News, Views, and Reviews. Cutaneous Hyperandrogenism: Role of AntiandrogenTherapy in Acne, Hirsutism, and Androgenetic Alopecia

November 2013 | Volume 12 | Issue 11 | Features | 1297 | Copyright © November 2013

Aimee Krausz BA and Adam J. Friedman MD

typically have systemic hyperandrogenism secondary to an adrenal or ovarian endocrinopathy, most commonly PCOS. Pharmacologic treatment of hirsutism with antiandrogen therapy is a commonly prescribed use of these medications. Meta-analysis of five trials of antiandrogen monotherapy for hirsutism showed significant hair reduction compared to placebo.43 No significant difference was observed between subgroups, making antiandrogen selection primarily based on patient preference and cost. Both antiandrogen and COC monotherapy were found equally effective,44 but the 2008 Endocrine Society Guidelines recommend COC as first line due to risks of pseudohermaphrodism in male fetuses with antiandrogens alone. Though COC and antiandrogen therapy together was more effective than COC alone, combination regimens should only be initiated after six months of suboptimal treatment with either agent alone. Guidelines recommend against GnRH agonists and flutamide due to toxic side effect profiles. Flutamide has less affinity for the androgen receptor than spironolactone and therefore higher doses are generally required. However, some researchers have reported doses as low as 62.5 mg/d of flutamide to be effective, thus limiting the risk of hepatotoxicity.38 Topical antiandrogens and insulin lowering drugs are also not recommended due to (inconsistent) data showing limited efficacy. Published guidelines are currently limited by poor quality evidence and larger randomized controlled trials are required for a more authoritative stance on the effectiveness of hormonal therapy for hirsutism.43

Androgenetic Alopecia

The hallmark of both male and female pattern baldness is follicular miniaturization with progressive shortening of the anagen phase. This leads to the transformation of terminal hairs into shorter, finer vellus hairs that fail to reach the scalp surface. Histological similarity does not necessarily confer a common etiology and while male pattern hair loss, appropriately referred to as male androgenetic alopecia (MAGA), has clearly been identified as an androgen mediated disease, the role of sex steroids in the female pattern is not well established. In addition, different prevalence rates, peak onset, and most importantly, the pattern of loss, are clinical evidence of their status as distinct entities.45
DHT is considered the main mediator of male pattern baldness.45 Evidence to support the central role of DHT stems from observations that individuals who lack the 5α reductase type II enzyme do not develop androgenetic alopecia,46 as well as studies showing an increased concentration of DHT in hairs plucked from balding scalps.47 Both AR expression and cellular levels of 5α reductase type II have been found to be increased in the bald frontoparietal scalp as compared to the occipital scalp, which explains why the occipital scalp is resistant to the effects of androgens.47 When treated with excess androgen, dermal papilla cells from a balding scalp lose their ability to stimulate keratinocyte proliferation and increase TGFβ secretion, a keratinocyte growth inhibitor. Genetic association studies have also highlighted AR genetic variation in the heritability of this complex, polygenic trait. A particular SNP found in the noncoding, exon 1 region of the AR gene is present in 100% of balding men and CAG and GGC polymorphisms in the amino terminal domain of the AR gene have been implicated with the risk of developing MAGA when shortened. Though neither mutation leads to an altercation in protein expression or function, these findings form the basis of the as yet controversial genetic susceptibility tests for pattern hair loss.48
The role of sex steroids in female pattern hair loss (FPHL) is less known and androgen excess is generally not a prerequisite for FPHL.45 Those with peripheral hyperandrogenism develop a male, not female, pattern of hair loss and there is conflicting results in the literature regarding the efficacy of antiandrogen therapy for women without overt hyperandrogenism.49 The pattern differences in MAGA and FPHL may be due to the influence of estrogens, which modify androgen metabolism at the hair follicle via inhibition of 5α reductase or conversion of testosterone to weaker androgens.33,50 Crashing levels of estrogen in the post pregnancy and menopausal states, and the accompanying hair loss, contribute to the suspicion that low levels contribute to FPHL. Topical estrogen therapy has been used outside the USA for the treatment of FPHL51 but efficacy has not been confirmed.
Finasteride 1mg/d is FDA approved for the treatment of MAGA. Conflicting reports on efficacy has led to the investigation of dutasteride, a dual type I and II 5a reductase inhibitor, which has shown increased potency in inhibiting both isozymes and can decrease serum DHT by more than 90%.49 Finasteride 1mg/d was found ineffective in postmenopausal women after 12 months of treatment52 and this study has been used to support the non-androgen nature of FPHL. However, the study did not evaluate premenopausal women and at higher doses and when combined with COC, finasteride has exhibited clinical efficacy.53 A topical preparation of 0.05% finasteride is being evaluated for both MAGA and FPHL.54 Spironolactone and cyproterone acetate are the most commonly prescribed antiandrogens for FPHL and have shown clinical efficacy,49,53 but larger randomized controlled trials are needed to fully assess the therapeutic potential of these agents. Topical spironolactone 2% solution has shown variable success when combined with minoxidil.33 A novel new topical antiandrogen, fluridil has shown efficacy in both MAGA and FPHL and though used throughout Europe, is currently awaiting FDA approval for use in the United States.


The pilosebaceous unit is not only influenced by androgens, but contributes to and regulates cutaneous androgen production. Increased local concentrations are thought to mediate the development of acne, hirsutism and androgenetic alopecia, which explains the well-established role of antiandrogen therapy in those disease states. Continued investigation into peripheral steroidogenesis will provide more targeted therapy for the treatment of androgen dependent dermatoses.