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

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

Djerassi C

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14 J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1)

The Pill at 50

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

* Portions of this article come from [1].

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

Which 50th Birthday?

How many people – other than those try-ing to hide their age – celebrate the samebirthday in successive years? And whyshould that happen to a drug? Yet in2001, several people (starting with CarlDjerassi [1]) celebrated the 50th birthdayof the Pill, while 9 years later a mediafrenzy exploded all over the world withanother 50th anniversary celebration ofthe Pill. And now, in 2011, we are doingit again by commemorating the date, 50years ago, when the Pill was introducedin Germany. In terms of this article’stitle, this would clearly mean that the Pillis thriving. And in a way it is, especiallyin light of two overwhelming facts of thelast half century – the global populationexplosion and the rise of women’s rights– without which oral contraceptiveswould just have been another medicaladvance and not an invention with enor-mous societal consequences. Yet in thisarticle, I shall also make the contradic-tory argument that the Pill is only surviv-ing, because nothing else is on the hori-zon in terms of fundamentally newmethods of birth control.

During those years, I have been inter-viewed, filmed, and encouraged to pon-tificate on the occasion of various birth-days of the Pill, perhaps because one ofthe ironies of the Pill’s career is that itsown conception has been so hard to pindown. It all depends (as any obstetricianwill tell you) on who is counting. In1997, I spoke at a medical congress inVienna commemorating the 35th anni-versary of the Pill in Austria – not an in-appropriate geographic choice as I willdemonstrate shortly – while in May

2010, I was bombarded by requests frommany American print, radio, and TV re-porters to comment on the “50th birth-day” of the Pill, because the media weredating the Pill’s debut to the formal ap-proval by the Food and Drug Adminis-tration (FDA). While such dates may beoccasions for celebrations, “birthdays”they are not. The Viennese event wasequivalent to celebrating a baby’s arrivalin a town far away from its original birth-place and the 50th “birthday”, especiallyhyped by the American media, couldbe equated to the date on which thebaptismal certificate was issued inWashington. As far as I am concerned(and I was concerned), the real birth dateof the Pill was October 15, 1951, the daywe completed at Syntex in Mexico Citythe first synthesis of a steroid eventuallydestined to be used for oral contracep-tion. A few days later, the first few pre-cious milligrams of “norethindrone”– the generic designation of the formallynamed “17α-ethynyl-19-nortestostero-ne” – was already in the mail fromMexico City to Dr. Elva G. Shipleyat Endocrine Laboratories Inc., a com-mercial establishment in Madison,Wisconsin, with the request that the sub-stance be tested for oral progestationalactivity.

Mothers of the Pill?

I mention Dr. Shipley here primarily be-cause her early participation in the Pill’shistory impinges on a claim often heard– that the scientists involved in the de-velopment of oral contraceptives wereuniformly males. This belief has gratedon women for decades. As MargaretMead [2] put it in the late 1960s: “[The

Pill] is entirely the invention of men. Andwhy did they do it? … Because they areextraordinarily unwilling to experimentwith their own bodies … and they’reextremely willing to experiment withwomen’s bodies … it would be muchsafer to monkey with men than monkeywith women.” While Mead’s irritationmay well be understandable, it neverthe-less represents a gross oversimplifica-tion that ignores that nature had pro-vided scientists with a crucial hint onwhich to build – women do not get preg-nant during pregnancy because of thecontinuous secretion of progesterone –whereas no such clue exists in male re-productive biology. Dr. Shipley’s contri-bution is significant for an additionalreason that may explain some of Mead’sindignation: fifty years ago women werestill largely excluded from many areas ofscientific research. In a field that was un-deniably a male province, Dr. Shipleyhad to do her work in a commercial labo-ratory she had founded next door to theUniversity of Wisconsin where her hus-band, Roland K. Meyer, was Professorof Zoology at a time when nepotismrules were still inviolate.

A pervasive sense of the ironies of thishistoric male bias has caused variouswriters and journalists to search far andwide for female heroes in the record ofthe Pill. Margaret Sanger is the favorite,probably for reasons stated in the finalparagraph of David Kennedy’s definitivebiography [3]: “Yet the praise MargaretSanger received often seemed out ofproportion to her achievement. Part ofthe hyperbole, undoubtedly, derivedfrom her personal magnetism, whichrarely failed to bring those who met her

This article describes in detail the history behind the chemical development of oral contraceptives, notably the synthesis of norethindrone, which repre-sents the chemical template from which virtually all subsequent oral contraceptives are derived. Attention is also paid to the introduction of the mostrecent oral contraceptives in Germany and reasons are provided for the dim overall prognosis about the future of contraception, namely that nothingfundamentally 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

For personal use only. Not to be reproduced without permission of Krause & Pachernegg GmbH.

The Pill at 50

J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) 15

into her orbit. But a larger part reflectedMrs. Sanger’s symbolic satisfaction of apervasive psychological need. Americansociety in this century has not realized itsfrequently stated ideal of equal status forwomen. Perhaps, therefore, the apo-theosization of a feminist heroine likeMargaret Sanger reflects society’s rec-ognition of the continuing victimizationof women, and the desire, in some way,to find a redemptress. For that role Mar-garet Sanger, at her best and at her worst,was well suited.”

Still, Sanger’s historic, though certainlynot scientific role in fostering the birthcontrol movement in the USA wouldvalidate her choice as one of the grand-mothers of the Pill. A more romanticizedcandidate is Katherine McCormick, awealthy philanthropist, who was per-suaded by Sanger in the early 1950s tosubsidize some of the biological work atthe Worcester Foundation for Experi-mental Biology that under the leadershipof Gregory Pincus contributed heavily tothe development of the Pill. Howevercommendable such philanthropy is,anointing Katherine McCormick as oneof “the indisputable mothers of the Pill”(as was done by one journalistic author,Bernard Asbell, in “A Biography of theDrug that changed the World” [4] andthen repeated by many others), is as far-fetched as calling John D. Rockefellerone of “the fathers of the Pill”. (TheRockefeller Foundation and its offspring,the Population Council, supported muchmore research in reproduction and con-traception than Mrs. McCormick everdid and has continued to do so over thecourse of many decades). A curious fact,not commented upon by any other writ-ers (e.g. [5]) on the role of GregoryPincus is that Pincus, though dedicatinghis opus magnum, “The Control of Fer-tility” [6] to “Mrs. Stanley McCormick”for “her steadfast faith in scientific in-quiry …” did not mention any financialsupport on her part in his acknowledg-ment section in spite of a lengthy list offunding agencies, individuals, and com-panies, notably G. D. Searle and Co.

Financial support, valuable as it may be,can never be equated with creativity;otherwise, the Medicis would be consid-ered the greatest artists of the Renais-sance. Instead, let me add the name ofElva G. Shipley as literally the first bi-ologist – male or female – who estab-

lished the high progestational activity oforally-administered norethindrone. Ifher results had been negative, we wouldhave dropped the project and wouldnever have sent the material to other bi-ologists, including Gregory Pincus,who, as I will demonstrate below, canrightfully be called a “father of the Pill”.

Since the Pill is so intimately connectedwith human reproduction, albeit in termsof preventing it, let me pursue the Pill’sgenealogy through the metaphor of re-production. Call the Pill the baby andfollow its birth through (1) the first (un-successful) attempts at conception, (2)the ovulation of a fertile egg, (3) theejaculation of various sperm, (4) the suc-cessful fertilization, (5) the implantationof the embryo, (6) the fetal development,and finally (7) the birth of the baby. Geo-graphically, the first step occurred inAustria, the second in Mexico, the next3 in the continental United States, andthe last in Puerto Rico – not untypical fora baby in the present highly mobile soci-ety.

The Overlooked Role of

Ludwig Haberlandt

The least-known character in the Pill’sstory is not a woman after all. It isLudwig Haberlandt, professor of physi-ology at the University of Innsbruck. Asearly as 1919, he carried out a crucialexperiment, in which he implanted theovaries of a pregnant rabbit into anotherrabbit, which, in spite of frequent coitus,remained infertile for several months – aresult that Haberlandt called “hormonaltemporary sterilization”. (Partisans ofMrs. McCormick might take note that thisand subsequent work of Haberlandt’swas supported financially by the Rocke-feller Foundation.) The problem withthis method, of course (other than its re-liance on surgery), as well as with subse-quent attempts to avoid surgery by theuse of “glandular extracts”, was thatthese extracts were not the pure hormoneresponsible for its contraceptive effect.A mixture of hormones and other pro-teins, they constituted a potential prob-lem of toxicity for the recipient. At-tempts to “purify” these extracts pre-sented the next hurdle to overcome onthe way to a practical oral contraceptive.

In numerous subsequent experimentsand publications over the course of ten

years, Haberlandt – invariably using thefirst person singular, so strikingly differ-ent from today’s insistence by scientistson the royal “we” – emphasized the ob-vious applicability of his animal experi-ments to human contraception. He fullyrecognized that the responsible factorwas a constituent of the corpus luteumand in 1931, in a remarkable book [7],“The Hormonal Sterilization of the Fe-male Organism” (Fig. 1), of less than15,000 words that hardly anyone nowliving seems to have read, Haberlandtoutlined in uncanny detail the contracep-tive revolution of some thirty years later.He pointed out that oral administration,which he actually demonstrated in mice,would be the method of choice as well asthe necessity for periodic withdrawalfrom the hormone to allow menses tooccur. He called for the use of such con-traception on clinical and eugenicgrounds, arguing that it would enableparents to have the desired number ofhealthy children. Objections by peoplelike the sexologist van de Velde that toomany women would take advantage ofhormonal contraception was dismissedby Haberlandt with the argument thatsuch preparations would require aphysician’s prescription and would notbe made available over the counter. Heended his manifesto with a visionaryclaim: “Unquestionably, practical appli-cation of the temporary hormonal steril-ization in women would markedly con-

Figure 1. Title page of Haberlandt's book.

Figure 2. Newspaper headlines (1927) about Pill forWomen.


The Pill at 50

tribute to the ideal in human societyalready enunciated a generation earlierby Sigmund Freud (1898). Theoretically,one of the greatest triumphs of mankindwould be the elevation of procreationinto a voluntary and deliberate act”.

Haberlandt did not limit his publicationsto the scientific literature. He also pub-lished in the popular press and gave in-terviews that led to huge newspaperheadlines (Fig. 2) like “My aim: fewerbut fully desired children!” (in theJanuary 20, 1927 issue of the Acht UhrAbendblatt, Berlin) complete with com-mentary by the now-familiar chorus ofphysicians, lawyers, and theologians.His obsession with the therapeutic po-tential of corpus luteum extracts was sowell known that his students hung a ban-ner by his home with the couplet,“Verdirb nicht Deines Vaters Ruhm mitDeinem Corpus Luteum” [Don’t maryour father’s renown with your corpusluteum]. But Haberlandt was not contentwith the visionary’s role only. He con-tacted several pharmaceutical compa-nies in an attempt to obtain consistentlyactive and nontoxic corpus luteum andplacental extracts for human clinical ex-periments. In his 1931 book, he finallyreported success in the following words:“I have been in contact for over threeyears with the therapeutic firm GideonRichter in Budapest [to this day, a com-pany active in the steroid field] and it islikely that in the near future a suitable‘sterilizing preparation’ under the name‘Infecundin’ will be available for sys-temic administration in clinical experi-ments as I had already announced inVienna [September 1930]”. He con-firmed that experiments in mice withorally-administered “Infecundin” haddemonstrated temporary infertility with-out toxic reactions, “since only in thismanner does the new method have anychance for clinical success”. A yearlater, the 47-year old Haberlandt com-mitted suicide [8] as a result of the inces-sant criticism of his work in conservativeAustria, but the name “Infecundin” sur-vived. In 1966, it became the trade nameof the first oral contraceptive producedin Hungary by the very same companyHaberlandt had contacted 40 years ear-lier.

Within 2 years of his death, pure proges-terone was isolated in no less than fourlaboratories in Germany, the US and

Switzerland; its chemical structure es-tablished by Karl Slotta (a Hitler refugeeeventually settling in Brazil); and itssynthesis from the soyasterol stigmas-terol accomplished by Fernholz inGöttingen and by Butenandt in Danzig.Had Haberlandt lived, there is no ques-tion that he would have pursued hisdream of temporary hormonal steriliza-tion in humans without resorting to cor-pus luteum extracts. But even with pureprogesterone, he could have shown onlythat ovulation can be inhibited by injec-tion as the appropriately named Ameri-can investigator A. W. Makepeace dem-onstrated in 1937 in rabbits and E. W.Dempsey in guinea pigs. For oral admin-istration, Haberlandt would have neededanother steroid – not naturally occur-ring, but waiting to be synthesized – andthat took 20 more years. Thus, nothingfurther happened, and Haberlandt’swork fell into such oblivion that the nextbiologist to take it up, Gregory Pincus(who clearly should have known better),did not even feel obligated to citeHaberlandt among the 1459 referencesin his own book [6]. Nor for that matterdid Pincus’s clinical collaborator, JohnRock, whose book The Time has Come[9] quotes Makepeace’s work but noneof Haberlandt’s pioneering earlier re-search. Yet if there ever was a grand-father of the Pill, the Austrian LudwigHaberlandt above all others deservesthat honor. Aside from not mentioningHaberlandt’s work, these 2 books byPincus and Rock, who are often calledthe 2 fathers of the Pill – an interestingvariant of parthenogenesis contain a sur-prising lacuna: zero reference to thechemical invention of the Pill, withoutwhich, of course, no biological or clini-cal research on today’s Pill could evenhave started.

Since the term “father of the Pill” carriesreproductive connotations, the develop-ment of oral contraceptives might welldeserve some reproductive metaphor.Thus one might ask why the metaphoricfathers, Pincus and Rock, did not referto the usual missing partner in such aprocess, namely a metaphoric mother?In my own writings, I have frequentlymade the point that for any syntheticdrug – oral contraceptive, antibiotic, anti-cancer or anti-anything – the organicchemist assumes the irreplaceable ma-ternal function. I anoint the chemist withthe maternal role, because I consider the

synthetic chemical – by definition in-vented and synthesized by the chemist –as the egg that needs to be fertilized. Thebiological experiments that are subse-quently conducted are then the father’ssperm, with the key biological experi-ment representing the crucial seminalevent that caused fertilization of the egg.Only then does the clinician enter thepicture as midwife. It is this triad, inwhich each component is indispensable,that deserves consideration and it isamazing to what extent the maternal roleof the chemist is often downplayed orignored outright in medicine. Conse-quently, much of what I have to say inthis article will focus on chemists andthe underlying chemistry.

What was the Real Role

of Russell Marker?

For mostly journalistic reasons, manyaccounts of the Pill’s early genealogystart with the name of Russell Marker, aresearch professor at Pennsylvania StateCollege in the late 1930s and early1940s. Perhaps what attracted the jour-nalists and TV filmmakers to add Markerto the list of fathers of the Pill wasMarker’s status as a maverick. Lackingthe formal union card of a Ph.D.,Marker’s true rank as one of the giants ofsteroid chemistry was recognized onlytwo decades after his sudden and totalwithdrawal from chemistry while still inhis forties. But despite his genuine claimto greatness in the larger field of steroidchemistry, in terms of oral contraceptionin particular he contributed nothing.

Which is not to say that Marker wasn’timportant, albeit indirectly, for makingthe raw materials of contraceptive re-search more readily available. Until themid-1940s, virtually all clinically usefulprogesterone was prepared in one way oranother from soyasterols or cholesterolin processes that required conversion ofsuch sterols into intermediate productsprior to final transformation into proges-terone. These intermediate steps repre-sented a bottleneck, as only limitedquantities of the necessary substancescould be generated at one time. Not sur-prisingly, this poor yield kept the priceof progesterone very high (approxi-mately US$ 80/gram in the early 1940s).All this changed dramatically whenMarker revolutionized the chemical pro-duction of progesterone. Within a few


The Pill at 50

years, as a result of his process, the costof progesterone dropped sufficiently thatit became inexpensive enough to be usedas the starting material for the synthesisof other steroids (for instance cortisone),rather than just serving as a clinicallyuseful drug for menstrual disorders. Butwhat, precisely, was the nature ofMarker’s discovery?

In the late 1930s and early 1940s, Markerconducted research on a group of ste-roids called “sapogenins”, compoundsof plant origin. They got their name be-cause, in their naturally-occurring form(where they are linked to sugars in com-pounds called “saponin”) they formsoapy lathers in water. Natives of Mexicoand Central America had long used themfor doing laundry and to daze or kill fish.Marker concentrated on the chemistry ofa member of this group called diosgenin,which was present in certain types of in-edible yams (Dioscorea species) grow-ing wild in Mexico. He succeeded in de-veloping a five-step, high-yield conver-sion of diosgenin into progesterone. Allkinds of apocryphal stories have beenwritten about Marker’s departure fromPennsylvania State College duringWorld War II and his move to Mexico,many embellished with mysterious dis-appearances into the Mexican jungle,newspaper-wrapped parcels containingthe equivalent of the world’s supply ofprogesterone, and the like. But in 1979(approaching the age of 80), he visitedme at Stanford University and permitteda taped interview, excerpts of whichhave appeared in book form [1].

The interview ended on a poignant note.A driver had come to take Marker frommy Stanford office to the San Franciscoairport from where he was supposed tofly to Mexico City for a brief visit. Heasked for the men’s toilet and as I ledhim there, he suddenly turned to me,“Tell me, where am I? What am I doinghere? What did we talk about?” Fearingthat he had suffered a sudden memoryloss, I reached into his jacket and drewout his plane ticket. After explaininggently where he was, I gave the ticket tothe driver, asking him not to just drop offMarker at the airport, but rather see to itthat he boarded the plane. A few weekslater, I learned that Marker had suffereda mild heart attack and had been takenoff the plane in Texas to a hospital. I hadconducted my taped interview in the

presence of my colleague, the late HarryMosher, then Emeritus Professor ofChemistry at Stanford, who had been agraduate student at Penn State and hadworked in the same laboratory asMarker. After Marker departed, Mosherturned to me. “There are other versionsas well”. And sometime later, after I hadpublished an autobiography [10] inwhich Marker was mentioned, I receiveda letter from a reader, an Americanchemist then living in Israel, who hadalso worked in the same laboratory atPenn State. It was a startlingly bitterletter, citing evidence to support his viewthat Marker had been virulently anti-Semitic around the outbreak of WorldWar II, a claim that was subsequentlyconfirmed by another independent wit-ness from the early 1940s.

In terms of the chemical history of thePill (though not in the eyes of a refugeefrom Hitler, like myself), Marker’s pur-ported anti-Semitism would appear to beirrelevant. But there is an intriguing as-pect to Marker’s alleged prejudice. HisPh.D. supervisor at the University ofMaryland was Morris Kharasch, one ofthe very first Jewish professors in theWASP-dominated university chemistryfaculties of pre-World War II America.For reasons that have never been com-pletely clarified, Marker never finishedhis doctorate at Maryland, but, followinga short industrial stint at Ethyl Corpora-tion, he spent 6 years at the RockefellerInstitute working under another well-known Jewish chemist, Phoebus Levene.That collaboration broke off so bitterlythat Marker – in a last gesture of defi-ance to a superior – removed the labelsof virtually all the research samples thathe left behind when he departed for hisnew position at Pennsylvania State Col-lege. Among chemists, only burningone’s laboratory notebooks would be aworse act of vandalism.

The only subsequent time I met Markerwas in 1984, when the annual RussellMarker Lectures in the Chemical Sci-ences at Pennsylvania State Universitywere inaugurated through his own funds.He requested that I present the first se-ries and I used that opportunity to payhomage to him by paraphrasing “Marker-at-Stanford” in front of Marker. Physi-cally and mentally, he was in fine fettleand I was pleased that he wanted me toinitiate the annual event established in

his honor. Still, Marker’s enduring con-tribution to contemporary chemistry,and indirectly also to pharmacology andmedicine, lies in his discovery that ste-roid hormones could be synthesizedfrom a naturally occurring and cheapplant source – research that I consideredso important that on one occasion Inominated Marker for a Nobel Prize.

Partial vs Total Synthesis

To appreciate the significance ofMarker’s work it is necessary to under-stand the difference between “total” and“partial” synthesis. To a chemist, “totalsynthesis” is making a molecule fromscratch – essentially from air, carbonsources (such as coal or petroleum), wa-ter and other elementary substances –not unlike building a house from clayand timber, iron and sand. “Partial syn-thesis”, on the other hand, involves start-ing with an advanced structure – say abarn – and then converting it into a hab-itable house with plumbing and centralheating. In Marker’s synthesis, the build-ing to be constructed was a “steroid” – aterm that one hears often enough in con-temporary life, but rarely (outside of or-ganic chemistry classes) in its properdefinition as the tetracyclic chemicalskeleton known generically by the for-bidding name “perhydrocyclopentano-phenanthrene” (Fig. 3).

Tens of thousands of synthetic, and sev-eral thousands of natural compounds arebased on this fundamental steroid skel-eton made up of carbon and hydrogenatoms only differing minutely in chemi-cal structure by the attachment of someadditional atoms (usually oxygen) atvarious locations. The variations, how-ever minute, produce dramatically dif-ferent biological results. Many of themost important biologically active mol-ecules in nature represent slight varia-

Figure 3. Steroid skeleton

The Pill at 50


tions on the steroid skeleton: the maleand female sex hormones, bile acids,cholesterol, vitamin D, the cardiac-ac-tive constituents of digitalis, the adrenalcortical hormones (related to cortisoneand usually referred to generically as“corticosteroids”) and many plant-de-rived and marine natural products.

When Marker started his research in the1930s, the total synthesis of steroids hadnot yet been accomplished. All steroidhormones then known (e.g. progester-one and testosterone) were producedonly by “partial” synthesis from natu-rally occurring steroid precursors,mostly from cholesterol and bile acids –both of animal origin. By pursuing syn-thesis from such a starting point, chem-ists were simply imitating nature, whichuses cholesterol as the starting materialfor the synthesis of steroids in the body.And although kilogram quantities of ste-roid hormones such as progesteronewere produced since the late 1930s bysome European drug companies, themethods were unwieldy. Marker’s con-tribution was to show that compoundsderived from plant sapogenins could betransformed much more cheaply into thedesired steroid “house” (e.g. progester-one) than could be generated from amore cumbersome “barn” such as cho-lesterol.

The Mexican Connection:

The Role of Syntex

As he recounted in his interview withme, after he was unable to convince anyAmerican pharmaceutical firm of thecommercial potential of diosgenin,Marker formed in Mexico in 1944 a smallcompany, Syntex, in partnership withtwo European immigrants, the Hun-garian Emeric Somlo and the GermanFederico Lehmann. A few months later,Syntex started to sell to other pharma-ceutical companies (but not to the gen-eral public) pure, crystalline progester-one prepared by Marker’s process in fivechemical steps from diosgenin. Within ayear the partners had a disagreement,and Marker left the company, taking histechnical expertise with him. For a time,Syntex was without its most profitableproduct.

Early in his academic career, however,while still at Pennsylvania State College,Marker had published a description of

his chemical processes in the Journal ofthe American Chemical Society [11].Since no one had taken out patents inMexico for his discoveries, the commer-cial production of progesterone from di-osgenin was up for grabs in that country.Somlo and Lehmann, looking for an-other chemist who could re-establishthe manufacture of progesterone fromdiosgenin at Syntex, recruited GeorgeRosenkranz from Havana. A Hungarianlike Somlo, Rosenkranz had immigratedto Cuba a few years earlier from Switzer-land, where he had received his doctor-ate under the Nobel laureate LeopoldRuzicka (one of the giants of early ste-roid chemistry) and was already familiarwith Marker’s publications. Within twoyears, Rosenkranz had re-instituted thelarge-scale manufacture of progesteronefrom diosgenin. Even more important,he had achieved the large-scale synthe-sis, from those same Mexican yams, ofthe commercially more valuable malesex hormone testosterone. Both synthe-ses were so much cheaper than the meth-ods used by the European pharmaceuti-cal companies then dominating the ste-roid hormone field – such as CIBA inSwitzerland, Schering in Germany, andOrganon in Holland – that in a shortwhile tiny Syntex broke the internationalhormone cartel. As a result, prices fell,and these hormones became much moreavailable. In the late 1940s, Syntexserved as bulk supplier to pharmaceuti-cal companies throughout the world, butfew people outside these firms evenknew of the existence of this smallchemical manufacturing operation inMexico City, which was soon to revolu-tionize steroid chemistry and the steroidindustry all over the world. By the late1950s, over half the world’s supply ofsteroid hormones originated fromMexico, where in the meanwhile otherAmerican and European pharmaceuticalcompanies had also started to establishmanufacturing subsidiaries based on thecommercial exploitation of diosgenin.

So why do I relegate Marker at best tothe role of a distant maternal grand-uncle in the genealogy of the Pill? Be-cause the availability of progesterone onan industrial scale did not contribute inany way whatsoever to the developmentof oral contraceptives. Certainly a sourceof pure progesterone was necessary, andin sufficient quantities to investigate itstherapeutic use. But the need of pro-

gesterone for contraception had beenHaberlandt’s insight, not Marker’s, andthe provision of pure progesteronehad already been achieved long beforeMarker in the 1930s, shortly afterHaberlandt’s death, through the work ofGerman scientists like Erhard Fernholzand Adolf Butenandt, who won a NobelPrize in 1939 for his steroid research.But nothing had happened, not becauseprogesterone was expensive, or in shortsupply, but simply because it was notsufficiently active by oral ingestion to betaken as a pill. By the time Marker ap-peared on the scene with a new and bet-ter synthesis of progesterone, the pro-gesterone contraceptive boat had alreadysunk. It took two other maternal unclesand a mother to construct a new one, anda father to make it seaworthy.

Without Marker, of course, there wouldnot have been any Syntex – the physicalsite in Mexico where the maternal rolewas played out. But there is no questionthat some other mother would haveappeared elsewhere soon thereafter, be-cause in the chemical sense, two olderGerman maternal relatives (MaximilianEhrenstein and Hans Herloff Inhoffen),often completely ignored, had inadvert-ently pointed the way for a chemicalmother to produce the requisite ripe egg– in other words, the creation of a syn-thetic steroid mimicking the biologicalrole of progesterone, but being active bymouth. Before describing that “mater-nal” process, a brief detour from oralcontraceptives to cortisone is warrantedbecause, while cortisone has no biologi-cal connection to the Pill, cortisone wasnevertheless the molecule that broughtme to Syntex in Mexico and hence to thePill.

Some Autobiographical

Observations: Cortisone

and Oral Progestins

By the fall of 1945, a 22-year-old, newly-naturalized American citizen with aPh.D. degree from the University ofWisconsin and a wife, I returned toCIBA (the pharmaceutical firm in NewJersey where I had worked for one yearafter graduation from Kenyon College)for another four years, to resume workon antihistamines and other drugs. Oneday in the spring of 1949, I received anunsolicited employment offer fromSyntex, a company I had never heard of.


The Pill at 50

Although the position, as associatedirector of chemical research, seemedtempting to me, the location of Syntex inthe scientific backwater of Mexico madethe offer seem ludicrous. Fortunately, Iam a tourist at heart; when I heard theinvitation, “Come and visit us in MexicoCity, all expenses paid”, I went. And asa bonus decided to include a visit toHavana in my itinerary.

George Rosenkranz, then technical di-rector of Syntex and barely past 30, im-pressed me enormously as a sophisti-cated steroid chemist; he also charmedme personally. Rosenkranz showed merather crude laboratories, but he prom-ised lots of laboratory assistants and sub-stantial research autonomy to devise apractical synthesis of cortisone and topursue other aspects of steroid chemistrythat might interest me. Furthermore,even though the labs were primitive,Syntex could boast of some advancedequipment such as an infrared spectrom-eter at a time when neither CIBA nor myalma mater, the University of Wisconsin,had such an instrument, which proved tobe enormously useful for steroid re-search.

I arrived at Syntex in the late autumn of1949, just around my 26th birthday. Ihave never regretted that decision, eventhough at that time my American col-leagues considered me mad to move toa country that, although famous formariachi music, bull fights, and pre-Columbian ruins, had only generated thebarest of blips on the radar screen of in-ternational chemical journals. Yet I wasconvinced that the best route to the aca-demic job still eluding me was to estab-lish a reputation in the scientific litera-ture. I felt intuitively that Mexico wasthe right place for me. Syntex had thesame objective I did: to establish a scien-tific reputation. Our common goal – the“partial” synthesis of cortisone from aplant raw material – was one of the hot-test scientific topics in organic chemistryat that time. I was young and willing togamble on a few years in Mexico – partlybecause living in another country andlearning another language appealed tome, but also because I thought that anyscientific achievement from a laboratoryin Mexico was likely, upon publication,to make a much bigger impression onacademia than one coming from theusual elite laboratories in North America

or Europe. Consequently, I really hadonly one requirement before I acceptedthe Syntex offer, and that was to publishany scientific discoveries promptly inthe chemical journals. Syntex agreed tothis and stuck to its bargain. From myprevious industrial experience, I fullyunderstood that discoveries have to bepatented by the firm in whose laboratorythe work is performed before they arewritten up for publication. But insteadof having patent attorneys decidingwhether and when to publish, at SyntexRosenkranz and I called the shots – ex-traordinary for a pharmaceutical com-pany. As a result of this policy, duringmy first two years at Syntex we pub-lished more rapidly in the chemical lit-erature than did any other pharmaceuti-cal company, or even many universitylaboratories.

Until 1951, the only source of cortisonewas through an extraordinarily complexprocess of 36 different chemical trans-formations starting from animal bile ac-ids – a tour de force pioneered by LewisSarrett of Merck and Co. For manyyears, this had proved to be the longestand most complicated synthesis of anychemical on an industrial scale. Now thatcortisone had emerged as a wonder drug,developing an alternative partial synthe-sis from a plant raw material became oneof the most acclaimed scientific projects,with a number of powerful academic andindustrial research groups competing tobe first. At the outset, nobody even real-ized that a small research team inMexico City had entered the race. Butwhen we completed ahead of everyoneelse in June of 1951 our synthesis of cor-tisone from diosgenin, the resulting pub-licity was astounding. Thus, long beforeSyntex sold drugs under its own name tothe medical profession, its internationalscientific reputation in chemistry waswell established. Ten years after my tem-porary move to Mexico, when ProfessorLouis F. Fieser of Harvard analyzed in1959 the references in the latest editionof his text Steroids [11], the recognizedbible of steroid research, he found thatno laboratory in the world – academic orindustrial – had published as much in thesteroid field as Syntex had in that time.Chemistry south of the Rio Grande hadfinally made the grade.

Which finally brings me back to the Pilland to a discussion of the maternal (i.e.

chemical) role in the birth of oral contra-ceptives as well as my personal involve-ment in the first synthesis of a steroidoral contraceptive. Within the confinesof the present article, it would be super-fluous to go into detail since I have de-scribed that story extensively in two au-tobiographical works [1, 10] addressedto a wider public and have cited all rel-evant chemical and biological literaturereferences in an earlier review article[12].

At the time that I became interested inthe chemistry of progestational steroids,one of the dogmas of steroid chemistrywas that almost any chemical alterationof the progesterone molecule would ei-ther diminish or destroy its biologicalactivity. This belief seemed puzzling inlight of the fact, well known at the time,that estrogenic steroid hormones, whichoccur naturally in a variety of forms, aswell as synthetic chemicals not evenbased on the steroid skeleton, displaymarked estrogenic potency. In 1944,Maximilian Ehrenstein (another emi-grant from Nazi Germany), then work-ing at the University of Pennsylvania,published a paper that was mostly over-looked, but had made a deep impressionon me while still a graduate student. Byan extremely laborious series of steps,Ehrenstein had transformed the natu-rally-occurring steroid cardiac stimulantstrophanthidin into a few milligrams ofimpure oily 19-norprogesterone (actu-ally called “10-norprogesterone” at thattime). To return to my earlier metaphor,Ehrenstein had transformed a very elabo-rate mansion (strophanthidin) into afunky little vacation house. While he hadobtained only enough material for bio-logical testing in two rabbits, in one ofthem his compound had displayedhigher progestational activity than theparent hormone. A positive test in oneanimal out of two could, of course,have been just a fluke. What madeEhrenstein’s results so unusual was whatthat “19-nor” in the compound’s namesignified. It meant that Ehrenstein hadremoved carbon atom No. 19 (betweenrings A and B of the steroid skeleton de-picted in Fig. 3) from the most inacces-sible site of the steroid molecule to re-place it with a hydrogen atom. On paper– or in words – the change sounds trivial.Given the state of the art of organic syn-thesis at the time, however, this was sodifficult an operation that it had required

The Pill at 50


several years for completion. Moreover,if the biological results were real,Ehrenstein’s observation demolished theprevious assumptions about the inviola-bility of the progesterone structure. Butthere was another problem: Ehrenstein’soily product was, as I indicated, impure:a mixture of at least three “stereo-isomers” – molecules that, while struc-turally identical, were, like mirror im-ages, as alike – and fundamentally dif-ferent – as your left hand and your right.In biochemistry, which often requiresmolecules to fit together like a hand in aglove, such a difference can be crucial.Which one of the components, if any,was responsible for the putative proges-tational activity? It took seven years forsomeone to come up with an answer.Our ability to do so led us almost straightto the Pill.

Part of my Ph.D. thesis at the Universityof Wisconsin in the early 1940s had dealtwith the partial synthesis of the then-in-accessible estrogenic hormones from themore readily available androgens, suchas testosterone. For years, the estrogenswere only available by isolation from theurine of pregnant women (and later ofpregnant mares, the source of one of themore-frequently prescribed estrogencompositions in use today for hormonereplacement therapy). In fact, the estro-genic hormones, such as estradiol andestrone, were the last steroid types toyield to partial synthesis, because noobvious precursor for them existed innature. All of the other naturally-occur-ring steroids are based on the skeleton inFigure 3; the estrogens, however, arebased on the structure for estradiolshown in Figure 4. Here, ring A haschanged from the ordinary six-sidedform to an “aromatic” form, where halfthe carbon-carbon bonds are double. Youdon’t need a Ph.D. in organic chemistryto note the other difference between theestrogens and all other steroids. This is

the absence of carbon atom 19 usuallyattached at position 10, which makespossible the doubling-up of carbon-car-bon bonds in ring A. Chemically speak-ing, the only difference between test-osterone (a conventional steroid withcarbon atom 19) and the estrogens (“aro-matic” steroids lacking C-19) – betweenmen and women – is that one carbon, butwhat a difference it makes!

The partial synthesis of steroid hor-mones such as testosterone and progest-erone could be extended to the estrogensif a process could be devised that wouldeliminate the key carbon atom No. 19and thus effect the “aromatization” ofring A so typical of the estrogens. HansH. Inhoffen, at Schering A.G. in Berlin,had demonstrated the practical feasibil-ity of such a chemical conversion, butthe work had been performed duringWorld War II and experimental detailswere scant and had to be partly recon-structed. Syntex had started to use theInhoffen process (which had not beenpatented in Mexico) for the productionof modest quantities of estrone and es-tradiol. Upon assumption of my researchposition there, I suggested to Rosenkranzthat Syntex examine another and poten-tially proprietary route to the estrogensdirectly from testosterone. In less thanthree months we succeeded in accom-plishing this aim, which in chemical jar-gon would be described as the “aromati-zation of ring A of conventional ste-roids”.

Our partial aromatization studies turnedinto the impetus that led us in a fairlystraight path to the first synthesis of anoral contraceptive. From a technicalstandpoint, I felt that the time was ripe to

follow up on Ehrenstein’s lead of 1944.Using various chemical methods devel-oped as part of our estrogen synthesis aswell as methodology perfected by theAustralian chemist, Arthur J. Birch (sub-sequently a long-term Syntex consult-ant), my Syntex colleagues and I pre-pared for the first time in 1951 pure,crystalline 19-norprogesterone (a ste-roid that like the estrogens lacked carbonatom 19) which, when assayed in rabbitsat Endocrine Laboratories in Wisconsin,was found to be four to eight times asactive as natural progesterone. In otherwords, Ehrenstein’s observation with anoily mixture tested in one rabbit wasmore than confirmed: replacement ofcarbon atom 19 by one hydrogen hadproduced the most active progestationalsteroid known at that time. This observa-tion was crucial, because Ehrenstein’smixture of stereoisomers had also thewrong configuration at C-17 – a changethat was known to destroy progestationalactivity in progesterone itself (see top 2compounds in Fig. 5) – and from an ex-periment in a single rabbit, it was notclear whether the beneficial effect of re-moving the angular methyl group be-tween rings A and B was real.

With that lead in hand, we turned to an-other accidental discovery that had beenmade in 1939 [12] in Germany, wherechemists at Schering, again under theleadership of Inhoffen, found that ifacetylene is added at position 17 of themale sex hormone testosterone (see17α-ethynyltestosterone in Fig. 5), itsbiological activity is changed markedly:

Figure 4. Chemical structure of estradiol.

Figure 5. Chemical structures of key steroids leadingto the Pill.

Figure 6. Syntex lab notebook (15 Oct. 1951) describ-ing last step in synthesis of norethindrone.


The Pill at 50

for unknown reasons this androgeniccompound has weak progestational ac-tivity. Far more important, it also provedto be orally active. On the reasonable as-sumption that removal of the 19-carbonatom increases progestational potencyand addition of acetylene confers oralefficacy, we at Syntex put both these ob-servations together. On October 15,1951 (see notebook page reproduced inFig. 6), Luis Miramontes, a young Mexi-can chemist doing his undergraduatebachelor’s thesis work at Syntex undermy tutelage, completed the synthesis ofthe 19-nor analogue of Inhoffen’s com-pound – that is, 19-nor-17α-ethynyl-testosterone (bottom left structure inFig. 5) or, for short, “norethindrone” –which turned out to be the first oral con-traceptive to be synthesized.

We immediately submitted the com-pound to our favorite commercial testinglaboratory in Wisconsin for biologicalevaluation and gloated happily whenDr. Elva G. Shipley reported back that itwas more active as an orally effectiveprogestational hormone than any othersteroid known at that time. In less thansix months, we had accomplished ourgoal of synthesizing a superpotent, orallyactive progestational agent! Returning tomy reproductive metaphor, I classify oursynthesis of norethindrone as the releaseof the fertile egg waiting now to be fertil-ized. Once that is understood, the rolesof Ehrenstein and Inhoffen as oldermaternal uncles become obvious. SinceEhrenstein (Fig. 7) lived in the States,our paths crossed in the 1950s at severalscientific meetings. I know that he was

pleased at our elevation of his original19-norprogesterone work from a pieceof chemical esoterica to one of seminalsignificance; we actually published [12]a joint paper in 1958 to establish thenature (“wrong” stereochemistry at C-14 and C-17 compared to that of naturalprogesterone) of one of the componentsof his original 19-norprogesterone mix-ture.

My encounter with Inhoffen was differ-ent. We met only once at an internationalscientific congress. There, his commentsseemed frosty, leaving the impressionthat my work as a graduate student at theUniversity of Wisconsin had constitutedan intrusion into his early work on thepartial synthesis of estrogens. But in1999, our paths crossed again, twice,though on his part posthumously. Earlythat year, I received the Inhoffen Medalat the Technical University of Braun-schweig, but a more moving event oc-curred later that year in Graz. I had givena typical academic talk on the History ofthe Pill and had done so in German,which meant that it moved slower than itwould have in English. When I realizedthat I would be running out of time, I de-cided to skip some slides. One of themwas a picture of Inhoffen together withthe father of Chinese steroid chemistry,Huang Minlon (Fig. 8). The room wascrowded and I had to cope with manyquestions before the audience broke up.Suddenly a tall, serious man, probablyaround 60 years old, approached me toask quietly, “Did you know Inhoffen andhis work?” Before explaining what I hadintended to say about Inhoffen, I pro-duced the slide (Fig. 8) I had broughtwith me but had skipped during my talk.That’s when I found out that I was speak-ing to Peter Inhoffen, a Catholic theo-

logian and only son of Prof. Inhoffen,from whom he had become estranged. Icouldn’t read his expression: was hisquestion prompted by curiosity or bystill smoldering filial pride?

Our patent application (Fig. 9) for nore-thindrone was filed on 22 November1951 (it is the first patent for a druglisted in the National Inventors Hall ofFame in Akron, Ohio), and I reported thedetails of our chemical synthesis, to-gether with the substance’s high oralprogestational activity, at the April 1952meeting of the American ChemicalSociety’s Division of Medicinal Chem-istry in Milwaukee. The abstract [12] ofthis report under the names of Djerassi,Miramontes and Rosenkranz was pub-lished in March 1952, and the full articlewith complete experimental details ap-peared in 1954 in the Journal of theAmerican Chemical Society [12]. Read-ers may well be irritated by such an ava-lanche of dates, but chronological preci-sion is the baggage of scientists preoccu-pied with priority – a foible I would bedisingenous to hide.

A few weeks after having synthesizedthe substance and having received fromDr. Shipley confirmation of its antici-pated oral progestational activity, wesent it to various endocrinologists andclinicians: first to Roy Hertz at the Na-tional Cancer Institute in Bethesda,Maryland and to Alexander Lipschutz inChile; later to Gregory Pincus at theWorcester Foundation in Shrewsbury,Massachusetts, to Robert Greenblatt inGeorgia, and to Edward Tyler of the Los

Figure 7. Maximilian Ehrenstein

Figure 8. Hans Herloff Inhoffen and Huang Minlon atSchering, Berlin.

Figure 9. First page of U.S. patent of norethindrone.


The Pill at 50

Angeles Planned Parenthood Center. Itwas Tyler who, in November 1954, pre-sented the first clinical results of usingnorethindrone for the treatment of vari-ous menstrual disorders and fertilityproblems. All of these biological investi-gations can be equated to sperm that issurrounding the egg. But since this is arecord of the history of the Pill, we needto address the source and origin of theparticular sperm that led to the fertiliza-tion of our chemical egg and thus to theultimate birth of an oral contraceptive.

While we were aware of Haberlandt’swork, initially, we were not focusing oncontraception when we developed anoral progestational compound, becausecontraception was of no interest in 1951to the pharmaceutical industry. Our re-search was undertaken because at thattime the natural hormone progesteronewas used clinically for treatment of men-strual disorders, for certain conditions ofinfertility, and at a research level, for thetreatment of cervical cancer in womenby local administration of a high dose ofthe hormone. Such administration wasextremely painful because it involved in-jecting a fairly concentrated oil solutionof large amounts of progesterone intothe cervix. What drove us was the desireto create a more powerful progestationalcompound that would be active orally.As it happened, the progesterone treat-ment of cervical cancer did not pan out,but the clinical use of our norethindrone(under the trade name Norlutin and li-censed to Parke, Davis and Company –at that time a large American pharma-ceutical company) for the treatment ofmenstrual disorders was approved by theFDA in 1957 and is one of its therapeuticindications to this day.

Each of the biologists mentioned abovehad his own area of expertise and inter-est in the field of progestational activity.Gregory Pincus and his colleague Min-Chueh Chang of the Worcester Foun-dation for Experimental Biology inShrewsbury, Massachusetts, were focus-

ing on how progesterone worked to in-hibit ovulation (the mechanism behindHaberlandt’s “temporary hormonal ster-ilization” and Makepeace’s confirma-tion). Among the many steroids tested in1953 by the Worcester Foundation groupfor such activity two substances(Fig. 10) stood out: our norethindroneand another substance, norethynodrel,that had been synthesized by FrankColton at G. D. Searle, a pharmaceuticalcompany in the Chicago area. Thechemical history of norethynodrel isworth telling, since it illustrates one ofthe less attractive features of scientificresearch: the drive for scientific priorityand the attempts to circumvent patentpriority. In this instance, the stakes werehigher than usual, since commercialconsiderations and financial returnsquickly entered the equation.

Norethindrone vs Nor-

ethynodrel

For historical accuracy and appropriatecredit, it is important to note that eventhough norethynodrel was only synthe-sized well over a year following the pub-lication of our successful synthesis ofnorethindrone, it was norethynodrel thatfirst entered the market as an oral contra-ceptive. M. C. Chang had found nore-thindrone and norethynodrel to havebeen the two most promising candidatesin his initial animal studies. But his boss,Gregory Pincus, who was a consultantfor Searle, selected the Searle compoundfor further work. Syntex, not having anybiological laboratories or pharmaceuti-cal marketing outlets at that time, li-censed Parke-Davis & Co. of Detroit topursue the FDA registration and marketthe product in the United States. (Thatchoice itself was ironic, since it wasParke-Davis that had sponsored theoriginal research work of Marker’s atPennsylvania State College, but had thenrefused continued support in Mexico,thus leading to the foundation of Syntex).It was only after 1957, when both nore-thindrone and norethynodrel had re-ceived FDA approval as drugs for non-contraceptive, gynecological purposes,that the paths of the two companiesdiverged.

Searle deserves full credit for reachingthe market first with an oral contracep-tive, norethynodrel, under the tradename Enovid, but its repeated claim to

have synthesized the substance indepen-dently and concurrently with Syntex’snorethindrone constitutes a blatant mis-representation of the facts. The recordbased entirely on published data is un-ambiguous. On August 31, 1953 – wellover one year after our first publication(March 1952) dealing with the synthesisof norethindrone, and 21 months afterour own November 1951 patent filingdate (Fig. 9) – Frank Colton of G.D.Searle & Company filed a patent appli-cation for the synthesis of a steroid thatdiffered trivially from norethindronethrough the position of one double bond(Fig. 10). Trivially different, becausetreatment of Colton’s isomer, norethyno-drel, with acid, or just human gastricjuice, converts it to some extent intoSyntex’s norethindrone – a conversionthat among others [12] was establishedby Gregory Pincus and his collaborators.Is synthesis of a patented compound inthe stomach an infringement of a validpatent? (Interestingly, years later, a simi-lar suit with a related oral contraceptivewas pursued by Wyeth, Inc. againstOrtho Pharmaceuticals and initially re-solved in favor of the plaintiff). I urgedthat we push this issue to a legal resolu-tion, but Parke-Davis, our American lic-ensee, did not concur.

Searle was selling a very successful anti-motion-sickness drug, Dramamine,which contained Parke-Davis’s antihis-tamine Benadryl. Given that the onlyFDA-approved uses of our norethindronein 1957 was the treatment of menstrualdisorders and certain conditions of infer-tility, the issue seemed small potatoes toParke-Davis, over which it was notworth fighting with a valued customer.

In the mid-1950s, Searle actively sup-ported clinical trials of the contraceptiveefficacy of norethynodrel. The work wasconducted in Puerto Rico, under thedirection of Pincus and especially JohnRock, a clinical endocrinologist andgynecologist from Harvard. Around thesame time in Mexico City and Los Ange-les, Syntex sponsored contraceptive tri-als with norethindrone. But fearing apossible religious backlash, Parke-Davissuddenly chose not to pursue these re-sults through the FDA approval process,and returned the contraceptive (but notgynecological) marketing license toSyntex. Alejandro Zaffaroni, Syntex’sExecutive Vice President, eventually ne-

Figure 10. Conversion of norethynodrel into norethin-drone.

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-con-trol field, but the shift to a new companymeant a delay of nearly two years beforeSyntex’s norethindrone received FDAapproval as a contraceptive. By 1964,three companies – Ortho, Syntex, andParke-Davis (having changed its mindafter realizing that no Catholic-inspiredboycott had developed) – were market-ing 2.0-milligram doses of Syntex’s nor-ethindrone (or its acetate), which by thenhad become the most widely used activeingredient of the Pill.

There is no question that Searle deserveskudos for marketing noethynodrel first –despite a possible consumer backlash byopponents of contraception. But giventhe extraordinary importance of thesesteroids, why does the Searle group tothis day not disclose in the peer-re-viewed literature any of the chemical re-search that led them to their pill? Theonly date supporting the claim for “inde-pendent simultaneous discovery” isSearle’s patent filing date of August 31,1953, a date that sounds “simultaneous”only without juxtaposition to the Octo-ber 15, 1951 lab book entry (Fig. 6) de-scribing the completion of the synthesisof norethindrone and the November 21,1951 filing date (Fig. 9) of Syntex’spatent application.

Colton and other researchers fromSearle had not otherwise been reluctantto publish their steroid research. Indeed,in 1957, they published an article [13] inthe Journal of the American ChemicalSociety about a new steroid anabolic,17α-ethyl-19-nortestosterone (Nilevar),that was produced in one step from our17α-ethynyl-19-nortestosterone (nor-ethindrone). In their article, the Searlechemists cited quite properly our earlierpublication, which predated theirs byover three years. Thus, their unaccount-able shyness about the most significantproduct in their corporate history, nor-ethynodrel, can only raise questions.Why, for instance, did Gregory Pincus,the person most responsible for persuad-ing Searle to market norethynodrel,make not a single reference to any chem-ist (not even Frank Colton) in his 1965opus magnum, “The Control of Fertil-ity?” Why does his book make no men-tion of how the active ingredient of the

Pill actually arrived in his laboratory?And even worse: why did Pincus dropHaberlandt’s name into a black hole ofanonymity?

Pincus and the Chemists

My preoccupation with establishing un-equivocally the priority – and thus themetaphoric maternal identity – is not justmy admittedly strong competitive drive.I am realistic enough to acknowledgethat it really does not make any differ-ence to the world who does what first.But giving credit to Syntex as the corpo-rate institution where it all first started isimportant to me (even though I severedall connections with that company in1972), because institutional memoriesare so short. Syntex was the first andpossibly the only significant example ofimportant research in such a highly com-petitive and technically sophisticatedfield being conducted in a developingcountry. Both qualitatively and quantita-tively, the research output of Syntex dur-ing the ‘fifties has never been matched inthe steroid field; the pride and self-assur-ance it provided to a cadre of Mexicanorganic chemists, virtually all of themtrained at Syntex, was moving to witness.Yet that company does not exist any-more, because in 1994 it was acquiredby the Swiss pharmaceutical colossusRoche and promptly swallowed anddigested. In that digestive process, theentire research division of Syntex inMexico, which had just moved into newquarters in Cuernavaca, was closed andall research personnel dismissed. To me,the cold-bloodedness of this corporateamputation seems unforgivable: I knowof no other pharmaceutical company inMexico that has currently any significantresearch presence.

Syntex, as a company, and Mexico, as acountry, deserve full credit as the institu-tional site for the first chemical synthesisof an oral contraceptive steroid – a state-ment that is not meant in any way todenigrate Searle’s successful drive to bethe first on the market with a steroid oralcontraceptive But there is a more charm-ing end to this story. In the process ofswallowing Syntex, Roche not onlyclosed the Mexican research laboratorieswhere norethindrone was first synthe-sized. Roche also decided to distance it-self from any involvement in the contra-ceptive field, and promptly sold the en-tire Syntex oral contraceptive line, stillbased in its entirety on norethindrone.Who was the purchaser? None otherthan G. D. Searle – the company thatwent to heroic lengths to circumvent theSyntex patent on norethindrone and nowhad to pay good money to market it as itslead oral contraceptive long after theoriginal patent had expired. But the storydoes not end there. G. D. Searle itselfwas acquired several times – first byMonsanto, but eventually by Pfizer, nowthe largest pharmaceutical company inthe world. Few are aware of the fact thataround 1954, Pfizer had an option fromSyntex to market norethindrone, an op-tion the company had not exercised be-cause its president, John McKeen, an ac-tive Roman Catholic layperson, felt thatPfizer should not touch any agent evenpotentially related to birth control. Yethalf a century later, Pfizer entered thecontraceptive market with norethindrone!What a closure to an historical circle!

Interestingly, Syntex-developed nore-thindrone is still a widely used active in-gredient of oral contraceptives, whereasSearle’s norethynodrel disappeared fromthe market many years ago, to be super-

Figure 11. Chemical structures of oral contraceptives.


The Pill at 50

seded by other 19-nor steroids, which, asshown in Figure 11, are close chemicalrelatives of norethindrone. The secondand third structures in Figure 11 are fur-ther examples of steroids, whose chiefraison d’etre was that they were not cov-ered by the original Syntex patent(Fig. 9) of norethindrone, yet are con-verted to a considerable extent in thebody into norethindrone and hence canall be considered qualitatively as “pro-drugs” of norethindrone.

On first glance, another alteration of thenorethindrone molecule by addition ofone methyl group in position 18, leadingto levonorgestrel (Fig. 11) also seems tobe just another example of a minorchemical change prompted by the desireto circumvent Syntex’s norethindronepatent. Though seemingly trivial, chemi-cally this was a drastic change since nonaturally occurring steroids were knownthat possessed an angular ethyl group atposition 13. Hence this substance couldonly be prepared by total synthesis andthis was accomplished in 1964 [14] byHerchel Smith and collaborators at theUniversity of Manchester. The patentrights to this higher homolog of nor-ethindrone were acquired by Wyeth, acompany that was active in hormone re-placement therapy, who developed levo-norgestrel into the “mother substance”of a second series of oral contraceptives(e.g. gestodene and desogestrel in Fig-ure 11). In fact, for the first forty years ofthe clinical use of steroid contraceptives,all of the hundreds of “Pills” sold allover the world under different tradenames were basically derivatives (seeFig. 11) of norethindrone or levonor-gestrel.

It should not be surprising that I, as achemist, in terms of my reproductivemetaphor that equates any syntheticdrug to an egg, spent the bulk of thischapter examining the maternal lineageof the Pill. But just as it is clear thatLudwig Haberlandt merits attribution asthe paternal grandfather, Gregory Pincus– despite the uncertainties of paternitygenerally – deserves to be called a fatherof the Pill. The initial rabbit experimentsby M. C. Chang in Pincus’s laboratoryclearly were the sperm that fertilized thechemical egg, and the subsequent im-plantation of the embryo and eventualfetal growth can largely, though not en-tirely, be ascribed to further experiments

conducted in Pincus’s laboratory. ButPincus was not only a prolific and highlyexperienced endocrinologist, he wasalso a charismatic entrepreneur. Manytimes, this latter quality is more difficultto find than mere scientific brilliance; ittook entrepreneurship of Pincus’s cali-ber to bring the steroids provided by thechemist to the stage where clinical trialsof the Pill could be initiated and whereJohn Rock, as leader of the clinical team,could assume the mantle of metaphoricobstetrician for the eventual birth of thePill. While Rock’s name is inexorablyconnected with that role, others, notablyCelso-Ramon Garcia (the first professorof OB/GYN at the University of PuertoRico Medical School) and Edith Rice-Wray (Medical Director of the PuertoRican Family Planning Association)contributed heavily to the planning andimplementation of the first clinical trialsin the San Juan area. Rice-Wray subse-quently directed a Family Planning clinicin Mexico City where she continued herclinical studies, this time with Syntex’snorethindrone.

Of the numerous talks and interviewsthat I have presented over the course ofdecades on the birth of the Pill, threestand out in my mind. Two of them wereformal occasions directly associatedwith Pincus’s memory: the GregoryPincus Memorial Lecture and Awardpresented in 1982 on his home turf, theWorcester Foundation for ExperimentalBiology, and the last Gregory PincusMemorial Lecture at the 50th and finalLaurentian Hormone Conference in1993. Ironically, this event was held inPuerto Rico – the site of the first oralcontraceptive clinical trials – althoughthese annual meetings, founded byPincus, usually met in the LaurentianMountains of Quebec. In the same year,I also gave the first A. S. Parkes Memo-rial lecture at Cambridge which com-memorated a British pioneer in repro-ductive biology. But the most relevantevent to my story is an unusual sessionheld Friday morning, May 5, 1978, in anold New England mansion on the out-skirts of Boston, the headquarters of theAmerican Academy of Arts and Sciences.The Academy was holding a closed two-day session on “Historical Perspectiveson the Scientific Study of Fertility”. Thepurpose of the meeting was to have afree-flowing dialogue among some ofthe key scientists who had been active in

the field of fertility in the United Statesduring the previous 40 years (therefore,it was not surprising that, as far as Icould tell, at age 55, I was the youngestof that group) in order to collect a recordthat historians of science might drawupon in the future.

The unedited transcript of that Fridaymorning session reads awfully: Nounsdo not match verbs, tenses get mixed,punctuation is lost, and many words aremisspelled or appear to be inaudible.Nevertheless, one gets a real flavor ofexcited human dialogue and interrup-tions, of hurt egos, of hitherto undis-closed vignettes. Here are 2 samples.

Hechter: May I take a couple of minutes?

Djerassi: I haven’t finished. I’d like tocontinue because I’ve only gotten to thefirst half of my story.

Reed: He can have my time. This is thefirst really fruitful … (inaudible)

Greep: This is history from the horse’smouth, and I think it’s very good.

Djerassi: I misunderstood. Did you wantme to continue?

Greep: Yes.

The scientific co-chairman of the BostonAcademy’s May 1978 meeting was RoyO. Greep, a distinguished endocrinolo-gist at Harvard, who had known person-ally most of the actors in this play. An-other key participant was Oscar Hechter,who for many years had been senior sci-entist of the Worcester Foundation forExperimental Biology. Though not di-rectly involved in the development oforal contraceptives, he had been an inti-mate collaborator of Gregory Pincus.James Reed of Rutgers University was ahistorian studying the birth controlmovement in America.

I felt that this was the one opportunity,years after Pincus’s death, where I couldfind out why he had been so ungra-ciously selective in not acknowledgingwork of others that was crucial to the de-velopment of the Pill. John Rock, whohad not behaved very differently, was inthe room, but he had reached an agewhere it was not any more possible forhim to contribute to the dialogue. His

The Pill at 50


was a silent, poignant presence. ButCelso-Ramon Garcia, Rock’s andPincus’s closest clinical colleague, waspresent, which led to the following ex-change:

Garcia: Basically, the monograph “Con-trol of Fertility” that Pincus wrote ex-presses in detail what his feelings wereabout who contributed to what.

Djerassi: Why did he not mention anychemists, do you happen to know that?

Garcia: He was a biologist, the same wayas you are principally presenting yourstory as a chemist.

Djerassi: That’s not true. That’s why Isubmitted a paper here with biologicalreferences, including yours.

Garcia: Well, okay, but the fact is thatprincipally you are a chemist and yourmajor contribution has been that of achemist.

Djerassi: But this would be like my de-scribing the history of oral contracep-tives without a single reference to Pincusor Rock or yourself!

In other words, Garcia – and by infer-ence Pincus – felt that it is sufficient tofocus on the paternal role in discussingthe history of the Pill. Hence as a chem-ist, I have tried to illuminate the equallyindispensable “maternal” role of thechemist. But since in 2011 we are cel-ebrating the 50th anniversary of the Pillin Germany, let me end with a discussionof the “German” role.

The 50th Birthday of the

Pill in Germany

It is curious, yet understandable, that in1961 Germany proved to be the thirdcountry after the USA and Australia toallow the use of an orally active proges-tational steroid for contraceptive pur-poses. Curious, because Germany at thattime was as conservative in the area offamily planning as many other Europeancountries where the Pill was only permit-ted years later; but also understandable,since in terms of scientific research andmedical applications of steroids, Ger-many was in many respects the most ad-vanced country in the world and espe-cially so in steroid chemistry with the

Nobel laureates Windaus, Wieland, andButenandt heading the list. Similarly,among pharmaceutical companies,Schering AG played a lead role in medi-cal applications of steroid hormones. Soit was not surprising that Schering wasalso the company that introduced thefirst Pill into Europe. However, in con-trast to the USA, it was not norethyno-drel (Fig. 10) but rather the acetate ofnorethindrone, which in the body is pri-marily metabolized into the parent nor-ethindrone, thus constituting a pro-drugof the latter. But in contrast to theSyntex-G. D. Searle commercial compe-tition outlined above, in this instanceSchering marketed norethindrone ace-tate under the trade name Anovlar underlicense from Syntex, which in turn hadanother amusing historical conse-quence: Parke Davis, the American phar-maceutical company who first distrib-uted norethindrone under Syntex licensefor menstrual disorders, but had then re-turned the rights to market is as contra-ceptive for fear of a Catholic boycott,subsequent to Schering’s launch of nore-thindrone acetate (Anovlar) changed itsmind and also marketed the substance asan oral contraceptive in the mid 1960s.

When Wyeth introduced Herchel Smith’slevonorgestrel (Fig. 11) into the Ameri-can market, Schering licensed it for dis-tribution in Germany. Thus for the firsttwenty years, Schering’s increasinglypowerful position worldwide in the fieldof contraception was based on externally

licensed steroids from Syntex and Wyeth.Only in the middle 1980s, when a levo-norgestrel analog with an additionaldouble bond in ring D (see Fig. 11) wassynthesized and introduced under thegeneric name Gestodene did Scheringmarket a proprietary steroid as a contra-ceptive, an achievement that was re-peated twice more during the last decadewith drospirenone [15] (Fig. 12) anddienogest (Fig. 13). A possible rationaleand commentary for these decisions fol-lows below in the final section.

The Future: Reflections

and Prognosis

The subtitle of this article – thriving orsurviving – implies some prognostica-tion and this is the theme with which Iwish to conclude: specifically do weneed new methods of contraception andif so, who is “we?” The answer is clear,once we accept that demographicallyspeaking, instead of dividing the worldinto “more developed” and “less devel-oped” nations, we need to accept that thedivision is now between geriatric andpediatric countries.

As seen in Table 1, with the exception ofAfghanistan, all of the top pediatriccountries are African, whereas with theexception of Japan, the most geriatriccountries (Tab. 2) are found in Europe.By examining Table 3, which lists theten world-wide most populous countriesexpected in 2050, Pakistan, Nigeria,Bangladesh, Ethiopia and partly alsoIndia fall into the pediatric category.

Clearly, the contraceptive needs of thepediatric countries, which are of nocommercial interest to the large interna-tional pharmaceutical firms, are not onlyurgent but also totally different fromthose of the geriatric countries. Whatmost of Africa and parts of Asia andLatin America need is not newer birthcontrol methods – in other words new“birth control hardware”, but rather im-provements in “birth control software” –meaning improvements in education,public health, and foremost changes inthe status of women, because improvingthose will cause an explosion in the useof existing methods of family planning.

The only market that could afford newmethods of birth control are the geriatriccountries, but those populations have al-

Figure 13. Chemical structure of dienogest.

Figure 12. Chemical structure of drospirenone.


The Pill at 50

ready learned how to limit their familiesby existing methods. In the large major-ity of European countries, the averagesized family (ca. 1.5 children) is far be-low replacement level (2.1 children). Forthose countries, the leitmotiv “contra-ception” in the field of reproductivemedicine has been replaced by “concep-tion”, whereas exactly the reverse ap-plies to the pediatric countries. I do notwish to imply that the geriatric countrieswould not be better off if there were amuch wider choice of contraceptive op-tions, including in those countries wherebirth control is already practiced by asubstantial portion of the population.So what new ones might make sense inEurope or Japan?

In 1989 [16], I listed 6 fundamentallynew methods (Tab. 4) – not piddling im-provements in existing ones – that, ifimplemented, would vastly expand thechoice for human fertility control for allconstituencies: poor and affluent, pro-choice and anti-abortion, female andmale. They would also make a differencein convenience, economic savings to theconsumer, and possibly even safety.

Note that improved efficacy is hardly anissue any more.

Twenty-two years later, only ovulationprediction (3. in Tab. 4) has been real-ized – in part because it required no tox-icity expenses and could focus entirelyon diagnostic efficacy and accuracy. Butin terms of usage, it is employed muchmore widely for purposes of conceptionrather than contraception. Work on anantiviral spermicide (1. in Tab. 4) is stillprogressing – primarily because of itsapplicability to the AIDS pandemicrather than for reasons of improved con-traception, but so far with little success.Easily reversible and reliable male steril-ization (4. in Tab. 4) would be of greatadvantage in both pediatric and geriatriccountries, since vasectomy is practicedwidely – notably in China and the US,though not in Germany – but mostly bymen who are already fathers and wish nomore children. If reversibility were guar-anteed – a very expensive proposition,requiring large numbers of volunteersand many years of observation then va-sectomy, since it is simple as well assafe, might well be practiced by many

young men before they ever had fatheredany children. For pharmaceutical com-panies, this approach would be of zerofinancial interest.

This leaves alternatives 2, 5 and 6, whichwould represent fundamental advancesthat would also fill enormous lacunae inour contraceptive armamentarium. Butthe costs for developing such agentswould be enormous (each easily exceed-ing US$ 1 billion), very time consuming[17] and very likely also prone to litiga-tion. Only the largest pharmaceuticalcompanies would have the necessaryscientific and financial resources forsuch an endeavor, and given their focuson the diseases of aging and deteriora-tion that afflict the ever increasing geri-atric populations of these rich countries,it is not surprising that not a single of the20 largest pharmaceutical companies iscurrently pursuing research and devel-opment work on a male contraceptive ora fertility vaccine. So what is left?

The few major drug companies that con-tinued after 1975 to pursue any researchin female contraception were those thathad a significant market share of the Pill.The two most important ones (Scheringin Germany and Organon in Holland)were both swallowed up in recent yearsby German (Bayer) and American(Merck-Schering-Plough) pharmaceuti-cal giants, not unlike what happened inthe 1990s with Syntex and the Swissdrug firm Roche. But since we are nowcelebrating the 50th anniversary of thearrival of the Pill in Germany, let us ex-amine what has happened during thepast decade when two more new steroids– drospirenone (Fig. 12) and dienogest(Fig. 13) were added to the list of theseven 19-norsteroids of the norethin-drone and levonorgestrel type (Fig. 11).But before doing so, it is nececessary toemphasize the main motivation in devel-oping the five new chemical modalitiesin Figure 11 aside from norethindroneand levonorgestrel. Clearly, it was tocarve out a proprietary position vis a visthese two 19-norsteroid prototypes bycreating minor chemical modificationsthat would offer patent protection.

Because of the huge cost of developingeven such minor chemical variants, aconsiderable effort was also directed bythese companies as well as some non-profit organizations such as the Popula-

Table 1. Countries with youngestpopulations (2010)

Country % ages < 15

Niger 50.1Uganda 48.7Burkina Faso 46.4Congo, Dem. Rep. 46.4Zambia 46.2Malawi 45.9Afghanistan 45.9Chad 45.6Somalia 44.9Tanzania 44.7

Table 2. Countries with oldest popu-lations (2010)

Country % ages 65+

Japan 22.6Germany 20.5Italy 20.4Sweden 18.3Greece 18.3Portugal 17.9Bulgaria 17.6Austria 17.6Latvia 17.4Belgium 17.4

Table 3. Most populous countries(2050)

Country Population(Millions)

India 1,748China 1,437United States 423Pakistan 335Nigeria 326Indonesia 309Bangladesh 222Brazil 215Ethiopia 174Congo, Dom. Rep. 166

Table 4. A priority list of new contra-ceptive methods [C. Djerassi, Science1989; 245: 356].

1. Spermicide with antiviral properties(effective during normal coitus)

2. Once-a-month pill effective asmenses inducer

3. Reliable ovulation predictor (“red” &“green” light)

4. Easily reversible and reliable malesterilization

5. Male contraceptive pill6. Antifertility vaccine

The Pill at 50


tion Council toward introducing newdelivery vehicles, such as injectables,silastic implants, vaginal rings, skinpatches and the like. In my opinion, suchapplied research is well justified in ex-tending the use of these steroid contra-ceptives to a wider population. But whatabout continuing to create “new” oralcontraceptives? Aside from narrow mar-keting considerations, is there a societalneed and would the money expended onsuch endeavor not be better justified if itaddressed the development of some fun-damentally new methods of the typeillustrated in Table 4? Again from a soci-etal standpoint, the answer must be a re-sounding affirmative, but what aboutcommercial economic considerations onthe part of a pharmaceutical company?In that regard, I am afraid that the answermust be negative. In fact, the market hasspoken because none of the major phar-maceutical companies is spending anymoney on such new areas for the obvi-ous reason that in terms of urgency in thegeriatric countries, birth control cannotand possibly even should not have a highpriority. Few will argue that spending afew billion dollars on a new contracep-tive would be more useful – societally orcommercially speaking – than a drugpreventing Alzheimer’s disease.

It is for this reason that in 1994 [18], Iproposed with Stanley Leibo a differentapproach to birth control in males thatwould not involve research nor market-ing by pharmaceutical giants. But sincemale contraception is not the focus ofthis article, I shall conclude with somepersonal reflections on the introductionof the two latest oral contraceptives,drospirenone (Fig. 12) and dienogest(Fig. 13) – both developed in Germany –which are sometimes called “fourth gen-eration” oral contraceptives. Are they re-ally new and why were they developed?

Chemically speaking, drospirenone(Fig. 12) is indeed unique among oralcontraceptives, since all the others(Figs. 10, 11) are based on the ubiqui-tous 19-norsteroid skeleton, whose ori-gin I have described in excruciating de-tail through the history of norethindrone;all of these substances were designedspecifically to act as orally active pro-gestins. Drospirenone, on the otherhand, was developed nearly 40 years agoas an aldosterone antagonist and onlymuch later discovered to possess ovula-

tion inhibiting properties. The reason fortaking an old chemical, whose patentcoverage had virtually expired, and thento launch it two decades later as a contra-ceptive was based on extensive biologi-cal scrutiny which showed that in termsof potential side effects, it seemed tooffer some advantage over all the other19-norsteroids because of its mild anti-androgenic and anti-aldosterone proper-ties. These became the basis of a suc-cessful marketing campaign in 2000which quickly propelled drospirenoneunder the trade name Yasmin into a topselling contraceptive. One might, there-fore, reach the conclusion that such anemphasis on ancillary hormonal at-tributes – separate from the contracep-tive properties – would constitute a logi-cal rationale for bringing a new steroidcontraceptive to the market.

While logical, it ignored a crucial lessonfrom history. As I described in great de-tail [1, 11], the first three oral contracep-tives (norethynodrel, norethindrone, andlevonorgestrel) were scrutinized medi-cally over a period of ca. 20 years to anextent that has never been equaled byany other drug in medicine, primarilybecause these were potent drugs thatwere given for years to “healthy” peoplefor preventive rather than curative pur-poses, which carried with it an almostunrealistic emphasis on safety. Amongthe main side effects studied were poten-tial thromboembolisms and cancers. Ittook at least two decades in the post-marketing phase to carry out these hugeepidemiological studies, which wouldbe impossible to perform in a pre-mar-keting period, because it would requireunrealistically high numbers of experi-mental subjects for financially too bur-densome time periods. In the process,one of the most significant positive sideeffects was uncovered, namely a protec-tive action against ovarian cancers innearly 50% of the user population. Be-cause such studies required many years,these were based on the then only exist-ing three Pills – norethynodrel, norethin-drone, and levonorgestrel. Indeed, therecent report by Hannaford et al [19]summarizing the results from a mam-moth study comparing 339,000 womanyears of never-users with 744,000woman years of ever-users of the Pill,contains the statement: “Many women,especially those who used the first gen-eration of oral contraceptives many

years ago, are likely to be reassured byour results. Our findings might not, how-ever, reflect the experience of women us-ing oral contraceptives today, if cur-rently available preparations have a dif-ferent risk to earlier products.”

This limitation applies even more dra-matically to a second article by the sameauthors [20] based on 46,112 women ob-served for up to 39 years which con-cludes that ever-users of oral contracep-tion had a significantly lower rate ofdeath from any cause, including all can-cers, all circulatory diseases, and someother diseases than the never-users. Iwould claim that from an overall publichealth standpoint, it is these conclusionsthat should carry much more weight thanrelatively minor differences in some ofthe hormonal effects of the newest com-pounds for whom such epidemiologicalstudies are not and most likely never willbe available.

Thus, in the case of drospirenone(Fig. 12) in 2010 a series of law suitswere initiated against Schering claimingan increased risk of thromboembolicdisorders and other vascular problemsin women using Yasmin compared tothose in women on oral contraceptivescontaining the older 19-norsteroids(Fig. 11). While this increased incidenceof thromboembolic problems is small, itclearly was enough to tarnish the reputa-tion of Yasmin. Was that the reason thatSchering introduced still another neworal contraceptive in 2009, this timebased on the 19-norsteroid dienogest(Fig. 13)?

Under the trade names Natazia andQlaira, the substance was touted as thefirst oral contraceptive to use as compan-ion estrogen estradiol valerate instead ofthe conventional ethynylestradiol – theimplication being that these were newchemicals. In point of fact, dienogesthad already been synthesized in 1979[21] by Kurt Ponsold and colleagues andlaunched under the tradename Valette in1990 by Jenapharm in combination withethynylestradiol as an oral contracep-tive. Its commercil success was appar-ently one of the reasons why Scheringthen acquired this East German concern.Estradiol valerate has been known forwell over half a century. Natazia isclaimed to be more effective than otheroral contraceptives in controlling heavy


The Pill at 50

menstrual bleeding. Is that really a rea-son for replacing the virtually identicalJenapharm product Valette with its 20-year long history of wide use with stillanother oral contraceptive containing a50-year old estrogen and at the sametime making it the most expensive oralcontraceptive on the market?

In my opinion, contraception is too im-portant a public health feature worldwide to have minimal marketing advan-tages be the reason to resurrect old drugsand claim them to be new “fourth gen-eration” advances, albeit in a more com-plicated polyphasic formulation. Sincethe National Health Service in the UKcovers contraceptives, its cost of thevarious steroid contraceptives is of con-cern as summarized in Table 5.

Does it really make sense to pay 10 to 15times more for such “new” agents bycomparison with oral contraceptives thatare still consumed by millions of womenand have been the subject of decades-long epidemiological studies [19, 20]?For the pediatric countries of the world,the answer is a resounding no. But is iteven justified for the geriatric countries– especially in these days of nearly un-sustainable increases in medical careduring economically troubled times?

In the long run, it will probably not makeany difference for two reasons. First, theonly entities with the scientific and fi-nancial resources to create new chemi-cally-based contraceptives are the largepharmaceutical firms. Continuing todabble with minor modifications of ex-isting steroid progestins combined withestradiol derivatives does not seem to meto be of overriding societal benefit. Afocus on improvements in postcoitalagents – the “morning after pills” –might well be more useful for consum-ers, but hardly to drug firms. Among thetwenty largest in the world, not one isworking on new methods for fertilitycontrol of the type summarized in

Table 5. Monthly cost in £ of oral con-traceptives [NHS New Drug EvaluationNo. 98, November 2009].

– Norethindrone 0.51–0.92– Levonorgestrel 0.96–1.32– Desogestrel 2.19– Drospirenone 4.90– Dienogest 8.39

Table 4, with the possible exception of aviral spermicide as a side issue related toresearch on drugs effective againstAIDS. As I pointed out, the reasons arelogical because these companies are fo-cusing on the crucially important andunsolved problems of an increasinglygeriatric population where the illusory“totally safe” criterion does not applynor does the enormous potential of li-ability suits. A cancer patient is unlikelyto sue as a result of side effects that auser of contraceptives or vaccines wouldconsider unacceptable. Pharmaceuticalcompanies are not philanthropic organi-zations, who can afford to ignore the fi-nancial bottom line.

But there is a second reason why I be-lieve that significant new work on con-traceptives will not occur as the empha-sis in Europe and other geriatric coun-tries shifts from “contraception” to“conception.” As I argued in both abook [1] and two plays [22, 23], withina few decades the option of preservingone’s gametes at a young age, say theearly twenties, followed by resorting toIVF for the one or two children thatEuropean families now have, would be-come a realistic option – especially forthose women who now postpone childbearing and thus would be in a positionto operationally extend their fertile lifetime. The obvious corollary would thenbe to consider early sterilization whichwould make contraception unnecessaryfor effective and desired family plan-ning. None of these shifts would in-volve the pharmaceutical industry andhence can be implemented as a matterof public policy as has been illustratedfor a male contraceptive alternative[18].

As a scientist, who at one time was alsoan executive of a pharmaceutical com-pany and who has turned into a play-wright of “science-in-theatre” plays, itseems only fitting that I present my pre-diction of the divorce of sex from repro-duction in dramatic form through a briefdialogic excerpt [22] from “An Immacu-late Misconception” between Dr. MelanieLaidlaw, a reproductive biologist and (inthe play) the inventor of intracytoplas-mic sperm injection (ICSI), and her clini-cal colleague, Dr. Felix Frankenthaler.

Melanie: Now, if ICSI works in humans…think of those women – right now, mostly

professional ones – who postpone child-bearing to their late thirties or even earlyforties. By then, the quality of their eggs…their own eggs… is not what it was whenthey were ten years younger. But withICSI, such women could draw on a bankaccount of their frozen young eggs andhave a much better chance of having anormal pregnancy later on in life. I’m nottalking about surrogate eggs.

Felix: Later in life? Past the meno-pause?

Melanie: You convert men in their 50sinto successful donors.

Felix: Then why not women? Are youserious?

Melanie: I see no reason why womenshouldn’t have that option … at leastunder some circumstances. But think be-yond that … to a wider vision of ICSI.I’m sure the day will come – maybe inanother 30 years or even earlier – whensex and fertilization will be separate. Sexwill be for love or lust.

Felix: And reproduction under themicroscope?

Melanie: And why not?

Felix: Reducing men to providers of asingle sperm?

Melanie: What’s wrong with that … em-phasizing quality rather than quantity?I’m not talking of test tube babies or ge-netic manipulation.

Felix: And then what?

Melanie: Each embryo will be screenedgenetically before the best one is trans-ferred back into the woman’s uterus. Allwe’ll be doing is improving the oddsover Nature’s roll of the dice. Before youknow it, the 21st century will be called“The Century of Art.”

Felix: Not science? Or technology?

Melanie: The science of… A… R… T:assisted reproductive technologies.Young men and women will open repro-ductive bank accounts full of frozensperm and eggs. And when they want ababy, they’ll go to the bank to check outwhat they need.

The Pill at 50


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

Melanie: Exactly. If my prediction is on target, contra-ception 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 allfor the good. It will first happen among the most affluentpeople… and certainly not all over the world.

Conflict of Interest

No financial conflict of interest.

All figures kindly provided by Carl Djerassi.

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15. Wiechert R. In: Janos Fischer J, Ganellin CR (eds). Analogue-Based Drug Discovery.WILEY-VCH Verlag, Weinheim 2006; 395–400.

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19. Hannaford PC, Selvaraj S, Elliott AM, Angus V, Iverson L, Lee AJ. Cancer riskamong users of oral contraceptives: cohort data from the Royal College of GeneralPractitioner’s oral contraception study. Br Med J 2007; 335: 651.

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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: ZweiTheaterstücke 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 thetitle “Phallstricke/Tabus: Zwei Theaterstücke aus den Welten der Naturwissenschaftund der Kunst”. Haymon Verlag, Innsbruck, 2006.

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