Maturitas
Volume 60, Issue 3 , Pages 185-201 , July 2008

Could transdermal estradiol+progesterone be a safer postmenopausal HRT? A review

  • Marc L’Hermite

      Affiliations

    • Department of Gynecology and Obstetrics, Université Libre de Bruxelles, Bruxelles, Belgium
    • Corresponding Author InformationCorresponding author at: Service de Gynécologie-Obstétrique, CHU Brugmann, 4 Place Van Gehuchten, B-1020 Bruxelles, Belgium. Tel.: +32 2 477 2534; fax: +32 2 477 2977.
  • ,
  • Tommaso Simoncini

      Affiliations

    • Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, University of Pisa, Pisa, Italy
  • ,
  • Sarah Fuller

      Affiliations

    • Department of Gynecology and Obstetrics, Université Libre de Bruxelles, Bruxelles, Belgium
  • ,
  • Andrea Riccardo Genazzani

      Affiliations

    • Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, University of Pisa, Pisa, Italy

Received 7 March 2008 ,Revised 10 July 2008 ,Accepted 21 July 2008.

References 

  1. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA. 1998;280:605–613
  2. Manson JE, Hsia J, Johnson KC, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003;349:523–534
  3. The Women′s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women′s Health Initiative Randomized Controlled Trial. JAMA 2004;291:1701–12.
  4. Vickers MR, MacLennan AH, Lawton B, et al. Main morbidities recorded in the women's international study of long duration oestrogen after menopause (WISDOM): a randomised controlled trial of hormone replacement therapy in postmenopausal women. Brit Med J. 2007;335:239–250
  5. Hsia J, Langer RD, Manson JE, et al. Conjugated equine estrogens and coronary heart disease: the Women′s Health Initiative. Arch Intern Med. 2006;166:357–365
  6. Clarkson TB, Appt SE. Controversies about HRT – lessons from monkey models. Maturitas. 2005;51:64–74
  7. Ouyang P, Michos E, Karas R. Hormone replacement therapy and the cardiovascular system. Lessons learned and unanswered questions. J Am Coll Cardiol. 2006;47:1741–1753
  8. Grodstein F, Manson J, Stampfer M. Hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation. J Women′s Health. 2006;15:35–44
  9. Wagner J, Clarkson T. The applicability of hormonal effects on atherosclerosis in animals to heart disease in postmenopausal women. Sem Reprod Med. 2005;23:149–156
  10. Machens K, Schmidt-Gollwitzer K. Issues to debate on the Women′s Health Initiative (WHI) study. Hormone replacement therapy: an epidemiological dilemma?. Hum Reprod. 2003;18:1992–1999
  11. Harman SM, Naftolin F, Brinton EA, Judelson DR. Is the estrogen controversy over? Deconstructing the Women's Health Initiative study: A critical evaluation of the evidence. Ann NY Acad Sci. 2005;1052:43–56
  12. Klaiber E, Vogel W, Rako S. A critique of the Women′s Health Initiative hormone therapy study. Fertil Steril. 2005;84:1589–1601
  13. Shapiro S. Risk of cardiovascular disease in relation to the use of combined postmenopausal hormone therapy: detection bias and resolution of discrepant findings in two Women′s Health Initiative studies. Climacteric. 2006;9:416–420
  14. Wassertheil-Smoller S, Hendrix S, Limacher M, et al. Effect of estrogen plus progestin on stroke in postmenopausal women: The Women′s Health Initiative: a randomized trial. JAMA. 2003;289:2673–2684
  15. Bath PMW, Gray LJ. Association between hormone replacement therapy and subsequent stroke: a meta-analysis. Brit Med J. 2005;330:342–345
  16. Lokkegaard E, Jovanovic Z, Heitmann BL, et al. Increased risk of stroke in hypertensive women using hormone therapy: analyses based on the Danish Nurse study. Arch Neurol. 2003;60:1379–1384
  17. Magliano D, Rogers S, Abramson M, Tonkin A. Hormone therapy and cardiovascular disease: a systematic review and meta-analysis. Brit J Obstet Gynaecol. 2006;113:5–14
  18. Wassertheil-Smoller S, Anderson G, Psaty BM, et al. Hypertension and its treatment in postmenopausal women: baseline data from the Women′s Health Initiative. Hypertension. 2000;36:780–789
  19. Modena MG, Sismondi P, Mueck A, et al. New evidence regarding hormone replacement therapies is urgently required. Transdermal postmenopausal hormone therapy differs from oral hormone therapy in risks and benefits. Maturitas. 2005;52:1–10
  20. Kuhl H. Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric. 2005;8(Suppl. 1):3–63
  21. Cauley JA, Robbins J, Chen Z, et al. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women′s Health Initiative randomized trial. JAMA. 2003;290:1729–1738
  22. Gerber LM, Sievert LL, Warren K, Pickering TG, Schwartz JE. Hot flashes are associated with increased ambulatory systolic blood pressure. Menopause. 2007;14:308–315
  23. Rosenthal T, Oparil S. Hypertension in women. J Hum Hypertens. 2000;14:691–704
  24. Reckelhoff JF, Fortepiani LA. Novel mechanisms responsible for postmenopausal hypertension. Hypertension. 2004;43:918–923
  25. Rossi R, Chiurlia E, Nuzzo A, Cioni E, Origliani G, Modena MG. Flow-mediated vasodilation and the risk of developing hypertension in healthy postmenopausal women. J Am Coll Cardiol. 2004;44:1636–1640
  26. Fadel PJ, Wang Z, Watanabe H, Arbique D, Vongpatanasin W, Thomas GD. Augmented sympathetic vasoconstriction in exercising forearms of postmenopausal women is reversed by oestrogen therapy. J Physiol (Lond). 2004;561:893–901
  27. Sitruk-Ware R, Plu-Bureau G, Menard J, et al. Effects of oral and transvaginal ethinyl estradiol on hemostatic factors and hepatic proteins in a randomized, crossover study. J Clin Endocrinol Metab. 2007;92:2074–2079
  28. Sitruk-Ware R, Menard J, Rad M, et al. Comparison of the impact of vaginal and oral administration of combined hormonal contraceptives on hepatic proteins sensitive to estrogen. Contraception. 2007;75:430–437
  29. Schunkert H, Danser AHJ, Hense H-W, Derkx FHM, Kurzinger S, Riegger GAJ. Effects of estrogen replacement therapy on the renin-angiotensin system in postmenopausal women. Circulation. 1997;95:39–45
  30. Hassager C, Riis B, Strom V, Guyene T, Christiansen C. The long-term effect of oral and percutaneous estradiol on plasma renin substrate and blood pressure. Circulation. 1987;4:753–758
  31. Harvey PJ, Morris BL, Miller JA, Floras JS. Estradiol induces discordant angiotensin and blood pressure responses to orthostasis in healthy postmenopausal women. Hypertension. 2005;45:399–405
  32. Ichikawa J, Sumino H, Ichikawa S, Ozaki M. Different effects of transdermal and oral hormone replacement therapy on the renin-angiotensin system, plasma bradykinin level, and blood pressure of normotensive postmenopausal women. Am J Hypertens. 2006;19:744–749
  33. Scuteri A, Bos AJG, Brant LJ, Talbot L, Lakatta EG, Fleg JL. Hormone replacement therapy and longitudinal changes in blood pressure in postmenopausal women. Ann Intern Med. 2001;135:229–238
  34. Ashraf M, Vongpatanasin W. Estrogen and hypertension. Curr Hypertension Reports. 2006;8:368–376
  35. Steiner AZ, Xiang M, Mack WJ, et al. Unopposed estradiol therapy in postmenopausal women: results from two randomized trials. Obstet Gynecol. 2007;109:581–587
  36. Vongpatanasin W, Tuncel M, Mansour Y, Arbique D, Victor RG. Transdermal estrogen replacement therapy decreases sympathetic activity in postmenopausal women. Circulation. 2001;103:2903–2908
  37. Akkad AA, Halligan AW, Abrams K, al-Azzawi F. Differing responses in blood pressure over 24h in normotensive women receiving oral or transdermal estrogen replacement therapy. Obstet Gynecol. 1997;89:97–103
  38. Seely EW, Walsh BW, Gerhard MD, Williams GH. Estradiol with or without progesterone and ambulatory blood pressure in postmenopausal women. Hypertension. 1999;33:1190–1194
  39. Simoncini T, Mannella P, Fornari L, et al. Differential signal transduction of progesterone and medroxyprogesterone acetate in human endothelial cells. Endocrinology. 2004;145:5745–5756
  40. Sorensen KE, Dorup I, Hermann AP, Mosekilde L. Combined hormone replacement therapy does not protect women against the age-related decline in endothelium-dependent vasomotor function. Circulation. 1998;97:1234–1238
  41. Szmuilowicz ED, Adler GK, Ricchiuti V, Hopkins PN, Seely EW. Relationships between endogenous sex hormone concentrations and vascular function in postmenopausal women. J Clin Endocrinol Metab. 2007;92:4738–4741
  42. Rylance P, Brincat M, Lafferty K, et al. Natural progesterone and antihypertensive action. Brit Med J. 1986;290:33–34
  43. Spritzer P, Vitola D, Vilodre L, et al. One year follow-up of hormone replacement therapy with percutaneous estradiol and low-dose vaginal natural progesterone in women with mild to moderate hypertension. Exp Clin Endocrinol Diabetes. 2003;111:267–273
  44. Kirwan LD, MacLusky NJ, Shapiro HM, Abramson BL, Thomas SG, Goodman JM. Acute and chronic effects of hormone replacement therapy on the cardiovascular system in healthy postmenopausal women. J Clin Endocrinol Metab. 2004;89:1618–1629
  45. The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 1995;273:199–208.
  46. Archer DF, Thorneycroft IH, Foegh M, et al. Long-term safety of drospirenone-estradiol for hormone therapy: a randomized, double-blind, multicenter trial. Menopause. 2005;12:716–727
  47. Preston R, Alonso A, Panzitta D. Additive effect of drospirenone/17-beta-estradiol in hypertensive postmenopausal women receiving enalapril. Am J Hypertens. 2002;15:816–822
  48. Preston R, Norris P, Alonso A, Pingping N, Hanes V, Karara A. Randomized placebo-controlled trial of the effects of drospirenone-estradiol on blood pressure and potassium balance in hypertensive postmenopausal women receiving hydrochlorothiazide. Menopause. 2007;14:408–414
  49. Conen D, Ridker PM, Buring JE, Glynn RJ. Risk of cardiovascular events among women with high normal blood pressure or blood pressure progression: prospective cohort study. Br Med J. 2007;335:432-
  50. Salpeter SR, Walsh JME, Ormiston TM, Greyber E, Buckley NS, Salpeter EE. Meta-analysis: effect of hormone-replacement therapy on components of the metabolic syndrome in postmenopausal women.. Diab Obes Metab. 2006;8:538–554
  51. Rosano G, Vitale C, Silvestri A, Fini M. Metabolic and vascular effects of progestins in post-menopausal women. Implications for cardioprotection. Maturitas. 2003;46S:S17–S29
  52. Fernandes CE, Pompei LM, Machado RB, Ferreira JAS, Melo NR, Peixoto S. Effects of estradiol and norethisterone on lipids, insulin resistance and carotid flow. Maturitas. 2008;59:249–258
  53. Margolis KL, Bonds DE, Rodabough RJ, et al. Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women's Health Initiative Hormone Trial. Diabetologia. 2004;47:1175–1187
  54. Kernohan A, Sattar N, Hilditch T, et al. Effects of low-dose continuous combined hormone replacement therapy on glucose homeostasis and markers of cardiovascular risk in women with type 2 diabetes. Clin Endocrinol. 2007;66:27–34
  55. Fenkci S, Fenkci V, Yilmazer M, Serteser M, Koken T. Effects of short-term transdermal hormone replacement therapy on glycaemic control, lipid metabolism. C-reactive protein and proteinuria in postmenopausal women with type 2 diabetes or hypertension. Hum Reprod. 2003;18:866–870
  56. Chu M, Cosper P, Nakhuda G, Lobo R. A comparison of oral and transdermal short-term estrogen therapy in postmenopausal women with metabolic syndrome. Fertil Steril. 2006;86:1669–1675
  57. Hulley S, Furberg C, Barrett-Connor E, et al. Noncardiovascular disease outcomes during 6.8 years of hormone therapy: heart and estrogen/progestin replacement study follow-up (HERS II). JAMA. 2002;288:58–64
  58. Sitruk-Ware R. Pharmacological profile of progestins. Maturitas. 2004;47:277–283
  59. Sitruk-Ware R. Progestogens in hormonal replacement therapy: new molecules, risks, and benefits. Menopause. 2002;9:6–15
  60. Kushner I, Rzewnicki D, Samols D. What does minor elevation of C-reactive protein signify?. Am J Med. 2006;119:166.e17–e28
  61. Prelevic GM, Kwong P, Byrne DJ, Jagroop IA, Ginsburg J, Mikhailidis DP. A cross-sectional study of the effects of hormone replacement therapy on the cardiovascular disease risk profile in healthy postmenopausal women. Fertil Steril. 2002;77:945–951
  62. Decensi A, Omodei U, Robertson C, et al. Effect of transdermal estradiol and oral conjugated estrogen on C-reactive protein in retinoid-placebo trial in healthy women. Circulation. 2002;106:1224–1228
  63. Modena MG, Bursi F, Fantini G, et al. Effects of hormone replacement therapy on C-reactive protein levels in healthy postmenopausal women: comparison between oral and transdermal administration of estrogen. Am J Med. 2002;113:331–334
  64. Vongpatanasin W, Tuncel M, Wang Z, Arbique D, Mehrad B, Jialal I. Differential effects of oral versus transdermal estrogen replacement therapy on C-reactive protein in postmenopausal women. J Am Coll Cardiol. 2003;41:1358–1363
  65. Lakoski S, Herrington D. Effects of hormone therapy on C-reactive protein and IL-6 in postmenopausal women: a review article. Climacteric. 2005;8:317–326
  66. Reuben D, Palla S, Hu P, et al. Progestins affect mechanism of estrogen-induced C-reactive protein stimulation. Am J Med. 2006;119:167.e1–e8
  67. Cushman M, Legault C, Barrett-Connor E, et al. Effect of postmenopausal hormones on inflammation-sensitive proteins. The postmenopausal estrogen/progestin interventions (PEPI) study. Circulation. 1999;100:717–722
  68. Hemelaar M, van der Mooren MJ, Rad M, Kluft C, Kenemans P. Effects of non-oral postmenopausal hormone therapy on markers of cardiovascular risk: a systematic review. Fertil Steril. 2008;90:642–672
  69. Pradhan AD, Manson JE, Rossouw JE, et al. Inflammatory biomarkers, hormone replacement therapy, and incident coronary heart disease: prospective analysis from the Women′s Health Initiative observational study. JAMA. 2002;288:980–987
  70. Ho JY-P, Chen M-J, Sheu WH-H, et al. Differential effects of oral conjugated equine estrogen and transdermal estrogen on atherosclerotic vascular disease risk markers and endothelial function in healthy postmenopausal women. Hum Reprod. 2006;21:2715–2720
  71. Wakatsuki A, Okatani Y, Ikenoue N, Fukaya T. Different effects of oral conjugated equine estrogen and transdermal estrogen replacement therapy on size and oxidative susceptibility of low-density lipoprotein particles in postmenopausal women. Circulation. 2002;106:1771–1776
  72. Bednarek-Tupikowska G, Tworowska U, Jedrychowskat I, et al. Effects of oestradiol and oestroprogestin on erythrocyte antioxidative enzyme system activity in postmenopausal women. Clin Endocrinol. 2006;64:463–468
  73. Bansal S, Buring JE, Rifai N, Mora S, Sacks FM, Ridker PM. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA. 2007;298:309–316
  74. Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA. 2007;298:299–308
  75. Parini P, Angelin B, Rudling M. Importance of estrogen receptors in hepatic LDL receptor regulation. Arterioscler Thromb Vasc Biol. 1997;17:1800–1805
  76. Lopez D, Sanchez MD, Shea-Eaton W, McLean MP. Estrogen activates the high-density lipoprotein receptor gene via binding to estrogen response elements and interaction with sterol regulatory element binding protein-1A. Endocrinology. 2002;143:2155–2168
  77. Cheng W, Lau OD, Abumrad NA. Two antiatherogenic effects of progesterone on human macrophages; inhibition of cholesteryl ester synthesis and block of its enhancement by glucocorticoids. J Clin Endocrinol Metab. 1999;84:265–271
  78. Ross R. Atherosclerosis – an inflammatory disease. N Engl J Med. 1999;340:115–126
  79. Simoncini T, Caruso A, Giretti MS, et al. Effects of dydrogesterone and of its stable metabolite, 20-alpha-dihydrodydrogesterone, on nitric oxide synthesis in human endothelial cells. Fertil Steril. 2006;86:1235–1242
  80. Simoncini T, Caruso A, Garibaldi S, et al. Activation of nitric oxide synthesis in human endothelial cells using nomegestrol acetate. Obstet Gynecol. 2006;108:969–978
  81. Simoncini T, Fu XD, Caruso A, et al. Drospirenone increases endothelial nitric oxide synthesis via a combined action on progesterone and mineralocorticoid receptors. Hum Reprod. 2007;22:2325–2334
  82. Blümel J, Castelo-Branco C, Leal T, et al. Effects of transdermal estrogens on endothelial function in postmenopausal women with coronary disease. Climacteric. 2003;6:38–44
  83. Xing D, Miller A, Novak L, Rocha R, Chen Y-F, Oparil S. Estradiol and progestins differentially modulate leukocyte infiltration after vascular injury. Circulation. 2004;109:234–241
  84. Otsuki M, Saito H, Xu X, et al. Progesterone, but not medroxyprogesterone, inhibits vascular cell adhesion molecule-1 expression in human vascular endothelial cells. Arterioscler Thromb Vasc Biol. 2001;21:243–248
  85. Simoncini T, Mannella P, Fornari L, Caruso A, Varone G, Genazzani AR. In vitro effects of progesterone and progestins on vascular cells. Steroids. 2003;68:831–836
  86. Miyagawa K, Rosch J, Stanczyk F, Hermsmeyer K. Medroxyprogesterone interferes with ovarian steroid protection against coronary vasospasm. Nat Med. 1997;3:324–327
  87. Register TC, Adams MR, Golden DL, Clarkson TB. Conjugated equine estrogens alone, but not in combination with medroxyprogesterone acetate, inhibit aortic connective tissue remodeling after plasma lipid lowering in female monkeys. Arterioscler Thromb Vasc Biol. 1998;18:1164–1171
  88. Adams MR, Kaplan JR, Manuck SB, et al. Inhibition of coronary artery atherosclerosis by 17-beta estradiol in ovariectomized monkeys. Lack of an effect of added progesterone. Arterioscler Thromb Vasc Biol. 1990;10:1051–1057
  89. Adams MR, Williams JK, Kaplan JR, Koh KK, Sakuma I. Estrogens, progestins, and atherosclerosis. Arterioscler Thromb Vasc Biol. 2004;24:e190–e191
  90. Rosano GMC, Webb CM, Chierchia S, et al. Natural progesterone, but not medroxyprogesterone acetate, enhances the beneficial effect of estrogen on exercise-induced myocardial ischemia in postmenopausal women. J Am Coll Cardiol. 2000;36:2154–2159
  91. Gerhard M, Walsh BW, Tawakol A, et al. Estradiol therapy combined with progesterone and endothelium-dependent vasodilation in postmenopausal women. Circulation. 1998;98:1158–1163
  92. Wakatsuki A, Okatani Y, Ikenoue N, Fukaya T. Effect of medroxyprogesterone acetate on endothelium-dependent vasodilation in postmenopausal women receiving estrogen. Circulation. 2001;104:1773–1778
  93. Vehkavaara S, Westerbacka J, Hakala-Ala-Pietila T, Virkamaki A, Hovatta O, Yki-Jarvinen H. Effect of estrogen replacement therapy on insulin sensitivity of glucose metabolism and preresistance and resistance vessel function in healthy postmenopausal women. J Clin Endocrinol Metab. 2000;85:4663–4670
  94. Kawecka-Jaszcz K, Czarnecka D, Olszanecka A, Rajzer M, Jankowski P. The effect of hormone replacement therapy on arterial blood pressure and vascular compliance in postmenopausal women with arterial hypertension. J Hum Hypertens. 2002;16:509–516
  95. Sumino H, Ichikawa S, Kasama S, et al. Different effects of oral conjugated estrogen and transdermal estradiol on arterial stiffness and vascular inflammatory markers in postmenopausal women. Atherosclerosis. 2006;189:436–442
  96. Minshall RD, Pavcnik D, Halushka PV, Hermsmeyer K. Progesterone regulation of vascular thromboxane A2 receptors in rhesus monkeys. Am J Physiol Heart Circ Physiol. 2001;281:H1498–H1507
  97. Minshall RD, Stanczyk FZ, Miyagawa K, et al. Ovarian steroid protection against coronary artery hyperreactivity in rhesus monkeys. J Clin Endocrinol Metab. 1998;83:649–659
  98. Minshall RD, Miyagawa K, Chadwick CC, Novy MJ, Hermsmeyer K. In vitro modulation of primate coronary vascular muscle cell reactivity by ovarian steroid hormones. FASEB J. 1998;12:1419–1429
  99. Clarkson TB. Estrogen effects on arteries vary with stage of reproductive life and extent of subclinical atherosclerosis progression. Menopause. 2007;14:373–384
  100. Lewandowski KC, Komorowski J, Mikhalidis DP, et al. Effects of hormone replacement therapy type and route of administration on plasma matrix metalloproteinases and their tissue inhibitors in postmenopausal women. J Clin Endocrinol Metab. 2006;91:3123–3130
  101. Le Gal G, Gourlet V, Hogrel P, Plu-Bureau G, Touboul P-J, Scarabin P-Y. Hormone replacement therapy use is associated with a lower occurrence of carotid atherosclerotic plaques but not with intima-media thickness progression among postmenopausal women. The vascular aging (EVA) study. Atherosclerosis. 2003;166:163–170
  102. Schnatz P. Hormonal therapy: does it increase or decrease cardiovascular risk?. Obstet Gynecol Survey. 2006;61:673–681
  103. Salpeter SR, Walsh JME, Greyber E, Salpeter EE. Coronary heart disease events associated with hormone therapy in younger and older women. A meta-analysis. J Gen Intern Med. 2006;21:363–366
  104. Prentice R, Langer R, Stefanick M, et al. Combined analysis of Women′s Health Initiative observational and clinical trial data on postmenopausal hormone treatment and cardiovascular disease. Am J Epidemiol. 2006;163:589–599
  105. Hodis HN, Mack WJ, Lobo RA, et al. Estrogen in the prevention of atherosclerosis: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2001;135:939–953
  106. Manson JE, Allison MA, Rossouw JE, et al. Estrogen therapy and coronary-artery calcification. N Engl J Med. 2007;356:2591–2602
  107. Lakoski SG, Greenland P, Wong ND, et al. Coronary artery calcium scores and risk for cardiovascular events in women classified as “low risk” based on Framingham risk score: the multi-ethnic study of atherosclerosis (MESA). Arch Intern Med. 2007;167:2437–2442
  108. Detrano R, Guerci AD, Carr JJ, et al. Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N Engl J Med. 2008;358:1336–1345
  109. Phillips L, Langer R. Postmenopausal hormone therapy: critical reappraisal and a unified hypothesis. Fertil Steril. 2005;83:558–566
  110. Simoncini T, Genazzani AR. Timing is everything. Gynecol Endocrinol. 2007;23:1–4
  111. Oger R the EPI-GETBO Study Group. Incidence of venous thromboembolism: a community-based study in western France. Thromb Haemost. 2000;83:657–660
  112. Miller J, Chan BKS, Nelson HD. Postmenopausal estrogen replacement and risk for venous thromboembolism: a systematic review and meta-analysis for the U.S. Preventive Services Task Force. Ann Intern Med. 2002;136:680–690
  113. Cushman M, Kuller LH, Prentice R, et al. Estrogen plus progestin and risk of venous thrombosis. JAMA. 2004;292:1573–1580
  114. Scarabin P-Y, Alhenc-Gelas M, Plu-Bureau G, Tainsne P, Agher R, Aiach M. Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial. Arterioscler Thromb Vasc Biol. 1997;17:3071–3078
  115. Koh K, Shin M-S, Sakuma I, et al. Effects of conventional or lower doses of hormone replacement therapy in postmenopausal women. Arterioscler Thromb Vasc Biol. 2004;24:1516–1521
  116. Hooibraaten E, Mowinckel M-C, De Ronde H, Bertina R, Sandset P. Hormone replacement therapy and acquired resistance to activated protein C: results of a randomized, double-blind, placebo-controlled trial. Br J Haematol. 2001;115:415–420
  117. Oger E, Alhenc-Gelas M, Lacut K, et al. Differential effects of oral and transdermal estrogen/progesterone regimens on sensitivity to activated protein C among postmenopausal women: a randomized trial. Arterioscler Thromb Vasc Biol. 2003;23:1671–1676
  118. Martinez C, Basurto L, Zarate A, Saucedo R, Gaminio E, Collazo J. Transdermal estradiol does not impair hemostatic biomarkers in postmenopausal women. Maturitas. 2005;50:39–43
  119. Scarabin P-Y, Oger E. Plu-Bureau G, on behalf of the EStrogen and THromboEmbolism Risk (ESTHER) Study Group. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet. 2003;362:428–432
  120. Canonico M, Oger E, Conard J, et al. Obesity and risk of venous thromboembolism among postmenopausal women: differential impact of hormone therapy by route of estrogen administration. The ESTHER study. J Thromb Haemost. 2006;4:1259–1265
  121. Straczek C, Oger E, Yon de Jonage-Canonico MB, et al. Prothrombotic mutations, hormone therapy, and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration. The ESTHER study. Circulation. 2005;112:3495–3500
  122. Jick S, Kaye J, Li L, Jick H. Further results on the risk of nonfatal venous thromboembolism in users of the contraceptive transdermal patch compared to users of contraceptives containing norgetimate and 35 mcg of ethinyl estradiol. Contraception. 2007;76:4–7
  123. Schindler AE. Antiandrogenic progestins for treatment of signs of androgenisation and hormonal contraception. Eur J Obstet Gynecol Reprod Biol. 2004;112:136–141
  124. Acs N, Vajo Z, Miklos Z, et al. The effects of postmenopausal hormone replacement therapy on hemostatic variables: a meta-analysis of 46 studies. Gynecol Endocrinol. 2002;16:335–346
  125. Lidegaard O, Edström B, Kreiner S. Oral contraceptives and venous thromboembolism: a five-year national case-control study. Contraception. 2002;65:187–196
  126. van Vliet H, Frolich M, Christella M, et al. Association between sex hormone-binding globulin levels and activated protein C resistance in explaining the risk of thrombosis in users of oral contraceptives containing different progestogens. Hum Reprod. 2005;20:563–568
  127. Douketis J, Julian J, Kearon C, et al. Does the type of hormone replacement therapy influence the risk of deep vein thrombosis? A prospective case-control study. J Throromb Haemost. 2005;3:943–948
  128. Writing Group for the Women′s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002;288:321–33.
  129. Curb J, Prentice R, Bray P, et al. Venous thrombosis and conjugated equine estrogen in women with a uterus. Arch Intern Med. 2006;166:772–780
  130. Canonico M, Oger E, Plu-Bureau G, et al. Hormone therapy and venous thromboembolism among postmenopausal women: Impact of the route of estrogen administration and progestogens: the ESTHER Study. Circulation. 2007;115:840–845
  131. Plotsky P, Cunningham E, Widmaier E. Cathecholaminergic modulation of corticotropin-releasing factor and adrenocorticotropin secretion. Endocr Rev. 1989;10:437–458
  132. Etgen A, Karkanias G. Estrogen regulation of noradrenergic signaling in the hypothalamus. Psychoneuroendocrinology. 1994;19:603–610
  133. Dickinson S, Curzon G. 5-hydroxytryptamine-mediated behaviour in male and female rats. Neuropharmacology. 1986;25:771–776
  134. Ladisich W. influence of progesterone on serotonin metabolism: a possible causal factor for mood changes. Psychoneuroendocrinology. 1977;2:257–266
  135. Luine V, Khylchevskaya R, McEwen B. Effect of gonadal steroids on activities of monoamine oxidase and choline acetylase in rat brain. Brain Res. 1975;86:293–306
  136. Holzbauer M, Youdim M. The oestrous cycle and monoamine activity. Br J Pharmacol. 1973;48:600–608
  137. Jiang N, Chopp M, Stein D, Feldblum S. Progesterone is neuroprotective after transient middle cerebral artery occlusion in male rats. Brain Res. 1996;735:101–107
  138. Genazzani A, Stomati M, Morittu A, et al. Progesterone, progestagens and the central nervous system. Hum Reprod. 2000;15(Suppl. 1):14–27
  139. Wang M, Wahlström G, Bäckström T. The regional brain distribution of the neurosteroids pregnenolone and pregnenolone sulfate following intravenous infusion. J Steroid Biochem Mol Biol. 1997;62:299–306
  140. Stoffel-Wagner B, Watska M, Schramm J, Bidlingmaier F, Klingmuller D. Expression of CYP19 (aromatase) mRNA in different areas of the human brain. J Steroid Biochem Mol Biol. 1999;70:237–241
  141. Baulieu E. Neurosteroids: a new function in the brain. Biol Cell. 1991;71:3–10
  142. Baulieu E. Neurosteroids: of the nervous system, by the nervous system, for the nervous system. Recent Progr Horm Res. 1997;52:1–32
  143. Schumacher M, Coirini H, McEwen B. Regulation of high affinity GABAA receptors in the dorsal hippocampus by estradiol and progesterone. Brain Res. 1989;487:178–184
  144. Bitran D, Purdy R, Kellogg C. Anxiolytic effect of progesterone is mediated by the neurosteroid allopreganolone and GABAA receptor function. Pharmacol Biochem Behav. 1993;45:423–428
  145. Bitran D, Shiekh M, McLeod M. Anxiolytic effect of progesterone is mediated by the neurosteroid allopreganolone at brain GABAA receptors. J Neuroendocrinol. 1995;7:171–177
  146. Frye C, Bayon L, Pursnani N, Purdy R. The neurosteroids, progesterone and 3alpha, 5alpha-THP, enhance sexual motivation, receptivity, and proceptivity in female rats. Brain Res. 1998;808:72–83
  147. Corpechot C, Young J, Calvel M, et al. Neurosteroids: 3 alpha-hydroxy-5 alpha-pregnan-20-one and its precursors in the brain, plasma and steroidogenic glands of male and female rats. Endocrinology. 1999;133:1003–1009
  148. Bernardi F, Pluchino N, Pieri M, et al. Progesterone and medroxyprogesterone acetate effects on central and peripheral allopregnanolone and beta-endorphin levels. Neuroendocrinology. 2006;24:348–359
  149. Schumacher M, Weill-Engerer S, Liere P, et al. Steroid hormones and neurosteroids in normal and pathological aging of the nervous system. Prog Neurobiol. 2003;71:3–29
  150. Thomas A, Nockels R, Pan H, Shaffrey C, Chopp M. Progesterone is neuroprotective after acute experimental spinal cord trauma in rats. Spine. 1999;24:2134–2138
  151. Gonzalez D, Lopez-Costa J, Saavedra J, et al. Progesterone protection in the wobbler mouse, a genetic model of spinal cord motor disease. Neurobiol Dis. 2002;11:457–468
  152. Yu W. Survival of motoneurons following axotomy is enhanced by lactation or by progesterone treatment. Brain Res. 1989;491:379–382
  153. Stein D. Brain damage, sex hormones and recovery: a new role for progesterone and estrogen?. Trends Neurosci. 2001;24:386–391
  154. Roof R, Duvdevani R, Heyburn J, Stein D. Progesterone rapidly decreases brain edema: treatment delayed up to 24h is still effective. Exp Neurol. 1996;138:246–251
  155. Roof R, Duvdevani R, Braswell L, Stein D. Progesterone facilitates cognitive recovery and reduces secondary neuronal loss caused by cortical contusion injury in male rats. Exp Neurol. 1994;129:64–69
  156. Nilsen J, Brinton RD. Impact of progestins on estrogen-induced neuroprotection: Synergy by progesterone and 19-norprogesterone and antagonism by medroxyprogesterone acetate. Endocrinology. 2002;143:205–212
  157. Peters A. Structural changes in the normally aging cerebral cortex of primates. Prog Brain Res. 2002;136:455–465
  158. Ghoumari A, Ibanez C, el-Etr M, et al. Progesterone and its metabolites increase myelin basic protein expression in organotypic slice cultures of rat cerebellum. J Neurochem. 2003;86:848–859
  159. Zandi PP, Carlson MC, Plassman BL, et al. Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache county study. JAMA. 2002;288:2123–2129
  160. Gruber CJ, Tschugguel W, Schneeberger C, Huber JC. Production and actions of estrogens. N Engl J Med. 2002;346:340–352
  161. Wiseman R. Breast cancer: critical data analysis concludes that estrogens are not the cause, however lifestyle changes can alter risk rapidly. J Clin Epidemiol. 2004;57:766–772
  162. Wren B. Menopause. 2007;14:1060–1068
  163. Söderqvist G, Isaksson E, von Schoultz B, Carlström K, Tani E, Skoog L. Proliferation of breast epithelial cells in healthy women during the menstrual cycle. Am J Obstet Gynecol. 1997;176:123–128
  164. Conner P, Söderqvist G, Skoog L, et al. Breast cell proliferation in postmenopausal women during HRT evaluated through fine needle aspiration cytology. Breast Cancer Res Treat. 2003;78:159–165
  165. Foidart J-M, Colin C, Denoo X, et al. Estradiol and progesterone regulate the proliferation of human breast epithelial cells. Fertil Steril. 1998;69:963–969
  166. Chang K-J, Fournier S, Lee T, de Lignières B, Linares-Cruz G. Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo. Fertil Steril. 1995;63:785–791
  167. Hofseth LJ, Raafat AM, Osuch JR, Pathak DR, Slomski CA, Haslam SZ. Hormone replacement therapy with estrogen or estrogen plus medroxyprogesterone acetate is associated with increased epithelial proliferation in the normal postmenopausal breast. J Clin Endocrinol Metab. 1999;84:4559–4565
  168. Desreux J, Kebers F, Noël A, et al. Effects of a progestogen on normal human breast epithelial cell apoptosis in vitro and in vivo. The Breast. 2003;12:142–149
  169. Wood C, Register TC, Lees C, Chen H, Kimrey S, Cline J. Effects of estradiol with micronized progesterone or medroxyprogesterone acetate on risk markers for breast cancer in postmenopausal monkeys. Breast Cancer Res Treat. 2007;101:125–134
  170. Wood C, Sitruk-Ware R, Yun-Yen T, Register TC, Lees C, Cline J. Effects of estradiol with oral or intravaginal progesterone on risk markers for breast cancer in a postmenopausal monkey model. Menopause. 2007;14:639–647
  171. Seeger H, Wallwiener D, Mueck AO. The effect of progesterone and synthetic progestins on serum- and estradiol-stimulated proliferation of human breast cancer cells. Horm Metab Res. 2003;35:76–80
  172. Franke H, Vermes I. Differential effects of progestogens on breast cancer cell lines. Maturitas. 2003;46S1:S55–S58
  173. Seeger H, Rakov V, Mueck AO. Dose-dependent changes of the ratio of apoptosis to proliferation by norethisterone and medroxyprogesterone acetate in human breast epithelial cells. Horm Metab Res. 2005;37:468–473
  174. Pasqualini JR. Differential effects of progestins on breast tissue enzymes. Maturitas. 2003;46(Suppl. 1):S45–54
  175. Druckmann R. Progestins and their effects on the breast. Maturitas. 2003;46(Suppl. 1):S59–S69
  176. Xu B, Kitawaki J, Koshiba H, et al. Differential effects of progestogens, by type and regimen, on estrogen-metabolizing enzymes in human breast cancer cells. Maturitas. 2007;56:142–152
  177. Wiebe J, Lewis M, Cialacu V, Pawlak K, Zhang G. The role of progesterone metabolites in breast cancer: potential for new diagnostics and therapeutics. J Steroid Biochem Mol Biol. 2005;93:201–208
  178. Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women′s Health Initiative randomized trial. JAMA. 2003;289:3243–3253
  179. Anderson GL, Chlebowski RT, Rossouw JE, et al. Prior hormone therapy and breast cancer risk in the Women′s Health Initiative randomized trial of estrogen plus progestin. Maturitas. 2006;55:103–115
  180. Clark J. A critique of Women′s Health Initiative studies (2002–2006). Nucl Recept Signal. 2006;4:e023
  181. Ravdin PM, Cronin KA, Howlader N, et al. The decrease in breast-cancer incidence in 2003 in the Unites States. New Engl J Med. 2007;356:1670–1674
  182. Berry DA, Ravdin PM. Breast cancer trends: a marriage between clinical trial evidence and epidemiology. J Natl Cancer Inst. 2007;99:1139–1141
  183. Bush TL, Whiteman M, Flaws JA. Hormone replacement therapy and breast cancer: a qualitative review. Obstet Gynecol. 2001;98:498–508
  184. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52 705 women with breast cancer and 108 411 women without breast cancer. Lancet 1997;350:1047–59.
  185. Ross R, Paganini-Hill A, Wan P, Pike MC. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. J Natl Cancer Inst. 2000;92:328–332
  186. Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L, Hoover R. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA. 2000;283:485–491
  187. Li CI, Malone KE, Porter PL, et al. Relationship between long durations and different regimens of hormone therapy and risk of breast cancer. JAMA. 2003;289:3254–3263
  188. Chen WY, Manson JE, Hankinson SE, et al. Unopposed estrogen therapy and the risk of invasive breast cancer. Arch Intern Med. 2006;166:1027–1032
  189. Stefanick ML, Anderson GL, Margolis KL, et al. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA. 2006;295:1647–1657
  190. Eliassen A, Colditz GA, Rosner B, Willett W, Kankinson S. Adult weight change and risk of postmenopausal breast cancer. JAMA. 2006;296:193–201
  191. Santen R, Allred D. The estrogen paradox. Nat Clin Pract Endocrinol Metab. 2007;3:496–497
  192. Song RX, Mor G, Naftolin F, et al. Effect of long-term estrogen deprivation on apoptotic responses of breast cancer cells to 17{beta}-estradiol. J Natl Cancer Inst. 2001;93:1714–1723
  193. Beral V, Reeves G, Banks E. Current evidence about the effect of hormone replacement therapy on the incidence of major conditions in postmenopausal women. Brit J Obstet Gynecol. 2005;112:692–695
  194. Tannen RL, Weiner MG, Xie D, Barnhart K. Estrogen affects post-menopausal women differently than estrogen plus progestin replacement therapy. Hum Reprod. 2007;22:1769–1777
  195. Kenemans P. Postmenopausal hormone therapy and breast cancer: what is the problem?. Maturitas. 2005;51:75–82
  196. Lyytinen H, Pukkala E, Ylikorkala O. Breast cancer risk in postmenopausal women using estrogen-only therapy. Obstet Gynecol. 2006;108:1354–1360
  197. Fournier A, Berrino F, Riboli E, Avenel V, Clavel-Chapon F. Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. Int J Cancer. 2005;114:448–454
  198. Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat. 2008;107:103–111
  199. Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003;362:419–27.
  200. Opatrny L, Dell Aniello S, Assouline S, Suissa S. Hormone replacement therapy use and variations in the risk of breast cancer. Br J Obstet Gynaecol. 2008;115:169–175
  201. Mueck AO, Seeger H. Breast cancer: are estrogen metabolites carcinogenic?. Climacteric. 2007;10(Suppl. 2):62–65
  202. Boyd N, Lockwood G, Martin L, et al. Mammographic densities and risk of breast cancer among subjects with a family history of this disease. J Natl Cancer Inst. 1999;91:1404–1408
  203. Şendağ F, Terek M, Ozsener S, et al. Mammographic density changes during different postmenopausal hormone replacement therapies. Fertil Steril. 2001;76:445–450
  204. Greendale GA, Reboussin BA, Slone S, Wasilauskas C, Pike MC, Ursin G. Postmenopausal hormone therapy and change in mammographic density. J Natl Cancer Inst. 2003;95:30–37
  205. de Lignières B, de Vathaire F, Fournier S, et al. Combined hormone replacement therapy and risk of breast cancer in a French cohort study of 3175 women. Climacteric. 2002;5:332–340
  206. Chevallier T, Daurès J-P, Micheletti M-C, Reginster J-Y. Groupe MISSION. Méthodologie de l’enquête MISSION (Ménopause, rISque de cancer du sein, mOrbidité et prévaleNce). J Gynecol Obstet Biol Reprod. 2005;34:658–665
  207. Espié M, Mares P, de Reilhac P, Chevallier T, Daurès J-P. Breast cancer in postmenopausal women with and without hormone replacement therapy: Preliminary results of the MISSION study. Gynecol Endocrinol. 2006;22:423–431
  208. Campagnoli C, Clavel-Chapelon F, Kaaks R, Peris C, Berrino F. Progestins and progesterone in hormone replacement therapy and the risk of breast cancer. J Steroid Biochem Mol Biol. 2005;96:95–108
  209. Campagnoli C, Abba C, Ambroggio S, Peris C. Pregnancy, progesterone and progestins in relation to breast cancer risk. J Steroid Biochem Mol Biol. 2005;97:441–450
  210. Sonnet E, Lacut K, Roudaut N, Mottier D, Kerlan V, Oger E. Effects of the route of oestrogen administration on IGF-1 and IGFBP-3 in healthy postmenopausal women: results from a randomized placebo-controlled study. Clin Endocrinol. 2007;66:626–631
  211. Tang M-X, Jacobs D, Stern Y, et al. Effect of oestrogen during menopause on risk and age at onset of Alzheimer′s disease. Lancet. 1996;348:429–432
  212. Gambacciani M, Pepe A, Cappagli B, Palmieri E, Genazzani AR. The relative contributions of menopause and aging to postmenopausal reduction in intervertebral disk height. Climacteric. 2007;10:298–305
  213. Torgerson DJ, Bell-Syer SEM. Hormone replacement therapy and prevention of nonvertebral fractures: a meta-analysis of randomized trials. JAMA. 2001;285:2891–2897
  214. Naessen T, Lindmark B, Lagerström C, Larsen H-D, Persson I. Early postmenopausal hormone therapy improves postural balance. Menopause. 2007;14:14–19
  215. Saltiki K, Doukas C, Kanakakis J, Anastasiou E, Mantzou E, Alevizaki M. Severity of cardiovascular disease in women: relation with exposure to endogenous estrogen. Maturitas. 2006;55:51–57
  216. Dubey RK, Jackson EK. Genome and hormones: Gender differences in physiology: Invited review: cardiovascular protective effects of 17{beta}-estradiol metabolites. J Appl Physiol. 2001;91:1868–1883
  217. Masi CM, Hawkley LC, Berry JD, Cacioppo JT. Estrogen metabolites and systolic blood pressure in a population-based sample of postmenopausal women. J Clin Endocrinol Metab. 2006;91:1015–1020
  218. Grodstein F, Manson JE, Stampfer MJ, Rexrode K. Postmenopausal hormone therapy and stroke: role of time since menopause and age at initiation of hormone therapy. Arch Intern Med. 2008;168:861–866
  219. Harman S, Brinton E, Cedars M, et al. KEEPS: the Kronos Early Estrogen Prevention Study. Climacteric. 2005;8:3–12
  220. Bhavnani B. Pharmacokinetics and pharmacodynamics of conjugated equine estrogens: chemistry and metabolism. Proc Soc Exp Biol Med. 1998;217:6–16
  221. Dey M, Lyttle R, Pickar J. Recent insights into the varying activity of estrogens. Maturitas. 2000;34S:S25–S33
  222. The Writing Group for the PEPI Trial. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The postmenopausal estrogen/progestin interventions (PEPI) trial. JAMA 1996;275:370–5.
  223. Ross D, Cooper A, Pryse-Davies J, et al. Randomized, double-blind, dose-ranging study of the endometrial effects of a vaginal progesterone gel in estrogen-treated postmenopausal women. Am J Obstet Gynecol. 1997;177:937–941
  224. Schumacher M, Guennoun R, Ghoumari A, et al. Novel perspectives for progesterone in hormone replacement therapy, with special reference to the nervous system. Endocr Rev. 2007;28:387–439

 Parts of this work were presented separately by L’Hermite, Simoncini and Genazzani at the 6th IMS symposium held in Pisa in December 2006; they can be consulted at www.6thimsworkshop.com. The present work has been, however, considerably extended and updated.

PII: S0378-5122(08)00204-1

doi: 10.1016/j.maturitas.2008.07.007

Maturitas
Volume 60, Issue 3 , Pages 185-201 , July 2008