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Hormonal Contraception

Mechanism of Action
The primary mechanism of action of hormonal
contraceptives is that they suppress the secretion
of gonadotropins (follicle stimulating
hormone, FSH and luteinizing hormone, LH)
through negative feedback inhibition. Through
various means of delivery (oral, depot injection,
implant, transdermal), a woman receives a
combination of estrogen and progesterone, or just
progesterone by itself. Progesterone with
estrogen naturally inhibits gonadotropin secretion
as, for instance, during the luteal phase of the
cycle. The goal is to suppress ovulation. The
inhibition provided by hormonal contraceptives
prevents the rise in FSH that is necessary to
initiate follicle development and selection of a
dominant follicle. This inhibition also prevents the
LH surge that is necessary to trigger ovulation.

There are other ways that hormonal contraceptives interfere with conception.
One important strategy is to interfere with the movement of sperm in the
female reproductive tract. Sperm are deposited in the vagina and must
traverse the cervix. In the follicular phase, estrogen promotes the production
of thin, watery mucus by the cervical glands. By contrast, progesterone
promotes secretion of thick cervical mucus, which acts as a barrier, and
inhibits sperm movement past the cervix. This effect on the cervical mucus is
particularly important for the efficacy of low-dose progesterone-only oral
contraceptives, because the low dose of progesterone does not consistently
suppress ovulation.

Hormonal contraceptives reduce endometrial growth, so it is theoretically

possible that they may also block conception by interfering with implantation.
However, since the other mechanisms of action are very effective at preventing
fertilization, it is difficult to know what role, if any, inhibiting implantation has
to play in contraceptive efficacy.

Types
Combination contraceptives

Combination contraceptives contain both an estrogen and a progestin (a drug

that binds to progesterone receptors). Most widely used are combination oral
contraceptives, which consist of pills that are taken every day for three weeks,
with one week of placebo pills. During the week when she is taking the
placebo pills, the woman experiences a withdrawal bleed. The withdrawal
bleed serves as a convenient signal that the woman has not become pregnant,
but it is not essential. There are also continuous-use oral contraceptives that
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eliminate the placebo pills. Continuous-use contraceptive pills are designed for
women who would like to have fewer menstrual periods because they suffer
from menorrhagia (excessive menstrual bleeding) or dysmenorrhea (painful
menstruation).

Because steroid hormones are nonpolar, they can be delivered topically.

Combination contraceptives using this method of administration are a patch
that is changed weekly, and a vaginal ring that is inserted and left in place for
three weeks.

Progesterone-only contraceptives

There are several different types of contraceptives that use only progestins.
The long-acting methods are useful in those women who don’t want to or can’t
remember to take a pill every day. Another advantage to these methods is that
the woman may have medical reasons to avoid exposure to increased levels of
estrogen.

Low-dose pills

These are not as effective as combination contraceptives at preventing

ovulation. Their effectiveness depends in part upon the ability of progesterone
to alter the cervical mucus. It is very important for these pills to be taken at
the same time each day, so that the plasma level of the progestin is sufficient
to affect the cervical mucus.

Why would a woman opt for this method if it is less effective? This type of
contraceptive is useful in women who need to avoid estrogen. Also, low-dose
progesterone only contraceptives are recommended for use in women who are
lactating and don’t wish to become pregnant because high levels of estrogen
and progesterone inhibit milk synthesis.

Long-acting methods

Long-acting progesterone-only contraceptives are the most effective methods

of hormonal contraception. These methods include an implantable rod that
releases a progestin (Nexplanon), an intrauterine device (IUD) that releases a
progestin, and an injection (Depo-Provera) that is given once every 3 months.
Of these methods, the implantable rods and the IUD have greater
contraceptive efficacy because once they are inserted they work effectively for
several years without any other action required. The progestin diffuses out at a
steady rate to prevent ovulation through negative feedback inhibition, and to
prevent fertilization through changes to the cervical mucus.

A concern with the injection method, Depo-Provera, has been that it causes
enough inhibition of estrogen production by the ovary to cause a decrease in
bone density (recall that estrogen prevents bone resorption by inhibiting the
activity of osteoclasts). However, the decrease in bone density is small, and
appears to reverse after contraceptive use is discontinued.

Emergency contraception

Emergency contraception is hormonal contraception that is used by a woman

after she has had unprotected intercourse. Note the timing of events
surrounding fertilization as depicted in the figure below. Because sperm are

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viable for several days, and because women can’t be sure of the exact timing
of ovulation, it may be possible to prevent fertilization by a contraceptive
method that blocks or delays ovulation. This is the principal mode of action of
emergency contraceptives.

Plan B ™ uses a higher dose of

progestin (levonorgestrel) than found
in typical oral contraceptives. It works
by delaying or inhibiting ovulation via
the same mechanism (negative
feedback inhibition of gonadotropin
secretion) as conventional hormonal
contraception. In a study in which LH
levels were measured (as a marker for
ovulation), it was found that
levonorgestrel emergency
contraception only worked when taken
before the LH surge. The figure at
right shows the pattern of hormone
secretion and indicates the start of the
LH surge (red arrow). Plan B is most
effective when used within 12 hours of
unprotected intercourse, but can be
effective for up to 5 days (120 hours)
following unprotected intercourse.

A new form of emergency

contraception, ulipristal (marketed as
Ella ™) has recently been approved. Ulipristal is classified as a selective
progesterone receptor modulator. In the ovary, it acts to block
progesterone action in the follicle. Note that there is a small increase in
progesterone secretion induced by the LH surge, and it appears that this is
necessary for ovulation to occur (blue arrow in figure). An advantage of
ulipristal is that it is still effective at delaying ovulation even if it taken after the
beginning of the LH surge. Ulipristal is not effective if taken after the peak of
the LH surge.

Progesterone is necessary to maintain the endometrium for implantation. Thus,

it is theoretically possible that ulipristal may work to prevent pregnancy
through post-fertilization mechanisms. However, ullipristal used for emergency
contraception is at a low dose that is not likely to affect the endometrium.

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Risks
Many women use hormonal contraceptives without experiencing any adverse
effects, while some experience minor adverse effects such as abnormal
menstrual bleeding, or weight gain. Below, only the most serious adverse
effects of hormonal contraceptives are considered, followed by a discussion of
the various benefits of hormonal contraceptives.

Cardiovascular risks

Cardiovascular disorders comprise the most serious adverse effects associated

with hormonal contraceptives. Although oral contraceptives increase the risk
for certain cardiovascular disorders, these disorders are extremely rare among
young women. A key thing to keep in mind is that pregnancy increases the risk
for these cardiovascular disorders to a greater degree.

Oral contraceptives promote thrombosis, having a variety of effects on the

coagulation system that make the formation of a clot more likely. Clot
formation in the venous system is known as venous thromboembolism
(VTE), the most serious consequence being a pulmonary embolism. If a clot
forms in the arterial system, it can lead to a myocardial infarction or
stroke. The increase in clotting is thought to be primarily an effect of
estrogen.

Oral contraceptives increase the risk for venous thromboembolism. This

increased risk was higher with the earliest formulations of contraceptives that
used higher doses of estrogen. Current formulations of combination
contraceptives increase the risk of VTE from 3-6 fold. This seems high, but it is
important to note that the absolute risk of VTE among young, reproductive age
women is only 1 in 10,000. Oral contraceptive use also increases the risk of
myocardial infarction and stroke, particularly among older users who smoke.

Breast cancer

Because many breast tumors may have their growth stimulated by estrogen, it
is reasonable to think that estrogen-containing contraceptives might increase
the risk of breast cancer. Several large case-control studies have shown there
is no increase in the risk of breast cancer among current and former users of
combined contraceptives, however these studies focused on older women.
There is evidence of an increased risk of breast cancer among young hormonal
contraceptive users compared to young non-users. It is important to keep in
mind that the number of young women who get breast cancer is very, very low
—most breast cancers are diagnosed in post-menopausal women.

Benefits
The major benefit of hormonal contraceptives is reliable, reversible
contraception. Hormonal contraceptives are the most effective methods of
reversible contraception available to woman, being 97-99% effective if used
properly. Furthermore, there are a number of non-contraceptive benefits
associated with hormonal contraceptives.

Menstrual symptoms
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Because hormonal contraceptives decrease endometrial proliferation, they are

beneficial for women who suffer from menorrhagia or dysmenorrhea. They
are particularly helpful for treating women with polycystic ovary syndrome
who do not wish to conceive, because they reduce endometrial proliferation
and normalize menstrual periods.

Endometrial cancer

Decreased endometrial proliferation probably also underlies the positive effect

on rates of endometrial cancer. Oral contraceptive use decreases the risk of
endometrial cancer, with longer duration of use causing a greater protective
effect.

Ovarian cancer

Many studies have shown a decreased risk for the development of ovarian
cancer among women who have ever used hormonal contraceptives. Like
endometrial cancer, the reduction in risk is greatest for those women who have
used hormonal contraception the longest. The hypothesis is that reduced risk is
related to reducing the lifetime number of ovulations, since there is also a
reduction in ovarian cancer risk associated with having been pregnant.

Androgen secretion

Hormonal contraceptives are used to treat hyperandrogenism because they

decrease gonadotropin stimulation of androgen production by the ovary.
Androgens may cause masculinization, and they also stimulate the production
of sebum, which promotes acne. Randomized, placebo-controlled trials have
shown that oral contraceptives are better than placebo at reducing the severity
of acne.

Further Reading (optional)

Optional

For those that are further interested in this topic, here are some useful review articles.

Marchbanks, P. A. et al. (2002) Oral Contraceptives and the Risk of Breast Cancer.
New England Journal of Medicine 346: 2025-32 (link)
URL: http://www.nejm.org/doi/full/10.1056/NEJMoa013202
Petitti, D. B. (2003) Combination Estrogen-Progestin Oral Contraceptives. New
England Journal of Medicine 349: 1443-50 (link)
URL: http://www.nejm.org/doi/full/10.1056/NEJMcp030751
Kaunitz, A. M. (2008) Hormonal Contraception in Women of Older Reproductive Age.
New England Journal of Medicine 358: 1262-70 (link)
URL: http://www.nejm.org/doi/full/10.1056/NEJMcp0708481
Gemzell-Danielsson, K. (2010) Mechanism of Action of Emergency Contraception.
Contraception 82(5): 404-409 (link)
URL: http://www.sciencedirect.com/science/article/pii/S0010782410003215
Raymond, E. G. and Cleland, K. (2015) Emergency Contraception. New England
Journal of Medicine 372: 1342-8 (link)
URL: http://www.nejm.org/doi/full/10.1056/NEJMcp1406328
Curtis, K. M. and Peipert, J. F. (2017) Long-Acting Reversible Contraception. New
England Journal of Medicine 376: 461-8 (link)
URL: http://www.nejm.org/doi/full/10.1056/NEJMcp1608736

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Hunter, D.J. (2017) Oral Contraceptives and the Small Increase of Breast Cancer.
New England Journal of Medicine 377: 2276-7 (link)
URL: https://www.nejm.org/doi/full/10.1056/NEJMe17096366

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Quick Quiz
Fill in Answer Correct False Correct Answer
1. The primary
mechanism of
action of hormonal
contraceptives is
that they suppress
secretion of
________ through
negative
feedback
inhibition.
2. Hormonal
contraceptives can
be delivered
transdermally (via
a patch) because
steroid hormones
are ________.
3. Name the
hormone that
promotes
secretion of thin,
watery mucus by
the cervical
glands.
4. Which of the
following methods
is the most
effective at
preventing
pregnancy?
[combination
contraceptive pill;
low-dose
progesterone-only
pill; IUD that
releases
progestin; Depo-
Provera injection]
5. How many days
after fertilization
does implantation
occur?
6. Emergency
contraception
most likely
prevents
pregnancy by
delaying or
inhibiting
_________.
7. Oral
contraceptives
increase the risk
for venous
thromboembolism
(VTE) because
they
___________.
8. Having fewer

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lifetime ovulations
causes a decrease
in the risk for
which type of
cancer?
9. Which of the
following is
blocked by
ulipristal? [LH
surge; positive
feedback by
estrogen; negative
feedback by
estrogen;
progesterone
receptor;
gonadotropin
secretion]
check answers
answers
(Spelling must be correct)

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