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

Figures & data

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.

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.

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.

Elsaie ML. Hormonal treatment of acne vulgaris: an update. Clin Cosmet Investig Dermatol. 2016;9:241–248. doi: 10.2147/CCID.S114830.

 PubMed Web of Science ®Google Scholar

Dart DA. Androgens have forgotten and emerging roles outside of their reproductive functions, with implications for diseases and disorders. J Endocr Disord. 2014;1(1):1005.

 Google Scholar

Lynn DD, Umari T, Dunnick CA, et al. The epidemiology of acne vulgaris in late adolescence. Adolesc Health Med Ther. 2016;7:13–25. doi: 10.2147/AHMT.S55832.

 PubMed Web of Science ®Google Scholar

Leyden JJ. A review of the use of combination therapies for the treatment of acne vulgaris. J Am Acad Dermatol. 2003;49(3 Suppl):S200–S210. doi: 10.1067/s0190-9622(03)01154-x.

 PubMed Web of Science ®Google Scholar

Kim YJ, Lee SB, Lee HB. Oleic acid enhances keratinocytes differentiation via the upregulation of miR-203 in human epidermal keratinocytes. J Cosmet Dermatol. 2019;18(1):383–389. doi: 10.1111/jocd.12543.

 PubMed Web of Science ®Google Scholar

Li WH, Zhang Q, Flach CR, et al. In vitro modeling of unsaturated free fatty acid-mediated tissue impairments seen in acne lesions. Arch Dermatol Res. 2017;309(7):529–540. doi: 10.1007/s00403-017-1747-y.

 PubMed Web of Science ®Google Scholar

Elias PM, Brown BE, Ziboh VA. The permeability barrier in essential fatty acid deficiency: evidence for a direct role for linoleic acid in barrier function. J Invest Dermatol. 1980;74(4):230–233. doi: 10.1111/1523-1747.ep12541775.

 PubMed Web of Science ®Google Scholar

Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016;74(5):1–9. doi: 10.1016/j.jaad.2015.12.037.

 PubMed Web of Science ®Google Scholar

Rosette C, Agan FJ, Mazzetti A, et al. Cortexolone 17alpha-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(5):412–418.

 PubMed Web of Science ®Google Scholar

WINLEVI® (clascoterone cream 1%). Prescribing information. Cranbury (NJ): Sun Pharmaceutical Industries, Inc.; 2022.

 Google Scholar

Borzyszkowska D, Niedzielska M, Kozłowski M, et al. Evaluation of hormonal factors in acne vulgaris and the course of acne vulgaris treatment with contraceptive-based therapies in young adult women. Cells. 2022;11(24):4078. doi: 10.3390/cells11244078.

 PubMed Web of Science ®Google Scholar

Zhang R, Zhou L, Lv M, et al. The relevant of sex hormone levels and acne grades in patients with acne vulgaris: a cross-sectional study in Beijing. Clin Cosmet Investig Dermatol. 2022;15:2211–2219. doi: 10.2147/CCID.S385376.

 PubMed Web of Science ®Google Scholar

Sardana K, Bansal P, Sharma LK, et al. A study comparing the clinical and hormonal profile of late onset and persistent acne in adult females. Int J Dermatol. 2020;59(4):428–433. doi: 10.1111/ijd.14748.

 PubMed Web of Science ®Google Scholar

Bansal P, Sardana K, Sharma L, et al. A prospective study examining isolated acne and acne with hyperandrogenic signs in adult females. J Dermatolog Treat. 2021;32(7):752–755. doi: 10.1080/09546634.2019.1708245.

 PubMed Web of Science ®Google Scholar

Shrestha S. Correlation of hormonal profile and lipid levels with female adult acne in a tertiary care center of Nepal. J Nepal Health Res Counc. 2018;16(2):222–227. doi: 10.33314/jnhrc.v16i2.1178.

 PubMedGoogle Scholar

Cappel M, Mauger D, Thiboutot D. Correlation between serum levels of insulin-like growth factor 1, dehydroepiandrosterone sulfate, and dihydrotestosterone and acne lesion counts in adult women. Arch Dermatol. 2005;141(3):333–338. doi: 10.1001/archderm.141.3.333.

 PubMed Web of Science ®Google Scholar

Thiboutot D, Gilliland K, Light J, et al. Androgen metabolism in sebaceous glands from subjects with and without acne. Arch Dermatol. 1999;135(9):1041–1045. doi: 10.1001/archderm.135.9.1041.

 PubMedGoogle Scholar

Mazzetti A, Moro L, Gerloni M, et al. 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.

 PubMed Web of Science ®Google Scholar

US Food and Drug Administration, Center for Drug Evaluation and Research. Clascoterone cream 1% NDA 213433 multidisciplinary review and evaluation. 2019. https://www.fda.gov/media/142578/download.

 Google Scholar

Data availability statement

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