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. The pill contains two important hormones:

progestin A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the natural female sex hormone progesterone in the body. A progestin is a '' synthetic'' progestogen. Pro ...

(a synthetic form of the hormone progestogen/progesterone) and

estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal a ...

(usually

ethinylestradiol Ethinylestradiol (EE) is an estrogen medication which is used widely in birth control pills in combination with progestins. In the past, EE was widely used for various indications such as the treatment of menopausal symptoms, gynecological dis ...

and 17β estradiol). When taken correctly, it alters the

menstrual cycle The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that make pregnancy possible. The ovarian cycle controls the production and release of eg ...

to eliminate

ovulation Ovulation is the release of eggs from the ovaries. In women, this event occurs when the ovarian follicles rupture and release the secondary oocyte ovarian cells. After ovulation, during the luteal phase, the egg will be available to be fertilize ...

and prevent

pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ...

. COCPs were first approved for contraceptive use in the United States in 1960, and are a very popular form of birth control. They are used by more than 100 million women worldwide and by about 9 million women in the United States. From 2015 to 2017, 12.6% of women aged 15–49 in the US reported using COCPs, making it the second most common method of contraception in this age range ( female sterilization is the most common method). Use of COCPs, however, varies widely by country, age, education, and marital status. For example, one third of women aged 16–49 in the United Kingdom currently use either the combined pill or

progestogen-only pill Progestogen-only pills or progestin-only pills (POP) are contraceptive pills that contain only synthetic progestogens (progestins) and do not contain estrogen. They are colloquially known as mini pills. Although such pills are sometimes called "p ...

(POP), British women aged 16–49: 24% currently use the pill (17% use Combined pill, 5% use Minipill, 2% don't know type) compared with less than 3% of women in Japan (as of 1950–2014). Combined oral contraceptives are on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...

. The pill was a catalyst for the

sexual revolution The sexual revolution, also known as the sexual liberation, was a social movement that challenged traditional codes of behavior related to sexuality and interpersonal relationships throughout the United States and the developed world from the ...

Medical use

Contraceptive use

Combined oral contraceptive pills are a type of oral medication that were originally designed to be taken every day at the same time of day in order to prevent pregnancy. There are many different formulations or brands, but the average pack is designed to be taken over a 28-day period (also known as a cycle). For the first 21 days of the cycle, users take a daily pill that contains two hormones, estrogen and progestogen. During the last 7 days of the cycle, users take daily

placebo A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like Saline (medicine), saline), sham surgery, and other procedures. In general ...

(biologically inactive) pills and these days are considered hormone-free days. Although these are hormone-free days, users are still protected from pregnancy during this time. Some COCP packs only contain 21 pills and users are advised to take no pills for the last 7 days of the cycle. Other COCP formulations contain 91 pills, consisting of 84 days of active hormones followed by 7 days of placebo ( Seasonale). Of recent innovation, COCP 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 COCPs containing active hormones and a placebo/hormone-free period are called cyclic COCPs. Once a pack of cyclical COCP treatment is completed, users start a new pack and new cycle. Most monophasic COCPs can be used continuously such that patients can skip placebo days and continuously take hormone active pills from a COCP pack. One of the most common reasons users do this is to avoid or diminish withdrawal bleeding. The majority of women on cyclic COCPs 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 COCP commencement. As such, a recent study reported that out of 1003 women taking COCPs 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.

Effectiveness

If used exactly as instructed, the estimated risk of getting pregnant is 0.3% which means that about 3 in 1000 women on COCPs will become pregnant within one year. However, typical use of COCPs by users often consists of timing errors, forgotten pills, or unwanted side effects. With typical use, the estimated risk of getting pregnant is about 9% which means that about 9 in 100 women on COCPs will become pregnant in one year. The perfect use failure rate is based on a review of pregnancy rates in clinical trials, and the typical use failure rate is based on a weighted average of estimates from the 1995 and 2002 U.S. National Surveys of Family Growth (NSFG), corrected for underreporting of abortions. Several factors account for typical use effectiveness being lower than perfect use effectiveness: # Mistakes on part of those providing instructions on how to use the method # Mistakes on part of the user # Conscious user non-compliance with instructions For instance, someone using COCPs 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 her COCP prescription. COCPs provide effective contraception from the very first pill if started within five days of the beginning of the

(within five days of the first day of

menstruation Menstruation (also known as a period, among other colloquial terms) is the regular discharge of blood and mucosal tissue from the inner lining of the uterus through the vagina. The menstrual cycle is characterized by the rise and fall of ...

). If started at any other time in the menstrual cycle, COCPs provide effective contraception only after 7 consecutive days of use of active pills, so a backup method of contraception (e.g.

condom A condom is a sheath-shaped barrier device used during sexual intercourse to reduce the probability of pregnancy or a sexually transmitted infection (STI). There are both male and female condoms. With proper use—and use at every act of inte ...

s) must be used in the interim. The effectiveness of COCPs 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: # Missing more than one active pill in a packet, # Delay in starting the next packet of active pills (i.e., extending the pill-free, inactive pill or placebo pill period beyond 7 days), # Intestinal

malabsorption Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal (GI) tract. Impairment can be of single or multiple nutrients depending on the abnormality. This may lead to malnutrition and a variety ...

of active pills due to

vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteri ...

diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin ...

, # Drug-drug interactions among COCPs and other medications of the user that decrease contraceptive estrogen and/or progestogen levels. 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 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.

Role of placebo pills

The role of the

pills is two-fold: to allow the user to continue the routine of taking a pill every day and to simulate the average

. By continuing to take a pill every day, users remain in the daily habit even during the week without hormones. Failure to take pills during the placebo week does not impact the effectiveness of the pill, provided that daily ingestion of active pills is resumed at the end of the week. 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 Iron () is a chemical element with symbol Fe (from la, ferrum) and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, right in ...

supplement. This replenishes iron stores that may become depleted during menstruation. As well, birth control pills, such as COCPs, are sometimes fortified with

folic acid Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing a ...

as it is recommended to take folic acid supplementation in the months prior to pregnancy to decrease the likelihood of

neural tube defect Neural tube defects (NTDs) are a group of birth defects in which an opening in the spine or cranium remains from early in human development. In the third week of pregnancy called gastrulation, specialized cells on the dorsal side of the embryo ...

in infants.

No or less frequent placebos

If the pill formulation is monophasic, meaning each hormonal pill contains a fixed dose of hormones, it is possible to skip withdrawal bleeding and still remain protected against conception by skipping the placebo pills altogether and starting directly with the next packet. Attempting this with bi- or tri-phasic pill formulations carries an increased risk of

breakthrough bleeding Intermenstrual bleeding, previously known as metrorrhagia, is uterine bleeding at irregular intervals, particularly between the expected menstrual periods. It is a cause of vaginal bleeding. In some women, menstrual spotting between periods occur ...

and may be undesirable. It will not, however, increase the risk of getting pregnant. 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 COCP's 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.

Non-contraceptive use

The hormones in the pill have also been used to treat other medical conditions, such as polycystic ovary syndrome (PCOS),

endometriosis Endometriosis is a disease of the female reproductive system in which cells similar to those in the endometrium, the layer of tissue that normally covers the inside of the uterus, grow outside the uterus. Most often this is on the ovaries, ...

, adenomyosis, acne, hirsutism,

amenorrhea Amenorrhea is the absence of a menstrual period in a woman of reproductive age. Physiological states of amenorrhoea are seen, most commonly, during pregnancy and lactation (breastfeeding). Outside the reproductive years, there is absence of mense ...

, menstrual cramps, menstrual migraines, menorrhagia (excessive menstrual bleeding), menstruation-related or fibroid-related anemia and

dysmenorrhea Dysmenorrhea, also known as period pain, painful periods or menstrual cramps, is pain during menstruation. Its usual onset occurs around the time that menstruation begins. Symptoms typically last less than three days. The pain is usually in the ...

(painful menstruation). Besides acne, no oral contraceptives have been approved by the U.S. FDA for the previously mentioned uses despite extensive use for these conditions.

PCOS

The cause of PCOS, or polycystic ovary syndrome, is multifactorial and not well-understood. Women with PCOS often have higher than normal levels of luteinizing hormone (LH) and androgens that impact the normal function of the ovaries. While multiple small follicles develop in the ovary, none are able to grow in size enough to become the dominant follicle and trigger ovulation. This leads to an imbalance of LH, follicle stimulating hormone, estrogen, and progesterone. Without ovulation, unopposed estrogen can lead to endometrial hyperplasia, or overgrowth of tissue in the uterus. This endometrial overgrowth is more likely to become cancerous than normal endometrial tissue. Thus, although the data varies, it is generally agreed upon by most gynecological societies that due to the unopposed estrogen, women with PCOS are at higher risk for endometrial cancer. 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 COCPs and progestin-only methods are recommended. It is the progestin component of COCPs that protects the endometrium from hyperplasia, and thus reduces a woman with PCOS's endometrial cancer risk. COCPs are preferred to progestin-only methods in women who also have uncontrolled acne, symptoms of hirsutism, and androgenic alopecia, because COCPs can help treat these symptoms.

Acne and hirsutism

COCPs are sometimes prescribed to treat symptoms of androgenization, including acne and hirsutism. The estrogen component of COCPs appears to suppress androgen production in the ovaries. Estrogen also leads to increased synthesis of sex hormone binding globulin, which causes a decrease in the levels of free testosterone. 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 FDA approved 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 Ortho- is a Greek prefix meaning “straight”, “upright”, “right” or “correct”. Ortho may refer to: * Ortho, Belgium, a village in the Belgian province of Luxembourg In science * arene substitution patterns, two substituents that ...

, Estrostep, Beyaz, and YAZ. 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, COCPs also work to treat these symptoms by lowering the levels of free circulating androgens.

Endometriosis

For pelvic pain associated with endometriosis, COCPs are considered a first-line medical treatment, along with NSAIDs, GnRH agonists, and aromatase inhibitors. COCPs work to suppress the growth of the extra-uterine endometrial tissue. This works to lessen its inflammatory effects. COCPs, along with the other medical treatments listed above, do not eliminate the extra-uterine tissue growth, they just reduce the symptoms. Surgery is the only definitive treatment. Studies looking at rates of pelvic pain recurrence after surgery have shown that continuous use of COCPs is more effective at reducing the recurrence of pain than cyclic use.

Adenomyosis

Similar to endometriosis, adenomyosis is often treated with COCPs to suppress the growth the endometrial tissue that has grown into the myometrium. Unlike endometriosis however, levonorgetrel containing IUDs are more effective at reducing pelvic pain in adenomyosis than COCPs.

Menorrhagia

In the average menstrual cycle, a woman typically loses 35 to 40 milliliters of blood. However, up to 20% of women experience much heavier bleeding, or menorrhagia. This excess blood loss can lead to anemia, with symptoms of fatigue and weakness, as well as disruption in their normal life activities. COCPs contain progestin, which causes the lining of the uterus to be thinner, resulting in lighter bleeding episodes for those with heavy menstrual bleeding.

Amenorrhea

Although the pill is sometimes prescribed to induce menstruation on a regular schedule for women bothered by irregular menstrual cycles, it actually suppresses the normal menstrual cycle and then mimics a regular 28-day monthly cycle. 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.

Contraindications

While combined oral contraceptives are generally considered to be a relatively safe medication, they are contraindicated for those with certain medical conditions. The

World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level o ...

and the

Centers for Disease Control and Prevention The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georg ...

publish guidance, called medical eligibility criteria, on the safety of birth control in the context of medical conditions.

Hypercoagulability

Estrogen in high doses can increase risk of blood clots. All COCP users have a small increase in the risk of venous thromboembolism compared with non-users; this risk is greatest within the first year of COCP use. Individuals with any pre-existing medical condition that also increases their risk for blood clots have a more significant increase in risk of thrombotic events with COCP use. These conditions include but are not limited to high blood pressure, pre-existing

cardiovascular disease Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, ...

(such as

valvular heart disease Valvular heart disease is any cardiovascular disease process involving one or more of the four valves of the heart (the aortic and mitral valves on the left side of heart and the pulmonic and tricuspid valves on the right side of heart). These ...

or ischemic heart disease), history of thromboembolism or pulmonary embolism, cerebrovascular accident, and a familial tendency to form blood clots (such as familial factor V Leiden). There are conditions that, when associated with COCP use, increase risk of adverse effects other than thrombosis. For example, women with a history of

migraine Migraine (, ) is a common neurological disorder characterized by recurrent headaches. Typically, the associated headache affects one side of the head, is pulsating in nature, may be moderate to severe in intensity, and could last from a few ho ...

with aura have an increased risk of stroke when using COCPs, and women who

smoke Smoke is a suspension of airborne particulates and gases emitted when a material undergoes combustion or pyrolysis, together with the quantity of air that is entrainment (engineering), entrained or otherwise mixed into the mass. It is commo ...

over age 35 and use COCPs are at higher risk of

myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which ...

Pregnancy and postpartum

Women who are known to be pregnant should not take COCPs. Those in the postpartum period who are

breastfeeding Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that bre ...

are also advised not to start COCPs until 4 weeks after birth due to increased risk of blood clots. While studies have demonstrated conflicting results about the effects of COCPs on lactation duration and milk volume, there exist concerns about the transient risk of COCPs on breast milk production when breastfeeding is being established early postpartum. Due to the stated risks and additional concerns on lactation, women who are breastfeeding are not advised to start COCPs until at least six weeks postpartum, while women who are not breastfeeding and have no other risks factors for blood clots may start COCPs after 21 days postpartum.

Breast cancer

The WHO currently does not recommend the use of COCPs in women with breast cancer. Since COCPs contain both estrogen and progestin, they are not recommended to be used in those with hormonally-sensitive cancers, including some types of breast cancer. Non-hormonal contraceptive methods, such as the Copper IUD or condoms, should be the first-line contraceptive choice for these patients instead of COCPs.

Other

Women with known or suspected endometrial cancer or unexplained uterine bleeding should also not take COCPs to avoid health risks. COCPs are also contraindicated for people with advanced diabetes, liver tumors, hepatic adenoma or severe

cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue repai ...

of the liver. COCPs are metabolized in the liver and thus liver disease can lead to reduced elimination of the medication. Additionally, severe hypercholesterolemia and hypertriglyceridemia are also currently contraindications, but the evidence showing that COCP's lead to worse outcomes in this population is weak.

Obesity Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...

is not considered to be a contraindication to taking COCPs.

Side effects

It is generally accepted that the health risks of oral contraceptives are lower than those from pregnancy and birth, and "the health benefits of any method of contraception are far greater than any risks from the method". Some organizations have argued that comparing a contraceptive method to no method (pregnancy) is not relevant—instead, the comparison of safety should be among available methods of contraception.

Common

Different sources note different incidence of side effects. The most common side effect is

. A 1992 French review article said that as many as 50% of new first-time users discontinue the birth control pill before the end of the first year because of the annoyance of side effects such as breakthrough bleeding and

. A 2001 study by the Kinsey Institute exploring predictors of discontinuation of oral contraceptives found that 47% of 79 people discontinued the pill. One 1994 study found that women using birth control pills blinked 32% more often than those not using the contraception. Another 2011 study, presented data that indicated 74% of the women experienced weight gain, and 51% recorded an appetite change. Another 47% of the women recorded vaginal dryness and 48% experienced low sex drive. On the other hand, the pills can sometimes improve conditions such as dysmenorrhea, premenstrual syndrome, and acne, reduce symptoms of endometriosis and polycystic ovary syndrome, and decrease the risk of anemia. Use of oral contraceptives also reduces lifetime risk of ovarian and endometrial cancer. Women have experienced amenorrhea, easy administration, and improvement in sexual function in some patients. 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.

Heart and blood vessels

Combined oral contraceptives increase the risk of venous thromboembolism (including

deep vein thrombosis Deep vein thrombosis (DVT) is a type of venous thrombosis involving the formation of a blood clot in a deep vein, most commonly in the legs or pelvis. A minority of DVTs occur in the arms. Symptoms can include pain, swelling, redness, and e ...

(DVT) and

pulmonary embolism Pulmonary embolism (PE) is a blockage of an artery in the lungs by a substance that has moved from elsewhere in the body through the bloodstream (embolism). Symptoms of a PE may include shortness of breath, chest pain particularly upon breathing ...

(PE)). While lower doses of estrogen in COC pills may have a lower risk of stroke and

compared to higher estrogen dose pills (50 μg/day), users of low estrogen dose COC 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 Norethisterone, also known as norethindrone and sold under many brand names, is a progestin medication used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication is available in ...

is 0.98, with norgestimate 1.19, with

desogestrel Desogestrel is a progestin medication which is used in birth control pills for women. It is also used in the treatment of menopausal symptoms in women. The medication is available and used alone or in combination with an estrogen. It is tak ...

(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 COCPs with drospirenone compared with non-users, compared with 360% higher for women taking birth control pills containing levonorgestrel. The U.S. Food and Drug Administration (FDA) initiated studies evaluating the health of more than 800,000 women taking COCPs and found that the risk of VTE was 93% higher for women who had been taking drospirenone COCPs for 3 months or less and 290% higher for women taking drospirenone COCPs 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 COCPs to include a warning that contraceptives with drospirenone may have a higher risk of dangerous blood clots. A 2015

systematic review A systematic review is a scholarly synthesis of the evidence on a clearly presented topic using critical methods to identify, define and assess research on the topic. A systematic review extracts and interprets data from published studies on t ...

and

meta-analysis A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting m ...

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.

Cancer

Decreased risk of ovarian, endometrial, and colorectal cancers

Usage of combined oral concetraption decreased the risk of

ovarian cancer Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different ...

, endometrial cancer, and colorectal cancer. Two large cohort studies published in 2010 both found a significant reduction in adjusted relative risk of ovarian and endometrial cancer mortality in ever-users of OCs compared with never-users. The use of oral contraceptives (birth control pills) for five years or more decreases the risk of ovarian cancer in later life by 50%. Combined oral contraceptive use reduces the risk of

by 40% and the risk of endometrial cancer by 50% compared with never users. The risk reduction increases with duration of use, with an 80% reduction in risk for both ovarian and endometrial cancer with use for more than 10 years. The risk reduction for both ovarian and endometrial cancer persists for at least 20 years.

Increased risk of breast, cervical, and liver cancers

A report by a 2005 International Agency for Research on Cancer (IARC) working group found that COCs increase the risk of cancers of the

breast The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues. In females, it serves as the mammary gland, which produces and s ...

cervix The cervix or cervix uteri (Latin, 'neck of the uterus') is the lower part of the uterus (womb) in the human female reproductive system. The cervix is usually 2 to 3 cm long (~1 inch) and roughly cylindrical in shape, which changes durin ...

and

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...

). A

in 2010 did not support an increased overall cancer risk in users of combined oral contraceptive pills, but did find a slight increase in

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or ...

risk among current users, which disappears 5–10 years after use has stopped; the study also found an increased risk of cervical and liver cancers. A 2013

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.

Weight

A 2013 Cochrane systematic review found that studies of combination hormonal contraceptives showed no large difference in weight when compared with placebo or no intervention groups. The evidence was not strong enough to be certain that contraceptive methods do not cause some weight change, but no major effect was found. This review also found "that women did not stop using the pill or patch because of weight change."

Sexuality

COCPs may increase natural

vaginal lubrication Vaginal lubrication is a naturally produced fluid that lubricates a vagina. Vaginal lubrication is always present, but production increases significantly near ovulation and during sexual arousal in anticipation of sexual intercourse. Vaginal ...

. Other women experience reductions in

libido Libido (; colloquial: sex drive) is a person's overall sexual drive or desire for sexual activity. Libido is influenced by biological, psychological, and social factors. Biologically, the sex hormones and associated neurotransmitters that act ...

while on the pill, or decreased lubrication. Some researchers question a causal link between COCP use and decreased libido; a 2007 study of 1700 women found COCP users experienced no change in sexual satisfaction. A 2005 laboratory study of genital arousal tested fourteen women before and after they began taking COCPs. The study found that women experienced a significantly wider range of arousal responses after beginning pill use; decreases and increases in measures of arousal were equally common. A 2006 study of 124 pre-menopausal 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. 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. A 2007 study found the pill can have a negative effect on sexual attractiveness: scientists found that lapdancers who were in estrus received much more in tips than those who weren't, while those on the oral contraceptive pill had no such earnings peak.

Depression

Low levels of serotonin, a neurotransmitter in the brain, have been linked to depression. High levels of estrogen, as in first-generation COCPs, and progestin, as in some progestin-only contraceptives, have been shown to lower the brain serotonin levels by increasing the concentration of a brain enzyme that reduces serotonin. A growing body of research evidence has suggested that hormonal contraception may have an adverse effect on women's psychological health. In 2016, a large Danish study of one million women (followed-up from January 2000 to December 2013) showed that use of COCPs, especially among adolescents, was associated with a statistically significantly increased risk of subsequent depression, although the sizes of the effects are small (for example, 2.1% of the women who took any form of oral birth control were prescribed anti-depressants for the first time, compared to 1.7% of women in the control group). Similarly, in 2018, the findings from a large nationwide Swedish cohort study investigating the effect of hormonal contraception on

mental health Mental health encompasses emotional, psychological, and social well-being, influencing cognition, perception, and behavior. It likewise determines how an individual handles stress, interpersonal relationships, and decision-making. Mental hea ...

amongst women (n=815,662, aged 12–30) were published, highlighting an association between hormonal contraception and subsequent use of psychotropic drugs for women of reproductive age. This association was particularly large for young adolescents (aged 12–19). The authors call for further research into the influence of different kinds of

hormonal contraception Hormonal contraception refers to birth control methods that act on the endocrine system. Almost all methods are composed of steroid hormones, although in India one selective estrogen receptor modulator is marketed as a contraceptive. The origi ...

on young women's psychological health. Progestin-only contraceptives are known to worsen the condition of women who are already depressed., which cites: : However, current medical reference textbooks on contraception and major organizations such as the American ACOG, the WHO, and the United Kingdom's

RCOG The Royal College of Obstetricians and Gynaecologists (RCOG) is a professional association based in London, United Kingdom. Its members, including people with and without medical degrees, work in the field of obstetrics and gynaecology, that is ...

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 currently depressed.

Hypertension

Bradykinin lowers blood pressure by causing blood vessel dilation. Certain enzymes are capable of breaking down bradykinin (Angiotensin Converting Enzyme, Aminopeptidase P). Progesterone can increase the levels of Aminopeptidase P (AP-P), thereby increasing the breakdown of bradykinin, which increases the risk of developing hypertension.

Other effects

Other side effects associated with low-dose COCPs are leukorrhea (increased vaginal secretions), reductions in menstrual flow, mastalgia (breast tenderness), and decrease in

acne Acne, also known as ''acne vulgaris'', is a long-term skin condition that occurs when dead skin cells and oil from the skin clog hair follicles. Typical features of the condition include blackheads or whiteheads, pimples, oily skin, and ...

. Side effects associated with older high-dose COCPs include

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...

, increases in

blood pressure Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressur ...

, and melasma (facial skin discoloration); these effects are not strongly associated with low-dose formulations. Excess estrogen, such as from birth control pills, appears to increase cholesterol levels in bile and decrease gallbladder movement, which can lead to

gallstones A gallstone is a stone formed within the gallbladder from precipitated bile components. The term cholelithiasis may refer to the presence of gallstones or to any disease caused by gallstones, and choledocholithiasis refers to the presence of ...

. Progestins found in certain formulations of oral contraceptive pills can limit the effectiveness of

weight training Weight training is a common type of strength training for developing the strength, size of skeletal muscles and maintenance of strength.Keogh, Justin W, and Paul W Winwood. “Report for: The Epidemiology of Injuries Across the Weight-Tra ...

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

, giving a relative risk of endometriosis of 0.63 during active use, yet with limited quality of evidence according to a

. Combined oral contraception decreases total

testosterone Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteris ...

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.

Drug interactions

Some

drug A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhal ...

s reduce the effect of the pill and can cause

, or increased chance of pregnancy. These include drugs such as rifampicin, barbiturates, phenytoin and

carbamazepine Carbamazepine (CBZ), sold under the trade name Tegretol among others, is an anticonvulsant medication used primarily in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other medi ...

. In addition cautions are given about broad spectrum antibiotics, such as

ampicillin Ampicillin is an antibiotic used to prevent and treat a number of bacterial infections, such as respiratory tract infections, urinary tract infections, meningitis, salmonellosis, and endocarditis. It may also be used to prevent group B stre ...

and doxycycline, which may cause problems "by impairing the

bacterial flora Microbiota are the range of microorganisms that may be commensal, symbiotic, or pathogenic found in and on all multicellular organisms, including plants. Microbiota include bacteria, archaea, protists, fungi, and viruses, and have been foun ...

responsible for recycling

from the large bowel" ( BNF 2003). The traditional medicinal herb St John's Wort has also been implicated due to its upregulation of the P450 system in the

which could increase the metabolism of ethinyl estradiol and progestin components of some combined oral contraception.

Mechanism of action

Combined oral contraceptive pills were developed to prevent

by suppressing the release of

gonadotropin Gonadotropins are glycoprotein hormones secreted by gonadotropic cells of the anterior pituitary of vertebrates. This family includes the mammalian hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the placental/ chori ...

s. Combined hormonal contraceptives, including COCPs, inhibit follicular development and prevent ovulation as a primary mechanism of action. pp. 257–258: Under normal circumstances, LH stimulates the

theca cells In biology, a theca (plural thecae) is a sheath or a covering. Botany In botany, the theca is related to plant's flower anatomy. The theca of an angiosperm consists of a pair of microsporangia that are adjacent to each other and share a commo ...

of the ovarian follicle to produce

androstenedione Androstenedione, or 4-androstenedione (abbreviated as A4 or Δ4-dione), also known as androst-4-ene-3,17-dione, is an endogenous weak androgen steroid hormone and intermediate in the biosynthesis of estrone and of testosterone from dehy ...

. The granulosa cells of the ovarian follicle then convert this androstenedione to estradiol. This conversion process is catalyzed by aromatase, an enzyme produced as a result of FSH stimulation. In individuals using oral contraceptives, progestogen

negative feedback Negative feedback (or balancing feedback) occurs when some function of the output of a system, process, or mechanism is fed back in a manner that tends to reduce the fluctuations in the output, whether caused by changes in the input or by othe ...

decreases the pulse frequency of

gonadotropin-releasing hormone Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and released ...

(GnRH) release by the

hypothalamus The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamus ...

, which decreases the secretion of

follicle-stimulating hormone Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, pubertal maturation, ...

(FSH) and greatly decreases the secretion of

luteinizing hormone Luteinizing hormone (LH, also known as luteinising hormone, lutropin and sometimes lutrophin) is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (Gn ...

(LH) by the anterior pituitary. Decreased levels of FSH inhibit follicular development, preventing an increase in

estradiol Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development o ...

levels. Progestogen negative feedback and the lack of estrogen

positive feedback Positive feedback (exacerbating feedback, self-reinforcing feedback) is a process that occurs in a feedback loop which exacerbates the effects of a small disturbance. That is, the effects of a perturbation on a system include an increase in th ...

on LH secretion prevent a

mid-cycle The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that make pregnancy possible. The ovarian cycle controls the production and release of eggs ...

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 sperm penetration through the

into the upper

genital tract The female reproductive system is made up of the internal and external sex organs that function in the reproduction of new offspring. In humans, the female reproductive system is immature at birth and develops to maturity at puberty to be a ...

(

uterus The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The ...

and

fallopian tube The fallopian tubes, also known as uterine tubes, oviducts or salpinges (singular salpinx), are paired tubes in the human female that stretch from the uterus to the ovaries. The fallopian tubes are part of the female reproductive system. In ...

s) by decreasing the water content and increasing the

viscosity The viscosity of a fluid is a measure of its resistance to deformation at a given rate. For liquids, it corresponds to the informal concept of "thickness": for example, syrup has a higher viscosity than water. Viscosity quantifies the inte ...

of the cervical mucus. The estrogen and progestogen in COCPs have other effects on the reproductive system, but these have not been shown to contribute to their contraceptive efficacy: * Slowing tubal motility and ova transport, which may interfere with

fertilization Fertilisation or fertilization (see spelling differences), also known as generative fertilisation, syngamy and impregnation, is the fusion of gametes to give rise to a new individual organism or offspring and initiate its development. Pro ...

. *

Endometrial The endometrium is the inner epithelial layer, along with its mucous membrane, of the mammalian uterus. It has a basal layer and a functional layer: the basal layer contains stem cells which regenerate the functional layer. The functional layer ...

atrophy and alteration of metalloproteinase content, which may impede sperm motility and viability, or theoretically inhibit implantation. * Endometrial edema, which may affect implantation. 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 COCP 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 COCPs.

Formulations

Oral contraceptives come in a variety of formulations, some containing both

and

s, and some only containing

. Doses of component hormones also vary among products, and some pills are monophasic (delivering the same dose of hormones each day) while others are multiphasic (doses vary each day). COCPs can also be divided into two groups, those with progestins that possess androgen activity ( norethisterone acetate, etynodiol diacetate,

levonorgestrel Levonorgestrel is a hormonal medication which is used in a number of birth control methods. It is combined with an estrogen to make combination birth control pills. As an emergency birth control, sold under the brand name Plan B One-Step amon ...

, norgestrel, norgestimate,

, gestodene) or antiandrogen activity ( cyproterone acetate, chlormadinone acetate, drospirenone, dienogest, nomegestrol acetate). COCPs have been somewhat inconsistently grouped into "generations" in the medical literature based on when they were introduced. * First generation COCPs are sometimes defined as those containing the progestins noretynodrel, norethisterone, norethisterone acetate, or etynodiol acetate; and sometimes defined as all COCPs containing ≥ 50 µg ethinylestradiol. * Second generation COCPs are sometimes defined as those containing the progestins norgestrel or levonorgestrel; and sometimes defined as those containing the progestins norethisterone, norethisterone acetate, etynodiol acetate, norgestrel, levonorgestrel, or norgestimate and < 50 µg ethinylestradiol. * Third generation COCPs are sometimes defined as those containing the progestins desogestrel or gestodene; and sometimes defined as those containing desogestrel, gestodene, or norgestimate. * Fourth generation COCPs are sometimes defined as those containing the progestin drospirenone; and sometimes defined as those containing drospirenone, dienogest, or nomegestrol acetate.

History

By the 1930s, Andriy Stynhach had isolated and determined the structure of the steroid hormones and found that high doses of androgens, estrogens or

progesterone Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...

inhibited

, but obtaining these hormones, which were produced from animal extracts, from European

pharmaceutical companies The pharmaceutical industry discovers, develops, produces, and markets drugs or pharmaceutical drugs for use as medications to be administered to patients (or self-administered), with the aim to cure them, vaccinate them, or alleviate sympto ...

was extraordinarily expensive. In 1939,

Russell Marker Russell Earl Marker (March 12, 1902 – March 3, 1995) was an American chemist who invented the octane rating system when he was working at the Ethyl Corporation. Later in his career, he went on to found a steroid industry in Mexico when he ...

, a professor of

organic chemistry Organic chemistry is a subdiscipline within chemistry involving the science, scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain carbon atoms.Clay ...

Pennsylvania State University The Pennsylvania State University (Penn State or PSU) is a public state-related land-grant research university with campuses and facilities throughout Pennsylvania. Founded in 1855 as the Farmers' High School of Pennsylvania, Penn State becam ...

, developed a method of synthesizing

from plant steroid sapogenins, initially using sarsapogenin from sarsaparilla, which proved too expensive. After three years of extensive botanical research, he discovered a much better starting material, the

saponin Saponins (Latin "sapon", soap + "-in", one of), also selectively referred to as triterpene glycosides, are bitter-tasting usually toxic plant-derived organic chemicals that have a foamy quality when agitated in water. They are widely distributed ...

from inedible Mexican yams ('' Dioscorea mexicana'' and '' Dioscorea composita'') found in the rain forests of

Veracruz Veracruz (), formally Veracruz de Ignacio de la Llave (), officially the Free and Sovereign State of Veracruz de Ignacio de la Llave ( es, Estado Libre y Soberano de Veracruz de Ignacio de la Llave), is one of the 31 states which, along with Me ...

near Orizaba. The saponin could be converted in the lab to its aglycone moiety

diosgenin Diosgenin, a phytosteroid sapogenin, is the product of hydrolysis by acids, strong bases, or enzymes of saponins, extracted from the tubers of ''Dioscorea'' wild yam species, such as the Kokoro. The sugar-free (aglycone) product of such hydrolys ...

. 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 Laboratorios Syntex SA (later Syntex Laboratories, Inc.) was a pharmaceutical company formed in Mexico City in January 1944 by Russell Marker, Emeric Somlo, and Federico Lehmann to manufacture therapeutic steroids from the Mexican yams called ''cab ...

with two partners in

Mexico City Mexico City ( es, link=no, Ciudad de México, ; abbr.: CDMX; Nahuatl: ''Altepetl Mexico'') is the capital and largest city of Mexico, and the most populous city in North America. One of the world's alpha cities, it is located in the Valley of ...

. When he left Syntex a year later the trade of the barbasco yam had started and the period of the heyday of the Mexican steroid industry had been started. Syntex broke the monopoly of European pharmaceutical companies on steroid hormones, reducing the price of progesterone almost 200-fold over the next eight years. Midway through the 20th century, the stage was set for the development of a hormonal contraceptive, but pharmaceutical companies, universities and governments showed no interest in pursuing research.

Progesterone to prevent ovulation

Progesterone, given by injections, was first shown to inhibit ovulation in animals in 1937 by Makepeace and colleagues. In early 1951, reproductive

physiologist Physiology (; ) is the scientific study of functions and mechanisms in a living system. As a sub-discipline of biology, physiology focuses on how organisms, organ systems, individual organs, cells, and biomolecules carry out the chemical ...

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 Margaret Higgins Sanger (born Margaret Louise Higgins; September 14, 1879September 6, 1966), also known as Margaret Sanger Slee, was an American birth control activist, sex educator, writer, and nurse. Sanger popularized the term "birth contr ...

at a

Manhattan Manhattan (), known regionally as the City, is the most densely populated and geographically smallest of the five Boroughs of New York City, boroughs of New York City. The borough is also coextensive with New York County, one of the List of co ...

dinner hosted by Abraham Stone, medical director and vice president of

Planned Parenthood The Planned Parenthood Federation of America, Inc. (PPFA), or simply Planned Parenthood, is a nonprofit organization that provides reproductive health care in the United States and globally. It is a tax-exempt corporation under Internal Reve ...

(PPFA), who helped Pincus obtain a small grant from PPFA to begin hormonal contraceptive research. Research started on April 25, 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 Suffrage, political franchise, or simply franchise, is the right to vote in public, political elections and referendums (although the term is sometimes used for any right to vote). In some languages, and occasionally in English, the right to v ...

and

philanthropist Philanthropy is a form of altruism that consists of "private initiatives, for the Public good (economics), public good, focusing on quality of life". Philanthropy contrasts with business initiatives, which are private initiatives for private goo ...

Katharine Dexter McCormick Katharine Dexter McCormick (August 27, 1875 – December 28, 1967) was a U.S. suffragist, philanthropist and, after her husband's death, heir to a substantial part of the McCormick family fortune. She funded most of the research necessary to ...

, 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 on June 6, 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 Gynaecology or gynecology (see spelling differences) is the area of medicine that involves the treatment of women's diseases, especially those of the reproductive organs. It is often paired with the field of obstetrics, forming the combined ar ...

John Rock, chief of gynecology at the Free Hospital for Women and an expert in the treatment of

infertility Infertility is the inability of a person, animal or plant to reproduce by natural means. It is usually not the natural state of a healthy adult, except notably among certain eusocial species (mostly haplodiploid insects). It is the normal st ...

, to lead clinical research with women. At a scientific conference in 1952, Pincus and Rock, who had known each other for many years, discovered they were using similar approaches to achieve opposite goals. In 1952, Rock induced a three-month anovulatory " pseudopregnancy" state in eighty of his infertility patients with continuous gradually increasing oral doses of an estrogen (5 to 30 mg/day diethylstilbestrol) and progesterone (50 to 300 mg/day), and within the following four months 15% of the women became pregnant. In 1953, at Pincus' suggestion, Rock induced a three-month anovulatory "pseudopregnancy" state in twenty-seven of his infertility patients with an oral 300 mg/day progesterone-only regimen for 20 days from

cycle Cycle, cycles, or cyclic may refer to: Anthropology and social sciences * Cyclic history, a theory of history * Cyclical theory, a theory of American political history associated with Arthur Schlesinger, Sr. * Social cycle, various cycles in soc ...

days 5–24 followed by pill-free days to produce withdrawal bleeding. This produced the same 15% pregnancy rate during the following four months without the

of the previous continuous estrogen and progesterone regimen. But 20% of the women experienced

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. Despite the incomplete inhibition of ovulation by oral progesterone, no pregnancies occurred in the two studies, although this could have simply been due to chance. However, Ishikawa et al. reported that the cervical mucus in women taking oral progesterone became impenetrable to sperm, and this may have accounted for the absence of pregnancies. 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. Instead, researchers would turn to much more potent synthetic progestogens for use in oral contraception in the future.

Progestins to prevent ovulation

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

and Searle's noretynodrel and norethandrolone. Chemists

Carl Djerassi Carl Djerassi (October 29, 1923 – January 30, 2015) was an Austrian-born Bulgarian-American pharmaceutical chemist, novelist, playwright and co-founder of Djerassi Resident Artists Program with Diane Wood Middlebrook. He is best known for his ...

, Luis Miramontes, and George Rosenkranz at Syntex in Mexico City had synthesized the first orally highly active progestin norethisterone in 1951. Frank B. Colton at Searle in

Skokie, Illinois Skokie (; formerly Niles Center) is a village in Cook County, Illinois, United States, neighboring the City of Chicago's northern border. Its population, according to the 2020 census, was 67,824. Skokie lies approximately north of Chicago's do ...

had synthesized the orally highly active progestins noretynodrel (an isomer of norethisterone) in 1952 and norethandrolone in 1953. 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 Brookline is a town in Norfolk County, Massachusetts, in the United States, and part of the Boston metropolitan area. Brookline borders six of Boston's neighborhoods: Brighton, Allston, Fenway–Kenmore, Mission Hill, Jamaica Plain, and ...

. Norethisterone or noretynodrel 5 mg doses and all doses of norethandrolone suppressed ovulation but caused breakthrough bleeding, but 10 mg and higher doses of norethisterone or noretynodrel suppressed ovulation without breakthrough bleeding and led to a 14% pregnancy rate in the following five months. Pincus and Rock selected Searle's noretynodrel for the first contraceptive trials in women, citing its total lack of androgenicity versus Syntex's norethisterone very slight androgenicity in animal tests.

Combined oral contraceptive

Noretynodrel (and norethisterone) were subsequently discovered to be contaminated with a small percentage of the estrogen mestranol (an intermediate in their synthesis), with the noretynodrel in Rock's 1954–5 study containing 4–7% mestranol. When further purifying noretynodrel to contain less than 1% mestranol led to breakthrough bleeding, it was decided to intentionally incorporate 2.2% mestranol, a percentage that was not associated with breakthrough bleeding, in the first contraceptive trials in women in 1956. The noretynodrel and mestranol combination was given the proprietary name Enovid. The first contraceptive trial of Enovid led by

Celso-Ramón García Celso-Ramón García (1922 – February 1, 2004) was an American physician who specialized in reproductive endocrinology and infertility. He oversaw early clinical trials of the first oral contraceptive pill in Puerto Rican women and later becam ...

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 Los Angeles ( ; es, Los Ángeles, link=no , ), often referred to by its initials L.A., is the largest city in the state of California and the second most populous city in the United States after New York City, as well as one of the wor ...

. On January 23, 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.

Public availability

United States

On June 10, 1957, the

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

(FDA) approved Enovid 10 mg (9.85 mg noretynodrel and 150 µg mestranol) for menstrual disorders, based on data from its use by more than 600 women. Numerous additional contraceptive trials showed Enovid at 10, 5, and 2.5 mg doses to be highly effective. On July 23, 1959, Searle filed a supplemental application to add contraception as an approved indication for 10, 5, and 2.5 mg doses of Enovid. The FDA refused to consider the application until Searle agreed to withdraw the lower dosage forms from the application. On May 9, 1960, the FDA announced it would approve Enovid 10 mg for contraceptive use, and did so on June 23, 1960. At that point, Enovid 10 mg had been in general use for three years and, by conservative estimate, at least half a million women had used it. Although FDA-approved for contraceptive use, Searle never marketed Enovid 10 mg as a contraceptive. Eight months later, on February 15, 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

in a woman using Enavid (Enovid 10 mg in the U.S.) 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

in oral contraceptive users who

or have

high blood pressure Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high b ...

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. The hearings were conducted by senators who were all men and the witnesses in the first round of hearings were all men, leading Alice Wolfson and other feminists to protest the hearings and generate media attention. Their work led to mandating the inclusion of

patient package insert A package insert is a document included in the package of a medication that provides information about that drug and its use. For prescription medications, the insert is technical, providing information for medical professionals about how to ...

s with oral contraceptives to explain their possible side effects and risks to help facilitate

informed consent Informed consent is a principle in medical ethics and medical law, that a patient must have sufficient information and understanding before making decisions about their medical care. Pertinent information may include risks and benefits of treatm ...

. Today's standard dose oral contraceptives contain an estrogen dose that is one third lower than the first marketed oral contraceptive and contain lower doses of different, more potent progestins in a variety of formulations. 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. Currently, pharmacists in

Oregon Oregon () is a state in the Pacific Northwest region of the Western United States. The Columbia River delineates much of Oregon's northern boundary with Washington, while the Snake River delineates much of its eastern boundary with Idah ...

California California is a state in the Western United States, located along the Pacific Coast. With nearly 39.2million residents across a total area of approximately , it is the most populous U.S. state and the 3rd largest by area. It is also the ...

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, and

New Mexico ) , population_demonym = New Mexican ( es, Neomexicano, Neomejicano, Nuevo Mexicano) , seat = Santa Fe, New Mexico, Santa Fe , LargestCity = Albuquerque, New Mexico, Albuquerque , LargestMetro = Albuquerque metropolitan area, Tiguex , Offi ...

have authority to prescribe birth control after receiving specialized training and certification from their respective state

Board of Pharmacy The National Association of Boards of Pharmacy''. The NABP membership is composed of 54 active members and 12 associate members. Active member boards include all 50 United States, the District of Columbia, Guam, Puerto Rico, and the Virgin Islands ...

. Other states are considering this legislation, including

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, and

New Hampshire New Hampshire is a state in the New England region of the northeastern United States. It is bordered by Massachusetts to the south, Vermont to the west, Maine and the Gulf of Maine to the east, and the Canadian province of Quebec to the nor ...

Australia

The first oral contraceptive introduced outside the United States was Schering's Anovlar ( norethisterone acetate 4 mg +

50 µg) on January 1, 1961, in Australia.

Germany

The first oral contraceptive introduced in Europe was Schering's Anovlar on June 1, 1961, in

West Germany West Germany is the colloquial term used to indicate the Federal Republic of Germany (FRG; german: Bundesrepublik Deutschland , BRD) between its formation on 23 May 1949 and the German reunification through the accession of East Germany on 3 O ...

. The lower hormonal dose, still in use, was studied by the Belgian Gynaecologist Ferdinand Peeters.

United Kingdom

Before the mid-1960s, the United Kingdom did not require pre-marketing approval of drugs. The British

Family Planning Association FPA (Family Planning Association) was a UK registered charity (number 250187) working to enable people to make informed choices about sex and to enjoy sexual health. It was the national affiliate for the International Planned Parenthood Federat ...

(FPA) through its clinics was then the primary provider of family planning services in the UK and provided only contraceptives that were on its Approved List of Contraceptives (established in 1934). In 1957, Searle began marketing Enavid (Enovid 10 mg in the U.S.) for menstrual disorders. Also in 1957, the FPA established a Council for the Investigation of Fertility Control (CIFC) to test and monitor oral contraceptives which began animal testing of oral contraceptives and in 1960 and 1961 began three large clinical trials in

Birmingham Birmingham ( ) is a city and metropolitan borough in the metropolitan county of West Midlands in England. It is the second-largest city in the United Kingdom with a population of 1.145 million in the city proper, 2.92 million in the We ...

, Slough, and

London London is the capital and List of urban areas in the United Kingdom, largest city of England and the United Kingdom, with a population of just under 9 million. It stands on the River Thames in south-east England at the head of a estuary dow ...

. 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 U.S.). 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 U.S.). 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.
On December 4, 1961,

Enoch Powell John Enoch Powell, (16 June 1912 – 8 February 1998) was a British politician, classical scholar, author, linguist, soldier, philologist, and poet. He served as a Conservative Member of Parliament (1950–1974) and was Minister of Health (1 ...

, then Minister of Health, announced that the oral contraceptive pill Conovid could be prescribed through the NHS at a subsidized price of 2 s per month. In 1962, Schering's Anovlar and Searle's Conovid-E were added to the FPA's Approved List of Contraceptives.

France

On December 28, 1967, the

Neuwirth Law The Neuwirth Law is a French law which lifted the ban on birth control methods on December 28, 1967, including oral contraception. It was passed by the National Assembly on December 19, 1967. The law is named after Lucien Neuwirth, the Gaullist p ...

legalized contraception in France, including the pill. The pill is the most popular form of contraception in France, especially among young women. It accounts for 60% of the birth control used in France. The abortion rate has remained stable since the introduction of the pill.

Japan

In Japan, lobbying from the Japan Medical Association prevented the pill from being approved for general use for nearly 40 years. The higher dose "second generation" pill was approved for use in cases of gynecological problems, but not for birth control. Two main objections raised by the association were safety concerns over long-term use of the pill, and concerns that pill use would lead to decreased use of condoms and thereby potentially increase sexually transmitted infection (STI) rates. However, when the Ministry of Health and Welfare approved Viagra's use in Japan after only six months of the application's submission, while still claiming that the pill required more data before approval, women's groups cried foul. The pill was subsequently approved for use in June 1999, when Japan became the last UN member country to do so. However, the pill has not become popular in Japan. According to estimates, only 1.3 percent of 28 million Japanese females of childbearing age use the pill, compared with 15.6 percent in the United States. The pill prescription guidelines the government has endorsed require pill users to visit a doctor every three months for pelvic examinations and undergo tests for sexually transmitted diseases and uterine cancer. In the United States and Europe, in contrast, an annual or bi-annual clinic visit is standard for pill users. However, beginning as far back as 2007, many Japanese

OBGYN Obstetrics and Gynaecology (also spelled as Obstetrics and Gynecology; abbreviated as Obs and Gynae, O&G, OB-GYN and OB/GYN) is the medical specialty that encompasses the two subspecialties of obstetrics (covering pregnancy, childbirth, an ...

s have required only a yearly visit for pill users, with multiple checks a year recommended only for those who are older or at increased risk of side effects. As of 2004, condoms accounted for 80% of birth control use in Japan, and this may explain Japan's comparatively low rates of AIDS.

Society and culture

The pill was approved by the FDA in the early 1960s; its use spread rapidly in the late part of that decade, generating an enormous social impact. ''

Time Time is the continued sequence of existence and events that occurs in an apparently irreversible succession from the past, through the present, into the future. It is a component quantity of various measurements used to sequence events, t ...

'' magazine placed the pill on its cover in April, 1967. In the first place, it was more effective than most previous reversible methods of birth control, giving women unprecedented control over their fertility. Its use was separate from intercourse, requiring no special preparations at the time of sexual activity that might interfere with spontaneity or sensation, and the choice to take the pill was a private one. This combination of factors served to make the pill immensely popular within a few years of its introduction.

Claudia Goldin Claudia Goldin (born May 14, 1946) is an American economic historian and labor economist who is currently the Henry Lee Professor of Economics at Harvard University. She is a co-director of the NBER's Gender in the Economy Study Group and was th ...

, 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 Premarital sex is sexual activity which is practiced by people before they are married. Premarital sex is considered a sin by a number of religions and also considered a moral issue which is taboo in many cultures. Since the Sexual Revolution ...

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 The Catholic Church, also known as the Roman Catholic Church, is the largest Christian church, with 1.3 billion baptized Catholics worldwide . It is among the world's oldest and largest international institutions, and has played a ...

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

Evangelical Church in Germany The Evangelical Church in Germany (german: Evangelische Kirche in Deutschland, abbreviated EKD) is a federation of twenty Lutheran, Reformed (Calvinist) and United (e.g. Prussian Union) Protestant regional churches and denominations in Germany, ...

(EKD), accepted the combined oral contraceptive pill. The

United States Senate The United States Senate is the upper chamber of the United States Congress, with the House of Representatives being the lower chamber. Together they compose the national bicameral legislature of the United States. The composition and ...

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 The United States secretary of health and human services is the head of the United States Department of Health and Human Services, and serves as the principal advisor to the president of the United States on all health matters. The secretary is ...

at the time, Robert Finch, announced the federal government had accepted a compromise warning statement which would accompany all sales of birth control pills.

Result on popular culture

The introduction of the birth control pill in 1960 allowed more women to find employment opportunities and further their education. As a result of women getting more jobs and an education, their husbands had to start taking over household tasks like cooking. Wanting to stop the change that was occurring in terms of gender norms in an American household, many films, television shows, and other popular culture items portrayed what an ideal American family should be. Below are listed some examples:

Poem

* '' The Pill Versus the Springhill Mine Disaster'' was the title poem of a 1968 collection by Richard Brautigan.

Music

* Singer

Loretta Lynn Loretta Lynn (; April 14, 1932 – October 4, 2022) was an American country music singer and songwriter. In a career spanning six decades, Lynn released multiple gold albums. She had numerous hits such as "You Ain't Woman Enough (To Take My Ma ...

commented on how women no longer had to choose between a relationship and a career in her 1974 album with a song entitled " The Pill", which told the story of a married woman's use of the drug to liberate herself from her traditional role as wife and mother.

Environmental impact

A woman using COCPs excretes from her

urine Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excreted from the body through the urethra. Cellular ...

and

feces Feces ( or faeces), known colloquially and in slang as poo and poop, are the solid or semi-solid remains of food that was not digested in the small intestine, and has been broken down by bacteria in the large intestine. Feces contain a rela ...

natural

s, estrone (E1) and

(E2), and synthetic estrogen

(EE2). These hormones can pass through

water treatment Water treatment is any process that improves the quality of water to make it appropriate for a specific end-use. The end use may be drinking, industrial water supply, irrigation, river flow maintenance, water recreation or many other uses, inclu ...

plants and into rivers. Other forms of contraception, such as the contraceptive patch, use the same synthetic estrogen (EE2) that is found in COCPs, and can add to the hormonal concentration in the water when flushed down the toilet. This

excretion Excretion is a process in which metabolic waste is eliminated from an organism. In vertebrates this is primarily carried out by the lungs, kidneys, and skin. This is in contrast with secretion, where the substance may have specific tasks afte ...

is shown to play a role in causing endocrine disruption, which affects the sexual development and reproduction of wild

fish Fish are aquatic, craniate, gill-bearing animals that lack limbs with digits. Included in this definition are the living hagfish, lampreys, and cartilaginous and bony fish as well as various extinct related groups. Approximately 95% ...

populations in segments of streams contaminated by treated sewage effluents. A study done in British rivers supported the hypothesis that the incidence and the severity of intersex wild fish populations were significantly correlated with the concentrations of the E1, E2, and EE2 in the rivers. A review of

activated sludge plant "Activated" is a song by English singer Cher Lloyd. It was released on 22 July 2016 through Vixen Records. The song was made available to stream exclusively on '' Rolling Stone'' a day before to release (on 21 July 2016). Background In an inte ...

performance found estrogen removal rates varied considerably but averaged 78% for estrone, 91% for estradiol, and 76% for ethinylestradiol (

estriol Estriol (E3), also spelled oestriol, is a steroid, a weak estrogen, and a minor female sex hormone. It is one of three major endogenous estrogens, the others being estradiol and estrone. Levels of estriol in women who are not pregnant are almos ...

effluent concentrations are between those of estrone and estradiol, but estriol is a much less potent

endocrine disruptor Endocrine disruptors, sometimes also referred to as hormonally active agents, endocrine disrupting chemicals, or endocrine disrupting compounds are chemicals that can interfere with endocrine (or hormonal) systems. These disruptions can cause ...

to fish). Several studies have suggested that reducing human population growth through increased access to

contraception Birth control, also known as contraception, anticonception, and fertility control, is the use of methods or devices to prevent unwanted pregnancy. Birth control has been used since ancient times, but effective and safe methods of birth contr ...

, including birth control pills, can be an effective strategy for

climate change mitigation Climate change mitigation is action to limit climate change by reducing emissions of greenhouse gases or removing those gases from the atmosphere. The recent rise in global average temperature is mostly caused by emissions from fossil fuels bu ...

as well as adaptation. According to Thomas Wire, contraception is the 'greenest technology' because of its cost-effectiveness in combating

global warming In common usage, climate change describes global warming—the ongoing increase in global average temperature—and its effects on Earth's climate system. Climate variability and change, Climate change in a broader sense also includes ...

— 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.

References

External links

The Birth Control Pill
��CBC Digital Archives
The Birth of the Pill
��slide show by ''

Life Life is a quality that distinguishes matter that has biological processes, such as Cell signaling, signaling and self-sustaining processes, from that which does not, and is defined by the capacity for Cell growth, growth, reaction to Stimu ...

'' magazine {{DEFAULTSORT:Combined Oral Contraceptive Pill Combined oral contraceptives Hepatotoxins Sexual revolution World Health Organization essential medicines