoms were reported more often amongAfrican American women and less often among Hispanic, Chinese, and Japanese womencompared with Caucasian women. 33,37 Japanese, Chinese, African American, and Hispanicwomen reported fewer mood symptoms compared to Caucasian women, 33,35,36 although“impaired social function” was reported among Hispanic women in two studies 34,70 and amongAfrican American women in one study. 34 Hispanic women also reported more bodily pain thanCaucasian women. 34 A cross-sectional study conducted outside the SWAN cohort found thatMexican American women had similar prevalence rates of vasomotor symptoms and vaginaldryness as Caucasian women. 72Age at Onset of the Menopause TransitionLong term studies evaluating menstrual cycles over many years among large cohorts ofwomen showed the median onset of menstrual irregularity to begin between the ages of 45 and47.5 years with a mean duration of the menopausal transition lasting 5 years. 94-96 Factorsassociated with earlier menopause include smoking, 97-99 shorter cycle length during menstruatingyears, 100 and shorter stature and leaner body weight. 101 Factors associated with later age atmenopause include higher gravidity or parity 98,99 and higher BMI. 99A cross-sectional study reported increased rates of hot flashes among women withmenopause prior to age 53 after adjustment for other factors. 88 Another found that earlier age ofinception of perimenopause was related to a longer perimenopause stage. 21Body Mass Index (BMI)Two good-quality cohort studies evaluated BMI and its effect on symptoms amongmenopausal or perimenopausal women and found that BMI was a significant predictor of urinaryincontinence, 56 but not positive mood. 55 A cross-sectional study reported a slight increase invasomotor symptoms (15 percent) among women with a BMI of 27 or greater, although,16

vasomotor symptoms were less common at the extremes of BMI. 37 Lower BMI wasindependently associated with increased hot flashes in another cross-sectional study. 88 Threecross-sectional studies 22,42,74 found no significant differences for increased BMI. Other studiesevaluating menopausal symptoms adjusted for BMI in multivariate models but did not report thecontribution of BMI to symptoms. 46,47,53,92Surgical Versus Natural MenopauseTwo good-quality 29,56 and one fair-quality cohort studies 63 reported data for women withsurgical menopause. The Ohio Midlife Women’s Study found that hysterectomy was not apredictor of anxiety or depression. 29 In contrast, a community-based study of women inManitoba, Canada reported that women with hysterectomies had increased odds of depression. 63In the Melbourne Women’s Midlife cohort, surgical menopause was not a significant predictor ofurinary incontinence. 56 Other symptoms were not addressed in these studies.Sixteen cross-sectional studies reported symptoms among women with surgical and naturalmenopause. 30,38,45,48,56,63-66,70,72,73,80,86,89,90 Four studies showed no significant differences invasomotor symptoms, 48,70,80,90 and three studies showed slightly higher rates of vasomotorsymptoms among women with surgical menopause (seven percent to eight percent higher). 64,66,73Vasomotor symptoms were similar among Japanese and Canadian women with surgical andnatural menopause in another study. 70 Three studies evaluated vaginal dryness; two showedsimilar rates, 48,72 and one reported a nine percent higher prevalence among women with surgicalcompared to natural menopause. 80 One cross-sectional study found no differences in rates ofsexual dysfunction by type of menopause, 48 and another showed higher rates of urinaryincontinence (36 percent vs. 22 percent) among women with surgical menopause. 86The prevalence of anxiety and depression was evaluated in four cross-sectionalstudies, 66,70,80,89 and two showed higher prevalence rates among women with surgicalmenopause. 66,80 In a cross-sectional study from the Massachusetts Women’s Health Studyevaluating depression, women who had undergone surgical menopause in the previous threemonths were twice as likely as the rest of the cohort to have elevated depression scores. 24DepressionThe interaction of baseline depression with menopausal stage and/or transition and thepresence or absence of symptoms was not evaluated in any cohort study. A cross-sectionalstudy reported that prior anxiety or depression did not predict menopausal symptoms. 48 Oneother cross-sectional study evaluating menopausal symptoms adjusted for depression in amultivariate model but did not report the contribution of depression to symptoms. 92SmokingThree good-quality studies from the Melbourne Women’s Midlife cohort examined theassociation of smoking status with mood symptoms and urinary incontinence. 54-56 In this cohort,current smoking was associated with negative mood, 54 but not positive mood, 55 and was notevaluated as an interaction term with menopausal transition or stage. Smoking was not asignificant predictor of urinary incontinence. 56 Two good-quality studies adjusted for smoking inmultivariate models, but did not report any data for this variable. 46,4717

Five cross-sectional studies provide data on smoking and menopausal symptoms. 35,37,48,62,88Two studies showed no association between smoking and menopausal symptoms, 37,62 onereported that smoking was associated with psychological distress but did not evaluate smoking asan interaction term, 35 and another showed that smoking at anytime in the past predicted greatervasomotor symptoms during menopause. 48 Another study reported no association between hotflashes and smoking, but identified higher rates of vasomotor symptoms among thin smokersthan among thin non-smokers. 88 Other studies evaluating menopausal symptoms adjusted forsmoking status in multivariate models but did not report the contribution of smoking status tosymptoms 39,74,92Summary• Included studies do not provide adequate details to characterize the onset, severity, andduration of specific symptoms. Frequency is described by prevalence data in KeyQuestion 1.• Race and ethnicity: The influence of race and ethnicity on menopausal symptoms has notbeen extensively studied. Prevalence rates of vasomotor and mood symptoms varyamong race and ethnic groups in the large SWAN cohort.• Age at onset of menopausal transition: Available studies are inconclusive.• Body mass index: Available studies are inconclusive.• Surgical versus natural menopause: Studies present mixed results regarding the impact ofsurgical menopause on vasomotor symptoms, vaginal dryness, and mood. Adjustmentfor confounders is necessary because women undergoing hysterectomy differ fromwomen with natural menopause in ways that may also influence their menopause relatedsymptoms.• Depression: Only one cross sectional study was included and reported that prior anxietyor depression did not predict menopausal symptoms.• Smoking: Available studies are inconclusive.18

Key Question 3. Benefits and Adverse Effects of TherapiesWhat is the evidence for the benefits and harms of commonly usedinterventions for relief of menopause-related symptoms?EstrogenThree recent good-quality systematic reviews and meta-analyses of randomized controlledtrials of estrogen, alone (unopposed) or combined with progestin or progesterone (opposed),describe benefits and harms of various forms, doses, and regimens for treating menopausalsymptoms. These include a Cochrane review of trials of oral estrogen for hot flashes, 16,102,103 ameta-analysis of trials of oral conjugated equine estrogen (CEE) and oral and transdermalestradiol for hot flashes, 15,104 and a review of commonly used types of estrogen for severalmenopausal symptoms. 15 Trials were conducted predominantly in the U.S. or western Europeand recruited participants from primary care or gynecology practices. Most trials focused onhealthy menopausal women in their early 50s with baseline symptoms that varied by study. Alltrials were double blind, of 12 weeks duration or more, and rated good or fair quality.Vasomotor symptoms. The Cochrane meta-analysis indicated a significant reduction infrequency of weekly hot flashes for oral estrogen compared to placebo with a pooled weightedmean difference of -17.9 hot flashes per week (95% confidence interval [CI], -22.9 to -13.0; ninetrials), equivalent to a 75.3 percent reduction in frequency (95% CI, 64.3 percent to 82.3percent). 16 Severity of symptoms was also significantly reduced compared to placebo (odds ratio[OR] 0.13; 95% CI, 0.07 to 0.23; 13 trials). Differences between types of estrogens were notdetermined, although trials of estradiol and CEE predominated. The review also found that thereduction in weekly hot flash frequency was similar for opposed and unopposed estrogenregimens compared to placebo (opposed: -19.9 per week; 95% CI, -26.7 to -12.6; three trials;unopposed: -14.7; 95% CI, -20.1 to -8.7; six trials). Symptom severity seemed to be bettertreated by opposed (OR 0.10; 95% CI, 0.06 to 0.19; 10 trials) than by unopposed estrogen (OR0.35; 95% CI, 0.22 to 0.56; four trials), although heterogeneity of trials could also explain thisdifference.Hot flash frequency, severity, or both improved in nine of 10 trials of oral estradiol and in all11 trials of transdermal estradiol compared to placebo in a review of these agents. 15 The pooledweighted mean differences in hot flashes were -16.8 per week (95% CI, -23.4 to -10.2; fivetrials) for oral estradiol, and -22.4 per week (95% CI, -35.9 to -10.4; six trials) for transdermalestradiol. Results were similar when opposed and unopposed regimens were consideredseparately. 15 All eight trials of oral CEE reported statistically significant improvements in hotflash frequency, severity, or both compared with placebo. One trial of CEE that provided datacomparable to the estradiol meta-analyses reported a mean reduction of -19.1 hot flashes perweek (95 percent CI, -33.0 to -5.1). Four trials comparing estrogen agents head-to-head (CEEcompared with oral or transdermal estradiol) indicated improved number and severity of hotflashes for all treatment groups with no significant differences between them (pooled weightedmean difference in hot flashes -0.3; 95 percent CI, -3.4 to 2.7; three trials).In a review of 32 trials of estrogen for treatment of vasomotor symptoms, all but five wereless than one year in duration and only three trials enrolled more than 500 participants, limiting19

evaluation of adverse effects. 15 Trials reported multiple specific adverse effects includingatypical bleeding and endometrial hypertrophy, nausea and vomiting, breast tenderness,headache, weight change, dizziness, venous thromboembolic events, cardiovascular events, rashand pruritus, cholecystitis, liver effects, and other adverse events. These outcomes were reportedunevenly across studies and could not be combined in summary statistics. Trials included in theCochrane review indicated similar adverse effects with breast tenderness and uterine bleedingmost commonly reported. 16Urogenital symptoms/sexual dysfunction. In a systematic review of good and fair-qualitytrials of a variety of estrogen agents, urogenital symptoms improved in eight of nine trials, andsexual function (including pain during intercourse and responses to questionnaires) in eight of 11trials. 15 Vaginal forms of estrogen were evaluated in five trials. In a placebo controlled trial,vaginal dryness and pain during intercourse improved with use of the estradiol intravaginal ringcompared to placebo. 105 A trial of the estradiol intravaginal ring and oral estradiol reportedimproved vaginal dryness, involuntary loss of urine, and pain during intercourse for bothgroups. 106 Head-to-head trials comparing the intravaginal estradiol ring with CEE vaginal creamamong women with signs and symptoms of urogenital atrophy indicated that the two agents werecomparable for relief of vaginal dryness and pain during intercourse, resolution of atrophic signs,improvement in vaginal mucosal maturation indices, and reduction in vaginal pH. 107,108 Similarfindings were reported in a trial of the estradiol vaginal tablet and CEE cream. 109Four placebo controlled trials of transdermal estradiol indicated improvements in some, butnot all, urinary and sexual symptoms. Two trials reported improvements in responses to theMcCoy Sex Scale Questionnaire compared to placebo, 9,110 although, another trial indicated nodifferences for symptoms of vaginal discomfort, loss of libido, and incontinence. 111 Another trialof transdermal estradiol indicated improvement in vaginal dryness, but not pain duringintercourse, frequent urination, dysuria, stress incontinence, and nocturia, compared toplacebo. 112A trial of oral CEE reported significantly improved vaginal dryness and urinary frequency,but no significant improvement on six other items related to sexual function on a General HealthQuestionnaire compared to placebo. 113 A trial comparing oral CEE and transdermal estradiolindicated that the majority of women reported either no change or improvements in vaginaldryness and itching, pain during intercourse, and urinary pain and burning in all treatment groupswith no major differences between groups. 114 All treatment groups demonstrated improvedvaginal cytology, measured by the maturation index, with the biggest improvement in the higherdose estradiol group (0.1 mg/day).Sleep disturbance. Improved measures of sleep were specifically reported in three trialsincluded in the systematic review. 15 Transdermal estradiol provided significant improvementsin sleep quality, sleep onset, and decreased nocturnal restlessness and awakening compared toplacebo. 115 In a subanalysis of the Women’s Health Initiative (WHI) that considered women ages50 to 54 years old who reported moderate to severe vasomotor symptoms at baseline, there was apositive effect on sleep disturbance with CEE compared to placebo. 116 In contrast, a trial ofCEE in women with hot flashes and nighttime awakening at baseline indicated improvement inmenopausal symptoms and measures of psychological well-being, but not in parameters of sleepquality such as total sleep time, sleep onset time, number of awakenings, and REM sleepduration compared to placebo. 11720

Mood symptoms. Thirteen trials of estrogen reporting mood and depression outcomes meteligibility criteria (Table 5, Appendix 6-2), including three trials rated good-quality, 118-120 fourfair, 121-124 and six poor. 125-130 Trials compared placebo with CEE, 119,121,124,126,128 oralestradiol, 120,122,125 transdermal estradiol, 118,126 piperazin oestrone sulphate, 129,130 and estropiate. 127Head-to-head comparisons included estradiol and estradiol valerate, 123 CEE and clonidine, 128CEE and raloxifene, 119 and estradiol and raloxifene. 120Two of the four good and fair-quality placebo controlled trials reporting between groupdifferences found improved depressive symptoms among women using transdermal estradiol 118and oral estradiol with norethindrone acetate. 122 No differences were found in trials comparingplacebo with CEE/medroxyprogesterone acetate (MPA) 121 or placebo with CEE. 119 There wereno differences in symptoms when comparing estradiol with estradiol valerate 123 and estradiolwith raloxifene. 120 Another trial indicated improved anxiety with raloxifene vs. CEE, but nodifferences in depressed mood. 119Reduced quality of life. In a systematic review, 15 four trials of transdermal estradiol, 112,131-133 two trials of oral estradiol, 122,134 and one trial of esterified estrogens 135 indicated improvedhealth related quality of life and well-being compared to placebo, as measured by variousinstruments. In a subanalysis of the WHI that considered women ages 50 to 54 years old whoreported moderate to severe vasomotor symptoms at baseline, there was no effect on healthrelatedquality of life measures on the RAND 36-item Health Survey, despite significantimprovements in vasomotor symptoms. 116 A head-to-head comparison of CEE vs. transdermalestradiol utilizing the Menopause Specific Quality of Life Questionnaire indicated improvementin all areas with no significant differences between groups. 136Progestin/progesteroneA total of 244 abstracts were identified and five randomized controlled trials met inclusioncriteria (Table 6), 137-141 including one rated good-quality, 137 one fair, 138 and three poor. 139-141Studies included transdermal progesterone, 137,138 intramuscular progesterone, 139medroxyprogesterone acetate (MPA) tablet, 141 and MPA injection. 140Two trials of transdermal progesterone report conflicting results. A good-quality trialreported no differences between progesterone (32 mg/day) and placebo groups for vasomotor orsomatic symptoms, mood, or sexual feelings as measured on previously validated instruments. 137A fair-quality trial of a lower dose (20 mg/day) reported significant reductions in vasomotorsymptoms, but not depression scores, with progesterone compared to placebo (83 percent vs. 19percent; p

poor 143,147-149,151 (Table 7, Appendix 6-3). Major limitations of studies include few subjects,undefined inclusion and exclusion criteria, use of unclear outcome measures, and using openlabel rather than double blind methodology. Two additional studies were reported in abstractform and are included only in the evidence table (Appendix 6-3). 152,153Trials used methyltestosterone, 142,143,145-149 testosterone undecanoate, 150,151 and transdermaltestosterone. 144 All trials combined testosterone with estrogen and compared it head-to-head withestrogen, and two studies compared it with placebo. 144,149 Outcomes included sexualdysfunction, 142,144-146,150,151 hot flashes, 143-149 mood, 144,145,147,149,150 sleep disturbances, 143,145,147-149vaginal dryness, 143,146-149 and quality of life. 144,145,150Only one good-quality and two fair-quality trials reported statistical comparisons betweentestosterone/estrogen and estrogen or placebo groups. 142,143,144 One trial indicated no differencesbetween testosterone/estrogen and estrogen alone for hot flash severity, vaginal dryness, or sleepproblems. 143 Sexual interest and responsiveness were improved with testosterone/estrogencompared to estrogen alone based on scores on the Sexual Interest Questionnaire in anothertrial. 142 Sexual symptoms were also improved in a trial comparing testosterone/estrogen withplacebo. 144Adverse effects were reported in all 10 trials. Acne 142,143,146,148 and hirsutism 146,148 occurredsignificantly more often among women using methyltestosterone/estrogen than with estrogenalone. Adverse effects were not always separated by treatment group, making it difficult todetermine which drug was responsible for the reported effect. 144,149-151Dehydroepiandrosterone (DHEA). One fair-quality 154 and one poor-quality 155 randomizedcontrolled trial met inclusion criteria (Table 7, Appendix 6-4). Studies were small, lacked clearexclusion criteria, 155 and had high losses to follow up. 154Trials used dehydroepiandrosterone (DHEA) 154 and dehydroepiandrosterone sulfate(DHEAS) 155 alone 154,155 or combined with transdermal estradiol. 155 No significant differencesbetween DHEA and placebo were determined on any measures of symptoms including hotflashes, vaginal dryness, insomnia, depression, urinary difficulties, libido, concentration,dizziness, forgetfulness, irritability, aches, anxiety, headaches, and fatigue in the one trialreporting between group differences. 154Adverse effects were reported for DHEA only and included paresthesia of an upperextremity. 154TiboloneA total of 162 abstracts were reviewed and 20 randomized controlled trials met inclusioncriteria (Table 8, Appendix 6-5) including three rated good-quality, 156-158 four fair, 159-162 and 13poor. 163-175 Four additional studies were reported in abstract form and are included only in theevidence table (Appendix 6-5). 176-179Trials compared tibolone with estrogen alone, 169 estrogen combined with progestin orprogesterone, 158-160,162,163,166,170,171,173-175 or placebo. 156,157,161,164,165,167,168,172 Outcomes included hotflashes, sexual dysfunction, mood, uterine bleeding, somatic complaints, vaginal dryness, sleepdisturbance, cognitive effects, urinary complaints, and quality of life.Three good or fair-quality trials reported between group differences for tibolone andplacebo. 156,157,161 Results indicated improved hot flashes, 157 sleep, 157 and somatic complaints 15622

with tibolone, but no differences between groups in Greene Climacteric Score, 156 quality oflife, 157,161 or mood, energy, pain, social isolation, or urinary symptoms. 157Four good or fair-quality trials reported between group differences for tibolone and estrogenalone or estrogen combined with progestin or progesterone. 158-160,162 Two trials indicatedimproved hot flashes with estrogen compared to tibolone. 159,160 Sexual interest, drive, and/orperformance were improved with tibolone compared to CEE/MPA in another trial. 160 Nodifferences between groups were determined for several other menopause related symptoms. 158-160,162Uterine bleeding was increased with tibolone in four trials, 157,167,168,180 decreased in two, 159,167and was not significantly changed in four others. 158,162,163,174 Uterine bleeding was dose related intwo studies. 168,180 Adverse effects that occurred significantly more often among women usingtibolone than placebo were reported in 16 of 20 trials and included bodypain, 156,160,163,164,166,170,174,175 weight gain, 156,158,160,164,166,169,175 and headache. 156,160,163,166,167,170Four studies did not report adverse effects. 162,171-173Antidepressant drugsA total of 184 abstracts were reviewed and eight randomized controlled trials met inclusioncriteria including one trial rated good-quality, 181 three fair, 182,183,188 and four poor 184-187 (Table 9,Appendix 6-6). Trials used paroxetine, 181 venlafaxine, 183 moclobemide, 188 and veralipride. 182,184-187 Most studies were limited by small sample sizes, short durations of follow-up, lack of followupdata, inadequate descriptions of inclusion criteria, and, in one trial, lack of blinding. 187Selective serotonin reuptake inhibitors (SSRIs). A good-quality trial of paroxetinereported statistically significant reductions in mean hot flash frequency and hot flash compositescore at two doses compared with placebo. 181 No differences were detected in sleep, depression,anxiety, sexual interest, disability, or side effects. 181 A fair-quality trial of venlafaxine reportedimprovement on a single item measuring how significantly hot flashes interfered with dailyactivities compared to placebo, but no differences in hot flash frequency or severity as measuredon daily diaries. 183 The venlafaxine group also had improved mood and vitality compared withplacebo. 183 Other trials of SSRIs enrolled women with breast cancer and are described below.Moclobemide. A fair-quality trial evaluating two doses of moclobemide showed reducedhot flash composite scores with moclobemide at both doses, although comparisons with placebowere not reported. 188 This trial was further limited by including only 30 participants and lastingonly five weeks.Veralipride. Veralipride, an antidopaminergic drug, was evaluated in five trials; one ratedfair-quality 182 and four poor-quality. 184-187 Two poor-quality trials comparing veralipride toplacebo reported reduced rates of hot flashes with veralipride. 184,185 Of the two studies comparingveralipride to estrogen, a poor-quality trial found that veralipride had less benefit, 187 and a fairqualitytrial found it to be equivalent. 182In four of the five studies, the side effects of mastodynia and/or galactorrhea occurred morefrequently in the veralipride group.23

Other DrugsA total of 51 abstracts were identified and 15 randomized controlled trials met inclusioncriteria (Appendix 6-7). Trials used clonidine, 128,189-197 gabapentin, 198 methyldopa, 199-201 andBellergal Retard. 202 Major limitations of trials include few subjects, lack of clear inclusion andexclusion criteria, high attrition or loss to follow up, no washout period in crossover trials, lackof data for pre-crossover comparisons, and short treatment duration.Clonidine. Clonidine was compared to placebo in eight trials, 189-195,197 and compared toother active drugs in trials with lisuride, sodium valproate, transdermal estradiol, 195 and CEE andmedrogestone 128,196 (Table 10). Two trials were rated fair-quality, 189,192 and eight werepoor. 128,190,191,193-197 Outcomes included hot flashes, insomnia, and mood symptoms.Of the trials for which pre-crossover statistics were provided or could be calculated, therewere no statistically significant differences between clonidine and placebo in the improvement ofhot flash symptoms. 189,191,192 In the non-crossover placebo controlled trials, one trial reportedthat clonidine was more effective than placebo in reducing hot flash frequency and intensity, 195and the other found no differences between groups in number of hot flashes, although women onclonidine were significantly more likely to report a decrease in subjective frequency, severity,and duration of hot flashes. 197 Of the 3 remaining crossover studies reporting only summarystatistics, 190,193,194 one trial demonstrated that clonidine was more effective than placebo inreducing the number of hot flashes and improving subjective hot flash measures. 193 Two headto-headtrials found that estrogen, not clonidine, effectively decreased the number of hot flashesand improved measures of depression and anxiety. 128,196 Two trials found no differencesbetween clonidine and placebo in measures of psychological symptoms, 191,192 and one found nodifference in frequency of insomnia. 192Adverse effects were reported in six of 10 trials; dry mouth occurred more frequently inwomen taking clonidine than placebo, 189,191,193 and blood pressure was not affected byclonidine. 189,190,192-194,197Methyldopa. Three crossover trials, two rated fair-quality 200,201 and one poor, 199 comparedmethyldopa with placebo (Table 11). All trials provided pre-crossover statistics regardingimprovement in hot flash frequency and none found significant differences between groups. Afair-quality study reporting post-crossover data separately found that methyldopa was moreeffective than placebo in reducing the number of hot flashes and improving Visual AnalogScores after crossover. 201All trials noted substantially more adverse effects with methyldopa than placebo. Fatigue ordrowsiness, dizziness, and dry mouth occurred more often among women using methyldopa thanplacebo. One patient on methyldopa developed a lupus-like rash. 200 No significant changes inblood pressure were noted, 199,201 however, one study reported orthostatic hypotension in onepatient. 200Gabapentin. In a good-quality study comparing gabapentin to placebo, hot flash frequencyand a composite menopause symptom score were significantly improved with gabapentin (Table11). 198 No significant differences in mood, quality of life, Patient Global Impression of Changescores, and sleep quality were detected. 19824

Gabapentin use reduced levels of albumin, total protein, total bilirubin, blood urea nitrogen,and platelets compared to placebo. Somnolence, dizziness, rash, and peripheral edema werereported for gabapentin but not placebo. Fifty percent of the gabapentin group and 28 percent ofthe placebo group reported at least one adverse event.Bellergal. One poor-quality trial compared Bellergal Retard, a combination of 0.6 mgergotamine, 40 mg phenobarbital, and 0.2 mg levorotatory alkaloids, with placebo (Table 11). 20There were no statistically significant differences between Bellergal and placebo in measures ofvasomotor symptoms, insomnia, nervousness, hyperirritability, headache, paresthesia, loss oflibido, and dizziness.Adverse effects were similar between groups and included dry mouth, dizziness, andsleepiness.PhytoestrogensA total of 195 abstracts were identified and 21 randomized controlled trials met inclusioncriteria (Table 12, Appendix 6-8). Trials used dietary soy isoflavones, 203-213 soy isoflavoneextracts, 214-218 other forms of phytoestrogens, 219-223 and phytoestrogens combined with otheragents. 224 Eight additional studies were reported in abstract form and are included only in theevidence table (Appendix 6-8). 225-232Soy isoflavones—dietary. Dietary forms of soy isoflavones were compared to placebo in 10trials (Table 12) that included soy powder, 203,204,211,213 cereal, 205 drink, 206,212 diet, 208,211 flour, 209and tablets. 207,210 Of these, seven were rated fair-quality, 203,204,206,207,209-212 and threepoor. 205,208,213 Outcomes included hot flashes, sleep, mood or depression, vaginal dryness, sexualsymptoms, scores on symptoms scales, and single trials reporting palpitations, headaches, andgeneral health.Of the eight trials providing between group comparisons, one fair-quality and one poorqualitytrial reported improved hot flashes with soy compared to placebo 203,204,213 and sixreported no differences. 205,206,209-212 A fair-quality trial of soy powder reported improved hotflash frequency with soy compared to placebo (44 percent vs. 31 percent, p

cognitive tests, including tests of memory, improved with soy compared to placebo in the twotrials evaluating this outcome. 214,215 Mood was not improved with soy in one trial. 215A trial reporting adverse effects of isoflavones indicated an increased rate of endometrialhyperplasia after five years of using 150 mg/day of isoflavone soy supplement. 233Other phytoestrogens. Phytoestrogens were compared to placebo in five trials (Table 12),including two rated fair-quality 221,223 and three poor. 219,220,222 Trials included diet, 219 topicalcream, 220,222 and genistein tablets. 221,223 One trial included a comparison group using estradioland noresthisterone. 221 Outcomes included hot flashes in all trials, vaginal dryness, scores onmenopausal symptom scales, mood, sexual symptoms, and energy level.Three of five trials providing between group comparisons and hot flash outcomes reportedimproved hot flash severity 219 or score 221,223 with phytoestrogen compared to placebo. Two trialsreported no differences compared to placebo in frequency and severity of hot flashes 222 orKupperman Index score, 223 and another indicated that the hot flash score was better withestradiol and noresthisterone than genistein. 221 Vaginal dryness was improved withphytoestrogen diet in one trial, 219 but there were no significant differences in overall symptomscores. 219 A trial of wild yam cream found no differences in mood, libido, or energy level. 222Combinations. A poor-quality trial of soy based isoflavones combined with C. racemosa(black cohosh) reported improved hot flush symptoms with treatment compared to placebo, asreported on a questionnaire. 224Complementary and Alternative MedicineA total of 1,237 abstracts were identified and 28 randomized controlled trials met inclusioncriteria (Table 13, Appendix 6-8). Trials used acupuncture, 234-236 Chinese herbs, 237-242 redclover, 243-248 black cohosh, 249 combinations, 250 other supplements, 251-259 manual therapies, 260 andenergy therapies. 261 Four trials were reported in abstract form and are included only in theevidence table (Appendix 6-8). 227,231,262,263Acupuncture. Four small trials compared a series of acupuncture treatments specific tomenopausal symptoms with alternate nonspecific acupuncture procedures (Table 13). 234-236,264 Ofthese, one trial was rated fair-quality 264 and three poor. 234-236 The fair-quality trial found nodifferences between groups in any measures, 236 while a poor-quality study reported improvedmood in the treatment group, but no differences in menopausal symptoms or well-being. 235 Apoor-quality trial compared acupuncture treatment specific to menopausal symptoms to bothnonspecific acupuncture and estrogen and found a more pronounced improvement in hot flasheswith estrogen than acupuncture. 264Chinese herbs. Three fair-quality trials 240-242 and three poor-quality trials 237-239 of Chineseherbs met criteria for this review. Five trials compared herbs against placebo 238-242 and twoagainst CEE/MPA 237,242 (Table 13). Treatments included specific formulations of herbs, 237,238ginseng, 239,241 dong quai, 240 and an herbal remedy (pueraria lobata) combined with isoflavone. 242Outcomes included hot flashes and other vasomotor symptoms, mood and depression, well-beingand quality of life, memory, somatic symptoms, sexual symptoms, and general health. Studieswere small, had short durations, and included highly selected populations.26

A fair-quality trial comparing ginseng with placebo reported significant improvements fordepression, well-being, and health scores on the Psychological General Well Being Index, but nodifferences in hot flashes or scores on other instruments. 241 Results of two other fair-qualityplacebo controlled trials indicated no differences between groups for menopausalsymptoms, 240,242 well-being, 240,242 or rate of learning. 242Red clover. Red clover isoflavone tablets (Promensil and Rimostil) were compared againstplacebo in six trials (Table 13) including one rated good-quality, 247 four fair, 243-245,248 and onepoor. 246 Outcomes included hot flashes and other vasomotor symptoms including measures fromthe Greene Climacteric Scale. One of five trials reporting between group comparisons indicatedimproved hot flashes with treatment compared to placebo, 248 and no trials reported differences inscores on the Greene Climacteric Scale or symptom diary. 243,244,246-248A good-quality meta-analysis of 25 trials of phytoestrogens for treatment of menopausalsymptoms included an analysis of red clover using five of the six studies in this review. 244-248Results of the meta-analysis indicated no significant differences in hot flash frequency betweentreatment and placebo groups (weighted mean difference –0.60; 95 percent CI, -1.71 to 0.51). 18Black cohosh. One fair-quality trial compared C. racemosa preparation (black cohosh) withestrogen and placebo (Table 13). 249 Between group comparisons indicated improved hot flusheswith estrogen vs. placebo only.Combinations. A small poor-quality trial of a botanical formula (burdock root, licorice root,motherwort, dong quai, and wild yam) compared with placebo indicated no differences betweengroups in the number and severity of hot flashes (Table 13). 250 Results indicated a significantdecrease in the total number of other types of symptoms after three months of therapy for thebotanical formula group compared to placebo (p

Energy therapies. A poor-quality trial of women undergoing nine sessions of reflexologyprovided over 19 weeks resulted in no differences in severity of hot flashes and night sweats ormeasures of health and well-being compared to women receiving standard foot massages (Table13). 261Behavioral InterventionsA total of 436 abstracts were identified and eight randomized controlled trials met inclusioncriteria (Table 14, Appendix 6-8). Trials consisted of exercise, 265-267 relaxation, 268-270 lowfrequency sound wave audiotape, 271 and education interventions. 272 Of these, three trials wererated fair-quality, 265,267,272 and five poor. 266,268-271 One additional trial was reported in abstractform and is included only in the evidence table (Appendix 6-8). 226Exercise. Two fair-quality studies evaluated the effects of aerobic exercise usingcomparison groups that underwent stretching activities 265 or received usual care 267 (Table 14).Outcomes included hot flashes and other vasomotor symptoms, mood and depression, cognitivefunction, sleep, well-being, and quality of life. Results of one trial indicated no differences inoutcomes in the exercise group compared to the stretching group. 265 A subset of womencategorized as recently entering menopause showed improved memory in the aerobic vs.stretching group. 265 In a trial of exercise compared to usual care, exercisers showed significantlyimproved quality of life on the Nottingham Health Profile. 267Other Interventions. A fair-quality trial compared health education with usual care andfound no differences between groups for measures of mood, health, vaginal dryness, or sexualrelationships. 272 Knowledge of menopause increased in the intervention group, while the controlgroup was more likely to attribute symptoms to menopause. 272 Other trials rated poor-quality dueto limitations in methods and/or small numbers of subjects evaluated biofeedback, relaxation,paced respiration, and use of audiotapes (Table 14).SummaryResults of trials of therapies providing between group comparisons are summarized in Table15. Although benefits and adverse effects of therapies were equally important in this review,most trials did not report adverse effects or reported them incompletely. Studies of estrogenprovided the most information. It is unclear how applicable the adverse effects reported fromother larger estrogen trials, such as the Women’s Health Initiative (WHI), are for younger,symptomatic women taking estrogen for brief periods. 104 For women in the WHI who reportedhaving menopausal symptoms, strokes and coronary heat disease events were not significantlyelevated. 273,274 Other important adverse outcomes, such as breast cancer, thrombosis, and gallbladder disease, have not been reported by age and symptom status in this trial.Main findings from trials of therapies include:• Estrogen, in either opposed or unopposed regimens, is the most consistently effectivetherapy for vasomotor symptoms, and demonstrates benefit in most trials evaluating28

urogenital symptoms. Some, but not all, trials evaluating sleep, mood and depression,sexual function, and quality of life outcomes also report benefit with estrogen comparedto placebo.• Breast tenderness and uterine bleeding are the most commonly reported adverseoutcomes in estrogen trials; others include nausea and vomiting, headache, weightchange, dizziness, venous thromboembolic events, cardiovascular events, rash andpruritus, cholecystitis, and liver effects.• Trials of progestin indicate mixed results for treatment of vasomotor symptoms.• Few trials of testosterone are available; one trial indicated no differences betweentestosterone/estrogen and estrogen alone for hot flash severity, vaginal dryness, or sleepproblems. Sexual symptoms were improved with testosterone/estrogen compared toestrogen alone or placebo in two other trials.• For women using testosterone combined with estrogen, acne and hirsutism occursignificantly more often than for women using estrogen alone.• Based on only a few fair or good-quality trials, tibolone demonstrated benefit forvasomotor symptoms, sleep, and somatic complaints compared to placebo, and wassimilar to estrogen for some, but not all, symptoms.• Uterine bleeding, body pain, weight gain, and headache were more common in tibolonevs. placebo groups.• Several agents demonstrate benefits in managing vasomotor symptoms in some, but notall trials, or in only a few available trials, including paroxetine, veralipride, gabapentin,soy isoflavones, and other phytoestrogens.• Trials of soy isoflavones and other complementary and alternative medicine therapiesreport benefits in improving nonvasomotor symptoms, although results vary widely,methods are lacking, and studies are typically small and not generalizable.• Placebo effects in trials are large reflecting underlying fluctuations of symptoms.Key Question 4. Therapies for Women with SpecificCharacteristicsWhat are the important considerations in managing menopauserelatedsymptoms in women with clinical characteristics orcircumstances that may complicate decision-making?29

Bilateral OophorectomyA large number of studies reported data on women with bilateral oophorectomies, but did notstratify results by this characteristic. 142,144-148,150,163,165,169,173,181,188,192,193,195,197,217,242,256 Trials ofestrogen that exclusively enrolled women with oophorectomies to take unopposed estrogenreported similar improvements in vasomotor symptoms as trials of women withoutoophorectomies taking opposed estrogen. 1630

Premature Ovarian FailureOnly one trial of soy isoflavones considered premature ovarian failure, but results were notreported specifically for women with this condition. 217Breast CancerA total of 200 abstracts were identified and 15 randomized controlled trials met inclusioncriteria (Table 16, Appendix 6-9). 275-289 Of these, 3 trials were rated good-quality, 278,280,285 10fair, 275-277,279,281-284,287,288 and 2 poor. 286,289 Major limitations of trials include small size, lack ofsufficient detail regarding recruitment and randomization, non blinding, and lack of intention-totreatanalyses. Two studies recruited women who either had a history of breast cancer or aperceived increased risk of breast cancer, 282,283 and all other trials included women who had priordiagnoses of breast cancer but no residual disease and who were no longer receivingchemotherapy or radiation. Most studies included women taking tamoxifen, although tamoxifenusersrepresented varying proportions of the study populations (31 percent to 100 percent).Results for tamoxifen-users were presented separately in only one trial, 276 and in three trials, allwomen were taking tamoxifen. 284-286 Study designs did not allow ascertainment of whethertreatments were addressing a side effect of tamoxifen therapy 284-286 or vasomotor symptoms thatoccur naturally in women with a history of breast cancer. All studies recruited women frombreast cancer clinics.Trials used conventional and complementary/alternative medical treatments includingvenlafaxine, 282 fluoxetine, 283 clonidine, 284,285 megestrol acetate, 280 various preparations ofsoy/isoflavone products, 277-279,288 black cohosh, 276,286 magnets, 289 vitamin E, 275 and apolycarbonphil-based vaginal moisturizer. 281 All compared treatments with placebo or usualcare. Outcomes included hot flashes, sleep disturbances, mood, somatic complaints, sexualdysfunction, vaginal dryness, quality of life, and overall menopausal symptoms. No trialsevaluated cognitive symptoms, urinary symptoms, or uterine bleeding.Clonidine, venlafaxine, and megestrol acetate were associated with significantly improvedmeasures of hot flashes. 280,282,284,285 A good-quality trial of oral clonidine indicated a 38 percentdecrease in hot flashes for clonidine (8 to 5 hot flashes/day) vs. 24 percent for placebo (7.4 to 5.7hot flashes/day). 285 In a fair-quality trial of transdermal clonidine, hot flashes decreased 44percent with clonidine (6.1 to 3.4 hot flashes/day) compared to 27 percent for placebo (7 to 5.1hot flashes/day). 284 Megestrol acetate reduced hot flashes by 74 percent compared to 27 percentfor placebo in a good-quality trial. 280 A fair-quality trial of venlafaxine reported a mean decreasein hot flashes of 30 percent to 58 percent for varying doses of venlafaxine vs. 19 percent forplacebo. 282 Vitamin E, black cohosh, isoflavones, magnets, and fluoxetine alone did not reducehot flashes.Results for other outcomes were mixed. Sleep was improved in a fair-quality trial evaluatingfluoxetine, 283 but not in a fair-quality trial using black cohosh. 276 None of the four fair-qualitytrials assessing mood (fluoxetine, venlafaxine, phytoestrogen and black cohosh) found them tobe effective. 276,279,282,283 Of the trials evaluating somatic complaints (headaches, palpitations,excessive sweating, nausea, fatigue), the only benefit reported was from a single fair-quality trialusing black cohosh showing improvement of excessive sweating. 276 Behavioral counseling withtailored therapies was effective at improving sexual functioning in one trial, 287 but a fair-qualitytrial of venlafaxine found no difference in libido. 282 The one trial evaluating polycarbophil-31

ased vaginal preparation found it no more effective than placebo in reducing vaginal dryness,but effective at improving dyspareunia scores. 281 Of the four trials evaluating quality of life,clonidine improved measures, 285 while fluoxetine, magnets, and behavioral counseling didnot. 282,287,289 Three trials assessed overall menopausal symptoms, of which only behavioralcounseling was effective. 287Adverse effects were reported in 12 of 15 trials. 275-285,289 Gastrointestinal adverse effectsoccurred more often among women using phytoestrogen products, 278,279 particularly a soybeverage preparation. 278 Two other trials reported no gastrointestinal adverse effects with soypreparations, 277,288 although one trial excluded all women with intolerance to soy prior torandomization. 288 Fluoxetine was associated with worse appetite, nausea, constipation and drymouth than placebo. 283 The clonidine patch was associated with dry mouth, constipation,itchiness under the patch, and drowsiness. 284 Clonidine tablets were associated with a trendtoward more difficulty sleeping than placebo. 285 Participants in the trial of magnets had difficultywith itching, redness, and perspiration at the site where magnets were affixed. 289 Polycarbophilbasedvaginal preparation was associated with an undesirable “wetness sensation.” 281Concurrent Use of Selective Estrogen Receptor Modulators (SERMs) and Other AgentsPatients using tamoxifen were enrolled in most of the trials of therapies in women with breastcancer. 275-279,282-287 One fair-quality study of black cohosh reported hot flash symptomsseparately for tamoxifen users vs. non-users, but found no significant differences betweengroups. 276 Other studies of treatment of menopausal symptoms did not describe how concurrentuse of SERMs affects therapy.Lifestyle and Behavioral FactorsFew trials considered lifestyle and behavioral factors such as smoking, alcohol use, diet, orothers, 161,162,169,170 and no trials reported results according to these factors.Recent Discontinuation of Menopausal Hormone TherapyMost trials required discontinuation of hormone therapy prior to enrollment, however, noresults were specifically reported for women with recent discontinuation.Very Low or Very High Body Mass Index (BMI)Some trials specified a range of acceptable BMIs in their eligibility criteria therebydisallowing enrollment of women with very high or low BMI. No studies reported resultsaccording to BMI.32

Summary• Evidence is not available to determine if the effectiveness of therapy or adverse effectsdiffer for women with bilateral oophorectomy, premature ovarian failure, concurrent useof SERMs or other potentially interacting agents, lifestyle and behavioral factors, recentdiscontinuation of menopausal hormone therapy, or very low or very high BMI.• For women with breast cancer, results of 15 randomized controlled trials indicate thatclonidine, venlafaxine, and megestrol acetate are associated with significantly improvedmeasures of hot flashes, and vitamin E, black cohosh, isoflavones, magnets, andfluoxetine are not. Result for nonvasomotor outcomes are mixed.Key Question 5. Future Research on TherapiesWhat are the future research directions for treatment of menopauserelatedsymptoms and conditions?Although many trials of several types of interventions have been published, results areconsistent and conclusive only for estrogen agents for the treatment of vasomotor and urogenitalsymptoms. Despite this evidence, many questions remain about the benefits and adverse effectsof estrogen for treating menopause related symptoms long-term. For nonestrogen therapies,larger, more rigorous, and more comprehensive trials are needed in order to determine benefitsand adverse effects. Funding for nonindustry sponsored trials would enable trials of non drugtherapies, including head-to-head trials comparing several types of drug and non druginterventions. Future research should include:• Determination of optimally effective doses, combination regimens, durations of use, andtiming of therapy.• Evaluation of approaches to identify optimal candidates for specific therapies (e.g.,identification of thrombophilias).• Head-to-head and placebo comparisons of estrogen alone and combined with other typesof therapies including non drug interventions.• Trials demonstrating how to discontinue estrogen when symptoms subside, including theeffectiveness of tapering doses and/or replacing with other therapies including non druginterventions.• Better reporting of adverse effects in trials and use of standardized categories of adverseeffects so data can be combined across trials.33

• Improved analysis of results including analysis by hysterectomy and oophorectomystatus, stage of menopause, age, concurrent conditions and medications, and other factors.• More comprehensive trials to determine the role of regular exercise, sleep management,optimal nutrition, healthy relationships, social support, and relaxation; effects of mindbodytechniques such as biofeedback and breathing; effects of a whole system approachwith Chinese medicine.• Additional, well-designed and controlled trials of phytoestrogens, botanicals, and bioidenticalhormones, especially estriol, estradiol, and progesterone. Further study ofantidepressants for vasomotor symptoms would be justified based on evidence ofcurrently available trials.• Enrollment of women with specific characteristics who have not previously beenevaluated such as nonwhite women, women with premature ovarian failure, those usingSERMs and other agents influencing symptoms concurrently, women with very high orlow BMI, and those with lifestyle and behavioral factors influencing symptoms. Trialsshould report data specific to these groups in order to interpret their influence on therapy.• Use of standard definitions, measures, and outcomes so results can be compared acrosstrials.34

Chapter 4. DiscussionBased on review of currently available cohort and cross-sectional population studies,vasomotor symptoms and vaginal dryness are symptoms most consistently associated with themenopausal transition. Sleep disturbance, somatic complaints, urinary complaints, sexualdysfunction, mood, and quality of life are inconsistently associated. No studies provide data oncognition and uterine bleeding problems, onset, duration, and severity of specific symptoms, orconclusive data on the influence of race/ethnicity, age of onset of menopause, BMI,oophorectomy status, presence of depression, or smoking status. The literature is limited bydifferences in how symptoms are defined and measured, variability of study populations, andincompatibility of data preventing direct comparisons between studies or pooling of results.Future research using standard and validated measures and uniform definitions for a morecomprehensive array of symptoms would improve knowledge of these associations.Trials of therapy are conclusive only for estrogen and its use in treating vasomotor andurogenital symptoms, although other therapies may prove effective if further studied.Undertaking trials to treat symptoms that are not clearly associated with the menopausaltransition would not be useful. Trials are limited in many ways including use of highly selectedsmall samples of women; short durations; inadequate reporting of loss to follow up, maintenanceof comparable groups, contamination, methods of analysis, and adverse events; use of dissimilarmeasures and outcomes that are often not standardized or validated; unclear inclusion andexclusion criteria; and industry sponsorship. Future research addressing these deficiencies, asoutlined in Key Question 5, would guide patient and clinician decision making when managingmenopause related symptoms.The evidence review is limited in several ways. For Key Questions 1 and 2, literaturesearches focused on population studies of women undergoing the menopausal transitionreporting symptoms, and did not include epidemiologic or biologically-based etiologic studies.In addition, studies that may not have been identified by searches include those in whichmenopause was not a primary focus of the study, but a predictor variable included in amultivariable model evaluating the outcome or symptom of interest. Studies potentially notidentified would be those that identified no association between menopausal stage and theoutcome of interest. Studies with a positive association would probably have reported it in theabstract and be identified by the searches. Also, the review was limited to English-languagerandomized controlled trials of therapies. Exploratory studies of agents may providecontributory data that were not included in this report.35

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Figures

Figure 1. Normal reproductive aging in womenFinal Menstrual Period (FMP)82Stages -5 -4 -3 -2 -1 +1+2ReproductiveMenopausal Transition PostmenopauseTerminology Early Peak Late Early Late* Early* Late*Perimenopausea bDuration of Stage variable variable until demise1yr 4yrsvariable >2 skippedvariablecycle length cycles andto(>7 days an intervalMenstrualregularregulardifferent ofCyclesfrom normal) amenorrheanone(>60 days)Amen. x 12mosEndocrinenormal FSH↑ FSH↑ FSH↑ FSH*Stages most likely to be characterized by vasomotor symptomsAdapted from Menopause Practice: A Clinician's Guide available at: http://www.menopause.org/edumaterials/cliniciansguide/cliniciansguidetoc.htm

Figure 2. Analytic frameworkInterventions3A, 4ASymptomspersistent,frequent, andsevere3A, 4AImprovedsymptomsImprovedfunction andquality of life83Womenundergoing1Presence ofsymptomsattributed tomenopause2Mild symptoms3B, 4BAdverseEffectsPresence ofsymptoms notattributed tomenopause; orno symptoms

Figure 3. Quality rating criteriaInternal Validity of Randomized Controlled Trials (RCTs) and Cohort StudiesCriteria• Initial assembly of comparable groups: RCTs—adequate randomization,including concealment and whether potential confounders were distributedequally among groups; cohort studies—consideration of potential confounderswith either restriction or measurement for adjustment in the analysis,consideration of inception cohorts.• Maintenance of comparable groups (includes attrition, cross-overs, adherence,contamination).• Important differential loss to follow-up or overall high loss to follow-up.• Measurements: equal, reliable, and valid (includes masking of outcomeassessment).• Clear definition of interventions.• Important outcomes considered.• Analysis: adjustment for potential confounders for cohort studies, or intention-totreatanalysis for RCTs.Definition of ratings based on above criteriaGood:Fair:Poor:Comparable groups are assembled initially and maintained throughout the study(follow-up at least 80 percent); reliable and valid measurement instruments areused and applied equally to the groups; interventions are spelled out clearly;important outcomes are considered; and appropriate attention to confounders inanalysis.Generally comparable groups are assembled initially but some question remainswhether some (although not major) differences occurred in follow-up;measurement instruments are acceptable (although not the best) and generallyapplied equally; some but not all important outcomes are considered; and somebut not all potential confounders are accounted for.Groups assembled initially are not close to being comparable or maintainedthroughout the study; unreliable or invalid measurement instruments are used ornot applied at all equally among groups (including not masking outcomeassessment); and key confounders are given little or no attention.External ValidityConsiderations• Similarities of the populations studied and target population.• Similarities of the test or intervention studied to those that would be routinelyavailable or feasible.• Clinical or social environmental circumstances in the studies that could modifythe results from those expected in the target population.84

Tables

Table 1. Measures of menopause related symptomsMeasureVasomotor symptoms/Global menopausal symptoms191, 211, 252Blatt Menopausal IndexClimacteric Index 258181, 227, 259Clinical Global Impression Improvement Scale (CGI-I)Daily Symptom Rating Calendar (DSR) 154156, 161General Health Questionnaire (GHQ)137, 156, 160, 162, 174, 175, 179, 181, 212, 217, 237, 238, 244, 246, 253, 288Greene Climacteric Scale (GCS)Hopkins Symptom Checklist 130Hot Flash Related Daily Interference Scale (HFRDIS) 289146, 148, 155, 203, 204, 220, 227, 236, 264Kupperman Index261, 263Measure Yourself Medical Outcome Profile (MYMOP)Menopausal Rating Scale 249Menopausal Symptom Index 276263, 287Menopausal Symptom Scale205, 219Menopausal Symptoms Questionnaire (MSQ)Menopause Representation Questionnaire (MRQ) 272Neugarten-Kraines Menopausal Index Scale 271126, 157, 267Nottingham Health Profile (NHP)Patient Global Impression of Change Scale 198183, 198, 242, 287Short Form-36 Health Survey (SF36)235, 266Symptom Check List-90 (SCL-90)129, 151, 181, 199, 201, 235, 243, 261, 264, 266, 276, 279Visual Analogue Scales (VAS)119, 120, 162, 187, 241, 261, 272Women's Health Questionnaire (WHQ)Sleep disturbances215, 238Epworth Sleepiness ScalePittsburgh Sleep Quality Index 198Sleep Dysfunction Test 236Sleep Problems Questionnaire 187215, 238Stanford Sleepiness ScaleMood symptomsBeck Anxiety Inventory II (BAI-II) 181124, 214, 282, 283Beck Depression Inventory (BDI)Center of Epidemiological Studies Depression Scale (CES-D) 154Eysenck Personality Inventory 125129, 258Hamilton Anxiety Scale (HAMA)129, 130, 154, 259Hamilton Depression Rating Scale (HAM-D)215, 238, 263Hospital Anxiety and Depression ScaleIrritability, Depression, and Anxiety (IDA) 162Leckie-Withers Test of Liability to Depressive Illness 128124, 259Minnesota Multiphasic Personality Inventory (MMPI)Personal Distress Scale (PDS) 153Profile of Mood Scale 154 86

Table 1. Measures of menopause related symptoms (continued)MeasureMood symptoms (continued)Profile of Mood States 198144, 150, 153, 160, 187, 241, 236Psychological General Well-Being Index (PGWBI)Rome Depression Inventory (RDI) 259Sabbatsberg Distress Self-Rating Scale (SDS) 125Self-Evaluations Depression Scale 253South African Personality Questionnaire 128253, 269Spielberger State-trait Anxiety InventoryZung Self-Rating Depression Scale Questionnaire 138Cognitive disturbancesAuditory Serial Addition Test 215Boston Naming Test 242Buschke Immediate Recall and Delayed Recall Tests 154Digit Symbol Substitution Test 154Hong Kong List-Learning Test 242Logical Memory and Recall 214Mini-Biography Questionnaire 128214, 242Mini-Mental State Examination (MMSE)National Adult Reading Test-Revised 238Neuropsychological Test Battery 214Symbol Copying Test 154Trail Making Test 242Wechsler Adult Intelligence Scales of Digit Span and Digit Symbol 124215, 238Weschler Memory ScaleWork Ability Index 279Sexual dysfunctionBem Sex Role Inventory 128142, 144, 145Brief Index of Sexual Function for Women (BISF-W)Local Urogenital Complaints Rating Scale (LUCRS) 160150, 167, 171, 174McCoy Sex Scale152, 153Profile of Female Sexual Function (PFSF)Sabbatsberg Revised Sexual Rating Scale (SRS) 145Sabbatsberg Sexual Self-Rating Scale (SSS) 125152, 153Sexual Activity Log (SAL)Sexual Behavior Questionnaire 187142, 145Sexual Interest Questionnaire (SIQ)Sexual Summary Scale 287Quality of lifeCancer Quality of Life Score (European Organization for Research and Treatment) 263137, 225, 229, 238Menopause Specific Quality of Life Questionnaire (MENQOL)Quality of Life Menopause Scale (QUALMS) 145Quality of Life, Enjoyment and Satisfaction Questionnaire (Q-LES-Q) 160SmithKline Beecham Quality of Life Self Report Questionnaire 15487

Table 1. Measures of menopause related symptoms (continued)MeasureQuality of life (continued)282, 283Uniscale QOL instrumentOtherCollins and Landgren Rating Scale 168Dyadic Adjustment Scale (DAS) 156Finger Tapping Test 242Food Frequency Questionnaire 242Halstead-Reitan 214Heat Stress Test (HST) 270Karolinska Scale 158Kellner and Sheffield Rating Scale 191Profile of Adaptation to Life 124Sheehan Disability Scale 181Uken Motherliness Test 128Vaginal Dryness Index 256Vaginal Health Index 257 88

Table 2. Descriptions of cohort studiesCohortAustralian Longitudinal Study onWomen's HealthDescriptionNumber ofpublicationsincluded inevidence review8,236 Australian women 45 to 50 years old in 1996. 2 46,47CopenhagenEindhovenGothenburg630 women 40 years old in 1976 selected from 4 municipalities and served by one hospital inCopenhagen, Denmark. Women using postmenopausal hormone therapy or who underwent prematureor surgical menopause were excluded.8,503 women recruited based on responses to an osteoporosis screening study in Eindhoven,Netherlands. Women were excluded if non-Dutch White, had hysterectomy with or withoutoophorectomy, had bilateral oophorectomy, are using postmenopausal hormone therapy, or werenoncompliant with one or more items in the questionnaire.1,462 women 38 to 60 years old randomly selected in 1968-69 and followed for over 25 years inGothenburg, Sweden. Measures were assessed through periodic medical exams and interviews.3 64-662 67,683 43-45Manitoba Project on Women and TheirHealth in the Middle YearsA cross-sectional and longitudinal cohort study that enrolled 2,500 women aged 40-59 years old fromthe general population of Manitoba, Canada.1 63Massachusetts Women's Health Study 2,500 premenopausal women from Massachusetts, U.S. 6 20-25Medical Research Council (MRC)National Survey for Health andDevelopment1,572 women identified from a socially stratified sample of all births in March 1943 in Britain. 4 48-51Melbourne Women's Midlife HealthProjectMinnesota/Tremin Trust LongitudinalResearch Program on Women's HealthCross-sectional and longitudinal, community-based cohort that enrolled 2,000 women 45 to 55 years oldfrom Melbourne, Australia. Longitudinal follow up of 492 women has been ongoing since 1991. Thestudy assesses women's health during midlife and the menopause including well being, sexuality,symptoms, and bone density and their relationship to a range of variables including hormones, age,stress, lifestyle, and other health experiences.Longitudinal study that initially consisted of 2,350 University of Minnesota women. Between 1961-1963,a second group of 1,600 women was added, and in 1965, a third group of 1,000 native Alaskan womenwere added. Women in the study range from teens to mid-nineties and represent fifty states and twentyfiveforeign countries.11 52-621 4089

Table 2. Descriptions of cohort studies (continued)CohortNational Health Examination Follow-upStudyDescriptionSample of 3,049 U.S. women 40 to 60 years old from the National Health and Nutrition ExaminationSurvey (NHANES).Number ofpublicationsincluded inevidence review1 30Ohio Midlife Women's StudyPennsylvania Ovarian Aging StudySeattle Midlife Women's Health Study208 women 40 to 60 years old, recruited with advertisements from a community in Ohio, U.S. Cohortincludes 57% Caucasian, 43% African-American women.Population-based cohort of 436 women from Philadelphia County, Pennsylvania, 35-47 years old atbaseline including 50% African American, 50% Caucasian. Ongoing longitudinal study.11,222 women from within Seattle, U.S. census tracts, 35 to 55 years old, including multiple ethnicitiesand income levels and followed for 3 years. All women had active menstrual periods at baseline andwere excluded if pregnant, using postmenopausal hormones, or non-English reading/speaking.1 292 41,423 26-28Study of Women's Health Across theNation (SWAN)U.S., community-based, multisite cross-sectional and longitudinal cohort study that enrolled 16,065women 40 to 55 years old. Longitudinal follow up of 3,306 women has been ongoing since 1995. Thegoal of the study is to describe the chronology of the biological and psychosocial characteristics of themenopausal transition and its effects on health and risk factors for age-related chronic diseases.8 31,32-3990

Table 3. Results of cohort studies of menopause related symptomsStudy, year Cohort Population N SymptomVasomotor symptomsBrown, 2002 46 Australian Longitudinal Mid-age (45-50 years) cohort 8,236 Hot flashes,Study on Women's selected from 41,500 Australiannight sweatsHealthwomen with national healthinsurance.Dennerstein, 2000 53 Melbourne Women'sMidlife Health ProjectCommunity-based cohort of 492women (45-55 years) living inMelbourne, Australia.172 Hot flashes,night sweatsAssociatedwith change inmenopausalstage?YesYesDirection of change with transitionHot flashes: pre-peri, peri-peri and HTgroups had significantly higher oddsratio vs. pre-pre.Night sweats: Significantly increasedodds ratio for all groups.Increased in late peri- and postmenopause.Hardy, 2002 51Medical ResearchCouncil (MRC)Socially stratified sample of all birthsin 1 week in March 1943 in Britain.1,572 VasomotorsymptomsYesIncreaseMitchell, 1996 26 Seattle Pre- and perimenopausal women(35-55 years) identified by censustract in Seattle, including minorities.301 Vasomotor No NAVaginal drynessDennerstein, 2000 53 Melbourne Women'sMidlife Health ProjectCommunity-based cohort of 492women (45-55 years) living inMelbourne, Australia.172 VaginaldrynessYesIncreased in late peri- andpostmenopause.91

Table 3. Results of cohort studies of menopause related symptoms (continued)ModifiersStudy, year Age at onset Body mass index Race/ ethnicity Smoking DepressionSurgicalmenopauseQualityratingVasomotor symptoms (continued)Brown, 2002 46 NR Adjusted for but NR Adjusted for but NR Adjusted for but NR Adjusted for but NR NR GoodDennerstein, 2000 53 NE NR NE Yes, for hot flashes NE Excluded GoodHardy, 2002 51 NR NR NR NR NR NR GoodMitchell, 1996 26 NA NE NE NE NE Excluded FairVaginal dryness (continued)Dennerstein, 2000 53 NE NR NE NR, presumed notsignificantNE Excluded Good92

Table 3. Results of cohort studies of menopause related symptoms (continued)Study, year Cohort Population N SymptomSleep disturbanceBrown, 2002 46 Australian Longitudinal Mid-age (45-50 years) cohort 8,236 DifficultyStudy on Women's selected from 41,500 AustraliansleepingHealthwomen with national healthinsurance.Associatedwith change inmenopausalstage?YesDirection of change with transitionPre-peri, peri-peri, pre/peri-post and HThad significantly higher odds ratios vs.pre-pre; only post-post was notsignificant.Dennerstein, 2000 53 Melbourne Women'sMidlife Health ProjectCommunity-based cohort of 492women (45-55 years) living inMelbourne, Australia.172 TroublesleepingYesIncreased gradually across menopausalstages.Mitchell, 1996 26 Seattle Pre- and perimenopausal women(35-55 years) identified by censustract in Seattle, including minorities.301 Insomnia No NAMood symptomsAvis, 1994 20Massachusetts Women'sHealth StudyCohort of premenopausal womensampled from Massachusetts, USA(born 1926-36).2,565 Depression No Increased odds ratio of depression(2.05; 95% CI 1.04-4.02) for peri-perigroup. No other significant odds ratioswith change in stage.Busch, 1994 30National HealthExamination Follow-upStudyU.S. women 40-60 years inNHANES.573 Depression No NADennerstein, 1999 54 Melbourne Women'sMidlife Health ProjectDennerstein, 2001 55 Melbourne Women'sMidlife Health ProjectCommunity-based cohort of 492women (45-55 years) living inMelbourne, Australia.Community-based cohort of 492women (45-55 years) living inMelbourne, Australia.354 Negative mood No NA267 Positive mood No NATable 3. Results of cohort studies of menopause related symptoms (continued)93

Table 3. Results of cohort studies of menopause related symptoms (continued)ModifiersStudy, year Age at onset Body mass index Race/ ethnicity Smoking DepressionSurgicalmenopauseQualityratingSleep disturbance (continued)Brown, 2002 46 NR Adjusted for but NR Adjusted for but NR Adjusted for but NR Adjusted for but NR NR GoodDennerstein, 2000 53 NE NR NE NR, presumed notsignificantNE Excluded GoodMitchell, 1996 26 NA NE NE NE NE Excluded FairMood symptoms (continued)Avis, 1994 20 NR NR NR NR Yes NR FairBusch, 1994 30 NR NR NR NR NR No PoorDennerstein, 1999 54 NE NE NE No NE Excluded GoodDennerstein, 2001 55 NE NS NE NS NE Excluded GoodTable 3. Results of cohort studies of menopause related symptoms (continued)Modifiers94

Study, year Cohort Population N SymptomMood symptoms (continued)Freeman, 2004 41 Pennsylvania OvarianAging StudyCohort of 436 African American andCaucasian women age 35-47 yearsfrom Pennsylvania, recruited byrandom digit dialing.Associatedwith change inmenopausalstage?Direction of change with transition332 Depression Yes Increased odds of CES-D scores >16 inearly and late transition. No increasedodds of major depressive disorder.Glazer, 2002 29Ohio Midlife Women'sStudyCommunity population based onmedia recruitment; 40-60 years.208 Anxiety No NAGlazer, 2002 29Ohio Midlife Women'sStudyCommunity population based onmedia recruitment; 40-60 years.208 Depression No NAHallstrom, 1985 44 Gothenburg Systematic sampling of women age38-60 years using Taxation OfficeRegister; psychiatric sampleselected from this group.899 Developmentof mentaldisorderNoNAHardy, 2002 51Medical ResearchCouncil (MRC)Socially stratified sample of all birthsin 1 week in March 1943 in Britain.1,572 Psychologicalsymptoms(anxiety ordepression)NoNAKaufert, 1992 63 Manitoba Community population of Manitoba,Canada 45-55 years.Maartens, 2002 68 Eindhoven Women born between 1941-1947living in Eindhoven, TheNetherlands, participating inEindhoven PerimenopausalOsteoporosis Study.469 Depression No NA2,103 Depression Yes Increase from pre-peri and peripostmenopause.McKinlay, 1989 24Massachusetts Women'sHealth StudyCohort of premenopausal womensampled from Massachusetts, USA(born 1926-36).2,466 Depression No Increased depression for those within 3months of hysterectomy.Table 3. Results of cohort studies of menopause related symptoms (continued)95

Study, year Age at onset Body mass index Race/ ethnicity Smoking DepressionMood symptoms (continued)Freeman, 2004 41 NE NS Yes, increased oddsof depression inAfrican Americansvs. CaucasiansNR in multivariatemodelSurgicalmenopauseQualityratingYes NE GoodGlazer, 2002 29 NE NE NE NE Yes Yes GoodGlazer, 2002 29 NE NE NE NE Yes Yes GoodHallstrom, 1985 44 NR NR NR NR NR Excluded PoorHardy, 2002 51 NR NR NR NR NR NR GoodKaufert, 1992 63 NE NE NE NE NE Increased odds ofbeing depressedFairMaartens, 2002 68 NE NE NE NE NE Excluded GoodMcKinlay, 1989 24 NR NR NR NR NR Yes PoorTable 3. Results of cohort studies of menopause related symptoms (continued)Modifiers96

Study, year Cohort Population N SymptomMood symptoms (continued)Mishra, 2003 47 Australian Longitudinal Mid-age (45-50 years) cohort 8,623 General mentalStudy on Women's selected from 41,500 AustralianhealthHealthwomen with national health(SF-36)insurance.Associatedwith change inmenopausalstage?NoDirection of change with transitionNAMitchell, 1996 26 Seattle Pre- and perimenopausal women(35-55 years) identified by censustract in Seattle, including minorities.301 DysphoricmoodNoNAWoods, 1997 28 Seattle Pre- and perimenopausal women(35-55 years) identified by censustract in Seattle, including minorities.347 DepressedmoodNoNASomatic complaintsBrown, 2002 46Australian LongitudinalStudy on Women'sHealthMid-age (45-50 years) cohortselected from 41,500 Australianwomen with national healthinsurance.8,236 Back pain Yes Only peri-peri had higher odds ratiothan pre-pre, others not significant.Brown, 2002 46Australian LongitudinalStudy on Women'sHealthMid-age (45-50 years) cohortselected from 41,500 Australianwomen with national healthinsurance.8,236 Headache No All odds ratios not significant.97

Study, year Age at onset Body mass index Race/ ethnicity Smoking DepressionSurgicalmenopauseQualityratingMood symptoms (continued)Mishra, 2003 47 NR Adjusted for weightbut NRNR Adjusted for but NR NR Excluded GoodMitchell, 1996 26 NA NE NE NE NE Excluded FairWoods, 1997 28 NE NE NE NE NE Excluded FairSomatic complaints (continued)Brown, 2002 46 NR Adjusted for but NR Adjusted for but NR Adjusted for but NR Adjusted for but NR NR GoodBrown, 2002 46 NR Adjusted for but NR Adjusted for but NR Adjusted for but NR Adjusted for but NR NR Good98

Table 3. Results of cohort studies of menopause related symptoms (continued)Study, year Cohort Population N SymptomSomatic complaints (continued)Brown, 2002 46 Australian Longitudinal Mid-age (45-50 years) cohort 8,236 SevereStudy on Women's selected from 41,500 AustraliantirednessHealthwomen with national healthinsurance.Associatedwith change inmenopausalstage?YesDirection of change with transitionSevere tiredness: pre-peri, peri-peri,and HT groups had significantly higherodds ratios vs. pre-pre; others notsignificant.Brown, 2002 46Australian LongitudinalStudy on Women'sHealthMid-age (45-50 years) cohortselected from 41,500 Australianwomen with national healthinsurance.8,236 Stiff/painfuljointsYesPre-peri, peri-peri, HT groups hadsignificantly higher odds ratios vs. prepre;others not significant.Brown, 2002 46Australian LongitudinalStudy on Women'sHealthMid-age (45-50 years) cohortselected from 41,500 Australianwomen with national healthinsurance.8,236 Constipation No Only HT group had significantly higherodds ratios than pre-pre; others notsignificant.Dennerstein, 2000 53 Melbourne Women'sMidlife Health ProjectCommunity-based cohort of 492women (45-55 years) living inMelbourne, Australia.172 BreastsorenessYesDecreased in late peri- and postmenopause.Dennerstein, 2000 53 Melbourne Women'sMidlife Health ProjectCommunity-based cohort of 492women (45-55 years) living inMelbourne, Australia.172 Somaticsymptoms(other thanbreastsoreness)NoNAMishra, 2003 47Australian LongitudinalStudy on Women'sHealthMid-age (45-50 years) cohortselected from 41,500 Australianwomen with national healthinsurance.8,623 Bodily pain(SF-36)YesOnly peri-peri and HT groups hadsignificantly worse scores for bodily painvs. pre-pre.99

Table 3. Results of cohort studies of menopause related symptoms (continued)ModifiersStudy, year Age at onset Body mass index Race/ ethnicity Smoking DepressionSurgicalmenopauseQualityratingSomatic complaints (continued)Brown, 2002 46 NR Adjusted for but NR Adjusted for but NR Adjusted for but NR Adjusted for but NR NR GoodBrown, 2002 46 NR Adjusted for but NR Adjusted for but NR Adjusted for but NR Adjusted for but NR NR GoodBrown, 2002 46 NR Adjusted for but NR Adjusted for but NR Adjusted for but NR Adjusted for but NR NR GoodDennerstein, 2000 53 NE NR NE NR NE Excluded GoodDennerstein, 2000 53 NE NR NE NR NE Excluded GoodMishra, 2003 47 NR Adjusted for weightchange and weightat baseline, butcontribution NRNR Adjusted for but NR NR Excluded Good100

Table 3. Results of cohort studies of menopause related symptoms (continued)Study, year Cohort Population N SymptomSomatic complaints (continued)Mishra, 2003 47 Australian Longitudinal Mid-age (45-50 years) cohort 8,623 General healthStudy on Women's selected from 41,500 AustralianperceptionHealthwomen with national health(SF-36)insurance.Associatedwith change inmenopausalstage?YesDirection of change with transitionOnly peri-peri and HT groups hadsignificantly worse general healthperceptions vs. pre-pre.Mitchell, 1996 26 Seattle Pre- and perimenopausal women(35-55 years) identified by censustract in Seattle, including minorities.301 Neuromuscular No NAMitchell, 1996 26 Seattle Pre- and perimenopausal women(35-55 years) identified by censustract in Seattle, including minorities.301 Somatic No NAUrinary complaintsBrown, 2002 46Australian LongitudinalStudy on Women'sHealthMid-age (45-50 years) cohortselected from 41,500 Australianwomen with national healthinsurance.8,236 Leaking urine Yes Only per-peri had significantly higherodds ratio than pre-pre; others notsignificant.Dennerstein, 2000 53 Melbourne Women'sMidlife Health ProjectCommunity-based cohort of 492women (45-55 years) living inMelbourne, Australia.172 UrinarysymptomsNoNASherburn, 2001 56Melbourne Women'sMidlife Health ProjectCommunity-based cohort of 492women (45-55 years) living inMelbourne, Australia.373 Urinary incontinenceNoNASexual dysfunctionDennerstein, 2001 57 Melbourne Women'sMidlife Health ProjectCommunity-based cohort of 492women (45-55 years) living inMelbourne, Australia.283 SexualdysfunctionYesIncreased101

Table 3. Results of cohort studies of menopause related symptoms (continued)ModifiersStudy, year Age at onset Body mass index Race/ ethnicity Smoking DepressionSurgicalmenopauseQualityratingSomatic complaints (continued)Mishra, 2003 47 NR Adjusted for weightchange and weightat baseline butcontribution NRNR Adjusted for but NR NR Excluded GoodMitchell, 1996 26 NA NE NE NE NE Excluded FairMitchell, 1996 26 NA NE NE NE NE Excluded FairUrinary complaints (continued)Brown, 2002 46 NR Adjusted for but NR Adjusted for but NR Adjusted for but NR Adjusted for but NR NR GoodDennerstein, 2000 53 NE NR NE NR NE Excluded GoodSherburn, 2001 56 NE Yes NE Not significant NE Yes GoodSexual dysfunction (continued)Dennerstein, 2001 57 NA NA NA NA NA Excluded Fair102

Table 3. Results of cohort studies of menopause related symptoms (continued)Study, year Cohort Population N SymptomSexual dysfunction (continued)Dennerstein, 2002 58 Melbourne Women'sMidlife Health ProjectCommunity-based cohort of 492women (45-55 years) living inMelbourne, Australia.226 SexualdysfunctionAssociatedwith change inmenopausalstage?YesDirection of change with transitionIncreased from early to late perimenopause.Reduced quality of lifeBusch, 1994 30 National HealthExamination Follow-upStudyDennerstein, 1997 52 Melbourne Women'sMidlife Health ProjectDennerstein, 2002 59 Melbourne Women'sMidlife Health ProjectU.S. women age 40-60 years inNHANES.Community-based cohort of 492women (45-55 years) living inMelbourne, Australia.Community-based cohort of 492women (45-55 years) living inMelbourne, Australia.573 Quality of life No NA438 Quality of life Yes Decreased across menopausalcategories226 Well-being Yes Increased from early to late peri- andpost menopause.Mishra, 2003 47Australian LongitudinalStudy on Women'sHealthMid-age (45-50 years) cohortselected from 41,500 Australianwomen with national healthinsurance.8,623 Quality of life Yes, for peri-periwomen onlyDecreasedAbbreviationsCI=Confidence Interval NE=Not Examined Pre=PremenopausalCES-D = Center for Epidemiologic Studies Depression Scale NR=Not Reported SF-36=Short Form-36 Health SurveyHT=Hormone Replacement TherapyPeri=PerimenopausalNA=Not ApplicablePost=Postmenopausal103

Table 3. Results of cohort studies of menopause related symptoms (continued)ModifiersStudy, year Age at onset Body mass index Race/ ethnicity Smoking DepressionSurgicalmenopauseQualityratingSexual dysfunction (continued)Dennerstein, 2002 58 NE NE NE NE NE Excluded FairReduced quality of life (continued)Busch, 1994 30 NR NR NR NR NR No PoorDennerstein, 1997 52 NR NR NR NR NR Excluded GoodDennerstein, 2002 59 NE NE NE NE NE Excluded GoodMishra, 2003 47 NR Similar body weightbetween groupsNR NR NR Excluded GoodAbbreviationsCI=Confidence Interval NE=Not Examined Pre=PremenopausalCES-D = Center for Epidemiologic Studies Depression Scale NR=Not Reported SF-36=Short Form-36 Health SurveyHT=Hormone Replacement TherapyPeri=PerimenopausalNA=Not ApplicablePost=Postmenopausal104

Table 4. Results of cross-sectional studies of menopause related symptomsStudy, yearVasomotorVaginalCognitivedryness Sleep MoodSomatic UrinaryUterinebleedingMain OutcomesSexualdysfunctionof lifeQuality Age atonsetRace/ethnicity BMISurgical/naturalmenopauseSmokingDepressionData from study cohortsAvis, 1997 21 X XAvis, 2000 22 X X X XAvis, 2001 33 X X xAvis, 2003 34 X XBromberger, 2001 35 X X X X XBromberger, 2003 36 X X X X XBusch, 1994 30XDennerstein, 1993 60 X X X X XDennerstein, 1994 61XGold, 2000 37 X X X X X X X X XGracia, 2004 42 X X XGuthrie, 1996 62 X XHunter, 1989 69 X X X X X X XKaufert, 1992 63 X XKoch, 1995 40 X X X XKoster, 1993 64 X X X XKoster, 1993 65 X XKoster, 2002 66 X X X X XKravitz, 2003 38 X X XKuh, 1997 48 X X X X X X X X X X XKuh, 1999 49 X XKuh, 2002 50XMcKinlay, 1987 23XMcKinlay, 1989 24XMcKinlay, 1992 25 X XMilsom, 1993 45 X XMitchell, 2001 27XRandolph, 2003 39 X X XSherburn, 2001 56 X X X105

Table 4. Results of cross-sectional studies of menopause related symptoms (continued)Study, yearVasomotorVaginalCognitivedryness Sleep MoodSomatic UrinaryUterinebleedingMain OutcomesSexualdysfunctionof lifeQuality Age atonsetRace/ethnicity BMISurgical/naturalmenopauseSmokingDepressionData from other populationsAvis, 1993 70 X X X XBardel, 2002 71 X X X XBell, 1995 72 X X X X X XFeldman, 1985 73 X XGroeneveld, 1993 74 X X X X XHagstad, 1986 75 X X XHammar, 1984 76 X X XHording, 1986 77XJansson, 2003 79 X XJaszmann, 1969 78 X X XKeenan, 2003 80 X X X X X X XLi, 2002 81 X X X X XMcKinlay, 1974 82 X X X XO'Connor, 1995 83 X X X X XOlofsson, 2000 84 X X X X X X X XPorter, 1996 85 X X X X X X XReckers, 1992 86 X X XRybo, 1971 87 X X X X XSchwingl, 1994 88 X X XSlaven, 1998 89 X X X X XThompson, 1973 90 X X X X XYoung, 2003 92 X X X XKeyX=statistically significant association between symptom and menopausal stage.106

Table 5. Trials of estrogen for depressionStudy, yearNBech, 151 Not1998 122 reportedMeanage(range) Therapy Comparison Duration1. Estradiol 2 mg/day andNETA 1 mg/day2. Estradiol 2 mg/day for 22days, 1 mg/day for 6 daysand NETA 1 mg/day for 10days of cyclePlacebo 12monthsBetween groupdifferencesMain resultsImproved scores on BeckDepression Inventory (12 & 21 itemscales) with both estrogen groupsvs. placebo (p

Table 5. Trials of estrogen for depression (continued)Study, yearNGerdes, 38 Not1982 128 reportedMeanage(range) Therapy Comparison DurationCEE 1.25 mg/day for 21days and medrogestrone 5mg/day from day 16 to 21followed by 7 days ofplacebo; cyclicHall, 1998 126 60 44-75 1. CEE 0.625 mg/day andMPA 5 mg/day; cyclic2. Estradiol 50 mcg patchand MPA 5 mg/day; cyclicKhoo, 105 461998 121 (40-52)Klaiber, 38 531996 127 (45-65)CEE 0.625 mg/day andMPA 10 mg/day days 14 to27; cyclicEstropiate 1.5 mg/day andnorethindrone 1 mg/day1. Placebo2. Clonidine 25 mcgtwice dailyBetween groupdifferences20 weeks Improved cheerfulness, health, andenergy with CEE vs. placebo(p

Table 5. Trials of estrogen for depression (continued)Study, yearNMeanage(range) Therapy Comparison DurationSaure,2000 123 376 49 Estradiol 1.5 mg/day for 24days and desogestrel 0.15mg/day for 12 days eachcycleSoares,2001 118 50 49 estradiol,50placebo;(40-55)Strickler, 373 552000 119 (47-60)Thomson, 42 491977 129 (45-55)Estradiol 100 mcg/daytransdermalEstradiol valerate 2mg/day for 21 daysand MPA 10mg/day for 10 daysof cycleCEE 0.625 mg/day 1. Raloxifene 60mg/day2. Raloxifene 150mg/day3. PlaceboPiperazin oestronesulphate 1.5mg twice a dayBetween groupdifferences6 months No differences in mooddisturbances between groups atend of study.Placebo 12 weeks Improved depressive symptoms indepressed women using estradiolvs. placebo (p

Table 6. Trials of progestinsStudy, yearProgesteroneNMain ResultsMeanage(range) Therapy Comparison Duration Between group differences Within group differences Qualityde Wit, 2001 139 10 50-72 Progesteroneintramuscular injections25, 50, or 100 mgweeklyPlacebo 4 weeks No differences in mood, cognition, orbehavior. Higher rating ofsluggishness in 100 mg group.Not reportedPoorLeonetti, 102 52 Progesterone1999 138 mg/day1998 231 ,transdermal cream 20Placebo cream12 monthsin 4 monthphasesImproved vasomotor symptoms withprogesterone vs. placebo (p

Table 7. Trials of AndrogensStudy,yearNTestosteroneMain resultsMean age(range) Therapy Comparison Duration Between group differences Within group differencesBarrett-Connor,1999 146 311 45 (21-65) 1. Esterified estrogen0.625 mg/day and MT1.25 mg/day2. Esterified estrogen1.25 mg/day and MT2.5 mg/dayDobs, 40 57 (41-76) Esterified estrogen 1.252002 145 mg/day and MT 2.5mg/day1. CEE 0.625 mg/day2. CEE 1.25 mg/dayEsterified estrogen 1.25mg/dayFloter,2002 150 50 54 (45-60) Estradiol valerate 2mg/day andtestosteroneundecanoate 40 mg/dayEstradiol valerate 2mg/day2 years Not reported Improved hot flashes and vaginaldryness in all groups; nonsignificanttrend toward greaterimprovement in well-being andsexual interest with MT/estrogen;no differences for somaticsymptoms (Modified KuppermanScale).16 weeks Not reported Improved symptoms in bothgroups. Significant improvementwith MT/estrogen in hot flashes(Quality of Life MenopauseScale), sexual functioning, andsomatic symptoms; no changes inmood and cognition.24 weekscrossoverImproved enjoyment of sex,satisfaction with frequency,interest in sex, and total McCoySex Scale score withtestosterone/estrogen vs.estrogen. No significant differentin psychological well-being.Improved mood (PsychologicalGeneral Well-Being Index), sexualsymptoms (McCoy Sex Scale),and quality of life (PsychologicalGeneral Well-Being Index) in bothgroups.QualityFairFairPoorHickok,1993 143 26 52treatment;50comparisonEsterified estrogen0.625 mg/day and MT1.25 mg/dayEsterified estrogen0.625 mg/day6 months No differences between groupsin hot flash symptom severity,vaginal dryness, sleep problems(4-point menopausal symptomscale).Improved hot flash symptomseverity, vaginal dryness, sleepproblems in both groups (4-pointmenopausal symptom scale).PoorLobo, 218 53 (40-65) Esterified estrogen2003 142 0.625 mg/day and MT1.25 mg/dayEsterified estrogen0.625 mg/day4 months Improved frequency sexualinterest/desire, responsivenessand total Sexual InterestQuestionnaire score with MT/estrogen vs. estrogen, p

Table 7. Trials of Androgens (continued)Study,yearNTestosterone (continued)Penotti,2001* , 151 40 57treatment;55comparisonRaisz,1996* , 147 18 60treatment;66comparisonMain resultsMean age(range) Therapy Comparison Duration Between group differences Within group differencesEstradiol 50 mcg/daytransdermal and MPA10 mg/day for 12days/month andtestosteroneundecanoate 40 mg/dayEsterified estrogen 1.25mg/day and MT 2.5mg/dayShifren,2000 144 75 47 (31-56) 1. Testosterone 150mcg/day transdermaland CEE2. Testosterone 300mcg/day transdermaland CEESimon,1999 149 93 54 1. Esterified estrogen0.625 mg/day and MT1.25 mg/day2. Esterified estrogen1.25 mg/day and MT2.5 mg/dayEstradiol 50 mcg/daytransdermal and MPA10 mg/day for 12days/month8 months No differences between groupsin sexual symptoms (VisualAnalogue Scores).Improved sexual desire andsatisfaction on Visual AnalogueScale in both groups.CEE 1.25 mg/day 9 weeks Not reported Improved psychosomatic andpsychological symptoms inMT/estrogen group. Improved hotflashes, vaginal dryness, andsomatic symptoms in both groups.(Modified Kupperman with 0-3scale).CEE at various doses(0.625, 0.9, 1.25, 1.8,or 2.5 mg/day)1. Esterified estrogen0.625 mg/day2. Esterified estrogen1.25 mg/day3. Placebo36 weekscrossoverImproved composite score(p=0.04), depressed mood(p=0.03), and positive well-being(p=0.04) (Psychological GeneralWell-Being Index), and improvedsexual symptoms (Brief Index ofSexual Function for Women) withtestosterone 300 mcg/day vs.placebo (p=0 03)Not reported3 months Not reported Improved somatic symptoms,vaginal dryness, and hot flashesin all nonplacebo groups; noeffect on sleep or mood(Kupperman Index). No treatmenteffect for psychosomatic orpsychological scores.QualityPoorPoorFairPoorWatts, 66 21-60 Esterified estrogen 1.251995 148 mg/d + MT 2.5 mg/dayEsterified estrogen 1.25mg/day2 years No differences between groupsfor hot flashes, vaginal dryness,or sleep (modified KuppermanIndex with 0-7 scale).Improved hot flashes, vaginaldryness and sleep in both groups(modified Kupperman Index with 0-7 scale).Fair112

Table 7. Trials of Androgens (continued)Study,yearNMain resultsMean age(range) Therapy Comparison Duration Between group differences Within group differencesDehydroepiandrosterone (DHEA)Barnhart,1999 154 60 48 (45-55) DHEA 50 mg/day Placebo 3 months No differences between groupsin hot flashes, vaginal dryness,sleep, mood, cognition, somaticsymptoms, urinary symptoms,sexual symptoms, and quality oflifeImproved total symptoms andhealth-related quality of life inboth groups.QualityFairStomati,1999 155 22 50-55 1. DHEAS 50 mg/day2. DHEAS 50 mg/dayand estradiol 50 mg/daytransdermalEstradiol 50 mg/daytransdermal3 months Not reported Similar improved KuppermanIndex score with all groups(p

Table 8. Trials of tiboloneStudy, yearNBaracat,2002* , 163 85 51treatment;53comparison(45-65)Main resultsMean age(range) Therapy Comparison Duration Between group differences Within group differences QualityTibolone 2.5 mg/day CEE 0.625 mg/dayand MPA 5 mg/day12 months No differences between groups inintensity and mean number hotflashes, sleep, mood, cognition,somatic complaints, and sexualsymptoms.Benedek-Jaszmann,1987 164 60 44-61 Tibolone 2.5 mg/day Placebo 12 months Improved hot flashes, irritability,and psychic instability withtibolone vs. placebo. Noconsistent differences betweengroups in depression, sleep,somatic complaints.De Aloysio, 168 Not reported Tibolone 2.5 mg/day 1. Placebo injection1987* , 165 2. No treatmentEgarter,1996* , 166 129 54 Tibolone 2.5 mg/day CEE 0.625 mg/dayand medrogestone10 mg/day for 12days/monthHammar, 437 55 Tibolone 2.5 mg/day Estradiol 2 mg/day1998 159 and NETA 1mg/day4 months Improved hot flashes with tibolonevs. placebo; no differencesbetween groups for sleep andsomatic symptoms.6 months No differences between groups inhot flashes, vaginal dryness,sleep, mood, somatic complaints,and sexual symptoms.48 weeks Improved hot flushes withestrogen/NETA vs. tibolone(p

Table 8. Trials of tibolone (continued)Study, yearNMain resultsMean age(range) Therapy Comparison Duration Between group differences Within group differences QualityHudita,2003 167 162 56 (40-65) 1. Tibolone 1.25mg/day2. Tibolone 2.5mg/dayLam, 100 50 Tibolone 2.5 mg/day Placebo 6 months2004 156 in eacharmLandgren,2002 168 775 52 (40-60) 1. Tibolone0.625 mg/day2. Tibolone 1.25mg/day3. Tibolone 2.5mg/day4. Tibolone5 mg/dayPlacebo 24 weeks Improved hot flashes, vaginaldryness, and sexual symptomswith both doses of tibolone vs.placebo; greater improvement inhot flashes and vaginal drynesswith 2.5 mg vs. 1.25 mg doses(Modified McCoy Sex Scale,menopausal symptoms scale).Increased bleeding with bothdoses of tibolone.Improved somatic complaints intibolone group. No difference intotal Greene Climacteric Score orany other subscales.Placebo 12 weeks Improved frequency of hot flashesand sweating at 1.25 mg, 2.5 mg,and 5.0 mg doses of tibolone vs.placebo (Collins and LandgrenRating Scale). Dose relatedvaginal bleeding.Improved hot flash and vaginaldryness in both tibolone groups,not in placebo.Improved vasomotor, urogenital,and sexual subscores in bothgroups; improved mood andsomatic complaints in tibolonegroup; (Greene Climacteric Scale,General Health Questionnaire,Dyadic Adjustment Scale). Nochange in psychological well-beingin either group.Not reportedPoorGoodPoorLloyd, 29 61 Tibolone 2.5 mg/day Placebo 6 months No differences between groups in2000 161 quality of life (General HealthQuestionnaire).Not reportedFair115

Table 8. Trials of tibolone (continued)Main resultsStudy, year NMean age(range) Therapy Comparison Duration Between group differences Within group differences QualityMeeuwsen,2002 157 85 54 Tibolone 2.5 mg/day Placebo 1 year Improved hot flashes and sleepwith tibolone vs. placebo (p

Table 8. Trials of tibolone (continued)Study, yearNMain resultsMean age(range) Therapy Comparison Duration Between group differences Within group differences QualityRoss,1999 162 36 52 (45-65) Tibolone 2.5 mg/day CEE 0.625 mg/dayand norgestrol 150mg/day for 12 daysof cycleVolpe,1986 173 113 Not reported Tibolone 2.5 mg/day 1. Placebo2. CE 0.625 mg/dayfor 21 days/mo andNETA 5 mg/day for10 days/mo2. CE 0.625 mg/dayfor 21days/mo andCPA 12.5 mg/dayfor 10 days/mo3. Estradiol valerate2 mg/day for 21days/mo and NETA5 mg/day for 10days/mo4. Estradiol valerate2 mg/day for 21days/mo and CPA12.5 mg/day for 10days/mo5. Estriol 2-4mg/day3 months No differences between groups forhot flashes, mood, cognition,somatic symptoms, uterinebleeding, and sexual symptoms(Women's Health Questionnaire,Irritability, Depression, andAnxiety, Greene ClimactericScale).Not reported6 months Not reported. Improved hot flashes in alltreatment groups (4 point scale).FairPoorWinkler,2000 158 60 54 (45-70) Tibolone 2.5 mg/day 1. Estradiol 2mg/day and Estriol1 mg/day andNETA 1 mg/day24 weeks No differences between groups inhot flashes and vaginal dryness(Karolinska Scale).Improved hot flashes and vaginaldryness in all treatment groups.(Karolinska Scale)Good117

Table 8. Trials of tibolone (continued)Study, yearWu, 2001* ,174NMain resultsMean age(range) Therapy Comparison Duration Between group differences Within group differences Quality48 51 (38-56) Tibolone 2.5 mg/day CEE 0.625 mg/dayand MPA 5 mg/day3 months Improved sexuality with tibolone.No differences between groups inhot flashes, mood, and somaticcomplaints.Climacteric symptoms, quality oflife, and sexuality improved in(McCoy Sex Scale, GreeneClimacteric Scale) both groups.PoorYang, 1999* ,17540 51 Tibolone 2.5 mg/day CEE 0.625 andMPA 5 mg/day 12days/month6 months No differences between groups inhot flashes, mood, cognition,somatic complaints, and sexualsymptoms.Improved hot flashes, mood,cognition, somatic complaints, andsexual symptoms in both groups(Greene Climacteric Scale).PoorAbbreviationsCE=Conjugated estrogenCEE =Conjugated equine estrogenCPA=Cyproterone acetateMPA=Medroxyprogesterone acetateNETA=Norethidrone acetate*Not a double-blind study (single blind or open).118

Table 9. Trials of antidepressant drugsStudy, yearNMean age(range) Therapy Comparison Duration Between group differences Within group differences QualityDavid, 50 32-81 Veralipride1988 186 100 mg/dayPlacebo Four 20daycoursesNot reportedMain resultsImproved hot flash frequency andseverity with veralipride (p=0.01).PoorEvans2005 183 80 51 Venlafaxine XR,37.5mg/day for 1week, then75mg/dayPlacebo 12 weeks No difference in hot flash frequencyor severity as measured by dailydiaries. Greater reduction in "selfperceivedhot flash score" invenlafaxine group. (p

Table 9. Trials of antidepressant drugs (continued)Study, yearNMean age(range) Therapy Comparison Duration Between group differences Within group differences QualityMelis, 40 48-56 Veralipride1988 184 100 mg/dayPlacebo 30 days Improved hot flash composite scorewith veralipride vs. placebo (66% vs.26%; p

Table 10. Trials of ClonidineStudy, yearNMain resultsMeanage(range) Therapy Comparison Duration Between group differences Within group differencesBolli, 1975 190† 20 51 1. Clonidine tablet0.0375 mg twice daily2. Clonidine tablet0.075 mg twice dailyClayden, 1974 189 100 50(41-62)Edington, 93 471980 193† (27-71)Clonidine tablet 0.025mg twice daily;increased if needed tomaximum 0.075 mgtwice dailyClonidine tablet 0.05mg twice dailyPlacebo crossoverPlacebo crossoverPlacebo crossover2 weekseachphase4 weekseachphase4 weekseachphaseNo differences between groups inmean number of hot flashes orsubjective measures of severity andduration. Results same for bothdoses.Prior to crossover: no differencesbetween groups in mean change innumber of hot flashes.After crossover: improvedsubjective scores of hot flashseverity (p=0.05) and durationImproved mean number of flushingepisodes (averaged over all 4 trials)with clonidine vs. placebo (p

Table 10. Trials of Clonidine (continued)Study, yearNagamani, 30 411987 197 (25-58)NMain resultsMeanage(range) Therapy Comparison Duration Between group differences Within group differencesClonidine transdermal0.1 mg/day, patchchanged weeklyPlacebo 8 weeks No differences between groups inmean reduction in hot flashes (diary)at weeks 4 and 8.* More women inthe clonidine group reportedimprovement on subjectivemeasures of frequency (p

†Pre-crossover data not reported123

Table 11. Trials of methyldopa, Bellergal, and gabapentinStudy,yearNMain resultsMeanage(range) Therapy Comparison Duration Between group differences Within group differences QualityAndersen, 40 511986 199 (46-60)Methyldopa 375 mg Placebonightly; increased by 1 crossovertablet every 2 weeks asneeded to maximumdose of 1,125 mg nightlyUp to 8weekseachphaseNo differences between groups in mediannumber of hot flashes; women onmethyldopa felt less troubled by hotflashes (Visual Analogue Scale) vs.placebo (p

Table 12. Trials of phytoestrogens and isoflavonesStudy, yearNMain resultsMean age(range) Therapy Comparison Duration Between group differences Within group differences QualitySoy isoflavones—dietaryAlbertazzi, 104 531999 2041998 203 ,(48-61)Soy powder 60grams (76 mgisoflavones)60 grams caseinpowder12 weeks Improved hot flash frequencywith soy vs. casein at 12 weeks(p

Table 12. Trials of phytoestrogens and isoflavones (continued)Study, yearNMain resultsMean age(range) Therapy Comparison Duration Between group differences Within group differences QualitySoy isoflavones—dietary (continued)Knight, 2001 212 24 52 soy; Soy isoflavone54 placebo; powder beverage 60(40-65) g/day (134.4 mg/dayisoflavones)Casein powder 12 weeks No differences between groupsin flushing frequency or GreeneMenopause Symptom Scores.Improved flushing frequency inboth groups.FairMurkies, 58 54 soy;1995 209 56 wheatSoy flour 45grams/dayWheat flour 45grams/day14 weeks No differences between groupsfor hot flashes and generalsymptom scores.Improved hot flashes andgeneral symptom scores in bothgroups at 12 weeks (p

Table 12. Trials of phytoestrogens and isoflavones (continued)Study, yearNMain resultsMean age(range) Therapy Comparison Duration Between group differences Within group differences QualitySoy isoflavones—extractDuffy, 2003 215 36 59 soy; Soy isoflavone57 placebo; supplement (60(50-65) mg/day)Placebo 12 weeks No differences between groupson the Greene ClimactericScore or mood. Improvedmemory with soy vs. placebo(delayed recall of pictures,p

Table 12. Trials of phytoestrogens and isoflavones (continued)Study, yearPhytoestrogensNMain resultsMean age(range) Therapy Comparison Duration Between group differences Within group differences QualityBrzezinski,1997 219 145 54 phytoestrogen;Phytoestrogen richdiet (tofu, soy drink,51 placebo; miso, flax seed,(43-65) approx 182 mgdaidzein, 255 mggenistein, 4 mglignans)Regular Israeli diet 12 weeks Improved hot flush severity(p=0.004) and vaginal drynessseverity (p=0.005) withphytoestrogen vs. control; nodifference in MenopauseSymptom Questionnaire score.Both groups improved on theMenopause SymptomQuestionnaire score.PoorCarranza-Lira, 30 52 phytoestrogen,2001 220 51 placeboPhytoestrogencream (4 mg/day)Placebo (identicalcold cream)1 month No differences in KuppermanIndex score between groups.Improved Kupperman Indexscore in both groups (p

Table 12. Trials of phytoestrogens and isoflavones (continued)Study, yearNMain resultsMean age(range) Therapy Comparison Duration Between group differences Within group differences QualityPhytoestrogens (continued)Sammartino, 70 51 Genistein 36 mg/day Placebo 12 months Improved Kupperman Index2003* ,223 score with genistein vs. placebo(p

Table 13. Trials of complementary and alternative therapiesStudy, yearAcupunctureNMain resultsMeanage(range) Therapy Comparison Duration Between group differences Within group differences QualityCohen, 18 472003 234 (43-53)6 acupuncturetreatments specific tomenopausal symptoms6 general tonicacupuncturetreatments (shenmein)9 weeks Not reported Improved mean monthly hot flushseverity (diary) at 2, 3, and 4months in treatment; month 4 incontrol. Improved sleepdisturbance in both groups.Improved mood change intreatment, not control.PoorSandberg, 30 542002 235 (48-60)14 electro-acupuncturetreatments specific tomenopausal symptomsSuperficialneedle insertion(sham)12 weeks Treatment group mood (MOODScale) improved vs. control at 8(p=0.05) and 12 weeks (p=0.01).No differences in climacteric orwell-being between groups.Improved mood (MOOD Scale) intreatment group; climactericsymptoms (Visual Analog Scale)and well-being (SCL-50) improvedin both groups.PoorWyon, 24 541995 236 (47-62)10 electro-acupuncture(2 Hz) treatmentsspecific to menopausalsymptoms over 8 weeksSuperficialneedle insertion(sham)8 weeks No differences between groups onany measure.Number of flushes/day (logbook)decreased in both groups;climacteric symptoms (VisualAnalogue Scale) decreased intreatment group, not control;Kupperman Index improved forboth groups; no change in wellbeingfor either group.PoorWyon, 45 51-55 (43- 14 electro-acupuncture2004 264 59) treatments specific tomenopausal symptomsSuperficialneedle insertion(sham) vs.conjugatedestrogen 0.625mg/day12 weeks For flushes, more pronouncedeffect in estrogen group vs. electroacupuncture(p

Table 13. Trials of complementary and alternative therapies (continued)Study, yearChinese herbsNMain resultsMeanage(range) Therapy Comparison Duration Between group differences Within group differences QualityChen, 62 50-52 (45- Chinese herbs2002 235 65) (JWSYS=a collection ofthirteen herbs)CEE 0.625mg/day andMPA 2.5 mg/day16 weeks No differences between groups intotal symptom score, anxiety,depression, somatic symptoms,and vasomotor symptoms(Greene Climacteric Score).Improved sexual symptoms withCEE/MPA vs. JWSYS (p

Table 13. Trials of complementary and alternative therapies (continued)Study, yearNMain resultsMeanage(range) Therapy Comparison Duration Between group differences Within group differences QualityChinese herbs (continued)Wiklund, 384 53-54 (45- Standardized ginseng1999 241 65) extract (Ginsana,containing 100 mg of thestandardized ginsengextract G115; 2capsules/day)Woo, 2003 242 136 56-57 (50-65)Pueraria lobata (PL) (atraditional Chineseherbal remedy) andisoflavone 100 mg/dayPlacebo 16 weeks Improved depression, well-being,and health scores with ginseng vs.placebo (p

Table 13. Trials of complementary and alternative therapies (continued)Study, yearNMain resultsMeanage(range) Therapy Comparison Duration Between group differences Within group differences QualityRed clover (continued)Jeri, 2002 245 30 51-52 Red clover isoflavonetablet (Promensil) 40mg/dayKnight, 37 54.51999 246 (40-65)1. Red clover isoflavonetablet (Promensil) 40mg/day2. Red clover isoflavonetablet (Promensil) 160mg/dayPlacebo 16 weeks Not reported Improved frequency and severityof hot flushes in treatment group(p

Table 13. Trials of complementary and alternative therapies (continued)Study, yearCombinationsNMain resultsMeanage(range) Therapy Comparison Duration Between group differences Within group differences QualityHudson, 13 Not1998 250 reportedBotanical formula 500mg 2 capsules threetimes per day (combineddry herb includingburdock root [2 parts],licorice root [2 parts],motherwort [1 part],Dong Quai root [2 parts]and Mexican wild yamroot [1 part])Placebo 3 months No differences between groups innumber and severity of hot flashes(diary).Improved number and severity ofhot flashes for both groups (diary).PoorOther supplementsBellipanni,2001 251 79 42-62 Melatonin 3 mg/day Placebo 6 months Improved mood and morningdepression (questionnaire) inmelatonin vs. placebo group(p

Table 13. Trials of complementary and alternative therapies (continued)Study, yearNMain resultsMeanage(range) Therapy Comparison Duration Between group differences Within group differences QualityOther supplements (continued)Cagnacci,2003 253 80 50-52 (47- 1. Kava kava 10053) mg/day + calcium1g/day2. Kava kava 200mg/day + calcium1g/dayCalcium 1g/day 3 months Improved anxiety with treatmentvs. placebo; no differencesbetween groups in GreeneClimacteric Score or depressionscore.Improved Greene ClimactericScore, anxiety, and depressionscore in both treatment groups.FairChenoy, 56 541994 254 (45-67)Evening primrose oil(gamolenic acid) 2,000mg/day with naturalvitamin E 10 mg/dayPlacebo 6 months Improved maximum number ofdaytime hot flushes (diary) withplacebo vs. treatment (p

Table 13. Trials of complementary and alternative therapies (continued)Study, yearNMain resultsMeanage(range) Therapy Comparison Duration Between group differences Within group differences QualityManual therapiesCleary, 30 50-60 Low force osteopathic1994 260 manipulation of pelvis,spine, and craniumSham low forcetouch in similarareas10 weekstreatmentImproved hot flushes and nightsweats (questionnaire), urinaryfrequency, depression, andinsomnia in treatment vs. controlgroup.FairEnergy therapiesWilliamson, 80 50.82002 261 (45-60)Reflexology with 9sessions over 19 weeksStandard footmassage9 sessionsoftreatmentover 19weeksNo differences between groups inseverity of hot flushes and nightsweats (Women's HealthQuestionnaire, Visual AnalogueScale, and a self-completedmeasure of quality of life).PoorAbbreviationsMPA=Medroxyprogesterone acetateCEE=Conjugated equine estrogenMMPI = Minnesota Multiphasic Personality Inventory*Not double blind study (open).136

Table 14. Trials of behavioral interventionsStudy, yearNMeanage(range) Therapy Comparison Duration Between group differences Within group differences QualityAiello, 173 61 Aerobic exercise2004 265 225 minutes/ weekStretching 45minutes/week12 months No differences between groups inhot flash frequency, sleep,depressive mood, or cognitivefunction. A subset of women withrecent menopause showedimproved memory in aerobic vs.stretching group.Main resultsNot reportedFairFreedman,1995 268 24 53 Paced respirationtraining in 8 1-hourbiweekly treatmentsessionsAlpha-EEGbiofeedback in 81-hour biweeklytreatmentsessions4 weeks Not reported Decreased hot flash frequency forthe paced-respiration group(p

Table 14. Trials of behavioral interventions (continued)Study, yearNIrvin, 1996 269 45 49-53(44-66)Meanage(range) Therapy Comparison Duration Between group differences Within group differences QualityRelaxation(diaphrag-maticbreathing 20minutes/day) andcharting hot flashes1. Reading andcharting hotflashes2. Charting hotflashes onlyMain results10 weeks Not reported Significant improvement in hot flashintensity, tension/anxiety, anddepression for the relaxation group(p

Table 15. Summary of benefits of therapiesTotal number of trialsQuality ratingReportedcomparisonsGood Fair PoorNumber of trials reporting benefit/total number of trialsHot flashesOther symptomsImproved orsame vs.othertherapyImproved orsame vs.othertherapyTherapyIncluded inreportImprovedvs. placeboOthertherapyImprovedvs. placeboOthertherapyEstrogenVasomotor symptoms*Estradiol (oral) 10 10 109/10Estradiol (transdermal) 11 11 1111/11Conjugated equine estrogen 8 8 88/8Urogenital symptoms* 9 9 93/4 5/5 ESexual function* 11 11 113/6 5/5 ESleep* 3 3 32/3Mood and depression 13 10 3 3 4 4/8 1/3 R, CQuality of life* 9 9 97/8 1/1 EProgestinProgesterone 3 3 1 1 1 1/2 0/3Medroxyprogesterone acetate 2 2 2 2/2 1/2AndrogenTestosterone with estrogen 10 6 1 4 1 2/2 E 1/1 5/5 E +/- PDehydroepiandrosterone 2 1 1 0/1 0/1Tibolone 20 19 3 4 12 5/5 8/10 E +/- P 6/7 11/11 E +/- PAntidepressantsParoxetine 1 1 1 1/1 0/1Moclobemide 1 0Venlafaxine 1 1 1 0/1 1/1Veralipride 5 4 1 3 2/2 1/2 E +/- P 1/2 0/1 E +/- POther DrugsClonidine 10 10 1 9 3/8 1/2 E + P 0/1 E + PMethyldopa 3 3 2 1 1/3Gabapentin 1 1 1 1/1 0/1Bellergal 1 1 1 0/1 1/1139

Table 15. Summary of benefits of therapies (continued)Total number of trialsNumber of trials reporting benefit/total number of trialsQuality rating Hot flashes Other symptomsImproved orImproved orReportedsame vs.same vs.Included in comparisonsGood Fair Poor vs. placebo therapy therapy vs. placebo therapy therapyImproved other Other Improved other OtherTherapyreportPhytoestrogensSoy isoflavones—dietary 10 8 6 2 2/8 1/5Soy isoflavones—extracts 5 5 4 1 3/3 2/2Phytoestrogen 5 5 2 3 4/5 0/1 E + P 1/2Combinations 1 1 1 1/1Complementary and Alternative MedicineAcupuncture 4 3 1 2 0/3 0/1 E 1/3Chinese herbs 6 6 3 3 0/5 2/2 E + P 3/4 2/2 E + PRed clover 6 5 1 3 1 1/5 0/5Black cohosh 1 1 1 0/1 0/1 ECombinations 1 1 1 0/1 1/1Other supplements 9 7 2 5 2/4 3/3 0/1 EManual therapies 1 1 1 1/1 1/1Energy therapies 1 1 1 0/1 0/1Behavioral Interventions 8 5 3 2 0/5 1/3 1/4AbbreviationsE=EstrogenP=ProgestinR=RaloxifeneC=Clonidine*Trials from published systematic reviews 15, 17140

Table 16. Trials in women with breast cancerMain resultsStudy, year N Population Therapy Comparison DurationBarton, 125 18 and older with Vitamin E succinate 800 IU1998 275 previous breast dailycancer; 54%taking tamoxifenPlacebocrossover4 weekseachphaseBetween groupdifferencesPrior to cross-over and in summary:No differences between groups inhot flash frequency or severity(diary questionnaire).Within groupdifferencesImprovements withingroups were notsignificant.QualityFairCarpenter, 15 18 and older with2002 289 previous breastcancer6 magnetic devices attachedto participants' skin overacupuncture/acupressuresites used to balance energyand treat hot flashesPlacebocrossover;placebo wasidentical butblinding noteffectivebecause ofmagnetproperties72 hours+ 2 daysfollow-upeachphaseSummary statistics: Improved hotflash frequency with placebo (10.5to 6.6) vs. magnet (9.6 to 8.3)(p=0.02); improved "bothersome"hot flashes with placebo (4.4 to 3.2)vs. magnets (4.2 to 4.1) (p=0.02).No differences between groups forhot flash severity, interferencescale, or overall quality of life.PoorGanz, 76 Mean age 54.5;2000 287 all have breastcancer; 56%taking tamoxifenCounseling by nursepractitioner, tailored therapy,and support. Therapyincludes any of the following:hot flashes—bellergal,clonidine patch, megestrol;behavioral symptoms—slowabdominal breathing; vaginaldryness—moisturizer orlubricant; urinarysymptoms—Kegel's, Replens,phenylpropanolamine;psychosocial—referral forcounseling or group support.Usual care 4 months Improved adjusted mean change inmenopause symptoms (p=0.0004)and adjusted mean change insexual functioning with interventionvs. usual care (p=0.04); nodifferences between groups forvitality score.Fair141

Table 16. Trials in women with breast cancer (continued)Study, year N Population Therapy Comparison DurationGoldberg,1994 284 116 54 (30-76);all have breastcancer andtaking tamoxifenHernandez 136 >35 years;Munoz,all have estrogen2003 286 receptor positivebreast cancerand takingtamoxifenClonidine transdermal 0.1mg/dayBlack cohosh 20 mg onetablet twice dailyPlacebo crossover4 weekseachphaseBetween groupdifferencesMain resultsPrior to cross-over: Improvedmedian hot flash frequency(p

Table 16. Trials in women with breast cancer (continued)Study, year N Population Therapy Comparison DurationLoprinzi,1994 280 97 Women withhistory of breastcancer;Loprinzi,1997 281 52 Women > 18with history ofbreast cancerand persistentvaginal drynessand/or itching for> 2 monthsMegestrol acetate 20 mgtwice daily.Polycarbophil-based vaginalmoisturizerPlacebo crossoverPlacebo (watersolublelubricating)4 weekseachphase4 weekseachphaseBetween groupdifferencesPrior to cross-over: Improved hotflash frequency (26% of baselinefor megestrol vs. 73% of baselinefor placebo, p

Table 16. Trials in women with breast cancer (continued)Main resultsStudy, year N Population Therapy Comparison DurationLoprinzi, 87 18 and older;2002 283 have breastcancer orperceived highrisk; 54% takingtamoxifenFluoxetine 20 mg/dayPlacebocrossover4 weekseachphaseBetween groupdifferencesPrior to cross-over: Fewer reportsof trouble sleeping sleep withfluoxetine vs. placebo (p=0.03). Nosignificant decrease in hot flashfrequency (p=0.54) or score(p=0.35).Within groupdifferencesQualityFairSummary statistics: Improved hotflash frequency (p=0.01), hot flashscore (p=0.02) with combined dataat end of both cross over periods;No overall differences betweengroups for sleep, quality of life,depression, or libido.Nikander, 62 Mean age 54 (35- Phytoestrogen tablet 114 mg;2003 279 69); all have 3 twice dailybreast cancer;5% had usedtamoxifen>5months priorPandya, 198 Mean age 53-552000 285 (35-77);all have breastcancer andtaking tamoxifenPlacebocrossover3 monthseachphaseClonidine 0.1 mg/day Placebo 8 weekstreatment+ 4 weeksfollow-upPrior to cross-over: No differencesbetween groups in KuppermanIndex, or hot flashes.Improved mean hot flashfrequency, hot flash score, andduration with clonidine vs. placebo.Improved quality of life score withclonidine vs. placebo. Nodifferences between groups in hotflash severity. Increased difficultysleeping with clonidine vs. placebo.Improved KuppermanIndex in both groups;improved hot flashintensity with placebo; noeffect on anxiety, workingability, or self confidencein either group.FairGood144

Table 16. Trials in women with breast cancer (continued)Main resultsStudy, year N Population Therapy Comparison DurationQuella,2000 277 182 women >18;previous breastcancer; 78% ontamoxifenSoy isoflavone 600 mg tabletone three times daily (eachcontains 50 mg of soyisoflavones: 40-45%genistein, 40-45% diadzein,and 10-20% glycitein)Placebocrossover4 weekseachphaseBetween groupdifferencesSummary statistics: No differencesin hot flash score or frequencybetween groups. For outcome ofreduction by half in hot flashfrequency, 36% for placebo vs.24% for soy (p=0.01).Within groupdifferencesQualityFairSecreto, 262 >35; women with2004 288 breast cancerincluded (

U.S. Department of Health and Human ServicesMike Leavitt, SecretaryOffice of Public Health and ScienceRichard H. Carmona, M.D., M.P.H., F.A.C.S., Surgeon General of the United StatesAgency for Healthcare Research and QualityCarolyn M. Clancy, M.D., Director

Appendix A. Technical Expert Panel MembersTechnical Expert Panel MembersRobert R. Freedman, PhDProfessorWayne State University School of MedicineDetroit, MichiganTori Hudson, NDMedical DirectorA Women’s TimePortland, OregonFredi Kroenenburg, PhDProfessor of Clinical Physiology in Rehabilitation MedicineThe Richard & Hinda Rosenthal Center for Complementary & Alternative MedicineNew York, New YorkKurt Kroenke, MDRegenstrief Institute for Health CareIndianapolis, IndianaDiana Petitti, MD, MPHDirector, Research and Evaluation Clinical ServicesKaiser Permanente Southern CaliforniaPasadena, CaliforniaSally Shumaker, PhDDepartment of Public Health SciencesWake Forest University School of MedicineWinston-Salem, North CarolinaLeon Speroff, MDProfessor, Department of Obstetrics and GynecologyOregon Health and Science UniversityPortland, OregonA-1

Appendix B. Expert ReviewersExpert ReviewersDeborah I. Allen, MDRepresenting American Academy of Family PhysiciansTori Hudson, NDMedical Director, A Women’s TimePortland, OregonBarbara L. Kass-Bartelmes, MPH, CHESAgency for Healthcare, Research, and QualityCarmen Kelly, Pharm DAgency for Healthcare, Research, and QualityAlastair MacLennan, MDProfessor, Department of Obstetrics & GynecologyWomen's and Children's HospitalAdelaide University, AustraliaSusan Meikle, MDAgency for Healthcare, Research, and QualityDiana Petitti, MD, MPHDirector, Research and Evaluation Clinical ServicesKaiser Permanente Southern CaliforniaPasadena, CaliforniaLeon Speroff, MDProfessor, Department of Obstetrics and GynecologyOregon Health and Science UniversityPortland, OregonStanley Zinberg, MD, MSRepresenting American College of Obstetricians and GynecologistsB-2

Appendix C. Literature Search StrategiesKQ1 MEDLINELiterature Search StrategiesSearched 1966 through mid-November 2004CognitiveDatabase: Ovid MEDLINE(R)Search Strategy:--------------------------------------------------------------------------------1 CLIMACTERIC/2 MENOPAUSE/3 1 or 24 exp Neurobehavioral Manifestations/5 3 and 46 cognit$.mp. [mp=title, original title, abstract, name of substance, mesh subjectheading]7 3 and 68 exp Delirium, Dementia, Amnestic, Cognitive Disorders/9 3 and 810 5 or 7 or 911 limit 10 to english language12 10 not 1113 limit 12 to abstracts14 11 or 13DepressionDatabase: Ovid MEDLINE(R)Search Strategy:--------------------------------------------------------------------------------1 CLIMACTERIC/2 MENOPAUSE/3 1 or 24 CLIMACTERIC/px [Psychology]5 MENOPAUSE/px [Psychology]6 4 or 57 DEPRESSION/8 exp Depressive Disorder/9 7 or 810 6 or 911 3 and 1012 limit 11 to english language13 11 not 1214 limit 13 to abstracts15 12 or 14C-1

Appendix C. Literature Search Strategies (continued)MoodDatabase: Ovid MEDLINE(R)Search Strategy:--------------------------------------------------------------------------------1 CLIMACTERIC/2 MENOPAUSE/3 1 or 24 exp Affect/5 exp Mood Disorders/6 mood$.mp.7 4 or 5 or 68 3 and 79 exp EMOTIONS/10 3 and 911 8 or 1012 limit 11 to english language13 11 not 1214 limit 13 to abstracts15 12 or 14Ovarian AgingDatabase: Ovid MEDLINE(R)Search Strategy:--------------------------------------------------------------------------------1 climacteric/ or menopause/2 exp OVARY/3 exp AGING/ or exp CELL AGING/4 senescen$.mp.5 3 or 46 1 and 2 and 5Quality of LifeDatabase: Ovid MEDLINE(R)Search Strategy:--------------------------------------------------------------------------------1 CLIMACTERIC/2 MENOPAUSE/3 1 or 24 "Quality of Life"/5 3 and 46 (qualit$ adj5 (life or living)).mp. [mp=title, original title, abstract, name of substance,mesh subject heading]7 3 and 68 5 or 79 exp Life Change Events/C-2

Appendix C. Literature Search Strategies (continued)10 3 and 911 8 or 1012 limit 11 to english language13 11 not 1214 limit 13 to abstracts15 12 or 14Sexual FunctionDatabase: Ovid MEDLINE(R)Search Strategy:--------------------------------------------------------------------------------1 CLIMACTERIC/2 MENOPAUSE/3 1 or 24 exp sex disorders/5 3 and 46 exp "Sexual and Gender Disorders"/7 3 and 68 (sex$ adj3 (disorder$ or dysfunctio$ or function$)).mp. [mp=title, original title,abstract, name of substance, mesh subject heading]9 3 and 810 (sex$ adj3 activ$).mp. [mp=title, original title, abstract, name of substance, meshsubject heading]11 3 and 1012 exp Sexual Behavior/13 3 and 1214 5 or 7 or 9 or 11 or 1315 limit 14 to english language16 14 not 1517 limit 16 to abstracts18 15 or 17SleepDatabase: Ovid MEDLINE(R)Search Strategy:--------------------------------------------------------------------------------1 CLIMACTERIC/2 MENOPAUSE/3 1 or 24 exp Sleep Disorders/5 3 and 46 exp SLEEP/7 3 and 68 5 or 79 (sleep$ or slept).mp. [mp=title, original title, abstract, name of substance, meshsubject heading]C-3

Appendix C. Literature Search Strategies (continued)10 3 and 911 insomn$.mp. [mp=title, original title, abstract, name of substance, mesh subjectheading]12 3 and 1113 5 or 8 or 10 or 1214 limit 13 to english language15 13 not 1416 limit 15 to abstracts17 14 or 16SomaticDatabase: Ovid MEDLINE(R)Search Strategy:--------------------------------------------------------------------------------1 CLIMACTERIC/2 MENOPAUSE/3 1 or 24 exp pain/5 somat$.mp.6 4 or 57 3 and 68 limit 7 to english language9 7 not 810 limit 9 to abstracts11 8 or 10UrinationDatabase: Ovid MEDLINE(R)Search Strategy:--------------------------------------------------------------------------------1 CLIMACTERIC/2 MENOPAUSE/3 1 or 24 exp Urination Disorders/5 3 and 46 incontinen$.mp. [mp=title, original title, abstract, name of substance, mesh subjectheading]7 3 and 68 5 or 79 urinat$.mp. [mp=title, original title, abstract, name of substance, mesh subjectheading]10 3 and 911 8 or 1012 limit 11 to english language13 11 not 1214 limit 13 to abstractsC-4

Appendix C. Literature Search Strategies (continued)15 12 or 14Uterine BleedingDatabase: Ovid MEDLINE(R)Search Strategy:--------------------------------------------------------------------------------1 CLIMACTERIC/2 MENOPAUSE/3 1 or 24 exp Uterine Hemorrhage/5 3 and 46 (((uterine or uterus) adj5 (bleed$ or bled or hemorrhag$)) or menorrhag$).mp.7 3 and 68 5 or 79 limit 8 to english language10 8 not 911 limit 10 to abstracts12 9 or 11Vaginal DrynessDatabase: Ovid MEDLINE(R)Search Strategy:--------------------------------------------------------------------------------1 CLIMACTERIC/2 MENOPAUSE/3 1 or 24 (vagina$ adj5 dry$).mp. [mp=title, original title, abstract, name of substance, meshsubject heading]5 3 and 46 exp VAGINA/mi, bs, ph, pp, en, se, ir, me [Microbiology, Blood Supply,Physiology, Physiopathology, Enzymology, Secretion, Innervation, Metabolism]7 3 and 68 5 or 79 limit 8 to english language10 8 not 911 limit 10 to abstracts12 9 or 11VasomotorDatabase: Ovid MEDLINE(R)Search Strategy:--------------------------------------------------------------------------------1 MENOPAUSE/2 CLIMACTERIC/3 1 or 24 vasomotor.mp. or exp vasomotor system/C-5

Appendix C. Literature Search Strategies (continued)5 3 and 46 (hot flash$ or hot flush$ or night sweat$).mp. [mp=title, original title, abstract, nameof substance, mesh subject heading]7 Body Temperature Regulation/ or SWEATING/8 6 or 79 3 and 810 5 or 911 limit 10 to english language12 10 not 1113 limit 12 to abstracts14 11 or 13KQ1 PSYCHINFOSearched 1974 through May 2004CognitiveDatabase: PsycINFOSearch Strategy:--------------------------------------------------------------------------------1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, heading word,table of contents, key concepts]2 (cognit$ or memor$ or dement$).mp. [mp=title, abstract, heading word, table ofcontents, key concepts]3 1 and 2MoodDatabase: PsycINFOSearch Strategy:--------------------------------------------------------------------------------1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, heading word,table of contents, key concepts]2 exp emotional states/3 (mood$ or depress$ or anxi$ or irritab$).mp. [mp=title, abstract, heading word, tableof contents, key concepts]4 2 or 35 1 and 4Quality of LifeDatabase: PsycINFOSearch Strategy:--------------------------------------------------------------------------------1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, heading word,table of contents, key concepts]2 exp "quality of life"/ or exp life satisfaction/ or exp lifestyle/ or exp lifestyle changes/or exp well being/C-6

Appendix C. Literature Search Strategies (continued)3 (qualit$ adj3 life).mp. [mp=title, abstract, heading word, table of contents, keyconcepts]4 2 or 35 1 and 4Sexual FunctionDatabase: PsycINFOSearch Strategy:--------------------------------------------------------------------------------1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, heading word,table of contents, key concepts]2 exp Sexuality/ or exp Psychosexual Behavior/3 (sex$ adj3 (function$ or dysfunction$ or activ$)).mp. [mp=title, abstract, headingword, table of contents, key concepts]4 2 or 35 1 and 4SleepDatabase: PsycINFOSearch Strategy:--------------------------------------------------------------------------------1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, heading word,table of contents, key concepts]2 sleep$.mp. [mp=title, abstract, heading word, table of contents, key concepts]3 (insomn$ or hypersomn$).mp. [mp=title, abstract, heading word, table of contents,key concepts]4 (awak$ or wak$).mp. [mp=title, abstract, heading word, table of contents, keyconcepts]5 2 or 3 or 46 1 and 5SomaticDatabase: PsycINFOSearch Strategy:--------------------------------------------------------------------------------1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, heading word,table of contents, key concepts]2 somat$.mp. [mp=title, abstract, heading word, table of contents, key concepts]3 exp pain/4 (pain$ or ache$).mp. [mp=title, abstract, heading word, table of contents, keyconcepts]5 2 or 3 or 46 1 and 5UrinationDatabase: PsycINFOC-7

Appendix C. Literature Search Strategies (continued)Search Strategy:--------------------------------------------------------------------------------1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, heading word,table of contents, key concepts]2 (urinat$ or urinar$ or incontin$).mp. [mp=title, abstract, heading word, table ofcontents, key concepts]3 1 and 2Uterine BleedingDatabase: PsycINFOSearch Strategy:--------------------------------------------------------------------------------1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, heading word,table of contents, key concepts]2 (uterin$ or uterus).mp. [mp=title, abstract, heading word, table of contents, keyconcepts]3 (hemorrhag$ or menorrhag$ or bleed$).mp. [mp=title, abstract, heading word, tableof contents, key concepts]4 2 or 35 1 and 4Vaginal DrynessDatabase: PsycINFOSearch Strategy:--------------------------------------------------------------------------------1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, heading word,table of contents, key concepts]2 vagin$.mp. [mp=title, abstract, heading word, table of contents, key concepts]3 1 and 2VasomotorDatabase: PsycINFOSearch Strategy:--------------------------------------------------------------------------------1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, heading word,table of contents, key concepts]2 fl#sh$.mp. [mp=title, abstract, heading word, table of contents, key concepts]3 sweat$.mp. [mp=title, abstract, heading word, table of contents, key concepts]4 vasomotor$.mp. [mp=title, abstract, heading word, table of contents, key concepts]5 body temperature.mp. [mp=title, abstract, heading word, table of contents, keyconcepts]6 2 or 3 or 4 or 57 1 and 6C-8

Appendix C. Literature Search Strategies (continued)KQ2 MEDLINESearched 1966 through mid-November 2004Age of OnsetDatabase: Ovid MEDLINE(R)Search Strategy:--------------------------------------------------------------------------------1 CLIMACTERIC/2 MENOPAUSE/3 1 or 24 "Age of Onset"/5 (age adj3 onset).mp. [mp=title, original title, abstract, name of substance, meshsubject heading]6 (age adj2 menopause).mp. [mp=title, original title, abstract, name of substance, meshsubject heading]7 (menopaus$ adj2 transit$).mp. [mp=title, original title, abstract, name of substance,mesh subject heading]8 4 or 5 or 6 or 79 3 and 810 exp Age Factors/11 exp Time Factors/12 10 or 1113 9 and 1214 limit 13 to english language15 13 not 1416 limit 15 to abstracts17 14 or 1618 from 17 keep 1-458BMIDatabase: Ovid MEDLINE(R)Search Strategy:--------------------------------------------------------------------------------1 CLIMACTERIC/2 MENOPAUSE/3 1 or 24 (body mass index or bmi).mp. [mp=title, original title, abstract, name of substance,mesh subject heading]5 3 and 46 limit 5 to english language7 5 not 68 limit 7 to abstracts9 6 or 8C-9

Appendix C. Literature Search Strategies (continued)DepressionDatabase: Ovid MEDLINE(R)Search Strategy:--------------------------------------------------------------------------------1 CLIMACTERIC/2 MENOPAUSE/3 1 or 24 CLIMACTERIC/px [Psychology]5 MENOPAUSE/px [Psychology]6 4 or 57 DEPRESSION/8 exp Depressive Disorder/9 7 or 810 Depress$.mp.11 6 and 1012 3 and 913 11 or 1214 limit 13 to english language15 13 not 1416 limit 15 to abstracts17 14 or 16EthnicityDatabase: Ovid MEDLINE(R)Search Strategy:--------------------------------------------------------------------------------1 CLIMACTERIC/2 MENOPAUSE/3 ((perimenopaus$ or menopaus$) adj3 (sign$ or symptom$)).mp.4 1 or 2 or 35 eh.fs.6 exp Population Groups/7 Cross-Cultural Comparison/8 5 or 6 or 79 4 and 810 limit 9 to english language11 9 not 1012 limit 11 to abstracts13 10 or 12SurgicalDatabase: Ovid MEDLINE(R)Search Strategy:--------------------------------------------------------------------------------1 CLIMACTERIC/2 MENOPAUSE/C-10

Appendix C. Literature Search Strategies (continued)3 1 or 24 surgical menopause.mp.5 exp OVARIECTOMY/6 3 and 57 (oophorectom$ or ovariectom$).mp. [mp=title, original title, abstract, name ofsubstance, mesh subject heading]8 (ovar$ adj3 remov$).mp. [mp=title, original title, abstract, name of substance, meshsubject heading]9 7 or 810 3 and 911 4 or 6 or 1012 limit 11 to human13 limit 12 to english language14 12 not 1315 limit 14 to abstracts16 13 or 15KQ2 PSYCHINFOSearched 1974 through May 2004DepressionDatabase: PsycINFOSearch Strategy:--------------------------------------------------------------------------------1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, heading word,table of contents, key concepts]2 exp emotional states/3 (mood$ or depress$ or anxi$ or irritab$).mp. [mp=title, abstract, heading word, tableof contents, key concepts]4 2 or 35 1 and 4KQ3 AMEDSearched 1985 through August 2004MenopauseDatabase: AMED (Allied and Complementary Medicine)Search Strategy:--------------------------------------------------------------------------------1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=abstract, heading words,title]C-11

Appendix C. Literature Search Strategies (continued)KQ3 COCHRANESearched through 2 nd Quarter 2004AlternativeDatabase: EBM Reviews - Cochrane Central Register of Controlled TrialsSearch Strategy:--------------------------------------------------------------------------------1 (exp menopause/ and climacterium/) or exp climacteric/ or (menopaus$ or climacter$or premenopaus$ or postmenopaus$ or perimenopaus$).mp.2 exp medicinal plant/ or exp plants, medicinal/ or exp plant medicinal product/ or expplant extracts/ or (botanical$ or herb or herbal or red clover or black cohosh or primroseor yam or ginseng or dong quai or progesterone cream).mp. [mp=title, original title,abstract, mesh headings, heading words, keyword]3 exp traditional medicine/ or exp alternative medicine/ or exp complementarytherapies/ or ((Alternative or complement$) adj5 (medic$ or treat$ or therap$)).mp.[mp=title, original title, abstract, mesh headings, heading words, keyword]4 (homeopath$ or naturopath$ or Ayurvedic).mp. [mp=title, original title, abstract,mesh headings, heading words, keyword]5 (acupunct$ or reflexol$ or magnet$ or electromagnet$ or tradition$ or folk).mp.[mp=title, original title, abstract, mesh headings, heading words, keyword]6 2 or 3 or 4 or 57 1 and 6AndrogensDatabase: EBM Reviews - Cochrane Central Register of Controlled TrialsSearch Strategy:--------------------------------------------------------------------------------1 (exp menopause/ and climacterium/) or exp climacteric/ or (menopaus$ or climacter$or premenopaus$ or postmenopaus$ or perimenopaus$).mp.2 exp androgens/ or androgen$.mp. or testosteron$.mp. [mp=title, original title,abstract, mesh headings, heading words, keyword]3 (dhea or dihydroepitestosteron$).mp. [mp=title, original title, abstract, meshheadings, heading words, keyword]4 dihydrotestosteron$.mp.5 2 or 3 or 46 1 and 57 from 6 keep 1-384AntidepressantsDatabase: EBM Reviews - Cochrane Central Register of Controlled TrialsSearch Strategy:--------------------------------------------------------------------------------1 (exp menopause/ and climacterium/) or exp climacteric/ or (menopaus$ or climacter$or premenopaus$ or postmenopaus$ or perimenopaus$).mp.C-12

Appendix C. Literature Search Strategies (continued)2 exp antidepressant agents/ or exp antidepressive agents/ or Antidepress$.mp.[mp=title, original title, abstract, mesh headings, heading words, keyword]3 fluoxetine.mp.4 venlafaxine.mp.5 paroxetine.mp.6 2 or 3 or 4 or 57 1 and 68 exp depression/9 exp depressive disorder/10 8 or 911 1 and 1012 7 or 11ExerciseDatabase: EBM Reviews - Cochrane Central Register of Controlled TrialsSearch Strategy:--------------------------------------------------------------------------------1 (exp menopause/ and climacterium/) or exp climacteric/ or (menopaus$ or climacter$or premenopaus$ or postmenopaus$ or perimenopaus$).mp.2 exp Exercise Movement Techniques/ or exp kinesiotherapy/ or exp exercise/3 (aerobic$ or exercis$ or yoga or tai chi or pilates).mp. [mp=title, original title,abstract, mesh headings, heading words, keyword]4 ((exp psychophysiology/ or exp feedback system/ or exp Mind-Body/) andRelaxation Techniques/) or (biofeedback$ or feedback$).mp. [mp=title, original title,abstract, mesh headings, heading words, keyword]5 ((pace or paced or pacing) adj3 (breath$ or respirat$)).mp. [mp=title, original title,abstract, mesh headings, heading words, keyword]6 2 or 3 or 4 or 57 1 and 6Hormones (covers estrogen and progestin)Database: EBM Reviews - Cochrane Central Register of Controlled TrialsSearch Strategy:--------------------------------------------------------------------------------1 exp pain/ or (Pain or pains or painful or ache or aching or ached or aches or headach$or migrain$ or somat$).mp.2 exp urination disorders/ or exp urinary dysfunction/ or ((vagina$ adj5 dry$) orenuresis or polyuria or oliguria or incontinen$ or (urin$ adj3 frequen$) or urinat$ orvaginit$ or vulvovaginit$).mp. [mp=title, original title, abstract, mesh headings, headingwords, keyword]3 exp Delirium, Dementia, Amnestic, Cognitive Disorders/ or exp memory disorder/ orexp memory disorders/ or exp cognitive defect/ or (Cognit$ or amnes$ or deliri$ ordement$ or memor$ or remember$ or think$).mp. [mp=title, original title, abstract, meshheadings, heading words, keyword]4 exp sexuality/ or exp Sexual behavior/ or exp sex disorders/ or exp sexualdysfunction/ or ((sex$ adj3 (disorder$ or dysfunctio$ or function$ or activ$ or desir$)) orC-13

Appendix C. Literature Search Strategies (continued)Dyspareuni$ or vaginismus).mp. [mp=title, original title, abstract, mesh headings,heading words, keyword]5 exp sleep/ or exp sleep disorders/ or exp sleep disorder/ or (Sleep$ or slept orinsomn$ or awak$).mp. [mp=title, original title, abstract, mesh headings, heading words,keyword]6 exp uterine bleeding/ or exp uterus bleeding/ or (((uterine or uterus) adj5 (bleed$ orbled or hemorrhag$)) or menorrhag$).mp.7 exp affect/ or exp mood disorders/ or exp mood disorder/ or exp mood/ or exptemperament/ or (mood$ or emotion$ or depression or depressive or irritat$ or anxi$ orAffective).mp. [mp=title, original title, abstract, mesh headings, heading words, keyword]8 exp quality of life/ or (qualit$ adj5 (life or living)).mp.9 exp body temperature regulation/ or exp body temperature disorder/ or expvasomotor disorder/ or exp vasomotor system/ or exp adrenergic system/ or (Vasomotoror fl#sh$ or sweat$).mp. [mp=title, original title, abstract, mesh headings, heading words,keyword]10 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 911 (exp menopause/ and climacterium/) or exp climacteric/ or (menopaus$ orclimacter$ or premenopaus$ or postmenopaus$ or perimenopaus$).mp.12 exp estrogens/ or exp estrogen/ or estrogen$.mp.13 exp hormone replacement therapy/ or exp hormone substitution/ or (hormonereplacement therapy or hormone substitution).mp.14 exp progesterone/ or exp progestins/ or exp gestagen/ or (progestin$ orprogesterone$ or gestegen$ or neta or mpa or megestrol).mp.15 12 or 13 or 1416 10 and 11 and 15Other DrugsDatabase: EBM Reviews - Cochrane Central Register of Controlled TrialsSearch Strategy:--------------------------------------------------------------------------------1 (exp menopause/ and climacterium/) or exp climacteric/ or (menopaus$ or climacter$or premenopaus$ or postmenopaus$ or perimenopaus$).mp.2 gabapentin.mp.3 clonidine.mp.4 methyldopa.mp. or exp METHYLDOPA/5 exp Ergotamine/ or bellergal.mp.6 2 or 3 or 4 or 57 1 and 6PhytoestrogensDatabase: EBM Reviews - Cochrane Central Register of Controlled TrialsSearch Strategy:--------------------------------------------------------------------------------1 (exp menopause/ and climacterium/) or exp climacteric/ or (menopaus$ or climacter$or premenopaus$ or postmenopaus$ or perimenopaus$).mp.C-14

Appendix C. Literature Search Strategies (continued)2 exp phytoestrogen/ or exp isoflavones/ or exp isoflavone derivative/ or(phytoestrogen$ or isflavone$ or soy or soya or soybean$ or genistein or flax).mp.[mp=title, original title, abstract, mesh headings, heading words, keyword]3 1 and 2TiboloneDatabase: EBM Reviews - Cochrane Central Register of Controlled TrialsSearch Strategy:--------------------------------------------------------------------------------1 (exp menopause/ and climacterium/) or exp climacteric/ or (menopaus$ or climacter$or premenopaus$ or postmenopaus$ or perimenopaus$).mp.2 tibolone.mp.3 1 and 2KQ3 MANTISSearched 1880 through July 2004MenopauseDatabase: MantisSearch Strategy:--------------------------------------------------------------------------------1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, descriptors]KQ3 MEDLINESearched 1966 through mid-November 2004AlternativeDatabase: Ovid MEDLINE(R)Search Strategy:--------------------------------------------------------------------------------1 exp CLIMACTERIC/ or (climacter$ or menopaus$).mp.2 limit 1 to complementary medicine3 (botanical$ or red clover or black cohosh or primrose or yam or ginseng or dong quaior progesterone cream).mp. [mp=title, original title, abstract, name of substance, meshsubject heading]4 exp Complementary Therapies/5 (homeopath$ or naturopath$ or Ayurvedic).mp. [mp=title, original title, abstract,name of substance, mesh subject heading]6 3 or 4 or 57 1 and 68 2 or 79 limit 8 to english language10 8 not 911 limit 10 to abstractsC-15

Appendix C. Literature Search Strategies (continued)12 9 or 1113 limit 12 to (guideline or meta analysis or randomized controlled trial)14 from 13 keep 1-310AndrogensDatabase: Ovid MEDLINE(R)Search Strategy:--------------------------------------------------------------------------------1 exp CLIMACTERIC/ or (climacter$ or menopaus$).mp.2 exp androgens/ or androgen$.mp. or testosteron$.mp. [mp=title, original title,abstract, name of substance, mesh subject heading]3 (dhea or dihydroepitestosteron$).mp. [mp=title, original title, abstract, name ofsubstance, mesh subject heading]4 dihydrotestosteron$.mp.5 2 or 3 or 46 1 and 57 limit 6 to female8 limit 7 to english language9 7 not 810 limit 9 to abstracts11 8 or 1012 limit 11 to (guideline or meta analysis or randomized controlled trial)AntidepressivesDatabase: Ovid MEDLINE(R)Search Strategy:--------------------------------------------------------------------------------1 exp CLIMACTERIC/ or (climacter$ or menopaus$).mp.2 exp Antidepressive Agents/3 fluoxetine.mp.4 venlafaxine.mp.5 paroxetine.mp.6 exp DEPRESSION/de, dt [Drug Effects, Drug Therapy]7 exp Depressive Disorder/dt [Drug Therapy]8 2 or 3 or 4 or 5 or 6 or 79 1 and 810 limit 9 to (guideline or meta analysis or randomized controlled trial)Estrogen/ProgestinDatabase: Ovid MEDLINE(R)Search Strategy:--------------------------------------------------------------------------------1 CLIMACTERIC/2 MENOPAUSE/3 (climacter$ or menopaus$ or perimenopaus$).mp. [mp=title, original title, abstract,name of substance, mesh subject heading]C-16

Appendix C. Literature Search Strategies (continued)10 limit 9 to abstracts11 8 or 1012 limit 11 to (guideline or meta analysis or randomized controlled trial)PhytoestrogenDatabase: Ovid MEDLINE(R)Search Strategy:--------------------------------------------------------------------------------1 exp CLIMACTERIC/ or (climacter$ or menopaus$).mp.2 exp Isoflavones/3 (phytoestrogen$ or isflavone$ or soy or soya or flax).mp. [mp=title, original title,abstract, name of substance, mesh subject heading]4 2 or 35 1 and 46 limit 5 to english language7 5 not 68 limit 7 to abstracts9 6 or 810 limit 9 to (guideline or meta analysis or randomized controlled trial)TiboloneDatabase: Ovid MEDLINE(R)Search Strategy:--------------------------------------------------------------------------------1 exp CLIMACTERIC/ or (climacter$ or menopaus$).mp.2 tibolone.mp.3 1 and 24 limit 3 to english language5 3 not 46 limit 5 to abstracts8 limit 7 to (guideline or meta analysis or randomized controlled trial)KQ3 PSYCHINFOSearched 1974 through May 2004AlternativeDatabase: PsycINFOSearch Strategy:--------------------------------------------------------------------------------1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, heading word,table of contents, key concepts]2 exp alternative medicine/ or exp dietary supplements/ or exp "medicinal herbs andplants"/3 (red clover or cohosh or herb or herbal$ or acupunct$ or reflex$).mp. [mp=title,abstract, heading word, table of contents, key concepts]C-18

Appendix C. Literature Search Strategies (continued)4 holist$.mp. [mp=title, abstract, heading word, table of contents, key concepts]5 (complementar$ adj2 (medic$ or therap$)).mp. [mp=title, abstract, heading word,table of contents, key concepts]6 (alternat$ adj2 (medic$ or therap$)).mp. [mp=title, abstract, heading word, table ofcontents, key concepts]7 2 or 3 or 4 or 5 or 68 1 and 7AntidepressantsDatabase: PsycINFOSearch Strategy:--------------------------------------------------------------------------------1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, heading word,table of contents, key concepts]2 exp Antidepressant Drugs/3 (fluoxetine or venlafaxine or paroxetine).mp. [mp=title, abstract, heading word, tableof contents, key concepts]4 exp Serotonin Reuptake Inhibitors/5 ssri.mp. [mp=title, abstract, heading word, table of contents, key concepts]6 antidepress$.mp. [mp=title, abstract, heading word, table of contents, key concepts]7 2 or 3 or 4 or 5 or 68 1 and 7ExerciseDatabase: PsycINFOSearch Strategy:--------------------------------------------------------------------------------1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, heading word,table of contents, key concepts]2 exp exercise/ or exp movement therapy/3 (exercis$ or (physical$ adj3 activ$)).mp. [mp=title, abstract, heading word, table ofcontents, key concepts]4 (pac$ adj2 respir$).mp. [mp=title, abstract, heading word, table of contents, keyconcepts]5 biofeed$.mp. [mp=title, abstract, heading word, table of contents, key concepts]6 (meditat$ or relax$).mp. [mp=title, abstract, heading word, table of contents, keyconcepts]7 2 or 3 or 4 or 5 or 68 1 and 7C-19

Appendix C. Literature Search Strategies (continued)Hormones (covers estrogen, progestin, and androgen)Database: PsycINFOSearch Strategy:--------------------------------------------------------------------------------1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, heading word,table of contents, key concepts]2 exp sex hormones/3 (estrogen$ or progestin$ or progesterone$ or estradiol$ or mpa or neta or megestrolor androgen$ or testosteron$ or dhea).mp. [mp=title, abstract, heading word, table ofcontents, key concepts]4 (hormon$ adj2 therap$).mp. [mp=title, abstract, heading word, table of contents, keyconcepts]5 2 or 3 or 46 1 and 5Other DrugsDatabase: PsycINFOSearch Strategy:--------------------------------------------------------------------------------1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, heading word,table of contents, key concepts]2 (gabpentin or clonidine or methyldopa or bellergal).mp. [mp=title, abstract, headingword, table of contents, key concepts]3 1 and 2PhytoestrogensDatabase: PsycINFOSearch Strategy:--------------------------------------------------------------------------------1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, heading word,table of contents, key concepts]2 (phytoestrogen$ or soy or soya or flax or isoflavon$).mp. [mp=title, abstract, headingword, table of contents, key concepts]3 (phytoestrogen$ or soy or soya or flax or isoflavon$ or genistein$).mp. [mp=title,abstract, heading word, table of contents, key concepts]4 1 and 3TiboloneDatabase: PsycINFOSearch Strategy:--------------------------------------------------------------------------------1 tibolone.mp.C-20

Appendix C. Literature Search Strategies (continued)KQ4 MEDLINESearched 1966 through mid-November 2004Breast CancerDatabase: Ovid MEDLINE(R)Search Strategy:--------------------------------------------------------------------------------1 exp Breast Neoplasms/co [Complications]2 (menopaus$ or perimenopaus$ or premenopaus$).mp. [mp=title, original title,abstract, name of substance, mesh subject heading]3 1 and 24 (breast adj (cancer$ or tumor$ or malignan$) adj3 survivor$).mp. [mp=title, originaltitle, abstract, name of substance, mesh subject heading]5 2 and 46 3 or 57 limit 6 to english language8 6 not 79 limit 8 to abstracts10 7 or 9SERMSDatabase: Ovid MEDLINE(R)Search Strategy:--------------------------------------------------------------------------------1 MENOPAUSE/2 CLIMACTERIC/3 1 or 24 exp Selective Estrogen Receptor Modulators/ad, ae, ct, tu, to [Administration &Dosage, Adverse Effects, Contraindications, Therapeutic Use, Toxicity]5 3 and 46 limit 5 to english language7 5 not 68 limit 7 to abstracts9 6 or 8All KQ’s DARESearched through 2 nd Quarter 2004MenopauseDatabase: EBM Reviews - Database of Abstracts of Reviews of EffectsSearch Strategy:--------------------------------------------------------------------------------1 menopaus$.mp. [mp=title, full text, keywords] (73)2 perimenopaus$.mp. [mp=title, full text, keywords] (4)3 climacter$.mp. [mp=title, full text, keywords] (6)C-21

Appendix C. Literature Search Strategies (continued)4 postmenopaus$.mp. [mp=title, full text, keywords] (63)5 1 or 2 or 3 or 4 (106)6 from 5 keep 1-10 (10)7 from 6 keep 1-10 (10)8 from 6 keep 1-10 (10)C-22

Appendix D. Inclusion and Exclusion CriteriaInclusion and Exclusion CriteriaCriteria for Reviewing AbstractsKey Question 1 (Symptoms)IncludeExcludeRelevant to questionCohort, cross-sectional, review, meta-analysis, or unclear study designCommunity or population basedU.S. applicableAppropriate sample sizeMid-aged femalesUndergoing menopauseNot relevant to questionWrong designNo dataWrong populationPaper only available in non-English languageComment or opinionKey Question 2 (Symptom characteristics and influencing factors)IncludeExcludeRelevant to questionCohort, cross-sectional, review, meta-analysis, or unclear study designCommunity or population basedU.S. applicableAppropriate sample sizeMid-aged femalesUndergoing menopauseNot relevant to questionWrong designNo dataWrong populationPaper only available in non-English languageComment or opinionD-1

Appendix D. Inclusion and Exclusion Criteria (continued)Key Question 3 (Benefits and adverse effects of treatments)IncludeExcludeRelevant to questionRCT, review, or meta-analysisOne or more listed interventionsOne or more menopause-related outcomesPerimenopausal or menopausal womenNot relevant to questionWrong study designNo dataWrong population: premenopausal or postmenopausal women or menAvailable in non-English languageNonhuman/animalMethodological fatal flawComment or opinionKey Question 4 (Specific characteristics and treatments)IncludeExcludeRelevant to questionRCT, review, or meta-analysisOne or more listed interventionsOne or more menopause-related outcomesPerimenopausal or menopausal womenNot relevant to questionWrong study designNo dataWrong population: premenopausal or postmenopausal women or menAvailable in non-English languageNonhuman/animalMethodological fatal flawComment or opinionD-2

Appendix D. Inclusion and Exclusion Criteria (continued)Criteria for Reviewing Full-Text PapersKey Question 1 (Symptoms)IncludeExcludeCohort, cross-sectional, review, or meta-analysisPeri, currently menopausal women, or early postmenopausal womenwith symptomsDescribes one of the symptoms in key question 1Population basedData specific to womenAppropriate outcomes measuresN > 100Major concurrent diseaseKey Question 2 (Symptom characteristics and influencing factors)IncludeExcludeCohort, cross-sectional, review, or meta-analysisPeri, currently menopausal women, or early postmenopausal womenwith symptomsDescribes one of the symptoms in key question 1 and/or one of thefactors in key question 2Population basedData specific to womenAppropriate outcomes measuresN > 100Major concurrent diseaseKey Question 3 (Benefits and adverse effects of treatments)IncludeExcludeRCT, review, or meta-analysisPeri, currently menopausal women, or early postmenopausal womenwith symptomsDescribes one of the treatments in key question 3Appropriate agent (currently available, non-injectable, etc.)Dose explicitly statedAppropriate length of treatment (e.g. > 12 weeks for estrogen use)Data specific to womenAppropriate outcome measuresAppropriate power (N)No major concurrent diseaseD-3

Appendix D. Inclusion and Exclusion Criteria (continued)Key Question 4 (Specific characteristics and treatments)IncludeExcludeRCT, review, or meta-analysisPeri, currently menopausal women, or early postmenopausal womenwith symptomsDescribes one of the specific characteristics in key question 4Appropriate agent (currently available, non-injectable, etc.)Dose explicitly statedAppropriate length of treatment (e.g. > 12 weeks for estrogen use)Data specific to womenAppropriate outcome measuresAppropriate power (N)No major concurrent diseaseD-4

Appendix E. Literature Search TreeLiterature Search TreeMEDLINE, PsycINFO, COCHRANE, AMED, MANTIS*, and DARESearched 1966–November 2004Total Number of Citations10,059E-1E-1KQ 1 & 2 †Symptoms andFactorsKQ 3InterventionsKQ 4 †CharacteristicsReview witheligibility criteria ‡6,342 4,078806Read full text; apply440 428eligibility criteria ‡Full text, quality ratedand included in71 § 134evidence report ‡9415* MANTIS was searched starting in 1880, and only for KQ 3g, h, i† COCHRANE database was not searched for KQ’s 1, 2, & 4‡Citations may overlap among key questions§Only cohort and cross-sectional from cohort studies could be quality rated

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/Year Umbrella NAvis, 1994 Massachusett'sWomen'sHealth StudyStudyDesignTypeControlGroupLength ofFollow-UpRecruitment(Data source)Population/ Setting2565 Cohort Internal 5 years Random sample of 8,050women ages 45-55 inMassachusetts, from which2,565 were identified ashaving menstruated in the past3 months, having a uterus and> one ovaryPopulation basedrecruitment ofpremenopausal womenRace/Ethnicity_Avis, 1997Massachusett'sWomen'sHealth Study454 (131for someanalyses)Crosssectionalanalysesfrom cohortInternal4.5 years Sample was part of larger Community-based,cohort of 8,050 women Massachusettsrandomly selected; 2,565 werepre- or early menopausalNRF-1

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearAvis, 1994Ascertainment ofAge (range)Inclusion/Exclusion CriteriaSymptoms Response Rate Withdrawals_ _ _ _ _Avis, 199745-55 in 1982(baseline)For this analysis, women who were premenopausalat baseline and naturally post-menopausal at thelast study f/u (4 yrs later, 6th clinic visit).Telephone andmailedquestionnaires94-95% retentionover 6 contacts forcohort of 2,565 preandearlymenopausalwomenF-2

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearAvis, 1994Measures UsedCES-D for depressionSeven measures of health careutilizationSelf-assessed health, physicalsymptoms, restricted activity andchronic conditions.Surgical menopause included eitherhysterectomy or BSO.Menopausal statusHysterectomyorBSO (#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use of SERMS(#/n)_ _ _ _ _Avis, 1997hot flashes and night sweats(frequency and bothersomeness)consult with MD regardingmenopauseAll women in this analysisprogressed from pre topost menopausal (natural)over the course of the f/uperiodExcluded Excluded NR NRF-3

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearAvis, 1994Behavior orLifestyle Factors(#/n)RecentdiscontinuationofHRT(#/n)High or Low BMI(#/n) Hot Flashes Vaginal Dryness Sleep_ _ _ _ _ _Avis, 1997Current smoking atbaseline 41%Excluded NR 23% were not botheredby HF/NS at any of thesix interviews.HF and NSbothersomeness werehighly correlated.Length ofperimenopause was notcorrelated with numberor bothersomeness ofsymptoms.Women with morenegative attitude towardmenopause reportHF/NS more frequently.F-4

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearAvis, 1994UterineMood Cognitive Somatic Urinary Bleeding_ _ _ _ _Avis, 1997F-5

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearAvis, 1994Sexual Dysfunc-tion Quality of Life Other Outcomes_ _ _Avis, 1997F-6

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearAvis, 1994Predictors studied(significant/not significant) Statistical Models_Used CES-D score of 16 as dichotomous outcomevariable. Logistic regressionmodel adjusted for HRT,menopausal symptoms at T2,T1-T2 menopausal transitionand T1 CES-D score.Significant predictors in multivariate(adjusted models)_Avis, 1997Smoking (;

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearAvis, 1994RR or OR_CommentsDepression at baseline was most predictive of subsequentdepression (OR 9.12, p

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/Year Umbrella NAvis, 2000 Massachusett'sWomen'sHealth StudyStudyDesign2000 Crosssectionalanalysesfrom cohortTypeControlGroupIntenralLength ofFollow-Up5 years(1986-91)Recruitment(Data source)Population/ SettingRandom pop-based sample of Community-based,8,050 women in Mass. 2,569 Massachusettswomen ages 45-55 selectedfor f/u. Of these 427 (78.6% of543) were eligible for thisstudy. 200 included in thisanalysis.NRRace/EthnicityF-9

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearAvis, 2000Age (range)51-61, meanage 54Inclusion/Exclusion CriteriaInclusion criteria:1. Intact uterus and 1 ovary2. No HRT in past 2 yrs3. Current sexual partner4. Living within 1 hr of Boston5.

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearAvis, 2000Measures UsedSexual activity questionnaire adaptedfor Amssachusetts male Agin StudySatisfaction with current sexualrelationshipFrequency of sexual intercourseSexual desireBelief that interest in sex declines withageLevel of arousalDifficulty reaching organsmPelvic area painMenopausal statusHysterectomyorBSO (#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Exlcuded Excluded Excluded ifwithin 5 yearsNRUse of SERMS(#/n)F-11

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearAvis, 2000Behavior orLifestyle Factors(#/n)Current smoking22%RecentdiscontinuationofHRT(#/n)Excuded(n=51)High or Low BMI(#/n) Hot Flashes Vaginal Dryness SleepBMI range 17-49,mean+SE=27.9+5.5F-12

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearAvis, 2000Mood Cognitive Somatic UrinaryOverall: 12.6% had CES-D score>16.39.8% had psychologicalsymptomsUterineBleedingF-13

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearAvis, 2000Sexual Dysfunc-tion Quality of Life Other OutcomesFewer perimenopausal women reported neverhaving difficulty reaching orgasm (NS).Level of sexual desire was lower among postmenopausalwomen compared withpremenopausal women (p

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearAvis, 2000Predictors studied(significant/not significant) Statistical ModelsThe following variables were Multiple regressionunrelated to any aspect ofsexual functioning:employment status,vasomotor symptoms, parterstress, alcohol , exercise andBMISignificant predictors in multivariate(adjusted models)Sexual Function:Recent vaginal dryness was related to pain during or after intercourse(OR 3.86) and difficulty reaching orgasm (OR 2.51).Menoapausal status was not related to either pain during intercourse ordifficulty reaching orgasm.Age was negatively related to difficulty reaching orgasm.F-15

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearAvis, 2000RR or ORCommentsF-16

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/Year Umbrella NStudyDesignAvis, 2001 SWAN 14,906 CrosssectionalTypeControlGroupLength ofFollow-UpRecruitment(Data source)Population/ SettingRace/Ethnicity_ _ _ _ _F-17

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearAvis, 2001Age (range)Inclusion/Exclusion Criteria47.1 (40-55) Exclusion:450 missing race/ethnicity data341 uncertain menopausal status55 pregnant or breastfeeding313 incomplete data on symptoms or covariatesAscertainment ofSymptoms Response Rate Withdrawals_ 87.70% _F-18

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearAvis, 2001Measures UsedMenopausal status_ Surgical 20.8%Postmenopausal 14.6%Perimenopausal 27.2%Premenopausal 29.7%Hormone user 7.7%HysterectomyorBSO (#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use of SERMS(#/n)_ _ _ _F-19

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearAvis, 2001Behavior orLifestyle Factors(#/n)RecentdiscontinuationofHRT(#/n)High or Low BMI(#/n) Hot Flashes Vaginal Dryness Sleep_ _ _ _ _ _F-20

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearAvis, 2001UterineMood Cognitive Somatic Urinary Bleeding_ _ _ _ _F-21

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearAvis, 2001Sexual Dysfunc-tion Quality of Life Other Outcomes_ _ Factor 1 - psychosomaticsymptomsFactor 2 - vasomotorsymptomsSymptoms had to load > 0.40on a factor for all ethnicgroups.F-22

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearAvis, 2001Predictors studied(significant/not significant)Age, education, selfassessedhealth, economicstrain, geographic siteinteraction terms forrace/ethnicity andmenopausal statusStatistical ModelsMultiple linear regression modelfor Factors 1 and multiplelogistic regression for Factor 2.Significant predictors in multivariate(adjusted models)Factor 1: Psychosomatic symptomsSignificant predictors (p

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearAvis, 2001RR or ORCommentsPsychosomatic symptom reporting differs by both race/ethnicityand by menopausal status. All other racial/ethnic groups reportsignificantly fewer symptoms than Caucasian women. Perimenopausalwomen, HRT users and women with surgicalmenopause report more symptoms than premenopausal women.Vasomotor symptom reporting also varies by race/ethnicity andmenopausal status. Effects are greater when looking 2symptoms vs. none. AA were more likely and Hispanic,Japanese, Chinese were less likely than Caucasian women toreport vasomotor symptoms. All menopausal groups reportedsignificantly more symptoms than premenopausal women.1.22-1.29; 1.38-2.58; 1.15-1.301.41; 1.59; 0.60; 0.65;1.69-1.961.05; 1.53-1.79; 1.69-3.72; 1.18-1.551.28-1.82; 0.25-0.77; 3.35-3.81; 0.74-0.75F-24

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/Year Umbrella NStudyDesignAvis, 2003 SWAN 3,193 CrosssectionalTypeControlGroupLength ofFollow-UpRecruitment(Data source)Population/ SettingRace/Ethnicity_ _ _ _ AA 28.15%Chinese7.68%H 8.44%J 8.63%W 47.1%Bromberger,2001SWAN 10,374 CrosssectionalN/A N/A _ _ AA 25.8%Chinese 5H 13.5J 6.3W 49.2F-25

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearAvis, 2003Age (range)Inclusion/Exclusion Criteria46.2 (42-52) Data on menopausal status and SF-36 outcomesmissing for 109 of 3302Ascertainment ofSymptoms Response Rate Withdrawals_ 96.70% _Bromberger,200140-55 5213 of 16065 were excluded for 1) exogenousmean 45.9 with hormone use preceding 3 months, 2) pregnancy, 3)distress hysterectomy, 4) no menses past 12 months due tomean 46.4 pregnancy, breast-feeding, severe weight loss, orwithout distress illness_ 64.57% _F-26

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearAvis, 2003Bromberger,2001Measures Used5 subscales of SF-36 as measures ofhealth related quality of life (HRQL):bodily pain, role limitations due tophysical health, role limitations due toemotional problems, socialfunctioning and vitalitymenopausal status,sociodemographic and lifestylevariables, health variablespsychosocial variables including theCenter for Epidemiological Studies(CES-D) scale, Perceived StressScale, Medical Outcomes StudySocial Support Survey12-item questionnaire of physical andpsychological symptomsPsychological distress = presence ofall 3 symptoms feeling tense ornervous, feeling blue or depressed,feeling irritable or grouchy (categorical- present or absent)Menopausal statusPremenopause 53.82 %Early perimenopause46.18%Late perimenopause 0%Post-menopause 0%Premenopause 43.2 %Early perimenopause 34Late perimenopause 5.8Post-menopause 16.8Proportion withpsychological distress:Premenopause 20.9 %Early perimenopause 28.9Late perimenopause 25Post-menopause 22HysterectomyorBSO (#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use of SERMS(#/n)_ _ _ _Ineligible NR NR NRF-27

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearAvis, 2003Behavior orLifestyle Factors(#/n)RecentdiscontinuationofHRT(#/n)High or Low BMI(#/n) Hot Flashes Vaginal Dryness Sleep_ _ _ _ _ _Bromberger,2001Smoking:current 22.5%past 23never 53.6_ _ Yes 32.5%No 67Those with vasomotorflushes (36.6%) weremore likely than thosewithout (18.0%) to havepsychological distress(p

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearAvis, 2003UterineMood Cognitive Somatic Urinary Bleeding_ _ _ _ _Bromberger,2001Psychological distress:Yes 24.1%No 75.9NR NR NR NRF-29

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearAvis, 2003Sexual Dysfunc-tion Quality of Life Other Outcomes_ _ _Bromberger,2001NR NR The following variable weresignificantly associated withpsychological distress(p

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearAvis, 2003Predictors studied(significant/not significant)SES, sociodemographic,health, lifestyle and socialcircumstance variablesStatistical ModelsAdjusted models for impairedfunction (women at or below the25th percentile) on the SF-36scalesSignificant predictors in multivariate(adjusted models)In unadjusted models, early perimenopause and ethnic group weresignificantly associated with Impaired Function.In models adjusted for health conditions, impaired function did not differby menopausal status.In adjusted models, Hispanic women were more likely than whites toreport bodily pain and impaired social functioning. Blacks were morelikely than Whites to report impaired social functioning.Bromberger,2001Significant:Multivariate association ofmenopause status, psychological distress withrace/ethnicity, education, menopausal statussmoking, availability ofperceived social support,close friends/relatives,paying for basics, perceivedhealth, health limitations,difficulty sleeping, vasomotorsymptoms, ageNot significant:employment status, maritalstatus, site, physical activity,number of reported medicalconditions,Early perimenopause as compared to premenopause was associatedwith increased odds of psychological distress (OR 1.2).AA, H, J, Chinese race as compared to W race was associated withdecreased odds of psychological distress (OR 0.73, 0.65, 0.61, 0.43).The presence of vasomotor symptoms was associated with increasedodds of psychological distress (OR1.96).F-31

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearAvis, 2003RR or OR_Comments"Symptoms are important mediators between physiologicalconditions and HRQL."Bromberger,2001_Early perimenopause and vasomotor symptoms were associatedwith increased odds of psychological distress. Lateperimenopause and post-menopause were not associated withincreased odds of psychological distress.F-32

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/Year Umbrella NBromberger,2003StudyDesignSWAN 3,161 CrosssectionalTypeControlGroupLength ofFollow-UpRecruitment(Data source)Population/ SettingRace/EthnicityN/A N/A _ _ AA 28.3 %Chinese 7.7H 8.2J 8.7W 47.2F-33

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearBromberger,2003Age (range)42-52mean 46.2Inclusion/Exclusion CriteriaWhite or site-predetermined ethnicity, menses withinthe previous 3 month, have uterus and at least oneovary, not pregnant, no use of reproductivehormones or birth control pills within the previous 3months.141 excluded because of missing data for dysphoricmood and menopausal statusAscertainment ofSymptoms Response Rate Withdrawals_ 95.73% N/AF-34

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearBromberger,2003Measures UsedSymptom checklists, SF-36 RoleEmotional scale, Medical OutcomesStudy Social Support Survey,modification of PsychiatricEpidemiology Research Interview,adapted Baecke questionnaireDysphoric mood = summary scale 0-16 (dichotomized 0-6 v 7-16) of the 4mood measures feeling blue, feelingirritable, feeling nervous, orexperiencing mood changes on > 6days in preceding 2 weeks.Menopausal statusPremenopausal 53.4 %Early perimenopausal 46.6%HysterectomyorBSO (#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use of SERMS(#/n)Ineligible Ineligible NR IneligibleF-35

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearBromberger,2003Behavior orLifestyle Factors(#/n)Nonsmokers82.9 %RecentdiscontinuationofHRT(#/n)High or Low BMI(#/n) Hot Flashes Vaginal Dryness SleepN/A NR None 89% NR Disturbed 31%F-36

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearBromberger,2003Mood Cognitive Somatic UrinaryUse of medication for nervouscondition 10%possible PMS 15.3%NRPain:severe/very severe 7.1%moderate 22%very mild/mild 54.2%NRUterineBleedingNRF-37

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearBromberger,2003Sexual Dysfunc-tion Quality of Life Other OutcomesNR NR _F-38

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearBromberger,2003Predictors studied(significant/not significant)Study site, menopausalstatus, ethnicity, age,difficulty of paying for basicnecessities, use ofmedication for nervousconditions, pain, disturbedsleep, vasomotor symptoms,possible premenstrualsyndrome, social support,number of upsetting events,relationship presence/quality,recreational/sport activity,study siteStatistical ModelsLogistic regression models foreach of four mood symptoms:Feeling blue, irritable, nervous,or experiencing mood changeson >= 6 days in preceding 2weeks.Logistic regression model ofdysphoric mood.Menopausal status, study site,age, race/ethnicity forced into alladjusted models.Significant predictors in multivariate(adjusted models)In comparison to premenopause, early perimenopause was associatedwith increased odds of :feeling irritable (OR 1.33)feeling nervous (OR 1.54)experiencing mood changes (OR 1.52). dysphoric mood score >= 7(OR 1.8)dysphoric mood in previous 2 weeks (OR 1.62).In comparison to W women, AA had decreased odds of:feeling blue (OR 0.62)feeling irritable (OR 0.61)feeling nervous (OR 0.46)Chinese women had decreased odds of:feeling blue (OR 0.35)feeling irritable (OR 0.30);J women had decreased odds of:feeling blue (OR 0.44)feeling nervous (OR 0.51).Vasomotor symptoms were associated with all of the mood symptoms(p

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearBromberger,2003RR or OR_CommentsEarly perimenopause was associated with increased odds ofmood symptoms and dysphoric mood particularly among womenwith lower educational attainment.F-40

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/Year Umbrella NBrown, 2002AustraliaAustralianLongitudinalStudy onWomen'sHealthStudyDesignTypeControlGroupLength ofFollow-UpRecruitment(Data source)8,236 Cohort Internal 2 years 41,500 women selected fromall over Australia usingnational Medicare healthinsurance database with overrepresentationof women livingin rural and remote areas.The mid-age cohort (age 45-50 years) was targeted forsurvey 2 in 1998.Population/ Setting_Race/EthnicityNRBusch, 1994NationalHealthExaminationFollow-upStudy395naturallymenopausal women+ 178surgicallymenopausal women.Drawnfrom asample of3,049womenage40-60inNHANESCohort(also hascrosssectionaldata)Internal 10 years NHANES (stratified probabilitysample of U.S.)F-41U.S.NR

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearBrown, 2002AustraliaAge (range)Mean age 49.7(sd 1.5) yreasat survey 2Inclusion/Exclusion CriteriaAscertainment ofSymptoms Response Rate Withdrawals_ _ 14,065 mid-agewomen respondedto the mailedsurvey; 54% ofthem agreed. Forsurvey 2, 92% of12,328 womenresponded (12,328represents womenwho consented tofurther contact andhad not died).6.5% did not return thesurvey, 1.5% declinedparticipation in survey 2Busch, 199440-60 Women who had participated in NHANES atbaseline and the 10 year follow-up study. Includedthose who were not menopausal at the baselineassessment.Exclusions:1. Insufficient data to determine menopausal status2. Cessation of menstruation for reasons other thannatural or surgical menopause3. Reporting surgical menopause but still having auterus and ovaries4. Reporting continued menstruation after age 58._ _ _F-42

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearBrown, 2002AustraliaMeasures UsedMenopausal status: self-reportedbleeding history or HRT (4categories); 6 change categories.Menopausal statusHysterectomyorBSO (#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use of SERMS(#/n)_ _ _ _ _Busch, 1994Women were selected at random toreceive the CES-D and the GWB(Global Well-Being) questionnaires.Sleep disturbance measures by threeNHEFS items summed to form ascale: "How often do you havetrouble falling asleep?"; "How often toyou have trouble with waking upduring the night?"; "How often do youhave trouble with waking up too earlyand not being able to fall sleepagain?"_178/573 had"surgicalmenopause"NR NR NRF-43

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearBrown, 2002AustraliaBehavior orLifestyle Factors(#/n)RecentdiscontinuationofHRT(#/n)High or Low BMI(#/n) Hot Flashes Vaginal Dryness Sleep_ _ _ Relative to pre-pre:Pre-peri: OR 1.3 (1.1,1.5)Peri-peri: 1.3 (1.1, 1.5)Pre/peri-Post: 1.0 (0.8,1.2) Not significantPost-post: 0.9 (0.7, 1.2)not significantHRT: 1.5 (1.3, 1.8)_Difficulty sleeping:Pre-peri: 1.3 (1.1, 1.5)Per-peri: 1.4 (1.2, 1.7)Pre/peri-Post: 1.5 (1.2,1.8)Post-post: 1.2 (0.9, 1.6)not significantHRT : 1.5 (1.3, 1.7)Busch, 1994NR NR NR NR NR No significant differencesbetween women indifferent menopausalchange groups, orbetween those ofsurgical vs. naturalmenopauseF-44

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearBrown, 2002AustraliaMood Cognitive Somatic Urinary_ _ Stiff or painful joints(compared to pre-pre):Pre-peri: 1.3 (1.1, 1.5)Peri-peri: 1.6 (1.4, 1.9)Pre/peri-Post: 1.1 (0.9,1.4)Post-post: 1.3 (1.0, 1.7)HRT: 1.4 (1.2, 1.7)Back pain (compared topre-pre):Pre-peri: 1.2 (1.0, 1.4)Peri-peri: 1.3 (1.1, 1.5)Pre/peri-Post: 1.0 (0.8,1.2)Post-post: 1.1 (0.9, 1.4)HRT: 1.2 (1.0, 1.4)Leaking urine (comparedto pr-pre):Pre-peri: 1.0 (0.8, 1.2)not significantPeri-peri: 1.3 (1.1, 1.6)Pre/peri-Post: 1.0 (0.8,1.3) not significantPost-post: 0.8 (0.6, 1.1)not significantHRT: 1.0 (0.8, 1.2) notsignificantUterineBleeding_Busch, 1994No significant differences betweenwomen in different menopausalchange groups, or between thoseof surgical vs. natural menopause(Mean CES-D score (s.d.) time 1vs. time 2) :Pre-pre: 8.9 (9.1) vs. 7.8 (9.0),n=172Pre-Peri: 10.3 (9.4 vs. 7.8 (6.5),n=58.Pre-Natural Menopause: 8.4(8.1vs 7.8 (7.5), n=114.Pre-Surgical Menopause: 9.6(7.5)vs 9.4 (11.1) n=50NR NR NR NRF-45

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearBrown, 2002AustraliaSexual Dysfunc-tion Quality of Life Other Outcomes_ _ _Busch, 1994NRNo significant differences betweenwomen in different menopausalchange groups, or between those ofsurgical vs. natural menopause(mean (s.d.) at time 1 vs. time 2):pre-pre:48.0 (10.9)vs 49.3(11.1),n=352.Pre-peri: 47.1 (12.6)vs. 47.7 (11.1),n=125.pre-Natural Menopause: 49.2(10.7)vs. 49.5 (10.1), n=281.pre-Surgical Menopause: 45.8(12.3) vs. 47.0 (13.1)._F-46

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearBrown, 2002AustraliaPredictors studied(significant/not significant) Statistical Models_Adjusted for symptom score atsurvey 1, physical activity ,weight, weight change, lifeevents, smoking status,occupation, country of birth,marital status, and area ofresidence and age.Significant predictors in multivariate(adjusted models)_Busch, 1994None No MV modeling _F-47

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearBrown, 2002AustraliaRR or OR_CommentsUsing pre-pre as the reference group, 1. Headache: OR werenot significantly different between groups (all CI crossed 1)2. Eyesight problems: OR were not significantly differentbetween groups (all CI crossed or included 1),3. Severe tiredness: OR were highest for HRT (OR 1.5, CI 1.3-1.8), then per-peri (OR 1.3, CI 1.1-1.5) and peri-peri (OR 1.3, CI1.1-1.5) and lowest for pre/peri-post (OR 0.9, 0.7-1.1) and postpost(OR 1.0, CI 0.7-1.3).4. Stiff or painful joints5. Back pain6. Leaking urine7. Constipation8. Difficulty sleeping9. Hot flashes10. Night sweatsBusch, 1994NAAssume that the categories used to report symptoms are thoseascertained at 10 year assessment, because everyone was premenopausalat baseline in order to be included.F-48

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/Year Umbrella NDennerstein,1993AustraliaMelbourneWomen'sStudyDesign1,897 CrosssectionalTypeControlGroupLength ofFollow-UpRecruitment(Data source)Population/ SettingRace/Ethnicity_ _ _ _ _Dennerstein,1994AustraliaMelbourneWomen's1,879 Crosssectional_ _ _ _ _Dennerstein,1997MelbourneWomen's405 Longitudinal _ 4 years _ _ _F-49

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearDennerstein,1993AustraliaAge (range)Inclusion/Exclusion CriteriaAscertainment ofSymptoms Response Rate Withdrawals_ _ _ 1897/2001 (94.8%)were available foranalysis_Dennerstein,1994Australia_ Current oc users excluded. _ _ _Dennerstein,199745-55 Inclusion:Women who were still experiencing menstrualcycles, or who had no more than 3 months ofamenorrhea, who were not taking hormone therapy,or oral contraceptives, had an intact uterus, and atleast one ovaryExclusions:HRT use, surgical removal of uterus and/or ovaries,women who refused blood drawsFace to faceinterviewSubset of cohort of2001 women92% retention rate afterthe 4th round ofinterviewsF-50

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearDennerstein,1993AustraliaPrematureOvarianFailure(#/n)Measures UsedMenopausal statusHysterectomyorBSO (#/n)BreastCancer(#/n)_ _ _ _ _ _Use of SERMS(#/n)Dennerstein,1994AustraliaSexual interest, frequency,dyspareuniasociodemographic and lifestylevariableshealth status, menopausal status_ _ _ _ _Dennerstein,1997Affectometer 2 (modified)E 2FSHTotal Testosterone (T)SHBGFree Androgen Index (FAI)Pre 37%Early Peri 34%Late Peri 17%1-2 years post 9%> 2 years post 3%Mean age increasedacross the menopausalcategories from 49.4 (pre)to 54.4 (> 2 years post),p

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearDennerstein,1993AustraliaDennerstein,1994AustraliaBehavior orLifestyle Factors(#/n)RecentdiscontinuationofHRT(#/n)High or Low BMI(#/n) Hot Flashes Vaginal Dryness Sleep_ _ _ By menstrual status:Post 39.4%Peri 31.5%Pre 9.8%_Trouble sleepingby menstrual status:Post 41.5%Peri 35.2%Pre 24%_ _ _ _ _ _Dennerstein,1997_ NR _ (% in the last 2 weeks)12.618.4 (p

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearDennerstein,1993AustraliaDennerstein,1994AustraliaFeeling sad or downheartedby menstrual status:Post 48.7%Peri 33%Pre 24.7%Mood Cognitive Somatic UrinaryDifficulty in concentratingby menstrual status:Post 18.3%Peri 27.5%Pre 20.3%_Problems with urinecontrol by menstrualstatus:Post 14%Peri 16%Pre 9.2%UterineBleeding__ _ _ _ _Dennerstein,1997Positive affect increased with age(p

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearDennerstein,1993AustraliaSexual Dysfunc-tion Quality of Life Other Outcomes_ _ _Dennerstein,1994Australia_ _ _Dennerstein,1997_ _ _F-54

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearDennerstein,1993AustraliaPredictors studied(significant/not significant)Significant predictors in multivariate(adjusted models)Statistical Models_ _ _Dennerstein,1994AustraliaAge, menopausal status,well-being, employmentstatus, years of education,vasomotor symptoms,cardiopulmonary symptoms,skeletal symptomsLogistic regression model ofdecrease in sexual interest overthe preceding yearNatural menopauseOn HRTwell-beingpart-time employmentno employment11-12 years of educationvasomotor symptomscardiopulmonary symptomsskeletal symptomsDennerstein,1997_Data from years 1-4 was pooledan analyzed as a whole.Generalized linear regression,forward stepwise approach.Significant coefficients after adjustment for age and hot flashes.None were significant for positive affect in any of the menopausalgroups compared with premenopausal group.The mean negarive affect score was higher in early peri (Beta 0.079,p

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearDennerstein,1993AustraliaRR or OR_CommentsDennerstein,1994AustraliaDennerstein,19971.93 (1.22-3.06)2.27 (1.42-3.63)0.76 (0.67-0.87)1.81 (1.34-2.45)1.56 (1.16-2.10)0.65 (0.50-0.87)1.25 (1.05-1.48)0.72 (0.61-0.84)1.32 (1.11-1.50)_Decline in sexual interest was associated with naturalmenopause, decreased well-being, decreasing employment,vasomotor symptoms, skeletal symptoms, and cardiopulmonarysymptoms. It was not associated with age._F-56

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/Year Umbrella NDennerstein,1999AustraliaMelbourneWomen'sStudyDesignTypeControlGroupLength ofFollow-UpRecruitment(Data source)Population/ SettingRace/Ethnicity354 Longitudinal _ 6 years _ _ _Dennerstein,2000AustraliaMelbourneWomen's172 Longitudinal _ 7 yearfollow-up_ _ _F-57

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearDennerstein,1999AustraliaAge (range)48.1 atbaselineInclusion/Exclusion CriteriaExclusions: dropouts (49), surgical menopause(29), oral contraceptive use at any year (6).Ascertainment ofSymptoms Response Rate WithdrawalsQuestionnaires,physical exam, bloodsamples, telephoneinterviewRetention rate forlongitudinal arm90% at 6 years.Percentage oforiginal cohorteligible for thisanalysis 80.8%._Dennerstein,2000Australia50.3 172 women of the 438 in the longitudinal cohortwere included. They were premenopausal atbaseline and either perimenopausal orpostmenopausal at follow-up.For women who had hysterectomy, bilateraloophorectomy, endometrial ablation (n=10) or tookHRT (n=53), only information prior to theintervention was used.Questionnaires,physical exam, bloodsamples, telephoneinterview89% for longitudinalcohort at 7yearfollow-up.Percentage oforiginal cohorteligible for thisstudy 39%._F-58

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearDennerstein,1999AustraliaMeasures UsedAffectometer-2sociodemographic variables,menopausal status, 22 symptomchecklist, self-rated health, lifestylefactors, blood samples FSH, E2,Inhibin, Factor 1 of PersonalExperiences QuestionnaireMenopausal statusHysterectomyorBSO (#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use of SERMS(#/n)_ _ _ _ _Dennerstein,2000AustraliaNorth American symptom checklist,sociodemographic, health and wellbeing,menstrual calendars, bloodsamples E2, FSHBy post-menopause, theaverage total number ofsymptoms reportedincreased by 17% from 4.2to 4.9 (p

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearDennerstein,1999AustraliaBehavior orLifestyle Factors(#/n)RecentdiscontinuationofHRT(#/n)High or Low BMI(#/n) Hot Flashes Vaginal Dryness Sleep_ _ _ _ _ _Dennerstein,2000Australia_ _ 33.6% BMI>25 Night sweats (p

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearDennerstein,1999AustraliaMood Cognitive Somatic UrinaryUterineBleedingSignificant decrease in negativemood with time (p=.005)_ _ _ _Dennerstein,2000Australia_ _ Somatic symptoms(other than breastsoreness) did notchange significantly withtransition to late-peri orpost-menopause.Urinary symptoms didnot change significantlywith transition to late-perior post-menopause._F-61

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearDennerstein,1999AustraliaSexual Dysfunc-tion Quality of Life Other Outcomes_ _ _Dennerstein,2000Australia_Breast soreness severityscores were reduced in lateperi and post-menopausecompared to pre and earlyperimenopause (p

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearDennerstein,1999AustraliaPredictors studied(significant/not significant)Statistical ModelsSignificant predictors in multivariate(adjusted models)_ _ Significant predictors of Magnitude of Negative Mood (p = 0.002 -0.02):premenstrual complaints, negative attitudes to aging and menopause,parity of one child, number of symptoms, poor self-rated health,negative feelings for the partner, lack of a partner, current smoking,exercising < once a week, >3 daily hassles, moderate or highinterpersonal stressSignificant predictors of Change in Negative Mood (mood changes iffactor changes) (p < 0.001 to p=0.05):symptoms, self-rated health, feelings for partner, marital status,interpersonal stressDennerstein,2000AustraliaFSH, E2, all predictors usedin the model are not listedLogistic regression to determinepredictors of symptoms in lateperimenopauseHot flash model:number of symptoms > 4occupation professionaloccupation sales/white collarsmoking pack years at early perimenopause>10estradiol at late perimenopause 30-100estradiol at late perimenopause 12 yTrouble sleeping model:well-being at early perimenopause 1.7-2.3well-being at early perimenopause >2.3Agree to statement of beliefs about menopauseHot flushes at late perimenopause - yesF-63

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearDennerstein,1999AustraliaRR or OR_CommentsNo direct link between the menopausal transition and negativemood level.However, menopausal transition interacts (amplifies negativeeffects of these variables on mood) with paid work, self-ratedhealth, daily hassles.Dennerstein,2000Australia6.20.10.27.020.55.01.10.30.30.15.55.0E2 is the best predictor for vasomotor symptoms.F-64

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/Year Umbrella NDennerstein,2001aAustraliaMelbourneWomen'sStudyDesignTypeControlGroupLength ofFollow-UpRecruitment(Data source)Population/ SettingRace/Ethnicity283 Longitudinal Internal 8 years _ _ _Dennerstein,2001bAustraliaMelbourneWomen's267 Longitudinal _ 8 years _ _ _F-65

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearDennerstein,2001aAustraliaAge (range)48.5 atbaselineInclusion/Exclusion CriteriaIncluded:Group M = 197 women who transitioned throughmenopauseGroup A = 44 stayed pre-or early perimenopausalGroup B = 42 stayed postmenopausal betweenyears 3 and 8Excluded: dropouts, surgical menopause, oralcontraceptive use at any year, had not passedthrough enough menopausal categories.Ascertainment ofSymptoms Response Rate WithdrawalsQuestionnaires,blood samples,telephone interview88% retention at 8years, percentageeligible for thisstudy 64.6%._Dennerstein,2001bAustralia48.8 years atbaselineExcluded: dropouts (57), surgical menopause (36),oral contraceptive use at any year (5), lack ofbaseline data on some measures (5), failure toreach late perimenopause during 8 years of study(26), HRT use before reaching late perimenopause(42).Questionnaires,physical exam, bloodsamples, telephoneinterview88% retention at 8years, percentageeligible for thisstudy 61%._F-66

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearDennerstein,2001aAustraliaMeasures UsedPersonal Experiences Questionnaire(SPEQ, based on the McCoy FemaleSexuality Questionnaire). PEQfactors include: feelings for partner,sexual responsivity, frequency ofsexual activities, libido, partnerproblems, vaginaldryness/dyspareuniaFSH, E2, menopausalstatus/menstrual diariesMenopausal statusHysterectomyorBSO (#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use of SERMS(#/n)_ _ _ _ _Dennerstein,2001bAustraliaAffectometer-2, menstrual status,sociodemographic variables, lifestylevariables_ _ _ _ _F-67

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearDennerstein,2001aAustraliaBehavior orLifestyle Factors(#/n)RecentdiscontinuationofHRT(#/n)High or Low BMI(#/n) Hot Flashes Vaginal Dryness Sleep_ _ _ _ _ _Dennerstein,2001bAustralia_ _ _ _ _ _F-68

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearDennerstein,2001aAustraliaUterineMood Cognitive Somatic Urinary Bleeding_ _ _ _ _Dennerstein,2001bAustraliaMean positive mood scores bystudy year did not show any lineartrend with time.No significant change in positivemood over the menopausaltransition.Premenopausal positive moodscores correlated significantly withlate perimenopausal (r=0.61) andpostmenopausal (r=0.66) positivemood scores.Late perimenopause positivemood scores correlated with postmenopausepositive mood scores(r=0.68)_ _ _ _F-69

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearDennerstein,2001aAustraliaDennerstein,2001bAustraliaSexual Dysfunc-tion Quality of Life Other OutcomesTotal SPEQ scores fell from early to lateperimenopause (p

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearDennerstein,2001aAustraliaPredictors studied(significant/not significant)Significant predictors in multivariate(adjusted models)Statistical Models_ _ _Dennerstein,2001bAustralia_General linear model of factorsaffecting positive moods duringmidlife.Final model: Predictors ofPositive Mood Late in theMenopausal TransitionPremenopausal positive mood scores were significantly influenced bybaseline interpersonal stress (B=-0.113, p=0.009) and baselineattitudes to aging (B=0.054, p=0.026).Postmenopausal positive mood scores were significantly influenced bypremenopausal positive mood scores (B=0.717, p=0.000), dysphoricsymptom change (B=-0.085, p=0.000), change in marital status(B=0.342, p=0.007), major life events (B=-0.124, p=0.042), dailyhassles (B=-0.016, p = 0.014), work satisfaction (B=0.493, p=0.000).Premenopausal positive mood scores (B=0.730, p=0.000)dysphoric symptom change (B=-0.108, p=0.000) change in maritalstatus (B=0.353, p=0.004) major life events (B=-0.136, p=0.019)daily hassles (B=-0.015, p = 0.011)work satisfaction (B=0.456, p=0.000).F-71

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearDennerstein,2001aAustraliaRR or OR_CommentsSexual responsivity (SPEQ2) decreases with time across allgroups. The other five domains of sexual functioning were notaffected by time but changed with the menopausal transition.Dennerstein,2001bAustralia_The most important predictor of positive mood in late peri- andpost-menopause is positive mood in pre- and earlyperimenopause.BMI was not a significant predictor of positive mood.Smoking was not a significant predictor of positive mood.F-72

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/Year Umbrella NDennerstein,2002aAustraliaMelbourneWomen'sStudyDesignTypeControlGroupLength ofFollow-UpRecruitment(Data source)Population/ SettingRace/Ethnicity226 Longitudinal _ 8 years _ _ _F-73

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearDennerstein,2002aAustraliaAge (range)Inclusion/Exclusion CriteriaParticipants included in this analysis could provideat least one measure of well-being during earlymenopausal transition, late transition and postmenopause.Yearly measures associated with HRTwere excluded.The original longitudinal cohort of 438 had 57 dropout, 36 had surgical menopause, 5 used oralcontraceptives. 226 of 340 eligible participants wereincluded.Ascertainment ofSymptoms Response Rate WithdrawalsQuestionnaires,physical exam, bloodsamples, telephoneinterviewRetention rate forlongitudinal arm88% at 8 years.Percentage oforiginal cohort(438) used in thisstudy 51.6%.Percentage ofthose eligible forthis analysis 66.5%._F-74

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearDennerstein,2002aAustraliaMeasures UsedWell-being using Affectometer-2symptomsdemographicslifestyle factorsBMImenopausal statusFSH, E2, TestosteroneMenopausal statusHysterectomyorBSO (#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use of SERMS(#/n)_ _ _ _ _F-75

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearDennerstein,2002aAustraliaBehavior orLifestyle Factors(#/n)RecentdiscontinuationofHRT(#/n)High or Low BMI(#/n) Hot Flashes Vaginal Dryness Sleep_ _ _ _ _ _F-76

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearDennerstein,2002aAustraliaMood Cognitive Somatic UrinaryUterineBleedingNo significant change in positivemood scores with menopausaltransition. Significant decrease innegative mood and significantimprovement in well-being scoresbetween early and lateperimenopause and early andpost-menopause._ _ _ _F-77

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearDennerstein,2002aAustraliaSexual Dysfunc-tion Quality of Life Other Outcomes_ _ _F-78

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearDennerstein,2002aAustraliaPredictors studied(significant/not significant)14 predictors includingbaseline measures ofphysical and moodsymptoms, lifestylemeasures, and well-beingStatistical ModelsMultifactor model of well-beingchange during midlife - latemenopausal transition model.Influence of vasomotorsymptoms and vaginal drynesson well-being.Influence of hormone levels onwell-being.Final model of well-being in thelate menopausal transition usingfindings from the previousmodels.(Results were the same for postmenopause.)Regression analysis on changein well-being from early to latemenopausal transition.Significant predictors in multivariate(adjusted models)Well-being in the early menopause was the only baseline variable thatinfluenced well-being in the late menopause.Well-being before late menopause (B 0.72, p 0.00)dysphoric symptoms (B -0.20, p 0.00)changing marital status (becoming married or taking a partner (B 0.46,p 0.02)change in satisfaction with work (B 0.63, p 0.00)experiencing a severe life event (B -0.2, p 0.03)increase of hassles (B -0.02, p 0.04).No significant effect of vasomotor symptoms, vaginal dryness, orhormones on well-being.Well-being before late menopause (B 0.63, p 0.00)changing marital status (becoming married or taking a partner (B 0.54,p 0.01)change in satisfaction with work (B 0.71, p 0.00)experiencing a severe life event (B -0.17, p 0.06)increase of hassles (B -0.03, p 0.00)Changing marital status (becoming married or taking a partner (B 0.71,p 0.00)change in satisfaction with work (B 0.80, p 0.00)experiencing a severe life event (B -0.23, p 0.03)F-79

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearDennerstein,2002aAustraliaRR or OR_CommentsAs women transition from early to late perimenopause and postmenopausethere is an improvement in measures of well-being.Well-being appears to be influenced by psychosocial factors.F-80

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/Year Umbrella NDennerstein,2002bAustraliaMelbourneWomen'sStudyDesignTypeControlGroupLength ofFollow-UpRecruitment(Data source)Population/ SettingRace/Ethnicity226 Longitudinal _ 8 years _ _ _Freeman, 2004 PennOvarianAging Study332 Longitudinal _ 4 years Random digit dialing to allhouseholds in PhiladelphiaCountyAfrican American andWhite womenAA 50%W 50%F-81

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearDennerstein,2002bAustraliaAge (range)Year 1 - meanage of womenin earlymenopausaltransition was49.1 years.Year 8 - meanage ofpostmenopausal women was57.1 years.Inclusion/Exclusion CriteriaWomen were excluded from analysis if theydropped out, had surgical menopause, took oralcontraceptives or hormones, or did not complete thesexuality measure or blood sampling. 226 oforiginal 438 were available for analysis.Ascertainment ofSymptoms Response Rate WithdrawalsQuestionnaires,physical exam, bloodsamples, telephoneinterview88% retention at 8years, percentageeligible for thisstudy 51.6%._Freeman, 200435-47 75% of eligible participants were enrolled in the fullcohort (218 AA, 218 W), 353 of these provided datafor this study, 332 did not have usable bloodsamples and were thus excludedQuestionnaire andinterview75% _F-82

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearDennerstein,2002bAustraliaMeasures UsedPersonal Experiences Questionnaire(SPEQ, based on the McCoy FemaleSexuality Questionnaire),Affectometer 2, FSH, E2, T(testosterone), DHEAS, SHBG (sexhormone-binding globulin,menopausal status/menstrual diariesMenopausal statusHysterectomyorBSO (#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use of SERMS(#/n)_ Excluded _ _ _Freeman, 2004CES-D, DSM-IV criteria for MDDWomen were initially allpremenopausal (n=332), byyearBreakdown:Pre 227/312Early transition 64/312Late transition 10/312Post 11/312Excluded _ _ _F-83

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearDennerstein,2002bAustraliaBehavior orLifestyle Factors(#/n)RecentdiscontinuationofHRT(#/n)High or Low BMI(#/n) Hot Flashes Vaginal Dryness Sleep_ _ _ _ _ _Freeman, 2004_ _ _ _ _ _F-84

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearDennerstein,2002bAustraliaMood Cognitive Somatic UrinaryUterineBleedingPositive and negative mood didnot correlate with any of thehormone measures. Positivemood increased with age (B 0.01,p 0.042) and negative mooddecreased with age (B -0.009, p0.012)._ _ _ _Freeman, 2004CES-D scores of 16 or higherincrased during the transition tomenopause and were lower aftermenopause (p=0.047)MDD present in 10-13% ofpremenopausal and < 4% intransition phases_ _ _ _F-85

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearDennerstein,2002bAustraliaSexual Dysfunc-tion Quality of Life Other Outcomes42% of women in early menopausal transitionat year 1 had SPEQ scores in-dicating sexualdysfunction com-pared with 88% ofpostmenopausal women at year 8 of follow-up.__Freeman, 2004_ _ _F-86

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearDennerstein,2002bAustraliaFreeman, 2004Predictors studied(significant/not significant) Statistical Models_"Repeated-measures linearregression was used to modeltotal and domain scores onSPEQ and mood scores as afunction of age, log of freetestosterone index, and log offree estradiol index."Race, age, history of Multivariate models of CES-Ddepression, menopausal scores and MDDstatus, severe PMS, poorsleep, not employed, hotflashes, FSH, antidepressantmedicationsSignificant predictors in multivariate(adjusted models)Total SPEQ score:age (B -0.2, p 0.0)log estradiol (B 0.13, p 0.01)log free estradiol index (B 0.12, p 0.014)Sexual responsivity:age (B -0.07, p 0.0)log estradiol (B 0.04, p 0.052)Frequency of sexual activities:age (B -0.05, p 0.0)Libido:age (B -0.45, p 0.0)log estradiol (B 0.087, p 0.001)log free estradiol index (B 0.08, p 0.001)No aspect of sexual functioning was correlated with any of theandrogen measures.CES-DMenopausal status (pre is reference group)Early transition OR 1.55 (CI 1.04-2.32)Late transition OR 2.89 (CI 1.29-6.45)Postmenopausal OR 0.78 (CI 0.1-6.17)Race (White is reference)AA OR 1.89 (CI 1.35-2.63)History of depression OR 2.45 (CI 1.61-3.72)MDDRace (White is reference)AA OR 1.52 (1.03-2.24)Menopausal status NSHistory of depression OR 4.75 (CI 3.17-7.13)F-87

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearDennerstein,2002bAustraliaRR or OR_Comments"Female sexual functioning declines with the natural menopausetransition." No association of androgen levels with sexualfunctioning. However, there was an association of decreasingestrogen levels with decline in sexual functioning.Freeman, 2004See Significant PredictorscolumnOnly relevant significant predictiors listed for these models.There were other significant predictors in the models.F-88

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/Year Umbrella NStudyDesignTypeControlGroupLength ofFollow-UpRecruitment(Data source)Population/ SettingRace/EthnicityGlazer, 2002 Ohio 208 Cohort Internal 27 months Community recruitment NR 57% White43% AfricanAmericanGold, 2000 SWAN 12,425 Crosssectional(baselinesurvey1995-7)N/A N/A _ _ AA 29.5%C 46.5J 5.7Chinese 4.4H 13.8F-89

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearGlazer, 2002Age (range)40-60 (mean48)Inclusion/Exclusion CriteriaAscertainment ofSymptoms Response Rate WithdrawalsReported Kupperman Index 208 recruited175 to 1st follow-up165 completed_Gold, 200040-55range %:40-43 28.3%44-47 31.0%48-51 24.0%52-55 16.7%3640 of 16065 were excluded because 1) menseshad stopped because of medication, radiotherapy,pregnancy/lactation, or extreme weight change, 2)reported use of exogenous female hormones in thepast 3 months, 3) reported race/ethnicity asmixed/other._ 77.34%F-90

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearGlazer, 2002Measures UsedCoping ScaleKaufert and Syrotvik IndexHobfoll Core EvaluationBowles Menopause Attitude ScaleDepression ScaleHealth Promoting ActivitiesMenopausal statusPre: 38%Peri: 17%Post: 14%SMP: 33%HysterectomyorBSO (#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use of SERMS(#/n)NR NR NR NRGold, 2000Yes/No questions regarding presenceof vasomotor, psychological, andphysical symptoms during theprevious 2 weeksSurgical 16%Postmenopausal 14.2Late perimenopausal 4.9Early perimenopausal 28.6premenopausal 36.31988/12425(16%)NR NR NRF-91

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearGlazer, 2002Behavior orLifestyle Factors(#/n)RecentdiscontinuationofHRT(#/n)High or Low BMI(#/n) Hot Flashes Vaginal Dryness SleepEvaluated NR _ _ _ _Gold, 2000Smoking:current 23.4%past 23.3never 53.3_BMI:=32 19.4%Compared to BMI19-26.9, OR for hotflashes (p 32 OR 1.18By menstrual status:surgical 46.9%post 48.8%late peri 56.8%early peri 36.9%pre 19.4%Compared to premenopausalstatus (p

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearGlazer, 2002UterineMood Cognitive Somatic Urinary Bleeding_ _ _ NR NRGold, 2000_Forgetfulnessby menstrual status:surgical 43.8%post 42%late peri 44.8%early peri 44%pre 31.2%Compared to premenopausalstatus (p

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearGlazer, 2002Sexual Dysfunc-tion Quality of Life Other OutcomesNR NR Menstrual irregularity andhysterectomy associated withsignificant level of increasedanxiety in univariate analysis,but not multivariate analysisGold, 2000NR NR _F-94

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearGlazer, 2002Gold, 2000Predictors studied(significant/not significant)Menopausal status includedin modelsEducation copingeffectiveness of resourcesAttitude toward menopauseCoping useAgeRaceJobIncomeMarital statusReligionStatistical ModelsMultivariate with 3 outcomesAge, education, employment Several multiple logisticstatus, difficulty paying for regression models for thebasics, race/ethnicity, marital following symptoms:status, parity, menstrual hot flashes/night sweats, urinestatus, BMI, smoking, leakage, vaginal dryness,physical activity, study site, stiff/sore, heart pounding,parityforgetful, difficulty sleeping.Predictors of anxiety:Loss of resourcesEducation levelCoping effectivenessPredictors of depression:Loss of resourcesEducationSignificant predictors in multivariate(adjusted models)Predictors of health promoting activities:Coping effectivenessAttitude towards menopauseSee Table 3 p.468 (Key points)-All symptoms were more frequent in women who were notpremenopausal (p=27(p

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearGlazer, 2002RR or OR_CommentsGold, 2000_F-96

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/Year Umbrella NGracia, 2004 PennOvarianAging StudyStudyDesign326 Crosssectionalanalysesfrom cohortTypeControlGroupLength ofFollow-UpRecruitment(Data source)Internal 4 years Women in Philadephia Countyindentified through randomdigit dialingPopulation/ SettingCommunity-based,PhiladephiaRace/EthnicityAA 48-51%Guthrie, 1996AustraliaMelbourneWomen's453 Crosssectional_3rd year offollow-up_ _ _F-97

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearGracia, 2004Age (range)Inclusion/Exclusion Criteria35-47 Excluded:Serious illness with potential to effect hormonelevelsAny hormone use in past 3 monthsPreganancy, lactation, or use of psychotropic drugsUse of alcohol/illicit drugs in past 1 yrAscertainment ofSymptoms Response Rate WithdrawalsSerum bloodsamplesQuestionnairesOf 578 eligible,75% agreed toparticipate. Ofthose participating,326 were eligiblefor this analysis.3 for medical problems,6 for family conflicts, 5moved, 2 deceased, 8too busy, 26 lost to f/u,27 had insufficienthormone measures, 3withdrew consent, 30gave no reason.Guthrie, 1996AustraliaBy menstrualgroupLongitudinal cohort, excluded if they had undergonehysterectomy by the time of follow-up_ _ _No change50.2Change in flow50.1F-98

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearGracia, 2004Measures UsedCES-DTotal testosterone, DHEASFSH, LH, E2Libido assessed with one question"Have you experience a decrease inlibido?"Menopausal statusPremenopausal 147 (45%)Early menopausal (variablecycle lengths) 140 (42%)Late menopausal (3-11 moof ammenorrhea)Post-menopausal 14(4.3%)HysterectomyorBSO (#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Excluded Excluded NR ExcludedUse of SERMS(#/n)Guthrie, 1996Australia_ _ _ _ _ _12%19%F-99

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearGracia, 2004Behavior orLifestyle Factors(#/n)NRRecentdiscontinuationofHRT(#/n)Excluded if Mean BMI 28HRT or anyhormonewithin past3 monthsHigh or Low BMI(#/n) Hot Flashes Vaginal Dryness SleepGuthrie, 1996AustraliaNo significantdifference insmoking statusbetween womenwho did and did nothave hot flashes forthe whole cohortand by menstrualgroup._BMI in kg/m2 didnot differ acrossmenstrual groups(p=.239)> 1 in last 2 weeks bymenstrual status(p

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearGracia, 2004Mood Cognitive Somatic UrinaryUterineBleedingGuthrie, 1996Australia_ _ _ _ _F-101

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearGracia, 2004Sexual Dysfunc-tion Quality of Life Other OutcomesAt 4 years (6th assessment): 27% (87 of 326women) reported a decreased in libido orsexual interest vs 73% (239) reported nochange.Women with decreased libido were more likelyto report vaginal dryness (38% vs 13%) anddepressive symptoms (52% vs 28%)Guthrie, 1996Australia_ _ FSH, E2, and inhibin (INH)levels by menstrual group.Compared to no change group(p

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearGracia, 2004Predictors studied(significant/not significant)Variables in the model: age,BMD, race, marital status,depression (CES-D),presence of child

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearGracia, 2004Guthrie, 1996AustraliaRR or ORCommentsSignificant predictors of No results for hormone levels or libido by menoapusal status.decreased libido were: No adjustment for menopausal status in the MV analysis.Having children < age 18at home OR 1.4 (CI 1.1,1.7), p=0.014Depression OR 3.4 (1.9,6.1), p

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/Year Umbrella NGuthrie, 1996Australia(continued)StudyDesignTypeControlGroupLength ofFollow-UpRecruitment(Data source)Population/ SettingRace/EthnicityF-105

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearGuthrie, 1996Australia(continued)Age (range)Change infrequency 59.8Inclusion/Exclusion CriteriaAscertainment ofSymptoms Response Rate WithdrawalsChange in flowand frequency51.2Amenorrhea>312 months53.7Hormonetherapy 52.7F-106

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearGuthrie, 1996Australia(continued)Measures UsedMenopausal status6%HysterectomyorBSO (#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use of SERMS(#/n)20%15%15%24%F-107

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearGuthrie, 1996Australia(continued)Behavior orLifestyle Factors(#/n)RecentdiscontinuationofHRT(#/n)High or Low BMI(#/n) Hot Flashes Vaginal Dryness Sleep25.625.926.726.225.3F-108

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearGuthrie, 1996Australia(continued)Mood Cognitive Somatic UrinaryUterineBleedingF-109

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearGuthrie, 1996Australia(continued)Sexual Dysfunc-tion Quality of Life Other OutcomesFSH 19.7E2 196.8Inhibin 170.2FSH 19.5E2 256.9Inhibin 165.2FSH 69.2E2 81.4Inhibin 98.9FSH 93.9E2 37.9Inhibin 76.2FSH 26E2 357.4Inhibin 89.5F-110

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearGuthrie, 1996Australia(continued)Predictors studied(significant/not significant)Statistical ModelsSignificant predictors in multivariate(adjusted models)F-111

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearGuthrie, 1996Australia(continued)RR or ORCommentsF-112

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/Year Umbrella NHallstrom, 1985SwedenStudyDesignTypeControlGroupLength ofFollow-UpRecruitment(Data source)Gothenburg 899 Cohort Internal 6 years Systematic sampling ofGothenburg Swedenpopulation using TaxationOffice Register. Samplingmethods described elsewhere.Unclear in this paper how the"psychiatric population" wasselected from the largersamplePopulation/ Setting_Race/EthnicityNRF-113

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearHallstrom, 1985SwedenAge (range)Inclusion/Exclusion CriteriaAscertainment ofSymptoms Response Rate Withdrawals38-60 _ _ 899 participated inthe first wave, ofthese 800 wereexamined. Ofthose 800 677(84.6%) wereexamined in thesecond wave12 died, 30 moved orcould not be reached,81 refused.F-114

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearHallstrom, 1985SwedenMeasures Used44 and regularly menstruating=premenopausalirregularmenstruations=perimenopausalamenorrhea for 12-35 months=earlymenopauseamenorrhea for 36 months=postmenopause.Global assessment of functioning,disability grade, diagnostic interviewfor diagnoses of major depression,anxiety states, neurastenic state,phobic disorder, obsessivecompulsive disorder, psychoses,alcoholism.Menopausal statusHysterectomyorBSO (#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use of SERMS(#/n)_ _ _ _ _F-115

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearHallstrom, 1985SwedenBehavior orLifestyle Factors(#/n)RecentdiscontinuationofHRT(#/n)High or Low BMI(#/n) Hot Flashes Vaginal Dryness Sleep_ _ _ _ _ _F-116

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearHallstrom, 1985SwedenMood Cognitive Somatic UrinaryCross-sectional data at baseline:Major depression N=55 (6.9%)anxiety N=18 (2.3%)Neurasthenic state N=14 (1.8%)Phobic disorder N=10 (1.3%)Obsessive compulsive disorderN=2 (0.3%)Pyschosis N=4 (0.5%)Alcoholism N=2 (0.3%)1 year onset rate of anypsychiatric symptoms:Pre climacteric: N=78 (15.5%) age 3 yearsago)UterineBleeding_ _ _ _F-117

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearHallstrom, 1985SwedenSexual Dysfunc-tion Quality of Life Other Outcomes_ _ _F-118

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearHallstrom, 1985SwedenPredictors studied(significant/not significant)Significant predictors in multivariate(adjusted models)Statistical Models_ No MV modeling _F-119

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearHallstrom, 1985SwedenRR or OR_CommentsProportion of women developing a mental disorder within oneyear after the menopause compared with the proportion ofwomen developing a mental disorder without life events one yearbefore: 9 (15.8%) after menopause vs. 15 (12.8%) prior tomenopause and without a life event (NS by Fisher's exact).Lumped all mental disorders together.F-120

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/Year Umbrella NHardy, 2002BritainMedicalResearchCouncil(MRC)NationalSurvey forHealth andDevelopmentStudyDesignTypeControlGroupLength ofFollow-UpRecruitment(Data source)1572 Cohort Internal 52 years Socially stratified sample of allbirths in March 1943 in BritainPopulation/ SettingSocially stratified birthcohort in Britain, thoseinterviewed in 1993(age 43) wererepresentative of thenative population of thatage.Race/EthnicityNRF-121

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearHardy, 2002BritainAge (range)Inclusion/Exclusion CriteriaAscertainment ofSymptoms Response Rate Withdrawals52 _ _ 2548 womenenrolled at birth(March1946).1778 still in contactas of 1993.1572 womenreturned at leastone questionnaire(84-90% RR) overthe next 4 years forthis study.232 living abroad; 296refused to participate;88 could not belocated; 154 had diedas of 1993.F-122

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearHardy, 2002BritainMeasures UsedChecklist of 20 health problems (1-4for each symptom)Menopausal statusHysterectomyorBSO (#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use of SERMS(#/n)_ _ _ _ _F-123

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearHardy, 2002BritainBehavior orLifestyle Factors(#/n)RecentdiscontinuationofHRT(#/n)High or Low BMI(#/n) Hot Flashes Vaginal Dryness Sleep_ _ _ Vasomotor symptomscore:Peri-peri: 12.31 (10.44,14.18)Post-post: 0.29 (-1.55,2.12)Hysterectomyhysterectomy:3.46(1.72, 5.19)HRT-HRT: -2.93 (-4.6, -1.26)Pre-peri: 8.44 (6.11,10.79)Vasomotor change in %score:Pre-post: 17.3 (6.33,29.13)Pre-HRT: 19.25 (12.96,25.52)Pre-hysterectomy: 9.87 (-0.37, 20.10)Pre-Peri: 8.44 (6.11,10.76)Post-Post: 0.29 (-1.55,2.12)__F-124

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearHardy, 2002BritainMood Cognitive Somatic UrinaryUterineBleedingPsychological change score:Pre-post: 4.74 (-1.74, 11.23)Pre-HRT: 6.4 (2.12, 10.69)Peri-HRT: 4.38 (1.54, 7.21)Pot-post: -0.12 (-1.40, 1.15)Peri-Hysterectomy: -1.12 (-8.36,6.15)Peri-Post: 1.58 (-0.65, 3.81)Peri-peri: 0.98 (-0.30, 2.26)Hysterectomy-hysterectomy: 0.41(-0.75, 1.57)Pre-peri: 1.57 (-0.15, 3.29)Pre-hysterectomy: 2.43 (-4.78,9.63)_ _ _ _F-125

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearHardy, 2002BritainSexual Dysfunc-tion Quality of Life Other Outcomes_ _ Found the largest change inpercentage vasomotorsymptom score betweenwomen who werepremenopausal and becamepostmenopausal (17.73) andthose who werepremenopausal and startedHRT (19.25). Change scoreswere high among those whowere peri-menopausal andremained peri-menopausalafter 6 years (12.31). Thosewho were post-menopausaland remained postmenopausalhad the lowestchange score (0.29).Change in percentagepsychological symptom scorewas highest among thosewomen who werepremenopausal and becamepost-menopausal (4.74); thosewho were pre-menopausal andwent on HRT (6.4), and thosewho were peri-menopausaland went on HRT (4.38).Lowest psychological changescores were found in thosewho were post- and remainedpost (-0.12) and those whoF-126

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearHardy, 2002BritainPredictors studied(significant/not significant) Statistical Models_MV models adjusted for priorpsychological status andpersonality (neuroticism scoreat age 16, present stateexamination (PSE) for anxietyand depression at age 36),health related behaviors, socioeconomicstatus (highesteducation, job held at age 43),attitude to menopause,smoking, BMI at age 36, ageand baseline score.Significant predictors in multivariate(adjusted models)Change in menopausal status.Change in work stress.Change in family stress.(true for both HR and psychological outcomes)F-127

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearHardy, 2002BritainRR or OR_CommentsF-128

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/Year Umbrella NHunter, 1989LondonStudyDesignNone 682 CrosssectionalTypeControlGroupLength ofFollow-UpRecruitment(Data source)_ _ Newspaper ads, radioprogram, volunteers forovarian cancer screeningPopulation/ SettingWomen aged 45-65years predominantlyfrom London and South-East EnglandRace/EthnicityNRF-129

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearHunter, 1989LondonAge (range)Inclusion/Exclusion Criteria52.3 (45-65) Excluded: Women receiving estrogen therapy,women who had undergone hysterectomyAscertainment ofSymptoms Response Rate WithdrawalsQuestionnaires78% (850/1090) toinitial postal survey,62.6% afterexclusions_F-130

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearHunter, 1989LondonMeasures Used"Women's Health Questionnaire"developed by the authorsPilowsky HypochondriasisQuestionnaireGeneral Health QuestionnaireMenopausal statusPremenopausal 18%Perimenopausal 26%Postmenopausal 56%HysterectomyorBSO (#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use of SERMS(#/n)Excluded _ _ _F-131

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearHunter, 1989LondonBehavior orLifestyle Factors(#/n)RecentdiscontinuationofHRT(#/n)High or Low BMI(#/n) Hot Flashes Vaginal Dryness Sleep_ _ _ Vasomotor symptomsincreased withmenopausal status.55% of peri- andpostmenopausal vs. 15%premenopausal women(p

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearHunter, 1989LondonMood Cognitive Somatic UrinaryDepressed Mood category of No significant differencesymptoms increased with by menopausal status.transition to peri- and postmenopause(p

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearHunter, 1989LondonSexual Dysfunc-tion Quality of Life Other OutcomesSexual problems increased with menopausalstatus (p

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearHunter, 1989LondonPredictors studied(significant/not significant)Menopausal status, age,reported current illness,marital status, social class,employment status (only 45-54 year olds included).Statistical ModelsMultiple regression for eachfactor score (symptom group)Significant predictors in multivariate(adjusted models)Symptoms groups with menopausal status as a significant predictor(p

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearHunter, 1989LondonRR or ORCommentsFactor analysis done prior to use of scores for ANCOVA andregression analysis.B 0.17B 0.17B 0.29B 0.16B 0.11F-136

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/Year Umbrella NStudyDesignKaufert, 1992 Manitoba 469 CrosssectionalandlongitudionalTypeControlGroupLength ofFollow-UpRecruitment(Data source)_ 3 years Mail survey of women fromgeneral population ofManitoba, CanadaAge 40-59 yearsPopulation/ SettingManitoba, CanadaRace/EthnicityNRKoch, 1995University ofMinnesotaand TreminTrustLongitudinalStudy391 Crosssectionalfrom cohortInternalPrevalenceCollege class852 eligible participantsfrom college class of1963 and the TreminTrust Longitudinal Study505 surveys returned391 eligible99% WhiteF-137

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKaufert, 1992Age (range)45-55 (mean48.4)Inclusion/Exclusion CriteriaInclusion: menstruated in the last 3 months, or hadpreviously had a hysterectomy, age 45 or olderAscertainment ofSymptoms Response Rate WithdrawalsMail and telephonesurveys68% to mail survey87% of thoseeligible forlongitudional followup agreed toparticipate_Koch, 1995Mean 46 Specified Survey _F-138

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKaufert, 1992Measures UsedCES-DModified Worsley's 'Role ProblemChecklist'Questions regarding recent lifeevents, menses, 4 health conditions(arthritis, allergies, high bloodpressure, thyroid problems), andpresent state of health (good, fair, orpoor)Menopausal status_HysterectomyorBSO (#/n)136 (nodifferentiationbyoophorectomystatus)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use of SERMS(#/n)NR NR NRKoch, 1995Survey Excluded NR NR NR NRF-139

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKaufert, 1992Behavior orLifestyle Factors(#/n)RecentdiscontinuationofHRT(#/n)High or Low BMI(#/n) Hot Flashes Vaginal Dryness Sleep_ _ _ _ _ _Koch, 1995NR NR 24% reported 36% in perimenopausalSignificantly related groupto age andmenopausal statusNRNRF-140

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKaufert, 1992Koch, 1995Mood Cognitive Somatic UrinaryUterineBleedingDepression_ _ _ _26% of all women were depressedat one interview or another.Across all 5 interviews, thepercentage of women with CES-D> 16 was 9-11%. All depressiondata was collapsed across the 5interviews to look at theassociation between depressionand transition from onemenopausal status to another. Awoman's menopausal status doesnot significantly alter the likelihoodof her becoming depressed(hysterectomized womenexcluded). Hysterectomizedwomen who were not depressedat baseline were more likely thanwomen in any other menopausalcategory to become depressed(OR 1.7, CI 1.15, 2.6).NR NR NR NR 46% notedchange inprior yearF-141

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKaufert, 1992Sexual Dysfunc-tion Quality of Life Other Outcomes_ _ _Koch, 1995NR NR AgeMarital statusMenopausal statusVaginal drynessHot flashesF-142

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKaufert, 1992Predictors studied(significant/not significant)Significant predictors in multivariate(adjusted models)Statistical Models_ _ _Koch, 1995Change in desire, maritalstatus, vaginal dryness,enjoyment with partner, age.Menopausal status notrelated to reduced desire,reduced orgasm, or lessj tLogistic regressionOnly Betas and x 2 reported for each predictor variableF-143

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKaufert, 1992RR or OR_Comments_Koch, 1995_ Premenopausal: 21%Perimenopausal: 79%F-144

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/Year Umbrella NStudyDesignKoster, 1993a Copenhagen 621 Crosssectionalfrom cohortTypeControlGroupLength ofFollow-UpRecruitment(Data source)Population/ SettingInternal 4 years NR Danish women born in1936, from 4municipalities inCopenhagenRace/Ethnicity100% DanishKoster, 1993b Copenhagen 621 Crosssectionalfrom cohortInternal 11 years NR Danish women born in1936, from 4municipalities inCopenhagen100% DanishF-145

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKoster, 1993aAge (range)Inclusion/Exclusion Criteria51 year olds Inclusion:In 1976, all 40 year old women born in 1936,resident in 4 municipalitites in Copenhagen, in goodgeneral healthAscertainment ofSymptoms Response Rate WithdrawalsQuestionnaire 526 (88%) By 1987, 22 died, 2emigrated (n=597)from original cohort526 usablequestionnairesreturnedKoster, 1993b40-51 year olds Inclusion:In 1976, all 40 year old women born in 1936,resident in 4 municipalitites in Copenhagen, in goodgeneral healthQuestionnaire andinterviewNR474 (76%) of originalcohort in this studyF-146

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKoster, 1993aKoster, 1993bMeasures UsedPostal questionniare and telephonecontactQuestionnaire, interview, clinicalassessment from a trainedpsychiatrist using diagnostic criteriadeveloped by Bollerup for TheGlostrup Population Studies(psychological health status), criteriafrom The Danish National Institute ofScoial Research (social status)Menopausal statusIn 1987Pre 47 (9%)Peri 91 (7%)Post 129 (25%)HRT 175 (33%)SM 84 (16%)In 1986Pre 66 (13%)Peri 121 (23%)Post 93 (18%)HRT 163 (31%)SM 83 (16%)In 1985Pre 135 (26%)Peri 95 (18%)Post 129 (25%)HRT 144 (27%)SM 81 (15%)In 1984Pre 205 (39%)Peri 67 (13%)Post 51 (10%)HRT 125 (24%)SM 78 (15%)HysterectomyorBSO (#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use of SERMS(#/n)Examined _ _ _See Koster 1993 Examined _ _ _F-147

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKoster, 1993aBehavior orLifestyle Factors(#/n)RecentdiscontinuationofHRT(#/n)High or Low BMI(#/n) Hot Flashes Vaginal Dryness Sleep_ Excluded _ Increased prevalencewithin groupsPre to peri: beta 0.81(p

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKoster, 1993aMood Cognitive Somatic UrinaryIncreased prevalence ofmoodiness within groupsPre to peri: beta 0.17 (p

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKoster, 1993aSexual Dysfunc-tion Quality of Life Other Outcomes_ _ _Koster, 1993bAnticipation of decreased sexuality at 40 yearswas only significant predictor of decreasedsexual desire (p

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKoster, 1993aPredictors studied(significant/not significant)Not significant:Headache, depression,moodiness from peri - postmenopausal statusStatistical ModelsLogistic regression modelsSignificant predictors in multivariate(adjusted models)_Koster, 1993bNot significant:Social background(education, marital, andsocial status), life-style(smoking, alcohol-intake,physical fitness)Multiple logistic regressionmodelsAgeMarital statusEmplyment statusSocial statusF-151

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKoster, 1993aRR or OROR (see symtomcolumns)Prevalence data reported.CommentsKoster, 1993bF-152

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/Year Umbrella NKoster, 2002DenmarkCopenhagen 621 invited548 initiallyenrolledStudyDesignCrosssectionalTypeControlGroupLength ofFollow-UpRecruitment(Data source)Population/ SettingInternal 20 years NR Women in DenmarkAge 40 in 1976Race/EthnicityNRF-153

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKoster, 2002DenmarkAge (range)Inclusion/Exclusion CriteriaAscertainment ofSymptoms Response Rate Withdrawals40 at baseline NR SurveyTelephonequestionnaires orpersonal interview65-88% NRF-154

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKoster, 2002DenmarkMeasures UsedSurvey evaluating sociodemographic,attitudes, symptoms, general health,sexualty, body image, medication, lifeevents, aging.Menopausal statusHysterectomyorBSO (#/n)Assessed bynumbers NRPrematureOvarianFailure(#/n)BreastCancer(#/n)Use of SERMS(#/n)NR NR NRF-155

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKoster, 2002DenmarkBehavior orLifestyle Factors(#/n)Assessed (seemeasures usedcolumn)RecentdiscontinuationofHRT(#/n)High or Low BMI(#/n) Hot Flashes Vaginal Dryness SleepNR NR Prevalence by age (%):40: NR45: NR51: 5660: 29Prevalence bymenopausal status (%):Pre: 31Peri: 46Post: 68HRT: 56Surgical menopause: 61NRF-156

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKoster, 2002DenmarkMood Cognitive Somatic UrinaryDepression by age (%):40: NR45: NR51: 1860: 20Depression by menopausal status(%):Pre: 12Peri: 21Post: 16HRT: 28Surgical menopause: 38Moodiness by age (%):51: 2860: 31Moodiness by menopausal status(%):Pre: 33Peri: 34Post: 32HRT: 49Surgical menopause: 60_ Headache by age (%):40: 5651: 4960: 38Headache bymenopausal status (%):Pre: 44Peri: 49Post: 38HRT: 56Surgical menopause: 61Fatigue by age (%):41: 4151: 3460: 29Fatigue by menopausalstatus (%):Pre: 21Peri: 30Post: 26HRT: 35Surgical menopause: 56NRUterineBleedingNRF-157

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKoster, 2002DenmarkSexual Dysfunc-tion Quality of Life Other OutcomesDecreased sexuality by age (%):51: 3760: 67__F-158

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKoster, 2002DenmarkPredictors studied(significant/not significant)Strongest predictor ofwoman's menopauseexperience was prior health.Sexuality depended on priorsexual experiences. Noassociation betweenmenopausal/perimenopausalanddepression/moodiness, buthot flashes and fatiguecorrelated with transition.Also, hot flashes with fatigueassociated with variouspsychosocial factors, whichexplained much variation insymptoms.Statistical Models_Significant predictors in multivariate(adjusted models)_F-159

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKoster, 2002DenmarkRR or OR_Comments_F-160

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/Year Umbrella NStudyDesignKravitz, 2003 SWAN 12,603 CrosssectionalTypeControlGroupLength ofFollow-UpRecruitment(Data source)Population/ SettingInternal N/A Random digit dialing Random selection ofwomen from multiplesites (Los Angeles,Pittsburgh, Newark,Boston, Chicago,Detroit, and Oakland)Race/EthnicityW=6,304AA=3,464Chinese=573Japanese=606Hispanic=1,656F-161

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKravitz, 2003Age (range)40-44(N=4,233)45-49(N=4,600)50-55(N=3,770)Inclusion/Exclusion Criteria_Ascertainment ofSymptoms Response Rate WithdrawalsSelf reportquestionnaires andinterviews81% _F-162

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKravitz, 2003Measures Used12-item symptom questionnaireMenopausal statusPre=4,425Early peri=3,521Late peri=607Natural post=1,739Surgical post=701Post on HRT=1,610HysterectomyorBSO (#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use of SERMS(#/n)701/12,603 NR NR NRF-163

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKravitz, 2003Behavior orLifestyle Factors(#/n)RecentdiscontinuationofHRT(#/n)High or Low BMI(#/n) Hot Flashes Vaginal Dryness SleepNR NR NR _ _ Overall prevalance ofsleep difficulty=38%Most prevalent insurgical post=48%Least prevalent inpre=31%Caucasian (40%) andHispanic (38%) womenreported highest rates ofsleep difficulty.F-164

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKravitz, 2003UterineMood Cognitive Somatic Urinary Bleeding_ _ _ _ _F-165

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKravitz, 2003Sexual Dysfunc-tion Quality of Life Other Outcomes_ _ _F-166

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearPredictors studied(significant/not significant)Statistical ModelsSignificant predictors in multivariate(adjusted models)Kravitz, 2003Ethnicity and ageBivariate associationsbewtween each covariate andsleep difficulty were examinedEthnicityAgeusing X 2 tests.Multivariate associations ereexamined using a multiplelogistic regression.F-167

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKravitz, 2003RR or ORSurgical post = 1.55 (1.25-1.92)Late peri = 1.33 (1.07-1.65)Natural post = 1.21 (1.03-1.43)Post on HRT = 1.12 (0.95-1.31)Early peri = 1.11 (0.99-1.24)Pre=100Comments_F-168

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/Year Umbrella NKuh, 1997BritainMedicalResearchCouncil(MRC)StudyDesign1498 (84%of thosewho weresent thequestionnaire)CrosssectionalTypeControlGroupLength ofFollow-UpRecruitment(Data source)Internal N/A National prospective birthcohort in England, Scotlandand WalesPopulation/ SettingSocially stratified birthcohort in Britain, thoseinterviewed in 1993(age 43) wererepresentative of thenative population of thatage.Race/Ethnicity_F-169

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKuh, 1997BritainAge (range)Inclusion/Exclusion CriteriaAscertainment ofSymptoms Response Rate WithdrawalsNR _ Mailed questionnaire 84% _F-170

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKuh, 1997BritainMeasures UsedSymptom checklistMenopausal statusAll women in study (all age47)HysterectomyorBSO (#/n)215 (14.3%)salpingohysterectomy,analyzedseparatelyPrematureOvarianFailure(#/n)BreastCancer(#/n)Use of SERMS(#/n)NR NR NRF-171

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKuh, 1997BritainBehavior orLifestyle Factors(#/n)RecentdiscontinuationofHRT(#/n)NR 172(11.4%) onHRT,analyzedseparatelyHigh or Low BMI(#/n) Hot Flashes Vaginal Dryness SleepNRHot flashes (n=1465):bothered a lot: 7%bothered a little: 24.4%none or not bothered:68.7%Cold/night sweats(n=1454):bothered a lot: 6.2%bothered a little: 20.0%none/notbothered:73.8%Vaginal Dryness(n=1399):bothered a lot: 4.2%bothered a little 15.7%none or not bothered80.1%Trouble sleeping:bothered a lot: 13.7%bothered a little 35.7%none/not bothered50.5%F-172

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKuh, 1997BritainMood Cognitive Somatic UrinaryAnxiety or depression (n=1427):bothered a lot:16.8%bothered a little: 36.0%none/not bothered:50.5%irritability (n=1419):bothered a lot:14.6%bothered a little: 40.2%none/not bothered: 45.2%tearfulness (n=1414)bothered a lot:11.7%bothered a little:30.1%none/not botherred:58.1%feelings of panic (1392):bothered a lot: 7.2%bothered a little: 17.2%none/not bothered: 75.6%Forgetfulness:bothered a lot: 13.1%bothered a little: 31.2%none/not bothered:55.7%Aches and pains(n=1422):bothered a lot:17.1%bothered a little: 42.5%none/not bothered:39.7%severe headaches(n=1413):bothered a lot: 10.9%bothered a little: 20.9%none/not bothered:68.2%breast tenderness(n=1422):bothered a lot: 10.1%bothered a little:33.4%none/not bothered:56.5%palpitations (1406):bothered a lot: 6.3%bothered a little:22.4%none/not bothered:71.3%pins and needles(n=1399):bothered a lot: 5.4%bothered a little:20.2%Urinary frequency(n=1410):bothered a lot:7.9%bothered a little:18.6%none/not bothered:73.5%UterineBleedingNRF-173

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKuh, 1997BritainSexual Dysfunc-tion Quality of Life Other OutcomesDifficulties with intercourse (n=1381):bothered a lot: 3.9%bothered a little: 9.1%none/not bothered: 87.0%NRSkin crawling sensations(n=1383):bothered a lot: 3.3%bothered a little: 11.1%none/not botherred:85.5%skin wrinkling (n=1389)bothered a lot: 3.3%bothered a little:15.5%none/not bothered: 81.6%hair loss (1383):bothered a lot: 2.1%bothered a little:5.9%none/not botherred:92.0%F-174

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKuh, 1997BritainPredictors studied(significant/not significant)Significant predictors in multivariate(adjusted models)Statistical Models_ _ _F-175

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKuh, 1997BritainRR or OR_CommentsWomen were all aged 47 years; anxiety and depression(assessed by PSE), and health status was assessed at age 36.F-176

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesTypeControlGroupLength ofFollow-UpStudy/Year Umbrella NStudyDesignRecruitment(Data source) Population/ SettingKuh, 1997_ _ _ _ _ _ _ _Britain(continued)Race/EthnicityKuh, 1997Britain(continued)_ _ _ _ _ _ _ _Kuh, 1997Britain(continued)_ _ _ _ _ _ _ _F-177

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKuh, 1997Britain(continued)Ascertainment ofAge (range)Inclusion/Exclusion CriteriaSymptoms Response Rate Withdrawals_ _ _ _ _Kuh, 1997Britain(continued)_ _ _ _ _Kuh, 1997Britain(continued)_ _ _ _ _F-178

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKuh, 1997Britain(continued)PrematureOvarianFailure(#/n)Measures UsedMenopausal statusHysterectomyorBSO (#/n)BreastCancer(#/n)_ Premenopausal women _ _ _ _Use of SERMS(#/n)Kuh, 1997Britain(continued)_ _ _ _ _ _Kuh, 1997Britain(continued)_ _ _ _ _ _F-179

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKuh, 1997Britain(continued)Behavior orLifestyle Factors(#/n)RecentdiscontinuationofHRT(#/n)High or Low BMI(#/n) Hot Flashes Vaginal Dryness Sleep_ _ _ Bothered by hot flashes(p

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKuh, 1997Britain(continued)UterineMood Cognitive Somatic Urinary Bleeding_ _ _ _ _Kuh, 1997Britain(continued)_ _ _ _ _Kuh, 1997Britain(continued)_ _ _ _ _F-181

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKuh, 1997Britain(continued)Sexual Dysfunc-tion Quality of Life Other Outcomes_ _ _Kuh, 1997Britain(continued)Difficulties with intercourse (bothered a little ora lot, p

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKuh, 1997Britain(continued)Predictors studied(significant/not significant)_Statistical ModelsSignificant predictors in multivariate(adjusted models)Logistic regression models to For vasomotor symptoms: significant predictors included menopausalpredict bothered a little/lot status, educational qualifications, work stress worse in past 12 months,adjusting for menopausal smoking at any time in past, 3+health problems at age 36. Stress instatus, life stress at age 36, family life was not a significant predictor.physical and emotional health atage 36, smoking behavior inearlier adult life, educationalbackground.Kuh, 1997Britain(continued)_ _ Significant predictors include: menopausal status, work stress andprevious history of 2+health problems at age 36. Not significant were:education, smoking, anxiety/depression in past, family life stress.Kuh, 1997Britain(continued)_ _ Significant predictors: menopausal status, current stress at home andat work, poorer physical and emotional health at age 36.F-183

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKuh, 1997Britain(continued)RR or ORAdjust OR for vasomotorsymptoms (postcompared to pre)=4.7(95%CI 2.6, 8.5). Othergroups: peri 2.5**,hysterectomy 2.5**, HRT3.4** compared to pre.Comments** data approximated from histogram or OR figure, referred togenerally in text.Kuh, 1997Britain(continued)Kuh, 1997Britain(continued)Adjusted OR for sexualdysfunction (combinesvaginal dryness anddifficulties withintercourse=~4**; Alsoincreased were OR forperi (2.2)**, hysterectomy(3.2)**, and HRT (2.4)**Adjusted OR for troublesleeping:post=3.4 (95% CI 1.9,6.2); peri =1.5 (95% CI1.1-02.0); hysterectomy2.6 (95% CI 1.8, 3.7); andhysterectomy 2.3 (95% CI1.5, 3.4) compared to pre.** data approximated from figure showing Ors for groups.Referred to in text as "almost fourfold increase post vs. pre._F-184

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/Year Umbrella NKuh, 1999BritainStudyDesignMRC 1378 Crosssectionalfrom cohortTypeControlGroupLength ofFollow-UpRecruitment(Data source)Population/ SettingRace/Ethnicity_ _ _ _ _F-185

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKuh, 1999BritainAge (range)Inclusion/Exclusion Criteria48 years All women with whom the investigators were still incontact from the original cohort of 2548 womenAscertainment ofSymptoms Response Rate WithdrawalsPostal questionnairesent to 1486 womenwhen they were 48years old93% toquestionnaire_F-186

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKuh, 1999BritainMeasures UsedQuestionnaire regarding incontinence(incont) symptoms (no statement ofquestionnaire validation)Menopausal statusStress incont symptoms bymenopausal status:Pre 49.8%Peri 52.7%Post 36.3 %Hyst 53.7%HRT 47.9%Urge incont symptoms bymenopausal statusPre 18.1%Peri 23.8%Post 18.6%Hyst 28.8%HRT 21.0%Severe incont symptoms bymenopausal statusPre 7.3%Peri 6.0%Post 9.8%Hyst 9.8%HRT 5.0%HysterectomyorBSO (#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use of SERMS(#/n)_ _ _ _F-187

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKuh, 1999BritainBehavior orLifestyle Factors(#/n)RecentdiscontinuationofHRT(#/n)High or Low BMI(#/n) Hot Flashes Vaginal Dryness Sleep_ _ _ _ _ _F-188

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKuh, 1999BritainMood Cognitive Somatic Urinary_ _ _ 55% in the cohortreported incontinence,see menopausal statusfor breakdown by group,odds of stress symptomswere lower in thepostmenopausal versusnot menopausal group(OR 0.57, CI 0.33-0.95),no association of urgesymptoms or severeincontinence withmenopausal statusUterineBleeding_F-189

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKuh, 1999BritainSexual Dysfunc-tion Quality of Life Other Outcomes_ _ _F-190

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKuh, 1999BritainPredictors studied(significant/not significant)Significant predictors in multivariate(adjusted models)Statistical Models_ _ _F-191

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKuh, 1999BritainRR or OR_Comments_F-192

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/Year Umbrella NKuh, 2002BritainMedical 2547Research women inCouncil initial(MRC) cohort.National 1023 wereSurvey of availableHealth & andDevelopment completedall sixquestionnairesbetween1993-1998StudyDesignCohort withCrosssectionaldataTypeControlGroupLength ofFollow-UpRecruitment(Data source)Internal _ All births to non-manual andagricultural workers and one infour births to manual workersin the 2nd week of march1946.Population/ SettingBritain, Scotland, WalesRace/Ethnicity_Maartens, 2001NetherlandsEindhoven 2450 Cohort Internal _ Invitation, method NR All women living inEindhoven respondingto screening recruitmentage 46-53 at baseline(n=8503; 6648 agreedto participate)_F-193

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKuh, 2002BritainAge (range)Inclusion/Exclusion CriteriaAscertainment ofSymptoms Response Rate Withdrawals52 _ Mailedquestionnaires__Maartens, 2001Netherlands46-53 Inclusion:1. Dutch, Caucasian women2. Natural menopause3. No HRTExclusion:1. Women with hysterectomy or bilateraloophorectomy2. HRT without surgical menopause3. Non-compliance with questionnaireQuestionnaires2450 respondedand eligible_F-194

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKuh, 2002BritainMeasures UsedMenopausal status_ Pre 272Peri 309Post 208Hysterectomy 240HRT 255HysterectomyorBSO (#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use of SERMS(#/n)240/1284 NR NR NRMaartens, 2001NetherlandsPopulation Survey _ Excluded _ _ _F-195

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKuh, 2002BritainBehavior orLifestyle Factors(#/n)_RecentdiscontinuationofHRT(#/n)HRT users255/1284High or Low BMI(#/n) Hot Flashes Vaginal Dryness SleepNR _ _ _Maartens, 2001NetherlandsNR NR NR PrevalenceHF OR 5.9 comparingpre to peri menopausalstatus and OR 1.9comparing peri to postmenopausal status andOR 13.4 comparing preto post menopausalstatusPrevalenceperi vs. post OR 1.6Prevalenceperi vs. post OR 1.3(insomnia)F-196

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKuh, 2002BritainUterineMood Cognitive Somatic Urinary Bleeding_ _ _ _ _Maartens, 2001NetherlandsMultivariate adjusted OR forchange (increase) in depressionscoreTransition:Pre to peri: not significantPre to post: 0.57 (statisticallysignificant)No statistical difference No statistical difference No urinary symptoms bystageNRF-197

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKuh, 2002BritainSexual Dysfunc-tion Quality of Life Other Outcomes_ _ _Maartens, 2001NetherlandsPain with intercourse:Pre-peri: not significantPeri-post: 1.86 (statistically significant)Pre-post: 2.13NRNRF-198

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKuh, 2002BritainPredictors studied(significant/not significant)Statistical ModelsSignificant predictors in multivariate(adjusted models)_ _ Menopausal status was not a significant predictor of psychologicalstress in multivariate modeling, adjusting for child and adult behavioraland psychological factors.Maartens, 2001NetherlandsPhysical symptomsDemographicCognitive/Mental SymptomsChi squareLogistic regression_F-199

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearKuh, 2002BritainMaartens, 2001NetherlandsRR or ORAge adjusted OR forpsychological symptomscore: "Women reportinghigher levels ofpsychological symptomsin midlife were muchmore likely than their lesssymptomatic peers tohave had health problemspreviously during theiradult life. There was novariation in psychologicalsymptoms according tomenopausal stage butHRT users had a higherlevel of (psychological)symptoms."OR shown on Table 3, allcross 1 except OR forHRT users (RegressionCoefficient=0.44 (0.20,0 69)_CommentsTables report regression coefficients rather than OR._F-200

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/Year Umbrella NMaartens, 2002NetherlandsStudyDesignEindhoven 6648 PrevalenceandprospectivecohortTypeControlGroupLength ofFollow-UpRecruitment(Data source)Internal 5 years Invitation to all women inEindhoven of which 6648(78%) participatedPopulation/ SettingAll women living inEindhoven respondingto screening recruitmentage 46-53 at baseline(n=8503; 6648 agreedto participate)Race/EthnicityWhiteMcKinlay, 1987 Massachusett'sWomen'sHealth Study2500 Crosssectionalanalysesfrom cohortInternal 27 months Random sample of 8,050women ages 45-55 inMassachusetts; 2,500identified as premenopausal.77% RRPopulation basedrecruitment ofpremenopausal womenNRF-201

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMaartens, 2002NetherlandsAge (range)Inclusion/Exclusion Criteria46-53 Inclusion:1. Dutch, Caucasian women2. Natural menopause3. No HRTExclusion:1. Women with hysterectomy or bilateraloophorectomy2. HRT without surgical menopause3. Non-compliance with questionnaireAscertainment ofSymptoms Response Rate WithdrawalsQuestionnaire Prevalence: 78%Follow-up of 2748with naturalmenopause and noHRT: 76%2103 (76%)participated_McKinlay, 1987_ _ CES-D given onceduring 1st 27months; combinedinto single crosssectional data set"after determiningthat depressionscores did notdepend on the followupin which the CES-D scale wasadministered.77% _F-202

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMaartens, 2002NetherlandsMeasures UsedMailed Edinburgh depression scaleGynecologic historyGeneral medical historyDemographic dataMenopausal statusHysterectomyorBSO (#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use of SERMS(#/n)_ Excluded NR NR NRMcKinlay, 1987CES-D _ _ NR NR NRF-203

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMaartens, 2002NetherlandsBehavior orLifestyle Factors(#/n)RecentdiscontinuationofHRT(#/n)High or Low BMI(#/n) Hot Flashes Vaginal Dryness SleepEvaluated Evaluated NR NR NR NRMcKinlay, 1987_ _ _ _ _ _F-204

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMaartens, 2002NetherlandsMood Cognitive Somatic UrinaryUterineBleedingPrevalence depression at baselineMean Score:pre - 5.6per - 6.5post - 7.8Prevalence depresssion at followuppre - 6.8per - 7.0post - 7.8NR NR NR NRMcKinlay, 1987Percentage of women with CES-Dscore>16 (estimated from figure1):pre: 7.5% (n=527)peri: 10.5% (n=1632)natural menopause: 8% (n=262)surgical menopause 18% (n=78)_ Women reporting > 2physical symptoms areabout 4 times as likely tobe depressed as womenreporting < 1 symptom(15.7% vs. 4.3%).__F-205

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMaartens, 2002NetherlandsSexual Dysfunc-tion Quality of Life Other OutcomesNR NR _McKinlay, 1987_ _ _F-206

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMaartens, 2002NetherlandsPredictors studied(significant/not significant)DemographicMajor life eventsPrior episodes depressionTime between baseline andfollow-up examStatistical ModelsT tests for changeSignificant predictors in multivariate(adjusted models)Multivariate adjusted OR for depression:Transition peri-post 1.8 (1.3-2.6)Transition pre-peri 1.8 (1.10-3.3)Prior depression 2.2 (1.6-3.0)Unemployment 2.4 (1.2-4.6)Death of partner 2.4 (1.1-5.6)Financial problems 3.4 (1.5-7.8)McKinlay, 19871. sociodemographicvariables:marital status, education,age, employment status,total number of persons inhousehold2. health status: selfassesssedhealth, physicalsymptoms, restricted activityand chronic conditions.3. utilization behavior:formal and informal healthresources, lay consultations,medication useLogistic regression with CES-D>16 as outcomeEducation and marital status were significantly associated with a CES-D score of >16; personal stress caused by others (person-inducedworry); number of health problems; use of tranquilizer medicationsF-207

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMaartens, 2002NetherlandsRR or OR_CommentsNot adjusted for sleep disturbanceMcKinlay, 1987Not given. RR presentedfor each of the significantvariables in predictormodel."menstrual change associated with the menopause appears tohave no significant effect on depression … those with a recentsurgical menopause were the most depressed group."F-208

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/Year Umbrella NMcKinlay, 1989 Massachusett'sWomen'sHealth StudyStudyDesign2,466 CrosssectionalandprospectivecohortTypeControlGroupLength ofFollow-UpRecruitment(Data source)Population/ SettingInternal 4.5 years Random sample 8051 women in theCommonwealth ofMassachusetts born1926-1936.Race/EthnicityNRF-209

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMcKinlay, 1989Age (range)Inclusion/Exclusion Criteria45-55 in 1982 A cohort of premenopausal women was chosenfrom the entire sample of women (8050)Ascertainment ofSymptoms Response Rate WithdrawalsQuestionnaires77% to initialsurvey, 85% overallin follow-up_F-210

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMcKinlay, 1989CES-DMeasures UsedMenopausal statusChange in menstrual statusover 3 years of follow-up(T0-T3, n=2466):menses in 3 months priorto T3 42.9%menses changed toirregular 16.9%amenorrhea < 12 months15.5%amenorrhea > 12 months20.4%Surgical menopause 4.4%HysterectomyorBSO (#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use of SERMS(#/n)_ _ _ _F-211

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMcKinlay, 1989Behavior orLifestyle Factors(#/n)RecentdiscontinuationofHRT(#/n)High or Low BMI(#/n) Hot Flashes Vaginal Dryness Sleep_ _ _ _ _ _F-212

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMcKinlay, 1989Mood Cognitive Somatic UrinaryUterineBleedingCES-D score related crosssectionallyto menstrual statusreveals women who haveundergone surgical menopause inprevious 3 months were twice aslikely as the rest of the cohort tohave CES-D scores >16 (19% v10%)._ _ _ _F-213

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMcKinlay, 1989Sexual Dysfunc-tion Quality of Life Other Outcomes_ _ _F-214

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMcKinlay, 1989Predictors studied(significant/not significant)Significant predictors in multivariate(adjusted models)Statistical Models_ _ _F-215

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMcKinlay, 1989RR or OR_Comments"Change in menstrual status associated with the menopauseappears to have no significant effect on depression, as definedby a CES-D score of 16 or greater."(Minimal data available for this finding.)Some data reported in this study is the same as that reported inMcKinlay, 1992F-216

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/Year Umbrella NMcKinlay, 1992 Massachusett'sWomen'sHealth StudyStudyDesign2,570 Longitudinaland crosssectionalanalysis ofcohort dataTypeControlGroupLength ofFollow-UpRecruitment(Data source)Internal 5 years Random sample of 8,050women ages 45-55 inMassachusetts, derived fromcensus lists. Of these, 2,570were identified as havingmenstruated in the past 3months, having a uterus and >one ovaryPopulation/ Setting8050 women in theCommonwealth ofMassachusetts born1926-1936.Race/EthnicityNRMilsom, 1993Goteberg,Sweden7,459 Crosssectional_ _ Random sampling ofpopulation registerBirth cohorts of 1900,1905, 1910, 1915, 1920,1930, 1940 fromSweden_F-217

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMcKinlay, 1992Age (range)Inclusion/Exclusion Criteria45-55 in 1982 Premenopausal women selected from initial sampleof 8,050Ascertainment ofSymptoms Response Rate WithdrawalsQuestionnaires ortelephone interviewsif questionnaires notreceived.77% of 8,050responded. Had 94-99% retention ofthe 2,570premenopausalcohort_Milsom, 199346-86 _ Questionnaireregarding urinaryincontinence74.60% _F-218

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMcKinlay, 1992Measures UsedSymptoms checklist (any in past 2weeks): hot flashes, cold sweats,vertigo, feeling blue or depressed,headaches, insomnia, palpitations,lack of energy, diarrhea and/orconstipation, persistent cough,backaches, upset stomach,aches/stiffness in joints, shortness ofbreath, sore throat, loss of appetite,menstrual problems, fluid retention,difficulty in concentrating, nervoustension, urinary tract/bladderinfections and "pins and needles" inhand or feet.Menopausal statusHysterectomyorBSO (#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use of SERMS(#/n)_ Excluded Excluded NR NRMilsom, 1993_ _ Hysterectomywasassociatedwith increasedrisk ofincontinencein the wholecohort, but notwithin theindividual ageF-219_ _ _

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMcKinlay, 1992Behavior orLifestyle Factors(#/n)33.5% ofpremenopausalcohort (n=1178)were currentsmokersRecentdiscontinuationofHRT(#/n)1% ofpremenopausal cohort(n=1178)were usingHRTHigh or Low BMI(#/n) Hot Flashes Vaginal Dryness SleepNR13.4% of premenopausalcohort had HF (n=1178)at baseline.For women 27 mo priorto perimenopause: 10%had HFs; Following thecessation of menses50% have HF; 4yrs postmenopause20% haveHF.NRNR except in aggregatewith all symptomsMilsom, 1993_ _ _ _ _ _F-220

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMcKinlay, 1992UterineMood Cognitive Somatic Urinary BleedingNR NR NR NR NRMilsom, 1993_ _ _ Menopausal status wasnot associated withincontinence(postmenopausal versuspremenopausal)_F-221

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMcKinlay, 1992Milsom, 1993Sexual Dysfunc-tion Quality of Life Other OutcomesNR NR Lumped HF, sweats andinsomnia into "menopausalsymptoms," and all othersymptoms into nonmenopausalsymptoms: foundthat at Time 6, the followingproportions of women reportboth types of symptoms:pre - 27%peri - 46.3%post - 37.7%_ _"Women who wereperimenopausal for only onecontact were consistently lesslikely to report hot flashesbefore, during and after themenopause than were womenwith a longer perimenopause.Women with short or noperimenopause: 39% had HFvs. remainder of women 51%of whom had HF_F-222

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMcKinlay, 1992Predictors studied(significant/not significant)Significant predictors in multivariate(adjusted models)Statistical Models_ _ _Milsom, 1993_ _ _F-223

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMcKinlay, 1992RR or OR_CommentsMilsom, 1993_Prevalence data is by birth cohort, not by menopausal status.F-224

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/Year Umbrella NMishra, 2003AustraliaAustralianLongitudinalStudy onWomen'sHealthStudyDesignTypeControlGroupLength ofFollow-UpRecruitment(Data source)Population/ Setting8,623 Cohort Internal 2 years Mailed questionnaires Random selection ofAustralian women aged45-50 in 1996 whocompletedquestionnaires in 1996and 1998Race/EthnicityNRF-225

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMishra, 2003AustraliaAge (range)Mean age atbaseline 47.7Inclusion/Exclusion CriteriaExclusions:1. Women salpingo hysterectomy or oophorectomy(n=3014)Ascertainment ofSymptoms Response Rate WithdrawalsSurvey 1996 and1998, mail (longversion, n=11,637)and phone (shorterfor those whocouldn't/didn'tcomplete the mailedversion, n=691)90.4% responserate for those whowere alive at thetime of the secondsurvey.6.9% did not return thesurvey, 1.5% declinedparticipation at followup,1.1% withdrew fromthe study.F-226

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMishra, 2003AustraliaMeasures UsedSF-36 scoresMenopausal statusDefined on the basis of selfreportedbleeding history.Pre: bleeding in last 12months and with samefrequency as in theprevious year (55.1% atBL).Peri: bleeding in last 12months but not in last 3months (25.4% at BL)Post: no bleeding in past12 months (7.0% at BL)HRT: on HRT (12.1% atBL; 20.2 at 2 years)HysterectomyorBSO (#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use of SERMS(#/n)Excluded NR NR NRF-227

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMishra, 2003AustraliaBehavior orLifestyle Factors(#/n)Current smokingpre: 12.5%peri: 17.9%post: 23.1%HRT: 20.6%(p

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMishra, 2003AustraliaMood Cognitive Somatic UrinaryAdjusted mean score (s.e.) for"general mental health" from theSF-36 at baselinepre: 73.4 (0.5)peri: 70.7 (0.6)*post: 71.0 (0.8)*HRT 68.1 (0.7)*NRAdjusted mean score forbodily pain from the SF-36 at baselinepre: 72.5 (0.7)peri: 68.2 (0.8)*post: 70.3 (1.1)*HRT 65.0 (0.9)*NRUterineBleedingNR* ;

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMishra, 2003AustraliaSexual Dysfunc-tion Quality of Life Other OutcomesNRAdjusted mean score (s.e.) for"general health perception" atbaselinepre: 73.4 (0.6)peri: 68.2 (0.8)*post: 70.3 (1.1)HRT: 65. (0.9)*_* ;

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMishra, 2003AustraliaPredictors studied(significant/not significant) Statistical ModelsAll mean scores calculated MV modeling only reported inafter adjusting after adjusting terms of adjustmentsfor age, physical activitylevel, weight, number of lifeevents, smoking status,occupation, country of birth,marital status, and area ofresidence.All mean changes calculatedafter adjusting for SF-36scores at baseline, physicalactivity levels at baseline andfollow-up, weight at baseline,change in weight, change innumber of life events, agesmoking status, occupation,country of birth, maritalstatus, and area ofresidence.Significant predictors in multivariate(adjusted models)NRF-231

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMishra, 2003AustraliaRR or OR_CommentsF-232

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/Year Umbrella NMitchell, 1996 Seattle 508enteredstudy301 year 1215 year 2200 year 3StudyDesignTypeControlGroupLength ofFollow-UpRecruitment(Data source)Cohort N/A 3 years Women in households withincensus tracts with mixedethnicity and income contactedby phone11,222 - from which 820eligiblePopulation/ SettingRace/EthnicityCensus tracts in Seattle W 79%AA 8.3%Asian 8.6%Native Am3.3%Mitchell, 2001 Seattle 230 CrosssectionalInternalPrevalenceWomen in households withincensus tracts with mixedethnicity and income contactedby phoneCensus tracts in Seattle 91% White5% AsianAmerican3% AfricanAmericanF-233

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMitchell, 1996Age (range)Inclusion/Exclusion Criteria35-55 Exclusion:1. Amenorrhea > 1 year2. Pregnant3. TAH BSO4. Could not read or speak English5. Irregular menstrual cycles6. HRT useAscertainment ofSymptoms Response Rate WithdrawalsInterview, cycle diary,health update11,222 phonecontacts820 eligible508 entered studyNAMitchell, 2001Mean 46.7Exclusion:1. Amenorrhea > 1 year2. Pregnant3. TAH BSO4. Could not read or speak English5. Irregular menstrual cycles6. HRT useInterviews508 initially; thissurvey conductedamong women stillparticipating 96-97N=230_F-234

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMitchell, 1996PrematureOvarianFailure(#/n)Measures UsedMenopausal statusHysterectomyorBSO (#/n)BreastCancer(#/n)Washington Women's Health Diary _ Excluded NR NR NRUse of SERMS(#/n)Mitchell, 2001Cycle analysis NR NR NR NR 68% partnered24%divorced/separated6% never partneredMean education 16yearsMean income 42,000F-235

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMitchell, 1996Behavior orLifestyle Factors(#/n)RecentdiscontinuationofHRT(#/n)High or Low BMI(#/n) Hot Flashes Vaginal Dryness SleepNR NR NR NR NR NRMitchell, 2001NR NR NR NR NR NRF-236

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMitchell, 1996Mood Cognitive Somatic UrinaryAt baseline dysphoric moodexplained 23.8% of varianceamong symptom clusters - highlystable over 3 years.NRSomatic symptomsexplain 6.5% of variance -highly stable over 3years.NRUterineBleedingNRMitchell, 2001142 women reported memorychange compared with 88 withoutmemory change.No association with age,education, income between the 2groups._ _ NR NRF-237

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMitchell, 1996Sexual Dysfunc-tion Quality of Life Other OutcomesNR NR _Mitchell, 2001NR NR _F-238

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMitchell, 1996Mitchell, 2001Predictors studied(significant/not significant)Factor analysisImportant factors identifiedincluded dysphoric mood,vasomotor symptoms,insomnia, neuromuscularsymptoms, somaticsymptoms.Dysphoric mood very stableover 3 years (explained 77%of variance).Neuromuscular symptomsstable (explained 74% ofvariance).Vasomotor symptomsmoderately stable over 3years.Statistical Models_Significant predictors in multivariate(adjusted models)_ _ _NAF-239

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMitchell, 1996RR or ORNACommentsAll premenopausal or early perimenopausal.Findings suggest that many symptoms described at baseline arestable over time and MP transition explains none over 3 years.Mitchell, 2001This study really only Based on cycle analysisevaluates women's Premenopausal: early menopause transition stage (MTS) 53attributions of causes for Mid-menopausal: MTS 54change in memory (selfreported).Stress, Postmenopausal: MTS 12Late menopausal: MTS 27physical health, and aging 96 on hormones or hysterectomy or were not classifiablemost frequently cited asattributing to memorychange.F-240

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/Year Umbrella NStudyDesignRandolph, 2003 SWAN 2,930 CrosssectionalTypeControlGroupLength ofFollow-UpRecruitment(Data source)Population/ SettingRace/Ethnicity_ _ _ _ AA 27.6%Chinese 7.4%H 8.8%J 9.0%W 47.1%Rodstrom, 2002SwedenGothenburg 1462 Cohort Internal 25+ years Randomly selected frompopulation1968-69 1462 womenaged 38-601302 re-examined 1974-75 (89%)1154 re-examined 1980-81 plus 47 new womenborn in 19304th exam 1992-93WhiteF-241

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearRandolph, 2003Ascertainment ofAge (range)Inclusion/Exclusion CriteriaSymptoms Response Rate Withdrawals46.3 253 of 3302 were excluded because of missing data _ 92.30%Rodstrom, 2002SwedenInitially 38-60None specified other than those with surgicalmenopauseStandardizedinterview__F-242

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearMeasures UsedRandolph, 2003 Height, weight, demographic andlifestyle data.Menopausal status, FSH, DHEAS,SHBG and E2 from venipuncture onday 2-7 of a spontaneous menstrualcycle occurring within 60d ofrecruitment then annually.Menopausal statusPremenopausal 54.3%early perimenopausal45.7%HysterectomyorBSO (#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use of SERMS(#/n)_ _ _ _Rodstrom, 2002Sweden_ Excluded NR NR NRF-243

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearRandolph, 2003Rodstrom, 2002SwedenBehavior orLifestyle Factors(#/n)Smoking:never 57.6%past 25.4%current 10/d12.1%Higher mean FSH,testosterone, andSHBG levels forcurrent compared tonever smokers inunadjusted analyses(p

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearRandolph, 2003UterineMood Cognitive Somatic Urinary Bleeding_ _ _ _ _Rodstrom, 2002SwedenNR NR NR NR NRF-245

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearRandolph, 2003Rodstrom, 2002SwedenSexual Dysfunc-tion Quality of Life Other Outcomes_ _ Unadjusted mean hormonelevels by menopausal status:E2 pg/ml (p NS):pre 74early peri 77FSH IU/L (p

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearRandolph, 2003Predictors studied(significant/not significant)Ethnicity, menopausalstatus, study site, day ofcycle, BMI, age, smoking,and alcoholStatistical ModelsAdjusted models for meanserum hormone concentrationsSignificant predictors in multivariate(adjusted models)E2:No affect of menopausal status and ethnicityFSH:Ethnicity (p

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearRandolph, 2003RR or OR_CommentsAdjusted FSH levels were significantly higher in AA and H thanW and Asian women.Adjusted FSH levels were significantly higher in earlyperimenopausal than premenopausal women.Adjusted DHEAS levels were 73% higher in Chinese than AA.Adjusted testosterone levels were slightly lower in in AA and Hthan W and Asian women.Rodstrom, 2002Sweden__F-248

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/Year Umbrella NSherburn, 2001AustraliaMelbourneWomen's1897,373StudyDesignCrosssectional,longitudinalTypeControlGroup_Length ofFollow-Up7 yearfollow-upRecruitment(Data source)Population/ SettingRace/Ethnicity_ _ _F-249

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearSherburn, 2001AustraliaAscertainment ofAge (range)Inclusion/Exclusion CriteriaSymptoms Response Rate Withdrawals_ _ _ _ _F-250

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearSherburn, 2001AustraliaMeasures Used_Menopausal statusBaseline % noted above.At 7 year follow-up n=373:stayed pre/peri 13.7%became post 54.7%HRT user 22.8%had surgical menopause8.8%HysterectomyorBSO (#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use of SERMS(#/n)_ _ _ _F-251

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearSherburn, 2001AustraliaBehavior orLifestyle Factors(#/n)RecentdiscontinuationofHRT(#/n)High or Low BMI(#/n) Hot Flashes Vaginal Dryness Sleep_ _ _ _ _ _F-252

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearSherburn, 2001AustraliaMood Cognitive Somatic Urinary_ _ _ Urinary incontinence atbaseline by menopausalstatus:pre 10.4%peri 17.3%*post 14%HRT 19%*surgical 17.7%*Total 15.3%*p

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearSherburn, 2001AustraliaSexual Dysfunc-tion Quality of Life Other Outcomes_ _ _F-254

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearSherburn, 2001AustraliaPredictors studied(significant/not significant) Statistical Models_Logistic regression model offactors associated with urinaryincontinenceSignificant predictors in multivariate(adjusted models)BMIOther gynecologic surgeryparticipating in lawn bowlsurinary tract infectiondiarrhea or constipationparityarthritisnegative mood score(menopausal status was not significant in this model)F-255

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearSherburn, 2001Australia1.52.172.264.751.951.471.551.64RR or ORComments"Urinary incontinence in middle-aged women is more closelyassociated with mechanical factors than with menopausaltransition."F-256

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudyDesignStudy/Year Umbrella NSowers, 2000 SWAN 16,065(methods paperCrosssectionalfor SWAN)3306longitudinalCrosssectionalandmultisitelongitudinalstudyTypeControlGroupLength ofFollow-UpOngoingsince1995Recruitment(Data source)Census data, lists, randomdigitdialing, "snow-balling"Population/ SettingCommunity based.Pittsburgh, Boston,Detroit, Chicago, LosAngeles, Oakland,NewarkRace/EthnicityEach siteenrolled non-HispanicCaucasiansand one sitespecificminorityAfrican-American,Japanese,Chinese, orHispanic.Woods, 1997 Seattle 347 Cohort Internal 2 years 822 eligible508 participated in interviews347 completed years 1 and 2surveysSeattlePopulation-basedsample chosen to overrepresent minoritiesSampling frame basedon phone numbers80% Whites8 AfricanAmericans8 AsianAmericansF-257

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearSowers, 2000(methods paperfor SWAN)Age (range)Inclusion/Exclusion Criteria40-55 Eligibility criteria for cross-sectional study:1) primary residence in designated geographic area,2) ability to speak English or other designatedlanguage, 3) age 40-55 years at time of contact, 4)cognitive ability to provide verbal informed consent,5) membership in a specific site's targeted ethnicgroupsEligibility criteria for longitudinal study:1) aged 42-52 years, 2) no surgical removal of theuterus and/or both ovaries, 3) not currently usingexogenous hormone preparations affecting ovarianfunction, 4) at least one menstrual period in theprevious 3 months, 5) self-identification with one ofeach site's designated race/ethnic groupAscertainment ofSymptoms Response Rate WithdrawalsInterview, written/oralsurvey,questionnaires, clinicmeasurements,specimen data,menstrual calendars,abstract medicalrecords forhysterectomy.Materials available inall relevantlanguages.46.6% crosssectional50.7% longitudinalWoods, 199735-45 (median41)Inclusion criteria:1) Non-lactating2) Non-pregnant3) Menses within last year4) English reading5) No hysterectomy6) Had at least 1 ovary_508 of 820 of which75% completed firstyear and 90%second year_F-258

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearSowers, 2000(methods paperfor SWAN)Measures UsedMenopausal statusHysterectomyorBSO (#/n)Too extensive to list _ None atenrollmentPrematureOvarianFailure(#/n)By definitionineligible forlongitudinalstudyBreastCancer(#/n)NRUse of SERMS(#/n)IneligibleWoods, 1997CES-D ScaleMenopausal ChangesNorbechs LES (Stressful LifeContext)Feminine SocializationSocialization for MidlifeHealth StatusFamily Resources_ Excluded NR NR NRF-259

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearSowers, 2000(methods paperfor SWAN)Behavior orLifestyle Factors(#/n)RecentdiscontinuationofHRT(#/n)High or Low BMI(#/n) Hot Flashes Vaginal Dryness Sleep_ _ _ _ _ _Woods, 1997NR NR NR NR NR NRF-260

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearSowers, 2000(methods paperfor SWAN)UterineMood Cognitive Somatic Urinary Bleeding_ NR NR NR NRWoods, 1997Patterns (chronic, resolved,emerging) of depressed moodrelated to stressful life context,past/present health status, andsocial learning about midlife.Menopausal status did notdifferentiate woen with depressionfrom non-depressed._ _ _ _F-261

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearSowers, 2000(methods paperfor SWAN)Sexual Dysfunc-tion Quality of Life Other Outcomes_ _ _Woods, 1997__F-262

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearSowers, 2000(methods paperfor SWAN)Predictors studied(significant/not significant)Significant predictors in multivariate(adjusted models)Statistical Models_ _ _Woods, 1997_ Factors prediction Social learning about midlifeStress life contextPast/present health statusF-263

Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studiesStudy/YearSowers, 2000(methods paperfor SWAN)RR or OR_CommentsWoods, 1997NABaseline: all premenopausalAt year 2 follow up: 22% perimenopausal, 31% hot flashesF-264

Appendix F. Evidence table 6-1. Key Question 1 and 2 cohort studiesKey/AbbreviationsAA = African Americanperi = PerimenopausalBL = BaselinePHS = Perceived health statusBMI = Body mass indexPMS = Premenstrual syndromeBSO = Bilateral Salpingo Oopherectomypost = PostmenopausalCES-D = Center for Epidemiologic Studies Depression Scale pre = PremenopausalDHEAS = DehydroepiandrosteronesPSE = Present state examinationE2 = EstradiolRR = Relative riskGWB = Global well-beingsd = Standard deviationH = HispanicSES = Socioeconomic statusHF = Hot flashSPEQ = Sexuality questionnaire of Personal Experiences QuestionnaireHRQL = Health related quality of lifeSWAN = Study of Women's Health Across the NationHRT = Hormone replacement therapyT = TestosteroneINH = InhibinT0 = Time zeroISRO = Index of Sex Role OrientationT1 - Time oneJ = JapaneseT2 = Time twoLES = Life event stressT3 = Time threeMRC = Medical Research CouncilTAH = Total abdominal hysterectomyMTS = Menopausal transition stageW = WhiteMV = MultivariateNA = Not applicableNHANES = National Health and Nutrition Examination SurveyNHEFS = National Health Examination Follow-up StudyNR = Not reportedNS = Not significantoc =Oral contraceptivesOR = Odds ratioPEQ = Personal Experiences QuestionnaireF-265

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionStudy/YearNType ofTrialComparisonDitkoff, 1991 36 RCT P 3monthsLengthof Trial Population Inclusion/Exclusion CriteriaAsymptomatic American-bornLatina women, aged 45-60,Salpingo hysterectomy, living inEast LA. Recruitment info NR.Inclusion:1. Age 45-602. Previous hysterectomy3. American born Latina4. Estradiol 1-year post-menopausalF-266

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionSpecific Characteristics of PopulationStudy/YearDitkoff, 1991Measures Used1. Minnesota MultiphasicPersonality Inventory-1682. Profile of Adaptation to Life3. Beck Depression Inventory4. Wechsler Adult IntelligenceScales of digit span and digitsymbolHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)36/36 NR NR 0 NR NR 0 NRFuruhjelm, 19841. Sabbatsberg GeneralSymptom Scale (for somatic andmental disturbances)2. Sabbatsberg Distress Self-Rating Scale (for depression)3. Eysenck Personality Inventory4. Sabbatsberg Sexual Self-Rating Scale5. Hormone levels, chemistry,physical exam, papNR NR NR NR NR NR 0 NRF-267

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionTreatmentMain OutcomesStudy/YearDitkoff, 1991Main Drug type; dose;regimenCEE, 0.625mg or 1.25mg,PO qd for days 1-25 eachmonthOther Drugs type;Vaginaldose; regimenHot Flashes DrynessSleepPlacebo None in either group NR NRFuruhjelm, 1984Period A: 2mg estradiol-17B and 1mg estriol for 12days, then 2mg estrodiol17B, 1mg estriol, and 1mgnoretristone acetate for 10days, then 1mg estradiol-17B and 0.5mg estriol;Period B: 4mg estradiol-17Band 2mg estriol for 12 days,then 4mg estrodiol 17B,2mg estriol, and 1mgnoretristone acetate for 10days, then 1mg estradiol-17B and 0.5mg estriol;Period C: 2mg estrodiol-17Band 1mg estriol for 28 daysPeriod D: placeboAll groups improved in prepostcomparison duringhormone treatment;placebo did not change;no comparison to placebogiven. All regimensgrouped together.NRNRF-268

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionMain Outcomes (continued)Study/YearDitkoff, 1991Mood Cognitive Somatic Urinary Uterine Bleeding1. No change in Minnesota Multiphasic PersonalityInventory;2. Significant decrease in Beck DepressionInventory for both doses of CEE pre-post; scoresincreased with placebo, but change not significant;no comparison between CEE and placebo given.3. Significant improvement in income managementscale pre-post in both CEE groups; no change withplacebo; no comparison between CEE andplacebo.No change NR NR NRFuruhjelm, 1984All groups improved in pre-post comparison ofmental distress during hormone treatment(p

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionStudy/YearDitkoff, 1991SexualDysfunctionQuality of Life Other Outcomes WithdrawalsWithdrawalsdue to AEsAdverseEffectsNR NR NR NR 0 NoneCommentsFuruhjelm, 1984NR NR NR 10/58 3/58 3 with heavybleedingOdd analysis ofcrossover-style study;can't separate outfirst treatment.F-270

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionType of ComparisonStudy/Year N TrialHall, 1998 60 RCT P & HH 1 year Postmenopausal women aged 44-NRLengthof Trial Population Inclusion/Exclusion Criteria75 with CAD in Sweden.Recruitment info NRF-271

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionSpecific Characteristics of PopulationStudy/YearHall, 1998Measures UsedNottingham health profile and"others evaluated by Wiklund et.al."Hysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)NR NR NR NR NR NR NR "all wereoverweight"; mean BMI25.9.F-272

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionTreatmentMain OutcomesStudy/YearMain Drug type; dose;regimenOther Drugs type;dose; regimenHot FlashesVaginalDrynessSleepHall, 1998CEE 0.625mg, alone for 18days, in combo withmedroxyprogesterone 5mgfor 10 daysPatch TTS E2 50 mcgalone for 18 days, incombo withmedroxyprogesterone5mg for 10 daysNR NR No change.F-273

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionMain Outcomes (continued)Study/YearHall, 1998Mood Cognitive Somatic Urinary Uterine BleedingSignificant improvement in depressed moods Improved in all 3 groups; NR NR NR(p=0.054) in CEE group; no change in E2 or no difference betweenplacebo; no comparison given between groups. groups.Overall improvement in mood reported in all groupswith no difference between groups.F-274

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionStudy/YearHall, 1998SexualDysfunctionQuality of Life Other Outcomes WithdrawalsWithdrawalsdue to AEsAdverseEffectsNR NR NR 14/60 7/60 Heavybleeding,edema,allergic skinreaction,palpitations,headache.(Numbers onlygiven for thosethat withdrew,not totalsample.)CommentsF-275

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionStudy/YearNType ofTrialComparisonHlatky, 2002 2,763 RCT P 36monthsLengthof Trial Population Inclusion/Exclusion CriteriaPostmenopausal women withCAD in HERS study from 20 USclinical centersInclusion:1. < 802. Postmenopausal:a) age >55 and no menses for 5 yearsb) no menses for 1 year and FSH >40c) documented bilateral oophorectomyd) reported oophorectomy and FSH > 40 andE2 < 253. CAD:a) prior MIb) angiography showing >50% narrowing ofmajor vesselc) prior coronary revascularization procedureExclusion:1. MI or revascularization procedure within 6months2. Prior hysterectomy3. Contraindication to HRT4. HRT within 3 months5. Other life-threatening illnesses6. Unable to return for follow-up visits.F-276

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionSpecific Characteristics of PopulationStudy/YearHlatky, 2002Measures Used1. Duke Activity Status;2. RAND 4-item scale onenergy/fatigue;3. RAND mental healthinventory;4. 8-item depression scaledeveloped for National Study ofMedical Outcomes;Hysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)0 NR NR NR NR NR 0 NRF-277

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionTreatmentMain OutcomesStudy/YearMain Drug type; dose;regimenOther Drugs type;dose; regimenHot FlashesVaginalDrynessSleepHlatky, 2002CEE, 0.625mg andmedroxyprogesteroneacetate 2.5mg PO qdPlacebo Reported elsewhere ReportedelsewhereReported elsewhereF-278

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionMain Outcomes (continued)Study/YearHlatky, 2002Mood Cognitive Somatic Urinary Uterine BleedingRAND mental health inventory had small decline inNR NR Reported Reported elsewhereall patients over time (p=0.05); no significantelsewhereinteraction between treatment group and time(p=0.10).Depressive symptoms decreased more over timeamong patients on HRT (p=0.005).In women with flushing at entry, HRT group hadimproved mental health (+2.6 vs. -0.5, p=0.04) anddepressive symptoms (-0.5 vs. +0/007, p=0.01)compared to placebo. No significant change inwomen without flushing.F-279

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionStudy/YearHlatky, 2002SexualDysfunctionQuality of Life Other Outcomes WithdrawalsNRMore rapid decline over timein physical function scores inwomen on HRT (p=0.03). Inwomen without flushing,HRT had greater decline inphysical function (-4.2 vs. -3.3, p=0.04) and worseningof energy/fatigue (-4.6 vs. -3.1, p=0.03) compared toplacebo. No significantdifference in women withflushing.Energy/fatiguescores declinedoverall (P

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionStudy/Year NStrickler, 2000 398(373 inanalysis)Type ofTrialComparisonLengthof Trial Population Inclusion/Exclusion CriteriaRCT P and HH 1 year Asymptomatic postmenopausalwomen aged 47-60; 2-8 yearsafter last menses; 32 study sites;recruitment info NR;Inclusion:1. Age 47-602. 2-8 years with no menses3. E2 < 204. BMD within 2.5 SD of premenopausal normalwomen.Exclusion:1. Intolerable menstrual symptoms requiringtreatment2. Uterine bleeding of unknown cause3. BMI < 18 or >314. History of DVT5. Use of corticosteroids, estrogen or progestin

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionSpecific Characteristics of PopulationStudy/YearStrickler, 2000Measures UsedHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)Women's Health Questionnaire NR NR NR NR NR NR 0 0High orLow BMI(#/n)F-282

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionTreatmentMain OutcomesStudy/YearMain Drug type; dose;regimenOther Drugs type;dose; regimenHot FlashesVaginalDrynessSleepStrickler, 2000CEE 0.625Raloxifene 60mg or150mg qd or placeboHRT improved vasomotorsymptoms compared toRaloxifene (p

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionMain Outcomes (continued)Study/YearStrickler, 2000Mood Cognitive Somatic Urinary Uterine BleedingNo difference in memory/NRconcentrationNo significant difference in depressed mood.Anxiety improved in Raloxifene 60mg (0.165)compared with placebo (0.028, p=0.03) andestrogen (-0.017, p=0.003). No difference withRaloxifene 150mg (0.076).No differencein somaticsymptomsMenstrual symptoms:estrogen (-0.169)worse than placebo(0.01, p=0.003).Comparisons withRaloxifene 60mg(-0.73) and 150mg(-0.063) not statisticallysignificant.F-284

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionStudy/YearStrickler, 2000SexualDysfunctionQuality of Life Other Outcomes WithdrawalsNodifference insexualbehaviorWithdrawalsdue to AEsAdverseEffectsCommentsNR NR 25/398 NR NR Asymptomaticpostmenopausalpopulation. Possibleerror due to multiplecomparisons.F-285

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionStudy/YearNType ofTrialComparisonLengthof Trial Population Inclusion/Exclusion CriteriaThomson, 1977 42 RCT P 8 weeks 45-55 yo women referred by localgeneral practitioners.Inclusion:1. 45-55 years old2. Amenorrhea > 3 months3. Symptoms of insomnia, depression, anxiety,and hot flashesExclusion:1. Other medications, contraindications toestrogen therapyF-286

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionSpecific Characteristics of PopulationStudy/YearThomson, 1977Measures UsedDaily visual analogue scales formood and anxiety and number ofhot flashes. Hamilton anxietyand depression scales.Hysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)NR NR NR NR 0 NR NR NRF-287

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionTreatmentMain OutcomesStudy/YearThomson, 1977Main Drug type; dose;regimenPiperazin oestrone sulphate1.5mg BIDOther Drugs type;dose; regimenHot FlashesVaginalDrynessSleepPlacebo No significant difference NR Improved sleep(interveningwakefulness,frequency ofawakenings, andstage of sleep)compared to placebo(p

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionMain Outcomes (continued)Study/YearThomson, 1977Mood Cognitive Somatic Urinary Uterine BleedingNo difference between groups; both groupsNR NR NR NRimproved (p

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionStudy/YearThomson, 1977SexualDysfunctionQuality of Life Other Outcomes WithdrawalsNR NR No difference inanxiety betweengroups; both groupsimproved(p

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionStudy/YearNType ofTrialComparisonLengthof Trial Population Inclusion/Exclusion CriteriaVestergaard,20021,006 RCT(Openlabel)No HRT5 years 45-58 year old women; recruitedby mailing to random sample.Inclusion:1. Women aged 45-58a) 3-24 months past last period orb) experiencing perimenopausal symptoms(irregular menses) with elevated FSH or2. Women aged 45-52 Salpingo hysterectomywith elevated FSH.Exclusion:1. Metabolic bone disease / osteoporosis2. HRT within 3 months3. Current or past treatment with glucocorticoids> 6 months4. Malignancy5. Newly diagnosed or uncontrolled chronicdisease6. Alcohol or drug addiction.F-291

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionSpecific Characteristics of PopulationStudy/YearVestergaard,2002Measures UsedModified Greene scale (visualanalogue scale from 0-4 forseverity of symptoms.)Hysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)192/1006 NR NR 0 NR NR 0 NRF-292

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionTreatmentMain OutcomesStudy/YearMain Drug type; dose;regimenOther Drugs type;dose; regimenHot FlashesVaginalDrynessSleepVestergaard,2002First line: E2 2mg days 1-12; E2 mg andnorethisterone 1mg days 13-22; E2 1mg days 23-28 forwomen with uterus. E22mg po qd for womenwithout uterus. Womenallowed to use otherregimens if they requestedchange.NoneHRT reduced severity ofHF compared to placebo(p

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionMain Outcomes (continued)Study/YearVestergaard,2002Mood Cognitive Somatic Urinary Uterine BleedingNo significant difference in mood swings. NR No significant No significantNRdifference in difference inheadaches. voidingfrequency orincontinence.F-294

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionStudy/YearVestergaard,2002SexualDysfunctionQuality of Life Other Outcomes WithdrawalsTrendtoward lessreduction inlibido withHRT(p=0.08)NRBlood pressuredecreased overall;no difference withHRT.54/502 on HRT;55/504 not onHRTWithdrawalsdue to AEsNR; 40%changedHRT regimenor terminatedHRT due toAEsAdverseEffects39 headaches;14 edema/fluidretention; 21mood swings/depressionCommentsOpen label study;high rate ofcontamination;outcome measuressingle items, less wellvalidated.Part ofDanish OsteoporosisPrevention Study.F-295

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionStudy/YearNType ofTrialComparisonLengthof Trial Population Inclusion/Exclusion CriteriaVoss, 2002 1,008 RCT HH 6 month Healthy postmenopausal womenin 129 gynecological practices inEurope, South Africa and Israel.Wheatley, 1977 58 RCT P 4 weeks Depressed women NRInclusion:1. Healthy ambulatory women age >652. Natural menopause > 2 years earlier3. Elevated FSH in women age < 57Exclusion:1. Hysterectomy, ovariectomy, breast cancer,estrogen-dependant cancer2. Any other cancer within 5 years3. DVT, liver disease, thyroid disease4. Did not qualify for therapy according toprescribing information for E2 or NETA5. Endometrial pathology6. Severe postmenopausal symptoms requiringHRT7. Treatment with estrogens within 6 months8. Treatment with hypolipidemic drugs within 3monthsNote: intravaginal estrogens and oral estriol up toF-296

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionSpecific Characteristics of PopulationStudy/YearVoss, 2002Measures UsedHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)Women's Health Questionnaire 0 0 NR 0 0 NR 0 NRWheatley, 1977Global rating; HamiltonDepression Scale; HopkinsSymptom ChecklistNR NR NR NR NR NR NR NRF-297

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionTreatmentMain OutcomesStudy/YearMain Drug type; dose;regimenOther Drugs type;dose; regimenHot FlashesVaginalDrynessSleepVoss, 2002Oestradiol 2mg andnorethisterone acetate 1mgRaloxifene 60mg qd HRT: -0.21R: -0.03p

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionMain Outcomes (continued)Study/YearVoss, 2002Mood Cognitive Somatic Urinary Uterine BleedingDepressed mood: HRT +0.03, R:-0.02, p=0.004 Memory/concentration: HRT: -0.02; NR Menstrual symptoms:favoring Raloxifene.HRT: -0.04;R: -0.01;HRT +0.10;Anxiety/fears: HRT 0.00; R: -0.01; p=0.6. R: +0.02; p=0.02 p=0.3.R: +0.02;favoring HRTp

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionStudy/YearSexualDysfunctionQuality of Life Other Outcomes WithdrawalsWithdrawalsdue to AEsAdverseEffectsCommentsVoss, 2002HRT: -0.11R:-0.02;p=0.007favoringHRTNRGreater treatmentsatisfaction(p=0.004) andcompliance(p

Appendix F: Evidence table 6-2. Key Question 3A Estrogens for depressionStudy/YearSexualDysfunctionQuality of Life Other Outcomes WithdrawalsWithdrawalsdue to AEsAdverseEffectsCommentsVoss, 2002HRT: -0.11R:-0.02;p=0.007favoringHRTNRGreater treatmentsatisfaction(p=0.004) andcompliance(p

Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depressionAbbreviationsAE = Adverse EffectCEE = Conjugated Equine EstrogensE2 = EstrodialHH = Head to headHRT = Hormone Replacement TherapyNETA=norethidrone acetateNR = Not reportedP = PlaceboRCT = Randomized Controlled TrialHF = Hot flashGI = GastrointestinalSD = Standard deviationMI = Myocardial infarctionCAD = Coronary artery diseaseDVT = Deep vein thrombosisR = RaloxifeneHERS = Heart and Estrogen/Progestin Replacement StudyRAND = RAND Mental Health InventoryBMI = Body mass indexSERMs = Selective Estrogen Receptor ModifiersBMD = Bone mineral densityF-299

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneComparisonHHStudy/Year NBarrett- 311 inConnor, 1999 4groupsBraunstein,2003(abstractonly)StudydesignDBRCT447 DBRCTLengthof Trial Population Inclusion/Exclusion Criteria2 years Surgically menopausalWhite women. Meanage approx 45 (21-65)P 24weeksSurgically menopausalwomen with hypoactivesexual desireInclusion:1. White women2. 21-65 years old3. Surgically menopausal: Undergone bilateral oophorectomy andhysterectomy > 3 months before but < 5 years prior to screening4. Within 75-125% of ideal body weight5. In stable relationship for > 6 monthsExclusion:1. Receiving estrogens or HRT in previous 6 weeks2. Receiving psychotropic drugs in the previous 4 weeks3. History of pelvic or breast malignancy4. Dependence on alcohol, tobacco, or illicit drugsInclusion:1. Surgically menopausal women2. Had Hypoactive Sexual Desire DisorderDavis, 2003(abstractonly)77 DBRCTP 24weeksSurgically menopausalwomen with hypoactivesexual desireInclusion:1. Surgically menopausal women2. Had Hypoactive Sexual Desire DisorderF-300

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneStudy/YearMeasures UsedBarrett- ModifiedConnor, 1999 Kupperman ScaleHysterectomy(#/n)BilateralOophorectomy(#/n)Specific Characteristics of PopulationPrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)Behavioror LifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)311 311 NR 0 NR NR No HRT inprior 6weeksHigh orLow BMI(#/n)Main Drug type;dose;regimenApproximately25 oral (CEE-L); CEECEE 0.625 mg/day1.25 mg/day oral(CEE);Braunstein,2003(abstractonly)SALPFSF447/447 NR NR NR NR NR 0 NR Testosterone 150,130, or 450 mcg/dayTransdermal patchtwice per weekDavis, 2003(abstractonly)SALPFSFPGWBPDS77/77 77/77 NR NR NR NR 0 NR Testosterone 300mcg/dayTransdermal twiceper weekF-301

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneMain OutcomesStudy/YearOther Drugs type;dose; regimenBarrett- E2 0.625 mg + MTConnor, 1999 1.25 mg/day oral(E+ A-L); E2 1.25mg + MT 2.5 mg/dayoral (E + A)Hot FlashesImproved in alltreatment groups(p value notreported)VaginalDryness Sleep Mood Cognitive SomaticImproved in alltreatment groups(p value notreported)NR NR NR No significantdifference betweentreatment groups.Braunstein,2003(abstractonly)Oral estrogen NR NR NR NR NR NRDavis, 2003(abstractonly)TransdermalestrogenNR NR NR NR NR Statistically significantpositive effect on thecomposite score ofPGWB in T group,p

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneMain Outcomes continuedStudy/YearBarrett-Connor, 1999UrinaryUterineBleeding Sexual Dysfunction Quality of Life Other OutcomesNR NR Non-significant trend toward greaterimprovement in well-being and sexualinterest in the E + A groups (data onKupperman scale.)NRSignificantly increased BMD in the E+Agroup at lumbar spine and hip incomparison to the CEE group at 24months. No statistically significantdifferences in hirsutism scores betweentreatment groups (Ferriman-Gallweyscale)Braunstein,2003(abstractonly)NR NR In the 300 mcg/d group, a 30% increase insatisfying sexual activity observed in T vs. P(p

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneStudy/YearWithdrawalsBarrett- 112 (non drugConnor, 1999 related-24, protocolviolation-21, loss tofollow-up-22)Withdrawalsdue to AEs Adverse Effects Comments45 Nausea (6% E+A-L; 3% E+A; 11% CEE-Land 22% CEE) Acne/hirsutism/chloasma (3in E+A-L; 4 in E+A;1 CEE)Participants in study not selected based onpresence/severity of menopausal symptoms.Braunstein,2003(abstractonly)NR NR NRDavis, 2003(abstractonly)NR NR NRF-304

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneStudy/Year NStudydesignDobs, 2002 40 DBRCTComparisonLengthof Trial Population Inclusion/Exclusion CriteriaHH 16weeksMenopausal womenMean age 56.9 (41.4-76.3)Inclusion:1. Surgically or naturally menopausal women2. Required to have been on HRT for > 3 months before screening toremove confounding hypoestrogenic symptomsExclusion:1. Uncontrolled hypertension or hyperlipidemia2. Medication known to affect lipids3. Poorly controlled diabetes mellitus4. Unstable angina or congestive heart failure5. Myocardial infarction < 3 months of study6. Preexisting liver disease7. Renal impairment8. Hepatic adenoma9. History of breast or uterine cancer10. Gall bladder disease11. History of thromboembolic eventsF-305

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneStudy/YearDobs, 2002Measures UsedBISF -WSRSSIQQUALMSHysterectomy(#/n)BilateralOophorectomy(#/n)Specific Characteristics of PopulationPrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)Behavioror LifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)Main Drug type;dose;regimenNR 21/40 NR NR NR NR 0 NR E2 1.25 mg/day +MT 2.5 mg/day oralorF-306

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneMain OutcomesStudy/YearOther Drugs type;dose; regimenHot FlashesVaginalDryness Sleep Mood Cognitive SomaticDobs, 2002E2 1.25 mg/day oralImproved inE2/MT at week 4(p=0.024) andweek 10(p=0.003)QUALMS ScaleNRImproved inE2/MT at week 4(p=0.024) andweek 10(p=0.003)QUALMS ScaleNo significantchangeNo significantchangeImproved in E2/MTgroup at week 4(p=0.004) and week10 (p=0.021)QUALMS ScaleF-307

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneMain Outcomes continuedStudy/YearDobs, 2002UrinaryUterineBleeding Sexual Dysfunction Quality of Life Other OutcomesNR NR Frequency/psycho-sexual (p=0.05) andpleasure/orgasm (p=0.041) scores of BISF-W increased.Total SRS score improved in E2/MT (p valuenot reported).Improved SIQ score in E2/MT at week 10(p=0.031) and week 16 (p=0.014).See QUALMSdataSex hormone levelsF-308

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneStudy/YearDobs, 2002Withdrawals3 3(E2/MT - 2E2 - 1)Withdrawalsdue to AEs Adverse Effects CommentsBloating/weight gain (E2/MT)Migraine (E2/MT)Hirsutism (E2/MT)Insomnia, breast swelling, headache (E2)Sexual function and quality of life secondaryoutcome.Healthier baseline sexual function reported in E2group compared to E2/MT (specific data notreported)F-309

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneStudy/Year NFloter, 2002 50 in 2groupsStudydesignRCTCrossoverComparisonLengthof Trial Population Inclusion/Exclusion CriteriaHH 24weeksSurgically menopausalwomenMean age 54 (45-60)Inclusion:1. 45-60 years old2. History of hysterectomy and bilateral salpingo ophorectomy for benigndisorders3. Body mass index between 18 and 29 kg/m24. Blood pressure > 170 mmHg systolic and/or 105 mmHg diastolic5. Normal mammogram within past yearExclusion:1. Previous use of HRT within past 2 months2. Other medication within past 2 months (other sex hormones, anabolicsteroids, corticosteroids, danazol, calcium antagonists, beta-blockingagents, barbiturates, carbamazepines, griseofulvins, hydantion, rifampicin,herbal/homeopathic therapy)3. History of or present premalignancies/malignancies4. Liver disease5. Cardiovascular, cerebrovascular, or thromboembolic disorders6. Present psychiatric disease7. Regular use of tranquillizers and/or antihistamines, alcohol abuse, orsmoking of > 10 cigarettes/day was allowedF-310

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneStudy/YearFloter, 2002Measures UsedMcCoy's SexScalePGWB-IHysterectomy(#/n)BilateralOophorectomy(#/n)Specific Characteristics of PopulationPrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)Behavioror LifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)50/50 50/50 NR 0/50 NR NR NR Mean25.7Main Drug type;dose;regimenEstradiol valerate 2mg/dayF-311

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneMain OutcomesStudy/YearFloter, 2002Other Drugs type;dose; regimenEstradiol valerate 2mg/day +testosteroneundecanoate 40mg/dayHot FlashesVaginalDryness Sleep Mood Cognitive SomaticNR NR NR Both treatment NRNRgroups withsignificantimprovement, p

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneMain Outcomes continuedStudy/YearFloter, 2002UrinaryUterineBleeding Sexual Dysfunction Quality of Life Other OutcomesNR NR Both treatment groups with significantimprovement (p< 0.01) on McCoy SexScale.Both treatmentgroups withsignificantimprovementon PGWBIndex, p< 0.05Sex hormone levelsF-313

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneStudy/YearFloter, 2002WithdrawalsWithdrawalsdue to AEs Adverse Effects Comments6 1 MigraineAcneHirsutismBody swellingF-314

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneStudy/Year NHickok, 1993 26 in 2groupsStudydesignDBRCTComparisonLengthof Trial Population Inclusion/Exclusion CriteriaHH 6monthsPostmenopausal Whitewomen 40-60 yearsMean age:E2=50E2 + MT= 52Inclusion:1. Women from Department of Obstetrics and Gynecology at OregonHealth and Science University2. Caucasian3. 40-60 years oldExclusion:1. Menstrual bleeding in the last 12 months2. History of steroid ingestion in 4 weeks prior to study3. Receiving adrenergic agonists or antagonists, peripheral vasodilators,cholesterol-lowering agents, beta-blockers, beta-mimetics, or thyroidhormones4. Smoking within the past 12 months5. History of genital tract disease6. Current or previous estrogen-dependent malignancy7. History of jaundice or elevated liver enzymes, gallbladder disease, orcardiovascular disease8. Current hypertriglyceridemia or severe hypertensionF-315

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneStudy/YearHickok, 1993Measures Used4 pointmenopausalsymptom scale (0-3)Hysterectomy(#/n)BilateralOophorectomy(#/n)Specific Characteristics of PopulationPrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)Behavioror LifestyleFactors(#/n)NR NR NR NR NR NonsmokersRecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)Main Drug type;dose;regimenNR NR E2 0.625 mg + MT1.25 mg/day oralF-316

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneMain OutcomesStudy/YearHickok, 1993Other Drugs type;dose; regimenE2 0.625 mg/dayoralHot FlashesDecrease insymptomseverity in bothgroups, p

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneMain Outcomes continuedStudy/YearHickok, 1993UrinaryUterineBleeding Sexual Dysfunction Quality of Life Other OutcomesNR NR NR NR Decreased symptom severity in othersymptoms measured.No significant differences between the 2groups.F-318

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneStudy/YearHickok, 1993WithdrawalsWithdrawalsdue to AEs Adverse Effects Comments0 0 Acne (E2 + MT - 5)Facial hair (E2 + MT - 2; E2 - 1)Menopausal symptoms measured on 4 pointscale (0=absent to 3=severe): hot flushes, coldsweats, vaginal dryness, cold hands and feet,breast pain or tenderness, numbness andtingling, skin crawls, edema, increased facial orbody hair, voice deepening, acne, troublesleeping, heart pounding, dizzy spells, pressureor tightness in head or body.F-319

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneStudy/YearLobo, 2003N218 in2groupsStudydesignDBRCTComparisonLengthof Trial Population Inclusion/Exclusion CriteriaHH 4monthsPostmenopausalwomen with hypoactivesexual desire. Meanage approx 53 (40-65)Inclusion:1. Healthy postmenopausal women (natural or surgical > 6 months)2. 40-65 years old3. Receiving estrogen (0.625 mg of conjugated equine estrogens for > 3months or equivalent of 0.9 mg if dose decreased for last cycle beforestudy)4. Experienced hypoactive sexual desire associated with onset ofmenopause (not overt mood disorders) scoring higher than 3.0 onThoughts/Desire Dimension of the BISF-W5. History of adequate sexual interest before onset of menopauseExclusion:1. Dyspareunia2. Unresolved or recent sexual abuse3. Depressive or anxiety symptoms4. Physical limitations that interfered with normal sexual functioning5. Abnormal mammogram6. Relevant clinical laboratory test abnormalities7. Recent previous high-dose HRT or other sex hormones8. Lipid-lowering agents9. Antidepressants (including SSRI's)10. Anxiolytics11. Thyroid replacement medication (unless a stable dose)12. Antihypertensive drugsF-320

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneStudy/YearMeasures UsedHysterectomy(#/n)BilateralOophorectomy(#/n)Specific Characteristics of PopulationPrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)Behavioror LifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)Main Drug type;dose;regimenLobo, 2003SIQBISF-WNRApproximately68/218(30.8 %EE/MT and31.5% EE)NR NR NR NR None E2 26.7 + E2 0.625 mg/day5.4 andE2/MToral and E2 0.625mg/day + MT 1.2525.5 + 4.6 mg/day oralF-321

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneMain OutcomesStudy/YearLobo, 2003Other Drugs type;dose; regimenHot FlashesVaginalDryness Sleep Mood Cognitive SomaticNR NR NR NR NR NR NRF-322

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneMain Outcomes continuedStudy/YearLobo, 2003UrinaryUterineBleeding Sexual Dysfunction Quality of Life Other OutcomesNR NR SIQ scores for mean sexual interest/desireand responsiveness significantly increased,p=.047 and p=.002, respectively.NRMean bioavailable T levels increased inE2/MT group, p< .010, decreased inHDL in EE/MT, p

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneStudy/YearLobo, 2003WithdrawalsE2 16/111 E2/MT20/107Withdrawalsdue to AEs Adverse Effects CommentsE2: 5E2/MT: 9Headache (E2/MT 9.3% vs. E2 7.2%)Infection (E2/MT 9.3% vs. E2 6.3%)Acne (E2/MT 5.6% vs. E2 2.7%)Hot flushes (E2/MT and E2 7%)Breast pain (E2/MT 3.7% vs. E2 7%)Acne (E2/MT 5.6% vs. E2 3%)Rhinitis (E2/MT 4% vs. E2 6%)F-324

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneStudy/Year NPenotti, 2001 40 in 2groupsRaisz, 1996 18 in 2groupsStudydesignOpenRCTOpenRCTComparisonLengthof Trial Population Inclusion/Exclusion CriteriaHH 8monthsHHPostmenopausalwomen. Mean age:HRT + T 57.4HRT 55.39 weeks Postmenopausalwomen. Mean age:CEE 65.7E2/MT 59.8Inclusion:1. Attending the Menopause Clinic of the Second Department ofObstetrics and Gynecology, University of Milan2. Receiving HRT > 1 year3. Receiving Transdermal E2 (50 ug/d) for between 1-5 years and cyclicmedroxyprogesterone acetate (10 mg/d) for 12 days every 2 monthsExclusion:1. Suffering from any major disease including hypertension, heart disease,diabetes, renal or peripheral vascular diseases2. Undergone surgical removal of the uterus or ovariesInclusion:1. Postmenopausal women (last spontaneous menstrual cycle occurred >5 years)2. Within 25% of ideal body weight3. Non-smoker4. Negative mammogram and Pap smear within 1 year and normalelectrocardiogramsExclusion:1. Receiving estrogens within last 6 months2. Prior history of estrogen-dependent cancer, hypercortisolism,hyperthyroidism, or metabolic bone disease3. Any prior treatment with drugs that might affect bone metabolism, otherthan calcium supplements and estrogens, or with drugs known to alterhepatic enzymes (including excess vitamin A and D, steroid hormones,cholesterol-lowering agents, heparin, anticonvulsants, high dosenonsteroidal anti-inflammatory drugs, and high dose thyroid hormonereplacementF-325

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneStudy/YearPenotti, 2001Measures UsedHysterectomy(#/n)BilateralOophorectomy(#/n)Specific Characteristics of PopulationPrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)Behavioror LifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)Main Drug type;dose;regimenVAS 0 0 NR NR NR NR None HRT + T HRT + Testosterone=24.1 and undecanoate 40HRT mg/day oral=24.9Raisz, 1996ModifiedKupperman with 0-3 scale0 CEE 3/15 NR 0 NR NonsmokersonlyNoestrogenfor 6monthspriorCEE CEE 1.25 mg/day=25.1 and oral orE2/MT=26.5 E2 1.25 mg + MT2.5 mg/day oralF-326

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneMain OutcomesStudy/YearPenotti, 2001Other Drugs type;dose; regimenHRT: E2 50mcg/dayTransdermal + MPA10 mg/day for12day/monthVaginalHot Flashes Dryness Sleep Mood Cognitive SomaticNR NR NR NR NR NRRaisz, 1996Oyster shell calciumtablet (Oscal) 500mg 1 or 2tablets/day oralDecreased inboth groups,p

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneMain Outcomes continuedStudy/YearPenotti, 2001UrinaryUterineBleeding Sexual Dysfunction Quality of Life Other OutcomesNR NR No difference observed between the 2groups of VAS scores at any of the timepoints (baseline, 4 months, 8 months)NRNRRaisz, 1996NR CEE 5E2/MT 4NR NR Markers of bone formation andresorption, lipids, and SHBGF-328

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneStudy/YearPenotti, 2001WithdrawalsHRT 2/20 and HRT+ T 5/20Withdrawalsdue to AEs Adverse Effects CommentsHRT + T: 3HyperandrogenismNausea, nervousness, and Aggressivenessin 2 patientsVAS (visual analogue scale ) used to evaluatechanges in psychological well-being and sexualdesire and satisfactionRaisz, 1996NR NR Headache (6 CEE; 2 E2/MT)Breast pain (6 CEE; 3 E2/MT)Acne (1 CEE; E2/MT)Bleeding (CEE 5; E2/MT 4)Results reported by 3 groupings:Somatic symptoms: hot flashes, sweatingepisodes, vaginal drynessPsychosomatic symptoms: fatigability, insomnia,palpitationsPsychological symptoms: irritability,nervousness, depression, anxiety, decreasedconcentration.F-329

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneStudy/Year NStudydesignShifren, 2000 75 DBRCTComparisonLengthof Trial Population Inclusion/Exclusion CriteriaP 36weeksSurgically menopausalwomen with impairedsexual function. Meanage 47 (31-56)Inclusion:1. Women 31-56 years old at nine clinics in the United States2. Undergone bilaterial salpingo-oophorectomy and hysterectomy beforenatural menopause between 1-10 years earlier3. Had serum testosterone concentrations < 30 ng/deciliter or serum freetestosterone concentrations < 3.5 pg/milliliter4. Received CEE of > 0.625/day orally for > 2 months5. Been in stable, monogamous, heterosexual relationship for > 1 year6. Had BMI between 19.5 - 33.57. Impaired sexual function determined by questionnaire (score < 33.6 onBrief Index of Sexual Functioning for Women)Exclusion:1. Received oral, topical, or vaginal androgen therapy in previous 3months, or injectaable or implantable androgen therapy in previous 6months2. Had > 20 moderate or severe hot flashes per week3. Had severe acne (grade 3 on Palatsi et al scale)4. Mild or severe hirsutism (score of > 6 on Loprinzi scale)5. Hyperlipidemia6. Psychiatric illness7. Dyspareunia8. Physical limitations that interferred with normal sexual functioning9. Receiving glucocorticoids, selective serotonin-reuptakeinhibitors, tricyclic antidepressants, antiandrogen agents,ginseng, yohimbine, phytoestrogens, dehydroepiandrosterone,or melatoninF-330

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneStudy/YearShifren, 2000Measures UsedBISF-WPGWBHysterectomy(#/n)BilateralOophorectomy(#/n)Specific Characteristics of PopulationPrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)Behavioror LifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)75/75 75/75 NR NR NR NR 0 25.8(19.5-33.5)Main Drug type;dose;regimenTestosterone 150 +300 mcg/dayTransdermalF-331

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneMain OutcomesStudy/YearShifren, 2000Other Drugs type;dose; regimenOral CEE 0.625mg/day - 41CEE 0.9 mg/day -12CEE 1.25 mg/day -20CEE 1.8 mg/day - 1CEE 2.5 mg/day - 1Hot FlashesNo change frombaselineVaginalDryness Sleep Mood Cognitive SomaticNR NR SignificantNRNRincrease indepressed -mood measureof PGWBI intestosterone 300mcg/d grouponly, p=0.03F-332

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneMain Outcomes continuedStudy/YearShifren, 2000UrinaryUterineBleeding Sexual Dysfunction Quality of Life Other OutcomesNR NR Composite score of BISF increased for alltreatment groups, p=0.05Meancompositescore ofPGWBIincreased forall treatmentgroups, p=0.04No significant effects on totalcholesterol, HDL, LDL, triglycerides,fasting glucose or insulin, blood counts,or LFT's.F-333

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneStudy/YearShifren, 2000WithdrawalsWithdrawalsdue to AEs Adverse Effects Comments18 4 Anxiety - 2Nipple discharge - 1Skin reaction - 1Participants on variable doses of estrogen.F-334

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneStudy/Year NSimon, 1999 93 in 5groupsWatts, 1995 66 in 2groupsStudydesignComparisonRCT P 3monthsDBRCTHHLengthof Trial Population Inclusion/Exclusion CriteriaNaturally menopausalwomen with mild tomoderate vasomotorsymptoms.Mean age 53.72 years Surgically menopausalwomenInclusion:1. Naturally menopausal women with both ovaries intact2. Recruited from Georgetown University (Washington, DC), TheWorcester Foundation for Experimental Biology (Worcester, MA), TheMiddleton Foundation (Olympia, WA)3. Experienced amenorrhea > 6 months duration (range 6 months - 14years) prior to study4. Had follicle-stimulating hormone levels > 55 mIU/mL, normal clinicallaboratory test results (biochemistry, hematology, thyroid function, and lipidprofile), normal Pap smear, EKG, and mammogram prior to entering study5. Experienced mild to moderate vasomotor symptoms6. Non-smoker7. Within + 25% of ideal body weight (based on Metropolitan LifeInsurance tables)8. In heterosexual relationships of > 1 year durationExclusion:1. Receiving estrogens, progestins, androgens, or anabolic steroids within8 weeks of study enrollment2. Active breast, uterine, or ovarian cancer or history thereof3. Recent history of vaginal bleedingInclusion:1. 21-60 years old2. Surgically menopausal: Undergone bilateral oophorectomy andhysterectomy at least 4 weeks before study entryExclusion:1. Had concomitant illnessF-335

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneStudy/YearSimon, 1999Measures UsedHysterectomy(#/n)BilateralOophorectomy(#/n)Specific Characteristics of PopulationPrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)Behavioror LifestyleFactors(#/n)Kupperman 0 0 NR 0 0 100% nonsmokersRecentdiscontinuationofHRT(#/n)NRHigh orLow BMI(#/n)Mean27.1Main Drug type;dose;regimenE2 0.625 + MT 1.25mg/dayE2 1.25 + MT 2.5mg/dayWatts, 1995ModifiedKupperman with 0-7 scale66/66 66/66 NR 0 NR NR NR E2-24.9E2/MT-25.8E2 1.25 mg/day oralF-336

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneMain OutcomesStudy/YearSimon, 1999Other Drugs type;dose; regimenE2 0.625 mg/dayE2 1.25 mg/dayHot FlashesAll activetreatment groupssharedsignificantimprovement (p< 0.05)VaginalDryness Sleep Mood Cognitive SomaticAll activetreatment groupssharedsignificantimprovement (p< 0.05)No treatmenteffectNo treatmenteffectNRAll active treatmentgroups sharedsignificantimprovement (p

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneMain Outcomes continuedStudy/YearSimon, 1999UrinaryUterineBleeding Sexual Dysfunction Quality of Life Other OutcomesNR NR NR Sex hormone levelsWatts, 1995NR NR NR NR Lipids and Spinal bone mineral densityF-338

Appendix F. Evidence table 6-3. Key Question 3C TestosteroneStudy/YearSimon, 1999Withdrawals3 1 - high doseestratestWithdrawalsdue to AEs Adverse Effects CommentsRashOnly somatic symptoms reportedWatts, 1995E2 3E2/MT 7E2 3E2+MT 5Headache (E2 16; E2/MT 9)Hot flashes (E2 7; E2/MT 3)Rdema (E2 10; E2/MT 10)Breast pain (E2 9; E2/MT 13)Hair disorder (E2 1; E2/MT 12)Acne (E2 2; E2/MT 10)Modified Kupperman scale used to assessmenopause symptoms.F-339

Appendix F: Evidence table 6-3. Key Question 3C TestosteroneA = AndrogenBISF-W = Brief Index of Sexual Function for WomenBMD = Bone mineral densityBMI = Body mass indexCEE= Conjugated equine estrogensDB = Double blindE = EstrogenE2 = EstradiolEE = Esterified EstrogenHH = Head to headHRT = Hormone replacement therapyMT = MethyltestosteroneNR = Not reportedP = PlaceboPDS = Personal Distress ScalePFSF = Profile of Female Sexual FunctionPGWB = Psychological General Well-BeingPGWB-I = Psychological General Well-Being IndexQUALMS = Quality of Life Menopause ScaleRCT = Randomized controlled trialSAL = Sexual Activity LogSERMs = Selective Estrogen Receptor ModifiersSIQ = Sexual Interest QuestionnaireSRS = Sabbatsberg Revised Sexual Rating ScaleSSRI = Selective Serotonin Reuptake InhibitorT = TestosteroneVAS = Visual Analogue ScaleKey/AbbreviationsF-340

Appendix F. Evidence table 6-4. Key Question 3C DHEAStudy/YearBarnhart,1999N60 in 2groupsStudydesignDBRCTComparisonPLengthof Trial Population Inclusion/Exclusion Criteria3 months Perimenopausalwomen with alteredmood and wellbeing.Mean age 48 (45-55)Inclusion:1. Perimenopausal women2. 45-55 years old3. Symptoms include fatigue, lack of energy, anxiety, tension, irritability,depression, insomnia, forgetfulness, concentration difficulties, decreasedlibido, or global reports of a decreased sense of well-beingExclusion:1. Any contraindication to HRT2. Exposure to injectable or implantable sex steroid within 6 months orsystemic steroid within 90 days of treatment3. Used antidepressants and/or antianxiolitics4. Current diagnosis of major psychiatric disorder, diabetes mellitus,hypercholesterolemia, or cardiovascular disease5. Abnormal renal or liver functionStomati, 1999 22 in 3groupsRCT HH 3 months Postmenopausalwomen (50-55years)Inclusion:1. Postmenopausal women2. 50-55 years old3. Climacteric complaints4. Normal body mass index5. Basal plasma DHEA levels < 5 ug/mlExclusion:1. Previous or current estrogen-dependent neoplasia, thromboembolicdisease, liver, pancreatic or renal disease, and diabetes mellitusF-341

Appendix F. Evidence table 6-4. Key Question 3C DHEAStudy/YearBarnhart,1999Measures UsedDSR (0-4 scale),Profile of MoodScale, Ham-D,SmithKlineBeecham Qualityof Life Self-ReportQuestionnaire,BuschkeImmediate Recalland DelayedRecall, SymbolCopying and DigitSymbolSubstitution TestsHysterectomy(#/n)BilateralOophorectomy(#/n)Specific Characteristics of PopulationBehaviorPrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)orLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)Main Drugtype; dose;regimenNR NR NR NR NR NR NR NR DHEA 50mg/day oralTreatmentOther Drugstype; dose;regimenPlaceboStomati, 1999Kupperman (0-3scale, where0=none and3=marked)NR NR NR NR NR NR NR NR DHEAs 50mg/day oralDHEAs 50mg/day +Estradiol 50mg/day transorEstradiol 50mg/dayF-342

Appendix F. Evidence table 6-4. Key Question 3C DHEAOutcomesStudy/YearBarnhart,1999Hot FlashesVaginalDryness Sleep Mood Cognitive Somatic UrinaryNo No No No No No Nosignificant significant significant significant significant significant significantdifference difference difference difference difference difference differencebetween between between between between between betweenstudy groups study study study study study studygroups groups groups groups groups groupsUterineBleedingNRSexualDysfunctionNosignificantdifferencebetweenstudygroupsQuality ofLifeNosignificantdifferencebetweenstudygroupsOtherOutcomesSexhormonesand lipidsStomati, 1999NR NR NR NR NR NR NR NR NR NR NRF-343

Appendix F. Evidence table 6-4. Key Question 3C DHEAStudy/YearBarnhart,1999WithdrawalsWithdrawalsdue to AEs Adverse Effects Comments6 3 Rash (placebo)Abdominalpain/fatigue (placebo)Paresthesia (DHEA)Subjects from both studygroups had decreased totalperimenopausal symptomsand improvements incomponents of health-relatedquality of life, p

Appendix F: Evidence table 6-4. Key Question 3C DHEABMI = Body mass indexDB = Double blindDHEA = DehydroepiandrosteroneDSR = Daily Symptom Rating CalendarHAM-D = Hamilton Depression Rating ScaleHH = Head to headHRT = Hormone replacement therapyNR = Not reportedP = PlaceboRCT = Randomized controlled trialSERMs = Selective Estrogen Receptor ModifiersKey/AbbreviationsF-345

Appendix F. Evidence table 6-5. Key Question 3D TiboloneStudy/YearNBaracat, 2002 85 in 2groupsBenedek-Jaszmann, 198760 in 2groupsStudydesignopenRCTDBRCTComparisonof Trial Population Inclusion/ExclusionLengthCriteriaHH 12monthsP 12monthsPostmenopausalwomen with intactuterus.EE/MPA mean age:53 (45-65)Tibolone mean age: 51Post-menopausalwomen attending amenopause clinic.Age 44-61Inclusion:1. Ages 45-65 years2. Intact uterus3. Natural menopause > 6 months prior4. > 4 hot flushes/dayExclusion:1. History or presence of clinically significant physical disease,undiagnosed vaginal bleeding, hypertension, obesity, excessivesmoking, alcohol or drug abuse2. >Pap smear class III3. Use of estrogens, progestins, androgens, Tibolone, or lipidloweringagents within 90 days of evaluation4. Known sensitivity to an investigational or a related drugInclusion:1. MenopausalExclusion:1. Current or past h/o cancer or thromboembolic diseaseBerning, 2000 94 in 3groupsRCT P 2 years Post-menopausal (1-3years), non-smoking,White, with a BMI < 27.Mean age 52.7Inclusion:1. White2. Non-smoking3. BMI

Appendix F. Evidence table 6-5. Key Question 3D TiboloneStudy/YearBaracat, 2002Measures Used4 point scale,hot flashescalculatedseparatelyHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)Specific Characteristics of PopulationBreastCancer(#/n)Use ofSERMS(#/n)Behavior orLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High or LowBMI(#/n)0 1/85 NR 0 NR NR Excluded CEE/MPA25.3Tibolone 25.0Benedek-Jaszmann, 19874 point scale NR NR NR 0/60 NR NR NR NRBerning, 2000NR 0/94 0/94 NR NR NR NR NR Median 24.3F-347

Appendix F. Evidence table 6-5. Key Question 3D TiboloneMain OutcomesStudy/YearBaracat, 2002Main Drug type; dose;regimenTibolone 2.5 mg/day oralOther Drugs type; dose;regimen Hot Flashes Vaginal Dryness SleepCEE/MPA 0.625/5 mg/dayoralDecreased intensityand mean number hotflashes in both groups.No significantdifference betweengroupsSignificantimprovement inboth treatmentgroups, p value notreported.Improvementin both groups.No significantdifferencebetweentreatmentgroups.Benedek-Jaszmann, 1987Tibolone 2.5 mg/day Placebo Improved in Tibolonegroup throughoutstudy, p

Appendix F. Evidence table 6-5. Key Question 3D TiboloneMain OutcomesStudy/YearBaracat, 2002Mood Cognitive Somatic Urinary Uterine Bleeding Sexual Dysfunction Quality of LifeImprovement in Improvemen Improvemen NR No significant difference between Improvement in both NRboth groups.No significantdifferencebetweentreatmentgroups.t in bothgroups. Nosignificantdifferencebetweentreatmentgroups.t in bothgroups. Nosignificantdifferencebetweentreatmentgroups.treatment groups.groups. No significantdifference betweentreatment groups.Benedek-Jaszmann, 1987Improved inTibolone groupat month 6 only,p

Appendix F. Evidence table 6-5. Key Question 3D TiboloneStudy/YearOther OutcomesWithdrawalsWithdrawalsdue to AEs Adverse Effects CommentsBaracat, 2002Cholesterol levelsWeight gainCEE/MPA: 5Tibolone: 4CEE/MPA: 4Tibolone: 3HeadacheT-2.5%, CEE 6.7%NauseaBreast pain T 2.5%, CEE 11%Vaginal bleeding CEE onlyPelvic pain T5%, CEE4.4%,Fatigue/HTN/leg cramps/lowback pain -T2.5% CEE2.2%,Dysuria-7.5%,4 point scale: 0 (absent) to 3 (severe). Hotflushes per cycled calculated as: sum of meannumber of hot flushes per day multiplied byrespective score 0 (absent) to 3 (severe).Benedek-Jaszmann, 1987Berning, 2000Cholesterol, Irritabilityimproved in Tibolonegroup at months 1, 6,12, p

Appendix F. Evidence table 6-5. Key Question 3D TiboloneStudy/YearDansuk, 2002(Abstract only)N140 in2groupsStudydesignComparisonof Trial Population Inclusion/ExclusionLengthCriteriaRCT HH 3monthsHysterctomizedpostmenopausalwomenInclusion:1. Women who were hysterectomized > 1 year priorExclusion:1. Previous estrogen use2. Use of lipid lowering drugsDe Aloysio,1987124 in3groupsOpenRCTP 4monthsPost-menopausalwomen attending amenopause clinic.Inclusion:1. Post-menopausalExclusion:1. No endometriosis, fibrocystic mastitis, estrogen-related tumors,anemia, thromboembolic or liver disease, HT preceding 6months, medications, early menopauseEgarter, 1996129 in2groupsUnblindedRCTHH 6monthsPostmenopausalwomen on no HRT forat least 6 months.Mean ageapproximately 53.5Inclusion:1. Spontaneous menopause > 12 months prior2. No use of HRT in last 6 monthsExclusion:1. Use of short-acting hormones within 3 months2. Hysterectomy3. Injection of long-acting estrogens within 6 months4. Existing or suspected hormone-dependent tumors, vaginalbleeding of unknown etiology, severe liver disorders, current orprevious cardiovascular or cerebrovascular disordersF-351

Appendix F. Evidence table 6-5. Key Question 3D TiboloneStudy/YearDansuk, 2002(Abstract only)Measures UsedHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)Specific Characteristics of PopulationBreastCancer(#/n)Use ofSERMS(#/n)Behavior orLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High or LowBMI(#/n)Kupperman 140/140 NR NR NR NR NR 0 NRDe Aloysio,1987NR 24/124 24/124 NR 0/124 NR NR No HRT inprior 6monthsTiboloneapprox 23Placeboapprox 25Controlapprox 25Egarter, 1996KuppermanIndex0/129 NR NR 0 NR NR No HRT inpast 6monthsNRF-352

Appendix F. Evidence table 6-5. Key Question 3D TiboloneMain OutcomesStudy/YearDansuk, 2002(Abstract only)Main Drug type; dose;regimenTibolone 2.5 mg/day oralOther Drugs type; dose;regimen Hot Flashes Vaginal Dryness SleepE2 0.05 mg/dayTransdermalNR NR NRDe Aloysio,1987Tibolone 2.5 mg/day n=35 Placebo IM injection n=46Control n=43Improved in Tibolonegroup, p

Appendix F. Evidence table 6-5. Key Question 3D TiboloneMain OutcomesStudy/YearDansuk, 2002(Abstract only)Mood Cognitive Somatic Urinary Uterine Bleeding Sexual Dysfunction Quality of LifeNR NR NR NR NR NR NRDe Aloysio,1987NR NR NR NR NR NR NREgarter, 1996Improvement inboth groups.Highersignificancelevel inTibolone group,p

Appendix F. Evidence table 6-5. Key Question 3D TiboloneStudy/YearDansuk, 2002(Abstract only)Other OutcomesWithdrawalsWithdrawalsdue to AEs Adverse Effects CommentsCholesterol levels 0 0 NR No difference in climacteric symptoms reportedbetween the 2 treatment groups. Specificcategories not reported.De Aloysio,1987Cholesterol, BMI, BP,electrolytes, coagulation,gonadal hormonesTibolone: 21Placebo: 10Control: 13Tibolone: 5Placebo: 2Uterine bleeding (T-3), Weightgain (P-1), Anxiety (P-1), GIdistress (T-2)Egarter, 1996Endometrial thickness Tibolone: 15CEE/medroge-stone: 18Tibolone: 3 Weight gain T-2, HRT-4CEE/medrogestone:6 Headache T-2, HRT-2Bleeding HRT-4Leg pain T-4Treatment groups were significantly different atbaseline with regard to nervousness.F-355

Appendix F. Evidence table 6-5. Key Question 3D TiboloneStudy/YearHammar, 1998N437 in2groupsStudydesignDBRCTComparisonof Trial Population Inclusion/ExclusionLengthCriteriaHH 48weeksSymptomaticmenopausal womenInclusion:1. Physically and mentally healthy women2. > 1 year since last menstrual bleeding3. Menopausal complaints4. Intact uterus5. BMI < 30kg/m2Exclusion:1. Usual exclusion criteria for HRT appliedHuber, 2002501 in2groupsDBRCTHH1 year Postmenopausalwomen with intactuterus < 65. Meanage: 55Inclusion:1. Postmenopausal women with last period > 12 months prior2. Under the age of 65 years3. If date of natural menopause is unknown due to HRT use,women must be > 53 years and received HRT for > 2 years with itending with progestin phase4. Intact uterus5. BMI of 18-29 kg/m2Exclusion:1. Presence or history of hormone-dependent malignancies,known or suspected hypercholesterolemia, hypertension, liverdisease, endometrial hyperplasia, undiagnosed vaginal bleeding,prophyria, haemoglobinopathie2. Presence or history of cardiovascular, cerebrovascular orthromboembolic disorders3. Use of HRT during last month prior to start4. Previous use of implantable or injectable HRT5. Concomitant use of sex hormones or any drugs that couldinterfere with trial medication6. Drinking > 4 glass of alcohol/dayF-356

Appendix F. Evidence table 6-5. Key Question 3D TiboloneStudy/YearHammar, 1998Measures UsedHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)Specific Characteristics of PopulationBreastCancer(#/n)Use ofSERMS(#/n)Behavior orLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High or LowBMI(#/n)5 point scale 0/437 NR NR NR NR NR NR Tibolone 24.6E2/NETA24.3Huber, 2002Q-LES-QPGWBIGCSLUCRS0/501 NR NR NR NR < 4 alcoholicbeveragesper dayNo HRT Tibolone 24.8one month CEE/MPAprior to trial 24.7F-357

Appendix F. Evidence table 6-5. Key Question 3D TiboloneMain OutcomesStudy/YearHammar, 1998Main Drug type; dose;regimenOther Drugs type; dose;regimen Hot Flashes Vaginal Dryness SleepTibolone 2.5 mg/day oral E2 NETA 2 mg/day oral Improvement with bothtreatments.Significantly greaterdecrease withE2/NETA at last visit,p

Appendix F. Evidence table 6-5. Key Question 3D TiboloneMain OutcomesStudy/YearHammar, 1998Mood Cognitive Somatic Urinary Uterine Bleeding Sexual Dysfunction Quality of LifeNR NR NR NR Decreased in Tibolone group,p

Appendix F. Evidence table 6-5. Key Question 3D TiboloneStudy/YearHammar, 1998Other OutcomesWithdrawalsNR Tibolone: 54E2/NETA: 68Withdrawalsdue to AEs Adverse Effects CommentsTibolone: 34E2/NETA: 55Breast tenderness T-44, E2-119Edema T-72, E2-61Nausea T-51, E2-63Bleeding T-9, E2-37Menopausal symptoms rated on a 5 point scale(1 = none; 5 = very severe).Huber, 2002Economic status scoreof Q-LES-Q higher at 3months for CEE/MPAgroup, p=0.029.Tibolone: 62CEE/MPA:50Tibolone: 38CEE/MPA: 33Vaginal bleeding T-20, HRT-15Breast tenderness T-6, HRT-43HeadacheT-22, HRT-17; Backpain T-13, HRT-11; Body painT-4, HRT-12; Depression T-11, HRT-10; Weight gain T-9,HRT-8; Anxiety T-8, HRT-3,Uterine bleeding T-20, HRT-15F-360

Appendix F. Evidence table 6-5. Key Question 3D TiboloneStudy/YearHudita, 2003Johannes, 1997(abstract only)N162 in2groups770 in4groupsStudydesignDBRCTDBRCTComparisonof Trial Population Inclusion/ExclusionLengthCriteriaP 24weeksP 12weeksNon-obesepostmenopausalwomen with intactuterus. Mean ageapproximately 56 (40-65).Non-hysterectomizedpost-menopausalwomen.Mean age: 52Inclusion:1. Age 40-65, intact uterus2. Amenorrhea for 12 months3. FSH >30 mIU/ml4. 17 beta-estradiol

Appendix F. Evidence table 6-5. Key Question 3D TiboloneStudy/YearHudita, 2003Measures UsedMcCoy SexScale(modified), 5point scale formenopausalsymptomsHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)Specific Characteristics of PopulationBreastCancer(#/n)Use ofSERMS(#/n)Behavior orLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)0/162 NR NR 0/162 0/162 NR Nohormones8 weeksprior tostudyHigh or LowBMI(#/n)Meanapproximately 25Johannes, 1997(abstract only)NR 0/770 NR NR NR NR NR NR 24.8Kö kçü, 2000(abstract only)Questionnaire NR NR NR NR NR NR NR NRF-362

Appendix F. Evidence table 6-5. Key Question 3D TiboloneMain OutcomesStudy/YearHudita, 2003Main Drug type; dose;regimenTibolone 1.25 mg/dayTibolone 2.5 mg/dayOther Drugs type; dose;regimen Hot Flashes Vaginal Dryness SleepPlaceboSignificantimprovement in bothtreatment groups at 4,12, and 24 weeks,p

Appendix F. Evidence table 6-5. Key Question 3D TiboloneMain OutcomesStudy/YearHudita, 2003Mood Cognitive Somatic Urinary Uterine Bleeding Sexual Dysfunction Quality of LifeNR NR NR NR Significantly increased bleeding at Significant improvement NRweek 12 in both treatment groups, in both treatmentp

Appendix F. Evidence table 6-5. Key Question 3D TiboloneStudy/YearHudita, 2003Other Outcomes WithdrawalsWithdrawalsdue to AEs Adverse Effects CommentsCholesterol levels 42 NR Breast discomfort (Tibolone1.25-2, Tibolone 2.5-4)Fluid retention (Tibolone 1.25-3, Tibolone 2.5-2)Vaginal spotting (Placebo-2,Tibolone 1.25-4, Tibolone 2.5-2)Headache (Placebo-2,Tibolone 1.25-3, Tibolone 2.5-2)Nausea (Placebo-1)Johannes, 1997(abstract only)NR NR NR BleedingKö kçü, 2000(abstract only)Both treatment groupswith significantimprovement insubjective well-beingand vasomotorsymptoms, p

Appendix F. Evidence table 6-5. Key Question 3D TiboloneStudy/YearLam, 2004N100 in2groupsStudydesignDBRCTcrossoverComparisonof Trial Population Inclusion/ExclusionLengthCriteriaP 13monthsPostmenopausalChinese women fromHormone ReplacementClinics. Mean ageapprox 50.Inclusion:1. Married2. Intact uterus3. FSH> 30 IU/L4. Estradiol < 100 pmol/LExclusion:1. Breast/endometrial cancer2. Liver/kidney disease3. Thromboembolic diseaseF-366

Appendix F. Evidence table 6-5. Key Question 3D TiboloneStudy/YearMeasures UsedHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)Specific Characteristics of PopulationBreastCancer(#/n)Use ofSERMS(#/n)Behavior orLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High or LowBMI(#/n)Lam, 2004GCS, GHQ,DAS (DyadicAdjustmentScale)0/100 NR NR 0/100 0/100 NR Nohormonesin prior 6monthsNRF-367

Appendix F. Evidence table 6-5. Key Question 3D TiboloneMain OutcomesStudy/YearLam, 2004Main Drug type; dose;regimenOther Drugs type; dose;regimen Hot Flashes Vaginal Dryness SleepTibolone 2.5 mg/day Placebo Both groups withsignificantly reducedvasomotor sub scoreof GCS; p

Appendix F. Evidence table 6-5. Key Question 3D TiboloneMain OutcomesStudy/YearLam, 2004Mood Cognitive Somatic Urinary Uterine Bleeding Sexual Dysfunction Quality of LifeNR SignificantNRBoth groups withNRreduction insignificantly reducedsomatic subsexual sub score ofscore ofGCS, p

Appendix F. Evidence table 6-5. Key Question 3D TiboloneStudy/YearOther OutcomesWithdrawalsWithdrawalsdue to AEs Adverse Effects CommentsLam, 2004Marital quality of couplesassessed by DASTibolone: 4Placebo: 2NRMuscle/bone pain (T-2; P-1)Weight gain (T-2, P-1)Headache (T-1)Modified McCoy Sex Scale used 5 pointsystem. GCS score significantly decreased inboth treatment group, p

Appendix F. Evidence table 6-5. Key Question 3D TiboloneStudy/YearLandgren, 2002N775 in5groupsStudydesignDBRCTComparisonof Trial Population Inclusion/ExclusionLengthCriteriaP 12weeksHealthy postmenopausal womenwith hot flushes andsweating. Mean ageapproximately 52 (40-60).Inclusion:1. Non-hysterectomized women aged 40-60 years2. Absence of spontaneous vaginal bleeding for > 10 monthsprior to start3. > 1 moderate-severe hot flush/day4. Body weight between 80%-130% of ideal weightExclusion:1. History or presence of any malignant disorder, cardiovascularor cerebrovascular disease, thromboembolism/thrombosis,hepatic or renal disease, epilepsy or classical migraine, vaginalbleeding of unknown etiology, hypertension, rheumatoid arthritis,diabetes mellitus, hyperlipidaemia, any serious disease orpsychiatric disorder, hypersensitivity to oestrogen and/orprogestin, disease for which exogenous hormonal steroids arecontraindicated2. Use of sex steroids within 6 weeks3. Ethinyloestradiol within the last 6 months4. Hormone implants at any time5. One or more of the following drugs during the last two months:hydantion, barbiturates, primidone, carbamazepine, rifampicine,griseofulbin, drugs for treating climacteric symptoms6. Alcohol abuse and/or drug abuse within the last 12 months7. Smoking > 10 cigarettes/dayF-371

Appendix F. Evidence table 6-5. Key Question 3D TiboloneStudy/YearLandgren, 2002Measures UsedCollins andLandgren RatingScaleHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)Specific Characteristics of PopulationBreastCancer(#/n)Use ofSERMS(#/n)Behavior orLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High or LowBMI(#/n)0/775 NR NR 0/775 NR NR NR Placebo -25.00.625mggroup - 24.51.25mggroup - 24.82.5mg group -24.95.0mg group -24.9F-372

Appendix F. Evidence table 6-5. Key Question 3D TiboloneMain OutcomesStudy/YearLandgren, 2002Main Drug type; dose;regimenTibolone0.625 mg/day1.25 mg/day2.5 mg/day5 mg/dayOther Drugs type; dose;regimen Hot Flashes Vaginal Dryness SleepPlaceboSignificant decrease in NRNRfrequency with 1.25mg, 2.5 mg, and 5.0mg doses, p

Appendix F. Evidence table 6-5. Key Question 3D TiboloneMain OutcomesStudy/YearLandgren, 2002Mood Cognitive Somatic Urinary Uterine Bleeding Sexual Dysfunction Quality of LifeNR NR NR NR Dose-related increased vaginalNRNRbleeding and spotting. Highestincidence in the 5 mg/d group.Observed throughout 12 weekstudy.F-374

Appendix F. Evidence table 6-5. Key Question 3D TiboloneStudy/YearLandgren, 2002Other OutcomesSweating episodessignificantly decreasedin the 1.25, 2.5, and5mg/d groups,p

Appendix F. Evidence table 6-5. Key Question 3D TiboloneStudy/YearNLloyd, 2000 29 in 2groupsStudydesignDBRCTComparisonof Trial Population Inclusion/ExclusionLengthCriteriaP 6monthsHypertensive postmenopausalwomen.Mean ageapproximately 61Inclusion:1. Women with hypertension2. > 1 year postmenopausalExclusion:1. Intrinsic renal disease, insulin dependent diabetes, past historyof an oestrogen dependent tumor2. Use of sex steroid compounds, previous HRT, progesterone,Tibolone, or tamoxifen within previous 3 monthsMeeuwsen,200285 in 2groupsDBRCTP1 year Health womenpostmenopausal for 1-15 years. Mean ageapproximately 54.Inclusion:1. > 1 year but < 15 years after natural menopauseExclusion:1. Presence or history of sex hormone dependent malignancies2. Use of HRT or other steroid medication or muscle growthaffecting drugs during last 6 months3. Hypertension, active liver disease4. Presence or history of endometrial hyperplasia with or withoutatypia, undiagnosed vaginal bleeding5. Presence or history of cardiovascular, cerebrovascular orthromboembolic disorders6. Consumption of > 4 alcoholic drinks/day7. Pophyria, haemoglobinopathy8. Use of sex hormones, anabolcs, corticosteroids, insulin, anticoagulantsor enzyme-inducing drugs9. Participating in a clinical trial during the last 3 months10. BMI below 18 kg/m2 or above 29 kg/m211. Concomitant medication that could interfere with the studyF-376

Appendix F. Evidence table 6-5. Key Question 3D TiboloneStudy/YearLloyd, 2000Measures UsedHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)Specific Characteristics of PopulationBreastCancer(#/n)Use ofSERMS(#/n)GHQ NR NR NR NR Notamoxifenwithin prior3 monthsBehavior orLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)3/30 No HRTwithin prior3 monthsHigh or LowBMI(#/n)Tibolone 33.9Placebo 29.6Meeuwsen,2002NHP Tibolone: 4Placebo: 50/85 NR NR NR NR No HRT 6 25 in bothmonths groupsprior to trialF-377

Appendix F. Evidence table 6-5. Key Question 3D TiboloneMain OutcomesStudy/YearLloyd, 2000Main Drug type; dose;regimenOther Drugs type; dose;regimen Hot Flashes Vaginal Dryness SleepTibolone 2.5 mg/day oral Placebo NR NR NRMeeuwsen,2002Tibolone 2.5 mg/day oral Placebo Significantlydecreased in Tiboloneat cycle 12 incomparison toplacebo, p

Appendix F. Evidence table 6-5. Key Question 3D TiboloneMain OutcomesStudy/YearLloyd, 2000Mood Cognitive Somatic Urinary Uterine Bleeding Sexual Dysfunction Quality of LifeNR NR NR NR NR NR No significantdifferenceswithin orbetweentreatment andplacebo atbaseline and 6months.Meeuwsen,2002No significantdifferencebetweentreatmentgroups by NHPscore.NRNosignificantdifferencebetweentreatmentgroups inenergy, pain,socialisolation.No significantdifferencebetweentreatmentgroups.Overall increased frequency inTibolone group, p

Appendix F. Evidence table 6-5. Key Question 3D TiboloneStudy/YearOther OutcomesWithdrawalsWithdrawalsdue to AEs Adverse Effects CommentsLloyd, 2000Blood pressure andlipidsTibolone: 2Placebo: 2Tibolone: 1Placebo: 1Headache (numbers notreported)Nausea (numbers notreported)Flushing (numbers notreported) , Uterine bleeding T-4 P-1Primary outcome was effect of Tibolone onblood pressure and biochemical cardiovascularrisk factors in hypertensive women. Quality oflife reported as a secondary outcome.Meeuwsen,2002NR Tibolone: 1Placebo: 2Tibolone: 1Placebo: 0Malaise T-2Vaginal bleeding (but noWithdrawal due to vaginalbleeding) T-16, P-4; Abnormalmammogram P-1NHP used to assess quality of life andorganized into 6 domains: emotional reactions,energy, pain, physical mobility, sleep, andsocial isolation.F-380

Appendix F. Evidence table 6-5. Key Question 3D TiboloneStudy/YearNMendoza, 2000 76 in 2groupsMendoza, 2002165 in3groupsStudydesignComparisonof Trial Population Inclusion/ExclusionLengthCriteriaRCT HH 1 year Surgically menopausalwomen < 50. Meanage not reportedRCT HH 1 year Postmenopausalwomen with intactuterus amenorrhea 1-5years. Mean ageapproximately 50.Inclusion:1. Women who underwent a hysterectomy or bilateraloophorectomy for benign gynecologic process2. 3-4 months from surgery to study entryExclusion:1. Prior use of HRT2. Previous malignant gynecologic process, oestrogen producingtumor, endocrinological or metabolic problems, cardiovasculardisease, uncontrolled hypertension, active hepatic disease,serious skin illness, intestinal sickness or chronic obstructiverespiratory disease3. Psychiatric problems or receiving anxiolytic or antidepressivedrugsInclusion:1. Intact uterus2. Amenorrhea for 1-5 years3. Under 60 years of ageExclusion:1. Hysterectomized women2. Use of HRT within 3 months prior to start3. History of a malignant gynecological processes, oestrogenproducing tumor, serious endocrine or metabolic disturbances,insulin dependent diabetes, obesity (BMI > 32 kg/m2), unstablehypertension, active liver disease, serious skin disease or chronicobstructive pulmonary disease4. Psychiatric disturbance or use of anxiolytics or antidepressantsF-381

Appendix F. Evidence table 6-5. Key Question 3D TiboloneStudy/YearMendoza, 2000Measures UsedKuppermanIndexHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)Specific Characteristics of PopulationBreastCancer(#/n)Use ofSERMS(#/n)Behavior orLifestyleFactors(#/n)76/76 76/76 NR 0 0 Alcohol:Tibolone 1/36Estradiol 0/37Smoking:Tibolone11/36Estradiol10/37RecentdiscontinuationofHRT(#/n)High or LowBMI(#/n)0 NRMendoza, 2002ModifiedKuppermanIndex0/165 NR NR NR NR No alcoholuse.SmokingTibolone18%.Cycliccombined23.6%.Intermittentprogesterone20%.No HRT 3monthsprior totrial.No BMI > 32F-382

Appendix F. Evidence table 6-5. Key Question 3D TiboloneMain OutcomesStudy/YearMendoza, 2000Main Drug type; dose;regimenTibolone 2.5 mg/day oralOther Drugs type; dose;regimen Hot Flashes Vaginal Dryness SleepEstradiol 50 mcg/dayTransdermalNo significantdifference betweentreatments. Bothgroups improved.NRNRMendoza, 2002Tibolone 2.5 mg/day oral orEstradiol 50 mcg/day x 14days, then Estradiol 50mcg/day + NETA0.25mg/day x 14 daysTransdermalEstradiol 50 mcg/dayTransdermal +progesterone 200 mg2x/week oral.No significantdifference betweentreatment groups (allimproved)NRNo significantdifferencetreatmentbetweengroups.F-383

Appendix F. Evidence table 6-5. Key Question 3D TiboloneMain OutcomesStudy/YearMendoza, 2000Mood Cognitive Somatic Urinary Uterine Bleeding Sexual Dysfunction Quality of LifeNo significant NR NR NR NR No significant difference NRdifferencebetween treatments.betweentreatments.Both groupsimproved.Mendoza, 2002No significantdifferencetreatmentbetweengroups.Nosignificantdifferencetreatmentbetweengroups.Nosignificantdifferencetreatmentbetweengroups.NR NR No significant differencetreatment betweengroups.NRF-384

Appendix F. Evidence table 6-5. Key Question 3D TiboloneStudy/YearMendoza, 2000Other OutcomesWithdrawalsLipids NR Tibolone: 3Estradiol: 1Withdrawalsdue to AEs Adverse Effects CommentsHeadache E2-1Nausea T-4, E2-1Skin irritationBreast tenderness E2-4Weight gain T-1, E2-2Edema T-1, E2-1Hirsutism T-1Nervousness T-1Endometriosis T-1Mendoza, 2002Lipid profiles Tibolone: 4Intermittentprogesterone: 3Cycliccombined: 1Tibolone: 4Intermittentprogesterone:3Cycliccombined: 1Vaginal bleeding T-3, HRT-25Headache T-4, HRT-2Skin irritation HRT-11Varicose veinsHypertension T-1Stomach pain T-3Anxiety HRT-1Dysmenorrheal HRT-1Mastalgia HRT-3Symptoms on Kupperman Scale evaluated byfrequency of occurrence (frequently,occasional, never). Symptoms divided into 4categories: vasomotor, psychological,osteoarticular, and sexual behavior.F-385

Appendix F. Evidence table 6-5. Key Question 3D TiboloneStudy/YearNathorst-Bö ö s,1997N437 in2groupsPalacios, 1995 28 in 2groupsStudydesignDBRCTSBRCTComparisonof Trial Population Inclusion/ExclusionLengthCriteriaHH 48weeksHH 12monthsPostmenopausalwomen of at least oneyear or using HRTmore than 2 years. Allparticipants > 53Menopausal women,ages 50-60, with nohistory of HRT, marriedonce, in a stablemarriageInclusion:1. Healthy women2. > 1 year postmenopausal or using HRT > 2 years3. > 53 years old at study entry4. Suffered from hot flushes and sweating5. Had BMI < 306. Had intact uterusExclusion:1. Receiving HRT < 1 month prior to study2. History of atypical endometrial hyperplasia3. Had severe metabolic or endocrine diseaseInclusion:1. Postmenopausal women2. 50-60 years old3. Intact uterus and ovaries4. Married only once and in stable relationship5. Normal bone densitometryExclusion:1. Received hormone therapy during menopause2. Had known associated diseasesRoss, 1999 36 in 2groupsRCT HH 3monthsPeri- and postmenopausalwomenwith climactericsymptoms. Mean age52 (45-65)Inclusion:1. English speaking women > 45 years of age2. Intact uterus3. Amenorrhea > 3 months4. No past psychotic history nor current use of antidepressants orpsychotherapeutic agents5. No contraindications to estrogen therapyF-386

Appendix F. Evidence table 6-5. Key Question 3D TiboloneStudy/YearNathorst-Bö ö s,1997Measures UsedMcCoy SexScale (Swedishversion)Hysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)Specific Characteristics of PopulationBreastCancer(#/n)Use ofSERMS(#/n)Behavior orLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)0/437 NR NR NR NR NR 437/437discontinued onemonth priorHigh or LowBMI(#/n)< 30Palacios, 19957 point scale 0 0 NR NR NR NR 0 NRRoss, 1999WHQIDAGCS0/36 NR NR NR NR Smokers:Tibolone 9/18CEE 14/18NRNRF-387

Appendix F. Evidence table 6-5. Key Question 3D TiboloneMain OutcomesStudy/YearNathorst-Bö ö s,1997Main Drug type; dose;regimenTibolone 2.5 mg/day oral E2 2 mg/day + NETA 1mg/day oralOther Drugs type; dose;regimen Hot Flashes Vaginal Dryness SleepNRImprovement withboth treatmentgroups. Nosignificantdifference betweengroups.NRPalacios, 1995Tibolone 2.5 mg/day oral Calcium 500 mg/day oral NR NR NRRoss, 1999Tibolone 2.5 mg/dayCEE 0.625 mg/dayNorgestrol 150 mg/day12 days of cycleNo significantdifference between thetreatment groups onGCS.NRNRF-388

Appendix F. Evidence table 6-5. Key Question 3D TiboloneMain OutcomesStudy/YearNathorst-Bö ö s,1997Mood Cognitive Somatic Urinary Uterine Bleeding Sexual Dysfunction Quality of LifeNR NR NR NR NR Greater improvement in NRthe Tibolone group inregard to the frequencyand enjoyment, p

Appendix F. Evidence table 6-5. Key Question 3D TiboloneStudy/YearNathorst-Bö ö s,1997Other OutcomesWithdrawalsWithdrawalsdue to AEs Adverse Effects CommentsNR 122 NR NRPalacios, 1995NR 4 0 NR One primary goal of study was to demonstratevalidity of sexual questionnaire designed byinvestigators. (10 item questionnaire scored ona 7 point scale.)Ross, 1999Tibolone: 2CEE: 6Tibolone: 2CEE: 4NRF-390

Appendix F. Evidence table 6-5. Key Question 3D TiboloneStudy/YearVolpe, 1986N113 in7groupsStudydesignComparisonof Trial Population Inclusion/ExclusionLengthCriteriaRCT P 6monthsPostmenopausalwomenInclusion:1. Postmenopausal women2. Physiological menopause or hysterectomy and oophorectomy3. Last menstrual period occurred 1-5 years prior to studyExclusion:1. Received hormone preparations < 8 weeks prior to study2. Histories or conditions which would contraindicate oestrogentherapyWinkler, 2000 60 in 2groupsDBRCTHH 24weeksHealthy postmenopausalwomen.Mean ageapproximately 54 (45-70)Inclusion:1. Healthy postmenopausal women aged 45-70 years2. Spontaneous menopause with last period > 36 months prior orartificial menopause with FSH >30IU/LExclusion:1. Presence of cardiovascular, cerebrovascular orthromboembolic disorders, hypertension, hypercholesterolemia,liver, renal, thyroid, parathyroid or adrenal disorders, insulindependent diabetes, undiagnosed vaginal bleeding, malignancy ifnot cured for > 10 years2. History or presence of hormone-dependent malignancy3. Chronic use of medication that might affect metabolism of sexsteroid4. Drug or alcohol abuse within last 12 months5. Use of investigational drugs with the last 3 months6. Cigarette smokingF-391

Appendix F. Evidence table 6-5. Key Question 3D TiboloneStudy/YearVolpe, 1986Measures UsedHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)Specific Characteristics of PopulationBreastCancer(#/n)Use ofSERMS(#/n)Behavior orLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High or LowBMI(#/n)4 point scale 32/113 32/113 NR NR NR NR NR NRWinkler, 2000Karolinska Scale 24/60 NR NR NR NR 0 smokers NR Tibolone 24.7HRT 26.0F-392

Appendix F. Evidence table 6-5. Key Question 3D TiboloneMain OutcomesStudy/YearVolpe, 1986Winkler, 2000Main Drug type; dose;regimen1. CE 0.625mg/day for 21days/month + NETA5mg/day for 10 days/month2. CE 0.625 mg/day for21days/month + CPA 12.5mg/day for 10 days/month3. Estradiol valerate 2mg/day for 21 days/month +NETA 5 mg/day for 10days/month4. Estradiol valerate 2mg/day for 21 days/month +CPA 12.5 mg/day for 10days/month5. Estnol 2-4 mg/dayTibolone 2.5 mg/day Estradiol 2 mg/day +Estradiol 1mg/day +norethindrone acetate 1mg/dayOther Drugs type; dose;regimen Hot Flashes Vaginal Dryness SleepPlaceboImproved in allNRNRtreatment groupsImproved in bothgroups. No significantdifference betweengroups, p values notreported.Improved in bothgroups. Nosignificantdifference betweengroups, p valuesnot reported.NRF-393

Appendix F. Evidence table 6-5. Key Question 3D TiboloneMain OutcomesStudy/YearVolpe, 1986Mood Cognitive Somatic Urinary Uterine Bleeding Sexual Dysfunction Quality of LifeNR NR NR NR NR NR NRWinkler, 2000NR NR NR NR No significant difference betweentreatment groups.NRNRF-394

Appendix F. Evidence table 6-5. Key Question 3D TiboloneStudy/YearVolpe, 1986Other OutcomesWithdrawalsWithdrawalsdue to AEs Adverse Effects CommentsCholesterol levels 11 NR NR Hot flushes scored on 4 point scale: 0(absent), 3 (mild), 6 (moderate), 9 (severe). Allother menopausal symptoms scored on 4 pointscale: 0 (absent) to 3 (severe).Winkler, 2000HemostasismeasurementsTibolone: 4HRT: 4Tibolone:HRT: 3Weight gain T-2Sleep disturbance T-1Breast tenderness T-3.4%,HRT 25.8%Vaginal bleeding HRT-1Climacteric symptoms reported as a secondaryoutcome. Primary outcome was hormoneeffect on clotting cascade.F-395

Appendix F. Evidence table 6-5. Key Question 3D TiboloneStudy/YearNWu, 2001 48 in 2groupsStudydesignSBRCTComparisonof Trial Population Inclusion/ExclusionLengthCriteriaHH 3monthsPostmenopausalwomen with at leastone climactericsymptom. Mean age51 (38-56).Inclusion:1. Women who were 12-36 months postmenopausal2. > 1 climacteric symptomYang, 1997(abstract only)40 in 2groupsRCT HH 6monthsWomen 1-3 years postmenopauseInclusion:1. Postmenopausal women (1-3 years)Yang, 1999 40 in 2groupsopenRCTHH 6monthsSymptomaticpostmenopausalwomen.CEE/MPA mean age:52Tibolone mean age: 51Inclusion:1. Women 1-3 years postmenopausal with significantmenopausal symptomsExclusion:1. Any of the following: known or suspected tumor; significantbone diseases; cardiovascular, cerebrovascular orthromboembolic disorders; vaginal bleeding of unknown etiology2. Active gastrointestinal or liver disease or gastrointestinalsurgery likely to influence drug absorption3. Diabetes, renal disease, epilepsy or history of epilepsy,rheumatic arthritis, osteoarthritis, or other arthritic processesseverely restricting mobility, thyroid function disorders or adrenaldisorders4. Abuse of drugs or alcohol5. Medication use that may affect bone/calcium metabolism6. Uncontrolled hypertension7. Heavy smokersF-396

Appendix F. Evidence table 6-5. Key Question 3D TiboloneStudy/YearWu, 2001Measures UsedMc Coy SexScaleGCSHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)Specific Characteristics of PopulationBreastCancer(#/n)Use ofSERMS(#/n)Behavior orLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High or LowBMI(#/n)NR NR NR NR NR NR NR NRYang, 1997(abstract only)GCS NR NR NR NR NR NR NR NRYang, 1999GCS NR NR NR 0 NR NR NR Tibolone 21.5CEE/MPA22.5F-397

Appendix F. Evidence table 6-5. Key Question 3D TiboloneMain OutcomesStudy/YearWu, 2001Main Drug type; dose;regimenTibolone 2.5 mg/day oral CEE 0.625 mg/day + MPA 5mg/dayOther Drugs type; dose;regimen Hot Flashes Vaginal Dryness SleepNo significantdifference betweentreatment groups.Improved inTibolone group,p

Appendix F. Evidence table 6-5. Key Question 3D TiboloneMain OutcomesStudy/YearWu, 2001Mood Cognitive Somatic Urinary Uterine Bleeding Sexual Dysfunction Quality of LifeNo significant NR NoNR At 3 months, Tibolone 2/16 Improved in Tibolone NRdifferencesignificantHRT 6/16group, p

Appendix F. Evidence table 6-5. Key Question 3D TiboloneStudy/YearWu, 2001Other OutcomesHormone andcholesterol levelsWithdrawalsWithdrawalsdue to AEs Adverse Effects Comments12 7 (3 Tibolone,4 HRT)Body discomfort T-3, HRT-4Yang, 1997(abstract only)Yang, 1999Improvement ofclimacteric symptomsreported in bothtreatment groups, pvalue not reported.Bone metabolismBone densityCholesterol levelsEffect on endometrium.NR NR NR4 NR Weight gain T-1Uterine bleeding T-6, HRT-20Insomnia T-2, HRT-2Backache T-1, HRT-1 (AllEffects in first 3 months)F-400

Appendix F: Evidence table 6-5. Key Question 3D TiboloneKey/AbbreviationsBMI = Body mass indexBP = Blood pressureCE = Conjugated estrogensCEE= Conjugated equine estrogensCPA = Cyproterone acetateDAS = Dyadic Adjustment ScaleDB = Double blindDM = Diabetes mellitusE2 = EstradiolEE = Esterified EstrogenGCS = Greene Climacteric ScaleGHQ = General Health QuestionnaireHH = Head to headHRT = Hormone replacement therapyHTN = HypertensionIDA = Irritability, Depression, and AnxietyLUCRS = Local Urogenital Complaints Rating ScaleMPA = Medroxyprogesterone acetateNETA=norethidrone acetateNHP = Nottingham Health ProfileNR = Not reportedP = PlaceboPGWB-I = Psychological General Well-Being IndexQ-LES-Q = Quality of Life, Enjoyment and Satisfaction QuestionnaireRCT = Randomized controlled trialSB = Single blindSERMs = Selective Estrogen Receptor ModifiersT = TiboloneVTE = Venous thromboembolismWHQ = Women's Health QuestionnaireF-401

Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugsStudy/YearNType ofTrialComparisonDavid 1988 50 RCT P 4 20-daycoursesLengthof Trial Population Inclusion/Exclusion CriteriaPatients from menopause clinic inIsrael; aged 32-81; manypostmenopausal for many yearsNREvans 2005 80 RCT P 12weeksPostmenopausal, symptomaticwomen. Recruited throughnewspapers, radio, direct mailings,and flyers posted in physicians'offices.Inclusion:1. Natural or surgical menopause2. > 14 hot flashes per weekExclusion:1. Known adverse reactions to antidepressants2. Receiving estrogens, progestins, antidepressants, orchemotherapyF-402

Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugsSpecific Characteristics of PopulationStudy/YearDavid 1988Measures UsedHF frequency; severity ofperspiration; FSH, LH, testosterone,E2Hysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors*(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)NR NR NR NR NR NR NR NREvans 2005Modified Health Survey Short Form36 mood scale; single-item 5-pointscale about hot flashes interfrerencewith daily living; daily hot flash diary(severity 1-4).16/80 NR NR NR NR Alcoholuse 14/40in controlsand 25/40intreatment0 NRF-403

Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugsTreatmentHot Flash OutcomesStudy/YearDavid 1988Main Drugtype; dose;regimenVeralipride100mg PO qd(V)Other Drugstype; dose;regimenPlaceboReduction in Hot FlashFrequencyPre-post comparisons only:Group 1 (V x 4): 80%reported almost completedisappearance of HF.Group 2 (Px2, Vx2): HFfrequency 18 at baseline; 12with P, almost completeresolution with V.Group 3 (Vx2, Px2):baseline 15, almost completeresolution with V; up to 6-12.Reductionin HotFlashSeverityReduction in Hot FlashComposite ScoreOther Hot FlashMeasureNR NR NREvans 2005VenlafaxineXR, 37.5mgdaily for 1week, then75mg dailyPlaceboNo difference betweengroups.Nodifferencebetweengroups.No difference between Venlafaxine 51%groups. Both groups reduction in patientperceivedhot flushhad reduction in HFscore (no p-value given). score; Placebo 15%reduction; p

Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugsOutcomesStudy/YearDavid 1988Other OutcomesAll groups had decrease ininsomnia and depression with nosignificant differences.VaginalDryness Sleep Mood Cognitive Somatic UrinaryNRAll groups haddecrease ininsomniaAll groups haddecrease indepressionUterineBleedingNR NR NR NREvans 2005NR NR NR Mental healthimproved in tx vs.P on SF36(p=0.005)NR NR NR NRF-405

Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugsOutcomes (cont.)Study/YearDavid 1988SexualWithdrawalsDysfunc-tion Quality of Life Other Outcomes Withdrawals due to AEs Adverse Effects CommentsNR NR LH, testosterone,Prolactin, DHEA3 0 NREvans 2005Possibly moresexualdysfunction intx than P(p=0.11)Vitality improved in tx vs.P on SF36 (p=0.005)NR11/40 in tx;8/40 in PDifficultysleepingdecreasedlibido,nausea andanxiety in txgroupGreater dry mouth,sleeplessness, anddecreased appetite in tx thanP, but dizziness, tremors,anxiety, diarrhea, and rashless in tx than P.F-406

Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugsComparisonStudy/YearLimouzin-Lanothe, 1994Type ofN Trial499 Non-blindRCTLengthof Trial Population Inclusion/Exclusion CriteriaHH 6monthsEnrolled by 101 physicians inFrance; all literate and "enjoyed acomfortable standard of living"Inclusion:1. Natural or surgical menopause with amenorrhea > 3months but < 3 years2. >4 HF/day and nocturnal sweatingExclusion:1. HRT since beginning of menopause2. Symptomatic TX within 1 month3. "Estrogen-dependent pathologic characteristic"Melis, 1988 40 DB RCT P 30 days Recruitment info NR; Italy Inclusion:1. Postmenopausal women aged 48-56 years2. Physiologic menopause >1 year3. Experiencing hot flashesExclusion:1. HRT within 30 daysF-407

Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugsSpecific Characteristics of PopulationStudy/YearLimouzin-Lanothe, 1994Measures UsedWomen's Health Questionnaire,Psychological General Well-BeingIndex, Sleep ProblemsQuestionnaire; Sexual BehaviorQuestionnaire.10 symptoms on a 4-point scaleHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors*(#/n)NR NR NR NR NR SimilarEducationRecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)0 NRMelis, 19881. HF frequency; HF severity (0-3);and vasomotor score (frequency xseverity) by diary;2. "Objective HF" by skin temp (for6 hours for 8 women in each group);3. Plasma LH, FSH, PRL, E2;NR NR NR NR NR NR 0/40 NRF-408

Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugsTreatmentHot Flash OutcomesStudy/YearLimouzin-Lanothe, 1994Main Drugtype; dose;regimenVeralipride100mg/dayfirst 20 days ofeach month(V)Other Drugstype; dose;regimenEstradermTTS 50 andchlormandinone 1st 12 daysof each monthReduction in Hot FlashFrequencyReductionin HotFlashSeverityReduction in Hot FlashComposite ScoreOther Hot FlashMeasureNR NR NR 1 or no HF:HRT: 183/240 (81%)V: 94/239 (44%)(p

Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugsOutcomesStudy/YearLimouzin-Lanothe, 1994Other OutcomesMeasures of quality of life, sleep,sexual function, depression,anxiety, general psychological wellbeing, somatic complaints,cognitive difficulties, social life,family life, professional life, andvitality significantly better with HRTthan V, but both groups improvedover 6 monthsVaginalDryness Sleep Mood Cognitive Somatic UrinaryNRHRT group HRT groupimproved more improved morethanthan VeraliprideVeralipride group (p

Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugsOutcomes (cont.)Study/YearLimouzin-Lanothe, 1994SexualWithdrawalsDysfunc-tion Quality of Life Other Outcomes Withdrawals due to AEs Adverse Effects CommentsHRT groupimproved morethanVeralipridegroup (p

Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugsStudy/YearNType ofTrialComparisonStearns, 2003 165 DB RCT P 6 weeks Menopausal women (recruitedfrom 17 US sites using newspaperads, women's groups andprofessional referral networks)Lengthof Trial Population Inclusion/Exclusion CriteriaTarim, 2002 30 DB RCT P 5 weeks Consecutive patients presenting tooutpatient menopause clinic of U inTurkeyInclusion:1. Women over 18 years2. Menopausala. Amenorrhea > 12 monthsb. 6 months amenorrhea with increased FSH and E2,orc. Surgical menopause3. 2-3 hot flashes/day or > 14/weekExclusion:1. Recent psychotropic medication use2. Major depression or "significant mood or anxietysymptoms"3. HRT within 6 weeks4. Active cancer, current chemo or XRT5. Active psychiatric disorder6. Intolerance to SSRIs7. Substance dependenceInclusion:1. Aged 35-55 years2. Post menopausal with amenorrhea of 1 year3. FSH > 404. At least 14 hot flashes a weekExclusion:1. CAD2. Any psychiatric disordersF-412

Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugsSpecific Characteristics of PopulationStudy/YearStearns, 2003Measures UsedDaily hot flash composite score(frequency x severity; severity is 1-4);Greene Climacteric Scale 21;sleep disturbance Visual AnalogueScale;Beck anxiety inventory II;Sheehan Disability Scale;Clinical Global Impression globalimprovement item.Hysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors*(#/n)RecentdiscontinuationofHRT(#/n)50/165 25/165 NR 12/165 12/165 NR 6 weekspriorHigh orLow BMI(#/n)NRTarim, 2002HF weekly severity score (frequencyx severity 1-4)NR P: 4/9M 150:1/10M 300:4/11NR NR NR NR NR NRF-413

Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugsTreatmentHot Flash OutcomesStudy/YearStearns, 2003Main Drugtype; dose;regimenParoxetine12.5Paroxetine 25Other Drugstype; dose;regimenReduction in Hot FlashFrequencyPlacebo Paroxetine 12.5 = 3.3Paroxetine 25 = 3.2Placebo = 1.8(p=0.01)Reductionin HotFlashSeverityReduction in Hot FlashComposite ScoreNR Paroxetine 12.5 = 62.2%Paroxetine 25 = 64.6%Placebo = 37.8%(p

Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugsOutcomesStudy/YearStearns, 2003Other OutcomesNo significant difference in sleep,depression, anxiety, sexualinterest, or disability for the groupsVaginalDryness Sleep Mood Cognitive Somatic UrinaryNR Adjusted mean Depression (BDI-I)difference from 12.5mg: -0.73;baseline in 25mg: -0.006;sleep P: -0.33 (notdisturbance significant);VAS: Anxiety (BAI-II)12.5mg: -1.38, 12.5mg: -0.7325mg: -1.6 25mg: -1.23P: -1.0 (not P: -1.11 (notsignificant) significant)UterineBleedingNR NR NR NRTarim, 2002NR NR No sleepdisturbancesreported byany groupNR NR NR NR NRF-415

Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugsOutcomes (cont.)Study/YearStearns, 2003SexualWithdrawalsDysfunc-tion Quality of Life Other Outcomes Withdrawals due to AEs Adverse Effects CommentsSexual InterestGCS12.5mg: -0.0225mg: -0.02P: -0.07 (notsignificant)NRGlobal climactericscore improvedDisability (SDS):12.5mg: 0.8325mg: 0.01P: 0.06 (notsignificant)12.5mg:7/5125mg: 14/58P: 5/5612.5mg:4/51;25mg: 8/58;P: 2/56Headaches, dizziness,nausea, dyspnea, insomnia,constipation, lethargy,somnolence - nonesignificant difference thanplacebo.Tarim, 2002NR NR NR 1 in P and 1in M due tosomnolence1 in P and 1in M due tosomnolenceSomnolence: 1 in eachgroup; No dizziness,nausea, sleep disturbanceF-416

Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugsStudy/YearNType ofTrialComparisonWesel, 1984 43 DB RCT HH 20 days Women attending a OB-GYNhospital in FranceLengthof Trial Population Inclusion/Exclusion CriteriaInclusion:1. Aged 40-60 years2. Spontaneous amenorrhea > 6 monthsExclusion:1. Genital or mammary cancer2. Oophorectomy3. HRT within 30 daysZichella, 1986 75 (5groupsof 15)RCT HH 20 days Postmenopausal womenRecruiting information NRAged 45-55Inclusion:1. Physiologic menopause 1-2 years ago2. Severe vasomotor symptoms.Exclusion:1. Endocrinologically active drugs within 6 monthsF-417

Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugsSpecific Characteristics of PopulationStudy/YearWesel, 1984Measures UsedHF frequency; HF severity (1-4); HFduration (1-6);Hysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors*(#/n)RecentdiscontinuationofHRT(#/n)0 0 NR 0/43 NR NR > 30 daysdiscontinueHigh orLow BMI(#/n)NRZichella, 1986HF frequency (0-3); HF severity (0-3);0 0 NR NR NR NR 0 NRF-418

Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugsTreatmentHot Flash OutcomesStudy/YearWesel, 1984Main Drugtype; dose;regimenVeralipride100mg/day (V)Other Drugstype; dose;regimenReduction in Hot FlashFrequencyCEE 1.25mg V: 54.1-15.6 = 38.5 (71%reduction)CEE: 65.2-14.0 = 51.2 (79%reduction)Not significantReductionin HotFlashSeverityReduction in Hot FlashComposite ScoreNR # x intensity (1-4)V: 73-17=56 (77% red.)CEE: 108-18=90 (83%red.)Not significantOther Hot FlashMeasureNRZichella, 1986Veralipride100mg qd (V)Bromocriptine3.75; Liposom40mg Imqd;domperidone10mg qdNR NR HF score: V: 3.5 + 0.3to 1.2 + 0.1; P: 3.0 + 0.2to 2.4 + 0.1 (p

Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugsOutcomesStudy/YearWesel, 1984Other OutcomesVaginalDryness Sleep Mood Cognitive Somatic UrinaryUterineBleedingNR NR NR NR NR NR NR NRZichella, 1986NR NR NR NR NR NR NR NRF-420

Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugsOutcomes (cont.)Study/YearWesel, 1984SexualWithdrawalsDysfunc-tion Quality of Life Other Outcomes Withdrawals due to AEs Adverse Effects CommentsNR NR NR 3 in CEEgroupNRV: 2 mastodynia, 2 sedation,4 headache, 3 nausea, 1asthenia, 1 pelvic pain, 1venous disorderCEE: 4 sedation3 stopped V TXdue to AE; 4stopped CEEdue to AE.Zichella, 1986NR NR NR 0 0 V: mastodynia 10;galactorhea 2.0 with placeboAlso looked atLipisom, BCT,DOM notabstractedF-421

Appendix F: Evidence table 6-6. Key Question 3E Antidepressant drugsAE = Adverse EffectBAI-II = Beck Anxiety Inventory IIBCT = BromocriptineBDI = Beck Depression InventoryBMI = Body mass indexCAD = Coronary artery diseaseCEE= Conjugated equine estrogensDB = Double blindDHEA = DehydroepiandrosteroneDOM = DomperidoneE2 = EstradiolGCS = Greene Climacteric ScaleHF = Hot flashHH = Head to headHRT = Hormone replacement therapyNR = Not reportedP = PlaceboRCT = Randomized controlled trialSDS = Sheehan Disability ScaleSERMs = Selective Estrogen Receptor ModifiersSF-36 = Modified Health Survey Short Form 36SSRI = Selective Serotonin Reuptake Inhibitortx = TreatmentVAS = Visual Analogue ScaleKey/AbbreviationsF-422

Appendix F. Evidence table 6-7. Key Question 3F other drugsStudy/YearNType ofTrialAndersen 1986 40 DB RCTwithcrossoverComparisonLength of Trial Population Inclusion/exclusion criteriaPUnclear.1 week run-in.2 week wash-outthen cross-over.Each treatmentperiod could lastup to 8 weekstotal or until"troublesome sideeffects".Women experiencing hot flushes inthe climacteric.Mean age 51 years (range 46-60).Duration of symptoms 0.5-16 years(mean 4 years).NorwayNRBergmans198771 DB RCT(medswererandomized)P8 weeks(4 week openstudy followed)Women reporting hot flashes andsweats.No mean age reported.Patients from 3 general teachinghospitals.Netherlands.Description of women included:All reported hot flushes and sweats with > 1 ofseveral other somatic complaints.Exclusion:ovariectomized patients, and several medicalconditionsF-423

Appendix F. Evidence table 6-7. Key Question 3F other drugsStudy/YearMeasuresAndersen 1986 Patients recorded the number of hotflashes experienced daily (run-in weekand last week of each treatmentperiod).Visual analogue scales used to denotetrouble caused by hot flashes andgeneral well-being.Interviewed about side effects andwhich treatment they preferred.Labs: creatinine, AST, ALT, GGT

Appendix F. Evidence table 6-7. Key Question 3F other drugsTreatmentStudy/YearMain Drug type; dose;regimenAlpha-Methyldopa 375 mg tabnightly, increased by 1 tab every 2weeks as needed to maximumdose of 1,125 mg nightlyDose adjusted every 2 weeks ifneeded to maximum dose thenmaintained for 4 weeks.Other Drugs type;dose; regimenPlaceboHot Flashes (corrected)Prior to crossover:No difference in median number between M and P (p > 0.05).Improved number of hot flashes for both P (12/19, pNR) and M (14/17,pNR).Andersen 1986Summary statistics:M group felt less troubled by hot flashes than P (p

Appendix F. Evidence table 6-7. Key Question 3F other drugsMain OutcomesStudy/YearHot FlashesAndersen 1986 No significant difference between alpha-methyldopa andplacebo in median number of hot flashes.Patients on alpha-methyldopa felt less troubled by hotflashes (p

Appendix F. Evidence table 6-7. Key Question 3F other drugsMain outcomes (cont.)Study/YearAndersen 1986QoL Other Outcomes WithdrawalsNo significant No significant change in blooddifference in pressure or body weight.feeling of wellbeingmeasures.No abnormal hematological(tendency is tofeel worse onM).16/40(14 dropouts and 2 excludedbecause flushing not severeenough)Withdrawalsdue to AEs8/40 (4 M, 4P)drowsiness, drymouth,headache, skinrashWithdrawals due toAdverse Effects"Substantially more" side effectswith M.drowsiness, dry mouth, vertigo,and depression.Bergmans1987NROverall efficacy assessed by 33/71participant and investigator at the 5 dropped out for personalend of the double blind and open reasons prior to startingstudy. BR was assessed as treatment,excellent or good in 51% of cases, 12 dropped out from BR andplacebo 21%, the difference was 16 from P.statistically significant in favor ofBR.10/33 BR group6/33 P group19/33 in BR group complained ofadverse reactions.18/33 in P group complained ofadverse reactions.F-427

Appendix F. Evidence table 6-7. Key Question 3F other drugsStudy/YearAndersen 1986Adverse Effects Reported Comments Overall findingsDistribution of symptomsappears quite different fordrop-outs than for thosecompleting the study.Measures questionable. The authorsconclude that M is efficacious for hotflashes. However, there was nodifference in the number of hot flashesand overall it appears that participantstended to feel worse when on M.What is the significance of a visualanalog score of the degree to whichyou are troubled by hot flashes? Thismeasure and 62.5% participantpreference for M is what drives theauthor's conclusion.Question-able benefitfor M with significantside effects noted.Bergmans1987Complaints included drymouth, dizziness, sleepiness,headache, and nausea.Early in the study some benefit of BRover P noted but effect gone by theend of the 8 week trial.Bellergal was not moreeffective than placebo.F-428

Appendix F. Evidence table 6-7. Key Question 3F other drugsStudy/YearNType ofTrialBolli 1975 12 DB RCTwithcrossoverComparisonLength of Trial Population Inclusion/exclusion criteriaP2 trials 4 weekseach;2 weeks C or Pthen cross-over(n=12);2 weeks higherdose C or P thencross-over (n=8)Hypertensive women withmenopausal flushing.Duration of flushing was 1-16months (mean 4 months).Mean age 51 years.Dunedin Hypertension Clinic, NewZealandNRCarranza-Lira200175(5groups15 each)SB RCT HH 3 months Healthy postmenopausal(> 1-5 years) women with vasomotorsymptoms and insomnia.No hormones or other treatment forhot flushes, FSH and estradiol in thepostmenopausal range.Mean age not reported.NRMexicoF-429

Appendix F. Evidence table 6-7. Key Question 3F other drugsStudy/YearBolli 1975MeasuresDaily number of hot flushes, changesin the severity and duration of hotflushes (more, same, less), severity ofconcomitant perspiration.Side effects.Hysterectomy+/- UO(#/n)HysterectomyBSO(#/n)BSO(#/n)Specific Characteristics of PopulationBreastCancer(#/n)Use ofSERMS(#/n)Recentdiscontinuation ofHRT(#/n)High or LowBMI(#/n)NR NR NR NR NR None had used HRT. NRCarranza-Lira2001Number of hot flashes per day,intensity of hot flashes on visual scale0-10, duration in minutes, insomniaand sweating (absent or present).NR NR NR NR NR None had used HRT orother treatment fortheir symptoms.NRF-430

Appendix F. Evidence table 6-7. Key Question 3F other drugsTreatmentStudy/YearMain Drug type; dose;regimenOther Drugs type;dose; regimenHot Flashes (corrected)Bolli 1975C 0.0375 mg tab twice daily for firsttrialC 0.075 mg tab twice daily forsecond trialPlaceboPrior to crossover:NRSummary statistics:Results were the same for Trials 1 and 2.No significant difference in mean number between C and P.No significant difference between C and P in subjective measures.Carranza-Lira2001C 0.10 mg tab every 12 hoursCEE 0.0625 mg tab daily(hysterectomizedpatients only)propranolol 20 mg tabevery 12 hoursveralipride 100 mg tabdaily from Monday-FridayPlacebo tab every 12hoursF-431

Appendix F. Evidence table 6-7. Key Question 3F other drugsMain OutcomesStudy/YearBolli 1975Hot FlashesAppears that data presented compares patients' Clonidinetrials to their placebo trials.No significant difference in mean # of hot flashes betweenP and C in trial one or two, although both showedsignificant decrease from baseline.VaginalDryness Sleep Mood SomaticUter-ineBleedingSexualDysfunctionNR NR NR NR NR NRCarranza-Lira2001Hot flash frequency decreased in the CEE and C groupscompared to the propranolol, veralipride and placebogroups.Hot flash intensity and duration in CEE users decreased incomparison to the other four groups.Hot flash intensity was lower in C compared to propranololand P.The presence of sweating was lower in CEE and Ccompared to propranolol and P.NRInsomniapresence wasgreater in thepropranololgroup whencompared toCEE, clonidineandveralipride.Frequency ofpresentation ofinsomnia wasgreater inpropranololthan in CEEand C.NR NR NR NRF-432

Appendix F. Evidence table 6-7. Key Question 3F other drugsMain outcomes (cont.)Study/YearBolli 1975QoL Other Outcomes WithdrawalsWithdrawalsdue to AEsWithdrawals due toAdverse EffectsNR No change in blood pressure withNone None NoneC.Carranza-Lira2001NR NR 4/75(1 CEE, 2 propranolol, 1veralipride)2/75 (1 CEE and1 veralipride fordrug intolerance)F-433

Appendix F. Evidence table 6-7. Key Question 3F other drugsStudy/YearBolli 1975Adverse Effects Reported Comments Overall findingsNausea in 1 patient on C. Data not reported clearly. Summary No difference betweenstates significant difference between C clonidine and placebo.and P at higher dose C (150 mcg), butdiscussions states results of this trialdid not reach statistical significance.Carranza-Lira2001NRMethod of randomization notdisclosed. States patients withcontraindication to CEE were randomlydistributed to the other 4 four groups.No statement that the patients wereblinded.Limited information given. Summarytable is essentially uninterpretable.F-434

Appendix F. Evidence table 6-7. Key Question 3F other drugsStudy/YearNType ofTrialClayden 1974 100 DB RCTwithcrossoverComparisonLength of Trial Population Inclusion/exclusion criteriaP9 weeks(1 week of notreatment toassess baselinethen4 weeks C or Pthen cross-over)Women with menopausal flushing ofsufficient severity to warranttreatment.Duration of flushing ranged from twoweeks to 23 years.42 received C firstInclusion:1. No other complicating illnessEdington 1980 93 DB RCTcrossover(4 weeksC or Pthencross)P16 weeks Women with dilatation of blood(4 phases each 4 vessels in all areas of the skin andweeks, first 2 trials profuse sweating. Mean age 47conducted by the years (range 27-71).same investigator)Inclusion:1. Dilatation of blood vessels in all areas of the skinand profuse sweating.2. > 30 attacks per week3. Symptoms for > 3 months but not > 12 months.Exclusion:1. Other interfering illnessF-435

Appendix F. Evidence table 6-7. Key Question 3F other drugsStudy/YearClayden 1974MeasuresPatient diary recording each attack offlushing.Nine visits throughout trial. At eachvisit, questions were asked aboutfrequency, severity, and duration ofattacks. 5 point scale ("much more" to"much less").Side effects question "Any problemwith the tablets?"Blood pressure/pulse.Hysterectomy+/- UO(#/n)HysterectomyBSO(#/n)BSO(#/n)Specific Characteristics of PopulationBreastCancer(#/n)Use ofSERMS(#/n)Recentdiscontinuation ofHRT(#/n)NR NR NR NR NR States all previousmedication for flushingwas stopped 2 weeksbefore entry to trial.High or LowBMI(#/n)Mean weight64.6 kg (44.4to 86.9 kg)Edington 1980Patient diary of the time, extent,severity and duration of flushing, andside effects.Blood pressure, pulse.NR NR 10/66 NR NR NR NRF-436

Appendix F. Evidence table 6-7. Key Question 3F other drugsTreatmentStudy/YearMain Drug type; dose;regimenOther Drugs type;dose; regimenPlaceboHot Flashes (corrected)Prior to crossover:No difference in mean change from baseline number to week 4between C and P (p=0.7)*.Summary statistics:Greater reduction in number while on C(C first p

Appendix F. Evidence table 6-7. Key Question 3F other drugsMain OutcomesStudy/YearClayden 1974Edington 1980Hot FlashesAppears that data presented compares patients' Clonidinetrials to their placebo trials, rather than doing the two trialsseparately.Reduction in number of hot flashes was greater duringclonidine period than placebo period (C first p

Appendix F. Evidence table 6-7. Key Question 3F other drugsMain outcomes (cont.)Study/YearQoL Other Outcomes WithdrawalsWithdrawalsdue to AEsWithdrawals due toAdverse EffectsClayden 1974NRBlood pressure and pulse. Nosignificant changes over the studyperiod (p NR).14 excluded for severalreasons (Table 1). 4/14 werefor side effects3C,1PEdington 1980NRBlood pressure and pulse. Nosignificant changes over the studyperiod (p NR).27/936 due to symptoms, 1nonmedical, 8 lost to follow up,12 patients did not keep properdiaries6/93 2/93 on P withdrew (1 headache,1 double vision), 4/93 on clonidinewithdrew (1 respiratory infection, 1depression, 2 headaches, 1nausea)F-439

Appendix F. Evidence table 6-7. Key Question 3F other drugsStudy/YearClayden 1974Adverse Effects Reported Comments Overall findings56 participants reported side No stats provided prior to cross-over.effects. 34 while on C, 36while on P.Effects nonspecific (Table V)and "well distributed" betweenC and P except dry mouthwhich was more frequent onC.No significantdifference between Cand P prior tocrossover. After crossover,C was moreeffective than P inreducing number of hotflashes.Edington 1980Headache 12C, 10PDry mouth 11C, 4PInsomnia 8C,4PFatigue 3C, 5PNausea 2C, 3POther 30C, 28P(p NR)Study done in 4 trials of 4 weeks each.Trial 3 was a single-blinded placeboonly trial. "The findings wereaveraged" from the 4 trials.I don't think this study can be used.Clonidine was moreeffective than placebo.However, statisticalmethod isquestionable.F-440

Appendix F. Evidence table 6-7. Key Question 3F other drugsStudy/YearNGerdes 1982 38(15/38defaulted)Therewerealso 10asymptomaticcontrolsType ofTrialComparisonLength of Trial Population Inclusion/exclusion criteriaDB RCT HH 20 weeks Menopausal women with symptoms.No mean age noted.Climacteric Clinic JohannesburgHospitalInclusion:1. Elevated FSH (>18mIU/ml) and LH (> 15mIU/ml)2. Hot flushesExclusion:1. Several medical conditionsF-441

Appendix F. Evidence table 6-7. Key Question 3F other drugsStudy/YearGerdes 1982MeasuresSouth African PersonalityQuestionnaire, Leckie-Withers Test ofLiability to Depressive Illness, BemSex Role Inventory, Items from UkenMotherliness Test, Mini-BiographyQuestionnaire, subjective assessmentconcerning pretreatment to posttreatment change on 5 point scale.Hysterectomy+/- UO(#/n)HysterectomyBSO(#/n)BSO(#/n)Specific Characteristics of PopulationBreastCancer(#/n)Use ofSERMS(#/n)Recentdiscontinuation ofHRT(#/n)High or LowBMI(#/n)NR NR NR Excluded NR NR NRF-442

Appendix F. Evidence table 6-7. Key Question 3F other drugsTreatmentStudy/YearMain Drug type; dose;regimenOther Drugs type;dose; regimenHot Flashes (corrected)Gerdes 1982Opposed Estrogen group:CEE 1.25 mg daily for 21 days +medrogestone 5mg daily from day16 to 21, then 7 days off, + placeboC 2 tab twice daily for 28 daysC group:placebo CEE daily 21days + placebomedrogestone days 16-21, then 7 days off, + C0.025 mg 2 tab twicedaily for 28 daysReported in Sonnendecker 1980F-443

Appendix F. Evidence table 6-7. Key Question 3F other drugsMain OutcomesStudy/YearGerdes 1982Hot FlashesVaginalDryness Sleep Mood SomaticReported in Sonnendecker 1980 NR NR Significant decreasein MBQdepressionscore for CEEcompared to C(p

Appendix F. Evidence table 6-7. Key Question 3F other drugsMain outcomes (cont.)Study/YearQoL Other Outcomes WithdrawalsWithdrawalsdue to AEsWithdrawals due toAdverse EffectsGerdes 1982NR38 women entered the studybut 15 defaulted (7 fromestrogen and 8 from clonidinegroup) leaving only 23remaining.NRNRF-445

Appendix F. Evidence table 6-7. Key Question 3F other drugsStudy/YearGerdes 1982Adverse Effects Reported Comments Overall findingsNR10 asymptomatic postmenopausalcontrols (not included in n)Onlyestrogen/progesteronecombination wasassociated withimprovement inmeasures ofdepression and anxiety(p

Appendix F. Evidence table 6-7. Key Question 3F other drugsStudy/YearNGuttuso 2003 59(246screened 187wereineligible)Type ofTrialComparisonLength of Trial Population Inclusion/exclusion criteriaDB RCT P 12 weeks(followed by a 5week open-labeltreatment phase)Postmenopausal women with hotflashes.Mean age 52.7 G, 53 P.Randomization was stratified bysurgical menopause status.Recruited by advertisement.New YorkInclusion:1. Average > 7 hot flashes/day accompanied bysweating2. Amenorrhea for > 12 months or 6-12 monthswith FSH>40 mIU/mL and estradiol 30 vasomotor flushes/week andserum FSH > 40 mIU/ml.States women were "normotensive, in good health,and had no medical contraindication to M."F-447

Appendix F. Evidence table 6-7. Key Question 3F other drugsSpecific Characteristics of PopulationStudy/YearMeasuresHysterectomy+/- UO(#/n)HysterectomyBSO(#/n)BSO(#/n)BreastCancer(#/n)Use ofSERMS(#/n)Recentdiscontinuation ofHRT(#/n)High or LowBMI(#/n)Guttuso 20034 patient clinic visits, bimonthly phonecalls and patient diaries.Serum FSH and estradiol, LH, CBCwith differential, platelets, chemistry-14panel, phosphate. Vitals signs, height,weight.Hot flash diary of frequency andseverity (scale 1-7) symptoms noted atoccurrence. Composite hot flashscore,Pittsburgh Sleep Quality Index, Profileof Mood States, Short Form-36 HealthSurvey, Patient Global Impression ofChange Scale. Adverse events.NR NR 8/30 G6/29 PNR1/30 G5/29 PStates could not be onHRT, leuprolide, ortamoxifen for 2 monthsprior to study.BMI NR onlyweight.Mean weightin pounds158.7 G and152.8 P.Hammond1984Diary of number of vasomotor flushesand objective 5 hour study periods ofcontinuous temperature monitoringand sampling for serum LH.NR NR NR NR NR States no HRT usedfor 6 months prior tostudy.NRF-448

Appendix F. Evidence table 6-7. Key Question 3F other drugsTreatmentStudy/YearMain Drug type; dose;regimenG 300 mg tab 3 times daily (900mg daily).Participants allowed to decreasedose if side effects.Other Drugs type;dose; regimenPlaceboHot Flashes (corrected)Statistically significant decrease between G and P in frequency atweeks 4 (p=0.03) and 12 (p=0.02) and composite score at weeks 4(p=0.01) and 12 (p=0.01).Results not altered by adjusting for baseline group differences induration of hot flashes and Total Mood Disturbance scores.Guttuso 2003In the open label trial the dose of Gcould be increased to maximum of2700 mg/day.Hammond1984Methyldopa 250 mg tab twice daily,increased after 1 week to 3 timesdailyPlaceboPrior to crossover:Both M and P resulted in decrease in hot flashes (pNR). No significantdifference in mean decrease in number between M and P.Summary statistics:Compared to baseline, significant decrease in number for M (p

Appendix F. Evidence table 6-7. Key Question 3F other drugsMain OutcomesStudy/YearHot FlashesVaginalDryness Sleep Mood SomaticUter-ineBleedingSexualDysfunctionGuttuso 2003Statistically significant decrease between G and P in hotflash frequency at weeks 4 (p=0.03) and 12 (p=0.02) andcomposite score at weeks 4 (p=0.01) and 12 (p=0.01).Results not altered by adjusting for baseline groupdifferences in duration of hot flashes and Total MoodDisturbance scores.NRPittsburghSleep QualityIndeximproved withG at week 4(p=0.01) butnot at week 12(p=0.09).No significantdifferencebetween Gand P inProfile ofMood States.NROnset ofmensesin 3 Pand 2 G.NRHammond1984In the first study period (i.e. before crossover) there wasno significant difference between M and P in meandecrease of hot flashes.In the second study period there was a significantdecrease in vasomotor flushes for M but not P (p

Appendix F. Evidence table 6-7. Key Question 3F other drugsMain outcomes (cont.)Study/YearGuttuso 2003QoL Other Outcomes WithdrawalsNo significant No significant difference betweendifference G and P in Patient Globalbetween G Impression of Change Scale.and P in Short Several lab studies done.Form-36 Significant differences were seenHealth Survey. in albumin, total protein, totalbilirubin, blood urea nitrogen, andplatelets.5 withdrawals from doubleblindstudy, 4 withdrawals fromopen-label studyWithdrawalsdue to AEs4/30 in G(dizziness, rash,heartpalpitations, andperipheraledema)1/29 in P(diarrhea)Two withdrawalsfor AE's from theopen- label study(dizziness,peripheraledema).Withdrawals due toAdverse EffectsHammond1984NRStatistically significant decrease inthe mean number of LH peaks perhour during M therapy (p

Appendix F. Evidence table 6-7. Key Question 3F other drugsStudy/YearGuttuso 2003Adverse Effects Reported Comments Overall findingsSomnolence, dizziness, rashand peripheral edema werereported in G but not P.15 (50%) in G and 8 (27.6%)in P reported at least oneadverse event.A few patients were taking raloxifeneor antidepressants during the study.81.5% of patients requested tocontinue G after completion of theopen-label study.G was more effectivethan P throughout thestudy.Hammond1984"Significant side effectsoccurred in 6/10 patientsreceiving methyldopa."Authors conclude that "because ofsignificant side effects and minimalsymptomatic improvement, M is notlikely to be an acceptable therapy."No significant effect ofM. Significant sideeffects.F-452

Appendix F. Evidence table 6-7. Key Question 3F other drugsStudy/YearNType ofTrialLindsay 1978 100 DB RCTwithcrossoverComparisonLength of Trial Population Inclusion/exclusion criteriaP 13 weeks (6weeks P or C thencross-over, 1week free inbetween)Menopausal women with symptoms.States all experienced "natural"menopause.Mean duration of symptoms 1.6years (1 month-5 years).Mean age 46.4 years (35-60)NRPatients selected from referrals on arandom basis. Glasgow.Nagamani198730 DB RCT P 10 weeks(2 weeks toSymptomatic women (6spontaneous menopause, 24assess baseline, 8 surgical).weeks C or P) Mean age 41 (range 25-58)TexasExclusion:1. Previous treatment with oral C,2. Other medical exclusions listedNappi 1991 35(5groupsof 7each)RCT HH 4 weeks Menstruating women undergoingTAH-BSO for benign indications.Mean age 43.5 years (range 30-50)Not more explicitly specified.F-453

Appendix F. Evidence table 6-7. Key Question 3F other drugsSpecific Characteristics of PopulationStudy/YearMeasuresHysterectomy+/- UO(#/n)HysterectomyBSO(#/n)BSO(#/n)BreastCancer(#/n)Use ofSERMS(#/n)Recentdiscontinuation ofHRT(#/n)High or LowBMI(#/n)Lindsay 1978No diaries.Interviews at weeks 4, 7, and 12.Blatt Menopausal Index (4 pointsscale).Flushing attacks assessed separately(4 point scale).Kellner and Sheffield rating scale forpsychological symptoms.NR NR NR NR NR # NR, states alltreatment of symptomsstopped at least 4weeks before entryNRNagamani1987Patient diary noting occurrence of hotflashes and side effects of treatment.At visit, patients were questioned aboutfrequency, severity (decrease orsame), and duration (decrease orsame) of hot flashes.Blood pressure, pulse, LH levels.NR NR 24/30 NR NR NR, states notreatment forsymptoms for at least30 days beforeinclusionNRNappi 1991Plasma LH and FSH.Patient diaries of frequency (0, 5-10/day scored 0-3) andintensity of hot flushes (0, mild,moderate, severe scored 0-3).None 35/35 35/35 NR NR NR BMI 23.1 + 1.5F-454

Appendix F. Evidence table 6-7. Key Question 3F other drugsTreatmentStudy/YearMain Drug type; dose;regimenOther Drugs type;dose; regimenPlaceboHot Flashes (corrected)Prior to crossover:Significant decrease in Blatt score for C (p

Appendix F. Evidence table 6-7. Key Question 3F other drugsMain OutcomesStudy/YearLindsay 1978Hot FlashesBlatt Menopausal Index. Significant decrease in first 6weeks for C (p

Appendix F. Evidence table 6-7. Key Question 3F other drugsMain outcomes (cont.)Study/YearLindsay 1978QoL Other Outcomes WithdrawalsWithdrawalsdue to AEsWithdrawals due toAdverse EffectsNR NR 62/100 2 2 withdrawals for nausea, drymouth and insomnia on CNagamani1987NR LH levels measured in 2participants without C and after 2weeks of C. No change in LHpulsatile secretion noted with C.No significant changes in bloodpressure and pulse.1/30 (excluded from analysis,dropped out after 2 weeks oftreatment)NoneNoneNappi 1991NR FSH, LH levels NR NR NRF-457

Appendix F. Evidence table 6-7. Key Question 3F other drugsStudy/YearLindsay 1978Adverse Effects Reported Comments Overall findings2 reported nocturia on C, 1reported nausea on P100 initially to be included. States only41 completed treatment in the trial.Three additional withdrawals noted,one did not return after initialassessment, 2 withdrew because ofside effects. Results are reported forthe remaining 38.No difference betweenclonidine and placebo.Nagamani1987Skin reactions (erythemaand/or itching) 4C, 3 P(no dryness of mouth ordizziness reported)How useful are the results of limitedsubjective measures?C was more effectivethan P in subjectivemeasures but not formean decrease innumber of hot flashes.Nappi 1991NRAll treatments started on the first dayafter surgery.Method of randomization notdisclosed. No report of blinding. Onesmall paragraph on hot flash results,more time spent discussing LH/FSHresults.Estrogen, clonidine,and Lisuridedecreased hot flashfrequency and intensitycompared to placebo.F-458

Appendix F. Evidence table 6-7. Key Question 3F other drugsStudy/YearNType ofTrialNesheim 1981 40 DB RCTwithcrossoverComparisonLength of Trial Population Inclusion/exclusion criteriaPNot clearly statedbut inferred; 1week baseline; 30day M or P then14 day washoutthen cross-overWomen with menopausal hotflushes.Mean age or age range NR.Patients referred by GeneralPractitioners in Akershus County,Norway.Exclusion:1. Use of antihypertensive, antidepressants, orsedating drugsSalmi 1979 40 DB RCTcrossover(not trueRCT,medicationpacksmade inrandomorder)Peachpatientis herowncontrol12 weeks,cross-over at 6weeksWomen with menopausalsymptoms. 10 still menstruating, 18spontaneous menopause.Mean age 50.5 years (range 41-57).Mean duration of symptoms 21.5months (range 1-131 months).Outpatients from Department ofOb/Gyn, University Central Hospital,Finland.Inclusion:1. Hot flushes, sweating, menopausal symptomsF-459

Appendix F. Evidence table 6-7. Key Question 3F other drugsSpecific Characteristics of PopulationStudy/YearMeasuresHysterectomy+/- UO(#/n)HysterectomyBSO(#/n)BSO(#/n)BreastCancer(#/n)Use ofSERMS(#/n)Recentdiscontinuation ofHRT(#/n)High or LowBMI(#/n)Nesheim 1981Patient recorded number of hot flashesper day.Patients were contacted weekly byphone and asked to use a VAS torecord degree they were troubled byhot flashes.Blood pressure.NR NR NR NR NR Participants were notallowed to takeestrogen for 4 weeksbefore the study.NRSalmi 1979Patient records and visits (3).Frequency of sweating episodes/hotflushes (none, 5, >10)Incidence of insomnia and depression,occurrence of possible anxiety states(none, less than before the medication,the same as before, more than before)Blood pressure, pulse, AST,cholesterol.Side effects.2/37 7/37 NR 1 of thepatients wasexcluded atthe beginningbecause ofcancer in amammarynode.NR NR NRF-460

Appendix F. Evidence table 6-7. Key Question 3F other drugsTreatmentStudy/YearMain Drug type; dose;regimenOther Drugs type;dose; regimenPlaceboHot Flashes (corrected)Nesheim 1981l-methyldopa 250 mg tab twice dailyincreased if needed to maximum of2 tabs twice dailyPrior to crossover:NRSummary statistics:Median reduction in number 38% P (pNS), 65% M (p

Appendix F. Evidence table 6-7. Key Question 3F other drugsMain OutcomesStudy/YearNesheim 1981Hot FlashesMedian number of hot flashes per week prior tomedication was 58 (14-315).16 participants received M first, 12 P first.Median number of hot flashes for M first was 42 (14-140and for P first was 70 (28-315). (Not reported if this wassignificantly different at baseline.)Hot flash frequency was reduced by both M and P,favoring M in both the first phase (p=0.06) and the secondphase (p =0.01) Combined results from both phasesfavors M (p=0.004).Median VAS score prior to treatment 8.4 cm (2.9-10)Improvement in score was greater with M than P(p=0.002) (patients compared to themselves). Medianimprovement 77% with M, 30% with P.VaginalDryness Sleep Mood SomaticUter-ineBleedingSexualDysfunctionNR NR NR NR NR NRSalmi 1979Sweating and hot flushes (day and night).No statistical difference (p NR) between C and P.NRInsomnia. Nostatisticaldifference (pNR) betweenC and P.Disturbancesof depressionand anxietystates.No statisticaldifference (pNR) betweenC and P.NR NR NRF-462

Appendix F. Evidence table 6-7. Key Question 3F other drugsMain outcomes (cont.)Study/YearQoL Other Outcomes WithdrawalsWithdrawalsdue to AEsWithdrawals due toAdverse EffectsNesheim 1981NRNo significant change in bloodpressure.12/40 (various reasonsreported)2 additional patients wereunable to keep record of theirhot flashes, only VAS dataavailable2/40 (specificeffects notstated)Salmi 1979NRNo changes in blood pressure andpulse during the trial.3 were excluded from initial 40,unclear if this was prior torandomization. 1 for cancerousnode, 1 for psychiatrictreatment, 1 for interruption ofmedication.noneNoneF-463

Appendix F. Evidence table 6-7. Key Question 3F other drugsStudy/YearNesheim 1981Adverse Effects Reported Comments Overall findingsTiredness 15 M, 3 PDry mouth 10 M, 7PSlight edema 3 MDiarrhea 1 M, 1PExanthem and Arthralgia 1 MSome results appeared to becombined across both treatmentperiods (i.e. patients compared tothemselves).Salmi 1979No significant differencesbetween C and P in sideeffect occurrence.(Various side effects listedTable 1)Serum aspartate amniotransferaseand cholesterol readings were done inall and there were no elevated valuesnoted.No difference betweenclonidine and placebo.F-464

Appendix F. Evidence table 6-7. Key Question 3F other drugsStudy/YearSonnendecker1980N38(15/38defaulted)Type ofTrialComparisonLength of Trial Population Inclusion/exclusion criteriaDB RCT HH 20 weeks Menopausal women with symptoms.No mean age noted.Climacteric Clinic JohannesburgHospitalInclusion:1. Elevated FSH (>18mIU/ml) and LH (> 15mIU/ml)2. Hot flushesExclusion:1. Several medical conditionsWren 1986 19 DB RCTwithcrossoverP10 weeks(2 weeks placebo,then 4 weeks C orP then cross-over)Postmenopausal women withsymptoms (all spontaneousmenopause).Mean age 50.6 (range 46-56)Menopause clinic at the royalHospital for Women, New SouthWalesInclusion:1. Spontaneous menopause2. Symptoms > 3 months but not > 12 months.Exclusion:1. Hysterectomy2. Previous C or anti-hypertensive useF-465

Appendix F. Evidence table 6-7. Key Question 3F other drugsStudy/YearSonnendecker1980MeasuresMammography, hot flushes in numberper day, FSH, LH, 17B-estradiol,progesterone, prolactin.Hysterectomy+/- UO(#/n)HysterectomyBSO(#/n)BSO(#/n)Specific Characteristics of PopulationBreastCancer(#/n)Use ofSERMS(#/n)Recentdiscontinuation ofHRT(#/n)High or LowBMI(#/n)NR NR NR Excluded NR NR NRWren 1986Frequency, severity, and duration ofvasovagal symptoms. Patient diariesof number of flushes/sweats, insomnia,anxiety, libido, headache, irritability,and depression.Exam and biochemical investigationevery 2 weeks.Excluded Excluded NR NR NR Excluded if previoususe C, antihypertensive,HRT orsedative, tranquilizer,or hypnotic drugsNRF-466

Appendix F. Evidence table 6-7. Key Question 3F other drugsTreatmentStudy/YearMain Drug type; dose;regimenOther Drugs type;dose; regimenC group:placebo CEE daily 21days + placebomedrogestone days 16-21, then 7 days off, + C0.025 mg 2 tab twicedaily for 28 daysHot Flashes (corrected)Mean change in number from pre- to post-trial follow up decreasedsignificantly with CEE (p

Appendix F. Evidence table 6-7. Key Question 3F other drugsMain OutcomesStudy/YearSonnendecker1980Hot FlashesNumber of hot flashes experienced daily was decreasedsignificantly in the estrogen group (p

Appendix F. Evidence table 6-7. Key Question 3F other drugsMain outcomes (cont.)Study/YearQoL Other Outcomes WithdrawalsWithdrawalsdue to AEsWithdrawals due toAdverse EffectsSonnendecker1980NRFSH, LH, and estradiol,progesterone and prolactin levelswere assessed. Mammographywas performed.38 women entered the studybut 15 defaulted (7 fromestrogen and 8 from clonidinegroup) leaving only 23remaining.NRNRWren 1986NRNo change in blood pressure orgonadotropin levels5/19 (not included in analysis,states withdrawal due tofrustration with lack of benefit)NoneNo adverse affects reported.F-469

Appendix F. Evidence table 6-7. Key Question 3F other drugsStudy/YearSonnendecker1980Adverse Effects Reported Comments Overall findingsNROnlyestrogen/progesteronecombination waseffective fordecreasing hot flashes.Wren 1986NR No p values reported in this paper No difference betweenclonidine and placebo.Statistical method isquestion-able.F-470

Appendix F: Evidence table 6-7. Key Question 3F other drugs*p value not reported by the authorsAE = Adverse EffectBMI = Body mass indexBR = Bellergal RetardBSO = Bilateral Salpingo OophorectomyC = ClonidineCEE = Conjugated Equine EstrogensDB = Double-blindECOG = Eastern Cooperative Oncology Group ScaleG = GabapentinHH = Head to headHRT = Hormone replacement therapyM = MethyldopaMBQ = Mini-Biography QuestionnaireNR = Not reportedP = PlaceboQoL = Quality of LifeRCT = Randomized Controlled TrialSERMs = Selective Estrogen Receptor ModifiersTAH = Total abdominal hysterectomyUO = Unilateral OophorectomyVAS = Visual Analogue ScaleKey/AbbreviationsF-471

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearNType ofTrialComparisonAiello, 2004 173 RCT HH 12monthsLengthof Trial Population Inclusion/Exclusion CriteriaPostmenopausal womenrecruited from the greaterSeattle area (50-75 years ofage) through mass mailingsand media placements.Average age 60.7 and 60.6SD (6.6 and 6.7years).Approximately 60% hadsome menopausalsymptoms.Inclusion:1. Sedentary at baseline (25.0 or over 24.0 with body fat>33%Exclusion:1. Taking HRT2. SmokerAlbertazzi, 1998&1999104 RCT P 12weeksMean age 53, range of 48-61.Women postmenopausalrequesting treatment forsevere hot flushes.Inclusion:1. > 6 months since the last menstrual period or > 6weeks since bilateral oophorectomy was performed2. Seven moderate to severe hot flushes, including nightsweats/24 hours during at least the last 2 weeks of the 4week prestudy period3. FSH>50 and estradiol

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/YearAiello, 2004Measures UsedAdherance to exercise via daily activitylogs, food frequency questionnaire,information on menopause symptomsand their severity was collected at0,3,6,9, and 12 months with a selfadministeredquestionnaire, which was amodified version of a questionnaire usedby the Women's Health Initiative, DEXAwas conducted at baseline and 12months for leannessHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)13-18% NR NR NR NR NR 35-38%had takenin theremotepastHigh orLow BMI(#/n)Averagewas 30.5and 30.6in eachgroupAlbertazzi, 1998&1999Daily diary; Kupperman Index NR NR NR NR Allowed NR Had to beoff at least6 weeksMeanwas 25.9for bothgroupswithrangefrom 18-36F-473

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearAiello, 2004Main Drug type;dose;regimen45 minutes ofmoderate-intensityexercise, 5 days/weekfor 12 monthsOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepControl was invitationto attend 45 minuteweekly stretchingsession for 12 monthsNo change in frequency over theyearNRNo change in eithergroup over the yearAlbertazzi, 1998&1999Casein 60 grams dailyfor 12 weeksSoy powder (SuproBrand ProteinTechnologies, St.Louis, MO) 60grams/day; thiscontained 76 mg ofisoflavones (aglyconeunits)Hot flash reduction was seen in Vaginal maturationboth group (43.6 % reduction in indices did notsoy group compared with 31.3% increase in the soyreduction in placebo group). Soy group, but didgroup had greater reduction than significantlycasein group at 12 weeks (p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearAiello, 2004Albertazzi, 1998&1999Sexual DysfunctionMood Cognitive Somatic Urinary Uterine BleedingQuality of LifeNR NR NR NR NRNo change indepressive feelingsin either group overthe year (only 13%had a baseline)No change in eithergroup over the year;when analyzed bytime sincemenopause thosewithin 5 years ofmenopause had asignificant decreasein memory problemsin the exercisegroup compared tothe controls (OR at6 mo=0.2; 95% CI,0.08-0.6). This wassustained at 9 and12 months.NR NR NR NR NR NR NRF-475

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearAiello, 2004Other OutcomesWhen analyzing the subset ofmoderate/severe menopausalsymptoms (n=11 exercisers, 10controls), a significant decrease inhot flashes was seen over the year inthe control group (p=0.02 but not inthe exercisers)Withdrawals6/87 in theexercisegroup; 2/86controlsWithdrawalsdue to AEsAdverseEffectsNCCAMCategoryCommentsNone None Mind-body Only RCT looking at exerciseAlbertazzi, 1998&1999Kupperman index values as a wholedid 'not change'25/51; 11 inthe soy groupand 14 in thecasein group14 patients, 7 in Gastrointestinaeach group l - constipationdropped due to 48%gastrointestinalside effects;lack of efficacycaused 3patients in thecasein groupand 1 person inthe soy group towithdrawBiologicallybasedtherapiesF-476

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearNType ofTrialComparisonAnarte, 1998 73 RCT HH 6monthsLengthof Trial Population Inclusion/Exclusion Criteria45-55 year oldpostmenopausal women withless than 3 years evolution,no previous treatment; allattending a Menopause Unitin Southern SpainNone reported other than population definition exceptthat patients in whom hormonal treatment wascontraindicated were excludedAtkinson, 2004 205 DB RCT P 1 year Women recruited from abreast clinic in Cambridge,UKExclusion:1. History of breast cancer, major breast surgery2. Use of HRTF-477

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/YearMeasures UsedHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)Anarte, 1998Kupperman Index, plus the emotionalalternation, anxiety and depressionscales of the Granada GynecologicalQuestionnair of Salvatierra et al.NR NR NR Those withcontraindication toHRTexcludedNR NR NopreviousNRAtkinson, 200428 day menopausal symptom diary atbaseline and 12 months; severity andfrequency of 21 symptoms associatedwith menopauseNR NR NR Excluded NR NR NR Measured but notreportedF-478

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearAnarte, 1998Main Drug type;dose;regimenTransdermal estrogenwith cyclicalprogesteroneOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepHRT plusIn both groups there wasPsychological significant improvement incounselingvasomotor symptoms (p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearAnarte, 1998Atkinson, 2004Mood Cognitive Somatic Urinary Uterine BleedingSexual DysfunctionQuality of LifeCombined treatment NR NR NR NR NR NRgroup has significantbenefit innervousness(p=0.0001), anxiety,depression,emotional alteration,melancholia(p=0.0001) overHRT only group,however, bothgroups hadsignificantimprovement inthese parametersfrom baseline. HRTonly nervousness(p=0.0001) andanxiety (p=0.0002);combined groupboth had p = 0.0001.NR NR NR NR NR NR NRF-480

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearOther OutcomesWithdrawalsWithdrawalsdue to AEsAdverseEffectsNCCAMCategoryCommentsAnarte, 1998Weakness and fatigue improved incombined group over HRT alonegroup (p=0.0001); same withpalpitations. Neither group hadimprovement in joint and muscle painor headache symptoms.NR NR NR Mind-bodyAtkinson, 2004NR 16/102withdrew fromPromensilgroup and 12/103 fromplacebowithdrewNone reported;most withdrewto go on HRTNoneBiologicallybasedtherapiesF-481

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearNType ofTrialComparisonBaber, 1999 51 DB RCT P 7monthsLengthof Trial Population Inclusion/Exclusion CriteriaUnpaid female volunteersInclusion:1. Aged 45-652. > 3 hot flushes/dayExclusion:1. Intercurrent medical problems2. HRT or antibiotics in previous 3 months3. FSH10g legumes per day)Baird, 1995 97 RCT ControlUsualcare4 weeks Volunteers recruited throughnewspaper ads, flyers, andradioInclusion:1. Age less than 652. No menses for > 2 years3. No use of estrogen or antibiotics > 6 months4. No use of prescription drugs known to effectoutcomes, such as corticosteroids.F-482

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/YearBaber, 1999Measures UsedHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)Greene Climacteric Scale Excluded NR NR NR NR Vegetarian> 10glegumes/dayexcludedRecentdiscontinuationofHRT(#/n)None for 3monthsHigh orLow BMI(#/n)Weightreportedin kg withmean 67-71 kg +/-11.0-12.8Baird, 1995Health habits and history questionnaire,Luteinizing hormone, follicle stimulatinghormone, vaginal cytology, urinaryphytoestrogenNR NR NR NR NR NR None for 6monthsNRF-483

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearBaber, 1999Baird, 1995Main Drug type;dose;regimenPromensil (NovogenLtd, Sydney);Promensil is astandardizedisoflavone supplementprepared from redclover extract in500mg tablet formcontaining 40mg/tablet; containsgenistein, daidzein,biochanin, andformononetin1/3 of calories to comefrom soy flourOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepPlaceboGreene score and flush frequency NRNRdecreased in both placebo andactive groups during the 3 monthsof treatment (p=0.003); nodifference between groupsControl was usual caredietNRNo change invaginal maturationindexNRF-484

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearBaber, 1999Mood Cognitive Somatic Urinary Uterine BleedingSexual DysfunctionQuality of LifeNR NR NR NR NR NR NRBaird, 1995NR NR NR NR NR NR NRF-485

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearOther OutcomesWithdrawalsWithdrawalsdue to AEsAdverseEffectsNCCAMCategoryCommentsBaber, 1999Significantly different (p=

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearNType ofTrialComparisonBalk, 2002 27 RCT P 6monthsLengthof Trial Population Inclusion/Exclusion CriteriaPostmenopausal womenwere recruited from clinicsand private gynecology,family practice, and internalmedicine offices inPittsburgh. Advertisementswere placed in newspapers,on radio, and on the web sitefor Magee-Women'sResearch Institute homepage.Inclusion:1. Over 40 years, postmenopausal, no vaginal bleedingfor 1 year or >30 years old with BSO or POF2. Omnivore3. Intact uterusExclusion:1. HRT in past year2. Use of SERMsF-487

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/YearBalk, 2002Measures UsedEndometrial biopsyMenopausal Symptoms Questionnaire byBrzeginski, et alHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)NR NR NR NR Excluded NR Over 1year to beeligibleHigh orLow BMI(#/n)MeanwasaverageF-488

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearBalk, 2002Main Drug type;dose;regimenOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness Sleep100 mg soy/cereal/day N/A No difference No difference Soy had moreinsomniaF-489

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearBalk, 2002No difference(depression)Sexual DysfunctionN/A N/A No difference N/A No difference(decreased libido)Mood Cognitive Somatic Urinary Uterine BleedingQuality of LifeN/AF-490

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearOther OutcomesWithdrawalsWithdrawalsdue to AEsAdverseEffectsNCCAMCategoryCommentsBalk, 2002Headache, palpitation, night sweats,no difference2/13 fromplacebo and6/14 from thesoy groupYesNumber notstatedFlatulence,poor taste - noimprovementBiologicallybasedtherapiesF-491

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearNType ofTrialComparisonBellipanni, 2001 79 RCT P 6monthsLengthof Trial Population Inclusion/Exclusion CriteriaNo relevant pathologies,taking no drugs, hormonesor herba preparation andconducting a normal lifestylewith typical Mediterraneandiet rich of carbohydratesand fresh vegetablesInclusion:1. Age 42-62F-492

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/YearBellipanni, 2001Measures UsedQuestionnaire in which life habits,physiological data, data concerningprevious pathologies, treatment-relatedside-effects, treatment-inducedalterations, effects on perimenopausalsymptoms (neurovegetative, sleep,psychological) werer recorded at time 0and at 3 and 6 months. Questionsconcerned duration and character of theirmenstrual cycle and/or psychosomatic,peri- and menopause related symptomssuch as irritability, morning mood anddepreession, insomnia, night sweatings,headache, stypsis, amnesia, hot flushes,palpitations, and body weight increase.Hysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)NR NR NR NR NR All nonsmokersand noalcoholabuseRecentdiscontinuationofHRT(#/n)NRHigh orLow BMI(#/n)NRF-493

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearBellipanni, 2001Main Drug type;dose;regimenOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness Sleep3 mg melatonin/day Placebo No significant difference betweengroupsNRNo significantdifference betweengroupsF-494

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearMood Cognitive Somatic Urinary Uterine BleedingSexual DysfunctionNRQuality of LifeNRBellipanni, 2001After analysis of allanswers, theevaluation ofdifferent typicalperimenopause ormenopause-relatedsymptoms oralternations did notdisclose a clear-cutdifference betweenthe two groups, withthe notableexception of a verysignificantimprovement ofmood and completedisappearance ofmorning depressionin the melatonintreatedwomen.NR NR NR Only episodicalimprovement ofregularity andduration ofmenstrua cycleswere reported.Six menopausalwomen (at 1 and2 years after totalcessation of themenses) reporteda re-acquisition ofnormal (bleedingand duration)menstrual cyclesF-495

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearOther OutcomesWithdrawalsWithdrawalsdue to AEsAdverseEffectsNCCAMCategoryCommentsBellipanni, 2001Information on LH, thyroid and FSHresultsNR NR NR BiologicallybasedPoor studyF-496

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearNType ofTrialComparisonBlatt, 1953 748 DB RCT 5 armswithcontrolsandplaceboLengthof Trial Population Inclusion/Exclusion Criteria3 years Climacteric women NRBoblitz, 2003(Abstract Only)179 RCT P 6 weeks Women with menopausalsymptomsNRF-497

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/YearBlatt, 1953Measures UsedMenopausal index, a validated scale thatrepresents a numerical conversion of theseverity of the 11 most commonmenopausal symptoms.Hysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)NR NR NR NR NR NR NR NRBoblitz, 2003(Abstract Only)Kupperman Menopause Index; CGIscores for anxiety, impaired drive,depressive mood andnervousness/irritabilityNR NR NR NR NR NR NR NRF-498

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearBlatt, 1953Boblitz, 2003(Abstract Only)Main Drug type;dose;regimenVitamin E 50-100mgtid (n=82) vs. ethinylestradiol 0.05mg(n=107) vs.conjugated equineestrogen 1.25mg(n=173) vs.phenobarbital 15mg tid(n=88).Remifemen Plus; 20mg black cohosh, 250mcg of hypericinOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepPlacebo (n=298) All results reported by menopausal NRNRindex of which several questionspertain to vasomotor symptoms.No p values are given in paperdue to date of publication.However, 66.5% of both estrogengroups had an excellent responseto treatment (as compared to13.4% of Vitamin E, 23.6% ofphenobarbital and 15.6% ofplacebo patient)Placebo NR NR NRF-499

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearBlatt, 1953Sexual DysfunctionMood Cognitive Somatic Urinary Uterine BleedingQuality of LifeNR NR NR NR NR NR NRBoblitz, 2003(Abstract Only)In all GreeneClimacteric Indexitems referring topsychologicalsymptoms,Remifemin Plus wassuperior to placebo(p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearBlatt, 1953Other OutcomesWithdrawalsWithdrawalsdue to AEsAdverseEffectsNCCAMCategoryNR NR NR NR BiologicallybasedCommentsBoblitz, 2003(Abstract Only)A decrease in Kupperman Index totalscore demonstrated significantsuperiority of the active to placebo(p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearNType ofTrialComparisonBrzezinski, 1997 145 RCT ControlIsraeli diet(usualcare)Lengthof Trial Population Inclusion/Exclusion Criteria12weeksWomen who were peri and Inclusion:postmenopausal (43-65 1. Natural or surgical menopause (> 3 months ofyears) with climacteric amenorrhea)complaints from the 2. FSH>30, LH>20, and low plasma estradiol level ( 1 of the following symptoms: hot flashes, nightat Hadassah Medical Center, sweats, insomnia, depression, vaginal dryness, orJerusalem, IsraeldyspareuniaExclusion:1. Evidence of acute medical illness2. Use of gonadal hormones or any medication known toinfluence menopausal symptoms or endocrine variabels3. Known or suspected allergic reaction to specific fooditems.Burke, 2003 241 DBRCTHH 24monthsWomen aged 45-55 were Inclusion:recruited from the communityand seen at Wake ForestUniversity.White: 88%Married: 79%High school diploma: 96%>$30,000 annual income:79%1. Perimenopausal (only 1 period in preceding 3 months)2. At least 1 vasomotor symptom a day3. No use of HRT for 3 months prior to study entryExclusion:1. Acute myocardial infarction or stroke within 6 months2. History of breast or endometrial cancer3. History of invasive cancer within 5 years4. Active thromboembolic disease5. Previous osteoporosis fractures being treated withhormones6. Low bone density7. Previous exposure to diethylstilbestrol8. An endometrial biopsy showing hyperplasiaF-502

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/YearBrzezinski, 1997Measures UsedMenopause symptoms questionnaire(MSQ); evaluates hot flashes, nightsweats, palpitations, headache,depression, vaginal dryness, urinarydiscomfort, insomnia, and decreasedlibido on a four point scale. Serumphytoestrogen concentrationsHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)Included Included NR NR NR NR Could notbe taken atthe time ofstudyHigh orLow BMI(#/n)26.24 +0.48 forPE groupand25.82 +0.87 incontrolgroupBurke, 2003Self report in symptom diaries. 56/241 NR NR Excluded NR NR 180/241 0/241F-503

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearBrzezinski, 1997Main Drug type;dose;regimenPhytoestrogen richdiet, approximately 1/4of their calories (PEgroup)Other Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepRegular Israeli diet; Significantly reduced in PE grouptold to avoid soy over controls (p=0.004)products and flax seedSignificantlyreduced in PE groupover control(p=0.005)NRBurke, 200325g of soy with 42mga day of isoflavonesor25g of soy with 58mga day of isoflavones25g of soy, alcoholwashed to removeisoflavones (Control)Rapid reduction in all groups,including control. No differencebetween groups.Significant reduction for all groupsfrom baseline (p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearBrzezinski, 1997Mood Cognitive Somatic Urinary Uterine BleedingSexual DysfunctionQuality of LifeNR NR NR NR NR NR Total score ofmenopausalsymptomatology(MSQ score) wasreduced greatly inboth groupsduring the studygroups, but thedifferencebetween thegroups was notsignificantBurke, 2003NR NR NR NR NR NR NRF-505

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearBrzezinski, 1997Burke, 2003Other OutcomesAverage of 100-fold increase in thephytoestrogen serum levels of the PEgroup; no change in the control groupWithdrawalsWithdrawals due to AEs31/145 4/95 in the PEgroup due tointolerance ofdiet; 2/95 in soygroup and 7/50in control groupwithdrew due tounbearablemenopausalsymptoms;other dropoutswere due topersonalreasonsAdverseEffectsNRNCCAMCategoryBiologicallybasedtherapiesNR NR NR NR BiologicallybasedtherapiesCommentsInteresting as came from food,tofu, soy milk, and flax seed largely170/241 used OCF-506

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearBygdeman,1996NType ofTrialComparison40 RCT HH 3monthsLengthof Trial Population Inclusion/Exclusion CriteriaPostmenopausal womencomplaining of vaginaldryness (aged 43-76, mean58.28 years)Exclusion:1. Hormonal-dependent tumors2. Known or suspected other serious diseases, abnormalgenital bleeding, past history of active thromboembolicdisorder, vaginal infection3. HRT in the last 3 months4. Vaginal use of any douche or lubricantCagnacci, 2003 80 RCT,openHH 3monthsWomen (age 47-53) inperimenopause referred tothe Menopause Center wereenrolled; mean age was50.2, 51.5 and 51.8Exclusion:1. Organic or neurological pathologies2. Used hormones, neuroactive or psychotropic drugs inthe 3 months preceedingF-507

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/YearBygdeman,1996Measures UsedSelf diary and vaginal dryness index(Bachmann)Hysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)NR 2/40 NR NR NR NR NR NRCagnacci, 2003State Trait Anxiety Inventory, Self-Evaluations Depression Scale, Greene'sClimacteric ScaleNR NR NR NR NR NR NR Mean26.0,26.9 and26.7F-508

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearBygdeman,1996Main Drug type;dose;regimenReplens: 1 vaginalapplication threetimes/week for 3monthsOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepDienoestrol vaginalcream (0.01%) 0.5mgdaily for 2 weeks thenthree times a week for3 monthsNRBoth groupsresulted in asignificant increasein the vaginaldryness index withcompared tobaseline valuesNRCagnacci, 2003Kava-Kava (KK)100m/day (15 women)vs. Kava-Kava200mg/day (19women)Control was 1000mgCalcium/day (34women)Both KK groups had significantdecline in Greene's score frombaseline, but not significantlydifferent from control group.NRNRF-509

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearBygdeman,1996Mood Cognitive Somatic Urinary Uterine BleedingSexual DysfunctionQuality of LifeNR NR NR NR NR NR NRCagnacci, 2003Anxiety; significantdecrease comparedto control in both KKgroups (p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearBygdeman,1996Other OutcomesWithdrawalsWithdrawalsdue to AEsAdverseEffectsNCCAMCategoryNR 1/40 NR NR BiologicallybasedCommentsCagnacci, 2003NR12/80; 6 in thecontrol group,and 5 in the100mg KKgroup and 1 inthe 200mg KKgroup2 for nausea nausea andand gastric pain gastric painBiologicallybasedF-511

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearCarranza-Lira,2001NType ofTrialComparisonLengthof Trial Population Inclusion/Exclusion Criteria30 DB RCT P 1 month Postmenopausal women Inclusion:who attended the Climacteric 1. No current or previous exposure to HRTClinic of the hospital studied 2. FSH >30 and estradiol 6 months previously2. No HRT for > 6 monthsExclusion:1. Severe metabolic, endocrine, or GI disease,concomitant heart disease, uncontrolled hypertension(>160/95), diabetes, endometriosis, undiagnosed vaginalbleeding and psychiatric illness2. Surgically induced menopause3. Previous or current estrogen-dependent tumors, othercurrent malignant or life-threatening disease,4. Previous or concomitant serious or chronic medicalconditions.5. Taking tranquilizers or antidepressantsF-512

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/YearCarranza-Lira,2001Measures UsedHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)Modified Kupperman Index NR NR NR NR NR NR NeverreceivedHigh orLow BMI(#/n)Nodifferencebetweengroups(averageBMI is28)Chen, 2003Greene Climacteric Scale Excluded Excluded Excluded Excluded NR NR Nonewithin 6months52-56 kgF-513

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearCarranza-Lira,2001Chen, 2003Main Drug type;dose;regimenPhytoestrogen cream4mg/day aloe vera;wild yam root extract;almond oil; cartamooil; jojoba oil;tocopheryl acetate;chamomile extract;sheepshkin rootextract oil of ass herb;siberian ginsengextract; to alternatingforearms/dayJWSYS (Sun TenPharmaceutical Co.,Taipei, Taiwan); 4grams tid; includesangelica Radix,Atractylodis rhizoma,Paeoniae Radix;Bupleuri Radix;Hoelen; GlycyrrhizaeRadix; Moutan Bark;Gardeniae Fructus;Zingiberis Rhizoma,Menthae HerbaOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepCold cream control A significant decrease inNRNRKupperman Index Score wasfound in both groups at the end oftreatment (p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearCarranza-Lira,2001Mood Cognitive Somatic Urinary Uterine BleedingSexual DysfunctionQuality of LifeNR NR NR NR NR NR NRChen, 2003Both groups hadsignificantimprovement inanxiety anddepression (p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearOther OutcomesWithdrawalsWithdrawalsdue to AEsAdverseEffectsNCCAMCategoryCommentsCarranza-Lira,2001A significant decrease in KI wasfound in both groups at the end of thetreatment (p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearNType ofTrialComparisonChenoy, 1994 56 DB RCT P 6monthsLengthof Trial Population Inclusion/Exclusion Criteria56 women were recruitedfrom the general gynecologyclinic of North StaffordshireHospital Center, London;from general practitioners'surgeries, and by self referralof volunteers.Inclusion:1. Menopausal women who had hot flushes at least threetimes/day2. Elevated FSH and LH or had amenorrhea for at least 6months, or both.Exclusion:1. Received estrogen replacement or essential fatty acidsupplements in the previous 2 months.2. Taking any form of HRT or other drug for menopausalsymptoms during the study, or systemic steroids, nonsteroidalanti-inflammatory agents, anticonvulsants,clonidine, and phenothiazides.Chiechi, 2003 187 RCT Usualcare6monthsHealthy postmenopausalasymptomatic woman aged39-60, living in SouthernItaly; mean age was 52.7yearsInclusion:1. Spontaneous menopause of > 6 months2. FSH>30, or bilateral oophorectomyExclusion:1. Age >602. Heavy drinkers3. Treatment with HRT, cholesterol-lowering,antiosteoporotic or other interfering drugs (i.e. tibolone)4. Diabetes or history of cancer5. In vegetarian or macrobiotic diet6. Presence of menopausal symptoms requiring therapyF-517

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/YearChenoy, 1994Measures UsedHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)Self reported symptom diary Excluded NR NR NR NR NR None for 2monthspriorHigh orLow BMI(#/n)NRChiechi, 2003Karyopycnotic index and maturationvalue of the vagina, FSH, estradiol,urinary daidzein, vaginal smearsIncluded NR NR NR NR NR NR 27.06-28.9meanF-518

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearChenoy, 1994Main Drug type;dose;regimenSix months oftreatment with eitherfour 500mg eveningprimrose oil with 10mgnatural Vitamin EOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepPlacebo was 500mgliquid paraffin; fourcapsules twice dailyAll women given placebo showeda significant positive differencebetween control cycle and lastcycle (p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearChenoy, 1994Mood Cognitive Somatic Urinary Uterine BleedingSexual DysfunctionQuality of LifeNR NR NR NR NR NR NRChiechi, 2003NR NR NR NR NR NR NRF-520

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearOther OutcomesWithdrawalsWithdrawalsdue to AEsAdverseEffectsNCCAMCategoryCommentsChenoy, 1994NR11/28 fromplacebo and10/28 fromgamolenicacid group2/11 fromplacebo due tonausea;however mainreason statedwas lack ofclinicalresponseLack of clinicalresponseBiologicallybasedtherapiesSignificant response to placebobut not to gamolenic acidChiechi, 2003NR22 out ofcontrol group;44 out of dietgroup; 31 outof HRT groupNR NR BiologicallybasedtherapiesToo high of drop out rate to bereliableF-521

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearNType ofTrialComparisonCleary, 1994 30 RCT P 15weeksLengthof Trial Population Inclusion/Exclusion CriteriaWomen age 50-60 yearswith menopausal symptomsrecruited through local andnational newspapersInclusion:1. < 4 periods in the previous 12 months2. Abnormal FSH/LH analysisExclusion:1. Current or past HRT in last 18 months2. Any debilitating medical condition3. Any facial or spinal surgery4. Taking medication likely to affect their hormonal orsympathetic systems, such as thyroxine, or beta-blockers5. Any past or present patient of the researcherCohen, 2003 18 RCT HH 12weeksWomen were recruited by Inclusion:flyers and by advertisements 1. Ability of self-identification of menopausal hot flushesin local newspapers in a New 2. Ceased previous treatment of menopausal symptomsEngland ; 11/17 women had with hormones, other medications, herbs, or acupunctureceased having menstrual at least 3 months prior to enrollment in the study to allowcycles within the past 2 years for a sufficient cleansing periodand the remaining 6 women Exclusion:had not had a period in 3-4 1. Women with hormonal supplementation, othermonths; Mean age was 47.3 pharmacologic therapies, herbal remedies, oryears (43-53)acupuncture (including acupressure).F-522

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/YearCleary, 1994Measures Used1. Weekly 1-10 scale Symptomquestionnaire during study2. Pre-, Week 5, and Week 15 bloodlevels of estradiol, FSH, LH, thyroxine,testosterone, sex hormone bindingglobulin, prolactin, cortisol, IGF/1, TSH,and GHHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)NR NR NR Excluded NR NR At least 18monthsHigh orLow BMI(#/n)NRCohen, 20034 scale daily symptom diary NR NR NR NR NR NR Excludedat least 3monthspriorNRF-523

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearCleary, 1994Main Drug type;dose;regimenThe spine and pelvisof each subject wastreated by a low-forceosteopathic techniquedeveloped by Fox, andthe cranium by cranialtechniques followingmechanical principlesweekly for 10 weeks,followed by a 5 weekobservation period.Other Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepPlacebo: low-forcetechnique delivered toa joint adjacent to arestricted joint, whereit will have no effect;force is so low in bothgroups that they areunaware they havereceived treatmentweekly for ten weeksfollowed by five weekobservation periodReduction in study group of hotflashes (p=0.016) at ten weeksand (p=0.007) at 15 weeks;Reduction in study group of nightsweats (p=0.021) at ten weeksand (p=0.016) at 15 weeksNRReduction ininsomnia vs controlgroup (p=0.098) atten weeks and(p=0.018) at 15weeksCohen, 20039 week acupuncturetreatment protocolconsisting of 1/weekfor 3 weeks then onceevery other week for atotal of 6 treatmentsfollowed by 3nontreatment weeks(20-30 minutes/treatment) (EA group)UB15, 23, 32; GV 20,H7; pericardium 6;SP6, 9; L3 forexperimental group;comparison is generaltonic (shen mein)L4;K7 and ear points(7)EA group showed a decrease inmean monthly hot flush severity(30%) for site-specificacupuncture from baseline tomonth 2 (p=0.05), baseline tomonth 3 (p=0.005) and baseline toposttreatment month 4 (p-0.019).The comparison acupuncturetreatment group had no change inseverity from baseline over thetreatment phase.NRSleep disturbancesin the EA groupdeclined over thestudy and reached astatisticallysignificant difference(0.05) from baselinein posttreatmentmonth. This alsoaccured in thecomparison group.F-524

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearCleary, 1994Mood Cognitive Somatic Urinary Uterine BleedingReduction indepression in studygroup compared tocontrols (p = 0.042)at ten weeks and(p=0.290) at 15weeks; Reduction inirritability is studygroup compared tocontrols (p = 0.184)at ten weeks and(p=0.271) at 15weeksNR NR Reduction inurinaryfrequency instudy group overcontrols(p=0.021) at tenweeks and(p=0.168) at 15weeksSexual DysfunctionQuality of LifeNR NR Averagesymptom scoredecreased in thestudy groupcompared to thecontrol groupover the study(p=0.005)Cohen, 2003Mood changesdecreased in bothgroups betweenbaseline andposttreatmentmonth of the study;EA group p=0.05;comparisonacupuncture group(0.056)NR NR NR NR NR NRF-525

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearOther OutcomesWithdrawalsWithdrawalsdue to AEsAdverseEffectsNCCAMCategoryCommentsCleary, 1994Of the 11 hormones studied therewas a significant difference intestosterone levels (decreased instudy group) (p=0.028); Reduction inpain was greater in the study group:(p=0.04) for neck pain, and (p=0.06)for back painNR NR NR ManualMedicineCohen, 2003NR 1/18 Withdrew priortorandomizationNoneAlternativeHealthSystemsF-526

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearNType ofTrialComparisonCrisafulli, 2004 90 RCT P, HH 1 year Healthy, ambulatory women,referred by the Departmentof Internal Medicine and theDepartment of OB/GYN atUniversity of Messina, Italy,age 47-57Lengthof Trial Population Inclusion/Exclusion CriteriaInclusion:1. No surgical menopause patients2. No period for 12 months, FSH>50 and estradiol level10 cigarettes/dayDalais, 1998 52 DB RCT HH 7months52 postmenopausal womenwere recruitedInclusion:1. Age 45-652. FSH > 403. > 14 hot flashes/week4. 12 months of amenorrhea5. No antibiotic or hormone replacement therapy use forthe preceding 3 months6. Non-smoker and non-vegetarianF-527

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/YearMeasures UsedHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)Crisafulli, 2004Self-reported diary of the number of hotflushes, 14 days before eachassessment; only number used, notseverityNotallowedNotallowedNR NR NR Notallowed ifsmoked> 10cigarettes/dayNone for12 monthsAveragefor allgroupswas 23-24Dalais, 1998Hot flush diary NR NR NR NR NR Nonsmokers;nonvegetariansNone for 3monthspriorNRF-528

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearCrisafulli, 2004Main Drug type;dose;regimen1mg/day estradiolcombined withnoresthisterone;genistein (n=30) at54mg/dayOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepPlaceboEstrogen group, flush scoreNRNRdecreased by 53% (p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearCrisafulli, 2004Mood Cognitive Somatic Urinary Uterine BleedingSexual DysfunctionQuality of LifeNR NR NR NR NR NR NRDalais, 1998NR NR NR NR NR NR NRF-530

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearCrisafulli, 2004Other OutcomesWithdrawalsWithdrawalsdue to AEsAdverseEffectsNCCAMCategoryNR 7 None None BiologicallybasedtherapiesCommentsFunding source not reported;important study due to length.Dalais, 1998Urinary excretion of daidzein,genistein, enterodiol andenterolactone increased significantly(10-30 fold) during soy and linseedingestion, respectively (p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearNType ofTrialComparisonDavis, 2001 55 DB RCT P 12weeksLengthof Trial Population Inclusion/Exclusion CriteriaWomen, age 45-70 yearswere recruited through theJean Hailes FoundationNewsletter, newspapers,radio station interviews andthe medical unit of the JeanHailes FoundaionInclusion:1. Non-Asian women who had lived in Australia for atleast ten years2. Postmenopausal (>12 months amenorrhea and FSH>25)3. Reported at least 14 hot flushes or night sweats/weekExclusion:1. Use of HRT, Chinese medicinal herbs (CMH), or othernatural therapies during the eight weeks before baseline2. Preexisting gastrointestinal, renal, or liver disease,diabetes mellitus requiring treatment, uncontrolledhypertension, undiagnosed vaginal bleeding, systemicglucocorticosteroid use3. Undergoing cancer therapy4. Women who had consumed a high phytoestrogen dietfor the four weeks before baselineF-532

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/YearDavis, 2001Measures UsedDaily diary of the frequency of hot flushesand night sweats for four weeks beforetreatment and for the entire 12 weeks ofthe study period. The MenopauseSpecific Quality of Life Questionnaire(MENQOL) and urinary phytoestrogenexcretionHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)NR NR NR NR NR NR 44.4% ofplacebogroup hadpreviouslyused HRT,and 53.6%of CMHhaspreviouslyused HRTHigh orLow BMI(#/n)Bodymassindexwas 26.1(24.3,27.9) inplacebogroup;and 25.7(23.9,27.5) inCMHgroupF-533

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearDavis, 2001Main Drug type;dose;regimenBoth placebo andCMH produced byNingbo DaekangHerbs Co Ltd (Ningbo,China)Other Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepPlacebo was Frequency of vasomotorNRNRcornstarch with a bitter symptoms were reduced in bothtaste enhancer CMH and placebo groups.Difference between groups wasnot significant (p =0.09) Aprogressive decline in thefrequency of vasomotor symptomswith treatment duration was seenin both groupsF-534

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearDavis, 2001Mood Cognitive Somatic Urinary Uterine BleedingSexual DysfunctionQuality of LifeNR NR NR NR NR NR A reduction inscore was seen inall four domainsof the MENQOLscores. 'This wassignificant only forthe physical,vasomotor, andsexual domains inthe CMH group,and the physicaldomain in theplacebo group.The differencebetween the twotreatment groupswas notsignificant for anyof the fourdomainsF-535

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearDavis, 2001Other OutcomesWomen with more than four years ofammenorrhea had a significantlygreater response to placebo than toCMH; significant greater reduction inscore was seen with CMH comparedwith placebo in the vasomotordomain of the MENQOL for age

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearNType ofTrialComparisonDuffy, 2003 36 DB RCT P 12weeksLengthof Trial Population Inclusion/Exclusion Criteria36 postmenopausal women Inclusion:aged 50-65 were recruited bycircular email at King'sCollege London from adatabase of those who hadpreviously participated in astudy on bone mineraldensity at Guy's Hospital.1. No menstruation for the previous 12 monthsExclusion:1. Had used HRT in previous 12 months2. Use of antibiotics in the previous 3 months3. Current illness or use of psychoactive medication.Three subjects were excluded during the course of thetreatment, two because they started treatment withamitryptiline and one because she started HRTFaure, 2002 75 DB RCT P 4monthsPostmenopausal womenrequesting treatment for hotflushes.Inclusion:1. > 6 months out from last menses2. FSH >403. > 7 moderate to severe hot flashes per 24 hours4. > 6 weeks since last HRT useF-537

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/YearDuffy, 2003Faure, 2002Measures UsedHospital Anxiety & Depression Scale;Greene Climmacteric Scale; StanfordSleepiness Scale; Epworth SleepinessScale; paced Auditory Serial Additiontest; plus short-term memory test fromthe Weschler Memory Scale; plussamples from the Cambridgeneuropsychological Test AutomatedBattery 'list all the animals they couldthink of in 1 minute'Hysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)13-22% Included NR NR NR All None innonsmoker past 12s; caffeine monthsand alcoholassessed,plus diet;alcoholintakesignificantly less insoy group(p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearDuffy, 2003Main Drug type;dose;regimenSoya isoflavonesupplement used wasSolgen 40 (SolbarPlant Extracts,Ashdod, Israel). Eachcapsule contained 30mg total isoflavoneequivalents. Dosewas two capsules/dayfor 12 weeksOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepIdentical looking No significant effects of treatment NR No differenceplacebo capsules; told on any of the menopausalto avoid Soya foods symptoms assessed by theand food products Greene Climacteric Scalecontaining Soya for theduration of the study,and for the two weekspriorFaure, 200270mg/day of Genistenand Diadzin(Phytosoya) 325mgfour/day = 70mg ofG/DPlaceboThe Intention-to-treat analysisindicated treatment effect on thechange in frequency of hot flashesfor the intervention group(p=0.01).NRNRF-539

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearDuffy, 2003No differenceMood Cognitive Somatic Urinary Uterine BleedingSexual DysfunctionQuality of LifeSignificantimprovement inmemory in Solgengroup (delayedrecall of pictures(p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearOther OutcomesWithdrawalsWithdrawalsdue to AEsAdverseEffectsNCCAMCategoryCommentsDuffy, 2003Improved time to learn complextasks greater in Solgen group thanplacebo (p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearNType ofTrialComparisonLengthof Trial Population Inclusion/Exclusion CriteriaFreedman, 1992 33 RCT HH 4 weeks 33 women were recruited Inclusion:from newspaper1. Amenorrheic > 1 yearadvertisements; mean age in 2. > 5 hot flashes/dayyears was 50.7 + 8.6 inpaced respiration group; 53.1+ 6.0 in muscle relaxationgroup; and 53.9 + in alphawave feedback groupFreedman, 1995 24 RCT HH 4 weeks Women recruited fromnewspaper advertisement;Inclusion:1. Amenorrheic > 1 yearage was 52.5 years + 1.6 for 2. > 5 hot flashes/daypaced respiration group; 52.7+ 1.6 years for alphafeedback groupF-542

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearFreedman, 1992Measures UsedAmbulatory monitoring of sternal skinconductancelevel and abdominal andthoracic ventilation; in addition thoracicand abdominal ventilation were recordedon two additional channels of the Medilogusing inductance plethysmography(Respitrace); serum epiHysterectomy(#/n)BilateralOophorectomy(#/n)Specific Characteristics of PopulationPrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)Included Included NR NR NR NR None for 1yearHigh orLow BMI(#/n)NR(meanweightwithvariationrecordedinpounds)Freedman, 1995Ambulatory monitoring of sternal skinconductancelevel and abdominal andthoracic ventilation; in addition thoracicand abdominal ventilation were recordedon two additional channels of the Medilogusing inductance plethysmography(Respitrace); serum epinephrine andnorepinephrineIncluded Included NR NR NR NR None for 1yearNR(meanweightwithvariationrecordedinpounds)F-543

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearFreedman, 1992Main Drug type;dose;regimen8 1-hour biweeklytreatment sessions ofpaced respirationtrainingOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness Sleep8 1-hour treatment Hot flash frequency declinedNRNRsessions of alpha-EEG significantly (p0.2) or alphamuscle relaxation by a wave feedback group (p>0.5).research assistantusing previouslypublished methodsFreedman, 19958 1-hour biweeklytreatment sessions ofpaced respirationtraining8 1-hour treatment Hot flash frequency declinedsessions of alpha-EEG significantly (p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearFreedman, 1992Mood Cognitive Somatic Urinary Uterine BleedingSexual DysfunctionQuality of LifeNR NR NR NR NR NR NRFreedman, 1995NR NR NR NR NR NR NRF-545

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearFreedman, 1992Other OutcomesAnalysis of vafriance on respirationrate showed a significant (p0.5)WithdrawalsWithdrawalsdue to AEsAdverseEffectsNCCAMCategoryNR NR NR Mind-bodyinterventionsCommentsFreedman, 1995The 24-hour patern of skinconductancelevel of significantlyaltered for the paced respirationgroup (p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearNType ofTrialComparisonGermaine, 1984 26 RCT HH 6monthsLengthof Trial Population Inclusion/Exclusion CriteriaMenopausal women, 44-61years (Mean=50.3 years); 12premenopausal women, allreporting regular menstrualperiods from 22-45 servedas controlsInclusion:1. > 2 hot flashes/day2. No HRT3. No periodsHan, 2002 82 DB RCT P 5monthsWomen, age 45-55 yearsInclusion:1. Intact uterus2. FSH > 253. Estradiol < 204. Presence of hot flashes5. 'in menopause' at least 12 months Exclusion:1. Using lipid-lowering drugs, antidiabetic medications,soybean-derived products, or herbal supplements2. History of uncontrolled hypertension, stroke or TIA3. Cancer diagnosed less than 5 years ago4. Previous myocardial infarctionF-547

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/YearGermaine, 1984Measures UsedHeat stress test (HST); this is 2circulating water pads maintained at 42°C to the subjects torso whild supine on abed in a 23° C room. Subjects wereinstructed to signal the earliestperception of a hot flash by pushing ahand-held button; following the HST 1 the14 menopausal women were randomlyassigned to receive 6 weekly sessions ofprogressive musle relaxation or alphaEEG biofeedback; HSTs were thenadministered 1 week later and then finaltest at the end of training.Hysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)NR NR NR NR NR NR NR NRHan, 2002Kupperman Index; height, weight, bloodpressure, lipid, and hormone levels,transvaginal sonographyExcluded NR NR Excluded ifwithin past5 yearsNRAll Noneexercised allowed forless than 12 monthsthreetimes/week; 30%smokers inplacebogroup; 20%smokers inisoflavonegroup;NRF-548

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearGermaine, 1984Main Drug type;dose;regimenProgressive musclerelaxation (PMR)Other Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepAlpha EEGbiofeedbackIncrease in heart rate during theheating period, whereaspremenopausal women declinedin heart rate. Significant reductionin PMR group compared tocontrols during third HST(Significant test p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearGermaine, 1984Mood Cognitive Somatic Urinary Uterine BleedingSexual DysfunctionQuality of LifeNR NR NR NR NR NR NRHan, 2002Isoflavone groupimproved score overplacebo inmelancholia,nervousness(p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearGermaine, 1984Other OutcomesWithdrawalsWithdrawalsdue to AEsAdverseEffectsNCCAMCategoryNR NR NR NR Mind-bodyinterventionsCommentsNovel way of confirming thepresence of hot flushesHan, 2002All measures of Kupperman scale(vasomotor, paresthesia, insomnia,nervousness, melancholia, vertigo,weakness, arthralgia and myalgia,headache, palpitation, formication)showed individual statisticalimprovement in isoflavone groupover placebo (p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearNType ofTrialComparisonHartley, 2003 34 DB RCT P 1 week Postmenopausal womenaged 53-65 were recruitedfrom those responding toarticles in national and localpressLengthof Trial Population Inclusion/Exclusion CriteriaInclusion:1. No period for 12 months and healthy.Exclusion:1. Use of HRT within the previous 12 months2. Smoking more than 20 cigarettes/day3. Current illness or use of psychoactive medication,including soya supplements, Ginkgo or ginseng (herbswere allowed)Hirata, 1997 71 DB RCT P 24weeksWomen (mean age 52.4 + 6years) were solicited throughradio, television, andnewspaper and magazineinformation; age range wasfrom 44.7-69.3 years in theplacebo group and from 44.5to 59.6 years in the dongquai group.Inclusion:1. FSH > 302. 'troublesome' hot flushes >14/week3. 'post menopausal' for > 6 months4. No HRT for 3 monthsExclusion:1. Weight >30% or < 15% of ideal weight2. Previous hysterectomy, serious illness3. Use of herbal therapy during the previous 3 months4. Gastrointestinal disorders that resulted in chronicdiarrhea or malabsorption5. History of breast cancer, pelvic irradiation,6. Tobacco use, or consumption of > 2 alcoholic drinksper day7. Active liver disease8. Chronic use of antibiotics9. Use of vaginal creams or corticosteroidsF-552

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/YearHartley, 2003Measures UsedNational Adult Reading Test-Revisedversion; Hospital Anxiety and DepressionScale, Greene Climacteric ScaleStanfordSleepiness Scale, Epworth SleepinessScale, Immediate and delayed paragraphrecall from the Weschler Memory Scale-Revised, and several other brain functionmeasuresHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)Included Included NR NR NR SmokersincludedRecentdiscontinuationofHRT(#/n)None for12 monthsprior tostudyHigh orLow BMI(#/n)Mean66kgHirata, 1997Kupperman Index; symptom diary; serumestradiol, estrone, and sex hormonebindingglobulin levels; vaginal cells,endometrial ultrasounographyExcluded NR NR Excluded NR Smokersexcluded;more than2 alcoholdrinks/dayexcluded;57% wereregularexercisersNo HRTallowed forprevious 3monthsExcludedfor weight>30% or< 15% ofidealweightF-553

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearHartley, 2003Main Drug type;dose;regimenGinkyo One-A-Day120mg tablet/daycontaining 25%Ginkgo flavonoids and6% terpenoidsOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepPlaceboNo significant effect of treatmentNR No effecton any of the menopausalsymptoms assessed by theGreene Scale, however allimproved from baseline (p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearHartley, 2003Sexual DysfunctionNR NR NR One parameter ofGreene's scalethat did notimprove over timeMood Cognitive Somatic Urinary Uterine BleedingNo differencebetween groupsNot significantbetween groupsQuality of LifeNRHirata, 1997NR NR NR NR NR NR NRF-555

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearOther OutcomesWithdrawalsWithdrawalsdue to AEsAdverseEffectsNRNCCAMCategoryBiologicallybasedCommentsHartley, 2003NR 3 One in theplacebo groupbecause of briefmenstrualperiod and twoin the Ginkgogroup becausetesting was toodemandingHirata, 1997Both groups has significant decreasein Kupperman scale from baseline at6, 12, and 24 months (p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearHochanadel,1999NType ofTrialComparison11 DB RCT P 12weeksLengthof Trial Population Inclusion/Exclusion CriteriaNaturally postmenopausalwomen over age 45NRHudson, 1998 13 DB RCT P 3monthsWomen recruited from a onesentence article in TheOregonian (local newspaper)Inclusion:1. Hhot flashes and one additional menopause symptom2. No HRT for the previous 3 months3. Natural physiologic menopause with no menses for >3 months4. No serious acute or chronic disease5. No cariovascular disease and normotensiveHunter, 1999 86 RCT P 5 years All women were over 50years who had beenrandomized to two 90 minuteeducation groups or nointervention at age 45;Inclusion:1. Premenopausal at age 45, from the age/sex registersof five general practices in south LondonDetailed exclusion/inclusion criteria outlined in Maturitas1998:29:215-24F-557

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/YearHochanadel,1999Measures UsedSomatic symptoms, mood and verballearning performance of naturally postmenopausalwomen were measuredHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)Excluded NR NR NR NR NR NR NRHudson, 1998Self-reported symptom diary (frequencyand severity)NR Excluded NR NR NR NR No HRT for3 monthspreviouslyNRHunter, 19991. Sociodemographic and healthinformation survey2. Knowledge about menopausequestionnaire3. Menopause RepresentationQuestionnaire (MRQ)4. Women's Health Questionnaire(WHQ)NR NR NR NR NR Smokers &exercisers29% takingHRTNRF-558

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearHochanadel,1999Main Drug type;dose;regimen100 mg/day ofencapsulated soyisoflavoneOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepPlacebo No improvement No improvement NRHudson, 1998Botanical formula thatcontained 500mgcombined dry herb:burdock root (2 part),licorice root (2 part),motherwort (1 part),Dong Quai root (2part) and Mexican wildyam root (1 part) 2capsules tidRice bran placebo withsimilar smell andappearance also 2 tid.100% improvement in severitysymptom score in verum group(n=7) and 67% improvement inplacebo group (n=6). 71% inverum group had improvement innumber of symptoms and 17%had improvement in number ofsymptoms in placebo group. Onesided Z-test showed p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearHochanadel,1999Sexual DysfunctionMood Cognitive Somatic Urinary Uterine BleedingQuality of LifeNo improvement NR No improvement NRNo significantdifference betweengroupsNo significantdifferences betweengroupsNo significantdifferencesbetween groupsHudson, 1998NR NR NR NR NR NR NRHunter, 1999No difference indepression oranxietySignificantdifference inknowledge ofmenopause(p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearOther OutcomesWithdrawalsWithdrawalsdue to AEsAdverseEffectsNCCAMCategoryCommentsHochanadel,1999None of the statistical comparisonsbetween the active and placeboconditions yielded findings in supportof the hypothesis that soy isoflavonesmay be useful fo the treatment ofthese post-menopausal cognitive orsomatic changesNR NR NR BotanicallybasedPoster. Don't have actual paperHudson, 1998NR None None NR BotanicallybasedSize of study was too smallHunter, 1999Women in intervention groupmaintained better knowledge & didnot attribute so many things tomenopause.Women in prepared group took moreexercise (p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearHyde, 1983(Abstract Only)NType ofTrialComparisonLengthof Trial Population Inclusion/Exclusion Criteria30 RCT HH NR Menopausal women NRIrvin, 1996 45 RCT HH, P 10weeksPostmenopausal womenfrom the greater Boston arearecruited through mediasources of public serviceannouncements andnewspaper advertisements,and through posted noticesat appropriate medical sites,age 44-66Inclusioin:1.General good health2. > 6 months without a menstrual period3. Experiencing > 5 hot flashes per 24 hours4. Willingness to monitor flashes and abide by theprotocolF-562

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/YearHyde, 1983(Abstract Only)Measures UsedMenopausal symptoms checklist forfrequency, intensity and duration ofmenopausal symptoms; Galvanic skinresponsesHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)NR NR NR NR NR NR NR NRIrvin, 1996Spielberger State-trait Anxiety Inventory;Profile of Mood States; daily hot flashdiaryNR NR NR NR NR NR NR NRF-563

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearHyde, 1983(Abstract Only)Main Drug type;dose;regimen12 contingent GalvanicSkin Responsefeedback conditioningsessions andprogressive relaxationtrainingOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness Sleep12 non-contingent Both groups improved; NoNRNRfeedback sessions significant difference betweenand were told simply to groups was observedrelaxIrvin, 1996Relaxation group(RR); reading group(R) which served asthe placebointervention group, orthe charting groupwhich was the controlgroupReading group wasinstructed to readleisure material;relaxation groupinstructed indiaphragmaticbreathing and breathawareness; both 20minutes/dayAll three groups had a change inflash frequency, but these did notreach statistical significance. TheRR group did have a significantdecrease (p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearHyde, 1983(Abstract Only)Mood Cognitive Somatic Urinary Uterine BleedingSexual DysfunctionQuality of LifeNR NR NR NR NR NR NRIrvin, 1996On the POMS theRR groupdemonstrated asignificant decreasein tension-anxiety(p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearHyde, 1983(Abstract Only)Other OutcomesWithdrawalsWithdrawalsdue to AEsAdverseEffectsNCCAMCategoryNR NR NR NR Mind-bodyinterventionsCommentsIrvin, 1996NR 12/45 4 left becausethey foundcharting to betoo intrusive intheir lives, 3dropped outdue to snow; 2because theystarted theirmenses again,2 lack ofinterest, and 1who went onestrogentreatmentSeewithdrawalsMind-bodyinterventionsInclusion:1. Postmenopausal womensymptomatic, having > 3flushes/day2. > 6 months of amenorrhea orbilateral oophorectomy, FSH >40Exclusion:1. HRT within the previous 6weeks2. Allergy to foodstuffs known tocontain isoflavones3. Current history of active bowel,liver or gall bladder disease4. Diabetes requiring drug therapy5. Malignancy (excluding skincancers)6. Contraindications to HRT use,vegetarians and/or regular soyproduct users,F-566

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearNType ofTrialComparisonJeri, 2002 30 DB RCT P 16weeksLengthof Trial Population Inclusion/Exclusion CriteriaNonvegetarian Peruvianwomen who had beenpostmenopausal for morethan 1 year; median age was52 + 0.7 years for treatmentgroup and 51 + 0.8 years forcontrol groupInclusion:1. < 60 with FSH>30, having > 5 hot flushes/ dayaveraged for more than 1 week2. Not using HRT, antidepressants, or other medicationor soy or other estrogen-active plan productsKnight, 1999 37 DB RCT HH, P 12weeksWomen, age 40-65, wererecruited through theUniversity Department ofOB/GYN at St. GeorgeHospital, Sydney, AustraliaInclusion:1. Postmenopausal women symptomatic, having > 3flushes/day2. > 6 months of amenorrhea or bilateral oophorectomy,FSH >40Exclusion:1. HRT within the previous 6 weeks2. Allergy to foodstuffs known to contain isoflavones3. Current history of active bowel, liver or gall bladderdisease4. Diabetes requiring drug therapy5. Malignancy (excluding skin cancers)6. Contraindications to HRT use, vegetarians and/orregular soy product users,7. Receiving medications that result in liver enzymeinductionF-567

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/YearJeri, 2002Measures UsedSelf reported diary of frequency andseverity of hot flushesHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)NR NR NR NR NR NR Excluded NRKnight, 1999Greene Menopause Scale;self-reporteddiary of hot flushesNR Included NR Excluded NR NR Nonewithin 6weeksNRF-568

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearJeri, 2002Knight, 1999Main Drug type;dose;regimenPromensil (40 mgstandardizedisoflavones (genistein,daidzein, formononetinand biochanin))/dayPlacebo vs. 40mg ofPromensil vs. 160mgof PromensilOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepPlaceboReduction in both frequency andNRNRseverity of hot flushes wasreported by women in thetreatment group; 14 Promensilwomen had a 48% reduction frombaseline in frequency of hotflashes (p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearJeri, 2002Mood Cognitive Somatic Urinary Uterine BleedingSexual DysfunctionQuality of LifeNR NR NR NR NR NR NRKnight, 1999NR NR NR NR NR NR NRF-570

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearOther OutcomesWithdrawalsWithdrawalsdue to AEsAdverseEffectsNCCAMCategoryCommentsJeri, 2002Significant reduction in FSH inPromensil group from baseline(59.27 to 48.60) P

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearNType ofTrialComparisonKnight, 2001 24 DB RCT P 12weeksLengthof Trial Population Inclusion/Exclusion Criteria24 subjects were recruitedthrough the UniversityDepartments of Obstetricsand Gynecology , SydneyAustraliaInclusion:1. Postmenopausal women, having > 3 hot flushes/day;amenorrhea for 6 months, FSH >40 or bilateraloophorectomy2. Aged 40-65Exclusion:1. HRT within the previous 6 weeks2. Current history of active bowel, liver or gall-bladderdisease; diabetes requiring drug therapy; malignancy;contraindications to HRT use3. Vegetarians and regular soy-product users.F-572

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/YearKnight, 2001Measures UsedDaily flush diary; Green MenopauseScaleHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)Included Included NR Excluded NR NR Nonewithin 6weeksHigh orLow BMI(#/n)Mean of66.1-70.2kgF-573

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearKnight, 2001Main Drug type;dose;regimenIsoflavone powder,TakeCare, 60g/day;isoflavones134.4mg/day;(aglycone formulations77.4mg/day)Other Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepCasein basedpowdered drinkFlushing frequency decreased inboth groups, but there was notdifference in flushing frequencybetween the active and placebogroups; no difference in GreeneMenopause Symptom ScoresNRNRF-574

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearKnight, 2001Mood Cognitive Somatic Urinary Uterine BleedingSexual DysfunctionQuality of LifeNR NR NR NR NR NR NRF-575

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearOther OutcomesWithdrawalsWithdrawalsdue to AEsAdverseEffectsNCCAMCategoryCommentsKnight, 2001NR 4/24 3/12 in theisoflavonegroup..couldnot toleratetasteNoneBiologicallybasedF-576

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearKomesaroff,2001NType ofTrialComparison50 DB RCT P 3monthsLengthof Trial Population Inclusion/Exclusion CriteriaHealthy menopausal women45-60 years, currentlyexperiencing symptoms ofthe menopause, recruitedfrom the Baker InstituteMenopause Clinic, and fromthe local community byadvertisements placed inlocal newspapers anddiscussion in the electronicmedia. Mean age was 53.3+ 1.1 yearsInclusion:1. No HRT for > 6 weeks2. Last period > 12 months before, FSH>30 or estradiol

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/YearKomesaroff,2001Measures UsedSymptom diary self reported includingnumber of episodes of flushing andscores for specific symptoms. Symptomscores were combined to produce valuesfor 'total', flushing', and total non-flushing'scores. This approach made possibleanalysis of specific scores relating tomood, breast symptoms, libido andenergy levels.Hysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)3/50 NR NR NR NR NR Nonewithin 6weeksHigh orLow BMI(#/n)Mean of27.3 +0.8F-578

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearKomesaroff,2001Main Drug type;dose;regimenWild yam preparation(Biogest) supplied in100gram tubs.Participants wereasked to apply oneteaspoonful twice dailyto the arms, legs orabdomen(manuractures claimthat each 1 gram ofbioGest containsDioscorea villosaextract 100mg, Linumusitatissmum oil 2grams, Perlargoniumgraveolens oil 100mg,Salvia officinalis oil100mg and alphatocopheryl acetate10mg in a vegetablecream base).Other Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepPlaceboNo significant difference between NRNRthe yam cream and placebo in anyof the three casesF-579

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearKomesaroff,2001Sexual DysfunctionMood Cognitive Somatic Urinary Uterine BleedingQuality of LifeNR NR NR NR NR NR NRF-580

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearOther OutcomesWithdrawalsWithdrawalsdue to AEsAdverseEffectsNCCAMCategoryCommentsKomesaroff,2001NR19/25 in theBiogest groupattributed tounrelievedsymptomsandunspecifiedpersonalcircumstances. 8/25 in theplacebo groupfor samereasonsNo adverseeffectsNRBiologicallybasedF-581

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearKotsopoulos,2003NType ofTrialComparison94 DB RCT P 3monthsLengthof Trial Population Inclusion/Exclusion CriteriaWomen were recruited froma larger trial.Average age: 59-60 yearsInclusion:1. Aged 50-75 years2. Non smokers3. Non vegetarians4. > 12 months amenorrheic5. FSH >20Exclusion:1. On HRT in previous 12 months2. On phytoestrogens or soy based proteins3. On antibiotics in previous 3 monthsKritz-Silverstein,200356 DB RCT P 6monthsWomen were recruitedthrough mass mailingsbased on voter registrationlists, newspaper ads, andpresentations at localorganizations.Average age: 61 yearsAverage age at menopause:49 yearsInclusion:1. Postmenopausal women aged 55-74 yearsLeonetti,World Congresson Fertility, 1998(Abstract Only)90 RCT P 1 year 5 years of menopause,surgical or naturalNRF-582

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/YearKotsopoulos,2003Measures UsedValidated questionnaire of menopauseassociatedsymptoms (measure notstated by name).Hysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)NR NR NR NR NR 0/94 0/94 0/94Kritz-Silverstein,2003Beck Depression Inventory (BDI)The Mini-mental Status Examination(MMSE)Trials A & B of the Halstead-ReitanNeuropsychological Test BatteryCategory FluencyLogical Memory and RecallNR NR Yesexactnumber notstatedNR NR 2/56 drinksoybeveragesevery dayYesexactnumber notstatedNRLeonetti,World Congresson Fertility, 1998(Abstract Only)NR NR NR NR NR NR NR NR NRF-583

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearKotsopoulos,2003Main Drug type;dose;regimenOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness Sleep118mg Isoflavones Placebo No change between groups. No change betweengroups. Interventiongroup had asignificantimprovement(p=0.01).NRKritz-Silverstein,2003110mg/day ofIsoflavonesPlacebo NR NR NRLeonetti,World Congresson Fertility, 1998(Abstract Only)20mg/day of naturalprogesterone creamPlacebo83% of natural progesteronecream patients had improvementor resolution of vasomotorsymptoms compared with 14% ofplacebo group (p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearKotsopoulos,2003Mood Cognitive Somatic Urinary Uterine BleedingNR No change No change within NRbetween groups groups.No change withingroups forpsychologicaloutcomesSexual DysfunctionNo changebetween groups,both interventionand placebogroups improved(p=0.009 andp=0.015,respectively).Quality of LifeNRKritz-Silverstein,2003NRWomen in thetreatment groupshowedimprovement onfour of five testscompared tocontrols (p=0.03)NR NR NR NR NRLeonetti,World Congresson Fertility, 1998(Abstract Only)NR NR NR NR NR NR NRF-585

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearKotsopoulos,2003Kritz-Silverstein,2003Other OutcomesBoth intervention and placebo groupshad a significant improvement infacial hair (p=0.04 and p=0.014,respectively) and dry skin (p=0.0027and p=0.011, respectively).Withdrawals19/9410 intreatmentgroup9 in placebogroupWithdrawalsdue to AEsGastrointestinalside effectsAll were due toAEs (19)AdverseEffectsNone seriousTreatmentgroup: 7 -intolerable; 1 -weight gain; 1 -menopausalsymptoms; 1 -unrelatedPlacebo group:6 - intolerable;2 -constipation; 1 -allergiesNCCAMCategoryBiologicallybasedNR NR NR NR BiologicallybasedtherapiesCommentsOutcome was significant improvedperformance on category fluencyLeonetti,World Congresson Fertility, 1998(Abstract Only)NR NR NR NR BiologicallybasedF-586

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearLewis, 2002(Abstract Only)NType ofTrialComparison99 DB RCT HH, P 16weeksLengthof Trial Population Inclusion/Exclusion CriteriaPostmenopausal womenNRLindh-Astrand,200475 RCT HH 12weeks75 postmenopausalsedentary women withvasomotor symptoms, 48-63years of age, recruited byadvertisement in the localpapers and at thegynecological outpatientclinic of a hospital inSweden; mean age ofexercise group was 54 yearswith BMI of 24.6; estrogentreated women had meanage of 50.9 years and BMI of25.6Inclusion:1. Spontaneous menopause > 6 months previouslyExclusion:1. Severe endocrine, metabolic or thrombo-embolicdisease, uncontrolled hypertension, or daily use ofsedatives, anxiolytic or antidepressant medication2. Exercising regularly more than 1 hour/weekF-587

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/YearLewis, 2002(Abstract Only)Measures UsedMenopause Specific Quality of Life(MENQOL), plus daily diary of frequencyand severity of hot flashesHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)NR NR NR NR NR NR NR NRLindh-Astrand,2004Number of flushes during the last dayand night in a log-book which was filled inat bedtime for two weeks before andduring the 12 week treatment. Alsomeasured the severity of flushes (0-10);also completed questionnaires onaspects of quality of life at baseline,4,8,12, and 24 weeks, Kupperman Index,VAS to general summary of the totalclimacteric symptom intensity anddistress, MOOD Scale, SCL-904 None NR NR NR NR NonepreviousSeepopulationF-588

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearLewis, 2002(Abstract Only)Main Drug type;dose;regimenFlaxseed muffin vs.soy flour muffinOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepWheat flour muffin NR NR NRLindh-Astrand,20043 times weeklyexercise (15 women);also compared to 8wait listed women and4 women beingobserved in a parallelstudy on hot flushes inwomen with breastcancerOral estrogen (15women); 45 otherwomen randomized tothree additional arms(2mg/day)The severity of flushes decreasedsignificnatly p=0.041 in the 5exercising women, who continuedthe complete follup-up time of 36weeks (exercising the entire timeperiod). In the estrogen group themean number of flushesdecreased (p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearLewis, 2002(Abstract Only)Sexual DysfunctionMood Cognitive Somatic Urinary Uterine BleedingQuality of LifeNR NR NR NR NR NR NRLindh-Astrand,2004NR NR NR NR NR NR Kupperman'sIndex and MoodScale onlychangedsignificantly in theestrogen group(p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearOther OutcomesWithdrawalsWithdrawalsdue to AEsAdverseEffectsNCCAMCategoryCommentsLewis, 2002(Abstract Only)ANOVA on 4 domains showed nosignificant time by dietary groupinteraction in quality of life:vasomotor, psychosocial, sexual,physical or in combined score, hotflash frequency of hot flash severity.No MENQOL domains or hot flashsymptoms showed significant groupdifferences: however, all groupsshowed improvement with time7/33 from flax,3/33 fromsoy;3/33 fromwheatNR NR BiologicallybasedtherapiesLindh-Astrand,2004SCL-90, Kupperman's and VAS allchanged significantly p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearNType ofTrialComparisonMakkonen, 1993 30 DB RCT P 6monthsLengthof Trial Population Inclusion/Exclusion CriteriaWomen, mean age of 52.3 +2.7 years for guar gumgroup; mean age of 53.6 +4.0 in placebo groupExclusion:1. Uncontrolled hypertension, diabetes mellitus, liverdisease or thromboembolic disease2. Hormone therapy taken during previous three monthsMurkies, 1995 58 DB RCT HH 14weeksWomen were recruited frominterested patients in ageneral practice inMelbourne, Australia andnewspaper advertisementsInclusion:1. > 12 months of amenorrhea, and FSH>25,2. Hot flushes > 14/week3. Non-smokers4. Stopped antibiotics or hormonal replacement > 3months priorNachtigall, 1994 30 RCT HH 12weeksPost menopausal womenInclusion:1. > 1 year past their last menstrual period2. Not on any other HRT3. Cancer free4. Experiencing vaginal discomfort or dyspareunia.F-592

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/YearMakkonen, 1993Measures UsedKupperman Index, weight, height, bloodpresuure, serum estrone, estradiol,testoserone, androstenedione, FSH, LH,SHBG, TSH, total cholesterol, HDLcholesterol, triglycerides and fastingblood glucoseHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)NR NR NR NR NR 3 weresmokers inguar gumgroup;none inplaceboRecentdiscontinuationofHRT(#/n)At least 3months offHigh orLow BMI(#/n)WeightrecordedinkilogramsMurkies, 1995Diet diary; flush diary to record dailynumber of flushes; subjective four pointscale of 'general menopause symptoms'(flushes, sweats, palpitations, headache,sleep disturbance, depression, tiredness,irritability/nervousenss, frequency/urge tourinate, vagninitis, loss of libido,dyspareunia; vaginal smearsNR NR NR NR NR NonsmokersNone for 3months26.5 +0.76 forsoygroup;25.6 +0.68 forwheatgroupNachtigall, 1994Pap smear done every 4 weeks withspecific criteria for atrophy; Vaginal fluidpH; Vaginal health indexNR NR NR NR NR NR NotallowedNRF-593

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearMakkonen, 1993Main Drug type;dose;regimenGuar gum (Guarem,Orion Pharmaceutica,Espoo, Finland) 5grams 3 times daily for6 monthsOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepPlacebo was wheatflour granulesBoth groups improved significantlyon the Kupperman scale(p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearMakkonen, 1993Mood Cognitive Somatic Urinary Uterine BleedingSexual DysfunctionQuality of LifeNR NR NR NR NR NR NRMurkies, 1995Nachtigall, 1994NR NR NR Urinary daidzeinexcretionincreasedsignifiantly over12 weeks in themajority ofwomen in thesoy group withsignicantdifferencebetween groups(p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearMakkonen, 1993Murkies, 1995Other OutcomesSee note under hot flashes regardingKupperman Index scoresNo change in lipid panels betweengroupsWithdrawals3 withdrawalsfrom theplacebo group,one due todepressionandexhaustion,and two due totravelling. Nowithdrawalsfrom the guar5/28 withdrewfrom soygroup; 6/30withdrew fromwheat groupWithdrawalsdue to AEsAdverseEffectsNCCAMCategoryNA NA BiologicallybasedtherapiesNR NR BiologicallybasedtherapiesCommentsSoy Products of Australia donateddebittered soy and unbleachedrefined wheat flourNachtigall, 1994Vaginal elasticity improved in bothgroups (p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearNassef, The10th WorldCongress on theMenopause.2002(Abstract Only)NType ofTrialComparison37 RCT P 3monthsLengthof Trial Population Inclusion/Exclusion CriteriaPostmenopausal EgyptianfemalesNRPenotti, 2003 62 DB RCT P 6monthsWomen patients attendingthe outpatient MenopauseClinic at the University ofMulanInclusion:1. High FSH and low BE22. LDL < 1603. > 7 hot flashes/day4. Post menopausal for > 6 months5. Aged 45-60 years6. T score > -2.5Exclusion:1. OsteoporosisF-597

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearNassef, The10th WorldCongress on theMenopause.2002(Abstract Only)BilateralOophorectomy(#/n)Specific Characteristics of PopulationPrematureOvarianFailure(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)Measures UsedHysterectomy(#/n)BreastCancer(#/n)Use ofSERMS(#/n)NR NR NR NR NR NR NR NR NRHigh orLow BMI(#/n)Penotti, 2003Daily diary for hot flash recording NR NR NR NR NR NR NR 23.2 bothgroupsF-598

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearNassef, The10th WorldCongress on theMenopause.2002(Abstract Only)Main Drug type;dose;regimenCimicifuga rhizome40mg/dayOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepPlaceboNo difference (p>0.05) betweenNRNRgroupsPenotti, 200336mg Soy Isoflavonesa dayN/ANo change between groups, bothgroups had a 40% reduction in hotflashesNRNRF-599

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearNassef, The10th WorldCongress on theMenopause.2002(Abstract Only)Penotti, 2003Mood Cognitive Somatic Urinary Uterine BleedingSexual DysfunctionQuality of LifeNR NR NR No difference in NR NR NRdysuria or stressurinaryincontinencebetween groups(p>0.05)NR NR NR NR NR NR NRF-600

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearNassef, The10th WorldCongress on theMenopause.2002(Abstract Only)Other OutcomesBone aches were significantlyimproved in phytoestrogen group(p0.05)WithdrawalsWithdrawalsdue to AEsAdverseEffectsNCCAMCategoryNR NR NR BiologicallybasedCommentsPenotti, 2003NR6 in soy group7 in placebogroup1 from soygroup due todiarrheaPersistent hotflashes in therestDiarrheaBiologicallybasedF-601

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearNType ofTrialComparisonLengthof Trial Population Inclusion/Exclusion CriteriaRachev, 2001 64 DB RCT P 60 days Women age 40-60 from the Inclusion:'maternity ward' of the 1.Evident anxious-depressive symptoms associated withUniversity Hospital in Sofia, physiological menopause lasting for at least one yearBulgaria; mean age was 51.5 2. No treatment with phospholipids > 4 weeks priorin LF group and 49.5 in 3. No antidepressant or anxiolytic therapy during theplacebo group.studyExclusion:1. Sensory organ deficiency not properly corrected byartificial aids2. Signs or symptoms of foci of cerebral lesions,3. Signs or symptoms of other neurological and/orpsychiatric diseases requiring treatment with neurolepticdrugs and/or other antidepressants4. Liver or kidney impairment, severe cardiovasculardiseases, past or ongoing neoplastic diseases, othersever ongoing internal or surgical pathologies5. Proven hypersensitivity to phospholipidRankin, 1989 40 RCT Notreatment2 weeks Women, age 40-60 whostated they wereexperiencing menopausalsymptoms; referred to thestudy by other healthprofessionals and recruitedfrom church groups andvarious women'sorganizations. Mean agewas 49.3 years, range from40-58Inclusion:1. Understand and write EnglishF-602

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/YearRachev, 2001Measures UsedHamilton Anxiety Scale (HAMA) and theClimacteric IndexHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)NR NR NR NR NR NR NR Weightwasexpressed inkilograms, mean of71.3 forLF groupand 79.0for PgroupRankin, 1989Neugarten-Kraines Menopausal IndexScale, Sound Wave Audiotapes41% NR NR NR NR NR 5 (2/sound,3/control)had takenHRT for 1-12 yearsNRF-603

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearRachev, 2001Main Drug type;dose;regimenLiposom Forte(phospholipidliposomes) 28mg/2mlas a singleintramuscular injectionevery other day for aperiod of 60 daysOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepPlacebo injectionevery other day for 60daysSignificant decline in theclimacteric index in LF and Pgroups from baseline (p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearRachev, 2001Sexual DysfunctionQuality of LifeNR NR NR NR NR See climactericindex scoresunder hot flashesMood Cognitive Somatic Urinary Uterine BleedingDecrease in the totalHAMA score in bothgroups was noted(p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearOther OutcomesWithdrawalsWithdrawalsdue to AEsAdverseEffectsNCCAMCategoryCommentsRachev, 2001NR 6/64 Allergy = 1anxiety = 1;asthenia = 1;drowsiness = 2;hypertension =1;petechia = 1;increasedsweating = 1;paroxysmaltachycardia = 1;weightincrease = 1NRBiologicallybasedtherapiesNot sure that they did a good job ofconfirming symptoms were relatedto menopauseRankin, 1989NR6/20 in soundgroup; 7/20 inthe controlgroup4 completed theprotocol late,others did notfollowinstructions, ordid not havetime.None Mind-body Poor studyF-606

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearNType ofTrialComparisonRao, 2003 30 RCT P 2monthsLengthof Trial Population Inclusion/Exclusion CriteriaWomen with menopausalsymptomsNRRusso, 2003 50 DB RCT P 3monthsWomen who were referred toa clinic in Rome, Italy.Average age: 53 yearsAverage age at onset ofmenopause: 51 yearsInclusion:1. Aged 48-54 years2. Recent menopause (1-2 years LMP)3. Symptomatic4. Caucasian5. Negative PAP testExclusion:1. Currently on HRT or off

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/YearRao, 2003Measures UsedHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)Menopause-specific Quality of Life NR NR NR NR NR NR NR NRRusso, 2003Self report questionnaire. NR NR NR Excluded NR Smokersexcluded> 6 monthsdiscontinuationObesityexcludedF-608

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearRao, 2003Main Drug type;dose;regimenBiogest cream (wildyam)Other Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepPlaceboSignificant effects were noted with NRNRsymptoms of hot flushes, nightsweats, and emotional symptomswith dramatic reductions in thesesymptoms occurring in theBioGest group when comparedwith placebo.Russo, 200332mg/day of Soy(Fitormil)- Specificformulation describedin paperPlacebo11/25 in soy group and 6/25 inplacebo group describedimprovement in symptoms(p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearRao, 2003Mood Cognitive Somatic Urinary Uterine BleedingSexual DysfunctionQuality of LifeNR NR NR NR NR NR NRRusso, 2003No significantreductions for eithergroup on anxiety.NR NR NR NR NR NRF-610

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearRao, 2003Other OutcomesWithdrawalsWithdrawalsdue to AEsAdverseEffectsNCCAMCategoryNR NR NR NR BiologicallybasedCommentsAbstract only availableRusso, 2003NR 3 1 due tospotting after15 daysSpottingBiologicallybasedCross over study, only using datafrom first 3 months before crossover.F-611

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearNType ofTrialComparisonSalmaggi, 1993 80 DB RCT P 30 days Age 45-59 (mean age is 51)women patientsconsecutively referred to anOb/Gyn department in ItalyLengthof Trial Population Inclusion/Exclusion CriteriaInclusion:1. Major depression within 6 to 36 months followingsurgical or natural menopause2. Free of antidepressants for > 1 weekExclusion:1. Considered at risk for suicide2. On estrogen therapy3. Major medical illness or bipolar illnessSammartino,200370 RCT HH 12cyclesof 28daysWomen attendingMenopause Clinic.Average Age: 51 yearsAverage time sincemenopause: 17 monthsAverage BMI: 24-26Inclusion:1. At least 12 months after spontaneous menopause2. FSH > 403. Estradiol < 204. At least 7 hot flashes of moderate to severe severity in24 hours during last 2 weeksExclusion:1. Neoplastic, metabolic and infectious diseases2. Concomitant use of any drug3. BMI < 304. Past or concomitant use of HRT or other drug used fortreatment of climacteric symptoms5. Endometrial thickness of >5mm or endometrialabnormalitiesF-612

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/YearSalmaggi, 1993Measures UsedHAM-D-21 (Hamilton Depression RatingScale) and the RDI (Rome DepressionInventory); MMPI (Minnesota MultiphasicPersonality Inventory); CGI-I (ClinicalGlobal Impression Improvement Scale)Hysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)Included Included NR NR NR NR Notincluded ifonestrogenHigh orLow BMI(#/n)NRSammartino,2003Kupperman scale - Baseline and 6, 12months0 0 0 0 NR NR Excluded Excludedif >30F-613

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearSalmaggi, 1993Main Drug type;dose;regimen1600mg SAMe perday divided into 4dosesOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepPlacebo NR NR NRSammartino,200336mg/day of Genistein Calcium supplements Significant decline in KuppermanScore for Genistein group(p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearSalmaggi, 1993Sammartino,2003Sexual DysfunctionMood Cognitive Somatic Urinary Uterine BleedingQuality of LifeNR NR NR NRHAM-D-21decreasedsignificantly (p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearOther OutcomesWithdrawalsWithdrawalsdue to AEsAdverseEffectsNCCAMCategoryCommentsSalmaggi, 1993NR10/40 fromeach groupdue to poorcomplianceNR NR BiologicallybasedSammartino,2003All women in Genistein group had 3 in Genisteindecreased climacteric symptoms (but 4 in Calciumnot specified by symptom).None None BiologicallybasedF-616

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearNType ofTrialComparisonSandberg, 2002 30 RCT HH 14weeks,Followupat 6monthsLengthof Trial Population Inclusion/Exclusion CriteriaWomen age 48-60, naturalmenopause of at least 6months were recruitedthrough advertisements inthe local press and atgynecological outpatientclinics.Inclusioin:1. FSH and estradiol levels confirms postmenopausalstate2. Natural menopause of > 6 months3. Aged 48-60 yearsExclusion:1. Severe metabolic, thromboemboic, endocrine ormalignant disease, uncontrolled hypertension2. Use of medication that could interfere with vasomotorsymptomsScambia, 2000 39 DB RCT P 12weeksWomen who wereoutpatients at Italian hospital(mean age was 54 + 7.1years)Inclusion:1. Spontaneous amenorrhea > 12 months2. Surgical or early menopause3. Normal endometrial thickness by ultrasound, negativemammography, and metabolic and biochemical indexwithin normal rangeF-617

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/YearMeasures UsedHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)Sandberg, 2002Visual Analog Scale (VAS)SCL-90UnclearNotincludedNotincludedNR NR Similarrates ofsmoking &exerciseNR howrecent, nottakenduringstudy26.7 vs.25.6Scambia, 2000Vasomotor symptoms were evalutedusina a special score card and theGreene climacteric scale. Special scorecard was filled out daily to evaluate thenumber and severity of hot flushes andbrought it to each visitNR 1/50 1/50 NR NR NR NR BMI =26.2 +1.7F-618

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearSandberg, 2002Main Drug type;dose;regimenElectro acupuncture(EA)Other Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepExtremely superficialneedle insertionBoth groups showed improvementin VAS at 3 and 6 monthsNRNRScambia, 2000Standardized soyextract containing 12%isoflavones and 35%saponins in a tabletwhich was 200mgSOYSELECT 2/daywhich wouldcorrespond to50mg/day ofisoflavones. After 6weeks of treatmentPremarin was alsogiven to eachparticipant at a dose of0.625 for 4 weeksPlacebo tabletcontaining lactoseIn the first 6-weeks of treatment,participants who were taking thestandardized soy extract had asignificant reduction (p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearSandberg, 2002Mood Cognitive Somatic Urinary Uterine BleedingSexual DysfunctionQuality of LifeSignificantNR NR NR NR NR NRimprovement inmood at 12 weeksin EA groupcompared tobaselineBoth groupsimproved in SCL-90Scambia, 2000NR NR NR NR NR NR NRF-620

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearOther OutcomesWithdrawalsWithdrawalsdue to AEsAdverseEffectsNCCAMCategoryCommentsSandberg, 2002NR 4/15Superficialneedleinsertion4/15 EAHot flashes Hot flashes Alternativehealth caresystemsScambia, 2000NR20 wereanalyzed insoy extractgroupsuggesting nowithdrawalsNausea in 1placebomemberNRBiologicallybasedF-621

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesComparisonStudy/YearSimkin-Silverman, 2003NType ofTrial535 RCT Lifestylevs.assessmentonlyLengthof Trial Population Inclusion/Exclusion Criteria5 years Women were recruited fromthe WHLP clinical trials andwere seen at the HealthStudies Clinic at theUniversity of Pittsburg.Inclusion:1. Aged 44-50 years2. Premenopausal by self report3. Not taking HRT4. BMI was 20-34Exclusion:1. Women taking lipid-lowering medication,antihypertensive medication, insulin, thyroid medication,or psychotropic medicationsSt. Germain,200169 RCT Placebo 24weeksTelephone interviews of age42-62 year old women;Inclusion:1. > 10 hot flushes and/or night sweats/week, within 12months of their last menstrual cycle2. Free from chronic diseases (cardiovascular disease orosteoporosis) or chronic medication use3. Not taking HRT or ERT at the time of the study or 12months previously4. 1 or both ovaries remaining5. BMI 20-316. FSH>30.F-622

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/YearSimkin-Silverman, 2003Measures UsedWeight, BMI and body fat weremeasured.Paffenbarger Activity QuestionnaireThe Block Food FrequencyQuestionnaireHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)NR NR NR NR NR NR NR 58/535High BMISt. Germain,20015 day Menopausal Index (modified fromthe Blatt instrument, 1953) at baseline,week 12 and week 2411withintactovariesExcluded NR NR NR NonsmokingNone for12 monthsprior tostudy20-31F-623

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearSimkin-Silverman, 2003Main Drug type;dose;regimenBehavioral, dietary andphysical activityinterventionOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepN/A NR NR NRSt. Germain,2001SPI+ (Supro 675 HG;Protein TechnologiesInternational, St.Louis, MO = 80.4mg/day aglyconecomponents which arethe unconjugatedparent forms ofisoflavones)SPI- (Supro 675 IF;Protein TechnologiesInternational) = 4.4mg/day aglyconecomponents; Group 3consumed wheyprotein (control)produced by ProMod;Ross Laboratories,Columbus, OhioNo treatment effect on the changein frequency of hot flushes; time ofstudy from baseline did have asignificant effect on hot flushfrequency in all groups (p.0.003)No significantdifference amongthe three groups atany time pointNRF-624

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearSimkin-Silverman, 2003Sexual DysfunctionMood Cognitive Somatic Urinary Uterine BleedingQuality of LifeNR NR NR NR NR NRNo signs ofincreased stress ordepressivesymptoms inintervention groupSt. Germain,2001No significantdifference amongthe three groups atany time pointNR NR No significantdifferenceamong the threegroups at anytime pointNRNo significantdifference amongthe three groupsat any time pointNRF-625

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearSimkin-Silverman, 2003Other OutcomesWomen lost significantly more weightin the intervention group (p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearNType ofTrialComparisonTeoman, 2004 81 RCT ControlUsualcareLengthof Trial Population Inclusion/Exclusion Criteria6 weeks Volunteer postmenopausalwomen (average age 51.0 +3.9 years)Inclusion:1. Natural menopause2. Taking HRT > 1 year (0.625 mg estrogen and 2.5 mgmedroxyprogesterone/day)3. Aged 45-65 years old4. No health problems that may prevent from doingexercise5. No high cardiac riskThompson,2002(Abstract only)53 DB RCT P 16weeksWomen with breast cancerwith menopausal symptomsNRF-627

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/YearTeoman, 2004Measures Used6 minute walking test, vertical jump test,static back extension test, sit up test,side bending test, sit and reach test,balance test, quality of life using theNottingham Health ProfileHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)NR Excluded NR NR NR NR Must be onfor 12monthsHigh orLow BMI(#/n)27.0 + inexercisegroupand 25.4+ 4.0 incontrolgroupThompson,2002(Abstract only)Measure Yourself Medical OutcomeProfile (MYMOP), Hospital Anxiety andDepression score, EuropeanOrganization for Research andTreatment in Cancer Quality of LifeScore, Menopausal Symptom ScaleNR NR NR Included NR NR NR NRF-628

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearTeoman, 2004Main Drug type;dose;regimen6 weeks aerobicexercise programmeOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepNon-exercise controlNR NR NRgroupThompson,2002(Abstract only)HomeopathicinterventionPlaceboBoth groups showed significantimprovement over the study periodby an average of 80%. Nostatistically significant differencebetweeen groupsNRNRF-629

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearTeoman, 2004Thompson,2002(Abstract only)Mood Cognitive Somatic Urinary Uterine BleedingSexual DysfunctionQuality of LifeNR NR NR NR NR NR At the end of the6 weeks, therewas a statisticallysignificant changein the exercisegroup accordingto NHP, indicatingan improvementin the quality oflife (

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearOther OutcomesWithdrawalsWithdrawalsdue to AEsAdverseEffectsNCCAMCategoryCommentsTeoman, 2004NR NR NR NR ExerciseMind/bodyTurkeyThompson,2002(Abstract only)NR 8/43 NR NR BiologicallybasedtherapiesAbstract only; included as onlyhomeopathic RCT that could befound.F-631

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearNType ofTrialComparisonTice, 2003 252 DB RCT HH 12weeksLengthof Trial Population Inclusion/Exclusion CriteriaWomen were recruited from3 academic clinical researchsites in Oakland, CA;Minneapolis, MN, and IowaCity, Iowa from the generalpopulation throughnewspaper and radioadvertising, flyers posted inclinics and at health fairs,and directed mailingsInclusion:1. Age 45-60 years old2. Experiencing > 35 hot flashes/week3. FSH > 304. > 2 consecutive months of amenorrhea prior toenrollment with > 6 months of amenorrhea in the yearprior to entry, or documented bilateral oophorectomy.Exclusion:1. Vegetarians2. Consumed soy products more than once/week3. Took medications affecting isoflavone absorption(antibiotics, antacids) or hormonal preparations duringthe three months prior to enrollment4. Significant gastrointestinal disease5. > 2 alcoholic beverages/day6. Allergic to red clover7. Regular users of dietary supplements containingisoflavones8. Consumed less than 80% of the expected studytablets during the 2-week placebo run-in periodUnfer, 2004 376 DB RCT P 5 years Healthy voluntarypostmenopausal women;mean age was 49 + 4.3years in soy group; 50 + 3.9years in placebo groupInclusion:1. Intact uterus2. Absence of menses for > 12 months3. FSH >304. Body weight range within 20% of normalExclusion:1 Use of medication containing estrogens, progestins, orandrogens within 8 weeks of the beginning of the study2. Presence of endometrial hyperplasiaF-632

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/YearTice, 2003Measures UsedGreene Climacteric Scale; used thepsychological (anxiety and depression),somatic, vasomotor, and sexual desire;hot flash diary cardsHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)NR Allowed NR NR NR Excluded ifdrank >2alcoholicbeverages/dayRecentdiscontinuationofHRT(#/n)None for 3monthspriorHigh orLow BMI(#/n)26.3 +5.1 inPromensil group;25.6 +4.2 inRimostilgroup;26.5 +5.4 inplacebogroupUnfer, 2004Endometrial biopsies at the beginning ofthe study, after 30 months, and at theend of the studyExcluded Excluded NR NR NR NR None for 8weeks67 kg +10.2 kg insoygroup;65.8 +10.7 kg incontrolgroupF-633

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearTice, 2003Main Drug type;dose;regimenPromensil contains anaverage of 41.0 mg oftotal isoflavones/tablet(red clover containinga higher proportion ofbiochanin A andgenistein); Rimostilcontains average of28.6 mg of totalisoflavones and ahigher proportion offormononetin anddaidzein. Participantstook two tablets daily.Other Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepPlacebo that had lessthan 0.04 mg totalisoflavoneDecrease in hot flush count wassignificant for all three groups(p0.20).NRNRUnfer, 2004Soy tablets (3/day)equaled 150mg/day ofisoflavones;isoflavones were 40-45% genistein, 40-45% diadzein, and 10-20% glyciteinPlacebo NR NR NRF-634

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearTice, 2003Mood Cognitive Somatic Urinary Uterine BleedingSexual DysfunctionQuality of LifeNR NR NR NR NR NR NRUnfer, 2004NR NR NR NR NR NR NRF-635

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearOther OutcomesWithdrawalsWithdrawalsdue to AEsAdverseEffectsNCCAMCategoryCommentsTice, 2003Greene Symptom Scales; over the 6/25212-week treatment period, there weresignificant improvements frombaseline in all three groups, but therewas no statistically significantdifferences between groups on anyof the Greene scaleswithdrew 2from each ofthe 3 arms; 84participantswere inPromensilgroup; 83participantswere inRimostilgroup; 85participantswere inplacebo group1 from theRimostil groupThere was nostatisticallysignificantassociation ofeither of thedietarysupplementswith adverseeventsBiologicallybasedUnfer, 2004No cases of endometrial hyperplasiaor malignancy were detected at 30months; at 5 years, 6 cases ofendometrial hyperplasia weredetected in Group A (soy), none inGroup B (p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearNType ofTrialComparisonUpmalis, 2000 177 DB RCT P 12weeksValente, 10world congresson themenopause,2000(Abstract Only)Lengthof Trial Population Inclusion/Exclusion CriteriaPostmenopausal women age> 50 years100 RCT HH NR Menopausal women NRInclusion:1. Overall good health2. Body weight within +/- 35% range for body mass index3. FSH >404. Estradiol levels of 25 pg/mL or less5. Average of > 5 vasomotor symptoms/day6. No menses for at least 6 months7. Discontinued HRT use at least 60 days before studyentryExclusion:1. History of breast cancer, hyperplasia, endometrialcarcinoma, or cervical neoplasia2. Positive pregnancy test3.Undiagnosed abnormal vaginal bleeding4. Bilateral oophorectomy or hysterectomy5. Thromboembolic disorders6. History of cardiovascular disease7. Liver disease8. History of chronic alcoholism9. Medication hypersensitivity, or allergy to dietarysupplement ingredients10. Uncontrolled addiction or severe depression11. Acute systemic infection12. Abnormal laboratory valuesF-637

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/YearUpmalis, 2000Measures UsedDaily symptom dairy cards for recordingthe number and severity of hot flushesand night sweatsHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)Excluded Excluded NR Excluded NR NR Discontinue > 60days priorHigh orLow BMI(#/n)SeeinclusioncriteriaValente, 10world congresson themenopause,2000(Abstract Only)Neurovegetative symptoms, vaginaldryness, endometrial pattern, lipids, bonedensityNR NR NR NR NR NR NR NRF-638

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearUpmalis, 2000Main Drug type;dose;regimenSoy isoflavone extracttablet. The extractwas standardized fortotal content ofgenistin and daidzin(approximately 50%each). The dosecontained in twotablets taken oncedaily wasapproximately 50mg intotal of genistin anddaidzinOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepPlaceboThere was a significant (p0.05) in frequencyof night sweatsValente, 10world congresson themenopause,2000(Abstract Only)50 women treated withphytoestrogens (25with oral and 25 withpatch, 75mg/day)50 with HRT, patch(Estradiol 2.5mg andLevonorgestrel 1mg)"Phytoestrogen therapy cannot beconsidered as valid as HRT"NRNRF-639

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearUpmalis, 2000Sexual DysfunctionMood Cognitive Somatic Urinary Uterine BleedingQuality of LifeNR NR NR NR NR NR NRValente, 10world congresson themenopause,2000(Abstract Only)NR NR NR NR NR NR NRF-640

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearOther OutcomesWithdrawalsWithdrawalsdue to AEsAdverseEffectsNCCAMCategoryCommentsUpmalis, 2000NR31/90 thoserandomized tosoy groupwithdrew;24/87withdrew fromplacebo groupFailure to meetinclusion/exclusion criteria;protocolviolations;voluntarydiscontinuation;NRBiologicallybasedtherapiesOdd study design in thatrandomization occurred prior toscreening for inclusion/exclusioncriteriaValente, 10world congresson themenopause,2000(Abstract Only)NR NR NR NR BiologicallybasedF-641

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/Yearvan de Weijer,2002NType ofTrialComparison30 DBRCT P 12weeksLengthof Trial Population Inclusion/Exclusion CriteriaSymptomaticpostmenopausal women,age 49-65Inclusion:1. > 5 hot flushes/day2. > 12 months amenorrheaExclusion:1. HRT or antibiotics within 12 weeks of study entry2. Undiagnosed vaginal bleeding, active liver or renaldisease3. History of allergy for foodstuffs4. Previous history of malignancy, cardiovascular diseaseor thromboembolismWashburn, 1999 51 DB RCT HH 6 weeksthencrossoverPerimenopausal womenaged 45-55 years; womenwere recruited throughadvertisements in a localnewspaperInclusion:1. Presence of menopausal symptoms (> one hot flushor night sweat daily)2. Not currently using HRT (or any HRT in the past 6months)3. Missing > 3 menstrual periods in the last 12 monthsand having last menstrual period not > 12 months beforeparticipating in the studyF-642

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/Yearvan de Weijer,2002Measures UsedGreene Climacteric Scale; self-reporteddiaryUrinary isoflavone levelsHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)NR NR NR Excluded NR NR None for12 weeksprior tostudyHigh orLow BMI(#/n)BMI was24.8 +3.0 forplacebogroupand 26.4+ 5.4 forPromensil groupWashburn, 1999Self reported symptom diary of hotflashes and night sweats; both frequencyand severity; A health related quality oflife questionnaire was administered atbaseline and at the end of each 6 weekintervention period. Using the healthrelated quality of life questionnaire data,an overall symptoms core was calculatedby using the Likert scale information forthe following content specific areas:estrogenic symptoms, general health,sleep disturbances, and gastrointestinalsymptoms. Specifically, the estrogensymptom score was calculated to providea continuous estimate of theintensity/frequency of symptoms knownto be estrogen-dependent (vasomotorsymptoms, vaginal dryness, sleepdisturbances, breast tenderness, moodNR NR NR NR NR NR > 6 months Meandiscontinua-weightionwas163.4lbsF-643

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/Yearvan de Weijer,2002Main Drug type;dose;regimenRed clover (Promensil)80 mg/dayOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepIdentical placebo No difference in the hot flushNRNRcount between the 2 groups atbaseline 1. At week 12 there hadbeen a significant decline in hotflushes in the isoflavone users(p=0.0154)Washburn, 1999Group 1: 20 gramscomplexcarbohydratedsupplement containingno phytoestrogen;Group 2: 20 grams ofsoy proteinsupplement containing34 mgphytoestrogen/day;Group 3: 20 grams soyprotein supplementcontaining 34 mgphytoestrogens splitinto two equal dosesconsumed twice daily.All supplements wereprovided by ProteinTechnologiesInternational, St.Louis, Missouri. Allidentical appearingpacketsNo significant differences wereobserved in the number of hotflushes or night sweats/week;however, severity of hot flasheswas lower in the soy groups vs.the carbohydrate group (p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/Yearvan de Weijer,2002Mood Cognitive Somatic Urinary Uterine BleedingSexual DysfunctionQuality of LifeNR NR NR NR NR NR Greene scoresdifferences didnot reachsignificanceWashburn, 1999NR NR NR NR NR NR General healthscore was notsignificantlydifferent betweengroupsF-645

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearOther OutcomesWithdrawalsWithdrawalsdue to AEsAdverseEffectsNCCAMCategoryCommentsvan de Weijer,2002Isoflavone urinary excretionincreased significantly for women inthe active treatment group (p=0.027).(p=0.0005) from baseline of 4 weekwashout period3/16 red clovergroup; 3/14control groupZeroWithdrawalswere due tolack of efficacyN/ABiologicallybasedtherapiesRed clover was manufacturedfrom three varieties of red cloverusing a standardized extractionand blending process to obtain aproprietary ratio of daidzein,genistein, biochanin andformononectin.Washburn, 1999Estrogenic symptom score' wassignificantly different from thecomparison group (p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearNType ofTrialComparisonWiklund, 1999 384 DB RCT P 16weeksWilliamson,200280 RCT HH 19weeksLengthof Trial Population Inclusion/Exclusion CriteriaWomen were recruitedthrough advertisements innewspapers. Womenseeking medical assistancedue to climacteric symptomswere asked to participate inthe trial as well.Women age 45-60 with noperiod for 3 months.Recruited by means ofnotices placed in primarycare surgeries.Inclusion:1. Healthy postmenopausal women, aged 45-642. No HRT for the previous 2 months3. No bleeding during the previous 6 months4. 6 episodes of hot flushes during at least 3 of the past 7days.Exclusion:1. Previous or concomitant serious or chronic medicalconditions2. Uncontrolled hypertension (>160/95)3. Psychiatric illness4. Unable to understand and complete the QoLquestionnaires5. Taking tranquilizersExclusion:1. Current HRT use or psychoactive medications2. Severe pathology of feet3. Previous reflexology treatment4. Current CAM treatment for menopausal symptoms or5. History of severe psychological illnessF-647

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/YearWiklund, 1999Williamson,2002Measures UsedWomen's Health Questionnaire;Psychological General Well-being Index;Visual Analog Scales (VAS); selfreporteddiaryWomen's Health Questionnaire; VAS forseverity of flushes and night sweats,MYMOP, a validated, self-completedmeasure of quality of lifeHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)NR NR NR Excluded NR NR None for 2monthsHigh orLow BMI(#/n)Reportedin kg,withmean71.1(11.6) forginsenggroup(n=193)and 69.9(11.5) forplacebogroup(n=191)NR NR NR NR NR NR Required NRF-648

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearWiklund, 1999Main Drug type;dose;regimenStandardized ginsengextract (Ginsana,containing 100mg ofthe standardizedginseng extract G115;Pharmaton SA,Lugano, Switzerland);2 capsules/dayOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepPlaceboBoth treatments improvedNRNRvasomotor symptoms comparedwith baseline (p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearWiklund, 1999Sexual DysfunctionQuality of LifeNR NR NR NR NR With regard to theprimary endpoint(total score of thePGWB index)only a tendencyfor slightly betteroverallsymptomaticrelief (p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearOther OutcomesWithdrawalsWithdrawalsdue to AEsAdverseEffectsNCCAMCategoryCommentsWiklund, 1999NR3/193 ginsenggroup; 2/191placebo group1/193 in theginseng groupdue to nauseaand lack ofefficacySeewithdrawalsBiologicallybasedWilliamson,2002Feelings of attractiveness no change. 5/38 controlp>0.2 for time-group interaction. 6/42p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearNType ofTrialComparisonWoo, 2003 136 RCT HH 3monthsLengthof Trial Population Inclusion/Exclusion Criteria50-65 year old women with Inclusion:no periods for the past 12 1. No period for 12 monthsmonths; contacted as part of Exclusion:a territorywide survey andrandom sampling of housingestates, and participants whoare registered with theFamily Medicine clinic of theChinese University of HongKong1. Hypertension, ischemic heart disease, stroke,dementia, diabetes, thyrotoxicosis, breastlump/malignancy, or abnormal Pap smear2. Taking lipid lowering drugs or HRTWuttke, 2003 62 DB RCT HH, P 12weeksNRInclusion:1. Postmenopausal women, 40-60 years of age2. BMI < 303. Last menstrual bleeding at least 6 months ago4. FSH>255. > 3 hot flushes/day6. Menopause rating scale (MRS) items 1-6, sum ofscores >1.7 at visits 1 and 2; MRS item 1 (hot flushes)>0.3 at visits 1 and 2.F-652

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/YearMeasures UsedHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)Woo, 2003Menopausal symptoms questionnaire;MMSE, plus four neuropsychologicaltests covering measurement of memory(Hong Kong List-Learning test, attention(Trail Making test), motor speed (FingerTapping Test), and word-finding ability(Boston Naming Test), quality of life(SF36), Food Frequency Questionnaire;lipid profile; urinary deoxypyridinoline;dietary phytoestrogen intake and urinaryphytoestrogen; estradiol; FSH and LH24% 18% NR Excluded NR 100% nonsmokersNotallowed24Wuttke, 2003Menopausal rating scale NR NR NR NR NR NR NR Excludedif >30F-653

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearWoo, 2003Main Drug type;dose;regimenPueraria lobata (PL)Isoflavone 100mg/day;plus a control groupwhere women weregiven no treatmentOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepHRT; Premelle(Wyeth) containingconjugated equineestrogen (o.625 mg)for first 14 daysfollowed by 14 days ofcombination ofestrogen plusprogesterone (5mg)No significant change inmenopausal symptoms betweenbaseline and 3 months in any ofthe groupsNRNRWuttke, 2003Cimicifung racemosa(CR BNO 1055) brandnameKlimadynon/Menofem,correlating to 40mgherbal drug/day; andplaceboConjugated estrogen0.6mg/dayMRS items 1-3 (#1 related to hotflashes) were significantly reducedby the CE compared to placebo(p=0.0461). CR BNO 1055showed a marked difference toplacebo, without reaching the levelof significance.NRNRF-654

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearWoo, 2003Sexual DysfunctionQuality of LifeNR NR NR NR SF-36, nodifferences in anygroupsMood Cognitive Somatic Urinary Uterine BleedingNR1. No change in anygroup except MMSEincreased for bothHRT & PL2. Delayed recallimproved in HRT vs.control3. Attention spanbetter in HRT & PL4. Performance inflexible thinking bestin PL groupWuttke, 2003NR NR Factor 3(questions 7-10on the MRSscale) whichrelate to urinaryand sexualsymptoms didshow significantimprovement withthe black cohoshvs placebo(p=0.0218); CEapproachedsignificance(p=0.0503)NR NR NR MRS score (items1-10)demonstrates anobvious placeboeffect over the 12-week treatmentperiod, which wasoutmatched byCR BNO 1055and CE. Theseeffectsapproachedsignificance,p=0.0506 andp=0.0513F-655

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearOther OutcomesWithdrawalsWithdrawalsdue to AEsAdverseEffectsNCCAMCategoryCommentsWoo, 2003NR5/48 HRT2/47 PL2/41 controlHRT = Abdominal Biologicallyabdominal pain, pain,baseddistension, and distention,acne or too acne, too busy,busy; PL group urticania= urticaria andbeing too busy;control group =being too busyp values not clear in articleregarding cognitive changes,probably

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearNType ofTrialComparisonWyon, 1995 24 RCT P 3monthsLengthof Trial Population Inclusion/Exclusion Criteria"Ordinary" women patientswho attended the outpatientclinic because of vasomotorsymptoms and were primarilyinterested in HRTMedian age was 54 with arange from 47-62Inclusion:1. Healthy women with vasomotor symptoms2. Natural menopause at least 1 year previouslyExclusion:1. Severe metabolic, thromboembolic, or endocrinedisease2. Uncontrolled hypertension (>95mg Hg diastolic)Wyon, 2004 45 RCT HH, P 12weekswith 6monthfollowupLocal newspaper andgynecological clinic inSwedenYoles, 2002(Abstract Only)102 RCT P 6monthsNRInclusion:1. Healthy women with vasomotor symptoms2. Age 48-63 years3. Natural menopause > six months prior (4 hadhysterectomy, however, none had bilateraloophorectomy)Exclusion:1. Severe metabolic, thrombo-embolic, or endocrinedisorders2. Severe hypertension (>95mg Hg diastolic)3. Use of sedatives, anxiolytics, or antidepressants, ornarcotics.NRF-657

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesSpecific Characteristics of PopulationStudy/YearWyon, 1995Measures UsedDaily symptom dairy; PsychologicalGeneral Well-Being Index; SleepDysfunction Test; modified KuppermanIndexHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)Excluded Excluded Excluded NR NR NR NotallowedHigh orLow BMI(#/n)NRWyon, 2004Kupperman Index; visual analog scale;self-reported daily symptom diary offrequency and severity of menopausalsymptoms4/45 Excluded NR NR NR Excluded ifexercised> 1hour/week;20-31%smokersNR 19.5-36.6;average25.6 -26.4Yoles, 2002(Abstract Only)Detailed questionnaire regarding patients15 variables of patients menopausalcomplaintsNR NR NR NR NR NR NR NRF-658

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesTreatmentMain OutcomesStudy/YearWyon, 1995Wyon, 2004Main Drug type;dose;regimenAcupuncture to VB 15,23, 32; GV20; H7; P6;LIV3; SPG, Eachtreatment given twicea week for 2 weeksand once week for 6weeks for 30 minuteseach.Electro acupuncture(EA) 14 treatmentsover 10 weeks sitesBL 15, 23, 32, HT 7,SP 6, 9 LR 3, PC 6,GV 20Other Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepSuperficial needleinsertionConjugated estrogen0.625mg/day vs.superficial needleinsertion (SNI) (shamacupuncture) atBaseline, Week 15,23, and 32No significant differences werefound between groups on anymeasure, before, during, or 3months after treatment; Number ofhot flushes/day decreasedsignificantly in both groups frombefore to the first as well as thesecond treatment period (p=0.013and 0.0033 in the EA group, p =0.005 and 0.0093 in the SNIgroup)Hot flushes decreased in all 3groups over the 12 weeks(p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesMain Outcomes (cont.)Study/YearWyon, 1995Mood Cognitive Somatic Urinary Uterine BleedingSexual DysfunctionQuality of LifePGWB index did not NR NR NR NR NR NRchange significantlyin any group duringtreatmentWyon, 2004NR NR NR NR NR NR NRYoles, 2002(Abstract Only)Nervousnessimproved in 56%takingphytoestrogen vs14% placebo(p

Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesStudy/YearOther OutcomesWithdrawalsWithdrawalsdue to AEsAdverseEffectsNCCAMCategoryCommentsWyon, 1995Visual analog scale decreasedsignificantly in the EA group but notthe SNI group (p=0.008); KuppermanIndex decreased significantly in bothgroups (p

Appendix F: Evidence table 6-8. Key Question 3G-I complementary and alternative therapiesKey/AbbreviationsAE = Adverse effectsBDI = Beck Depression InventoryBMI = Body mass indexBSO = Bilateral Salpingo OophorectomyCAM = Complimentary and Alternative MedicineCE = Conjugated estrogenCGI = Clinical Global Impression Improvement ScaleCMH = Chinese medicinal herbsDB = Double blindEA = Electro acupunctureERT = Estrogen replacement therapyG/D = Genisten and Diadzin combination therapyGI = GastrointestinalHAMA = Hamilton Anxiety ScaleHAM-D-21 = Hamilton Depression Rating ScaleHH = Head to headHRT = Hormone replacement therapyHST = Heat stress testKK = KavaKavaLF = Liposom Forte (phospholipid liposomes)LMP = Last menstrual periodMENQOL = Menopause Specific Quality of Life QuestionnaireMMPI = Minnesota Multiphasic Personality InventoryMMSE = Mini-mental Status ExaminationMRQ = Menopause Representation QuestionnaireMRS = Menopause rating scaleMSQ = Menopause symptoms questionnaireMYMOP = Measure Yourself Medical Outcome ProfileNA = Not applicableNHP = Nottingham Health ProfileNR = Not reportedOC = Oral ContraceptivesP = PlaceboPE = PhytoestrogenPGWB-I = Psychological General Well-being IndexPL = Pueraria lobataPMR = Progressive muscle relaxationPOF = Premature ovarian failurePOMS = Profile of Mood StatesQoL = Quality of lifeR = ReadingRCT = Randomized controlled trialRDI = Rome Depression InventoryRR = RelaxationSAMe = S-adenosyl-L-methionineSD = Standard deviationSERMs = Selective Estrogen Receptor ModifiersSNI = Superficial needle insertionTCM = Traditional chinese medicineTIA = Transient ischemic attackVAS = Visual Analogue ScaleWHLP = Women's Healthy Lifestyle ProjectWHQ = Women's Health QuestionnaireF-662

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerStudy/Year N Type of TrialBarton, 1998 125 RCT crossoverComparisonPLengthof Trial Population Inclusion/Exclusion Criteria9 weeks Women over age 18 with ahistory of breast cancer.Inclusion:1. Hot flashes for > 1 month with a frequency of > 14 times perweek.2. Life expectancy > 6 months.3. ECOG performance status of 0 or 1.4. Tamoxifen allowedExclusion:1. Current or planned therapy with corticosteroids,progestational agents, estrogens, androgens, chemotherapy,any other agen used for treating hot flashes, or more than 60 IUof vit E daily.2. Pregnant or lactating women.3. Women with a history of bleeding tendencies, immunedeficiencies or thrombophlebitis.Barton, 2002(abstract)80 Open trial HH 4 weeks NR NRF-663

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerSpecific Characteristics of PopulationStudy/YearMeasures UsedHysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)Barton, 1998Documentation of hot flashesnumber and severity using adiary questionnaire (citesBergman, Loprinzi studies).NR NR NR 100% 54% Vitaminuse inTable 1NRNRBarton, 2002(abstract)Hot flash diary: frequencyand score (daily frequency xscore)NR NR NR 100% NR NR NR NRF-664

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerTreatmentMain OutcomesStudy/YearBarton, 1998Main Drug type; dose;regimenVitamin E succinate 800 IU daily for 4weeks followed by placeboOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepPlacebo for 4 weeksfollowed by vitaminEAt the end of 4 weeks, HF frequencydecreased 25% in vitamin E group ascompared to 22% in the P (p=0.90). HFscore decreased 28% with vitamin E and20% with P (p=-0.68). Both groups hadstatistically significant within groupdecreases by Wilcoxon's sign rank.At the end of 9 weeks, vitamin E/P grouphad decrease in HF frequency and HFscore that was greater than the P/vitaminE group, P

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerMain Outcomes (contiued)Study/YearBarton, 1998UterineMood Cognitive Somatic Urinary Bleeding Sexual Dysfunc-tion Quality of LifeNR NR NR NR NR NR NRBarton, 2002(abstract)NR NR NR NR NR NR NRF-666

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerStudy/YearBarton, 1998Other Outcomes Withdrawals Withdrawals due to AEs Adverse Effects Comments102 women responded toquestion about preferenceat the conclusion of thestudy:32% preferred vitamin E;29% preferred placebo;38% did not have apreference.4 prior toinitiation of drug.NoneNo significantdifferences inreporting of:1. headaches16/120in vitamin E; 17/120 inP (p=0.85)2. nausea 11/120 invitamin E; 11/120 in P(p=0.99)3. fatigue 20/120 invitamin E; 25/120 in P(p=0.31)4. other: 18/120 invitamin E; 13/120 in P(p=0.43).125 women randomized; 5 in theplacebo group withdrew before startingtheir medication.RCT cross-over tiral, but stratified byage (18-49 vs 50 and older), currenttamoxifen use, duration of hot flashes(>/< 9 mo), average frequency offlushes and current MVI use.Barton, 2002(abstract)"these antidepressantsappear to ameliorate othermenopausal relatedsymptoms such as difficultysleeping, anger anddepression."NR NR NR Pilot of 4 anti-depressant medications(venlafaxine, nefazadone, citalopram,mirtazapine)F-667

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerStudy/Year N Type of TrialBertelli, 1999 71 Open label(abstract)RandomizedComparisonLengthof Trial Population Inclusion/Exclusion CriteriaHH 6 weeks NR 71 post-menopausal breast cancer survivors with at least 7HF/week.Carpenter,200215 RCT crossoverP72 hours Postmenopausal women Inclusion:ecah >18 years (some1. Women > 18 yearsarm postmenopausal at early age 2. 1st time diagnosis of breast cancerfollowed due to chemotherapy)by 2daysobservationperiodand 10daywashout3. No other type of cancer4. Currently free of cancer or competing treatment5. > 12 months of ammenorrhea6. Expereincing HF7. Able to speak, write, and read EnglishExclusion:1. Contraindication to magnets (i.e. implanted devices)2. Concurrent use of magnets for other symptoms3. Concurrent use of other HF treatmentsF-668

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerStudy/YearBertelli, 1999(abstract)BilateralOophorectomySpecific Characteristics of PopulationPrematureOvarianFailureBehaviororLifestyleFactorsRecentdiscontinuationofHRTMeasures UsedHysterectomy(#/n) (#/n) (#/n)BreastCancer(#/n)Use ofSERMS(#/n) (#/n) (#/n)High orLow BMI(#/n)HF frequency and score NR NR NR 100% NR NR NR NRCarpenter,20021. HF monitor - ambulatorysternal skin conductancemonitoring2. HF diary (number of HF,date/time, severity 0-10,degree of bothered 0-10)3. HF related dailyinterference scale (HFRDIS) -10 item scale measuresdegree to which HF interfereswith 9 daily activities andoverall quality of lifeNR NR NR 100% NR NR NR Mean 28.8(SD 5.7)F-669

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerTreatmentMain OutcomesStudy/YearBertelli, 1999(abstract)Main Drug type; dose;regimenOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepDepot IM medroxyprogesterone acetate MPA vs MA HF frequency was reduced by 87% andNRNR(MPA) 500 mg IM on days 1, 14, and 28HF score was reduced by 89% asvs oral megestrol acetate (MA) 40compared to baseline, with no significantmg/day for 6 weeks.diffferences between groups.Response (>50% reduction in HF)observed in 28/37 (75%) off MPA and22/34 (64%) of MA groups, p=0.7Follow-up 6 months after randomization:25/28 (89%) of MPA vs 10/22 (42%) MAmaintained response (p

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerMain Outcomes (contiued)Study/YearBertelli, 1999(abstract)UterineMood Cognitive Somatic Urinary Bleeding Sexual Dysfunc-tion Quality of LifeNR NR NR NR NR NR NRCarpenter,2002NR NR NR NR NR NR Overal quality of life was notsignificantly different betweengroups.F-671

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerStudy/YearBertelli, 1999(abstract)Other Outcomes Withdrawals Withdrawals due to AEs Adverse Effects CommentsNR NR NR "less side effectswere reported withMPA than MA"2 MPA vs 7 MA ptshad vaginal bleeding.0 MPA vs 6 MAstopped treatmentearly for toxicity.Carpenter,2002NR Only 11participants (of15) completedboth arms of thestudy.Reasons for 4 notcompleting the 2nd arm ofthe study.Perspiration (unable tokeep device attached toskin) = 1Lack of interest = 2Itching from tape = 1Several problemswere reported in bothplacebo and magnetarms in first week(27%)1 - Perspiration1 - Redness1 - ItchingBy end of 2nd week 6reported itching.Willingness tocontinue with placebowas 8.2 vs. treatmentat 9.3Data not presented prior to cross-over.No wash out period reporte betweenarms of cross-over.F-672

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerStudy/Year N Type of TrialComparisonLengthof Trial Population Inclusion/Exclusion CriteriaGanz, 2000 76 RCT UsualCare4monthsMean age: 54.5 yearsDisease-free, female breastcancer patients between 8months and 5 years afterdiagnosis of stage I or IIdiseaseInclusion:1. Perimenopausal or postmenopausal (defined byammenorrhea > 6 months)2. All chemotherapy or radiation therapy completed > 4 monthsprior to enrollment, but could be taking tamoxifen3. Presence of > 1 target symptom that was moderate tosevere in intensity4. Willing to accept behavioral or pharmacologic treatment for> 1 target symptomExclusion:1. History of other cancers except non-melanoma skin cancer2. Serious medical conditions that might influence theassessment of helath related quality of life3. An abnormal Pap smear showing dysplasia or more severechanges4. curent symptoms of majoy psychiatric illness that were notbeing treated or were not being controlled with medication.5. Inability to read and write English6. Active alcohol or substance abuse7. Use of ERT within the past 3 months8. Major cognitive impairment or inability to provide informedconsentF-673

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerSpecific Characteristics of PopulationStudy/YearGanz, 2000Measures Used1. Menopausal SymptomScale Score adapted from theBreast Cancer PreventionTrial Symptom Checklist2.Vitality Scale from theRAND 36 Item Health Survey1.0 (also known as theMedical Outcomes Study SF-36)3. Sexual Summary scalefrom the CancerRehabilitation EvaluationSystem (CARES)Hysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)NR NR NR 100% 40 (56%)onTamoxifenBehaviororLifestyleFactors(#/n)NRRecentdiscontinuationofHRT(#/n)Excluded ifany ERTuse withinlast 3months.High orLow BMI(#/n)NRF-674

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerTreatmentMain OutcomesStudy/YearGanz, 2000Main Drug type; dose;regimenOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepNP counselling, tailored therapy and Usual Care (UC) NR NR NRsupport.1. Assessment: symptom diary, indepthinterview focused on symptomsand influencing factors, and astandardized psychosocial evaluation.2. Symptom Management: With helpof nurse, patient chose 1 of 3 symptomsto focus on, developed an individualizedplan of care that included education,counseling and specific pharmologicand/or behavioral interventions (for HF:pharmacologic = bellergal, clonidinepatch, or megestrol; behavioral = slowabdominal breathing; for vaginaldryness: moisturizer or lubricant; forSUI: behavior = Kegel's; pharm =replens, phyenylpropanolamine; forpsychosocial problems = referral forcounseling or group support3. Follow-up: telephone call 2 weeksafter intervention, visits at 2 months and4 months. Patients had ability tochange or alter treatment until symptomrelief achieved.F-675

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerMain Outcomes (contiued)Study/YearGanz, 2000Mood Cognitive Somatic UrinaryUterineBleeding Sexual Dysfunc-tion Quality of LifeNR NR NR NR NR Intervention group had No differenece in the meansignificantly higher change change score for the RANDscore in CARES sexual vitality scale between UC andfunctioning scale both INT groups (UC 2.3 vs INTunadjusted and adjusted 0.8, p=0.72). Same results(unadjusted mean change after adjustment, and afterscore 0.11 UC vs 0.46 Int, adjustment using clonidine asp=0.03)a covariate.F-676

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerStudy/YearGanz, 2000Other Outcomes Withdrawals Withdrawals due to AEs Adverse Effects CommentsChange in overall 4 people droppedNone NR 1. Groups were random, but notmenopause symptom scale out, all from theequivalent at baseline: interventionwas significantly greater inthe intervention group(reduced symptoms) asinterventiongroup: 2 hadfamily member'sgroup had lower urinary symptomscores and higher RAND vitality scores(p=0.05 for both).compared to the usual care illness, 22. Also, cannot distinguishgroup (true both forunadjusted scores andscore adjusted for age,tamoxifen use, priorchemotherapy, race,partner status ad RANDscore): unadjusted meanchange score: 0.09 UC vs0.57 INT, p

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerStudy/Year N Type of TrialComparisonLengthof Trial Population Inclusion/Exclusion CriteriaGoldberg,1994116 DBRCTX P 9 weeks(1weekof P toassessbaseline4 weeksC or Pthen X)Adult women on tamoxifenfor breast cancer with hotflashes.Median age 54 years (30-76).Stratified by age, duration oftamoxifen use, duration ofhot-flash symtpoms, andaverage frequency /severityof hot flashes.Inclusion:1. Hot flashes present >1 month and > 7 per week2. Life expectancy of > 6 months3. ECOG performance status of 0 or 1.Exclusion:1. Many listedHernandezMunoz, 2003136 RCT HH 12monthsWomen > 35 years attendinga breast cancer clinic inVenezuelaInclusion:1. Women > 35 years who were premenstrual2. Diagnosis of ER+ breast cancer treated with tamoxifen3. Hot flush symptomsF-678

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerSpecific Characteristics of PopulationStudy/YearGoldberg,1994Measures UsedSelf administered questionnairesof number of hotflashes, severity (mild, mod,severe, or very severe graded1-4), and drug toxicities.Composite score of meanfrequency times meanseverity.Contacted by nurses every 2-3 weeks to assesscompliance, toxicities, andanswer questions.Hysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)NR NR NR 116/116 116/116 NR NRmultipledrugexclusionsincludinghormonaltherapiesHigh orLow BMI(#/n)NRHernandezMunoz, 2003HF diary (number andintensity)10% (withretention oftheadnexae).NR NR 100% 100% ontamoxifenNR NR NRF-679

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerTreatmentMain OutcomesStudy/YearGoldberg,1994Main Drug type; dose;regimenClonidine transdermal 0.1 mg/day,patch changed weeklyOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepPatients were on No baseline differences in severity,NRNRtamoxifen for frequency or hot flash score between Ctreatment of breast and P groups.cancer.Statistically significant decrease in medianfrequency (p

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerMain Outcomes (contiued)Study/YearGoldberg,1994Mood Cognitive Somatic UrinaryUterineBleeding Sexual Dysfunc-tion Quality of LifeNR NR NR NR NR NR NRHernandezMunoz, 2003NR NR NR NR NR NR NRF-681

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerStudy/YearGoldberg,1994Other Outcomes Withdrawals Withdrawals due to AEs Adverse Effects CommentsPatient preferences for 6/116 omitted C was associated with 21/116 omitted from Does not appear to be limited totreatment option noted at from analyses (1 significant increase in dry efficacy analyses due menopausal womenthe end of the study. 2-to-1 ineligible, 1 didn't mouth (p

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerStudy/Year N Type of TrialJacobson,200185 RCT,stratified bytamoxi-fenuseComparisonLengthof Trial Population Inclusion/Exclusion CriteriaP 60 days Women over age 18previously treated for breastcancer, who reportedexperiencing daily hot flasesInclusion:1. Completion of primary therapy including chemo andradiation > 2 months prior.Exclusion:1. HRT for HF2. Pregnancy3. Major psychiatric illness4. Known recurrent or metastatic breast cancerF-683

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerStudy/YearJacobson,2001Measures Used1. Menopausal symptomindex2. Changes in LH and FSHfrom start to end of study3. Visual analog scale ofoverall health and well-being.4. HF diaryHysterectomy(#/n)BilateralOophorectomy(#/n)Specific Characteristics of PopulationPrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)NR NR NR 100% 59/85 ontamoxifenat baselineBehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)NR NR NRF-684

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerTreatmentMain OutcomesStudy/YearJacobson,2001Main Drug type; dose;regimenBlack cohosh, 1 tablet bid with mealsOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepWomen permitted toNRuse othernonhormonalmedication while instudy, but asked notto initiate newtherapy for HF.1. mean HF number at end of study (nosignificant difference by ANOVA):tam+tx:27.9tam+placebo: 31.6tx alone: 26.7placebo alone: 29.82. mean HF intensity (no significantdifference by ANOVA):tam+tx: 1.94tam+placebo:2.06tx alone: 1.97placebo alone: 1.74Included inmenopausalsymptomscale, bothgoupsimproved,notsignificantly differentfrom eachotherF-685

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerMain Outcomes (contiued)Study/YearJacobson,2001Mood Cognitive Somatic UrinaryUterineBleeding Sexual Dysfunc-tion Quality of LifeIrritability and NR 1. Headaches and NR NR NR NRnervousness andpalpitationsdepressionincluded inincluded inmenopausalmenopausalsymptom scale,symptom scale,both goupsboth goupsimproved, notimproved, notsignificantlysignificantlydifference fromdifference fromeach othereach other2. Excessivesweating improvedin both groups butthe treatmentgroup reportedmore improvementthat placebo group(p=0.04, wilcoxontest)F-686

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerStudy/YearJacobson,2001Other Outcomes Withdrawals Withdrawals due to AEs Adverse Effects CommentsSafety outcomes werechanges in mean levels ofFSH and LH: bothtamoxifen groups had lowerFSH than the nontamoxifengroups but notstatistically significant, andno signficant change; nosignificant changes in LHlevelsRandomization procedure described.9 participantsdeclined furtherparticipation afterbaselineassessments.16 (includes the9) failed tocomplete the HFdiary at the endof the study.reasons for dropouts:1. Adverse effect3 tx; 1 placebo2. Forgot pillswhile traveling 1tx; 1 placebo3. unknown 5 tx,5 placebo4 Lack of change in LHand FSH levelsreported.3 serious AE'soccurred:hysterectomy(tam+tx), breastcancer recurrence(tam+tx),appendectomy(tam+placebo)10 minor AE'soccurred:constipation (tam+tx),swolllen finger(tam+placebo),arrhythmia (tx alone),weight gain (tam+tx),endometrialhyperplasia(tam+tx),diliation andcurrettage(tam+tx),cramping (tx alone),indigestion(tam+tx),vaginalbleeding(tam+tx), andrash on abdomen(tam+placebo).F-687

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerStudy/Year N Type of TrialKimmick, 62 DBRCT2001Cross-over(abstract)ComparisonPLengthof Trial Population Inclusion/Exclusion Criteria6 weeks Data from 47 women Inclusion:mean age 53.9 (range 36.6- 1. Women on tamoxifen experiencing > 1 HF/day77.1)89% post-menopausal85.5% CaucasianLoprinzi, 1994 97 DBRCT P 4 weekseachperiod,no washoutperiodbetween97 women with history ofbreast cancer, 66 men withprostate cancer who hadundergone androgendeprivationtherapy.Inclusion:1. Breast or prostate cancer with either surgical or medicalorchiectomy2. Bothersome hot flashesF-688

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerStudy/YearKimmick,2001(abstract)Measures UsedHR frequency and score(frequency x severity)Hysterectomy(#/n)BilateralOophorectomy(#/n)Specific Characteristics of PopulationPrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)NR NR NR 100% 100% ontamoxifenBehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)NR NR NRLoprinzi, 1994HF frequency NR NR NR 100% 78/97women(80%) wereusingtamoxifenNR NR NRF-689

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerTreatmentMain OutcomesStudy/YearKimmick,2001(abstract)Main Drug type; dose;regimenOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepSertraline 50 mg qAM Placebo At 6 weeks:NRNR36% of women on sertraline (N=25) vs27% of women on placebo(N=22)reported a decrease in thefrequency of HF by 50% (p=0.7)At 13 weeks:Women were asked which tablet/periodworked best for their HF: 28% had nopreference; 49% preferred sertraline; 11%preferred placebo.Loprinzi, 1994Megestrol acetate 20 mg twice daily. Placebo After 4 weeks (results for women only):HF frequency was 26% of baseline inmegestrol group vs 73% in placebo group,p

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerMain Outcomes (contiued)Study/YearKimmick,2001(abstract)Mood Cognitive Somatic UrinaryUterineBleeding Sexual Dysfunc-tion Quality of LifeNR (in process NR NR NR NR NR NR (in process analyzedanalyzedaccording to abstract)according toabstract)Loprinzi, 1994NR NR NR NR NR NR NRF-691

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerStudy/YearKimmick,2001(abstract)Other Outcomes Withdrawals Withdrawals due to AEs Adverse Effects CommentsNR NR NR NRLoprinzi, 1994NROf 100 womenenrolled in thetrial, 2 wereineligible and 1withdrew beforestarting anymedication.Approximately82% of womenprovided usabledata for theanalysis ofefficacy.NRAssessed weekly forvaginal symptoms(dryness, irritation ordischarge), change inappetite, fluidretnetion.vaginalbleeding reported asa side effect by15(31%) women, whogot megestrol firstand had bleedingwhile on placebo. Nosuggestion thatmegestrol acetatewas related to othervaginal symptoms,fluid retention orapetite change.Stratified by duration of HF (< or > 9months), type of orchiectomy, durationof androgen ablation (men), age andtamoxifen use (women).F-692

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerStudy/Year N Type of TrialLoprinzi, 1997 52 DBRCTCross-overComparisonLengthof Trial Population Inclusion/Exclusion CriteriaP 4 weeks NReachperiodwith 1weekwashoutbetweenInclusion:1. Women > 18 years with a history of breast cancer andsignificant vaginal complaints defined as persistent vaginaldryness and/or itching2. Symptoms present for > 2 months.Exclusion:1. Evidence of active vaginal infection2. Current anti-neoplastic therapy with estrogen3. Pregnancy or lactation4. Previous use of Replens5. Planned use of any vaginal preparation during study period6. Use of any vaginal product during prior 1 week.Loprinzi, 2000 229(191withdata)RCT P 4 weeks Breast cancer or perceivedhigh risk of breast cancerInclusion:1. > 14 bothersome hotflashes per week for > 1 month (but nomenopause criteria needed)2. Age 18 or over3. Breast cancer or perceived increased risk of breast cancer4. Performance status of 0-1 on ECOG5. Tamoxifen and raloxifene o.k. if started 4 weeks prior tostudy and continued for 5 weeks6. Not on chemo, estrogens, androgens, progestins,antidepressants, clonidine, Bellergal.Exclusion:1. Venlafaxine ever2. Antidepressants past 2 years3. Pregnancy, breastfeeding4. Other hot flash treatments in past 2 weeks5. Uncontrolled HTN.F-693

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerStudy/Year Measures UsedLoprinzi, 1997 Vaginal atrophy index:summed score of vaginalelasticity, secretions, mucosalintegrity and moisturecollected from pelvic exam.Questionnaire gradingsymptoms of vaginal dryness,itching and discomfort duringintercourse.Hysterectomy(#/n)BilateralOophorectomy(#/n)Specific Characteristics of PopulationPrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)NR NR NR 100% NR NR NR NRLoprinzi, 2000Daily hot flash score(frequency x severity 1-4); hotflash frequency; Beckdepression inventory;uniscale QOL instrumentNR NR NR NR NR NR NR NRF-694

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerTreatmentMain OutcomesMain Drug type; dose;Study/YearregimenLoprinzi, 1997 Replens daily for 5 days in 1st week,then 3x/week for next 3 weeks.During washout period, placebo wasgiven 3x/week.Other Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepPlacebo consisting NRVaginal dryness NRof hydroxymethylcellulose,scores improved inglycerin-both groupsdelta lactone,(decreased by 64%hydrogenated palmin Replens groupoil glyceride andand 62% in placebowater.group after 4 wks,p=0.3).No furthersubstantivechanges in vaginaldryness in eitherstudy arm.Loprinzi, 2000Venlafaxine 37.5mg (V 37.5)Venlafaxine 75mg (V 75)Venlafaxine 150mg (V 150)Placebo See table 1.(Reduction in score and frequency for allarms compared to placebo)NRNRF-695

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerMain Outcomes (contiued)Study/YearLoprinzi, 1997Mood Cognitive Somatic UrinaryUterineBleeding Sexual Dysfunc-tion Quality of LifeNR NR NR NR NR Dyspareunia scores decreasedNRin both groups after 4 weeks:decreased 60% in Replensgroup and 41% in placebogroup, p=0.05.During cross-over period, therewere no further substantialchanges in either arm fordyspareunia scores comparedwith the end of the first 4-weekperiod.Loprinzi, 2000BDI reduction:P = 1.6;V 37.5 = 2.4;V 75 = 4.8;V 150 = 3.2. NSNR NR NR NR All improved; NS betweenarms.See figure 5.Tx: +3;P:-3; p=0.02F-696

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerStudy/YearLoprinzi, 1997Other Outcomes Withdrawals Withdrawals due to AEs Adverse Effects CommentsVaginal itching: not presentat baseline in the majorityof women and nosignificant impact of eitherReplens or placebo on thissymptom.NRParticipants asked whichlubricant worked best: of36 responding, 41% choseReplens, 24% choseplacebo and 35% had nopreference (p=0.68).Of 52 patientsentering trial, 1patient canceledbefore recevingany therapy and6 patients did notanswer any ofthe weeklyquestionnaires.7 of the 45 patientsterminated theirparticipation before theend of full 9-week period.Anecdotal evidencesuggests that patients didnot like "feeling wet" andthat amount of agentand/or discomfort withapplicator contirubted totheir decision to quit thestudy.Patients stratified by 1) age, 2) whetherthey were receiving current chemo orhormonal therapy and 3) pt perceptionof vaginal symptoms (mild, moderate,severe).Loprinzi, 20008 prior to study;P - 6; V 37.5 - 7;V 75 - 12; V 150 -5NRDry mouth, decreasedappetite, nausea, andconstipation more intx. No difference intiredness, dizziness,nervousness, moodchanges, sweating,sleepiness or sleeptrouble.F-697

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerStudy/Year N Type of TrialLoprinzi, 2002 81 RCT - crossoverComparisonLengthof Trial Population Inclusion/Exclusion CriteriaP 2 Breast cancer or perceivedperiods; high risk of breast cancer4 weeksperperiodInclusion:1. > 14 bothersome hotflashes per week for > 1 month (but nomenopause criteria needed)2. Breast cancer or perceived increased risk of breast cancer3. No current evidence of malignant disease4. Not on chemo, estrogens, androgens, progestins orcoumadin5. Tamoxifen or raloxifene ok as long as planning to continuefor duration of study6. No previous use of fluoxetine7. No antidepressants for 2 years8. No other treatments of hot flashesNikander,200362 RCT crossoverP 3monthsWomen being treated forbeast cancer at universityhospital who volunteered forstudy.Mean age: 54+6, range 35-69.Age at diagnosis of breastcancer 49.9+7.8 (range 29.9-68.1).Inclusion:1. No residual malignant disease2. Incapacitiating climacteric complaints3. FSH>30 U/LExclusion:1. Use of sex steroids including tamoxifen2. Use of natural products with possible estrogenic activity3. Use of drugs possibly affecting climacteric symptoms,metabolism or absorption of drug (ie abx)F-698

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerStudy/Year Measures UsedLoprinzi, 2002 Daily hot flash score(frequency x severity 1-4); hotflash frequency; Beckdepression inventory;uniscale QOL instrumentHysterectomy(#/n)BilateralOophorectomy(#/n)Specific Characteristics of PopulationPrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)NR NR NR NR NR NR NR NRNikander,20031. Kuperman Index2. Severity of menopausalsymptoms with 10 cm longvisual analogue scale.3. Self-rating 1-5 of 5physical and mental workingcapacity, and present overallwork capacity (scale of 1-10)in relation to lifetime best.These all factored into WorkAbility Index.4. Depressive mood5. Anxiety6. Self-confidence10 (18%) NR NR 100% 3/56(5.4%)usedtamoxifen>5 monthsprior13 (23%)smoking22/56(39.3%)had usedHRT atsome point>5 monthspriorNRF-699

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerTreatmentMain OutcomesMain Drug type; dose; Other Drugs type;Study/Yearregimendose; regimen Hot Flashes Vaginal Dryness SleepLoprinzi, 2002 Fluoxetine 20mg Placebo Not significant at end of 4-week periodNR Troublesleeping :Cross-over analysis:44%median Hot Flash frequency reduction 1.5Fluoxetine,(19%, p=0.01) and score reduction 3.171% P,(24%, p=0.02)p=0.03 for1st studyperiodonly.NotsignificantoverallNikander,2003114 mg phytoestrogen (6 tab/day total,3 bid)PlaceboKupperman Index decreased significantlyin both groups compared to baseline: by4.2+9.6 (15.5%) in phytoestrogen groupand by 4.0+8.1 (14.7%) in the P group.Not significantly different between groups.HF not different when evaluatedseparately.Intensity of HF was significantly decreasedin P group (-0.3, p=0.006) but not inphytoestrogen group.NRNRF-700

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerMain Outcomes (contiued)UterineStudy/Year Mood Cognitive Somatic Urinary Bleeding Sexual Dysfunc-tion Quality of LifeLoprinzi, 2002 Trend for lower NR NR NR NR Fluoxetine: 1 decreased, 11 NS (see p.1581)BDI scores withincreased;FluoxetinePlacebo: 3 decreased, 9(p=0.08);increased.dichotomousanalysis NSNikander,2003No significantdecrease inanxiety amongeither P orphytoestrogengroup.NR NR NR NR NR No effect on working ability orself confidenceF-701

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerStudy/YearLoprinzi, 2002Other Outcomes Withdrawals Withdrawals due to AEs Adverse Effects Comments6 prior to study; 9had no baselinedata (5 placebo,4 tx); 5 hadno 5week data (1 P, 4tx); 2 had no 9week data (1 P, 1tx).NRDry mouth (45 vs23%, p=0.07); nodifference in appetite,nausea, dizziness,constipation,nervousness, moodchanges, fatigue,abnormal sweating.Sleep improved inperiod one on tx.Nikander,2003No change in overallseverity of menopausalsymptoms by VAS:55.7+20 before (all);46.5+26.5 afterphytoestrogen; 49.3+23after placebo (p=0.469).25 (44.6%) preferred thephytoestrogen; 15 (26.8%)preferred placebo; 16(28.6%) had no preference6 peoplewithdrew: 4phytoestrogengroup (2stomach ache, 1recurrent breastcancer, 1personal); 2 inplacebo group (1lack of effect, 1vaginal bleeding)2 women in phytoestrogengroup withdrew becauseof GI AE (stomach ache);1 woman in the P groupwithdrew because ofvaginal bleedingStomach acheSerum values reported: daidzein,genistein, equol.RCT cross-over with 2 month washoutbetween each 3 month treatmentperiodF-702

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerStudy/Year N Type of TrialComparisonLengthof Trial Population Inclusion/Exclusion CriteriaPandya, 2000 198 RCT P 12weeks(8weeksofinterventionandfollowup 4weekslater)Postmenopausal women ontamoxifen for breast cancerwith hot flushes.Mean age 53 in C group, 55in P group (p=0.15) Range35-77Stratified by time sincemenopause, duration oftamoxifen therapy, andbaseline frequency of hotflushes.Recruited from clinicalpractices of medicaloncologists fromparticipating NCI CommunityClinical Oncology Programs.Inclusion:1. Postmenopausal women on tamoxifen for breast cancer for >1 month with > 1 hot flash daily.Exclusion:1. Premenopausal women2. Women on chemotherapy or other endocrine therapy forbreast cancer3. Multiple other exclusionsF-703

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerSpecific Characteristics of PopulationStudy/YearPandya, 2000Measures UsedPatient diary daily at baseline,and weeks 4, 8 and 12.Number, severity (mild,moderate, severe, or verysevere, grade 1-4) andduration of hot flashes.Combined score (meanfrequency x mean severity).Symptom checklist for 18potential side effects (grade 0-4).Quality of life on a scale from1 (worst possible life) to 10(best possible life).Blood pressure.Hysterectomy(#/n)BilateralOophorectomy(#/n)PrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)NR NR NR 198/198 198/198 NRmultipledrugexclusionsincludinghormonaltherapiesRecentdiscontinuationofHRT(#/n)NRHigh orLow BMI(#/n)F-704

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerTreatmentMain OutcomesStudy/YearPandya, 2000Main Drug type; dose;regimenClonidine 0.1 mg tab at bedtimeOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepPatients were onNRtamoxifen for at leastone month fortreatment of breastcancer.No baseline differences in severity,frequency or hot flash score between Cand P groups.Statistically significant decrease in meanfrequency at weeks 4 (p=0.001) and 8(p=0.006) and hot flash score at weeks 4(p=0.002) and 8 (p=0.006).Statistically significant difference in hotflash duration at week 12 (p=0.023).No siginifcant difference in hot flashseverity at weeks 4, 8, or 12.Reportedas a sideeffect.Increaseddifficultysleepingwasreportedby 41% onC and 21%on P(p=0.02)F-705

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerMain Outcomes (contiued)Study/YearPandya, 2000Mood Cognitive Somatic UrinaryUterineBleeding Sexual Dysfunc-tion Quality of LifeNR NR NR NR NR NR Quality of life scores improvedin the C group compared to Pat weeks 4 (p=0.003) and 8(p=0.022). No difference inmedian score.F-706

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerStudy/YearPandya, 2000Other Outcomes Withdrawals Withdrawals due to AEs Adverse Effects CommentsEffects of clonidine by thestratification variablesduration of tamoxifen useStates patientwithdrawals weredue to patientand years past menopause. preferenceStates blood pressure wasnot adversely affected.45/198 did not completethe full 12 weeks of thestudy, 31/198 did notcomplete the 8-weekintervention.4/198 randomized but didnot provide baseline dataand were consideredunevaluable.Participants wereasked to complete asymptom checklistincluding 18 potentialside effects. The onlydiffference was indifficulty sleeping.Alternate analyses were done toaccount for patient drop outs/missingdata. The results were similar except for1) QOL at 8 weeks (p=0.082) and 2)significantly greater benefit of C for hotflash symptoms and QOL at 12 weeks.F-707

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerStudy/Year N Type of TrialComparisonLengthof Trial Population Inclusion/Exclusion CriteriaQuella, 1998 132 Retrospective None(openlabel forlong termfollow-up)74 men; 58 women55 (93%) had been onmegestrate continually for 3years.Contactwas 3yearsafterend ofinitialstudyInclusion:1. Female breast cancer survivors and male prostate cancersurvivors who underwent androgen depreivation therapy.F-708

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerStudy/YearQuella, 1998Measures UsedTelephone interview, unclearhow data elicitedHysterectomy(#/n)BilateralOophorectomy(#/n)Specific Characteristics of PopulationPrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)NR NR NR NR NR NR NR NRF-709

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerTreatmentMain OutcomesStudy/YearQuella, 1998Main Drug type; dose;regimenMegestrol acetate: doses ranged from

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerMain Outcomes (contiued)Study/YearQuella, 1998UterineMood Cognitive Somatic Urinary Bleeding Sexual Dysfunc-tion Quality of LifeNR NR NR NR NR NR NRF-711

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerStudy/YearQuella, 1998Other Outcomes Withdrawals Withdrawals due to AEs Adverse Effects CommentsNR NR Reasons forToxicity:Retrospective data collection of ptsdiscontinuation of the drug 3 women (17%) had participating in an RCT placebo(men and womencombined):no benefit: 17vaginalspotting/bleeding/carmpinchillls once their HFwere eliminated.5 women reportedappetite stimulation16 men and womencontrolled trial of megestrol acetate; atthe end of that trial all patients weregiven option to take open labelmegestrol at the lowest dose necessaryto control HF.g: 14taking too many otherlisted weight gain as a Where given data reported for women.possible side effect (8 Other SE occurred in men (1 haddrugs: 13HF resolved: 12wt gain/appetitestimulation : 9chills: 5drug too expensive: 4depression: 4severe hand/wristnumbness/tingling: 3reported wt gain of headaches, 1 indigestion, 1 RLEthromboembolic event). Where datanot broken down, reported here as Mand W.Hand/wristnumbness/tingling wasattributed to carpal tunnel,a syndrome previouslyassociated withmegestrol.Symptoms resolved within4-6 weeks of withdrawingthe drug.

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerStudy/Year N Type of TrialQuella, 2000 182 RCT, crossoverafter 4weeksComparisonPLengthof Trial Population Inclusion/Exclusion Criteria9 weeks Women age 18 and olderwith history of breast cancerbut no residual maligantdisease.Inclusion:1. Tamoxifen or raloxifene allowed if started 4 weeks prior andplanning to continue through the trial.2. All suffering from HF > 14 times/wk and "of such severity towarrant intervention" and HFfor > 1 month.3. Life expectancy > 6 months4. ECOG=0 or 1.Exclusion:1. Curent treatment with antineoplasitc chemotherapies,androgens, estrogens, prgestational agesnts, or corticosteroids2. Use of any other agent to treat hot flashes such asmegestrol acetate, vitamin E and belladonna, phenobarbital andergotamine tartrate, or other soy products.Secreto, 2004 262 DB RCT HH & P 3monthsWomen age 49-57 years inItalyInclusion:1. Postmenopausal women aged > 352. Last menstrual flow > 6 months before recruitment3. Any condition for which classic HRT is not recommended4. Written informed consentExclusion:1. Breast cancer therapy (hormone or chemotherapy) or RTduring the previous 3 months2. Overt endocrinopathy (diabetes mellitus, hyperthyroidism,etc.)3. Intolerance to soyF-713

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerStudy/YearQuella, 2000Measures Used1. Frequency and intensity ofhot flashes2. Toxicity: diarrhea, nausea,vomitting, gas/bloating, other3. ComplianceHysterectomy(#/n)BilateralOophorectomy(#/n)Specific Characteristics of PopulationPrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)NR NR NR 100% 68 (78%)ontamoxifenBehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)NR Excluded NRSecreto, 2004Greene Climacteric Scale Included Included NR Included Excluded NR None for 3monthspriorMean was23.8 - 25.0for groupswithvariation of21.5-26.8F-714

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerTreatmentMain OutcomesStudy/YearQuella, 2000Main Drug type; dose;regimen600 mg tablets containging 50 mg ofsoy isoflavones: 40-45% genistein, 40-45% diadzein, and 10-20% glycitein.Subjects instructed to take 1 tablet TID(total of 150mg isoflavones/day). Soyphytoestrogen and placebos providedby pharmavite, Mission Hills, CA.Other Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepPlaceboANOVA for HF score and frequencyNRNRproduced non-significant p values for alltreatment effect comparisons, regardlessof period, sequence, or week ofobservation.Among pateints receviving placebo, 36%reported that HF frequency had been cutin half compared with only 24% of patientsreceiving soy (p=0.01).Secreto, 2004Group 1: midday, isoflavones 40mg;evening, isoflavones 40mg+melatonin 3mg;Group 2: midday and evening,isoflavones 40mg;Group 3: midday, placebo; evening,melatonin 3mgGroup 4: midday andevening, placeboNR NR NRF-715

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerMain Outcomes (contiued)Study/YearQuella, 2000UterineMood Cognitive Somatic Urinary Bleeding Sexual Dysfunc-tion Quality of LifeNR NR NR NR NR NR NRSecreto, 2004NR NR NR NR NR NR NRF-716

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerStudy/YearQuella, 2000Other Outcomes Withdrawals Withdrawals due to AEs Adverse Effects CommentsNo difference in percent of 149 (85%) had NoneNo difference in 1. Authors do not present resultspatients reporting daily use usable data attoxicity between the separately after the 1st 4 wks, prior toof medications(compliance) andpercentage reportinghaving missed

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerStudy/Year N Type of TrialComparisonLengthof Trial Population Inclusion/Exclusion CriteriaThompson,2002(abstractonly)53 DB RCT P 16weeksWomen with breast cancerwith menopausal symptomsNot listedF-718

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerStudy/YearThompson,2002(abstractonly)Measures UsedMeasure Yourself MedicalOutcome Profile (MYMOP),Hospital Anxiety andDepression score, EuropeanOrganization for Researchand Treatment in CancerQuality of Life Score,Menopausal Symptom ScaleHysterectomy(#/n)BilateralOophorectomy(#/n)Specific Characteristics of PopulationPrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)BehaviororLifestyleFactors(#/n)RecentdiscontinuationofHRT(#/n)High orLow BMI(#/n)NR NR NR Included NR NR NR NRF-719

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerTreatmentMain OutcomesStudy/YearThompson,2002(abstractonly)Main Drug type; dose;regimenOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepHomeopathic intervention Placebo Both groups showed significantNRNRimprovement over the study period by anaverage of 80%. No statisticallysignificant difference betweeen groupsF-720

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerMain Outcomes (contiued)Study/YearThompson,2002(abstractonly)UterineMood Cognitive Somatic Urinary Bleeding Sexual Dysfunc-tion Quality of LifeNR NR NR NR NR NR NRF-721

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerStudy/YearThompson,2002(abstractonly)Other Outcomes Withdrawals Withdrawals due to AEs Adverse Effects CommentsNR 8/43 NR NR Abstract only; included as onlyhomeopathic RCT that could be found.F-722

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerStudy/Year N Type of TrialComparisonLengthof Trial Population Inclusion/Exclusion CriteriaVan Patten,2002157 RCT P 12weeks263 eligible women; 157randomized; 123 completedthe study (59 soy, 64placebo).Inclusion:1. Breast cancer with completion of treatment >4 months prior2. No use of HRT for >4 months3. Tamoxifen allowedAge at study entry 55.5+6.3; 4. Troublesome HF: score>10/wk (frequency x intensity).P 54.9+6.5.Conducted in Canada5. Other medications + CAM allowed if no change in >4months.Exlusion:1. Smokers2. Use of abx3. Diagnosis of IBD, liver impairment or recurrent breastcancer4. Allergy to or regular consumption of soyF-723

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerStudy/YearVan Patten,2002Measures Used1. Frequency and intensity (0-5 scale) of HF, daily diary.Hysterectomy(#/n)"Hysterectomy+oophorectomy"soy 23(39%)P 28 (44%)BilateralOophorectomy(#/n)Specific Characteristics of PopulationPrematureOvarianFailure(#/n)BreastCancer(#/n)Use ofSERMS(#/n)NR NR 100% Tamoxifenuse:soy -9(15%)P - 6 (9%)BehaviororLifestyleFactors(#/n)NRRecentdiscontinuationofHRT(#/n)(No use for4 monthsprior tostart ofstudy):soy 26(44%)placebo 28(44%)High orLow BMI(#/n)Mean BMI:soy (n=59)26.8+4.5placebo(n=64)26.6+4.2F-724

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerTreatmentMain OutcomesStudy/YearVan Patten,2002Main Drug type; dose;regimenOther Drugs type;dose; regimen Hot Flashes Vaginal Dryness SleepAverage concentration of isoflavone in PlaceboNone of the HF reductions wereNRNRthe soy veberage was 45significantly different between groups.+13mg/250mL; isoflavones were24 hour HF number and score baseline vsundetectable in the rice beverage. Totalfinal 4 weeks of treatment: number: soyisoflavones consumed by soy women:(7.1+ 4.3 vs 5.3 +4.1); placebo (7.4+6.4 vs90 mg/day.4.9+3.9).Score (intensity x frequency): soy(18.0+13.9 vs 12.6+13.4); placebo18.9+18.9 vs 11.4+11.3).(also reported for day and night, also NSchange).F-725

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerMain Outcomes (contiued)Study/YearVan Patten,2002Mood Cognitive Somatic UrinaryUterineBleeding Sexual Dysfunc-tion Quality of LifeNR NR NR NR OnlyNRNRreported asan adverseeffect oftreatmentwith soy(see AEcolumn).F-726

Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancerStudy/YearVan Patten,2002Other Outcomes Withdrawals Withdrawals due to AEs Adverse Effects CommentsOn the study exitAfter10 women dropped outquestionnaire, a large randomization 34 because of intolerance tonumber of women in bothsoy and placebo groupsperceived a marginaldecrease in HF number inthe day (54%soy vs 58%P)and night (48%soy vs56%P), and in the severityof HF in the day (50%soyvs 56%P) and night(52%soy vs 55%placebo).At completion, only half ofthe women in the soy andplacebo groups (48% and52% respectively) couldcorrectly identify wichbeverage they wereconsuming.(22%) womendropped out ofthe study.study beverage (7 fromsoy group; 3 fromplacebo).25 dropped out becauseof time committment6 dropped out for otherreasons9 women becameinellgible afterrandomization (6 hadinsufficient HF, 2 hadregular consumption ofsoy; 1 had IBD).Frequent and severegastrointestinal sideeffects in soy group:overall 28 soy womenreported GI AE; 14 Pwomen reported GIAE (list includesabdominal bloating,gas/flatulence,constipation, gastritis,diarrhea, nausea,vomiting, heartburn).This does not includethe 10 women whodropped out of thestudy for intolerance(7 soy; 3 P).Weight gain occurredequally in both groups(5 soy vs 4 P).Vaginal spotting wasreported by 4 womenconsuming soy and 1consuming placebo.No mention of intention to treat, butnegative study anyway.Other CAM and Rx therapiescommmon in both group: blackcohosh, wild yam, red clover 3 or fewer;flaxsee and SSRI 6 women; vit E andprimrose oil more common but equal inboth groups.Serum values reported.F-727

Appendix F: Evidence table 6-9. Key Question 4C therapies in women with breast cancerAE = Adverse EffectBMI = Body mass indexC = ClonidineCAM = Complimentary and alternative medicineECOG = Eastern Cooperative Oncology Group ScaleER + = Estrogen Receptor PositiveERT = Estrogen replacement therapyGI = GastrointestinalHF = Hot flashHH = Head to headHRT = Hormone Replacement TherapyHTN = HypertensionIBD = Irritable Bowel DisorderINT = InterventionMVI = MultivariateNR = Not reportedNS = Not significantP = PlacebOQoL = Quality of lifeRAND = RAND Mental Health InventoryRCT = Randomized Controlled TrialSD = Standard deviationSERMs = Selective Estrogen Receptor Modifierstam = Tamoxifenetx = TreatmentUC = Usual careAbbreviationsF-728