The effect of 5α-reductase-2 deficiency on human fertility

Abstract

A most interesting and intriguing male disorder of sexual differentiation is due to 5α-reductase-2 isoenzyme deficiency. These male infants are born with ambiguous external genitalia due to a deficiency in their ability to catalyze the conversion of T to dihydrotestosterone. Dihydrotestosterone is a potent androgen responsible for differentiation of the urogenital sinus and genital tubercle into the external genitalia, urethra, and prostate. Affected males are born with a clitoral-like phallus, bifid scrotum, hypospadias, blind shallow vaginal pouch from incomplete closure of the urogenital sinus, and a rudimentary prostate. At puberty, the surge in mainly T production prompts virilization, causing most boys to choose gender reassignment to male. Fertility is a challenge for affected men for several reasons. Uncorrected cryptorchidism is associated with low sperm production, and there is evidence of defective transformation of spermatogonia into spermatocytes. The underdeveloped prostate and consequent low semen volumes affect sperm transport. In addition, semen may not liquefy due to a lack of prostate-specific antigen. In the present review, we discuss the 5α-reductase-2 deficiency syndrome and its impact on human fertility.

Keywords: 5-alpha-reductase-2 deficiency; genetic steroid disorders; genotype; infertility; phenotype.

Figure 1

An illustration of gene mutations in the human 5a-reductase-2 gene. The 61 mutations identified in the 5aRD2 gene, so far, are found throughout all five exons of the gene, and range from a single-point defect to a gene deletion. These mutations include 50 missense mutations, six small deletions, three splicing junction alterations, one single nucleotide insertion, and a large deletion involving the entire gene. Adapted and updated from reference (Zhu YS and Imperato-McGinley J: Disorders in male sexual differentiation: molecular genetics, gender identity, and cognition, in Hormones, Brain and Behavior. Pfaff DW, Arnold AP, Etgen AM, Fahrbach SE and Rubin RT (eds), 2nd ed, Vol 5, Academic Press, San Diego, CA. pp2787–2824, 2009).

Figure 2

Illustration of the role of testosterone and dihydrotestorone in male sexual differentiation in utero. Adapted from reference (Imperato-McGinley J, Guerrero L, Gautier T, and Peterson RE (1974) Steroid 5α -reductase deficiency in man: An inherited form of male pseudohermaphroditism. Science 186:1213–1216).