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findings were remarkable because a pure antiestrogen would have been expected to promote rather than inhibit bone loss. Because clomiphene is a racemic mixture of enclomiphene and zuclomiphene, primacy in the SERM field must be accorded to tamoxifen. However, the discovery that tamoxifen was, in some patients, capable of endometrial stimulation leading to hyperplasia or neoplasia 61 precluded its development as a bone antiresorptive agent that would be free of uterine bleeding and, it was hoped, breast safe. The concept of selective ER modulation has been demonstrated subsequently for a number of compounds, including raloxifene, droloxifene, GW5638, idoxifene, and FC–1271. Toremifene and idoxifene are molecules similar to tamoxifen; despite their potential as SERMs, they have been targeted for the treatment of advanced breast cancer. Droloxifene is known to have efficacy as a breast cancer drug but is also a SERM at bone sites. 62 Raloxifene was developed because it held promise for multiple applications. It is used in the prevention of bone loss and fracture in postmenopausal women and is being tested against tamoxifen in the Study of Tamoxifen and Raloxifene (STAR) for the prevention of breast cancer in high-risk postmenopausal women. 63 Additionally, raloxifene reduces circulating cholesterol concentrations 64 and may be efficacious to reduce risk for endometrial cancer. 55 The main drawback of the drug is that it does not reduce the occurrence of hot flushes, which could hinder compliance. Similar pharmacologic profiles are shared by idoxifene and FC–1271, which were shown to have beneficial effects on bone metabolism in rat models and to act like estrogens in bone and on circulating lipoprotein concentrations, with little estrogenic activity in the uterus. 37,65 A number of SERMs are in preclinical or clinical development (table 6–1). The molecular mechanisms of the different effects of SERMs in different organs are summarized above (“Molecular Mechanisms of Antiestrogen Action”) and in figure 6–5. 114 The challenge for the future in the development of ligands for the ERs will be to refine the target specificity of SERMs and, it is hoped, amplify their scope of action. For instance, a SERM with a profile similar to idoxifene or raloxifene in the peripheral organs and CNS might protect against Alzheimer’s disease and hot flushes, while helping prevent osteoporosis, CAD, and breast and endometrial cancers. 4. FUTURE NEEDS The availability of drugs selective for ERα and ERβ will constitute a major milestone toward the development of drugs with specificity of action. On the other hand, the acquired knowledge of the molecular mechanisms of estradiol activity in different cells might suggest novel paths to be followed for the development of molecules active through the ERs. For example, ER turnover is differentially regulated in various organs (e.g., following gonadectomy, ERα mRNA is increased in the uterus but significantly decreased in the liver66 ). Drugs aimed at modulating the synthesis of ERs in specific organs may enable fine tuning of the activity of the hormone. Antisense oligonucleotides have been able to block ER synthesis in cells in culture. The development of such molecules as drugs might allow their future clinical use. 67 Alternatively, novel preparations of estradiol in which its bioavailability is modified might have pharmacologic profiles of interest. For instance, a formulation allowing a very rapid intraplasmic release of estradiol and its rapid clearance (e.g., transnasal administration of appropriately modified estrogens) could have a quite different profile of action compared with estradiol administered orally or transdermally. Such a drug could rapidly activate the receptors but, because of its rapid clearance from the blood, might have little effect on ER down-regulation or might affect it differently in the various targets.
TABLE 6–1 Selective Estrogen Receptor Modulators Under Development Drug Pharmaceutical Company Phase of Development Therapeutic Class SERM 339 Aventis Phase IIa HM 144 Hormos Medical Preclinical Anti-Alzheimer LY 139,478 Eli Lilly and Company Preclinical Bone calcium regulation LY 326,391 Eli Lilly and Company Preclinical Cytostatic, bone calcium regulation ERA 932 Ligand Pharmaceuticals Phase I Cytostatic NNC 450,320 Novo Nordisk Preclinical Bone calcium regulation NNC 450,781 Novo Nordisk Preclinical Bone calcium regulation M.D.L 101,986 Aventis Pharma Preclinical Cytostatic, bone calcium regulation Fc1271A Hormos Medical Phase II Other drugs for the musculoskeletal system Arzoxifene Eli Lilly and Company Phase II Cytostatic Research program Signal Pharmaceutical Preclinical Cytostatic, SERMs bone calcium regulation Lasozifene Pfizer Phase II Bone calcium regulation Research Program Ligand Pharmaceuticals /Pfizer Preclinical Cytostatic, SERMs bone calcium regulation, anti-Alzheimer SR 1,634 SRI International Preclinical Cytostatic 115
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National Heart, Lung, and Blood Ins
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CHAIRS AND EDITORS Chair and Editor
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Anne McTiernan, M.D., Ph.D. Associa
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Lenore Manderson, Ph.D. Director an
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Michael Mendelsohn, M.D. Director,
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TABLE OF CONTENTS Preface XIII 1 Ex
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PREFACE Women’s health and menopa
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CHAPTER 1: EXECUTIVE SUMMARY Nanett
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TABLE 1-1 Evidence Categories Evide
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TABLE 1-2 (continued) Possible Bene
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symptom measures, cultural factors,
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5. PHYSIOLOGICAL ROLE OF ESTROGEN A
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The atherogenic risk profile of old
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• Hormone replacement therapy: Fi
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tion of the remaining ridge in area
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9.3.1 Interventions • In many cas
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Parkinson’s disease, no overall p
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TABLE 1-3 (continued) Sexuality •
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CHAPTER 2: THE MENOPAUSE AND AGING
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oped and are less prepared to addre
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FIGURE 2-4 Diabetes Mellitus. Estim
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Sarcopenia, defined as reduced musc
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Perimenopause WHO The term “perim
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decrease about 2 years before the F
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4.3 Menstrually Defined Menopausal
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to be under stress and to hold part
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21 Brincat MP. Hormone replacement
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62 Orentreich N, Brind JL, Rizer RL
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CHAPTER 3: SYMPTOMS AND THE MENOPAU
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women who may have reached natural
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numb-tingling feelings, headaches,
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(47 percent), problems sleeping (39
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FIGURE 3-2 Proportion of Women Both
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tomized hypogonadotropic women expe
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5.1 Exercise It has been suggested
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to consume 20-150 mg/day of isoflav
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REFERENCES 1 Stewart AL, Hays RD, W
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48 Avis NE, Crawford SL, McKinlay S
Page 79: 92 Albertazzi P, Pansini F, Bonacco
Page 82 and 83: Hällström wrote that the psycholo
Page 84 and 85: countries. Perhaps, as the authors
Page 86 and 87: Beyene used a systematic ethnograph
Page 88 and 89: ange of variables, such as genetic
Page 90 and 91: REFERENCES 1 Gannon L, Ekstrom B. A
Page 92 and 93: 47 George T. Women in a south India
Page 94 and 95: 9. Estrogen and inhibins produced b
Page 96 and 97: HRT) display tissue-selective estro
Page 98 and 99: a partial agonist. In contrast, wit
Page 100 and 101: 3. UROGENITAL TRACT ERα and ERβ a
Page 102 and 103: 4. BONE: DEVELOPMENT AND HOMEOSTASI
Page 104 and 105: in response to estrogen. 106,105 In
Page 106 and 107: lation of sleep, motor behavior, an
Page 108 and 109: 7. HORMONE REPLACEMENT THERAPY: TRA
Page 110 and 111: REFERENCES 1 Jensen EV, Jacobsen HI
Page 112 and 113: 40 Power RF, Mani SK, Codina J, Con
Page 114 and 115: 83 Oursler MJ, Pederson L, Fitzpatr
Page 116 and 117: 125 Gabrielsson BG, Carmignac DF, F
Page 118 and 119: 169 Renier MA, Vereecken A, Buytaer
Page 120 and 121: FIGURE 6-1 Structural features of E
Page 122 and 123: ound, the conformation of the recep
Page 124 and 125: with extremely potent estrogenic ac
Page 126 and 127: Its potency as an antiestrogen was
Page 128 and 129: The observation that the degree of
Page 132 and 133: Recently, the use of phage display
Page 134 and 135: 20 Crawley G. Non steroidal estroge
Page 136 and 137: 65 Qu Q, Zheng H, Dahllund J, et al
Page 138 and 139: in their survey of postmenopausal w
Page 140 and 141: where over half the world’s popul
Page 142 and 143: The Danish study of Koster and Gard
Page 144 and 145: Many studies of sexual interest in
Page 146 and 147: 7. ASSESSING SEXUAL ACTIVITY Clinic
Page 148 and 149: None of these studies evaluated the
Page 150 and 151: estrogen-androgen group during the
Page 152 and 153: REFERENCES 1 Sarrel PM, Whitehead M
Page 154 and 155: 52 Utian WH. The true clinical feat
Page 156 and 157: 140
Page 158 and 159: outes of administration and differe
Page 160 and 161: FIGURE 8-2 Change in Age-Adjusted D
Page 162 and 163: fied as overweight or obese. 32 The
Page 164 and 165: TABLE 8-1 148 Guide to Risk Reducti
Page 166 and 167: TABLE 8-1 (continued) 150 Recommend
Page 168 and 169: TABLE 8-1 (continued) 152 Recommend
Page 170 and 171: Interesting differences in atherosc
Page 172 and 173: similar effects in both patients wi
Page 174 and 175: a lowering of triglycerides, 140 an
Page 176 and 177: may account for a substantial propo
Page 178 and 179: associated with an independent prot
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eases preoperatively. Quality of li
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excess risk of 6-18 per 10,000 per
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REFERENCES 1 NHLBI Morbidity and Mo
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36 Samaras K, Hayward CS, Sullivan
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79 Collins P, Rosano GM, Jiang C, L
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121 Mäkelä S, Savolainen H, Aavik
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162 Clarke S, Kelleher H, Lloyd-Jon
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201 Rahimtoola SH, Bennett AJ, Grun
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243 Varas-Lorenzo C, Garcia-Rodriqu
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7. A connection between menopausal
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3. PATHOGENESIS OF FRACTURE Fractur
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Diagnosis of osteoporosis according
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density and has a favorable effect
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How should this information be inco
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emergence of proved treatment alter
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Data on the relation between skelet
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REFERENCES 1 Osteoporosis Preventio
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42 Gluer CC. Quantitative ultrasoun
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85 Ettinger B, Pressman A, Silver P
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130 Jeffcoat MK, Lewis CE, Reddy M,
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1. INTRODUCTION Perimenopausal wome
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for breast cancer are at increased
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findings on biopsy in women with an
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thra. Patients typically describe l
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Biofeedback: Used in conjunction wi
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There has been one systematic revie
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ence in pelvic organ prolapse. The
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21 Ferenczy A. Endometrial carcinom
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65 Wyman JF, Fantl JA, McClish DK,
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222
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1. INTRODUCTION Worldwide, breast c
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difficult to compare because of com
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Although HRT has been related to an
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cyclic use and 2.9 (95 percent CI 2
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TABLE 11-3 Selected Studies on Horm
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TABLE 11-3 (continued) Thus, a stro
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TABLE 11-4 236 Cohort Studies on Ho
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TABLE 11-5 238 Case-Control Studies
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TABLE 11-5 (continued) 240 Adjustme
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When the same women in NSABP were r
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REFERENCES 1 Pisani P, Parkin DM, B
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47 Day NE. Epidemiology: the role o
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93 Rodriguez C, Patel AV, Calle EE,
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139 Parazzini F, La Vecchia C, Negr
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1. INTRODUCTION Menopause is associ
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inverse relation with nonverbal mem
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ease decreased significantly with i
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of households selected to be repres
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standard antipsychotic drugs increa
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5. FUTURE NEEDS • Explore the pos
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19 Berman KF, Schmidt PJ, Rubinow D
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64 Lerner A, Koss E, Debanne S, Row
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114 Smith R, Studd JW. A pilot stud
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162 Klein BE. Lens opacities in wom
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patients with strong personal convi
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Therefore, convincing evidence of t
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3.1.1 Risk Factors Many factors are
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278 lower dosages of estrogen will
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• Diabetes: Women with diabetes b
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Lipids and lipoproteins • LDL cho
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284 persists but is less steep in w
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5.2.3 Pharmacotherapy Breast Cancer
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• There is no clinical trial evid
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Sirtori CR, Pazzucconi F, Colombo L
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Hansson L, Zanchetti A, Carruthers
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Dementia and Mental Health Forette
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CRP C-reactive protein CT computed
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PTCA percutaneous transluminal coro
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U.S. DEPARTMENT OF HEALTH AND HUMAN
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