Consequences of steroid-5α-reductase deficiency and inhibition in vertebrates

In 1974, a lack of 5α-dihydrotestosterone (5α-DHT), the most potent androgen across species except for fish, was shown to be the origin of a type of pseudohermaphrodism in which boys have female-like external genitalia. This human intersex condition is linked to a mutation in the steroid-5α-reductase type 2 (SRD5α2) gene, which usually produces an important enzyme capable of reducing the Δ⁴-ene of steroid C-19 and C-21 into a 5α-stereoisomer. Seeing the potential of SRD5α2 as a target for androgen synthesis, pharmaceutical companies developed 5α-reductase inhibitors (5ARIs), such as finasteride (FIN) and dutasteride (DUT) to target SRD5α2 in benign prostatic hyperplasia and androgenic alopecia. In addition to human treatment, the development of 5ARIs also enabled further research of SRD5α functions. Therefore, this review details the morphological, physiological, and molecular effects of the lack of SRD5α activity induced by both SRD5α mutations and inhibitor exposures across species. More specifically, data highlights 1) the role of 5α-DHT in the development of male secondary sexual organs in vertebrates and sex determination in non-mammalian vertebrates, 2) the role of SRD5α1 in the synthesis of the neurosteroid allopregnanolone (ALLO) and 5α-androstane-3α,17β-diol (3α-diol), which are involved in anxiety and sexual behavior, respectively, and 3) the role of SRD5α3 in N-glycosylation. This review also features the lesser known functions of SRD5αs in steroid degradation in the uterus during pregnancy and glucocorticoid clearance in the liver. Additionally, the review describes the regulation of SRD5αs by the receptors of androgens, progesterone, estrogen, and thyroid hormones, as well as their differential DNA methylation. Factors known to be involved in their differential methylation are age, inflammation, and mental stimulation. Overall, this review helps shed light on the various essential functions of SRD5αs across species.