Control of Androgen Action and Medicinal Applications

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In the early 1960s, we found that As can rapidly enhance RNA synthesis in target organs, such as the ventral prostate of rats, suggesting that As act by modulating gene expression in target cell nuclei (2-4). Subsequently, we (5, 6) and Bruchovsky and Wilson (7) showed that, in many target organs, testosterone, the major A produced by testis and circulating in blood, is converted by 5a-reductase to 5a-dihydrotestosterone (5a-DHT). 5a-DHT is the active A that binds to a specific nuclear androgen receptor (AR) (8-12). The 5a-DHT-AR complex, apparently in conjunction with other chromosomal proteins (13), then regulates specific transcription of genes and production of specific proteins that modulate cellular activities and organ functions. Cloning and sequence determination ofthe genes for AR (10, 11) and 5a-reductase (14) have shown that mutations of these genes are responsible for A-insensitivity syndromes, including pseudo-hermaphroditism.

The molecular steps required for A action in target cells provide two effective methods for control of testosterone-regulated responses: (a) the use of a 5a-reductase inhibitor to suppress 5a-DHT production, and (b) the use of anti-androgens to block the interaction of with AR (12). Both methods are now being utilized as therapies for A-related disorders including PCA, prostate enlargement, as well as male pattern baldness. As will be described below, both 5a-reductase inhibitors and anti-androgens are useful in the study of PCA progression and treatment.

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