Russell Marker had no interest in contraception. To his dying day, he was uncomfortable with the title “Father of the Birth Control Pill,” a name that numerous articles singing the praises of his chemical exploits bestowed upon him. But the truth is that the pioneering work of this remarkable but peculiar man did indeed lead to the development of “The Pill.” Actually, it did more than that. Marker’s ingenious chemistry gave birth to the synthetic steroid industry, legal and illegal.
Marker graduated with a master’s degree in chemistry from the University of Maryland in 1924 and immediately enrolled in a PhD program. He was so adept at laboratory work that within a year, he had amassed enough data to meet the requirements for a degree. But there was a slight problem. Doctoral candidates were obliged to take courses as well as carry out research. Marker had no desire to take these, particularly the physical chemistry courses that he considered irrelevant to his work, and therefore a waste of time. His research director, Professor Morris Kharasch, warned him that if he refused to take the prescribed courses he would not be granted a degree, and he would end up as a “urine analyst.” At that point, the stubborn Marker left the university and found a job at the Ethyl Corporation, where he developed the octane rating system for gasoline still used today. That alone would have secured his fame in chemical history, but Marker sought new horizons. He became interested in the fledgling field of steroid chemistry, and secured a research position funded by the Parke-Davis pharmaceutical company at Penn State College.
Steroids are a class of naturally occurring compounds that have a common basic molecular structure consisting of four rings of carbon atoms. The female hormones progesterone and estradiol are typical examples, and indeed were some of the first steroids ever identified. But they were difficult to come by. In the early 1930s, it took 4 tons of sow ovaries to isolate 12 milligrams of estradiol, and dozens of pregnant sows were needed to produce a few milligrams of progesterone. As the name implies (“for gestation”), progesterone was found to be the hormone that prepared the uterus for the implantation of a fertilized egg. This raised the possibility that the compound could be used to prevent miscarriage and to treat certain menstrual disorders. There was even a theory that progesterone could be useful in the treatment of cervical cancer. Extraction from natural sources was very difficult, and the only available progesterone came from a multi-step synthesis starting from cholesterol, the first steroid ever isolated, way back in the 1700s. It sold for about $80 a gram, a stunning price in those days. Could it possibly be produced more cheaply? Now that was the kind of challenge that Russell Marker liked.
Marker knew that steroids could also be found in plant products. He was particularly interested in sarsaponegin, which had been isolated from the sarsaparilla root in 1914 and had a chemical similarity to progesterone. By 1938 the clever chemist had developed a series of reactions to convert sarsaponegin into progesterone, but the starting material was still hard to come by. Could another plant be a better source of steroids? Marker began to look through botany texts for plants that looked like ones known to produce steroids and was taken by pictures of the Dioscoria species. The scientific literature revealed that a steroid known as diosgenin had indeed been extracted from these plants. He could probably convert diosgenin into progesterone, Marker thought, and began a systematic search for plants of the genus Dioscoria, hoping to find a variety that produced diosgenin in good yield. He first scoured the southwest us, but eventually ended up in Mexico, and it was there that his efforts finally bore fruit. Actually, they bore a root. The root of a Mexican yam looked like a good candidate to Marker, and he smuggled a sample back into the us, where analysis revealed that it did indeed contain a wealth of diosgenin. It took Marker just five chemical steps to convert diosgenin to progesterone, and eight to make testosterone, the main male hormone.
Surprisingly, Marker was unable to interest major pharmaceutical companies in his synthesis, so he decided to go it alone. He left his wife, moved to Mexico, and set up a crude laboratory to extract diosgenin from yams and convert it to progesterone. Marker single-handedly gathered about 10 tons of root, from which he produced an astounding 2 kilograms of progesterone. Its commercial value was about $160,000, but Marker had no idea how to market his windfall. Looking through the Mexico City telephone book, he chanced upon “Laboratorios Hormona,” which sounded like a potentially interesting connection. Marker took his progesterone, wrapped it in newspaper, and marched down to meet Emeric Somlo and Frederick Lehmann, the two European refugees who had founded the small drug-marketing firm. Never before had anyone seen so much progesterone at one time! Somlo and Lehmann were duly impressed, and before long, the three had formed a new company, Syntex, to begin commercial production of progesterone. Within a year they had produced 30 kilograms of progesterone, and were supplying various pharmaceutical companies, which sold the hormone to treat menstrual and menopausal problems.
It didn’t take long for the mercurial Marker to have a falling-out with his partners, and in 1945, he left Syntex in a huff, taking many of the details of progesterone synthesis with him. His former partners, Emeric Somlo and Frederick Lehmann, were desperate to find a chemist who could pick up the pieces and realize the profits that synthetic progesterone promised. Physicians and their patients were excited about the substance that offered hope for preventing miscarriage and for treating the symptoms of menopause. Somlo and Lehmann searched high and low, and finally found their man in Cuba.
George Rosenkrantz was born in Hungary and trained in Switzerland under Nobel Prize winner Leopold Ruzicka, who had identified the sex hormones as belonging to the family of compounds known as steroids. In the 1930s, Ruzicka offered positions to many Jewish scientists who fled Eastern Europe, but he became particularly closely associated with Rosenkrantz. Although Switzerland was nominally neutral, Rosenkrantz worried that his mentor’s friendship with Jews might affect his career, and therefore decided to head west, and eventually ended up in Cuba. Here he maintained his interest in steroids, and having heard about Marker’s work, even produced small amounts of progesterone from sarsaparilla root. Somlo and Lehmann heard about this and invited Rosenkrantz for an interview. When in an impromptu performance he carried out one of the steps in the progesterone synthesis, the job was his. Within two months, Rosenkrantz had resuscitated Syntex, and the company began to fulfill its orders for progesterone. He then went on to synthesize testosterone, the main male sex hormone, using progesterone as starting material, and managed to convert it to the female hormone estrone. “Adam goes into the test tube,” Rosenkrantz quipped, “and Eve comes out.”
Then Rosenkrantz set his sights on a target that he thought would be even more lucrative than progesterone. In 1948, a researcher at the Mayo Clinic in Minnesota tantalized the medical community with a film he had made of bedridden arthritic patients who got up and danced after being treated with an apparently miraculous substance. The drug was cortisone, an adrenal gland hormone, which had previously shown potential in the treatment of various diseases, including arthritis, asthma, skin disorders, and even leukemia. But extraction from adrenal glands was extremely difficult, and the only viable source was a complicated thirty-six-step synthesis that had been developed by the Merck Company. Now the dancing patients triggered a race between Merck, a group at Harvard, and Rosenkrantz’s team to come up with a practical synthesis. At Syntex, the task fell to a promising young chemist, Carl Djerassi, whom Rosenkrantz had enticed away from the CIBA pharmaceutical company in New Jersey. In just two years, Life magazine trumpeted Syntex’s triumph with the headline “Cortisone from a Giant Yam: Scientists with Average Age of 27 Find Big Supply in Mexican Root.”
Djerassi’s cortisone synthesis did not prove to be an economic success because, just a few months later, the Upjohn Company came out with a cheap process to make hydrocortisone, a compound that basically performed as well as cortisone. Syntex, however, was not left out in the cold. The raw material that Up-john needed to make hydrocortisone was progesterone, which could only be supplied in the desired amounts by Syntex! Now the company had funds to pursue further research. One of the synthetic targets was estradiol, the female hormone that was being explored for the treatment of menopausal symptoms. Rosenkrantz and Djerassi thought that estradiol could perhaps be made from progesterone, of which of course they had a plentiful supply.
The synthesis proved unsuccessful, but one of the compounds that emerged, 19-norprogesterone, aroused their attention. When tested, it performed like progesterone, but was far more potent. Now, this was interesting! One of the drawbacks of progesterone had been the need to inject it into the bloodstream, because it was not stable to stomach acid. But perhaps enough of the more potent compound would survive in the stomach, allowing oral use. Alas, such was not the case. Djerassi’s appetite was whetted, though, and he searched through the scientific literature for steroids that were stable to acid. He discovered that a German chemist, Hans Inhoffen, had found a way to alter the estradiol molecule to make it stable to acid. Djerassi now applied this reaction to his 19-norprogesterone and produced norethindrone, which behaved just like progesterone, but was more potent and, amazingly, could be taken orally! This would be a great improvement. Women did not relish progesterone injections even if these were effective treatments for fertility and menstrual problems. Little did Djerassi dream that his compound would eventually be referred to as the “first oral contraceptive ever synthesized.” Neither did he dream that Frank Colton at Searle would soon come up with a similar substance, norethynodrel, which would beat his compound to be the active ingredient in the first birth control pill.
The connection to birth control was made by Gregory Pincus, a biologist, who had been approached by birth control activists Margaret Sanger and Katherine McCormick about the possibility of coming up with a physiological way to prevent pregnancy. Pincus had made somewhat of a name for himself by fertilizing rabbit eggs in a test tube (the press sometimes depicted him as a “Dr. Frankenstein”) and took on the challenge. Knowing that a pregnant woman could not get pregnant a second time because ovulation was suppressed by progesterone, Pincus immediately recognized the potential of Djerassi’s and Colton’s work. He enlisted the help of John Rock, a Harvard fertility expert who, in his practice, had witnessed the suffering of women burdened by unwanted pregnancies. Tests carried out on volunteers in Puerto Rico in 1956 showed that norethynodrel was effective in preventing pregnancy. Pincus had used Searle’s compound because the company had previously supported its research. By 1957 both norethynodrel and norethindrone had been approved as drugs, but only for menstrual and fertility disorders.
There was great hesitancy among pharmaceutical companies to apply for approval of a contraceptive pill because of opposition from the Catholic Church and other religious groups. Searle finally took the bold step and in 1960 received FDA approval for its Enovid as the first birth control pill. It contained 10 milligrams of norethynodrel and a little estrogen to reduce side effects. Syntex had licensed its drug to Parke-Davis, but the company was worried that religious opposition would lead to a boycott of all its products if it got into the chemical contraception game. Thus, Djerassi’s norethindrone, the “first oral contraceptive ever synthesized,” was not the active ingredient in the first commercial birth control pill. In 1962, Djerassi’s compound finally made it to market under agreement with Ortho pharmaceuticals. Syntex went on to become a multibillion-dollar company, eventually introducing Naprosyn and Anaprox, two widely sold non-steroidal anti-inflammatory drugs (NSAIDS). But of course none of that would have happened without Russell Marker’s original work on steroids. So who was the father of “The Pill,” the drug that, for more than forty-five years, more people have taken than any other prescribed medicine in the world? Well, you decide.