Risks of Hormones in Early Menopause Challenged

Medically Reviewed by Brunilda Nazario, MD on October 05, 2012

Oct. 5, 2012 -- Is it possible to safely take hormone replacement therapy (HRT)? That question is at the heart of a small new study testing whether better timing and refined delivery may help early menopausal women get the benefits of hormones relatively safely and without long-term risks.

For some women, menopause brings mental and physical symptoms that can make life a misery.

Replacing estrogen and progestin may help relieve complaints like hot flashes, irritability, brain fog, and vaginal dryness. But studies show that taking hormones, even temporarily, has risks.

In a large, government-funded trial called the Women’s Health Initiative (WHI) that was released about a decade ago, postmenopausal women who took HRT had higher risks of blood clots, strokes, heart disease, and breast cancer.

But the WHI enrolled women ages 50-79, many of whom started hormones when they were over age 65 and well past menopause.

Many doctors have wondered if replacement hormones might be safer if they are given as soon as they start to drop naturally in the body, around age 50 or so. It’s a theory called the timing hypothesis.

Testing the Timing Hypothesis

Preliminary results from the new four-year study, called the Kronos Early Estrogen Prevention Study (KEEPS), were presented Wednesday at the annual meeting of the North American Menopause Society in Orlando, Fla.

The study tested two forms of estrogen, in either a patch or a pill, along with progesterone, against a placebo in 737 women who were near menopause. The average age of women in the KEEPS study was 52, or within three years of entering menopause, and none had any evidence of heart disease.

Along with looking at two different ways to deliver estrogen, doctors lowered the usual dose, from 0.625 milligrams to 0.45 milligrams a day. The progesterone used in the study was taken for just 12 days of the month.

“We tried to simulate as much as we could the normal menstrual cycle hormonal changes,” says researcher Sanjay Asthana, MD, director of the Geriatric Research, Education and Clinical Center at the University of Wisconsin in Madison.

For four years, doctors have kept an eye on the participants' mental and physical health, watching for changes in heart, brain, bone, and sexual health.

The study was funded by the Kronos Longevity Research Institute in Phoenix, Ariz. An arm of the study that looked at mental function and memory was funded by the National Institute on Aging, which is a part of the National Institutes of Health.

Weighing Benefits and Risks

The study found that both forms of hormone therapy relieved menopausal symptoms like hot flashes and night sweats better than the placebo. Hormones also showed significant benefits for sexual health. Both pain with intercourse and vaginal dryness improved in women taking estrogen. Women on the patch, but not the pill, saw increases in their libido.

Hormone therapy had a mixed effect on some measures of heart health. Hormones didn’t raise blood pressure, as had been seen in other studies. Women taking hormones also had small, positive changes in their cholesterol, with an increase in good cholesterol, HDL, and a decrease in bad LDL levels, compared to women on the placebo. But hormones also raised blood fats called triglycerides and C-reactive protein, an indicator of inflammation. Both markers are linked to an increased risk of heart disease.

Nearly 700 women agreed to participate in the part of the study that looked at mental function. They took tests at the start of the study and at 18, 36, and 48 months, designed to measure mood and memory.

“We found symptoms related to depression were significantly improved for women who got the oral form of estrogen. The skin patch [on the] arm didn’t show benefits or harm for mood,” Asthana says.

Estrogen pills, but not patches, seemed to improve anxiety and tension compared to a placebo, he says.

Women on hormones in the KEEPS study showed no memory loss over the course of the study. That was a relief, Asthana says, because the WHI found that women taking hormones were at higher risk for dementia than those who did not take them.

But he acknowledges that four years may not be enough time to measure meaningful changes to memory.

Safety Issues

The women in the KEEPS study were also more than a decade younger than women in the WHI. Hormones may affect the brain in ways that may only show up as women age, says Rowan T. Chlebowski, MD, PhD, a medical oncologist at the David Geffen School of Medicine at UCLA.

Chlebowski has been a lead researcher in the WHI. He was not involved in the current study.

“The big thing for me, as a medical oncologist, is that it doesn’t address the safety issue of cancer,” he says. “Estrogen plus progestin in the WHI significantly increased the risk for breast and lung cancer, the two leading causes of cancer death in women.”

“In a three- or four-year study, you really can’t say anything about breast cancer safety,” Chlebowski says.

Researchers acknowledge that their study was too small to show significant differences in the numbers of serious side effects like heart attacks, strokes, and cancers between women who took hormones and those who did not.

But they say it should reassure women who need to take hormones for a short time.

“The KEEPS study shows there are a lot of benefits of starting hormone therapy,” Asthana says. “The findings suggest that the risk benefit ratio is shifted a bit more toward benefits. Until now, it was the risk that was dominating.”

But Chlebowski says when it comes to hormone therapy with both estrogen and progesterone, women still need to carefully consider all the evidence.

“I don’t think this changes things very much, if at all. Some women will need to take it because they have limiting symptoms, but since there’s a risk associated with its use, I think they should carefully consider whether they need it,” he says.

These findings were presented at a medical conference. They should be considered preliminary as they have not yet undergone the "peer review" process, in which outside experts scrutinize the data prior to publication in a medical journal.

Show Sources


23rd annual meeting of the North American Menopause Society, Orlando, Fla., Oct. 3-6, 2012.

News release, The North American Menopause Society.

News release, The University of Wisconsin-Madison.

Sanjay Asthana, MD, director, Geriatric Research, Education and Clinical Center, University of Wisconsin at Madison.

Rowan T. Chlebowski, MD, PhD, medical oncologist, professor of medicine, David Geffen School of Medicine, UCLA, Los Angeles, Calif.

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