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

DHT exhibiting a 5-10-fold greater affinity for the AR.1-3,5,8 Other hormone receptors present in sebaceous glands, such as corticotropin-releasing hormone (CRH) receptors, melanocyte stimulating hormone (MSH) receptors 1 and 5, and some neuropeptides from closely associated neurons (ie, substance P), may also selectively contribute to modulation of sebocyte differentiation, lipid synthesis, and inflammatory cytokine production.3 Although the AR appears to be the most important therapeutic target for skin diseases such as AV and AGA, some of these other receptors may also serve as potential targets for drug development, especially AV.

Sebaceous gland development increases along with the natural progression of androgen production and stimulation at adrenarche/puberty.1-5 Other than ectopic sebaceous glands at specific anatomic sites (ie, oral mucosa, eyelids, genitalia), sebaceous glands connect via their duct to the infundibulum of the pilosebaceous unit. Sebocytes that comprise the gland, after a differentiation lifespan of two to three weeks, fully disintegrate and excrete their lipid contents (sebum) into the duct (holocrine secretion).3,5 The density of sebaceous glands varies in different anatomic locations, and is highest on the scalp, face, and upper chest and back.1-3,8 The function of sebaceous glands is not limited to sebum production. These glands also play important roles in innate immunity, androgen metabolism, cytokine production, and antimicrobial peptide activity.3,12 The effects of androgens and sebum in AV pathophysiology are addressed later in this manuscript.

ARs are intracellular protein transcription factors with three functional domains: the ligand-binding domain, the DNAbinding domain, and the transactivation domain.1,6 Importantly, the AR genetic profile is not fixed in its structure or type of androgenic activity. Rather, the AR genetic structure exhibits marked polymorphism primarily in the length of trinucleotide CAG (cytosine-adenine-guanine) repeats that encode a polyglutamine stretch in the transactivation domain.6 The basal and ligand-induced AR transactivational activity correlates inversely with the length of the AR CAG repeat.6,7,13,14 From a clinical perspective, this indicates that the magnitude and type of androgenic effect that an AR modulates is dependent on its structure (CAG repeat length). Coactivator proteins that may vary within different tissues can modulate the impact induced by the CAG repeat length on androgenic activity.6 Studies evaluating the normal ranges of CAG chain repeat lengths have started to define differences among ethnic populations that may define relative androgenicity and also associations with various disease states.1,2,4,6,7,13,14

Sebaceous Glands, Sebum, and Acne Vulgaris
Sebaceous glands are present at birth with an initial high level of sebum production that declines rapidly within months until the onset of adrenarche and emergence of pubery.3,8 Androgen stimulation of sebaceous glands begins in the neonatal period with luteinizing hormone (LH) stimulating testicular production of T in boys over six to twelve months, and by the adrenal “fetal zone”, which produces DHEA-S/DHEA with involution by age one year.8 Androgen levels are then very low and sebaceous glands remain quiescent until adrenarche (around 7-8 years of age) at which time adrenal glands start to produce DHEA-S.3,8 Sebaceous gland growth and increased sebum production are primarily induced by androgens, especially DHT which exhibits potent androgenic activity.3 Single androgen compounds appear to be unable to modulate sebocyte differentiation and lipogenesis, requiring participation by peroxisome proliferatoractivated receptors (PPAR).5,12,15 Specific PPARs have been identified in basal sebocytes and in differentiated sebocytes.5