How a Crash Program Developed an Efficient Oral Contraceptive in Less Than a Decade
A good beginning for this story is a meeting in early 1951 of three remarkable people—the greatest feminist of our age, a great philanthropist who was as notably eccentric as she was fantastically wealthy, and a biological scientist whose subsequent world fame was achieved in large part because of this meeting. Would that it could be described in circumstantial detail and invested with the drama it should have in view of what followed from it.
Alas, this cannot be done with any assurance of accuracy. Only the three principals could have told precisely where (a New York hotel? a Worcester research laboratory?) or when (January? February?) their initial encounter took place. None made a written record of it. And since the three died within a few months of one another in 1966 and 1967, all we can now be sure of is that there was a meeting, and that it was far more than an interchange among three extraordinary people. Viewing it in historical perspective, we may see it as a convergence of two lines of historic force whose technological product, the Pill, has often been compared to the Bomb in its impact upon social attitudes and individual lives.
Of one of these lines of force, Margaret Sanger was the personification.
In 1951 she was sixty-eight years old—a small, slender, frail-looking woman who, nevertheless, impressed others as a flaming youthful spirit, wedded to life and defiant of death. Her copper-colored hair, crowning glory of her beauty as a girl, remained but slightly touched with gray. Her eyes were as quick and eager as they had been when, nearly forty years before (in 1914), she introduced into our language the phrase “birth control” through a monthly magazine of which she was founder and editor. The name of her magazine, The Woman Rebel , accurately labeled the life role she had by then assumed. As a young nurse specializing in obstetrical cases she had again and again witnessed and been outraged by the agonies, often fatal, imposed upon women by unwanted pregnancies—pregnancies that could have been avoided if religious prejudice and prudery, both mightily sustained by what would later be called “male chauvinism,” had not forbidden all knowledge of contraceptive methods. Her outrage had been highly emotional, yet from the first, her battle for birth control was guided by a clear sense of social, economic, and cultural context. This enabled her to endure with rare equanimity the torrent of insult and abuse, the repeated arrests and imprisonments (she was jailed eight times), that were inevitably provoked by her assault upon the prevailing legal code and its underlying assumptions. It also enabled her to widen the basis for her campaign from that of women’s rights to that of large-scale population control when the urgent necessity for the latter, especially in underdeveloped countries, became obvious to all with eyes to see during the years immediately following World War II.
As early as 1930, impressed and depressed by the imperfections of existing contraceptive measures, Sanger had become interested in the possibility of developing a safe and efficient physiological contraceptive. In that year she was told that scientists in the Soviet Union had actually done so—had created a spermatoxin which, injected in women, immunized them against pregnancy for several months without bad side-effects. Four years later, she herself visited Russia and talked with the scientist, a Doctor Tushnov, who had tested the spermatoxin on thirty women, immunizing twenty-two of them for prolonged periods. But she then learned to her dismay that further experiments along this line were now prohibited by Soviet authorities: in a typically abrupt reversal of Communist policy, population growth had become the official aim (there was a Soviet “labor shortage”).
By this time, more because of her efforts than anyone else’s, the almost total religious opposition to her cause was breaking down. The National Council of Jewish Women had endorsed birth control; so had major Jewish religious organizations and Protestant Christian denominations. In the spring of 1931 the powerful Federal Council of the Churches of Christ, representing well over 20,000,000 Protestants, had not only sanctioned the separation of the sexual act from procreation when performed between loving husband and wife, but also had called for a “new morality” grounded in knowledge and personal freedom rather than in ignorance and fear—“just what I would have written myself,” as a joyful Margaret Sanger told the press.
Powerful religious opposition yet remained, however, from the Roman Catholic hierarchy and also from numerous Protestant fundamentalist sects. It was sufficient to deny government funding to any research directly aimed at the control of human fertility. And this was increasingly tantalizing and frustrating to Margaret Sanger as the terrifying statistics of “population explosion” added a new argument to her battery. She had no scientific expertise, but by 1950 she knew that biological scientists were opening up new and promising approaches to physiological contraception. She was persuaded that adequately funded research along the indicated lines just might provide a safe, unprecedentedly effective means of birth control within a few years. And she deplored with some bitterness the priorities which assigned millions of tax dollars annually to the improvement of livestock breeds, while denying any money at all to research whose success might immensely reduce human misery in the process of increasing, perhaps as greatly, the survival chances of civilization.
It was thus with intense interest that Margaret Sanger received in late 1950 a letter from a wealthy, long-time friend asking her pointedly “what the present prospects are for further “ contraceptive research.” Her friend was Mrs. Stanley (Katharine Dexter) McCormick—a woman of formidable appearance, tall, stately, and so rich she could not even “spend the interest on her interest ,” as her lawyer once said. Her father, a prominent and prosperous Chicago lawyer, had early recognized her rare intelligence and encouraged her enrollment in the Massachusetts Institute of Technology, where, in 1904, she took a B.S. in biology—the second woman ever to graduate from that institution. Shortly thereafter she married the youngest son of Cyrus McCormick, inventor of the mechanical reaper and founder of International Harvester. Then came tragedy: her young husband became a hopeless schizophrenic. Mrs. McCormick totally withdrew from the brilliant society in which she had formerly moved, lived ever after as a semirecluse, and continued to dress pretty much as she had in her bridal year, as if her wearing of the long skirts and fussy hats of the Teddy Roosevelt era would retain for her vestiges of the happiness she had then known. Her other major response to tragedy was quietly to endow a number of projects that were highly worthy by her criteria but highly unpopular, and so unlikely to gain financial support elsewhere. One of these was birth control. To its importance she was “awakened,” as she said, by Margaret Sanger’s trial and imprisonment in 1917. To it she made substantial financial contributions after she and Sanger became personal friends in the late 1920’s.
It is probable that, when Mrs. McCormick wrote Sanger in 1950, she, already had in mind a man to whom she might make her research grant. One object of her earlier largess, natural in her circumstances, was research into the biochemistry of schizophrenia—this after intensive psychiatric treatment had failed to better her husband’s condition. In 1927 she had established an organization called the Neuroendocrine Research Foundation whose clinical work with schizophrenics was concentrated in the Worcester State Hospital (Worcester, Massachusetts). Involved in it during the late thirties and early forties were two biological scientists of Worcester’s Clark University. One was Dr. Hudson Hoagland, chairman of Clark’s biology department, whose field was neurophysiology; the other was Dr. Gregory Goodwin (“Goody”) Pincus, an expert in endocrinology and mammalian reproduction. In 1944, Hoagland, and Pincus, having rebelled against the administration of a notably authoritarian and reactionary Clark president, broke away from the university to establish the Worcester Foundation for Experimental Biology, endowed (due mostly to Hoagland’s remarkable fund-raising talents) by several of Worcester’s wealthiest families. There, as the 1940’s ended, Pincus and the group of young scientists who had gathered around him were hard at work on basic researches into the biochemistry of mammalian reproduction. Probably Hoagland told his friend Mrs. McCormick about these researches one day in the autumn of 1950, after she had expressed her desire to encourage experiments specifically designed to develop new and better means of birth control.
At any rate, it was with Dr. Pincus that she and Margaret Sanger conferred at that crucial meeting in 1951. The two women were certain by then that no man was better equipped to answer the key question: could a physiological contraceptive be developed for safe mass use within the next few years if all relevant information and skill were applied to that end? Pincus’ answer was a carefully hedged yes (no one could know for certain ). Well, then, would he himself, adequately funded, be willing to undertake such research at the foundation? Again Pincus’ answer was essentially yes: the proposed project seemed a natural outgrowth of his past work. How much money would he need to get started? According to Pincus’ widow, this question was asked several times by Mrs. McCormick, Pincus dodging it until finally, forced by her insistence, he snatched “off the top of my head” (so he told his wife) a figure—$125,000. Whereupon Mrs. McCormick made out a check for $40,000, promising the remaining $85,000 as soon as she could make arrangements with her “financial man.” Ultimately she would give nearly $2,000,000 to the Worcester Foundation in support of Pincus’ enterprise.
To appreciate Pincus’ role requires some knowledge of the special branch of science in which he worked. It was in the mid-1890’s that a Viennese gynecologist, Emu Knauer, demonstrated experimentally that a substance or substances secreted by the ovary controlled the development of female sexual characteristics. In 1897 it was suggested (by J. Beard) that one such secretion might come from a theretofore wholly mysterious body known as the corpus luteum (“yellow body”), which begins to grow in the ovarian envelope in which the human egg is formed immediately after the egg has been discharged from it to travel down the Fallopian tube, which leads from ovary to uterus. The egg is either fertilized or not in the upper part of the Fallopian, depending upon whether or not a vigorous spermatozoan is encountered there. If the egg is not fertilized, the corpus luteum soon disintegrates. If the egg is fertilized, the corpus luteum persists through the pregnancy period, growing very large before it begins to atrophy as pregnancy nears its end. Such order of events indicated that one function of the substance secreted by the corpus luteum might be to facilitate implantation of the fertilized egg in the uterus. Another function, it seemed, might be to inhibit further ovulation during pregnancy.
When these investigations were made, the biological substances involved had not yet been given a generic name. They were given one, however, very shortly thereafter. They were classed with other secretions from ductless (endocrine) glands, such as the thyroid and the pituitary—secretions whose function is that of chemical messenger carrying a specific command through the bloodstream to a specific target organ—and the generic name given all these (by a classicist friend of pioneer endocrinologist Ernest Starling) was “hormone,” from the Greek word meaning “to excite” or “arouse to activity.”
This was in 1905. In that year, Gregory Pincus was two years old.
He was the son of Russian Jewish immigrants who in the nineteenth century became members of a farm colony near Woodbine, New Jersey, where he was born in 1903. He grew up in a farming community, and one of his uncles was dean of agriculture at Rutgers, so it was natural for him to enroll in agriculture at Cornell, majoring initially in pomology, with apple growing as his vocational aim. This specialty soon proved too narrowly confining, however. He became interested in plant genetics, then animal genetics, and when he entered Harvard’s graduate school, after taking his B.S. at Cornell, his doctoral field was mammalian genetics. It was at Harvard that he met and became friends with Hudson Hoagland, who, after taking an A.B. at Columbia and an M.S. in chemical engineering at the Massachusetts Institute of Technology, was working toward a Ph.D. in experimental psychology. Both received their doctorates in 1927, and both received National Research Council Fellowships for postdoctoral work. Pincus used his for a year and a half of work at Cambridge University, in England, where he first became interested in reproductive physiology, followed by a half year of work in genetics at the Kaiser Wilhelm Institute in Berlin. He returned to Harvard as an instructor in general physiology in the fall of 1930. Two years later he was given a threeyear appointment as assistant professor.
By that time, very considerable progress had been made in sex hormone research. While Pincus was studying practical agricultural subjects as a Cornell freshman, an Austrian physiologist, Ludwig Haberlandt, was summarizing the results of experiments he had made with the sex glands of animals. Haberlandt had transplanted the ovaries of pregnant guinea pigs, and of pregnant rabbits, into nonpregnant guinea pigs and rabbits, and had found that the latter became temporarily sterile. This led him to suggest, in 1921, that extracts from the ovaries of pregnant animals might inhibit ovulation in human females—might be used, in other words, as a contraceptive far more effective than any previously used. Meanwhile, biochemists struggled to isolate and chemically identify the female sex hormones. In 1928 two scientists of the University of Rochester (George W. Corner and Willard M. Allen) identified the hormone produced by the corpus luteum . The hormone was named for its principal function: progesterone, a combination of the Latin pro (“in favor of”) with the Latin gestare (“to bear”), although its concomitant function of preventing ovulation during pregnancy had not been forgotten. In the following year a scientist at Washington University in St. Louis (Edward Doisy) established experimentally that sexual desire and readiness in female rats is induced by a hormone produced in the rat ovary. This hormone, essential to the sexual organization of all mammalian females, was called estrogen, a combination of the Greek oistros (”frenzy,” or “mad desire”) with gennein (“to beget”).
Within a few years thereafter each of the hormones had been proved by laboratory analysis to be not a single substance, but a family of compounds whose chemical structures are very similar (there are in fact some twenty estrogens); and both estrogen and progesterone were being manufactured commercially from such source material as pigs’ ovaries and human urine. The manufacturing process was elaborate and time-consuming. The living body easily makes steroids (fat-soluble compounds, including all the sex hormones) out of cholesterol, but laboratory chemistry can do so only with difficulty—and alternative sources of raw material which could be more easily processed had not yet been discovered. Hence the production costs and unit price of estrogen and progesterone were very high and the supply severely limited, while the market for them swiftly grew. Estrogen had been found effective as a medicine for dysmenorrhea (painful menstruation) and irregular periods. Progesterone was in demand for women who were deficient in this hormone and consequently “chronic aborters.” And both hormones were needed in growing quantity by scientists for laboratory studies of mammalian reproduction.
Early in the 1930’s Gregory Pincus made a name for himself, not only among scientific colleagues but also with the public at large, when he managed by chemical and mechanical means to cause unfertilized rabbit eggs to grow and divide in test tubes, thereby producing rabbits having mothers but no fathers. Sensationalized reports of this appeared in the press, and there ensued much popular excitement about the possibility of producing human babies in the same way, though Pincus himself emphatically disavowed any intention of experimenting toward that end. In 1936, the year in which he published The Eggs of Mammals , a classic in its field, he was experimenting with the ways in which progesterone operates to facilitate implantation. He was also studying the effect of estrogen on ovulation in mated rabbits (rabbits do not ovulate unless mated).
Simultaneously, of course, as part and parcel of his own work, he kept close tabs on the reported experiments and hypotheses of others laboring in his field. He read Carl C. Hartman’s highly influential Time of Ovulation in Women (1936), wherein conclusions about the role of hormones and the endocrine system in human reproduction were boldly drawn from recent research results. It is highly probable that he read a paper entitled “The Prospects for Hormonal Sterilization” by Columbia University gynecologist Raphael Kuzrok, a paper published in 1937 wherein Kuzrok speculated about the possibility of using sex hormones to prevent ovulation. It is certain that Pincus read, in that same year, a paper by A. W. Makepeace, G. L. Weinstein, and M. H. Friedman of the University of Pennsylvania reporting an experiment in which progesterone was administered to mated female rabbits, with the result that the rabbits did not ovulate. This greatly impressed him: fourteen years later he was to make a duplication of the reported experiment the starting point for his work toward the Pill.
Meanwhile, Pincus faced a major crisis in his personal life; his professional career was in jeopardy. That he had done brilliant work at Harvard, none could deny. When the university issued a pamphlet in 1936 as part of its tercentenary celebration, Pincus’ parthenogenic rabbit was cited in it as one of the outstanding scientific achievements of the institution’s three hundred years. Hence the total unexpectedness of the blow dealt him by the university less than a year later. He was then notified that he would not be promoted to associate professor at the end of his second three-year term as assistant professor, which meant, by the administrative rules then in force, his dismissal from Harvard’s faculty the following year. It was perhaps fortunate for his emotional equilibrium that a prior arrangement enabled him to spend the last year of his Harvard appointment in Cambridge, England (he worked in the Strangeway Laboratory there), rather than in Cambridge, Massachusetts. Certainly it was fortunate for his career that his friend, Hudson Hoagland, who had become chairman of the biology department at Clark University in 1931, was, in his own words, “incensed” by Pincus’ dismissal. Hoagland was convinced, as he wrote later, “that academic politics, including some antisemitism [and] jealousy toward Pincus on the part of some… were the reasons for his discontinuance.” There was nothing passive about Hoagland’s indignation. When no other position was opened to Pincus in America as the year wore on, Hoagland obtained private funds to bring him to Clark as a “visiting professor” in 1938.
During the immediately following years, as World War II began and raged—and for a number of years after the Foundation for Experimental Biology was established—Pincus’ attention was largely diverted from reproduction and allied phenomena to war-related research. For this, he and Hoagland made a well-balanced team. Their superficially widely separate specialties were at base quite closely complementary. Internal message communication, the exchange of information among component elements, is of the essence in any functioning organization, including the human body. There are two very different ways in which vital messages are transmitted from one part of the body to another. Pincus as endocrinologist was concerned with one of these—the chemical messages (hormones) flowing in blood through the circulatory system. Hoagland as neurophysiologist was concerned with the other, namely, messages sent as electrical impulses along the nervous system. So the two men could and did collaborate for several years in investigations of the relationship of hormones to stress and combat fatigue, in addition to studies of adrenal cortical function in schizophrenic patients.
After war’s end, the Hoagland-Pincus research collaboration waned, ceasing altogether in the late 1940’s, as Hoagland’s time and energy were increasingly absorbed into the financing and administration of the foundation, where he demonstrated a major talent for organization and executive direction. Pincus, meanwhile, had gathered around him, first at Clark and then at the foundation, a group of brilliant young investigators, most of whom were as devoted to him personally as they were dedicated to their work, for he had a rare ability to inspire a personal devotion fused with scientific dedication in those closely associated with him. The foundation swiftly grew. In a dozen years its scientific personnel (originally fifteen) increased tenfold and its annual budget (originally $100,000) fortyfold, fed by private donations and governmental grants-in-aid, and by research grants from individuals, private foundations, the federal government, and pharmaceutical companies. One of the latter, G. D. Searle of Chicago, played an especially important role in the earliest history of the foundation and subsequently, with great profit to itself, in the development and marketing of the Pill. A grant from Searle financed Pincus’ first research (on the pituitary) at Clark; shortly thereafter he was hired by Searle as a scientific consultant, a post he retained for many years.
The chief among Pincus’ recruits was a man enticed from Cambridge University, with which institution both Hoagland and Pincus retained close ties. This recruit was a tall, slender, ironically humorous young Chinese named MinChueh Chang. He had come to Cambridge from his native land just as World War II began and, while Britain endured the rumble and terror of war, had earned not only a doctoral degree but also a justified reputation as a phenomenally skilled laboratory technician whose skill was guided by an acute and profoundly informed scientific intelligence. He arrived at Worcester in 1945, when the foundation was less than a year old. Soon thereafter he was immersed in an exceedingly difficult but highly successful study (using rabbits) of the role played by the seminal plasma, which is ejaculated with the sperm, in rendering sperm capable of fertilizing the egg.
And it was with rabbits that Chang made the first of the long series of experiments and tests that led directly, by specific prior design, to production of a mass-marketable oral contraceptive. The experiment, as has been indicated, was a repetition at Pincus’ behest of the 1937 experiment by Makepeace and others at the University of Pennsylvania. It began on April 21,1951 (Chang made careful note of the date, as if he sensed it might become historic), not long after Pincus’ meeting with Sanger and McCormick.
By then it was known that estrogen is an effective inhibitor of ovulation in women; the fact had been abundantly documented in the clinical reports of the use of estrogen as a medicine for dysmenorrhea. Indeed, Harvard professor Fuller Albright had been led by this to suggest, in 1945, the use of estrogen as an oral contraceptive: a daily pill of one of the then just-developed synthetic estrogens could accomplish “birth control by hormone therapy,” he said. But it was also known from animal tests, to which Albright in his paper did not refer, that estrogen posed certain risks which progesterone, evidently, did not ; which is why Pincus and Chang focused at the outset on progesterone. And when repetition of the Makepeace et al experiment confirmed its conclusion—progesterone was indeed an effective inhibitor of ovulation in rabbits—Chang went on to make what Pincus called the “logical extension” of this observation, namely, “a more intensive study of the nature of the progesterone action as well as the action of certain derivatives and putative metabolites [substances acted upon in metabolism].” The results of this extension were published in 1952, by which time Chang was experimenting with progesterone on rats—animals that are more like humans than rabbits in their reproductive physiology, since the female rat regularly ovulâtes, whether mated or not. Masses of information as to the dosage required to be effective were accumulated, and it was found (as was to be expected) that a much larger dose was needed when taken by mouth than when injected beneath the skin.
Meanwhile, Dr. John Rock, professor of gynecology at Harvard, working with volunteer subjects at the Free Hospital for Women in Boston, was conducting an experiment whose immediate aim was the precise opposite of Pincus’. He was using estrogen and progesterone, orally administered, not to prevent pregnancy but to induce it in married women who desperately wanted children but were unable to have any. His hypothesis was that female sterility is often caused by subnormal uterine and Fallopian tube development, and that the necessary development would be stimulated if sex hormone levels were raised, by administration from the outside, to the amount normally attained during ovulation, fertilization, and implantation. The hypothesis seemed confirmed by the experimental results. For when Rock’s eighty experimental subjects were taken off the treatment, thirteen promptly became pregnant.
The treatment, however, had grave disadvantages. For one thing, it was known that estrogen in massive doses induces cancers of various kinds in at least five animal species. Rock, therefore, when he met Pincus at a scientific conference at this time and compared notes with him, was amenable to Pincus’ suggestion that he now experiment with progesterone alone (no estrogen) and that he have the subject take the hormone for only twenty days running, beginning on the fifth day of the menstrual cycle. He should then have her stop taking it so that she (it was assumed) would discharge normally, though without having ovulated, resuming the hormone intake on the fifth day of the new cycle. Rock promptly began doing this with thirty volunteer women. The results were again definitely confirmative of Rock’s initial hypothesis: all the women ovulated normally as soon as they were off progesterone, and of the women who stayed the course (several did not), four became pregnant shortly thereafter. But had they ovulated while the experiment was under way? This question was of crucial importance to Pincus’ enterprise, and a battery of elaborate tests had failed to give clear answers to it. There were instances in which the test results were flatly contradictory, some saying that a given subject had ovulated, others that she had not. It seemed that progesterone had not been proved totally effective as a preventer of ovulation. Even if it had been it would have remained, on the evidence of this experiment and Rock’s earlier one, an impossibly cumbrous and expensive means of birth control for the masses. As was later realized, natural hormones are rapidly degraded and inactivated by body enzymes. Hence, taken by mouth, a daily dose of three to four hundred milligrams of natural progesterone was required.
So Pincus began to cast around for a substitute for natural progesterone that would produce the desired effect more efficiently, at smaller cost. He wrote to a dozen or so pharmaceutical companies. And at this point the line of research he had been following luckily intersected that which had been followed by organic chemists since the late 1930’s, when the immense potential market for commercially manufactured sex hormones, reasonably priced, became obvious.
The great pioneer of the latter research was an eccentric genius named Russell E. Marker. In 1939, when he was professor of organic chemistry at Pennsylvania State College, Marker turned from animal to vegetable material in his search for a better, cheaper source of raw material from which the desired hormones could be made. He ultimately found it in a substance he named diosgenin, extracted from the root of a member of the sarsaparilla family called cabezo de negro ( Dioscorea mexicana ) which grows exclusively in Mexican jungles. (All subsequent efforts to grow it commercially in the United States failed.) He brought sacks of this root back to a makeshift laboratory he had established in a shed behind the Mexico City house he had rented; and there, working alone, he quickly devised a method of converting diosgenin to progesterone much more efficiently than progesterone had ever been or could ever be derived from animal fat. He showed the first product of his process (several pounds of progesterone in white, crystalline, powder form, worth around $110,000 at the price then current) to a couple of Central European émigrés who operated a small hormone-supply company in Mexico City. The two were naturally astonished, and then delighted to join with Marker in formation of a new company, incorporated in Mexico City as Syntex S.A., primarily to manufacture progesterone by the new means. This was in January, 1944. Not long afterward, Marker, whose genius for acrimony approximated his genius for chemistry, suddenly left Mexico City, having bitterly quarreled with his partners. He made one more major contribution to cheap progesterone. In early 1950, he and Norman Applezweig, working in a Mexico City company called Hormosynth, discovered quite by accident a source of diosgenin even better than Dioscorea mexicana —a closely related plant, barbasco ( Dioscorea composita ), which also grows in Mexican jungles but more abundantly; its root contains five to ten times as much diosgenin per unit weight as does cabezo de negro .
Marker’s sudden departure dealt a hard blow to Syntex, for he took with him all his notes on the synthesizing process; but the firm quickly recovered. It recruited George Rosenkranz from a Havana pharmaceutical firm—and Rosenkranz promptly reconstructed from published Marker papers, and his own research experience, the Marker process. In 1949 the firm also recruited a Viennese, Carl Djerassi, whose research genius was of the same order as Marker’s. Syntex’s progesterone production grew exponentially, with a proportionate drop in price. The hormone was sold for eighteen dollars a gram in 1945; in 1952, Syntex sold ten tons of it to a single company, Upjohn, for only forty-eight cents a gram.
For Pincus’ purpose, however, this synthetic hormone was no better than the other kind, since it was ineffective when taken by mouth. Not until 1952 did Djerassi report his synthesis of a type of progesterone which—when tested on rabbits, guinea pigs, monkeys, and finally, three women suffering from grave menstrual problems, at the National Institute of Child Health and Human Development in Bethesda, Maryland—proved to be immensely more potent (by a factor of ten or more) than the natural hormone, whether injected or orally administered. It was called norethindrone; and simultaneously with its public announcement Syntex applied for a patent on it. Three years later, or nineteen months after a full report of Djerassi’s work had been published in the American Chemical Society’s Journal , G. D. Searle of Chicago filed for a patent on a close isomer of norethindrone which Searle’s Frank Colton had allegedly developed in work wholly independent of Djerassi’s. Called norethynodrel, it proved orally effective, and in due course, it, like Syntex progesterone, received full patent protection.
Searle and Syntex were of course on the list of companies to whom Pincus addressed his letters of inquiry; and when he received, in prompt response, consignments of fifteen different progestational compounds, Searle’s norethynodrel and Syntex’s norethindrone were among them. Moreover, of all the fifteen these two proved most effective in the tests Chang soon made of them on laboratory animals. The two were then tested, in cooperation with Rock, on volunteer women, employing the same regimen that had been used with natural progesterone—a pill a day for twenty days beginning on the fifth day of the cycle. It was found that a mere forty milligrams of norethindrone, or a mere twenty of norethynodrel, as compared with three to four hundred of natural progesterone, sufficed effectively to prevent ovulation.
Now came the final, most daring phase of Pincus’ enterprise—the phase in which his personal qualities and energy became indispensable to the project’s success. Called into full exercise were his stubborn optimism, his drive, his ability as an organizer, his capacity to inspire a research team with a sense of mission, and (perhaps most important of all) his supreme self-confidence and consequent willingness to take chances that a less confident man would not have risked.
While the tests of synthetic progesterone were being completed, there impended a conference (the fifth) of the International Planned Parenthood Federation, a world body founded by Margaret Sanger in 1952. It was to be held in Tokyo in late October, 1955. Pincus proposed to Rock that the two of them attend it and present to the assembled delegates, and to the world press, a report on the work in progress. Rock demurred, emphatically: the test results thus far, though encouraging, were far from conclusive; the conference was in essence a propaganda forum for birth control; and any scientist who there talked hopefully of developing a contraceptive pill would make world headlines at grave risk to his professional reputation. Rock not only refused to go, he urged Pincus not to go either. Pincus went all the same, accompanied by Chang, their ways paid by Mrs. McCormick. Both men presented papers. Chang’s was simply a review of possible ways in which a physiological contraceptive might someday be developed. It mentioned hormone-level manipulations as one of the ways but stressed that too little was known about “the basic mechanisms of … reproductive physiology” to enable scientists to proceed as yet in other than a “hit or miss” fashion. Pincus, on the other hand, having presented the results of the tests he and Chang and Rock had made of norethindrone and norethynodrel, boldly inferred from these that the “delicately balanced sequential processes involved in normal mammalian reproduction” could be disrupted “in such a way that no physiological cost to the organism is involved.” This, he said, was the objective of the Worcester Foundation’s work and would “undoubtedly be attained.“” His implication, which attracted world press attention, was that the attainment would be soon.
Thus did Pincus make sure that there would be adequate funding, mostly from Mrs. McCormick, for what was bound to be by far the most expensive as it was the most risky part of the entire undertaking—the conduct of field trials with thousands of women, and dozens of professional people.
Shortly after the Tokyo conference, Puerto Rico was selected as the initial testing ground. There were good reasons: Puerto Rico had a horrendous and officially recognized population problem, it had operating birth control clinics, its government was eager to cooperate, and the island population was relatively immobile, which meant that the experimental subjects and control groups were likely to “stay put.” The trials began in April, 1956, in a suburb of San Juan where slum clearance was being joined with a large-scale housing project.
By that time the decision had been made to field-test Searle’s norethynodrel only. Syntex’s norethindrone was abandoned. The stated reason was that in animal tests norethindrone, unlike norethynodrel, gave some sign of slightly increasing masculinity in the process of inhibiting ovulation. Of course there were other reasons also. Pincus’ long professional association with Searle naturally inclined him to favor Searle’s harvest of whatever profitable fruit might grow from his endeavors. Moreover, Searle had an efficient marketing system through which to promote widespread use of a finished product, whereas Syntex, a wholesale manufacturing firm, did not. (It must be emphasized, however, that Searle in the spring of 1956 and for two or three years afterward was by no means sure that it wanted to go into the contraceptive business, which was regarded as a rather sleazy enterprise. The firm’s public relations people warned that doing so might destroy Searle’s theretofore “impeccable reputation.”)
By that time, too, a significant change had been made in the product to be tested. It had been noted that, among women dosed with one batch of norethynodrel, there occurred “breakthrough” bleeding if not actual ovulation (this last was suspected, because of the bleeding) in a small and yet, by project standards, disturbingly large percentage of cases. Among women dosed with another batch, however, this did not occur. Why? Chemical analysis revealed that the batch permitting breakthrough consisted of absolutely pure progesterone, whereas the other batch contained minute quantities of the starting material for its manufacture (mestranol), which has estrogen in it. So Searle was instructed to add, in future, a tiny amount of mestranol (150 meg.) to the progestogen from which each tablet was made. This, then, was the pill taken by volunteer women in Puerto Rico and, beginning a year later (at the urgent invitation of dictator “Papa Doc” Duvalier), in Haiti. It was patented by Searle as Enovid-10®, thus becoming Searle’s exclusive property. (Pincus might easily have obtained a share of the patent for the Worcester Foundation had he moved to do so. Why didn’t he? mourns Chang, who, while greatly admiring Pincus, has no love for pharmaceutical companies and deplores this lost opportunity to divert to the service of pure science a portion of what became a huge Searle profit.)
Surely nothing could be more revealing of the yetprimitive stage of the science which was now being forced into technology than this abrupt modification of the experimental Pill on the very eve of extensive human testing of it. Every science begins as a loose collection of more or less random observations. Initially, since nothing is known of the “basic mechanisms” whereby observed phenomena or desired results are produced, experiments are conducted “hit or miss,” to quote again from Chang’s Tokyo paper. Not until multiple lucky “hits” have provided a solid ground for logical inference can meaningful patterns be discerned or general descriptive laws be developed for the guidance of future experiment and the prediction, with growing accuracy, of future observations. Empiricism then gives way to induction. Thus a science becomes “mature” to the degree that it becomes inductive—and it may be stated as a general rule for the safety of mankind that no technology having possible massive human or environmental impact should be permitted to be made from other than a fully matured science.
Certainly this rule was in this case broken. Were the reasons for breaking it sufficiently compelling, were the assessments of alternative risks and of the overall riskbenefit ratio sufficiently accurate to justify the act?
One of the key members of the research team that went to Puerto Rico and Haiti was Anne Merrill, a Pincus research assistant at the foundation. She has stressed in conversation the degree of ignorance, and the resultant magnitude of risk, with which the field trials were begun. As regards the tablet’s effectiveness in birth control, the researchers could proceed with confidence: they had by then good reason to believe that Enovid-10 would prove to be a virtually 100 per cent effective contraceptive. But not enough was known about the dynamic hormonal balance in the human body (it is continually shifting, fluctuating, in response to biological needs and environmental stimuli) to permit more than educated guesses as to what the present “disruption” of it would do beyond its single prescribed purpose. There was the recognized possibility that synthetic estrogen might cause cancer. “We didn’t even know for sure that a woman who took the pill, and then went off it to become pregnant, would not produce all boys, or all girls,” says Anne Merrill.
She and her colleagues also stress, however, that their occasional nightmare visions of possible catastrophe were, from the moment of their arrival in Puerto Rico, overwhelmed by their daylight vision of actual human tragedy—the poverty and disease and ugly death directly consequent upon the continuing population explosion. There was certainly no reluctance on the part of Puerto Rican women to take such personal chances as the experiment would involve. As soon as word of the impending trial was spread abroad, they flocked to birth control clinics to volunteer for it. Each woman was then informed of the distinct possibility of highly unpleasant side effects and of the further possibility, real if remote, that a side effect would be permanently damaging, even fatal. Seldom was a woman’s eagerness to take part reduced in the slightest by such warning: her greatest fear in almost every case was that, upon physical examination, she would be judged unfit for the test and therefore condemned to the agony and potentially fatal danger of further pregnancy and childbirth. “The gratitude of those selected was pitiful,” says Anne Merrill, echoed by Mary Ellen Johnson of the Worcester Foundation, who was also on the team. Even worse than conditions in San Juan were those in Haiti. There the cruelty of circumstances was augmented by the brutal political tyranny, itself partly caused by the miseries of overpopulation.
Moreover, as the field tests proceeded, the worst fears were one by one allayed. There were unhappy side effects: nausea, dizziness, headaches, edema, tender breasts, and menstrual irregularities. These suggested that the amount of progesterone and estrogen should be reduced, if this could be done without reduction of contraceptive effectiveness. (It was done in later pills.) But there were no unexpected side effects, as Enovid-10 proved to be 100 per cent effective in preventing ovulation when taken as prescribed by more than 15,000 Puerto Rican and Haitian volunteers, many of whom were “on the Pill” for a half-dozen years or more. The women who went off the Pill to become pregnant had normal pregnancies; they produced boy and girl babies in the normal proportion. Most reassuring of all were the negative results of tests and statistical studies to determine whether the tiny amounts of estrogen in the tablets had any carcinogenic effect. A couple of the cancer studies on the islands seemed to indicate that Enovid-10 might actually have some anti carcinogenic effect. A major test for possibly precancerous cells in women is the Papanicolaou vaginal smear; this test was made of women who had been on the Pill for two years or more, the results being compared with those of the same test on a control group. It was found that possibly precancerous conditions occurred in 3.6 per cent of 3,000 women not using the Pill as compared with only 1.6 per cent of 6,000 women who were using it. Similarly with breast cancer. In Puerto Rico the incidence of breast cancer for women in the 25-39 age group was twenty per thousand; there was no breast cancer among the 6,000 women on the Pill.
In June, 1960, Enovid-10® (its complete name) was formally approved by the U.S. Pood and Drug Administration for use as an oral contraceptive. There were safeguards. Enovid was to be available by medical prescription only, its use closely monitored by a physician; warnings of possible unpleasant side effects were to go to physicians and pharmacists, along with a strong recommendation (later relaxed) that use be continuous for no more than two years.
All the same, the decision was bold by any standard; it was dismayingly reckless in the view of some; and one can only hope that the prospect of great monetary profit for pharmacists and pharmaceutical firms was not, consciously or unconsciously, directly or indirectly, a factor in it. For though massive testing over half a decade had uncovered no evidence of immediate adverse irreversible effects, there could be no certainty in 1960 that the Pill (it was at once thus capitalized in the public mind) would not prove harmful and perhaps disastrous in the long run. Would the twenty-day cyclic dosage of estrogen, tiny though it was per day, have cumulative carcinogenic effect if continued for eight years, or ten, or more? Would women who went off the Pill after so prolonged a period of use still be fertile? And if they were, would the babies born to them be healthy? Such questions could not but remain open—they must continue to be answered solely in terms of probabilities—for many years to come.
In the early popular controversy, while women by the million applied to their doctors for the prescription needed for their use of the Pill, its safety was assumed: the vehemently argued questions were religious, moral, social. Religious people, especially Roman Catholics, asked whether the Pill was a manifestation or a violation of the Divine Plan. A typical answer was that of John Rock, himself a devout Catholic. The prevention of pregnancy by hormones was, said he, far more “natural” than the hierarchy-approved but notoriously unreliable “rhythm method.” Sociologists asked what effect the Pill would have on sex mores. Would it loose a flood of licentious sexuality, fatally weakening the family as basic social unit? To this question there could be no certain answer. The most that can now be said is that the Pill’s introduction coincided with a radical shift toward sexual “freedom” on the part of the young in the 1960’s and that there was probably some causal connection between the two phenomena.
It was not until the latter part of the decade, by which time several rivals of Enovid-10 had appeared in the marketplace, that questions about the Pill’s safety became the center of popular controversy. In 1966, elaborate statistical studies by Britain’s Medical Research Council revealed Pill users to be far more susceptible than nonusers to thromboembolism (blood clotting which can do great and even fatal injury to lungs or heart or brain). Statistically, according to this study, a Pill user is about nine times more likely to be hospitalized for blood clotting, and about seven times more likely to die of it, than a nonuser. Yet the percentage risk, this same study showed, is very small—smaller than for many widely used drugs. Of 100,000 Pill users, aged twenty to thirty, 1.3 will die of thromboembolism in a given year, say the statistics; of 100,000 aged thirty-five to forty-four, 3.4 will die. Incidentally, this compares with 30 deaths per 100,000 per year from thromboembolism caused by pregnancy itself.
Another seeming and dangerous effect of the Pill, according to many medical scientists, including Edward Klaiber, an endocrinologist M.D. now on the staff of the Worcester Foundation, is its encouragement of certain kinds of mental illness, notably depression. And it is worth noting that sex therapists Masters and Johnson, when women come to them with problems of anxiety and depression centered on sex, immediately order these women off the Pill if they have been on it. Often this solves the problem. But here again the percentage risk seems small (there are no firm statistical data from which to draw conclusions); and one must bear in mind that anxiety, depression, irritability (the “middle-ofthe-month blues”) are a common accompaniment of the menstrual cycle, whether a woman is on the Pill or not.
Recently there has been an increase in popular fears that the Pill is carcinogenic, due in part to a highly publicized court case in which a judge ruled in favor of a plaintiff who claimed that the spread of her breast cancer, ultimately fatal, was due to the estrogen in the Pill. This fearful belief may be effecting a considerable reduction in mass Pill usage as this is written. No support for it is provided, however, by the numerous statistical studies of cancer vis-à-vis the Pill conducted in the last few years. It would appear that on this score, too, where the initial risk was perhaps greatest, the FDA has won the gamble it made when it approved this means of birth control.
Such, at least, is the conclusion suggested by staff members of the department of medical and public affairs in the George Washington University Medical Center, Washington, D.C., who have made detailed studies of the immense volume of available statistics on the question. Although the heading for a May, 1977, report dealing exclusively with statistical studies of oral contraceptives and neoplasia (that is, tumors) is “Answers Remain Elusive,” the report itself observes: “Oral contraceptives have brought millions of women relief from the burdens of childbearing and the fear of unwanted pregnancy and have contributed to happier family and sexual lives, better health, and an improved standard of living. Oral contraceptives have helped reduce illness and death due to childbearing and, in many places, have facilitated the slowing of population growth. These benefits are clear and large. No known adverse effects on the incidence of neoplasia outweigh these benefits or argue for restricting the availability of orals.”