Treating Acne Vulgaris: Systemic, Local and Combination Therapy

Laura J Savage; Alison M Layton

Disclosures

Expert Rev Clin Pharmacol. 2010;13(4):563-580. 

In This Article

Androgen Receptor Blockers

Sebum production can be suppressed by anti-androgen agents including CPA, spironalactone, dropirenone and flutamide. The degree of reduction in seborrhea is drug and dose dependent.[106–108]

Cyproterone Acetate

Cyproterone acetate is a progestional anti-androgen that directly inhibits the androgen receptor. While not available in the USA, it is widely prescribed in an oral contraceptive formulation in Europe for the treatment of acne (Dianette® [Schering Health Care Ltd, Sussex, UK] and Estelle 35® [Douglas Pharmaceuticals Ltd, Auckland, New Zeland]).[106–108] Co-cyprindol combines 2 mg CPA with 35 µg ethinyl estradiol and it has been suggested that the higher amount of estrogen in these agents carries a greater potential for VTE compared with conventional lower estrogen-containing COCs.[109] However, evidence for adverse effects of co-cyprindol concerning higher VTE risk suggests it is no greater than with third-generation COCs.[110,111] This would suggest that co-cyprindol can be continued safely once acne control has been achieved. A recent study also confirmed that increased VTE risk is less likely after prolonged use of second- and third-generation COCs.[111]

Co-cyprindol reduces sebum production by no more than 30%, but its success in acne is enhanced by its direct effects on androgen-medicated comedogenesis.[112] It is as effective as oral tetracycline (1 g/day) given over a 6-month period, although it is slower in action.[113] It is therefore of potentially beneficial to females with acne are resistant to other therapies. An overall improvement in acne has been reported in up to 90% of patients treated with higher doses of CPA (50–100 mg/day), with or without ethinyl estradiol.[114,115] The clinical effectiveness of co-cyprindol can therefore be enhanced by prescribing an extra 50–100 mg CPA from day 5 to 14 of the menstrual cycle.

In males, 25 mg CPA has been demonstrated to improve acne, although its success is constrained by unacceptable feminization effects, such as reduced libido, gynecomastia and azoospermia. Therefore, it is only recommended as a treatment for female acne.[116] General side effects of CPA, although uncommon, include fatigue, headache, nausea, weight fluctuation, liver dysfunction and blood clotting abnormalities.[13]

Spironalactone

Spironalactone has inhibitory actions on both the androgen receptor and 5α-reductase. It is an effective treatment for acne and can reduce sebum production by 30–75% depending on the dose.[117–120] It is usually prescribed at a dose of 50–100 mg daily with meals, but many women with sporadic outbreaks can be successfully managed with as little as 25 mg daily.[120] Despite a consensus on the clinical benefit observed with spironalactone, there is a surprising paucity of data to confirm its efficacy in acne.[121] In one study of 85 women with acne, 93% demonstrated at least partial improvement in their acne, with 66% showing a marked improvement or complete clearance.[122] As with other hormonal therapies, response is slow and it may take up to 3 months of continuous treatment before any benefit is observed.[123]

Spironalactone is not without side effects, although these are largely dose dependent. Menstrual irregularities, potential hyperkalemia, breast tenderness, fatigue, headache, fluid retention and, rarely, melasma have been observed. Animal studies have reported an association with breast carcinoma in rodents but this has not been replicated in human studies.[124] Owing to the potential for feminization effects, spironalactone should not be prescribed for male patients and females should be advised to avoid pregnancy owing to potential abnormalities to the male fetus. All patients should undergo regular monitoring of their electrolytes owing to the potassium-retaining effects on the kidney.

Flutamide

Flutamide is a nonsteroidal potent androgen antagonist, most routinely used in the treatment of prostate cancer. It has been demonstrated to be efficacious in treating androgen-mediated acne and hirsutism when administered at a dose of 125–250 mg daily. Calaf et al. demonstrated significant reductions in acne severity score and hirsutism in 119 women with polycystic ovarian syndrome who were randomized to receive flutamide plus COC and compared with placebo at 6 and 12 months.[125] In a comparative trial between flutamide and spironalactone, Cusan et al. reported superior efficacy with flutamide with reducing total acne count and seborrhea level at 3 months.[126] However, given that spironalactone takes this period to clinically improve acne, few conclusions can be drawn regarding the overall superiority of flutamide. Like all hormonal agents, it should not be prescribed for male patients and owing to the risks of teratogenicity, pregnancy should be avoided.

In terms of safety, fatal hepatotoxicity has been reported with flutamide and, therefore, its use in acne is not widely advocated in the UK.[127] Initial warnings of hepatotoxicity were departed from patients using doses of 750 mg daily and reported prior to any dose-response studies being undertaken.[128] As a result, doses of 250–500 mg daily became the primary recommendation for women with androgen excess.[129] Recent studies allude to the incidence of hepatic impairment being dose dependent in women with androgen excess, with minor toxicity occurring relatively frequently (~3%) in the dosing range of 250–500 mg/day.[130,131] Whilst most cases are minor, prescribers should be aware that one case of fatal liver failure has been reported in a female taking no more than 250–375-mg flutamide daily,[132] and many countries now prohibit the prescription of flutamide as a treatment for androgen-mediated acne and hirsutism.

The use of lower doses of flutamide is currently under investigation. No cases of hepatic impairment with flutamide doses of 125 mg/day or less have been reported, and placebo-controlled data suggest that lower doses may be as effective as 250–375 mg/day in antagonizing androgen production in females, especially when combined with a drospirenone-containing contraceptive.[133] However, given the severity of flutamide-related adverse events, the safety and efficacy of low-dose (50–125 mg/day) flutamide must be demonstrated through large randomized multicenter trials. Therefore, authors the will not recommend the use of flutamide in females with androgen excess until such data are available.

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