History of oral contraception

Abstract

On the 50th birthday of the pill, it is appropriate to recall the milestones which have led to its development and evolution during the last five decades. The main contraceptive effect of the pill being inhibition of ovulation, it may be called a small miracle that this drug was developed long before the complex regulation of ovulation and the menstrual cycle was elucidated. Another stumbling block on its way was the hostile climate with regard to contraception that prevailed at the time. Animal experiments on the effect of sex steroids on ovulation, and the synthesis of sex steroids and orally active analogues were the necessary preliminaries. We owe the development of oral contraceptives to a handful of persons: two determined feminists, Margaret Sanger and Katherine McCormick; a biologist, Gregory Pincus; and a gynaecologist, John Rock. Soon after the introduction of the first pills, some nasty and life-threatening side effects emerged, which were due to the high doses of sex steroids. This led to the development of new preparations with reduced oestrogen content, progestins with more specific action, and alternative administration routes. Almost every decade we have witnessed a breakthrough in oral contraception. Social and moral objections to birth control have gradually disappeared and, notwithstanding some pill scares, oral contraceptives are now one of the most used methods of contraception. Finally, all's well that ends well: recent reports have substantiated the multiple noncontraceptive health benefits paving the way for a bright future for this 50-year-old product.

Key words:

• Oral contraceptives
• The pill
• History

Introduction

This year we celebrate the 50th anniversary of the first oral contraceptive (OC), now universally known as ‘The Pill’. The birth of the pill was the result of a combination of:

• biochemical advances in the production of sex steroids and their synthetic analogues;

• studies on the effect of sex steroids on ovulation and, paradoxically, the search for fertility enhancing drugs;

• the unremitting pressure of Margaret Sanger, a feminist and pioneer in the field of family planning, and the financial support of her friend Mrs Katherine McCormick;

• and also, as with so many inventions, pure serendipity.

The name, however, that remains associated with the development of oral contraceptives is that of Gregory Pincus, who started as an agricultural scientist but later moved to the field of reproductive and hormonal biology¹. Since then we have witnessed stepwise changes in dosage and composition of the pill to end in 2010 with an array of safe and efficacious brands of oral contraceptives. This evolution was not without minor and major upheavals, controversies and several waves of pill scares which we will address in this article.

The Pioneers^1–4

It had already been known for several decades that sex hormones were able to suppress ovulation in animals. Ludwig Haberlandt, an Austrian physiologist is sometimes called the grandfather of the pill. Indeed, in 1921 he found that rabbits and guinea pigs became temporarily sterile after transplantation of ovaries from pregnant animals. These experiments paved the way for pharmacological studies on the effect of progesterone on ovulation. The anti-ovulatory effect of progesterone was demonstrated by A. W. Makepeace and co-workers in 1937 who injected progesterone in mated female rabbits. Large-scale experiments with progesterone, which hitherto had been extracted from animal ovaries became possible after Russell E. Marker, a professor of organic chemistry, found that progesterone could be manufactured from a substance named diosgenin, extracted from the root of a plant (Dioscorea mexicana) which grows in Mexican jungles.

Pincus made his name in the field of experimental biology when, in 1934, he produced rabbits in vitro by parthenogenesis. In 1944, he established the Worcester Foundation for Experimental Biology where he surrounded himself with a group of brilliant young investigators. One of them was a Chinese immigrant, Min-Chueh Chang, who repeated and refined the experiments of Makepeace and established the experimental model to study the anti-ovulatory effect of sex steroids. The impetus for converting findings of animal experiments into human hormonal contraception was given by Margaret Sanger, founder of the Planned Parenthood Federation of America (PPFA). She approached Pincus in 1951 and provided a small grant to begin hormonal contraceptive research. In the same period, John Rock, an expert in the treatment of infertility, was experimenting with the oral administration of high doses of oestrogen (diethylstilboestrol) and progesterone to induce pseudo-pregnancy in infertile women. He reasoned that high doses of sex steroids promoted the growth of the uterus and the Fallopian tubes and so restored fertility; but he also found that this treatment suppressed ovulation. The biologist Pincus and the gynaecologist Rock shared their experience and their intention to develop a hormonal oral contraceptive. Progesterone, however, is barely absorbed when given orally. What was needed was an orally active, chemical compound with strong progestogenic activity. The first progestin which was highly active when given orally, norethindrone, was synthesised by the chemist Carl Djerassi, working at the Syntex company. One year later, Frank Colton working with the Searle Company developed norethynodrel, a close isomer of norethindrone. With these two compounds, Rock continued his experiments to induce pseudo-pregnancy in infertile patients and could prove that ovulation was effectively suppressed in all women and that no breakthrough bleeding occurred with a daily dose of 10 mg of norethynodrel. This set the stage for the first contraceptive trials in woman using norethynodrel as the only compound of the pill. Using a more purified version of norethynodrel, however, more breakthrough bleeding occurred than with the original compound. It was subsequently discovered that the original compound was contaminated with mestranol, a synthetic oestrogen. This remarkable observation led to the addition of mestranol, a synthetic oestrogen, to the purified norethynodrel which led to the birth of the first contraceptive pill, Enovid®, containing 10 mg of norethynodrel and 150 μg of mestranol.

Clinical trials with a contraceptive could not be done in the United States because dispensing contraception was still a criminal offence at that time. The initial trials therefore were carried out in Puerto Rico. In 1957, the Food and Drug Administration (FDA) approved the use of Enovid® 10 mg for the treatment of menstrual disorders and extended that product's approved indications to include contraception in 1960. The Searle Company, however, did not market Enovid® 10 mg as a contraceptive pill because the lower dosed Enovid containing either 5 mg or 2.5 mg of norethynodrel, which in trials had proved to be equally effective, were initially not approved by the FDA.

The First Pills⁵,⁶

It was only in 1961 that Searle obtained the approval for the first contraceptive pill, Enovid®, containing 5 mg norethynodrel and 75 μg mestranol. It took another ten years before unmarried women were authorised to access OCs in the United States!

In the early sixties, clinical trials with another oral contraceptive containing 4 mg norethisterone and 50 μg ethinylestradiol were initiated by the Schering Company, Berlin, Germany and were conducted mainly in the United Kingdom and in Belgium. This formula was brought on the market under the name of Anovlar®. One year later the Organon company, in the Netherlands, followed suit with another brand, Lyndiol®, whose tablets contained 2.5 mg lynestrenol, a 3-desoxo-derivate of norethisterone, and 75 μg mestranol.

Other researchers focused on the effect of oestrogens on ovulation. Although the mechanism was not fully understood at the time, it was clear that oestrogens alone also were effective in suppressing ovulation. This led Joseph Goldzieher, working at the Syntex Company, to develop a sequential pill whose scheme consisted in the administration of an oestrogen alone during two weeks, followed by that of a combination of that same oestrogen and a progestin for another six days.

Ethinylestradiol had been synthesised as far back as in 1938, by Hans Herloff Inhoffen and Walter Hohlweg at Schering. The natural oestradiol is poorly absorbed when taken orally and is also quickly inactivated by the liver. Substitution at C17 with an ethinyl group results in ethinylestradiol, which is much more resistant to degradation. The latter oestrogen has subsequently replaced mestranol, a 3-methylether which is a prodrug of ethinylestradiol, as the oestrogenic component of all other contraceptive pills. Pills containing a natural oestrogen have only recently been successfully developed.

The Role of Oestrogen and Progestins

The initial observation that the addition of oestrogen reduced breakthrough bleeding was at the basis of the composition of all later pills, namely, a combination of an oestrogen and a progestin. Beside their proliferative effect on the endometrium, oestrogens have an anti-ovulatory effect of their own. They suppress the rise of FSH and, as a result, follicular growth. Progestins, on the other hand, add to the contraceptive effect by suppressing the ovulatory LH surge. They also thicken the cervical mucus, thereby hindering sperm migration into the upper genital tract, and they have an antiproliferative effect on the endometrium, making it less receptive for implantation. Both sex steroids have dose-related side effects. Progestins do not exclusively bind to the progesterone receptor but can also to a certain degree activate other steroid receptors. Oestrogens promote the synthesis of several hepatic proteins and have a well established prothrombotic effect.

Evolution of Oral Contraceptives⁷ , ⁸

There is a vast difference between the original pill and the current forms of hormonal contraception. This evolution was characterised by the reduction of hormonal dosages, introduction of new progestins, elaboration of various oestrogen-progestin administration schemes and the development of alternative routes of administration. It was driven by the search for oral contraceptives causing less side effects, but also by competition between pharmaceutical companies, and was facilitated by advances in the knowledge of hormonal mechanisms and the monitoring of the endocrine and metabolic effects OCs elicit.

Oestrogen dose reduction

The first alarm concerning an increased risk for thromboembolism related to the dose of oestrogen in oral contraceptives was raised less than ten years after their advent. Epidemiological studies by the Medical Research Council, in the UK, revealed that pill users were more susceptible than nonusers to thromboembolism⁹. On second thoughts, this complication could be anticipated because of the established link between high oestrogen levels and thromboembolism during pregnancy. Later, it was shown that oestrogens and ethinylestradiol in particular stimulate the synthesis of several clotting factors and hepatic proteins among which the renin substrate angiotensinogen, responsible for pill-induced hypertension in susceptible women. This first pill scare led to the gradual reduction in the dosage of ethinylestradiol from 50 to 30, 20 and even 15 μg. This dose reduction was associated with less side effects such as breast tenderness, nausea and bloating. But, even at these low doses, oral contraceptives still exert a prothrombotic effect.

Different administration schemes

Although the original sequential pill is no longer available, it paved the way for the development of various and changing combinations of oestrogens and progestins aimed at mimicking better the hormonal changes of the menstrual cycle and hence reducing the incidence of breakthrough bleeding. Goldzieher's sequential pill was followed by the marketing of so-called biphasic and triphasic OCs. These administration schemes allowed the lowering of the total dose of progestins ingested per cycle but, with the advent of low dose combined monophasic pills, this advantage does not hold any longer. That biphasic and triphasic pills better mimic the natural cycle was a purely commercial argument because the progestin effect on the endometrium, even in low doses, is dominant. This does not mean that phasic pills are superfluous; they widen the choice of available OCs among which the individual woman may choose that one which is most appropriate for her.

Second generation progestins and progestin dose reduction

A first reduction in progestin dosage was made possible by the development of levonorgestrel (LNG), a so-called second generation progestin. Oral contraceptives containing doses of LNG from 250 μg to 100 μg in later years, combined with 50, 30 or 20 μg ethinylestradiol were marketed at the end of the 1960s and are still nowadays the pills most frequently used. Due to the dose reduction of oestrogens and progestins, extension of the pill intake to 24 days became necessary to ensure sufficient suppression of follicular development.

Extended and continuous regimens of pill intake

The imitation of a 28-day menstrual cycle achieved by giving the pill for 21 days followed by a pill-free interval of 7 days was based on the popular belief that menstruation every 28 days is a sign of a normal reproductive female function. Moreover, Pincus had been told by Searle that they would not participate in any experiments that would alter the pattern of the menstrual cycle. In fact, Enovid 10 mg was approved by the Food and Drug Administration already in 1957 but only for the treatment of menstrual disorders. Only three years later would it also be approved for contraceptive use. Regulation of the menstrual cycle by the pill is of course purely symptomatic and it suppresses the physiological function and meaning of menstruation. Only in the last ten years has this been acknowledged leading to the promotion of extended regimens. Bi- and three-cycling (i.e., taking the combined monophasic OC uninterruptedly during 42 or 63 days, respectively, before allowing withdrawal bleeding to take place) were initially advised to women with perimenstrual distress but currently, some women are taking their pill in a continuous fashion for up to one year at a stretch¹⁰ , ¹¹.

Third generation progestins and the second wave of pill scare

In the search for progestins with minimal androgenic and metabolic effects, two new progestins, gestodene and desogestrel, were derived from LNG. They belong to a group called ‘third generation progestins’. Both progestins were combined with either 30 or 20 μg ethinylestradiol in pills that were trumpeted as being first choice and actually were on their way to displace second generation OCs from the top. But in 1995–1996 three papers, which were almost simultaneously published in The Lancet, revealed that the relative risk of venous thromboembolism associated with the use of third-generation pills was twice as important as that of second-generation pills^12–14. These results were extensively and without any critical comment spread by the mass media leading to the second wave of pill scare. Many women discontinued their hormonal contraception with increased rates of unplanned pregnancies and abortions as a result. Subsequent analyses, have mitigated but not totally disproved these epidemiological findings but the debate on the precise effects of different hormonal contraceptives on the haemostatic system is still going on^15–17.

Alternative routes of administration

Parenteral administration of sex steroids, mainly oestrogen, has a long tradition in hormone replacement therapy. The alleged advantage of this route is the avoidance of the first pass effect on the liver. Ten years ago clinical trials with a vaginal ring containing etonogestrel and ethinylestradiol, and a transdermal patch containing norelgestromin (an active metabolite of norgestimate) and ethinylestradiol, were completed and both systems were brought onto the market almost simultaneously, in 2001. Contraceptive efficacy and side effects are comparable with those of the combined pill. There is no evidence that these new modalities of administration of sex steroids are in any way superior to OCs but they extend the choice women have among safe and efficacious means of hormonal contraception.

New progestins¹⁸ , ¹⁹

Several new progestins have emerged over the last ten years three of which have been incorporated in novel pill formulas. Dienogest is a 19-nor testosterone derivative devoid of androgenic, oestrogenic or mineralocorticoid properties, and with a rather strong anti-androgenic activity. Drospirenone is a spironolactone analogue with anti-mineralocorticoid and moderate anti-androgenic effects. Its anti-aldosteronic effect is claimed to make it specifically indicated for oral contraception in women who complain of fluid retention and weight gain when taking classical pills. Nomegestrol acetate is a 19-norprogesterone derivative which binds almost exclusively to the progesterone receptor and therefore is referred to as a pure progestational compound.

Natural oestradiol

Several attempts were made to replace ethinylestradiol with the natural oestrogen oestradiol, but these attempts were abandoned because of problems with cycle control and contraceptive efficacy. These problems were overcome by the establishment of a four-phasic combination of oestradiol valerate, which is cleaved to oestradiol, and dienogest as the progestin in an extended cycle of 26/28 days. A second OC containing 17β-oestradiol and nomegestrol acetate, administered according to a 24/4 regimen, is about to be launched in the near future²⁰. Whether the inclusion of a natural oestrogen instead of the synthetic ethinylestradiol will offer additional advantages compared to the classical pill remains to be evaluated in the coming years.

Noncontraceptive benefits and therapeutic use of the pill

The health benefits of OCs are numerous and outweigh the risks of their use. Definitive evidence exists regarding the protective effect of combined OCs against ovarian and endometrial cancers and, to a lesser extent, colon cancer. The pill also reduces the incidence of benign breast disease, functional ovarian cysts, pelvic inflammatory disease requiring hospitalisation, ectopic pregnancy, and iron-deficiency anaemia. Whether solely with a view to treat these symptoms or in conjunction with contraception, the pill can also be prescribed for the treatment of several gynaecological disorders such as dysmenorrhoea, irregular or excessive bleeding, acne, hirsutism, and endometriosis-associated pain. These health benefits cannot be overestimated because most people are unaware of them and they get too little attention from the mass media.

Concerns About The Pill

Moral and religious concerns

Fifty years ago, contraception was still taboo in many countries and promoting it, let alone providing contraception, was liable to punishment by law. Only after ten years of existence could the pill be obtained in most countries, except for Japan where it was approved for use as late as in 1999. Initially, there was fear that access to OCs would promote promiscuity and premarital sex. The advent of the pill was concomitant with the sexual revolution of the 1960s and played a facilitating role, but it did not spark this movement. The fiercest resistance to the pill and in fact to all effective forms of contraception came from the Catholic Church and it persists to this very day as a result of the age-old but still adhered to Augustinian doctrine that sex should only be allowed as a means of reproduction.

Safety concerns

From the early days of the pill on, concerns have been expressed about the cardiovascular and cancer risks and each publication on the alleged risk was greatly overstated by the mass media, in accordance with their credo that ‘good news is no news, and bad news sells well’. In reality, however, use of combined OCs significantly reduces the incidence of ovarian and endometrial cancer and to a lesser extent that of colon cancer, contributing to the overall better life expectancy of pill users²¹. There is no doubt that oestrogens augment the risk of thromboembolism 2- to 4-fold. Although epidemiological studies indicate that the thrombogenic effect of oestrogens is modulated by the type of associated progestin, it is still debated whether a first-user effect and/or preferential prescribing are also involved^15–17. Be that as it may, fatal thromboembolism among young women is extremely rare and this increased risk should be balanced against the 5- to 10-fold increased risk associated with normal pregnancy. Taking also into account the numerous noncontraceptive benefits, the balance of overall wellbeing is clearly in favour of the pill.

Efficacy concerns

There is a great gap between the theoretical efficacy (method effectiveness) of the pill which approaches 100% and the clinical efficacy (typical use effectiveness) which depends on patients' compliance. The typical use effectiveness during the first year ranges from 2 to 8% depending on the population being studied while the perfect use pregnancy rate is 0.3%²². Several factors account for the patient-related pill failures: skipping one or more pills, starting pill intake too late in the cycle, unfamiliarity with the precautions in case of unintended cessation of pill intake, or conscious non-compliance with instructions may all be responsible. Rarely, the contraceptive efficacy is impaired by intestinal malabsorption due to vomiting or diarrhoea or interactions with drugs that decrease the contraceptive oestrogen and/or progestin levels.

Conclusion

Reliable contraception is a major achievement of the last century and a boon particularly for women. It not only is instrumental in addressing the problem of overpopulation. It has brought millions of women relief from the fear of unwanted pregnancy and has made it possible to avoid innumerable deaths from illegal abortion and childbirth. Moreover, contraception gives women the opportunity to determine the time and the number of their pregnancies, allowing them to plan their study and professional career.

But there is more to sex than reproduction. Contraception has enabled one to experience pleasure and to develop bonding through sex. The development and refinement of oral contraception was the most spectacular among all forms of birth control; it paved the way for the development and adoption of alternative contraceptive modalities. The acceptability of the pill is illustrated by the fact that well over 100 million women worldwide are using it; it is the most common form of contraception women in Western countries resort to. Numerous changes in the composition of the pill were progressively introduced to reduce side effects without compromising efficacy. The latest of these is the incorporation of oestradiol in place of a synthetic oestrogen. But not all side effects have been eliminated and morbidity and mortality, although extremely low, have yet to be reduced to nought. Hence, there is still room for improvement.

Declaration of interest: The author declares no conflict of interest. The author alone is responsible for the content and the writing of the paper.