Central Medical Journal of Obstetrics and Gynecology

Short Communication *Corresponding authors Wilma Bergfeld, Cleveland Clinic Foundation Department of Dermatology, 9500 Euclid Ave, Androgen Excess in Alopecia Cleveland, OH 44106, USA, Tel: (216) 444-5729; Email: Submitted: 24 April 2017 Areata, an Unexpected Finding Accepted: 06 June 2017 Published: 08 June 2017 Geraldine Cheyana Ranasinghe1,2, Melissa Piliang1, and Wilma ISSN: 2333-6439 1 Bergfeld * Copyright 1 Department of Dermatology, Cleveland Clinic Foundation, USA © 2017 Bergfeld et al. 2George Washington University School of Medicine and Health Sciences, USA OPEN ACCESS Abstract Keywords Studies on the pathophysiology and comorbidities associated with alopecia • Androgens areata (AA) are limited. The purpose of this study was to determine the prevalence of • PCOS androgen excess in AA and its subtypes, in relation to demographics and comorbidities. • Dermatology Medical records of 1,587 Patchy AA, AT, AU, and ophiasis patients seen in the • Alopecia areata Department of Dermatology at the Cleveland Clinic Foundation in Ohio between 2005 and 2015 were reviewed. Out of this cohort, 220 patients met the inclusion criteria. Androgen excess was identified in 42.5% (n=96) of the 220 patients with AA and all subtypes (p<0.001). The androgen excess group was significantly more likely to present with adult acne, hirsutism, PCOS, and/or ovarian cysts (p<0.001). This study was limited by being retrospective. Our study demonstrated that AA is associated with androgen excess.

ABBREVIATIONS Hair loss can be divided into two major categories- scarring and non-scarring alopecia. Alopecia areata (AA) is a non-scarring PCOS: Polycystic Ovary Syndrome; DHEAS: relapsing form of alopecia that equally affects both sexes and all Dehydroepiandrosterone Sulfate; AA: Alopecia Areata; AT: ethnicities. AA affects approximately 1 in 50 individuals during Alopecia Totalis; AU: Alopecia Universalis their lifetime [6]. Classically, AA lesions are sharply demarcated, INTRODUCTION round to oval, nonscarring skin-colored alopecia patches [7,8] (Figure 1). Since AA can present as a spectrum of hair loss, Androgen excess is one of the most common endocrine patients are categorized based on the extent and/or pattern of disorders among reproductive females, affecting 6% of the hair loss. Patchy AA is seen in 75% of AA patients and only affects normal population [1]. Polycystic ovary syndrome (PCOS) is the the scalp creating a patchy distribution of alopecia, alopecia hallmark of androgen excess disorders; however, there are other disorders associated with androgen excess, such as metabolic syndrome, idiopathic hyperandrogenism, idiopathic hirsutism and androgen-secreting tumors [2]. Patient’s with androgen excess disorders can present with amenorrhea, infertility, diabetes, increase abdominal fat and SAHA syndrome [3,4]. The SAHA syndrome describes the cutaneous clinical evidence that suggests androgen excess. SAHA stands for seborrhea, acne, hirsutism on face, trunk and extremities, and alopecia [4]. The anagen bulb is an androgen dependent area, requiring androgen and cortisol metabolism for normal function. The of peripheral testosterone conversion via 5a reductase. DHT shortensmost influential the growth androgen phase onof thethe hairhair cycle follicle and is miniaturizes DHT, a product the hair follicle. Along with DHT, the microenvironment surrounding the anagen hair follicle consists of insulin, corticotropin releasing hormone, vitamin D and A, iron, zinc, cytokines and various growth factors. It is reasonable to suggest that a disruption in the microenvironment, such as excess androgen, will create damage Figure 1 Alopecia Areata. AA lesions are sharply demarcated, round to oval, nonscarring skin-colored alopecia patches. to the hair follicle [5].

Cite this article: Ranasinghe GC, Piliang M, Bergfeld W (2017) Androgen Excess in Alopecia Areata, an Unexpected Finding. Med J Obstet Gynecol 5(3): 1104. Bergfeld et al. (2017) Email: Central totalis (AT) describes complete loss of scalp hair, and alopecia dysfunction on various characteristics. One-sided one-sample universalis (AU) is complete loss of scalp and body hair [7,8]. t-tests compared diagnosis groups against the lower normal limit Although rare, patients can present with ophiasis type pattern of for vitamin D (20ng/mL). Analyses were performed using SAS hair loss in the parieto-temporo-occipital area [8]. software (version 9.3; Cary, NC). Current evidence suggests that environmental triggers, RESULTS AND DISCUSSION such as emotional stress, increase the release of stress induced corticotropin-relasing hormone altering the hormonal The demographic and clinical data are summarized in Table microenvironment of the hair follicle, resulting in alopecia areata 1. The majority of the subjects were white (59%). The mean age [9-11].Whether other hormonal abnormalities, such as elevated of these patients was 43 years. In this study 80.5% of patients had androgens, affect the hair follicle in patients with AA remains Patchy AA, 4.1% had AT, 10.5% had AU and 5.0% were ophiasis. undetermined. Menstrual irregularities were noted in 25.5% of the study A previous study conducted by our clinical team established a relationship between androgen excess and lichen planopilaris, Table 1: General characteristics of AA patients (N = 220). a scarring form of alopecia that is characteristically found in n Total (%) the postmenopausal female population [5]. Since alopecia Demographics areata predominantly affects premenopausal females, a study Gender (F) 220(100) Race clinical markers of androgen excess in AA and its subtypes was White 130(59.0) performed.of the prevalence of androgen excess and identification of Black, African American 65(29.5) Middle Eastern 7(3.2) MATERIALS AND METHODS Hispanic 1(0.46) A retrospective study was conducted using an institutional Asian 11(5.0) review board approved database of 1,587 AA patients who American Indian 2(0.91) were diagnosed with AA at the Department of Dermatology at Unknown 4(1.82) Age (years) 43.2±14.9 campuses from 2005 to 2015. The diagnosis of AA was based Weight (kilograms) 210 77.1±20.4 the Cleveland Clinic Foundation Main Campus and all affiliated on clinical and/or histological features, and patients were Height (cm) 143 164.4±7.7 categorized into one of four subtypes: patchy alopecia, alopecia AA Variant ophiasis, alopecia totalis, alopecia universalis. Patchy AA 177(80.5) A total of 220 women met the inclusion criteria for the AT 9(4.1) study (i.e. exhibited abnormal circulating hormone levels, and/ AU 23(10.5) or history of ovarian dysfunction, and/or clinical evidence Ophiasis AA 11(5.0) of androgen excess). We evaluated race, weight, and age of Female Gynecologic History disease onset, alopecia subtype, and location of most hair loss. Trouble conceiving 21(9.6) We evaluated female’s past and family gynecological history, Irregular menstrual cycle 56(25.5) OCP 4(1.8) menopause, menopausal procedures, hormone replacement HRT 15(6.8) therapysuch as (in menstrual the past or irregularities, currently taking), OCP’s, and difficulty any form conceiving, of ovarian Menopausal 78(35.5) dysfunction (simple cyst, complex cyst, ovarian failure, ovarian Menopausal Procedures* 44 hyperstimulation). We also evaluated past medical history and Ultrasound 24(54.5) family history for adult acne, anemia, decreased androgens, Hysterectomy 20(45.5) diabetes, metabolic syndrome, excess androgens, hirsutism, Polycystic Ovary Syndrome 25(11.4) obesity, polycystic ovary syndrome, and seborrhea dermatitis. Ovarian Cyst 52(23.6) Lastly, we evaluated laboratory values for 17-OH progesterone, Ovarian Failure 6(2.7) androstenedione, DHEA-S, FSH, glucose, fasting glucose, insulin, Ovarian Hyperstimulation 2(0.91) LH, prolactin, serum ferritin, testosterone free, testosterone free Complex Ovarian Cyst 4(1.8) Comorbidities %, totalCategorical testosterone, factors and were vitamin summarized D deficiency. as frequency and Obesity 86(39.1) percentage, while continuous measures were described by mean Hirsutism 83(37.7) and standard deviation. Overall summaries for each patient group Adult Acne 70(31.8) were created, and then summaries by disease subtype were also Overweight 50(22.7) performed. Variables with no valid responses, or too few to allow Metabolic Syndrome 13(5.9) for subtyping were excluded from the analysis. Seborrhea Dermatitis 29(13.2) Diabetes 19(8.6) The distribution of clinical markers was compared using Values presented as Mean ± SD or N (column %). *Menopausal Procedures for postmenopausal bleeding or uterine one-sample goodness of fit chi-square tests. Pearson chi-square tests were used to compare groups defined by diagnosis or fibroids. Med J Obstet Gynecol 5(3): 1104 (2017) 2/4 Bergfeld et al. (2017) Email: Central population, and 40.41% of women had a history of either PCOS or an ovarian abnormality. The most prevalent comorbidities in hirsutism, irregular menses, trouble conceiving, polycystic our subjects were obesity (39.1%), hirsutism (37.7%), and adult ovarygroup syndromewas significantly (PCOS), more and/or likely ovarian to present cysts with (p<0.001). adult acne, It is acne (31.8%). important to note the androgen excess group was not receiving therapies that would alter androgen secretion. Diabetes and All patients were categorized into a dysfunction category seborrheic dermatitis did not demonstrate a notable association described in Table 2. Patients with elevation in any or all with androgen excess. androgens (DHEAS, free testosterone, free testosterone %, total testosterone), and/or had PCOS were placed in the CONCLUSION Androgen Excess/PCOS group. Patients with decrease in any or all androgens listed above were placed in the Low Androgens hyperandrogenism. Based on our study we provide clinical group (17.3%). Subjects with history of only ovarian cysts, and We report a significant association between AA and no hormonal abnormalities, were placed in the Cyst Only group guidelines to follow when androgen excess is of question (16.4%). Patients with only history of hirsutism were placed in for patient presentation. An important recommendation to Hirsutism Only group (13.%). Androgen excess/PCOS was the gynecologists and dermatologists is to take a brief gynecological history and family history of androgen excess conditions or all subtypes 42.5% (n=96) (p<0.001). associated symptoms. Since some of the clinical markers of most common dysfunction identified in 220 patients with AA and androgen excess in AA patients are not present, we suggest Table 3 evaluates the distribution of clinical markers screening laboratory tests to assess circulating hormone levels associated with AA patients. Among all AA patients, those with (total testosterone, free testosterone, free testosterone %, clinical evidence only and those with ovarian dysfunction were DHEAS and androstenedione) in female patients with a clinical history of menstrual irregularities, trouble conceiving, PCOS or significantly more likely to have no labs. The androgen excess Table 2: Distribution of dysfunction types in AA & Subtypes. Overall Dysfunction N = 220 Summary P-value (<0.001) . Clinical: Hirsutism Only 29(13.2) . Adrenal: Androgen Excess/PCOS 96(42.5) . Adrenal: Low Androgens 39(17.3) . Adrenal: Concurrent Low/High Androgens 10(4.4) . Adrenal: Hirsute/Low Androgens 4(1.8) . Ovarian: Cyst Only 37(16.4) . Ovarian: Cyst/Low Testosterone 5(2.2)

Table 3: Distribution of clinical markers associated with AA & Subtypes. And. Excess Clinical Evidence Other Adrenal Ovarian Dysfunction Clinical Markers PCOS p-value (N=29) (N=53) (N=42) (N=96) No Labs 19(54.3) 23 3(3.1) 14 0(0.0) 14 27(64.3) 23 <0.001c Anemia* 9(26.5) 24(25.0) 18(34.0) 13(31.0) 0.67c Irregular Menses* 5(14.7) 25(26.0) 9(17.3) 17(41.5) 0.023c Trouble Conceiving* 1(2.9) 6(6.3) 10(19.2) 4(9.8) 0.034c Seborrheic Dermatitis 2(5.7) 19(19.8) 5(9.4) 3(7.1) 0.057c Adult Acne 8(22.9) 39(40.6) 4 17(32.1) 6(14.3) 2 0.013c Hirsutism 29(100.0) 234 32(33.3) 14 14(26.4) 14 2(4.8) 123 <0.001c Obesity 13(37.1) 37(38.5) 20(37.7) 16(38.1) 0.99c Overweight 4(11.4) 24(25.0) 11(20.8) 11(26.2) 0.36c Diabetes 4(11.4) 5(5.2) 7(13.2) 3(7.1) 0.34c Polycystic ovaries 0(0.0) 2 21(21.9) 14 3(5.7) 1(2.4) 2 <0.001c Ovarian Cyst 1(2.9) 4 10(10.4) 4 8(15.1) 4 33(78.6) 123 <0.001c FH Diabetes 15(42.9) 35(36.5) 23(43.4) 21(50.0) 0.50c *Data not available for all subjects. Values presented as N (column %). p-values: c=Pearson's chi-square test. 1

2 3: Significantly different from 1.Clinical Evidence 4: Significantly different from 2.And. Excess/PCOS : Significantly different from 3.Other Adrenal : Significantly different from 4.Ovarian Dysfunction A significance level of 0.008 was used for pairwise ad-hoc comparisons. Med J Obstet Gynecol 5(3): 1104 (2017) 3/4 Bergfeld et al. (2017) Email: Central ovarian cysts. The assessment for androgen excess in the alopecia inputting process. Also, to James Bena for the statistical analysis. areata patient population is challenging for clinicians, especially The statistical analysis was supported by Dermatology Plastics in patients with AU. The recommended additional laboratory Surgery Institute. screening criteria should provide the clinician with the essential information. REFERENCES 1. Attaran M. Polycystic ovary syndrome. 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Our study suggests that the alopecia areata female patient An ancillary study of the Brazilian Longitudinal Study of Adult Health (ELSA-Brazil).identification ofMaturitas. polycystic 2015; ovary 81: 398-405. syndrome following menopause: is an at risk population of patients for androgen excess and its sequel. Future prospective studies are needed to confirm our findings.ACKNOWLEDGEMENTS Special thanks to Anastasiya Kalinina for assisting in the data

Cite this article Ranasinghe GC, Piliang M, Bergfeld W (2017) Androgen Excess in Alopecia Areata, an Unexpected Finding. Med J Obstet Gynecol 5(3): 1104.

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