Androgen Metabolism and the Androgen Receptor

Androgen metabolism comprises glandular and extraglandular production, transport, target cell metabolism, and cellular response.

The androgen metabolism pathway begins with pregnenolone, a 21 carbon steroid substrate, converted from cholesterol. Testosterone is the major circulating androgen. In women, systemic levels of testosterone are low compared with men, but the more abundant weak androgens serve as a source of precursors for potent androgens, which provide the physiologic or pathophysiologic androgen activity. Only a small fraction of androgens exists as free steroids in the circulation, with an equilibrium between free hormones and protein-bound androgens. The most important protein for androgen binding is sex-hormone binding globulin (SHBG). Normally 70% of testosterone is bound to SHBG, and 19% to albumin. The remainder is circulating unbound. Inmost target organs testosterone can be metabolized to DHT by the enzyme steroid 5a-reductase. Based on its affinity for the androgen receptor, DHT is fivefold more potent than testosterone. DHT is implicated in the pathogenesis of several disorders, including benign prostatic hyperplasia, prostate cancer, hirsutism, acne vulgaris, and AGA.

The skin and pilosebaceous unit are enzymatically equipped for local metabolism and conversion of sex steroids (Kaufman, 1996). The skin is capable of synthesizing active androgens from the systemic precursor DHEA sulfate (DHEA-S). Remarkably, some target tissues, such as the hair follicle, show enhanced androgen metabolism and androgen sensitivity. The activity of enzymes involved in androgen metabolism within the skin has been studied in a variety of tissue preparations.  More recently, both men and women with AGA were shown to have higher levels of 5a-reductase enzyme activity in frontal follicles than in their own occipital follicles, whereas higher levels of aromatase were found in their occipital follicles (Sawaya and Price, 1997).  

Androgen receptor (AR): Finally, the absence of balding in individuals with very high levels of free testosterone, induced by the androgen-insensitivity syndrome who lack functional AR clearly demonstrates the need for AR for AGA to occur (Quigley, 1998). All steroid hormones act by diffusing through the plasma membrane into the target cell and binding to specific intracellular receptors. The AR is believed to be responsible for determining the sensitivity of cells to androgens. Expression of the AR has also been found to be increased in balding scalp (Randall et al., 1992; Sawaya and Price, 1997). Most recently, polymorphism of the AR gene has been found to be associated with male pattern baldness (Ellis et al., 2001).

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