www. AJOG.

org

The state of hormonal contraception today: benefits

and risks of hormonal contraceptives: combined
estrogen and progestin contraceptives
Lee P. Shulman, MD

ver the course of the past 50 years,

modifications have been made to
improve the effectiveness, acceptability,
and tolerability of hormonal contraceptives. Initially, the doses of the estrogen
and progestin components were lowered
and formulations were developed containing only progestin. Subsequently,
new progestins were developed to decrease androgenic side effects, and, more
recently, alternative delivery systems
were introduced to improve tolerability
and continuance, and convenience of
use.1 All combination hormonal contraceptives are highly effective in preventing pregnancy when used properly; the
changes that have been made to pill regimens and components along the course
of the past 5 decades have been undertaken to improve tolerability and increase the likelihood of consistent and
correct use to improve overall contraceptive effectiveness and maximize the
noncontraceptive benefits associated
with contraceptive use.

Benefits and risks of combination

hormonal contraceptives
Understanding the benefits and risks of
contraceptive methods and being able to
communicate those to women are criti-

From the Division of Clinical Genetics,

Feinberg School of Medicine Northwestern
University; Department of Medicinal
Chemistry and Pharmacognosy, University
of Illinois at Chicago College of Pharmacy,
Chicago, IL.
Received Feb. 15, 2011; revised June 2, 2011;
accepted June 10, 2011.
Publication of this article was supported by the
Potomac Center for Medical Education.
The author reports no conflict of interest.
Reprints will not be available.
0002-9378/$36.00
2011 Mosby, Inc. All rights reserved.
doi: 10.1016/j.ajog.2011.06.057

Discussion of effective birth control methods can be a challenging process for clinicians
because the adoption and consistent use of contraception may be influenced by patients
fears, myths, and misperceptions. Over the years, new progestins have been included in
combination contraceptives or are used alone to provide effective contraception as well as
to decrease androgenic side effects and ameliorate the symptoms of premenstrual dysphoric disorder. Alternative delivery systems and regimens have also been introduced to
improve tolerability and continuance and convenience of use. This is a review of estrogen
and progestin combinations and their effects.
Key words: androgenic effects, contraceptive side effects, menstrual cycle control,
venous thromboembolism

cal to improved acceptability and appropriate use of effective birth control. Providing detailed counseling to women at
the outset that addresses the advantages,
disadvantages, benefits, and risks of various contraceptive methods, invariably
leads to better outcomes in the future.
Frequently, misconceptions exist with
regard to the safety of hormonal contraceptives. Clinicians must balance risks
against the benefits of contraception in
the context of a particular womens
health history. Unintended pregnancy is
usually the result of a lack of contraceptive use or failure of the chosen contraceptive method. The impact of unintended pregnancy can be significant and
encompasses health risks as well as adverse social and economic consequences.
Health risks usually pertain to absent or
poor prenatal care and include an increased risk of maternal and neonatal
morbidity and mortality. Social and economic consequences include reduced
maternal education and employment
options, and an increased likelihood of
welfare dependency. As such, unintended pregnancies place a substantial
social, medical and economic burden on
women and society.
In addition to preventing unintended
pregnancy, hormonal contraceptives
have been shown to provide numerous
noncontraceptive benefits.2 Oral contra-

ceptives have been shown to reduce the

risk of ovarian epithelial cancer and endometrial cancer without increasing the
risk for breast cancer.3 Combination
hormonal contraceptives generally reduce androgenic symptoms, with several
oral contraceptive regimens having been
formally approved for the treatment of
mild to moderate acne.2 Many women of
childbearing age experience some degree
of physical and emotional symptoms related to their impending menses. Some
of these menstrual-related health issues
include heavy menstrual bleeding, headache, dysmenorrhea and behavioral,
emotional, and physical symptoms associated with premenstrual dysphoric disorder. Combination hormonal contraceptives have been shown to ameliorate
or effectively treat these problems. Recently, in women choosing to use oral
contraceptives for pregnancy prevention, the 20 mcg EE/3 mg drospirenone
24/4 regimen was approved by the US
Food and Drug Administration (FDA)
for the treatment of the symptoms of
premenstrual dysphoric disorder4 and
the multiphasic E2V/DNG regimen was
approved in Europe for the treatment of
heavy menstrual bleeding in women.5
As with any therapeutic agent, there is
invariably an increased risk for side effects and adverse events that is concomitant with the benefits accrued by its use.

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FIGURE 1

Percent of women discontinuing a contraceptive based on choice offered

Shulman. Risks and benefits of hormonal contraceptives. Am J Obstet Gynecol 2011.

Clinicians are in the position to weigh

the risks and benefits of hormonal contraceptives for each individual patient so
as to empower that woman to decide
which method, if any, to use to prevent
pregnancy. The use of combination oral
contraceptives is associated with an increased risk for thromboembolic events.
In addition, other cardiovascular risks
are increased especially among women
who are smokers, are obese, or have personal or family histories of cardiovascular and other disease. However, many
women believe that hormonal contraceptives are associated with great risk to
their health and well-being. Much of this
concern stems from women reading the
lay press, which highlights women who
have experienced considerable morbidity or even death while using such methods.6 Unfortunately, such reports rarely,
if ever, present information as to the relative safety of such methods, especially in
comparison to unintended pregnancy,
which is characterized by profoundly
higher rates of overall morbidity and
mortality. Such fears have a powerful
impact on women and all too often lead
women either to choose less effective
methods of contraception or to use no
method at all, thus placing them at a
much higher risk for pregnancy and its
adverse outcomes.
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Eliciting a womans choice for contraception during consultation is critical to

the process of her finding a method of contraception that she can successfully incorporate into her lifestyle. Although some
women may find the recommendations of
her clinician to be important, it is the patient who best knows the type of contraceptive regimen that she is likely to use correctly and gain the maximal contraceptive
and noncontraceptive benefits associate
with her choice of contraception. Indeed, a
study to determine factors associated with
sustained use of contraceptives found that
when the choice of birth control was denied by providing the patient with a popular method of oral contraception at the
time of the study, about 72% of women
discontinued its use within 12 months,
whereas only 8.9% of those whose preferred choice was granted eventually discontinued the contraceptive (Figure 1).7
Whereas the disparity between those who
continued with their birth control and
those who did not is impressive, the discontinuation rate among those denied a
choice is even more remarkable.
Adoption of effective birth control
methods can be a challenging process for
clinicians because of patient barriers
fears, myths, and misperceptions. These
can include unrealistic expectations, media scares, and lack of awareness of nu-

American Journal of Obstetrics & Gynecology Supplement to OCTOBER 2011

merous noncontraceptive benefits. Offering women choices, discussing benefits

and risks, engaging women in birth-control decision making, and listening to
women about their concerns and needs all
support effective use.

Nondaily, nonoral combination

hormonal contraceptives
Two nonoral, nondaily combination contraceptive methods are available, the vaginal ring and a transdermal patch.8,9 These
methods have a number of characteristics
that make them especially attractive to
women: they are highly effective, convenient, and easy to use. Because these methods require less frequent attention to the
method than other birth control, they are
less likely to be subject to inconsistent use.
In addition, these methods likely have the
noncontraceptive benefits associated with
other hormonal methods while not requiring daily administration.
Vaginal ring
The vaginal ring is a flexible transparent
ring that is inserted like a tampon. It provides steady and continuous delivery of
low-dose hormone (120 mcg/d of etonogestrel and 15 mcg/d of ethinyl estradiol)
over 3 weeks, after which it is removed
for a hormone-free week.8 Lower doses
of estrogen afforded by vaginal administration may reduce the effects associated
with higher doses of estrogen, such as
breast tenderness, nausea, and headache.10 The pharmacokinetics of the ring
show that contraceptive levels of etonogestrel and ethinyl estradiol are maintained to 35 days of use, suggesting that
women can extend use and may experience lighter or even absent withdrawal
bleeding during the ring-free week.11
Efficacy, cycle control, and acceptability were studied in a population of 2322
women using the vaginal ring and followed for more than 23,000 cycles.12 Efficacy, measured by the Pearl Index, was
0.77 in the per-protocol population and
1.18 in the intent-to-treat group. This
study found that the majority of completers (96%) were very satisfied with the
ring and 90% of them indicated that they
would recommend the ring to others.
Contraceptive acceptability and continuance of use are influenced by many

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factors, key among which is cycle control. The Dieben et al12 study reported
good cycle control among the ring users.
Almost all women experienced withdrawal bleeding, which did not generally
occur outside the ring-free week, and,
when it did, it was mainly spotting rather
than bleeding.12 In another study, the
profile of irregular bleeding was more favorable with the ring than with an oral
levonorgestrel/ethinyl estradiol contraceptive.10 In this study and in clinical observation, the incidence of irregular
bleeding in the combination oral contraceptive (COC) group was particularly
high during the first cycle.10 This was not
the experience among women using the
ring, although this may be attributed to
the fact that women starting the pill usually do so on day 1 of the cycle, whereas
the ring users started on day 5.10
Transdermal patch
The transdermal patch contains 6.00 mg
norelgestromin and 0.75 mg ethinyl estradiol and is a highly effective method of
contraception, applied weekly for 3
weeks with a fourth week off.13 An analysis of pooled data from 3 open-label
studies reported a Pearl Index of 0.88
and a low failure probability of 0.6%
with the patch.14
The patch is also well accepted by
women, and it may offer advantages over
COCs, including convenience and better
continuance of use. Using data pooled
from 3 studies, researchers assessed compliance patterns of the patch compared
with those of an established oral contraceptive.15 For all cycles, adherence to the
weekly dosing schedule of the patch was
significantly better than that of the oral
contraceptive regardless of age of the
women (P .001) (Figure 2).15
A pharmacokinetic study showed mean
steady-state concentrations ranged from
0.3051.53 ng/mL for the progestin component and from 11.2-137 pg/mL for the
estrogen component of the patch.13 In a
study that compared the patch with a COC
containing 250 mcg norelgestromin and
35 mcg ethinyl estradiol, the overall exposure to these steroids (area under the
curve) was greater with the patch.13 A
study examining the pharmacokinetic

FIGURE 2

Percent of women adherent to their assigned contraceptive

regimen (transdermal patch or oral contraceptive)

LNG, levonorgestrel.9
Shulman. Risks and benefits of hormonal contraceptives. Am J Obstet Gynecol 2011.

properties of 3 hormonal contraceptive

formulations (a vaginal ring, the transdermal patch, and a COC containing 30 mcg
ethinyl estradiol) found that the maximal
blood level of ethinyl estradiol with the
patch was about 60% less than that of the
COC.16,17 A case-controlled study compared the risk of nonfatal venous thromboembolism (VTE) in women using the
transdermal patch to that of women using
a COC containing 35 mcg of ethinyl estradiol. The study found that the odds ratio
for VTE for transdermal patch users was
0.9, representing no increased risk for VTE
and similar to the risk observed in new users of the COC comparator.17 Another
study found a 2-fold increased risk for VTE
with the patch.18 Based on this negative information, the US FDA issued a warning
concerning the possible increased risk of
VTE with patch use. Since then, a third report of a case-controlled study using postmarketing data found that in women under 40 years of age, there was no increased
risk of VTE with the transdermal patch,
compared with a levonorgestrel-containing COC.19 The authors concluded that
the risk of idiopathic VTE in users of the
transdermal patch was not different from
that of users of levonorgestrel-containing
COCs in women 39 years of age or
younger.

Combination oral contraceptives

The daily COC remains the most commonly used nonbarrier method of reversible contraception. When properly
used, it is more than 99% effective.20 In
reality, about half of women use COCs
correctly and consistently,21 a study of
use patterns showed that 37% of women
reported that they discontinued their
COC because of side effects.21 Serious
complications, like deep vein thrombosis or pulmonary embolism, are rare, and
aside from a few persistent intolerable
side effects breast tenderness, spottingthe pill has few absolute contraindications and several noncontraceptive
benefits. Refer to the package insert to
review the complete list of contraindications and special considerations. Recent
developments in OCs have focused on:
The development of a pill or pill regimen that improves tolerability and acceptability.
Lowering doses and altering delivery
patterns of estrogen and progestins.
The development of new progestins.
Drospirenone-containing COC
Drospirenone is a novel progestin not
derived from 19-nortestosterone but
rather from 17alpha-spirolactone and
has antimineralocorticoid and antian-

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FIGURE 3

Comparison of risk for venous thromboembolism in 2 prospective trials

comparing oral contraceptives with and without drospirenone

CI, confidence interval; DVT, deep vein thrombosis; EURAS, European Active Surveillance Study; OC, oral contraceptive; PE, pulmonary
embolism; TE, thromboembolism; VTE, venous thromboembolism.18,19
Shulman. Risks and benefits of hormonal contraceptives. Am J Obstet Gynecol 2011.

drogenic activity.22 Combined with ethinyl estradiol, it is an effective oral contraceptive23,24 and has favorable effects in
women who have premenstrual dysphoric disorder (PMDD).22 In addition,
its antimineralocorticoid properties have
the potential to lower body weight (through
water weight change and not loss of fat)
and blood pressure.22
Two prospective studies have been undertaken to examine the cardiovascular
effects of the drospirenone-containing
COC one conducted in Europe25 and
the other in an American population.26
Both studies found that deep vein
thrombosis and pulmonary embolism
occurred with equal frequency in the
ethinyl estradiol/drospirenone COC and
other COC users (Figure 3).25,26 The US
study observed that a clinician can expect to find one case of thromboembolism among 769 women over the course
of 1 year if they were prescribed the drospirenone-containing COC.26
Two more-recent studies, both using
European populations, have also examined thrombotic events in users of
COCs.27,28 The Dutch study found an
increased risk of venous thrombosis,
which differed by type of progestin and
dose of estrogen, with all of the COCs.28
S12

The Danish study also found an increased

risk, which differed by type of progestin,
that decreased with duration of use and decreasing estrogen dose.27 All of the study
results are now included in the prescribing
information for the drospirenone-containing COCs; however, the FDA also
added a statement that the results of the
Dutch and Danish studies do not provide
convincing evidence of an increased risk
for VTE, given the relatively few number of
VTE cases among drospirenone users in
the Dutch study and a likelihood of ascertainment bias in the Danish study.
The rationale for shortening the hormone-free interval in women using
COCs was improvement in ovarian suppression as well as reduction of adverse
symptoms experienced during the hormone-free interval.29-31 An early study
found that by adding 2 days to the COC
regimen, ovarian suppression improved
contraceptive efficacy.32 This was tested
in the extended use of a low-dose 20-mcg
ethinyl estradiol COC, and results showed
that the efficacy of the 24-day low-dose
COC improved efficacy.33

The COCS of the future

Two COCs in development are a 26-day
multiphasic regimen of estradiol valerate

American Journal of Obstetrics & Gynecology Supplement to OCTOBER 2011

and dienogest and a COC containing 17

beta-estradiol and nomegestrol acetate.34-36 Although the use of estradiol valerate may have some advantages over ethinyl estradiol, there are no head-to-head
studies of ethinyl estradiol and estradiolcontaining pills to date. The 26-day multiphasic combination of estradiol valerate
and dienogest provides reliable contraception and, with only 2 days off, may provide
lighter withdrawal bleeding than does a
traditional pill containing ethinyl estradiol
and levonorgestrel.34
The other new pill contains 17 betaestradiol and nomegestrol acetate in a
monophasic regimen. A recent pharmacologic and pharmacokinetic study indicates good ovulation suppression with
this combination, with mean maximum
follicular diameter decreased from 19.3
mm before treatment to between 6.9 and
8.2 mm during treatment.36 The findings
from this study are consistent with ovulation inhibition produced by oral contraceptives containing ethinyl estradiol
and drospirenone.
As the investigation of new compounds continues, it will add to the array
of effective combination hormonal contraceptives available to women. The expansion of contraceptive choice can only
improve the likelihood that a woman
will find a method of contraception that
she will successfully incorporate into her
lifestyle and use consistently and correctly for as long as she chooses not to be
pregnant. As many hormonal methods
carry similar capabilities to prevent pregnancy, it will be the availability of methods with unique noncontraceptive benefits that will help women find a method
that is right for them. It is important that
research continues to improve tolerability and acceptability of contraceptive options, preserve efficacy, and delineate
noncontraceptive benefits, while lowering hormone exposure and improving
f
the safety profile.
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