Estrogen-only therapy less risky than first thought

Although many women have sworn off hormone therapy, a new analysis from the clinical trial that first unearthed the hormones’ risks shows taking estrogen alone for menopausal symptoms, even for several years, may be safer than first thought.

The new finding — the latest from the Women’s Health Initiative, a federally funded trial that tracked thousands of women taking hormones or placebo pills for years — looked at women who have had hysterectomies and thus can take estrogen unaccompanied by another hormone, progestin. (Women with a uterus take progestin to protect against uterine cancer.) It found that a heightened risk of stroke from taking estrogen faded with time, while a reduced risk of breast cancer held steady.

That news, published Tuesday in the Journal of the American Medical Assn., may weaken — for this group of women — the current recommendation from doctors that hormones to treat hot flashes and other menopausal symptoms should be taken in the smallest doses possible for the shortest amount of time.

“This study is very good news for women without a uterus,” said Andrea LaCroix, the lead author of the study and an epidemiologist at the Fred Hutchinson Cancer Research Center in Seattle.


The so-called estrogen-only arm of the Women’s Health Initiative, which began with more than 10,000 women ages 50 to 79 who’d had hysterectomies, was halted prematurely in 2004 after researchers discovered that the risk of stroke was slightly higher — 12 more cases among 10,000 people — in women who had taken estrogen for an average of six years compared with those who received placebo pills. At the same time, the hormone failed to reduce the risk of heart disease, which had been the principal hope of the study.

LaCroix and her colleagues examined data from 7,645 of the participants more than four years after they had stopped therapy. The scientists found that a slightly higher risk of blood clots in the legs, corresponding to six additional cases per 10,000 women, vanished along with the increased risk of stroke. So too did a benefit: A small decreased risk of hip fracture seen during the intervention — six fewer hip fractures per 10,000 women — returned to baseline after the women stopped taking estrogen.

“What’s very interesting is the fact that the reduction of breast cancer in this particular group persisted while all the other risks and benefits disappeared,” said Dr. Margery Gass, executive director of the North American Menopause Society and a consultant at the Cleveland Clinic, who was not involved in this particular Women’s Health Initiative report. “It’s very hard to explain.”

Estrogen is thought to promote breast cancer in some women by stimulating cell growth and inhibiting the natural suicide of cells, a process called apoptosis. Other research, however, has hinted that a period of years with no hormones — such as natural menopause — followed by a period of hormone exposure produces anti-cancer effects.

“In these circumstances, estrogen acts like it stimulates apoptosis,” said Dr. Rowan T. Chlebowski, a medical oncologist at the Los Angeles Biomedical Research Institute and a coauthor of the study. By so doing, it could cause precancerous cells in the breast to self-destruct before they cause problems. He called the finding on breast cancer risk reduction “definitive.”

The analysis also sheds some light on whether the risks and benefits of taking estrogen differ depending on a woman’s age. Some have criticized the Women’s Health Initiative because many of the participants were age 60 or older when the study began. In normal medical settings, women begin taking hormones for relief of symptoms such as hot flashes that occur at the time of menopause, which for most women is in their early 50s.

The safety profile for the younger women appeared better than for older women in the study, LaCroix and her colleagues reported: The younger women were less likely to have heart attacks or die from other diseases. Based on these findings, the scientists calculated that if 10,000 women ages 50 to 59 took estrogen for 10 years and seven months, there would be 12 fewer acute heart attacks, 13 fewer deaths from any cause and 18 fewer adverse events related to chronic diseases, such as diabetes, compared with women taking placebo pills.

In contrast, in 10,000 women ages 70 to 79, there would be 16 more heart attacks, 19 more deaths and 48 more adverse events related to chronic diseases compared with women taking placebos.


“Six years of use followed by stopping appears to be very safe for younger women, with the exception of blood clots,” LaCroix said. “But for women in their 70s, this does not appear to be a safe medicine.”

It’s unlikely that the study will reignite women’s passion for hormones, said researchers from Washington University School of Medicine in St. Louis in an editorial accompanying the study. Prescriptions have plummeted in the last seven years as hopes were dashed that hormone therapy would generally improve women’s health in the later part of life.

“Instead of women taking a pill they thought was going to protect against heart disease and osteoporosis and all these other effects, you now offer a pill that has benefits and risk that equal out,” said Dr. Graham Colditz, a coauthor of the editorial. “Most people aren’t going to run out to take something that may cause them to have a stroke.”

But other experts said the persistent reduction in breast cancer risk needed to be explored further.


“The effects on breast cancer risk are much different than people thought,” Chlebowski said. “There are time-dependent and exposure-dependent effects that are complicated and aren’t well understood.”