Combined oral contraceptive pill

reduced.[14] Most brands of combined pills are packaged

in one of two dierent packet sizes, with days marked
o 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 a 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. There are also two newer combination birth control
pills (Yaz 28 and Loestrin 24 Fe) that have 24 days of
active hormone pills, followed by 4 days of placebo.[15]

The Pill redirects here. For other meanings, see Pill (disambiguation). This article is
about daily use of COC. For occasional use, see
Emergency contraception.
The combined oral contraceptive pill (COCP), often referred to as the birth control pill or colloquially
as "the pill", is a birth control method that includes a
combination of an estrogen (estradiol) and a progestogen
(progestin). When taken by mouth every day, these pills
inhibit female fertility. They were rst approved for contraceptive use in the United States in 1960, and are a very
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.[8] Use varies
widely by country,[9] age, education, and marital status.
One third of women aged 1649 in the United Kingdom
currently use either the combined pill or a progestogenonly "minipill",[10][11] compared to only 1% of women in
Japan.[12]

1.1 Placebo pills

The placebo pills allow the user to take a pill every
day; remaining in the daily habit even during the week
without hormones. Placebo pills may contain an iron
supplement,[16][17] as iron requirements increase during
menstruation.
Failure to take pills during the placebo week does not impact the eectiveness of the pill, provided that daily ingestion of active pills is resumed at the end of the week.

Instruction for missed pills: 1_less than 12 hours : just

take delay one. 2_ more than 12 hours ask about how
many pills are missed if : a_ more than or equal 7 pills ,
after nishing the back take 7 days break. b_less than 7
days , after nshing the back , start the next back without
break. [13]

The withdrawal bleeding that occurs during the break

from active pills was thought to be comforting, as a physical conrmation of not being pregnant.[18] The 28-day
pill package also simulates the average menstrual cycle,
though the hormonal events during a pill cycle are significantly dierent from those of a normal ovulatory menstrual cycle. The pill suppresses the normal cycle, and
the withdrawal bleeding occurs while the placebo pills
are taken. The withdrawal bleeding is also predictable.
Unexpected breakthrough bleeding can be a possible side
eect of longer term active regimens.[19]

Medical use

1.2 No or less frequent placebos

Main article: Extended cycle combined oral contraceptive pill
If the pill formulation is monophasic, it is possible to skip
withdrawal bleeding and still remain protected against
conception by skipping the placebo pills and starting directly with the next packet. Attempting this with bi- or
Half-used blister pack of LevlenED
tri-phasic pill formulations carries an increased risk of
Combined oral contraceptive pills should be taken at the breakthrough bleeding and may be undesirable. It will
same time each day. If one or more tablets are forgotten not, however, increase the risk of getting pregnant.
for more than 12 hours, contraceptive protection will be Starting in 2003, women have also been able to use a
1

2 DRUG INTERACTIONS

three-month version of the Pill.[20] Similar to the eect

of using a constant-dosage formulation and skipping the
placebo weeks for three months, Seasonale gives the benet 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.

The eectiveness of the combined oral contraceptive pill

appears to be similar whether the active pills are taken
continuously for prolonged periods of time or if they are
taken for 21 active days and 7 days as placebo.[24]

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 eect of going longer periods of time without breaks from active
pills.[21]

1.4 Non-contraceptive use

1.3

Eectiveness

The estimated probability of pregnancy during the rst

year of perfect use of the pill is 0.3%, and the estimated
probability of pregnancy during the rst year of typical
use of the pill is 9%.[1] The perfect use failure rate is
based on a review of pregnancy rates in clinical trials, 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.[1]
Several factors account for typical use eectiveness being
lower than perfect use eectiveness:

The hormones in the Pill have also been used to

treat other medical conditions, such as polycystic ovary
syndrome (PCOS), endometriosis, amenorrhea, menstrual cramps, adenomyosis, menorrhagia (excessive
menstral bleeding), menstruation-related anemia and
dysmenorrhea (painful menstruation).[25] Though extensively used for these conditions, no oral contraceptives
have been approved by the U.S. FDA for those uses because of lack of convincing scientic evidence that the
benets outweigh the risks. In addition, oral contraceptives are sometimes prescribed as medication for mild or
moderate acne, although none are approved by the U.S.
FDA for that sole purpose.[26] Three dierent oral contraceptives have been FDA approved to treat moderate
acne if the person is at least 14 or 15 years old, have already begun menstruating, and need contraception. They
include Ortho Tri-Cyclen, Estrostep, and YAZ.[27] 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.

mistakes on the part of those providing instructions

on how to use the method
Women who are experiencing menstrual dysfunction due
to female athlete triad are sometimes prescribed oral
mistakes on the part of the user
contraceptives as pills can create menstrual bleeding
conscious user non-compliance with instructions.
cycles.[28] However, the conditions underlying cause is
energy deciency and should be treated by correcting the
For instance, someone using oral forms of hormonal birth imbalance between calories eaten and calories burned by
control might be given incorrect information by a health exercise. Oral contraceptives should not be used as an
care provider as to the frequency of intake, or by mistake initial treatment for female athlete triad.[28]
not take the pill one day, or simply not go to the pharmacy
on time to renew the prescription.
COCPs provide eective contraception from the very
rst pill if started within ve days of the beginning of
the menstrual cycle (within ve days of the rst day of
menstruation). If started at any other time in the menstrual cycle, COCPs provide eective contraception only
after 7 consecutive days use of active pills, so a backup
method of contraception must be used until active pills
have been taken for 7 consecutive days. COCPs should
be taken at approximately the same time every day.[22][23]

2 Drug interactions
Some drugs reduce the eect 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 ora responsible for
recycling ethinylestradiol from the large bowel (BNF
2003).[29][30][31][32]

Contraceptive ecacy may be impaired by: 1) missing

more than one active pill in a packet, 2) delay in starting the next packet of active pills (i.e., extending the pillfree, inactive or placebo pill period beyond 7 days), 3)
intestinal malabsorption of active pills due to vomiting The traditional medicinal herb St Johns Wort has also
or diarrhea, 4) drug interactions with active pills that de- been implicated due to its upregulation of the P450 syscrease contraceptive estrogen or progestogen levels.[22]
tem in the liver.

4.2

Cancer

Common side eects

3
combined oral contraceptives containing levonorgestrel
(LNG), and with the same dose of estrogen and duration of use, the rate ratio of deep venous thrombosis for
combined oral contraceptives with norethisterone is 0.98,
with norgestimate 1.19, with desogestrel (DSG) 1.82,
with gestodene 1.86, with drospirenone (DRSP) 1.64,
and with cyproterone acetate 1.88.[45] In comparison, venous thromboembolism occurs in 100200 per 100.000
pregnant women every year.[45]

Dierent sources note dierent incidences of side eects.

The most common side eect is breakthrough bleeding.
A 1992 French review article said that as many as 50%
of new rst-time users discontinue the birth control pill
before the end of the rst year because of the annoyance of side eects such as breakthrough bleeding and
amenorrhea.[33] One study found that women using birth
control pills blinked 32% more often than those not using One study showed more than a 600% increased
the contraception.[34]
risk of blood clots for women taking COCPs with
On the other hand, the pills can sometimes improve drospirenone compared to non-users, compared to 360%
taking birth control pills containing
conditions such as pelvic inammatory disease, dys- higher for women
[46]
levonorgestrel.
The
U.S. Food and Drug Administra[35]
menorrhea, premenstrual syndrome, and acne,
retion
(FDA)
initiated
studies
evaluating the health of more
duce symptoms of endometriosis and polycystic ovary
than
800,000
women
taking
COCPs and found that the
[36]
syndrome, and decrease the risk of anemia.
Use of
risk
of
VTE
was
93%
higher
for women who had been
oral contraceptives also reduces lifetime risk of ovarian
taking
drospirenone
COCPs
for
3 months or less and
[37][38]
cancer.
290% higher for women taking drospirenone COCPs for
Nausea, vomiting, headache, bloating, breast tenderness, 712 months, compared to women taking other types of
swelling of the ankles/feet (uid retention), or weight oral contraceptives.[47]
change may occur. Vaginal bleeding between periods
(spotting) or missed/irregular periods may occur, espe- Based on these studies, in 2012 the FDA updated the label for drospirenone COCPs to include a warning that
cially during the rst few months of use.[39]
contraceptives with drospirenone may have a higher risk
of dangerous blood clots.[48]

Major side eects

It is generally accepted by medical authorities that the

health risks of oral contraceptives are lower than those
from pregnancy and birth,[40] and the health benets
of any method of contraception are far greater than
any risks from the method.[41] Some organizations have
argued that comparing a contraceptive method to no
method (pregnancy) is not relevantinstead, the comparison of safety should be among available methods of
contraception.[42]

4.1

Venous thromboembolism

Combined oral contraceptives increase the risk of

venous thromboembolism (including deep vein thrombosis [DVT] and pulmonary embolism [PE]).[43] These
blood clots can cause permanent disability or death. COC
pills also confer a risk of rst ischemic stroke,[5] and current use signicantly increases the risk of cardio-vascular
disease among those at high risk.[6] 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.[44]
The overall absolute risk of venous thrombosis per
100.000 woman years in current use of combined oral
contraceptives is approximately 60, compared to 30 in
non-users.[45] The risk of thromboembolism varies with
dierent types of birth control pills; compared with

4.2 Cancer
A systematic review in 2010 did not support an increased
overall cancer risk in users of combined oral contraceptive pills, but did nd a slight increase in breast cancer risk
among current users, which disappears 510 years after
use has stopped.[49]

4.2.1 Protective eects

COC decrease the risk of ovarian cancer, endometrial
cancer,[22] and colorectal cancer.[3][35][50] Two large cohort studies published in 2010 both found a signicant
reduction in adjusted relative risk of ovarian and endometrial cancer mortality in ever-users of OCs compared to
never-users.[2][51]
The use of oral contraceptives (birth control pills) for
ve years or more decreases the risk of ovarian cancer
in later life by 50%.[50] 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.[22]

4
4.2.2

4
Increased risks

A report by a 2005 International Agency for Research on

Cancer (IARC) working group said COCs increase the
risk of cancers of the breast (among current and recent
users),[3] cervix and liver (among populations at low risk
of hepatitis B virus infection).[3] A 2013 meta-analysis
concluded that ever 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 human papilloma virus is increased.[52] A similar
small increase in breast cancer risk was seen in other meta
analyses.[53][54]

4.3

Weight

A 2011 Cochrane systematic review found that studies

of combination hormonal contraceptives showed no large
dierence in weight when compared with placebo or
no intervention groups.[55] The evidence was not strong
enough to be certain that contraceptive methods do not
cause some weight change, but no major eect was
found.[55] This review also found that women did not
stop using the pill or patch because of weight change.[55]

4.4

MAJOR SIDE EFFECTS

4.5 Depression
Low levels of serotonin, a neurotransmitter in the brain,
have been linked to depression. High levels of estrogen,
as in rst-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. This observation, along with some small research
studies[62] have inspired speculation that the pill causes
depression.
Progestin-only contraceptives are known to worsen the
condition of women who are already depressed.[63]
However, current medical reference textbooks on
contraception[22] and major organizations such as the
American ACOG,[64] the WHO,[65] and the United Kingdoms RCOG[66] 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.

4.6 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.[67]

Sexuality
4.7 Other eects

COCPs may increase natural vaginal lubrication.[56]

Other women experience reductions in libido while on
the pill, or decreased lubrication.[56][57] Some researchers
question a causal link between COCP use and decreased
libido;[58] a 2007 study of 1700 women found COCP
users experienced no change in sexual satisfaction.[59] A
2005 laboratory study of genital arousal tested fourteen
women before and after they began taking COCPs. The
study found that women experienced a signicantly wider
range of arousal responses after beginning pill use; decreases and increases in measures of arousal were equally
common.[60]
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.[61] 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 unspecicity of its sex
hormone binding.

Other side eects associated with low-dose COCPs are

leukorrhea (increased vaginal secretions), reductions in
menstrual ow, mastalgia (breast tenderness), and decrease in acne. Side eects associated with older highdose COCPs include nausea, vomiting, increases in blood
pressure, and melasma (facial skin discoloration); these
eects 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.[68] Progestins found in certain formulations of oral contraceptive
pills can limit the eectiveness of weight training to increase muscle mass.[69] This eect is caused by the ability of some progestins to inhibit androgen receptors. One
study claims that the pill may aect what male body odors
a woman prefers, which may in turn inuence her selection of partner.[70] Use of combined oral contraceptives
is associated with a reduced risk of endometriosis, giving a relative risk of endometriosis of 0.63 during active
use, yet with limited quality of evidence according to a
systematic review.[71]

5
Combined oral contraception decreases total testosterone
levels by approximately 0.5 nmol/l, free testosterone
by approximately 60%, and increases the amount of
sex hormone binding globulin (SHBG) by approximately
100 nmol/l. Contraceptives containing second generation progestins and/or estrogen doses of around 20
25 mg EE were found to have less impact on SHBG
concentrations.[72]

Contraindications

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
hypercholesterolemia (high cholesterol level), and in
smokers over age 35.

and fallopian tubes) by decreasing the water content and

increasing the viscosity of the cervical mucus.[73]
The estrogen and progestogen in COCPs have other effects on the reproductive system, but these have not been
shown to contribute to their contraceptive ecacy:[73]
Slowing tubal motility and ova transport, which may
interfere with fertilization.
Endometrial
atrophy
and
alteration
of
metalloproteinase content, which may impede
sperm motility and viability, or theoretically inhibit
implantation.
Endometrial edema, which may aect implantation.

Insucient evidence exists on whether changes in the endometrium could actually prevent implantation. The primary mechanisms of action are so eective that the possibility of fertilization during COCP use is very small.
Since pregnancy occurs despite endometrial changes
COC are also contraindicated for women with liver tuwhen the primary mechanisms of action fail, endometrial
mors, hepatic adenoma or severe cirrhosis of the liver,
changes are unlikely to play a signicant role, if any, in
those who have migraine with aura and for those with
the observed eectiveness of COCPs.[73]
known or suspected breast cancer. (WHO category 4).

Mechanism of action

7 Formulations
Main article: Oral contraceptive formulations

Combined oral contraceptive pills were developed

to prevent ovulation by suppressing the release of
gonadotropins. Combined hormonal contraceptives,
including COCPs, inhibit follicular development
and prevent ovulation as a primary mechanism of
action.[73][74][75][76]

Oral contraceptives come in a variety of formulations,

some containing both estrogen and progestins, and some
only containing progestin. Doses of component hormones also vary among products, and some pills are
monophasic (delivering the same dose of hormones each
Progestogen negative feedback decreases the pulse fre- day) while others are multiphasic (doses vary each day).
quency of gonadotropin-releasing hormone (GnRH) reCOCPs have been somewhat inconsistently grouped into
lease by the hypothalamus, which decreases the secretion
generations in the medical literature based on when
of follicle-stimulating hormone (FSH) and greatly dethey were introduced.[77][78]
creases the secretion of luteinizing hormone (LH) by the
anterior pituitary. Decreased levels of FSH inhibit fol First generation COCPs are sometimes dened
licular development, preventing an increase in estradiol
as those containing the progestins norethynodrel,
levels. Progestogen negative feedback and the lack of esnorethindrone, norethindrone acetate, or ethynodiol
trogen positive feedback on LH secretion prevent a midacetate;[77] and sometimes dened as all COCPs
cycle LH surge. Inhibition of follicular development and
containing 50 g ethinyl estradiol.[78]
the absence of a LH surge prevent ovulation.[73][74][75]
Second generation COCPs are sometimes dened
Estrogen was originally included in oral contraceptives
as those containing the progestins norgestrel or
for better cycle control (to stabilize the endometrium and
levonorgestrel;[77] and sometimes dened as those
thereby reduce the incidence of breakthrough bleeding),
containing the progestins norethindrone, norethinbut was also found to inhibit follicular development and
drone acetate, ethynodiol acetate, norgestrel, levhelp prevent ovulation. Estrogen negative feedback on
onorgestrel, or norgestimate and < 50 g ethinyl
the anterior pituitary greatly decreases the secretion of
estradiol.[78]
FSH, which inhibits follicular development and helps prevent ovulation.[73][74][75]
Third generation COCPs are sometimes dened
Another primary mechanism of action of all progestogencontaining contraceptives is inhibition of sperm penetration through the cervix into the upper genital tract (uterus

as those containing the progestins desogestrel or

gestodene;[78] and sometimes dened as those containing desogestrel, gestodene, or norgestimate.[77]

8
Fourth generation COCPs are sometimes dened
as those containing the progestin drospirenone;[77]
and sometimes dened as those containing
drospirenone, dienogest, or nomegestrol acetate.[78]

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,[79][80][81][82] but obtaining them from European pharmaceutical companies produced from animal
extracts was extraordinarily expensive.[83]
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 saponin from inedible Mexican yams
(Dioscorea mexicana and Dioscorea composita) found in
the rain forests of Veracruz near Orizaba. The saponin
could be converted in the lab to its aglycone moiety
diosgenin. Unable to interest his research sponsor ParkeDavis in the commercial potential of synthesizing progesterone from Mexican yams, Marker left Penn State
and in 1944 co-founded Syntex with two partners in
Mexico City. When he left Syntex a year later the
trade of the barbasco yam had started and the period
of the heyday of the Mexican steroid industry had been
started. Syntex broke the monopoly of European pharmaceutical companies on steroid hormones, reducing the
price of progesterone almost 200-fold over the next eight
years.[22][83][84][85][86][87][88][89][90][91][92][93][94]
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.[87]

8.1

Studies of progesterone to prevent ovulation

In early 1951, reproductive physiologist Gregory Pincus, a leader in hormone research and co-founder of
the Worcester Foundation for Experimental Biology
(WFEB) in Shrewsbury, Massachusetts, rst met American birth control movement founder Margaret Sanger at a
Manhattan dinner hosted by Abraham Stone, medical director and vice president of Planned Parenthood (PPFA),
who helped Pincus obtain a small grant from PPFA to begin hormonal contraceptive research.[95][96][97] Research
started on April 25, 1951 with reproductive physiologist
Min Chueh Chang repeating and extending the 1937 experiments of Makepeace et al. that showed injections of
progesterone suppressed ovulation in rabbits. In October

HISTORY

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.[83][88][98]
In March 1952, Sanger wrote a brief note mentioning Pincus research to her longtime friend and supporter, suragist and philanthropist Katharine Dexter
McCormick, who visited the WFEB and its co-founder
and old friend Hudson Hoagland in June 1952 to learn
about contraceptive research there. Frustrated when research stalled from PPFAs lack of interest and meager
funding, McCormick arranged a meeting at the WFEB
on June 6, 1953 with Sanger and Hoagland, where she
rst met Pincus who committed to dramatically expand
and accelerate research with McCormick providing fty
times PPFAs previous funding.[88][99]
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
scientic 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 estrogen
(diethylstilbestrol 530 mg/day) and progesterone (50
300 mg/day) and within the following four months an encouraging 15% became pregnant.[88][89][100]
In 1953, at Pincus suggestion, Rock induced a threemonth anovulatory pseudo-pregnancy state in twentyseven of his infertility patients with an oral 300 mg/day
progesterone-only regimen for 20 days from cycle days
524 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 rst 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.[101]

8.2 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
Syntexs norethindrone and Searles norethynodrel and
norethandrolone.[102]
Chemists Carl Djerassi, Luis Miramontes, and George
Rosenkranz at Syntex in Mexico City had synthesized the
rst orally highly active progestin norethindrone in 1951.

8.4

Public availability

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.[83]
In December 1954, Rock began the rst studies of the
ovulation-suppressing potential of 550 mg doses of the
three oral progestins for three months (for 21 days per
cycledays 525 followed by pill-free days to produce
withdrawal bleeding) in fty of his infertility patients in
Brookline, Massachusetts. Norethindrone or norethynodrel 5 mg doses and all doses of norethandrolone suppressed ovulation but caused breakthrough bleeding, but
10 mg and higher doses of norethindrone or norethynodrel suppressed ovulation without breakthrough bleeding and led to a 14% pregnancy rate in the following ve oral contraceptives, 1970s
months. Pincus and Rock selected Searles norethynodrel
for the rst contraceptive trials in women, citing its total lack of androgenicity versus Syntexs norethindrones additional contraceptive trials showed Enovid at 10, 5,
and 2.5 mg doses to be highly eective. On July 23,
very slight androgenicity in animal tests.[103][104]
1959, Searle led a supplemental application to add contraception as an approved indication for 10, 5, and 2.5 mg
8.3 Development of an eective combined doses of Enovid. The FDA refused to consider the application until Searle agreed to withdraw the lower dosage
oral contraceptive
forms from the application. On May 9, 1960, the FDA
Norethynodrel (and norethindrone) were subsequently announced it would approve Enovid 10 mg for contracepdiscovered to be contaminated with a small percentage tive use, and did so on June 23, 1960. At that point, Enof the estrogen mestranol (an intermediate in their syn- ovid 10 mg had been in general use for three years and,
thesis), with the norethynodrel in Rocks 19545 study by conservative estimate, at least half a million women
containing 47% mestranol. When further purifying had used it.[90][109][115]
norethynodrel to contain less than 1% mestranol led to Although FDA-approved for contraceptive use, Searle
breakthrough bleeding, it was decided to intentionally in- never marketed Enovid 10 mg as a contraceptive. Eight
corporate 2.2% mestranol, a percentage that was not as- months later, on February 15, 1961, the FDA apsociated with breakthrough bleeding, in the rst contra- proved Enovid 5 mg for contraceptive use. In July
ceptive trials in women in 1956. The norethynodrel and 1961, Searle nally began marketing Enovid 5 mg (5 mg
mestranol combination was given the proprietary name norethynodrel and 75 g mestranol) to physicians as a
Enovid.[104][105]
contraceptive.[90][91]
The rst contraceptive trial of Enovid led by CelsoRamn Garca and Edris Rice-Wray began in April 1956
in Ro Piedras, Puerto Rico.[106][107][108][109][110][111][112]
A second contraceptive trial of Enovid (and norethindrone) led by Edward T. Tyler began in June 1956 in
Los Angeles.[86][113] On January 23, 1957, Searle held a
symposium reviewing gynecologic and contraceptive research on Enovid through 1956 and concluded Enovids
estrogen content could be reduced by 33% to lower the
incidence of estrogenic gastrointestinal side eects without signicantly increasing the incidence of breakthrough
bleeding.[114]

8.4
8.4.1

Public availability
United States

On June 10, 1957, the Food and Drug Administration

(FDA) approved Enovid 10 mg (9.85 mg norethynodrel
and 150 g mestranol) for menstrual disorders, based on
data from its use by more than 600 women. Numerous

Although the FDA approved the rst 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.[87][91]
The rst published case report of a blood clot and
pulmonary embolism 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.[109][116][117] 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.[90] 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.[118] The hearings were

9 SOCIETY AND CULTURE

conducted by senators who were all men and the witnesses

in the rst round of hearings were all men, leading Alice
Wolfson and other feminists to protest the hearings and
generate media attention.[91] Their work led to mandating the inclusion of patient package inserts with oral contraceptives to explain their possible side eects and risks
to help facilitate informed consent.[119][120][121] Todays
standard dose oral contraceptives contain an estrogen
dose that is one third lower than the rst marketed oral
contraceptive and contain lower doses of dierent, more
potent progestins in a variety of formulations.[22][90][91]
8.4.2

Australia

of Health, announced that the oral contraceptive pill

Conovid could be prescribed through the NHS at a subsidized price of 2s per month.[130][131] In 1962, Scherings
Anovlar and Searles Conovid-E were added to the FPAs
Approved List of Contraceptives.[109][127][128]
8.4.5 France
On December 28, 1967, the Neuwirth Law legalized contraception in France, including the pill.[132] 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.[133]

The rst oral contraceptive introduced outside the United

States was Schering's Anovlar (norethindrone acetate 4
mg + ethinyl estradiol 50 g) on January 1, 1961 in 8.4.6 Japan
Australia.[122]
In Japan, lobbying from the Japan Medical Association
prevented the Pill from being approved for general use for
8.4.3 Germany
nearly 40 years. The higher dose second generation pill
was approved for use in cases of gynecologic problems,
The rst oral contraceptive introduced in Europe was but not for birth control. Two main objections raised by
Scherings Anovlar on June 1, 1961 in West Ger- the association were safety concerns over long-term use
many.[122] The lower hormonal dose, still in use, of the Pill, and concerns that the Pill use would lead to diwas studied by the Belgian Gynaecologist Ferdinand minished use of condoms and thereby potentially increase
Peeters.[123][124]
sexually transmitted infection (STI) rates.[134]
8.4.4

Britain

Before the mid-1960s, the United Kingdom did not require pre-marketing approval of drugs. The British
Family Planning Association (FPA) through its clinics
was then the primary provider of family planning services in Britain 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, Slough, and London.[109][125]
In March 1960, the Birmingham FPA began trials of
norethynodrel 2.5 mg + mestranol 50 g, but a high
pregnancy rate initially occurred when the pills accidentally contained only 36 g of mestranolthe trials were
continued with norethynodrel 5 mg + mestranol 75 g
(Conovid in Britain, Enovid 5 mg in the U.S.).[126] In
August 1960, the Slough FPA began trials of norethynodrel 2.5 mg + mestranol 100 g (Conovid-E in Britain,
Enovid-E in the U.S.).[127] In May 1961, the London FPA
began trials of Scherings Anovlar.[128]
In October 1961, at the recommendation of the Medical
Advisory Council of its CIFC, the FPA added Searles
Conovid to its Approved List of Contraceptives.[129]
On December 4, 1961, Enoch Powell, then Minister

However, when the Ministry of Health and Welfare approved Viagras use in Japan after only six months of
the applications submission, while still claiming that the
Pill required more data before approval, womens groups
cried foul.[135] The Pill was subsequently approved for use
in June 1999. However, the Pill has not become popular in Japan.[136] 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 OBGYNs
have required only a yearly visit for pill users, with triannual visits only recommended for those who are older
or at increased risk of side eects.[12] As of 2004, condoms accounted for 80% of birth control use in Japan,
and this may explain Japans comparatively low rates of
AIDS.[12]

9 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 magazine placed the
pill on its cover in April, 1967.[137] In the rst place, it was

9
more eective 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.[84][91] Claudia
Goldin, among others, argue that this new contraceptive
technology was a key player in forming womens modern economic role, in that it prolonged the age at which
women rst 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.[138] From an
economic point of view, the birth control pill reduced the
cost of staying in school. The ability to control fertility
without sacricing sexual relationships allowed women to
make long term educational and career plans.
Because the Pill was so eective, and soon so widespread,
it also heightened the debate about the moral and health
consequences of pre-marital sex and promiscuity. Never
before had sexual activity been so divorced from reproduction. For a couple using the Pill, intercourse became purely an expression of love, or a means of physical pleasure, or both; but it was no longer a means of
reproduction. While this was true of previous contraceptives, their relatively high failure rates and their less
widespread use failed to emphasize this distinction as
clearly as did the Pill. The spread of oral contraceptive use thus led many religious gures and institutions
to debate the proper role of sexuality and its relationship
to procreation. The Roman Catholic Church in particular, after studying the phenomenon of oral contraceptives,
re-emphasized the stated teaching on birth control in the
1968 papal encyclical Humanae vitae. The encyclical reiterated the established Catholic teaching that articial
contraception distorts the nature and purpose of sex.[139]

our knowledge and ignorance in these matters and that

all women should be made aware of this so she can decide
to take the Pill or not.[140]
The Secretary of Health, Education, and Welfare at the
time, Robert Finch announced the federal government
had accepted a compromise warning statement which
would accompany all sales of birth control pills.[140]
At the same time, society was beginning to take note of
the impact of the Pill on traditional gender roles. Women
now did not 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 womans use of the drug to liberate herself from her traditional role as wife and mother.
According to writer Margaret Wente, The pill decoupled
sex and marriage, and it also decoupled marriage and procreation. The purpose of marriage was mutual satisfaction, not children, and once that happened, gay marriage
probably became inevitable.[141]

10 Environmental impact

A woman using COCPs excretes from her urine and

feces natural estrogens, estrone (E1) and estradiol (E2),
and synthetic estrogen ethinylestradiol (EE2).[142] These
hormones can pass through water treatment plants and
into rivers.[143] 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 ushed down the
toilet.[144] This excretion is shown to play a role in causing endocrine disruption, which aects the sexual develThe United States Senate began hearings on the Pill in opment and the reproduction, in wild sh populations
1970 and there were dierent viewpoints heard from in segments of streams contaminated by treated sewage
medical professionals. Dr. Michael Newton, President euents.[142][145] A study done in British rivers supported
of the College of Obstetricians and Gynecologists said:
the hypothesis that the incidence and the severity of intersex wild sh populations were signicantly correlated
with the concentrations of the E1, E2, and EE2 in the
The evidence is not yet clear that these still
rivers.[142]
do in fact cause cancer or related to it. The
FDA Advisory Committee made comments
A review of activated sludge plant performance found
about this, that if there wasn't enough evidence
estrogen removal rates varied considerably but averto indicate whether or not these pills were reaged 78% for estrone, 91% for estradiol, and 76% for
lated to the development of cancer, and I think
ethinylestradiol (estriol euent concentrations are bethats still thin; you have to be cautious about
tween those of estrone and estradiol, but estriol is a much
them, but I don't think there is clear evidence,
less potent endocrine disruptor to sh).[146] Euent coneither one way or the other, that they do or don't
centrations of ethinylestradiol are lower than estradiol
cause cancer.[140]
which are lower than estrone, but ethinylestradiol is more
potent than estradiol which is more potent than estrone in
Another physician, Dr. Roy Hertz of the Population the induction of intersex sh and synthesis of vitellogenin
Council, said that anyone who takes this should know of in male sh.[147]

10

11

11

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contraceptives (COCs)". In Hatcher, Robert A.; Trussell,
James; Nelson, Anita L.; Cates, Willard Jr.; Kowal, Deborah; Policar, Michael S. (eds.). Contraceptive technology (20th revised ed.). New York: Ardent Media. pp.
249341. ISBN 978-1-59708-004-0. ISSN 0091-9721.
OCLC 781956734. pp. 257258:
Mechanism of action
COCs prevent fertilization and, therefore,

13

qualify as contraceptives. There is no signicant evidence that they work after fertilization. The progestins in all COCs provide
most of the contraceptive eect by suppressing ovulation and thickening cervical mucus, although the estrogens also make a small
contribution to ovulation suppression. Cycle
control is enhanced by the estrogen.
Because COCs so eectively suppress ovulation and block ascent of sperm into the upper
genital tract, the potential impact on endometrial receptivity to implantation is almost academic. When the two primary mechanisms
fail, the fact that pregnancy occurs despite the
endometrial changes demonstrates that those
endometrial changes do not signicantly contribute to the pills mechanism of action.
[74] Spero, Leon; Darney, Philip D. (2011). Oral contraception. A clinical guide for contraception (5th ed.).
Philadelphia: Lippincott Williams & Wilkins. pp. 19
152. ISBN 978-1-60831-610-6.
[75] Levin, Ellis R.; Hammes, Stephen R. (2011). Estrogens
and progestins. In Brunton; Chabner, Bruce A.; Knollmann, Bjrn C. Goodman & Gilmans pharmacological
basis of therapeutics (12th ed.). New York: McGraw-Hill
Medical. pp. 11631194. ISBN 978-0-07-162442-8.
[76] Glasier, Anna (2010). Contraception. In Jameson,
J. Larry; De Groot, Leslie J. Endocrinology (6th ed.).
Philadelphia: Saunders Elsevier. pp. 24172427. ISBN
978-1-4160-5583-9.
[77] Nelson, Anita L.; Cwiak, Carrie (2011). Combined oral
contraceptives. In Hatcher, Robert A.; Trussell, James;
Nelson, Anita L.; Cates, Willard Jr.; Kowal, Deborah;
Policar, Michael S. (eds.). Contraceptive technology (20th
revised ed.). New York: Ardent Media. pp. 253254.
ISBN 978-1-59708-004-0. ISSN 0091-9721. OCLC
781956734.
Ten dierent progestins have been used
in the COCs that have been sold in the
United States. Several dierent classication
systems for the progestins exist, but the one
most commonly used system recapitulates
the history of the pill in the United States by
categorizing the progestins into the so-called
generations of progestins. The rst three
generations of progestins are derived from
19-nortestosterone. The fourth generation is
drospirenone. Newer progestins are hybrids.
First-generation progestins. First-generation
progestins include norethynodrel, norethindrone, norethindrone acetate, and ethynodiol
diacetate These compounds have the
lowest potency and relatively short half-lives.
The short half-life did not matter in the early,
high-dose pills but as doses of progestin
were decreased in the more modern pills,
problems with unscheduled spotting and
bleeding became more common.
Second-generation progestins.
To solve
the problem of unscheduled bleeding and

spotting, the second generation progestins

(norgestrol and levonorgestrel) were designed
to be signicantly more potent and to have
longer half-lives than norethindrone-related
progestins... The second-generation progestins have been associated with more
androgen-related side-eects such as adverse
eect on lipids, oily skin, acne, and facial
hair growth.
Third-generation progestins.
Thirdgeneration progestins (desogestrel, norgestimate and elsewhere, gestodene) were
introduced to maintain the potent progestational activity of second-generation
progestins, but to reduce androgeneic side
eects. Reduction in androgen impacts allows a fuller expression of the pills estrogen
impacts. This has some clinical benets
On the other hand, concern arose that the
increased expression of estrogen might increase the risk of venous thromboembolism
(VTE). This concern introduced a pill scare
in Europe until international studies were
completed and correctly interpreted.
Fourth-generation progestins. Drospirenone
is an anologue of spironolactone, a
potassium-sparing diuretic used to treat
hypertension.
Drospirenone possesses
anti-mineralocorticoid and anti-androgenic
properties. These properties have led to new
contraceptive applications, such as treatment
of premenstrual dysphoric disorder and
acne In the wake of concerns around possible increased VTE risk with less androgenic
third-generation formulations, those issues
were anticipated with drospirenone. They
were clearly answered by large international
studies.
Next-generation progestins. More recently,
newer progestins have been have developed
that have properties that are shared with different generations of progestins. They have
more profound, diverse, and discrete eects
on the endometrium than prior progestins.
This class would include dienogest (United
States) and nomegestrol (Europe).
[78] Spero, Leon; Darney, Philip D. (2011). Oral contraception. A clinical guide for contraception (5th ed.).
Philadelphia: Lippincott Williams & Wilkins. p. 40.
ISBN 978-1-60831-610-6.
[79] Goldzieher JW, Rudel HW (October 21, 1974). How the
oral contraceptives came to be developed. JAMA 230 (3):
421425. doi:10.1001/jama.230.3.421. PMID 4606623.
[80] Goldzieher JW (May 1982). Estrogens in oral contraceptives: historical perspective. Johns Hopkins Medical
Journal 150 (5): 165169. PMID 7043034.
[81] Perone N (Spring 1993). The history of steroidal
contraceptive development: the progestins.
Perspectives in Biology and Medicine 36 (3): 347362.
doi:10.1353/pbm.1993.0054. PMID 8506121.

14

[82] Goldzieher JW (Spring 1993). The history of steroidal

contraceptive development: the estrogens.
Perspectives in Biology and Medicine 36 (3): 363368.
doi:10.1353/pbm.1993.0066. PMID 8506122.
[83] Maisel, Albert Q. (1965). The Hormone Quest. New
York: Random House. OCLC 543168.

11

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12

External links

The Birth Control PillCBC Digital Archives

The Birth of the Pillslide show by Life magazine

EXTERNAL LINKS

17

13
13.1

Text and image sources, contributors, and licenses

Text

Combined oral contraceptive pill Source: http://en.wikipedia.org/wiki/Combined_oral_contraceptive_pill?oldid=665844642 Contributors: AxelBoldt, The Epopt, Mav, Wesley, Bryan Derksen, Tarquin, Manning Bartlett, Alex.tan, Shsilver, Karen Johnson, Jtoomim, Kurt
Jansson, Edward, Patrick, Two16, Karada, Ellywa, Ahoerstemeier, Docu, Den fjttrade ankan~enwiki, Brettz9, Ugen64, Nikai, Tristanb, Rob Hooft, Ericthesh, Viajero, Zoicon5, Selket, Omegatron, Samsara, Owen, Catskul, Zandperl, Romanm, Modulatum, Kwi,
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13.2

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License:
Public domain Contributors: Patient Package Insert for Oral Contraceptives (FDA 079) Original artist: The U.S. Food and Drug
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Contributors: ? Original artist: User:Tristanb
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13.3

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