www. AJOG.

org

The state of hormonal contraception today: benefits and risks

of hormonal contraceptives: progestin-only contraceptives
Anne E. Burke, MD, MPH

The progestin component of hormonal contraceptives accounts for most of their contraceptive
effects. Several dosage forms of progestin-only contraceptives have been developed, including
pills, injectables, implants, and intrauterine devices. Emergency contraceptives may also contain progestin only and are indicated for prevention of pregnancy following unprotected intercourse or contraceptive failure. Each form has benefits, some specific to the form. An understanding of benefits and risks allows clinicians a wider choice when recommending effective
hormonal contraception.
Key words: emergency contraception, etonogestrel, levonorgestrel,
medroxyprogesterone acetate, norethindrone

Types and characteristics of

progestin-only contraceptives
The progestin component of hormonal contraceptives induces changes in the estrogenprimed endometrium, alters cervical mucus,
and, in some cases, inhibits ovulation.
The introduction of newer progestin-only
methods provides additional contraceptive
choices and maximizes effectiveness.
Four types of progestin-only contraceptives are currently available in the United
States:
Progestin-only daily oral contraceptives.
Injectable 3-month contraceptives (depot
medroxyprogesteroneacetate[DMPA]),
administered subcutaneously or intramuscularly.
Etonogestrel single-rod implant, which
provides effective contraception for at
least 3 years.
Intrauterine contraceptive (IUC) containing levonorgestrel, effective for at
least 5 years.
From Gynecology and Obstetrics, The Johns
Hopkins University, Bayview Medical
Center, Baltimore, MD.
Received Feb. 15, 2011; accepted April 22,
2011.
Publication of this article was supported by an
educational grant from Bayer Healthcare
Pharmaceuticals.
The author reports no conflict of interest.
Reprints not available from the authors.
0002-9378/$36.00
2011 Mosby, Inc. All rights reserved.
doi: 10.1016/j.ajog.2011.04.033

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Emergency contraceptive pills (ECs)

also contain progestin. Two forms of
oral ECs are available in the United
States. One form delivers a total of 1.5
mg levonorgestrel.1,2 The other form is a
newly approved single pill containing 30
mg ulipristal acetate, a progesterone agonist/antagonist.3 The effectiveness of
ECs appears to result primarily from the
inhibition or delay of ovulation. The
levonorgestrel formulation should be
taken within 72 hours,1,2 whereas the
ulipristal acetate formulation can be
taken up to 120 hours (5 days) after unprotected intercourse or known or suspected contraceptive failure.3
Progestin-only contraceptives have
several effects. The injectables and implants suppress ovulation, as may progestin-only pills (POPs) in some cases. In
addition, progestin-only methods suppress endometrial activity. Over time,
this causes endometrial atrophy, further
contributing to the contraceptive effect
and reducing the amount of menstrual
blood loss.4,5 Finally, progestin thickens
cervical mucus and impairs sperm transport, contributing to its effectiveness.5
Newer progestins, such as drospirenone
and desogestrel, have been developed to
minimize the androgenic side effects that
were attributed to their predecessors.6

Benefits of progestinonly contraception

Benefits of progestin-only contraceptives include effectiveness, safety, and

American Journal of Obstetrics & Gynecology Supplement to OCTOBER 2011

improvements in menstrual symptoms.

The long-lasting reversible contraceptive
methodsimplants and IUCare among
the most effective reversible contraceptives, thanks to their forgettability:
they are independent of daily action or
intervention at the time of coitus.5,7
Noncontraceptive health benefits of progestin-only contraception include improvement in such symptoms as dysmenorrhea, menorrhagia, premenstrual
syndrome, and anemia.5

Progestin-only oral contraceptives

In clinical studies, POPs were associated
with 12-month pregnancy rates ranging
from 1-13%.8,9 Typical-use failure rates
are estimated at about 8-9% per year,
with perfect-use failure rates at 0.3% per
year.10 Because serum progestin levels
can be undetectable as early as 24 hours
after POP ingestion, there is concern that
their failure rates may be higher than
combined oral contraception (COC)
due to need for stricter adherence. A recent Cochrane Review found that there
was insufficient evidence to determine
whether effectiveness of POPs differs
from that of COC.11 POPs containing
norethindrone are available in the
United States, whereas levonorgestrel
and desogestrel pills are available internationally. POPs are taken every day,
with no placebo or pill-free interval and
no change in pill formulation. This feature can help some women maintain a
regular pill schedule. Use of POPs may
improve menstrual symptoms. POPs have
traditionally been recommended for
breast-feeding women because they have
no adverse effect on lactation,12 but may
also be a good option for other women.
DMPA
DMPA inhibits the secretion of gonadotropins, prevents follicular maturation
and ovulation, and thins the endometrium.9 With perfect use of DMPA, the
pregnancy rate is about 0.3 per 100
women annually, while typical-use preg-

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nancy rates are closer to 3 per 100
women per year.10 A benefit of DMPA is
the potential for amenorrhea or decreased menstrual blood loss over time.
A review of both DMPA and levonorgestrel subdermal implants found that
about 50% of women became amenorrheic after 1 year.13 After 1 injection,
10% of women may experience diminished or no menses, which may be of particular interest to those who have heavy
menstrual bleeding or anemia or find
menses inconvenient. DMPA has noncontraceptive health benefits as well. It
may reduce painful crises in women with
sickle cell disease14 and has been reported to decrease seizure activity in
women with epilepsy in some studies.15
DMPA has also been shown to improve
endometriosis symptoms at least as well
as leuprolide acetate.16 Furthermore, because of endometrial suppression with
medroxyprogesterone acetate, DMPA
has a protective effect against the development of endometrial cancer.17 There
are no known interactions between
DMPA and other drugs.

Progestin implant
The etonogestrel-containing implant is a
long-acting, reversible contraceptive
that suppresses ovulation, increases viscosity of the cervical mucus, and alters
the endometrium.18 It has a very low failure (pregnancy) rate, with a Pearl index
of 0.38 pregnancies per 100 women.18
Ovulation resumes within 3 weeks of removal in 90% of women.7 The etonogestrel implant is cost-effective, providing 3 years of reliable contraception with
relatively low expenditure when cost is
averaged over time.19
The noncontraceptive benefits of the
etonogestrel-containing implant include
improvement in endometriosis symptoms, improvement in dysmenorrhea,
and decreased bleeding in some women.20-22 A series of case studies showed
that the implant relieved pelvic pain in
women with severe pelvic endometriosis.22 A review of data from 11 clinical trials, including 900 women, found that
bleeding patterns were improved in 75%
of women, and 77% of women who had
baseline dysmenorrhea experienced complete resolution of their symptoms.21

Progestin intrauterine system

The levonorgestrel-releasing intrauterine system (LNG-IUS) provides highly
effective contraception for 5 years, with a
failure rate between 0-0.2 per 100 womanyears and a low ectopic pregnancy rate of
0.01% per year.7,23 About 80% of women
who wished to become pregnant conceived within 12 months of removal.23
With the LNG-IUS, menstrual bleeding
is decreased by 75%, which is attributed
to the progestin-induced decidualization and suppression of the endometrium.7 Amenorrhea is observed by
about 20% of women after 1 year of use,
with more women becoming amenorrheic over time.23-25 In addition to improving menorrhagia, anemia, and dysmenorrhea, the LNG-IUS likely also
protects against endometrial cancer because of its suppression of the endometrium, although further research is
needed to confirm this.
Risks of progestinonly contraceptives
There are few serious risks associated
with the use of progestin-only contraceptives. The World Health Organization (WHO) and the Centers for Disease
Control and Prevention eligibility guidelines list conditions for which use of progestin-only contraception may represent
unacceptable health risks (category 3 or 4
recommendations).26,27 These conditions are:
Breast cancer.
Severe, decompensated cirrhosis of
the liver.
Liver tumors.
Acute or recurrent deep vein thrombosis, pulmonary embolism.
Stroke.
Unlike combination hormonal contraceptives, however, progestin-only methods may safely be used in women with a
history of hepatitis or in those with a history of venous thrombosis. Women with
certain medical conditions such as multiple cardiac risk factors, vascular disease, or
lupus often can use progestin-only methods, although the WHO advises that such
women should perhaps consider other
progestin-only methods than DMPA,
which cannot be discontinued once
injected.26,28

Contraceptive implant
There are a few risks associated specifically with contraceptive implants. Although fairly uncommon, clinicians may
experience complications of insertion
and removal: if the rod is inserted too
deeply or incorrectly, it may be difficult
to remove. In early US trials, the rate of
removal complications was 2%.28 Another caution concerns drug interactions.
Etonogestrel is metabolized in liver microsomes by the cytochrome P450 enzyme
system, and other medications that are
metabolized similarly, specifically antiinfective agents and anticonvulsants, can result in drug/drug interactions. These pharmacokinetic changes raise the concern that
such interactions will decrease the efficacy
of the implant.18 Use of the implant is not
contraindicated in such cases, however,
and drug interactions may be more of a
concern with POPs.27
LNG-IUS
Risks of IUC use can include uterine perforation or expulsion, which may be accompanied by uterine bleeding and/or
pain. The risk of expulsion is about
2-10% in the first year.23 Women who
have expelled an IUC may be at increased
risk for expulsion of subsequently placed
devices.29 Women who have uterine
anomalies preventing proper placement
or unexplained vaginal bleeding should
not use LNG-IUS. Women with fibroids
may use LNG-IUS as long as these fibroids do not distort the cavity and interfere with insertion.23,26 Like other
progestin-only contraceptives, the LNGIUS lowers risks of pelvic infection to
0-2%, although insertion in the presence
of active chlamydial or gonorrheal infection may increase the risk up to 5%.30
Side effects of progestinonly contraceptives
Progestin-only oral contraceptives
Irregular bleeding can be a side effect of
POPs, as with other progestin-only
methods. Over time, consistent use may
lead to amenorrhea, which for some
women may represent a benefit. Approximately 40% of women report regular cycles with POPs.31 Pharmacokinetic evidence suggests that some POPs could be
less effective than combined pills: serum

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Supplement
hormone levels may be undetectable 27
hours after the last pill was taken. It is
therefore recommended that women
take the pills at the same time every
day.6,32 Recent data, however, suggest
that effectiveness of oral contraceptives
is about the same for combined hormone and progestin-only formulations.13 Because there are few types of
POPs available and they are not commonly used, their availability may be
more limited than are COCs, which, in
turn, can increase costs for some women.

DMPA
The perceived side effects of DMPA are a
frequent reason for discontinuation, and
counseling should anticipate this. Menstrual irregularities can cause discontinuation during the first year of use. Both
bleeding and spotting are frequent during the first 3 months of DMPA use but
decrease with each subsequent injection.13 The incidence of unscheduled
bleeding/spotting days is about 70% in
the first year and diminishes to about
10% thereafter. About 50% of DMPA
users experience amenorrhea by year 1 of
use13 and about 70% after 2 years of
use.33
Some clinical studies have found lipid
changes, specifically decreased levels of
high-density lipoprotein cholesterol
and/or increased levels of low-density lipoprotein cholesterol in women using
DMPA.34,35
Women using DMPA may report
weight gain. In a recent prospective
study, two-thirds of adolescent women
using DMPA gained 2 kg (4.4 lb),36
whereas another study reported that
some adult DMPA users maintained
their initial body mass index (BMI) over
time.37 The amount of weight gain can
increase with longer use.38 A study of
700 women found that, after 3 years,
DMPA users who completed the study
had more weight gain than did COC users and nonusers of hormonal contraception.39 A systematic review found
that weight gain with DMPA was not associated with baseline weight or BMI in
adults but that obese/overweight adolescents gained more weight than did nonusers or DMPA users who were not overweight.40 There are no data to suggest
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that DMPA is less effective in obese
women. Based on the results of 1 prospective study, DMPA seems to provide
efficacious contraception to women
even in higher BMI categories.41,42
In 2004, the Food and Drug Administration issued a black box warning
concerning the potential for loss of bone
mineral density (BMD) in young women
using DMPA.12 This warning was precipitated by the interpretation of studies
suggesting that women using DMPA had
reduced BMD compared with nonusers.
However, losses in BMD, both in adolescents and adult women, are largely reversed when DMPA is discontinued.43-48
Importantly, DMPA has not been linked
to increased fracture risk.49 Concerns
about future skeletal health should not
prevent the consideration of DMPA as
an effective contraceptive choice for
adults or adolescents.

after a year. Women may experience

cramping after insertion, and systemic
absorption of levonorgestrel may vary
causing progestin sensitivity in some
women.
For all progestin-only methods, including long-acting options, effective
counseling on bleeding changes and anticipated side effects can improve user
satisfaction and increase continuation.50

Progestin implant
The most frequently reported side effects
of the implant include irregular bleeding
patterns. Although many women do
have less bleeding overall, the bleeding/
spotting episodes can occur at unpredictable intervals.21 A data review found
that the etonogestrel implant was associated with the following bleeding irregularities: amenorrhea (22%), infrequent
bleeding (34%), and frequent or prolonged bleeding (24%).21 Only 11% of
women discontinued because of bleeding irregularities. Bleeding patterns may
actually improve over time for the majority of women.21
Other side effects of the etonogestrel
implant include headache, breast tenderness, mood effects, and dysmenorrhea; these often resolve with time.
Weight gain, about 4 lb in 2 years according to product labeling,18 seems to parallel what might be expected in nonusers.
Over 3 years of implant use, about 14%
of women may be expected to discontinue the product because of such adverse events.50

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LNG-IUS
Side effects of LNG-IUS include irregular bleeding patterns, which tend to be
more common early in use and diminish
over time, and amenorrhea in about 20%

American Journal of Obstetrics & Gynecology Supplement to OCTOBER 2011

Summary
Several types of progestin-only contraceptives are available in the United States
and worldwide. Some of these methods
are highly effective. Progestin-only contraceptives are safe for most women and
may offer noncontraceptive health benefits. Counseling women about expected
side effects can improve their overall
satisfaction and increase continuation
f
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