Controversies in Science and Technology: From Maize to Menopause

13 The History of Hormone Replacement Therapy: A Timeline

13 The History of Hormone Replacement Therapy: A Timeline Barbara Seaman I am a science journalist who has followed the “hormone story” for about forty-five years. I have watched the rise and fall and resurrection of various drugs, and seen patients’ lives both helped and hurt by them. In the pages that follow, I try to provide an outline of many crucial events in the extended history of hormone replacement therapy (HRT). As much information in the timeline indicates, many scientists were aware of the dangers of the medicinal use of hormones well before the July 2002 decision to halt the estrogen plus progestin arm of the Women’s Health Initiative study. I would ask the reader to wonder why it took more than half a century from initial research on the dangers of hormone use to the widespread recognition of the dangers of HRT. Could it be that some significant causes of this lag are the blindness created by drug industry profits, sexism, patients ’ wishful thinking, and/or professional arrogance? 1890s • Merck manufactures Ovariin, a coarse brownish powder derived from the pulverized ovaries of the cow, for the treatment of menopause. It remains on the market until 1932. 219 1922 • The anatomist Edgar Allen describes the hormone cycle in a female mouse. With the biochemist Edward Doisy, he develops the AllenDoisy test to measure estrogen content. Early 1930s • Menopause products are derived from human pregnancy urine by the biochemists Adolph Butenandt, financed by Schering in Germany, and James Bertram Collip, financed by Ayerst Laboratories in Canada. • In 1932, Antoine Lacassagne of the Institute Pasteur administers Butenandt ’s estrogen (Folliculin) to mice and induces mammary cancer. • Due to the instability of the dosages, as well as the odor, by the late 1930s these formulations are succeeded by products from the urine of pregnant mares. The Canadian version, Premarin (or PREgnant MAres’ uRINe), will become the most popular menopause treatment in the United States. 1937 • Schering patents ethinyl estradiol, now the most widely used contraceptive estrogen. It is also used in menopause treatments such as Pfizer’s Femhrt. 1938 • In an effort to stop Hitler from cornering world estrogen markets, Edward Charles Dodds, a London biochemist and consulting physician to King George, publishes his formula for diethylstilbestrol (known as stilbestrol, and later as DES), a synthetic estrogen, in Nature magazine. In the months after Dodds’s formula is published—free to copy by all comers, effective by mouth, and inexpensive—dozens of drug companies worldwide begin to manufacture it. Dodds soon becomes alarmed at the unproven uses—the drug is prescribed for everything from preventing miscarriage to maintaining youth—and begins a personal crusade to raise awareness of his formula’s dangers. He notes: “Within a few months of the first publication of the synthesis of stilbestrol, the 220 s e a m a n substance was being marketed throughout the world. No long term toxicity tests on animals were done first.” • The Journal of the American Medical Association (JAMA) and Endocrinology publish influential reports on the use of estrogen in menopause , confirming the benefits of the hormone in curbing hot flashes but also warning that long-term use might be carcinogenic. Neither paper suggests that estrogen could delay aging in any way. 1940 • In May, Eli Lilly asks the U.S. Food and Drug Administration (FDA) for permission to market diethylstilbestrol. Lilly’s application papers include a report by Drs. K. K. Chen and P. N. Harris listing studies in mice and rats that show that males as well as females may get breast cancer when administered diethylstilbestrol. Inter-sexuality appears in male rats, mice, and chickens; milk production in animals is reduced, and abortion in cows is observed. • In November, Lilly withdraws its application after the FDA advises that it will be rejected. Ten other companies, including Squibb, Upjohn, Abbott Laboratories, and Sharp & Dohme withdraw their applications for the same reason. 1941 • The companies that wish to market diethylstilbestrol meet in Washington , D.C. What follows is the first blueprint for joint spin-doctoring by the drug companies, and it provides the basis for Big Pharma (Pharmaceutical Research and Manufacturer of America). The group hires Carson P. Frailey, executive vice president of the American Drug Manufacturers Association, to guide them in a strategy. He advises them to enlist doctors from around the country in a letter-writing campaign to the FDA...