The contraceptive pill The birth of the pill Most primitive societies knew of plants that would control their fertility, but until 1960 there was no clinically proven drug that provided a reliable method of contraception. Fifty years on, John Mann reports on the conception and evolution of the contraceptive pill In Mexico City in 1943, the small the same basic ring system as carry out similar chemistry on the company Laboratorios Hormona In short cholesterol but with an oxidised more accessible diosgenin from the occupied a niche in the market The first cheap and side-chain. He was intrigued by the genus Dioscorea. for pharmaceuticals. Its founders, simple route to make possibility of using these oxidised Being something of a botanist as Hungarian Emeric Somlo and progesterone, a key sites to affect a cleavage of the well as a chemist, Marker headed German Federico Lehmann, were hormone in the pill, was side-chain and make the degraded across the border into Mexico in making a modest living selling developed in the 1940s structures of the sex hormones. search of Dioscorea mexicana – the natural hormones extracted from The first pill was This is, of course, exactly what Mexican yam that the locals called animal organs. launched in 1960, and by happens in the enzyme-mediated cabeza de negro. After considerable Imagine their surprise when one 1966 more than 5 million oxidative metabolism of cholesterol difficulties he found a good source day a rather eccentric American US women were using to produce progesterone (see near the city of Orizaba in Veracruz professor of chemistry called Russell oral contraceptives Chemistry World, November 2009, State, and transported large Marker arrived in their office There have been no p54). In 1939 he devised chemistry quantities of the yam back to his bearing 2kg of pure progesterone major changes to the pill’s that worked on sarsasapogenin but laboratories at Pennsylvania State worth around $160 000 (£107 000) formulations over the realising that this sapogenin was College. at that time (many tens of millions of past 50 years; but new relatively expensive, he sought to During 1942 he perfected his dollars at today’s prices). The high delivery methods such oxidative degradation to make cost of this sex hormone, and others as coils and patches have progesterone from diosgenin in such as testosterone and oestradiol, come onto the market just five chemical steps. Unable was due to the multistep syntheses to interest US pharmaceutical required to make them. Marker had companies in his process, he headed achieved what previously seemed back across the border and ended up impossible – a cheap five-stage at Laboratorios Hormona. Unlike synthesis of progesterone from the their US counterparts, Somlo and natural product diosgenin. Lehmann immediately recognised the novelty and merit of Marker’s Marker makes his mark work. The three men set up a new Marker’s pivotal discovery arose company, Syntex, in January 1944 to from studying a class of plant exploit the process. Initially Marker natural products called sapogenins. Russell Marker devised synthesised several more kilograms He elucidated the structure of a five-stage synthesis of progesterone, but then left Syntex sarsasapogenin, from sarsaparilla to progesterone in the after a number of disagreements. CARL DJERASSI CARL root, and discovered that it had early 1940s This left the company short of the 56 | Chemistry World | September 2010 www.chemistryworld.org DAVID MACK / SCIENCE PHOTO LIBRARY LIBRARY PHOTO SCIENCE / MACK DAVID www.chemistryworld.org Chemistry World | September 2010 | 57 The contraceptive pill necessary chemical expertise to continue his work. The gap was immediately filled by another Hungarian, George Rosenkranz. And four years later the chemist who has become known as the ‘father of the pill’ – Carl Djerassi – also joined the firm. Syntex rapidly became the leading supplier of sex hormones including progesterone, testosterone and various oestrogens, all made from diosgenin. Then, in June 1951, the company reported what was surely the highlight of their academic research – the 20-stage chemical synthesis of the most clinically important steroid of the era – cortisone. Previously this key anti- inflammatory steroid could only be made using a 32-stage synthesis pioneered by the company Merck & Co. The Mexican group completed their historic synthesis a few weeks DJERASSI CARL ahead of the major research groups of both Robert Woodward and Maximilian Ehrenstein at the The team at Syntex the lack of a 19-methyl group and Louis Fieser at Harvard University, University of Pennsylvania in the celebrating the successful inverted stereochemistry at C-14 US – a huge public relations US had synthesised a small amount 20-stage synthesis of and 17). triumph for Syntex. of 19-norisoprogesterone from the cortisone in June 1951 In 1951, Djerassi and Later they went on to improve natural product strophanthidin (an Rosenkranz prepared a sample of their route by preparing cortisone arrow poison from an African plant). 19-norprogesterone (with correct from a very cheap sapogenin called Surprisingly this also exhibited stereochemistry) from progesterone hecogenin that comes from the progesterone-like activity (despite and confirmed that it was more sisal plant. This process was later licensed to the pharmaceutical firm Glaxo and formed the basis of that company’s world-leading steroid chemistry, leading to blockbuster drugs such as Betnovate (betamethasone) and Becotide (beclomethasone). With their expertise in steroid chemistry established, the Syntex group were now well prepared for the discoveries that were to cement their place in history. The pill’s humble beginnings The discovery of the contraceptive pill was, like so many seminal discoveries in medicinal chemistry, a mixture of serendipity and inspired chemistry. While Syntex was marketing progesterone as a drug to prevent miscarriage and to alleviate menstrual problems, its water insolubility and short half-life (about 5 minutes) in serum meant that oral delivery was impossible. Two unconnected discoveries triggered the research undertaken by Djerassi and Rosenkranz. Firstly a group at pharma firm Schering in Berlin, Germany, had synthesised ethisterone (a testosterone analogue with an ethynyl group at C-17) in Russell Marker’s five-step synthesis of 1938, which had progesterone-like progesterone from diosgenin, a natural activity and was orally available. product found in the Mexican yam plant Even more importantly, in 1944 58 | Chemistry World | September 2010 www.chemistryworld.org active than progesterone. They then Carl Djerassi is known as by Gregory Pincus of the Worcester tackled the synthesis of a steroid that the father of the pill Foundation for Experimental combined the loss of the 19-methyl Biology in Massachusetts, US, and CARL DJERASSI CARL group (19-nor-series) with an John Rock the Harvard-based ethynyl group at C-17 by preparing clinician in 1956. 19-norethisterone (later called Almost by chance it was norethindrone), and demonstrated discovered that small amounts of the that it had greater progestational synthetic oestrogen mestranol were activity than any other known also present in samples of these new steroid and was orally active. synthetic progestins and seemed to They filed for a patent in enhance the anti-ovulatory effect. As November 1951 and then described a result, the first contraceptive pill their research at an American formulations contained a mixture of Chemical Society conference in April the 19-norprogestogens and small 1952, a whole year before the US amounts of mestranol. pharmaceutical company G D Searle The three original Extensive clinical trials took place announced norethynodrel. These hormones used in Puerto Rico (and to a lesser extent two progestogens were destined to in contraceptive in Mexico) between 1956 and 1958, be the main constituents of the first formulations and the hugely positive results (only contraceptive formulations. Oestrogen’s role Progesterone had long been associated with an anti-ovulatory effect as well as its ability to prevent contraction of the uterus thus helping to prevent expulsion of an embryo. The first demonstration that norethindrone and norethynodrel were effective as anti-ovulatory agents was revealed Male contraceptives In China in the 1950s, it was found that using 20 years, and initially showed promise as an crude cottonseed oil for cooking seemed antiviral agent. Now Frances Platt’s group to be associated with an increase in male has shown that the compound impairs sperm infertility. This led to evaluation of the oil’s formation in mice. N-butyl deoxynojirimycin major constituent gossypol in animal studies. appears to render sperm unable to penetrate These were successful and clinical trials on the female egg. Since fertility returns once male volunteers began in 1972. Participants the drug is no longer taken – and appears to were initially fed daily doses of 20mg of have no harmful effects on body weight, the gossypol until their sperm counts dropped testes, liver and kidneys – its use in humans below what was deemed necessary for might be worth exploring. procreation (usually less than 1 million sperm per ml of seminal fluid). The 4000 volunteers The natural approach then received maintenance doses of A more natural form of male fertility control 75–100mg twice monthly for periods of up to may arise from studies of gonadotropin- 4 years with a claimed 99.9 per cent success inhibitory hormone. This small