1: THE PREGNANT MARE'S LESSON

In a former British colony, most healers believed the conventional wisdom that a distillation of fluids extracted from the urine of horses, if dried to a powder and fed to aging women, could act as a general tonic, preserve youth, and ward off a variety of diseases. The preparation became enormously popular throughout the culture, and was used widely by older women in all strata of society. Many years later modern scientific studies revealed that long-term ingestion of the horse-urine extract was useless for most of its intended purposes, and that it caused tumors, blood clots, heart disease, and perhaps brain damage.

The former colony is the United States; the time is now; the drug is the family of hormone replacement products that include Prempro and Premarin (manufactured from pregnant mares' urine, hence its name). For decades, estrogen replacement in postmenopausal women was widely believed to have "cardio-protective" properties; other papers in respected medical journals reported that the drugs could treat depression and incontinence, as well as prevent Alzheimer's disease. The first large, well-conducted, controlled clinical trial of this treatment in women was not published until 1998; it found that estrogen replacement actually increased the rate of heart attacks in the patients studied. Another clinical trial published in 2002 presented further evidence that these products increased the risk of heart disease, stroke, and cancer. Further reports a year later found that rather than preventing Alzheimer's disease, the drugs appeared to double the risk of becoming senile. The studies resulted in a reduction, but not an end, to the long-term use of these products.

For decades, these were among the most widely prescribed drugs in the nation. How did we get such an important question so wrong for so long?

Despite the deer-in-the-headlights astonishment with which the nation greeted the 2002 report that hormone replacement caused more harm than good, signs of trouble had been emerging for several years. The estrogen debacle was a case study waiting to happen, and its story can tell us much, both good and bad, about how the health care system evaluates and deploys medications. The fabric of modern medical care is woven of the belief by doctors and patients that the prescription drugs we use have been exhaustively studied and shown to work. The spectacular downfall of estrogen replacement therapy drew attention to the question of just how we determine that a drug actually "works," and why the system broke down in this very high profile case. For years, I've studied how we know what we know about drug benefits and risks, an inquiry I think of as "pharmaco-epistemology." The hormone replacement story is a perfect case study in this domain; it has much to teach us about how fragile our knowledge base can be concerning a drug's ultimate effects.

The word "estrogen" itself comes from the Latin oestrus and the Greek oistros, which mean "gadfly" and, by extension, "frenzy." The roots were chosen by early physiologists to depict the sexual arousal the hormones can cause in animals. They are also related to the semantic lineage of the word "ire," which derives from the Old English words for "haste" and "zeal" as well as from the Greek heiros, or "holy." What better linguistic pedigree for a once-sacred clinical concept that was promoted in haste and defended with zeal, and whose demise precipitated both frenzy and anger? Most important for the present context, the estrogen story has become a gadfly that is provoking a reconsideration of just how we know what we know about a drug’s effectiveness.

The shared delusion about long-term hormone replacement therapy started innocently enough. For centuries, women of a certain age (and their spouses) knew t