ARTICLE: Androgens, Androgen Receptors, and the Skin: From the Laboratory to the Clinic With Emphasis on Clinical and Therapeutic Implications

March 2020 | Volume 19 | Issue 3 | Supplement Individual Articles | 30 | Copyright © March 2020


Published online February 25, 2020

James Q. Del Rosso , Leon H. Kircik , Linda Stein Gold , Diane Thiboutot

aJDR Dermatology Research/Thomas Dermatology, Las Vegas, NV; Touro University Nevada, Henderson, NV bIcahn School of Medicine at Mount Sinai, New York, NY; Indiana University Medical Center, Indianapolis, IN; Physicians Skin Care, PLLC Louisville, KY; DermResearch, PLLC, Louisville, KY; Skin Sciences, PLLC, Louisville, KY cHenry Ford Health System, Detroit, MI dPenn State University College of Medicine, Hershey, PA

(some agents FDA-approved for AV), or combination therapy using both agents.4,8,20-27 In the US, use of oral flutamide (not FDA-approved for AV), a competitive inhibitor of AR binding by DHT, has been reported; its use has been limited primarily due to adverse effects and pregnancy-related concerns.4,8,20 In Europe and Canada, cyproterone acetate has long been used as both an oral antiandrogen and progestin that exhibits marked efficacy for AV both as monotherapy and in combination with estrogen as an oral contraceptive, however, it is not available in the US.4,8,20,21 At present, topical antiandrogen therapy is not available. However, topical clascoterone (cortexolone 17α propionate), an AR inhibitor, has completed the formal drug development process and has been submitted to the FDA to be evaluated for approval for treatment of AV.28-30 Clascoterone has been shown to bind the androgen receptor (AR) with high affinity in vitro, inhibit AR-regulated transcription, and antagonize androgen-mediated lipid and inflammatory cytokine production in human sebocytes, with a greater ability to inhibit inflammatory cytokine synthesis from sebocytes when compared to spironolactone.28 These research findings reported with clascoterone further support the significance of direct inhibition of AR in the management of AV, with potential application for other androgen mediated skin disorders.

CONCLUDING REMARKS

Advances in understanding of androgen physiology including both central and local tissue mechanisms, enzymatic functions that modulate androgen synthesis and degradation, and AR functionality including the impact of genetic polymorphisms have furthered our understanding of androgen-related diseases states and potential therapeutic options. The above, coupled with increased understanding of receptors and pathways that modulate sebaceous gland activities has also expanded our perspectives on potential therapies for AV. Further elucidation of the functions of androgens and androgen receptors in specific skin disorders can help to shift our focus to the development of therapies that selectively target AR and other receptor pathways that can effectively modify disease and hopefully reduce the risk of adverse effects.

DISCLOSURES

Dr. Del Rosso has served as an advisory board member for Cassiopea, Inc. Dr. Kircik has served as an advisory board member and a consultant for Cassiopea, Inc. Dr. Stein Gold has served as a research investigator and advisor for Cassiopea Inc. Dr. Thiboutot has served as a research investigator and advisory board member for Cassiopea Inc.

REFERENCES

1. Ceruti JM, Leiros GJ, Balana ME. Androgens and androgen receptor action in skin and hair follicles. Mol Cell Endocrinol. 2018;465:122-133.
2. Zouboulis ChC, Degitz K. Androgen action on human skin – from basic research to clinical significance. Exp Dermatol. 2004;13(Suppl 4);5-10.
3. Schaller M, Plewig G. Structure and function of eccrine, apocrine, and sebaceous glands. In: Bolognia JL, Schaffer JV, Cerroni L, Eds, Dermatology, 4th Edition. Elsevier, Philadelphia, PA, USA, 2018;580-587.
4. Elsaie ML. Hormonal treatment of acne vulgaris: an update. Clin Cosmet Investig Dermatology. 2016;9:241-248.
5. Nelson AM, Thiboutot DM. Sebum. In: Shalita AR, Del Rosso JQ, Webster GF, Eds, Acne Vulgaris. Informa Healthcare, London, United Kingdom, 2011;3-11.
6. Zitzmann M, Nieschlag E. The CAG repeat polymorphism with the androgen receptor gene and maleness. Intl J Androl. 2003;26(2):76-83.
7. Ackerman CM, Lowe LP, Lee H, et al. Ethnic variation in allele distribution of the androgen receptor (AR) (CAG)n repeat. Int J Androl. 2012;33(2):210-215.
8. Zaenglein A, Thiboutot D. Acne vulgaris. In: Bolognia JL, Schaffer JV, Cerroni L, Eds, Dermatology, 4th Edition. Elsevier, Philadelphia, PA, USA, 2018;588-603.
9. Thiboutot D, Gilliland K, Light J, Lookingbill D. Androgen metabolism in sebaceous glands from subjects with and without acne. Arch Dermatol. 1999;135(9):1041-1045.
10. Lookingbill DP, Horton R, Demers LM, et al. Tissue production of androgens in women with acne. J Am Acad Dermatol. 1985;12(3):481-487.
11. 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(3):308-314.
12. Zouboulis CC. Acne and sebaceous gland function. Clin Dermatol. 2004;22(5):360-366.
13. Sawaya ME, Shalita AR. Androgen receptor polymorphisms (CAG repeat lengths) in androgenetic alopecia, hirsutism, and acne. J Cutan Med Surg. 1998;3(1):9-15.
14. Ferlin A, Bartoloni L, Rizzo G, et al. Androgen receptor gene CAG and GGC repeat lengths in idiopathic male infertility. Mol Hum Reprod. 2004;10(6):417-421.
15. Trivedi NR, Cong Z, Nelson AM, et al. Peroxisome proliferator-activated receptors increase human sebum production. J Invest Dermatol. 2006;126(9):2002-2009.
16. Lee WJ, Jung HD, Chi SG, et al. Effect of dihydrotestosterone on the upregulation of inflammatory cytokines in cultured sebocytes. Arch Dermatol Res. 2010;302(6):429-433.
17. Nakatsuji T, Kao MC, Zhang L, et al. Sebum free fatty acids enhance the innate immune defense of human sebocytes by upregulating beta-defensin-2 expression. J Invest Dermatol. 2010;130(4):985-994.
18. Lee DY, Yamasaki K, Rudsil J, et al. Sebocytes express functional cathelicidin antimicrobial peptides and can act to kill Propionibacterium acnes. J Invest Dermatol. 2008;128(7):1863-1866.
19. Wang C, Christenson P, Swerdloff R. Clinical relevance of racial and ethnic differences in sex steroids. J Clin Endocrinol Metabolism. 2007;92(7):2433- 2435.
20. Keri J, Berson DS, Thiboutot DM. Hormonal treatment of acne in women. In: Shalita AR, Del Rosso JQ, Webster GF, Eds, Acne Vulgaris. Informa Healthcare, London, United Kingdom, 2011;146-155.
21. Barros B, Thiboutot D. Hormonal therapies for acne. Clin Dermatol. 2017;35(2):168-172.
22. Harper JC. Use of oral contraceptives for management of acne vulgaris: practical considerations in real world practice. Dermatol Clin. 2016;34(2):159-165.
23. Kim GK, Del Rosso JQ. Oral spironolactone in post-teenage female patients with acne vulgaris: practical considerations for the clinician based on current data and clinical experience. J Clin Aesthet Dermatol. 2012;5(3):37-50.
24. Layton AM. Top ten list of clinical pearls in the treatment of acne vulgaris. Dermatol Clin. 2016;34:147-157.
25. Villasenor D, Berson DS, Kroshinsky D. Treatment guidelines in adult women. In: Shalita AR, Del Rosso JQ, Webster GF, Eds, Acne Vulgaris. Informa Healthcare, London, United Kingdom, 2011;198-207.
26. Marson JW, Baldwin HE. An overview of acne therapy, part 2: hormonal therapy and isotretinoin. Dermatol Clin. 2019;37(2):195-203. 27. Del Rosso JQ, Harper JC, Graber EM, et al. Status report from the American Acne & Rosacea Society on medical management of acne in adult women, part 3: oral therapies. Cutis. 2015; 96(6):376-382.
28. Rosette C, Agan FJ, Mazzetti A, et al. Cortexolone 17α-propionate (clascoterone) is a novel androgen receptor antagonist that inhibits production of lipids and inflammatory cytokines from sebocytes in vitro. J Drugs Dermatol. 2019;18:412-418.
29. Mazzetti A, Moro L, Gerloni M, Cartwright M. A phase 2b, randomized, double- blind vehicle controlled, dose escalation study evaluating clascoterone 0.1%, 0.5%, and 1% topical cream in subjects with facial acne. J Drugs Dermatol. 2019;18(6):570.
30. Mazzetti A, Moro L, Gerloni M, Cartwright M. Pharmacokinetic profile, safety, and tolerability of clascoterone (cortexolone 17-alpha propionate, CB-03- 01) topical cream, 1% in subjects with acne vulgaris: an open-label phase 2a study. J Drugs Dermatol. 2019;18(6):563.