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

The development of AV correlates directly with the emergence of puberty which is associated with increased androgen levels and production of sebum.1-4,8 Sebum, an admixture of triglycerides, diglycerides, wax esters, squalene, cholesterol, and sterol esters, is produced by sebocytes, with some contribution by lipases produced by commensal bacteria (Cutibacterium acnes [formerly Propionibacterium acnes]) within the follicular canal, which hydrolyze triglycerides to free fatty acids (FFA).3,5 Sebum production varies among individuals and races, and from the end of puberty remains relatively constant through mid-adulthood, followed by a decline in both genders later in life.3 In addition, androgen (ie, DHT) stimulation also appears to contribute to lipogenic differentiation by functional ARexpressive sebocytes and can increase both sebum production and pro-inflammatory cytokine production by sebocytes.1,16 It is also recognized that sebaceous glands and sebum play a role in innate immunity and antimicrobial defense.3,5,8 Sebaceous glands/sebocytes express certain pattern recognition receptors (ie, Toll-like receptors) involved in cutaneous innate immune defense.5 Several antimicrobial peptides (ie, cathelicidins, defensins, psoriasin) are expressed within sebaceous glands, and FFAs in sebum are active against gram-positive bacteria via upregulation of β-defensin-2 expression.5,17,18

Although increased androgens and sebum contribute to AV development, presence of sebum alone is not sufficient to induce AV.3 Overall, AV is associated with larger sebaceous glands and higher sebum production.3 Sebum in individuals with AV is similar overall in composition to sebum from non-acne affected skin, but with higher levels of squalene monosaturated FAs and less linoleic acid.8 A major role of sebum in AV pathophysiology is to provide a follicular microenvironment and nutrient source for C acnes proliferation within the pilosebaceous unit which stimulates innate immune response and pro-inflammatory cytokine production by sebocytes, keratinocytes, and perifollicular monocytes.1,8 C acnes lipases also convert sebum triglycerides and diglycerides into FFAs which may promote follicular keratinization and stimulate chemotaxis.3,8 Inhibition of androgen stimulation that augments sebaceous gland proliferation and sebum production can produce downstream therapeutic benefit by reducing the microenvironment conducive to C acnes-related activity in AV.

Androgen Physiology, Androgen Receptors, and Cutaneous Diseases Including Impact of Gender and Ethnicity/Race
The close interplay that circulating androgens, local tissue androgen production/ degradation, and AR functionality have with sebaceous gland activity and sebum production can play a major role in AV pathophysiology, especially when genetic polymorphisms and AR dysfunctions occur. In fact, aberrations in sex hormone physiology, AR genetic polymorphisms, and/ or enzymatic abnormalities have been shown to be associated with a variety of systemic diseases (ie obesity, diabetes, prostate cancer, male infertility) and cutaneous diseases (ie AV, AGA, hirsutism, hidradenitis suppurativa).1,2,13,14,19 With regard to cutaneous disease states, AV is the focus of discussion in this manuscript, however, the roles of androgens and AR functionality in other cutaneous diseases have been reviewed elsewhere.1,2,13

Several observations have been associated with androgenrelated physiology including gender-related characteristics. Table 2 depicts important observations related to androgen activity and also gender-related factors.

Ethnic/racial variations in physiologic responses, enzyme function, chemical/drug metabolism, and disease propensities are well recognized. These differences appear to occur due to genetic polymorphisms, tissue receptor functionality and distribution, tissue enzyme activity and distribution, circulating hormone levels, and environmental/exogenous factors.19

Within the normal range of AR CAG repeat chain lengths, ethnic differences have been observed in healthy men. The