Spironolactone and Topical Retinoids in Adult Female Cyclical Acne

February 2014 | Volume 13 | Issue 2 | Original Article | 126 | Copyright © February 2014

Erin Lessner MD,a Samantha Fisher MD,b Katherina Kobraei MD,b Michael Osleber MD,b Rebecca Lessner BS,c Lauren Elliott MD,d and Stanton Wesson MDb

aDepartment of Ophthalmology, University of South Carolina, Columbia, SC
bDepartment of Dermatology, University of Florida, Gainesville, FL
cLincoln Memorial University, DeBusk School of Medicine, Harrogate, TN
dDepartment of Emergency Medicine, University of California San Diego, San Diego, CA

5α-dihydrotestosterone (DHT) receptors in human prostate and human skin.5 This binding likely plays a large role in its beneficial effects in dermatologic therapies and explains some of its potential side effects, such as decreased libido.
Animal studies have also shown spironolactone leads to destruction of cytochrome P-450 in the testicles and adrenal glands specifically, leading to a decrease in function of steroid hydroxylation. These effects lead to a decrease in both testicular testosterone formation as well as in plasma testosterone levels. Studies in humans have shown variable results in serum androgen levels. In women, spironolactone has been shown to decrease serum testosterone, while dehydroepiandosterone sulfate (DHEAS) levels either remain stable or decrease. Evaluation in males has shown either little or no decrease in serum testosterone levels. An increase in the clearance of testosterone has been demonstrated, shifting the ratio of testosterone to estrogen in favor of estrogen. This shift has been postulated to be the reason for the development of gynecomastia in males taking spironolactone.5
Aside from its effect on salt and water balance, the anti-androgenic effects of spironolactone account for its role in dermatology. Competitive inhibition of DHT in the skin as well as the variable effects on serum testosterone and DHEAS levels help modulate these hormones’ effects in androgenic driven skin conditions, including acne, hirsutism, and androgenic alopecia.

Spironolactone in Dermatology

The off-label use of spironolactone in dermatology has been a growing area of therapeutics in the management of female cyclical acne and female pattern hair loss. The use of spironolactone as a first line agent for treatment of hirsutism and PCOS has been reviewed in the literature.5,6,7 The appeal of utilizing spironolactone for these applications include its long-term safety, increasing data supporting efficacy, and relative lack of side effects, making spironolactone an attractive alternative to those failing traditional therapy or as a primary treatment.

Female Cyclical Acne

Although acne is typically thought of as a disorder of adolescents, there is a significant number of women that continue to struggle with acne into adulthood, and a large subset of women that present with new onset acne in their mid 20s and 30s. These patients classically present with worsening of their acne around menstruation, inflammatory papules and pustules, occasionally nodules or cysts on their lower face and neck, corresponding to the “beard area” in men. We typically describe this subset of patients as having “female cyclical acne” in our practice. These patients are therapeutically challenging as they typically present having failed multiple traditional treatments. In a study evaluating the features of post-adolescent acne in which 76% of the patients were women, 82% of the patients had failed to respond to multiple courses of antibiotics and as high as 32% relapsed after treatments with one or more courses of isotretinoin.8
The role of androgens and their effect on the sebaceous gland in increasing sebum production and causing follicular hyperkeratinization have been implicated in driving this subtype of acne, and therefore the therapeutic use of androgen receptor blocker medications such as spironolactone have been increasingly utilized in the treatment of hormonal acne. Studies have shown 30-50% reduction in sebum excretion with spironolactone administration.9,10 The majority of women that present with female cyclical acne have normal systemic androgen levels; therefore the comedogenic effects of androgens are hypothesized to occur on the pilosebaceous units as a local imbalance of the androgen metabolism. Alternatively androgen receptor polymorphisms may cause local sensitivity to androgens, as well as abnormal post binding responses.11,12
In the literature there have been two randomized control trials and several uncontrolled studies reporting the efficacy of spironolactone in the treatment of acne in women, with all studies showing 50-100% improvement in acne. In the a recent retrospective review of the evaluation of the therapeutic effect of spironolactone in acne, efficacy was seen even in lower doses (50-100mg/day) with complete clearance or marked improvement in 66% of patients. 10,13,14,15,16,17 Studies have shown that clinical response can take up to 3 months, which is similar to other hormonal treatments.18

Adverse Effects

Common Side Effects

Spironolactone is generally well tolerated in the lower doses prescribed in dermatology (50-100 mg daily). Reported side effects include breast tenderness, urinary frequency, menstrual irregularities, hyperkalemia, fatigue, headache, dizziness, lethargy, hypotension, and birth defects. Menstrual irregularities may be minimized with the use of concomitant oral contraceptive pills. Mid-cycle spotting is among the most common irregularities.19 The most dreaded side effect is hyperkalemia, which in most healthy patients, is clinically insignificant.20,21 Approximately 13.7% of patients will experience detectable increases in their serum potassium levels.22
Other reported serious adverse effects include spironolactone- induced hepatitis.23 In addition, DRESS syndrome from spironolactone has also been reported.24 As mentioned earlier, gynecomastia has been reported in patients undergoing treatment for acne with spironolactone, developing within the first few months of treatment.21,25,26

Malignancy Potential

Although theoretically possible, estrogen-dependent malignancies have not been substantiated. Rodents given 25-250 times the usual human dose developed proliferative tumors such as benign thyroid and testicular adenomas, and malignant breast