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a lowering of triglycerides, 140 and the more androgenic steroids lower Lp(a) by approximately 20 percent. 141,142 This effect could prove beneficial as Lp(a) may be an independent risk factor for CHD in women. 15 Recent evidence from HERS suggests that Lp(a) is an independent risk factor for recurrent CHD events. 14 In the placebo arm of the study, women in the second, third, and fourth quartiles of Lp(a) levels had increased relative hazards compared with the lowest quartile. Treatment with HRT significantly reduced Lp(a) levels compared with placebo. In a randomized subgroup comparison, women with higher baseline Lp(a) levels had a less adverse-trend during the first year and more benefit thereafter. 4.1.2 Inflammatory Factors Two studies of oral CEEs plus or minus MPA or progesterone have shown rapid increases in the concentration of the inflammatory factor CRP and a reduction in the concentration of soluble E-selectin. 143 In a crosssectional study, CRP levels were increased in postmenopausal women taking HRT, 144 and in postmenopausal women exposed to short-term HRT of either oral estrogen or estrogen sequentially combined with a progestin. 145 In another prospective randomized controlled study of oral 17β-estradiol combined with 5 or 10 mg of dydrogesterone, there was a 15percent decrease in plasma levels of endothelin-1, a 21-percent decrease in soluble thrombomodulin, and a 14-percent decrease in von Willebrand factor. 146 Standard prevention therapies, including lipid lowering, are as effective in women as in men. These changes were observed at 3 months and sustained after 15 months. It is possible that the increase in CRP is due to first pass effect on hepatic synthesis of the protein, while the decrease in markers of endothelial function and other inflammatory markers is due to direct vascular effects. It is unclear whether estrogen increases or decreases vascular inflammation or whether differ- 158 ent forms, doses, and routes of administration have different effects on vessel physiology. One potential mechanism by which there may be an early adverse effect (such as that found in the HERS trial) followed by a later favorable effect is through effects on matrix metalloproteinases (MMP). 147 Preliminary reports indicate that MMP–9 is increased markedly by estrogen and may play a role in the destabilization of vulnerable plaques, thus precipitating a clinical event. However, over the long term, MMP–9 may help keep vessels compliant as it may play a role in removing excess connective tissue. Monocyte activation is associated with atheromatous plaque disruption and acute coronary syndromes (ACS). Increased serum concentration of neopterin, a pterydine derivative secreted by macrophages after stimulation by interferon-gamma, has been observed in patients with ACS as compared with control subjects and patients with stable angina pectoris. 148 Women with unstable angina have significantly higher neopterin concentrations than women with chronic stable angina. Neopterin concentrations may be a marker of risk in women with CHD. 149 HRT has also been shown to significantly reduce the levels of the cell adhesion molecules E-selectin, intracellular adhesion molecule 1 (ICAM–1) and vascular cell adhesion molecule–1 (VCAM–1) with similar magnitude of reduction from placebo values in women on CEE alone compared with women on combination HRT. 150 4.1.3 The Effect of Hormone Replacement Therapy Combined With Other Lipid- Lowering Agents A number of studies have recently reported the effects of a combination of statin and HRT on serum lipid levels in menopausal women. 151–154 One study also assessed the vascular effects of this combination in hypercholesterolemic postmenopausal women. 155 The studies investigated the effect of differing doses of CEEs, either alone or combined with MPA, and compared the lipid-lowering effects to simvastatin or pravastatin.
Overall, these studies show that oral CEEs plus MPA in combination with a statin is complementary, in that the statins are better at lowering LDL cholesterol levels, the hormones are better at raising HDL cholesterol levels, and the effects on triglycerides cancel each other: thus the combination yields the most optimal lipid profile. The combination is only modestly additive, that is, hormones add little to the LDL-lowering effect of statins, and statins add only modestly to the HDL-raising effect of hormones. Hormones reduce Lp(a) levels, while statins do not. No studies have yet been published comparing other types and routes of administration of HRT combined with a statin. In one study, 155 28 women were randomized to continuous equine estrogen (0.625 mg daily), simvastatin 10 mg, and their combination daily for 6 weeks. As shown in the previous studies, all therapies lowered total and LDL cholesterol levels from baseline, with a greater effect on LDL cholesterol from simvastatin and from the combination of HRT and simvastatin. This study also assessed the vascular effects of this therapy; flow mediated dilatation of the brachial artery improved on CEE, simvastatin, and continuous equine estrogen combined with simvastatin, and this was similar among the therapies. Only therapies including CEE lowered levels of PAI–1 and the cell adhesion molecule E-selectin. Only therapies including estrogen improved markers of fibrinolysis and vascular inflammation. Thus, it may be that such a combination will be synergistic in vascular protection. 4.1.4 Coagulation Factors The effects on coagulation factors are complicated, diverse, and contradictory. For example, lowering of fibrinogen and PAI–I could be counterbalanced by increases in factor VII and decreases in antithrombin III. In general, it appears that estrogen is procoagulant but, at the same time, profibrinolytic. 156 The net effect is likely to be procoagulant, as evidenced by the observational studies and the HERS clinical trial (see elsewhere). However, the net effect of estrogen on coagulation can depend on the form of estrogen used and on the dose, route, and duration of therapy. There may be critical differences between oral and transdermal delivery of estrogen. In contrast to oral administration, transdermal estrogen does not result in any measurable perturbation of coagulation factors. 156 4.2 Hormone Use and Prevention of CHD Risk Observational studies comparing current hormone users with non-users have shown consistent reductions in CHD risk of 35–50 percent. In the Nurses’ Health Study, the risk reduction was seen at the most commonly used dose of CEEs (0.625 mg/day). 157 There appeared to be a similar risk reduction at the lower dose of 0.3 mg/day, but this was not statistically significant. At higher doses, there was no apparent benefit. The findings from these observational studies have been important in promoting the belief that HRT prevents CHD. However, the findings have to be viewed with caution because several sources of potential bias could result in an overestimation of potential benefits and an underestimation of risks. 158,159 Women are approximately half as likely as men to receive known beneficial These biases include therapies, such as beta- that women who elect to blocking agents, aspirin, take hormones are thrombolysis, acute healthier, and those that remain on hormones for cardiac catheterization, many years are by defi- percutaneous transluminal nition good compliers and are under medical coronary angioplasty surveillance. (See also (PTCA), or bypass surgery. ch. 4 for biases in sampling.) Thus, they would be taking other steps to improve their health, and early detection and treatment of risk factors would also reduce disease risk. Furthermore, women who stop therapy often do so because of the development of a health condition; thus those who remain on therapy are the healthy survivors. These biases 159
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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
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92 Albertazzi P, Pansini F, Bonacco
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Hällström wrote that the psycholo
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countries. Perhaps, as the authors
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Beyene used a systematic ethnograph
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ange of variables, such as genetic
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REFERENCES 1 Gannon L, Ekstrom B. A
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47 George T. Women in a south India
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9. Estrogen and inhibins produced b
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HRT) display tissue-selective estro
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a partial agonist. In contrast, wit
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3. UROGENITAL TRACT ERα and ERβ a
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4. BONE: DEVELOPMENT AND HOMEOSTASI
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in response to estrogen. 106,105 In
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lation of sleep, motor behavior, an
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7. HORMONE REPLACEMENT THERAPY: TRA
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REFERENCES 1 Jensen EV, Jacobsen HI
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40 Power RF, Mani SK, Codina J, Con
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83 Oursler MJ, Pederson L, Fitzpatr
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125 Gabrielsson BG, Carmignac DF, F
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169 Renier MA, Vereecken A, Buytaer
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FIGURE 6-1 Structural features of E
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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 130 and 131: findings were remarkable because a
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 176 and 177: may account for a substantial propo
Page 178 and 179: associated with an independent prot
Page 180 and 181: eases preoperatively. Quality of li
Page 182 and 183: excess risk of 6-18 per 10,000 per
Page 184 and 185: REFERENCES 1 NHLBI Morbidity and Mo
Page 186 and 187: 36 Samaras K, Hayward CS, Sullivan
Page 188 and 189: 79 Collins P, Rosano GM, Jiang C, L
Page 190 and 191: 121 Mäkelä S, Savolainen H, Aavik
Page 192 and 193: 162 Clarke S, Kelleher H, Lloyd-Jon
Page 194 and 195: 201 Rahimtoola SH, Bennett AJ, Grun
Page 196 and 197: 243 Varas-Lorenzo C, Garcia-Rodriqu
Page 198 and 199: 7. A connection between menopausal
Page 200 and 201: 3. PATHOGENESIS OF FRACTURE Fractur
Page 202 and 203: Diagnosis of osteoporosis according
Page 204 and 205: density and has a favorable effect
Page 206 and 207: How should this information be inco
Page 208 and 209: emergence of proved treatment alter
Page 210 and 211: Data on the relation between skelet
Page 212 and 213: REFERENCES 1 Osteoporosis Preventio
Page 214 and 215: 42 Gluer CC. Quantitative ultrasoun
Page 216 and 217: 85 Ettinger B, Pressman A, Silver P
Page 218 and 219: 130 Jeffcoat MK, Lewis CE, Reddy M,
Page 220 and 221: 1. INTRODUCTION Perimenopausal wome
Page 222 and 223: 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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