The Women's Health Initiative in Perspective: The Last Straw for Estrogen Therapy?


Medical Author: Carolyn Crandall, MD.,FACP
Medical Editor: William C. Shiel, Jr., MD, FACP, FACR

If we piled up all the medical research that's been done in the last 30 years about estrogen therapy in menopausal women, we could probably fill up a mega-warehouse. The strange thing is that such a small portion of the research was done in a way that was scientifically rigorous and demanding, and not a single reliable study told us the overall benefits that healthy women could expect after using estrogen therapy for several years...until now.

The Women's Health Initiative (WHI) was the first randomized controlled trial of estrogen/progestin therapy (EPT) designed to determine the long-term balance of benefit versus risk in healthy menopausal women. It was the first randomized trial assessing whether EPT has a benefit on coronary heart disease incidence in healthy women. The results were reported in a series of articles in JAMA in 2002 and 2003.

Why should we hold out for large randomized controlled trials? A randomized trial assigns each woman to either EPT or placebo (sugar pill) without her knowing and without the researchers knowing, which therapy she is taking. Unfortunately, we learned from the past that women who take estrogen tend to be healthier in general than women who do not choose to take estrogen. Frequently the reason women who chose to be on estrogen had fewer heart attacks, or less dementia was because they were healthier for other reasons. Women who take estrogen often have healthier diets, more money, more education, lower body weight, and exercise more - things that on their own predict fewer heart attacks or dementia. Therefore, we need to have research in which the women who were taking the EPT were as similar as possible in these health characteristics to the women in the study taking the placebo. Studies in which women can choose to take or not take estrogen are not going to give us the answers we need. Before the WHI, many people thought estrogen would be protective against heart disease, dementia, and stroke, on the basis of studies that were not randomized. Fortunately, the WHI came along to give definite answers. The answers surprised many people.

The First surprise was that the WHI study was stopped early, after just 5.2 years, because there were early signs of increased harm (increase in coronary heart disease, stroke, and blood clots in the lungs) that outweighed the benefits (decreased fractures and colon cancer).

The WHI estimates that out of 10,000 women who take the particular EPT combination over the course of a year, we can expect additional cases of several serious health problems: 

At the same time, however, there would be 6 fewer colorectal cancers and 5 fewer hip fractures. Many are women who are "hanging on" to EPT because of fear of Alzheimer's disease running in her family, only to be disappointed by the WHI study results.

The increase in breast cancer became especially apparent after 3-5 years, but the increase in heart disease and pulmonary emboli occurred early on, in the first year.

Some physicians, and their patients, would say that we finally have the answer, but we don't necessary like it. On the other hand, many points are worth emphasizing:

  1. There is still nothing that works better than estrogen therapy for hot flashes, moreover, no other therapy besides estrogen is approved for hot flashes.

  2. Women in the WHI study were not picked because they had hot flashes, so we really don't know the long-term risks and benefits for younger women who are beginning EPT when they are actively battling hot flashes.

  3. The increase in risk to an individual woman is still small.

  4. Many women in the WHI study were older yet most women begin EPT when they're younger.

  5. It seems that the progesterone part of the EPT may be the "bad guy" regarding breast cancer risk. (Progesterone is given to protect against uterine cancer during estrogen therapy). The part of the WHI study that is following women after hysterectomy who are taking estrogen alone is still ongoing. Maybe estrogen alone will be found to be a little safer in certain aspects, possibly reassuring to women with a hysterectomy.

  6. Only one type of EPT was used in the WHI study. We don't know how other brands and doses compare. For now, we have to assume the same risks apply to other preparations, until proven otherwise.

The upshot:

EPT is still the best therapy for hot flashes, and many women remain good candidates for EPT therapy, despite the WHI study. This is especially true if EPT is limited to the shortest duration possible, optimally less than 5 years. Women shouldn't stop EPT suddenly. They should wean down slowly to avoid having withdrawal symptoms. EPT should not be used to prevent or treat either Alzheimer's disease, heart disease, or stroke. Some alternatives to EPT are available to women who cannot or do not wish to take EPT, although these alternatives don't work as well as EPT to treat hot flashes and are not FDA-approved to treat hot flashes. Women (and men) should always question whether medical research comes from randomized controlled trials (the highest quality research method).

In regard to the use of EPT as osteoporosis prevention, many non-hormonal alternatives exist to treat osteoporosis.

As a final thought, women should speak to their physicians on an individual basis to determine the right treatment plan for them. At least that's something that still hasn't changed.


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