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Synthesising orally active progesterone

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Discovering that progesterone is not orally active
Carl Djerassi Scientist
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Now, the biologist, particularly there is a very important biologist whom I think one justifiably could call 'the father', or at least a father of the pill, and that is a man named Gregory Pincus, who was not at Syntex, he was 1000 miles away, he was in... at the Worcester Foundation for Experimental Biology, who did some of the early... not the very first, but the very early biological... important biological work. But what was much more important about him, he was an extraordinary entrepreneur, and I mean this in a positive sense, not in any critical, or derogatory one, because it took really, a scientific entrepreneur to drive that through. It’s one thing to just do work, but it’s another thing to convince other people that it’s important and should be pursued, and he was obsessed by that. So he wrote a major book, he died in the late 1960s. He wrote a major book about, about contraception, The Control of Fertility, which was really, sort of, his opus magnum, in which he recorded the whole thing, and it had... I forgot, 1500, or 2000 references in it. There was not one reference to a chemist, there was not even the name of a chemist, never mind whether it was us, because in the end he used another compound, but he just... as far as he was concerned that somehow appeared from... from the sky. So, that’s bad enough, but it was worse than that, because the idea was not really his. That idea is... the idea of oral contraception, and of the pill, was propagated in writing, in publications, in a book, and in newspaper articles in the 1920s, by an Austrian physiologist named Ludwig Haberlandt. And I think the story has to start with Ludwig Haberlandt, who is the maternal... who is the paternal grandfather, I would say, because he was a physiologist, not a chemist, and he was the first one to point out that something that was more or less recognised at that time, is that there is a natural contraceptive in nature, and that is progesterone. That women do not get pregnant during pregnancy, absolutely not, it’s a 100% effective contraceptive, and the question he asked, and he was the first one to ask that question, others already had started to understand the biological role of progesterone, but he was the first to ask why not use progesterone as a contraceptive in humans. And he published an extraordinary book, which hardly anyone seems to have paid any attention to, which is really called The Hormonal Sterilisation... I’m translating in English... The Hormonal Sterilisation of the Female [sic]. It was published, I think, in '30... 1930, '31, and he died the following year. Now, progesterone was not even known at that time as a pure compound. One knew it existed as a glandular extract of both the corpus luteum and of the placenta, and he actually worked with such extracts, and used them in animal experiments to show that they inhibited ovulation, which of course is the process by which oral contraception also works, and that this was a mechanism. And he then convinced a pharmaceutical company, an important Hungarian pharmaceutical company that is even to this day the biggest Hungarian pharmaceutical company, Gedeon Richter, and who do market hormones, and did them already then, glandular extracts, and now do market oral contraceptives, to market the compound under a trade name, which he even invented, Infecundin. And Infecundin, interestingly enough became the trade name of the first oral contraceptive that Gedeon Richter released on the market in the 1960s, in other words, 30 years after the man had died. So he convinced them to try and collect this huge number of glandular extracts, and he worked on making concentrates of this, and he was hoping that this would be orally active, but he died before anything could be consummated.

A couple of years later, around the early 1930s, in Germany, the structure of progesterone was isolated in a pure form, its crystalline compound, by chemists, Karl Slotta, another Jewish émigré, who then left for Brazil, and was one of the persons who started really some... a certain amount of science in São Paulo, and much of the faculty of the University of São Paulo, in chemistry in particular, were the German refugees of the 1930s, and that became one of the leading chemical departments in Latin America. Well anyway, it was Slotta and Butenandt and other people who then isolated and established the structure of progesterone in the 1930s, and then synthesised it by this form of partial synthesis that I mentioned. At that time, primarily from stigmasterol, a soybean sterol, partly from cholesterol, and partly from bile acids. So, progesterone was then introduced in a medicine. Now, one actually tried it for ovulation inhibition, and discovered that while, of course progesterone does it, it is not orally active, so that any dream that Haberlandt might have had if he’d lived just a few years... He died in his 40s, so he could have, if he had been just a reasonably mature man who had lived, and he certainly would have deserved to do that, he would have found that his dream was not realisable unless he got himself the right chemist, which obviously he didn’t have, because it was not orally active, and women might inject themselves daily for diabetes and insulin, but not for contraception.

Austrian-American Carl Djerassi (1923-2015) was best known for his work on the synthesis of the steroid cortisone and then of a progesterone derivative that was the basis of the first contraceptive pill. He wrote a number of books, plays and poems, in the process inventing a new genre, 'science-in-fiction', illustrated by the novel 'Cantor's Dilemma' which explores ethics in science.

Listeners: Tamara Tracz

Tamara Tracz is a writer and filmmaker based in London.

Tags: Worcester Foundation for Experimental Biology, The Control of Fertility, Hormonal sterilization of female animals, Gedeon Richter, Progesterone, Infecundin, Stigmasterol, Soybean sterol, Gregory Goodwin Pincus, Ludwig Haberlandt, Karl Heinrich Slotta, Adolf Butenandt

Duration: 6 minutes, 18 seconds

Date story recorded: September 2005

Date story went live: 24 January 2008