Progesterone Causes Less Bleeding than Most Hormone Replacement Therapies

May Also Be Less Likely to Cause Health Risks

Identified in Recent Women’s Health Initiative Study

Excessive bleeding, a troublesome side-effect that causes many women to stop taking hormone replacement therapies (HRT), is less likely with progesterone than with more commonly used synthetic versions.

Results from a national clinical trial published in the November issue of the Journal of Obstetrics and Gynecology, show that a combination of estrogen and micronized progesterone (MP) causes fewer days and less intense bleeding than the most commonly used combination. Previous studies have shown that unacceptable bleeding is the reason that most women discontinue HRT during the first year of therapy.

Estrogen plus MP is a different combination therapy than estrogen plus medroxyprogesterone acetate (MPA), the most widely-used HRT. Continuous estrogen plus MPA was used in the Women’s Health Initiative study which recently found that this form of HRT increased the risk of breast cancer, heart attack and stroke. While MPA is a strong synthetic compound that mimics the action of progesterone, MP is chemically and functionally identical to the progesterone that women naturally make before menopause. Progestogens like MP and MPA are used to prevent problems that can develop in the uterus when estrogen is used by itself. MP is just as effective as MPA for that purpose.

“During the first six months, when many women stop taking HRT because of bleeding problems, we found that estrogen plus MP caused significantly less bleeding than the other combinations using MPA,” said the study’s senior author, Robert D. Langer, M.D., M.P.H., professor of Family and Preventive Medicine, University of California, San Diego (UCSD) School of Medicine. “Over three years, the number of unexpected bleeding episodes was virtually identical for placebo and estrogen plus MP, and about half as great as for the next best treatment, cyclical estrogen plus MPA.”

“We also believe that the form of HRT with the least bleeding ? estrogen plus MP ? may be the form less likely to cause the increased health risks associated with estrogen plus MPA,” Langer noted.

He said that previous results from the same study, the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, found that estrogen plus MP differed little from estrogen alone in effects on key heart disease risk factors, while MPA tempered some of those benefits. He added that studies in non-human primates have shown that MPA blocks both short-term and long-term benefits of estrogen in the coronary arteries, while those benefits are preserved with the more natural progesterone. Although data are sparse for breast effects, Langer said that one small study in breast cancer cell lines showed that MPA causes a larger increase in tumor marker proteins than progesterone.

The new report comes from the PEPI trial that studied 875 women over a three-year period at seven sites in the U.S. The participants took either a placebo, estrogen alone, estrogen plus a continuous form of MPA, estrogen plus a cyclical form of MPA, or estrogen plus a cyclical form of MP. The estrogen used in the study was conjugated equine estrogen, the most common form used HRTs.

A cyclical regimen uses estrogen every day and the progesterone for 12 days per 28 day cycle, mimicking a menstrual cycle with bleeding near the end of the progesterone phase. A continuous HRT regimen uses the same dose of estrogen and progesterone every day and is expected to cause less bleeding. Excess bleeding was considered to be any bleeding on a continuous regimen, or more than one episode per month with cyclical treatment.

Langer and the study’s first author, Etta A. Lindenfeld, M.D., MPH, UCSD assistant clinical professor of psychiatry, noted that the mean number of excess bleeding episodes at each six-month clinic visit varied widely by treatment. Considering the active treatments, cyclical estrogen plus MP had the lowest number of unexpected bleeding episodes, and they occurred in the fewest women. Cyclical estrogen plus MPA was next best with a slightly greater number of epidoses, but 2-3 times more women were affected. These rates went up by 2-3 times again for women with a uterus who took estrogen alone. The greatest number of episodes occurred in the continuous estrogen plus MPA group with 4 to 6 times as many women experiencing about 3 times more episodes of unexpected bleeding compared with the cyclical estrogen plus MP group.