Estrogen Therapy Benefits, Harms Tied to Age, Ovary Status

Marcia Frellick

September 09, 2019

Menopausal estrogen-only therapy appears to lower risk of mortality significantly without harmful side effects among women treated in their 50s who had a hysterectomy and their ovaries removed, according to long-term follow-up from a study conducted at 40 US centers.

Results from the randomized, double-blind Women's Health Initiative (WHI) Estrogen-Alone Trial, published online today in the Annals of Internal Medicine, followed 9939 women ages 50 to 79 years for an average 18 years.

However, the mortality benefits of conjugated equine estrogens (CEE) did not extend to women who started estrogen therapy in their 60s or 70s, whether or not their ovaries were removed, write JoAnn E. Manson, MD, DrPH, from  Harvard Medical School and Brigham and Women's Hospital in Boston, Massachusetts, and colleagues.

The authors note that between one third and one half of women who undergo a hysterectomy also have both ovaries removed (bilateral salpingo oophorectomy [BSO]), to reduce their risk of developing ovarian cancer. Yet, the resultant menopause and loss of estrogen has been linked with other health risks.

The new study results have important messages for physicians and patients, JoAnn Pinkerton, MD, professor of obstetrics and gynecology and director of midlife health at the University of Virginia Health System in Charlottesville, told Medscape Medical News.

32% Reduction in Mortality for Some Women

Younger women (50 to 59) with BSO who were randomly assigned to the CEE group saw a statistically significant 32% reduction in all-cause mortality in the follow-up years (hazard ratio, 0.68; 95% confidence interval, 0.48 - 0.96). They also saw nonsignificant trends with 15% to 33% risk reductions in coronary heart disease (CHD), breast cancer and a global index for CHD, breast cancer, and mortality combined.

Younger women whose ovaries were intact did not experience a reduction.

The mortality reduction associated with CEE among younger women with BSO was most notable when women had the surgical procedure before age 45 years, the authors write.

An unfavorable balance of risk and benefits was particularly pronounced for those women, ages 70 to 79 at baseline, who were randomly assigned to CEE. The reason for those findings is unclear, the authors say.

Practical Applications

Pinkerton, who is the executive director emeritus for the North American Menopause Society, told Medscape Medical News that the thinking has been that if you have early surgical menopause before age 45 or so, women should  definitely take estrogen until age 51, the average age of menopause, and then reevaluate.

This study looked at slightly older women — ages 50 to 59 — who had their ovaries removed; researchers found a reduction in all-cause mortality in those women.

"[W]e've known for a while that estrogen by itself — when it was used in that large women's health study — actually has more benefits than risks because we saw a reduction in the number of breast cancers instead of an increase," Pinkerton said. "So we felt comfortable using it for menopausal symptoms in that group. Now we can say [that] not only can we use it for menopausal symptoms and feel comfortable that's there's not a significant increase risk of breast cancer, but you may also have a reduction in death from taking the hormones."

The results should change practice and may alleviate fears, she said.

"Women and providers are still very frightened about estrogen therapy and hormone therapy," Pinkerton said. "Even though we've shown that estrogen by itself or estrogen with progesterone, if you have a uterus, is safe and has benefits, women are still frightened to take it."

This study, she said, further emphasizes that women who have hysterectomies and ovaries removed ought to strongly consider estrogen therapy around the time of menopause for the benefits — not only to combat hot flashes and night sweats, but potentially to lower their risk of heart disease and all-cause death.

"On the other side," Pinkerton added, "women who are over 70 and have had hysterectomies and ovaries removed saw an increased risk from taking estrogen. And that fits with earlier analysis. Age and time are very important when you're counseling women about hormone therapy."

The bottom line, she said, is that if you are young and your ovaries are removed, strongly consider estrogen. If you are under 60, within 10 years of menopause, and you've had your uterus and ovaries removed, you're a strong candidate for estrogen.

She added, "You may also be a candidate if you haven't had your ovaries or uterus out, but that would be primarily for menopausal symptoms."

Study First of Its Kind

The authors say this research is the first randomized study to test whether  outcomes of estrogen therapy in menopause differ by whether women still have their ovaries.

The authors acknowledge a limitation that only one dose, formulation, and administration method was tested.

They also note that recommendations about who should have both ovaries removed have changed in the two decades since recruitment for this trial started.

They write, "Growing consensus is that BSO, particularly before the average age at menopause, should be considered only in women at high risk for ovarian cancer, breast cancer, or both, such as those with high-risk BRCA gene variants, but not in women at usual risk for these outcomes."

Therefore, generalizability to this high-risk BSO population is uncertain.

The WHI program is funded by the Heart, Lung, and Blood Institute; National Institutes of Health; and the US Department of Health and Human Services. Wyeth Ayerst donated the study drugs.

Coauthors report personal fees from AstraZeneca, Novartis, Genentech, PUMA, Immunomedics, and Amgen during the conduct of the study; grants from Bayer, Allergan, Mithra, and Therapeutics MD; and personal fees from Bayer, Mithra, and Pfizer outside the submitted work. The full list of disclosures can be found with the original article. Pinkerton has disclosed no relevant financial relationships.

Ann Intern Med. Published online September 9, 2019. Abstract

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