Clinics in Dermatology (2014) 32, 502515

Contraceptive use in acne

Charlene Lam, MD, MPH a , Andrea L. Zaenglein, MD a,b,
a

Department of Dermatology, Penn State University/Hershey Medical Center, Hershey, Pennsylvania

Department of Pediatrics, Penn State University/Hershey Medical Center, Hershey, Pennsylvania

Abstract Acne vulgaris is an inflammatory disorder of the pilosebaceous follicle. It is well established
that androgen hormones play a major role in sebum production and excretion, and are vital in the
pathogenesis of acne. Isotretinoin notwithstanding, hormonal therapies such as combined oral
contraceptives (COCs) and spironolactone are the only treatments that can affect sebum production and
the androgen component of acne. Contraceptives are also used during isotretinoin therapy for pregnancy
prevention. It is important for a dermatologist to be familiar with all the available methods of
contraception to provide essential counseling to patients. The aim of this paper is to review the role of
hormones in acne pathogenesis, discuss the use of hormonal therapies for acne, and detail various
alternative contraceptive methods in relation to isotretinoin treatment and pregnancy prevention.
2014 Elsevier Inc. All rights reserved.

Introduction
Androgens play an important role in sebum production
and excretion. This subsequently contributes to the formation
of acne lesions. Hormonal therapies such as spironolactone
and combined oral contraceptives (COCs) are important
adjunctive acne therapies for female patients with acne.
Understanding how they work and knowing the benefits and
risks of using hormonal therapies is vital for any practitioner.
In dermatology, in addition to using COCs for acne,
hormonal therapies are also used in the context of
contraception during isotretinoin therapy. Although COCs
can often conveniently undertake both tasks, treating acne
and preventing pregnancy, there are other available options
of contraception that may better suit the needs of the patient.
It is important to be aware of these contraceptive options
in order to effectively counsel patients on prevention of
unplanned pregnancies. The goals of this paper are to review
the hormonal aspects of acne pathogenesis, detail the most

Corresponding author.
E-mail address: azaenglein@hmc.psu.edu (A.L. Zaenglein).
http://dx.doi.org/10.1016/j.clindermatol.2014.05.002
0738-081X/ 2014 Elsevier Inc. All rights reserved.

commonly used hormonal therapies in acne, and discuss the

different contraceptive methods currently available for use
during isotretinoin therapy.

Pathogenesis
The pathogenesis of acne is centered on the pilosebaceous
unit.1 The four main factors involved in the pathogenesis
of acne include (1) follicular epidermal hyperproliferation,
(2) inflammation, (3) concentration and activity of Propionibacterium acnes, and (4) excess sebum production.2
The pilosebaceous unit is comprised of the hair follicle
and sebaceous gland. Sebaceous glands, mostly concentrated
on the face and scalp, can be found throughout the body, with
exception of palms and soles. Sebaceous gland productivity
is closely linked to the presence of androgens. Although
the majority of androgens are manufactured by the zona
reticularis of the adrenal glands and gonads, the sebaceous
gland expresses all the necessary enzymes to produce
androgens locally (Figure 1).
Androgen receptors are found on the basal layer of sebaceous
glands and keratinocytes on the outer root sheath of the

Contraceptive use in acne

hair follicle.3,4 Functional androgen receptors are necessary for
sebum production and subsequent acne formation.5
The steroid-metabolizing enzymes in sebaceous glands
are 3-hydroxysteriod dehydrogenase, 17-hydroxysteriod
dehydrogenase, and 5-reductase. Dehydroepiandrosterone
(DHEA) in sebaceous glands is converted to androstenedione by 3-hydroxysteriod dehydrogenase. Androstenedione
is then altered via 17-hydroxysteriod dehydrogenase
to testosterone. After cellular uptake, testosterone is converted
to 5-dihydrotestosterone (DHT) with type I 5-reductase
(Figure 1). DHT leads to the growth of sebaceous glands
and sebum production. Testosterone can also play a role,
although DHT has a 5- to 10-fold greater affinity for androgen
receptors.6
When DHT or testosterone binds to the androgen receptors
on sebaceous glands and keratinocytes, transcription of
androgen-responsive genes is initiated, producing enzymes
involved in lipogenesis. One study showed DHT augmented
intracellular lipid droplet formation with an increase in

503
triglycerides in hamster sebocytes.7 In hamster ear sebaceous
glands, DHT leads to the proliferation and differentiation of
sebocytes and induction of lipogenesis via the sterol responseelement-binding protein (SREBP) pathway.8,9

Androgens
Although androgens play a crucial role in the pathogenesis of acne, the exact correlation is difficult to determine.
Clinically, most patients with acne have normal serum
androgens levels; however, compared with those without
acne, patients with acne have higher plasma androgen
levels.10 It has been suggested that androgens perhaps play
a permissive role in the initiation or priming of acne.
On the other hand, acne formation could also be a result of
local overproduction of androgens or the actual number and
receptiveness of androgen receptors.1

Fig. 1 Steroid metabolism. ACTH, adrenocorticotropic hormone; DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate;
LH, luteinizing hormone; LHRH, luteinizing hormonereleasing hormone; 3-HSD, 3-hydroxysteroid dehydrogenase; 17-HSD, 17-hydroxysteroid
dehydrogenase. Adapted from Ebede TL, Arch EL, Berson D. Hormonal treatment of acne in women. J Clin Aesthet Dermatol. 2009:2:16-22.

504
Increased sebum production and excretion is associated
with the development of acne. In primary culture of human
sebocytes and hamster sebaceous glands, researchers
have observed a stimulatory effect of testosterone and DHT
on sebocyte proliferation.11 Interestingly, in vitro human
sebocytes are responsive to androgen level concentrations
above physiologic levels.1
Hyperkeratinization of the infrainfundibulum of the hair
follicle results in microcomedo formation, the precursor lesion
of acne vulgaris, formation of which may also be androgen
related. The follicular infrainfundibulum has been shown to
have higher activity levels of type I 5-reductase, which may
cause abnormal differentiation of keratinocytes.12

Estrogen
There are two pathways to produce estrogen: (1) testosterone can be converted to the major active estrogen, estradiol, by
aromatase; or (2) androstenedione through aromatase can
produce estrone, which is converted to estradiol (Figure 1).
The effect of estrogen on sebum production is not yet well
delineated. Systemically, in sufficient amounts, estrogen can
suppress sebum production; however, the amount of estrogen
required to reduce sebum production differs individually,13
and clinically some women can experience an exacerbation
in acne during high-estrogen periods such as pregnancy.
There are several proposed mechanisms on estrogens influence
in sebaceous gland activity: (1) direct antagonism of androgens
within the sebaceous glands, (2) androgen production inhibition
in the gonads via negative feedback loops on gonadotropin
release in the pituitary, or (3) gene regulation that negatively
influence sebaceous gland proliferation and lipogenesis.14

Clinical characteristics
Without a doubt, hormones influence acne, especially adult
female pattern acne, also known as hormonal pattern acne.15
Adult female pattern acne tends to be mild to moderate, though
persistent in nature. It is usually seen along the face, especially
the jawline and lower third of the face, and the upper trunk.
Comedonal lesions are more likely to be found on the forehead
and sides of the face. In contrast, inflammatory papules are
more commonly found around the chin and perioral region.
These lesions tend to flare premenstrually16; furthermore,
studies have demonstrated standard therapies of topicals and
antibiotics are unable to provide adequate control in hormonal
pattern acne.17,18
Although the majority of women with hormonal pattern acne
have normal levels of circulating androgens, it is important to be
aware that acne may be a sign of systemic hyperandrogenism.
Other signs of hyperandrogenism include irregular menses,
excess facial or chest hair, androgenic alopecia, seborrhea,

C. Lam, A.L. Zaenglein

Cushinoid features, increased libido, clitoromegaly, deepening
of the voice, hyperhidrosis, and acanthosis nigricans. The two
most common causes of hyperandrogenism are polycystic
ovarian syndrome (PCOS) and congenital adrenal hyperplasia
(CAH). In women with PCOS, acne usually involves the face,
and up to 50% experience acne on their neck, chest, and upper
back.15 If an endocrine abnormality is suspected, screening
tests to elucidate the etiology should be performed: dehydroepiandrosterone sulfate (DHEAS), total testosterone, free
testosterone, and luteinizing hormone/follicle-stimulating
hormone (LH/FSH). Ideally, serum studies should be obtained
during the luteal phase (ovulation) of the menstrual cycle or
2 weeks before the onset of menses. Many women with PCOS
have abnormal menstrual cycles; thus, timing of laboratory
studies may be irrelevant. All patients need to stop hormonal
contraceptives at least 1 month before testing; even hormonereleasing intrauterine devices can affect results. Repeat testing is
prudent with abnormal results. Previous reviews have discussed
the interpretation of these serum studies (Table 1).14,19

Hormonal treatment of acne

Current acne therapies target individual factors contributing to the formation of acne lesions. Ideally, treatment
regimens combine therapies to address multiple pathogenic
factors simultaneously. Given the prominent role of
hormones in acne, antiandrogen therapy is naturally a
vital tool in a dermatologists armamentarium. Methods to
treat the hormonal component of acne can be divided into
four groups: (1) androgen receptor blockers, (2) ovarian
androgen blockers, (3) adrenal androgen production blockers,
and (4) enzyme inhibitors. Previous reviews have extensively
discussed all these options.14,20 In this paper, we will examine
the two most commonly used agents in the United States:
spironolactone (an androgen receptor blocker) and COCs
(ovarian androgen blockers).
Table 1 Endocrine laboratory evaluation and diagnostic
considerations14,19
Laboratory test

Hormone level
(ng/dl)

Suspected diagnosis

DHEAS

N 8000
4000-8000
N 200

Adrenal tumor
CAH
Ovarian
androgen-secreting
tumor
PCOS
Hyperandrogenism

Total testosterone

Free testosterone

LH/FSH ratio

N 150
Elevation
from normal
range
N 2:3

PCOS

CAH, congenital adrenal hyperplasia; DHEAS, dehydroepiandrosterone

sulfate; FSH, follicle-stimulating hormone; LH, leutinizing hormone;
PCOS, polycystic ovarian syndrome.

Contraceptive use in acne

Spironolactone
Originally founded as an antihypertensive agent, spironolactone is typically used as an adjunctive therapy for acne
in dermatology.19 It has been used for more than two decades
in acne, although it is an off-label use. Spironolactone has
antiandrogenic effects. It competes with testosterone and DHT
for androgen receptors on sebaceous glands and reduces the
sebocyte proliferation.21 Additionally, it has been shown to
suppress the cytochrome P450 pathway, inhibit steroidogenesis,
and reduce 5-reductase activity.2224 In vitro studies demonstrate spironolactone can reduce sebum excretion by 30-50%.25
The evidence for spironolactone in acne is unclear. A
recent updated Cochrane review on the use of spironolactone
in hirsutism and acne concluded that there is no evidence
for the effectiveness of spironolactone in acne.26 The review
included three studies2729 on acne and spironolactone.
One study, of 31 patients, did not demonstrate a reduction in
sebum excretion with topical 3% and 5% spironolactone
cream compared with topical canrenoate (an aldosterone
antagonist).27 A randomized, placebo-controlled, doubleblind, crossover trial examined the effectiveness of 200 mg
of spironolactone daily in 29 women.28 In comparison to
placebo, spironolactone significantly reduced the number of
inflamed lesions (P b .001); however, intention-to-treat
analysis was not performed and the spironolactone group
was more severe at baseline.28 Another study examined
sebum production after 3 months treatment with 4 doses
(50-200 mg daily) of spironolactone compared with placebo
in 36 patients.29 It concluded the maximum subjective and
objective benefit was found at doses of 150 to 200 mg.
Unfortunately, the statistics were not reported and the small
sample size makes establishing significance unlikely.29
On the other hand, there have been positive clinical
experiences and case reports on the use of spironolactone in
acne.14,15,19,20 In a case series of 14 female patients who failed
previous systemic treatment, spironolactone 75 to 150 mg
daily revealed a reduction 50% of lesions in 6 patients.30 Some
authors argue that perhaps appropriate patient selection for
spironolactone could make a difference.31 Ultimately, there
has not been an ideal and conclusive study to determine the effects
of spironolactone on female patients with acne. Dermatologists
are dependent on their clinical judgment and experience when
choosing spironolactone for the treatment of acne.31
Typical acne dosages for spironolactone range from 25
to 200 mg daily. Initiation requires low doses with careful
stepwise escalations.19 After reaching a desired endpoint,
maintenance doses of 25 to 50 mg daily can control sporadic
outbreaks of inflammatory or isolated cystic lesions.
Hormonal contraceptives used in conjunction with spironolactone can be beneficial for acne in addition to tempering some
of the adverse side effects. Oral contraceptives may help
decrease the side effects of spironolactone, such as dysmenorrhea, irregular menses, and breast tenderness. These side effects
are dose dependent and common with spironolactone use.19

505
As a concurrent form of birth control, hormonal contraceptives remove the concern of hypospadias and testicular
feminization of fetuses caused by prenatal spironolactone
exposure; however, these concerns may be more theoretical
and are based on mice studies.32 There have been no
prospective studies on the adverse effects of spironolactone
exposure in pregnant women. One surveillance study
examined 229,101 completed pregnancies, occurring between
1985 and 1992, of which 31 newborns had been exposed to
spironolactone during the first trimester of pregnancy. There
were two major defects; one was expected for other reasons,
and the other was an oral cleft defect. There were no anomalies
in terms of hypospadias, cardiovascular defects, spinda
bifida, polydactyly, or limb reduction defects.19 Additionally,
there has been a case report of two healthy males with no birth
defects after exposure to high doses of spironolactone
(200-400 mg daily) for maternal Bartters syndrome.33
As a potassium-sparing diuretic, there is a risk of
hyperkalemia with spironolactone. Laboratory monitoring
may be indicated in some instances, such as in older women
with multiple medical conditions, in patients with cardiac
disease, or when used in conjunction with a drospirenonecontaining oral contraceptive. In a young, healthy population,
it is usually clinically insignificant. One study examined
the use of 100 mg of spironolactone and a combined oral
contraceptive with 30 g of ethinyl estradiol and 3 mg of
drospirenone and confirmed no significant increase in
potassium levels. Subjects (85%) experienced excellent
improvement in their acne after 6 months.34

Combined oral contraceptives

Combined oral contraceptives (COCs) can be very useful
when treating the hormonal component of acne. COCs
contain an estrogen, ethinyl estradiol, and a varying
progestin. The estrogen inhibits LH and FSH, which
suppress ovulation and ovarian androgen production. This
subsequent reduction in androgens results in a decreased
activation of androgen receptors at the level of the sebaceous
gland. Estrogen also stimulates the production of steroid
hormonebinding globulin (SHBG) in the liver, which
decreases circulating levels of testosterone.
The effect of progestin on acne is unclear. Some studies
suggest it can lower androgen effects by inhibiting 5reductase or competitively inhibiting androgen receptors31,35;
however, progestins, especially first generation ones such as
norgestrel and levonorgestrel, can interact with androgen
receptors, resulting in an exacerbation of acne, hirsutism, and
androgenic alopecia.14,15,31 Worsening of acne is reported in
about 11% of women with progestin-only contraceptives.36
Although the accepted principle is that all COCs can
lower sebum production and induce SHBG, certain COCs
have been specifically examined for use in acne. The U.S.
Food and Drug Administration (FDA) approved three COCs

506

C. Lam, A.L. Zaenglein

for acne treatment: Ortho Tri-Cylen (McNeil Janssen

Pharmaceuticals, Raritan, NJ), Estrostep (Warner-Chilcott,
Rockaway, NJ), and, most recently, Yaz (Bayer, Montville, NJ).
All of them contain ethinyl estradiol in combination with
different progestins (Table 2). Generic versions of each of
these formulations are available.
In a recent updated Cochrane review on COCs in
acne, the outcomes of available studies were examined.37
In the six studies examining the efficacy of COCs compared
with placebo, COCs demonstrated reduction in lesion counts.
The analysis of the 13 studies that compared various COCs
was inconclusive due to the methodologic diversity and
conflicting results.37
In the original phase III trials, Ortho Tri-Cylen,
containing 35 g of ethinyl estradiol with a triphasic regimen
of norgestimate, revealed a 50-60% reduction in inflammatory
lesions, increased SHBG, and improved global assessment
after 6 months of therapy.38,39 One phase III, multicenter,
double-blind, placebo-controlled trial examining 231 women
for 6 months noted a mean decrease in total lesion count:
29.1 (53.1%) versus 14.1 (26.8%) in the COC and placebo
group, respectively.38
In Estrostep, the dose of ethinyl estradiol increases:
20 g for the first 5 days to 30 g for the next 7 days, then
35 g the following 9 days. In two randomized, doubleblind phase II trial, Estrostep showed a 47% reduction in
inflammatory lesions compared with placebo.40
Yaz specifically contains drospirenone, a more recently
developed progestin. It is a 17-spironolactone derivative
with both antiandrogenic and antimineralocorticoid properties.
The additional antimineralocorticoid activity can offset the
estrogen-related fluid retention and weight gain. Drospirenone
at 3 mg is equivalent to 25 mg of spironolactone.41 When
using Yaz with spironolactone, potassium levels should be
monitored at baseline and repeated in 4 to 6 weeks.14 Yaz
obtained its FDA approval to treat acne after two multicenter,
double-blind, randomized, placebo-controlled trials demonstrated a 42-46% reduction in total lesion counts.4244

Coronary artery disease

Increased coronary artery events were associated with
higher-dose oral contraceptives; however, low-dose oral
contraceptives have reduced this risk. Among healthy,
nonsmoking women, studies have demonstrated COCs
containing less than 50 g estrogen do not increase myocardial
Table 3 Contraindications to combination oral contraceptives
(COCs)LDL, low-density lipoprotein
Category

Contraindications

General

Pregnancy
Breast-feeding (b 6 weeks postpartum)
Smoking and age 35 +
Breast cancer
Endometrial cancer
Liver tumor (benign or malignant)
Viral hepatitis (active)
Severe cirrhosis
Deep venous thrombosis
Pulmonary embolism
Thromboembolic disorders
Prolonged immobilization
Heart disease
Uncontrolled hypertension
Hypercholesterolemia
(LDL N 160 mg/dl)
Diabetes with end organ
damage and age 35 +
Migraine headaches with focal
neurologic symptoms
Migraine headaches and age 35 +
Stroke
Renal insufficiency

Neoplastic

Liver
Hematologic

Risks
Patient selection is important when prescribing oral
contraceptives. A detailed medical and family history should

Table 2

be obtained to screen for contraindications (Table 3). For more

complete and specific recommendations with updates on
unique clinical situations, refer to the U.S. Medical Eligibility
Criteria for Contraceptive Use.45 The safety profile of COCs
has been demonstrated on millions of women. A study of
23,000 users found similar mortality rates between users and
nonusers46; however, there are potential risks associated with
COCs, and they differ significantly depending on the amount
of estrogen and type of progestin. The early oral contraceptives
contained ethinyl estradiol of up to 100 g; however, those are
not in use anymore. Current pills average 30 to 35 g. Any
pill with less than 50 g of ethinyl estradiol is considered
low-dose, whereas newer ultra low-dose pills contain 20 to
25 g of ethinyl estradiol.47 The risks of coronary artery
disease and venous thromboembolism have been reduced with
the low-dose COCs.14,15 Note that none of the FDA-approved
COC formulations for acne contains more than 35 g of
ethinyl estradiol (Table 2).

Cardiovascular

FDA-approved combined oral contraceptive pills for acne

Trade name

Estrogen

Progestin

Ortho Tri-Cylen

35 g

Estrostep

20, 30, 35 g

Yaz

20 g

Norgestimate 180,
215, 250 mg
Norethindrone
acetate 1 mg
Drospirenone 3 mg

Ortho Tri-Cylen, McNeil Janssen Pharmaceuticals, Raritan, NJ; Estrostep,

Warner-Chilcott, Rockaway, NJ; Yaz, Bayer, Montville, NJ.
All three contain ethinyl estradiol.

Endocrine
Neurologic

Drospirenone
associated

Adrenal insufficiency
Hyperkalemia

Contraceptive use in acne

infarction (MI) risk48; however, women who are older than age
35 and smoking 15 or more cigarettes daily do confer an
increased risk for MI. Other concomitant factors that increase MI
risk include hypertension, dyslipidemia, diabetes, and obesity.

Venous thromboembolism
The association of venous thromboembolism (VTE) and
COCs is known with an estrogen dosedependent relationship.49 During reproductive years, women taking COCs with
ethinyl estradiol are at a six to eight times higher risk for VTE
than nonusers, depending on the kind of contraceptive used.50
This is likely secondary to the alternation of clotting factors and
fibrinolysis due to the COCs effect on liver metabolism and
possible reversible activated protein C resistance.51 Although
COCs do increase ones risk for VTE, the risk of VTE during
pregnancy and the postpartum period is much higher than
during use of any COC.5255 Other than COCs, women of
reproductive age have risks factors for VTE (Table 4).50,56
The estrogen component of COCs is typically the causative
factor in the development of VTE; however, there have been
reports of potential additive effects with new generation
progestins, such as drospirenone.57 The FDA recently issued a
statement of its continued review of VTE in drospirenone oral
contraceptives. Preliminary results demonstrated a 1.5-fold
increase in VTE in women who use drospirenone-containing
birth control pills compared with other hormonal contraceptives.58 New studies demonstrate the risk for VTE with COCs
containing third- and fourth-generation progestins such as
drospirenone compared with first- and second-generation
progestins (norethisterone, norgestrel, levonorgestrel, norgestimate) is doubleda sixfold increase compared to nonusers.56
Experts in the field are currently recommending secondgeneration COCs (norgestrel, levonorgestrel, norgestimate) for
first-time users.50,56,59,60
Patients traditionally have been counseled to discontinue
COCs 4 to 6 weeks before surgeries associated with
immobilization; however, some authors recommend continuation of COCs with pharmacologic thromboprophylaxis after
surgery because the risk of VTE with COCs does not return to
normal until 8 to 12 weeks after cessation.50 Other risk factors
that increase VTE in COC use include age, high body mass
index (BMI), smoking, vasculitis, and immobility. Genetic
thrombophilia (eg, factor V Leiden mutation, protein C
deficiency, protein S deficiency, antithrombin deficiency,
antiphospholipid antibodies, hyperhomocysteinemia) are contraindications for COCs. Unfortunately, it is often not until use
of COCs in adolescence or young adulthood that these genetic
traits are revealed.

Stroke

507
Table 4

Venous thromboembolism risk factors in women56

Risk factor
Inherited
Family disposition
Leiden factor V mutation heterozygote
Leiden factor V mutation homozygote
Protein C deficiency
Protein S deficiency
Acquired
Age
Pregnancy
BMI 30 kg/m2
Oral contraceptives
Immobilization
Connective tissue diseases
Varicose veins

Prevalence Relative
(%)
risk
5
6-10
0.4-1
0.05
0.1

2
8
64
11
32

50
4
8
35
?
4
8

4
4-28
2
3-6
2-5
3
2

BMI, body mass index.

Close relative.

30 years of age and younger vs. 30 years of age and older.

Due to travel or surgery.

thromboembolic strokes. In healthy, young women, the risk

of ischemic stroke is extremely low, but concomitant COC
use and smoking increases the risk significantly.61

Breast cancer
The evidence demonstrating a link between breast cancer
and hormone exposure is marginal and controversial.62 In a
large meta-analysis of 54 studies including 53,000 women with
breast cancer and 100,000 controls, there was a 1.24 relative
risk of breast cancer in current users of oral contraceptives.
This increased risk was eliminated within 10 years of COC
cessation.63 Another case-control study demonstrated no
association between oral contraceptive use (current or former)
and significant increased breast cancer risk.64 Furthermore, the
initial studies were based on contraceptives containing more
than 50 g of ethinyl estradiol.65

Cervical cancer
There may be an association between cervical cancers in
women who use oral contraception; however, the association
is reduced with cessation of the pill, and by 10 years, the
risk of cervical cancer is similar to never users.66 There are
also confounding variables, including women on COCs may
have more unprotected sexual encounters and increased
exposure to human papillomavirus, a known risk factor for
cervical cancer.67 Patients should be encouraged to get the
HPV vaccine to prevent cervical cancer.

Prescribing COCs
The evidence regarding oral contraceptives and stroke
is unclear. Most studies are small, do not control for major
risk factors, and do not distinguish between hemorrhagic and

Prescribing COCs is not difficult, and the risks are not

necessarily greater than other commonly used dermatologic

508
therapies; however, many dermatologists remain hesitant to
prescribe COCs due to lack of familiarity with available
formulations, prescribing guidelines, and perceived risks.
The advantage to having a dermatologist prescribe their
own therapy is increased access to treatment; the patient
will not require an additional visit to a primary care provider,
potentially delaying treatment for weeks to months.
Similar with all acne medications, patient expectations need to
be managed. COCs do not improve acne rapidly. Improvement
may not be appreciated for at least 3 to 4 months. During this
period, adjunctive combination therapies such as topical
retinoids and antibiotics may help with overall reduction
of lesions.68
There are several ways to start COCs: (1) the first day of
patients next menses, (2) the first Sunday during or directly
following menses, and (3) immediately, also known as the
quick start method. If the patient chooses option three, it is
important to obtain a negative pregnancy test before starting
and the patient needs to use backup contraception for 1 to
3 weeks if she is using the COC for contraception as well.
Studies have shown increased compliance with this method
without an increased side effect profile.6972 The quick
start" method is especially useful when starting in conjunction with isotretinoin, which requires a pregnancy test
already, and timing with the iPLEDGE program in the
United States is vital.68
Patients are instructed to take their oral contraceptives daily,
at approximately the same time, even if they are not using it for
contraception. Irregular use impedes treatment; in addition,
patients may experience unscheduled bleeding and a false
sense of contraception security. On average, adolescents miss
up to three pills per cycle; consequently, although the perfect
use failure rate is about 0.3%, the typical use failure rate is 9%
(Table 4).73 Patients are encouraged to set an alarm on their
cellular devices as a daily reminder to routinely take their pill.
If the daily pill is forgotten or missed, patients should take
the missed pill as soon as they realize. If one whole day is
missed, the patient should take both pills at the same time.68
Because the COC is used to regulate hormonal cycles, patients
should be counseled that irregular use and missed pills will be
counterproductive to the aim of therapy.
Initial bleeding or spotting is normal during the first
3 months of treatment and should resolve after the body
adjusts to the new hormonal levels. Other common side effects
include nausea, vomiting, weight gain, mood changes,
and breast tenderness. Weight gain is an often cited barrier
to treatment; however, a recent Cochrane review indicated no
large effect of COCs on weight gain, although the current
evidence was not quite adequate.74 It is important to inform all
patients that COCs do not protect against sexually transmitted
infections (STIs). If a patient is using COCs for treatment of
acne and contraception, she should be evaluated regularly by a
primary care provider for STI counseling and surveillance.
Monitoring blood pressure for several months after starting
COCs should also be done at follow-up visits because they
may cause hypertension.47

C. Lam, A.L. Zaenglein

There is a common misconception that pelvic examinations
are required before starting oral contraceptives. Through the
years, the American College of Obstetricians and Gynecologists (ACOG) has supported less stringent requirements for
prescribing oral contraceptives. In 1996 ACOGs guidelines
stated that initial visits for COCs do not have to include a
pelvic examination if patients opt to defer. In 1999, ACOG
stated pelvic examinations are not necessary for the initiation
of COCs in teenagers. Most recently, ACOG guidelines
recommend less frequent cervical screening in general: 3 years
after onset of sexual activity or at the age of 21. Furthermore,
the decision to prescribe COCs is not determined by the pelvic
examination findings. COCs can be safely prescribed based
on careful review of medical history and blood pressure
evaluation.75,76 Although we advocate and encourage routine
well-women exams, it is acceptable to start COCs with future
follow-up with a gynecologist or primary care physician.
Potential drug interactions with COCs that can potentially
decrease the effectiveness of contraception have also been a
concern. Theoretically, it has been suggested that antibiotics
alter intestinal bacterial flora, thereby reducing the estrogen
absorption; however, pharmacokinetic studies indicate that
commonly used acne medications tetracycline and doxycycline
do not alter estrogen levels.77,78 Overall, there has been no
evidence to suggest an adverse interaction between oral
contraceptives and commonly used antibiotics for acne
treatment. Studies have reported no difference in pregnancy
rates between women who took antibiotics with COCs and
those who took COCs alone.79,80 On the other hand, rifampin
and griseofulvin can interact with COCs by accelerating
COC metabolism through the cytochrome p450 (CYP) 3A4
pathway.81 Antiepileptics such as carbamazepine and phenytoin
can also enhance the metabolism of COCs through the same
pathway, resulting in the risk of contraception failure.
COCs are rarely used as monotherapy for acne. In most
instances, patients are already taking a combination therapy
of topical retinoids, topical benzoyl peroxide, and antibiotics.
There are several scenarios where the addition of COCs
is appropriate: (1) women who desire regulation of their
menstrual cycle; (2) inadequate traditional, combination
therapy; (3) acne flares corresponding with menstrual cycles;
(4) complaints of oiliness; and (5) contemplation of isotretinoin
therapy.68 Younger patients and parents can initially present
with reluctance and anxiety at the suggestion of starting COCs.
Often a strategy to reduce the discomfort involves emphasizing
the hormonal component in the pathophysiology. It can also be
presented as a stepwise approach to isotretinoin therapy.

Contraception concerns with use of isotretinoin

Combined oral contraceptives are commonly used
for pregnancy prevention in female patients undergoing
isotretinoin treatment. The method of combining condoms
and another reversible contraceptive method is the standard for
sexually active adolescents, because it prevents unintended

Contraceptive use in acne

pregnancy and STIs.82 This method is also a requirement for
isotretinoin therapy in the United States. The FDA-mandated
iPLEDGE program stipulates that any female of childbearing
potential must use two forms of highly effective contraception.
Unacceptable forms of birth control include (1) oral hormonal
pills without estrogen (progestin only "mini-pills"), (2)
intrauterine device (IUD) progesterone T (discontinued in
2001), (3) female condoms, (4) natural family planning
(rhythm method or breastfeeding), (5) fertility awareness,
(6) withdrawal, and (7) cervical shield.83 It is imperative to
have appropriate contraceptive counseling techniques given
the teratogenicity of isotretinoin. Dermatologists tend to be
familiar with COCs given its efficacy in treatment of hormonal
acne; however, when prescribing hormonal therapies for
contraception, there are other excellent options with which
dermatologists should familiarize themselves. When recommending a birth control method, multiple factors need to be
considered: maturity, finances, access to care and prescriptions,
confidentiality, medical risks and benefits, and contraindications. We will review alternatives to COCs that are acceptable
forms of contraception in the adolescent and young adult
population.
There are approximately 750,000 pregnancies annually
among teenagers aged 15 to 19 in the United States, with more
than 80% of them unplanned.84 About one third of teenagers in
high school (15-19 years of age) are sexually active and more
than 40% have ever had sexual intercourse.85 The prevalence
of teenagers having sexual intercourse for the first time
before age 13 years is 6.2%.85 User-dependent contraceptive
methods (eg, condoms, pills, patch, ring, injections) have
a higher typical use failure rates (Table 5).73,86 The pregnancy
rate during typical use (including inconsistent or incorrect use)
for condoms is 18%.73 The percentage is lower for the pill,
patch, and ring (9%) and depot medroxyprogesterone acetate
(DMPA) (6%)73,86; furthermore, a recent study demonstrated
a twofold increase in contraceptive failure in women
younger than 21 years using the pill, patch, or ring, compared
with older women. Additionally, with long-acting reversible
contraception (LARC) (eg, IUDs, implants), adolescents have
a similar low failure rate as women 21 years of age and older.87
LARC is user independent. After initial insertion, there is
no maintenance, resulting in similar typical and perfect use
failure rates.86 For any female patient starting isotretinoin,
with a known history of nonadherence with hormonal
therapy or other prescriptive routines, these alternate forms
of contraception should be strongly recommended by
the dermatologist.

Skin patch and vaginal ring

The skin patch (SP) (Ortho Erva, Ortho-McNeil-Janssen
Pharmaceuticals, Titusville, NJ) and vaginal ring (VR)
(NuvaRing, Organon Int., Oss, The Netherlands) are two
alternative forms of birth control. Similar to COCs, they
contain estrogen and progestin. Although the skin patch and

509
vaginal ring are still user-based methods and are often grouped
with daily COCs for adherence studies,73 both were designed
to increase user adherence by avoiding the daily motivation
requirement; therefore, they may be good options for
adolescents who desire a lower maintenance contraceptive
but would like more control over possible discontinuation due
to side effects. Currently the typical and perfect use estimates
between the SP and VR are equal to COCs (Table 5). Superior
efficacy has not been demonstrated in randomized trials. One
randomized trial showed the failure rate of the SP was 1.2%
compared with COCs at 2.2%; however, it was not statistically
significant (P = .6).88 In a subsequent paper, authors continued
to advocate better adherence with the SP, but to fully
demonstrate the superiority and significance in a study, the
sample size required would not be practical.89 Two studies
have examined the pregnancy rates in women randomly
assigned to the VR and COCs.90,91 One90 showed identical
pregnancy rates, and the other91 did not demonstrate a
statistical difference.

Skin patch
The SP is a transdermal patch containing 6 mg of
norelgestromin and 0.75 mg of ethinyl estradiol, applied weekly
for 3 consecutive weeks, followed by a patch-free week.

Table 5 Percentage of women experiencing an unintended

pregnancy during the first year of typical use and perfect use of
contraception and the percentage continuing use at the end of
the first year in the United States
Method

No method
Male condom
COCs
Skin patch
Vaginal ring
DMPA
ENG subdermal implant
IUDs
CuT380A
LNG-IUS

Percentage of women
experiencing unintended
pregnancy within first
year of use
Typical use

Perfect use

85
18
9
9
9
6
0.05

85
2
0.3
0.3
0.3
0.2
0.05

0.8
0.2

0.6
0.2

COC, combination oral contraceptives; CuT380A, copper T380A;

DMPA, depot medroxyprogesterone; ENG, etonogestrel; LNG-IUS,
levonorgestrel intrauterine system; IUD, intrauterine device.
Adapted from reference 73.
The percentage of women who experience accidental pregnancy
during the first year if they do not stop use for any other reason among
typical couples who initiate use of a method.

The percentage of women who experience accidental pregnancy

during the first year if they do not stop use for any other reason among
couples who initiate use of a method and who use it perfectly (consistently
and correctly).

510
There has been concern that the SP is less effective in women
weighing more than 198 lb.47
In 2008, the FDA approved additional warnings on
the Ortho Erva patch label of the higher risk of VTE
compared with women taking oral contraceptive pills.92
There are conflicting studies on the association the patch and
thrombotic events.9397 As part of the Boston Collaborative
Drug Surveillance Program, two case-control studies reported no increased risk (odds ratio [OR] ~ 1.0) of VTE in patch
users compared with norgestimate-containing oral contraceptives.94,96 In a postmarketing, case-control study using
PharMetrics/IMS and MarketScan databases, the authors
found the OR of VTE in patch users compared with
levonorgestrel-containing oral contraceptives was 2.0 (CI
0.9-4.1) and 1.3 (CI 0.8-2.1) in Pharmetrics and MarketScan
databases, respectively. When restricted to women 39 years
or younger, the OR was 1.4 (CI 0.6-3.0) and 1.2 (CI 0.7-2.0),
respectively97; however, another case-control study found an
increased odds ratio of VTE of 2.4 in patch users compared
with norgestimate-containing oral contraceptives.93 A recent
retrospective Danish cohort study concluded that patch users
had a 7.9 and 2.3 relative risk of VTE compared with
nonusers and levonorgesterel-containing COC users, respectively. 98 Interestingly, this same study also noted VR
users have a 6.5 and 1.9 relative risk of a VTE compared
with nonusers and levonorgesterel-containing COC users,
respectively.98

Vaginal ring
The vaginal ring (VR) is a once-a-month, soft, flexible
transparent ring (54 mm in a diameter and 4 mm thick) that
is inserted by the patient into the vagina. It stays for 3 weeks
and is removed by the patient for a ring-free week for
withdrawal bleeding. The VR does require comfort with
inserting the ring into vaginal canal. There have been mixed
reviews on preference. Although dosing is less frequent, one
survey of college-aged women demonstrated an eightfold
preference for COCs over the ring99; however, in another
survey examining the attitudes of 164 adolescents aged 14 to
21, 58% approved of the idea of a VR for contraception.
Associated factors for preference of the VR included using
at least one vaginal product and having had at least one
pelvic examination.100
In a recent Cochrane review of 15 trials, comparing the
SP and VR with COCs, it showed that all three methods
had similar pregnancy rates (5 compared the 667 SP with
COCs; 10 compared VR with COCs). SP users were more
likely to drop out from trials compared with COC users,
possibly secondary to more side effects of breast discomfort, painful periods, nausea, and vomiting. Despite the side
effects, patch users used their contraceptive technique more
consistently. Compared with COC users, VR users were not
more likely to drop out and reported less nausea, acne,
irritability, and depression. Although VR users had fewer

C. Lam, A.L. Zaenglein

bleeding problems, they did report more vaginal irritation
and discharge.101

Injectables
Injectables, either combination or single hormone, are
acceptable primary forms of contraception in the iPLEDGE
program.83 Lunelle (Pfizer, New York, NY) was the first
combination monthly injectable containing 25 mg medroxyprogesterone acetate and 5 mg estradiol cypionate; however,
it was discontinued in the United States in 2003. There are
similar injectables (eg, Cyclofem, Upjohn, Mxico City,
Mxico; Mesigyna, Schering AG, Berlin, Germany) that are
available in other countries.
Depot medroxyprogesterone acetate (DMPA) is a progestin-only, 150-mg intramuscular injection every 11 to
13 weeks. With perfect use, the failure rate is 0.2% and the
typical use failure rate is 6% (Table 5).73 Other advantages
include privacy and no daily compliance requirement. The
disadvantages are irregular vaginal bleeding, weight gain,
possible exacerbation of depression, and delay in return to
fertility after discontinuation. It can also make acne worse. As a
depot in the muscle, it cannot be immediately discontinued if
these side effects occur. Caution should be placed if the
adolescent has had a known history of depression.102
The most controversial issue with DMPA in adolescents is
its effect on bone mineral density (BMD). In 2004, the FDA
issued a black box warning regarding its association with
significant BMD loss that may not be reversible. Its use
should be limited to 2 years. Decreased BMD during teenage
years is crucial because girls gain 40-50% of their skeletal
mass in adolescence. The highest rate of accrual occurs
during 11 to 15 years of age; after 18 years of age, the skeletal
mass increase is only about 10%. Peak bone mass occurs
between the ages of 16 to 22.103 Current studies demonstrate
a statistically significant loss of BMD in DMPA users, but
there is a trend toward regaining BMD after cessation.104,105
The clinically significant effect (osteoporotic fractures later
in life) of DMPA use on peak bone mass is unknown. Until
there is more long-term evidence, the benefits of DMPA
outweigh the risks102; additionally, when prescribed as a
contraceptive for isotretinoin use, the patient would only be
required to use DMPA for approximately 7 to 8 months,
limiting its effects on BMD.

Long-acting reversible contraception

LARC methods include IUDs and subdermal implants.
Both methods require a clinician visit for insertion and
removal. Theses contraceptives are either hormone free
(ParaGard) or progestin only (Mirena, Implanon), which
means they are suitable for patients with genetic thrombophilias.50 These forms of contraception should be strongly
considered in sexual active female patients in monogamous

Contraceptive use in acne

Table 6 Long-acting reversible contraceptives (LARC)
contraindications113
Intrauterine device
Pregnancy
PID
Untreated cervicitis
Postpartum sepsis
Genital tract malignancy
Breast cancer (LNG-IUS)
Wilsons disease (CuT380A)
Subdermal implant
Pregnancy
Active liver disease
Undiagnosed abnormal uterine bleeding
Breast cancer (current or history)
Hypersensitivity to implant
CuT380A, copper T380A; LNG-IUS, levonorgestrel intrauterine system;
PID, pelvic inflammatory disease.

heterosexual relationships and female patients undergoing

long-term use of isotretinoin.

Intrauterine devices
There are two available IUDs in the United States:
levonorgestrel intrauterine system (LNG-IUS) (Mirena,
Bayer Pharmaceuticals, West Haven, CT) and the Copper
(Cu) T380A IUD (ParaGard, Duramed Pharmaceuticals,
Pomona, NY). As long as pregnancy is ruled out, they can be
inserted at any point in the menstrual cycle and even
immediately after delivery or abortion.45 In addition to
excellent prevention rates, other benefits include the prevention of endometrial cancer106108 and cervical cancer.109 It is
hypothesized that the inflammatory response and reduced
endometrial proliferation (LNG-IUS) thwarts endometrial
cancer.110,111 The way it prevents cervical cancer is not well
understood, though one theory involves the initiation of
cellular immunity.
There has been some concern regarding the use of IUDs
in adolescents resulting in pelvic inflammatory disease (PID)
and infertility. ACOG recently stated IUDs do not increase
an adolescents risk of PID, STI, or infertility112; however,
the incidence of STIs is increased among adolescents and young
adults; therefore, it is prudent to test for Neisseria gonorrhoeae
and Chlamydia trachomatis in sexually active adolescents at
the time of insertion or before. IUD insertion should be delayed
if there is evident mucopurulent discharge or cervicitis at time of
pelvic exam.113
Another concern is the IUD expulsion rate among
adolescents. Current data are limited and inconsistent.
The reported expulsion rates range from 2-10%.114 Finally,
the discomfort involved in the insertion of IUD may be a
barrier to some patients. The reported discomfort ranges from

511
minimal to severe.113 A recent Cochrane review reported that
there is no conclusive evidence on interventions to improve
peri-insertional pain.115

Levonorgestrel intrauterine system (LNG-IUS)

The LNG-IUS is a T-shaped polyethylene apparatus
containing 52 mg of levonorgestrel that releases 20 g
daily for 5 years, after which the daily dose is reduced by
50%. 116 The LNG-IUS averts pregnancy through a
combination of mechanisms. The majority is through the
prevention of fertilization, but the hormonal component
contributes via thickening the cervical mucus, thinning of
the endometrial lining, and suppression of ovulation in
some women. 114 Benefits include reducing monthly blood
loss and improving dysmenorrhea.113

Copper (Cu) T380A

The CuT380A IUD is a T-shaped, nonhormonal
polyethylene apparatus wrapped in copper wire (surface
area of copper: 380/mm2). It prevents pregnancy by inhibiting
fertilization as copper ions are spermicidal.117 The benefits
are its cost effectiveness, because it can last for 10 years,118
and its nonhormonal qualities, allowing for rapid return
fertility.107,108 It may not be as cost effective for short-term
purposes such as isotretinoin therapy. There is no improvement in menorrhagia or dysmenorrhea. There was a slightly
lower continuation rates among CuT380A adolescent users
compared with older women using this method; however,
its rate is still higher compared with those adolescents using
non-LARC methods.119

Table 7 Recommendations for medical conditions and long-acting

reversible contraceptives (LARC) in adolescents113
Medical condition

Implant

LNG-IUS

CuT380A

Nulliparity
Obese
Thrombogenic mutation
Epilepsy
Past STI/PID
Current cervicitis/STI
Thalassemia/sickle cell
Depression

1
1
2
1
1
1
1
1

2
1
2
1
1
4/2
1
1

2
1
1
1
1
4/2
2
1

1, No restriction for use of contraceptive method; 2, the advantages of

the method generally outweighs the theoretical or proven risks of the
condition; 3, the risks of the condition outweighs the advantages of the
method; 4: unacceptable health risk if method is used.
CuT380A, copper T380A; LNG-IUS, levonorgestrel intrauterine system;
PID, pelvic inflammatory disease; STI, sexually transmitted infection.
If STI is suspected at the time of insertion of IUD, insertion should
be deferred until the treatment is complete; however, if the IUD is
already in place, treatment of STI is usually sufficient.

512

Subdermal implant
The etonogestrel-releasing (ENG) subdermal implant is
the only contraceptive implant available in the United States.
The current implant, Implanon (Merck & Co., White
Station, NJ) is soon to be replaced by Nexplanon (Merck &
Co., White Station, NJ), which is identical to Implanon but
with a barium radiographic identifier and new inserter
mechanism.120 It is a 4-cm rod with 2-mm diameter that
contains progestin only. Its mechanism of action involves
ovulation inhibition, thickening of the cervical mucus, and
thinning of the endometrial lining. It is FDA approved for
prolonged use of 3 years.
It appears the ENG implant may be a popular choice
among adolescents who are offered the choice. The CHOICE
project is an ongoing prospective cohort trial designed to
increase LARC use among adolescents by eliminated
financial and knowledge barriers. At baseline, 64% of the
participants choose a LARC method. Among the LARC
users aged 14 to 17 years, 63% opted for the implant.121 The
ENG implant is inserted in the arm under local anesthesia,
avoiding the need for pelvic exams and IUD insertion.
Studies suggest an improvement in dysmenorrhea and
acne.122,123 One study examining the safety and efficacy of
Implanon noted that approximately 60% of subjects who
reported acne at baseline had a subjective decrease in acne at
last assessment.122 The main disadvantage of this method is
the unpredictable bleeding patterns ranging from amenorrhea
to heavy flow.122
There are a few contradictions to LARC in adolescents
(Table 6); but in most cases the advantages of this method
outweigh the risks (Table 7). In the end, LARCs are safe in
adolescents with low failure rates and are user independent.
They provide an option for providers who feel that
isotretinoin therapy is essential but question patients
compliance with contraception. Although dermatologists
most likely will not be participating in the actual insertion of
these devices, they easily could due to the simplicity of use;
however, it is still imperative to have knowledge of these
methods to provide comprehensive contraceptive advice
to patients.

Conclusions
With the role of androgens in acne formation, the
importance of hormonal therapies, such as spironolactone
and COCs, in acne cannot be denied. Although COCs can be
part of the stepwise approach to acne treatment, some
patients may not be ideal candidates for COCs and
dermatologists should be familiar with the risks and benefits
of the various contraceptive methods available; additionally,
it is important to recognize that using COCs for the treatment
of acne and using them for contraception has different
concerns and monitoring recommendations. Awareness of
the role of pelvic exams, STI counseling, and alternative

C. Lam, A.L. Zaenglein

contraceptive methods are critical as the needs of patients
vary. Proper contraceptive counseling is the cornerstone
for pregnancy prevention when using isotretinoin in females
of childbearing potential. It is the responsibility of the
dermatologist to be familiar with the contraceptive choices
available to their patients to ensure safe treatment and
continued availability of isotretinoin.

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