Hormone Therapy for the Primary Prevention of Chronic Conditions in Postmenopausal Persons

Project Summary Title and Description

Hormone Therapy for the Primary Prevention of Chronic Conditions in Postmenopausal Persons
Background: Hormone therapy plays an important role in the clinical management of menopausal symptoms. Because of an increased risk of harms, hormone therapy is currently not recommended for the primary prevention of chronic conditions. Purpose: To update evidence on the effectiveness of hormone therapy in reducing risk of chronic conditions, its adverse effects, and differences among population subgroups for the U.S. Preventive Services Task Force. Data Sources: We searched MEDLINE, the Cochrane Library, and Embase for English-language articles (through October 12, 2021). We conducted searches for unpublished literature by searching ClinicalTrials.gov, HSRProj, the World Health Organization’s International Clinical Trials Registry Platform, and NIH RePORTER. In addition, we reviewed reference lists of pertinent review articles and studies meeting our inclusion criteria. We conducted surveillance of the literature through June 1, 2022. Study Selection: We dually reviewed the literature and included randomized, placebo-controlled trials and large controlled cohort studies that provided information on the primary prevention of chronic conditions with hormone therapy and reported health outcomes. Data Extraction: We abstracted details about participants, study design, analysis, followup, and results; study quality and strength of evidence were rated using established criteria. Data Synthesis: Twenty fair- or good-quality trials and three large controlled cohort studies met eligibility criteria. The Women’s Health Initiative was the largest study and most applicable to the target population. Results of our review indicate differences in the risk-benefit profile between treatment formulations. Women using estrogen only had statistically significantly lower risk (per 10,000 women over 6.8 to 7.2 years) of diabetes (134 fewer cases) and fractures (388 fewer cases) than women taking placebo. However, risk (per 10,000 women over 5.4 to 7.1 years) was statistically significantly increased for gallbladder disease (377 more cases), stroke (79 more cases), and venous thromboembolism (77 more cases). Women using estrogen plus progestin therapy experienced statistically significantly lower risk (per 10,000 women over 5.0 to 5.6 years) for colorectal cancer (34 fewer cases), diabetes (78 fewer cases), and fractures (230 fewer cases) than women taking placebo. Risk (per 10,000 women over 4 to 5.6 years) of invasive breast cancer (51 more cases), probable dementia (88 more cases), gallbladder disease (260 more cases), stroke (52 more cases), and venous thromboembolism (120 more cases) was statistically significantly increased compared with women taking placebo. The risk of urinary incontinence (562 more cases per 10,000 women) was increased during a followup of 1 year. Meta-analyses rendered no statistically significant differences in all-cause mortality between women receiving hormone therapy and those receiving placebo (over 2 to 7.2 years for estrogen-only therapy and over 3.2 to 5.6 years for estrogen plus progestin therapy). Limitations: Few trials or subgroup analyses were powered for prevention outcomes. No comparative evidence on type, dose, and mode of delivery of hormone therapy is available. The applicability of results to younger women who initiate hormone therapy to manage menopausal symptoms and to women of non-White ethnic backgrounds might be limited. Conclusions: Women undergoing hormone therapy for the primary prevention of chronic conditions experience some beneficial effects but also an increased risk of harms.
RTI-UNC Evidence-based Practice Center
Authors of Report
Gerald Gartlehner, MD, MPH, Sheila V. Patel, PhD, Shivani Reddy, MD, MS, Caroline Rains, MPH, Manny Coker-Schwimmer, MPH, Leila Kahwati, MD, MPH
Methodology description
Systematic Review
The data was entered prospectively using SRDR+'s data abstraction function and templates. Final report available here: https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/menopausal-hormone-therapy-preventive-medication
Funding Source

Key Questions

1. 1. What are the benefits of menopausal hormone therapy when used for the primary prevention of chronic conditions?
2. 2. What are the harms of menopausal hormone therapy when used for the primary prevention of chronic conditions?
3. 3. Do the benefits and harms of menopausal hormone therapy when used for the primary prevention of chronic conditions differ by subgroup (race or ethnicity; women with premature menopause; women with surgical menopause; age during use; duration of use; type, dose, and mode of delivery; and comorbid condition) or by timing of intervention (initiation during perimenopause vs. postmenopause)?

Associated Extraction Forms


Associated Studies (each link opens a new tab)

Title Authors Year
Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials Manson, J. E.; Chlebowski, R. T.; Stefanick, M. L.; Aragaki, A. K.; Rossouw, J. E.; Prentice, R. L.; Anderson, G.; Howard, B. V.; Thomson, C. A.; LaCroix, A. Z.; Wactawski-Wende, J.; Jackson, R. D.; Limacher, M.; Margolis, K. L.; Wassertheil-Smoller, S.; Beresford, S. A.; Cauley, J. A.; Eaton, C. B.; Gass, M.; Hsia, J.; Johnson, K. C.; Kooperberg, C.; Kuller, L. H.; Lewis, C. E.; Liu, S.; Martin, L. W.; Ockene, J. K.; O'Sullivan, M. J.; Powell, L. H.; Simon, M. S.; Van Horn, L.; Vitolins, M. Z.; Wallace, R. B. 2013
Long-term effects on cognitive function of postmenopausal hormone therapy prescribed to women aged 50 to 55 years Espeland, M. A.; Shumaker, S. A.; Leng, I.; Manson, J. E.; Brown, C. M.; LeBlanc, E. S.; Vaughan, L.; Robinson, J.; Rapp, S. R.; Goveas, J. S.; Wactawski-Wende, J.; Stefanick, M. L.; Li, W.; Resnick, S. M.; Group, Whimsy Study 2013
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 1995
Effects of estrogen replacement on the progression of coronary-artery atherosclerosis Herrington, D. M.; Reboussin, D. M.; Brosnihan, K. B.; Sharp, P. C.; Shumaker, S. A.; Snyder, T. E.; Furberg, C. D.; Kowalchuk, G. J.; Stuckey, T. D.; Rogers, W. J.; Givens, D. H.; Waters, D. 2000
A randomized double-blind trial of the effects of hormone therapy on delayed verbal recall in older women Tierney, M. C.; Oh, P.; Moineddin, R.; Greenblatt, E. M.; Snow, W. G.; Fisher, R. H.; Iazzetta, J.; Hyslop, P. S.; MacLusky, N. J. 2009
Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a randomized controlled trial Waters, D. D.; Alderman, E. L.; Hsia, J.; Howard, B. V.; Cobb, F. R.; Rogers, W. J.; Ouyang, P.; Thompson, P.; Tardif, J. C.; Higginson, L.; Bittner, V.; Steffes, M.; Gordon, D. J.; Proschan, M.; Younes, N.; Verter, J. I. 2002
Combination treatment with estrogen and calcitriol in the prevention of age-related bone loss Gallagher, J. C.; Fowler, S. E.; Detter, J. R.; Sherman, S. S. 2001
The effect of hormone replacement on physical performance in community-dwelling elderly women Greenspan, S. L.; Resnick, N. M.; Parker, R. A. 2005
Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial Hodis, H. N.; Mack, W. J.; Lobo, R. A.; Shoupe, D.; Sevanian, A.; Mahrer, P. R.; Selzer, R. H.; Liu Cr, C. R.; Liu Ch, C. H.; Azen, S. P. 2001
Results from the Estonian postmenopausal hormone therapy trial [ISRCTN35338757] Veerus, P.; Hovi, S. L.; Fischer, K.; Rahu, M.; Hakama, M.; Hemminki, E. 2006
Effects of ultralow-dose transdermal estradiol on bone mineral density: a randomized clinical trial Ettinger, Bruce; Ensrud, Kristine E.; Wallace, Robert; Johnson, Karen C.; Cummings, Steven R.; Yankov, Vladimir; Vittinghoff, Eric; Grady, Deborah 2004
Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial Shumaker, Sally A.; Legault, Claudine; Rapp, Stephen R.; Thal, Leon; Wallace, Robert B.; Ockene, Judith K.; Hendrix, Susan L.; Jones, Beverly N., 3rd; Assaf, Annlouise R.; Jackson, Rebecca D.; Kotchen, Jane Morley; Wassertheil-Smoller, Sylvia; Wactawski-Wende, Jean; Investigators, Whims 2003
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 Hulley, S.; Grady, D.; Bush, T.; Furberg, C.; Herrington, D.; Riggs, B.; Vittinghoff, E. 1998
The Women's Health Initiative Study of Cognitive Aging (WHISCA): a randomized clinical trial of the effects of hormone therapy on age-associated cognitive decline Resnick, S. M.; Coker, L. H.; Maki, P. M.; Rapp, S. R.; Espeland, M. A.; Shumaker, S. A. 2004
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 Vickers, M. R.; MacLennan, A. H.; Lawton, B.; Ford, D.; Martin, J.; Meredith, S. K.; DeStavola, B. L.; Rose, S.; Dowell, A.; Wilkes, H. C.; Darbyshire, J. H.; Meade, T. W. 2007
Effects of hormone therapy on cognition and mood in recently postmenopausal women: findings from the Randomized, Controlled KEEPS-Cognitive and Affective Study Gleason, C. E.; Dowling, N. M.; Wharton, W.; Manson, J. E.; Miller, V. M.; Atwood, C. S.; Brinton, E. A.; Cedars, M. I.; Lobo, R. A.; Merriam, G. R.; Neal-Perry, G.; Santoro, N. F.; Taylor, H. S.; Black, D. M.; Budoff, M. J.; Hodis, H. N.; Naftolin, F.; Harman, S. M.; Asthana, S. 2015
Cognitive effects of estradiol after menopause: a randomized trial of the timing hypothesis Henderson, V. W.; St John, J. A.; Hodis, H. N.; McCleary, C. A.; Stanczyk, F. Z.; Shoupe, D.; Kono, N.; Dustin, L.; Allayee, H.; Mack, W. J. 2016
Long-term effects on cognitive trajectories of postmenopausal hormone therapy in two age groups Espeland, M. A.; Rapp, S. R.; Manson, J. E.; Goveas, J. S.; Shumaker, S. A.; Hayden, K. M.; Weitlauf, J. C.; Gaussoin, S. A.; Baker, L. D.; Padula, C. B.; Hou, L.; Resnick, S. M. 2017
Inverse associations of dietary fiber and menopausal hormone therapy with colorectal cancer risk in the Multiethnic Cohort Study Park, S. Y.; Wilkens, L. R.; Kolonel, L. N.; Henderson, B. E.; Le Marchand, L. 2016
The influence of hormone therapies on type I and II endometrial cancer: a nationwide cohort study Mrch, L. S.; Kjaer, S. K.; Keiding, N.; Lkkegaard, E.; Lidegaard, 2016
A prospective study of reproductive factors and exogenous hormone use in relation to ovarian cancer risk among Black women Bethea, T. N.; Palmer, J. R.; Adams-Campbell, L. L.; Rosenberg, L. 2017
Effects of hormone therapy on brain structure Kantarci, K.; Tosakulwong, N.; Lesnick, T. G.; Zuk, S. M.; Gunter, J. L.; Gleason, C. E.; Wharton, W.; Dowling, N. M.; Vemuri, P.; Senjem, M. L.; Shuster, L. T.; Bailey, K. R.; Rocca, W. A.; Jack, C. R.; Asthana, S.; Miller, V. M. 2016

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