In 2002, the federally funded Women’s Health Initiative (WHI),1 a randomized, placebo-controlled clinical trial investigating menopausal hormone therapy for healthy menopausal women, was abruptly halted when it was determined that taking estrogen and progestin hormones after menopause increased the risk of breast cancer, heart disease, and circulatory disorders. A 20-year follow-up to the WHI explored the long-term influence of menopausal hormone therapy on ovarian and endometrial cancers.
The researchers found that in women who had had a prior hysterectomy, the use of conjugated equine estrogen alone significantly increased ovarian cancer incidence and mortality. In contrast, in women with an intact uterus, combination estrogen plus medroxyprogesterone acetate did not increase ovarian cancer incidence or mortality. In addition, combination hormone therapy reduced the incidence of endometrial cancer.
These findings should help inform decisions regarding menopausal hormone therapy use, according to Rowan T. Chlebowski, MD, PhD, FASCO, and colleagues, who presented the findings during the 2024 ASCO Annual Meeting.2
Rowan T. Chlebowski, MD, PhD, FASCO
Study Methodology
The researchers examined data from the WHI, which was funded by the National Institutes of Health from 1993 to 1998. It had recruited 27,347 postmenopausal women (aged 50–79) without a history of breast cancer or invasive cancer within 10 years (and no baseline endometrial pathology in the women receiving the combination hormone therapy) from 40 centers in the United States. Of the 16,608 women with a uterus, 8,506 were randomly assigned to receive daily doses of 0.625 mg/d of estrogen plus 2.5 mg/d of estrogen plus progestin, and 8,102 received a placebo.
In 10,739 women who had a prior hysterectomy, 5,310 were randomly assigned to receive daily doses of 0.625 mg/d of estrogen alone, and 5,429 received a placebo. Intervention was stopped for cause before the planned 8.5-year intervention after 5.6 years for the combination and after 7.2 years for estrogen alone. The researchers verified cancer diagnoses by central pathology report review. Mortality findings were enhanced by serial National Death Index queries. The primary study outcomes were ovarian cancer and endometrial cancer incidence and related mortality.
Key Results
The 20-year follow-up included mortality information for more than 98% of WHI participants; in the initial WHI report on the influence of estrogen alone on ovarian cancer vs placebo, estrogen alone significantly increased ovarian cancer incidence (35 cases [0.041% annualized rate] vs 17 cases [0.020%]; hazard ratio [HR] = 2.04; 95% confidence interval [CI] = 1.14–3.65; P = .01) and ovarian cancer mortality (HR = 2.79; 95% CI = 1.30–5.99; P = .006). Kaplan-Meier plot estimates and cumulative hazard ratios indicated a persistent adverse effect of estrogen alone on ovarian cancer incidence, which emerged after 12 years of follow-up and did not diminish (P = .006).
In contrast, researchers found that the use of the estrogen/progestin combination, vs placebo, did not increase ovarian cancer incidence (75 cases [0.051%] vs 63 cases [0.045%]; HR = 1.14; 95% CI = 0.82–1.59; P = .44) or ovarian cancer mortality (HR = 1.21; 95% CI = 0.84–1.74). In addition, conjugated equine estrogen plus medroxyprogesterone acetate did significantly lower the incidence of endometrial cancer (106 cases [0.073%] vs 140 cases [0.10%]; HR = 0.72; 95% CI = 0.56–0.92; P = .01) without a statistically significant influence on endometrial mortality (HR = 0.58; 95% CI = 0.29–1.16).
Study Conclusions
The researchers concluded that in randomized, placebo-controlled, clinical trial settings, conjugated equine estrogen alone significantly increased ovarian cancer incidence and increased ovarian cancer mortality in women with a prior hysterectomy; however, in contrast to most observational studies, estrogen plus medroxyprogesterone acetate did not in women with a uterus. They also found that estrogen plus medroxyprogesterone acetate reduced the incidence of endometrial cancer.
DISCLOSURE: Dr. Chlebowski has served as a consultant or advisor to Pfizer and UpToDate.
REFERENCES
1. 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 310:1353-1368, 2013.
2. Chlebowski RT, Aragaki AK, Pan K, et al: Menopausal hormone therapy and ovarian and endometrial cancers: Long-term follow-up of the Women’s Health Initiative randomized trials. 2024 ASCO Annual Meeting. Abstract 10506. Presented June 1, 2024.
