TY - JOUR
AU - Reynolds, Rachel V.
AB - As dermatologists, we pride ourselves on being Sherlock Holmes in the House of Medicine, employing our keen clinical diagnostic skills as we expertly read the signs of internal disease that manifest on the skin. While much attention is paid to the dermatologic aspects of paraneoplastic, inflammatory, and autoimmune disorders, abnormalities of the endocrine system also deserve no less of our attention. In this issue of JAMA Dermatology, 2 articles highlight the important role that the dermatologist plays in identifying and characterizing patients with common skin disorders who may be at risk for metabolic and androgen-mediated disease. Schmidt et al1 describe cutaneous findings and their associations with insulin resistance and hyperandrogenemia among a group of women referred to their multidisciplinary center deemed at high risk for polycystic ovary syndrome (PCOS). In a standardized fashion, they evaluated clinical and laboratory findings that distinguished women who met diagnostic criteria for PCOS as compared with those who did not within this referral population. Next, Nagpal et al2 report, to our knowledge, the largest cohort to date examining the prevalence of insulin resistance and metabolic syndrome in postadolescent males with acne of varying severity. Polycystic ovary syndrome is a multifaceted syndrome of unclear etiology that reflects a complex interplay between excess androgen production and hyperinsulinemia that manifests clinically as chronic oligo-ovulation, hyperandrogenism, polycystic ovaries, and metabolic abnormalities. It is one of the most common endocrinopathies among women of reproductive age. Prevalence estimates range from up to 8% using the National Institutes of Health criteria to up to 18% when the broader Rotterdam diagnostic criteria are applied.3 Whereas clinical manifestations can vary among women, each aspect is associated with significant long-term health consequences. Menstrual irregularities in women with PCOS represent the most common cause of anovulatory infertility and also put women at risk for the development of endometrial hyperplasia and endometrial carcinoma. When women with PCOS do become pregnant, they are more likely to experience complications such as gestational diabetes, pregnancy-induced hypertension, preeclampsia, and premature delivery.4 Metabolic abnormalities are also commonly seen in women with PCOS. Up to 47% meet criteria for the metabolic syndrome, which manifests as obesity, hypertension, impaired glucose tolerance, and dyslipidemia. While it is controversial as to whether PCOS represents an independent risk factor for the development of cardiovascular disease, these patients do require close monitoring and strategies for risk factor modification. Of further consequence are higher rates of obstructive sleep apnea, nonalcoholic steatohepatitis, and psychiatric disorders, such as anxiety, depression, and eating disorders, associated with this syndrome. Women with PCOS also report decreased quality of life, with hirsutism and obesity playing the most prominent roles.5,6 Positioned at the interface between the skin and the endocrine system, dermatologists play a central role in the identification and diagnosis of women with PCOS. All of the clinical manifestations of hyperandrogenism are cutaneous: acne, hirsutism, and, less commonly, androgenic alopecia. Acanthosis nigricans, a known marker of hyperinsulinemia, is also commonly present, but its relationship to hyperandrogenemia is less well known.7 Up to 37% of women with moderate to severe acne meet the diagnostic criteria for PCOS, and up to 60% of women with PCOS will manifest hirsutism. Traditionally, acne that is localized to the jaw and neck, has its onset or worsens in adulthood, or is associated with hirsutism and premenstrual flares has been considered “hormonal” acne. It is a challenge for dermatologists to determine who among these patients may have PCOS because this form of acne commonly results from the local effects of increased androgen receptor sensitivity and increased activity of 5α-reductase within the pilosebaceous unit rather than from hyperandrogenemia related to an underlying endocrinopathy. Similarly, whereas hirsutism can be a marker of elevated serum androgen levels, it can also result from increased local follicular 5α-reductase activity and can vary significantly by ethnicity, with higher prevalence among South Asian women and lower rates among Japanese women.3 A typical indication for a PCOS workup among women with hormonal acne and/or hirsutism is accompanying menstrual irregularity. However, 16% of women with PCOS have normal menses and therefore relying on menstrual history alone to trigger a workup may be insufficient.8 The findings of the retrospective cross-sectional study by Schmidt et al1 offer guidance for the dermatologist faced with determining whether their patient warrants a workup for PCOS. This is one of the largest studies published to date that offers characterization of a PCOS population from the dermatologic perspective, and the most important of its kind published in a major dermatology journal. Strengths of the work include the authors’ efforts to collect laboratory data prospectively and their use of standardized disease severity scales to measure acne, hirsutism, and insulin resistance in their clinic population. Of 401 women referred to their center for workup, 69% received a diagnosis of PCOS using the Rotterdam criteria,8 12% did not meet criteria, and the remaining patients had insufficient data, exclusions, or declined to participate in the study. Women with a diagnosis of PCOS had higher rates of hirsutism, acne, acanthosis nigricans, and elevated total testosterone compared with those who had suspected PCOS but did not meet criteria. Hirsutism was more severe on the trunk and acanthosis nigricans predominated in the axillae within the PCOS group. Among women with PCOS, hirsutism (especially truncal) and acanthosis nigricans were associated with elevations in free testosterone levels, insulin resistance, and dyslipidemia. Acne, although more prevalent in the PCOS group, was not associated with hyperandrogenemia or any difference in severity or distribution compared with the control group and therefore was deemed an unreliable marker for PCOS. These findings underscore that in addition to hyperinsulinemia, acanthosis nigricans is also a sign of hyperandrogenemia, and its presence warrants a workup for androgen excess. From these results, the authors emphasize the importance of a complete cutaneous examination in patients suspected of having PCOS because hirsutism on the trunk and acanthosis nigricans of the axillae proved to be the most specific and strongest clinical predictors of elevated serum androgen levels and a PCOS diagnosis. These findings are novel and have potential to improve the diagnostic abilities of the dermatologist caring for these patients. This study represents a substantial advance in our understanding of this common yet underdiagnosed syndrome; however, it does have some limitations. Although patients enrolled in the study were required to discontinue oral contraceptive use for 1 month prior to workup, they were allowed to continue systemic and topical therapies for acne, as well as hair removal practices, for up to 1 week prior to evaluation. Hence, the reported prevalence of acne and hirsutism may underestimate actual rates. Furthermore, there is no mention as to whether any patients were taking spironolactone, a commonly used medication in this population, which would affect not only cutaneous findings but also menstrual regularity and serum androgen levels, potentially altering PCOS diagnoses.9 As noted by the authors, because the comparison group was already suspected of having PCOS, relative rates of cutaneous findings are not generalizable to the general population but rather help to highlight those most likely to have PCOS among a high-risk group. In their cross-sectional study, Nagpal et al2 recruited 100 men with acne, divided them into 4 groups of 25 on the basis of severity using a standardized scale, and compared them with 100 age-matched controls. They found significantly higher rates of insulin resistance and hypertension, but not metabolic syndrome, among the affected group. Similarly to Schmidt et al,1 these findings did not vary according to acne severity; however, they did note significantly higher body mass index (BMI) in the most severely affected group compared with the least affected group. Their findings were limited by study size, cross-sectional design, and a lack of mention of current therapy in the acne group. Nevertheless, these findings encourage the clinician to consider evaluating their adult male patients with acne for components of the metabolic syndrome. In contrast to the well-established literature on PCOS and its relationship to acne and to metabolic abnormalities, the potential association between acne and insulin resistance in men has not been as well studied. Hyperinsulinemia is implicated in the pathogenesis of acne through insulin-like growth factor 1, which stimulates increased sebum excretion, increased serum androgen levels, and the inflammatory pathways implicated in acne.10-13 Interestingly, the sebaceous gland is further linked to the endocrine and neuroendocrine systems through binding of melanocortins and corticotropin-releasing hormone to their receptors on sebocytes, aggravating sebum production and acne development.13 Once again, the role of the sebaceous gland reminds us of the intimate relationship between the skin and the endocrine system. The presence of acne in women and men provides a window into the complex hormonal milieu of the skin and potential underlying endocrinopathies. The findings of these 2 studies remind us that as dermatologists, our detective work goes beyond identifying patterns on the surface to clinch a diagnosis. Thoughtful evaluation of even the most common of skin disorders provides the opportunity to take a deeper dive into the understanding of our patients’ general physical and emotional well-being. Back to top Article Information Corresponding Author: Rachel V. Reynolds, MD, Department of Dermatology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215 (rreynold@bidmc.harvard.edu). Published Online: December 23, 2015. doi:10.1001/jamadermatol.2015.4500. Conflict of Interest Disclosures: None reported. References 1. Schmidt TH, Khanijow K, Cedars MI, et al. Cutaneous findings and systemic associations in women with polycystic ovary syndrome [published online December 23, 2015]. JAMA Dermatol. doi:10.1001/jamadermatol.2015.4498.Google Scholar 2. Nagpal M, De D, Handa S, Pal A, Sachdeva N. Insulin resistance and metabolic syndrome in young men with acne [published online December 23, 2015]. JAMA Dermatol. doi:10.1001/jamadermatol.2015.4499.Google Scholar 3. Housman E, Reynolds RV. Polycystic ovary syndrome: a review for dermatologists: part I. diagnosis and manifestations. J Am Acad Dermatol. 2014;71(5):847.e1-847.e10.PubMedGoogle ScholarCrossref 4. Palomba S, de Wilde MA, Falbo A, Koster MP, La Sala GB, Fauser BC. Pregnancy complications in women with polycystic ovary syndrome. Hum Reprod Update. 2015;21(5):575-592.PubMedGoogle ScholarCrossref 5. Hahn S, Janssen OE, Tan S, et al. Clinical and psychological correlates of quality-of-life in polycystic ovary syndrome. Eur J Endocrinol. 2005;153(6):853-860.PubMedGoogle ScholarCrossref 6. Veltman-Verhulst SM, Boivin J, Eijkemans MJ, Fauser BJ. Emotional distress is a common risk in women with polycystic ovary syndrome: a systematic review and meta-analysis of 28 studies. Hum Reprod Update. 2012;18(6):638-651.PubMedGoogle ScholarCrossref 7. Lee AT, Zane LT. Dermatologic manifestations of polycystic ovary syndrome. Am J Clin Dermatol. 2007;8(4):201-219.PubMedGoogle ScholarCrossref 8. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004;81(1):19-25.PubMedGoogle ScholarCrossref 9. Ganie MA, Khurana ML, Nisar S, et al. Improved efficacy of low-dose spironolactone and metformin combination than either drug alone in the management of women with polycystic ovary syndrome (PCOS): a six-month, open-label randomized study. J Clin Endocrinol Metab. 2013;98(9):3599-3607.PubMedGoogle ScholarCrossref 10. Smith TM, Gilliland K, Clawson GA, Thiboutot D. IGF-1 induces SREBP-1 expression and lipogenesis in SEB-1 sebocytes via activation of the phosphoinositide 3-kinase/Akt pathway. J Invest Dermatol. 2008;128(5):1286-1293.PubMedGoogle ScholarCrossref 11. Borisov N, Aksamitiene E, Kiyatkin A, et al. Systems-level interactions between insulin-EGF networks amplify mitogenic signaling. Mol Syst Biol. 2009;5:256.PubMedGoogle ScholarCrossref 12. Vora S, Ovhal A, Jerajani H, Nair N, Chakrabortty A. Correlation of facial sebum to serum insulin-like growth factor-1 in patients with acne. Br J Dermatol. 2008;159(4):990-991.PubMedGoogle ScholarCrossref 13. Das S, Reynolds RV. Recent advances in acne pathogenesis: implications for therapy. Am J Clin Dermatol. 2014;15(6):479-488.PubMedGoogle ScholarCrossref
TI - New Insights Into the Relationship Between the Skin and Endocrine Disorders
JF - JAMA Dermatology
DO - 10.1001/jamadermatol.2015.4500
DA - 2016-04-01
UR - https://www.deepdyve.com/lp/american-medical-association/new-insights-into-the-relationship-between-the-skin-and-endocrine-z1sboeekd6
SP - 377
EP - 379
VL - 152
IS - 4
DP - DeepDyve
ER -