0013-7227/91/1293-1144$03.00/0 Endocrinology Copyright © 1991 by The Endocrine Society

Vol. 129, No. 3 Printed in U.S.A.

Memoir—The Beginning of Oral Contraceptives As we filed into the conference room at the Searle Laboratories in Skokie, Illinois, none of us realized then that we were participating in an historical occasion, or that we were starting a revolution. The meeting that followed had been called by I. C. Winter, Medical Director of Searle, later Vice President. Winter, a physician who also held a doctorate in pharmacology, was temporary Director of Biological Research while the company searched for a senior biologist, a position later filled by Victor A. Drill. During the meeting, Winter, or I. C. as he was known, explained that he had just returned from a meeting where, in discussion with various physicians, he had identified a medical need for an orally effective progestational agent to be used therapeutically for habitual abortion, endometriosis, dysmenorrhea, and control of irregular menstrual cycles; he suggested that we go find one. Searle was a propitious place for such an effort—the research division was already committed to a steroid program. It was the summer of 1952. The structure of cortisone had recently been defined by Kendall and Hench had shown its therapeutic potential in arthritis; Reichstein, the Taits, and others were surveying the adrenal effluent for other active compounds; the gonadal steroids had been defined structurally during the 1930s, but the second World War had prevented extensive therapeutic exploitation of these agents. However, estrogens, both natural steroids and synthetic steroid analogs and testosterone were used for various deficiency states and injectable progesterone was employed in an effort to salvage pregnancies in women who miscarried regularly. Pharmaceutical scientists were actively searching for corticoids, for new estrogens, particularly nonsteroidal agents related to stilbestrol, and anabolic agents that had the metabolic effects of testosterone, but lacked its masculinizing effects. Searle was one of the more aggressive companies in this regard, building up to a steroid group of some 40 synthetic organic chemists, supported by a series of endocrinologists that started with Francis J. Saunders and me. Initially, Saunders and I tried to cover all bases, but we were soon joined by Lee G. Hershberger and Charles M. Kagawa from R. K. Meyer's Received March 25,1991. "Remembrance," articles discuss people and events as remembered by the author. The opinion(s) expressed are solely those of the writer and do not reflect the view of the Journal or The Endocrine Society.

lab at Wisconsin and Richard L. Elton, a student of M. X. Zarrow from Purdue. The final organization had Saunders working primarily on the androgens, Hershberger on glucocorticoids, Kagawa on mineralocorticoids, Elton on progestagens, and me on estrogens and their antagonists. Significant input to the program was also provided by Gregory Pincus of the Worcester Foundation who functioned as a consultant. As a result of this burgeoning steroid program, Searle Research was ready when Frank Colton synthesized norethynodrel in 1952. The year before Carl Djerassi of Syntex had synthesized norethindrone, but at the time Syntex was a small Mexican chemical company lacking in biological or medical departments, and was not prepared rapidly to exploit newly prepared compounds. Norethynodrel and a range of other structural relatives of 19-nortestosterone were studied in the Skokie Laboratories and were submitted to the Worcester Foundation for evaluation. Work carried out at Worcester was summarized by Pincus and associates in 1956, while Searle work was presented by Drill and Riegel at the Laurentian Hormone Conference in 1957. By the mid-1950s ideas about the therapeutic use of progestagens had expanded and their potential as contraceptives was recognized. Clinical evaluation of norethynodrel as a contraceptive was actively pursued by John Rock in Boston and by Celso-Ramon Garcia and Edris Rice-Wray in Puerto Rico, while Edward T. Tyler was evaluating norethindrone in Los Angeles. It soon became apparent that progestagens alone were not satisfactory as contraceptives and that an estrogen was also needed to control abnormal uterine bleeding. The incorporation of estrogens in oral contraceptive formulations was the result of clinical observations and bioassays carried out in my laboratory. This was, of course, before the identification of receptors, a decade later, or the development of RIA techniques: quantification was based on uterine growth or vaginal cornification in rodents, but these assays were superior to chemical techniques available at the time. Understanding the need for estrogen is itself an interesting story. The early samples of norethynodrel and norethindrone were contaminated with the 3-methyl ether of ethynyl estradiol, now known as mestranol, an intermediate in the synthesis of norethynodrel, which itself was the penultimate intermediate in the synthesis 1144

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REMEMBRANCE

of norethindrone. As purification of the progestagen proceeded, the incidence of intermenstrual bleeding in women increased leading to the incorporation of fixed amounts of first mestranol and later ethynyl estradiol in the final preparation. It was I. C. Winter who fixed on the contraceptive combination of 0.150 mg mestranol with 9.85 mg norethynodrel, which was marketed by Searle in 1960 as Enovid. Two years later norethindrone at 10 mg with mestranol at 0.06 mg was marketed by Ortho under license by Syntex. This was soon followed by a spate of preparations that combined various progestagens with mestranol or ethynyl estradiol and the race to reduce dose of first the progestagen and later the estrogen began. In the U.S. over the next decade Syntex released norethindrone/mestranol, Parke Davis, norethindrone acetate and ethynyl estradiol, Searle ethynodiol diacetate and mestranol, Wyeth norgestrel and EE, while Upjohn and Lilly marketed preparations based on acetoxyprogesterone derivatives. In the 30 years since Enovid was first marketed, the progestagens related to 19-nortestosterone have continued to dominate the oral contraceptive market while

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those based on progesterone itself have disappeared in the U.S. at least. Norethynodrel, also, has vanished from the oral contraceptive market: as early as the late 1950s and early 1960s it was apparent that the conjugated form, norethindrone, was superior to its A5(10) analog. Newer progestagens such as desogestrel, norgestimate, and gestodene are norgestrel derivatives, basically nortestosterones, but their long-term success remains to be determined. However, that research conference in 1952 led to the first oral contraceptive, which sparked the "sexual revolution" and permitted aspects of the feminist movement as we know it now. It was a good meeting—I'm glad I was there. Richard A. Edgren Director Scientific Affairs Syntex Laboratories, Inc. References 1. Pincus G, Chang MC, Zarrow MX, Hafez ESE, Merrill A 1956 Studies of the biological activity of certain 19-nor steroids in female animals. Endocrinology 59:695-707 2. Drill VA, Riegel B 1958 Structural and hormonal activity of some new steroids. Recent Prog Hormone Res 14:29-67

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Memoir--the beginning of oral contraceptives.

0013-7227/91/1293-1144$03.00/0 Endocrinology Copyright © 1991 by The Endocrine Society Vol. 129, No. 3 Printed in U.S.A. Memoir—The Beginning of Ora...
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