The Pill at 50 (In Germany): Thriving Or Surviving? Djerassi C J

Journal für Reproduktionsmedizin und Endokrinologie – Journal of Reproductive Medicine and Endocrinology –

Andrologie • Embryologie & Biologie • Endokrinologie • Ethik & Recht • Genetik Gynäkologie • Kontrazeption • Psychosomatik • Reproduktionsmedizin • Urologie

The Pill at 50 (in Germany): Thriving or Surviving? Djerassi C J. Reproduktionsmed. Endokrinol 2011; 8 (Sonderheft 1), 14-31

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Wir freuen uns auf Sie! The Pill at 50

The Pill at 50 (in Germany): Thriving or Surviving? *

C. Djerassi

This article describes in detail the history behind the chemical development of oral contraceptives, notably the synthesis of norethindrone, which represents the chemical template from which virtually all subsequent oral contraceptives are derived. Attention is also paid to the introduction of the most recent oral contraceptives in Germany and reasons are provided for the dim overall prognosis about the future of contraception, namely that nothing fundamentally new is on the horizon. J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1): 14–31. Key words: norethindrone, norethynodrel, levonorgestrel, chemistry of oral contraceptives, Ludwig Haberlandt

 Which 50th Birthday? 2010, I was bombarded by requests from Pill] is entirely the invention of men. And many American print, radio, and TV re- why did they do it? … Because they are How many people – other than those try- porters to comment on the “50th birth- extraordinarily unwilling to experiment ing to hide their age – celebrate the same day” of the Pill, because the media were with their own bodies … and they’re birthday in successive years? And why dating the Pill’s debut to the formal ap- extremely willing to experiment with should that happen to a drug? Yet in proval by the Food and Drug Adminis- women’s bodies … it would be much 2001, several people (starting with Carl tration (FDA). While such dates may be safer to monkey with men than monkey Djerassi [1]) celebrated the 50th birthday occasions for celebrations, “birthdays” with women.” While Mead’s irritation of the Pill, while 9 years later a media they are not. The Viennese event was may well be understandable, it neverthe- frenzy exploded all over the world with equivalent to celebrating a baby’s arrival less represents a gross oversimplifica- another 50th anniversary celebration of in a town far away from its original birth- tion that ignores that nature had pro- the Pill. And now, in 2011, we are doing place and the 50th “birthday”, especially vided scientists with a crucial hint on it again by commemorating the date, 50 hyped by the American media, could which to build – women do not get preg- years ago, when the Pill was introduced be equated to the date on which the nant during pregnancy because of the in Germany. In terms of this article’s baptismal certificate was issued in continuous secretion of progesterone – title, this would clearly mean that the Pill Washington. As far as I am concerned whereas no such clue exists in male re- is thriving. And in a way it is, especially (and I was concerned), the real birth date productive biology. Dr. Shipley’s contri- in light of two overwhelming facts of the of the Pill was October 15, 1951, the day bution is significant for an additional last half century – the global population we completed at Syntex in Mexico City reason that may explain some of Mead’s explosion and the rise of women’s rights the first synthesis of a steroid eventually indignation: fifty years ago women were – without which oral contraceptives destined to be used for oral contracep- still largely excluded from many areas of would just have been another medical tion. A few days later, the first few pre- scientific research. In a field that was un- advance and not an invention with enor- cious milligrams of “norethindrone” deniably a male province, Dr. Shipley mous societal consequences. Yet in this – the generic designation of the formally had to do her work in a commercial labo- article, I shall also make the contradic- named “17α-ethynyl-19-nortestostero- ratory she had founded next door to the tory argument that the Pill is only surviv- ne” – was already in the mail from University of Wisconsin where her hus- ing, because nothing else is on the hori- Mexico City to Dr. Elva G. Shipley band, Roland K. Meyer, was Professor zon in terms of fundamentally new at Endocrine Laboratories Inc., a com- of Zoology at a time when nepotism methods of birth control. mercial establishment in Madison, rules were still inviolate. Wisconsin, with the request that the sub- During those years, I have been inter- stance be tested for oral progestational A pervasive sense of the ironies of this viewed, filmed, and encouraged to pon- activity. historic male bias has caused various tificate on the occasion of various birth- writers and journalists to search far and days of the Pill, perhaps because one of  Mothers of the Pill? wide for female heroes in the record of the ironies of the Pill’s career is that its the Pill. Margaret Sanger is the favorite, own conception has been so hard to pin I mention Dr. Shipley here primarily be- probably for reasons stated in the final down. It all depends (as any obstetrician cause her early participation in the Pill’s paragraph of David Kennedy’s definitive will tell you) on who is counting. In history impinges on a claim often heard biography [3]: “Yet the praise Margaret 1997, I spoke at a medical congress in – that the scientists involved in the de- Sanger received often seemed out of Vienna commemorating the 35th anni- velopment of oral contraceptives were proportion to her achievement. Part of versary of the Pill in Austria – not an in- uniformly males. This belief has grated the hyperbole, undoubtedly, derived appropriate geographic choice as I will on women for decades. As Margaret from her personal magnetism, which demonstrate shortly – while in May Mead [2] put it in the late 1960s: “[The rarely failed to bring those who met her

* Portions of this article come from [1].

Received and accepted: February 24, 2011 Correspondence: Carl Djerassi, Department of Chemistry, Stanford University, Stanford, CA 94305-5080; e-mail: [email protected]

14 J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) For personal use only. Not to be reproduced without permission of Krause & Pachernegg GmbH. The Pill at 50 into her orbit. But a larger part reflected lished the high progestational activity of Mrs. Sanger’s symbolic satisfaction of a orally-administered norethindrone. If pervasive psychological need. American her results had been negative, we would society in this century has not realized its have dropped the project and would frequently stated ideal of equal status for never have sent the material to other bi- women. Perhaps, therefore, the apo- ologists, including Gregory Pincus, theosization of a feminist heroine like who, as I will demonstrate below, can Margaret Sanger reflects society’s rec- rightfully be called a “father of the Pill”. ognition of the continuing victimization of women, and the desire, in some way, Since the Pill is so intimately connected to find a redemptress. For that role Mar- with human reproduction, albeit in terms garet Sanger, at her best and at her worst, of preventing it, let me pursue the Pill’s was well suited.” genealogy through the metaphor of reproduction. Call the Pill the baby and Figure 1. Title page of Haberlandt's book. Still, Sanger’s historic, though certainly follow its birth through (1) the first (un- not scientific role in fostering the birth successful) attempts at conception, (2) control movement in the USA would the ovulation of a fertile egg, (3) the validate her choice as one of the grand- ejaculation of various sperm, (4) the suc- mothers of the Pill. A more romanticized cessful fertilization, (5) the implantation candidate is Katherine McCormick, a of the embryo, (6) the fetal development, wealthy philanthropist, who was per- and finally (7) the birth of the baby. Geo- suaded by Sanger in the early 1950s to graphically, the first step occurred in subsidize some of the biological work at Austria, the second in Mexico, the next Figure 2. Newspaper headlines (1927) about Pill for the Worcester Foundation for Experi- 3 in the continental United States, and Women. mental Biology that under the leadership the last in Puerto Rico – not untypical for of Gregory Pincus contributed heavily to a baby in the present highly mobile soci- years, Haberlandt – invariably using the the development of the Pill. However ety. first person singular, so strikingly differ- commendable such philanthropy is, ent from today’s insistence by scientists anointing Katherine McCormick as one  The Overlooked Role of on the royal “we” – emphasized the ob- of “the indisputable mothers of the Pill” vious applicability of his animal experi- (as was done by one journalistic author, Ludwig Haberlandt ments to human contraception. He fully Bernard Asbell, in “A Biography of the The least-known character in the Pill’s recognized that the responsible factor Drug that changed the World” [4] and story is not a woman after all. It is was a constituent of the corpus luteum then repeated by many others), is as far- Ludwig Haberlandt, professor of physi- and in 1931, in a remarkable book [7], fetched as calling John D. Rockefeller ology at the University of Innsbruck. As “The Hormonal Sterilization of the Fe- one of “the fathers of the Pill”. (The early as 1919, he carried out a crucial male Organism” (Fig. 1), of less than Rockefeller Foundation and its offspring, experiment, in which he implanted the 15,000 words that hardly anyone now the Population Council, supported much ovaries of a pregnant rabbit into another living seems to have read, Haberlandt more research in reproduction and con- rabbit, which, in spite of frequent coitus, outlined in uncanny detail the contracep- traception than Mrs. McCormick ever remained infertile for several months – a tive revolution of some thirty years later. did and has continued to do so over the result that Haberlandt called “hormonal He pointed out that oral administration, course of many decades). A curious fact, temporary sterilization”. (Partisans of which he actually demonstrated in mice, not commented upon by any other writ- Mrs. McCormick might take note that this would be the method of choice as well as ers (e.g. [5]) on the role of Gregory and subsequent work of Haberlandt’s the necessity for periodic withdrawal Pincus is that Pincus, though dedicating was supported financially by the Rocke- from the hormone to allow menses to his opus magnum, “The Control of Fer- feller Foundation.) The problem with occur. He called for the use of such con- tility” [6] to “Mrs. Stanley McCormick” this method, of course (other than its re- traception on clinical and eugenic for “her steadfast faith in scientific in- liance on surgery), as well as with subse- grounds, arguing that it would enable quiry …” did not mention any financial quent attempts to avoid surgery by the parents to have the desired number of support on her part in his acknowledg- use of “glandular extracts”, was that healthy children. Objections by people ment section in spite of a lengthy list of these extracts were not the pure hormone like the sexologist van de Velde that too funding agencies, individuals, and com- responsible for its contraceptive effect. many women would take advantage of panies, notably G. D. Searle and Co. A mixture of hormones and other pro- hormonal contraception was dismissed teins, they constituted a potential prob- by Haberlandt with the argument that Financial support, valuable as it may be, lem of toxicity for the recipient. At- such preparations would require a can never be equated with creativity; tempts to “purify” these extracts pre- physician’s prescription and would not otherwise, the Medicis would be consid- sented the next hurdle to overcome on be made available over the counter. He ered the greatest artists of the Renais- the way to a practical oral contraceptive. ended his manifesto with a visionary sance. Instead, let me add the name of claim: “Unquestionably, practical appli- Elva G. Shipley as literally the first bi- In numerous subsequent experiments cation of the temporary hormonal steril- ologist – male or female – who estab- and publications over the course of ten ization in women would markedly con-

J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) 15 The Pill at 50 tribute to the ideal in human society Switzerland; its chemical structure es- synthetic chemical – by definition in- already enunciated a generation earlier tablished by Karl Slotta (a Hitler refugee vented and synthesized by the chemist – by Sigmund Freud (1898). Theoretically, eventually settling in Brazil); and its as the egg that needs to be fertilized. The one of the greatest triumphs of mankind synthesis from the soyasterol stigmas- biological experiments that are subse- would be the elevation of procreation terol accomplished by Fernholz in quently conducted are then the father’s into a voluntary and deliberate act”. Göttingen and by Butenandt in Danzig. sperm, with the key biological experi- Had Haberlandt lived, there is no ques- ment representing the crucial seminal Haberlandt did not limit his publications tion that he would have pursued his event that caused fertilization of the egg. to the scientific literature. He also pub- dream of temporary hormonal steriliza- Only then does the clinician enter the lished in the popular press and gave in- tion in humans without resorting to cor- picture as midwife. It is this triad, in terviews that led to huge newspaper pus luteum extracts. But even with pure which each component is indispensable, headlines (Fig. 2) like “My aim: fewer progesterone, he could have shown only that deserves consideration and it is but fully desired children!” (in the that ovulation can be inhibited by injec- amazing to what extent the maternal role January 20, 1927 issue of the Acht Uhr tion as the appropriately named Ameri- of the chemist is often downplayed or Abendblatt, Berlin) complete with com- can investigator A. W. Makepeace dem- ignored outright in medicine. Conse- mentary by the now-familiar chorus of onstrated in 1937 in rabbits and E. W. quently, much of what I have to say in physicians, lawyers, and theologians. Dempsey in guinea pigs. For oral admin- this article will focus on chemists and His obsession with the therapeutic po- istration, Haberlandt would have needed the underlying chemistry. tential of corpus luteum extracts was so another steroid – not naturally occur- well known that his students hung a ban- ring, but waiting to be synthesized – and  What was the Real Role ner by his home with the couplet, that took 20 more years. Thus, nothing “Verdirb nicht Deines Vaters Ruhm mit further happened, and Haberlandt’s of Russell Marker? Deinem Corpus Luteum” [Don’t mar work fell into such oblivion that the next For mostly journalistic reasons, many your father’s renown with your corpus biologist to take it up, Gregory Pincus accounts of the Pill’s early genealogy luteum]. But Haberlandt was not content (who clearly should have known better), start with the name of Russell Marker, a with the visionary’s role only. He con- did not even feel obligated to cite research professor at Pennsylvania State tacted several pharmaceutical compa- Haberlandt among the 1459 references College in the late 1930s and early nies in an attempt to obtain consistently in his own book [6]. Nor for that matter 1940s. Perhaps what attracted the jour- active and nontoxic corpus luteum and did Pincus’s clinical collaborator, John nalists and TV filmmakers to add Marker placental extracts for human clinical ex- Rock, whose book The Time has Come to the list of fathers of the Pill was periments. In his 1931 book, he finally [9] quotes Makepeace’s work but none Marker’s status as a maverick. Lacking reported success in the following words: of Haberlandt’s pioneering earlier re- the formal union card of a Ph.D., “I have been in contact for over three search. Yet if there ever was a grand- Marker’s true rank as one of the giants of years with the therapeutic firm Gideon father of the Pill, the Austrian Ludwig steroid chemistry was recognized only Richter in Budapest [to this day, a com- Haberlandt above all others deserves two decades after his sudden and total pany active in the steroid field] and it is that honor. Aside from not mentioning withdrawal from chemistry while still in likely that in the near future a suitable Haberlandt’s work, these 2 books by his forties. But despite his genuine claim ‘sterilizing preparation’ under the name Pincus and Rock, who are often called to greatness in the larger field of steroid ‘Infecundin’ will be available for sys- the 2 fathers of the Pill – an interesting chemistry, in terms of oral contraception temic administration in clinical experi- variant of parthenogenesis contain a sur- in particular he contributed nothing. ments as I had already announced in prising lacuna: zero reference to the Vienna [September 1930]”. He con- chemical invention of the Pill, without Which is not to say that Marker wasn’t firmed that experiments in mice with which, of course, no biological or clini- important, albeit indirectly, for making orally-administered “Infecundin” had cal research on today’s Pill could even the raw materials of contraceptive re- demonstrated temporary infertility with- have started. search more readily available. Until the out toxic reactions, “since only in this mid-1940s, virtually all clinically useful manner does the new method have any Since the term “father of the Pill” carries progesterone was prepared in one way or chance for clinical success”. A year reproductive connotations, the develop- another from soyasterols or cholesterol later, the 47-year old Haberlandt comment of oral contraceptives might well in processes that required conversion of mitted suicide [8] as a result of the inces- deserve some reproductive metaphor. such sterols into intermediate products sant criticism of his work in conservative Thus one might ask why the metaphoric prior to final transformation into proges- Austria, but the name “Infecundin” sur- fathers, Pincus and Rock, did not refer terone. These intermediate steps repre- vived. In 1966, it became the trade name to the usual missing partner in such a sented a bottleneck, as only limited of the first oral contraceptive produced process, namely a metaphoric mother? quantities of the necessary substances in Hungary by the very same company In my own writings, I have frequently could be generated at one time. Not sur- Haberlandt had contacted 40 years ear- made the point that for any synthetic prisingly, this poor yield kept the price lier. drug – oral contraceptive, antibiotic, anti- of progesterone very high (approxi- cancer or anti-anything – the organic mately US$ 80/gram in the early 1940s). Within 2 years of his death, pure proges- chemist assumes the irreplaceable ma- All this changed dramatically when terone was isolated in no less than four ternal function. I anoint the chemist with Marker revolutionized the chemical pro- laboratories in Germany, the US and the maternal role, because I consider the duction of progesterone. Within a few

16 J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) The Pill at 50 years, as a result of his process, the cost presence of my colleague, the late Harry of progesterone dropped sufficiently that Mosher, then Emeritus Professor of it became inexpensive enough to be used Chemistry at Stanford, who had been a as the starting material for the synthesis graduate student at Penn State and had of other steroids (for instance cortisone), worked in the same laboratory as rather than just serving as a clinically Marker. After Marker departed, Mosher useful drug for menstrual disorders. But turned to me. “There are other versions what, precisely, was the nature of as well”. And sometime later, after I had Marker’s discovery? published an autobiography [10] in which Marker was mentioned, I received In the late 1930s and early 1940s, Marker a letter from a reader, an American conducted research on a group of ste- chemist then living in Israel, who had Figure 3. Steroid skeleton roids called “sapogenins”, compounds also worked in the same laboratory at of plant origin. They got their name be- Penn State. It was a startlingly bitter his honor. Still, Marker’s enduring con- cause, in their naturally-occurring form letter, citing evidence to support his view tribution to contemporary chemistry, (where they are linked to sugars in com- that Marker had been virulently anti- and indirectly also to pharmacology and pounds called “saponin”) they form Semitic around the outbreak of World medicine, lies in his discovery that ste- soapy lathers in water. Natives of Mexico War II, a claim that was subsequently roid hormones could be synthesized and Central America had long used them confirmed by another independent wit- from a naturally occurring and cheap for doing laundry and to daze or kill fish. ness from the early 1940s. plant source – research that I considered Marker concentrated on the chemistry of so important that on one occasion I a member of this group called diosgenin, In terms of the chemical history of the nominated Marker for a Nobel Prize. which was present in certain types of in- Pill (though not in the eyes of a refugee edible yams (Dioscorea species) grow- from Hitler, like myself), Marker’s pur-  Partial vs Total Synthesis ing wild in Mexico. He succeeded in de- ported anti-Semitism would appear to be veloping a five-step, high-yield conver- irrelevant. But there is an intriguing as- To appreciate the significance of sion of diosgenin into progesterone. All pect to Marker’s alleged prejudice. His Marker’s work it is necessary to under- kinds of apocryphal stories have been Ph.D. supervisor at the University of stand the difference between “total” and written about Marker’s departure from Maryland was Morris Kharasch, one of “partial” synthesis. To a chemist, “total Pennsylvania State College during the very first Jewish professors in the synthesis” is making a molecule from World War II and his move to Mexico, WASP-dominated university chemistry scratch – essentially from air, carbon many embellished with mysterious dis- faculties of pre-World War II America. sources (such as coal or petroleum), wa- appearances into the Mexican jungle, For reasons that have never been com- ter and other elementary substances – newspaper-wrapped parcels containing pletely clarified, Marker never finished not unlike building a house from clay the equivalent of the world’s supply of his doctorate at Maryland, but, following and timber, iron and sand. “Partial syn- progesterone, and the like. But in 1979 a short industrial stint at Ethyl Corpora- thesis”, on the other hand, involves start- (approaching the age of 80), he visited tion, he spent 6 years at the Rockefeller ing with an advanced structure – say a me at Stanford University and permitted Institute working under another well- barn – and then converting it into a hab- a taped interview, excerpts of which known Jewish chemist, Phoebus Levene. itable house with plumbing and central have appeared in book form [1]. That collaboration broke off so bitterly heating. In Marker’s synthesis, the build- that Marker – in a last gesture of defi- ing to be constructed was a “steroid” – a The interview ended on a poignant note. ance to a superior – removed the labels term that one hears often enough in con- A driver had come to take Marker from of virtually all the research samples that temporary life, but rarely (outside of or- my Stanford office to the San Francisco he left behind when he departed for his ganic chemistry classes) in its proper airport from where he was supposed to new position at Pennsylvania State Col- definition as the tetracyclic chemical fly to Mexico City for a brief visit. He lege. Among chemists, only burning skeleton known generically by the for- asked for the men’s toilet and as I led one’s laboratory notebooks would be a bidding name “perhydrocyclopentano- him there, he suddenly turned to me, worse act of vandalism. phenanthrene” (Fig. 3). “Tell me, where am I? What am I doing here? What did we talk about?” Fearing The only subsequent time I met Marker Tens of thousands of synthetic, and sev- that he had suffered a sudden memory was in 1984, when the annual Russell eral thousands of natural compounds are loss, I reached into his jacket and drew Marker Lectures in the Chemical Sci- based on this fundamental steroid skel- out his plane ticket. After explaining ences at Pennsylvania State University eton made up of carbon and hydrogen gently where he was, I gave the ticket to were inaugurated through his own funds. atoms only differing minutely in chemi- the driver, asking him not to just drop off He requested that I present the first se- cal structure by the attachment of some Marker at the airport, but rather see to it ries and I used that opportunity to pay additional atoms (usually oxygen) at that he boarded the plane. A few weeks homage to him by paraphrasing “Marker- various locations. The variations, how- later, I learned that Marker had suffered at-Stanford” in front of Marker. Physi- ever minute, produce dramatically dif- a mild heart attack and had been taken cally and mentally, he was in fine fettle ferent biological results. Many of the off the plane in Texas to a hospital. I had and I was pleased that he wanted me to most important biologically active mol- conducted my taped interview in the initiate the annual event established in ecules in nature represent slight varia-

18 J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) The Pill at 50 tions on the steroid skeleton: the male his chemical processes in the Journal of gesterone for contraception had been and female sex hormones, bile acids, the American Chemical Society [11]. Haberlandt’s insight, not Marker’s, and cholesterol, vitamin D, the cardiac-ac- Since no one had taken out patents in the provision of pure progesterone tive constituents of digitalis, the adrenal Mexico for his discoveries, the commer- had already been achieved long before cortical hormones (related to cortisone cial production of progesterone from di- Marker in the 1930s, shortly after and usually referred to generically as osgenin was up for grabs in that country. Haberlandt’s death, through the work of “corticosteroids”) and many plant-de- Somlo and Lehmann, looking for an- German scientists like Erhard Fernholz rived and marine natural products. other chemist who could re-establish and Adolf Butenandt, who won a Nobel the manufacture of progesterone from Prize in 1939 for his steroid research. When Marker started his research in the diosgenin at Syntex, recruited George But nothing had happened, not because 1930s, the total synthesis of steroids had Rosenkranz from Havana. A Hungarian progesterone was expensive, or in short not yet been accomplished. All steroid like Somlo, Rosenkranz had immigrated supply, but simply because it was not hormones then known (e.g. progester- to Cuba a few years earlier from Switzer- sufficiently active by oral ingestion to be one and testosterone) were produced land, where he had received his doctor- taken as a pill. By the time Marker ap- only by “partial” synthesis from natu- ate under the Nobel laureate Leopold peared on the scene with a new and bet- rally occurring steroid precursors, Ruzicka (one of the giants of early ste- ter synthesis of progesterone, the pro- mostly from cholesterol and bile acids – roid chemistry) and was already familiar gesterone contraceptive boat had already both of animal origin. By pursuing syn- with Marker’s publications. Within two sunk. It took two other maternal uncles thesis from such a starting point, chem- years, Rosenkranz had re-instituted the and a mother to construct a new one, and ists were simply imitating nature, which large-scale manufacture of progesterone a father to make it seaworthy. uses cholesterol as the starting material from diosgenin. Even more important, for the synthesis of steroids in the body. he had achieved the large-scale synthe- Without Marker, of course, there would And although kilogram quantities of ste- sis, from those same Mexican yams, of not have been any Syntex – the physical roid hormones such as progesterone the commercially more valuable male site in Mexico where the maternal role were produced since the late 1930s by sex hormone testosterone. Both synthe- was played out. But there is no question some European drug companies, the ses were so much cheaper than the meth- that some other mother would have methods were unwieldy. Marker’s con- ods used by the European pharmaceuti- appeared elsewhere soon thereafter, be- tribution was to show that compounds cal companies then dominating the ste- cause in the chemical sense, two older derived from plant sapogenins could be roid hormone field – such as CIBA in German maternal relatives (Maximilian transformed much more cheaply into the Switzerland, Schering in Germany, and Ehrenstein and Hans Herloff Inhoffen), desired steroid “house” (e.g. progester- Organon in Holland – that in a short often completely ignored, had inadvert- one) than could be generated from a while tiny Syntex broke the international ently pointed the way for a chemical more cumbersome “barn” such as cho- hormone cartel. As a result, prices fell, mother to produce the requisite ripe egg lesterol. and these hormones became much more – in other words, the creation of a syn- available. In the late 1940s, Syntex thetic steroid mimicking the biological  The Mexican Connection: served as bulk supplier to pharmaceuti- role of progesterone, but being active by cal companies throughout the world, but mouth. Before describing that “mater- The Role of Syntex few people outside these firms even nal” process, a brief detour from oral As he recounted in his interview with knew of the existence of this small contraceptives to cortisone is warranted me, after he was unable to convince any chemical manufacturing operation in because, while cortisone has no biologi- American pharmaceutical firm of the Mexico City, which was soon to revolu- cal connection to the Pill, cortisone was commercial potential of diosgenin, tionize steroid chemistry and the steroid nevertheless the molecule that brought Marker formed in Mexico in 1944 a small industry all over the world. By the late me to Syntex in Mexico and hence to the company, Syntex, in partnership with 1950s, over half the world’s supply of Pill. two European immigrants, the Hun- steroid hormones originated from garian Emeric Somlo and the German Mexico, where in the meanwhile other  Some Autobiographical Federico Lehmann. A few months later, American and European pharmaceutical Observations: Cortisone Syntex started to sell to other pharma- companies had also started to establish and Oral Progestins ceutical companies (but not to the gen- manufacturing subsidiaries based on the eral public) pure, crystalline progester- commercial exploitation of diosgenin. By the fall of 1945, a 22-year-old, newly- one prepared by Marker’s process in five naturalized American citizen with a chemical steps from diosgenin. Within a So why do I relegate Marker at best to Ph.D. degree from the University of year the partners had a disagreement, the role of a distant maternal grand- Wisconsin and a wife, I returned to and Marker left the company, taking his uncle in the genealogy of the Pill? Be- CIBA (the pharmaceutical firm in New technical expertise with him. For a time, cause the availability of progesterone on Jersey where I had worked for one year Syntex was without its most profitable an industrial scale did not contribute in after graduation from Kenyon College) product. any way whatsoever to the development for another four years, to resume work of oral contraceptives. Certainly a source on antihistamines and other drugs. One Early in his academic career, however, of pure progesterone was necessary, and day in the spring of 1949, I received an while still at Pennsylvania State College, in sufficient quantities to investigate its unsolicited employment offer from Marker had published a description of therapeutic use. But the need of pro- Syntex, a company I had never heard of.

J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) 19 The Pill at 50

Although the position, as associate or Europe. Consequently, I really had chemical) role in the birth of oral contra- director of chemical research, seemed only one requirement before I accepted ceptives as well as my personal involve- tempting to me, the location of Syntex in the Syntex offer, and that was to publish ment in the first synthesis of a steroid the scientific backwater of Mexico made any scientific discoveries promptly in oral contraceptive. Within the confines the offer seem ludicrous. Fortunately, I the chemical journals. Syntex agreed to of the present article, it would be super- am a tourist at heart; when I heard the this and stuck to its bargain. From my fluous to go into detail since I have de- invitation, “Come and visit us in Mexico previous industrial experience, I fully scribed that story extensively in two au- City, all expenses paid”, I went. And as understood that discoveries have to be tobiographical works [1, 10] addressed a bonus decided to include a visit to patented by the firm in whose laboratory to a wider public and have cited all rel- Havana in my itinerary. the work is performed before they are evant chemical and biological literature written up for publication. But instead references in an earlier review article George Rosenkranz, then technical di- of having patent attorneys deciding [12]. rector of Syntex and barely past 30, im- whether and when to publish, at Syntex pressed me enormously as a sophisti- Rosenkranz and I called the shots – ex- At the time that I became interested in cated steroid chemist; he also charmed traordinary for a pharmaceutical com- the chemistry of progestational steroids, me personally. Rosenkranz showed me pany. As a result of this policy, during one of the dogmas of steroid chemistry rather crude laboratories, but he prom- my first two years at Syntex we pub- was that almost any chemical alteration ised lots of laboratory assistants and sub- lished more rapidly in the chemical lit- of the progesterone molecule would ei- stantial research autonomy to devise a erature than did any other pharmaceuti- ther diminish or destroy its biological practical synthesis of cortisone and to cal company, or even many university activity. This belief seemed puzzling in pursue other aspects of steroid chemistry laboratories. light of the fact, well known at the time, that might interest me. Furthermore, that estrogenic steroid hormones, which even though the labs were primitive, Until 1951, the only source of cortisone occur naturally in a variety of forms, as Syntex could boast of some advanced was through an extraordinarily complex well as synthetic chemicals not even equipment such as an infrared spectrom- process of 36 different chemical trans- based on the steroid skeleton, display eter at a time when neither CIBA nor my formations starting from animal bile ac- marked estrogenic potency. In 1944, alma mater, the University of Wisconsin, ids – a tour de force pioneered by Lewis Maximilian Ehrenstein (another emi- had such an instrument, which proved to Sarrett of Merck and Co. For many grant from Nazi Germany), then work- be enormously useful for steroid re- years, this had proved to be the longest ing at the University of Pennsylvania, search. and most complicated synthesis of any published a paper that was mostly over- chemical on an industrial scale. Now that looked, but had made a deep impression I arrived at Syntex in the late autumn of cortisone had emerged as a wonder drug, on me while still a graduate student. By 1949, just around my 26th birthday. I developing an alternative partial synthe- an extremely laborious series of steps, have never regretted that decision, even sis from a plant raw material became one Ehrenstein had transformed the natu- though at that time my American col- of the most acclaimed scientific projects, rally-occurring steroid cardiac stimulant leagues considered me mad to move to with a number of powerful academic and strophanthidin into a few milligrams of a country that, although famous for industrial research groups competing to impure oily 19-norprogesterone (actu- mariachi music, bull fights, and pre- be first. At the outset, nobody even real- ally called “10-norprogesterone” at that Columbian ruins, had only generated the ized that a small research team in time). To return to my earlier metaphor, barest of blips on the radar screen of in- Mexico City had entered the race. But Ehrenstein had transformed a very elabo- ternational chemical journals. Yet I was when we completed ahead of everyone rate mansion (strophanthidin) into a convinced that the best route to the aca- else in June of 1951 our synthesis of cor- funky little vacation house. While he had demic job still eluding me was to estab- tisone from diosgenin, the resulting pub- obtained only enough material for bio- lish a reputation in the scientific litera- licity was astounding. Thus, long before logical testing in two rabbits, in one of ture. I felt intuitively that Mexico was Syntex sold drugs under its own name to them his compound had displayed the right place for me. Syntex had the the medical profession, its international higher progestational activity than the same objective I did: to establish a scien- scientific reputation in chemistry was parent hormone. A positive test in one tific reputation. Our common goal – the well established. Ten years after my tem- animal out of two could, of course, “partial” synthesis of cortisone from a porary move to Mexico, when Professor have been just a fluke. What made plant raw material – was one of the hot- Louis F. Fieser of Harvard analyzed in Ehrenstein’s results so unusual was what test scientific topics in organic chemistry 1959 the references in the latest edition that “19-nor” in the compound’s name at that time. I was young and willing to of his text Steroids [11], the recognized signified. It meant that Ehrenstein had gamble on a few years in Mexico – partly bible of steroid research, he found that removed carbon atom No. 19 (between because living in another country and no laboratory in the world – academic or rings A and B of the steroid skeleton de- learning another language appealed to industrial – had published as much in the picted in Fig. 3) from the most inacces- me, but also because I thought that any steroid field as Syntex had in that time. sible site of the steroid molecule to re- scientific achievement from a laboratory Chemistry south of the Rio Grande had place it with a hydrogen atom. On paper in Mexico was likely, upon publication, finally made the grade. – or in words – the change sounds trivial. to make a much bigger impression on Given the state of the art of organic syn- academia than one coming from the Which finally brings me back to the Pill thesis at the time, however, this was so usual elite laboratories in North America and to a discussion of the maternal (i.e. difficult an operation that it had required

20 J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) The Pill at 50

Figure 4. Chemical structure of estradiol. several years for completion. Moreover, if the biological results were real, Ehrenstein’s observation demolished the previous assumptions about the inviola- Figure 5. Chemical structures of key steroids leading to the Pill. bility of the progesterone structure. But there was another problem: Ehrenstein’s the absence of carbon atom 19 usually oily product was, as I indicated, impure: attached at position 10, which makes Figure 6. Syntex lab notebook (15 Oct. 1951) describ- a mixture of at least three “stereo- possible the doubling-up of carbon-car- ing last step in synthesis of norethindrone. isomers” – molecules that, while struc- bon bonds in ring A. Chemically speak- turally identical, were, like mirror im- ing, the only difference between test- follow up on Ehrenstein’s lead of 1944. ages, as alike – and fundamentally dif- osterone (a conventional steroid with Using various chemical methods devel- ferent – as your left hand and your right. carbon atom 19) and the estrogens (“aro- oped as part of our estrogen synthesis as In biochemistry, which often requires matic” steroids lacking C-19) – between well as methodology perfected by the molecules to fit together like a hand in a men and women – is that one carbon, but Australian chemist, Arthur J. Birch (sub- glove, such a difference can be crucial. what a difference it makes! sequently a long-term Syntex consult- Which one of the components, if any, ant), my Syntex colleagues and I pre- was responsible for the putative proges- The partial synthesis of steroid hor- pared for the first time in 1951 pure, tational activity? It took seven years for mones such as testosterone and progest- crystalline 19-norprogesterone (a ste- someone to come up with an answer. erone could be extended to the estrogens roid that like the estrogens lacked carbon Our ability to do so led us almost straight if a process could be devised that would atom 19) which, when assayed in rabbits to the Pill. eliminate the key carbon atom No. 19 at Endocrine Laboratories in Wisconsin, and thus effect the “aromatization” of was found to be four to eight times as Part of my Ph.D. thesis at the University ring A so typical of the estrogens. Hans active as natural progesterone. In other of Wisconsin in the early 1940s had dealt H. Inhoffen, at Schering A.G. in Berlin, words, Ehrenstein’s observation with an with the partial synthesis of the then-in- had demonstrated the practical feasibil- oily mixture tested in one rabbit was accessible estrogenic hormones from the ity of such a chemical conversion, but more than confirmed: replacement of more readily available androgens, such the work had been performed during carbon atom 19 by one hydrogen had as testosterone. For years, the estrogens World War II and experimental details produced the most active progestational were only available by isolation from the were scant and had to be partly recon- steroid known at that time. This observa- urine of pregnant women (and later of structed. Syntex had started to use the tion was crucial, because Ehrenstein’s pregnant mares, the source of one of the Inhoffen process (which had not been mixture of stereoisomers had also the more-frequently prescribed estrogen patented in Mexico) for the production wrong configuration at C-17 – a change compositions in use today for hormone of modest quantities of estrone and es- that was known to destroy progestational replacement therapy). In fact, the estro- tradiol. Upon assumption of my research activity in progesterone itself (see top 2 genic hormones, such as estradiol and position there, I suggested to Rosenkranz compounds in Fig. 5) – and from an ex- estrone, were the last steroid types to that Syntex examine another and poten- periment in a single rabbit, it was not yield to partial synthesis, because no tially proprietary route to the estrogens clear whether the beneficial effect of re- obvious precursor for them existed in directly from testosterone. In less than moving the angular methyl group be- nature. All of the other naturally-occur- three months we succeeded in accom- tween rings A and B was real. ring steroids are based on the skeleton in plishing this aim, which in chemical jar- Figure 3; the estrogens, however, are gon would be described as the “aromati- With that lead in hand, we turned to an- based on the structure for estradiol zation of ring A of conventional ste- other accidental discovery that had been shown in Figure 4. Here, ring A has roids”. made in 1939 [12] in Germany, where changed from the ordinary six-sided chemists at Schering, again under the form to an “aromatic” form, where half Our partial aromatization studies turned leadership of Inhoffen, found that if the carbon-carbon bonds are double. You into the impetus that led us in a fairly acetylene is added at position 17 of the don’t need a Ph.D. in organic chemistry straight path to the first synthesis of an male sex hormone testosterone (see to note the other difference between the oral contraceptive. From a technical 17α-ethynyltestosterone in Fig. 5), its estrogens and all other steroids. This is standpoint, I felt that the time was ripe to biological activity is changed markedly:

J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) 21 The Pill at 50

Figure 8. Hans Herloff Inhoffen and Huang Minlon at Schering, Berlin.

pleased at our elevation of his original 19-norprogesterone work from a piece Figure 7. Maximilian Ehrenstein of chemical esoterica to one of seminal Figure 9. First page of U.S. patent of norethindrone. significance; we actually published [12] for unknown reasons this androgenic a joint paper in 1958 to establish the logian and only son of Prof. Inhoffen, compound has weak progestational ac- nature (“wrong” stereochemistry at C- from whom he had become estranged. I tivity. Far more important, it also proved 14 and C-17 compared to that of natural couldn’t read his expression: was his to be orally active. On the reasonable as- progesterone) of one of the components question prompted by curiosity or by sumption that removal of the 19-carbon of his original 19-norprogesterone mix- still smoldering filial pride? atom increases progestational potency ture. and addition of acetylene confers oral Our patent application (Fig. 9) for nore- efficacy, we at Syntex put both these ob- My encounter with Inhoffen was differ- thindrone was filed on 22 November servations together. On October 15, ent. We met only once at an international 1951 (it is the first patent for a drug 1951 (see notebook page reproduced in scientific congress. There, his comments listed in the National Inventors Hall of Fig. 6), Luis Miramontes, a young Mexi- seemed frosty, leaving the impression Fame in Akron, Ohio), and I reported the can chemist doing his undergraduate that my work as a graduate student at the details of our chemical synthesis, to- bachelor’s thesis work at Syntex under University of Wisconsin had constituted gether with the substance’s high oral my tutelage, completed the synthesis of an intrusion into his early work on the progestational activity, at the April 1952 the 19-nor analogue of Inhoffen’s com- partial synthesis of estrogens. But in meeting of the American Chemical pound – that is, 19-nor-17α-ethynyl- 1999, our paths crossed again, twice, Society’s Division of Medicinal Chem- testosterone (bottom left structure in though on his part posthumously. Early istry in Milwaukee. The abstract [12] of Fig. 5) or, for short, “norethindrone” – that year, I received the Inhoffen Medal this report under the names of Djerassi, which turned out to be the first oral con- at the Technical University of Braun- Miramontes and Rosenkranz was pub- traceptive to be synthesized. schweig, but a more moving event oc- lished in March 1952, and the full article curred later that year in Graz. I had given with complete experimental details ap- We immediately submitted the com- a typical academic talk on the History of peared in 1954 in the Journal of the pound to our favorite commercial testing the Pill and had done so in German, American Chemical Society [12]. Read- laboratory in Wisconsin for biological which meant that it moved slower than it ers may well be irritated by such an ava- evaluation and gloated happily when would have in English. When I realized lanche of dates, but chronological preci- Dr. Elva G. Shipley reported back that it that I would be running out of time, I de- sion is the baggage of scientists preoccu- was more active as an orally effective cided to skip some slides. One of them pied with priority – a foible I would be progestational hormone than any other was a picture of Inhoffen together with disingenous to hide. steroid known at that time. In less than the father of Chinese steroid chemistry, six months, we had accomplished our Huang Minlon (Fig. 8). The room was A few weeks after having synthesized goal of synthesizing a superpotent, orally crowded and I had to cope with many the substance and having received from active progestational agent! Returning to questions before the audience broke up. Dr. Shipley confirmation of its antici- my reproductive metaphor, I classify our Suddenly a tall, serious man, probably pated oral progestational activity, we synthesis of norethindrone as the release around 60 years old, approached me to sent it to various endocrinologists and of the fertile egg waiting now to be fertil- ask quietly, “Did you know Inhoffen and clinicians: first to Roy Hertz at the Na- ized. Once that is understood, the roles his work?” Before explaining what I had tional Cancer Institute in Bethesda, of Ehrenstein and Inhoffen as older intended to say about Inhoffen, I pro- Maryland and to Alexander Lipschutz in maternal uncles become obvious. Since duced the slide (Fig. 8) I had brought Chile; later to Gregory Pincus at the Ehrenstein (Fig. 7) lived in the States, with me but had skipped during my talk. Worcester Foundation in Shrewsbury, our paths crossed in the 1950s at several That’s when I found out that I was speak- Massachusetts, to Robert Greenblatt in scientific meetings. I know that he was ing to Peter Inhoffen, a Catholic theo- Georgia, and to Edward Tyler of the Los

22 J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) The Pill at 50

ing on how progesterone worked to in- have synthesized the substance indepen- hibit ovulation (the mechanism behind dently and concurrently with Syntex’s Haberlandt’s “temporary hormonal ster- norethindrone constitutes a blatant mis- ilization” and Makepeace’s confirma- representation of the facts. The record tion). Among the many steroids tested in based entirely on published data is un- 1953 by the Worcester Foundation group ambiguous. On August 31, 1953 – well for such activity two substances over one year after our first publication Figure 10. Conversion of norethynodrel into norethin- (Fig. 10) stood out: our norethindrone (March 1952) dealing with the synthesis drone. and another substance, norethynodrel, of norethindrone, and 21 months after Angeles Planned Parenthood Center. It that had been synthesized by Frank our own November 1951 patent filing was Tyler who, in November 1954, pre- Colton at G. D. Searle, a pharmaceutical date (Fig. 9) – Frank Colton of G.D. sented the first clinical results of using company in the Chicago area. The Searle & Company filed a patent appli- norethindrone for the treatment of vari- chemical history of norethynodrel is cation for the synthesis of a steroid that ous menstrual disorders and fertility worth telling, since it illustrates one of differed trivially from norethindrone problems. All of these biological investi- the less attractive features of scientific through the position of one double bond gations can be equated to sperm that is research: the drive for scientific priority (Fig. 10). Trivially different, because surrounding the egg. But since this is a and the attempts to circumvent patent treatment of Colton’s isomer, norethyno- record of the history of the Pill, we need priority. In this instance, the stakes were drel, with acid, or just human gastric to address the source and origin of the higher than usual, since commercial juice, converts it to some extent into particular sperm that led to the fertiliza- considerations and financial returns Syntex’s norethindrone – a conversion tion of our chemical egg and thus to the quickly entered the equation. that among others [12] was established ultimate birth of an oral contraceptive. by Gregory Pincus and his collaborators.  Norethindrone vs Nor- Is synthesis of a patented compound in While we were aware of Haberlandt’s the stomach an infringement of a valid work, initially, we were not focusing on ethynodrel patent? (Interestingly, years later, a simi- contraception when we developed an For historical accuracy and appropriate lar suit with a related oral contraceptive oral progestational compound, because credit, it is important to note that even was pursued by Wyeth, Inc. against contraception was of no interest in 1951 though norethynodrel was only synthe- Ortho Pharmaceuticals and initially re- to the pharmaceutical industry. Our re- sized well over a year following the pub- solved in favor of the plaintiff). I urged search was undertaken because at that lication of our successful synthesis of that we push this issue to a legal resolu- time the natural hormone progesterone norethindrone, it was norethynodrel that tion, but Parke-Davis, our American lic- was used clinically for treatment of men- first entered the market as an oral contra- ensee, did not concur. strual disorders, for certain conditions of ceptive. M. C. Chang had found nore- infertility, and at a research level, for the thindrone and norethynodrel to have Searle was selling a very successful anti- treatment of cervical cancer in women been the two most promising candidates motion-sickness drug, Dramamine, by local administration of a high dose of in his initial animal studies. But his boss, which contained Parke-Davis’s antihis- the hormone. Such administration was Gregory Pincus, who was a consultant tamine Benadryl. Given that the only extremely painful because it involved in- for Searle, selected the Searle compound FDA-approved uses of our norethindrone jecting a fairly concentrated oil solution for further work. Syntex, not having any in 1957 was the treatment of menstrual of large amounts of progesterone into biological laboratories or pharmaceuti- disorders and certain conditions of infer- the cervix. What drove us was the desire cal marketing outlets at that time, li- tility, the issue seemed small potatoes to to create a more powerful progestational censed Parke-Davis & Co. of Detroit to Parke-Davis, over which it was not compound that would be active orally. pursue the FDA registration and market worth fighting with a valued customer. As it happened, the progesterone treat- the product in the United States. (That ment of cervical cancer did not pan out, choice itself was ironic, since it was In the mid-1950s, Searle actively sup- but the clinical use of our norethindrone Parke-Davis that had sponsored the ported clinical trials of the contraceptive (under the trade name Norlutin and li- original research work of Marker’s at efficacy of norethynodrel. The work was censed to Parke, Davis and Company – Pennsylvania State College, but had then conducted in Puerto Rico, under the at that time a large American pharma- refused continued support in Mexico, direction of Pincus and especially John ceutical company) for the treatment of thus leading to the foundation of Syntex). Rock, a clinical endocrinologist and menstrual disorders was approved by the It was only after 1957, when both nore- gynecologist from Harvard. Around the FDA in 1957 and is one of its therapeutic thindrone and norethynodrel had re- same time in Mexico City and Los Ange- indications to this day. ceived FDA approval as drugs for non- les, Syntex sponsored contraceptive tri- contraceptive, gynecological purposes, als with norethindrone. But fearing a Each of the biologists mentioned above that the paths of the two companies possible religious backlash, Parke-Davis had his own area of expertise and inter- diverged. suddenly chose not to pursue these re- est in the field of progestational activity. sults through the FDA approval process, Gregory Pincus and his colleague Min- Searle deserves full credit for reaching and returned the contraceptive (but not Chueh Chang of the Worcester Foun- the market first with an oral contracep- gynecological) marketing license to dation for Experimental Biology in tive, norethynodrel, under the trade Syntex. Alejandro Zaffaroni, Syntex’s Shrewsbury, Massachusetts, were focus- name Enovid, but its repeated claim to Executive Vice President, eventually ne-

24 J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) The Pill at 50 gotiated a favorable marketing arrange- ment with the Ortho Division of Johnson & Johnson, a company with a long- standing commitment to the birth-control field, but the shift to a new company meant a delay of nearly two years before Syntex’s norethindrone received FDA approval as a contraceptive. By 1964, three companies – Ortho, Syntex, and Parke-Davis (having changed its mind after realizing that no Catholic-inspired boycott had developed) – were marketing 2.0-milligram doses of Syntex’s norethindrone (or its acetate), which by then had become the most widely used active Figure 11. Chemical structures of oral contraceptives. ingredient of the Pill. Pill actually arrived in his laboratory? Syntex, as a company, and Mexico, as a There is no question that Searle deserves And even worse: why did Pincus drop country, deserve full credit as the institu- kudos for marketing noethynodrel first – Haberlandt’s name into a black hole of tional site for the first chemical synthesis despite a possible consumer backlash by anonymity? of an oral contraceptive steroid – a state- opponents of contraception. But given ment that is not meant in any way to the extraordinary importance of these  Pincus and the Chemists denigrate Searle’s successful drive to be steroids, why does the Searle group to the first on the market with a steroid oral this day not disclose in the peer-re- My preoccupation with establishing un- contraceptive But there is a more charm- viewed literature any of the chemical re- equivocally the priority – and thus the ing end to this story. In the process of search that led them to their pill? The metaphoric maternal identity – is not just swallowing Syntex, Roche not only only date supporting the claim for “inde- my admittedly strong competitive drive. closed the Mexican research laboratories pendent simultaneous discovery” is I am realistic enough to acknowledge where norethindrone was first synthe- Searle’s patent filing date of August 31, that it really does not make any differ- sized. Roche also decided to distance it- 1953, a date that sounds “simultaneous” ence to the world who does what first. self from any involvement in the contra- only without juxtaposition to the Octo- But giving credit to Syntex as the corpo- ceptive field, and promptly sold the en- ber 15, 1951 lab book entry (Fig. 6) de- rate institution where it all first started is tire Syntex oral contraceptive line, still scribing the completion of the synthesis important to me (even though I severed based in its entirety on norethindrone. of norethindrone and the November 21, all connections with that company in Who was the purchaser? None other 1951 filing date (Fig. 9) of Syntex’s 1972), because institutional memories than G. D. Searle – the company that patent application. are so short. Syntex was the first and went to heroic lengths to circumvent the possibly the only significant example of Syntex patent on norethindrone and now Colton and other researchers from important research in such a highly com- had to pay good money to market it as its Searle had not otherwise been reluctant petitive and technically sophisticated lead oral contraceptive long after the to publish their steroid research. Indeed, field being conducted in a developing original patent had expired. But the story in 1957, they published an article [13] in country. Both qualitatively and quantita- does not end there. G. D. Searle itself the Journal of the American Chemical tively, the research output of Syntex dur- was acquired several times – first by Society about a new steroid anabolic, ing the ‘fifties has never been matched in Monsanto, but eventually by Pfizer, now 17α-ethyl-19-nortestosterone (Nilevar), the steroid field; the pride and self-assur- the largest pharmaceutical company in that was produced in one step from our ance it provided to a cadre of Mexican the world. Few are aware of the fact that 17α-ethynyl-19-nortestosterone (nor- organic chemists, virtually all of them around 1954, Pfizer had an option from ethindrone). In their article, the Searle trained at Syntex, was moving to witness. Syntex to market norethindrone, an op- chemists cited quite properly our earlier Yet that company does not exist any- tion the company had not exercised be- publication, which predated theirs by more, because in 1994 it was acquired cause its president, John McKeen, an ac- over three years. Thus, their unaccount- by the Swiss pharmaceutical colossus tive Roman Catholic layperson, felt that able shyness about the most significant Roche and promptly swallowed and Pfizer should not touch any agent even product in their corporate history, nor- digested. In that digestive process, the potentially related to birth control. Yet ethynodrel, can only raise questions. entire research division of Syntex in half a century later, Pfizer entered the Why, for instance, did Gregory Pincus, Mexico, which had just moved into new contraceptive market with norethindrone! the person most responsible for persuad- quarters in Cuernavaca, was closed and What a closure to an historical circle! ing Searle to market norethynodrel, all research personnel dismissed. To me, make not a single reference to any chem- the cold-bloodedness of this corporate Interestingly, Syntex-developed nore- ist (not even Frank Colton) in his 1965 amputation seems unforgivable: I know thindrone is still a widely used active in- opus magnum, “The Control of Fertil- of no other pharmaceutical company in gredient of oral contraceptives, whereas ity?” Why does his book make no men- Mexico that has currently any significant Searle’s norethynodrel disappeared from tion of how the active ingredient of the research presence. the market many years ago, to be super-

J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) 25 The Pill at 50 seded by other 19-nor steroids, which, as conducted in Pincus’s laboratory. But the field of fertility in the United States shown in Figure 11, are close chemical Pincus was not only a prolific and highly during the previous 40 years (therefore, relatives of norethindrone. The second experienced endocrinologist, he was it was not surprising that, as far as I and third structures in Figure 11 are fur- also a charismatic entrepreneur. Many could tell, at age 55, I was the youngest ther examples of steroids, whose chief times, this latter quality is more difficult of that group) in order to collect a record raison d’etre was that they were not cov- to find than mere scientific brilliance; it that historians of science might draw ered by the original Syntex patent took entrepreneurship of Pincus’s cali- upon in the future. (Fig. 9) of norethindrone, yet are con- ber to bring the steroids provided by the verted to a considerable extent in the chemist to the stage where clinical trials The unedited transcript of that Friday body into norethindrone and hence can of the Pill could be initiated and where morning session reads awfully: Nouns all be considered qualitatively as “pro- John Rock, as leader of the clinical team, do not match verbs, tenses get mixed, drugs” of norethindrone. could assume the mantle of metaphoric punctuation is lost, and many words are obstetrician for the eventual birth of the misspelled or appear to be inaudible. On first glance, another alteration of the Pill. While Rock’s name is inexorably Nevertheless, one gets a real flavor of norethindrone molecule by addition of connected with that role, others, notably excited human dialogue and interrup- one methyl group in position 18, leading Celso-Ramon Garcia (the first professor tions, of hurt egos, of hitherto undis- to levonorgestrel (Fig. 11) also seems to of OB/GYN at the University of Puerto closed vignettes. Here are 2 samples. be just another example of a minor Rico Medical School) and Edith Rice- chemical change prompted by the desire Wray (Medical Director of the Puerto Hechter: May I take a couple of minutes? to circumvent Syntex’s norethindrone Rican Family Planning Association) patent. Though seemingly trivial, chemi- contributed heavily to the planning and Djerassi: I haven’t finished. I’d like to cally this was a drastic change since no implementation of the first clinical trials continue because I’ve only gotten to the naturally occurring steroids were known in the San Juan area. Rice-Wray subse- first half of my story. that possessed an angular ethyl group at quently directed a Family Planning clinic position 13. Hence this substance could in Mexico City where she continued her Reed: He can have my time. This is the only be prepared by total synthesis and clinical studies, this time with Syntex’s first really fruitful … (inaudible) this was accomplished in 1964 [14] by norethindrone. Herchel Smith and collaborators at the Greep: This is history from the horse’s University of Manchester. The patent Of the numerous talks and interviews mouth, and I think it’s very good. rights to this higher homolog of nor- that I have presented over the course of ethindrone were acquired by Wyeth, a decades on the birth of the Pill, three Djerassi: I misunderstood. Did you want company that was active in hormone re- stand out in my mind. Two of them were me to continue? placement therapy, who developed levo- formal occasions directly associated norgestrel into the “mother substance” with Pincus’s memory: the Gregory Greep: Yes. of a second series of oral contraceptives Pincus Memorial Lecture and Award (e.g. gestodene and desogestrel in Fig- presented in 1982 on his home turf, the The scientific co-chairman of the Boston ure 11). In fact, for the first forty years of Worcester Foundation for Experimental Academy’s May 1978 meeting was Roy the clinical use of steroid contraceptives, Biology, and the last Gregory Pincus O. Greep, a distinguished endocrinolo- all of the hundreds of “Pills” sold all Memorial Lecture at the 50th and final gist at Harvard, who had known person- over the world under different trade Laurentian Hormone Conference in ally most of the actors in this play. An- names were basically derivatives (see 1993. Ironically, this event was held in other key participant was Oscar Hechter, Fig. 11) of norethindrone or levonor- Puerto Rico – the site of the first oral who for many years had been senior sci- gestrel. contraceptive clinical trials – although entist of the Worcester Foundation for these annual meetings, founded by Experimental Biology. Though not di- It should not be surprising that I, as a Pincus, usually met in the Laurentian rectly involved in the development of chemist, in terms of my reproductive Mountains of Quebec. In the same year, oral contraceptives, he had been an inti- metaphor that equates any synthetic I also gave the first A. S. Parkes Memo- mate collaborator of Gregory Pincus. drug to an egg, spent the bulk of this rial lecture at Cambridge which com- James Reed of Rutgers University was a chapter examining the maternal lineage memorated a British pioneer in repro- historian studying the birth control of the Pill. But just as it is clear that ductive biology. But the most relevant movement in America. Ludwig Haberlandt merits attribution as event to my story is an unusual session the paternal grandfather, Gregory Pincus held Friday morning, May 5, 1978, in an I felt that this was the one opportunity, – despite the uncertainties of paternity old New England mansion on the out- years after Pincus’s death, where I could generally – deserves to be called a father skirts of Boston, the headquarters of the find out why he had been so ungra- of the Pill. The initial rabbit experiments American Academy of Arts and Sciences. ciously selective in not acknowledging by M. C. Chang in Pincus’s laboratory The Academy was holding a closed two- work of others that was crucial to the de- clearly were the sperm that fertilized the day session on “Historical Perspectives velopment of the Pill. John Rock, who chemical egg, and the subsequent im- on the Scientific Study of Fertility”. The had not behaved very differently, was in plantation of the embryo and eventual purpose of the meeting was to have a the room, but he had reached an age fetal growth can largely, though not en- free-flowing dialogue among some of where it was not any more possible for tirely, be ascribed to further experiments the key scientists who had been active in him to contribute to the dialogue. His

26 J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) The Pill at 50 was a silent, poignant presence. But licensed steroids from Syntex and Wyeth. Celso-Ramon Garcia, Rock’s and Only in the middle 1980s, when a levo- Pincus’s closest clinical colleague, was norgestrel analog with an additional present, which led to the following ex- double bond in ring D (see Fig. 11) was change: synthesized and introduced under the generic name Gestodene did Schering Garcia: Basically, the monograph “Con- market a proprietary steroid as a contra- trol of Fertility” that Pincus wrote ex- ceptive, an achievement that was re- presses in detail what his feelings were peated twice more during the last decade about who contributed to what. with drospirenone [15] (Fig. 12) and Figure 12. Chemical structure of drospirenone. dienogest (Fig. 13). A possible rationale Djerassi: Why did he not mention any and commentary for these decisions fol- chemists, do you happen to know that? lows below in the final section.

Garcia: He was a biologist, the same way  The Future: Reflections as you are principally presenting your story as a chemist. and Prognosis The subtitle of this article – thriving or Djerassi: That’s not true. That’s why I surviving – implies some prognostica- submitted a paper here with biological tion and this is the theme with which I references, including yours. wish to conclude: specifically do we Figure 13. Chemical structure of dienogest. need new methods of contraception and Garcia: Well, okay, but the fact is that if so, who is “we?” The answer is clear, principally you are a chemist and your Nobel laureates Windaus, Wieland, and once we accept that demographically major contribution has been that of a Butenandt heading the list. Similarly, speaking, instead of dividing the world chemist. among pharmaceutical companies, into “more developed” and “less devel- Schering AG played a lead role in medi- oped” nations, we need to accept that the Djerassi: But this would be like my de- cal applications of steroid hormones. So division is now between geriatric and scribing the history of oral contracep- it was not surprising that Schering was pediatric countries. tives without a single reference to Pincus also the company that introduced the or Rock or yourself! first Pill into Europe. However, in con- As seen in Table 1, with the exception of trast to the USA, it was not norethyno- Afghanistan, all of the top pediatric In other words, Garcia – and by infer- drel (Fig. 10) but rather the acetate of countries are African, whereas with the ence Pincus – felt that it is sufficient to norethindrone, which in the body is pri- exception of Japan, the most geriatric focus on the paternal role in discussing marily metabolized into the parent nor- countries (Tab. 2) are found in Europe. the history of the Pill. Hence as a chem- ethindrone, thus constituting a pro-drug By examining Table 3, which lists the ist, I have tried to illuminate the equally of the latter. But in contrast to the ten world-wide most populous countries indispensable “maternal” role of the Syntex-G. D. Searle commercial compe- expected in 2050, Pakistan, Nigeria, chemist. But since in 2011 we are cel- tition outlined above, in this instance Bangladesh, Ethiopia and partly also ebrating the 50th anniversary of the Pill Schering marketed norethindrone ace- India fall into the pediatric category. in Germany, let me end with a discussion tate under the trade name Anovlar under of the “German” role. license from Syntex, which in turn had Clearly, the contraceptive needs of the another amusing historical conse- pediatric countries, which are of no  The 50th Birthday of the quence: Parke Davis, the American phar- commercial interest to the large interna- maceutical company who first distrib- tional pharmaceutical firms, are not only Pill in Germany uted norethindrone under Syntex license urgent but also totally different from It is curious, yet understandable, that in for menstrual disorders, but had then re- those of the geriatric countries. What 1961 Germany proved to be the third turned the rights to market is as contra- most of Africa and parts of Asia and country after the USA and Australia to ceptive for fear of a Catholic boycott, Latin America need is not newer birth allow the use of an orally active proges- subsequent to Schering’s launch of nore- control methods – in other words new tational steroid for contraceptive pur- thindrone acetate (Anovlar) changed its “birth control hardware”, but rather im- poses. Curious, because Germany at that mind and also marketed the substance as provements in “birth control software” – time was as conservative in the area of an oral contraceptive in the mid 1960s. meaning improvements in education, family planning as many other European public health, and foremost changes in countries where the Pill was only permit- When Wyeth introduced Herchel Smith’s the status of women, because improving ted years later; but also understandable, levonorgestrel (Fig. 11) into the Ameri- those will cause an explosion in the use since in terms of scientific research and can market, Schering licensed it for dis- of existing methods of family planning. medical applications of steroids, Ger- tribution in Germany. Thus for the first many was in many respects the most ad- twenty years, Schering’s increasingly The only market that could afford new vanced country in the world and espe- powerful position worldwide in the field methods of birth control are the geriatric cially so in steroid chemistry with the of contraception was based on externally countries, but those populations have al-

J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) 27 The Pill at 50

young men before they ever had fathered Table 1. Countries with youngest Table 3. Most populous countries populations (2010) (2050) any children. For pharmaceutical companies, this approach would be of zero Country % ages < 15 Country Population financial interest. (Millions) Niger 50.1 Uganda 48.7 India 1,748 This leaves alternatives 2, 5 and 6, which Burkina Faso 46.4 China 1,437 would represent fundamental advances Congo, Dem. Rep. 46.4 United States 423 that would also fill enormous lacunae in Zambia 46.2 Pakistan 335 our contraceptive armamentarium. But Malawi 45.9 Nigeria 326 the costs for developing such agents Afghanistan 45.9 Indonesia 309 would be enormous (each easily exceed- Chad 45.6 Bangladesh 222 ing US$ 1 billion), very time consuming Somalia 44.9 Brazil 215 [17] and very likely also prone to litiga- Tanzania 44.7 Ethiopia 174 tion. Only the largest pharmaceutical Congo, Dom. Rep. 166 companies would have the necessary scientific and financial resources for Table 2. Countries with oldest popu- such an endeavor, and given their focus lations (2010) on the diseases of aging and deteriora- Table 4. A priority list of new contra- tion that afflict the ever increasing geri- Country % ages 65+ ceptive methods [C. Djerassi, Science atric populations of these rich countries, 1989; 245: 356]. Japan 22.6 it is not surprising that not a single of the Germany 20.5 1. Spermicide with antiviral properties 20 largest pharmaceutical companies is Italy 20.4 (effective during normal coitus) currently pursuing research and devel- Sweden 18.3 2. Once-a-month pill effective as opment work on a male contraceptive or menses inducer Greece 18.3 a fertility vaccine. So what is left? 3. Reliable ovulation predictor (“red” & Portugal 17.9 “green” light) Bulgaria 17.6 4. Easily reversible and reliable male The few major drug companies that con- Austria 17.6 sterilization tinued after 1975 to pursue any research Latvia 17.4 5. Male contraceptive pill in female contraception were those that Belgium 17.4 6. Antifertility vaccine had a significant market share of the Pill. The two most important ones (Schering in Germany and Organon in Holland) ready learned how to limit their families Note that improved efficacy is hardly an were both swallowed up in recent years by existing methods. In the large major- issue any more. by German (Bayer) and American ity of European countries, the average (Merck-Schering-Plough) pharmaceuti- sized family (ca. 1.5 children) is far be- Twenty-two years later, only ovulation cal giants, not unlike what happened in low replacement level (2.1 children). For prediction (3. in Tab. 4) has been real- the 1990s with Syntex and the Swiss those countries, the leitmotiv “contra- ized – in part because it required no tox- drug firm Roche. But since we are now ception” in the field of reproductive icity expenses and could focus entirely celebrating the 50th anniversary of the medicine has been replaced by “concep- on diagnostic efficacy and accuracy. But arrival of the Pill in Germany, let us ex- tion”, whereas exactly the reverse ap- in terms of usage, it is employed much amine what has happened during the plies to the pediatric countries. I do not more widely for purposes of conception past decade when two more new steroids wish to imply that the geriatric countries rather than contraception. Work on an – drospirenone (Fig. 12) and dienogest would not be better off if there were a antiviral spermicide (1. in Tab. 4) is still (Fig. 13) were added to the list of the much wider choice of contraceptive op- progressing – primarily because of its seven 19-norsteroids of the norethin- tions, including in those countries where applicability to the AIDS pandemic drone and levonorgestrel type (Fig. 11). birth control is already practiced by a rather than for reasons of improved con- But before doing so, it is nececessary to substantial portion of the population. traception, but so far with little success. emphasize the main motivation in devel- So what new ones might make sense in Easily reversible and reliable male steril- oping the five new chemical modalities Europe or Japan? ization (4. in Tab. 4) would be of great in Figure 11 aside from norethindrone advantage in both pediatric and geriatric and levonorgestrel. Clearly, it was to In 1989 [16], I listed 6 fundamentally countries, since vasectomy is practiced carve out a proprietary position vis a vis new methods (Tab. 4) – not piddling im- widely – notably in China and the US, these two 19-norsteroid prototypes by provements in existing ones – that, if though not in Germany – but mostly by creating minor chemical modifications implemented, would vastly expand the men who are already fathers and wish no that would offer patent protection. choice for human fertility control for all more children. If reversibility were guar- constituencies: poor and affluent, pro- anteed – a very expensive proposition, Because of the huge cost of developing choice and anti-abortion, female and requiring large numbers of volunteers even such minor chemical variants, a male. They would also make a difference and many years of observation then va- considerable effort was also directed by in convenience, economic savings to the sectomy, since it is simple as well as these companies as well as some non- consumer, and possibly even safety. safe, might well be practiced by many profit organizations such as the Popula-

28 J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) The Pill at 50 tion Council toward introducing new tion inhibiting properties. The reason for years ago, are likely to be reassured by delivery vehicles, such as injectables, taking an old chemical, whose patent our results. Our findings might not, how- silastic implants, vaginal rings, skin coverage had virtually expired, and then ever, reflect the experience of women us- patches and the like. In my opinion, such to launch it two decades later as a contra- ing oral contraceptives today, if cur- applied research is well justified in ex- ceptive was based on extensive biologi- rently available preparations have a dif- tending the use of these steroid contra- cal scrutiny which showed that in terms ferent risk to earlier products.” ceptives to a wider population. But what of potential side effects, it seemed to about continuing to create “new” oral offer some advantage over all the other This limitation applies even more dra- contraceptives? Aside from narrow mar- 19-norsteroids because of its mild anti- matically to a second article by the same keting considerations, is there a societal androgenic and anti-aldosterone proper- authors [20] based on 46,112 women ob- need and would the money expended on ties. These became the basis of a suc- served for up to 39 years which con- such endeavor not be better justified if it cessful marketing campaign in 2000 cludes that ever-users of oral contracep- addressed the development of some fun- which quickly propelled drospirenone tion had a significantly lower rate of damentally new methods of the type under the trade name Yasmin into a top death from any cause, including all can- illustrated in Table 4? Again from a soci- selling contraceptive. One might, there- cers, all circulatory diseases, and some etal standpoint, the answer must be a re- fore, reach the conclusion that such an other diseases than the never-users. I sounding affirmative, but what about emphasis on ancillary hormonal at- would claim that from an overall public commercial economic considerations on tributes – separate from the contracep- health standpoint, it is these conclusions the part of a pharmaceutical company? tive properties – would constitute a logi- that should carry much more weight than In that regard, I am afraid that the answer cal rationale for bringing a new steroid relatively minor differences in some of must be negative. In fact, the market has contraceptive to the market. the hormonal effects of the newest com- spoken because none of the major phar- pounds for whom such epidemiological maceutical companies is spending any While logical, it ignored a crucial lesson studies are not and most likely never will money on such new areas for the obvi- from history. As I described in great de- be available. ous reason that in terms of urgency in the tail [1, 11], the first three oral contracep- geriatric countries, birth control cannot tives (norethynodrel, norethindrone, and Thus, in the case of drospirenone and possibly even should not have a high levonorgestrel) were scrutinized medi- (Fig. 12) in 2010 a series of law suits priority. Few will argue that spending a cally over a period of ca. 20 years to an were initiated against Schering claiming few billion dollars on a new contracep- extent that has never been equaled by an increased risk of thromboembolic tive would be more useful – societally or any other drug in medicine, primarily disorders and other vascular problems commercially speaking – than a drug because these were potent drugs that in women using Yasmin compared to preventing Alzheimer’s disease. were given for years to “healthy” people those in women on oral contraceptives for preventive rather than curative pur- containing the older 19-norsteroids It is for this reason that in 1994 [18], I poses, which carried with it an almost (Fig. 11). While this increased incidence proposed with Stanley Leibo a different unrealistic emphasis on safety. Among of thromboembolic problems is small, it approach to birth control in males that the main side effects studied were poten- clearly was enough to tarnish the reputa- would not involve research nor market- tial thromboembolisms and cancers. It tion of Yasmin. Was that the reason that ing by pharmaceutical giants. But since took at least two decades in the post- Schering introduced still another new male contraception is not the focus of marketing phase to carry out these huge oral contraceptive in 2009, this time this article, I shall conclude with some epidemiological studies, which would based on the 19-norsteroid dienogest personal reflections on the introduction be impossible to perform in a pre-mar- (Fig. 13)? of the two latest oral contraceptives, keting period, because it would require drospirenone (Fig. 12) and dienogest unrealistically high numbers of experi- Under the trade names Natazia and (Fig. 13) – both developed in Germany – mental subjects for financially too bur- Qlaira, the substance was touted as the which are sometimes called “fourth gen- densome time periods. In the process, first oral contraceptive to use as compan- eration” oral contraceptives. Are they re- one of the most significant positive side ion estrogen estradiol valerate instead of ally new and why were they developed? effects was uncovered, namely a protec- the conventional ethynylestradiol – the tive action against ovarian cancers in implication being that these were new Chemically speaking, drospirenone nearly 50% of the user population. Be- chemicals. In point of fact, dienogest (Fig. 12) is indeed unique among oral cause such studies required many years, had already been synthesized in 1979 contraceptives, since all the others these were based on the then only exist- [21] by Kurt Ponsold and colleagues and (Figs. 10, 11) are based on the ubiqui- ing three Pills – norethynodrel, norethin- launched under the tradename Valette in tous 19-norsteroid skeleton, whose ori- drone, and levonorgestrel. Indeed, the 1990 by Jenapharm in combination with gin I have described in excruciating de- recent report by Hannaford et al [19] ethynylestradiol as an oral contracep- tail through the history of norethindrone; summarizing the results from a mam- tive. Its commercil success was appar- all of these substances were designed moth study comparing 339,000 woman ently one of the reasons why Schering specifically to act as orally active pro- years of never-users with 744,000 then acquired this East German concern. gestins. Drospirenone, on the other woman years of ever-users of the Pill, Estradiol valerate has been known for hand, was developed nearly 40 years ago contains the statement: “Many women, well over half a century. Natazia is as an aldosterone antagonist and only especially those who used the first gen- claimed to be more effective than other much later discovered to possess ovula- eration of oral contraceptives many oral contraceptives in controlling heavy

J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) 29 The Pill at 50

Table 4, with the possible exception of a professional ones – who postpone child- Table 5. Monthly cost in £ of oral contraceptives [NHS New Drug Evaluation viral spermicide as a side issue related to bearing to their late thirties or even early No. 98, November 2009]. research on drugs effective against forties. By then, the quality of their eggs… AIDS. As I pointed out, the reasons are their own eggs… is not what it was when – Norethindrone 0.51–0.92 logical because these companies are fo- they were ten years younger. But with – Levonorgestrel 0.96–1.32 cusing on the crucially important and ICSI, such women could draw on a bank – Desogestrel 2.19 unsolved problems of an increasingly account of their frozen young eggs and – Drospirenone 4.90 geriatric population where the illusory have a much better chance of having a – Dienogest 8.39 “totally safe” criterion does not apply normal pregnancy later on in life. I’m not nor does the enormous potential of li- talking about surrogate eggs. menstrual bleeding. Is that really a rea- ability suits. A cancer patient is unlikely son for replacing the virtually identical to sue as a result of side effects that a Felix: Later in life? Past the meno- Jenapharm product Valette with its 20- user of contraceptives or vaccines would pause? year long history of wide use with still consider unacceptable. Pharmaceutical another oral contraceptive containing a companies are not philanthropic organi- Melanie: You convert men in their 50s 50-year old estrogen and at the same zations, who can afford to ignore the fi- into successful donors. time making it the most expensive oral nancial bottom line. contraceptive on the market? Felix: Then why not women? Are you But there is a second reason why I be- serious? In my opinion, contraception is too im- lieve that significant new work on con- portant a public health feature world traceptives will not occur as the empha- Melanie: I see no reason why women wide to have minimal marketing advan- sis in Europe and other geriatric coun- shouldn’t have that option … at least tages be the reason to resurrect old drugs tries shifts from “contraception” to under some circumstances. But think be- and claim them to be new “fourth gen- “conception.” As I argued in both a yond that … to a wider vision of ICSI. eration” advances, albeit in a more com- book [1] and two plays [22, 23], within I’m sure the day will come – maybe in plicated polyphasic formulation. Since a few decades the option of preserving another 30 years or even earlier – when the National Health Service in the UK one’s gametes at a young age, say the sex and fertilization will be separate. Sex covers contraceptives, its cost of the early twenties, followed by resorting to will be for love or lust. various steroid contraceptives is of con- IVF for the one or two children that cern as summarized in Table 5. European families now have, would be- Felix: And reproduction under the come a realistic option – especially for microscope? Does it really make sense to pay 10 to 15 those women who now postpone child times more for such “new” agents by bearing and thus would be in a position Melanie: And why not? comparison with oral contraceptives that to operationally extend their fertile life are still consumed by millions of women time. The obvious corollary would then Felix: Reducing men to providers of a and have been the subject of decades- be to consider early sterilization which single sperm? long epidemiological studies [19, 20]? would make contraception unnecessary For the pediatric countries of the world, for effective and desired family plan- Melanie: What’s wrong with that … em- the answer is a resounding no. But is it ning. None of these shifts would in- phasizing quality rather than quantity? even justified for the geriatric countries volve the pharmaceutical industry and I’m not talking of test tube babies or ge- – especially in these days of nearly un- hence can be implemented as a matter netic manipulation. sustainable increases in medical care of public policy as has been illustrated during economically troubled times? for a male contraceptive alternative Felix: And then what? [18]. In the long run, it will probably not make Melanie: Each embryo will be screened any difference for two reasons. First, the As a scientist, who at one time was also genetically before the best one is trans- only entities with the scientific and fi- an executive of a pharmaceutical com- ferred back into the woman’s uterus. All nancial resources to create new chemi- pany and who has turned into a play- we’ll be doing is improving the odds cally-based contraceptives are the large wright of “science-in-theatre” plays, it over Nature’s roll of the dice. Before you pharmaceutical firms. Continuing to seems only fitting that I present my pre- know it, the 21st century will be called dabble with minor modifications of ex- diction of the divorce of sex from repro- “The Century of Art.” isting steroid progestins combined with duction in dramatic form through a brief estradiol derivatives does not seem to me dialogic excerpt [22] from “An Immacu- Felix: Not science? Or technology? to be of overriding societal benefit. A late Misconception” between Dr. Melanie focus on improvements in postcoital Laidlaw, a reproductive biologist and (in Melanie: The science of… A… R… T: agents – the “morning after pills” – the play) the inventor of intracytoplas- assisted reproductive technologies. might well be more useful for consum- mic sperm injection (ICSI), and her clini- Young men and women will open repro- ers, but hardly to drug firms. Among the cal colleague, Dr. Felix Frankenthaler. ductive bank accounts full of frozen twenty largest in the world, not one is sperm and eggs. And when they want a working on new methods for fertility Melanie: Now, if ICSI works in humans… baby, they’ll go to the bank to check out control of the type summarized in think of those women – right now, mostly what they need.

30 J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) The Pill at 50

Felix: And once they have such a bank account… get sterilized?

Melanie: Exactly. If my prediction is on target, contraception will become superfluous.

Felix: I see. And the pill will end up in a museum… of 20th century ART?

Melanie: Of course it won’t happen overnight… But A… R… T is pushing us that way… and I’m not saying it’s all for the good. It will first happen among the most affluent people… and certainly not all over the world.

 Conflict of Interest No financial conflict of interest.

All figures kindly provided by Carl Djerassi.

References: 1. Djerassi C. This Man’s Pill: Reflections on the 50th birthday of the Pill. Oxford Univer- sity Press, Oxford 2001. The German translation was published under the title “This Man’s Pill: Sex, die Kunst und Unsterblichkeit”. Haymon Verlag, Innsbruck, 2001. 2. McCurdy P. Scientists argue problems of “hinge of history”. Chem Eng News 1971; 49: 24–5. 3. Kennedy D. Birth Control in America: The Career of Margaret Sanger. Yale University Press, New Haven, 1970. 4. Asbell B. The Pill: A Biography of the Drug that changed the World. Random House, New York, 1995. 5. Speroff L. A Good Man: Gregory Goodwin Pincus. The Man, his Story, the Birth Con- trol Pill. Arnica Publ., Portland, 2009. 6. Pincus G. The Control of Fertility. Academic Press, New York, 1965. 7. Haberlandt L. Die hormonale Sterilisierung des weiblichen Organismus. G. Fischer, Jena, 1931. 8. Haberlandt E. Ludwig Haberlandt – A pioneer in hormonal contraception. Wiener klinische Wochenschrift, 2009; 121: 746–9. 9. Rock J. The Time Has Come. Knopf, New York, 1963. 10. Djerassi C. The Pill, Pygmy Chimps, and Degas’ Horse. Basic Books, New York, 1992. 11. Fieser LF, Fieser M. Steroids. Reinhold Publ. Corp., 1959. 12. Djerassi C. Steroid oral contraceptives. Science 1966; 151: 1055–61. 13. Colton F B, Nysted L N, Riegel B, Raymond A. L. 17-Alkyl-19-nortestosterones. J Am Chem Soc 1957; 79: 1123–7. 14. Smith H, Hughes GA, Douglas GH, et al. Totally synthetic steroid hormones. Part II. 13β-Alkylgona-1,3,5(10)-trienes, 13β-alkygon-4-en-3-ones, and related compounds. J Chem Soc 1964: 4472–92. 15. Wiechert R. In: Janos Fischer J, Ganellin CR (eds). Analogue-Based Drug Discovery. WILEY-VCH Verlag, Weinheim 2006; 395–400. 16. Djerassi C. The bitter Pill. Science 1989; 245: 356–61. 17. Djerassi C. Birth control after 1984. Science 1970; 169: 941–51. 18. Djerassi C, Leibo SP. A new look at male contraception. Nature 1994; 370: 11–2. 19. Hannaford PC, Selvaraj S, Elliott AM, Angus V, Iverson L, Lee AJ. Cancer risk among users of oral contraceptives: cohort data from the Royal College of General Practitioner’s oral contraception study. Br Med J 2007; 335: 651. 20. Hannaford PC, Iverson L, Macfarlane TV, Elliott AM, Angus V, Lee AJ. Mortality among contraceptive pill users. BMJ 2010; 340: c927. 21. Ponsold K, Hübner M, Schade W, Oettel M, Freund R. Progestagens of the 17α- CH2X-substituted 19-nortestosterone derivative type. Pharmazie 1978; 33: 792–8. 22. Djerassi C. An Immaculate Misconception. Imperial College Press, London, 2000. The German version was published under the title “Kalkül/Unbefleckt: Zwei Theaterstücke aus der Welt der Wissenschaft”. Haymon Verlag, Innsbruck, 2003. 23. Djerassi C. Sex in an Age of Technological Reproduction: ICSI and Taboos. Univer- sity of Wisconsin Press, Madison, 2008. The German version was published under the title “Phallstricke/Tabus: Zwei Theaterstücke aus den Welten der Naturwissenschaft und der Kunst”. Haymon Verlag, Innsbruck, 2006.

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