Homeostasis of sebaceous gland is androgen dependent so that secretion, differentiation and proliferation of sebocytes is closely interrelated with active androgen molecules such as dehydroepiandrosterone (DHEA), androstandione and testosterone in the skin  . In addition, testosterone, major circulating androgen, is converted intracellularly by 5-alpha reductase to dihydrotestosterone (5α-DHT), major tissue androgen . Androgens exerts their effects on sebaceous glands through binding to androgen nuclear receptors . Therefore, the term hormonal acne appears as intuitive as inflammatory acne as acne vulgaris is a disease of pilosebaceous unit which is essentially an endocrine organ.
Interestingly, keratinocytes demonstrate a distinguished role in androgens metabolism in the skin compare to that of sebocytes. Seemingly, catabolism of tissue-active androgens is more efficiently performed in keratinocytes in contrast to sebocytes which are capable of synthesizing androgen receptor binding and tissue-active compounds from the adrenal androgen DHEA, circulating in serum . Schematic model of interaction between androgens and other molecules in differentiation, proliferation and lipogenesis of sebocytes .
The human skin, especially the sebaceous gland is a sterioidogenic organ similar to the gonads and adrenal cortex, processing all the enzymes necessary for steroid sex-hormone synthesis and metabolism . This finding is evidenced by detecting sex-hormone gene expression in sebocytes. Immortalization of human sebocytes with SV40 antigen has allowed intensive investigation and advancement in our understanding of sebaceous gland function and homeostasis . Immortalized sebocytes express stereodogenic proteins, cofactors and transcription factors as evidenced by immunohistochemistry and western blot . De novo synthesis of androgens from cholesterol has been suggested by the same study.
Further evidence for androgenesis of sebocytes coming from isotretinoin studies that pertain serum DHT levels to sebocyte activity. Isotretinoin-produced depressions in the serum levels of DHT, believed to be the result, rather than the cause, of a reduction in the size of the sebaceous glands . This evidence explains the amount of tissue-derived androgens that sebaceous glands normally contribute to the circulating pool.
Moreover, synthesis of androgens by sebaceous glands can explain normal serum and urine level of these hormones in acne subjects . Dihydrotestosterone, the most potent androgen, is produced in sebaceous glands by 5-alpha-reduction of testosterone and mediates its effect by binding to its nuclear receptors. Sebaceous glands have receptors for many hormones and substances including nuclear receptors for androgens. Activation of these receptors is associated with differentiation, proliferation and lipid synthesis of sebocytes .
The activity of 5-alpha reductase varies according to its location. In sebaceous glands of facial and scalp regions this enzyme demonstrates more activity . This may explain the difference seen in severity of response seen with DHT on facial and non-facial sebocytes. Comparably, more exaggerated response has been experienced with DHT on facial sebocytes and a more modest impact on other regions of the body .
Effect of DHT on sebaceous lipogenesis either could not be seen or has been shown to be modest in vitro without presence of an additional cofactor . A peroxisome proliferator-activated receptor (PPAR) ligand such as linoleic acid has been postulated as a cofactor that can promote DHT-mediated lipogenesis. Known for their role in lipid biosynthesis, PPARs are nuclear receptors for hormones with alpha (mostly expressed in keratinocytes), gamma and delta (mostly expressed in sebocytes) subtypes .
Conversely, LY191704, a 5-alpha-reductase inhibitor has been shown to prevent influence of DHT on sebocytes through manipulation of PPAR . Finally, DHT exerts its effect on sebocyte differentiation through PPAR-gamma . Experimentally, rosiglitazone has been shown for having a synergistic effect with DHT in sebaceous cell differentiation .
Sebocytes differentiation after DHT treatment has been compared to that of thiozolidinedione. Synergistic effect of DHT and rosiglitazone is seen in very left column .