Androgens are important hormones for expression of the male phenotype. They have characteristic roles during male sexual differentiation, but also during development and maintenance of secondary male characteristics and during initiation and maintenance of spermatogenesis (1). The two most important androgens in this respect are testosterone and 5α-dihydrotestosterone [Figure 1]. While acting through the same androgen receptor, each androgen has its own specific role during male sexual differentiation: testosterone is directly involved in development and differentiation of wolffian duct derived structures (epididymides, vasa deferentia, seminal vesicles and ejaculatory ducts) [Figure 2A], whereas 5α-dihydrotestosterone, a metabolite of testosterone, is the active ligand in a number of other androgen target tissues, like urogenital sinus and tubercle and their derived structures (prostate gland, scrotum, urethra, penis) [Figure 2B] (2,3). The interaction of both androgens with the androgen receptor is different. Testosterone has a two fold lower affinity than 5α-dihydrotestosterone for the androgen receptor, while the dissociation rate of testosterone from the receptor is five-fold faster than of 5α-dihydrotestosterone (4). However, testosterone can compensate for this "weaker" androgenic potency during sexual differentiation and development of wolffian duct structures via high local concentrations due to diffusion from the nearby positioned testis. In more distally located structures, like the urogenital sinus and urogenital tubercle the testosterone signal is amplified via conversion to 5α-dihydrotestosterone.
Figure 2a. Specific actions of Testosterone (T). T is synthesized in the testis under control of luteinizing hormone (LH) from the pituitary . After entering the target cells (in the hypothalamus, pituitary, testis and wolffian duct) T is directly bound to the androgen receptor (AR) and the complex T-AR binds to specific DNA sequences and regulates gene transcription, which can result in negative feedback regulation of gonadotrophin synthesis and secretion, in initiation and regulation of spermatogenesis and in differentiation and development of the wolffian duct.
Figure 2b. Specific actions of 5α-Dihydrotestosterone (DHT). T is synthesized in the testis under control of luteinizing hormone (LH) from the pituitary. After entering the target cells (in the urogenital sinus, urogenital tubercle, and several additional androgen target tissues) T is metablized to 5α-Dihydrotestosterone (DHT) by the enzyme 5α-Reductase type 2. DHT binds directly to the androgen receptor (AR) and the complex DHT-AR interacts to specific DNA sequences and regulates gene transcription, which can result in differentiation and development of the prostate, the external genitalia and at puberty in several secondary male characteristics.
