Pincus, Djerassi and Oral Contraceptives Bob Weintraub, Director of the Libraries, Sami Shamoon College of Engineering, Beersheva and Ashdod
“More than 100 years ago, W. E. H. Lecky, in his book, made the following observation: ‘The causes which most disturbed or accelerated the normal progress of society in antiquity were the appearance of great men; in modern times they have been appearance of great inventions. ‘The discovery of the Pill was a great invention. And I hope that I have made it clear that it was the result of a major effort by hundreds of men and women driven by a variety of motives, among which, however, the urge of scientific inquiry was always predominant, and so was indeed the role played by Gregory Pincus. As he puts it with modesty with a minimum of rhetoric: ‘The era of oral contraception by ovulation inhibitors appears to have been ushered into existence by the clinical application of our animal studies with progesterone and the gestagenic 19-norsteroids.’” (E. Diczfalusy: J. Steroid Biochemistry, 1979)When Carl Djerassi was asked as to what he considered to be his most important contribution to science, he answered in part as follows: “From a societal point of view, the first synthesis of an oral contraceptive is without doubt the most important. This was almost 45 years ago, October 15, 1951. It’s a very specific date recorded in our lab notebook when we synthesized the steroid that was the active ingredient of oral contraceptives eventually taken by hundreds of millions of people. There are very few synthetic drugs that have been around for forty-some years. I don’t really know if there has been any more important discovery from a societal standpoint during the postwar period.” (in Candid Science, I. Hargittai). Carl Djerassi was the first recipient in 1978 of the Wolf Prize in Chemistry for his work in bioorganic chemistry, application of new spectroscopic techniques, and his support of international cooperation. He has been at Stanford University since 1959. I am grateful to Prof. Djerassi for clarifying for me several points. In 1919 Ludwig Haberlandt, professor of physiology at the University of Innsbruck, implanted the ovaries of a pregnant rabbit under the skin of a non-pregnant one, making it infertile for several months despite frequent coitus. Haberlandt appreciated the significance of his experiment - that a hormone secreted by the corpus luteum inhibited ovulation - and he suggested that a substance with similar biological properties could be the basis for a human oral contraceptive. According to Djerassi, “if there ever was a grandfather of the Pill, Ludwig Haberlandt above all others deserves that honor.
Carl Djerassi was born in 1923 in Vienna to Jewish parents, his father Bulgarian and his mother Viennese. The routine of his family life ended abruptly in 1938 with the Anschluss: “Our second-floor apartment had a long balcony overlooking the Donau Kanal, a branch of the Danube separating the fashionable first Bezirk from the largely Jewish second one. The day after the Anschluss, I crouched behind the balcony’s balustrade to watch the Brown Shirts with the swastika armbands pour across the bridge. In retrospect, it seems strange that I had no foreboding of Hitler’s takeover of Austria.” In 1939 at age 16 Djerassi fled Europe via Bulgaria for the United States, where he was aided by the Hebrew Immigrant Aid Society, known as HIAS. During the Nazi period protests from the Bulgarian people saved the Bulgarian Jews from deportation to death camps. In 1945 Djerassi earned his Ph.D. in Chemistry from the University of Wisconsin with a thesis on the transformation of testosterone into estradiol and related syntheses. In 1949, after working at the Swiss company Ciba in New Jersey, he accepted a position to head a research team at Syntex in Mexico City. Djerassi was to attempt a practical synthesis of cortisone. Syntex was using Mexican Yams as the source of diosgenin as the starting material to synthesize the hormones testosterone and progesterone, needed for therapeutic uses. During the war cortisone was important to the military as it was thought to reduce stress levels in fighter pilots and after the war cortisone was found to have anti-arthritic properties. There was an immense international effort to find a cheaper
synthesis, the number of researchers working on cortisone being greater than that of any other medical project since the development of penicillin. In 1951 Djerassi’s group achieved the first chemical synthesis of cortisone from a plant source, diosgenin, but about the same time the Upjohn Company of Kalamazoo patented an easier to achieve synthesis of cortisone starting from progesterone by a fermentation process. The impact of the massive research effort on cortisone and consequently on that of steroids in general laid the foundation for advances in contraceptive steroid work that was soon to follow. Djerassi and his colleagues worked on novel steroid compounds. “Initially, we were not focusing on contraception when we developed an oral progestational compound. Our research was undertaken because at that time progesterone was used clinically for treatment of menstrual disorders, for certain conditions of infertility, and at a research level, for the treatment of cervical cancer in women by local administration of a high dose of the hormone. Such administration was extremely painful because it involved injecting a fairly concentrated oil solution of large amounts of progesterone into the cervix. What drove us was the desire to create a more powerful progestational compound that would be active orally. “ In 1951 Syntex filed a patent based on the work of Djerassi’s group for the compound 19-nor-17α-ethynyltestosterone, known as norethisterone or norethindrone. Nor indicates a missing CH group. In
1953 a patent was filed by G. D. Searle Laboratories of Skokie, Illinois, for the synthesis and uses of norethynodrel, prepared by Dr. Frank B. Colton. These two compounds were several times as potent as the natural hormone progesterone and could be administered orally. Both compounds were chemically similar and both Djerassi and Colton did not see their potential for contraceptive purposes. Djerassi’s compound was stable in the stomach, while Colton’s compound is largely converted into Djerassi’s by the action of stomach acids.
Gregory Pincus (1903-1967):
Gregory Goodwin Pincus was born in Woodbine, New Jersey, to Russian Jewish immigrants.Woodbine was organized in 1891 and was one of the agricultural settlements founded in the United States by Baron de Hirsch as a haven for Jews from Eastern Europe. Pincus’ father was at one time the editor of the The Jewish Farmer. Pincus earned his doctorate in biology at Harvard in 1927 and joined the faculty in 1930. J. Segal (Pincus’ friend and colleague): “When he took up Margaret Sanger’s challenge in 1950 to develop an oral contraceptive, he had already achieved in vitro fertilization of rabbit eggs, foreshadowing later successes in assisted human reproduction that have enabled tens of thousands of couples to overcome infertility. The controversy generated by this pioneering work probably cost him tenure at Harvard, prompting his move to Clark University in Worcester, Mass. Screaming headlines about “test-tube babies” and “fatherless rabbits” had elicited anti-science and anti-Semitic attacks. This notoriety may have made Harvard too uncomfortable to keep Pincus on the faculty, but it did not prevent the University from citing his work as one of Harvard’s outstanding scientific achievements in its 300-year history. At Clark, Pincus teamed up with Hudson Hoagland, another scientific pioneer-explorer, to create the Worcester Foundation for Experimental Biology in 1944. Pincus attracted Cambridge-trained physiologist M.C. Chang to the foundation.” (Popul Today, 2000)Pincus: “In 1937, Makepeace, Weinstein, and Friedman noted the effectiveness of progesterone as an ovulation inhibitor in the rabbit, but the logical extension of this observation into a more intensive study of the nature of the progesterone derivatives and the putative metabolites were not reported by us until 1953. Why this “logical extension” occurred after a latent period of approximately 16 years is a question concerning which we have raised some speculation. .In our case, the special demands of “war” research
accounted for a shift of interest to studies of adrenocortical function, particularly in relation to physical and mental stress, and this interest has continued to a greater or lesser degree. Indeed, World War II probably accounts for the lapse observed generally. In our case, the increase of activity as indicated by publications from 1950 on has been due to two overtly ascertainable factors: (a) a visit from Mrs. Margaret Sanger in 1951 and (b) the emergence of the appreciation of the importance of the ‘population explosion’. At the time of her visit, Mrs Sanger’s interest in the world-wide dissemination of information on birth control was at a high tide. Her experience as President of the International Planned Parenthood Federation had made her aware of the deficiencies of conventional contraceptive methods, particularly in underdeveloped areas of the world. Her hope, expressed to us, was that a relatively simple and fool-proof method might be developed through laboratory research. Drs. Chang and Pirie and I had already had some experience with hyaluronidase inhibitors in the rabbit, but we had found that such potent inhibitors could act only on direct contact with sperm and that there was no possibility of an effect by parenteral administration. Although some preliminary experiments by the late Dr. Abraham Stone had indicated that at least one of these inhibitors might be quite active as the component of an intravaginal preparation in the human, the limitations to its use still appeared to be rather formidable. Accordingly, Dr. Chang and I drew up a modest project proposal that received support under a grant from the Planned Parenthood Federation of America. Work under this grant resulted in a paper on the rabbits mentioned above and in the finding that the compounds that we found to be potent as ovulation inhibitors in the rabbit were also quite active as antifertility agents in the rat. “The rabbit ovulates within ten hours of mating. The rat ovulates periodically making the monitoring of experiments more difficult but give the findings added relevance to the reaction in the human female”. Pincus: “. the definition of progestational activities is essential to the understanding of their roles in the regulation of reproductive processes. A true progestin may be defined as a compound which acts upon the uterus to induce endometrial proliferation and myometrial activity characteristic of pregnancy and which maintains pregnancy in ovariectomized animals carrying fertilized ova or fetuses; both of these functions may be enhanced by the committan use of small amounts of estrogen, but the progestin alone should be sufficient at adequate dose.”Gregory Pincus teamed up with Dr. John Rock, Professor of Gynecology at Harvard, to collaborate on human testing and clinical trials. Rock was interested in progestins as a cure for certain types of infertility and Pincus was interested in progestins as a means to prevent pregnancy. Pincus’ group screened over 200 synthetic compounds for oral progestin activity. At about this time two synthetic steroids became available for testing, each of which was claimed to be orally effective for menstrual cycle regulation. One was norethindrone from Syntex prepared by Carl Djerasi and the other norethynodrel from G.D. Searle, prepared by Dr. Frank Colton. Pincus recognized their value for use as oral contraceptives. In 1955 Pincus reported their preliminary results on the possibility of using progestational compounds for human oral contraception. Following clinical trials, in 1957, the U.S. Food and Drug Administration (FDA) approved the use of Syntex’s norethindrone and of Searle’s norethynodrel for oral treatment of menstrual disorders and for certain conditions of infertility. In 1960, the FDA approved the use for oral contraception, Searle’s norethynodrel (under the trade name Enovid) and two years later, Syntex’s norethinodrone (under the trade name Ortho-Novum). Pincus (1965): Birth control and the allied areas of sexual physiology and sexual behavior have long been battlegrounds of opinion-voicers. They have suffered from clashes among differing culture
patterns, theologies, moralities, even politics. These struggles still continue, but they are being more and more delimited by the findings of science. Objective appraisal is surely but slowly replacing heated partisanship.The mystery and wonder of conception becomes describable in terms of gamates and their movements, in terms of fertilization reactions and the operation of replication mechanisms, in terms of oviduct chemistry and hormonal regulation. In each of these is also mystery and wonder, for there is still more to discover than we now know. But in the blazing or flickering light of what we do know a priori judgements and willful prejudices fade. And our considered and tested knowledge offers a firm basis for what we can and should do.
Stamp issued by the Austrian Post Office, in honor of Carl Djerassi on his 80th birthday. For more information on the stamp see:Autobiography of a Stamp by Carl Djerassi, Philatelia Chimica et Physica 27, 68, 2005. http://www.cpossu.org/Djerassistamp.pdf
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