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.
Conclusion
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.
