Post Menopausal Hormones: A Cautionary Tale
By Maryann Napoli

Always read the information that comes with your prescription drug. That’s the take-home message from the recent announcement that postmenopausal hormones cause more harm than good. The woman who took the time to wade through the multiple pages of tiny type in the “patient packet insert” included* within her estrogen/progestin prescription would not have been surprised at the recent news that this combination causes far more harm than good.

For well over a decade, there had been an informal consensus building among gynecologists who seemed to think that virtually all women should consider lifelong hormone therapy, primarily to prevent heart disease. It’s doubtful that many doctors took the time to explain the uncertain safety of combining estrogen with progestin or the iffy nature of the heart protective effects. But the patient packet insert that comes with Prempro, the most widely prescribed estrogen/progestin combination, contains the following information listed under Precautions: “A causal relationship between estrogen replacement therapy and reduction of cardiovascular disease in postmenopausal women has not been proven. Furthermore, the effect of added progestins on this putative [reputed] benefit is not yet known.” Yes, it could have been written in a jargon-free style, but the key information about the “unknowns” is there.

Estrogen was approved by the Food and Drug Administration in 1942 to alleviate the symptoms of menopause. Ironically, the whole point of adding progestin to the regimen was to overcome an adverse reaction to estrogen (an increased risk of endometrial cancer) that was identified 35 years later. Now the combination has been shown to be far more dangerous than estrogen alone.

The story of postmenopausal hormones provides yet another illustration of how long a drug must be in use before a full picture of its safety and effectiveness becomes clear. It also shows the importance of randomized clinical trials. The National Institutes of Health-sponsored trial, called the Women’s Health Initiative (WHI) is the first large study ever to compare hormones with a placebo. The 16,608 healthy participants, aged 50 to 79 years, had been randomly assigned to take Prempro or a placebo. Those who had had a hysterectomy were randomly assigned to take estrogen or a placebo.

The main part of the WHI was stopped three years short of its intended goal because the women taking Prempro showed a higher rate of heart attacks, breast cancer, stroke, and blood clots than the women taking the placebo. These risks showed up after only four years on the drug. Though the women taking Prempro had a decreased risk of colon cancer and fractures, these benefits were far outweighed by the harms. The WHI continues to study the women without a uterus who presently show no significant benefit or risk from taking estrogen alone.

You might wonder why the heart-protective benefit remained so fixed within the belief system of the average gynecologist. For example, a small increase in the number of heart attacks, strokes, and blood clots in the lungs showed up in the first one to two years of use of estrogen and progestin. But doctors reasoned that this small risk (less than 1% altogether) would disappear after two years, so the trial was allowed to continue. But, in the next years, the women on the hormone combination showed a continued increase in heart attacks, strokes, and blood clots. The same disturbing results showed up in an earlier randomized trial that explored the question of whether hormones could prevent heart attacks in women with heart disease.

But gynecologists, as a group, had managed to convince themselves that the heart benefits would eventually be verified. Previous trials did show estrogen’s good effect on what doctors call “markers” for heart disease, such as cholesterol. And there were many observational studies, indicating that women who took hormones had a lower incidence of heart disease. But upper-income women tend to have lower rates of heart disease, and this is the same group that was more likely to take hormones. As Susan M. Love, MD, author of Dr. Susan Love’s Hormone Book, is fond of saying, “We don’t know whether the hormones made the women in these observational studies healthy, or whether healthy women took hormones.” Definitive information did not arrive until the WHI announced its findings last month in the Journal of the American Medical Association (JAMA, 7/17/02).

The same issue of that journal included another study that reported an increased risk of ovarian cancer to be associated with the use of estrogen alone. The risk was especially relevant to women who took estrogen for ten or more years. This study, however, was not a randomized trial, so it is possible that the ovarian cancer risk will not be confirmed in future, well-designed clinical trials.

There are many women who take hormones solely for the purpose of alleviating menopausal symptoms or osteoporosis prevention. For these women, both pharmaceutical and non-pharmaceutical alternatives are described in one of the Web sites listed below.

Resources:
-Consult the Physicians’ Desk Reference, which is available at most community libraries, before taking any prescription drug. Though quite daunting in language and format, the PDR is the only source of accessible information for consumers who want the most complete information about any prescription drug they are about to take. The book is updated yearly and can be purchased at most major chain bookstores. The patient packet insert referred to in this article is the same information provided in the PDR. Unlike other drug reference books, the PDR describes what has been proven in terms of effectiveness in the pre-approval clinical trials and how long the trials followed the participants.

-For alternatives to hormone therapy, including supplements and other drugs, visit the Web site of the North American Menopause Society (www.menopause.org). NAMS has received funding over the years from Wyeth, makers of Prempro, Premarin, and other estrogen drugs, and it has been the prime force behind the inappropriate promotion of these drugs for prevention of heart disease. At this Web site you can also read the organization’s position papers and expert comments on the WHI findings.

-The Food and Drug Administration Web site (www.fda.gov) has prescription drug information, but it is better at providing it for newly approved drugs. If you can find your way to “advisory committee transcripts,” that is where the pre-approval discussions of a drug’s pros and cons can be found.

-Our Web site (www.medicalconsumers.org) grants free access to the March 2002 HealthFacts article on postmenopausal hormones.

*Hormone drugs are in a rare category of prescription drugs. Their manufacturers are mandated by law to include written information for consumers in their products. How well they comply has yet to be studied. To find this important information for all prescription drugs, see “Resources.”

(August 2002)