Will Hormones HuRT You?

In 2002, a study was published which claimed that hormone replacement therapy (HRT) increased the risk of stroke for older women. And this was no piddling fly-by-night affair - this was a randomized, double blind, placebo-controlled Women's Health Initiative study of 20,000 post-menopausal subjects conducted by the NIH. Since the investigators had hoped to show that estrogen had a protective effect on women's health, this unexpected result generated a lot of publicity and caused many alarmed women and their physicians to back off hastily from widely used hormonal treatments of menopausal symptoms.

But not so fast. How relevant are the results of this study to women in the real world? In a recent lecture at the University of Washington, Seattle, Dr. Phyllis Wise clued me in to the considerable caveats.

First of all, the women in the experimental group did not receive the standard doses of hormones used in treating menopausal symptoms; instead they were given relatively high, continuous doses of CEE (conjugated equine estrogen) along with MPA (which mimics progesterone and androgen and could interfere with estrogen). This was so that the investigators would be more likely to observe an effect, but was not an accurate re-creation of usual medical treatments.

Second, because this was a double blind study (no one was supposed to be able to tell who received treatment and who received placebo), only women who exhibited no menopausal symptoms were selected for the study. In other words, the investigators deliberately gave hormones to a group of women who would NOT normally seek hormone replacement therapy. Therefore, there is every reason to believe that the experimental group was not representative of the population of women who undergo HRT, meaning that results from this study cannot safely be generalized to the patient population.

Most critically, the participants were women aged 50-79 (average 63) years at the beginning of the study, and many of them had never received hormone replacement therapy. Prior to the experimental treatment, these women had no estrogen circulating in their bodies for an average of TWELVE YEARS.

Why is this so important? Because, biologically speaking, as many lactose-intolerants and former high school athletes have realized, if you don't use it, you lose it. Estrogen, like other hormones, is a signal that has to be received in order to work. Only tissues that make a protein receptor for the estrogen molecule can be instructed by it. And guess what - if there hasn't been any estrogen around for years, the body stops wasting its resources on making estrogen receptors. After that, taking estrogen won't help a damned thing. It's like holding up a stop sign to a driver who has his eyes closed.

This idea is supported by a really cool series of studies by Dr. Wise's group in an animal model for stroke. Researchers removed the ovaries from rats to mimic menopause and later used a suture to block a cerebral artery, temporarily stopping bood flow to one side of the brain. If the rats were given estrogen treatments immediately after removal of their ovaries, they suffered much less tissue death upon blockage of blood flow. However, if estrogen treatment was delayed (for a time equivalent to the years human women spent between menopause and hormone treatment in the WIH study), there was no longer any health benefit. This was because the estrogen receptor (ER-alpha) that mediated the effect of estrogen on brain tissue damage, and would normally be produced at high levels in response to brain injury, was no longer present following prolonged estrogen deprivation.

So the authors of the famous WHI study can't conclude anything about the possible health risks or benefits of standard hormone replacement therapy for women who come to their doctors complaining of menopausal symptoms. No matter how large the study, if it can't accurately represent the relevant treatment method or patient population, then the results cannot reliably inform our medical decisions.


References

Writing Group for the Women’s Health Initiative Investigators, Risks and benefits of estrogen plus progestin in healthy postmenopausal women principal results from the Women’s Health Initiative randomized controlled trial, JAMA 288 (2002), pp. 321–333.

P.M. Wise (2006). Estrogen therapy: Does it help or hurt the adult and aging brain? Insights derived from animal models. Neuroscience 138(3):831-5.