Does Menopausal Hormone Therapy Influence Gynecologic Cancer Risk?

A recent analysis from the Women’s Health Initiative (WHI) randomized clinical trials has provided long-term data on the effects of menopausal hormone therapy regimens on ovarian and endometrial cancer incidence and mortality. Findings highlight distinct risks and benefits associated with conjugated equine estrogen (CEE) alone versus CEE combined with medroxyprogesterone acetate (MPA).

Menopausal hormone therapy has been widely used to manage menopausal symptoms, but its long-term influence on gynecologic cancers remains unclear. This study aimed to clarify the risks and benefits of two commonly used hormone therapy regimens by examining their effects on ovarian and endometrial cancer incidence and mortality after an extended follow-up period of 20 years.

The trials included 27,347 postmenopausal women aged 50–79 years. Women with an intact uterus (n = 16,608) were randomized to daily CEE (0.625 mg) plus MPA (2.5 mg) or placebo. Women with a prior hysterectomy (n = 10,739) were randomized to daily CEE-alone (0.625 mg) or placebo. The interventions were stopped early, after 5.6 years for the CEE plus MPA arm and after 7.2 years for the CEE-alone arm, due to safety concerns. Cancer outcomes were tracked more than 20 years, including incidence and mortality rates for ovarian and endometrial cancers.

The results showed an increase in ovarian cancer incidence and mortality associated with CEE-alone. The incidence of ovarian cancer was higher in the CEE-alone group (35 cases, 0.041%) compared with placebo (17 cases, 0.020%), with a hazard ratio (HR) of 2.04 (95% CI, 1.14–3.65; P = .014). Mortality from ovarian cancer was also significantly higher in the CEE-alone group (P = .006). By contrast, CEE plus MPA did not increase ovarian cancer incidence (HR, 1.14; 95% CI, 0.82–1.59; P = .44) or mortality compared with placebo.

Regarding endometrial cancer, CEE plus MPA showed a protective effect. Women in this group had a lower incidence of endometrial cancer (106 cases, 0.073%) compared with placebo (140 cases, 0.10%), corresponding to a hazard ratio of 0.72 (95% CI, 0.56–0.92; P = .01). This reduction was not observed with CEE-alone, as all participants in this group had undergone hysterectomy and thus did not have a uterus at risk.

“In randomized clinical trials, CEE-alone increased ovarian cancer incidence and ovarian cancer mortality, while CEE plus MPA did not,” the study authors concluded. “By contrast, CEE plus MPA significantly reduced endometrial cancer incidence.”

Reference

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. J Clin Oncol. 2024;42(30):3537-3549. doi:10.1200/JCO.23.01918