Evolution of steroid-5α-reductases and comparison of their function with 5β-reductase
2010
In marked contrast, the reproductive functions of SRD5b are largely unexplored because of the long held view that 5b-DHT does not have androgenic effects (Kokontis and Liao, 1999). Some experimental evidence supports the view that the 5b-androstanes are not androgenic and it has been demonstrated that 5b-DHT does not compete for the androgen-binding site in mammalian prostate (Mainwaring, 1977). This was explained by a steric effects on the A ring in 5b-androstanes since induction of androgenic activity needs an electronic effect on the A ring (Liao et al., 1973). The 5b-androstanes failed to induce a negative feedback on plasma luteinizing hormone and follicle stimulating hormone (Davies et al., 1980), failed to stimulate cloacal gland growth (Massa et al., 1980) and failed to induce comb development in male chicken (Mori et al., 1974). Furthermore, intrahypothalamic 5b-DHT implants did not induce male sexual behavior in birds (Adkins, 1977; Steimer and Hutchison, 1981); while testosterone and 5a-DHT implants induced the erect threat posture in chicks (Groothuis and Ros, 2005). However, there are numerous reports to the contrary that indicate important biological functions of SRD5b and 5b-DHT. For example, sexual behavior studies indicate important roles of SRD5b, including the regulation of steroid production by testosterone inactivation and/or direct inhibition of aromatase (estrogen synthase) by 5b-reduced metabolites of testosterone in the brain of birds (Balthazart et al., 1981; Hutchison and Steimer, 1981; Steimer and Hutchison, 1981). Hutchison and Steimer (1981) suggested that inactivation of testosterone by conversion to 5b-DHT by SRD5b regulates brain sensitivity to androgens under changing hormonal conditions. Long-term castrated doves showed increased levels of 5b-DHT in the preoptic area (androgen sensitive) compared to intact males (Steimer and Hutchison, 1981) suggesting that 5b-reduction regulates low androgen levels during non-breeding seasons. Furthermore, 5b-DHT has also been shown to exhibit direct biological activities. Exposure to 5b-DHT inhibited mammary development in mice (Yanai et al., 1977), and induced vasorelaxation in thoracic aorta (Montano et al., 2008) and vas deferens (Lafayette et al., 2008) in rats. Even though 5b-DHT does not affect directly male secondary sexual development (compared to 5a-DHT), 5b-DHT can induce other androgen-related functions and 5b-reduction can regulate testosterone availability.
