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Recently, the use of phage display has allowed the identification of peptides that interact specifically with estradiol- or tamoxifen-activated ERα. Some peptides were shown to regulate ER transcriptional activities. 68 Such studies demonstrate that ER activity can be regulated even by targeting sites that are outside the ligand-binding pocket of the protein. This is not surprising within the current view of ER interactions with other proteins relevant in transcription. Such results have pharmacologic implications of interest because they provide new targets for drug activities and more opportunities for the development of drugs that will modulate the activity of ERs in selected cells or even at specific genes. Finally, increased knowledge of the physiologic relevance of unliganded activation of ERs might lead to the development of pharmacologic compounds that will activate ERs through membrane receptors. 116 These and other molecular developments will in the near future represent starting points for the preclinical and clinical development of estrogen compounds, of both natural and synthetic origins, with selective spectrums of action, as the following points summarize: • Developing drugs with receptor specificity (ERα or ERβ) • Modulating the activity of the hormone interfering with the synthesis of ERs • Attaining different profiles of action for exogenous estradiol through use of different formulations • Obtaining higher specificity of action by identification of new target molecules involved in gene transcription • Increasing knowledge of the mechanisms involved in ER activation through membrane receptors to develop new pharmacologic compounds acting along these pathways
REFERENCES 1 Mangelsdorf DJ, Thummel C, Beato M, et al. The nuclear receptor superfamily: the second decade (review). Cell 1995;83(6):835–9. 2 Ma ZQ, Santagati S, Patrone C, Pollio G, Vegeto E, Maggi A. Insulin-like growth factors activate estrogen receptor to control the growth and differentiation of the human neuroblastoma cell line SK-ER3. Mol Endocrinol 1994;8(7):910–8. 3 Ignar-Trowbridge DM, Nelson KG, Bidwell MC, et al. Coupling of dual signaling pathways: epidermal growth factor action involves the estrogen receptor. Proc Natl Acad Sci USA 1992;89(10):4658–62. 4 Smith CL, Conneely OM, O’Malley BW. Modulation of the ligand-independent activation of the human estrogen receptor by hormone and antihormone. Proc Natl Acad Sci USA 1993;90(13):6120–4. 5 Kato S, Endoh H, Masuhiro Y, et al. Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science 1995;270(5241):1491–4. 6 Patrone C, Gianazza E, Santagati S, Agrati P, Maggi A. Divergent pathways regulate ligand-independent activation of ERα in SK-N-BE neuroblastoma and COS-1 renal carcinoma cells. Mol Endocrinol 1998;12(6):835–41. 7 Cenni B, Picard D. Ligand-independent activation of steroid receptors: new roles for old players. Trends Endocrinol Metab 1999;10(2):41–6. 8 Brzozowski AM, Pike AC, Dauter Z, et al. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 1997;389(6651):753–8. 9 Shiau AK, Barstad D, Loria PM, et al. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 1998;95(7):927–37. 10 Heery D, Kalkhoven E, Hoare S, Parker MG. A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature 1997;387(6634):733–6. 11 Collingwood TN, Urnov FD, Wolffe AP. Nuclear receptors: coactivators, corepressors and chromatin remodeling in the control of transcription (review). J Mol Endocrinol 1999;23(3):255–75. 12 Westin S, Rosenfeld MG, Glass CK. Nuclear receptor coactivators (review). Adv Pharmacol 2000;47:89–112. 13 Struhl K. Histone acetylation and transcriptional regulatory mechanisms (review). Genes Dev 1998;12(5):599–606. 14 Beato M, Herrlich P, Schutz G. Steroid hormone receptors: many actors in search of a plot (review). Cell 1995;83(6):851–7. 15 Paech K, Webb P, Kuiper GG, et al. Differential ligand activation of ERs ERα and ERβ at AP1 sites. Science 1997;277:1508–10. 16 Pettersson K, Delaunay F, Gustafsson JÅ. Estrogen receptor beta acts as a dominant regulator of estrogen signaling. Oncogene 2000;19(43):4970–8. 17 Hartmann BW, Kirchengast S, Albrecht A, Soregy G, Knogler W, Huber JC. Absorption of orally supplied natural estrogens correlated with age and somatometric parameters. Gynecol Endocrinol 1994;8(2):101–7. 18 de Visser J, Coert A, Feenstra H, van der Vies J. Endocrinological studies with (7 a, 17 a)-17hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3one (Org OD 14). Arzneimittelforschung 1984;34(9):1010–7. 19 Cagnacci A, Mallus E, Tuveri F, Cirillo R, Setteneri AM, Melis GB. Effect of tibolone on glucose and lipid metabolism in postmenopausal women. J Clin Endocrinol Metab 1997;82(1):251–3. 117
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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
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 130 and 131: findings were remarkable because a
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
Page 180 and 181: 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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