Most women who traverse menopause experience significant symptoms and many require at least temporary pharmacological treatment for maintenance of quality of life. Despite the controversy surrounding it, hormone therapy (HT) with either estrogen alone (E) or estrogen plus progestin (E+P) remains the most effective treatment for menopausal symptoms. This article provides a brief history of menopausal hormone therapy (HT) and discusses practical aspects of treatment and discontinuation.
HT from the 1950s to WHI
HT has had a cyclical history of high acceptance and uptake, followed by reduced use related to emergence of risk. Its efficacy for symptoms was recognized in the 1950s and 1960s.1 Shortly thereafter, increased risk of endometrial cancer associated with E preparations was followed by the addition of progestin to regimens for women with a uterus, and a transient reduction in enthusiasm for HT.2
In the 1980s, the strong observational association between hormone use and reduced risk of coronary heart disease (CHD)3 led to exploration of systemic benefits of HT beyond symptom relief, which triggered another surge in use. However, when the effectiveness of HT as a preventive medication was tested in a randomized clinical trial, the Women’s Health Initiative (WHI), there was no observed reduction in CHD in women with or without a uterus, and a small signal for initial harm emerged, with differential risks depending upon whether a woman had a uterus and was randomized to E+P or had a hysterectomy and therefore took E Alone (Table 1).4,5 Differences in treatment with E+P compared to E alone reveal an elevated risk of CHD, venous thromboembolism (VTE), breast cancer in the E+P arm and no risk for breast cancer in the E-only arm (Table 1). The association between breast cancer in the E+P arm was further corroborated by an 11-year follow-up study among participants of the WHI study, which demonstrated a small increase in breast cancer incidence (HR, 1.25 [95%CI 1.07-1.46; P = 0.004]) and mortality (HR, 1.96 [95%CI: 1.00-4.04, P = 0.49]).6 After publication of these findings, HT prescriptions dropped by 32% overall with a > 60% drop in prescriptions for conjugated equine estrogen (CEE)/medroxyprogesterone acetate (MPA).7
Based upon these findings, HT is not recommended for preventive use by The American College of Obstetricians and Gynecologists, the Endocrine Society, or the North American Menopause Society (Table 2).8-10 Despite its rigor, the WHI was designed in the late 1980s and was constructed to test the hypothesis that CHD would be prevented by the then-commonly-used preparation of CEE plus MPA (in women with a uterus) or CEE alone in women without a uterus. Subclinical coronary disease was not considered in participant recruitment, and women were stratified into 10-year age bins that included many women who would otherwise not be taking HT for current indications (i.e., symptom relief). This makes some of the endpoints difficult to interpret when advising a current patient in her early 50s who requires symptom control.
Dr. Santoro is on the Scientific Advisory Boards of Astellas/Ogeda and Menogenix, Inc., and holds stock options in Menogenix, Inc. The other authors have nothing to disclose.
- Wilson RA. Feminine Forever: M. Evans and Company, Inc.; 1966.
- Weiss NS, Szekely DR, English DR, Schweid AI. Endometrial cancer in relation to patterns of menopausal estrogen use. JAMA. 1979;242(3):261-264.
- Stampfer MJ, Colditz GA, Willett WC, Manson JE, Rosner B, Speizer FE, et al. Postmenopausal estrogen therapy and cardiovascular disease. Ten-year follow-up from the nurses’ health study. N Engl J Med. 1991;325(11):756-762.
- Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-333.
- Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA. 2004;291(14):1701-1712.
- Chlebowski RT, Anderson GL, Gass M, Lane DS, Aragaki AK, Kuller LH, et al. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA. 2010;304(15):1684-1692.
- Majumdar SR, Almasi EA, Stafford RS. Promotion and prescribing of hormone therapy after report of harm by the Women’s Health Initiative. JAMA. 2004;292(16):1983-1938.
- ACOG Practice Bulletin No. 141: management of menopausal symptoms. Obstet Gynecol. 2014;123(1):202-16.
- The NHTPSAP. The 2017 hormone therapy position statement of The North American Menopause Society. Menopause. 2017;24(7):728-753.
- Stuenkel CA, Davis SR, Gompel A, Lumsden MA, Murad MH, Pinkerton JV, et al. Treatment of Symptoms of the Menopause: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015;100(11):3975-4011.
- Manson JE, Aragaki AK, Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, et al. Menopausal hormone therapy and long-term all-cause and cause-specific mortality: The Women’s Health Initiative randomized trials. JAMA. 2017;318(10):927-938.
- LaCroix AZ, Chlebowski RT, Manson JE, Aragaki AK, Johnson KC, Martin L, et al. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA. 2011;305(13):1305-1314.
- Miller VM, Naftolin F, Asthana S, Black DM, Brinton EA, Budoff MJ, et al. The Kronos Early Estrogen Prevention Study (KEEPS): what have we learned? Menopause (New York, NY). 2019.
- Hodis HN, Mack WJ, Henderson VW, Shoupe D, Budoff MJ, Hwang-Levine J, et al. Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol. N Engl J Med. 2016;374(13):1221-1231.
- Sherman S, Miller H, Nerurkar L, Schiff I. Research opportunities for reducing the burden of menopause-related symptoms. Am J Med. 2005;118 Suppl 12B:166-171.
- Crandall CJ, Hovey KM, Andrews CA, Chlebowski RT, Stefanick ML, Lane DS, et al. Breast cancer, endometrial cancer, and cardiovascular events in participants who used vaginal estrogen in the Women’s Health Initiative Observational Study. Menopause. 2018;25(1):11-20.
- Attarian H, Hachul H, Guttuso T, Phillips B. Treatment of chronic insomnia disorder in menopause: evaluation of literature. Menopause. 2015;22(6):674-684.
- Xiao YP, Tian FM, Dai MW, Wang WY, Shao LT, Zhang L. Are estrogen-related drugs new alternatives for the management of osteoarthritis? Arthritis Res Ther. 2016;18:151.
- de Klerk BM, Schiphof D, Groeneveld FP, Koes BW, van Osch GJ, van Meurs JB, et al. Limited evidence for a protective effect of unopposed oestrogen therapy for osteoarthritis of the hip: a systematic review. Rheumatology (Oxford). 2009;48(2):104-112.
- Chlebowski RT, Cirillo DJ, Eaton CB, Stefanick ML, Pettinger M, Carbone LD, et al. Estrogen alone and joint symptoms in the Women’s Health Initiative randomized trial. Menopause. 2018;25(11):1313-1320.
- Rovinski D, Ramos RB, Fighera TM, Casanova GK, Spritzer PM. Risk of venous thromboembolism events in postmenopausal women using oral versus non-oral hormone therapy: A systematic review and meta-analysis. Thromb Res. 2018;168:83-95.
- 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;364:k4810.
- Santoro N, Allshouse A, Neal-Perry G, Pal L, Lobo RA, Naftolin F, et al. Longitudinal changes in menopausal symptoms comparing women randomized to low-dose oral conjugated estrogens or transdermal estradiol plus micronized progesterone versus placebo: the Kronos Early Estrogen Prevention Study. Menopause. 2017;24(3):238-246.
- Prior JC. Progesterone for treatment of symptomatic menopausal women. Climacteric. 2018;21(4):358-365.
- Barrett-Connor E, Slone S, Greendale G, Kritz-Silverstein D, Espeland M, Johnson SR, et al. The Postmenopausal Estrogen/Progestin Interventions Study: primary outcomes in adherent women. Maturitas. 1997;27(3):261-74.
- Thompson JJ, Ritenbaugh C, Nichter M. Why women choose compounded bioidentical hormone therapy: lessons from a qualitative study of menopausal decision-making. BMC Women’s Health. 2017;17(1):97.
- Cobin RH, Goodman NF. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on menopause-2017 update. Endocrine Pract. 2017;23(7):869-880.
- Simon JA, Kaunitz AM, Kroll R, Graham S, Bernick B, Mirkin S. Oral 17beta-estradiol/progesterone (TX-001HR) and quality of life in postmenopausal women with vasomotor symptoms. Menopause. 2019;26(5):506-512.
- Kharode Y, Bodine PV, Miller CP, Lyttle CR, Komm BS. The pairing of a selective estrogen receptor modulator, bazedoxifene, with conjugated estrogens as a new paradigm for the treatment of menopausal symptoms and osteoporosis prevention. Endocrinology. 2008;149(12):6084-6091.
- Pickar JH, Boucher M, Morgenstern D. Tissue selective estrogen complex (TSEC): a review. Menopause (New York, NY). 2018;25(9):1033-45.
- Shin JJ, Kim SK, Lee JR, Suh CS. Ospemifene: A novel option for the treatment of vulvovaginal atrophy. J Menopausal Med. 2017;23(2):79-84.
- Labrie F, Archer DF, Koltun W, Vachon A, Young D, Frenette L, et al. Efficacy of intravaginal dehydroepiandrosterone (DHEA) on moderate to severe dyspareunia and vaginal dryness, symptoms of vulvovaginal atrophy, and of the genitourinary syndrome of menopause. Menopause. 2016;23(3):243-256.
- Aslan E, Bagis T, Kilicdag EB, Tarim E, Erkanli S, Kuscu E. How best is to discontinue postmenopausal hormone therapy: immediate or tapered? Maturitas. 2007;56(1):78-83.
- Canonico M, Oger E, Plu-Bureau G, Conard J, Meyer G, Levesque H, 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(7):840-845.
- American College of Obstetricians and Gynecologists. ACOG committee opinion no. 556: Postmenopausal estrogen therapy: route of administration and risk of venous thromboembolism. Obstet Gynecol. 2013;121(4):887-890.