Androgens are C-19
steroids that provide major regulatory influences on male reproductive function.
Testosterone, the principal androgenic
steroid, is secreted by the Leydig cells of the testes. Both
testosterone and its 5 alpha reduced derivative
5 alpha-dihydrotestosterone (DHT) are physiological
ligands for the
androgen receptor (AR).
Ligand-activated AR acts as a nuclear
transcription factor and mediates
androgen action. AR, along with receptors for a number of
C-21 steroids such as
glucocorticoid,
mineralocorticoid, and
progesterone, share the same 15 base pair consensus
element composed of 5'-GGA/TACAnnnTGTTCT-3'. Despite this cross-reactivity at the level of the
DNA, physiologically,
androgens regulate their target genes with a high degree of receptor specificity. Such a regulatory specificity appears to be due to multiphasic interactions involving enzymatic activation/inactivation of the
steroid ligand, interaction with specific receptor-associated nuclear factors on or around the
hormone response element, and differential regulation of the receptor gene expression. Conversion of
testosterone to
5 alpha-dihydrotestosterone in target cells is a widespread activation mechanism that amplifies the androgenic signal. Unlike the
testosterone-AR complex, DHT-activated AR has a longer half-life, and thus prolongs
androgen action. Oxido-reduction of
androgens by 17 beta-
hydroxysteroid dehydrogenase and sulfurylation by
androgen sulfotransferase are two major pathways of
androgen inactivation in target cells. Prenatal deprivation of
androgen action, due to mutations in either the AR or the
5 alpha-reductase gene, results in developmental abnormalities of male reproductive tissues and also cause partial or
complete androgen-insensitivity syndromes. Elucidation of various molecular steps in
androgen action is allowing development of improved therapeutic agents for the management of disorders of
androgen action such as the
prostatic hypertrophy and
neoplasia.