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Chemical birth of the pill

2006; Elsevier BV; Volume: 194; Issue: 1 Linguagem: Inglês

10.1016/j.ajog.2005.06.010

1097-6868

Carl Djerassi,

Publishing no less than 2 autobiographies—first, Steroids Made It Possible,1Djerassi C. Steroid research at Syntex: “the pill” and cortisone.Steroids. 1992; 57: 631-641Crossref PubMed Scopus (74) Google Scholar, 2Djerassi C. This man's Pill: reflections on the 50th birthday of the Pill. Oxford University Press, Oxford2001Google Scholar, 3Djerassi C. Steroids made it possible.Washington (DC): American Chemical Society; 1990.Google Scholar addressed to professional chemists, and then The Pill, Pygmy Chimps, and Degas' Horse,4Djerassi C. The Pill, pygmy chimps, and Degas' horse. Basic Books, New York1992Google Scholar written for a general, nonscientific audience—has taught me an important lesson: autobiography is a special genre of fiction because of its heavy component of automythology. Hence, in this account of the chemical birth of “the Pill,” I shall try, as far as possible, to resist the siren song of memory and instead cite the published record. Fortunately, the early chemical contributions from Syntex—at that time a minute chemical company in Mexico City—to the development of the Pill are particularly rich in that respect. To my knowledge, at no time in the history of organic chemistry has industry contributed so much to the published (as contrasted to the more conventional patent) record of a chemical subdiscipline as it did during the heyday of steroid chemistry—the mid 1930s to the late 1950s. Much of the proclivity for rapid publication of industrial steroid research, at least in North America, was stimulated by the aggressive and progressive publication policy initiated at Syntex in Mexico City. As a professional bigamist, having spent over 3 decades simultaneously in industry and academe, I have no reason to favor one over the other. Rather, I cite as authority for the above ode to the academic prowess of the pharmaceutical industry in steroid chemistry none other than Louis F. Fieser (1899-1977), the senior author of this field's bible, Steroids.5Fieser L.F. Fieser M. Steroids. Reinhold, New York1959Google Scholar At one of the fabulous Gordon Conferences on Natural Products in the 1950s, Fieser presented an analysis (Table I) of the institutional origin of the 2543 literature references cited in the latest (1959) edition of his opus magnum.Table IInstitutional origin of references in Steroids5Fieser L.F. Fieser M. Steroids. Reinhold, New York1959Google ScholarUniversities1465Research institutes449Industrial laboratories629 Syntex192 CIBA (Basel)146 Merck81 Squibb53 British Drug Houses38 Schering (Berlin)36 Upjohn23 Roche (Basel)23 Others38 Open table in a new tab As shown in Table I, Syntex—by far the youngest and smallest entrant in the Fieser Steroids competition, and the only one from a developing country—“won” hands down, with nearly 30% of all industrial citations referring to Syntex research performed in Mexico City in less than a decade. This unique and never again repeated example in the pharmaceutical field of a major research player from a scientific third-world country appearing out of nowhere in the international big leagues is, in my opinion, worth emphasizing, especially because it proved to be the site of the first synthesis of a steroid oral contraceptive. I arrived at Syntex in the late autumn of 1949, just around my 26th birthday, to assume the position of associate director of chemical research. At that time, my American colleagues considered me mad to move to a country that had only generated the barest of blips on the radar screen of international chemical journals. These blips had consisted mostly of some long articles on steroidal sapogenins by Russell E. Marker in the Journal of the American Chemical Society6Marker R.E. Lopez J. Steroidal sapogenins. No. 160. The conversion of pseudosapogenins to sapogenins and neosapogenins.J Am Chem Soc. 1947; 69 (Subsequent 11 articles in same issue (No. 10) of J Am Chem Soc.): 2373-2375Crossref PubMed Scopus (2) Google Scholar that, although identified as originating from the Hotel Geneve, Mexico City, were (correctly) interpreted as the swan song of a maverick gringo chemist who was in the process of retiring permanently from the chemical scene before having reached the age of 50. I knew, of course, that Marker and his discovery of a simple degradation of the steroidal sapogenin side chain had been the raison d'être of Syntex, because his discovery formed the basis of a simple and cheap process of producing progesterone in 4 steps from the sapogenin diosgenin, which in turn could be isolated from wildly growing Mexican yams. This story is covered in detail in my 2 autobiographies,3Djerassi C. Steroids made it possible.Washington (DC): American Chemical Society; 1990.Google Scholar, 4Djerassi C. The Pill, pygmy chimps, and Degas' horse. Basic Books, New York1992Google Scholar but for me personally, Marker (whom I did not meet until 20 years later) was at that time only important in that he made me focus on steroidal sapogenins as starting materials for the synthesis of estrone and estradiol—steroid hormones that had not been part of his synthetic repertoire. Even though I came to Syntex to lead, together with George Rosenkranz, a program on the synthesis of cortisone from diosgenin, the seeming sideline of estrogen synthesis from diosgenin preoccupied me first. In less than 3 months we succeeded in accomplishing this ambitious aim and published the results in 3 papers in the Journal of the American Chemical Society7Kaufmann S. Pataki J. Rosenkranz G. Romo J. Djerassi C. Partial synthesis of 6-dehydroestrone and equilenin.J Am Chem Soc. 1950; 72: 4531-4534Crossref Scopus (35) Google Scholar, 8Djerassi C. Rosenkraz G. Romo J. Kaufmann S. Pataki J. A new partial synthesis of the estrogens.J Am Chem Soc. 1950; 72: 4534-4540Crossref Scopus (65) Google Scholar, 9Djerassi C. Rosenkranz G. Romo J. Pataki J. Kaufmann S. The dienone-phenol rearrangement in the steroid series: synthesis of a new class of estrogens.J Am Chem Soc. 1950; 72: 4540-4544Crossref Scopus (20) Google Scholar within my very first year at Syntex. Interestingly, this genesis of estrogens by partial aromatization of androgens was not only 1 of our more notable early research triumphs, but it also turned into the impetus that led us in a fairly straight path to the first synthesis of an oral contraceptive in the same year (1951) in which we also announced the first synthesis of cortisone from a plant raw material—at that time arguably the hottest problem in synthetic organic chemistry. The utilization at Syntex in the middle 1940s of Marker's diosgenin degradation for the industrial production of progesterone was important because that hormone had already found medical applications in the treatment of menstrual disorders and spontaneous abortion. One of the dogmas of steroid (Figure 1) chemistry at that time10Ehrenstein M. Synthesis of steroids of the progesterone series.Chem Rev. 1948; 42: 457-489Crossref PubMed Scopus (5) Google Scholar was that almost any chemical alteration of the progesterone molecule would either diminish or destroy its biologic activity, in marked contrast to the estrogenic steroid hormones, in which substantial chemical modification retained or even increased estrogenic potency. In 1944, Maximilian Ehrenstein, an emigrant from Nazi Germany, then working at the University of Pennsylvania, published an article with Willard M. Allen11Allen W.M. Ehrenstein M. 19-Norprogesterone, a physiologically active lower homolog of progesterone.Science. 1944; 100: 251-252Crossref PubMed Scopus (14) Google Scholar that was mostly overlooked, but had made a deep impression on me while still a graduate student. By an extremely laborious series of steps, Ehrenstein had transformed the naturally occurring steroid cardiac stimulant strophanthidin into 8 mg of oily impure “19-norprogesterone,” sufficient only for biologic testing in 2 rabbits. In 1 of them his compound had displayed higher progestational activity than the parent hormone. A positive test in 1 animal of 2 could, of course, have been just a fluke. What made these results so unusual was what that “19-nor” in the compound's name signified. It meant that Ehrenstein had removed carbon atom number 19 (between rings A and B of the steroid skeleton depicted in Figure 1) from the most inaccessible site of the steroid molecule to replace it with a hydrogen atom. On paper—or in words—the change sounds trivial. Given the state of the art of organic synthesis at the time, however, this was so difficult an operation that it had required several years for completion. Moreover, if the biologic results were real, this observation demolished the previous assumptions about the inviolability of the progesterone structure. But there was another problem: this oily product was, as I indicated, impure: a mixture of at least 3 “stereoisomers”—molecules that, although structurally identical, were, like mirror images, as alike—and fundamentally different—as one's left and right hand. Which one of the components, if any, was responsible for the putative progestational activity? It took 7 years for someone to come up with an answer. Our ability to do so led us almost straight to the Pill. From a technical standpoint, I believed the time was ripe to follow-up on Allen and Ehrenstein's lead. Using various chemical methods developed as part of our estrogen synthesis7Kaufmann S. Pataki J. Rosenkranz G. Romo J. Djerassi C. Partial synthesis of 6-dehydroestrone and equilenin.J Am Chem Soc. 1950; 72: 4531-4534Crossref Scopus (35) Google Scholar, 8Djerassi C. Rosenkraz G. Romo J. Kaufmann S. Pataki J. A new partial synthesis of the estrogens.J Am Chem Soc. 1950; 72: 4534-4540Crossref Scopus (65) Google Scholar, 9Djerassi C. Rosenkranz G. Romo J. Pataki J. Kaufmann S. The dienone-phenol rearrangement in the steroid series: synthesis of a new class of estrogens.J Am Chem Soc. 1950; 72: 4540-4544Crossref Scopus (20) Google Scholar from diosgenin as well as methodology perfected by the Australian chemist, Arthur J. Birch12Birch A.J. Hydroaromatic steroids: part 1, 10-Nortestosterone.J Chem Soc. 1950; (For biologic activity, see: Birch AJ. Homocyclic compounds. Ann Rept Prog Chem Soc Lond 1950;47:177-219): 367-368Crossref Scopus (27) Google Scholar (subsequently a long-term Syntex consultant), enabled us in 195113Djerassi C. Miramontes L. Rosenkranz G. 19-Norprogesterone, a potent progestational hormone.J Am Chem Soc. 1953; 75 (Preliminary Communication: i. 1951;73:3540): 4440-4442Crossref Scopus (17) Google Scholar to synthesize pure, crystalline 19-norprogesterone (Figure 2), which, when assayed in rabbits at Endocrine Laboratories in Wisconsin, was found to be 4 to 8 times as active as natural progesterone. In other words, Allen and Ehrenstein's observation with an oily mixture tested in 1 rabbit was more than confirmed: replacement of carbon atom 19 by 1 hydrogen had produced the most active progestational steroid known at that time. Because progesterone itself is practically inactive when administered orally, we immediately set out to synthesize a potent, orally effective, progestational agent based on an earlier lead from Hans H. Inhoffen's laboratory at Schering A.G. in Berlin. In 1938, his group14Inhoffen H.H. Logemann W. Hohlweg W. Serini A. Untersuchungen in der sexualhormon-Reihe.Chem Ber. 1938; 71: 1024-1032Crossref Scopus (43) Google Scholar had introduced an acetylene substituent into position 17 of estradiol and of testosterone (Figure 2), respectively. The resulting product in the estrogenic series, 17α-ethynylestradiol (Figure 2), proved to be highly active by the oral route, and some 3 decades later became 1 of the estrogenic components of the combination oral contraceptive pill. Even more surprising were the results with the transformation product, 17α-ethynyltestosterone14Inhoffen H.H. Logemann W. Hohlweg W. Serini A. Untersuchungen in der sexualhormon-Reihe.Chem Ber. 1938; 71: 1024-1032Crossref Scopus (43) Google Scholar (Figure 2), in the androgenic series, because this substance now exhibited perceptible progestational, rather than just androgenic, activity by the oral route. This was precisely the hint we needed in the summer of 1951. Having demonstrated conclusively that removal of the angular 19-methyl group of progesterone greatly increased biologic activity by the injectable route, we decided to ignore Birch's report12Birch A.J. Hydroaromatic steroids: part 1, 10-Nortestosterone.J Chem Soc. 1950; (For biologic activity, see: Birch AJ. Homocyclic compounds. Ann Rept Prog Chem Soc Lond 1950;47:177-219): 367-368Crossref Scopus (27) Google Scholar that such a chemical change supposedly led to diminished activity in the testosterone series, and proceeded to remove the 19-methyl group of 17α-ethynyltestosterone (generically known as ethisterone) to determine whether such a molecular alteration also increased oral progestational activity. The first synthesis of 19-nor-17α-ethynyltestosterone (Figure 2), subsequently known as norethisterone or norethindrone, was completed in our laboratory on 15 October 1951, which can thus be called the chemical birthday of the Pill. Figure 3 depicts a portion of page 114 from the laboratory notebook of Luis Miramontes, a young Mexican chemist, who was then performing his BS thesis work at Syntex under my supervision. The page contains the complete chemical and spectroscopic characterization of norethindrone. The product was immediately submitted to a commercial laboratory (Endocrine Laboratories, Madison, Wisc) for biologic evaluation and was found to be the most active, orally effective progestational hormone described up to that time. Our patent application (Figure 4) was filed on November 22, 1951,15Djerassi C, Miramontes L, Rosenkranz G. US Patent 2,744,122. (November 22, 1951).Google Scholar and the chemical results, together with the biologic activity, were reported by me at the April 1952 national meeting of the American Chemical Society's Division of Medicinal Chemistry16Djerassi C, Miramontes L, Rosenkranz G. 19-Nor-17α-ethynyltestosterone and 19-nor-17α-methyltestosterone. [Abstracts, p.18-JG.] Division of Medicinal Chemistry, American Chemical Society Semi-annual Meeting, Milwaukee, Wisc, 1952.Google Scholar held in Milwaukee, the full article with complete experimental details appearing in the Journal of the American Chemical Society.17Djerassi C. Miramontes L. Rosenkranz G. Sondheimer F. Synthesis of 19-nor-17α-ethynyltestosterone and 19-nor-17α-methyltestosterone.J Am Chem Soc. 1954; 76: 4092-4094Crossref Scopus (99) Google Scholar We supplied our material to various investigators, including Roy Hertz of the National Cancer Institute, Bethesda, Md; Alexander Lipschutz in Santiago, Chile; Gregory G. Pincus of the Worcester Foundation for Experimental Biology in Shrewsbury, Mass; Robert Greenblatt of the Medical College of Georgia; and Edward Tyler in Los Angeles. In fact, few people now recall that Tyler18Tyler E.T. Comparative evaluation of various types of administration of progesterone.J Clin Endocrinol Metab. 1955; 15: 881Google Scholar of the Los Angeles Planned Parenthood Center was the very first person—before Pincus, John Rock, and other early pioneers—to have presented in November 1954 clinical results with an orally active 19-nor steroid, specifically norethindrone, for the treatment of various menstrual disorders and fertility problems.Figure 4Our patent application filed November 22, 1951 and issued May 1, 1956.View Large Image Figure ViewerDownload (PPT) On August 31, 1953, well over a year after our first public report,16Djerassi C, Miramontes L, Rosenkranz G. 19-Nor-17α-ethynyltestosterone and 19-nor-17α-methyltestosterone. [Abstracts, p.18-JG.] Division of Medicinal Chemistry, American Chemical Society Semi-annual Meeting, Milwaukee, Wisc, 1952.Google Scholar Frank Colton of G. D. Searle and Co. filed a patent19Colton FB. US Patent 2,725,389. August 31, 1953.Google Scholar for the synthesis of the double bond isomer of norethindrone. As shown in Figure 5, mild treatment of Colton's isomer, named norethynodrel, with acid, or just human gastric juice, converts it to a large extent into Syntex's norethindrone.20McGinty D.A. Djerassi C. Some Chemical and biological properties of 19-nor-17α-ethynyltestosterone.Ann NY Acad Sci. 1958; 71: 500-515Crossref PubMed Google Scholar, 21Arai K. Golab T. Layne D.S. Pincus G. Metabolic fate of orally administered norethynodrel in rabbits.Endocrinol. 1962; 71: 639-648Crossref PubMed Scopus (20) Google Scholar, 22Murugesan K. Hingorani K. Laumas K.R. In vitro metabolism of tritiated norethynodrel in the human endometrium and myometrium.Acta Endocrinol. 1973; 74: 576-591PubMed Google Scholar Is synthesis of a patented compound in the stomach an infringement of a valid patent? I urged that we push this issue to a legal resolution, but Parke-Davis, our American licensee, did not concur. Searle was selling a very important antimotion sickness drug, Dramamine, which contained Parke-Davis's antihistamine Benadryl. As already indicated, Gregory Pincus was one of the endocrinologists to whom we had supplied our orally active norethindrone for more detailed biologic scrutiny. Among the many steroids tested by his group at the Worcester Foundation for ovulation inhibition,23Pincus G. Chang M.C. Hafez E.S.E. Zarrow M.X. Merril A. Effects of certain 19-nor steroids on reproductive processes in animals.Science. 1956; 124: 890-891Crossref PubMed Scopus (32) Google Scholar norethindrone and norethynodrel were found to be the 2 most promising candidates. Pincus, who was a consultant for Searle, selected the Searle compound for further work, whereas Syntex, not having any biologic laboratories or pharmaceutical marketing outlets at that time, licensed Parke-Davis to pursue the Food and Drug Administration (FDA) registration and market the product in the United States. It was only after 1957, when both norethindrone and norethynodrel had entered the market as drugs for noncontraceptive gynecologic purposes, that the paths of the 2 companies diverged. The Syntex-sponsored contraceptive trials with norethindrone were conducted first by Tyler18Tyler E.T. Comparative evaluation of various types of administration of progesterone.J Clin Endocrinol Metab. 1955; 15: 881Google Scholar and subsequently by Joseph W. Goldzieher in San Antonio, Texas, and other groups, but Parke-Davis suddenly chose not to pursue these results through the FDA-approval process, because of possible religious backlash, and returned the contraceptive marketing license to Syntex. In turn, they then chose the Ortho Division of Johnson & Johnson, a company with a long-standing commitment to the birth-control field. These negotiations with Ortho and the subsequent need to repeat certain biologic studies that Park-Davis was unwilling to hand over to Ortho caused a delay of nearly 2 years before Syntex's norethindrone received FDA approval for contraceptive indications, whereas norethynodrel had obtained the FDA go-ahead sign in 1960. In the end, such a delay was probably a blessing in disguise, because the initial clinical dosage of norethynodrel was exceptionally high (10 mg/d). By 1964, 3 companies—Ortho, Syntex (under its own label after having established its American branch in Palo Alto, Calif after I had moved to Stanford University), and Parke-Davis (having changed their mind after realizing that no Catholic-inspired boycott had developed)—were marketing 2.0-mg doses of Syntex's norethindrone (or its acetate), which by then had become the most widely used active ingredient of the Pill. There is no question that Searle's norethindrone double-bond isomer, norethynodrel, was the first steroid active ingredient of an FDA-approved contraceptive pill, and that the company deserves enormous credit for marketing the product in 1960, despite a possible backlash by consumer opponents of contraception. But what about the fact that this substance was synthesized at least a year and a half after Syntex's synthesis of norethindrone and at least a year after my first public report16Djerassi C, Miramontes L, Rosenkranz G. 19-Nor-17α-ethynyltestosterone and 19-nor-17α-methyltestosterone. [Abstracts, p.18-JG.] Division of Medicinal Chemistry, American Chemical Society Semi-annual Meeting, Milwaukee, Wisc, 1952.Google Scholar and disclosure of its high oral progestational activity? Given the extraordinary importance of these steroids, why did Colton never disclose any of that chemical work in the peer-reviewed literature? Why did Gregory Pincus, one of the greatest entrepreneurs and most important figures in the early days of oral contraception, and the person most responsible for persuading G. D. Searle to pursue the commercialization of norethynodrel, make not the slightest reference in his opus magnum, “The control of fertility”,24Pincus G. The control of fertility. Academic Press, New York1965Crossref Google Scholar to any chemist (not even Searle's Frank Colton) or to how the active ingredient of the Pill actually arrived in his laboratory? The 19-norsteroids studied by Pincus23Pincus G. Chang M.C. Hafez E.S.E. Zarrow M.X. Merril A. Effects of certain 19-nor steroids on reproductive processes in animals.Science. 1956; 124: 890-891Crossref PubMed Scopus (32) Google Scholar, 24Pincus G. The control of fertility. Academic Press, New York1965Crossref Google Scholar and eventually making the Pill a reality did not occur in nature, nor did he purchase them in a drugstore. Was this just a reflection of the low opinion Pincus and other biologists had of the role chemists play in the development of a new drug? A partial answer to this question is provided by the records of an unusual session held Friday morning, May 5, 1978, at a closed 2-day session on “Historical Perspectives on the Scientific Study of Fertility” under the auspices of the American Academy of Arts and Sciences. The purpose of the meeting was to have a free-flowing dialogue among some of the key scientists who had been active in the field of fertility in the United States during the previous 40 years to collect a record that historians of science might draw on in the future. The scientific co-chairman of the Boston Academy's May 1978 meeting was Roy O. Greep, a distinguished endocrinologist at Harvard University, who had known personally most of the actors in this play. Another key participant was Oscar Hechter, who for many years had been senior scientist of the Worcester Foundation for Experimental Biology. Though not directly involved in the development of oral contraceptives, he had been an intimate collaborator of Gregory Pincus. James Reed of Rutgers University in New Jersey, was a historian studying the birth control movement in America. The unedited transcript of that session reads awfully: Nouns do not match verbs, tenses get mixed, punctuation is lost, and many words are misspelled or appear to be inaudible. Nevertheless, one gets a real flavor of excited human dialogue and interruptions, of hurt egos, of hitherto undisclosed vignettes. The following are 2 samples.2Djerassi C. This man's Pill: reflections on the 50th birthday of the Pill. Oxford University Press, Oxford2001Google ScholarHechter: May I take a couple of minutes?Djerassi: I haven't finished. I'd like to continue because I've only gotten to the first half of my story.Reed: He can have my time. This is the first really fruitful… (inaudible)Greep: This is history from the horse's mouth, and I think it's very good.Djerassi: I misunderstood. Did you want me to continue?Greep: Yes. I felt that this was the first opportunity, years after Pincus's death, where I could find out why he had been so ungraciously selective in not acknowledging work of others that was crucial to the development of the Pill. (A particularly striking example is the total omission of Ludwig Haberlandt's papers from the 1920s among the 1459 references in Pincus's The Control of Fertility.24Pincus G. The control of fertility. Academic Press, New York1965Crossref Google Scholar Yet, the Innsbruck physiologist Haberlandt was unquestionably the “grandfather” of the Pill, who some 30 years earlier had outlined in uncanny detail the eventual contraceptive revolution through the use of progestational hormones). John Rock, who had not behaved very differently, was in the room, but he had reached an age where it was not possible for him to contribute to the dialogue. His was a silent, poignant presence. However, Celso-Ramon Garcia, Rock's and Pincus's closest clinical colleague, was present, which led to the following exchange:Garcia: Basically, the monograph “Control of Fertility” that Pincus wrote expresses in detail what his feelings were about who contributed to what.Djerassi: Why did he not mention any chemists, do you happen to know that?Garcia: He was a biologist, the same way as you are principally presenting your story as a chemist.Djerassi: That's not true. That's why I submitted a paper here with biological references, including yours.Garcia: Well, okay, but the fact is that principally you are a chemist and your major contribution has been that of a chemist.Djerassi: But this would be like my describing the history of oral contraceptives without a single reference to Pincus or Rock or yourself! By citing the published record—the relevant notebook page (Figure 3), the filing dates of the relevant patents, and the first published peer-reviewed papers16Djerassi C, Miramontes L, Rosenkranz G. 19-Nor-17α-ethynyltestosterone and 19-nor-17α-methyltestosterone. [Abstracts, p.18-JG.] Division of Medicinal Chemistry, American Chemical Society Semi-annual Meeting, Milwaukee, Wisc, 1952.Google Scholar, 17Djerassi C. Miramontes L. Rosenkranz G. Sondheimer F. Synthesis of 19-nor-17α-ethynyltestosterone and 19-nor-17α-methyltestosterone.J Am Chem Soc. 1954; 76: 4092-4094Crossref Scopus (99) Google Scholar—I have presented the objective, historical justification for my statement at the beginning of this article that Syntex deserves credit as the institutional site for the first chemical synthesis of an oral contraceptive steroid. Interestingly, Syntex-developed norethindrone is still a widely used active ingredient of oral contraceptives some 50 years after its initial synthesis in October 1951; Searle's norethynodrel had disappeared from the market many years ago, to be superseded by other 19-nor steroids. Space does not permit me to develop the arguments I presented first in 197025Djerassi C. Birth control after 1984.Science. 1970; 169: 941-951Crossref PubMed Scopus (45) Google Scholar and in numerous subsequent papers26Djerassi C. The bitter pill.Science. 1989; 245: 356-361Crossref PubMed Scopus (38) Google Scholar, 27Djerassi C. Sex in an age of mechanical reproduction.Science. 1999; 285: 53-54Crossref PubMed Scopus (5) Google Scholar about the increasingly dismal prognosis for fundamentally new approaches to birth control. Of the 20 largest pharmaceutical companies in the world, only 2 are still active in terms of modest research and development efforts on newer methods of birth control. Virtually all of these efforts are limited to minor chemical modifications of the original norethindrone molecule. The reason, of course, is obvious: most research and development funds and manpower are now dedicated to diseases of aging and deterioration in an increasingly geriatric segment of the most affluent countries. Contraception does not fall within these priorities, which means that birth control during the next few decades will not differ in any fundamental way from the 1960s, with the Pill, condoms, and sterilization continuing to play the key roles. With an increasing emphasis on in vitro fertilization techniques, the growing separation27Djerassi C. Sex in an age of mechanical reproduction.Science. 1999; 285: 53-54Crossref PubMed Scopus (5) Google Scholar of sex (“in bed”) and fertilization (“under the microscope”) may well lead to the scenario outlined in the following dialog from my play, An Immaculate Misconception,28Djerassi C. An immaculate misconception: sex in an age of mechanical reproduction. Imperial College Press, London2000Crossref Google Scholar which has already been translated into 11 languages and broadcast by the BBC World Service:MELANIE: Before you know it, the 21st century will be called “The Century of ART.”FELIX: Not science? Or technology?MELANIE: The science of …A…R…T: assisted reproductive technologies. Young men and women will open reproductive bank accounts full of frozen sperm and eggs. And when they want a baby, they'll go to the bank to check out what they need.FELIX: And once they have such a bank account…get sterilized?MELANIE: Exactly. If my prediction is on target, contraception will become superfluous.FELIX: (Ironic): I see. And the pill will end up in a museum…of 20th century ART?