The History of Steroidal Contraceptive Development: The Progestins

THE HISTORY OF STEROIDAL CONTRACEPTIVE DEVELOPMENT: THE PROGESTINS NICOLA PERONE* The introduction of oral contraception in 1960 was not the result of one person's fortuitous discovery as happened with X rays or penicillin. It was, rather, the product of small accretions of knowledge resulting from the effort, talent, and determination of many people over a period of years. The Chemical History of the Pill The chemical history of the pill begins with the isolation of progesterone in May 1933 by Corner and Allen [I]. With the help of Dr. Hickman from the research laboratory of the Eastman Kodak Company, they used high-vacuum distillation of the oils extracted from corpora lutea to isolate the hormone in a crystalline form which they named progestin. Before the end of that year, Wintersteiner and Allen [2] determined the structural formula of the hormone (C21 H30 O2). This admittedly was not difficult, since the structural formula of pregnanediol was known from previous work by Butenandt [3]. As Allen later recalled [4], the correct structural formula of progesterone had originally been sketched on a napkin during a lunch with William Strain, long before the definitive structural proof was furnished [2, 4]! In the summer of 1934 the isolation of crystalline progesterone hormone was announced also by Butenandt and Westfall in Danzig [5], by Slotta et al. [6] in Breslau, and in Switzerland by Hartman and Wettstein [7]. A short time later Butenandt and Schmidt [3] converted pregnandiol to progesterone, and Fernholz succeeded in synthesizing progesterThe author thanks R. E. Marker, C. Djerassi, F. Colton, M. C. Chang, C. Ramon-Garcia, E. Rice-Wray, and J. W. Goldzieher for their helpful comments. *Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Texas, Health Science Center at Houston. Correspondence address: 1631 North Loop West, Suite 560, Houston, Texas 77008.© 1993 by The University of Chicago. All rights reserved. 0031-5982/93/3603-0833$01.00 Perspectives in Biology and Medicine, 36, 3 ¦ Spring 1993 347 one from stigmasterol. This international race for the isolation of the hormone did not proceed without incidents. [4] In December of 1934 Wintersteiner received a letter from Slotta and Butenandt in which he was informed that the two had agreed to call the new hormone luteosterone , unaware of the previous name progestin given by Allen and Corner in 1930. In his answer Corner suggested as a compromise to name the new hormone progesterone or progestenone. The question of the name for the new hormone was eventually settled in 1935 during a garden party in London given by Sir Henry Dale, and attended by Allen, Butenandt, and Slotta. The conference had been specifically organized to collect standard samples of progesterone, estradiol, estradiol benzoate , and androsterone, and to define an international unit for each of these sex steroids. Sir Henry was able to convince Butenandt and Slotta that progesterone was, after all, a composite of Allen's progestin and their luteo-sterone, and thus an acceptable compromise. A few years later (1945) an international legal controversy arose. Percy Julian, a chemist with the Glidden paint company, had been making progesterone from the oils used in the manufacture of paint. The Schering Company filed suit against Glidden for infringement of the German patent, based on Butenandt's work. When told of the suit by Julian, Allen started to prepare for the trial by diligently reviewing his notes, which clearly indicated his priority in the isolation of the hormone . The contest was eventually settled out of court. The early production of progesterone was extremely complex and laborious and the resulting product prohibitively expensive. Butenandt required a ton of cholesterol, obtained from the brains and spinal cords of cattle and the grease from sheep's wool, to obtain 20 lbs of starting material from which commercial quantities of progesterone could be produced. Progesterone, when available, was quoted at $l,000/gm. What opened the door for the development of the pill were two advances in steroid chemistry: the introduction of a new technique that changed progesterone from an expensive rarity to the cheapest of all steroid hormones, and the subsequent modification of the progesterone molecule to make it effective orally. The first of these two discoveries...