The combined oral contraceptive pill ( COCP), often referred to as the birth control pill or colloquially as " the pill", is a type of birth control that is designed to be taken orally by women. It is the oral form of combined hormonal contraception. The pill contains two important : a progestin (a synthetic form of the hormone progestogen/progesterone) and estrogen (usually ethinylestradiol or Estradiol). When taken correctly, it alters the menstrual cycle to eliminate ovulation and prevent pregnancy.
Combined oral contraceptive pills were first approved for contraceptive use in the United States in 1960, and remain a very popular form of birth control. They are used by more than 100 million women worldwide
Combined oral contraceptives are on the World Health Organization's List of Essential Medicines. The pill was a catalyst for the sexual revolution.
Combined oral contraceptives ( COCs) are commonly classified into generations, referring to their order of development in history. This discussion may also help identify some key features in a variety of products. According to EMA, the first generation of combined oral contraceptives, which made use of a high concentration of oestrogen only, were those invented in the 1960s. In the second generation of products, progestogens were introduced into the formulation while the concentration of oestrogen was reduced. Starting from the 1990s, the progression in the development of combined oral contraceptives has been directed towards varying the type of progestogen incorporated. These products are referred as the third and fourth generation.
Oestrogen ingredients: estradiol, ethinylestradiol, estetrol.
1st generation progestin: norethindrone acetate, ethynodiol diacetate, lynestrenol, Noretynodrel.
2nd generation progestin: levonorgestrel, Norgestrel.
3rd generation progestin: norgestimate, gestodene, desogestrel.
Menstruation marks the beginning of proliferative phase in day 1-14. In this period, the pituitary gland located near the brain secretes follicle-stimulating hormone (FSH) into the bloodstream to signal the development of Ovarian follicle in ovary in the female reproductive system. While follicle serves as the chamber of ovum development, it secretes Estrogen, a hormone that not only triggers the thickening of Endometrium in preparation for implantation, but also inhibits the secretion of FSH in pituitary via a negative feedback mechanism.
Specifically in ovulation, transient positive feedback by Oestrogen on FSH and Luteinising Hormone (LH) secretion from pituitary is permitted so that the release of mature Egg cell from follicle is triggered.
In secretory phase on day 14-28, this follicle then transforms into corpus luteum and continues releasing Oestrogen with Progesterone into bloodstream. While Oestrogen and Progesterone primarily aid the maintenance of thickness in uterine lining, the negative feedback in pituitary allows them to inhibit FSH and LH secretion. In the absence of LH, corpus luteum degenerates and ultimately causes blood Oestrogen and Progesterone levels to decline. Without these thickness maintaining agents, uterine lining breaks down and hence the presentation of menstruation.
Combined oral contraceptive pills were developed to prevent ovulation by suppressing the release of . Combined hormonal contraceptives, including combined oral contraceptive pills, inhibit follicular phase and prevent ovulation as a primary mechanism of action.
Under normal circumstances, luteinizing hormone (LH) stimulates the theca cells of the ovarian follicle to produce androstenedione. The of the ovarian follicle then convert this androstenedione to estradiol. This conversion process is catalyzed by aromatase, an enzyme produced as a result of follicle-stimulating hormone (FSH) stimulation. In individuals using oral contraceptives, progestogen negative feedback decreases the pulse frequency of gonadotropin-releasing hormone (GnRH) release by the hypothalamus, which decreases the secretion of FSH and greatly decreases the secretion of LH by the anterior pituitary. Decreased levels of FSH inhibit follicular development, preventing an increase in estradiol levels. Progestogen negative feedback and the lack of estrogen positive feedback on LH secretion prevent a menstrual cycle LH surge. Inhibition of follicular development and the absence of an LH surge prevent ovulation.
Estrogen was originally included in oral contraceptives for better cycle control (to stabilize the endometrium and thereby reduce the incidence of breakthrough bleeding), but was also found to inhibit follicular development and help prevent ovulation. Estrogen negative feedback on the anterior pituitary greatly decreases the secretion of FSH, which inhibits follicular development and helps prevent ovulation.
Another primary mechanism of action of all progestogen-containing contraceptives is inhibition of spermatozoon penetration through the cervix into the upper genital tract (uterus and ) by decreasing the water content and increasing the viscosity of the cervical mucus.
The estrogen and progestogen in combined oral contraceptive pills have other effects on the reproductive system, but these have not been shown to contribute to their contraceptive efficacy:
Insufficient evidence exists on whether changes in the endometrium could actually prevent implantation. The primary mechanisms of action are so effective that the possibility of fertilization during combined oral contraceptive pill use is very small. Since pregnancy occurs despite endometrial changes when the primary mechanisms of action fail, endometrial changes are unlikely to play a significant role, if any, in the observed effectiveness of combined oral contraceptive pills.
Combined oral contraceptive pills have been somewhat inconsistently grouped into "generations" in the medical literature based on when they were introduced.
Some combined oral contraceptive pill packs only contain 21 pills and users are advised to take no pills for the last 7 days of the cycle. Other combined oral contraceptive pill formulations contain 91 pills, consisting of 84 days of active hormones followed by 7 days of placebo (Seasonale). Combined oral contraceptive pill formulations can contain 24 days of active hormone pills followed by 4 days of placebo pills (e.g. Yaz 28 and Loestrin 24 Fe) as a means to decrease the severity of placebo effects. These combined oral contraceptive pills containing active hormones and a placebo/hormone-free period are called cyclic combined oral contraceptive pills. Once a pack of cyclical combined oral contraceptive pill treatment is completed, users start a new pack and new cycle.
Most monophasic combined oral contraceptive pills can be used continuously such that patients can skip placebo days and continuously take hormone active pills from a combined oral contraceptive pill pack. One of the most common reasons users do this is to avoid or diminish withdrawal bleeding. The majority of women on cyclic combined oral contraceptive pills have regularly scheduled withdrawal bleeding, which is vaginal bleeding mimicking users' menstrual cycles with the exception of lighter menstrual bleeding compared to bleeding patterns prior to combined oral contraceptive pill commencement. As such, a study reported that out of 1003 women taking combined oral contraceptive pills approximately 90% reported regularly scheduled withdrawal bleeds over a 90-day standard reference period. Withdrawal bleeding usually occurs during the placebo, hormone-free days. Therefore, avoiding placebo days can diminish withdrawal bleeding among other placebo effects.
To acquire immediate contraceptive effects, the initiation of hormonal oral contraceptive dosing is recommended within the 1st-5th day from menstruation in order to discard other means of Birth control. Specific to Progesterone only pills, even if dosing is initiated within five days, backup contraception is suggested in the first 48 hours since the first pill. In the case of dosing initiated after the 5th day from menstruation, effects usually take place after seven days and other contraceptive methods should remain in place until then.
Several factors account for typical use effectiveness being lower than perfect use effectiveness:
For instance, someone using combined oral contraceptive pills might have received incorrect information by a health care provider about medication frequency, forgotten to take the pill one day or not gone to the pharmacy in time to renew a combined oral contraceptive pill prescription.
Combined oral contraceptive pills provide effective contraception from the very first pill if started within five days of the beginning of the menstrual cycle (within five days of the first day of menstruation). If started at any other time in the menstrual cycle, combined oral contraceptive pills provide effective contraception only after 7 consecutive days of use of active pills, so a backup method of contraception (e.g. ) must be used in the interim.
The effectiveness of combined oral contraceptive pills appears to be similar whether the active pills are taken continuously or if they are taken cyclically. Contraceptive efficacy, however, could be impaired by numerous means. Factors that may contribute to a decrease in effectiveness:
In any of these instances, a backup contraceptive method should be used until hormone active pills have been consistently taken for 7 consecutive days or drug-drug interactions or underlying illnesses have been discontinued or resolved. According to the US Centers for Disease Control and Prevention (CDC) guidelines, a pill is considered "late" if a user takes the pill after the user's normal medication time, but no longer than 24 hours after this normal time. If 24 hours or more have passed since the time the user was supposed to take the pill, then the pill is considered "missed". CDC guidelines discuss potential next steps for users who missed their pill or took it late.
The placebo, or hormone-free, week in the 28-day pill package simulates an average menstrual cycle, though the hormonal events during a pill cycle are significantly different from those of a normal ovulatory menstrual cycle. Because the pill suppresses ovulation (to be discussed more in the Mechanism of action section), birth control users do not have true menstrual periods. Instead, it is the lack of hormones for a week that causes a withdrawal bleed. The withdrawal bleeding that occurs during the break from active pills has been thought to be reassuring, a physical confirmation of not being pregnant. The withdrawal bleeding is also predictable. Unexpected breakthrough bleeding can be a possible side effect of longer term active regimens.
Since it is not uncommon for menstruating women to become anemic, some placebo pills may contain an iron supplement. This replenishes iron stores that may become depleted during menstruation. As well, birth control pills, such as combined oral contraceptive pills, are sometimes fortified with Folate as it is recommended to take folic acid supplementation in the months prior to pregnancy to decrease the likelihood of neural tube defect in infants.
Starting in 2003, women have also been able to use a three-month version of the pill. Similar to the effect of using a constant-dosage formulation and skipping the placebo weeks for three months, Seasonale gives the benefit of less frequent periods, at the potential drawback of breakthrough bleeding. Seasonique is another version in which the placebo week every three months is replaced with a week of low-dose estrogen.
A version of the combined pill has also been packaged to eliminate placebo pills and withdrawal bleeds. Marketed as Anya or Lybrel, studies have shown that after seven months, 71% of users no longer had any breakthrough bleeding, the most common side effect of going longer periods of time without breaks from active pills.
While more research needs to be done to assess the long term safety of using combined oral contraceptive pills continuously, studies have shown there may be no difference in short term adverse effects when comparing continuous use versus cyclic use of birth control pills.
To reduce the risk of endometrial cancer, it is often recommended that women with PCOS who do not desire pregnancy take hormonal contraceptives to prevent the effects of unopposed estrogen. Both combined oral contraceptive pills and progestin-only methods are recommended. It is the progestin component of combined oral contraceptive pills that protects the endometrium from hyperplasia, and thus reduces a woman with PCOS's endometrial cancer risk. Combined oral contraceptive pills are preferred to progestin-only methods in women who also have uncontrolled acne, symptoms of hirsutism, and androgenic alopecia, because combined oral contraceptive pills can help treat these symptoms.
Ultimately, the drop in the level of free androgens leads to a decrease in the production of sebum, which is a major contributor to development of acne. Four different oral contraceptives have been approved by the US FDA to treat moderate acne if the patient is at least 14 or 15 years old, has already begun menstruating, and needs contraception. These include Ortho Tri-Cyclen, Estrostep, Beyaz, and Drospirenone.
Hirsutism is the growth of coarse, dark hair where women typically grow only fine hair or no hair at all. This hair growth on the face, chest, and abdomen is also mediated by higher levels or action of androgens. Therefore, combined oral contraceptive pills also work to treat these symptoms by lowering the levels of free circulating androgens.
Studies have shown that combined oral contraceptives are effective in reducing both Inflammation and non-inflammatory facial acne lesions. However, comparisons between different combined oral contraceptives have not been studied to understand if any brand is superior than the others. Oestrogen decreases sebum production by shrinking the sebaceous gland, increasing Sex hormone-binding globulin (SHBG) production to reduce unbound testosterone, and regulating LH and FSH levels. Studies have not shown that POPs are effective against acne lesions.
Women who are experiencing menstrual dysfunction due to female athlete triad are sometimes prescribed oral contraceptives as pills that can create menstrual bleeding cycles. However, the condition's underlying cause is energy deficiency and should be treated by correcting the imbalance between calories eaten and calories burned by exercise. Oral contraceptives should not be used as an initial treatment for female athlete triad.
In the two types of hormonal oral contraceptives, only combined oral contraceptives can achieve amenorrhea, while POPs can only reduce the amount of blood. The method of using combined oral contraceptives for menstrual suppression is to skip the 7 placebo pills and continue taking active pills after the 21 active pills. This can be used in extended method or continuous method. For extended method, patients who take active pills for 3, 4, or 6 months and then take placebo pills for a period of time will more likely experience withdrawal bleeding. The interval can be decided by the patients according to their own preferences. For continuous method, people can take combined oral contraceptives for a year continuously without any placebo pills. In the first few months of extended or continuous use of combined oral contraceptives, unscheduled bleeding or spotting may occur. However, the bleeding or spotting is expected to resolve after a few months of use.
Menstrual suppression is commonly used for convenience especially when women go on vacation. It is also used for gynecologic disorders such as dysmenorrhea (commonly known as menstrual pain), symptoms related to premenstrual hormone change and excessive bleeding related to . Patients can also benefit from menstrual suppression for bleeding disorders or chronic anemia.
In terms of protection in sexual intercourse, a sole reliance on hormonal oral contraceptives does not defend one from sexually transmitted infections such as HPV. Additionally, breakthrough bleeding and spotting are exceptionally prevalent in the early stage of using hormonal oral contraceptives. Although most reported side effects including nausea, headache, or will disappear as the therapy progresses or upon switching formulation, elevated blood pressure or blood clots in patients with cardiovascular conditions are documented side effects that requires medical attention if not termination of hormonal oral contraceptives. It is because combined oral contraceptives uses have been found to be related to an increased risk of Stroke or myocardial infarction, especially in combined oral contraceptives with >50 μg Oestrogen. Besides, some ongoing studies giving evidence on the association between hormonal oral contraceptive use and escalated breast cancer risks cannot be neglected.
According to WHO Medical Eligibility Criteria for Contraceptive Use 2015, Category 3 implies that the use of such contraception is usually not recommended, unless other more appropriate methods are neither available nor acceptable and with good resources of clinical judgment; Category 4 implies that the contraceptive method should not be used even with good resources of clinical judgment. Both categories suggest that the contraceptive method should not be used with limited resources for clinical judgment. The tables below summarise conditions of category 3 and 4 from World Health Organization Medical Eligibility Criteria for Contraceptive Use 2015.
+ !Condition !Category | |
Breastfeeding | |
for < 6 weeks postpartum | 4 |
for ≥ 6 weeks to < 6 months postpartum | 3 |
Postpartum (non-breastfeeding) | |
< 21 days postpartum without other risk factors for VTE | 3 |
< 21 days postpartum with other risk factors for VTE | 4 |
≥ 21 days to 42 days postpartum with other risk factors for VTE | 3 |
Smoking | |
age ≥ 35 years and smoking < 15 cigarettes/day | 3 |
age ≥ 35 years and smoking ≥ 15 cigarettes/day | 4 |
Multiple risk factors for Vascular disease | 3/4* |
Hypertension | |
history of hypertension, where blood pressure CANNOT be evaluated | 3 |
adequately controlled hypertension, where blood pressure CAN be evaluated | 3 |
elevated blood pressure levels (properly taken measurements) with systolic 140–159 or diastolic 90–99 mm Hg | 3 |
elevated blood pressure levels (properly taken measurements) with systolic ≥ 160 or diastolic ≥ 100 mm Hg | 4 |
elevated blood pressure levels (properly taken measurements) with Vascular disease | 4 |
Deep vein thrombosis (DVT) / Pulmonary embolism (PE) | |
with History of DVT/PE | 4 |
with acute DVT/PE | 4 |
with DVT/PE and established on anticoagulant therapy | 4 |
with Major surgery with prolonged immobilization | 4 |
Known thrombogenic mutations | 4 |
Current and history of ischemic heart disease | 4 |
Stroke (history of cerebrovascular accident) | 4 |
Complicated valvular heart disease | 4 |
Positive (or unknown) antiphospholipid antibodies Systemic Lupus Erythematous | 4 |
Headache | |
migraine without aura of age ≥ 35 years (for initiation of combined oral contraceptives) | 3 |
migraine without aura of age < 35 years (for continuation of combined oral contraceptives) | 3 |
migraine without aura of age ≥ 35 years (for continuation of combined oral contraceptives) | 4 |
migraine with aura, at any age (for initiation and continuation of combined oral contraceptives) | 4 |
Breast cancer | |
current Breast cancer | 4 |
past Breast Cancer and no evidence of current disease for 5 years | 3 |
Kidney disease/retinopathy/neuropathy | 3/4* |
Other vascular disease or diabetes of > 20 years' duration | 3/4* |
Medically treated symptomatic gall bladder disease | 3 |
Current symptomatic gall bladder disease | 3 |
Past-combined oral contraceptive related history of Cholestasis | 3 |
Acute or flare viral hepatitis (for initiation of combined oral contraceptives) | 3/4* |
Severe cirrhosis (decompensated) | 4 |
Liver tumors | |
hepatocellular adenoma | 4 |
malignant (hepatoma) | 4 |
On anticonvulsant therapy | |
with phenytoin, carbamazepine, , primidone, topiramate, oxcarbazepine | 3 |
with Lamotrigine | 3 |
On antimicrobial therapy with Rifampicin or rifabutin therapy |
Nausea, vomiting, headache, bloating, breast tenderness, swelling of the ankles/feet (fluid retention), or weight change may occur. Vaginal bleeding between periods (spotting) or missed/irregular periods may occur, especially during the first few months of use.
While lower doses of estrogen in combined oral contraceptive pills may have a lower risk of stroke and myocardial infarction compared to higher estrogen dose pills (50 μg/day), users of low estrogen dose combined oral contraceptive pills still have an increased risk compared to non-users. These risks are greatest in women with additional risk factors, such as smoking (which increases risk substantially) and long-continued use of the pill, especially in women over 35 years of age.
The overall absolute risk of venous thrombosis per 100,000 woman-years in current use of combined oral contraceptives is approximately 60, compared with 30 in non-users. The risk of thromboembolism varies with different types of birth control pills; compared with combined oral contraceptives containing levonorgestrel (LNG), and with the same dose of estrogen and duration of use, the rate ratio of deep venous thrombosis for combined oral contraceptives with norethisterone is 0.98, with norgestimate 1.19, with desogestrel (DSG) 1.82, with gestodene 1.86, with drospirenone (DRSP) 1.64, and with cyproterone acetate 1.88. In comparison, venous thromboembolism occurs in 100–200 per 100.000 pregnant women every year.
One study showed more than a 600% increased risk of blood clots for women taking combined oral contraceptive pills with drospirenone compared with non-users, compared with 360% higher for women taking birth control pills containing levonorgestrel. The US Food and Drug Administration (FDA) initiated studies evaluating the health of more than 800,000 women taking combined oral contraceptive pills and found that the risk of VTE was 93% higher for women who had been taking drospirenone combined oral contraceptive pills for 3 months or less and 290% higher for women taking drospirenone combined oral contraceptive pills for 7–12 months, compared with women taking other types of oral contraceptives.
Based on these studies, in 2012, the FDA updated the label for drospirenone combined oral contraceptive pills to include a warning that contraceptives with drospirenone may have a higher risk of dangerous blood clots.
A 2015 systematic review and meta-analysis found that combined birth control pills were associated with 7.6-fold higher risk of cerebral venous sinus thrombosis, a rare form of stroke in which blood clotting occurs in the cerebral venous sinuses.
An association between use of birth control pills and liver cancer has been suspected, but subsequent large population research has failed to confirm such an association.
Increased risk of breast cancer was reported in women who take combined oral concetraption. The relative risk of breast cancer in the current combined oral concetraption users was 1.24 (95% confidence interval CI, 1.15–1.33), and this increased risk disappeared 10 years after discontinuation. There was also a higher risk of premature deaths due to breast cancer in the population who used COCP ( P < 0.0001) for longer duration. 24 observational studies showed a higher risk of cervical cancer in women who use COCP, especially with an increased duration of COCP use.
A 2013 meta-analysis concluded that every use of birth control pills is associated with a modest increase in the risk of breast cancer (relative risk 1.08) and a reduced risk of colorectal cancer (relative risk 0.86) and endometrial cancer (relative risk 0.57). Cervical cancer risk in those infected with HPV is increased. A similar small increase in breast cancer risk was observed in other meta analyses. A study of 1.8 million Danish women of reproductive age followed for 11 years found that the risk of breast cancer was 20% higher among those who currently or recently used hormonal contraceptives than among women who had never used hormonal contraceptives. This risk increased with duration of use, with a 38% increase in risk after more than 10 years of use.
In 2012, The Journal of Sexual Medicine published a review of research studying the effects of hormonal contraceptives on female sexual function that concluded that the sexual side effects of hormonal contraceptives are not well-studied and especially in regards to impacts on libido, with research establishing only mixed effects where only small percentages of women report experiencing an increase or decrease and majorities report being unaffected. In 2013, The European Journal of Contraception & Reproductive Health Care published a review of 36 studies including 8,422 female subjects in total taking combined oral contraceptive pills that found that 5,358 subjects (or 63.6 percent) reported no change in libido, 1,826 subjects (or 21.7 percent) reported an increase, and 1,238 subjects (or 14.7 percent) reported a decrease. In 2019, Neuroscience & Biobehavioral Reviews published a meta-analysis of 22 published and 4 unpublished studies (with 7,529 female subjects in total) that evaluated whether women expose themselves to greater health risks at different points in the menstrual cycle including by sexual activity with partners and found that subjects in the last third of the follicular phase and at ovulation (when levels of endogenous estradiol and luteinizing hormones are heightened) experienced increased sexual activity with partners as compared with the luteal phase and during menstruation.
A 2006 study of 124 Menopause women measured sex hormone-binding globulin (SHBG), including before and after discontinuation of the oral contraceptive pill. Women continuing use of oral contraceptives had SHBG levels four times higher than those who never used it, and levels remained elevated even in the group that had discontinued its use.
In 2004, the published a study where pairs of digital photographs of the faces of 48 women at Newcastle University and Charles University between the ages 19 and 33 who were not taking hormonal contraceptives during the study were photographed in the late follicular and early mid-luteal phases of their menstrual cycles and the photographs were then rated by 261 blinded subjects (130 male and 131 female) at their respective universities who compared the facial attractiveness of each photographed woman in their photograph pairs, and found that the subjects perceived the late follicular phase images of the photographed women as being more attractive than the luteal phase images by more than Expected value by Bernoulli trial.
In 2007, Evolution and Human Behavior published a study where 18 professional recorded their menstrual cycles, work shifts, and tip earnings at Strip club for 60 days that found by a mixed model analysis of 296 work shifts (or approximately 5,300 lap dances) that the 11 dancers with normal menstrual cycles earned US$335 per 5-hour shift during the late follicular phase and at ovulation, US$260 per shift during the luteal phase, and US$185 per shift during menstruation, while the 7 dancers using hormonal contraceptives showed no earnings peak during the late follicular phase and at ovulation. In 2008, Evolution and Human Behavior published a study where the voices of 51 female students at the State University of New York at Albany were recorded with the women counting from 1 to 10 at four different points in their menstrual cycles were rated by blinded subjects who listened to the recordings to be more attractive at the points of the menstrual cycle with higher probabilities of conception, while the ratings of the voices of the women who were taking hormonal contraceptives showed no variation over the menstrual cycle in attractiveness.
In 2006, a study presented at the annual conference of the Cognitive Science Society surveyed 176 female undergraduate students at Michigan State University (with a mean age of 19.9 years) in a decision-making experiment where the subjects chose between an option with a guaranteed outcome or an option involving risk and indicated the first day of their last menstruations, and found that the subjects risk aversion preferences varied over the menstrual cycle (with none of the subjects at ovulation preferring the risky option) and only subjects not taking hormonal contraceptives showed the menstrual cycle effect on risk aversion. In the 2019 Neuroscience & Biobehavioral Reviews meta-analysis, the research reviewed also evaluated whether the 7,529 female subjects across the 26 studies showed greater risk recognition and avoidance of potentially threatening people and dangerous situations at different phases of the menstrual cycle and found that the subjects displayed better risk accuracy recognition during the late follicular phase and at ovulation as compared to the luteal phase.
Current medical reference textbooks on contraception and major organizations such as the American ACOG, the WHO, and the United Kingdom's RCOG agree that current evidence indicates low-dose combined oral contraceptives are unlikely to increase the risk of depression, and unlikely to worsen the condition in women that are depressed.
Excess estrogen, such as from birth control pills, appears to increase cholesterol levels in bile and decrease gallbladder movement, which can lead to gallstones. Progestins found in certain formulations of oral contraceptive pills can limit the effectiveness of weight training to increase muscle mass. This effect is caused by the ability of some progestins to inhibit androgen receptors. One study claims that the pill may affect what male body odors a woman prefers, which may in turn influence her selection of partner. Use of combined oral contraceptives is associated with a reduced risk of endometriosis, giving a relative risk of endometriosis of 0.63 during active use, yet with limited quality of evidence according to a systematic review.
Combined oral contraception decreases total testosterone levels by approximately 0.5 nmol/L, free testosterone by approximately 60%, and increases the amount of sex hormone binding globulin (SHBG) by approximately 100 nmol/L. Contraceptives containing second generation progestins and/or estrogen doses of around 20 –25 mg EE were found to have less impact on SHBG concentrations. Combined oral contraception may also reduce bone density.
The traditional medicinal herb St John's Wort has also been implicated due to its upregulation of the P450 system in the liver which could increase the metabolism of ethinyl estradiol and progestin components of some combined oral contraception.
In 1939, Russell Marker, a professor of organic chemistry at Pennsylvania State University, developed a method of synthesizing progesterone from plant steroid , initially using sarsapogenin from Smilax regelii, 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.
In 1951, reproductive physiologist Gregory Pincus, a leader in hormone research and co-founder of the Worcester Foundation for Experimental Biology (WFEB) in Shrewsbury, Massachusetts, first met American birth control movement founder Margaret Sanger at a Manhattan dinner hosted by Abraham Stone, medical director and vice president of Planned Parenthood (PPFA), who helped Pincus obtain a small grant from PPFA to begin hormonal contraceptive research. 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 October 1951, G. D. Searle & Company refused Pincus' request to fund his hormonal contraceptive research, but retained him as a consultant and continued to provide chemical compounds to evaluate.
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 menstrual cycle days 5–24 followed by pill-free days to produce menstrual cycle. This produced the same 15% pregnancy rate during the following four months without the amenorrhea of the previous continuous estrogen and progesterone regimen. But 20% of the women experienced breakthrough bleeding and in the first cycle ovulation was suppressed in only 85% of the women, indicating that even higher and more expensive oral doses of progesterone would be needed to initially consistently suppress ovulation. Similarly, Ishikawa and colleagues found that ovulation inhibition occurred in only a "proportion" of cases with 300 mg/day oral progesterone.
Progesterone was abandoned as an oral ovulation inhibitor following these clinical studies due to the high and expensive doses required, incomplete inhibition of ovulation, and the frequent incidence of breakthrough bleeding.
Pincus asked his contacts at pharmaceutical companies to send him chemical compounds with progestogenic activity. Chang screened nearly 200 chemical compounds in animals and found the three most promising were Syntex's norethisterone and Searle's noretynodrel and norethandrolone.
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.
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.
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.
The first published case report of a blood clot and pulmonary embolism in a woman using Enavid (Enovid 10 mg in the US) at a dose of 20 mg/day did not appear until November 1961, four years after its approval, by which time it had been used by over one million women. 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 tobacco smoking or have high blood pressure or other cardiovascular or cerebrovascular risk factors. These risks of oral contraceptives were dramatized in the 1969 book The Doctors' Case Against the Pill by feminist journalist Barbara Seaman who helped arrange the 1970 Nelson Pill Hearings called by Senator Gaylord Nelson.
Beginning in 2015, certain states passed legislation allowing pharmacists to prescribe oral contraceptives. Such legislation was considered to address physician shortages and decrease barriers to birth control for women. 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.
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.
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 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.
Claudia Goldin, among others, argue that this new contraceptive technology was a key player in forming women's modern economic role, in that it prolonged the age at which women first married allowing them to invest in education and other forms of human capital as well as generally become more career-oriented. Soon after the birth control pill was legalized, there was a sharp increase in college attendance and graduation rates for women. From an economic point of view, the birth control pill reduced the cost of staying in school. The ability to control fertility without sacrificing sexual relationships allowed women to make long term educational and career plans.
Because the pill was so effective, and soon so widespread, it also heightened the debate about the moral and health consequences of pre-marital sex and promiscuity. Never before had sexual activity been so divorced from reproduction. For a couple using the pill, intercourse became purely an expression of love, or a means of physical pleasure, or both; but it was no longer a means of reproduction. While this was true of previous contraceptives, their relatively high failure rates and their less widespread use failed to emphasize this distinction as clearly as did the pill. The spread of oral contraceptive use thus led many religious figures and institutions to debate the proper role of sexuality and its relationship to procreation. The Roman Catholic Church in particular, after studying the phenomenon of oral contraceptives, re-emphasized the stated teaching on birth control in the 1968 papal encyclical Humanae vitae. The encyclical reiterated the established Catholic teaching that artificial contraception distorts the nature and purpose of sex. On the other side Anglican and other Protestant churches, such as the Protestant Church in Germany (EKD), accepted the combined oral contraceptive pill.
The United States Senate began hearings on the pill in 1970 and where different viewpoints were heard from medical professionals. Dr. Michael Newton, President of the College of Obstetricians and Gynecologists said:
Another physician, Dr. Roy Hertz of the Population Council, said that anyone who takes this should know of "our knowledge and ignorance in these matters" and that all women should be made aware of this so they can decide to take the pill or not.
The Secretary of Health, Education, and Welfare at the time, Robert Finch, announced the federal government had accepted a compromise warning statement which would accompany all sales of birth control pills.
A review of activated sludge performance found estrogen removal rates varied considerably but averaged 78% for estrone, 91% for estradiol, and 76% for ethinylestradiol (estriol effluent concentrations are between those of estrone and estradiol, but estriol is a much less potent endocrine disruptor to fish).
Several studies have suggested that reducing human population growth through increased access to contraception, including birth control pills, can be an effective strategy for climate change mitigation as well as adaptation. According to Thomas Wire, contraception is the 'greenest technology' because of its cost-effectiveness in combating global warming — each $7 spent on contraceptives would reduce global carbon emissions by 1 tonne over four decades, while achieving the same result with low-carbon technologies would require $32.
Cancer
Decreased risk of ovarian, endometrial, and colorectal cancers
Increased risk of Breast, cervical, and liver cancers
Weight
Sexual function and risk aversion
Sexual desire
Description of the study results in Medical News Today: Theoretically, an increase in SHBG may be a physiologic response to increased hormone levels, but may decrease the free levels of other hormones, such as androgens, because of the unspecificity of its sex hormone binding. In 2020, The Lancet published a cross-sectional study of 588 premenopausal female subjects aged 18 to 39 years from the states of Queensland, New South Wales, and Victoria with regular menstrual cycles whose SHBG levels were measured by immunoassay that found that after controlling for age, body mass index, cycle stage, smoking, parity, partner status, and psychoactive medication, SHBG was inversely correlated with sexual desire.
Sexual attractiveness and function
Risk-taking behaviour
Depression
Hypertension
Thyroid
Other effects
Drug interactions
Accessibility
History
By the 1930s, scientists had isolated and determined the structure of the steroid hormones and found that high doses of , estrogens or progesterone inhibited ovulation,
but obtaining these hormones, which were produced from animal extracts, from European pharmaceutical companies was extraordinarily expensive.
Introduction of first-generation birth control pills 1961 1966 1962 1963 1963 ? – – – 1965 – 1965 1968 – 1972 – 1969 Sources:
Progesterone to prevent ovulation
Progestins to prevent ovulation
Combined oral contraceptive
Public availability
United States
Australia
Germany
United Kingdom
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 2Shilling per month.
In 1962, Schering's Anovlar and Searle's Conovid-E were added to the FPA's Approved List of Contraceptives.
France
Japan
Society and culture
Result on popular culture
Poem
Music
Environmental impact
See also
Further reading
External links
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