This manuscript serves to review the diverse roles of androgens in skin, regulation of sebocyte activity by androgen receptors in health and disease, fluctuation in androgen receptors during puberty in both genders, differences in androgen receptors based on genetic and ethnic variables, and factors influencing clinical presentations of androgen-sensitive skin disorders, with emphasis on AV. Therapeutic agents that target androgen activities and hormonal aspects of skin diseases are also summarized, including discussion of sebaceous glands, sebocytes, and sebum. An important disclaimer is that information on androgen physiology and pathophysiology, including androgen receptor functionality, local tissue variability, gender differences, impact of genetic polymorphisms, ethnic/ race-related variables, enzyme function and tissue distribution, and androgen-related disease pathophysiology are “moving targetsâ€. As a result, the information presented here is based on our best interpretation of available data at this time. It is important that the reader maintain an open mind as new research information is sure to develop and can alter our understanding of specific aspects of this subject.
Androgen Receptors and Skin
Androgens elicit their physiologic activity through androgen receptors (AR), which are located primarily in epidermal and follicular keratinocytes of the hair follicle outer root sheath, dermal papilla cells, the basal layer of the sebaceous gland, and dermal fibroblasts.2,3,5
The AR is a soluble molecule compartmentalized in cytoplasm and complexed with specific heat shock proteins (HSPs).1 When an androgen (ie, DHT, T) ligands with the AR, dissociation of the AR from the HSP complex occurs leading to transport of the AR-ligand to the nucleus. Within the nucleus, the AR can then interact with specific response elements located in the promoter regions of androgen-regulated genes resulting in elicitation of signaling cascades that produce clinical effects.1,2 The direct relationship between androgen stimulation, sebaceous gland proliferation and activity, and sebum production suggests that the AR is an important therapeutic target for AV treatment, as well as other androgen-related cutaneous disease states.1,2,4,8
Cutaneous Metabolism of Androgens
It would simplify our understanding of this subject if the relationship between androgens and their physiologic and/ or pathologic effects via ARs related only to the concentration of circulating androgens. However, this is not the only factor. In fact, androgen physiology is a complicated subject that is at present only partially understood. Serum levels of T do not necessarily correlate uniformly with sebaceous gland activity and despite markedly higher levels of serum T in males versus females, sebum secretion rates are only slightly higher in males overall, with marked overlap noted between genders.5,9 The majority of females with AV exhibit serum androgen levels that trend higher than in females without AV, but are still within normal levels.5,10 It has also been shown that preadolescent girls exhibiting early onset of AV exhibit higher circulating levels of DHEA-S, but not free and total T levels or serum concentrations of several other sex steroid hormones (ie, estrogen, progesterone), as compared to those without AV; this supports the importance of interindividual variability and differences in activity among various androgens.11 The influence of local tissue synthesis of major androgens at different anatomic sites, affected also by genetic and age-related factors, appears to play an important role.1,2,5,7,9 Therefore, the local synthesis and enzymatic degradation of androgens within skin warrants attention as correlations with pathophysiology or therapeutic approaches are likely to be relevant.
Multiple enzymes appear to be operative in the metabolism of androgens within skin, with the three major enzymes within sebaceous glands reported to be 3β-hydroxysteroid dehydrogenase type 1 (3β-HSD), 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD) and 5α-reductase (type 1).2,5,9 The relative presence and/or activity of these enzymes and their isoforms can vary in anatomic distribution and clinical significance. For example, 17β-HSD, located within the pilosebaceous unit and epidermal keratinocytes exists in multiple isoforms, with some increasing the reductive formation of active androgens (types 1, 3, 5), whereas other isoforms of 17β-HSD (types 2, 4) inactivate potent androgens via oxidation.2 Interestingly, the face has been shown to exhibit greater 17β-HSD reductive isoform activity within sebaceous glands than in non-acne prone skin sites which supports greater local androgen production on facial skin.2 Human sebaceous glands exhibit the cellular capability to transcribe genes required to incite both the reductive and oxidative isoforms of 17β-HSD which allows for the onset or offset of androgen production locally; variations in 17β-HSD isoform activity also exists within outer root sheath of hair follicles.2 The multiplicity of enzyme isoforms and their functions demonstrates that skin tissues are dynamic, and have the localized potential to either increase androgen activity or protect against excessive androgenic effects.
Table 1 summarizes the enzymes involved in androgen metabolism within skin. It is important to recognize that the activity of these enzymes is not fixed in relative magnitude or within anatomic sites among different individuals which explains the heterogenous presentations of androgen activities within “normal†populations and between various disease states.
Androgens, Sebaceous Glands, and Androgen Receptor Functionality
The androgens DHT and T are the predominant agents that stimulate sebaceous gland development, sebocyte proliferation, and sebum production via AR interactions, with
Androgen Receptors and Skin
Androgens elicit their physiologic activity through androgen receptors (AR), which are located primarily in epidermal and follicular keratinocytes of the hair follicle outer root sheath, dermal papilla cells, the basal layer of the sebaceous gland, and dermal fibroblasts.2,3,5
The AR is a soluble molecule compartmentalized in cytoplasm and complexed with specific heat shock proteins (HSPs).1 When an androgen (ie, DHT, T) ligands with the AR, dissociation of the AR from the HSP complex occurs leading to transport of the AR-ligand to the nucleus. Within the nucleus, the AR can then interact with specific response elements located in the promoter regions of androgen-regulated genes resulting in elicitation of signaling cascades that produce clinical effects.1,2 The direct relationship between androgen stimulation, sebaceous gland proliferation and activity, and sebum production suggests that the AR is an important therapeutic target for AV treatment, as well as other androgen-related cutaneous disease states.1,2,4,8
Cutaneous Metabolism of Androgens
It would simplify our understanding of this subject if the relationship between androgens and their physiologic and/ or pathologic effects via ARs related only to the concentration of circulating androgens. However, this is not the only factor. In fact, androgen physiology is a complicated subject that is at present only partially understood. Serum levels of T do not necessarily correlate uniformly with sebaceous gland activity and despite markedly higher levels of serum T in males versus females, sebum secretion rates are only slightly higher in males overall, with marked overlap noted between genders.5,9 The majority of females with AV exhibit serum androgen levels that trend higher than in females without AV, but are still within normal levels.5,10 It has also been shown that preadolescent girls exhibiting early onset of AV exhibit higher circulating levels of DHEA-S, but not free and total T levels or serum concentrations of several other sex steroid hormones (ie, estrogen, progesterone), as compared to those without AV; this supports the importance of interindividual variability and differences in activity among various androgens.11 The influence of local tissue synthesis of major androgens at different anatomic sites, affected also by genetic and age-related factors, appears to play an important role.1,2,5,7,9 Therefore, the local synthesis and enzymatic degradation of androgens within skin warrants attention as correlations with pathophysiology or therapeutic approaches are likely to be relevant.
Multiple enzymes appear to be operative in the metabolism of androgens within skin, with the three major enzymes within sebaceous glands reported to be 3β-hydroxysteroid dehydrogenase type 1 (3β-HSD), 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD) and 5α-reductase (type 1).2,5,9 The relative presence and/or activity of these enzymes and their isoforms can vary in anatomic distribution and clinical significance. For example, 17β-HSD, located within the pilosebaceous unit and epidermal keratinocytes exists in multiple isoforms, with some increasing the reductive formation of active androgens (types 1, 3, 5), whereas other isoforms of 17β-HSD (types 2, 4) inactivate potent androgens via oxidation.2 Interestingly, the face has been shown to exhibit greater 17β-HSD reductive isoform activity within sebaceous glands than in non-acne prone skin sites which supports greater local androgen production on facial skin.2 Human sebaceous glands exhibit the cellular capability to transcribe genes required to incite both the reductive and oxidative isoforms of 17β-HSD which allows for the onset or offset of androgen production locally; variations in 17β-HSD isoform activity also exists within outer root sheath of hair follicles.2 The multiplicity of enzyme isoforms and their functions demonstrates that skin tissues are dynamic, and have the localized potential to either increase androgen activity or protect against excessive androgenic effects.
Table 1 summarizes the enzymes involved in androgen metabolism within skin. It is important to recognize that the activity of these enzymes is not fixed in relative magnitude or within anatomic sites among different individuals which explains the heterogenous presentations of androgen activities within “normal†populations and between various disease states.
Androgens, Sebaceous Glands, and Androgen Receptor Functionality
The androgens DHT and T are the predominant agents that stimulate sebaceous gland development, sebocyte proliferation, and sebum production via AR interactions, with
