USPSTF Reaffirms Recommendations Against Using Menopausal Hormone Therapy to Prevent Chronic Conditions

Menopause — a normal stage in a woman’s life when menstrual cycles cease due to decreased estrogen and progestin levels — typically occurs around age 50 to 52.[1] On average, U.S. women live about 30 years past this age.[2]

For women experiencing menopause-related symptoms, the Food and Drug Administration (FDA) has approved the use of standard menopausal hormone therapy (hereafter, hormone therapy) — mainly estrogen-only (such as conjugated estrogens [PREMARIN])[3] and combined estrogen and progestin (such as conjugated estrogens and medroxyprogesterone [PREMPHASE, PREMPRO])[4] — for the treatment of moderate-to-severe menopausal symptoms (including hot flashes [feelings of warmth in the face, chest and neck or sudden strong feelings of heat and sweating]) and vaginal or vulvar atrophy.[5] The agency also has approved some of these medications for the prevention, but not treatment, of postmenopausal osteoporosis (bone thinning), which increases the risk of fractures. These approved uses were based on evidence from well-designed clinical trials.[6] Importantly, the agency has recommended using “the lowest effective doses” of these medications “for the shortest duration” to avoid their risks.

However, the FDA has not approved the use of hormone therapy to prevent chronic conditions (including cancer, heart disease, diabetes, dementia and stroke), whose rates of occurrence increase after menopause. Historically, many physicians prescribed hormone therapy on a long-term basis for postmenopausal women who do not have chronic conditions in the hope that these medications would prevent these conditions.[7] This practice — which is known as “primary prevention” — was not backed with evidence from well-designed clinical trials. For years, the U.S. Preventive Services Task Force (USPSTF) — a federally funded, independent, voluntary panel of experts that makes evidence-based recommendations about the effectiveness of specific preventive-care services for patients — consistently has recommended against using hormone therapy for the primary prevention of chronic conditions in postmenopausal women.[8],[9] Once again, in its latest recommendation statement[10] — published in the Nov. 1, 2022, issue of the Journal of the American Medical Association — the USPSTF has reiterated its opposition to such use because the net benefits do not outweigh the risks.[11]

The updated USPSTF evidence review and recommendations

The USPSTF defined hormone therapy as the use during or after menopause of oral or transdermal (systemic) formulations of either (a) combined estrogen and progestin in women with an intact uterus or (b) estrogen alone in women who had their uterus removed (through a hysterectomy).[12] Importantly, a progestin is taken alongside estrogen in women with an intact uterus because estrogen-alone therapy increases the risk of uterine cancer. Notably, using hormone therapy for purposes other than the primary prevention of chronic conditions was not part of this USPSTF work.

The USPSTF identified 20 clinical trials that compared use of hormone therapy with use of a placebo to prevent chronic conditions in postmenopausal persons.[13] Of these trials, the Women’s Health Initiative (WHI) trials[14] (large, government-sponsored, randomized, placebo-controlled trials) were the only studies that were robust enough to assess the effectiveness of hormone therapy for the primary prevention of various chronic conditions. The WHI trials enrolled postmenopausal persons aged 50 to 79 years and had up to 21-year follow-up periods after treatment for an average of six to seven years of hormone therapy.

Collective evidence from the reviewed trials demonstrated that although estrogen-only therapy lowered risks of diabetes and fractures, it increased risks of gallbladder disease, stroke, blood clots and urinary incontinence. Likewise, combined estrogen and progestin therapy lowered risks of colorectal cancer, diabetes and fractures but increased risks of invasive breast cancer, gallbladder disease, stroke and blood clots. It also probably increased the risks of dementia and urinary incontinence. This led the USPSTF to conclude with moderate certainty that the benefits of hormone therapy do not outweigh its risks.[15] Therefore, as shown in the Table, below, the USPSTF recommended against using combined estrogen and progestin hormone therapy for the primary prevention of chronic conditions in postmenopausal persons. It also recommended against using estrogen-alone hormone therapy for the primary prevention of chronic conditions in postmenopausal persons who have had a hysterectomy.

Particularly, the USPSTF indicated that there is no good evidence to support an “early-timing” effect of hormone therapy, meaning that the net benefits of hormone therapy are not increased if it begins early during menopause.

The USPSTF Recommendations for the Use of Hormone Therapy to Prevent Chronic Conditions*[16]

**These recommendations do not apply to individuals who are considering hormone therapy to manage menopausal symptoms or those who have had premature or surgically induced menopause.

What You Can Do

Women undergoing menopause who think hormone therapy will keep them free from chronic conditions should heed the USPSTF recommendations and avoid using these medications for this purpose. Those troubled with moderate-to-severe menopausal symptoms who are not at risk of heart disease, blood clots, breast cancer or stroke may use the lowest effective dose of these medications for the shortest time possible to relieve these symptoms.

Effective strategies to prevent postmenopausal osteoporosis include engaging in regular exercise and eating a healthful diet that is high in calcium and vitamin D. Postmenopausal women age 65 or older who have been diagnosed with osteoporosis and are at high risk of fractures may consider limited use of oral bisphosphonates, such as alendronate (BINOSTO, FOSAMAX), bearing the risks of these medications in mind, as explained in our October 2021 issue of Worst Pills, Best Pills News.[17]

Report all serious adverse events related to medications to the FDA’s MedWatch adverse-event reporting program by visiting http://www.fda.gov/MedWatch or by calling 800-FDA-1088.
 

References

[1] Gold EB, Crawford SL, Avis NE, et al. Factors related to age at natural menopause: Longitudinal analyses from SWAN. Am J Epidemiol. 2013;178(1):70-83.

[2] Arias E, Tejada-Vera B, Kochanek KD, Ahmad FB. Provisional life expectancy estimates for 2021. Vital Statistics Rapid Release; no 23. Hyattsville, MD: National Center for Health Statistics. August 2022.

[3] Pfizer, Inc. Label: Conjugated estrogens (PREMARIN). November 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/004782s176lbl.pdf. Accessed February 7, 2023.

[4] Pfizer, Inc. Label: conjugated estrogens and medroxyprogesterone (PREMPRO). November 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020527s065lbl.pdf. Accessed February 7, 2023.

[5] Food and Drug Administration. Menopause: Medicines to help you. August 22, 2019. https://www.fda.gov/consumers/free-publications-women/menopause-medicines-help-you. Accessed February 8, 2023.

[6] Food and Drug administration. FDA facts: The risks of promoting unapproved uses. December 21, 2017. https://www.fda.gov/about-fda/innovation-fda/fda-facts-risks-promoting-unapproved-uses. Accessed February 8, 2023.

[7] Ibid.

[8] Huang AJ, Grady D. Menopausal hormone therapy for prevention of chronic conditions: When is enough, enough? JAMA. 2022;328(17):1712-1713.

[9] US Preventive Services Task Force, Grossman DC, Curry SJ, et al. Hormone therapy for the primary prevention of chronic conditions in postmenopausal women: US Preventive Services Task Force recommendation statement. JAMA. 2017;318(22):2224-2233.

[10] US Preventive Services Task Force, Mangione CM, Barry MJ, et al. Hormone therapy for the primary prevention of chronic conditions in postmenopausal persons: US Preventive Services Task Force recommendation statement. JAMA. 2022;328(17):1740-1746.

[11] Gartlehner G, Patel SV, Reddy S, et al. Hormone therapy for the primary prevention of chronic conditions in postmenopausal persons: Updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2022;328(17):1747-1765.

[12] US Preventive Services Task Force, Mangione CM, Barry MJ, et al. Hormone therapy for the primary prevention of chronic conditions in postmenopausal persons: US Preventive Services Task Force recommendation statement. JAMA. 2022;328(17):1740-1746.

[13] Gartlehner G, Patel SV, Reddy S, et al. Hormone therapy for the primary prevention of chronic conditions in postmenopausal persons: Updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2022;328(17):1747-1765.

[14] Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310(13):1353-1368.

[15] US Preventive Services Task Force, Mangione CM, Barry MJ, et al. Hormone therapy for the primary prevention of chronic conditions in postmenopausal persons: US Preventive Services Task Force recommendation statement. JAMA. 2022;328(17):1740-1746.

[16] Ibid.

[17] Oral bisphosphonates for osteoporosis: Important warnings. Worst Pills, Best Pills News. October 2021. https://www.worstpills.org/newsletters/view/1425. Accessed February 10, 2023.