Wednesday, March 3, 2021
There are some fascinating stories surrounding the pioneers who were responsible for the development of the Pill. It is fitting to recall these as we celebrate the introduction of the Pill into New Zealand 60 years ago in 1961.
Dr Russell Marker (1902-1995). In 1940 progesterone was a rare and expensive drug selling for $200 per gram.
It was extracted from animal sources and was in great demand for the treatment of women with recurrent miscarriage. Marker, a Professor of Organic Chemistry at Pennsylvania State University was convinced that he could find a better source in plants.
In the summer of 1940 he visited a Mexican jungle to locate a wild yam with a lumpy root. As he predicted, this plant was an excellent source of diosgenin, a precursor of progesterone. No-one would finance his project so he left his University job and set up his own laboratory in a shed in Mexico City. Single-handedly he developed the first mass supply of progesterone and in doing so became a rich man.
For a few years, he was involved in the pharmaceutical production of progesterone with Syntex Laboratories, which he co-founded. In 1949 at the age of 47 he retired to make replicas of antique silver and never returned to science. However Penn State University hold an annual scientific lecture in his honour. Another innovation by Marker was the octane rating system for gasoline.
Dr Carl Djerassi (1923-2015) was born in Vienna and brought up in Bulgaria. His parents were doctors and at 16 he and his mother emigrated to the United States.
When Russell Marker left Syntex Laboratories Carl Djerassi was appointed as the head of steroid research. His great achievement was for his team to produce an orally active form of progesterone. Prior to that progesterone had to be given by injection.
In 1951 Syntex produced the first progestogen, the term used for substances which act like progesterone. This one was called norethindrone, better known in New Zealand as norethisterone, which incredibly is still used in pills today such as the combined pills Norimin and Brevinor and the progestogen-only pill Noriday.
It was not however the progestogen chosen for use in the first Pill trials; that was norethynodrel produced a year later by Searle, but because of side effects, not as enduring. Not only is Djerassi a distinguished chemist but he is also a poet, novelist and playwright. His play Oxygen was performed at Circa Theatre Wellington in 2003. In 2004 he published an autobiography This Man’s Pill: Reflections on the 50th birthday of the pill. Of course, there are many other anniversaries associated with the development of the Pill.
Now we come to two women who were close friends.
Margaret Sanger (1879-1966) trained as a nurse and was a long time campaigner for birth control. In 1916 she established the first American birth control clinic in Brooklyn, New York and for this daring venture she served 30 days in jail. After her release she won an appeal, opening the way for physicians to give birth control advice.
She founded the American Birth Control League, the forerunner of Planned Parenthood and in 1927 organised the first World Population Conference. She was one of the founders of the International Planned Parenthood Federation (IPPF) at a meeting in India in 1952. She travelled widely.
In her private life she married twice, first to Bill Sanger, the father of her three children, and then to an older millionaire, Noah Slee, who was able to finance her projects.
In 1938 she wrote her autobiography recounting the events that motivated her especially the effect of too frequent child bearing on the health of women and the death of a young woman from septic abortion. Other books have been written of her full, interesting and controversial life.
Katharine McCormick (1875-1967) came from a privileged background. Her father supported education for women and she was the first woman biologist to graduate from MIT.
After graduation she married Stanley McCormick but two years later he was diagnosed as suffering from schizophrenia and then dementia. For fear of passing on the illness she chose not to have children.
She met Margaret Sanger in 1917, was a keen supporter of birth control, was a feminist, a suffragist, and a philanthropic supporter of education for women, and schizophrenia research.
In 1947 Stanley died and she inherited his wealth, largely generated from McCormick combine harvesters. Now over 70, she was free to pursue her own, rather than the McCormick family interests and provided almost the entire $2 million for the development of the Pill.
Dr Gregory Pincus (1903-1967) was an American biologist and reproductive physiologist. In 1951 Margaret Sanger met Pincus at a dinner hosted by Dr Abraham Stone, Vice-President of Planned Parenthood.
She implored him to find a better method of contraception for women. Planned Parenthood provided a small grant for Pincus to begin hormonal contraceptive research. He confirmed earlier animal research that showed progesterone alone would stop ovulation.
In 1952 Margaret Sanger told her friend Katharine McCormick about Pincus’s research. In 1953 the two women met with Pincus and encouraged him to dramatically expand the scope of his research and Katharine provided the funding.
His team screened nearly 200 chemical compounds and it was norethynodrel that was chosen as the progestogen in the first Pill. But Pincus was not a clinician. In order to prove the safety of the Pill in human trials he worked closely with Dr John Rock.
Dr John Rock (1890-1984) was Clinical Professor of Gynaecology at Harvard. His specialty was infertility. In 1953 he was already using hormones to stop ovulation for a three-month period to see if the ovaries would spring back into activity after a rest period. About 15% of women became pregnant following this treatment.
In 1954 he trialled three different progestogens but not as a contraceptive because that was still a felony in the State of Massachusetts. Of the three compounds, Searle’s norethynodrel gave the best cycle control. It was then discovered that the drug was accidentally contaminated with a small amount of oestrogen, and this was the reason for the better cycle control. That is why the first Pill Enovid developed by Searle, kept this combination using norethynodrel (as the progestogen) and mestranol (as the oestrogen).
In June 1957 Enovid was approved by the FDA for menstrual conditions but it was not approved as a contraceptive until May 1960. Later on Searle introduced other pills using the same two components, but in a lower dose, called Conovid and Conovid E.
Enovid 10mg norethynodrel + 150mcg mestranol
Conovid 5mg norethynodrel + 75mcg mestranol
Conovid E 2.5mg norethynodrel + 100mcg mestranol
Rock was a catholic and a father of five. At the age of 70, he launched a one-man campaign to persuade the Vatican to approve the Pill arguing that using the Pill was a more precise way of natural family planning.
In 1963 he published The Time Has Come: A Catholic Doctor’s Proposals to End the Battle over Birth Control which received wide publicity. It was a devastating setback in July 1968 when the Pope officially banned the Pill in the encyclical Humanae Vitae. Rock withdrew from the church and when he died at the age of 94 he was still frustrated that the Church refused to change its stance on the Pill.
Dr Edris Rice-Wray (1904-1990)
After the success of preliminary trials in Boston in 1954 and 1955, Rock and Pincus needed to confirm their findings in a large scientific trial. Given the strong opposition to birth control in America in the 1950s, Pincus looked further afield and chose Puerto Rico. It was a densely populated U.S. island territory, and despite being predominantly Catholic, supported birth control with a well-established network of clinics.
Trials commenced in April 1956, using Searle’s Enovid. The success of this venture is largely credited to the supervision by Dr. Edris Rice-Wray, a Public Health physician of the Puerto Rico Medical School and Medical Director of the Puerto Rico Family Planning Association. She reported positively on the effectiveness of the Pill but also negatively on the side effects. In later years, Pincus's team would be accused of exploiting poor women of colour but in the 1950s, the accepted standards for research involving human subjects were much less rigorous than they are today.
This has been a very brief account of the birth of the Pill: an eccentric chemist who was absolutely driven to find a better source of progesterone; another chemist who made it easy to swallow; two elderly women with a life-long passion to improve the lot of women and with the money to finance their dreams; a reproductive scientist who accepted their challenge, a Catholic doctor who saw no contradiction between infertility and the control of fertility; and the astute appointment of a family planning doctor to supervise important fieldwork.
These exceptional people are duly recognised. Unrecognised are those trusting Puerto Rican women whose participation was essential, the true pioneers.
So far this is an American-based account. However another pioneer was an unassuming European doctor, sometimes referred to as “the stepfather of the pill”.
Dr Ferdinand “Nand” Peeters (1918-1998) was head of the Obstetrics Department of the hospital in Turnhout, a small town in northern Belgium. He closely followed the development of various hormones and their uses in the 1950s and was aware of the work of Pincus. He knew that the German pharmaceutical firm Schering AG was a leader in the development of steroid hormones, and when a representative of Schering, told him that the firm had combined two of them, norethisterone acetate (a progestogen) and ethinylestradiol (an oestrogen) into an experimental preparation for the treatment of dysmenorrhea (painful periods), he asked for permission to test it on a number of his patients. The idea of developing this combination into a contraceptive pill stemmed from Peeters, not from Schering, partly because of a sensitivity to the Nazi history of human experimentation.
In 1959 he chose patients for his studies for whom a further pregnancy would have been life-threatening, or who would risk a stillbirth due to Rhesus incompatibility. He told the women that this was a new medication, and sought their permission to use it. The results of his small-scale trial led him to conclude that a dose of 3 to 4mg of norethisterone acetate and 'at least' 50mcg of ethinylestradiol was promising. He published his results in 1960 showing it was highly effective as a contraceptive with fewer side effects than Enovid. Schering was impressed and even before publication organised larger trials in Germany, Australia, Japan and the USA.
This combination, which was named Anovlar by the Australian arm of Schering research, was first launched in February 1961 in Australia, and later that year in Germany and Switzerland. Others followed: Austria (1962), France (1964), Spain (1964), and Belgium (1965). Peeters was reticent about publicity because of strict Belgian legislation which still considered references to birth control obscene. Even his own family were unaware of his contribution. Although a Catholic father of six, like John Rock he did not support the position of the Church but his research stopped in 1968 due to the Pope’s ban of artificial contraception. However, by then not only Schering but also a number of other pharmaceutical firms had realised the commercial potential in marketing a drug that healthy women would need to take long-term. Significantly Peeter’s motivation had been to help his women patients, not to achieve fame or wealth.
These early pills, Enavid (UK spelling of Enovid), Conovid E, Conovid and Anovlar made their way to New Zealand and that is another story.
Jean H. Baker. Margaret Sanger: A Life of Passion. New York: Hill and Wang; 2011.
Karl van den Broeck, Dirk Janssens, Paul Defoort. A forgotten founding father of the Pill: Ferdinand Peeters European Journal of Contraception and Reproductive Health Care, 17:321-328; 2012.
Jonathan Eig. The Birth of the Pill. New York: Norton; 2014.
MUVS The Museum of Contraception and Abortion https://muvs.org/en/
Gert J. Wlasich. The early history of the Pill. Gynaecology Forum Vol. 5, No 4; 2000.
Dame Margaret Sparrow
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