The WHI (now over a decade old) remains the largest randomly controlled trial of women’s hormonal medicines. The original publication of WHI identified increased risks of breast cancer, stroke, and cardiovascular disease associated with hormone therapy. These findings flew in the face of medical practice at the time, and disagreed with a wealth of smaller observational studies as well large European observational trials.

The WHI suffered from poor design.  The average age of menopause is 51, but the average WHI participant was 63 (and the oldest was 79). Medication dosages were not adjusted for age. In essence, older women were overdosed. It provided results that confused and frightened the medical community and women in general.

However, the new analysis of the WHI subset of women age 50-59 reverses the original conclusions: Women who received hormone therapy before age 60 had significant reductions (>25%) in cardiovascular disease, which is the primary cause of death in women. In the years prior to menopause, women have 15% of the cardiac risk of men. Within ten years of menopause, their risk rises to 250% of men. Women who had previous hysterectomies and received only estrogen had decreased heart disease. In short, estrogen can protect women from heart disease.

The WHI claim of increased incidence of breast cancer was misstated. The headline talk about “doubling” the risk, but the formal statement of absolute difference was 2.6 vs. 1.3 deaths per 10,000 women per year.  If we look at survival difference, 99.984% of the untreated vs. 99.977% of the treated all lived. Balance a less than 1% breast cancer risk against a 25% improvement in heart disease risk, and it becomes clear how beneficial hormones can be. Any decisions about risk and benefit must be individualized; women with a family history or a genetic predisposition to breast cancer may perceive these risks quite differently.

Perhaps the problem started with the concept that women needed hormone replacement. What has been learned over the last fifty years is that menopause is highly variable, with estrogen levels plummeting for some women and gradually declining in others. A better concept is hormone supplementation, where one periodically measures hormones and then adds or blocks hormones as needed.

For example, a crude estimate of the dose of estrogen to suppress “hot flashes” is 1.25 mg/day, but the dose to prevent osteoporosis is only 0.15 mg day. (For the record, control of “hot flashes” and “night sweats” are dependent on more than a simple estrogen replacement – welcome to integrative medicine.) Since estrogen has increasing risks with increasing doses, a woman who has no hot flashes may opt for osteoporosis prevention only. The real brass ring is figuring out which supplementary dose of which hormones will create that maximal reduction in coronary disease (possibly more than 25%) while creating no increased risk of breast cancer.

James Katz MD

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