For many years, physicians regularly prescribed the hormones estrogen and progestin to women in perimenopause, menopause and postmenopause. Women were told that the treatment, called hormone replacement therapy (HRT) or hormone therapy (HT), would help not only with hot flashes, night sweats and vaginal dryness, but would also protect them from a variety of ills, including heart disease.
In 2002, the Women’s Health Initiative, the first major clinical trial to assess hormone therapy use by healthy women, found that the specific regimen of estrogen and progestin did not protect against heart disease and stroke. In fact, the results showed that women taking the hormones had an increased risk for breast cancer, stroke, heart attack, and blood clots.
How did a scientifically unproven treatment become the standard of care for millions of women? This question can best be answered by looking at the history of hormone therapy in the United States.
In 1942, the FDA approved Premarin, an estrogen product made from pregnant mare’s urine, for treatment of hot flashes. The drug was clearly effective, and many women who had troublesome, frequent and intense hot flashes and night sweats experienced great relief.
But starting in the 1960s, the list of reasons that women were advised to take hormones began to grow. In 1966, the book Feminine Forever became a best seller with its claim that “menopause is completely preventable.” The book’s author, Robert A. Wilson, wrote that because the estrogen level in a woman’s body dropped after menopause, postmenopausal women who didn’t receive treatment were no longer truly female. Wilson traveled the country, lecturing on this topic and promising that with the help of estrogen therapy, “Every woman alive today has the option to remain feminine forever.”
Some women’s health advocates became concerned that using hormone treatment might actually be harmful to women’s health. A few had raised warning ﬂags as early as the 1950s, and the concern grew more intense in the mid-1970s when two studies linked estrogen to endometrial cancer. But researchers soon discovered that adding a progestogen to estrogen (combined treatment) reduced this risk.
After that, doctors began prescribing combined hormone treatment to women who still had a uterus and thus were at risk of endometrial cancer, while women who had undergone hysterectomy continued to take estrogen alone.
In 1977, Barbara Seaman’s book “Women and the Crisis in Sex Hormones” alerted women to evidence that taking hormones could cause breast cancer, strokes, and blood clots and warned against the overpromotion of hormones for the treatment of menopause. Like Feminine Forever, Seaman’s book became a best seller, educating a generation of women about the health risks of hormones.
The FDA had initially approved hormone treatment for hot ﬂashes, not for disease prevention. However, in the late 1980s and the 1990s, some observational studies (in which women who chose to take or not take HT were followed over time) suggested that HT prevented heart disease, while other studies suggested that HT increased the risk of breast cancer and blood clots. In 1990, the FDA found that the research done to date was not adequate to support adding heart disease prevention to the list of approved uses.
But doctors are allowed to prescribe drugs for uses that are not approved by the FDA. Encouraged by the research suggesting that hormone treatment might be helpful for prevention, as well as by extensive drug company marketing efforts, many health care providers did just that. Such off-label prescribing is common practice in medicine when research to support new claims has not been completed, though in many cases it means that people are taking drugs that haven’t been adequately proven to be safe or effective for the purposes for which they are being used.
During the decades that followed, drug companies promoted and doctors prescribed hormones to women to prevent and treat an increasingly broad range of ailments and experiences associated with aging, from wrinkles and general aches and pains to Alzheimer’s disease, depression, and heart attack.
Against a background of seemingly conﬂicting data, with some research suggesting beneﬁts and other studies indicating dangers, hormone treatment soon became the most prescribed drug in the country.
The first randomized control trial to challenge the theory that HT was beneficial for heart disease was the Heart and Estrogen/ Progestin Replacement Study (HERS), a study of women with cardiovascular disease in which older women with heart disease took HT or a placebo. In 1998, HERS found no benefit of the top-selling HT formulation for preventing cardiovascular events. But hormone treatment proponents discounted the HERS results, saying that they didn’t apply to healthy women.
The Women’s Health Initiative (WHI), a national study designed to address the most common causes of death, disability, and poor quality of life in postmenopausal women, included the first randomized clinical trials to assess hormone therapy use by healthy women.
The WHI included two hormone therapy trials — an estrogen plus progestin study of women with a uterus and an estrogen-alone study of women who had had hysterectomies. Both studies showed that there are serious health risks associated with the long-term use of hormones.
The estrogen plus progestin arm of the study was halted in July of 2002, three years before its scheduled conclusion, because investigators found increases in breast cancers, heart disease, strokes, and blood clots in the women who took the pills. Continuation of the study was considered unethical because of these effects, even though the same women had less colon cancer and fewer fractures.
Additional analysis of the data showed that the estrogen-progestin combination did not help with depression, sexual function, vitality, or cognition, and doubled the risk of developing dementia. The combination did reduce the risk of fractures and colon cancer.
The estrogen-alone study was stopped in March 2004. It also showed an increase in blood clots and stroke, while fractures were prevented. No significant increase in breast cancer was shown for estrogen alone, and there was no difference in colorectal cancer risk. Women sixty-five and older taking HT had no protection against mild cognitive impairment, and there was a small increased risk of dementia.
Since that time, there have been ongoing discussion and controversy about what the WHI and significant debate about how to interpret many of the results.
One important limitation of the WHI was that it tested only Premarin, a synthetic estrogen made from the urine of pregnant mares, and PremPro, a combination of Premarin and the progestin Provera. Those products were used at the time by the vast majority of U.S. women taking HT. (The choice of Premarin and PremPro for the WHI was in part the result of their product being donated by the company, Wyeth-Ayerst, now a part of Pfizer.) As a result, the WHI findings did not answer questions about the safety and effectiveness of other hormone formulations, regimens, and delivery methods.
A third of the women in the WHI were in their fifties, making this the largest randomized controlled trial ever done of women in this age group. However, the majority of the participants were more than a decade past their final menstrual period, raising a question as to whether the trial’s results apply only to older women.
The results of the WHI contributed to an evolution away from the concept that menopause begins a time of estrogen deficiency and that hormone “replacement” is a necessary thing. Rather, low levels of reproductive hormones after menopause are normal and may not be problematic.
Understanding of HT continues to change— and tomorrow’s headline may contradict today’s. In the meantime, decades of drug company ads and promotions have influenced both women and health care providers. Many claims are made — both pro and con — about different products, including ones sold without a prescription that are not regulated by the FDA. Until research identifies the harms and benefits of the variety of available hormone regimens, women should be cautious about unproved claims.
The hormone controversy raises an important bioethical issue. The standards for using unproved treatments on healthy populations should be more stringent than those for treating people who are ill and are willing to take risks in hopes of a cure. The marketing of bisphosphonates to women with osteopenia is an example of encouraging women to use drugs for a nondisease condition, as was the pre-WHI marketing of HT to women for prevention of possible future problems.
Perimenopause and menopause are not disease states; if we feel well, treatments should not be pushed on us. On the other hand, a certain number of women don’t feel healthy during this time, and it’s important to have options for treatment. Any type of medication—whether hormones or drugs such as bisphosphonates, antidepressants, and statins—may result in unanticipated negative effects, so every woman’s decision to use hormones and other medications needs to be a personal, well-researched assessment of potential harms and benefits. And the decision needs to be revisited regularly as more is learned about the drugs and their effects.