Originally published in 2013 by Planned Parenthood Advocates of Arizona.
Part 1: Hormones, Our “Chemical Messengers”
Underneath the surface of a large swath of Southern Mexico’s jungles lay the enormous roots of a wild yam, Dioscorea composita, known locally as barbasco. Mostly it was considered a nuisance, as it could get in the way of subsistence agriculture, but it did have its uses. Indigenous people used it as a fish poison, and traditional Mesoamerican healers used it to treat rheumatism, snakebites, muscular pain, and skin conditions. When the root was fermented in alcohol and put on aching joints, it was believed to work as a pain reliever.
The idea of a birth control pill was born in 1912 when Margaret Sanger dreamed of a “magic pill.”
Barbasco’s medicinal uses might not be surprising, given that scientists derived a chemical from the yam that led to the development of cortisone and oral contraceptives, both of which had sizable impacts on medicine and society. Oral contraceptives would not have been possible without a cheap and abundant source of progesterone, which was easily synthesized from the root after an American chemist, Russell Marker, discovered a process for converting a cholesterol found in barbasco’s roots to progesterone, a key ingredient in the Pill.
In the decades before this chemist’s excursion to Mexico, first-wave feminism was brewing in turn-of-the-century United States, and birth-control pioneer Margaret Sanger demanded access to contraception — in 1915, she invented the term “birth control,” and as early as 1912, the idea of a birth control pill had been envisioned — again, by Sanger, who wrote of her hope for a “magic pill.” A nurse, Sanger was spurred to action by the horror of watching women die prematurely after having too many children, while other women died from botched abortions.
Coinciding with feminist agitation, scientists were piecing together the complex system of the body’s “chemical messengers,” hormones. Between 1890 and 1905, they learned that ovaries secrete hormones that are transported through the bloodstream and which have physiological effects. By the end of the 1920s, it was known that ovaries secrete different chemicals depending on whether or not there is a pregnancy; and after ovulation the hormone progesterone is secreted, during which time no new eggs are released by the ovary.
After determining the function of hormones, scientists sought to isolate them. Initially they contracted with slaughterhouses and extracted them from the glands of animals. By the ’30s the hormone industry was based in Europe, and sex hormones were generally derived from cholesterol from cattle’s spinal cords. Sex hormones could also be derived from the urine of humans, but this method resulted in very small quantities.
There was much to discover about hormones’ functions, and scientists had some interesting hypotheses and conducted equally interesting experiments. For example, in 1937, scientists at the University of Pennsylvania postulated that a body could be “tricked” into thinking it was pregnant. They injected rabbits with progesterone and found that their ovaries didn’t release eggs when expected to do so — the progesterone sent a signal to the rabbit’s brain that it was already pregnant, which suppressed ovulation.
However, during the ’30s and ’40s, when scientists were kicking such ideas around, there was no known method of extracting enough progesterone from animals to provide the therapy to the people who needed it — 80,000 pigs’ ovaries were needed to extract a minuscule amount of estrogen — and cost would have been prohibitive to virtually anyone who wanted such a drug. Science needed to find a cost-effective method of producing large quantities of hormones, such as progesterone.
Part 2: Barbasco and the Roots of Hormonal Contraception
Russell Marker was born to Maryland sharecroppers in 1903. Hoping to escape rural life, Marker was one of only two students in his junior-high class to attend high school. He graduated in three years and enrolled at the University of Maryland, where he earned bachelor’s and master’s degrees in chemistry. He needed one more class to receive his doctorate, but refused to take it, believing he had already mastered his chosen subject, organic chemistry. He was only interested in working in the lab and thought the required course would be a waste of his time. (The university did eventually award him an honorary doctorate in 1987.)
A wild-growing yam in Mexico provided chemicals that could be refined into progesterone, the active ingredient in the Pill.
At the time, the scientific community was abuzz with discoveries being made about hormones. They held tremendous potential for research, but scientists couldn’t figure out how to isolate large quantities of them for study. Up for a challenge, Marker set out to find a way to synthesize one hormone, called progesterone, in abundance. He hypothesized that plants from the genus Dioscorea, which includes yams and agaves, would be cheap sources of steroid hormones. Marker was specifically hoping to find plants rich in sapogenins, which are chemically similar to cholesterol.
Our bodies can alter the chemical structure of cholesterol and convert it into sex hormones such as progesterone, but the process could not be replicated in the lab. Marker, however, believed that he could convert cholesterol to progesterone by manipulating pH and temperature levels. He and his assistant conducted scores of experiments, each process tedious and slow. Eventually, though, they produced something that was one step away from human pregnanediol, which itself was easily converted to progesterone. They had done this by bringing sapogenin (derived from sarsaparilla) to 200 degrees Fahrenheit overnight in a sealed tube of acetic anhydride. This technique, still in use today, became known as the Marker degradation.
Having found a successful technique for converting plant-derived sapogenin to progesterone, Marker sought a plant that could produce progesterone in greater abundance. In the early ’40s, while visiting a botanist in Texas, Marker looked through his host’s library and found a photograph taken in Veracruz, Mexico, of a large tuber, cabeza de negro, which could supposedly reach several hundred pounds. Despite political unrest and an inability to speak Spanish, Marker traveled to rural Mexico and enlisted local help in locating cabeza de negro, which he learned was slow-growing and would thus be impractical to cultivate agriculturally — but the wild supply seemed to be without limit. Back in the United States, he was able to extract sapogenin from a dried portion of the root, and converted it into progesterone.
In October 1942, Marker, with half of his life’s savings, returned to Mexico on his own, where locals helped him collect 10 tons of the root. It was chopped with machetes into chips, sun-dried, and taken to Mexico City to be ground into a powder. He extracted the dried root with alcohol and evaporated it until it became a syrup. He returned to the United States with this syrup, and produced more than three kilograms of progesterone — the biggest batch of progesterone that had ever been in one place. In January 1944, having relocated to Mexico City, he co-founded a lab named Syntex — a portmanteau of “synthesis” and “Mexico” — to synthesize progesterone on a large scale.
In May 1945 he left Syntex over financial disputes and founded a competing lab in Texcoco, 30 miles from Mexico City, called Botanica-Mex. However, he was having trouble obtaining cabeza de negro as his root collectors were mysteriously dying or being attacked — these crimes were believed to be perpetrated by Syntex, eager to retain their monopoly. Marker started to collect other varieties of wild yams in Mexico, including one that contained a nearly pure sapogenin (a subtype called diosgenin). This particular wild yam was called barbasco by the indigenous population, and it became the industry’s choice for the raw material in hormone synthesis. While cabeza de negro took six to nine years before it contained enough diosgenin to be commercially viable, barbasco matured in half that time.
Barbasco proved an even greater boon when chemists at Upjohn discovered how to use an enzyme to attach an additional oxygen atom to the molecule, enabling them to produce cortisone and all of its derivatives from diosgenin. Thus, barbasco not only yielded progesterone for birth control pills, but could be synthesized into cortisone, another chemical that revolutionized medicine. Mexico’s hormone industry was further strengthened by the inability to grow barbasco outside of its native range — it was never successfully transplanted in the United States, and even when it could be grown in other places, the diosgenin content was significantly lower when compared with those growing wild in Mexico.
Now that we had a way to produce progesterone in abundance, we were one step closer to being able to create the “magic pill” that Margaret Sanger dreamed of.
Part 3: From Injection to Ingestion
In 1949, Russell Marker dropped out of science — “I considered all chemists to be crooks,” he bitterly opined — and a scientist named Carl Djerassi was hired to head the lab at Syntex, the hormone-synthesizing laboratory in Mexico that Marker had co-founded in 1944. Within a few years, Syntex was a major player on the synthetic-hormone scene in Europe and the Americas.
After Luis Miramontes’ successful experiments, all of the elements for Sanger’s “magic pill” were in place.
Although progesterone could be manufactured in large quantities at this time, it could only be given intravenously. Progesterone was being used therapeutically to prevent miscarriage and treat excessively heavy menstrual periods. The lack of alternatives to injections represented a problem for these people — a daily pill would be easier and more convenient than frequent injections. In 1950, Syntex set their sights on the development of a synthetic form of progesterone that was more effective in smaller doses and could be administered orally rather than by intravenous injections. Such a development would be necessary before Margaret Sanger’s dream of a “magic pill” could come true.
Djerassi found a scientific article from 1944 that described a seed extract called strophanthidin, which made progesterone more potent when taken orally. Strophanthidin was chemically similar to progesterone; it just lacked a carbon atom. The experiments described in the article were inconclusive, so Djerassi decided to perform followup experiments. He attempted to rearrange the yam-derived progesterone to resemble the seed-derived molecule described in the paper. When the resulting substance was injected into rabbits it was found to have four to eight times natural progesterone’s potency.
Additionally, in pre-WWII Germany, a scientist had introduced a gas, acetylene, into one of the rings of an estradiol molecule, which converted it into a chemical that remained stable when taken orally. This could also help chemists create a form of progesterone that could be administered by pill rather than by syringe.
Luis Ernesto Miramontes, working at Syntex, was tasked to find an oral replacement for progesterone injections. By 1951 he had done so. Miramontes and Djerassi tested it, first on nonhuman animals and then on human subjects who suffered from excessively heavy menstrual periods. The new compound seemed hugely successful — when administered orally, it was eight times more potent than the progesterone synthesized by the body. A vehicle for Sanger’s “magic pill” had been discovered. It was called norethindrone.
Neither Marker nor Djerassi had envisioned anything resembling Sanger’s dream for a pill that would put women in charge of their own reproductive destinies, a pill that could be manufactured cheaply and made accessible worldwide. The scientists were mostly interested in the challenges involved in basic research. But thanks to researchers’ work over the first half of the 20th century, all of the elements for Sanger’s “magic pill” were in place: Progesterone was known to inhibit ovulation, it could be synthesized cheaply, and it could be taken orally. These disparate threads did not come together, however, until Sanger teamed up with a wealthy benefactor.
Part 4: Margaret Sanger’s “Magic Pill”
Katharine McCormick was born into a moneyed family and was, in 1904, the second female graduated by the Massachusetts Institute of Technology. After receiving her degree in biology, she married a wealthy man, but shortly into the marriage she gained control of her husband’s estate due to his illness. She put a lot of this money to good use: In the 1920s, she aided Margaret Sanger’s efforts to smuggle diaphragms into the country.
Katharine McCormick, a philanthropist and one of the first scientifically trained women, provided early funding for the Pill.
Her involvement with Sanger didn’t end there; indeed, both Sanger and McCormick had a lot in common, despite Sanger’s working-class childhood and McCormick’s privileged upbringing. According to historian Elaine Tyler May, McCormick and Sanger both had “a tremendous faith in the possibility of science,” and Sanger “believed that science held the key to contraception and to women’s emancipation.” Back in the ’20s, Sanger wrote:
Science must make woman the owner, the mistress of herself. Science, the only possible savior of mankind, must put it in the power of woman to decide for herself whether she will or will not become a mother.
In 1950, McCormick again joined forces with Sanger. In the mid-’40s, after a countrywide tour of family-planning clinics, Sanger had come to the conclusion that the diaphragm was not an adequate form of birth control, revitalizing her hope for a “magic pill.” Neither pharmaceutical companies nor the government wanted to invest in contraceptive research, considering it a “disreputable” area of study, so Sanger hatched a scheme to bankroll the independent development of an oral contraceptive. At Sanger’s behest, McCormick provided the lion’s share of funding for the project — more than $2 million (compared to the value of a dollar in the year 2000, that would be about the equivalent of $12 million). Sanger and McCormick tapped Gregory Pincus to conduct the research. McCormick, thanks to her education in biology, oversaw the research in addition to funding it.
In the 1930s, while a professor at Harvard, Pincus was the first to fertilize a rabbit’s ova in a test tube, a technique that later formed the basis for in vitro fertilization. At the time, this was considered morally outrageous and, although Harvard recognized his achievement as one of the most significant in its history, Pincus was denied tenure in 1936.
After that debacle, Pincus became an independent researcher. He and colleague Min-Chueh Chang experimented with synthetic progesterone, hoping to discover a cure for infertility. In their initial experiments, Pincus’ lab used progesterone synthesized by Russell Marker’s method. They confirmed previous experiments on small mammals, but found that large doses of progesterone were required to inhibit ovulation.
In 1952, Pincus encountered Harvard gynecologist John Rock, who was engaged in experiments with progesterone — also with the goal of treating infertility. While Pincus was experimenting on rabbits, Rock was already conducting trials on humans. Rock’s treatment involved blocking ovulation for two years, under the hypothesis that a period of “rest” would lead to a “rebound” that would jump-start fertility. Because preventing pregnancy wasn’t the purpose of his treatment, he was able to skirt Massachusetts’ legal ban against the distribution of information about birth control. Many of Rock’s patients suffered from irregular periods, and once on the experimental therapy many became convinced they were pregnant, as the side effects mimicked pregnancy. Pincus suggested that instead of administering hormone therapy daily, it be administered for 21 days with a seven-day reprieve, allowing the subjects to experience regular menstruation. The benefit of this would be twofold, as patients would have regular periods and also be disabused of the notion that they were pregnant.
In any case, Pincus was shocked to find out that, for all intents and purposes, a hormonal contraceptive was already being tested on human subjects. Still, the drug needed to be tested as a contraceptive, rather than as a treatment for infertility.
However, the dilemma of potency still remained — the drugs were being injected intravenously at high doses, and weren’t yet effective when administered orally. This dilemma was solved by the independent discoveries of Luis Ernesto Miramontes of Syntex and Frank Colton of Searle, who had synthesized a variety of progesterone that was effective in pill form. These drugs were intended as “menstrual-cycle regulators,” but it seemed to Pincus that a contraceptive pill’s chemical structure had already been produced by other scientists, none of whom had appreciated its contraceptive potential. Pincus’ lab tested these compounds on rabbits and rats, evaluating their effectiveness and safety. With successful animal testing under his belt, Pincus set his sights on testing progesterone as a contraceptive in humans.
Pincus sought a gynecologist to co-lead the clinical trials, and chose John Rock. Despite her Catholic background, Sanger objected to this choice, thinking a Catholic “would not dare advance the cause of contraceptive research.” McCormick, however, approved of him, believing that he could keep his scientific pursuits separate from his religious beliefs; Sanger eventually came to look highly upon him as “[a] good R.C. and as handsome as a god.” Rock’s Catholicism probably also helped mitigate the scandalous nature of their research, if ever so slightly. Pincus, in fact, had ruled out working with a fellow Jew, believing that such a partnership would further stigmatize his research. Rock and Pincus masked their early clinical trials under the cover of Rock’s research into infertility. These preliminary tests led to large-scale field trials.
Part 5: Clinical Trials
John Rock, Gregory Pincus, and Min-Chueh Chang had collaborated in the Pill’s development; now it was time to conduct clinical trials. The first study observed 60 women, some of whom were infertility patients while others were nurses. These small trials involved daily temperature readings, vaginal smears, and urine samples, as well as monthly endometrial biopsies. Although the initial results seemed promising, the sample size was small and few of the subjects complied with the protocol.
The approval of the Pill in 1960 marked a turning point in our history.
More test subjects were needed. At this point, historians’ accounts differ. Elaine Tyler May claims that, unable to locate an acceptable pool of volunteers, the researchers tested the Pill on subjects who could not give their consent, such as psychiatric patients. According to Bernard Asbell, however, Rock was scrupulous when it came to informed consent, despite it not being a legal requirement — or even much of a concept at all at this time in history.
Willing participants notwithstanding, conducting such trials in the United States posed a challenge, due to laws against contraception. So the first large-scale clinical trials were conducted in Puerto Rico in 1956. Puerto Rico was densely populated and there was a high demand for alternatives to permanent sterilization, which was widespread on the island due to funding from a wealthy eugenicist named Clarence Gamble, who advocated sterilization for the world’s poor. The clinical trials in Puerto Rico were conducted by Drs. Edris Rice-Wray and Adaline Sattherthwaite; the brand of birth control pill tested was named Enovid. Volunteers were so easy to come by that some clinics had waiting lists.
Test subjects’ health was meticulously monitored. Side effects included nausea, headaches, and dizziness, reported by 17 percent of volunteers. Rice-Wray considered these side effects to be unacceptable, even though the Pill proved completely effective in preventing pregnancy. Rock and Pincus, however, did not think these symptoms were alarming — Pincus, for his part, claimed that they were psychosomatic. In any case, the side effects may have been responsible for many subjects dropping out of the study, always a problem in clinical trials. According to May, others dropped out of the study under pressure from “priests and disapproving husbands,” and there was some concern that “Nordic whites” were using “the colored races as ‘guinea pigs.’”
In 1956, data on 221 subjects had been collected. The report stated, “Enovid gives one hundred percent protection against pregnancy in 10-milligram doses taken for twenty days each month … However, it causes too many side reactions to be acceptable generally.” Rock wondered if the side effects were actually nocebo effects — a phenomenon in which the expectation to experience side effects makes a subject more likely to notice or experience these side effects. A placebo-controlled trial seemed to confirm this, as 17 percent of subjects in the placebo group reported side effects, compared to the 6 percent of subjects who experienced side effects in an experimental group to whom no warning about side effects was given. It is interesting that being given advance warning of possible side effects correlated with an increased chance of experiencing these side effects, and shows how our expectations can shape our experiences.
Test groups were composed of mothers who were for the most part less than 40 years of age, and those who took the Pill as instructed did not get pregnant. After a propaganda campaign by a Catholic group, 10 percent of subjects dropped out of the study, and all of them became pregnant soon after. These dropouts were tracked, and their subsequent babies were examined to ensure that earlier use of the Pill did not have consequences for offspring. The sex ratio was evenly divided between male and female, and infant health was fine.
All told, the trials spanned three countries with more than 20,000 test subjects. Clinical trials in Puerto Rico and Haiti saw 1.7 pregnancies for every 100 women per year. Another field trial in Mexico City reported a failure rate of 0.6. In 1957, the Pill was approved as a treatment for “various gynecological disorders” (such as infertility and menstrual disorders), after which its developers sought to have it approved as a contraceptive.
The FDA began to investigate the Pill’s safety. While most physicians surveyed found the Pill to be “safe and effective for short-term use in treating gynecological problems,” there were some dissenters, including Dr. Edward Tyler, a researcher and head of the Planned Parenthood Clinic in Los Angeles. He was concerned about the Pill’s safety, as the side effects had been, in his experience, often severe: abnormal bleeding, weight gain, fluid retention, and more. In 1958, an FDA official heard Tyler’s concerns at a meeting. Because Tyler was considered to be a more neutral source than either Rock or Pincus, his concerns were given a lot of weight, and the approval process was slowed.
Eventually, however, in 1960 the Pill was approved as a contraceptive. Due to lingering concerns about the safety of long-term use, prescriptions were limited to two years. But 1960 marked an incredible turning point in our history — able to control their reproductive destinies, people with uteruses could choose their family sizes, choose not to have children at all, and have easier access to higher education and find futures in the labor force. Truly, thank goodness for the Pill!
Part 6: Los Campesinos
In 1960, the FDA approved oral contraceptives for marketing. At this time, more than 2 million Americans were already using the Pill — and more than 100,000 Mexican campesinos (a Spanish word for peasants) were harvesting barbasco, the wild yam necessary for its production. By 1974, 125,000 Mexicans were collecting and selling barbasco. Every week, during the barbasco trade’s peak, an excess of 10 tons of the plant were removed from tropical Mexico.
Until the barbasco supply started to dwindle in the 1970s, Mexico enjoyed prominence as the world’s supplier of progesterone.
Though they were paid subsistence-level wages for their labors (half a peso per kilo of dried root), and the work itself was dangerous and backbreaking, they were putting Mexico on the map in the scientific community. After establishing a hormone synthesis industry in Mexico, the European stranglehold on hormones was loosened and the price of progesterone plummeted from $80 per gram to less than a dollar per gram. By 1954, Syntex, a Mexican laboratory, was the largest producer of steroids in the world, having usurped Europe’s monopoly.
Scientists depended on the campesinos’ knowledge of soil conditions and growth cycles, as well as their ability to differentiate between different species of yams. The campesinos relied on their knowledge of weather patterns, differences in root coloration, and size variations to determine when they could dig up roots with the highest concentrations of sapogenin, the chemical that was converted into progesterone in the laboratory. Over the decades, the campesinos slowly gained an education in organic chemistry. According to Gabriela Soto Laveaga,
Eduardo Domínguez of Amatepec explained that his dry region yielded a poor quality barbasco, and hence he and his neighbors were paid less than most barbasequeros. After observing the process and independently experimenting they discovered that they could manipulate the percentage yield of diosgenin content by adding what Domínguez shrewdly described as “something.” Laboratory representatives were astounded when a purer diosgenin content began to emerge from the Amatepec beneficios. These campesinos were experimenting with basic steroid hormones.
The processing of barbasco involved being fermented, dried, bundled up, and delivered to Syntex in Mexico City. After being gathered, it had to be delivered to a collection site as soon as possible, since it starts to rot and shrivel within hours of harvest, affecting its value as it was sold by the kilogram.
The barbasco trade was confined to Mexico because the wild yam was never successfully transplanted in the United States, and even when it could be grown in other places, such as Guatemala and Puerto Rico, the concentration of the desired chemicals was significantly lower when compared with plants in their native range.
Until 1975 more than 2,000 tons of barbasco were processed annually, all in Mexico. The country dominated the global steroid industry, but this situation could not remain tenable. In the 1970s, public consciousness was raised about the exploitation of the campesinos’ labor, and in 1975, Mexican President Luis Echeverría created Proquivemex, a regulatory body that, among other things, increased wages for the barbasco gatherers. At the same time, the barbasco supply was dwindling. Reportedly, barbasco had become extinct in some areas by 1976 or 1977 due to overharvesting. This led to massive price increases, which in turn spurred pharmaceutical companies to search for alternative raw materials.
The Mexican steroid industry was also suffering as pharmaceutical companies were finding ways to reduce dosages, while other scientists were experimenting with plants like soy, from which molecularly similar compounds could be derived. In fact, decades earlier a scientist named Percy Lavon Julian had figured out an effective method for deriving progesterone from soybean oil.
In response to price hikes, pharmaceutical companies investigated ways to use microbes to convert soybean-derived steroids, sitosterol and stigmasterol, into progesterone. Unable to find a microorganism that could perform the necessary chemical conversions, researchers induced mutations in microbes using ultraviolet light or mutagenic chemicals. In a typical experiment, a microorganism was exposed to a mutagen and then placed into a medium with cholesterol and a hormone such as testosterone. Researchers would hope for growth on the cholesterol but not on the hormone — indicating that the organisms could digest the relevant parts of the cholesterol, but would not further degrade the cholesterols once their structure had been broken down into that of a hormone.
By the end of the 1970s, barbasco was obsolete. Methods for converting cheap and abundant starting materials using microbes were developed, and the Mexican steroid industry relinquished its dominance. Soybean byproducts replaced barbasco as the starting material for progesterone and other steroids, which hammered the nail into the Mexican steroid industry’s coffin. Barbasco still grows in Mexico’s jungles, and university-level science education in Mexico owes a debt to the boost it was given when the country enjoyed its prominence as the world’s supplier of progesterone.
Thanks for reading our series on the history of the birth control pill. We hope you will agree that the Pill’s history tells an inspiring story of human inquiry and the triumph of scientific investigation, which had a positive impact on our society as a whole and the individuals within it.
Anna C. Christensen, MPH 