Figure 1 shows the three principal ways in which testosterone can interact at target sites. In many target tissues, typified by the skeletal muscle, unmodified testosterone interacts with the androgen receptor (AR) to bring about the appropriate biological responses.
Fig1. Testosterone action pathways. In many target tissues of androgens, typified by the skeletal muscle, testosterone (T) is the molecule that interacts with the androgen receptor (AR) to generate biological responses. In other tissues, of which the hair follicles of the skin and the prostate gland are examples, testosterone undergoes 5α-reduction to form 5α-dihydrotestosterone (DHT), which interacts with the AR with greater affinity than does T; 5–10% of T secreted by the testis undergoes this transformation in target tissues. Finally, a small, but important, amount of T is aromatized in target tissues to form estradiol (E2) which interacts with the estrogen receptor (ER). Cells in the bone and the brain provide examples of this pathway.
In others, characterized by (but not limited to) the prostate and hair follicles, testosterone is reduced at the 5α position to form 5α-dihyrotesterone or DHT and it is this steroid that interacts with the AR to cause biological change. Because DHT has a greater affinity for the AR than does testosterone, this is sometimes referred to as the amplification pathway. In some tissues, exemplified by bone and brain, the active derivative of testosterone is estradiol, produced locally by aromatase, which then interacts with the estrogen receptor (ER). This has been referred to as the diversification pathway.
1. Testosterone 5α-Reductase
The enzyme responsible for the conversion of T into DHT is a Δ4-3-ketosteroid-5α-oxidoreductase that requires NADPH as a cofactor. In rodents and humans, there are two forms of 5α-reductase. Type 1 5α-reductase is expressed in skin, liver, and brain and is thought to be responsible for the inactivating catabolism of testosterone. Type 2 5α-reductase is found in the prostate and other male accessory sex glands, hair follicles, liver, and brain. This is the enzyme that catalyzes the activity amplification step of DHT production. The two reductases are encoded by separate genes and share about 50% amino acid homology.
DHT has both a higher affinity for the androgen receptor than testosterone and a greater capacity for stimulating changes in gene expression once bound to the AR. In tissues that have Type 2 5α-reductase, testosterone itself is relatively inactive. Evidence for this in humans comes from the study of males with inactivating mutations in the gene for Type 2 5α-reductase. At birth these individuals display markedly undermasculinized genitalia, demonstrating the necessity for conversion of T to DHT in these tissues during embryogenesis.
A second area of the clinical importance of the 5α-re duction of testosterone involves the potential to control the effects of endogenous testosterone on, for example, the prostate, through inhibitors of the Type 2 5α-reductase. For example, the orally active steroids finasteride and dutasteride are used to treat complications related to benign prostate hyperplasia. Finally, as indicated in section III.A previously, considerable effort has been directed towards synthesizing androgens that cannot undergo 5α-reduction and will therefore have selective actions on tissues sensitive to testosterone such as skeletal muscle, sparing the prostate from growth stimulation.
2. Aromatase
Aromatization of testosterone to estradiol occurs in several tissues of the adult male, including adipose, testis (Sertoli cells and Leydig cells), brain, bone, breast, liver, and blood vessels. In these tissues androstenedione can also be aromatized, yielding the weak estrogen estrone, which can then be metabolized to estradiol through reduction of the 17-keto group by 17β-hydroxysteroid dehydrogenase.
