Journal Article

Menopausal Hormone Therapy: Limited Benefits, Significant Harms

FUGH-BERMAN, ADRIANE, MD, MINTZES, BARBARA, PhD

2025

Overview

Between 1993 and 1998, the WHI randomized 16,608 women with an intact uterus to placebo or conjugated equine estrogen, 0.625 mg/day, combined with medroxyprogesterone, 2.5 mg/day, (to counter the risk of endometrial cancer) and randomized 10,739 women without a uterus to conjugated equine estrogen, 0.625 mg/day.14–16 Both arms of the WHI were stopped early (in 2002 and 2004) because of harm.15,16 Combined estrogen-progestin increased the risk of invasive breast cancer, pulmonary embolism, stroke, and a global index of harm.17 Estrogen-only treatment increased the risk of stroke but not breast cancer or pulmonary embolism.17 Menopausal hormone therapy use plummeted after the WHI results were reported, and breast cancer rates subsequently dropped dramatically in all countries with registries.18 The US Preventive Services Task Force report on hormone therapy for preventing chronic illness notes that combined menopausal hormone therapy is associated with 5 excess breast cancers per 1,000 women.19 Combined hormone therapy increased gallbladder disease and deaths from lung cancer and doubled the risk of probable dementia among women older than 65 years.20,21 Estrogen alone increased ovarian cancer incidence and mortality.22 Overall, the WHI found that an additional 1 in 500 women per year experienced serious harm with combined menopausal hormone therapy.15 The WHI study also found benefits of menopausal hormone therapy. Combined therapy reduced risks of hip fracture and endometrial cancer and slightly lowered the risk of diabetes.17,22,23 Estrogen alone decreased breast cancer incidence at 10- and 20-year follow-up and decreased fracture risk.17,24 Critics claim that women in the WHI were too old and too far from menopause, that harms occurred only in older women, and that the findings do not apply to current formulations.25 However, although the average age was 63 years, 8,833 (32%) of the 27,347 women randomized were in their 50s, making this the largest RCT of menopausal hormone therapy use among women in their 50s.25 Also, 7,135 (26%) of women were within 10 years of starting menopause.26 An analysis of outcomes in women aged 50 to 59 years found greater harm than benefit with combined and estrogen-only menopausal hormone therapy.17 Although younger women experienced fewer harms than older women, long-term use remained more harmful than beneficial. Menopausal hormone therapy is not recommended for long-term use or for chronic disease prevention because RCT evidence indicates that harms outweigh benefits (reduced risk of hip fracture and diabetes).17,20 The 2022 US Preventive Services Task Force statement on menopausal hormone therapy recommends against its use for primary prevention of chronic conditions because of a lack of net benefit.31 Menopause is a positive life experience for many women32 and should not be medicalized. ADRIANE FUGH-BERMAN, MD, Georgetown University Medical Center, Washington, District of Columbia BARBARA MINTZES, PhD, University of Sydney School of Pharmacy and Charles Perkins Centre, Faculty of Medicine and Health, New South Wales, Australia, and University of British Columbia School of Population and Public Health, Vancouver, Canada Author disclosure:

• Publisher: American Academy of Family Physicians
• Subject: Breast cancer / Chronic illnesses / Endocrine therapy / Endometrial cancer / Estrogens / Family Medicine/General Medicine / Hormone replacement therapy / Internal Medicine / Menopause / Pulmonary embolisms / Stroke / Womens health