Central Medical Journal of Obstetrics and Gynecology

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.

*Corresponding authorsWilma Bergfeld, Cleveland Clinic Foundation Department of Dermatology, 9500 Euclid Ave, Cleveland, OH 44106, USA, Tel: (216) 444-5729; Email:

Submitted: 24 April 2017

Accepted: 06 June 2017

Published: 08 June 2017

ISSN: 2333-6439

Copyright© 2017 Bergfeld et al.

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Short Communication

Androgen Excess in Alopecia Areata, an Unexpected FindingGeraldine Cheyana Ranasinghe1,2, Melissa Piliang1, and Wilma Bergfeld1*1Department of Dermatology, Cleveland Clinic Foundation, USA2George Washington University School of Medicine and Health Sciences, USA

Keywords•Androgens•PCOS•Dermatology•Alopecia areata

ABBREVIATIONSPCOS: Polycystic Ovary Syndrome; DHEAS:

Dehydroepiandrosterone Sulfate; AA: Alopecia Areata; AT: Alopecia Totalis; AU: Alopecia Universalis

INTRODUCTIONAndrogen excess is one of the most common endocrine

disorders among reproductive females, affecting 6% of the normal population [1]. Polycystic ovary syndrome (PCOS) is the 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 most influential androgen on the hair follicle is DHT, a product of peripheral testosterone conversion via 5a reductase. DHT shortens the growth phase of the hair cycle and miniaturizes 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 to the hair follicle [5].

Hair loss can be divided into two major categories- scarring and non-scarring alopecia. Alopecia areata (AA) is a non-scarring relapsing form of alopecia that equally affects both sexes and all ethnicities. AA affects approximately 1 in 50 individuals during their lifetime [6]. Classically, AA lesions are sharply demarcated, round to oval, nonscarring skin-colored alopecia patches [7,8] (Figure 1). Since AA can present as a spectrum of hair loss, patients are categorized based on the extent and/or pattern of hair loss. Patchy AA is seen in 75% of AA patients and only affects the scalp creating a patchy distribution of alopecia, alopecia

Abstract

Studies on the pathophysiology and comorbidities associated with alopecia areata (AA) are limited. The purpose of this study was to determine the prevalence of androgen excess in AA and its subtypes, in relation to demographics and comorbidities. Medical records of 1,587 Patchy AA, AT, AU, and ophiasis patients seen in the 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.

Figure 1 Alopecia Areata. AA lesions are sharply demarcated, round to oval, nonscarring skin-colored alopecia patches.

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totalis (AT) describes complete loss of scalp hair, and alopecia universalis (AU) is complete loss of scalp and body hair [7,8]. Although rare, patients can present with ophiasis type pattern of hair loss in the parieto-temporo-occipital area [8].

Current evidence suggests that environmental triggers, such as emotional stress, increase the release of stress induced corticotropin-relasing hormone altering the hormonal microenvironment of the hair follicle, resulting in alopecia areata [9-11].Whether other hormonal abnormalities, such as elevated androgens, affect the hair follicle in patients with AA remains undetermined.

A previous study conducted by our clinical team established a relationship between androgen excess and lichen planopilaris, a scarring form of alopecia that is characteristically found in the postmenopausal female population [5]. Since alopecia areata predominantly affects premenopausal females, a study of the prevalence of androgen excess and identification of clinical markers of androgen excess in AA and its subtypes was performed.

MATERIALS AND METHODSA retrospective study was conducted using an institutional

review board approved database of 1,587 AA patients who were diagnosed with AA at the Department of Dermatology at the Cleveland Clinic Foundation Main Campus and all affiliated campuses from 2005 to 2015. The diagnosis of AA was based on clinical and/or histological features, and patients were categorized into one of four subtypes: patchy alopecia, alopecia ophiasis, alopecia totalis, alopecia universalis.

A total of 220 women met the inclusion criteria for the study (i.e. exhibited abnormal circulating hormone levels, and/or history of ovarian dysfunction, and/or clinical evidence of androgen excess). We evaluated race, weight, and age of disease onset, alopecia subtype, and location of most hair loss. We evaluated female’s past and family gynecological history, such as menstrual irregularities, OCP’s, difficulty conceiving, menopause, menopausal procedures, hormone replacement therapy (in the past or currently taking), and any form of ovarian dysfunction (simple cyst, complex cyst, ovarian failure, ovarian hyperstimulation). We also evaluated past medical history and family history for adult acne, anemia, decreased androgens, diabetes, metabolic syndrome, excess androgens, hirsutism, obesity, polycystic ovary syndrome, and seborrhea dermatitis. Lastly, we evaluated laboratory values for 17-OH progesterone, androstenedione, DHEA-S, FSH, glucose, fasting glucose, insulin, LH, prolactin, serum ferritin, testosterone free, testosterone free %, total testosterone, and vitamin D deficiency.

Categorical factors were summarized as frequency and percentage, while continuous measures were described by mean and standard deviation. Overall summaries for each patient group were created, and then summaries by disease subtype were also performed. Variables with no valid responses, or too few to allow for subtyping were excluded from the analysis.

The distribution of clinical markers was compared using one-sample goodness of fit chi-square tests. Pearson chi-square tests were used to compare groups defined by diagnosis or

dysfunction on various characteristics. One-sided one-sample t-tests compared diagnosis groups against the lower normal limit for vitamin D (20ng/mL). Analyses were performed using SAS software (version 9.3; Cary, NC).

RESULTS AND DISCUSSIONThe demographic and clinical data are summarized in Table

1. The majority of the subjects were white (59%). The mean age of these patients was 43 years. In this study 80.5% of patients had Patchy AA, 4.1% had AT, 10.5% had AU and 5.0% were ophiasis. Menstrual irregularities were noted in 25.5% of the study

Table 1: General characteristics of AA patients (N = 220).n Total (%)

DemographicsGender (F) 220(100)RaceWhite 130(59.0)Black, African American 65(29.5)Middle Eastern 7(3.2)Hispanic 1(0.46)Asian 11(5.0)American Indian 2(0.91)Unknown 4(1.82)Age (years) 43.2±14.9Weight (kilograms) 210 77.1±20.4Height (cm) 143 164.4±7.7AA VariantPatchy AA 177(80.5)AT 9(4.1)AU 23(10.5)Ophiasis AA 11(5.0)Female Gynecologic HistoryTrouble conceiving 21(9.6)Irregular menstrual cycle 56(25.5)OCP 4(1.8)HRT 15(6.8)Menopausal 78(35.5)Menopausal Procedures* 44Ultrasound 24(54.5)Hysterectomy 20(45.5)Polycystic Ovary Syndrome 25(11.4)Ovarian Cyst 52(23.6)Ovarian Failure 6(2.7)Ovarian Hyperstimulation 2(0.91)Complex Ovarian Cyst 4(1.8)ComorbiditiesObesityHirsutism

86(39.1)83(37.7)

Adult Acne 70(31.8)Overweight 50(22.7)Metabolic Syndrome 13(5.9)Seborrhea Dermatitis 29(13.2)Diabetes 19(8.6)Values presented as Mean ± SD or N (column %).*Menopausal Procedures for postmenopausal bleeding or uterine fibroids.

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population, and 40.41% of women had a history of either PCOS or an ovarian abnormality. The most prevalent comorbidities in our subjects were obesity (39.1%), hirsutism (37.7%), and adult acne (31.8%).

All patients were categorized into a dysfunction category described in Table 2. Patients with elevation in any or all androgens (DHEAS, free testosterone, free testosterone %, total testosterone), and/or had PCOS were placed in the Androgen Excess/PCOS group. Patients with decrease in any or all androgens listed above were placed in the Low Androgens group (17.3%). Subjects with history of only ovarian cysts, and no hormonal abnormalities, were placed in the Cyst Only group (16.4%). Patients with only history of hirsutism were placed in Hirsutism Only group (13.%). Androgen excess/PCOS was the most common dysfunction identified in 220 patients with AA and all subtypes 42.5% (n=96) (p<0.001).

Table 3 evaluates the distribution of clinical markers associated with AA patients. Among all AA patients, those with clinical evidence only and those with ovarian dysfunction were significantly more likely to have no labs. The androgen excess

group was significantly more likely to present with adult acne, hirsutism, irregular menses, trouble conceiving, polycystic ovary syndrome (PCOS), and/or ovarian cysts (p<0.001). It is important to note the androgen excess group was not receiving therapies that would alter androgen secretion. Diabetes and seborrheic dermatitis did not demonstrate a notable association with androgen excess.

CONCLUSIONWe report a significant association between AA and

hyperandrogenism. Based on our study we provide clinical guidelines to follow when androgen excess is of question for patient presentation. An important recommendation to gynecologists and dermatologists is to take a brief gynecological history and family history of androgen excess conditions or associated symptoms. Since some of the clinical markers of androgen excess in AA patients are not present, we suggest screening laboratory tests to assess circulating hormone levels (total testosterone, free testosterone, free testosterone %, DHEAS and androstenedione) in female patients with a clinical history of menstrual irregularities, trouble conceiving, PCOS or

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.

Clinical Markers Clinical Evidence (N=29)

And. Excess PCOS (N=96)

Other Adrenal (N=53)

Ovarian Dysfunction (N=42) p-value

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: Significantly different from 1.Clinical Evidence2: Significantly different from 2.And. Excess/PCOS3: Significantly different from 3.Other Adrenal4: Significantly different from 4.Ovarian DysfunctionA significance level of 0.008 was used for pairwise ad-hoc comparisons.

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

Cite this article

ovarian cysts. The assessment for androgen excess in the alopecia areata patient population is challenging for clinicians, especially in patients with AU. The recommended additional laboratory screening criteria should provide the clinician with the essential information.

Being a retrospective study creates a limitation, since patient information recorded by various physicians was not presented in a standardized format. There were a significant number of patients that had either only clinical evidence or an ovarian dysfunction, but no laboratory data available. The lack of information creates a limitation on our study, since we could not determine if these patients had androgen abnormalities. In this study we captured a snapshot screen of androgen excess, by recording testosterone, free testosterone, DHEAS, and androstenedione. If we conducted a cortical stimulation test and worked with an endocrinologist we could have increased our yield. We believe that if a cortical stimulation test were completed there would be a 30% increased detection of androgen excess patients [12,13]. Based on our findings, we recommend to gather appropriate lab values for patients presenting with clinical evidence of androgen excess or ovarian dysfunction, and if these lab values are normal to refer the patient to an endocrinologist for a cortical stimulation test to locate the cause of patient presentation.

Since there was a group of patients without laboratory data, this made us question whether there were other indicators, besides biochemical lab results, that could direct the physician to diagnose an AA patient with androgen excess. Table 3 demonstrated how adult acne, hirsutism, PCOS, and ovarian cysts are significant makers to differentiate androgen excess from the other dysfunction groups. Some evidence of overall differences in menstrual irregularities and ability to conceive were also observed overall, but group differences could not be identified. Unfortunately, metabolic syndrome and dysmetabolic syndrome were too rare to analyze. We believe that if laboratory testing was conducted on patients with these clinical indicators, our androgen excess yield would have increased.

Current evidence has shown that there is a significant difference among alopecia areata patients and the normal population regarding depression and anxiety [14]. AA patients with androgen excess may also suffer from an androgynous appearance, diabetes, obesity, metabolic syndrome and cardiovascular disease [15]. By improving the clinician’s role in screening AA patients, it is possible to alleviate complications caused by androgen excess and address their psychological distress.

Our study suggests that the alopecia areata female patient is an at risk population of patients for androgen excess and its sequel. Future prospective studies are needed to confirm our findings.

ACKNOWLEDGEMENTSSpecial thanks to Anastasiya Kalinina for assisting in the data

inputting process. Also, to James Bena for the statistical analysis. The statistical analysis was supported by Dermatology Plastics Surgery Institute.

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