By the 1930s, scientists had isolated and determined the structure of the
steroid hormones and found that high doses of
androgens,
estrogens or
progesterone inhibited
ovulation, but obtaining these hormones, which were produced from animal extracts, from European
pharmaceutical companies was extraordinarily expensive. In 1939,
Russell Marker, a professor of
organic chemistry at
Pennsylvania State University, developed a method of synthesizing
progesterone from plant steroid
sapogenins, initially using sarsapogenin from
sarsaparilla, which proved too expensive. After three years of extensive botanical research, he discovered a much better starting material, the
saponin from inedible Mexican yams (
Dioscorea mexicana and
Dioscorea composita) found in the rain forests of
Veracruz near
Orizaba. The saponin could be converted in the lab to its aglycone moiety
diosgenin. Unable to interest his research sponsor
Parke-Davis in the commercial potential of synthesizing progesterone from Mexican yams, Marker left Penn State and in 1944 co-founded
Syntex with two partners in
Mexico City. When he left Syntex a year later the
trade of the barbasco yam had started and the period of the heyday of the
Mexican steroid industry had been started. Syntex broke the monopoly of European pharmaceutical companies on steroid hormones, reducing the price of progesterone almost 200-fold over the next eight years. Midway through the 20th century, the stage was set for the development of a
hormonal contraceptive, but pharmaceutical companies, universities and governments showed no interest in pursuing research.
Progesterone to prevent ovulation Progesterone, given by injections, was first shown to inhibit ovulation in animals in 1937 by Makepeace and colleagues. Research started in April 1951, with reproductive physiologist
Min Chueh Chang repeating and extending the 1937 experiments of Makepeace et al. that was published in 1953 and showed that injections of progesterone suppressed ovulation in rabbits. In March 1952, Sanger wrote a brief note mentioning Pincus' research to her longtime friend and supporter,
suffragist and
philanthropist Katharine Dexter McCormick, who visited the WFEB and its co-founder and old friend
Hudson Hoagland in June 1952 to learn about contraceptive research there. Frustrated when research stalled from PPFA's lack of interest and meager funding, McCormick arranged a meeting at the WFEB in June 1953, with Sanger and Hoagland, where she first met Pincus who committed to dramatically expand and accelerate research with McCormick providing fifty times PPFA's previous funding. Pincus and McCormick enlisted
Harvard clinical professor of
gynecology John Rock, chief of gynecology at the
Free Hospital for Women and an expert in the treatment of
infertility, to lead clinical research with women. At a scientific conference in 1952, Pincus and Rock, who had known each other for many years, discovered they were using similar approaches to achieve opposite goals. In 1952, Rock induced a three-month
anovulatory "
pseudopregnancy" state in eighty of his infertility patients with continuous gradually increasing oral doses of an estrogen (5 to 30 mg/day
diethylstilbestrol) and progesterone (50 to 300 mg/day), and within the following four months 15% of the women became pregnant. In 1953, at Pincus' suggestion, Rock induced a three-month anovulatory "pseudopregnancy" state in twenty-seven of his infertility patients with an oral 300 mg/day progesterone-only regimen for 20 days from
cycle days 5–24 followed by pill-free days to produce
withdrawal bleeding. This produced the same 15% pregnancy rate during the following four months without the
amenorrhea of the previous continuous estrogen and progesterone regimen. Despite the incomplete inhibition of ovulation by oral progesterone, no pregnancies occurred in the two studies, although this could have simply been due to chance. However, Ishikawa et al. reported that the
cervical mucus in women taking oral progesterone became impenetrable to sperm, and this may have accounted for the absence of pregnancies. Instead, researchers would turn to much more potent synthetic progestogens for use in oral contraception in the future. In December 1954, Rock began the first studies of the ovulation-suppressing potential of 5–50 mg doses of the three oral progestins for three months (for 21 days per cycle—days 5–25 followed by pill-free days to produce withdrawal bleeding) in fifty of his patients with infertility in
Brookline, Massachusetts. Norethisterone or noretynodrel 5 mg doses and all doses of norethandrolone suppressed ovulation but caused breakthrough bleeding, but 10 mg and higher doses of norethisterone or noretynodrel suppressed ovulation without breakthrough bleeding and led to a 14% pregnancy rate in the following five months. Pincus and Rock selected Searle's noretynodrel for the first contraceptive trials in women, citing its total lack of androgenicity versus Syntex's norethisterone very slight androgenicity in animal tests.
Combined oral contraceptive Noretynodrel (and norethisterone) were subsequently discovered to be contaminated with a small percentage of the estrogen
mestranol (an intermediate in their synthesis), with the noretynodrel in Rock's 1954–5 study containing 4–7% mestranol. When further purifying noretynodrel to contain less than 1% mestranol led to breakthrough bleeding, it was decided to intentionally incorporate 2.2% mestranol, a percentage that was not associated with breakthrough bleeding, in the first contraceptive trials in women in 1954. The noretynodrel and mestranol combination was given the proprietary name
Enovid. The first
contraceptive trial of Enovid led by
Celso-Ramón García and
Edris Rice-Wray began in April 1956 in
Río Piedras, Puerto Rico. A second contraceptive trial of Enovid (and norethisterone) led by Edward T. Tyler began in June 1956 in
Los Angeles. In January 1957, Searle held a symposium reviewing gynecologic and contraceptive research on Enovid through 1956 and concluded Enovid's estrogen content could be reduced by 33% to lower the incidence of estrogenic gastrointestinal side effects without significantly increasing the incidence of breakthrough bleeding. While these large-scale trials contributed to the initial understanding of the pill formulation's clinical effects, the ethical implications of the trials generated significant controversy. Of note is the apparent lack of both autonomy and informed consent among participants in the Puerto Rican cohort prior to the trials. Many of these participants hailed from impoverished, working-class backgrounds.
United States In June 1957, the
Food and Drug Administration (FDA) approved Enovid 10 mg (9.85 mg noretynodrel and 150 μg mestranol) for menstrual disorders, based on data from its use by more than 600 women. Numerous additional contraceptive trials showed Enovid at 10, 5, and 2.5 mg doses to be highly effective. In July 1959,
Searle filed a supplemental application to add contraception as an approved indication for 10, 5, and 2.5 mg doses of Enovid. The FDA refused to consider the application until Searle agreed to withdraw the lower dosage forms from the application. In May 1960, the FDA announced it would approve Enovid 10 mg for contraceptive use, and did so in June 1960. At that point, Enovid 10 mg had been in general use for three years and, by conservative estimate, at least half a million women had used it. Although FDA-approved for contraceptive use, Searle never marketed Enovid 10 mg as a contraceptive. Eight months later, in February 1961, the FDA approved Enovid 5 mg for contraceptive use. In July 1961, Searle finally began marketing Enovid 5 mg (5 mg noretynodrel and 75 μg mestranol) to physicians as a contraceptive. Although the FDA approved the first oral contraceptive in 1960, contraceptives were not available to married women in all states until
Griswold v. Connecticut in 1965, and were not available to unmarried women in all states until
Eisenstadt v. Baird in 1972. It would take almost a decade of
epidemiological studies to conclusively establish an increased risk of
venous thrombosis in oral contraceptive users and an increased risk of
stroke and
myocardial infarction in oral contraceptive users who
smoke or have
high blood pressure or other cardiovascular or cerebrovascular risk factors. The hearings were conducted by senators who were all men and the witnesses in the first round of hearings were all men, leading
Alice Wolfson and other feminists to protest the hearings and generate media attention. Today's standard dose oral contraceptives contain an estrogen dose that is one third lower than the first marketed oral contraceptive and contain lower doses of different, more potent progestins in a variety of formulations. Pharmacists in Oregon, California, Colorado, Hawaii, Maryland, and New Mexico have authority to prescribe birth control after receiving specialized training and certification from their respective state
Board of Pharmacy. , pharmacists in 29 states can prescribe oral contraceptives. A progestin-based birth control pill (
Opill) was approved by the FDA in 2023 and is available over the counter. Estrogen-based pills still require prescriptions as of 2024.
Australia The first oral contraceptive introduced outside the United States was
Schering's Anovlar (
norethisterone acetate 4 mg +
ethinylestradiol 50 μg) in January 1961, in Australia.
Germany The first oral contraceptive introduced in Europe was Schering's
Anovlar in June 1961, in
West Germany.
United Kingdom Before the mid-1960s, the United Kingdom did not require pre-marketing approval of drugs. The British
Family Planning Association (FPA) through its clinics was then the primary provider of family planning services in the UK and provided only contraceptives that were on its Approved List of Contraceptives (established in 1934). In 1957, Searle began marketing Enavid (Enovid 10 mg in the US) for menstrual disorders. Also in 1957, the FPA established a Council for the Investigation of Fertility Control (CIFC) to test and monitor oral contraceptives which began animal testing of oral contraceptives and in 1960 and 1961 began three large clinical trials in
Birmingham,
Slough, and
London. In March 1960, the Birmingham FPA began trials of noretynodrel 2.5 mg + mestranol 50 μg, but a high pregnancy rate initially occurred when the pills accidentally contained only 36 μg of mestranol—the trials were continued with noretynodrel 5 mg + mestranol 75 μg (Conovid in the UK, Enovid 5 mg in the US). In August 1960, the Slough FPA began trials of noretynodrel 2.5 mg + mestranol 100 μg (Conovid-E in the UK, Enovid-E in the US). In May 1961, the London FPA began trials of Schering's Anovlar. In October 1961, at the recommendation of the Medical Advisory Council of its CIFC, the FPA added Searle's Conovid to its Approved List of Contraceptives. In December 1961,
Enoch Powell, then
Minister of Health, announced that the oral contraceptive pill Conovid could be prescribed through the
NHS at a subsidized price of 2
s per month. In 1962, Schering's Anovlar and Searle's Conovid-E were added to the FPA's Approved List of Contraceptives. The pill is the most popular form of contraception in France, especially among young women. It accounts for 60% of the birth control used in France. The abortion rate has remained stable since the introduction of the pill.
Japan In Japan, lobbying from the
Japan Medical Association prevented the pill from being approved for general use for nearly 40 years. The higher dose "second generation" pill was approved for use in cases of gynecological problems, but not for birth control. Two main objections raised by the association were safety concerns over long-term use of the pill, and concerns that pill use would lead to decreased use of condoms and thereby potentially increase
sexually transmitted infection (STI) rates. However, when the Ministry of Health and Welfare approved
Viagra's use in Japan after only six months of the application's submission, while still claiming that the pill required more data before approval, women's groups cried foul. The pill was subsequently approved for use in June 1999, when Japan became the last UN member country to do so. However, the pill has not become popular in Japan. According to estimates, only 1.3 percent of 28 million Japanese females of childbearing age use the pill, compared with 15.6 percent in the United States. The pill prescription guidelines the government has endorsed require pill users to visit a doctor every three months for pelvic examinations and undergo tests for sexually transmitted diseases and uterine cancer. In the United States and Europe, in contrast, an annual or bi-annual clinic visit is standard for pill users. However, beginning as far back as 2007, many Japanese
OBGYNs have required only a yearly visit for pill users, with multiple checks a year recommended only for those who are older or at increased risk of side effects. As of 2004, condoms accounted for 80% of birth control use in Japan, and this may explain Japan's comparatively low rates of AIDS. ==Society and culture==