JAMES MACKENZIE LECTURE 1979 The happiness pill? CLIFFORD R. KAY, cbe.md.ph.d.frcgp General Practitioner, Manchester; Director, Manchester Research Unit, Royal College of General Practitioners The james Mackenzie women throughout the world were taking oral contra-' Lecture 1979 was de¬ ceptives.an almost incredible degree of mass medi¬ livered at Imperial cation. But now doubts are creeping in and the use of College, London, on hormones is declining. It seems an appropriate time, 17 November 7979. therefore, 20 years after the introduction of oral contra¬ ceptives, to review the history of this medicosocial revolution, and to trace its course, since our College has had an important influence on its progress. Synthetic progesterone Before the second world war, several workers had shown that oestrogens, or progesterone, when injected into a rabbit could inhibit ovulation (Makepeace et al., 1937; Sturgis and Albright, 1940). Research was seriously hampered, however, by the enormous cost and scarcity of these hormones, which could be derived only /^\VER the past 20 to 30 years, we have seen the from animal sources. To obtain 25 of ^^ milligrams pure introduction of a new application of the use of oestradiol required four tons of sows' ovaries. A cheap drugs. Women have been encouraged to take hormones source of synthetic hormones was required before any continuously over many years, not as a cure for a progress could be made. disease, but as a means of prevention. During the Russell Marker was an organic chemist. A man of reproductive years, the hormonal contraceptives have eccentric personality, he had no patience with admin¬ proved to be the most convenient and effective way ever istrative routine, and several times walked out of highly devised of preventing unwanted pregnancy, and after responsible posts without bothering about such trivi- normal menstruation has ceased, oestrogens have been alities as giving notice. In 1939 he was a professor in the recommended to prevent the effects of declining natural State College of Pennsylvania, and that year managed function of the ovaries. to synthesize small quantities of progesterone from When post-menopausal hormone therapy began to be extracts of the root of the sarsaparilla plant. The yield promoted by the popular press in Britain, the tablets was low, however, so he begged botanists to send him were called 'the happiness pill'. I do not need to plants from all over the world. Soon his laboratory was stretch literary licence very far to include oral contra¬ filled with decaying vegetation. ceptives in the same term, for they have played a major In 1940, he found that the root of a species of yam part in promoting a new degree of freedom, equality, growing wild in Mexico gave him a good yield. He and, I hope, happiness for millions of women through¬ immediately attempted to get financial backing for out the world. manufacturing in Mexico, but the whole world was now No scientist has ever believed that such advantages in conflict, and Mexico was not the most eligible of could be gained without some degree of risk, but until countries for developing new industry. He rapidly lost fairly recently the price that had to be paid seemed to be patience with cautious financiers, threw up his post in small, and the value great. The use of the hormones Pennsylvania, and bought himself a house in Mexico expanded dramatically, and in 1977 over 80 million City. Using mules for transport, he explored the wilds of Mexico for the plants he needed. He set up a The James Mackenzie Lecture was delivered at the twenty-seventh Annual General Meeting of the Royal College of General Prac¬ makeshift laboratory in the stables of his house and, titioners and is printed by kind permission of the Editor of The working almost single-handed, began the synthesis of Practitioner. progesterone from a substance called diosgenin ex- Journal ofthe Royal College of General Practitioners, 1980, 30, tracted from the root of a wild vine, a member of the 8-19. Dioscorea species. Journal ofthe Royal College ofGeneral Practitioners, January 1980 James Mackenzie Lecture 1979 Two European refugees, Dr Somlo from Hungary 19-/iorethisterone, and this proved to be a highly active and Dr Lehman from Germany, had set up in Mexico progestogen when taken by mouth. It was not produced City a small pharmaceutical business, which they called from ethisterone, however. Djerassi and Rosenkranz Laboratorios Hormona. One day in 1943, Marker synthesized it in several stages, starting with the veg- walked into their building carrying two pickle jars etable product diosgenin that Russell Marker had used. wrapped in newspaper. The jars contained four and a 19-norethisterone became known simply as norethis- half pounds of pure progesterone, worth well over a terone everywhere except the USA, where the name was million dollars at present prices. The three men agreed later changed to norethindrone. to set up a new company to manufacture the hormone. Biological and chemical testing of the new compound It was incorporated in Mexico City on 21 January 1944. took several years. In 1954, Dr Roy Hertz (Hertz et al., They called the company Syntex. 1954) was one of the first to put it to clinical use at the Satisfactory progress did not continue for long. Pre- National Institutes of Health at Bethesda, near Wash¬ dictably, Marker had a disagreement with Somlo and ington. He used it for the treatment of menstrual Lehman and he left the company abruptly in 1945, disorders. taking his process notes with him. Production of pro¬ gesterone ceased, and Marker virtually disappeared for over 20 years. The idea of an oral contraceptive were now in serious but Dr Somlo Syntex trouble, The was also sent for to found a fellow who had taken compound biological testing 29-year-old Hungarian Massachussetts.where there was a his doctorate in Switzerland and was then in Shrewsbury, private working research laboratory called the Worcester Foundation Havana. George Rosenkranz, who is now President of for the moved to Mexico and Experimental Biology. parent Syntex company, City director of this foundation was a called re-established Marker's At The biologist rapidly process. many points Dr Goodman Pincus. Pincus had no doubts he had to new chemical reactions to substitute for Gregory apply about the use to which he wished to the new the recorded in the notes Marker had taken put steps only progestogen. He had always been interested in the with him. Soon, were progesterone in Syntex supplying problems of fertilization in animals. In 1951, the year bulk to pharmaceutical companies in the United States and that norethisterone was synthesized, a meeting was Europe. arranged between Pincus and two remarkable ladies, Mrs Katharine McCormick and Mrs Margaret Sanger. Mrs Sanger was the doyen of the US birth control Orally active progestogens movement. A formidable lady, who suffered repeated The production of synthetic progesterone was a major vilification and even imprisonment for championing her advance, but like natural progesterone it had the dis¬ cause, she combined many of the characteristics of Mrs advantage of having very low activity when given by Pankhurst and Dr Marie Stopes. mouth. Hormones were now being used for the treat¬ The connection between the International Harvester ment of gynaecological disorders and for threatened Company and oral contraceptives is not immediately abortion, but they usually had to be given by injection. apparent. In fact, the one had an important influence An orally active preparation was badly needed. on the other (Reed, 1978). The Company was founded In 1949, a new chemist joined the Syntex company. by Cyrus McCormick, whose son, Stanley, married Karl Djerassi was 25 years old. Born in Vienna, he was a Katharine in 1904. Two years later, Stanley developed naturalized American citizen and was trained in the severe schizophrenia from which he never recovered, University of Wisconsin. His Professor there, Dr A. L. although he lived until 1947. After a battle in the courts Wilds, had been developing the observations of with her father-in-law, Katharine obtained control of Ehrenstein at the University of Pennsylvania, and Birch her husband's fabulous wealth derived from the Inter¬ in England, that if carbon atom number 19 was re¬ national Harvester Company, and devoted the rest of moved from the progesterone molecule, the new sub- her life to supporting the suffragette and birth control stance behaved biologically as a progestogen, but the movement in the USA. In this way she became a close activity (that is the potency) was different from that of friend and financial supporter of Margaret.Sanger. In progesterone (Allen and Ehrenstein, 1944; Birch and 1950, Katharine wrote to Mrs Sanger to ask her opinion Mukherji, 1949; Wilds and Nelson, 1953). about the priorities for birth control. Margaret Sanger Djerassi, working with Rosenkranz, methodically set replied: "I consider that the world and almost our about the task of removing the carbon 19 atom from the civilization for the next 25 years is going to depend upon molecule of all the known synthetic progestogens. One a simple, cheap, safe contraceptive to be used in of them, called ethisterone, had been synthesized by the poverty-stricken slums, jungles, and amongst the most Schering company in Berlin, as far back as 1938. Iri ignorant people." It is one of the many ironies in the 1951, the Syntex team produced a compound that was story of the Pill that when the miraculous product for identical to ethisterone, except that it was without the which Mrs Sanger had prayed became available, it was number 19 carbon atom. It was, therefore, called used predominantly by educated women in the western Journal oftheRoyal College ofGeneralPractitioners, January 1980 JamesMackenzie Lecture 1979 world, and to this day has barely penetrated to the but not all, failed to ovulate during treatment.