Risks and benefits of menopausal hormone therapy
Article information
J Korean Med Assoc. 2019;62(3):150-159
Publication date (electronic) : 2019 March 19
doi :
https://doi.org/10.5124/jkma.2019.62.3.150
Received 2019 February 26; Accepted 2019 March 11.
Abstract
Menopausal hormone therapy (MHT) was widely used to improve quality of life by controlling menopausal symptoms, including vasomotor symptoms and urogenital atrophy. Furthermore, observational studies consistently reported beneficial effects of MHT on late problems of menopause, such as osteoporosis, coronary heart disease (CHD), and possibly dementia. However, circumstances changed abruptly after the 2002 publication of the first findings from the Women's Health Initiative (WHI) study, which was conducted in postmenopausal women (average age, 63 years) using conventional doses of conjugated equine estrogen (CEE) and medroxyprogesterone acetate. CEE with medroxyprogesterone acetate increased the risk of breast cancer and did not prevent CHD. However, CEE alone showed a tendency to decrease the risk of both breast cancer and CHD, with significant differences between the two therapies. A subgroup analysis by age and years since menopause led to a timing hypothesis regarding the effects of MHT on CHD. Indeed, CEE alone in women aged 50 to 59 significantly reduced CHD risk by 35% after 13 years of follow-up. In 2015, a Cochrane meta-analysis of MHT trials reported a 48% reduction in CHD, no change in stroke, and most importantly, a 30% decrease in total mortality in women with less than 10 years since menopause. Long-term follow-up of WHI participants confirmed beneficial impacts of CEE on breast cancer incidence and mortality. Further, fracture reduction in women with osteopenia was observed during the intervention phase of the WHI study. If initiated early after menopause, MHT could again be considered to improve menopause-related quality of life and decrease all-cause mortality.
Keywords: Menopausal hormone therapy; Osteoporosis; Coronary heart disease; Dementia; All-cause mortality
References
1. Crawford SL, Crandall CJ, Derby CA, El Khoudary SR, Waetjen LE, Fischer M, Joffe H. Menopausal hormone therapy trends before versus after 2002: impact of the Women's Health Initiative Study Results. Menopause 2018;12. 21. 10.1097/GME.0000000000001282. [Epub].
2. Manson JE, Chlebowski RT, Stefanick ML, Aragaki AK, Rossouw JE, Prentice RL, Anderson G, Howard BV, Thomson CA, LaCroix AZ, Wactawski-Wende J, Jackson RD, Limacher M, Margolis KL, Wassertheil-Smoller S, Beresford SA, Cauley JA, Eaton CB, Gass M, Hsia J, Johnson KC, Kooperberg C, Kuller LH, Lewis CE, Liu S, Martin LW, Ockene JK, O'Sullivan MJ, Powell LH, Simon MS, Van Horn L, Vitolins MZ, Wallace RB. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA 2013;310:1353–1368.
3. Manson JE, Aragaki AK, Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Chlebowski RT, Howard BV, Thomson CA, Margolis KL, Lewis CE, Stefanick ML, Jackson RD, Johnson KC, Martin LW, Shumaker SA, Espeland MA, Wactawski-Wende J. WHI Investigators. Menopausal hormone therapy and long-term all-cause and cause-specific mortality: the Women's Health Initiative Randomized Trials. JAMA 2017;318:927–938.
4. Schierbeck LL, Rejnmark L, Tofteng CL, Stilgren L, Eiken P, Mosekilde L, Kober L, Jensen JE. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ 2012;345e6409.
5. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998;280:605–613.
6. Schneider HPG, Birkhauser M. Quality of life in climacteric women. Climacteric 2017;20:187–194.
7. Wells G, Tugwell P, Shea B, Guyatt G, Peterson J, Zytaruk N, Robinson V, Henry D, O'Connell D, Cranney A. Osteoporosis Methodology Group and The Osteoporosis Research Advisory Group. Meta-analyses of therapies for postmenopausal osteoporosis. V. Meta-analysis of the efficacy of hormone replacement therapy in treating and preventing osteoporosis in postmenopausal women. Endocr Rev 2002;23:529–539.
8. Effects of hormone therapy on bone mineral density: results from the postmenopausal estrogen/progestin interventions (PEPI) trial. The Writing Group for the PEPI. JAMA 1996;276:1389–1396.
9. Lindsay R, Gallagher JC, Kleerekoper M, Pickar JH. Effect of lower doses of conjugated equine estrogens with and without medroxyprogesterone acetate on bone in early postmenopausal women. JAMA 2002;287:2668–2676.
10. Farr JN, Khosla S, Miyabara Y, Miller VM, Kearns AE. Effects of estrogen with micronized progesterone on cortical and trabecular bone mass and microstructure in recently postmenopausal women. J Clin Endocrinol Metab 2013;98:E249–E257.
11. Khosla S, Oursler MJ, Monroe DG. Estrogen and the skeleton. Trends Endocrinol Metab 2012;23:576–581.
12. Chen Z, Beck TJ, Cauley JA, Lewis CE, LaCroix A, Bassford T, Wu G, Sherrill D, Going S. Hormone therapy improves femur geometry among ethnically diverse postmenopausal participants in the Women's Health Initiative hormone intervention trials. J Bone Miner Res 2008;23:1935–1945.
13. Boivin G, Vedi S, Purdie DW, Compston JE, Meunier PJ. Influence of estrogen therapy at conventional and high doses on the degree of mineralization of iliac bone tissue: a quantitative microradiographic analysis in postmenopausal women. Bone 2005;36:562–567.
14. Cauley JA, Robbins J, Chen Z, Cummings SR, Jackson RD, LaCroix AZ, LeBoff M, Lewis CE, McGowan J, Neuner J, Pettinger M, Stefanick ML, Wactawski-Wende J, Watts NB. Women's Health Initiative Investigators. 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.
15. Jackson RD, Wactawski-Wende J, LaCroix AZ, Pettinger M, Yood RA, Watts NB, Robbins JA, Lewis CE, Beresford SA, Ko MG, Naughton MJ, Satterfield S, Bassford T. Women's Health Initiative Investigators. Effects of conjugated equine estrogen on risk of fractures and BMD in postmenopausal women with hysterectomy: results from the women's health initiative randomized trial. J Bone Miner Res 2006;21:817–828.
16. Siris ES, Chen YT, Abbott TA, Barrett-Connor E, Miller PD, Wehren LE, Berger ML. Bone mineral density thresholds for pharmacological intervention to prevent fractures. Arch Intern Med 2004;164:1108–1112.
17. Robbins JA, Aragaki A, Crandall CJ, Manson JE, Carbone L, Jackson R, Lewis CE, Johnson KC, Sarto G, Stefanick ML, Wactawski-Wende J. Women's Health Initiative clinical trials: interaction of calcium and vitamin D with hormone therapy. Menopause 2014;21:116–123.
18. Cummings SR, Ettinger B, Delmas PD, Kenemans P, Statho-poulos V, Verweij P, Mol-Arts M, Kloosterboer L, Mosca L, Christiansen C, Bilezikian J, Kerzberg EM, Johnson S, Zanchetta J, Grobbee DE, Seifert W, Eastell R. LIFT Trial Investigators. The effects of tibolone in older postmenopausal women. N Engl J Med 2008;359:697–708.
19. Grodstein F, Newcomb PA, Stampfer MJ. Postmenopausal hormone therapy and the risk of colorectal cancer: a review and meta-analysis. Am J Med 1999;106:574–582.
20. Effects of. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial. JAMA 1996;275:370–375.
21. Archer DF, Hendrix S, Gallagher JC, Rymer J, Skouby S, Ferenczy A, den Hollander W, Stathopoulos V, Helmond FA. Endometrial effects of tibolone. J Clin Endocrinol Metab 2007;92:911–918.
22. Breast cancer. collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet 1997;350:1047–1059.
23. Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Gass M, Lane D, Rodabough RJ, Gilligan MA, Cyr MG, Thomson CA, Khandekar J, Petrovitch H, McTiernan A. WHI Investigators. 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.
24. Stefanick ML, Anderson GL, Margolis KL, Hendrix SL, Rodabough RJ, Paskett ED, Lane DS, Hubbell FA, Assaf AR, Sarto GE, Schenken RS, Yasmeen S, Lessin L, Chlebowski RT. WHI Investigators. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA 2006;295:1647–1657.
25. Rohan TE, Negassa A, Chlebowski RT, Habel L, McTiernan A, Ginsberg M, Wassertheil-Smoller S, Page DL. Conjugated equine estrogen and risk of benign proliferative breast disease: a randomized controlled trial. J Natl Cancer Inst 2008;100:563–571.
26. Anderson GL, Chlebowski RT, Rossouw JE, Rodabough RJ, McTiernan A, Margolis KL, Aggerwal A, David Curb J, Hendrix SL, Allan Hubbell F, Khandekar J, Lane DS, Lasser N, Lopez AM, Potter J, Ritenbaugh C. Prior hormone therapy and breast cancer risk in the Women's Health Initiative randomized trial of estrogen plus progestin. Maturitas 2006;55:103–115.
27. Prentice RL, Chlebowski RT, Stefanick ML, Manson JE, Pettinger M, Hendrix SL, Hubbell FA, Kooperberg C, Kuller LH, Lane DS, McTiernan A, Jo O'Sullivan M, Rossouw JE, Anderson GL. Estrogen plus progestin therapy and breast cancer in recently postmenopausal women. Am J Epidemiol 2008;167:1207–1216.
28. Harman SM, Black DM, Naftolin F, Brinton EA, Budoff MJ, Cedars MI, Hopkins PN, Lobo RA, Manson JE, Merriam GR, Miller VM, Neal-Perry G, Santoro N, Taylor HS, Vittinghoff E, Yan M, Hodis HN. Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women: a randomized trial. Ann Intern Med 2014;161:249–260.
29. Cushman M, Kuller LH, Prentice R, Rodabough RJ, Psaty BM, Stafford RS, Sidney S, Rosendaal FR. Women's Health Initiative Investigators. Estrogen plus progestin and risk of venous thrombosis. JAMA 2004;292:1573–1580.
30. Boardman HM, Hartley L, Eisinga A, Main C, Roque i, Bonfill Cosp X, Gabriel Sanchez R, Knight B. Hormone therapy for preventing cardiovascular disease in post-menopausal women. Cochrane Database Syst Rev 2015;(3)CD002229.
31. Kenemans P, Bundred NJ, Foidart JM, Kubista E, von Schoultz B, Sismondi P, Vassilopoulou-Sellin R, Yip CH, Egberts J, Mol-Arts M, Mulder R, van Os S, Beckmann MW. LIBERATE Study Group. Safety and efficacy of tibolone in breast-cancer patients with vasomotor symptoms: a double-blind, randomised, non-inferiority trial. Lancet Oncol 2009;10:135–146.
32. Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ 2019;364k4810.
33. Grodstein F, Manson JE, Colditz GA, Willett WC, Speizer FE, Stampfer MJ. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med 2000;133:933–941.
34. 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.
35. Renoux C, Dell'aniello S, Garbe E, Suissa S. Transdermal and oral hormone replacement therapy and the risk of stroke: a nested case-control study. BMJ 2010;340c2519.
36. Simon JA, Hsia J, Cauley JA, Richards C, Harris F, Fong J, Barrett-Connor E, Hulley SB. Postmenopausal hormone therapy and risk of stroke: the Heart and Estrogen-progestin Replacement Study (HERS). Circulation 2001;103:638–642.
37. Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, Horwitz RI. A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med 2001;345:1243–1249.
38. Grodstein F, Stampfer MJ, Manson JE, Colditz GA, Willett WC, Rosner B, Speizer FE, Hennekens CH. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med 1996;335:453–461.
39. Humphrey LL, Chan BK, Sox HC. Postmenopausal hormone replacement therapy and the primary prevention of cardiovascular disease. Ann Intern Med 2002;137:273–284.
40. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial. JAMA 1995;273:199–208.
41. Mendelsohn ME, Karas RH. Molecular and cellular basis of cardiovascular gender differences. Science 2005;308:1583–1587.
42. Rossouw JE, Prentice RL, Manson JE, Wu L, Barad D, Barnabei VM, Ko M, LaCroix AZ, Margolis KL, Stefanick ML. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007;297:1465–1477.
43. Manson JE, Hsia J, Johnson KC, Rossouw JE, Assaf AR, Lasser NL, Trevisan M, Black HR, Heckbert SR, Detrano R, Strickland OL, Wong ND, Crouse JR, Stein E, Cushman M. Women's Health Initiative Investigators. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003;349:523–534.
44. Hsia J, Langer RD, Manson JE, Kuller L, Johnson KC, Hendrix SL, Pettinger M, Heckbert SR, Greep N, Crawford S, Eaton CB, Kostis JB, Caralis P, Prentice R. Women's Health Initiative Investigators. Conjugated equine estrogens and coronary heart disease: the Women's Health Initiative. Arch Intern Med 2006;166:357–365.
45. Bots ML, Evans GW, Riley W, McBride KH, Paskett ED, Helmond FA, Grobbee DE. OPAL Investigators. The effect of tibolone and continuous combined conjugated equine oestrogens plus medroxyprogesterone acetate on progression of carotid intima-media thickness: the Osteoporosis Prevention and Arterial effects of tiboLone (OPAL) study. Eur Heart J 2006;27:746–755.
46. Cherry N, Gilmour K, Hannaford P, Heagerty A, Khan MA, Kitchener H, McNamee R, Elstein M, Kay C, Seif M, Buckley H. ESPRIT team. Oestrogen therapy for prevention of reinfarction in postmenopausal women: a randomised placebo controlled trial. Lancet 2002;360:2001–2008.
47. Kim YJ, Han JW, So YS, Seo JY, Kim KY, Kim KW. Prevalence and trends of dementia in Korea: a systematic review and meta-analysis. J Korean Med Sci 2014;29:903–912.
48. Yoon BK, Chin J, Kim JW, Shin MH, Ahn S, Lee DY, Seo SW, Na DL. Menopausal hormone therapy and mild cognitive impairment: a randomized, placebo-controlled trial. Menopaus 2018;25:870–876.
49. Yaffe K, Sawaya G, Lieberburg I, Grady D. Estrogen therapy in postmenopausal women: effects on cognitive function and dementia. JAMA 1998;279:688–695.
50. Hogervorst E, Williams J, Budge M, Riedel W, Jolles J. The nature of the effect of female gonadal hormone replacement therapy on cognitive function in post-menopausal women: a meta-analysis. Neuroscience 2000;101:485–512.
51. Shao H, Breitner JC, Whitmer RA, Wang J, Hayden K, Wengreen H, Corcoran C, Tschanz J, Norton M, Munger R, Welsh-Bohmer K, Zandi PP. Cache County Investigators. Hormone therapy and Alzheimer disease dementia: new findings from the Cache County Study. Neurology 2012;79:1846–1852.
52. Shumaker SA, Legault C, Kuller L, Rapp SR, Thal L, Lane DS, Fillit H, Stefanick ML, Hendrix SL, Lewis CE, Masaki K, Coker LH. Women's Health Initiative Memory Study. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study. JAMA 2004;291:2947–2958.
53. Resnick SM, Maki PM, Rapp SR, Espeland MA, Brunner R, Coker LH, Granek IA, Hogan P, Ockene JK, Shumaker SA. Women's Health Initiative Study of Cognitive Aging Investigators. Effects of combination estrogen plus progestin hormone treatment on cognition and affect. J Clin Endocrinol Metab 2006;91:1802–1810.
54. Maki PM, Gast MJ, Vieweg AJ, Burriss SW, Yaffe K. Hormone therapy in menopausal women with cognitive complaints: a randomized, double-blind trial. Neurology 2007;69:1322–1330.
55. Mulnard RA, Cotman CW, Kawas C, van Dyck CH, Sano M, Doody R, Koss E, Pfeiffer E, Jin S, Gamst A, Grundman M, Thomas R, Thal LJ. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. Alzheimer's Disease Cooperative Study. JAMA 2000;283:1007–1015.
56. Asthana S, Baker LD, Craft S, Stanczyk FZ, Veith RC, Raskind MA, Plymate SR. High-dose estradiol improves cognition for women with AD: results of a randomized study. Neurology 2001;57:605–612.
57. Yoon BK, Kim DK, Kang Y, Kim JW, Shin MH, Na DL. Hormone replacement therapy in postmenopausal women with Alzheimer's disease: a randomized, prospective study. Fertil Steril 2003;79:274–280.
58. US Preventive Services Task Force. Grossman DC, Curry SJ, Owens DK, Barry MJ, Davidson KW, Doubeni CA, Epling JW Jr, Kemper AR, Krist AH, Kurth AE, Landefeld CS, Mangione CM, Phipps MG, Silverstein M, Simon MA, Tseng CW. Hormone Therapy for the Primary Prevention of Chronic Conditions in Postmenopausal Women: US Preventive Services Task Force Recommendation Statement. JAMA 2017;318:2224–2233.
59. Bae JM, Yoon BK. The role of menopausal hormone therapy in reducing all-cause mortality in postmenopausal women younger than 60 years: an adaptive meta-analysis. J Menopausal Med 2018;24:139–142.
60. Kontis V, Bennett JE, Mathers CD, Li G, Foreman K, Ezzati M. Future life expectancy in 35 industrialised countries: projections with a Bayesian model ensemble. Lancet 2017;389:1323–1335.
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