After Margaret Sanger’s visit, Pincus began the search for the “universal contraceptive.” In 1951, he took up the line of research that Makepeace and his colleagues had initiated in 1937: the effects of progesterone on ovulation. As a first step, Pincus had two of his staff members, the chemist Min-Chueh Chang and the biologist Anne Merrill, administer various amounts of synthetic progesterone to female rabbits to investigate the dosage and timing required to inhibit ovulation. They succeeded in duplicating the long-ignored Pennsylvania experiment and reconfirmed that progesterone could work as a contraceptive, at least in animals (McLaughlin 1982:108).
The next step, testing the compounds’ ovulation inhibiting potential in humans, could not be taken in the laboratory. For this Pincus needed a clinic. At a scientific conference in 1952, he happened to meet John Rock, a professor of gynecology at Harvard, with whom Pincus had collaborated on an earlier research project.13 Rock, the director of the Free Hospital for Women, one of the busiest infertility clinics in the United States, was a major advocate of the application of hormone research to clinical gynecology (Reed 1984:354). At this conference Pincus learned about Rock’s clinical studies, in which he tested progesterone among his women patients for a purpose totally opposite from that of Pincus: the treatment of infertility.14 The Free Hospital promised to be an ideal test site for Pincus’s purposes. The hospital attracted many leading gynecologists and functioned as a private research clinic (McLaughlin 1982:41). Despite their different missions, Rock and Pincus seemed to follow similar approaches. Actually, they were working on different aspects of the same problem—the manipulation of the process of conception—and they shared an interest in the same hormones (Rock 1963: 163). Cooperation between the laboratory and the clinic could be of mutual interest: it would provide Pincus with the required conditions for testing progesterone as a contraceptive in women, while Rock might profit from the cooperation since it promised a much broader investigation into the development of infertility drugs. Rock, who well knew the contraceptive effect of the treatment with progesterone (McLaughlin 1982:110), accepted Pincus’s request to extend his research on progesterone to the compound’s potential use as a contraceptive.15
Pincus’s animal experiments and Rock’s clinical studies were a step forward in the search for hormonal contraceptives but nevertheless confronted them with a serious problem. Progesterone seemed to be more active if it was injected than if it was given by mouth. Pincus anticipated that injections were not suitable for a “universal contraceptive”: women would not be in favor of repeated injections. Oral administration seemed a much more promising alternative (Christian Johnson 1977:71; Vaughan 1972:3031). Pincus’s animal experiments indicated that progesterone could be used as an oral contraceptive only in large doses, making it rather expensive. The
making of an “aspirin-like” contraceptive required a synthetic progesterone that would be effective at a lower dosage, and thus cheaper to produce (Reed 1984:355).
At this moment, a third actor appeared on the stage: the pharmaceutical industry. Pincus approached the major hormone-producing companies and asked them to send him samples of all the synthetic progesterones that they had manufactured (Maisel 1965:12). Following this request, Pincus received nearly two hundred compounds, which were subsequently tested in his laboratory for their oral activity on “a small army of rabbits and rats” (Maisel 1965:122; Ramirez de Arellano and Seipp 1983:107) Initially, Pincus chose the products of two companies, Searle and Syntex, as the most promising oral progestins: compounds known as 19 nor-steroids.16 Later he switched exclusively to Searle’s product. As noted, Pincus already had strong alliances with the Searle Company in his role as scientific advisor and as screener of the firm’s hormonal compounds. Rock was also acquainted with the firm, which had provided the required progestins for his infertility studies (McLaughlin 1982:135-136). The delivery of progestins for the contraceptive research project further cemented the relationships between Pincus, Rock and Searle into a strong network of mutual dependencies. Both Pincus and Rock depended on the pharmaceutical company for the delivery of oral progestins. Searle, in its turn, required Pincus’s laboratory and Rock’s clinic for the organization of tests to decide whether 19 nor-steroids could be made into contraceptives. In this emerging network, Pincus was the pivot on which the other actors hinged. He mediated the contacts between Searle and Rock, transmitting Rock’s findings to the company (Christian Johnson 1977: 75). Chang, who performed almost all the experimental work on oral progestins in Pincus’s laboratory, characterized Pincus’s role as follows:
Without his wide knowledge of endocrinology, his organizational ability, and his good relations with the pharmaceutical industry as well as the medical profession, and above all, without his daring enterprise, all this work would be on the library shelves.
(Vaughan 1972:43-44)
The irony of this history is that these developments, which would eventually lead to the manufacturing and marketing of the first oral contraceptive, took place in Massachusetts, a state where rigid laws against birth control still functioned. As Rock put it:
Life has a way now and then of mocking man’s more questionable designs. It must have amused some citizens of the Commonwealth of Massachusetts, with its rigid law against birth control, to discover that the first breakthrough in contraceptive technology in 75 years suffered and survived its labor pains in the environs of Worcester and Boston.
(Rock 1963:159)
This restrictive climate, however, had an enormous impact on Pincus’s and Rock’s work: the testing of progestins as contraceptives can best be described as a testing in disguise. Rock’s infertility studies turned out to be the ideal “undercover” strategy for the organization of clinical trials for the testing of the oral progestins that Pincus had selected in his animal studies. The contraceptive potential of their compounds could be tested in a research project designed for a totally opposite purpose: the stimulation of conception! Both Sanger and McCormick were enthusiastic about this location for the organization of the first trials on humans, very much aware of the fact that Rock’s clinic provided a perfect “alibi” for research that clearly violated the law (McLaughlin 1982:123).
The first testing of oral contraceptives thus took place as a parallel study in Rock’s infertility studies. In 1953, Rock started a second series of clinical trials in which twenty-seven women were enlisted, all patients with infertility complaints drawn from the Free Hospital clinic, this time with the explicit aim of testing the trial compounds on ovulation (McLaughlin 1982:115). The trials consisted of a rather extensive and complicated set of tests, all with the purpose of determining whether the trial compounds stopped ovulation. Rock’s staff at the Free Hospital charted the length of the menstrual cycle and daily basal body temperatures, and also took daily smears of the vagina, a 48-hour hormone assay of the urine, and a monthly biopsy of the endometrium of the uterus (Rock and Pincus 1956:892). In the clinic these trials were nicknamed the ‘PPP,’ the Pincus Progesterone Project, also known as the “pee, pee, pee project” because of the regular urine specimens that had to be checked (McLaughlin 1982:117).
At Pincus’s suggestion, the design of the trial was modified to adjust to the changed research goal. To quote Rock: “As a result of our discussions I instituted certain changes in our second series of 27 women” (Rock 1963: 163). One of these changes consisted of an adjustment in the regimen of taking the pills. Rock’s infertility patients were quite distressed when they noticed that their menstruation ceased during the treatment with oral progestins (Maisel 1965:119). If these women were distressed, Pincus and Rock reflected, it would be very likely that women taking progestins for contraceptive purposes would experience similar reactions. A contraceptive that suppresses menstruation did not meet the requirements of a “universal” contraceptive. Pincus therefore changed the medication. The pills should be taken for twenty days, starting on the fifth day after menstruation, as was the practice in the hormonal treatment of menstrual irregularities in the 1940s (McLaughlin 1982:110).17 This suggestion set the standard for the administration of progestins in all later trials and eventually for the use of the contraceptive pill in the 1960s.
The choice of this regime of medication was also shaped by moral objections to any drugs that would interfere with menstruation. Pincus was directly confronted with this norm by Searle’s director of biological research, who let Pincus know that he did not want to take part in the development of any compound that might interfere with the menstrual cycle (McLauglin 1982:111). In later publications both Pincus and Rock presented the effect of progestin on menstruation as a way of mimicking nature: women would still have their menstrual periods. In 1958, Pincus legitimized the regime of medication as follows:
Actually, in view of the ability of this compound to prevent menstrual bleeding as long as it is taken, a cycle of any desired length could presumably be produced. We had chosen our standard day 5 through day 24 regime in the expectation that “normal” cycle length would occur.
(Pincus 1958:1,338)
Pincus and Rock emphasized that the pill was not “going against nature.”18 Or to quote Rock in recapitulating the development of the pill in 1963:
Today, more than one million women of many countries are taking the pills, not simply because of their great effectiveness but also because they provide a natural means of fertility control such as nature uses after ovulation and during pregnancy.
(Rock 1963:167)19
This choice of the regime of administration exemplifies how medical technologies are modified to meet the needs of their users as well as moral attitudes toward intervening into nature.
The results of this first trial did not yet answer the question of whether the oral progestins could be made into the “cheap and safe” contraceptives that Sanger had envisioned. The women participating in this trial were after all suffering from infertility problems, and were not exactly the ideal subjects to test contraceptives. Rock and Pincus thought this test nevertheless informative. In their report in Science in 1956 they concluded:
 |
Despite adequate coitus, none of the 50 women became pregnant during the months of medication. Their long-standing infertility may make this zero figure of no import. Nevertheless, it seems of at least passing interest that within only 5 months of the last treated cycle, seven patients conceived.
Both Rock and Pincus felt that more clinical trials were needed. A single study of fifty and then of twenty-seven infertile women did not suffice to convince their colleagues. Actually, Pincus met severe criticism when he first presented their findings in public. At the fifth meeting of the International Planned Parenthood Federation (Margaret Sanger’s brainchild) held in Tokyo in 1955, Pincus’s presentation was received with yawns and skepticism. The tests used by Rock to check whether women had ovulated were criticized by other scientists as rather inconclusive (McLaughlin 1982:121; Vaughan 1972:36). With Rock’s methods, the diagnosis of the incidence of ovulation could be assessed only by indirect testing. Clinical tests for a direct diagnosis of the suppression of ovulation, as against a diagnosable pregnancy, were not available (Clarke 1985; Rock et al. 1957: 326-327). The chairman of Pincus’s session, Solly Zuckerman, professor of anatomy at Birmingham University, concluded at the end of the session:
Promising though they may appear at first sight, I think it is fair to conclude that the observations reported by Dr. Pincus do not bring us as close as we should like to the goals of our researches.
(Zuckerman as cited in Vaughan 1972:36)
Reservations concerning possible side-effects of daily ingestion of the pill were uttered as well.20 To quote Zuckerman again: “We need better evidence about the occurrence of side-effects in human beings…. There is an urgent need for prolonged observation before we draw any firm conclusions” (Vaughan 1972:37). Rock, who had not accompanied Pincus to the Tokyo meeting, shared this opinion. Women participating in his trials had indeed complained of unpleasant side-effects.21 To quote Rock:
The none too positive assurance of the slightly uneasy experimenter was not entirely conducive to sublime confidence that all would be well.. In view of these results, it seemed advisable after 18 months to declare a short recess for renewed contemplation and appraisal.
(Rock et al. 1957:324)
This cautious attitude concerning possible risks for the subjects was not the only constraint delaying an extension of the trials to fertile women. Large — scale clinical trials for the explicit purpose of developing contraceptives were practically impossible to carry out since they would have violated the law. Rock and Pincus knew that legally they could not organize these trials at the Free Hospital without risking criminal prosecution in Massachusetts (McLaughlin 1982:118).
Pincus considered an escape route: Puerto Rico, a location outside the continental USA. In Puerto Rico, laws prohibiting contraception did not exist
at that time.22 Pincus approached the dean of the University of Puerto Rico Medical School, who agreed to undertake the clinical trials. Neither Pincus nor Rock participated directly in the trial. The progestin study was carried out by one of Pincus’s collaborators: Celso-Ramon Garcia, a Manhattan-born Spanish-American gynecologist. Rock functioned merely as medical advisor, personally examining the women’s tissue samples, which were sent to him at his clinic in Brookline, Massachusetts (McLaughlin 1982:118).
In Puerto Rico, Pincus kept on his guard as well. The trial was labeled a study of the effect of progestins on the menstrual cycle rather than a study of contraception (McLaughlin 1982:118). Pincus did not under-estimate the political risks of his work. His colleague, Hudson Hoagland from the Worcester Foundation, has revealed how he and Pincus “used to get threats that we’d be killed” (Hoagland in Anonymous 1978:49). Garcia described the political climate at that time as “so hostile that you couldn’t get a physician in Puerto Rico to carry out any work.” During the later field trials Garcia and his staff also received threats, particularly from the medical profession, including that “they would be barred from the hospital privileges, that they would be barred from taking board examinations, that they would be given every possible impediment if they collaborated any further with the programs in Puerto Rico” (Garcia in Anonymous 1978:49).
This experiment in the clinic in Puerto Rico did not last long. The recruitment of volunteers was quite problematic. Most of the medical students dropped out, due to graduation and a reluctance to adhere to the troublesome requirements of the test: taking daily temperature and vaginal smears, collecting urine samples and submission to an endometrial biopsy. The trial included twenty-three women medical students, of whom only thirteen remained in the project for three months. Disciplining women to the rigorous conditions of the trials was obviously not an easy task. Pincus’s correspondence shows that even the students who completed the pilot-study “did not comply strictly with the demands of the experimental procedures.” The student was held accountable for “irresponsible behavior” during the experiment, which would be held “against her when considering grades.”23 Garcia, after a vain attempt to recruit new students, then turned to female prisoners as potential subjects. These women, however, expressed objections to participation in the trial. The final setback for this Puerto Rican trial came when university officials learned about the contraceptive implications of the study and withdrew their support for the research project (McLaughlin 1982: 119; Ramirez de Arellano and Seipp 1983:110).
After this debacle in Puerto Rico, Pincus tried another escape route: a mental hospital. He approached the Worcester State Hospital, a mental institution located near his laboratory, with which he had cooperated in earlier experiments.24 The hospital’s director agreed to the organization of a clinical trial with fifteen patients, all classified as psychotics. The group consisted of seven women and eight men, the first (and last) male test subjects in the research project.25 Despite the fact that the hormone preparations had a definite contraceptive effect in the male patients, men were not included in later trials due to the occurrence of side-effects. In this trial one subject was found to have smaller testicles after five months of taking progestin tablets.26 Pincus met other constraints as well. The psychotic men did not exactly make easy subjects. The men’s mental disturbances made it rather difficult to collect semen samples, one of the requirements for investigating the effects of progestin (McLaughlin 1982: 120; Vaughan 1972: 39, 40). The results of this trial, to put it mildly, did not give the decisive answer to Pincus’s quest for the “universal contraceptive.”
The restrictive political climate not only directed the choice of clinical testing locations, but also shaped the publication behavior of the scientists and clinicians involved in the project. The titles of the early publications do not inform the reader at all about the topic they are actually dealing with. All the papers published in this period bear rather misty titles, with neutral terms such as “progestins” and “menstrual cycle” as keywords. The first report that Pincus and Rock published in Science, for instance, is entitled “Effects of Certain 19-Nor Steroids on the Normal Human Menstrual Cycle”. (Rock and Pincus 1956). In these early publications the authors only casually mention the inhibiting effect of progestins on ovulation, but make no claims about the possible use of progestins as contraceptives.
In this respect Rock, given his Catholic background and his reluctance to make any premature claims, seems to have acted more cautiously than Pincus. This was clearly the case at the conferences where they first presented their research. While Pincus had openly discussed the possible use of progestins as contraceptives at the conference in Tokyo in 1955, Rock avoided mention of it when he presented their research findings at the Thirteenth Laurentian Conference in 1956. He concluded only that: “We are led to suspect that ovulation has been inhibited in at least a very high proportion of the cases” (Rock et al. 1957).
This was a rather non-committal claim that had been made earlier by other scientists as well. Rock made no statement about the contraceptive potential of progestin. His audience, including representatives of the major hormone — producing pharmaceutical companies from all over the world, was clever enough to read between the lines. (McLaughlin 1982: 122; Tausk 1978:387). In the concluding session, one of the conference participants remarked: “One fact which stood out in this study is that Dr. Rock has unwittingly given us an excellent oral contraceptive which may be employed with little untoward effect” (Rock et al. 1957).27 The word was out that the Boston scientists and clinicians were on the track of a new contraceptive. It was clear as well that Pincus and Rock needed more substantial data to convince the scientific community of the success of their endeavor.
This episode of the making of the pill illustrates in a very livery way that Pincus’s quest to find relevant contexts in which his claims about the contraceptive activity of hormones could be established was not an easy one. Initially, the selection of Rock’s clinic seemed to be a perfect solution. The clinic provided Pincus with access to women who could be made into the first test subjects for the contraceptive-in-the-making. Pincus quite successfully reoriented Rock’s research from conception to contra-ception. Nevertheless, Rock’s clinic, and the other settings which Pincus selected, failed to provide the conditions for the testing of the contraceptive activity of hormones. The development of progestins into contra-ceptives required access to large groups of healthy, fertile women. Large-scale trials, however, could not be organized in the gynecological clinics of medical schools, since these trials were even harder to conceal than small-scale trials. Pincus and Rock had to create a testing location outside the domain of the established medical institutions. They needed a politically feasible location where the development of progestins into contraceptives could be put to the final test.
At this point, Pincus explicitly linked his research to the domain of birth control. He shifted his research activities from the gynecological clinic to the family planning movement. Pincus took refuge, again, in Puerto Rico, where the family planning movement had a widespread institutional base in the form of birth control programs and clinics. Or to summarize the situation in Garcia’s words:
The attempt was at first to go to the University of Puerto Rico and that’s how I got involved in it. The attempt was to stay within a group of academic scientists. When that failed, then they went to seek out patients and the most logical place to find them was in the Planned Parenthood clinic.