Birth Control

"In Britain, government control over the manufacture and supply of pharmaceutical drugs had been tightened in 1947 and 1957. Such restrictions, however, primarily concerned dangerous drugs and self-medication drugs, as well as biological products (e.g., antibiotics, vaccines, and insulin, all of which had to best and ardized by biological techniques). Products had to be scrutinized to insure that their manufacturing methods and potency testing met the stipulated requirements. Drugs subject to these restrictions were only a small minority in the pharmacopoeia. All other drugs could be released onto the British market without submitting to any formal procedure. In general, the British government took a laissez-faire approach toward pharmaceutical companies in the1950s. The only restriction imposed on drugs in this period was that they could not be advertised as curing cancer, venereal disease, or Bright’s disease. Britain and the United States thus had very limited testing requirements when the first pill was initially approved, and Enovid underwent governmental premarket review only in the United States. The 1938 Food, Drug and Cosmetic Act specified that a drug is not defined by its ability or lack of ability to treat a disease, but rather as any product “affecting the structure or function of the body.” This language had been incorporated into the 1938 law for the explicit purpose of giving the FDA jurisdiction over products such as obesity drugs (obesity was not considered a disease), nose straighteners, and especially contraceptive devices such as pessaries and condoms, which, like oral contraceptives, had both therapeutic and contraceptive applications. Therefore, by definition, Enovid was a product that clearly fell under the jurisdiction of the FDA."

"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."

"In January 1970 experts assembled in the stately Senate chamber and began giving their testimony on the hazards of the Pill. Alice Wolfson, a member of the radical collective D.C. Women's Liberation, was sitting in the audience listening to the experts. Her group had come to the hearings because they had all taken the Pill at one time or another and had experienced side effects. The group was outraged that their doctors had never informed them of the risks when they prescribed the Pill. As they sat in the chamber and heard one male witness after another describe serious health risks, they were furious that there wasn't a single woman who had taken the Pill there to testify. After hearing one expert say, "Estrogen is to cancer what fertilizer is to wheat," the women spectators could no longer contain their anger. They stood up and started hurling questions at the men on the dais. The feminists set the room abuzz when they demanded, "Why are you using women as guinea pigs?" and "Why are you letting the drug companies murder us for their profit and convenience?" When told by Senator Nelson to sit down and remain quiet, they retorted, "We are not going to sit quietly! We don't think the hearings are more important than our lives!" Although Senator Nelson was the driving force behind the hearings, the young protesters were so angered by his failure to include women in the hearings -- and by what they viewed as his patronizing behavior --that they went on the attack. The group decided to protest the structure of the hearings and the men leading them, in addition to speaking out about the medical dangers of the Pill. The feminists' grievances gained national attention. National television networks covered the proceedings, and Wolfson's group appeared frequently on the nightly news during the hearings. An estimated eighty-seven percent of women between the ages of twenty-one and forty-five fol-lowed the hearings. Eighteen percent of them quit taking the oral contraceptive as a result of the hearings. In the hearings' aftermath, hormone levels in the Pill were lowered to a fraction of the original doses. A few years after the hearings, prescription rates rebounded, and the number of users in the United States peaked at approximately nineteen million. The real impact of the hearings was not on Pill usage, but on the nascent consumer health movement. D.C. Women's Liberation succeeded for the first time in making informed consent a national issue. In the aftermath of the hearings, the U.S. government would require the pharmaceutical industry to include a patient information sheet with complete information on side effects in every package of birth control pills sold. The growing women's movement was prompting women to assert control over their bodies, and in doing so it changed forever the way Americans take prescription medications."

"With the arrival of the birth control pill in 1960, many believed the Church was about to change the position it had held for centuries. The Church was in the midst of reform, and in this climate of modernization it seemed possible that the Vatican might bend on birth control. Since 1957, Church law had allowed women with "irregular" cycles to take the Pill to regularize their cycle and enable them to better practice the rhythm method. Approval of the contraceptive pill, many believed, was soon to follow. Pro-Pill Catholics had a powerful ally on their side. John Rock, the eminent Catholic physician who had carried out Pill trials with Dr. Gregory Pincus, publicly argued that the Pill was merely an extension of the body's normal functioning. Since the Pill used the same hormones already present in the female reproductive system and did not tamper with sperm, Rock believed the Church should view the Pill as a "natural" form of contraception. The Vatican convened a commission to study the question of the Pill, but the Church would take eight years to determine its policy towards the Pill. In the interim, the Pill quickly became the most popular method of birth control among American women —regardless of religion."

"I invented the pill at the request of a woman."

"Historically, contraception was believed to affect the voice negatively. However, more recent studies using low-dose oral contraceptive pills (OCPs) show that they stabilize the voice. However, stabilization generally occurs only during sustained vowel production; connected speech appears unaffected. Therefore, singers may be the only population that experiences clinically increased vocal stability as a result of taking hormonal contraceptives."

"The history of the development of oral contraceptives (OCs) has been a progressive reduction in dosage to what is now probably the lowest does that is compatible with the desired therapeutic effect -- to inhibit ovluation. Yet, controversy and argument continue."

"There is not the slightest doubt that a woman who is over 35, who smokes, and who, in addition, may be obese and has hypertension should not use OCs. Progestogen (mini) OCs have a slightly higher failure rate and a greater incidence of irregular bleeding than have combined OCs. The mini OC has little place in women who need effective hormonal contraception and good cycle control. The mini OC may have a place in a patient who finds other contraception unacceptable and in whom estrogens are contraindicated specifically."

"McCormick's involvement with the Pill is extraordinary. I think she's one of the most underappreciated figures in not just Pill history, but the entire history of scientific and technological innovation. First of all, it was very uncommon for a woman in the 1950s to have the kind of fortune that McCormick had. She had a fortune that was so vast that, as John Rock said at one point, she couldn't even spend the interest on the money that she had. So she was unique from the get-go in simply having this access to capital... At the time, the pharmaceutical companies which had historically been involved in some kinds of birth control production, like condom production and diaphragm production, saw the Pill project also as too controversial. Many large companies had passed on the opportunity to develop the Pill, including Pfizer and Merck, because they just didn't want to touch it. And so, were it not for McCormick, it's unclear how the Pill would have been developed. She really deserves credit for single-handedly financing one of the most important developments of the 20th century."

"Introduction of the birth control pill in the United States in 1960 marked the end of a relatively short period of time (< 10 years) to intentionally produce an oral contraceptive, and the beginning of a relatively long period of controversy surrounding the use of the pill. Availability of the pill had an impact on various aspects of social life, including women's health, fertility trends, laws and policies, religion, interpersonal relationships and family roles, feminist issues, and gender relations, as well as sexual practices among both adults and adolescents. The pill proved to be highly effective from the outset. Although safety issues developed with the earlier formulations, continued evolution of pill hormones and doses has resulted in a greatly improved and safe oral contraceptive. A broad range of noncontraceptive health benefits also is associated with the pill. These health effects are significant, as they in-clude protection against potentially fatal diseases, including ovarian and endometrial cancers, as well as against other conditions that are associated with substantial morbidity and potential hospitalization and associated costs. The popularity of the pill has remained high, with rates of use in the past 30 years in the United States ranging from one-quarter to almost one-third of women using contraception. Almost 40 years after its introduction, the pill's contraceptive efficacy is proven, its improved safety has been established, and the focus has shifted from supposed health risks to documented and real health bene-fits."

"Progestin-only contraceptives are known to alter the cervical mucus, exert a progestinal effect on the endometrium, interfering with implantation, and, in some patients, suppress ovulation."

"Oral contraceptives (OC) convey a protection against ovarian, endometrial and perhaps colorectal cancer. However, OC use is associated with excess risk of breast (current or recent use only), cervical and liver cancer. Benefits and risks of OC use on cancer were reviewed in 2005 by a Working Group at the International Agency for Research on Cancer, which concluded that combined OCs are carcinogenic to humans, based on an increased risk for hepatocellular carcinoma, cervical and (for current use only) breast cancers. The Working Group also concluded that there is conclusive evidence that OCs have a protective effect against cancers of the ovary and endometrium."

"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."

"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, re-sponsible 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."

"ON June the United States celebrated the fortieth anniversary of the approval of Enovid, the first oral contraceptive. From the time of the first clinical trials to the present, nearly million women have swallowed various formulations of the contraceptive pill, making it one of the most widely consumed class of drugs in the world. By the end of the twentieth century oral contraceptives had become a feature of everyday life, with more than 70 million women reaching for their pill packet on a daily basis around the globe. Widely regarded as a revolutionary drug in its early years, the pill might retrospectively be considered the first “designer” or “lifestyle” drug of the twentieth century."

"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."

"Developed in the1950s, the pill was once optimistically hailed as a scientific cure for the world’s rising population and its consequent social and political ills. Historians, however, have begun to show that the oral contraceptive did not prove to be the social panacea envisioned by its inventors, and that its history is more complex. Much of its history cannot be disentangled from the wider political, economic, and social issues of the day .Watkins, for instance, has shown that the availability of the pill in the United States had a major impact on the relationship between doctors and female patients in the1960s. Similarly, Critchlow has illustrated how the contraceptive controversy in American politics started with the appearance of the pill and continued with the debates surrounding RU-486, the abortion pill. More recently, Marks has challenged previous histories, which have championed the pill as a North American product that fuelled the sexual revolution, suggesting that its roots and subsequent adoption were much more diverse in origin and can only be understood within a wider international framework."

"Adding to the growing knowledge about the pill and its wide spread influence on twentieth-century history, we offer a detailed cross-cultural (or at least transatlantic) history of the actual processes by which the first pill formulation, Enovid (U.S.) and Enavid (U.K.) came onto the market. Such a detailed account of the marketing of the pill emphasizes that the birth control pill was introduced in various stages, rather than simply approved at a single point in time. The drug was first marketed in 1957 for treating gynecological disorders. Only in 1960 was it allowed to carry a contraceptive claim, and only after 1961 did reports begin to appear that the drug could cause serious, albeit rare, thrombotic complications (blood clots). Between the time that Enovid was approved as a menstrual regulator and then as a contraceptive, attitudes regarding the perception of safety changed greatly, as did the evaluations carried out to assess risk and efficacy."

"By 1967, British scientists had conclusively linked the pill with thrombosis, but they did so relying largely on epidemiological data. This increasing reliance on statistical evidence supported and advanced a more analytical and less communally determined drug approval process. This change in the risk-benefit equation calculations of a new drug, of course, may have been inevitable and had been initiated with an earlier drug, chloramphenicol, but it was the stature and novelty of Enovid that propelled it forward so dramatically. In the United States, concerns about the safety of the pill before 1967 led to the creation of the Food and Drug Administrations ”first permanent advisory committee, further changing the nature of the drug approval process and initiating what Jasanoff would later call the “fifth branch” of government in the United States."

"Much of the criticism of the pill, however, as Watkins has shown, arose from the fact that the pill altered the relationship between women and their physicians. In retrospect, it is clear that women’s rejection of medical paternalism underlay much of the social criticism leveled at the pill. We believe that the unique decision-making processes that introduced oral contraceptives and allowed them to remain on the market even after potentially dangerous side effects were discovered are an important and instructive example of the intermingling of science, policy, and practicability in the approval process for a revolutionary twentieth-century drug."

"Once marketed in the United States and Britain, Enovid/Enavid was freely available to women whose doctors would prescribe it, either as a treatment for infertility or for menstrual disorders. Medical doctors in both countries could then, as they can now, prescribe drugs for purposes other than those approved because neither country has ever sought to regulate the practice of medicine. The fact that so many women may (or may not) have had access to Enocid/Enavid years before it was formally approved by FDA as a contraceptive makes any discussion about the approval of the pill which centers upon numbers very difficult. The most commonly cited figure is that by 1959 more than 500,000 women were taking the drug for menstrual disorders in the United States."

"By the end of the fourth quarter of 1964, more than 4 million women had used Searle’s pill. Such unexpected and unprecedented popularity not only surprised the pharmaceutical industry, but amazed physicians, family planners, social reformers and politicians as well. The early enthusiasm for oral contraceptives, however, was soon dampened as the high hormonal doses of the first pill produced nausea, headaches, and dizziness so severe that some women abandoned the pill as quickly as they had embraced it."

"As Watkins has discussed, the Nelson hearings infuriated many women. During the 1960s many feminists had begun to protest against the paternalistic attitudes of the state and male-dominated medicine. After the hearings, women were critical of the process, which excluded testimony from female patients, and angry about the analogies to women as guinea pigs. Many responded by parading in front of the hearings carrying placards demanding “Feed the Pill to your guinea pigs at the FDA not live women.” After the hearings, women’s groups, particularly the Washington D.C.-based Women’s Liberation group, called for new separate hearings centered around women’s concerns, angrily arguing that, “In spite of the fact that it is women who are taking the pill and taking the risks, it was the legislators, the doctors, and the drug company’s representatives, all men of course, who were testifying and dissecting women as if they were no more important than the laboratory animals they work with every day.” In this charged atmosphere, there is no doubt that what feminists took away from the writings of journalists and the Nelson hearing proceedings was that women had indeed served as guinea pigs as drug companies prospered, and that, even ten years later, physicians were still not sure if the pill was safe."

"By the 1970s, however, there had been a sea tide of change in the evaluation of the safety of oral contraceptives since 1960. In 1962, before the British researchers established the statistical link with thrombosis, many physicians felt that the whole question of the pill’s side effects had been magnified, not by the actual danger, but by the concerns over thalidomide. No one disputed, however, that there was a need for more research to substantiate the concerns. By the time of the Nelson hearings, several large-scale studies of the pill and of thrombotic phenomena had been designed, and others were underway. The American Cancer Society, to cite a single example, initiated a seven-year study comparing 5000 pill users with 5000 nonusers. Experience with such large studies and interpretation of their results, as well as the new drug evaluation methods mandated by laws and regulations enacted in the wake of the thalidomide disaster, strengthened the entire new drug approval system worldwide."

"On June 23, 1960, a decade after the tests began, the hormonal birth control pill hit the market. The idea was simple: Take a little white pill once a day, avoid accidental pregnancy. The implications were revolutionary. Women could work without fear of becoming pregnant. Sex before marriage be-came less risky. Sex after marriage became less fraught. Feminist historians herald this day as the be-ginning of the sexual revolution—but the story of the birth control pill is also one of conflicting ideologies and medical exploitation. The Harvard-educated scientists who formulated the pill relied on invasive tests and shaky medical consent."

"After her husband died on January 19, 1947, Katharine D. McCormick came into $35 million. A life-long feminist and birth control advocate, she spent the money on what Margaret Sanger, famous feminist and Planned Parenthood founder, explained to her as “the greatest need of the whole [Planned Parenthood] movement”—“a simple, cheap, contraceptive.” Feminists had dreamed of a birth control pill a woman could take without a man’s knowledge, and Rock and Pincus were their best chance yet."

"[M]edical history is often swept clean, praising progress without remembering those who suffered to create it. For the most part, the popular narrative of the pill is one of celebration. When a 2009 Harvard Gazette story discussed Harvard’s role in creating the birth control pill, they did so without referencing the Puerto Rican trials or the asylum testing. Pincus and Rock are largely remembered for their contributions to women’s reproductive empowerment, without reference to their troubling methods."

"By the beginning of the 20th-century, the idea of oral contraception in conventional medicine had died. It was not to be revived until the century was half over. The woman who made it happen was Margaret Sanger (Riddle, 1992)."

"G.D. Searle and Company made the first American application for the approval of Enovid to the FDA in 1957.The company sought approval for the use of Enovid in cases of menstrual irregularities, including amenorrhea, dysmenorrhea, and menorrhagia, as well as endometriosis (a painful proliferation of uterine tissue outside the uterus) and infertility. Incases of infertility, it had been shown that women who were given the drug for several months-to “rest” their ovaries-often went on to conceive, a phenomenon often referred to as the “Rock Rebound” effect. Although the original submission addressed only gynecological disorders, it was well known among many scientists that this particular formulation could prevent ovulation and therefore could be used as a contraceptive. Publications worldwide had reported Pincus’s work and has speculated on the pills clinical prospects."

"It is known that pills which contain only progestin alter the cervical mucus. They also interfere with implantation by affecting the endometrium and suppressing ovulation in some patients by reducing the presence of follicle-stimulating hormone (FSH). This mechanism is confirmed by the United States Food and Drug Administration (FDA), which stated that "Progestin-only contraceptives are known to alter the cervical mucus, exert a progestinal effect on the endometrium, interfering with implantation, and, in some patients, suppress ovulation." The manufacturers of the minipills also acknowledge this mode of action. For example, Syntex Laboratory spokesman Russ Wilks announced that its progestin-only Pill "... did not interfere with ovulation ... It seems to affect the endometrium so that a fertilized egg cannot be implanted.""

"The most dangerous and well-documented side effects commonly associated with the Pill are heart attacks and strokes. The eight-year Nurse's Health Study at Harvard Medical School found that Pill users are 250 percent as likely to have heart attacks and strokes than those who don't use the Pill, probably because the Pill excessively increases blood clotting ability."

"[I]t is obvious that the Pill has contributed greatly to our country's exploding divorce rate, which was about 18 percent in 1965 and now stands at about 50 percent."

"G.D. Searle and Company was only able to patent the specific steroids developed in its laboratories, not the term “The Pill” or the concept of using steroids as contraceptives. And Searle never would have supplied Pincus with the experimental drugs he needed if in doing so they had risked their right to exclusive control over compounds they developed. Nevertheless, Pincus only encouraged McCormick to make all of her contributions directly to the foundation after G.D. Searle had begun supporting the pill project with both experimental drugs and specific research grant."

"McCormick apparently never understood that Searle had paid a large portion of Pincus’ salary for years. Rather, as McCormick explained to Abraham Stone, Pincus was “acquainted with some one [sic] in the Searl [sic] Company.” Exactly how he was able to convince them to provide free experimental drugs for the project on a large scale was never explained. In fact, Searle’s steroid chemists played an important role in the pill’s development. Although similar feats were being duplicated in a number of competing industrial laboratories, the large number of synthetic hormones that a they were producing gave Pincus an essential variety of compounds with a wide range of effects that he could try on animals, selecting for clinical trial only a few of the most promising out of the dozens that had some contraceptive effect. But McCormick has shielded from the commercial aspects of the project she was subsidizing. Nevertheless, her contribution was vital. She provided the funds that turned a desultory PPFA project into a crash program to develop an oral contraceptive. Pincus asked Searle for substantial help on the project only after he had suppressed ovulation in women with a progesterone regimen. By then he knew that he could develop an oral contraceptive. Searle’s cooperation simply hastened the process. When the first successful use of synthetic steroids as an oral contraceptive in women was announced in ‘’Science’’ in 1956, Sanger wrote McCormick: You must, indeed, feel a certain pride in your judgment. Gregory Pincus had been working for at least ten years on the progesterone of the reproductive process in animals. He had practically no money for this work and Dr. Stone and I did our best to get a few dollars for him and I think that the amount we collected went to pay the expenses of Chang [senior scientist, WFEB]. Then you came along with your fine interest and enthusiasm and with your faith and . . .things began to happen and at last the reports . . . are now out in the outstanding scientific magazine and the conspiracy of silence has been broken. Although “conspiracy of silence” may have been an exaggeration, throughout the late 1950s few scientists believed an oral contraceptive was at hand."

"Controversy has surrounded "the Pill" ever since it was first marketed in the United States in 1960. It has been studied medically, sociologically and morally, and yet much confusion still exists concerning these potent artificial steroids. The billions of dollars at stake in the marketing of the Pill and the power of the birth control industry to lobby both lawmakers and the media can easily divert the average person from the truth. Research has been published, books have been written, and common sense should make one cautious."

"The Pill manufacturers and many in organized medicine are mainly concerned about the Pill's medical side effects and its effectiveness in preventing pregnancies and are less concerned about how the drug achieves its effectiveness. Unfortunately, many "otherwise" pro-life physicians and pharmacists find it hard to admit that these abortifacient properties exist because they would have to discontinue prescribing and dispensing the Pill if they were to remain consistent in their respect for life at all its stages of development. Pro-abortion organizations and their lawyers readily admit the early abortion potential of the Pill. In February 1992, writing in opposition to a Louisiana law banning abortion, Ruth Colker, a Tulane Law School professor, wrote, "Because nearly all birth control devices, except the diaphragm and condom, operate between the time of conception...and implantation.., the statute would appear to ban most contraceptives." In 1989, attorney Frank Sussman argued before the U. S. Supreme Court that ". . . IUDs (and) low dose birth control pills. . . act as abortifacients.""

"When Searle notified the FDA in 1959 that it wished to submit a supplemental application for Enovid to expand the drug’s labeling indications to include use as an oral contraceptive, it rapidly became clear that the American federal government wanted little to do with the process and saw it as no more than routine bureaucratic process of new drug review and approval at the FDA. As Critchlow and Watkins have discussed in great detail, there mere mention of contraception as a credible component of overseas aid had drawn the opposition of American Catholic bishops. Moreover, with the 1960 presidential election looming, neither President Eisenhower nor the Catholic presidential candidate, John Kennedy, wanted to make an issue out of contraception and the pending approval of the contraceptive pill. In Britain, the central government also vigorously refused to initiate debate over the pill. The British Ministry of Health had stated as early as 1955 that it did not want any involvement with contraceptive testing and approval. Again, in 1956, when news emerged of the possible availability of a contraceptive pill in the United States, the Medical Research Council, the main British government body responsible for clinical trials since 1919, refused to sponsor any monitoring of the new drug on the grounds that it was too politically and morally sensitive an issue for them to handle."

"Searle had originally asked the FDA to consider simultaneously an application for three dosages of Enovid: 10, 5, and 2.5 milligrams. Searle was particularly interested in promoting the lower dosage forms of Enovid because one of the chief criticisms of the pill up to this point had not been a medical one, but rather an economic one. Partly developed in response to concerns about world hunger, it was feared that Enovid would prove far too expensive for woen in poorer countries. The cost of the hormone was directly proportionate to the cost of the drug and the dose. Lowering the dose significantly lowered the cost of Enovid. Searle, therefore, had great incentive to prove the safety and efficacy of its lower dosage pills. As far as Searle officials were concerned, the lower dose of Enovid should not have required a separate NDA because they considered it merely an alternative dose of the same drug. As one Searle representative wrote when seeking approval of the lower dosage: “[I find it] very difficult to understand how less of a drug can be more dangerous than a larger dose...a basic fact of any drug use is adjustment of the dosage to a particular individual’s requirement. That’s all we are trying to do with the lower dosage forms of Enovid....I find it impossible to understand how one increases danger by reducing the dose.” The FDA, however, viewed the dosage question as an issue of efficacy and possibly safety in 1959. The lower doses produced an increased incidence of breakthrough bleeding. It was not immediately clear whether this was an indication that ovulation had not been effectively suppressed. If so, it would have undermined Enovid’s effectiveness as a contraceptive, rendering it unapprovable. The FDA was therefore very cautious in considering any alteration in the original dose formulation of the pill."

"The original class of birth control pills contained a high dosage of both estrogen and progestin, which led to a variety of side effects, including blurred vision, nausea, cramping, irregular menstrual bleeding, headaches, and possibly breast cancer. Beginning in about 1975, the manufacturers of the Pill, in reaction to adverse publicity generated about the severe side effects caused by the high-dosage pills, steadily decreased the content of estrogen and progestin in their products."

"On October 29, 1959, the pharmaceutical company G.D. Searle filed an application with the U.S. Food and Drug Administration (FDA) to license their drug Enovid for use as an oral contraceptive. Less than a decade after birth control activist Margaret Sanger first told scientist Gregory Pincus about her hopes for a "magic pill," it appeared that success was imminent. The trials presented in the application for FDA approval of Enovid as an oral contraceptive were the largest drug trials ever run. In the trials, 897 women had taken 10,427 cycles of the Pill with no side effects the doctors considered harmful. In 1959 the main hurdle to FDA approval for any new drug was that it be proven safe. Effica-cy was not yet a requirement. Since the FDA had already reviewed the issue of safety when it approved Enovid's use for menstrual disorders in 1957, Searle assumed the application would glide through the process. Searle and the Pill researchers were soon disappointed. The FDA sat on the application, and months went by without any word. Safety wasn't the issue clogging up the review process. It was the revolutionary nature of the Pill itself. Oral contraceptives would be the first drugs whose purpose was not to cure a medical ailment. Instead, the Pill would be given to healthy women for long-term use for a social purpose, and the FDA was uncomfortable with the concept."

"In the early 1950s, Frank Colton and Carl Djerassi, two chemists working independently at separate pharmaceutical companies, took Marker's work one step farther. The scientists each created a highly potent oral form of synthetic progesterone. Working for Syntex, a pharmaceutical company based in Mexico, Djerassi invented norethindrone. This synthetic progesterone was not only orally effective, it was also eight times more potent than natural progesterone. At Searle, Colton created another version of orally effective synthetic progesterone called norethynodrel. With the advent of these new drugs, the Pill came into existence. Although neither Djerassi or Colton developed the drug for contraceptive purposes, both Searle and Syntex had an oral contraceptive right under their noses. Although Djerassi synthesized his version of the drug first, Searle beat Syntex to market. Less than a decade after Colton and Djerassi's breakthrough, with Gregory Pincus making the connection to contraception, Searle's Pill would reach American consumers."

"The use of contraceptives can be morally acceptable in other contexts as well, again, because such uses do not constitute acts of contraception. For example, when a woman has severe menstrual bleeding, or pain from ovarian cysts, the hormonal regimen contained in the Pill may sometimes provide a directly therapeutic medical treatment for the bleeding or the pain. This use of contraceptives is an act of medical therapy to address a pathological situation, not an act of contraception. The secondary effect from the treatment, namely, marital infertility, is only tolerated, and should not be willed, desired, or in-tended in any way by the couple. It is worth noting that it would not be acceptable to make use of contraceptives like the Pill for these medical cases if other pharmacological agents or treatments were available which would offer the same therapeutic benefits and effects without impeding fertility."

"When in 1953 Gregory Pincus approached Rock about collaborating on a study of the contraceptive effects of progesterone, Rock unhesitatingly signed on. The two scientists had known each other since the 1930s and closely followed each other’s work. Rock’s finding, in the course of his research on in-fertility treatments, that small amounts of female hormones inhibited ovulation, helped validate Pincus’s similar results in animal trials. Pincus needed someone with Rock’s clinical experience to ex-tend research trials to human subjects. And it helped in terms of fund-raising and public relations that Rock had an unimpeachable reputation as physician and medical researcher. Their cooperative work was made possible by an influx of funds from Katharine Dexter McCormick, whom Sanger had convinced to support Pincus’s promising research. Starting in the summer of 1953, McCormick began to immerse herself in the project and sent regular progress reports to Sanger mentioning Rock’s involvement. In November 1953 McCormick informed Sanger that Rock and Pincus had begun the first human trials in the study. But Sanger, who was preoccupied with setting up the International Planned Parenthood Federation (IPPF), did not appear to be aware of the extent of Rock’s participation. Nor did she feel completely comfortable with his involvement."

"Although American scientists had been busy studying hormones in the 1930s and 1940s, Marga-ret Sanger's dream of a pill for birth control improbably came to fruition because of the discovery of a wild Mexican yam. The yam was key to the development of synthetic hormones, a scientific advance necessary for the creation of the Pill."

"Oral contraception is now one of the most scrutinised medicinal products on the market. Two British investigations that celebrated their 40th anniversaries in 2008 have been major contributors to the evidence base for current clinical practice. Both illustrate the enormous research opportunity of NHS clinical records. The Oxford/Family Planning Association (Oxford/FPA) Study began in 1968, when 17 family planning clinics in England and Scotland started recruiting 17 000 white, married women using oral contraception, the IUD or the diaphragm.3 The Royal College of General Practitioners' (RCGP) Oral Contraception Study started at the same time, with 1400 GPs throughout the UK recruiting 47 000 mainly white, married (or living as married) women, half of whom were using oral contraception. Both studies have followed up their cohorts through a mixture of clinic or practice reports, personal contact, and the cancer and death notification services of the NHS Central Registries. Each study has provided, in different ways, key insights into the effects of different contraceptives; as well as novel information about other women's health issues. For example, the RCGP study was the first to show that the risk of cardiovascular disease is much higher in pill users who smoke,5 especially among older women, and that the risk of hypertension and arterial disease is related to the combined pill's progestogen content.6 The Oxford/FPA study assessed the effectiveness, safety, and return to fertility after stopping different methods. Long-term mortality and cancer results from both studies have been reassuring."

"By 1960 the world's population had grown to around 3 billion people, having taken just 33 years to increase from 2 billion.1 Although many agreed that growth rates needed to fall, couples at the time had few reversible contraceptive choices: mainly barrier methods, spermicides, and a few plastic-only and metal-based intrauterine devices (IUDs). Many relied on ‘withdrawal’. This was soon to change dramatically because during the 1950s scientists had patented two synthetic progestogens, norethisterone and norethynodrel.2 Clinical studies showed that these hormones inhibited ovulation, although some accompanying oestrogen (initially mestranol, now ethinylestradiol) was needed for acceptable breakthrough bleeding and pregnancy rates. The first combined oral contraceptive was marketed in the US in 1960, and in the UK the following year. Many women enthusiastically embraced ‘the pill’; for some because it separated contraception from the act of intercourse and for others because it could be used without their partner's knowledge. Early on, howev-er, concerns were expressed about the method's carcinogenic potential, and about reports of associated venous thromboembolic and other cardiovascular events.2 Furthermore, the unfolding thalidomide tragedy of the early 1960s provided a powerful reminder of the epidemiological truth that when millions of people use a medicinal product small increases in risk still result in many people affected."

"We now have a clearer picture of the cancer risks associated with combined oral contraception. Compared with non-users, current users have an increased risk of being diagnosed with breast,11 cervical,12 or hepatocellular cancer.13 Hepatocellular cancer is rare in developed countries. The breast and cervical cancer risks decline after stopping oral contraception, returning to that of non-users within about 10 years.11,12 Conversely, combined oral contraceptive users have a reduced risk of endometrial,13 ovarian,14 and colorectal cancer.13 The ovarian and endometrial benefits appear to persist for many years after stopping oral contraception, perhaps more than 15 years.13,14 Limited evidence suggests that today's lower oestrogen dose formulations provide similar protection against endometrial and ovarian cancer as older, higher-dose preparations.15,16 At least within the RCGP cohort, the long-term cancer benefits appear to counterbalance the short-term harmful ones; indeed there may even be a net public health gain.8 Collectively, the research shows that benefits of oral contraception use outweigh risks, when provided appropriately. Importantly, prolonged use of oral contraception does not appear to reduce future fertility.17"

"Ludwig Haberlandt is the 1st great name in hormonal contraception. As early as 1919 he was conducting studies which showed that transplants of tissues or extracts of these tissues (now known to contain progesterone) could produce infertility in rabbits and mice. In 1930 Reiprich of Breslau suggested that the antifertility action of estrogen might be the result of pituitary inhibition. In 1938 ethinyl estradiol was synthesized and 1 year later Dodds and his group reported the synthesis of a series of nonsteroidal estrogens (stilbestrol, hexestrol, and dienestrol). None of the clinical trials conducted in the 1940s could have demonstrated the superiority of 1 estrogen over another with respect to ovulation inhibition at equivalent estrogenic dosage. Studies of this aspect lagged until the 1960s. At that time it was clearly demonstrated that the ethinyl side-chain imparted an augmented pituitary inhibiting potency to estradiol as compared either to other natural estrogens or to other synthetics. It was a fortunate accident that the early clinical preparations of contraceptive progestins contained about 1% contamination with mestranol from the process of manufacture. While this quantity appeared trivial to the chemists, the presence of about 150 mcg of mestranol in the original 10 mg doses of the 19-norprogestins could have accounted totally for their contraceptive efficacy. It was not until several years later than estrogen-free norprogestins were prepared and their intrinsic antiovulatory action proven. When these purified progestins were used for contraceptive therapy, an increased incidence of menstrual irregularities appeared. One standardized quantity of ethinyl estrogen was reincorporated into contraceptive preparations for the control of menstrual regularity, but without any idea that a contribution was being made to contraceptive effectiveness. Clinical studies with continuous low-dose progestin only formulations have demonstrated that their effectiveness in inhibiting ovulation is substantially lower than that of sequential or combination type preparations. A progestational agent added to a baseline estrogen dose appears to produce a greater suppression of plasma gonadotropins than estrogen by itself. While cyclic estrogen administration is capable of inhibiting ovulation with a high degree of efficiency, such a therapeutic regimen is impractical from the point of view of menstrual regularity. The entire matter of cardiovascular hazards related to OC use has been called into question by studies of mortality statistics in the U.S., Great Britain, and Taiwan. In none of these studies is the predicted mortality from cardiovascular disease in OC users confirmed."

"Women excrete estrogen naturally, and women on birth control pills also secrete the synthetic estrogen in those pills. And these estrogens, depending on the level of wastewater treatment, may not be completely broken down during sewage treatment, so they get discharged into rivers and streams. It doesn't take a lot of estrogen to feminize male fish and, based on the results of our experiment, to impact fish populations."

"As more companies bought into the idea, the week of placebo pills was here to stay. Doctors liked that they made explaining the instructions to women easy. Women liked having one fewer thing to remember about their birth control. Few questioned why women on the pill should be having a “period” at all. Today there are a small handful of options that reduce or eliminate monthly bleeding: Seasonale, a form of the pill sold in packets of 84 active pills and seven placebos that make it so bleeding happens just four times a year, became available in 2003. In 2007, the F.D.A. approved Lybrel, the first oral contraceptive to provide continuous active pills, with no breaks for withdrawal bleeding. Doctors agree that a menstrual cycle can be a useful indicator of overall health, and yet it still isn’t necessary. When Dr. Lori Picco’s patients ask if they can skip the inactive pills, she says she tells them to go right ahead. “It’s completely fine — there’s no medical concerns,” says Dr. Picco, a gynecologist at Capital Women’s Care in Washington and a fellow of the American College of Obstetrics and Gynecology. “Honestly, I would think people would want to do it all the time.”"