50 years of the PillJOSE A. BUFILL
On May 9, 1960, the FDA took the momentous step of approving the contraceptive pill for birth control.
I will focus on the 50 year period from 1910—the year of the birth of reproductive endocrinology as a scientific discipline—to 1960—the year in which the first orally active hormonal contraceptive was first approved for sale to the general public in the US.
At the turn of the 20th century, there was growing confidence in the power of the medical sciences to finally understand human physiology and the patho-physiology of diseases. The source of this confidence was due in no small part to advances in the field of endocrinology: the study of hormones and the glands that produce them.
The term "hormone" was coined in 1905 by the British physiologist Ernest Starling, after the Greek word meaning "to incite to activity". In the early 20th century, a variety of chemicals were found to have "hormonal" effects in humans: they were produced in one tissue, entered the bloodstream and incited a specific effect on another distant and unrelated tissue. Insulin, thyroxine,testosterone and cortisone were discovered at this time and were found to have remarkable restorative properties when given to patients with a number of common diseases.
This enthusiasm for the therapeutic potential of "hormones" also extended to the area of human reproduction In the late 19th century, Professor Brown-Sequard, at the age of 72, injected himself with the extracts of guinea pig testicles and was astounded at their rejuvenating effects.
Between 1910 and 1930, the hormones estrogen and progesterone were found to play important roles in the physiology of female mammalian reproduction, and so by around 1940, it became apparent that in human females, fertility depended upon the complex interactions of a hierarchy of hormones which affected the ovaries first, and then the uterus. The ovaries were found to be the source of a "female factor" in human development (the ova or egg):complementary to and just as necessary for human reproduction as the"male factor". This picture—which seems so clear today—was in fact a dramatic insight, considering that even in the second half of the 19th century many scientists still believed that conception occurred when the male factor—a seed—was sown into the female womb– the soil. A woman's contribution to conception was thought to be that off a passive receptacle offering a favorable environment for the germination of the seed.
The picture that now emerged meant that fertility in women was in the normal case orderly and cyclical, and therefore predictable. This new understanding of human reproduction seemed to lift the veil on an awesome event that, until then, had been shrouded in mystery. Science began to expose the mystery, to reveal the mechanics of how human beings came about, and made that event accessible and open to manipulation.
The notion that fertility in mammals could be controlled by the manipulation of reproductive hormones was first proposed by the Austrian physiologist Ludwig Haberlandt, who based his hypothesis on his own work with laboratory animals He and others observed that the ovarian follicle would not mature and ovulation would not occur during normal pregnancy, and that this suppressive effect was mediated by progesterone. Progesterone is produced by the corpus luteum during the second half of thenormal menstrual cycle, and its blood levels remain elevated only ifpregnancy occurs. As long as certain levels of progesterone persist in the circulation, hormonal signals favoring the ripening of additional ovarian follicles, thickening of the endometrium and release the ova, would not occur.
So scientists like Haberlandt, who would seek to develop a birth control pill, focused their efforts on finding a chemical that would mimic the normal effects of progesterone. In effect, they sought a chemical that would induce a pseudo-pregnant state Haberlandt was probably the first to propose that "hormonal sterilization" -- which he had successfully induced in several animal models -- could and should be applied to humans. He even developed a progestin-based oral contraceptive which—a few decades after his death in 1932—was studied and distributed as the contraceptive "Infecundin" in Eastern Europe by Marxist governments. His original observations on the contraceptive potential of progesterone in animals proved to be of use to others years later in planning strategies for control of human fertility.
Overcoming cultural and religious hurdles
Before moving on with the story,a brief digression: it is worth noting that while scientists were unraveling the mysteries of human reproduction, cultural attitudes during the first half of the 20th century strongly discouraged public discussion of sexual matters, and many—if not most—people agreed that the use of contraceptive devices was somehow wrong. In many states, dispensing contraceptives or information about them was a felony So advocates of the birth control pill had to overcome not only important scientific hurdles but also widely held cultural and religious objections. There was the clear perception among early advocates of birth control that acceptance of a contraceptive pill would be difficult to achieve.
Margaret Sanger led the campaign in the US that would gradually -- over decades—desensitize the general public on matters of sex. A brilliant and remarkably tenacious woman, she wrote pamphlets, published newspapers and books, smuggled birth control devices, founded birth control clinics and got arrested—all to raise the issue of birth control from the perspective of women's rights, at the same time publicly downplaying her own anarchist and eugenicist leanings She succeeded in her efforts, and she and her friends were pleasantly surprised when after the pill's release in 1960, popular opposition to birth control rapidly diminished.
While Sanger was primarily a political activist using the language and methods of class warfare to foster grassroots support for her movement, others sought to justify the need for birth control through geopolitical arguments. Generously funded by important private foundations, eugenicist academics like Frank Notestein and Kingsley Davis developed demographic models that were appealing by virtue of their simplicity and logic. They were also founded on a vision of the human person where self-interest was the driving force of every human action and a human being's capacity for transcendence was a priori disallowed.
Aided by their academic prestige and an abundance of financial resources, they argued the need for birth control as the most effective way of avoiding the otherwise inevitable depletion of the earth' resources by a growing population of consumers. Both these groups skillfully influenced public opinion in the post-war period to soften opposition to the pill.
The scientific obstacles to development of the pill were substantial as well. Most experts had settled on progesterone as the preferred agent, but progesterone --like estrogen and most other steroid hormones—was digested, not absorbed, when taken by mouth. Chemists sought to alter the structure of the naturally occurring hormone so that it could be absorbed orally and still retain its natural effects. Raw progesterone was very expensive because it was very hard to come by. Until the 1940s,European pharmaceutical firms held a virtual monopoly on steroid hormone production, but their sources were limited to crude biological material from animal products: glands obtained from slaughterhouses,hormone derivatives obtained from the urine of pregnant animals. For example, the drug "Premarin", commonly used as an estrogen supplement,is an acronym of the terms "pregnant mare urine". These inefficient low-yield processes were inadequate to meet the high demand for hormones
The challenge was to discover alternate sources of steroid molecules. This was possible because the hormones involved in human reproduction belonged to a large group of natural chemical compounds with a very similar structure. All the steroids have4 basic rings and their different effects in the body depend upon the addition or deletion of side chains to the rings.
Among those taking up the challenge was Russell Marker, a botanist and biochemist who sought and found an important source of steroid hormones in plants. Between 1939 and 1943,Marker and his team demonstrated that plant compounds called"sapogenins", could be used as precursors of steroid synthesis. He devoted himself to identifying plants with high concentrations of sapogenins. In 1941, while on a search for plant sources in New Mexico he stumbled on a reference book describing a tuberous plant of the Dioscorea family: a common yam plant called "barbasco" by the natives of eastern Mexico (Veracruz) where it grew abundantly. He decided to analyze Dioscorea plants, obtained samples and confirmed very high levels of a sapogenin called diosgenin. The yam species Dioscorea villosa was particularly suited to his work.
The Mexican connection
Marker developed a simple,five-step method of converting diosgenin to progesterone, a process called the "Marker degradation". He approached Parke-Davis, an American pharmaceutical firm that had supported his early research at Penn State, encouraging them to set up a production center in Mexico, but they declined.
Being a pragmatic person, he sought local support by checking the Mexico City telephone book for chemistry labs that might be willing and able to work with steroid hormones. He found"Laboratorios Hormona", a company founded by two eastern European emigres, Emeric Somlo and Federico Lehmann. When they first met, Marker showed them a sample of his work: 80 grams of pure progesterone,representing almost one third of the world's supply of the chemical. They agreed to form a new company, naming it Syntex Laboratories, from"synthesis" and "Mexico". After a year of successful work, Marker and his partners disagreed over finances, and he left the company, taking the instructions for synthesizing progesterone from diosgenin along with him.
Syntex executives then hired George Rosenkranz, a Swiss-trained Hungarian chemist who had been stranded in Havana since 1942. The Pearl Harbor attack occurred while he was on his way to Quito, Ecuador to found a university chemistry department there. Rosenkranz was eventually able to piece together Marker's process, and within a year Syntex was once again producing progesterone from diosgenin. By the 1970s, Syntex had become a billion dollar corporation, and one of the world's largest producers of steroid hormones
It should be noted that Syntex sought first to produce industrial amounts of corticosteroids. Progesterone derivates were a secondary priority. But when Upjohn and Pfizer in the US beat out the Eastern Europeans from Syntex in developing efficient techniques for mass production of cortisone, Syntex priorities shifted. The Mexican chemist and technicians who had been assigned to the lower priority research—synthesizing an orally absorbed version of progesterone -- now held the key to the company's future.
It was a young Mexican chemist, Luis Miramontes, who succeeded under the supervision of the Austrian-born Carl Djerassi. They called the orally-active progestational substance norethindrone. Djerassi later claimed that they did not at that time intend to produce a hormonal contraceptive specifically, simply a compound with potentially marketable uses. Regardless, he has been identified and identifies himself as the father of the birth control pill, and he has expressed his sense of fatherhood artistically.
The American connection
Syntex proved to be a very efficient hormone factory, but as a Mexican company, they lacked access to the US market and so sought to develop partnerships with established US firms. Their efforts eventually led them to Shrewsbury,Massachusetts and the Worcester Foundation for Experimental Biology.
Gregory Pincus was a zoologist, an authority in the reproduction of mammals and an eccentric. He was the first to succeed at in vitro fertilization in mammals. He used rabbits. Later in the 1930s, he produced a rabbit by parthenogenesis, and he allowed his work to be profiled in Collier's magazine. In that article—the cover story -- he was misquoted admitting his intention to attempt IVF in humans. As a result, according to pill biographer Bernard Asbell, the public came to view him as kind of Dr Frankenstein. He was denied tenure at Harvard, and so became an independent consultant, founding the Worcester Foundation for Experimental Biology in 1944.
The Worcester Foundation was intended to be a place for drug companies to send promising chemicals to test their pharmacological effects in animals. Their initial attempts, working primarily for GD Searle, were disasters and the Worcester Foundation almost went out of business several times. The change in his fortunes began in 1951 when he met Margaret Sanger at a dinner hosted by Abraham Stone, an executive of the Planned Parenthood Federation.
Sanger had been looking for a scientist with his skills, who would also be willing to take on a controversial project Pincus' collaboration with Sanger and Planned Parenthood started him down the path to the pill, but their financial support was sporadic and limited. Real progress in identifying an orally active birth control pill did not occur until Katherine Dexter McCormick became involved, lending abundant financial support to the project.
McCormick was the heiress by marriage to the International Harvester fortune. Born into a distinguished family of progressive Chicago attorneys, she was the second woman ever to graduate from MIT, the first with a degree in the sciences. She gave up plans to study medicine and reluctantly married Stanley McCormick, who within 18 months had to be institutionalized for schizophrenia. They had no children, and lived apart for most of their lives. She was an ardent supporter of women's suffrage and birth control, having first crossed paths with Margaret Sanger in 1917.
After Mr. McCormick's death in 1947, she immediately stopped funding schizophrenia research, and shifted her attention to other projects, in particular birth control. Historians acknowledge the critical importance of her financial backing in accelerating the development of the pill. Because of McCormick and a few other private benefactors, the pill was produced using not a single dollar of public money.
The road to the Pill
With McCormick's close involvement and funding, Pincus was able to ratchet up his efforts. He andd his colleague, Min Chueh Chang, screened hundreds of hormonal products in animal models, and in the end concluded that two –norethindrone, discovered by Miramont and Djerassi at Syntex in 1951; and d norethinodrel, an almost identical compound produced by Frank Colton at GD Searle two years later – were the best candidates for human trials. Pincus found that both of these compounds retained potent progestational effects when given orally and were effective contraceptives in a variety of mammals.
The next step along the path to approval of the Pill would require studying these compounds in women, and so they turned to a physician – John Rock—who was an obstetrician-gynecologist. Harvard-trained, a pioneer in the treatment of human infertility and Irish-Catholic, Rock -– from the perspective of politically astute birth control activists—was the perfect man for the job. When he was approached by advocates of birth control, Rock had already devoted decades to the study of infertility and was renowned for being the first -– along with his Harvard colleague Arthur Hertig -– to successfully fertilize a human egg in vitro.
Pincus and Rock had known each other in the1930s. Pincus had followed Rock's attempts to develop methods to detect ovulation and had provided him with chemicals for clinical testing. They had lost touch in the 1940s, but renewed their contact during a chance meeting at a scientific convention in 1952. At the meeting, they learned that both were using the same compounds—estrogen and progesterone – to achieve opposite ends: Pincus contraception infertile rabbits and Rock conception in infertile women. Within a short time, they agreed to collaborate to develop an oral contraceptive pill.
Clinical trials begin
In 1954, Rock began the first clinical trials under the guise of another fertility study. This was the first-ever human trial of an oral contraceptive. The drug Rock used was the one developed by Colton at Searle, named norethinodrel. Rock and Pincus selected norethinodrel because Djerassi's version –norethindrone—caused the enlargement of male rat's testicles and so it was feared that it might have "masculinizing effects" that would hamper the acceptance of an oral contraceptive. What they did not know was that the Searle product they selected had been inadvertently contaminated with a small amount of estrogen, and that likely masked the androgenic effect of norethinodrel.
The first human trials of norethinodrel were designed to measure ovulation rates and other effects on the reproductive system. It was first tested in Brookline, Massachusetts,on 50 women who were patients of Rock's infertility clinic. None of them showed evidence of ovulation while taking the pill. The second group tested included 23 female medical students from the University of Puerto Rico.
Within a few months of the trial, half of the women withdrew from the study—despite veiled threats of adverse academic repercussions by some of the investigators—citing side effects and cumbersome data collection requirements. A third group --patients at the local psychiatric hospital in Worcester—was also given norethinodrel and provided data that eventually led to the approval of large-scale trials to monitor its contraceptive effects specifically
The first large-scale study of norethinodrel's contraceptive effect was conducted in Puerto Rico, a site not chosen randomly. Comstock laws were never in force there; it was an island with very high population density; and the local government was very cooperative, having established a network of family planning clinics with the assistance of Planned Parenthood years before In addition, Pincus noted that the US press would be less likely to interfere if studies were conducted away from the mainland. The study began in April, 1956 under the supervision of Edris Rice-Wray, an American-trained physician with ties to the medical school, the public health department of Puerto Rico. She had run a family planning clinic there, and trained health care workers in contraceptive use. Norethinodrel proved to be a highly effective contraceptive, despite the side effects that began to emerge.
Pincus, Rock and Searle executives were soon satisfied that the contraceptive efficacy of norethinodrel had been adequately demonstrated. In 1957, G.D. Searle marketed norethinodrel as Enovid -- not for contraception but for "menstrual problems". The package insert prominently noted as a "warning" that the drug could induce temporary infertility as a side effect. This was in effect Searle's trial balloon. They quickly learned that prescriptions for the Pill far exceeded the number of women who had previously complained of menstrual problems.
Three years later—on May 9,1960—the FDA approved the Pill to be used for birth control. This was the first product to be approved by the FDA that was not designed to treat an illness but rather to modify a normal process.
The half century defined by the emergence of the science of human reproduction around 1910 and the approval of the first hormonal contraceptive pill in 1960 was a period of dramatic scientific and social change. Science demystified human reproduction,breaking down the process into its basic components and making it accessible to manipulation.
These new scientific insights offered some people—a relatively small group of influential individuals persuaded by a materialist worldview and eugenicist principles—an opportunity to advance their ideology of social engineering on a global scale. They were radical political activists working together with brilliant,ambitious scientists and academics, and wealthy agnostics, who eventually succeeded in presenting birth control as a moral imperative for modern societies. An analysis of the effects of the hormonal contraceptive on individuals and societies over the ensuing 50 years should provide important opportunities to value the mystery of the generation of new human life more fully.
Sexual Chemistry is an excellent scholarly work on the history of the Pill. A briefer history is related in On the Pill. The Fertility Doctor is a recent account of the tragedy of John Rock, written by two sisters, one a historian the other a gynecologist. Birth Control in America: The Career of Margaret Sanger steers a course between hagiography and hostility. Katherine Dexter McCormick: Pioneer for Women's Rights takes a benevolent view of its subject, but does not skate over her troubled life. Carl Djerassi has written two entertaining books about his own role, This Man's Pill and The Pill, Pygmy Chimps and Degas' Horse.
Jose A. Bufill. "50 years of the Pill." MercatorNet (January 15, 2010).
Reprinted with permission of MercatorNet.com.
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THE AUTHORJose A. Bufill, MD, lives in South Bend, Indiana where he works as a cancer specialist His articles on bioethics have appeared in the opinion pages of major US newspapers. Some of them may be read at www.brasstack.blogspot.com.
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