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Review

Acne in the adult female patient: a practical approach


Faranak Kamangar1, BSc, and Kanade Shinkai2, MD, PhD

1
San Francisco Psoriasis Skin and Abstract
Treatment Center, University of Acne vulgaris is a common reason why adult women present to dermatologists and can be
California, School of Medicine,
a clinical challenge to treat. It may also be an important sign of an underlying endocrine
University of California, Davis, and
2
UCSF Department of Dermatology,
disease such as Polycystic Ovary Syndrome (PCOS). Although standard acne therapies
University of California, San Francisco, can be successfully used to treat acne in adult female patients, hormonal treatment is a
CA, USA safe and effective therapeutic option that may provide an opportunity to better target acne
in this population, even when other systemic therapies have failed. In this article, a practi-
Correspondence
cal approach to the adult female patient with acne will be reviewed to enhance the derma-
Dr. Kanade Shinkai, MD, PhD
Assistant Professor of Clinical
tologists ability to use hormonal acne therapies and to better identify and evaluate patients
Dermatology with acne in the setting of a possible endocrine disorder.
UCSF Department of Dermatology
1701 Divisadero Street
San Francisco,
CA 94115
USA
E-mail: shinkaik@derm.ucsf.edu

Conflicts of interest: Dr Shinkai and


Ms Kamangar have no financial
conflicts of interest to declare.

study of 1013 adults over the age of 20 years showed


Background and evidence for acne in adult
that the disparity between male and female report of acne
women
is present at all ages but increases with advancing age,
Acne vulgaris is a common skin condition with 85% life- with 50.9% women vs. 42.5% men reporting acne in the
time prevalence.1,2 This condition is almost ubiquitous in third decade of life and 26.3% women vs. 12% men
adolescents; in one study performed in New Zealand3 reporting acne in the fifth decade of life.7
surveying high school students over the age of 16 years, Self-report studies should be interpreted with caution,
91% of males and 79% of females reported acne. While as there are few reports of investigator-confirmed studies
acne is commonly viewed as a disorder of adolescence, it in the literature. In one study by Goulden et al.5,8 on
may persist into adulthood and often may present for the facial acne in 749 adults over the age of 25 years, 54%
first time in adulthood.1 Adult acne is a common reason of females vs. 40% of males reported acne; however,
for patients to present for dermatological evaluation, and clinician examinations of survey-takers reported clinically
adults in fact make up a large portion of the patient pop- significant acne in 12% of females vs. 3% of males in the
ulation seen by dermatologists for acne. Epidemiology of study. This study also assessed the severity of the acne
office visits for acne in one American study demonstrated lesions, and females were four times more likely to have
that adult patients with acne, mostly women, comprise more severe acne than their male counterparts.5
the majority of visits (61.9%), with adolescents (peak age In a questionnaire-based study characterizing features
1517 years) presenting in 36.5% of visits.4 The actual of acne present in adult women, Poli et al.6 reported an
prevalence of acne in the adult population has not been acne prevalence of 41% in a population of 3305 women.
well defined; various studies have reported acne preva- Acne morphology included both comedonal and inflam-
lence in the range of 4154% in women and 3440% in matory types, and the chin was the most commonly
men.5,6 Several studies suggest that women are more reported site of involvement. Half of the patients reported
1162 likely to report acne than men. Self-report of acne in a sequelae of scarring and pigmentation. Nearly half of

International Journal of Dermatology 2012, 51, 11621174 2012 The International Society of Dermatology
Kamangar and Shinkai Acne in adult females Review 1163

respondents had no history of childhood acne. Of these to hormonal therapies.18 Third, even in women with nor-
women, 78% experienced premenstrual flares of their acne, mal androgen levels, hormonal-based therapies such as
and 97% reported self-manipulation of acne lesions. oral contraceptives and anti-androgen medications are
Acne in adult women has also been shown to have a effective treatments for acne.18 Fourth, rising levels of
late onset and become persistent. Goulden et al.9 con- dehydroepiandrosterone sulfate (DHEA-S) are associated
ducted a study of 200 patients with acne over the age of with the onset of acne in pre-menarchal girls, and higher
25 years, to assess when acne presents in adults. The levels in pre-menarche may predict the development of
majority of patients in the study were women (76%), and more clinically severe acne in puberty.14 Elevated DHEA-
most had persistent acne. Late-onset acne, defined as pre- S also correlates with clinical acne in a subset of patients
senting for the first time in adulthood after age 25 years, with PCOS.19
was more common in women than men (18% vs. 8%). Androgens in women derive from three sources: the
Acne was found predominantly on the face in women. ovaries; adrenal glands; and peripheral conversion.
The study did not find a role for cosmetics, medications, Ovarian-derived androgens include androstenedione and
or occupation in causing this acne but did suggest that testosterone, whereas adrenal glands produce dehydroepi-
chronicity of acne increased the risk of scarring. androsterone (DHEA), DHEA-S, androstenedione, and
Taken together, these studies suggest that acne in adult testosterone. Peripheral conversion of androstenedione
women is common, may continue from childhood or and DHEA also generates testosterone in women.
present for the first time in adulthood, and persists into Androgen-stimulated sebum production contributes to
the later decades of life. These findings are important the pathophysiology of acne in women.13 In skin, andro-
because adult acne has significant psychosocial implica- gen receptors are located in sebaceous glands and in the
tions, comparable to psoriasis vulgaris,10 a disease well outer root sheath of the hair follicle.17 Androgens in the
known for its impact on quality of life. The psychosocial sebaceous gland are metabolized through a multi-step
morbidity associated with acne may be more significant process from DHEA to 5-alpha-dihydrotestosterone, stim-
in women as compared with men.11 Females account for ulating sebocyte proliferation and activity.20 Sebum pro-
2/3 of visits made to dermatologists for acne, and 1/3 of duction is also regulated by other hormones, including
all office visits for acne are by women over the age of estrogens, growth hormone, insulin, insulin-like growth
25 years.4 A proportion of patients with acne report factor-1, glucocorticoids, adrenocorticotropic hormone,
depression (8.8%),4 with women accounting for almost and melanocortins.18
twice the number of respondents with depression as com- Fluctuations in androgens during the menstrual cycle
pared with men (10.6% vs. 5.3%);4 it is important to may account for cyclical flares, including the frequently
note that reported depression does not correlate with the reported premenstrual flares of acne. Few studies have
clinical severity of the acne. There is also a high preva- documented this phenomenon in the clinical setting. In a
lence of acne in patients with eating disorders, such as survey-based study of women aged 1252 years, 44% of
anorexia and bulimia nervosa.10 women reported premenstrual flares of acne, and women
over the age of 33 years had an increased likelihood of
reporting a premenstrual flare as compared with women
Pathogenesis of adult female acne
aged 2233 years.21 There was no difference in severity
Pathogenesis of acne in adult women is complex, involv- of acne, ethnicity, or oral contraceptive pill (OCP) use
ing androgens in addition to other important factors well between women who reported a premenstrual flare and
accepted for their role in the pathogenesis of acne: sebum those who did not. A clinical study by Lucky22 of adult
production; follicular plugging; genetics; Propionibacterium women aged 1844 years, involving clinical observation
acnes; diet; medications; innate immunity; and alterations of women at multiple time points over two menstrual
in follicular keratinization and differentiation.5 While the cycles, noted an increase in premenstrual acne of both
role of cosmetics has been suggested, one study did not inflammatory and comedonal types. Investigators noted
find an association with cosmetic practices and severity of that 63% of women in this study had a 25% increase in
acne.5,12 premenstrual inflammatory acne in the late-luteal phase;
The role of androgens in adult women with acne has 54% of women had a 21% increase in premenstrual
been well supported in the literature,1315 and four clini- comedonal acne in the late-luteal phase.
cal observations highlight this important role. First, The premenstrual flare may be explained by increased
androgen-insensitive individuals do not produce sebum testosterone to estrogen ratios during specific segments of
and do not develop acne.16,17 Second, conditions of the menstrual cycle. Following the peak in testosterone
hyperandrogenism, such as polycystic ovary syndrome and estrogen at the time of ovulation, typically on day 14
(PCOS), are associated with acne that is highly responsive of the menstrual cycle, hormone levels decrease with

2012 The International Society of Dermatology International Journal of Dermatology 2012, 51, 11621174
1164 Review Acne in adult females Kamangar and Shinkai

progression into the luteal phase; an increased testoster- ical exam. Information should include use of medications
one to estrogen ratio likely explains the late-luteal flare in and supplements, social history with specific questions
acne, akin to the skewed androgen to estrogen ratio seen regarding tobacco and street drug use, menstrual history
in perimenopausal women, but further evidence is needed (age of onset and regularity, history of infertility), and
to prove this association. prior or current treatments for acne. A complete review
of systems is necessary to identify signs of hyperandroge-
nism or other endocrine disorder. While time limitations
Clinical features of acne in adult women
pose a special challenge in collecting necessary informa-
Acne in adult female patients may occur more frequently tion, a written questionnaire can serve as a great tool to
on the lower one-third of the face (Fig. 1), especially at increase efficiency and to avoid missing important diag-
the jaw line and chin, with a broad clinical spectrum of nostic clues (Fig. S1).
comedones, papules, pustules, cysts, and/or nodules.6 The common differential diagnosis of adult female acne
Studies in adult and pre-pubertal females reveal a signifi- includes: rosacea; seborrheic dermatitis; acne cosmetic;
cant comedonal component, a possibly under-recognized pomade acne; medication-induced acne (danazol, testos-
morphological feature.23 In one study of adult women terone, progestins, glucocorticoids, lithium, selective sero-
with acne, the majority (85%) were observed to have tonin reuptake inhibitor, isoniazid, phenytoin, vitamin
comedonal acne.23 Women with comedonal acne were, B2, vitamin B6, vitamin B12, halogens, epidermal growth
on average, older in comparison to adult women with factor receptor inhibitor chemotherapy); and hyperan-
papulopustular acne (39 years old vs. 32 years old) and drogenism (including PCOS).25 A targeted history may
reported notably higher rates of smoking than their coun- ask about these specific considerations in the differential
terparts with papulopustular acne (70% vs. 30%).23 diagnosis.
Comedonal acne present in adult women may recapitulate An underlying endocrine disorder, especially hyperan-
morphological features seen in pre-menarchal acne. In a drogenism, is an important diagnostic consideration in
study of pre-menarchal girls aged 811 years, Lucky any female patient with acne, and a suggestive historical
et al.24 noticed a predominance of comedonal acne and a clue is rapid recurrence of acne following isotretinoin
correlation between higher DHEA-S levels and acne sever- therapy.26 Signs and symptoms of hyperandrogenism
ity. This study also noted rising prevalence and severity include amenorrhea or oligomenorrhea (defined as less
of acne with advancing sexual maturation, with acne pre- than eight menstrual cycles per year), and virilization, as
ceding other external signs of puberty. evidenced by deepening of the voice, clitoromegaly,
increased muscle mass, and decreased breast size.13,18
Cutaneous signs of hyperandrogenism include acne, hir-
Medical considerations and differential
sutism, seborrhea, and alopecia. Hirsutism is the most
diagnosis of acne in adult women
common manifestation (7080%) and is highly associated
The medical evaluation of the adult female patient with with elevated levels of free testosterone;27 70% of hirsute
acne should include a thorough medical history and phys- women have hyperandrogenism.13,18 It is also important
to note that many women remove excessive hair, and it is
thus important to inquire about these practices, as hirsut-
ism may not be clinically evident.
Signs or symptoms of hyperandrogenism should prompt
a diagnostic work-up for an underlying hormonal disor-
der. The most common cause of hyperandrogenism is
PCOS (80%), but the differential diagnosis includes
androgen-secreting neoplasm (adrenal gland or ovary),
non-classic congenital adrenal hyperplasia, the syndrome
of Hyperandrogenism, Insulin Resistance, Acanthosis
Nigricans (HAIR-AN), the syndrome of Seborrhea, Acne,
Hirsutism and Alopecia (SAHA), and exogenous andro-
gens (testosterone, DHEA).13,18

Polycystic Ovary Syndrome (PCOS)


Figure 1. Adult female patient with predominantly
nodulocystic acne affecting the lower chin and jawline, also PCOS is the most common cause of hyperandrogenism,
with papules, pustules and comedones with a prevalence of 510% in the general population.2830

International Journal of Dermatology 2012, 51, 11621174 2012 The International Society of Dermatology
Kamangar and Shinkai Acne in adult females Review 1165

In the USA, MexicanAmerican women have higher rates clinical features, such as irregular menstrual history or
as compared with Caucasian and African-American ultrasonographic evidence of polycystic ovaries, and may
women.29 In the UK, there may be increased rates of PCOS be challenging to diagnose. All types with abnormal ovar-
in emigrant populations originating from the Indian sub- ian morphology on ultrasound are associated with obes-
continent and in women of Australian aboriginal ity, insulin resistance, and likely carry a higher risk of
decent.31,32 long-term sequelae of the disease.25 The normoandrogenic
The diagnostic criteria for PCOS remain a topic of subtype lacks these associations and morbidity, and some
great debate. The most recent consensus criteria (Rotterdam, investigators do not define this type as a disease state.
2003)33 defines a diagnosis of PCOS as two of the It is important to recognize PCOS as a systemic disorder
following three criteria: amenorrhea or oligomenor- associated with high morbidity and mortality due to endo-
rhea; biochemical or clinical hyperandrogenism; and crine, cardiovascular, reproductive, and oncological com-
ultra-sonographic documentation of increased follicle plications.26,34 In women diagnosed with PCOS, 10%
count (>12) or follicular volume (>10 cm3) per ovary. A develop diabetes in the third or fourth decade, 40% have
transvaginal ultrasound is required to accurately visualize impaired glucose tolerance, and 40% are obese. The
ovarian cysts. It is important to note that the presence of increased cardiovascular risk in this disease is controver-
regular menstrual cycles, according to these criteria, does sial, but it is known that risk factors traditionally known
not exclude the diagnosis of PCOS; furthermore, lab tests to increase cardiovascular risk are commonly present in
or ovarian ultrasound may be normal. The pathophysiol- PCOS, including obesity, insulin resistance, hyperlipid-
ogy also remains poorly defined, with a strong correlation emia, hypertension, and fatty liver. Long-term exposure to
between the presence of ovarian cysts and androgens, unopposed estrogen due to anovulation theoretically
caused by excessive stimulation by insulin, luteinizing increases the risk of endometrial carcinoma. Many women
hormone, or both.18,26,34 The pathophysiology and clini- with PCOS experience fertility issues, require assistance in
cal presentations in PCOS is an area of active research. reproduction, and experience increased complications of
Acne is an important and common cutaneous sign of pregnancy.26 PCOS patients also have a 30-fold increased
PCOS. Other dermatological signs associated with PCOS risk of obstructive sleep apnea (OSA), even in women with
include hirsutism, androgenic alopecia, seborrhea, and normal body mass index,40 and chronic OSA may result
acanthosis nigricans.3538 Hirsutism is the most common in pulmonary hypertension. All of these sequelae may be
cutaneous manifestation of PCOS, present in 6573% of positively impacted by hormonal therapy and/or interven-
patients, and strongly correlated with elevated androgens tions such as lifestyle modification, including exercise and
and polycystic ovaries on ultrasound.38 Hirsutism also diet.26,41 General goals of treatment of PCOS focus on
has a significant impact on the quality of life of patients uterine protection, establishing menstrual regularity, low-
and is often underestimated by clinicians; a full body ering androgens, reversing insulin resistance and dyslipide-
skin exam is required to accurately assess hair growth mia, weight loss, as well as improving cardiovascular
patterns, and a modified FerrimanGallway score of >8 fitness and targeting cutaneous signs.
indicates clinical hirsutism.38 Androgenic alopecia also Dermatologists should be familiar with the diagnostic
strongly correlates with polycystic ovaries, and is preva- work-up of PCOS, which consists of two components:
lent in 33% of women with PCOS. Seborrhea occurs assessment of endocrine and metabolic parameters, which
with a prevalence of 35% in this population, strongly includes evaluation for important considerations in the
correlates with elevated androgens, but may be a differential diagnosis, including other rare causes of
nonspecific finding. Acanthosis nigricans may be present hyperandrogenism (Table 2).
on the nape, knuckles, intertriginous regions, or on the
face, especially on the zygomatic cheeks or in a periocu-
The treatment of acne in the adult female
lar distribution; it may be found in 5% of women with
patient: a practical approach
PCOS37 and is likely associated with hyperinsulinemia.
As patients may present for evaluation of these cutane- In the treatment of adult female patients with acne, all of
ous signs commonly seen in the disorder, dermatologists the central tenets of acne management are true. A system-
play an important role in the recognition of PCOS. atic treatment algorithm for acne should be utilized;42,43
However, PCOS is likely a clinical spectrum of disease however, with several important caveats. Women over
with subtypes (Table 1)26,39 including classic types, as age 25 years have higher rates of treatment failure; 82%
well as ovulatory PCOS, with emerging recognition of a fail multiple courses of systemic antibiotics,9 and 32%
controversial fourth subtype termed mild or normoandro- relapse after isotretinoin.9 Recurrence shortly after treat-
genic PCOS. The classic form of PCOS fulfills all three ment with isotretinoin should trigger suspicion for an
diagnostic criteria. Other subtypes may lack important underlying hormonal disorder.35 A thorough review of

2012 The International Society of Dermatology International Journal of Dermatology 2012, 51, 11621174
1166 Review Acne in adult females Kamangar and Shinkai

Table 1 Features of PCOS

Type I classic Type II classic Ovulatory PCOS Normoandrogenic or


PCOS (A, HA, PCO) (A, HA) (HA, PCO) mild PCOS (A, PCO, HA)

Menstrual cycle26 Irregular Irregular Normal Irregular


Ultrasound26 Polycystic Normal Polycystic Polycystic
Serum androgens26 High High High Normal or slightly elevated
Hirsutism39 + + + )
Obesity39 + + + )
Insulin resistance26 Present Present Present Not present
Long-term sequelae26 Potential long-term Potential long-term Unknown Unknown
Prevalence26,39 5361% 78.9% 1629% 816%

A, anovulation; HA, hyperandrogenism; PCO, polycystic ovary.

Table 2 Diagnostic work-up of PCOS divided into: (i) hyperandrogenic work-up and special diagnostic considerations; and (ii)
metabolic work-up

Diagnostic work-up Suggestive of PCOS Special considerations20

(i) Endocrine evaluation Total testosteronea >150 ng/dl >200 ng/dl consider ovarian
androgen-secreting tumor
Free testosteronea Increased level
DHEA-Sa Increased level >8000 ng/dl adrenal tumor 40008000 ng/dl
congenital adrenal hyperplasia
Androstenedionea Increased level
17-Hydroxyprogesterone >200 ng/dl late-onset congenital
adrenal hyperplasia
LH : FSH ratio Ratio > 3 : 1
SHBG Normal
Prolactin Normal Consider pituitary disease or pituitary
tumor (i.e. prolactinoma) if increased
TSH Normal Consider thyroid disease and further
work-up if abnormal
(ii) Metabolic work-up BMI
Fasting lipids panel
2-h Glucose challenge (both glucose and insulin at fasting and at 2 h)

BMI, body mass index; DHEA-S, dehydroepiandrosterone sulfate; FSH, follicle-stimulating hormone; LH, luteinizing hormone;
PCOS, polycystic ovary syndrome; SHBG, sex hormone-binding globulin; TSH, thyroid-stimulating hormone.
a
PCOS associated with increased androgens, but not all lab abnormalities are seen in all patients.

systems for an underlying endocrine disorder should be women present with comedonal disease, hormonal thera-
performed prior to initiating isotretinoin. pies can be utilized across the entire clinical spectrum of
Isotretinoin remains a highly viable and important non- acne, including mild and/or comedonal-only disease.20
hormonal treatment option for acne in adult women.43 In Evidence-based recommendations supporting an algorithm
this patient population, there are special considerations of for use of hormonal therapies in acne are currently lacking.
teratogenicity, and individuals over 35 years old may Figure 2 is the authors proposed algorithm for the treat-
have increased risk of adverse skeletal side effects.43 Low- ment of hormonal acne. Although not evidence based, this
dose isotretinoin (1020 mg/day) can be used to minimize algorithm may be a useful tool in conjunction with the
side effects associated with systemic retinoid therapy, and dermatologists clinical judgment.
this is an effective treatment of choice in this popula-
tion.44,45
Hormonal treatment of acne
Hormonal therapies, such as OCP and anti-androgen
therapy, also provide an important and effective opportu- An important goal of hormonal treatment is to reduce
nity to increase treatment options for acne. As many adult sebum production. The mainstay of hormonal acne therapy

International Journal of Dermatology 2012, 51, 11621174 2012 The International Society of Dermatology
Kamangar and Shinkai Acne in adult females Review 1167

Figure 2 Algorithm for treatment of hormonal acne in adult female patients

in the USA includes OCP and spironolactone; other treat- diol [EE]), EstroStep (norethindrone acetate 1 mg + EE
ment options include flutamide and cyproterone.4 Hor- 20/30/35 mcg + 7 day hormone-free interval or ferrous
monal therapy provides an effective adjunct to the current fumarate), and Yaz (drospirenone 3 mg + EE 20 mcg +
acne treatments or may serve as primary therapy. Patients 4 day hormone-free interval). Although these are the
should be educated that this strategy will require time, up three preparations FDA-approved for the treatment of
to several months, to see results, and may require long-term acne, many other preparations likely have equivalent ther-
systemic treatment and ongoing monitoring for side effects. apeutic benefit. An important consideration in the selec-
Hormonal therapy is safe and effective in post-menarchal tion of OCPs for acne is that most OCPs also contain
females over the age of 14 years, even those with normal progestins. Unlike endogenous progesterone, synthetic
androgen levels. Indications for starting hormonal therapy progestins have androgenic activity that may exacerbate
are reviewed in Table 3.46 or trigger acne, and thus the treatment of acne necessi-
tates choosing an OCP that contains a progestin with low
androgenic properties,25 such as the third-generation
Oral contraceptive pills (OCP)
progestins, norgestimate, and desogestrel.
OCPs work by several mechanisms to reduce acne. OCPs There are many safety considerations in prescribing
stimulate hepatic synthesis of sex hormone-binding glo- OCPs, including contraindications and adverse side
bulin, which bind circulating androgens, decrease free effects. Current OCPs have significantly lower levels of
testosterone and DHEA-S, and likely reduce sebum pro- hormone than first-generation oral contraceptive prepara-
duction. OCPs also inhibit 5-a-reductase, decreasing tions; lower levels of hormone, specifically estrogen, dra-
peripheral conversion of testosterone, as well as decreas- matically increase their safety profile, especially in OCPs
ing production of ovarian and adrenal androgens. OCPs containing 35 lg of EE or less.25 Starting an OCP has
are effective in the treatment of acne, with studies demon- also become logistically easier, as the consensus between
strating 4070% reduction in lesion counts.25 WHO, ACOG, and Planned Parenthood has eliminated
There are currently three OCPs approved by the FDA the requirement for a baseline pelvic exam or cervical
for the indication of acne treatment: Ortho Tri-Cyclen Papanicolaou smear in healthy women prior to starting
(norgestimate 180/215/250 mcg + 35 mcg ethinyl estra- an OCP.47 Although many advocate the prescription of

2012 The International Society of Dermatology International Journal of Dermatology 2012, 51, 11621174
1168 Review Acne in adult females Kamangar and Shinkai

Table 3 Indications and contraindications of hormonal treat- and several studies have corroborated these reports.50
ment in acne Patients should be counseled that risk factors for cardio-
vascular events include smoking (any amount), hyperten-
OCP Spironolactone sion, and diabetes. Patients of any age with a history of
migraine headaches with precedent aura or women over
Indications for hormonal therapy for acne46
When oral contraception is desired X
the age of 35 years with any history of migraine head-
For contraception during treatment X aches are at increased risk of thrombotic events such as
with isotretinoin stroke.
In women, as an alternative when X X The association of breast cancer in OCP use has been a
repeated courses of isotretinoin needed
topic of ongoing controversy. In 1996, the collaborative
Women with severe premenstrual acne flare X X
Women whose acne is not responding X X
group on hormonal factors in breast cancer51 conducted a
to conventional therapy meta-analysis of a total of 54 studies, representing 53,297
PCOS X X women with breast cancer and 100,239 control patients.
Women with clinical signs of X X Women currently on OCP were found to have an
hyperandrogenism, such as
increased relative risk of 1.24 of developing breast cancer,
androgenic alopecia, SAHA
(seborrhea, acne, hirsutism, alopecia)
with risk declining up to 10 years following cessation of
Proven ovarian hyperandrogenism X X OCP; after 10 years of cessation of OCP, there was no
Proven adrenal hyperandrogenism X X significant increase in the relative risk of breast cancer. A
Contraindications for hormonal therapy20,47 history of current or past history of breast cancer is cur-
Pregnancy X X rently a contraindication for OCP use. In other individu-
Breastfeeding X X
als, the data should be considered in concert with the
<6 months post-partum X
History of stroke X
efficacy of OCPs in acne as well as data highlighting pro-
History of venous thromboembolism X tective effect of OCPs with respect to endometrial52 and
History of myocardial infarction X ovarian cancer.53
Smoking of any amount and above X Side effects of OCPS are common; appropriate patient
35 years old
counseling may improve patient medication adherence.
Uncontrolled hypertension X
(SBP > 160, DBP > 100)
The most common side effects of OCPs are unscheduled
History of migraine with focal symptoms/aura X bleeding, nausea, and breast tenderness.47,54 All of these
History of migraine and age above 35 years X symptoms, except for bleeding, are alleviated by lowering
Current or past history of breast cancer X the estrogen dose in the OCP. A common concern of
Hypercholesterolemia (LDL > 160) X
many women is weight gain, yet patients should be coun-
Diabetes and age above 35 years X
End-organ damage (liver, kidney) X X
seled that average weight gain with OCP use is 12 kg,
Viral hepatitis or cirrhosis X which occurs in 30% of patients and is most often due to
Liver tumor (any type) X fluid retention.54 Rare side effects include decreased
Upcoming major surgery with prolonged X libido, melasma, and mood changes.54 Concomitant use
immobilization (relative contraindication,
of OCPs and systemic antibiotic is likely safe, as high-
as it is a risk factor for DVT)
lighted by two important studies55,56 demonstrating
pregnancy rates in women taking both medications as
DBP, diastolic blood pressure; DVT, deep venous thrombo-
equal to the rare failure rate of OCPs as a contraceptive.
sis; LDL, low-density lipoprotein; OCP, oral contraceptive
pill; PCOS, polycystic ovary syndrome; SBP, systolic blood
Rifampin, a 3A4 inducer, may be an important excep-
pressure. tion that can alter the metabolism of OCPs, and
increased rates of pregnancy with concurrent use of
rifampin and OCPs have been reported.56 Concomitant
OCPs by dermatologists, an important caveat is the use of OCPs and tetracycline class antibiotics is likely
reported association of poor patient adherence with OCPs safe.55
prescribed by dermatologists.48
Contraindications to OCP use are included in Table 3.
Spironolactone
Notable contraindications include risk factors for vascular
thrombotic events. Cardiovascular risks are not signifi- Spironolactone is a highly effective treatment for acne
cantly increased in non-smokers.49 One study reported in adult women and may surpass the efficacy of OCPs.
that the risk of deep vein thrombosis increases from 1 per A potassium-sparing diuretic, spironolactone at low
10,000 woman-years to 3.4 per 10,000 woman-years dur- doses (25 mg/day) blocks aldosterone and at higher
ing the first year of OCP use and decreases thereafter, doses (50100 mg/day) blocks androgens at the receptor

International Journal of Dermatology 2012, 51, 11621174 2012 The International Society of Dermatology
Kamangar and Shinkai Acne in adult females Review 1169

level.57,58 Drospirenone is a synthetic progestin that is CPA is a 17-hydroxyprogesterone derivative with


an analog to spironolactone; in commonly-available potent androgen blockade.25 CPA is available in two
OCP preparations, the 3 mg drospirenone is estimated forms: in combination OCP or in a non-OCP form that
to have anti-androgenic activity equivalent to 25 mg of can be used in combination with OCP or spironolactone.
spironolactone. Spironolactone is not FDA approved for As a non-OCP medication, CPA is given on days 110 of
the indication of acne, but spironolactone alone or the menstrual cycle (day 1 marking the first day of men-
combined with an OCP at a dose of 50200 mg/day is struation).25
effective in 3385% reduction in acne lesion counts This medication is most commonly used in OCPs also
and also improves seborrhea. Studies with lower dose containing EE, which is not available in the USA (i.e.
spironolactone (50100 mg/day) demonstrated 33% Diane, Dianette). In this form, it is effective for the treat-
improvement, suggesting a dosage effect. Studies with a ment of hirsutism and acne in women and, in one study,
higher dose of 100 mg plus drospirenone demonstrated reduced acne lesion counts by 7590%.20,61 A trial evalu-
an 85% improvement in acne, suggesting a highly effec- ating the efficacy of drospirenone + EE (Yasmin) vs.
tive combination treatment.59 Nine studies on higher CA + EE (Diane) found equivalent efficacy of these treat-
dose spironolactone have also demonstrated an ments (62% vs. 59%) in reducing acne lesion counts.62
improvement in the subjective report of hirsutism, but
clinician observation did not corroborate a significant
Algorithm for the hormonal treatment of acne
difference.57
Spironolactone is a safe and well-tolerated medication, It is well established that both OCPs and spironolactone
yet patients should be counseled on potential side are effective for the management of acne in adult women,
effects.20,25,60 A study conducted over an eight-year span but evidence-based recommendations on how and when
specifically focused on the safety profile of spironolac- to use these medications in combination is lacking. It is
tone in the treatment of acne and reported no serious important to note that anti-androgen therapies such as
complications.60 Side effects included breast tenderness spironolactone may be 5080% effective even if a patient
(17%), menstrual irregularities (22%), headache (13%), has failed OCPs in the past.25 Given spironolactones effi-
fatigue (15%), blood pressure reduction (with mean cacy (vs. OCP) to reduce acne lesion counts, strong
decrease of 5 mmHg systolic, 2.6 mmHg diastolic blood consideration should be given to this agent being first-line
pressure), and a minimal rise in serum potassium levels in hormonal therapy for the management of acne in adult
13% with no cardiovascular or renal sequelae. The investi- women who have failed topical therapies or other stan-
gators recommended checking potassium levels at baseline dard treatments. However, using spironolactone as
and at 4 weeks in certain patient populations, including monotherapy is highly controversial, given its side effect
patients over the age of 45 years, those with cardiac or profile and teratogenicity, and careful patient selection
renal disease, or those on concomitant drospirenone.20 should be utilized to identify appropriate candidates for
Menstrual irregularities caused by spironolactone are mini- this therapy. Combination treatment of spironolactone
mized by concomitant use of OCPs or intrauterine device. and OCPs is likely the safest approach, reducing adverse
Contraindications are listed in Table 3. Importantly, effects, and is supported by evidence that it is the most
spironolactone is a potential teratogen associated with effective treatment for acne. In sexually active patients
hypospadias and feminization of male fetuses and is not who prefer to take a single systemic therapy first, one rea-
recommended in pregnancy. There is also a black box sonable approach is to try three months of OCP alone; if
warning of benign tumors in animal studies at high doses acne does not clear during this trial period on the OCP
of spironolactone, an association that has not been demon- alone, follow by addition of androgen blockade with spir-
strated in studies on human patients. onolactone or CPA where available. Spironolactone is
best tolerated at starting doses of 50100 mg/day and can
be titrated up to 100 mg twice daily (total 200 mg). Hor-
Other hormonal treatment for acne: flutamide
monal therapy may be sufficient to clear acne in this
and cyproterone acetate (CPA)
patient population; concomitant use of almost all other
Flutamide is a nonsteroidal androgen-receptor blocker standard acne therapies is acceptable.
used in prostate cancer and is effective in the treatment of
hirsutism and acne in women.20,25 Typical doses are 250
Therapeutic alliance and special
500 mg/day. Due to its risk of hepatotoxicity, it is rarely
considerations
used in the management of acne. Other side effects
include gastrointestinal upset, hot flashes, and decreased Treatment of adult female acne can be challenging
libido. and, given the high failure rates of many standard acne

2012 The International Society of Dermatology International Journal of Dermatology 2012, 51, 11621174
1170 Review Acne in adult females Kamangar and Shinkai

therapies, many different medications or combinations of folate supplementation is required if used, especially in
treatments may need to be tried over time. It is impera- the first trimester. Isotretinoin and OCPs are contraindi-
tive to build a strong therapeutic alliance with the patient cated in pregnancy, and spironolactone should be
and set realistic goals of treatment. Long-term goals of avoided.64
care should be established early in the relationship, espe-
cially regarding the patients plans for family planning,
Conclusion
acceptance of systemic and specifically hormonal therapy,
and expectations of length of therapy. Frequent evalua- Acne is common in adults and especially in women. Acne
tion (every 68 weeks) initially is important, as this likely in adult women has significant psychosocial comorbidity
increases patient adherence and enables monitoring and and may be challenging to treat. It may also be a sign of
management of undesired adverse effects. Patient counsel- an underlying systemic disorder such as PCOS; dermatol-
ing is important, and self-manipulation of acne lesions ogists likely play a critical role in the diagnosis of PCOS
should be discouraged (a practice reported in 97% of as acne is a common cutaneous and presenting sign. It is
patients in one study).6 important to look for and ask about potential symptoms
Patient concerns regarding treatment and cosmetic and signs of hyperandrogenism and to exclude an under-
practices should also be addressed. Adult patients may be lying hormonal disorder by complete history and physical
intolerant to drying effects of common treatments, includ- exam. Isotretinoin remains a highly-viable treatment
ing benzoyl peroxide and topical retinoids. Scarring and option. Hormonal therapies are also safe and effective,
hyperpigmentation are also common concerns. Hyperpig- even when androgen levels are normal, and they provide
mentation can be treated with azeleic acid, topical reti- an important opportunity to better treat this patient pop-
noid creams, hydroquinone, and salicylic or glycolic acid ulation. Hormonal therapies such as OCPs and spirono-
peels. Compliance with use of topical medications should lactone are effective even when other standard therapies
be discussed, as women may report strong preferences for acne have failed, including antibiotics and isotretin-
regarding medications when also applying make-up. If a oin. A strong therapeutic alliance with the patient is vital
patient has a limited number of lesions and does not want in this patient population, to attempt different combina-
to undergo systemic treatments, localized treatments such tions of therapies and to identify the best personalized
as intralesional corticosteroid (2.5 mg/ml) triamcinolone treatment for acne.
acetonide may be a viable option.63
Acne in the adult female patient: a practical
Treatment of acne during pregnancy approach
Treatment of acne in pregnant women or women trying 10 multiple-choice questions
to conceive has special considerations. The safety of both 1. (True/False) Comedones are a common clinical find-
topical and systemic treatments should be carefully con- ing in adult female patients who present with acne.
sidered; however, there is a significant discrepancy A. True
between different drug safety classifications used around B. False
the world with regards to safety in pregnancy.64,65 If pos-
2. Which is the most common cutaneous symptom of
sible, treatment during the first trimester should be
PCOS?
avoided, or a regimen with the safest safety profile based
A. Hirsutism
on evidence should be utilized.64 Recommended topical
B. Alopecia
agents64 include azelaic acid, metronidazole, erythromy-
C. Acne
cin, clindamycin, and glycolic acid. Systemic therapies64
D. Acanthosis nigricans
with adequate safety data in pregnancy include penicil-
lins, cephalosporins, erythromycin (base or ethyl succinate 3. (True/False) The diagnosis of PCOS can be excluded
forms, not estolate due to risk of hepatotoxicity in second if a female patient reports regular menstrual cycles.
trimester), and azithromycin (second choice after erythro- A. True
mycin). Penicillins and cephalosporins are considered B. False
first-line systemic therapies in acne, with erythromycin as
4. (True/False) Common side effects of OCPs used for
second-line due to reports of increased risk of cardiac sep-
acne treatment include unscheduled menstrual bleed-
tal defects and pyloric stenosis. Sulfonamides should be
ing, nausea, and breast tenderness; all three of these
avoided during the peripartum phase of pregnancy due to
symptoms may be alleviated by lowering the dose of
increased risk of hyperbilirubinemia and kernicterus.
estrogen in the OCP preparation.
Trimethoprim interferes with folate metabolism, and thus

International Journal of Dermatology 2012, 51, 11621174 2012 The International Society of Dermatology
Kamangar and Shinkai Acne in adult females Review 1171

A. True 5 Goulden V, Stables GI, Cunliffe WJ. Prevalence of


B. False facial acne in adults. J Am Acad Dermatol 1999; 41:
577580.
5. (True/False) If a woman with acne does not improve 6 Poli F, Dreno B, Verschoore M. An epidemiological study
after 6 months of treatment with OCPs, then the of acne in female adults: results of a survey conducted in
addition of spironolactone is not likely to add a France. J Eur Acad Dermatol Venereol 2001; 15: 541545.
therapeutic benefit. 7 Collier CN, Harper JC, Cafardi JA, et al. The prevalence
A. True of acne in adults 20 years and older. J Am Acad
B. False Dermatol 2008; 58: 5659.
8 Goulden V, McGeown CH, Cunliffe WJ. The familial
6. (True/False) Serum potassium levels should be moni- risk of adult acne: a comparison between first-degree
tored in every patient taking spironolactone. relatives of affected and unaffected individuals. Br J
A. True Dermatol 1999; 141: 297300.
B. False 9 Goulden V, Clark SM, Cunliffe WJ. Post-adolescent acne:
a review of clinical features. Br J Dermatol 1997; 136:
7. Which of the following acne treatments should not 6670.
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A. Oral erythromycin ethyl succinate 11 Lasek RJ, Chren MM. Acne vulgaris and the quality of
B. Topical metronidazole cream life of adult dermatology patients. Arch Dermatol 1998;
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D. Oral cephalexin 12 Kligman AM, Mills OH Jr. Acne cosmetica. Arch
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A. Normal serum androgen levels 14 Lucky AW, Biro FM, Huster GA, et al. Acne vulgaris in
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aura
15 Lucky AW, Biro FM, Huster GA, et al. Acne vulgaris in
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17 Imperato-McGinley J, Gautier T, Cai LQ, et al. The
A. Norethindrone
androgen control of sebum production. Studies of
B. Desogestrel
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C. Levonorgestrel
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19 Chen MJ, Chen CD, Yang JH, et al. High serum
A. True
dehydroepiandrosterone sulfate is associated with
B. False
phenotypic acne and a reduced risk of abdominal obesity
in women with polycystic ovary syndrome. Human
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58 Shaw JC. Low-dose adjunctive spironolactone in the patients is at risk for systemic complications of
treatment of acne in women: a retrospective analysis of PCOS.
85 consecutively treated patients. J Am Acad Dermatol
2000; 43: 498502. 4. False. Unscheduled menstrual bleeding, nausea and
59 Krunic A, Ciurea A, Scheman A. Efficacy and tolerance breast tenderness are all common adverse effects of
of acne treatment using both spironolactone and a OCPs. Nausea and breast tenderness may be allevi-
combined contraceptive containing drospirenone. J Am ated by lowering the estrogen dose in the OCP prepa-
Acad Dermatol 2008; 58: 6062. ration; however, unscheduled menstrual bleeding is
60 Shaw JC, White LE. Long-term safety of spironolactone not. Melasma, mood changes and decreased libido
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62 van Vloten WA, van Haselen CW, van Zuuren EJ, et al. 80%.
The effect of 2 combined oral contraceptives containing
either drospirenone or cyproterone acetate on acne and 6. False. Clinically significant hyperkalemia is a rare
seborrhea. Cutis 2002; 69: 215. side-effect of spironolactone in healthy patients with-
63 Williams C, Layton AM. Persistent acne in women: out cardiac or renal disease. In one study, a minimal
implications for the patient and for therapy. Am J Clin rise in potassium was noted in 13% with no associ-
Dermatol 2006; 7: 281290. ated cardiovascular or renal sequelae.60 Routine
64 Murase J. Fulfilling great expectations: caring for new monitoring of spironolactone is not required for all
mothers and mothers-to be American Academy of Derma- patients taking spironolactone.
tology 69th Annual Meeting. New Orleans, LA, 2011.
65 Sannerstedt R, Lundborg P, Danielsson BR, et al. Drugs 7. C. Spironolactone is a potential teratogen associated
during pregnancy: an issue of risk classification and with hypospadias and feminization of male genitalia.
information to prescribers. Drug Saf 1996; 14: 6977. Evidence supports penicillin and cephalosporin class
antibiotics are first-line treatment for severe acne dur-
Answers ing pregnancy. Of the macrolides, erythromycin is the
first choice based on numerous studies; erythromycin
1. True. Studies suggest that comedonal morphology is a base or erythromycin ethyl succinate are the safest, as
common feature of acne presenting in adult female erythromycin estolate has been associated with rare
patients. In the study by Capitanio et al. (JAAD, cases of transaminitis during the second trimester of
2010),23 comedonal acne was noted in 85% of adult pregnancy.
women with acne.
8. C. OCP can be started in women with normal andro-
2. A. Hirsutism, acne and alopecia are all common cuta- gen levels. The consensus between ACOG, WHO and
neous manifestations of hyperandrogenism, including Planned Parenthood is that in healthy patients a pel-
PCOS. Hirsutism is the most common cutaneous vic exam or pap smear is not necessary prior to start-
manifestation (7080%) of PCOS, and 70% of hir- ing an OCP. A prior history of migraine headaches
sute women have hyperandrogenism. Acanthosis nig- with focal aura is a contraindication for initiating
ricans is seen in patients with PCOS who also present OCPs, as it is a risk factor associated with ischemic
with hyperinsulinemia, but is not a typical finding strokes. Patients who are 6 months post-partum may
associated with elevated androgen levels. start OCPs if they are no longer breastfeeding.
3. False. The diagnosis of PCOS is challenging, and 9. B. Progestins are synthetic analogs of progesterone.
requires fulfillment of two of the three following cri- Many first- and second-generation progestins have
teria: amenorrhea or oligomenorrhea (<8 menstrual androgenic properties and may exacerbate acne. In
cycles per year); elevated serum androgens or clinical the treatment of acne, preparations with early genera-
findings consistent with hyperandrogenism; ultraso- tion progestins should be avoided. Third-generation
nographic evidence of increased ovarian follicle count progestins, such as norgestimate and desogestrel, have
or follicular volume. In one subtype of PCOS (ovula- low androgenic activity. Norethindrone (A) is a first-
tory PCOS), women report regular menstrual cycles generation progestin. Levonorgestrel and norgestrel
yet have biochemical or clinical hyperandrogenism are second-generation progestins.
and typical ovarian ultrasonographic findings. The
recognition of normal menstrual cycling in certain 10. True. Large studies now suggest that most systemic
patients with PCOS is important, as this subset of antibiotics do not reduce the efficacy of OCPs. One

2012 The International Society of Dermatology International Journal of Dermatology 2012, 51, 11621174
1174 Review Acne in adult females Kamangar and Shinkai

potential exception is rifampin, a 3A4 inducer, that Figure S1. Sample acne questionnaire.
may accelerate metabolism of OCPs and may be
associated with OCP failure. More data are needed. Please note: Wiley-Blackwell are not responsible for the
content or functionality of any supporting materials sup-
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