Continuous, Combined Hormone Replacement Therapy Protects Against Endometrial Cancer


The ASCO Post

By Caroline Helwick
December 15, 2013, Volume 4, Issue 20

According to an analysis of the Women’s Health Initiative, continuous combined use of estrogen plus progestin reduces the risk of endometrial cancer among postmenopausal women. The study was reported at the 2013 European Cancer Congress byRowan T. Chlebowski, MD, PhD, Professor and Chief of Medical Oncology/Hematology at the David Geffen School of Medicine at UCLA and Harbor-UCLA Medical Center, Los Angeles.1

Important Findings

“In postmenopausal women with a uterus and nonproliferative endometrial histology [at baseline], continuous combined estrogen/progestin use reduces endometrial cancer incidence by 35%,” Dr. Chlebowski said. “According to our review, this is the first randomized clinical trial evidence that shows this.”

A second important finding of the Estrogen-Progestin Trial was the association between obesity and endometrial cancer risk. Women with a body mass index (BMI) > 35 had approximately a sevenfold increased risk, the study found.

“BMI > 35 could be a unique target for a cancer prevention intervention in the future,” he suggested.

Study Details

The Women’s Health Initiative enrolled 16,608 postmenopausal women from 40 U.S. clinical centers into a randomized, double-blind placebo-controlled trial. Women aged 50 to 70 with an intact uterus and normal endometrial histology were assigned to once-daily 0.625 mg conjugated equine estrogen plus 2.5 mg medroxyprogesterone acetate or to placebo.

After 5.6 years of the intervention and 6.8 years of additional follow-up, 66 women in the combined hormone therapy group were diagnosed with endometrial cancer, compared with 95 in the placebo group, which translated to a 35% reduction in risk (P = .007). The analysis at 5.6 years had shown a 17% relative risk reduction that was not statistically significant.

Estrogen/Progestin Broadly Protective

In the current analysis, women in the estrogen/progestin group who did develop cancer tended to have fewer poorly differentiated/anaplastic tumors and less regional and distant disease, he added.

Although there were fewer endometrial cancers during the intervention period of the trial (25 vs 30), the difference between the arms largely emerged in the postintervention period, where there were 41 cases in the combined hormone group and 65 in the placebo group, a 41% reduction in risk (P = .008). “After about 5 years is when we see a separation of the curve,” Dr. Chlebowski noted.

In a sensitivity analysis that adjusted for adherence, the reduction in risk was 51% (P = .004). Adjusting for hysterectomy also did not change the results.

There was no difference in the effect according to age or time from menopause. Additionally, there was no significant interaction with race or ethnicity, smoking, physical activity, or prior estrogen alone or estrogen/progestin use.

The favorable effects of estrogen/progestin were broadly observed, including a protective effect in women in the highest BMI categories, who have a substantially increased risk of endometrial cancer.

“We saw a rapid and high-level rise of endometrial cancer in the obese women,” he said. Women with a BMI ≥ 40 had a relative risk of 7.40, and those with a BMI of 35–50 had a 6.66 relative risk (BMI < 25 served as the reference point). Women with BMI ≥ 40 had a 43% reduction in risk.

Deaths were also reduced in the estrogen/progestin group—5 vs 11—but this was not statistically significant.

Breast Cancer Risk

Dr. Chlebowski noted that combined estrogen/progestin use has “opposite effects on breast and endometrial cancers.” Estrogen/progestin reduces endometrial cancer incidence but increases breast cancer incidence and breast cancer–related deaths, he noted.

The Women’s Health Initiative previously showed a 28% increased risk of breast cancer with combined hormone replacement therapy after 5.6 years of the intervention.

“Interventions that reduce both endometrial cancer and breast cancer are needed,” he said. ■

Disclosure: Dr. Chlebowski reported no potential conflicts of interest.


1. Chlebowski R, Anderson GL, Sarto G, et al: Continuous combined oestrogen plus progestin and endometrial cancer in postmenopausal women in the Women’s Health Initiative randomized clinical trial. 2013 European Cancer Congress. Abstract LBA13. Presented September 30, 2013.,-2013/continuous,-combined-ho...