Before the Women’s Health Initiative (WHI) of 2002, there were two main reasons for prescribing hormone replacement therapy (HRT): it relieved perimenopausal symptoms like hot flashes, and it helped prevent osteoporosis and fractures. There was good reason to believe that estrogen might also reduce the risk of heart attacks, but very few doctors (if any) ever prescribed it for the sole purpose of reducing heart risks. And doctors were always aware that estrogen and progestins were powerful drugs and were not risk-free.
There was a time in the mid-20th century when estrogen was thought to be a fountain of youth and women were encouraged to start taking it at menopause and continue for the rest of their lives. That attitude quickly changed as we realized these hormones were associated with blood clots, strokes, and increased rates of some cancers. We also learned that unopposed estrogen caused uterine cancer, and women who still had their uterus had to take progestins along with their estrogen.
I remember prescribing HRT in the 80s. I would discuss the pros and cons with the patient. We would consider how bad her menopausal symptoms were and what her risk factors were. We would discuss the potential side effects of HRT. And we would decide together on an individual basis. The published evidence available at that time showed that HRT improved cardiac risk factors, but I never prescribed it for that purpose. I prescribed it for what I thought were other good reasons, and I considered the reduction of cardiac risk just an extra added bonus. I think my approach was typical of what most doctors were doing at that time.
The WHI was a wake-up call. A very large randomized trial of estrogen/progestin vs placebo in women aged 50-79, it was stopped early because the women on HRT were developing more cardiovascular disease than those on placebo. The message that some people got from the media was that HRT was killing women, but that wasn’t true. Over 10,000 person-years, women on estrogen plus progestin had 7 more coronary events, 8 more strokes, 8 more pulmonary emboli, and 8 more invasive breast cancers than women who didn’t take hormones; but they also had 6 fewer colorectal cancers and 5 fewer hip fractures, and the same number of deaths overall.
Instead of reporting the absolute risks, the media reported relative risks which sounded much worse. A 29 percent increase in risk of heart attack sounds pretty bad, but it translates to 37 heart attacks on HRT therapy versus 30 heart attacks on placebo per 10,000 women-years of treatment. These statistics are for all women including those who smoke, have strong family histories of heart disease, are overweight, etc.; those with no other cardiac risk factors would be less likely to have heart attacks.
I’ve seen alarmist claims that “doctors have killed millions of women by prescribing HRT.” That’s clearly not true. Women weren’t dying from HRT. They were more likely to develop some diseases and less likely to develop others, and overall the risk was greater than the benefit, but the risk of death did not increase. Current recommendations are to use HRT for a limited time only to control perimenopausal symptoms, and not to use it for disease prevention.
To help women make an informed decision, there is a good overview of the WHI, PEPI and HERS study results, of the pros and cons of HRT, and of other treatment options at this link.
The WHI is not the last word. It had flaws that have been extensively critiqued. Some of its findings were consistent with other studies, but some were not; the discrepancies need to be explained. There was a high dropout rate, and a preponderance of older women: only 1 in 6 were within 5 years of menopause. Current thinking is that HRT may have cardioprotective effects or at least be more benign if started in the perimenopausal period. More studies are needed in that age group.
Heart disease is multifactorial, and it is overly simplistic to look at the effects of HRT in isolation. HRT might conceivably benefit women with one risk factor profile but not with another. And just going by the data of the WHI, you might think that if a woman has a low risk of heart disease and breast cancer and a high risk of colon cancer and osteoporosis, HRT might just offer her more benefit than risk. Hip fracture can be devastating to elderly women: a substantial percentage never walk again, and older women are at greater risk for death after hip fracture than after breast cancer,
One thing seems clear. Estrogen is the most effective treatment we have for perimenopausal symptoms like hot flashes. Because of the WHI scare, thousands of women stopped their HRT. Many of those ended up going back to it in desperation when nothing else controlled their symptoms.
Of several proposed herbal alternatives, black cohosh was the most promising, but several recent studies (here, here, and here) have shown that it is no better than placebo, and there are concerns about possible liver toxicity.
Anything that has enough estrogenic effects to relieve hot flashes is likely to have all the risks and side effects that go along with estrogens themselves. We can’t assume other remedies are safer until they have been tested as rigorously as conventional HRT has been tested. The fad of so-called “bioidentical” hormone replacement a la Suzanne Somers is not based on science; the less said about it the better. The compounding pharmacies that make up the “bioidenticals” produce inconsistent products and the FDA is concerned about the need for better regulation.
Sales of Premarin plummeted when the news from the WHI first came out: from $2 billion to $880 million. Sales are now rising again. As we learn more about the risks and benefits of hormone replacement for different subsets of the population, our current recommendations will change. Individual advice may be based on the individual genome in the near distant future. We may learn that progesterone is better than progestins; we may learn that some forms of estrogen or some routes of administration are safer (so far there are lots of speculations and plenty of strong opinions but not much data). One thing is certain: estrogen and progestins will be a source of controversy for a long time to come.
This article was originally published in the Science-Based Medicine Blog.