Hormone-Replacement Follies: A Brief History

Hormone replacement therapy at menopause is not good for all, nor bad for all. It clearly can confer benefit, but it depends how it is done, and for whom.
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Once upon a time, the first human woman outlived the biological limits of her ovarian hormone production, and menopause was born. None can give the date for this event, but we can be confident it was a very, very, very long time ago.

Medical menopause, however, was born much more recently. For this, we can give a date -- situated in the early 1940s when the FDA approved estrogen replacement for the treatment of menopause and its related symptoms.

We like to believe that necessity is the mother of invention, and indeed it may often be so. But Jared Diamond shrewdly pointed out that as often at least, invention is the mother of necessity. When we invented medical menopause, the necessity of treatments that ensued grew into a multi-billion-dollar industry. The invention of that industry propagated more necessity. For a span of decades, science fostered this trend with observational studies suggesting the many benefits of hormone replacement.

The practice that came to prevail, even though many true authorities on the topic were dubious all the while, was the use of Prem/Pro, a combination of Premarin (conjugated equine estrogen, or, to spell it right out: estrogen derived from the urine of pregnant female horses), and Provera (medroxyprogesterone acetate, a synthetic progesterone many times more potent in its action than the native human variety).

The popular view for those recent decades, propagated in all the ways we might imagine by both our limited knowledge, and large sums of money changing hands, was that hormone replacement was good, and that Prem/Pro was good hormone replacement.

I hasten to add that the alternative to "good" need not be bad. A good alternative to good is "good on occasion," or "good for some." I am by no means suggesting that hormone replacement therapy is a bad idea, or wrong for all women. It can clearly be very important at times. I am simply pointing out that we tended, over the last half century, to be entirely in love, or entirely out of love with the concept as a society, and as a medical community.

One of the dominant themes in modern medicine is "evidence-based" practice. As attention, over the past 30 years or so, focused more on standards of evidence, misgivings began to arise -- at least as far back as the 1980s -- about the observational data on which enthusiasm for HRT was mostly based. Seeing X and Y happen together in a large group of people does not reliably mean that X is causing Y. It may be that everyone who does X happens to have Z, and Z causes Y. This is a salient limitation of observational research. As an example, people who don't have televisions are more prone to tuberculosis -- but not because TVs prevent TB! Rather, not having a television is proxy for poverty, and poverty in turn is associated with a number of the factors that truly do increase TB risk.

For a while longer, early misgivings about the evidence base for HRT were just small waves on the placid sea of prevailing conviction. Our boat wasn't severely rocked until the HERS trial results were published in 1998. HERS was the first significant randomized, placebo-controlled trial of hormone replacement therapy, and it suggested an overall lack of benefit for cardiovascular disease prevention. Nearly 3,000 were enrolled.

Then, with publication of the Women's Health Initiative (WHI) results in 2002, the boat of consensus opinion was capsized outright. This randomized trial in nearly 20,000 women showed net harm from hormone replacement therapy, and advised directly against the practice.

The latest news is again courtesy of the WHI. In a paper just published in JAMA, the long-term experience of women in the WHI who had undergone a hysterectomy and received only estrogen is reported, and reveals a clear reduction in breast cancer risk. The study is evoking widespread media attention, and some rekindling of that love we had all lost for hormone replacement therapy.

Looking at all this in hindsight, we never had as much cause to love or hate HRT as our behavior during any interval suggested. Our enthusiasm for hormone replacement got well ahead of the data demonstrating net benefit for most women. Then, our renunciation of the practice was far more expansive than the data warranted. Both the HERS and WHI trials used the same kind of hormones, and both enrolled women a long time after menopause.

Studies since suggest that the benefits of hormone replacement appear to be most robust when the practice is applied as soon after menopause as possible. The benefits are greater when women are carefully selected; those with increased risk for blood clots should not participate, for instance. And there are many options -- and most would say many far better options- than Prem/Pro, including other estrogen/progesterone combinations, estrogen alone, bio-identical hormones, and the synthetic estrogen-like drugs such as raloxifene.

There are two take-away messages. The first is that hormone replacement therapy at menopause is not good for all, nor bad for all. It clearly can confer benefit, but it depends how it is done, and for whom. When the right hormone preparations are thoughtfully applied in the right women for the right reasons, I am convinced considerable benefit can come of it. I am equally convinced of the potential for harm when the wrong preparations are thoughtlessly used for the wrong reasons in the wrong women. You and a doctor you can really talk to should sort this out together.

The other message is that science is as it ever was: incremental and evolutionary, rarely revolutionary. Evidence accumulates over time, and the weight of evidence tips toward the truth. When science becomes a teeter-totter of sequentially opposed truths, we have lost our way.

That has been the history to date of hormone replacement therapy: rather half-witted over-reactions to the half-truths that any given trial provided. Those who do not learn from the follies of this history are destined to repeat them. Again.

PS- for a good source of professional information about hormone replacement options and menopause in general, visit http://www.menopause.org/. I also recommend http://www.menopausemakeover.com/ for a hefty dose of menopause mastery and empowerment.

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