in sebum composition are also observed in patients with acne and could contribute to the pathogenicity of sebum.5 In order of abundance, human sebum mainly consists of esters of glycerol, wax, free fatty acids, squalene, and cholesterol.10,11 Sebum analysis conducted in individuals with and without acne suggests that patients with acne generally have higher levels of squalene, and especially its pro-inflammatory oxidation byproducts,12 and less linoleic acid in their sebum relative to patients without acne.5,10,11,13,14 Triglycerides, lipoperoxides, and free fatty acids can promote C. acnes proliferation and inflammation by activation of the peroxisome proliferator-activated receptors signaling pathway.7
Role of Androgens in Acne
Testosterone and dihydrotestosterone (DHT) are produced by the testes or ovaries, adrenal glands, and locally within the pilosebaceous unit.4,15 Testosterone produced by the testes is converted to DHT by 5α-reductase.4 The ovaries release estrogen, progesterone, and androstenedione; androstenedione is first converted to testosterone, then to DHT by 5α-reductase.16 Testosterone and DHT bind to androgen receptors in the pilosebaceous unit15; the androgen-receptor complex dimerizes and translocates to the cell nucleus,15 where it promotes the expression of genes involved in the production of sebum and inflammatory cytokines.4,15
Ample evidence supports the role of androgens in acne pathogenesis in both male and female patients.4,5 Some people with acne have elevated serum androgen levels, and the conversion of testosterone to DHT is more rapid in skin affected by acne relative to unaffected skin.17,18 Patients with medical conditions characterized by high androgen levels, or patients receiving testosterone replacement therapy or anabolic steroids, are also prone to develop acne.5 Acne is also a clinical manifestation of hyperandrogenism caused by polycystic ovary syndrome, congenital adrenal hyperplasia, and androgen-secreting tumors.5,19,20 Acne without evidence of hyperandrogenism may be attributable to hypersensitivity of the androgen receptor21; in a prospective clinical study conducted between 2016 and 2017 in patients with severe and very severe acne (n = 199), there was a significant association between a CAG repeat polymorphism in the androgen receptor and nodulocystic acne in women without hormonal imbalance and hirsutism.21 In support of the hypothesis that adequate control of androgen-stimulated sebum production can contribute to the success of acne treatment, oral contraceptives including combinations of ethinyl estradiol/drospirenone, ethinyl estradiol/desogestrel, ethinyl estradiol/chlormadinone, or ethinyl estradiol/cyproterone acetate can significantly reduce sebum excretion while improving several skin parameters (numbers of acne lesions, epidermal barrier function, pore size, and sebum production) in patients with acne.22-25 Spironolactone (50-200 mg daily) also reduces sebum production in patients with severe acne.26 Furthermore, acne remission was accompanied by reduced sebum excretion rates in a prospective study of patients with moderate to severe acne (n = 30) receiving isotretinoin treatment.27
The traditional anti-androgen therapies for acne include 4 combined oral contraceptive pills approved by the FDA for acne treatment in adult women who desire contraception. Spironolactone and flutamide are also used off-label for acne treatment due to their anti-androgenic properties. None of these are suitable for male or pregnant patients due to systemic anti-androgenic effects.1 Acne therapies targeting this pathway may take time to result in improvement. Spironolactone efficacy has generally been evaluated only after 12 weeks,28 and improvements in acne with oral contraceptives also take time, with significant effects usually observed after at least 3 cycles (28-day cycle, in a 24/4-day regimen).1,29-31
Current Acne Guidelines and Their Limitations
The AAD guidelines recommend a combination of multiple agents to target different aspects of acne pathogenesis as the first line of treatment.1 Topical agents are recommended as the foundational treatment across all degrees of acne severity and may be used as monotherapy or in combination with other topical or oral treatments to address the different components of acne pathogenesis.1 Based on the degree of acne severity, topical medications recommended for patients with mild and moderate acne include benzoyl peroxide, antibiotics, retinoids, and dapsone; topical azelaic acid is considered a useful adjunctive therapy, especially for the treatment of postinflammatory dyspigmentation.1 For patients with moderate to severe acne, a combination of topical therapy plus oral medications, including oral contraceptives or spironolactone in female patients is recommended, with oral isotretinoin reserved for the most severe or refractory cases.1
Unfortunately, although topical medications are the mainstay of acne treatment, none of those currently recommended by the guidelines address all 4 key factors of acne pathogenesis32; in fact, no topical medications target excess sebum production.32 Among oral medications, hormonal therapy can successfully moderate sebum production and related inflammation but has no direct effect on hyperkeratinization and C. acnes colonization; isotretinoin is the only treatment that can act on all 4 contributors to acne pathogenesis.1,32 Although these systemic treatment options can be effective, they are not suitable for all patients. Isotretinoin is teratogenic and is contraindicated in patients who are pregnant and those who can become pregnant and are not willing to take contraceptives.1,32 Hormonal therapies are not recommended for men, pregnant or lactating patients, and women ≥35 years old who are heavy smokers, and they are not advisable in patients receiving testosterone.1,32,33 Spironolactone is associated with adverse effects including diuresis, menstrual
