- Historic Sites
The Story Of The Pill
How a Crash Program Developed an Efficient Oral Contraceptive in Less Than a Decade
August/September 1978 | Volume 29, Issue 5
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 .