The AR and Androgens

The AR, a member of the nuclear receptor superfamily, functions as a ligand-inducible transcription factor that regulates the expression of target

Hypothalamus

LH-RH

Estrogens LH-RH agonists ^^ LH-RH antagonists

Pituitary gland

ACTH

Pituitary gland

ACTH

Adrenal androgen inhibitors

Fig. 1. Strategies for hormonal therapy. LH-RH = Luteinizing hormone-releasing hormone; CRH=corticotropin-releasing hormone; LH = luteinizing hormone; ACTH=adrenocorticotropic hormone; T = testosterone; 5a-R=5a-reductase; DHT = 5a-dihydrotestosterone; AR=androgen receptor.

Adrenal androgen inhibitors

Fig. 1. Strategies for hormonal therapy. LH-RH = Luteinizing hormone-releasing hormone; CRH=corticotropin-releasing hormone; LH = luteinizing hormone; ACTH=adrenocorticotropic hormone; T = testosterone; 5a-R=5a-reductase; DHT = 5a-dihydrotestosterone; AR=androgen receptor.

genes in response to ligands in target cells.3,4 Recent studies have also revealed that the AR modulates transcription by recruitment of coregula-tors that influence a number of functional properties of the receptor, including ligand selectivity and DNA binding capacity (reviewed in Ref. 5).

Testosterone is secreted by Leydig cells in the testis and is the major sex hormone circulating within the blood of males. In a variety of androgen-sensitive tissues like the prostate, testosterone is irreversibly converted by 5a-reductases to the more potent androgen, DHT.4,6 Upon binding of androgens, the androgen-AR complexes form homodimers, and they translocate into the nucleus and bind to androgen responsive elements located on target genes, such as prostate-specific antigen (PSA), which is clinically used for the detection and monitoring of PCa recurrence and progression. Besides testosterone and DHT, several precursors of testosterone mainly secreted by adrenal glands, dehydroepiandrosterone (DHEA), DHEA sulfate, A4-androstenedione, and A5-androstenediol, can also stimulate the AR through their conversion to testosterone/DHT in peripheral tissues, including the prostate, or by directly binding to the AR.7-10

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