Everything about The Combined Oral Contraceptive Pill totally explained
The
Combined Oral Contraceptive Pill (
COCP), often referred to as "
the Pill", is a combination of an
estrogen (
oestrogen) and a
progestin (
progestogen), taken by mouth to inhibit normal female fertility. Combined oral contraceptives were developed by
Gregory Goodwin Pincus,
John Rock, and
Min Chueh Chang. They were first approved for contraceptive use in the
United States in 1960, and are still a popular form of
birth control. They are currently used by more than 100 million women worldwide and by almost 12 million women in the United States. Usage varies widely by country, age, education, and marital status: one quarter of women aged 16–49 in
Great Britain currently use the Pill (combined pill or
minipill),
compared to only 1% of women in
Japan.
History
By the 1930s, scientists had isolated and determined the structure of the
steroid hormones and found that high doses of
androgens,
estrogens or
progesterone inhibited
ovulation,
but obtaining them from European
pharmaceutical companies produced from animal extracts was extraordinarily expensive.
In 1939,
Russell Marker, a professor of
organic chemistry at
Pennsylvania State University, developed a method of synthesizing
progesterone from plant steroid sapogenins, initially using sarsapogenin from
sarsaparilla which proved too expensive. After three years of extensive botanical research he discovered a much better starting material, the aglycone moiety of the
saponin,
diosgenin, from inedible Mexican
wild yams found in the jungles of
Veracruz near
Orizaba. 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 before leaving Syntex a year later. 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 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.
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 "pseudo-pregnancy" state in eighty of his infertility patients with continuous gradually increasing oral doses of
estrogen (
diethylstilbestrol 5 – 30 mg/day) and progesterone (50 – 300 mg/day) and within the following four months an encouraging 15% became pregnant.
In 1953, at Pincus' suggestion, Rock induced a three-month anovulatory "pseudo-pregnancy" state in twenty-seven of his infertility patients with an oral 300 mg/day progesterone-only regimen for 20 days from
cycle days 5 – 24 followed by pill-free days to produce
withdrawal bleeding. This produced the same encouraging 15% pregnancy rate during the following four months without the troubling
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.
Studies of 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
norethindrone and Searle's
norethynodrel and
norethandrolone.
Chemists
Carl Djerassi,
Luis Miramontes, and
George Rosenkranz at Syntex in Mexico City had synthesized the first orally highly active progestin norethindrone in 1951. Chemist
Frank B. Colton at Searle in
Skokie, Illinois had synthesized the orally highly active progestins norethynodrel (an isomer of norethindrone) in 1952 and norethandrolone in 1953.
Development of an effective combined oral contraceptive
Norethynodrel (and norethindrone) were subsequently discovered to be contaminated with a small percentage of the estrogen
mestranol (an intermediate in their synthesis), with the norethynodrel in Rock's 1954-5 study containing 4-7% mestranol. When further purifying norethynodrel to contain less than 1% mestranol led to breakthrough bleeding, it was decided to intentionally incorporate 2.2% mestranol, a percentage that wasn't associated with breakthrough bleeding, in the first contraceptive trials in women in 1956. The norethynodrel and mestranol combination was given the proprietary name
Enovid.
The first contraceptive trial of
Enovid led by Edris Rice-Wray began in April 1956 in Río Piedras, Puerto Rico. A second contraceptive trial of Enovid (and norethindrone) led by Edward T. Tyler began in June 1956 in Los Angeles. 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.
Public availability
United States
On June 10, 1957, the
FDA approved
Enovid 10 mg (9.85 mg norethynodrel 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, which it did on June 23, 1960, by which time
Enovid 10 mg had been in general use for three years during which time, 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 norethynodrel and 75 µg mestranol) to physicians as a contraceptive. It would take almost a decade of
epidemiological studies to conclusively establish an increased risk of
venous thrombosis in oral contraceptive users and an increased risk of
stroke and
myocardial infarction in oral contraceptive users who
smoke or have
high blood pressure or other cardiovascular or cerebrovascular risk factors. The hearings were conducted by Senators who were all men and the witnesses in the first round of hearings were all men, leading
Alice Wolfson and other feminists to protest the hearings and generate media attention. Today's standard dose oral contraceptives contain an estrogen dose that's one third lower than the first marketed oral contraceptive and contain lower doses of different, more potent progestins in a variety of formulations.
Germany
The first oral contraceptive introduced in
Europe was Schering's
Anovlar on June 1, 1961 in
West Germany.
In March 1960, the Birmingham FPA began trials of norethynodrel 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 norethynodrel 5 mg + mestranol 75 µg (
Conovid in Britain,
Enovid 5 mg in the U.S.).
In August 1960, the Slough FPA began trials of norethynodrel 2.5 mg + mestranol 100 µg (
Conovid-E in Britain,
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, then
Minister of Health, announced that the oral contraceptive pill
Conovid could be prescribed through the
NHS at a subsidized price of 2
s per month.
In 1962, Schering's
Anovlar and Searle's
Conovid-E were added to the FPA's Approved List of Contraceptives. The pill is the most popular form of contraception in France, especially among young women. 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 nearly 40 years. Two main objections raised by the association were safety concerns over long-term use of the Pill, and concerns that the Pill use would lead to diminished use of condoms and thereby potentially increase
sexually transmitted infection (STI) rates. As of 2004, condoms accounted for 80% of birth control use in Japan, and this may explain Japan's comparably low rates of AIDS. Most brands of combined pills are packaged in one of two different packet sizes, with days marked off for a 28 day cycle. For the 21-pill packet, a pill is consumed daily for three weeks, followed by a week of no pills. For the 28-pill packet, 21 pills are taken, followed by week of placebo or
sugar pills. A woman on the pill will have a withdrawal bleed sometime during the placebo week, and is still protected from pregnancy during this week.
Placebo pills
The purpose of the placebo pills is that the user can take a pill on every day of her menstrual cycle, remaining in this daily habit even during the week without hormones. Placebo pills may contain an
iron supplement, as iron requirements increase during menstruation.
Failure to take pills during the placebo week has no effect on the effectiveness of the pill provided that daily ingestion of active pills is resumed at the end of the week.
The presence of placebo pills is thought to be comforting, as menstruation is a physical confirmation of not being pregnant. The 28-day pill package also simulates the average
menstrual cycle, though the hormonal events during a pill cycle are completely different from those of a normal ovulatory menstrual cycle, and the bleeding is triggered by different hormonal cues. Breakthrough bleeding also becomes a more common side effect as a woman attempts to go longer periods of time between menstrual periods.
Less frequent placebos
If the pill formulation is monophasic, it's possible to skip
menstruation and still remain protected against conception by skipping the placebo pills and starting directly with the next packet. Attempting this with bi- or tri-phasic pill formulations carries an increased risk of
breakthrough bleeding 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 completely 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.
Effectiveness
The effectiveness of COCPs, as of most forms of
contraception, can be assessed two ways.
Perfect use or
method effectiveness rates only include people who take the pills consistently and correctly.
Actual use, or
typical use effectiveness rates are of all COCP users, including those who take the pills incorrectly, inconsistently, or both. Rates are generally presented for the first year of use. Most commonly the
Pearl Index is used to calculate effectiveness rates, but some studies use
decrement tables.
The typical use pregnancy rate among COCP users varies depending on the population being studied, ranging from 2-8% per year. The perfect use pregnancy rate of COCPs is 0.3% per year.
Contraceptive efficacy may be impaired by: 1) missing more than one active pill in a packet, 2) delay in starting the next packet of active pills (for example extending the pill-free, inactive or placebo pill period beyond 7 days), 3)
intestinal malabsorption of active pills due to
vomiting or
diarrhea, 4) drug interactions with active pills that decrease contraceptive estrogen or progestogen levels.
Progestagen
negative feedback decreases the pulse frequency of
gonadotropin-releasing hormone (GnRH) release by the
hypothalamus, which decreases the release of
follicle-stimulating hormone (FSH) and greatly decreases the release of
luteinizing hormone (LH) by the
anterior pituitary. Decreased levels of FSH inhibit follicular development, preventing an increase in
estradiol levels. Progestagen negative feedback and the lack of estrogen
positive feedback on LH release prevent a
mid-cycle LH surge. Inhibition of follicular development and the absence of a LH surge prevent ovulation., while yet other scientists argue the existing data supports such mechanisms. The controversy is currently unresolved.
Drug interactions
Some
drugs reduce the effect of the Pill and can cause
breakthrough bleeding, or increased chance of pregnancy. These include drugs such as
rifampicin,
barbiturates,
phenytoin and
carbamazepine. In addition cautions are given about broad spectrum antibiotics, such as
ampicillin and
doxycycline, which may cause problems "by impairing the
bacterial flora responsible for recycling
ethinylestradiol 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
liver.
Side-effects
Different sources note different incidences of side effects. A
University of New Mexico Student Health Center webpage says the majority (about 60%) of women report no side effects at all, and the vast majority of those who do, have only minor effects. A 1992 French review article said that as many as 50% of new first-time users discontinue the Pill before the end of the first year because of nuisance bleeding irregularity side effects such as breakthrough bleeding and
amenorrhea.
Weight
The same 1992 French review article noted that in the subgroup of adolescents 15–19 years of age in the 1982
National Survey of Family Growth (NSFG) who had stopped taking the Pill, 20–25% reported they stopped taking the Pill because of either
acne or weight gain, and another 25% stopped because of fear of cancer.
Many clinicians consider the public perception of weight gain on the Pill to be inaccurate and dangerous. The aforementioned 1992 French review article noted that one unpublished 1989 study by Professor Elizabeth Connell at
Emory University of 550 women found that 23% of the 6% of women who discontinued the Pill because of poor cycle control experienced subsequent unwanted pregnancies.
Sexuality
The Pill may have a positive effect on a woman's sexuality. Because neither the woman (who uses the Pill) nor her partner need take any special action before or during intercourse, it makes birth control "invisible" and sex spontaneous, more natural, or both.
However, some say the Pill can also have a negative effect on a woman's sexuality. Dr. John Bancroft (a senior research fellow at the Kinsey Institute at Indiana University) estimates that one in four women on the pill experience some negative sexual effect. These effects may include a decreased frequency of sexual thoughts, increased difficulty in becoming aroused, or decreased lubrication, which can make sex painful. Recent research co-authored by Dr. Irwin Goldstein (a urologist in Boston) suggests such effects may continue for up to four months after a woman stops taking the Pill.
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 promote the lowering of brain serotonin levels by increasing the concentration of a brain enzyme that reduces serotonin.
Current medical reference textbooks on contraception the
WHO, and the United Kingdom's
RCOG agree that current evidence indicates low-dose oral contraceptives are unlikely to increase the risk of depression, and unlikely to worsen the condition in women who are currently depressed.
Contraceptive Technology states that low-dose COCPs have not been implicated in disruptions of serotonin or
tryptophan.
Other effects
Other possible side effects are:
vaginal discharge, changes in
menstrual flow,
breakthrough bleeding,
nausea,
vomiting,
headaches, changes in the
breasts, changes in
blood pressure, loss of scalp hair,
skin problems and skin improvements. The insert included with each pill packet usually has a more extensive list of recognized side effects.
Formulations
Oral contraceptives come in a variety of formulations. The main division is between combined oral contraceptive pills, containing both
estrogen and
progestins and
progestin only pills. Combined oral contraceptive pills also come in varying types, including varying doses of estrogen, and whether the dose of estrogen or progestin changes from week to week.
Cautions and contraindications
Oral contraceptives may influence
coagulation, increasing the risk of
deep venous thrombosis (DVT) and
pulmonary embolism,
stroke and
myocardial infarction (heart attack). Combined oral contraceptives are generally accepted to be contraindicated in women with pre-existing
cardiovascular disease, in women who have a familial tendency to form blood clots (such as familial
factor V Leiden), women with severe
obesity and/or
hypercholesterolaemia (high cholesterol level), and in
smokers over age 35.
Research into the relationship between
breast cancer risk and
hormonal contraception is complex and seemingly contradictory.
The large 1996 collaborative reanalysis of individual data on over 150,000 women in 54 studies of breast cancer found that:
"The results provide strong evidence for two main conclusions. First, while women are taking combined oral contraceptives and in the 10 years after stopping there's a small increase in the relative risk of having breast cancer diagnosed. Second, there's no significant excess risk of having breast cancer diagnosed 10 or more years after stopping use. The cancers diagnosed in women who had used combined oral contraceptives were less advanced clinically than those diagnosed in women who had never used these contraceptives."
This data has been interpreted to suggest that oral contraceptives have little or no biological effect on breast cancer development, but that women who seek gynecologic care to obtain contraceptives have more early breast cancers detected through screening.
It is generally accepted by medical authorities 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) isn't relevant - instead, the comparison of safety should be among available methods of contraception.
Non-contraceptive uses
The hormones in "the Pill" can be used to treat some medical conditions, such as
polycystic ovary syndrome (PCOS),
endometriosis,
adenomyosis, anemia related to menstruation, and painful menstruation (
dysmenorrhea). In addition, oral contraceptives are often prescribed as medication for mild or moderate acne. The pill can also induce menstruation on a regular schedule for women bothered by irregular menstrual cycles and certain disorders where there's
dysfunctional uterine bleeding.
Combined oral contraceptive use reduces the risk of
ovarian cancer by 40% and the risk of
endometrial cancer by 50% compared to 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.
A backlash against oral contraceptives occurred in the early and mid-1970s, when reports and speculations appeared that linked the use of the Pill to
breast cancer. Until then, many women in the
feminist movement had hailed the Pill as an "equalizer" that had given them the same sexual freedom as men had traditionally enjoyed. This new development, however, caused many of them to denounce oral contraceptives as a male invention designed to facilitate male sexual freedom with women at the cost of health risk to women.
At the same time, society was beginning to take note of the impact of the Pill on traditional gender roles. Women now didn't have to choose between a relationship and a career; singer
Loretta Lynn commented on this 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
Human
excretion in
urine and
feces of the natural
estrogens
estrone and
estradiol and excretion of the synthetic estrogen
ethinylestradiol by women using COCPs are likely to play a role in causing
endocrine disruption in wild
fish populations in some segments of
streams contaminated by
treated sewage effluents.
A review of
activated sludge plant 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).
Effluent concentrations of ethinylestradiol are lower than estradiol which are lower than estrone, but ethinylestradiol is more potent than estradiol which is more potent than estrone in the induction of intersex fish and synthesis of
vitellogenin in male fish.
Footnotes
Further Information
Get more info on 'Combined Oral Contraceptive Pill'.
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