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British researchers found that among more than 500,000 women aged 50 to 79, those who'd used hormone replacement therapy (HRT) were at relatively greater risk of breast cancer. The connection was strongest among women who'd used combined HRT -- estrogen plus progestin -- for at least five years.
But, the researchers said, the increased risk was not as great as a widely cited 2019 study suggested. And once women stopped HRT, the breast cancer risk declined more rapidly than those earlier estimates.
The new findings, published online Oct. 28 in the medical journal BMJ, are the latest chapter in the saga of hormone replacement therapy and its long-term health effects.
And experts said it shows, again, the issue is not clear-cut.
"It's very complicated," said Dr. Stephanie Faubion, director of the Mayo Clinic's Center for Women's Health, in Rochester, Minn. "No one is ever going to be able to say hormone therapy is completely safe." Faubion, who is also medical director of the North American Menopause Society, was not involved in the new research.
But in 2002, the results of a large U.S. trial called the Women's Health Initiative made waves: It found that combined HRT actually raised women's risk of heart disease, blood clots and breast cancer.
On the other hand, women given estrogen-only hormone therapy had a reduced likelihood of breast cancer. That therapy, however, is reserved for women who've had a hysterectomy, since taking estrogen alone raises the odds of uterine cancer.
After the Women's Health Initiative, prescriptions for HRT plummeted. But research since then has painted a more complicated picture.
Women in the trial were typically older, in their early 60s. More recent evidence suggests that when women begin HRT early in menopause, before age 60, the risks are smaller, and hormones might even help prevent heart problems.
It's a confusing issue for doctors and patients, according to Faubion. "But at the end of the day," she said, "for most women in their 50s, the benefits of HRT will outweigh the risks."
Now comes the new study. Unlike the Women's Health Initiative, which tested a particular HRT formulation, this study looked at medical records from women in the general population, to gauge the relationship between different "real-world" HRT approaches and breast cancer.
"What this study adds to the bigger picture is a much greater level of detail," said lead researcher Yana Vinogradova of the University of Nottingham in the United Kingdom.
Overall, Vinogradova said, the pattern fit with what's been seen before. Combined HRT, used for at least five years -- and within the past five years -- carried the highest risk. In that group, there were an extra 15 to 36 cases of breast cancer for every 10,000 women each year. The range varied according to age, with women in their 50s being on the lower end and women in their 70s on the higher end.
That confirms, Vinogradova said, that older women have "notably higher increased risks associated with HRT than younger women."
But she noted that things were even more nuanced than that: Different forms of progestin carried different risks. The highest was tied to norethisterone and the lowest to dydrogesterone.
"Long-term combined HRT seems to be the biggest problem," Faubion said. "But not all progestins are the same, either." The excess breast cancer risk did decline after women stopped combined HRT. But it did not disappear: Women who'd used it more than five years ago had a 15% greater risk of the disease than never-users.
Most medical groups advise against HRT for preventing chronic diseases. If women use hormones for severe hot flashes, they say, it should be at the lowest dose and shortest duration possible.
SOURCES: Yana Vinogradova, PhD, MSc, senior research fellow, faculty of medicine and health sciences, University of Nottingham, U.K.; Stephanie Faubion, MD, MBA, director, Mayo Clinic Center for Women's Health, Rochester, Minn./Jacksonville, Fla., and medical director, North American Menopause Society, Pepper Pike, Ohio; BMJ, Oct. 28, 2020, online
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