The contraceptive pill The birth of the pill Most primitive societies knew of that would control their , 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 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 from the occupied a niche in the market  The first cheap and side-chain. He was intrigued by the genus . for pharmaceuticals. Its founders, simple route to make possibility of using these oxidised Being something of a botanist as Hungarian Emeric Somlo and , 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 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 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, , in January 1944 to from studying a class of exploit the process. Initially Marker natural products called . 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, . And four years later the chemist who has become known as the ‘father of the pill’ – – 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 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 (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- (later called Almost by chance it was norethindrone), and demonstrated discovered that small amounts of the that it had greater progestational synthetic oestrogen 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 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 . 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 peptide, rate in terms of pregnancy prevention. It produced by the hypothalamus, prevents was also claimed that fertility completely A ‘male pill’ has been considered for decades the synthesis of FSH (follicle-stimulating recovered when the men stopped taking hormone) and LH (luteinising hormone) in the gossypol. However, this method of fertility Several other studies have used pituitary gland. And once the balance between control never became established. combinations of testosterone derivatives in this inhibitory hormone and gonadotropin- As long ago as 1939 it was shown that conjunction with synthetic progestins, and releasing hormone are understood at the testosterone propionate could cause a low while most of these combinations produced neural level, it may be possible to design small sperm count (). And in the most acceptable levels of azoospermia, there peptides that disrupt the delicate balance and recent and extensive study, the Chinese have were usually unacceptable side-effects most therefore affect the production of oestrogens turned to the administration of testosterone importantly loss of . and testosterone. This research is at an early undecanoate (500mg monthly). A multicentre stage, and as one of the leaders in this area Phase III study, involving 1045 men over a Here we go round the mulberry bush – George Bentley of University of California 30 month period, revealed a near complete A further intriguing compound is under Berkeley, US – claims that ‘in male rats the and reversible result for azoospermia with a examination at the department of hormone reduces copulation felicitation, contraceptive failure rate of 1.1 per 100 men pharmacology at the University of Oxford, that is the rats lose interest, and this is not a during this period. However, the trial’s leading UK. The N-butyl derivative of the natural desirable strategy for human use’. So there is scientist Yiqun Gu told Chemistry World that product deoxynojirimycin, found in mulberry clearly much to do before this type of therapy no further studies are under way. leaves, has been of interest for at least would be acceptable.

www.chemistryworld.org Chemistry World | September 2010 | 59 The contraceptive pill those women who withdrew from ‘The pill is not Reaping the benefits the trials became pregnant) led to US Over the years there have been Food and Drug Administration (FDA) associated with a number of scares concerning approval of Enovid (norethynodrel an increased the potential for the pill to cause and mestranol) for contraceptive use. thrombosis, but these problems have In 1960, it was launched by long-term risk been largely overcome through the G D Searle, and Ortho-Novum of death indeed, use of low-dose -only (norethindrone and mestranol) was formulations. In addition, there released jointly by the firms Ortho a net benefit is is a well substantiated long-term and Syntex in 1962. Then in 1964, apparent’ protective effect against both ovarian Syntex launched its low dose oral and endometrial cancers. In a March contraceptive pill Norinyl with each 2010 article in the British Medical pill containing 2mg of norethindrone an ) RU-486 or Journal, that reviewed a study of and 0.1mg of mestranol; and this kind in 1982, which acts by more than 46 000 women over a of formulation has remained the blocking progesterone receptors in period of 39 years, Philip Hannaford mainstay of the pill ever since. the uterus. of the University of Aberdeen, UK, There have been attempts to wrote: ‘oral contraception was not A booming market develop a non-steroidal drug for associated with an increased long- By 1966 more than 5 million US fertility control, but the only widely term risk of death indeed, a net women were using the new oral used drug is which acts benefit was apparent.’ contraceptives. In the UK, the first upon oestrogen receptors in cells of One of the main issues with the prescriptions were written in 1961 the uterus (and breast) to modulate introduction of the contraceptive with 480 000 users by 1964, though gene expression in these cells. In this pill was the fact that men no longer the pill was initially only available to respect, the drug has a similar mode needed to worry about insemination, married women and wider use only of action to the breast cancer drug meaning the responsibility lay solely occurred when the Brook Family tamoxifen. Ormeloxifene has been with the women. This was partially Planning Clinics opened in 1964. in use in for around 20 years overcome with the appearance of Since the mid-1960s many new and has recently been introduced HIV and Aids in the 1980s and the variants of the original into South America, but there are no urgent need to avoid unprotected have been introduced, but the licences as yet for use in Europe or sex. In addition, the development most successful strategies have North America. of the and its reversal changed little over the past 50 Finally, the potential use of provided men with a means for years. These include: a combined so-called microbicides has been controlling their own fertility, and in oral formulation of progestogen highlighted at a recent conference consequence there has been a limited and oestrogen; an oral formulation (Microbicides 2010, Pittsburg, May) ongoing search for chemical methods containing only progestogen; and on these interesting antimicrobial to control male fertility (see box, p59). slow release formulations using an peptides. These compounds might be So after 50 years of use how can we IUD ( or a coil), tailored to be both spermicidal and to rate the success of the contraceptive transdermal patch, implantation or a offer protection against HIV and other pill? It is currently used by an . pathogens. However, since they would estimated 100 million women of The only major innovation probably have to be applied prior to The contraceptive childbearing age worldwide, though has been the introduction of the sexual activity, they would not be as coil slowly releases the percentage use ranges from less emergency contraceptive (actually convenient as the contraceptive pill. hormones into the body than 5 per cent in parts of Africa and Asia to as much as 60 per cent in the developed world. While its use has undoubtedly helped women to take control of their fertility, in those societies where for reasons of religion, social unrest or poverty the use is restricted, there are an estimated half million unplanned conceptions every day, many of which are terminated by chemical or SATURN STILLS / SCIENCE PHOTO LIBRARY LIBRARY PHOTO SCIENCE / STILLS SATURN surgical intervention. As Djerassi wrote in his 2001 book One man’s pill: ‘there is one categorical answer that can be given to the question of the pill’s benefits versus its risks, I am referring to the number of unwanted children and – the sheer mass of human suffering – prevented over the years.’

John Mann is emeritus professor of chemistry at Queen’s University Belfast, UK. He worked as a postdoctoral scientist at Syntex, Palo Alto, US, during 1971

60 | Chemistry World | September 2010 www.chemistryworld.org