development of the pill, and despite Pincus often mentioning him, Chang's contribution remained unacknowledged by Searle until 1967 (Chang 1968).
Running concurrently with Syntex's work on synthesising progesterone, Pincus and Chang began their search for effective compounds which exerted an intense progesterone effect in small doses when taken by mouth. Chang and Pincus ( 1953) also tested phosphorylated hesperidin and concluded that it was an unlikely anti-fertility agent despite Sieve's (1952) earlier report of an experiment with 300 couples that had raised the hopes of family planners around the world^^ Pincus wrote to a number of pharmaceutical companies in 1953 requesting supplies of potential compounds (Searle 1990). Among the samples that Pincus received were Searle's norethindrone and Syntex's norethynodrel. Pharmaceutical companies played an important role in the production and development of the pill. Indeed, by the end of the Second world War, 'the manufacture and sale of sex hormones had become a highly commercialized business. In 1951, sales of sex hormones in the UK were valued at £684,000 (Pfeffer 1993: 78).
By April 1951 DJerassi and the others at the Syntex laboratory had announced, and confirmed the effectiveness of, the synthesis of analogues of progesterone (Syntex 1966: 47). DJerassi had had no practical means of testing the biological activity of the compounds produced, so Syntex sent a sample of the substance to a commercial laboratory in Madison, Wisconsin. The laboratory confirmed that the compound had a highly effective progestational activity. The compound was then promptly sent to the National Cancer Institute, where Tullner and Hertz confirmed that the product possessed 5 - 8 times the biological activity of progesterone, thus making it the most powerful progestational hormone known at that time (DJerassi et al 1954).
On request, Syntex's 19-norprogesterone was sent to Pincus. The compound was also sent to other researchers. Other initial experimenters included Roy Hertz at the National Cancer Institute in Bethseda, Maryland, (who was using progesterone in the treatment of cervical cancer), Alexander Lipschutz in Chile, Robert Greenblatt (pioneer of steroid hormone therapy) in Augusta, Georgia and Dr Edward Tyler (who used it to treat menstruation and fertility problems) in Los Angeles (Robertson 1990: 128, DJerassi 1979: 247).
39. Prompted by reports of Sieve's work, an editorial in the British journal of the FPA (Family Planning Vol. 1 No. 4 January 1953) noted, under the headline 'Birth Control by Mouth?' that 'it scarcely needs to be argued that to devise a contraceptive that could be taken by mouth would be a great advance'.
To summarize, Djerassi and his team at Syntex synthesized the first orally active progestational agent, norethindrone, in 1951. But it was G. D. Searle & Co. that eventually launched the first oral contraceptive pill. Why a different compound than that produced by Djerassi was initially taken up and marketed as the Pill needs further enquiry. The answers lie in the social-technical-scientific networks that were operating in the early-mid 1950s.
Patents and Patients
The application for a patent for a slightly revised compound was made in November 1951. On August 31, 1953 Frank Colton of G. D. Searle & Co. filed a patent for the synthesis of the double bond isomer of norethindrone, named norethynodrel. This analogue was different enough to be patented, but Djerassi disputed the difference between the two compounds, questioning the validity of Searle's patent.
Confessing to what he admits is 'pure speculation', Djerassi (1992c: 637) alludes to imitation on the part of Colton, Searle's chemist. Djerassi has remained sceptical about the lack of disclosure of any of Searle's chemical work in the peer reviewed literature. He ponders over why Pincus made not 'the slightest reference in his opus magnum. The Control o f Fertility, to any chemist (eg. Frank Colton) or to how the active ingredient of the Pill actually arrived in his laboratory'.
Relating confidences of Leon Simon, a respected patent attorney who served as Syntex's, independent patent counsel, Djerassi (1992c: 637) suggests that:
'in January 1952 Dr Emeric Somlo, then the owner of Syntex S.A., had some negotiations with the Searle family about their possible purchase of Syntex. In order to assess Syntex's non financial assets, Somlo instructed Simon to permit Dr A. L. Raymond, Searle's research Vice-President to inspect in Simon's Washington office all of the then pending Syntex patent applications. One of these was the Mexican patent application of November 22 1951, which disclosed the structure, the progestational activity, and the specific experimental details for the synthesis of norethindrone. What, if anything, Raymond did consciously or subliminally with this proprietary information after returning to the headquarters of G. D. Searle & Co. in Skokie, Illinois, will never be known.'
Parke-Davis, Syntex's American licensee, did not want to pursue a legal dispute because of links with Searle. Parke-Davis sold the antihistamine Benadryl to Searle so that Searle could make the important anti-motion sickness drug, Dramamine. Syntex's norethindrone 'seemed small potatoes over which it was not worth fighting a valued customer' (Djerassi 1992c: 636).
Syntex sponsored contraceptive trials with norethindrone, first conducted by Edward Tyler and subsequently by Joseph W Goldzieher in San Antonio, Texas, as well as conducting their own toxicology and monkey experiments (Djerassi 1992a: 60). Parke-Davis received FDA approval for use of norethindrone as a menstrual regulator and the treatment of infertility in 1956. Syntex collaborated with Parke-Davis, and signed over the license to produce and market norethindrone, but 'just as it became obvious that oral contraception was about to become a practical reality, Parke- Davis got cold feet and refused to even consider marketing norethindrone as an oral contraceptive'^ (Djerassi 1979: 253). Parke- Davis chose not to pursue the results because of the possible religious backlash (although Parke- Davis did contribute $5000 to the Foundation) (Syntex 1966: 50).
The marketing license was returned to Syntex, who then negotiated a new agreement with Ortho Division of Johnson and Johnson. But the delay incurred through this abandonment by Parke-Davis, as well as their unwillingness to hand over the results of biological trials to Ortho, meant that Syntex's nor-progesterone received FDA approval for contraceptive use nearly two years after Searle. Syntex thus lost out to Searle because it was unable to 'enrol' a larger pharmaceutical company, a marketer or a distributor^!. A US patent number was issued to Fred Colton of G. D. Searle & Company on November 29 1955 and to Djerassi and others at Syntex on May 2 1 9 5 6 ^ 2
Hogg (1992: 611) has also suggested that Upjohn was able, but not willing, to offer products for contraception in the mid-1950s. Instead the first orally active
4 0 . Interestingly, the same fears and threats appear to be circulating in the US in the 1990s with the introduction o f RU 4 8 6 the 'abortion pill' (see Klein et al 1991).
4 1 . Reed (1978: 3 57) also notes that Searle managed to acquire Productos Esteroides, Syntex's chief competitor, and its American marketing agent. Roots Chemicals.
4 2 . I am grateful to Djerassi (personal communication) for clarifying the important difference between patent issuance and filing dates: 'Pharmaceutical companies try to delay the issuance dates ... as long as possible ... because the 17-year proprietary clock o f a US patent starts running with the issuance of the patent and a good apart o f that period is cannibalized by development work long before the product is actually marketed'. It is the filing date that establishes legal priority.
progestin, 17 a-acetoxyprogesterone, was developed for pet use in the veterinary division. This 'testing' of the pill on animals was never isolated from humans. Not only were crucial lessons in reproductive control learnt, but as Busfield and Padon found (1977: 244), potential consumers of the pill were also influenced. Stating that the pill did not appeal to her, one woman said: 'It's rather silly, I suppose, b u t... the time I was interested in farming they used to give these types of drugs to cows ... In the 1940s it was quite a new thing and very interesting because you can make the heifer come on heat just when you wanted to, and the idea of me taking drugs of this sort is repugnant. I think one's personality depends tremendously on one's hormones and I don't want mine mucked about with'.
Searle was the first company to make the policy decision to market an oral contraceptive pill. Searle therefore has received the retrospective credit for daring to launch a contraceptive into a 'hostile' (male-defined) market^^. Djerassi (1992c) notes that 'there is no question that Searle's norethindrone double-bond isomer norethynodrel was the first steroid active ingredient of an FDA-approved contraceptive pill, and that the company deserves enormous credit for marketing the product in 1960 despite a possible backlash by consumer opponents of contraception'. Colton (1992: 628) confirms this, adding that 'the management of Searle deserves special commendation for its foresight and willingness to get involved and wholeheartedly support what appeared at the time, four decades ago, such a socially controversial, financially questionable, and scientifically challenging area as oral contraception'. Nevertheless, Reed (1978: 356) documents that even Searle had reservations about their involvement in the field of contraception. It was felt that interference of the menstrual cycle would not be acceptable for regular use by healthy women. Vaughan (1970: 36) also cites an interview in 1969 with a Searle spokesman:
'We recognised right from the start this was going to be as controversial as hell, and we moved very cautiously. If anyone had told us the pill was going to be discussed at bridge parties and across dinner tables, well, frankly, we would have disbelieved it'.
Despite these fears Searle continued to support Pincus, but cautioned him not to publicize their involvement. Davis (1978: 89) emphasises that 'Searle was by no means sure that it wanted to go into the contraceptive business, which was
43. A report in Time M agazine (February 17 Vol. 77 1961: 33) noted interestingly that 'Searle sells