The cutaneous effects of androgens and androgen-mediated sebum production and their pathophysiologic and therapeutic importance in acne vulgaris

Abstract

Background: The recognition of an association between the development of acne vulgaris (AV) and pubertal hormonal changes during adolescence dates back almost 100 years. Since these formative observations, a significant role of circulating hormones in the pathophysiology of AV and other cutaneous disorders has been established.

Aims: This review article aims to provide an overview of clinical and preclinical evidence supporting the influences of androgens on the skin and their therapeutic importance in AV pathophysiology.

Results: The cutaneous effects of hormones are attributable, to a large extent, to the influence of steroid hormones, particularly androgens, on sebocyte development and sebum production in both sexes. Androgen-mediated excess sebum production is implicated as a necessary early step in AV pathophysiology and is therefore considered an important therapeutic target in AV treatment. Although the local production and/or activity of androgens within the skin is believed to be important in AV pathophysiology, it has received limited therapeutic attention.

Conclusions: We have summarized the current evidence in support of the therapeutic benefits of targeted hormonal treatment to decrease androgen-stimulated sebum production for the effective and safe treatment of AV in both male and female patients.

Keywords:

• Acne vulgaris
• androgen
• sebum
• pathophysiology
• topical
• therapy

1. Introduction

Acne vulgaris (AV) is a multifactorial skin condition affecting the pilosebaceous follicles (1) that is estimated to affect at least 80% of adolescents and young adults between 11 and 30 years of age (2). The onset of AV typically coincides with the onset of adrenarche and subsequent puberty and is due to the stimulatory effects of increased circulating levels of sex hormones, particularly androgens, on sebaceous gland development and sebum production in both sexes (2,3). Androgens are steroid hormones best known for their roles in the development of male sex characteristics and are primarily synthesized within the reproductive organs as well as in peripheral tissues, where they are synthesized from androgen precursors (e.g., androstenedione) derived from the adrenal glands (4). Potent androgens such as dihydrotestosterone (DHT) and testosterone can also be synthesized within the sebaceous gland and other skin structures (5,6); their activity within the skin is implicated in the disease process of AV as well as other androgenetic skin disorders (2,4).

The importance of circulating hormones in the development of AV has long been recognized, stemming from early observations of the increased prevalence of AV during puberty and its association with the development of secondary sex characteristics (7). Androgens are now known to play a crucial role in the regulation of sebaceous gland activity and sebum production (2,4,8), and a marked androgen-mediated increase in sebum production is implicated as a necessary early step in AV pathophysiology (9). The ability of the sebaceous gland to synthesize potent androgens from adrenal precursors (5,6) suggests that the local production of androgens within the skin may be important in AV pathophysiology and warrants further therapeutic attention. While systemic hormonal therapies are a mainstay of AV treatment in female patients, they are associated with many adverse side effects and are not suitable for use in all patients (2). This review covers the influences of androgens on the skin and their therapeutic importance in acne pathophysiology, and summarizes current evidence supporting the potential benefits of targeted hormonal therapy in patients with AV.

2. Local synthesis and actions of androgens in the skin

In addition to being a target of circulating androgens, cells within the pilosebaceous unit are capable of both de novo androgen synthesis from cholesterol (10) and biosynthesis of testosterone and DHT from androgenic precursors via local enzymatic activity (11). The sebaceous gland possesses the enzymatic machinery necessary to convert circulating androgenic precursors such as dehydroepiandrosterone into more potent androgens (e.g., DHT). Radiolabeling and histochemical studies confirm the localization within sebaceous gland tissue of the androgen-synthesizing enzymes 17β-hydroxysteroid dehydrogenase (17β-HSD) and 5α-reductase, responsible for the synthesis of testosterone and DHT, respectively (5,6,11–13). There are multiple isoforms of 17β-HSD and 5α-reductase that differ in their localization within the skin, with 17β-HSD type 2 and 5α-reductase type 1 expressed as the predominant isoforms in the sebaceous glands (11–13). Interestingly, skin biopsy sections from individuals with AV demonstrate localization of the type 2 isoform of 5α-reductase within comedonal walls and endothelial cells from sections of inflammatory lesions (11), suggesting a possible role of 5α-reductase type 2 in the development of AV lesions.

The biological actions of androgens are primarily mediated through binding to the androgen receptor (AR), a member of the steroid hormone nuclear receptor family that functions as a ligand-dependent nuclear transcription factor (14). Using immunohistochemistry, AR expression was identified within several types of cells within the skin, with a similar distribution in both sexes (15). ARs are located in keratinocytes, dermal papilla cells, eccrine glands, and sebaceous glands (15,16), underscoring the importance and numerous influences of androgens on the skin. In their unbound state, ARs are located within the cytoplasm in a complex containing heat shock and chaperone proteins (14). The binding of androgens to an AR induces a conformational change that allows it to dissociate from these proteins and translocate to the nucleus, where the androgen/AR complex binds to androgen response elements within target genes to regulate transcription (14). In addition to DNA binding–dependent (i.e., genomic) signaling, androgens can also exert their biological effects through more rapid ligand-independent (i.e., nongenomic) signaling pathways via the activation of second messenger cascades (17). It is believed that some of the nongenomic actions of androgens are mediated through the activation of membrane-bound ARs that can rapidly trigger downstream intracellular signaling pathways (14,18). However, the presence of membrane-bound ARs within skin tissues is not confirmed, and their potential physiologic significance is not fully understood.

3. Hormonal influences on sebaceous glands in acne vulgaris

The sebaceous gland is a component of the pilosebaceous unit containing specialized cells, referred to as sebocytes, that synthesize and secrete sebum, a substance consisting of a mixture of lipids including triglycerides, squalene, and wax and cholesterol esters (19,20). Once secreted from the sebaceous glands, sebum triglycerides are hydrolyzed into free fatty acids that contribute to the antibacterial responses of the skin (21). Findings from studies in mice genetically deficient in differentiated sebocytes confirm that sebaceous lipids are important for many functions relevant to skin physiology, including waterproofing, protection against ultraviolet radiation–induced cell damage, body temperature regulation, and epidermal homeostasis (22,23). Consistent with these observations, alterations in sebaceous gland activity are implicated in the disease mechanism of AV (9). Sebaceous gland activity and sebum production are strongly influenced by androgens, as evidenced by the marked absence of sebum in androgen-insensitive individuals and in those with AR gene mutations (24,25). Thus, AR is an important therapeutic target for reducing excess androgen-mediated sebum production in AV treatment (26).

3.1. Importance of androgen-mediated sebum production in acne

The pathophysiology of AV is thought to originate with excess production of sebum within sebaceous glands, providing a favorable environment for bacterial colonization with Cutibacterium acnes and subsequent activation of innate immune responses (1,9). In addition, excess levels of sebum fatty acids such as oleic acid can accelerate keratinocyte differentiation and lead to excessive stratum corneum thickening (27,28), potentially through upregulation of growth factors from dermal fibroblasts (29), and also promote the expression of proinflammatory cytokines (28). Therefore, the facilitatory actions of androgens on sebocyte activity lie upstream of numerous pathophysiologic factors implicated in the formation of both noninflammatory and inflammatory acne lesions, and the beneficial effects of hormonal therapies in AV treatment are generally attributable to decreasing circulating levels of androgens and/or blocking their activity at ARs (1) (Figure 1).

Figure 1. The role of androgen-mediated sebum production in acne pathophysiology. Androgens such as DHT regulate sebaceous gland activity via binding to ARs expressed in sebocytes within the sebaceous gland and stimulating the expression of genes that promote sebum production (2,4,8). Excess sebum provides a favorable environment for bacterial growth and facilitates colonization with Cutibacterium acnes (9). In addition, fatty acids present in sebum can accelerate keratinocyte differentiation and induce epidermal barrier dysfunction associated with comedone formation (2,27,28,30). Proliferation of Cutibacterium acnes in addition to other inflammatory mediators within the pilosebaceous unit, such as defensins and cytokines, triggers inflammatory mechanisms involved in the formation of acne lesions (28,31–34). Hormonal agents used in acne treatment function to reduce circulating levels of androgens and/or block their activity at ARs (1,35,36). AR: androgen receptor; DHT: dihydrotestosterone.

Individuals with AV exhibit not only increases in the amount of sebum excretion but also alterations in the composition of sebum compared with individuals without AV. Skin surface and comedonal lipids collected from patients with AV possess lower levels of linoleic acid and higher proportions of fatty acids (37,38), and hormonal treatment using high-dose cyproterone acetate-ethinyl estradiol increases the proportions of linoleic acid in female AV patients (39). In another study evaluating the proportions of sebaceous lipids in isolated epidermal acylceramides, increased rates of sebum secretion were associated with decreased levels of linoleate and increases in sapienate, a fatty acid present in human sebum, suggesting that sebum fatty acids can enter into and become incorporated into epidermal lipids (38). Further, reductions in levels of linoleic acid and/or excess levels of oleic acid in sebum may contribute to epidermal barrier dysfunction (28,30) and thereby increase permeability to inflammatory mediators. Overall, these changes in sebum lipid composition are thought to initiate proinflammatory cascades that contribute to the development of AV lesions.

3.2. Androgens, sebum, and inflammation

The initiation of inflammatory pathways in the pilosebaceous unit is a key step in the development of AV lesions and involves complex mechanisms that include both innate and acquired immune responses (1). As previously mentioned, the proliferation of Cutibacterium acnes induces immune responses via activation of toll-like receptor 2 (31,32). Numerous other inflammatory mediators, including defensins, peptidases, and cytokines, are also implicated in AV pathophysiology (33). Sebum free fatty acids stimulate inflammatory responses through upregulation of β-defensin-2 expression (34) and increased expression of the proinflammatory cytokine interleukin (IL)-1α in vitro (28). The actions of androgens within sebaceous glands appear to contribute to some of these inflammatory mechanisms via increasing the expression of proinflammatory cytokines in vitro. The addition of DHT to cultured sebocytes significantly increases the expression of IL-6 and tumor necrosis factor α detected by a quantitative reverse transcriptase-polymerase chain reaction and immunocytofluorescence (40). Further, pharmacologic inhibition of the AR with clascoterone (cortexolone 17α-propionate) decreases androgen-mediated inflammatory cytokine production in cultured sebocytes (35). The clinical relevance of these actions is supported by evidence that antiandrogen therapies for acne treatment significantly reduce the number of AV lesions in patients (1,41).

It is now well established that the actions of androgens within sebocytes are mediated in part by activation of peroxisome proliferator-activated receptors (PPARs), a family of ligand-activated transcription factors. Early pivotal studies demonstrated that activation of PPAR_γ is critical for the effects of DHT on sebocyte differentiation and sebogenesis in vitro (42,43), and subsequent studies confirm the important roles of PPAR_γ in sebogenesis and inflammation (44–46). These findings have raised interest in PPAR_γ as a potential therapeutic target for the treatment of AV (47).

3.3. Importance of other hormones in acne pathophysiology

In addition to ARs, sebocytes express several other hormone receptors that act to modulate inflammatory pathways and sebum production, including insulin and insulin-like growth factor 1 (IGF-1). Dietary factors, particularly dietary glycemic load/index, have long been associated with AV pathophysiology and severity (1,48–51), and accumulating evidence suggests that insulin resistance may contribute to the risk of developing AV (1,52–55). These associations may be attributable to increases in the concentration of IGF-1, which promotes sebum production and increases the expression of proinflammatory cytokines in cultured sebocytes (56). Additionally, concentrations of IGF-1 are frequently elevated in patients with acne compared with individuals without acne (50,57–59). Based on evidence from randomized controlled studies, people on a low glycemic load diet exhibit significant reductions in acne severity and IGF-1 concentrations (48,49,60), and recent reports indicate that therapies that reduce IGF-1 concentration (e.g., metformin) are effective in patients with AV (61,62). Collectively, these findings suggest that therapies that lower insulin or IGF-1 concentrations may be beneficial for the treatment of certain individuals with AV.

4. Abnormalities in androgen levels in patients with acne: Clinical findings

While the importance of androgens in the pathophysiology of AV is well established, it is important to acknowledge that most AV patients do not demonstrate laboratory evidence of abnormal hormone levels (1). This suggests that the relationship between androgen concentration and acne severity is not linear, and/or that circulating levels of androgens are not necessarily reflective of their biological activity at ARs or of sebaceous gland activity. As summarized in Table 1, serum levels of testosterone and DHT are commonly higher in female patients with AV compared with those without AV (63–69) but are still mostly within the normal range (64). The marked increase in the prevalence of acne during adolescence compared to adulthood, even though circulating concentrations of androgen remain relatively stable until middle-to-late adulthood (70), also suggests that a key driver of hormone-induced AV is fluctuations in androgen production and not solely androgen excess. The influence of hormonal fluctuation on AV severity is further supported by the reported prevalence of premenstrual exacerbation of adult female AV (71–74). Adult female AV can also be associated with clinical features of hyperandrogenism, including irregular menstruation, hirsutism, polycystic ovaries, and androgenetic alopecia (65–67). Thus, endocrinologic testing is recommended for patients with AV and additional indicators of hyperandrogenism (1).

Table 1. Clinical studies evaluating hormonal parameters in patients with acne vulgaris.

Study	Patients enrolled, (N)/sex/age	Hormonal parameters	Outcomes
Borzyszkowska et al. 2022 (63)	168/female/18–31 years of age	Androstenedione, DHEA-S, T, SHBG, LH, FSH, PRL, ACTH, and cortisol	Measures of T, androstenedione, and FAI were significantly higher in female participants with acne prior to treatment compared with those in the control group, while SHBG levels were significantly lower (all p = .001); after treatment,^a levels of T (p = .001) and androstenedione (p = .026) were still significantly higher in participants with acne compared with those in the control group, while levels of SHBG and FAI were significantly higher and lower, respectively (both p = .001)
Zhang et al. 2022 (64)	696/male and female/20–30 years of age	FSH, LH, estradiol, P, T, PRL, and A:E	Acne severity in male and female participants was negatively correlated with estradiol and positively correlated with T and the A:E ratio (all p <.001)
Sardana et al. 2020 (65)	120/female/25 years of age and older	TT, SHBG, FAI, AMH, 17-OHP, DHEA-S, FSH, LH, TSH, and PRL	Of 120 patients, 86 (71.67%) had signs of clinical hyperandrogenism, including 31 (25.83%) with a history of irregular menses, 60 (50.0%) with hyperseborrhea, 48 (40.0%) with hirsutism, and 68 (56.67%) with androgenetic alopecia
Bansal et al. 2021 (66)	120/female/25 years of age and older	TT, SHBG, FAI, AMH, 17-OHP, DHEA-S, FSH, LH, TSH, and PRL	The mean ± SD score on the Global Acne Rating System was 15.57 ± 4.04 in all patients and 16.09 ± 4.21 in those with androgenic signs; 86 (71.66%) patients had acne with signs of hyperandrogenism, including 48 (55.81%) with hirsutism, 56 (65.12%) with hyperseborrhea, 68 (79.07%) with androgenetic alopecia, and 31 (36.05%) with irregular menstruation; mean hormonal values were similar in patients with hyperandrogenic signs vs those without
Shrestha 2018 (67)	100/female/25 years of age and older	TT, SHBG, DHEA-S, LH:FSH, TSH, and C-peptide	Hormonal abnormalities were observed in 29 of 78 (37.2%) patients, of which hyperandrogenism was reported in 14 (17.9%) patients
Cappel et al. 2005 (68)	34/male and female/18–45 years of age	IGF-1, IGFBP-3, androstenedione, T, DHEA-S, and DHT	Female patients with acne exhibited significant increases in serum levels of androstenedione, T, and DHEA-S, and increased levels of DHT approaching statistical significance (p = .06) relative to those without acne; no significant differences in androgen levels were observed in male participants based on the presence of acne
Thiboutot et al. 1999 (69)	34/male and female/18–45 years of age	Serum androgens (androstenedione, DHEA-S, T, DHT) and enzyme activity (5α-reductase and 17β-HSD)	No significant differences in the activity of 5α-reductase or 17β-HSD were observed between participants with acne and those without acne; significant increases in serum levels of DHEA-S, androstenedione, T, and DHT were associated with the presence of acne in female but not in male participants

17-OHP: 17-hydroxyprogesterone; 17β-HSD: 17β-hydroxysteroid dehydrogenase; A:E: ratio of androgen to estrogen; ACTH: adrenocorticotropic hormone; AMH: anti-Mullerian hormone; DHEA-S: dihydroepiandrosterone sulfate; DHT: dihydrotestosterone; FAI: free androgen index; FSH: follicle-stimulating hormone; IGF-1: insulin-like growth factor 1; IGFBP-3: insulin-like growth factor binding protein 3; LH: luteinizing hormone; LH:FSH: ratio of luteinizing hormone to follicle-stimulating hormone; P: progesterone; PRL: prolactin; SD: standard deviation; SHBG: sex hormone binding globulin; T: testosterone; TSH: thyroid-stimulating hormone; TT: total testosterone.

^aPatients were divided into 3 treatment groups and received an oral contraceptive agent, an oral contraceptive agent with cyproterone acetate, or an oral contraceptive agent with isotretinoin.

4.1. Importance of cutaneous production of androgens in AV

The production of androgens within the skin is believed to be important in AV based on the presence of androgen-synthesizing enzymes. While individuals with AV had increased DHT production in skin biopsies relative to those without AV in one study (75), in another study, there were no significant differences in the activity of 5α-reductase type 1 in sebaceous glands based on the presence of AV (69). The small sample size in the second study may have limited the statistical power. Additional studies are needed to better characterize acne-associated changes in androgen metabolism within sebaceous glands and their importance in AV development.

4.2. Androgen-related gene polymorphisms and acne

Genetic differences within the AR gene that influence receptor activity may also contribute to the risk of developing AV. In contrast to the highly conserved DNA- and ligand-binding domains of the AR protein, the transactivation domain contains a region encoded by CAG trinucleotide repeats that is highly polymorphic in length; the number of CAG repeats may vary from 8 to 35, with the normal range being 11 to 31 (14,76). Based on evidence from in vitro studies, there is an inverse relationship between the number of CAG repeats and the activity of the AR (77), and clinical evidence supports an association between shorter CAG lengths and the development of AV and other androgenetic disorders (78). However, additional larger studies are needed to characterize the role of variations in CAG repeat length in the risk of developing AV.

There is also evidence suggesting that variants in genes involved in the synthesis and metabolism of androgens may be associated with AV severity. In a large prospective study in 1252 Chinese participants, of which 600 had AV and 652 were healthy controls, single nucleotide polymorphisms of the CYP21A2 gene were significantly associated with severe AV, particularly in male patients (79). The CYP21A2 gene encodes the synthesis of steroid 21-hydroxylase, an enzyme necessary for the biosynthesis of adrenal steroid hormones (80). Individuals with genetic variants in CYP21A2 exhibit a higher production of adrenal androgen precursors compared to those without genetic variants (81,82). Increased androgen precursors may drive excess synthesis of androgens via classical or alternative pathways of androgen biosynthesis recently implicated in androgen-related disease states (83). However, further studies are needed to explore the precise mechanism by which genetic variants in CYP21A2 influence AV susceptibility, which may yield new therapeutic strategies for AV treatment.

5. Demographic factors in acne pathogenesis and treatment

There are differences in the presence of AV and associated disease characteristics based on race and ethnicity that are likely mediated by a plethora of factors, including genetic AR polymorphisms, variations in tissue sensitivity or responsiveness to androgens, and circulating hormone levels (84,85). Shorter CAG repeat lengths are observed in males of African vs European origin, indicating differences in the number of CAG repeats within the AR gene based on race (84). Although these differences are likely to influence both the predisposition toward developing AV and responsiveness to AV treatment, non-White and Hispanic individuals are often underrepresented or underreported in dermatologic clinical trials (86). Thus, increased efforts to improve clinical trial participant diversity will be necessary to better characterize the safety and efficacy of treatments for dermatologic disorders in patients of diverse racial and ethnic backgrounds.

6. Hormonal therapies in acne treatment

Hormonal agents currently in use for the treatment of AV in the US now include both systemic therapies (spironolactone, combined oral contraceptives [COCs]) and topical therapies (clascoterone cream 1%; Table 2). Spironolactone is an aldosterone receptor antagonist used off-label to treat AV in female patients that suppresses androgen activity both by decreasing testosterone production and by inhibiting their binding to ARs (1). Chronic use of spironolactone is associated with a potential risk of systemic adverse effects, most significantly gynecomastia (89), and is therefore not suitable for use in male patients. Spironolactone has been tested in several topical formulations, and recent findings suggest that topical spironolactone may be efficacious for AV treatment with fewer side effects compared with oral spironolactone (90,91); however, additional large randomized clinical trials in AV with this therapeutic strategy are needed, and no specific dose or formulation of topical spironolactone has been standardized or approved by the Food and Drug Administration (FDA) for use in clinical practice (91).

Table 2. Antiandrogen therapies currently available in the US for the treatment of acne vulgaris.

	Systemic therapies		Topical therapies
	Spironolactone	COCs	Clascoterone
Indication	Spironolactone is an aldosterone receptor antagonist that is used off-label for the treatment of acne vulgaris in female patients Contraindications: Addison’s disease, hyperkalemia, and concomitant use of eplerenone	COCs are indicated for the treatment of acne vulgaris in female patients who also desire contraception and are 14 years and older Contraindications: Pregnancy, risk of estrogen-sensitive malignancy, cardiovascular disease, migraines, hematologic disorders, smoking, and >35 years of age	Clascoterone is an AR inhibitor indicated for the topical treatment of acne vulgaris in patients 12 years of age and older Contraindications: None
Mechanism of action	Spironolactone is an aldosterone receptor antagonist that exhibits antiandrogenic activity through decreasing production of testosterone and preventing binding of androgens to ARs. It may also inhibit 5α-reductase	COCs exhibit antiandrogenic activity through the reduction of androgen synthesis by the ovaries, reduction of circulating levels of androgens, suppression of 5α-reductase, and AR blockade	Clascoterone is an AR inhibitor that is thought to compete with DHT for binding to ARs in the skin to attenuate signaling pathways involved in acne pathogenesis
Adverse effects/toxicities	Hyperkalemia: Monitoring of serum potassium is recommended Hypotension and worsening renal function Electrolyte and metabolic abnormalities Gynecomastia Impaired neurologic function in patients with hepatic impairment, cirrhosis, and ascites	Spotting Breast pain/tenderness Gastrointestinal disorders Headache Depression	Local irritation (most commonly erythema, pruritus, and scaling/dryness) HPA axis suppression was reported in a maximal-use study^a Hyperkalemia: Elevated potassium levels were observed in both clascoterone-treated and vehicle-treated patients during clinical trials^b
Limitations	Not suitable for use in male patients	Use is limited to female patients who also desire contraception	Combined treatment with clascoterone and other topical medications has not been evaluated

^aHPA axis suppression was observed in a maximal-use pharmacokinetic trial of clascoterone. All patients returned to normal HPA axis function at follow-up 4 weeks after the end of treatment. (87)

^bNo instances of elevated potassium levels were reported as AEs or resulted in study discontinuation in the clascoterone Phase 1 and Phase 2 studies. (88)

AE: adverse event; AR: androgen receptor; COC: combined oral contraceptive; DHT: dihydrotestosterone; HPA: hypothalamic-pituitary-adrenal.

COCs are available for the treatment of AV in female patients who also desire contraception and are over 14 years of age (1) but are similarly not suitable for use in male patients and may be associated with numerous systemic adverse effects (Table 2) (2). The mechanism of action of COCs in AV treatment is attributed to their antiandrogenic actions, which include decreasing androgen synthesis, suppressing 5α-reductase activity, and blocking the AR (1). The efficacy of COCs in AV treatment has been evaluated in numerous randomized clinical trials; evidence from these studies show that COCs are effective in reducing both inflammatory and noninflammatory acne lesions in female patients (1). In a recent study, female patients with AV exhibited significant reductions from pretreatment values in concentrations of testosterone, androstendione, and sex hormone binding globulin, along with reductions in AV severity following treatment with an oral contraceptive agent containing ethinyl estradiol and drospirenone (63). According to a recent meta-analysis, the efficacy of COCs varied widely across studies, with the highest efficacy observed for those containing ethinyl estradiol and chlormadinone acetate (92). Additional studies are needed to determine whether any COC consistently exhibits superior efficacy over other COCs in AV treatment.

Clascoterone cream 1% is a topical AR inhibitor that received FDA approval in 2020 for the treatment of AV in male and female patients 12 years of age and older (36) based on results of 2 identical, randomized, 12-week, Phase 3 studies (41) and one 9-month open-label extension study in patients with moderate-to-severe acne (93). Clascoterone reduces DHT-mediated sebum production and inflammation in vitro, supporting the hypothesis that it competes with androgens for binding to ARs to attenuate signaling pathways involved in AV pathophysiology (35). Clascoterone is rapidly metabolized by plasma esterases to the inactive metabolite cortexolone, resulting in limited systemic activity (94), and systemic effects associated with antiandrogens such as gynecomastia have not been observed in patients treated with clascoterone in Phase 3 or long-term extension studies (41,93). These findings from studies with clascoterone underscore the advantages of targeted inhibition of ARs within the skin for safe and effective treatment of AV in both male and female patients, and possibly for other androgenetic skin disorders such as androgenetic alopecia (87,88,95,96).

7. Conclusions and therapeutic implications

The understanding of the complex influences of hormones on the skin and their importance in the development of numerous skin conditions has advanced significantly in the past few decades. Overall, a combination of factors, including abnormalities in hormone levels, differences in androgen metabolism, increased sensitivity to effects of androgens within the skin, genetic variability, and demographic factors, appears to contribute to the pathophysiology of AV. Hormonal therapies are clinically efficacious in AV treatment, which is attributable, to a large extent, to their antiandrogenic actions. Importantly, the lack of a clear correlation between circulating hormone levels and AV disease activity suggests that the local production and/or activity of androgens within the skin is important in AV development and deserves further therapeutic attention. Clinical evidence from large-scale studies with clascoterone cream 1% demonstrates that topical antiandrogen therapy that exerts localized activity within the pilosebaceous regions of skin with limited systemic exposure allows for efficacious treatment of AV in both male and female patients while reducing the potential for systemic adverse effects. The addition of more targeted hormonal therapies to the armamentarium of AV treatment allows clinicians to effectively and safely address androgen-stimulated sebocyte activity and sebum production, a necessary early step in the process of AV lesion formation, in both male and female patients.

Acknowledgments

Manuscript preparation and editorial support were provided by Dana Lengel, PhD, of AlphaBioCom, a Red Nucleus company, and funded by Sun Pharma.

Disclosure statement

JDR has served as a research investigator, consultant, and/or speaker for Allergan, Almirall, Amgen, Arcutis, Bayer Healthcare Pharmaceuticals, Bausch Health (Ortho Dermatologics), Beiersdorf, Biorasi, Bristol Myers Squibb, Cassiopea, Celgene, Cutera, Dermavant Sciences, Dr Reddy, Eli Lilly, EPI Health, Evommune, Ferndale, Galderma, JEM Health, Johnson & Johnson, Journey, LEO Pharma, L’Oréal, Mayne Pharma, Novan, Sebacia, Sol-Gel, Sun Pharma, Strata, and Vyne. LK has served as an investigator, speaker, advisory board member, or consultant for 3 M, Abbott, Aclaris Therapeutics, Allergan, Amgen, Anacor Pharmaceuticals, Assos Pharmaceuticals, Astellas Pharma US, Asubio Pharma, Bayer Healthcare Pharmaceuticals, Berlex Laboratories (Bayer Healthcare Pharmaceuticals), Biogen, BioLife, Biopelle, Blue Willow Biologics, Boehringer Ingelheim, Breckenridge Pharmaceutical, Celgene Corporation, Centocor, ColBar LifeScience, CollaGenex Pharmaceuticals, Combimatrix Molecular Diagnostics, Connetics Corporation, Coria Laboratories, Dermik Laboratories, Dermira, Dow Pharmaceutical Sciences, DUSA Pharmaceuticals, Eli Lilly, Embil Pharmaceutical, EOS Pharmaceutical, Ferndale, Galderma, Genentech, GSK, Healthpoint, Idera Pharmaceuticals, Innocutis Medical, Innovail, Johnson & Johnson, Laboratory Skin Care, LEO Pharma, L’Oréal, Maruho, Medical International Technologies, Medicis Pharmaceutical, Merck, Merz Pharma, Novartis AG, Noven Pharmaceuticals, Nucryst Pharmaceuticals, Obagi Medical Products, Ortho Neutrogena, Pediapharma, Pfizer, PharmaDerm, Promius Pharma, PuraCap Pharmaceutical, QLT, Quatrix, Quinnova Pharmaceuticals, Serono (Merck-Serono International), SkinMedica, Stiefel Laboratories, Sun Pharma, Taro Pharmaceutical Industries, TolerRx, Triax Pharmaceuticals, UCB, Valeant Pharmaceuticals North America, Warner Chilcott, XenoPort, and ZAGE.

Data availability statement

Data sharing is not applicable to this article as no data sets were generated or analyzed during the current study.

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The author(s) reported there is no funding associated with the work featured in this article.