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Q&A: Benefits, harms of estrogen therapy in women who had ovaries removed

JoAnn E. Manson

For women who had a hysterectomy and their ovaries removed, estrogen therapy was associated with long-term benefits if the therapy began before the age of 60 years, but it led to adverse events in those aged 70 years or older, according to a study published in the Annals of Internal Medicine.

Researchers conducted a subgroup analysis of 9,939 women in a randomized trial who had previously undergone a hysterectomy from the Women’s Health Initiative Estrogen-Alone Trial.

Participants in the study were randomly assigned to receive estrogen therapy or placebo at ages 50 to 79 years and were followed up for a median of 7.2 years of treatment and 18 years in total.

Overall, the effects of estrogen therapy did not significantly differ between those who did and did not have their ovaries removed. However, when stratifying by age, researchers found that estrogen therapy was significantly associated with adverse events in women aged 70 years and older (HR for global index = 1.42; 95% CI, 1.09-1.86), but not in younger women.

Women aged 50 to 59 years who had their ovaries removed and received hormone therapy experienced a reduced risk for all-cause mortality (HR = 0.68; 95% CI, 0.48-0.96) over long-term follow up (18 years). Older women did not have a reduced risk for all-cause mortality.

Lead researcher JoAnn E. Manson, MD, DrPH, chief of the division of preventive medicine at Brigham and Women's Hospital and professor of medicine at Harvard Medical School, discussed the study with Healio Primary Care. – by Erin Michael

Q: How do the findings from this study compare with previous research?

A: This is the first study in a randomized trial setting to analyze the health risks and benefits of estrogen therapy for women who have had their ovaries removed; thus, it fills an important knowledge gap and helps to inform clinical practice on the care of these patients. Previous studies have been observational (not randomized trials) — most have suggested that women who have early surgical menopause (bilateral oophorectomy before age 45 or so) have increased risks of cardiovascular disease, osteoporotic fractures, and all-cause mortality, which are attenuated by use of estrogen therapy. However, such studies have not addressed differences in risk by age of the women when using estrogen. Removal of both ovaries has also been linked to a reduced risk of ovarian cancer and breast cancer.

Q: How might the study findings influence clinical practice?

A: The study highlights that age is a critically important factor to consider when making decisions about estrogen therapy in women who have had their ovaries removed. Women below age 60 had a 32% reduction in mortality over long-term follow-up, whereas women above age 70 had overall harmful effects from estrogen therapy. Women need to be informed about the risks and benefits of hormone therapy so that they can share in decision-making about this treatment. The findings suggest that many mid-life and younger women who have had their ovaries removed, especially if they have moderate to severe hot flashes or other menopausal symptoms, are likely to have a favorable benefit/risk profile on estrogen therapy. In contrast, women aged 70 or older, who have had prolonged periods of low estrogen levels, are likely to have a net adverse effect and should avoid starting hormone therapy so late after menopause onset. For women who have hysterectomy and intact ovaries, estrogen therapy appears to have generally neutral health effects, regardless of age.

Q: What should physicians consider before prescribing menopausal estrogen therapy in patients who have had a hysterectomy ?

A: It will depend on whether the ovaries have been removed and it will also depend on the age of the woman, in particular the time interval since the onset of menopause, the underlying risk factor status of the patient, and other factors. Currently, the clinical guidelines suggest that for women who have had early surgical menopause, before age 45 in particular, and in the absence of contraindications, it is very reasonable to treat with estrogen therapy up until the average age at natural menopause because of the increased risk of heart disease and osteoporotic fracture. Similar guidelines are used for premature natural menopause. However, after the natural age of menopause, the use of estrogen is guided primarily by the presence of menopausal symptoms. After that point, if a woman is having moderate to severe hot flashes or night sweats, estrogen therapy or continuing estrogen therapy is very appropriate. This study suggests that women who have had estrogen therapy below age 60 tend to do well and in the long-term have a reduction in all-cause mortality and favorable benefit/risk profile from estrogen therapy. Whereas, if the estrogen is initiated after age 70, the net affects are adverse, the risks outweigh the benefits, and there are no mortality benefits. What other factors would be considered? A woman who has a strong family history of osteoporosis or personal risk factors for osteoporosis — with a high FRAX score — may be a candidate for estrogen therapy. We found that generally, the benefits tend to outweigh the risks of hormone therapy when women are also at low risk for both cardiovascular disease and breast cancer.

Q: Based on the study findings, should physicians stop initiating estrogen therapy in patients aged 70 years and older who have had their ovaries removed?

A: Yes — but this scenario is very uncommon in current practice because if a woman is a candidate for hormone therapy, if she has an early menopause or if she’s having moderate to severe hot flashes or night sweats, it is generally early in menopause when she is started on hormone therapy. Decades ago, it was an increasingly common clinical practice to start hormone therapy later in life, even in a woman’s seventies or eighties, in an effort to prevent heart disease or cognitive decline. It’s now become clear that this is not an advisable practice, and in fact, the risks of late initiation tend to outweigh the benefits. Another reason a woman might be considered for starting estrogen later in life is osteoporosis and her risk for fracture, and that has to be an individualized decision. If a woman is at risk for osteoporosis and she’s not a candidate for other osteoporosis treatments, an individual woman’s benefits may outweigh her risks. But this study — the first randomized trial looking at the effects of estrogen therapy in women who have had their ovaries removed — suggests the women who were randomized to treatment at age 70 and older have an unfavorable net effect from hormone therapy.

Reference:

Manson JE, et al. Ann Intern Med. 2019;doi:10.7326/M19-0274.

Disclosures: Manson reports no relevant financial disclosures. Please see study for all other authors’ relevant financial disclosures.