Acne in the adult female patient: a practical approach

Transcription

1 Review Acne in the adult female patient: a practical approach Faranak Kamangar 1, BSc, and Kanade Shinkai 2, MD, PhD 1 San Francisco Psoriasis Skin and Treatment Center, University of California, School of Medicine, University of California, Davis, and 2 UCSF Department of Dermatology, University of California, San Francisco, CA, USA Correspondence Dr. Kanade Shinkai, MD, PhD Assistant Professor of Clinical Dermatology UCSF Department of Dermatology 1701 Divisadero Street San Francisco, CA USA shinkaik@derm.ucsf.edu Abstract Acne vulgaris is a common reason why adult women present to dermatologists and can be a clinical challenge to treat. It may also be an important sign of an underlying endocrine disease such as Polycystic Ovary Syndrome (PCOS). Although standard acne therapies can be successfully used to treat acne in adult female patients, hormonal treatment is a 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 practical approach to the adult female patient with acne will be reviewed to enhance the dermatologist s ability to use hormonal acne therapies and to better identify and evaluate patients with acne in the setting of a possible endocrine disorder. Conflicts of interest: Dr Shinkai and Ms Kamangar have no financial conflicts of interest to declare Background and evidence for acne in adult women Acne vulgaris is a common skin condition with 85% lifetime prevalence. 1,2 This condition is almost ubiquitous in adolescents; in one study performed in New Zealand 3 surveying high school students over the age of 16 years, 91% of males and 79% of females reported acne. While acne is commonly viewed as a disorder of adolescence, it may persist into adulthood and often may present for the first time in adulthood. 1 Adult acne is a common reason for patients to present for dermatological evaluation, and adults in fact make up a large portion of the patient population seen by dermatologists for acne. Epidemiology of office visits for acne in one American study demonstrated that adult patients with acne, mostly women, comprise the majority of visits (61.9%), with adolescents (peak age years) presenting in 36.5% of visits. 4 The actual prevalence of acne in the adult population has not been well defined; various studies have reported acne prevalence in the range of 41 54% in women and 34 40% in men. 5,6 Several studies suggest that women are more likely to report acne than men. Self-report of acne in a study of 1013 adults over the age of 20 years showed that the disparity between male and female report of acne is present at all ages but increases with advancing age, with 50.9% women vs. 42.5% men reporting acne in the third decade of life and 26.3% women vs. 12% men reporting acne in the fifth decade of life. 7 Self-report studies should be interpreted with caution, as there are few reports of investigator-confirmed studies in the literature. In one study by Goulden et al. 5,8 on facial acne in 749 adults over the age of 25 years, 54% of females vs. 40% of males reported acne; however, clinician examinations of survey-takers reported clinically significant acne in 12% of females vs. 3% of males in the study. This study also assessed the severity of the acne lesions, and females were four times more likely to have more severe acne than their male counterparts. 5 In a questionnaire-based study characterizing features of acne present in adult women, Poli et al. 6 reported an acne prevalence of 41% in a population of 3305 women. Acne morphology included both comedonal and inflammatory types, and the chin was the most commonly reported site of involvement. Half of the patients reported sequelae of scarring and pigmentation. Nearly half of

2 Kamangar and Shinkai Acne in adult females Review 1163 respondents had no history of childhood acne. Of these women, 78% experienced premenstrual flares of their acne, and 97% reported self-manipulation of acne lesions. Acne in adult women has also been shown to have a late onset and become persistent. Goulden et al. 9 conducted a study of 200 patients with acne over the age of 25 years, to assess when acne presents in adults. The majority of patients in the study were women (76%), and most had persistent acne. Late-onset acne, defined as presenting for the first time in adulthood after age 25 years, was more common in women than men (18% vs. 8%). Acne was found predominantly on the face in women. The study did not find a role for cosmetics, medications, or occupation in causing this acne but did suggest that chronicity of acne increased the risk of scarring. Taken together, these studies suggest that acne in adult women is common, may continue from childhood or present for the first time in adulthood, and persists into the later decades of life. These findings are important because adult acne has significant psychosocial implications, comparable to psoriasis vulgaris, 10 a disease well known for its impact on quality of life. The psychosocial morbidity associated with acne may be more significant in women as compared with men. 11 Females account for 2/3 of visits made to dermatologists for acne, and 1/3 of all office visits for acne are by women over the age of 25 years. 4 A proportion of patients with acne report depression (8.8%), 4 with women accounting for almost twice the number of respondents with depression as compared with men (10.6% vs. 5.3%); 4 it is important to note that reported depression does not correlate with the clinical severity of the acne. There is also a high prevalence of acne in patients with eating disorders, such as anorexia and bulimia nervosa. 10 Pathogenesis of adult female acne Pathogenesis of acne in adult women is complex, involving androgens in addition to other important factors well accepted for their role in the pathogenesis of acne: sebum production; follicular plugging; genetics; Propionibacterium acnes; diet; medications; innate immunity; and alterations in follicular keratinization and differentiation. 5 While the role of cosmetics has been suggested, one study did not find an association with cosmetic practices and severity of acne. 5,12 The role of androgens in adult women with acne has been well supported in the literature, and four clinical observations highlight this important role. First, androgen-insensitive individuals do not produce sebum and do not develop acne. 16,17 Second, conditions of hyperandrogenism, such as polycystic ovary syndrome (PCOS), are associated with acne that is highly responsive to hormonal therapies. 18 Third, even in women with normal androgen levels, hormonal-based therapies such as oral contraceptives and anti-androgen medications are effective treatments for acne. 18 Fourth, rising levels of dehydroepiandrosterone sulfate (DHEA-S) are associated with the onset of acne in pre-menarchal girls, and higher levels in pre-menarche may predict the development of more clinically severe acne in puberty. 14 Elevated DHEA- S also correlates with clinical acne in a subset of patients with PCOS. 19 Androgens in women derive from three sources: the ovaries; adrenal glands; and peripheral conversion. Ovarian-derived androgens include androstenedione and testosterone, whereas adrenal glands produce dehydroepiandrosterone (DHEA), DHEA-S, androstenedione, and testosterone. Peripheral conversion of androstenedione and DHEA also generates testosterone in women. Androgen-stimulated sebum production contributes to the pathophysiology of acne in women. 13 In skin, androgen receptors are located in sebaceous glands and in the outer root sheath of the hair follicle. 17 Androgens in the sebaceous gland are metabolized through a multi-step process from DHEA to 5-alpha-dihydrotestosterone, stimulating sebocyte proliferation and activity. 20 Sebum production is also regulated by other hormones, including estrogens, growth hormone, insulin, insulin-like growth factor-1, glucocorticoids, adrenocorticotropic hormone, and melanocortins. 18 Fluctuations in androgens during the menstrual cycle may account for cyclical flares, including the frequently reported premenstrual flares of acne. Few studies have documented this phenomenon in the clinical setting. In a survey-based study of women aged years, 44% of 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 aged years. 21 There was no difference in severity of acne, ethnicity, or oral contraceptive pill (OCP) use between women who reported a premenstrual flare and those who did not. A clinical study by Lucky 22 of adult women aged years, involving clinical observation of women at multiple time points over two menstrual cycles, noted an increase in premenstrual acne of both inflammatory and comedonal types. Investigators noted that 63% of women in this study had a 25% increase in premenstrual inflammatory acne in the late-luteal phase; 54% of women had a 21% increase in premenstrual comedonal acne in the late-luteal phase. The premenstrual flare may be explained by increased testosterone to estrogen ratios during specific segments of the menstrual cycle. Following the peak in testosterone and estrogen at the time of ovulation, typically on day 14 of the menstrual cycle, hormone levels decrease with

3 1164 Review Acne in adult females Kamangar and Shinkai progression into the luteal phase; an increased testosterone to estrogen ratio likely explains the late-luteal flare in acne, akin to the skewed androgen to estrogen ratio seen in perimenopausal women, but further evidence is needed to prove this association. Clinical features of acne in adult women Acne in adult female patients may occur more frequently on the lower one-third of the face (Fig. 1), especially at the jaw line and chin, with a broad clinical spectrum of comedones, papules, pustules, cysts, and/or nodules. 6 Studies in adult and pre-pubertal females reveal a significant comedonal component, a possibly under-recognized morphological feature. 23 In one study of adult women with acne, the majority (85%) were observed to have comedonal acne. 23 Women with comedonal acne were, on average, older in comparison to adult women with papulopustular acne (39 years old vs. 32 years old) and reported notably higher rates of smoking than their counterparts with papulopustular acne (70% vs. 30%). 23 Comedonal acne present in adult women may recapitulate morphological features seen in pre-menarchal acne. In a study of pre-menarchal girls aged 8 11 years, Lucky et al. 24 noticed a predominance of comedonal acne and a correlation between higher DHEA-S levels and acne severity. This study also noted rising prevalence and severity of acne with advancing sexual maturation, with acne preceding other external signs of puberty. Medical considerations and differential diagnosis of acne in adult women The medical evaluation of the adult female patient with acne should include a thorough medical history and physical exam. Information should include use of medications and supplements, social history with specific questions regarding tobacco and street drug use, menstrual history (age of onset and regularity, history of infertility), and prior or current treatments for acne. A complete review of systems is necessary to identify signs of hyperandrogenism or other endocrine disorder. While time limitations pose a special challenge in collecting necessary information, a written questionnaire can serve as a great tool to increase efficiency and to avoid missing important diagnostic clues (Fig. S1). The common differential diagnosis of adult female acne includes: rosacea; seborrheic dermatitis; acne cosmetic; pomade acne; medication-induced acne (danazol, testosterone, progestins, glucocorticoids, lithium, selective serotonin reuptake inhibitor, isoniazid, phenytoin, vitamin B2, vitamin B6, vitamin B12, halogens, epidermal growth factor receptor inhibitor chemotherapy); and hyperandrogenism (including PCOS). 25 A targeted history may ask about these specific considerations in the differential diagnosis. An underlying endocrine disorder, especially hyperandrogenism, is an important diagnostic consideration in any female patient with acne, and a suggestive historical clue is rapid recurrence of acne following isotretinoin therapy. 26 Signs and symptoms of hyperandrogenism include amenorrhea or oligomenorrhea (defined as less than eight menstrual cycles per year), and virilization, as evidenced by deepening of the voice, clitoromegaly, increased muscle mass, and decreased breast size. 13,18 Cutaneous signs of hyperandrogenism include acne, hirsutism, seborrhea, and alopecia. Hirsutism is the most common manifestation (70 80%) and is highly associated with elevated levels of free testosterone; 27 70% of hirsute 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 hirsutism may not be clinically evident. Signs or symptoms of hyperandrogenism should prompt a diagnostic work-up for an underlying hormonal disorder. 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 androgens (testosterone, DHEA). 13,18 Figure 1. Adult female patient with predominantly nodulocystic acne affecting the lower chin and jawline, also with papules, pustules and comedones Polycystic Ovary Syndrome (PCOS) PCOS is the most common cause of hyperandrogenism, with a prevalence of 5 10% in the general population

4 Kamangar and Shinkai Acne in adult females Review 1165 In the USA, Mexican American women have higher rates as compared with Caucasian and African-American women. 29 In the UK, there may be increased rates of PCOS in emigrant populations originating from the Indian subcontinent and in women of Australian aboriginal decent. 31,32 The diagnostic criteria for PCOS remain a topic of great debate. The most recent consensus criteria (Rotterdam, 2003) 33 defines a diagnosis of PCOS as two of the following three criteria: amenorrhea or oligomenorrhea; biochemical or clinical hyperandrogenism; and ultra-sonographic documentation of increased follicle count (>12) or follicular volume (>10 cm 3 ) per ovary. A transvaginal ultrasound is required to accurately visualize ovarian cysts. It is important to note that the presence of regular menstrual cycles, according to these criteria, does not exclude the diagnosis of PCOS; furthermore, lab tests or ovarian ultrasound may be normal. The pathophysiology also remains poorly defined, with a strong correlation between the presence of ovarian cysts and androgens, caused by excessive stimulation by insulin, luteinizing hormone, or both. 18,26,34 The pathophysiology and clinical presentations in PCOS is an area of active research. Acne is an important and common cutaneous sign of PCOS. Other dermatological signs associated with PCOS include hirsutism, androgenic alopecia, seborrhea, and acanthosis nigricans Hirsutism is the most common cutaneous manifestation of PCOS, present in 65 73% of patients, and strongly correlated with elevated androgens and polycystic ovaries on ultrasound. 38 Hirsutism also has a significant impact on the quality of life of patients and is often underestimated by clinicians; a full body skin exam is required to accurately assess hair growth patterns, and a modified Ferriman Gallway score of >8 indicates clinical hirsutism. 38 Androgenic alopecia also strongly correlates with polycystic ovaries, and is prevalent in 33% of women with PCOS. Seborrhea occurs with a prevalence of 35% in this population, strongly correlates with elevated androgens, but may be a nonspecific finding. Acanthosis nigricans may be present on the nape, knuckles, intertriginous regions, or on the face, especially on the zygomatic cheeks or in a periocular distribution; it may be found in 5% of women with PCOS 37 and is likely associated with hyperinsulinemia. As patients may present for evaluation of these cutaneous signs commonly seen in the disorder, dermatologists play an important role in the recognition of PCOS. However, PCOS is likely a clinical spectrum of disease with subtypes (Table 1) 26,39 including classic types, as well as ovulatory PCOS, with emerging recognition of a controversial fourth subtype termed mild or normoandrogenic PCOS. The classic form of PCOS fulfills all three diagnostic criteria. Other subtypes may lack important clinical features, such as irregular menstrual history or ultrasonographic evidence of polycystic ovaries, and may be challenging to diagnose. All types with abnormal ovarian morphology on ultrasound are associated with obesity, insulin resistance, and likely carry a higher risk of long-term sequelae of the disease. 25 The normoandrogenic subtype lacks these associations and morbidity, and some investigators do not define this type as a disease state. It is important to recognize PCOS as a systemic disorder associated with high morbidity and mortality due to endocrine, cardiovascular, reproductive, and oncological complications. 26,34 In women diagnosed with PCOS, 10% develop diabetes in the third or fourth decade, 40% have impaired glucose tolerance, and 40% are obese. The increased cardiovascular risk in this disease is controversial, but it is known that risk factors traditionally known to increase cardiovascular risk are commonly present in PCOS, including obesity, insulin resistance, hyperlipidemia, hypertension, and fatty liver. Long-term exposure to unopposed estrogen due to anovulation theoretically increases the risk of endometrial carcinoma. Many women with PCOS experience fertility issues, require assistance in reproduction, and experience increased complications of pregnancy. 26 PCOS patients also have a 30-fold increased risk of obstructive sleep apnea (OSA), even in women with normal body mass index, 40 and chronic OSA may result in pulmonary hypertension. All of these sequelae may be positively impacted by hormonal therapy and/or interventions such as lifestyle modification, including exercise and diet. 26,41 General goals of treatment of PCOS focus on uterine protection, establishing menstrual regularity, lowering androgens, reversing insulin resistance and dyslipidemia, weight loss, as well as improving cardiovascular fitness and targeting cutaneous signs. Dermatologists should be familiar with the diagnostic work-up of PCOS, which consists of two components: assessment of endocrine and metabolic parameters, which includes evaluation for important considerations in the differential diagnosis, including other rare causes of hyperandrogenism (Table 2). The treatment of acne in the adult female patient: a practical approach In the treatment of adult female patients with acne, all of the central tenets of acne management are true. A systematic treatment algorithm for acne should be utilized; 42,43 however, with several important caveats. Women over age 25 years have higher rates of treatment failure; 82% fail multiple courses of systemic antibiotics, 9 and 32% relapse after isotretinoin. 9 Recurrence shortly after treatment with isotretinoin should trigger suspicion for an underlying hormonal disorder. 35 A thorough review of

5 1166 Review Acne in adult females Kamangar and Shinkai Table 1 Features of PCOS Type I classic PCOS (A, HA, PCO) Type II classic (A, HA) Ovulatory PCOS (HA, PCO) Normoandrogenic or mild PCOS (A, PCO, ±HA) Menstrual cycle 26 Irregular Irregular Normal Irregular Ultrasound 26 Polycystic Normal Polycystic Polycystic Serum androgens 26 High High High Normal or slightly elevated Hirsutism ) Obesity ) Insulin resistance 26 Present Present Present Not present Long-term sequelae 26 Potential long-term Potential long-term Unknown Unknown Prevalence 26, % 7 8.9% 16 29% 8 16% 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 considerations 20 (i) Endocrine evaluation Total testosterone a >150 ng/dl >200 ng/dl consider ovarian androgen-secreting tumor Free testosterone a Increased level DHEA-S a Increased level >8000 ng/dl adrenal tumor ng/dl congenital adrenal hyperplasia Androstenedione a 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 performed prior to initiating isotretinoin. Isotretinoin remains a highly viable and important nonhormonal treatment option for acne in adult women. 43 In this patient population, there are special considerations of teratogenicity, and individuals over 35 years old may have increased risk of adverse skeletal side effects. 43 Lowdose isotretinoin (10 20 mg/day) can be used to minimize side effects associated with systemic retinoid therapy, and this is an effective treatment of choice in this population. 44,45 Hormonal therapies, such as OCP and anti-androgen therapy, also provide an important and effective opportunity to increase treatment options for acne. As many adult women present with comedonal disease, hormonal therapies can be utilized across the entire clinical spectrum of acne, including mild and/or comedonal-only disease. 20 Evidence-based recommendations supporting an algorithm for use of hormonal therapies in acne are currently lacking. Figure 2 is the authors proposed algorithm for the treatment of hormonal acne. Although not evidence based, this algorithm may be a useful tool in conjunction with the dermatologist s clinical judgment. Hormonal treatment of acne An important goal of hormonal treatment is to reduce sebum production. The mainstay of hormonal acne therapy

6 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 treatment options include flutamide and cyproterone. 4 Hormonal therapy provides an effective adjunct to the current acne treatments or may serve as primary therapy. Patients should be educated that this strategy will require time, up to several months, to see results, and may require long-term systemic treatment and ongoing monitoring for side effects. Hormonal therapy is safe and effective in post-menarchal females over the age of 14 years, even those with normal androgen levels. Indications for starting hormonal therapy are reviewed in Table Oral contraceptive pills (OCP) OCPs work by several mechanisms to reduce acne. OCPs stimulate hepatic synthesis of sex hormone-binding globulin, which bind circulating androgens, decrease free testosterone and DHEA-S, and likely reduce sebum production. OCPs also inhibit 5-a-reductase, decreasing peripheral conversion of testosterone, as well as decreasing production of ovarian and adrenal androgens. OCPs are effective in the treatment of acne, with studies demonstrating 40 70% reduction in lesion counts. 25 There are currently three OCPs approved by the FDA for the indication of acne treatment: Ortho Tri-Cyclen (norgestimate 180/215/250 mcg + 35 mcg ethinyl estradiol [EE]), EstroStep (norethindrone acetate 1 mg + EE 20/30/35 mcg + 7 day hormone-free interval or ferrous fumarate), and Yaz (drospirenone 3 mg + EE 20 mcg + 4 day hormone-free interval). Although these are the three preparations FDA-approved for the treatment of acne, many other preparations likely have equivalent therapeutic benefit. An important consideration in the selection of OCPs for acne is that most OCPs also contain progestins. Unlike endogenous progesterone, synthetic progestins have androgenic activity that may exacerbate or trigger acne, and thus the treatment of acne necessitates choosing an OCP that contains a progestin with low androgenic properties, 25 such as the third-generation progestins, norgestimate, and desogestrel. There are many safety considerations in prescribing OCPs, including contraindications and adverse side effects. Current OCPs have significantly lower levels of hormone than first-generation oral contraceptive preparations; lower levels of hormone, specifically estrogen, dramatically increase their safety profile, especially in OCPs containing 35 lg of EE or less. 25 Starting an OCP has also become logistically easier, as the consensus between WHO, ACOG, and Planned Parenthood has eliminated the requirement for a baseline pelvic exam or cervical Papanicolaou smear in healthy women prior to starting an OCP. 47 Although many advocate the prescription of

7 1168 Review Acne in adult females Kamangar and Shinkai Table 3 Indications and contraindications of hormonal treatment in acne OCP Indications for hormonal therapy for acne 46 When oral contraception is desired For contraception during treatment with isotretinoin In women, as an alternative when repeated courses of isotretinoin needed Women with severe premenstrual acne flare Women whose acne is not responding to conventional therapy PCOS Women with clinical signs of hyperandrogenism, such as androgenic alopecia, SAHA (seborrhea, acne, hirsutism, alopecia) Proven ovarian hyperandrogenism Proven adrenal hyperandrogenism Contraindications for hormonal therapy 20,47 Pregnancy Breastfeeding <6 months post-partum History of stroke History of venous thromboembolism History of myocardial infarction Smoking of any amount and above 35 years old Uncontrolled hypertension (SBP > 160, DBP > 100) History of migraine with focal symptoms/aura History of migraine and age above 35 years Current or past history of breast cancer Hypercholesterolemia (LDL > 160) Diabetes and age above 35 years End-organ damage (liver, kidney) Viral hepatitis or cirrhosis Liver tumor (any type) Upcoming major surgery with prolonged immobilization (relative contraindication, as it is a risk factor for DVT) Spironolactone DBP, diastolic blood pressure; DVT, deep venous thrombosis; LDL, low-density lipoprotein; OCP, oral contraceptive pill; PCOS, polycystic ovary syndrome; SBP, systolic blood pressure. OCPs by dermatologists, an important caveat is the reported association of poor patient adherence with OCPs prescribed by dermatologists. 48 Contraindications to OCP use are included in Table 3. Notable contraindications include risk factors for vascular thrombotic events. Cardiovascular risks are not significantly increased in non-smokers. 49 One study reported that the risk of deep vein thrombosis increases from 1 per 10,000 woman-years to 3.4 per 10,000 woman-years during the first year of OCP use and decreases thereafter, and several studies have corroborated these reports. 50 Patients should be counseled that risk factors for cardiovascular events include smoking (any amount), hypertension, and diabetes. Patients of any age with a history of migraine headaches with precedent aura or women over the age of 35 years with any history of migraine headaches are at increased risk of thrombotic events such as stroke. The association of breast cancer in OCP use has been a topic of ongoing controversy. In 1996, the collaborative group on hormonal factors in breast cancer 51 conducted a meta-analysis of a total of 54 studies, representing 53,297 women with breast cancer and 100,239 control patients. Women currently on OCP were found to have an increased relative risk of 1.24 of developing breast cancer, with risk declining up to 10 years following cessation of OCP; after 10 years of cessation of OCP, there was no significant increase in the relative risk of breast cancer. A history of current or past history of breast cancer is currently a contraindication for OCP use. In other individuals, the data should be considered in concert with the efficacy of OCPs in acne as well as data highlighting protective effect of OCPs with respect to endometrial 52 and ovarian cancer. 53 Side effects of OCPS are common; appropriate patient counseling may improve patient medication adherence. The most common side effects of OCPs are unscheduled bleeding, nausea, and breast tenderness. 47,54 All of these symptoms, except for bleeding, are alleviated by lowering the estrogen dose in the OCP. A common concern of many women is weight gain, yet patients should be counseled that average weight gain with OCP use is 1 2 kg, which occurs in 30% of patients and is most often due to fluid retention. 54 Rare side effects include decreased libido, melasma, and mood changes. 54 Concomitant use of OCPs and systemic antibiotic is likely safe, as highlighted by two important studies 55,56 demonstrating pregnancy rates in women taking both medications as equal to the rare failure rate of OCPs as a contraceptive. Rifampin, a 3A4 inducer, may be an important exception that can alter the metabolism of OCPs, and increased rates of pregnancy with concurrent use of rifampin and OCPs have been reported. 56 Concomitant use of OCPs and tetracycline class antibiotics is likely safe. 55 Spironolactone Spironolactone is a highly effective treatment for acne in adult women and may surpass the efficacy of OCPs. A potassium-sparing diuretic, spironolactone at low doses (25 mg/day) blocks aldosterone and at higher doses ( mg/day) blocks androgens at the receptor

8 Kamangar and Shinkai Acne in adult females Review 1169 level. 57,58 Drospirenone is a synthetic progestin that is an analog to spironolactone; in commonly-available OCP preparations, the 3 mg drospirenone is estimated to have anti-androgenic activity equivalent to 25 mg of spironolactone. Spironolactone is not FDA approved for the indication of acne, but spironolactone alone or combined with an OCP at a dose of mg/day is effective in 33 85% reduction in acne lesion counts and also improves seborrhea. Studies with lower dose spironolactone ( mg/day) demonstrated 33% improvement, suggesting a dosage effect. Studies with a higher dose of 100 mg plus drospirenone demonstrated an 85% improvement in acne, suggesting a highly effective combination treatment. 59 Nine studies on higher dose spironolactone have also demonstrated an improvement in the subjective report of hirsutism, but clinician observation did not corroborate a significant difference. 57 Spironolactone is a safe and well-tolerated medication, yet patients should be counseled on potential side effects. 20,25,60 A study conducted over an eight-year span specifically focused on the safety profile of spironolactone in the treatment of acne and reported no serious complications. 60 Side effects included breast tenderness (17%), menstrual irregularities (22%), headache (13%), fatigue (15%), blood pressure reduction (with mean decrease of 5 mmhg systolic, 2.6 mmhg diastolic blood pressure), and a minimal rise in serum potassium levels in 13% with no cardiovascular or renal sequelae. The investigators recommended checking potassium levels at baseline and at 4 weeks in certain patient populations, including patients over the age of 45 years, those with cardiac or renal disease, or those on concomitant drospirenone. 20 Menstrual irregularities caused by spironolactone are minimized by concomitant use of OCPs or intrauterine device. Contraindications are listed in Table 3. Importantly, spironolactone is a potential teratogen associated with hypospadias and feminization of male fetuses and is not recommended in pregnancy. There is also a black box warning of benign tumors in animal studies at high doses of spironolactone, an association that has not been demonstrated in studies on human patients. Other hormonal treatment for acne: flutamide and cyproterone acetate (CPA) Flutamide is a nonsteroidal androgen-receptor blocker used in prostate cancer and is effective in the treatment of hirsutism and acne in women. 20,25 Typical doses are mg/day. Due to its risk of hepatotoxicity, it is rarely used in the management of acne. Other side effects include gastrointestinal upset, hot flashes, and decreased libido. CPA is a 17-hydroxyprogesterone derivative with potent androgen blockade. 25 CPA is available in two forms: in combination OCP or in a non-ocp form that can be used in combination with OCP or spironolactone. As a non-ocp medication, CPA is given on days 1 10 of the menstrual cycle (day 1 marking the first day of menstruation). 25 This medication is most commonly used in OCPs also containing EE, which is not available in the USA (i.e. Diane, Dianette). In this form, it is effective for the treatment of hirsutism and acne in women and, in one study, reduced acne lesion counts by 75 90%. 20,61 A trial evaluating the efficacy of drospirenone + EE (Yasmin) vs. CA + EE (Diane) found equivalent efficacy of these treatments (62% vs. 59%) in reducing acne lesion counts. 62 Algorithm for the hormonal treatment of acne It is well established that both OCPs and spironolactone are effective for the management of acne in adult women, but evidence-based recommendations on how and when to use these medications in combination is lacking. It is important to note that anti-androgen therapies such as spironolactone may be 50 80% effective even if a patient has failed OCPs in the past. 25 Given spironolactone s efficacy (vs. OCP) to reduce acne lesion counts, strong consideration should be given to this agent being first-line hormonal therapy for the management of acne in adult women who have failed topical therapies or other standard treatments. However, using spironolactone as monotherapy is highly controversial, given its side effect profile and teratogenicity, and careful patient selection should be utilized to identify appropriate candidates for this therapy. Combination treatment of spironolactone and OCPs is likely the safest approach, reducing adverse effects, and is supported by evidence that it is the most effective treatment for acne. In sexually active patients who prefer to take a single systemic therapy first, one reasonable approach is to try three months of OCP alone; if acne does not clear during this trial period on the OCP alone, follow by addition of androgen blockade with spironolactone or CPA where available. Spironolactone is best tolerated at starting doses of mg/day and can be titrated up to 100 mg twice daily (total 200 mg). Hormonal therapy may be sufficient to clear acne in this patient population; concomitant use of almost all other standard acne therapies is acceptable. Therapeutic alliance and special considerations Treatment of adult female acne can be challenging and, given the high failure rates of many standard acne

9 1170 Review Acne in adult females Kamangar and Shinkai therapies, many different medications or combinations of treatments may need to be tried over time. It is imperative to build a strong therapeutic alliance with the patient and set realistic goals of treatment. Long-term goals of care should be established early in the relationship, especially regarding the patient s plans for family planning, acceptance of systemic and specifically hormonal therapy, and expectations of length of therapy. Frequent evaluation (every 6 8 weeks) initially is important, as this likely increases patient adherence and enables monitoring and management of undesired adverse effects. Patient counseling is important, and self-manipulation of acne lesions should be discouraged (a practice reported in 97% of patients in one study). 6 Patient concerns regarding treatment and cosmetic practices should also be addressed. Adult patients may be intolerant to drying effects of common treatments, including benzoyl peroxide and topical retinoids. Scarring and hyperpigmentation are also common concerns. Hyperpigmentation can be treated with azeleic acid, topical retinoid creams, hydroquinone, and salicylic or glycolic acid peels. Compliance with use of topical medications should be discussed, as women may report strong preferences regarding medications when also applying make-up. If a patient has a limited number of lesions and does not want to undergo systemic treatments, localized treatments such as intralesional corticosteroid (2.5 mg/ml) triamcinolone acetonide may be a viable option. 63 Treatment of acne during pregnancy Treatment of acne in pregnant women or women trying to conceive has special considerations. The safety of both topical and systemic treatments should be carefully considered; however, there is a significant discrepancy between different drug safety classifications used around the world with regards to safety in pregnancy. 64,65 If possible, treatment during the first trimester should be avoided, or a regimen with the safest safety profile based on evidence should be utilized. 64 Recommended topical agents 64 include azelaic acid, metronidazole, erythromycin, clindamycin, and glycolic acid. Systemic therapies 64 with adequate safety data in pregnancy include penicillins, cephalosporins, erythromycin (base or ethyl succinate forms, not estolate due to risk of hepatotoxicity in second trimester), and azithromycin (second choice after erythromycin). Penicillins and cephalosporins are considered first-line systemic therapies in acne, with erythromycin as second-line due to reports of increased risk of cardiac septal defects and pyloric stenosis. Sulfonamides should be avoided during the peripartum phase of pregnancy due to increased risk of hyperbilirubinemia and kernicterus. Trimethoprim interferes with folate metabolism, and thus folate supplementation is required if used, especially in the first trimester. Isotretinoin and OCPs are contraindicated in pregnancy, and spironolactone should be avoided. 64 Conclusion Acne is common in adults and especially in women. Acne in adult women has significant psychosocial comorbidity and may be challenging to treat. It may also be a sign of an underlying systemic disorder such as PCOS; dermatologists likely play a critical role in the diagnosis of PCOS as acne is a common cutaneous and presenting sign. It is important to look for and ask about potential symptoms and signs of hyperandrogenism and to exclude an underlying hormonal disorder by complete history and physical exam. Isotretinoin remains a highly-viable treatment option. Hormonal therapies are also safe and effective, even when androgen levels are normal, and they provide an important opportunity to better treat this patient population. Hormonal therapies such as OCPs and spironolactone are effective even when other standard therapies for acne have failed, including antibiotics and isotretinoin. A strong therapeutic alliance with the patient is vital in this patient population, to attempt different combinations of therapies and to identify the best personalized treatment for acne. Acne in the adult female patient: a practical approach 10 multiple-choice questions 1. (True/False) Comedones are a common clinical finding in adult female patients who present with acne. A. True B. False 2. Which is the most common cutaneous symptom of PCOS? A. Hirsutism B. Alopecia C. Acne D. Acanthosis nigricans 3. (True/False) The diagnosis of PCOS can be excluded if a female patient reports regular menstrual cycles. A. True B. False 4. (True/False) Common side effects of OCPs used for acne treatment include unscheduled menstrual bleeding, nausea, and breast tenderness; all three of these symptoms may be alleviated by lowering the dose of estrogen in the OCP preparation.

10 Kamangar and Shinkai Acne in adult females Review 1171 A. True B. False 5. (True/False) If a woman with acne does not improve after 6 months of treatment with OCPs, then the addition of spironolactone is not likely to add a therapeutic benefit. A. True B. False 6. (True/False) Serum potassium levels should be monitored in every patient taking spironolactone. A. True B. False 7. Which of the following acne treatments should not be used in pregnant patients during the second or third trimester? A. Oral erythromycin ethyl succinate B. Topical metronidazole cream C. Spironolactone D. Oral cephalexin 8. Which of the following is a contraindication to starting an estrogen-containing OCP? A. Normal serum androgen levels B. No baseline pap smear and pelvic exam C. Patient reports migraine headaches with focal aura D. Patient is 8 months post-partum and just completed breastfeeding 9. In choosing an OCP for the treatment of acne, which is the best (least androgenic) progestin? A. Norethindrone B. Desogestrel C. Levonorgestrel D. Norgestrel 10. (True/False) Tetracycline antibiotics can be taken safely with OCPs for the treatment of acne. A. True B. False References 1 Kraning KK, Odland GF. Prevalence, morbidity, and cost of dermatologic diseases. J Invest Dermatol 1979; 73: James WD. Clinical practice. Acne. N Engl J Med 2005; 352: Lello J, Pearl A, Arroll B, et al. Prevalence of acne vulgaris in Auckland senior high school students. NZ Med J 1995; 108: Yentzer BA, Hick J, Reese EL, et al. Acne vulgaris in the United States: a descriptive epidemiology. Cutis 2010; 86: Goulden V, Stables GI, Cunliffe WJ. Prevalence of facial acne in adults. J Am Acad Dermatol 1999; 41: Poli F, Dreno B, Verschoore M. An epidemiological study of acne in female adults: results of a survey conducted in France. J Eur Acad Dermatol Venereol 2001; 15: Collier CN, Harper JC, Cafardi JA, et al. The prevalence of acne in adults 20 years and older. J Am Acad Dermatol 2008; 58: Goulden V, McGeown CH, Cunliffe WJ. The familial risk of adult acne: a comparison between first-degree relatives of affected and unaffected individuals. Br J Dermatol 1999; 141: Goulden V, Clark SM, Cunliffe WJ. Post-adolescent acne: a review of clinical features. Br J Dermatol 1997; 136: Gupta MA, Gupta AK. The psychological comorbidity in acne. Clin Dermatol 2001; 19: Lasek RJ, Chren MM. Acne vulgaris and the quality of life of adult dermatology patients. Arch Dermatol 1998; 134: Kligman AM, Mills OH Jr. Acne cosmetica. Arch Dermatol 1972; 106: Harper JC. Evaluating hyperandrogenism: a challenge in acne management. J Drugs Dermatol 2008; 7: Lucky AW, Biro FM, Huster GA, et al. Acne vulgaris in premenarchal girls. An early sign of puberty associated with rising levels of dehydroepiandrosterone. Arch Dermatol 1994; 130: Lucky AW, Biro FM, Huster GA, et al. Acne vulgaris in early adolescent boys. Correlations with pubertal maturation and age. Arch Dermatol 1991; 127: Thiboutot D. Acne: hormonal concepts and therapy. Clin Dermatol 2004; 22: Imperato-McGinley J, Gautier T, Cai LQ, et al. The androgen control of sebum production. Studies of subjects with dihydrotestosterone deficiency and complete androgen insensitivity. J Clin Endocrinol Metab 1993; 76: Lolis MS, Bowe WP, Shalita AR. Acne and systemic disease. Med Clin North Am 2009; 93: Chen MJ, Chen CD, Yang JH, et al. High serum dehydroepiandrosterone sulfate is associated with phenotypic acne and a reduced risk of abdominal obesity in women with polycystic ovary syndrome. Human Reprod 2011; 26: George R, Clarke S, Thiboutot D. Hormonal therapy for acne. Semin Cutan Med Surg 2008; 27: Stoll S, Shalita AR, Webster GF, et al. The effect of the menstrual cycle on acne. J Am Acad Dermatol 2001; 45: Lucky AW. Quantitative documentation of a premenstrual flare of facial acne in adult women. Arch Dermatol 2004; 140: Capitanio B, Sinagra JL, Bordignon V, et al. Underestimated clinical features of postadolescent acne. J Am Acad Dermatol 2010; 63:

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