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 acneâ€
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
