by Christopher Minson, Ph.D., Associate Professor and Department Head, Human Physiology

Millions of women use hormone therapy for treatment of menopausal symptoms and gynecological syndromes, contraception, assisted reproductive techniques, and combating osteoporosis. Early reports on the use of estrogen replacement therapy were very promising in terms of improving cardiovascular and bone health, but the results of two major clinical trials were disappointing and alarming, resulting in millions of women stopping hormone therapy. 

The findings suggested that estrogen replacement did not provide a cardiovascular-protective benefit and were associated with increased risk of cancer. A specific synthetic progesterone called a progestin was actually associated with increased risk of cardiovascular disease, even when prescribed with estrogen. 

Regardless, the overall recommendation for women following the most recent of these clinical trials, the Women’s Health Initiative trial, suggested that women only take estrogen replacement therapy for treatment of menopausal symptoms, and at the lowest dose for the shortest possible time.

One concern, however, was that hormone replacement therapy was not started early enough following menopause. The goal of a new clinical trial on hormone replacement therapy, the Kronos Early Estrogen Prevention Study (KEEPS), is to start estrogen replacement therapy within thirty-six months of the subject’s final menstrual period. Women will receive progesterone (synthetic, but identical to natural progesterone) rather than a progestin (synthetic, but structurally different from progesterone) for twelve days per month with estrogen as part of the hormone replacement program. 

Synthetic Hormone Use by Young Women

Although this is an exciting “next step,” other important issues are not being addressed. Many young women are now suppressing natural fluctuations in their hormones that drive the menstrual cycle, known to provide cardiovascular protection, by using the exact same synthetic hormones found to be associated with increased cardiovascular risk in older women. Even more troubling, these young women are often taking synthetic hormones for longer periods of time than the older women were, and often at higher doses. 

The injectable contraceptive Depo-Provera, for example, contains the same synthetic progesterone given to postmenopausal women in the Women’s Health Initiative trials, and is prescribed without estrogen. Originally designed to be used as a contraceptive in women over age thirty-five or smokers (those most at risk of developing a blood clot), Depo-Provera is currently being used by many young women who want the ease of an intramuscular injection given every twelve weeks rather than a daily pill. Many women are staying on contraceptives for decades, only stopping when they wish to become pregnant. 

Clearly, the recommendation of “the lowest dose for the shortest amount of time” is not being followed by younger women. Long-term use of certain types of these hormones may not allow women to reach the menopausal transition with a healthy vascular profile, greatly increasing the risk of early cardiovascular disease.

Providing Unbiased Information

Reproductive-aged women have many options for hormone therapy. Some alternatives may be safe and confer benefits for both cardiovascular and bone health while also providing contraception. But the predominance of studies on the safety aspects of hormone use in reproductive-aged women have been funded by pharmaceutical companies with a clear financial stake in the outcome. 

We also do not know whether studies in older women can be reliably translated to provide suggestions for tens of millions of younger women using hormone treatments. We see a profound lack of studies by which to guide younger women and their health-care providers to make the most informed choices. 

Funded by the National Institutes of Health, our current studies in the Department of Human Physiology are designed to address some of these issues. Our long-term goal is to provide unbiased information about the risks and benefits to specific hormone treatment options.

Although too early for recommendations, it is becoming clear that many factors can have an impact on how synthetic hormones affect the health of the cardiovascular system, including the specific dose of estrogen, the route of hormone administration, and the specific type of synthetic progesterone. In the long term, we believe the findings from these studies will help lead to the development of strategies for contraceptive use and hormone replacement therapy that do not compromise, and may even improve, cardiovascular health in women of all ages.