Skin as an Endocrine Organ
The historical picture of the skin as a simple end target for hormones
has been replaced by a more complex understanding of
its role as an independent endocrine organ.1 The skin possesses
full enzymatic capacity for the cutaneous synthesis and metabolism
of hormones via cell specific expression of enzymes.2 Newly
synthesized hormones act in a paracrine and intracrine fashion
and exert increased local activity independent of systemic levels.
This localization of effect has been extensively studied with regard
to androgens as a means of understanding how androgen
mediated disorders seem to occur even in patients with normal
circulating hormone levels. Though cutaneous steroidogenesis
is modest, less than 1% of total synthesis, it is this local overproduction
and increased receptor sensitivity that have been
implicated in androgen-dependent dermatoses.3-5
Steroidogenic Activity of Skin
Growing interest in dermato-endocrinology has led to the identification of multiple hormones, receptors and classical steroidogenic enzymes in skin.5 The on-site synthesis of hormones, termed “intracrinology†is thought to contribute to the cutaneous hyperandrogenism mediating androgen-dependent diseases.6,7 The skin, especially the pilosebaceous unit, is capable of synthesizing cholesterol de novo from acetate and expresses the steroidogenic acute regulatory protein (StAR) which controls the translocation of cholesterol from the outer to inner mitochondrial membrane necessary for the initiation of steroid synthesis. In addition, transcription factors regulating steroidogenesis in classical organs, such as SF-1, DAX-1, and WT-1 have been detected in skin.4,8 However, skin cells do not typically initiate the process of sex hormone synthesis and are more involved in the peripheral conversion of adrenal prohormones into testosterone and DHT, the main androgens active in skin. This occurs due to expression of key regulatory enzymes by sebocytes, dermal papilla cells and sweat glands, with sebocytes acting as the main regulators of local steroid activity.9,10 Steroid sulfatase, 3βHSD, 17βHSD3 and 5α reductase are involved in androgen synthesis, whereas 17βHSD2, 3α HSD and aromatase are counter regulators and suppress local activity.7 The mechanistic significance of these enzymes has yet to be determined and future research lies in designing specific inhibitors of androgen metabolizing enzymes in skin, such as those targeting 5α reductase.Androgen-Dependent Dermatoses
The clinical association of hyperandrogenism with acne,
hirsutism and androgenetic alopecia, and the efficacy of antiandrogen
therapy have reinforced the pathogenic role of
androgens in these disease states. Testosterone and DHT are
the main androgens that interact with the androgen receptor
(AR) found on sebaceous glands and the dermal papilla cells
of the hair follicle. DHT is peripherally converted from testosterone
via 5α reductase, which is found in two isoforms; type I
is primarily expressed by sebocytes while type II is expressed
in hair follicles.11,12 Expression of type III 5α reductase was also
recently found in sebocyte cell lines, but the physiologic significance
is unknown.11 The prime target of androgens is the
pilosebaceous unit, starting with the mediation of vellus follicles
into sexual hair follicles and sebaceous glands at puberty.
This differentiation is location specific; in the forehead and
cheeks androgen excess stimulates sebaceous gland hyperplasia
while in the axilla, genitalia and face it leads to terminal
hair differentiation.13,14 The follicular response to androgen
stimulation is not consistent and, paradoxically, androgen
binding can cause miniaturization of the hair follicle, rather
than growth, in the vertex of genetically susceptible individuals.
If transplanted to a different site, those vertex hairs will
continue to miniaturize, while occipital hairs transplanted to
the vertex will maintain their androgen insensitivity.15,16 This
phenomenon, known as ‘donor dominance,’ emphasizes how
the intrinsic sensitivity and distribution of the androgen receptor
contributes to disease pathogenesis. The site-specific
pattern is proposed to occur due to the activation of different
second messengers; IGF-1 induces sexual hair growth while
TGFβ exerts an opposite effect and suppresses growth on the
genetically predisposed frontal and vertex scalp.17 In addition,
the presence of coactivators of AR in the bald frontal scalp as
opposed to the occipital scalp can explain the location specific
response of the hair follicle to androgens.
Hormonal Therapy
Therapies designed to suppress the effects of androgen stimulation have been utilized off-label for acne, hirsutism and androgenetic alopecia. Only combined oral contraceptives (COC) have been FDA approved for acne, but other agents are widely used in clinical practice as well. Table 1 summarizes the mechanism of action and evidence based recommended dosages of these agents. Larger controlled studies are still required to formulate explicit guidelines defining usage of these medications.Acne, Sebocytes, and Androgens
Androgen receptors localized to the basal layer of sebocytes are
found in the highest density in human skin. With the onset of
puberty, systemic and locally derived testosterone and DHT increase
sebum production via AR binding and are also implicated
