Male pseudohermaphroditism secondary to 5α-reductase deficiency—A model for the role of androgens in both the development of the male phenotype and the evolution of a male gender identity

Abstract

Male pseudohermaphroditism secondary to 5α-reductase deficiency is reviewed. At birth, the affected males (46 XY) have a clitoral-like phallus, bifid scrotum and urogenital sinus with the testes in the inguinal canals or labial-scrotal folds. At puberty, a muscular male habitus develops with growth of the phallus and without gynecomastia. When compared to aged matched male controls the mean plasm testosterone (T) levels in affected adults are significantly higher; while the mean plasma 5α-dihydrotestosterone (DHT) levels are significantly lower. The plasma T:DHT ratios range from 24 to 84, compared to a normal range of 8–16. After administration of hCG, the T:DHT ratios in the affected prepubertal male children range from 35 to 172 compared to a range of 3–26 in the controls. The metabolic clearance rates of T and DHT are normal, but the conversion ratio of T to DHT is decreased to less than 1%. The endogenous mean urinary etiocholanolone (5β) to androsterone (5α) ratios, and the urinary 5β to 5α ratios after infusion of radioactive T are significantly higher than in normal males. Studies with cortisol and corticosterone (11-oxo, C-21) Δ4–11β-hydroxyandrostenedione (11-deoxy, C-19) and testosterone and androstenedione (11-deoxy, C-19) have shown that the fractional conversion of the infused parent steroids to 5α reduced produced products is markedly decreased in individuals with 5α-reductase deficiency and may reflect a generalized defect in steroid metabolism. Decreased 5α-reductase activity has been demonstrated in fibroblasts cultured from nongenital and genital skin of affected subjects, in cell free extracts from epididymis and fibroblasts cultured from genital skin and in genital skin slices. Characterization of the enzyme activity in four kindreds reveals that 5α-reductase enzyme activity in each kindred has different properties. Pedigree analysis from the large Dominican kindred reveals inheritance to be autosomal recessive. This model of inheritance is further documented by the fact that some sibling sisters show the same biochemical defect, and obligate carrier parents show an intermediate defect. The affected subjects provide a clinical model for delineating the roles of T and DHT in sexual differentiation and development.

Because of the appearance of the genitalia at birth, 18 of the affected males from the Dominican kindred were raised as girls. Extensive psychosexual evaluation was conducted by interviewing the affected subjects, parents, siblings and wives, and it was found that in spite of the rearing as female throughout childhood 16 of 18 changed gender identity and role with puberty. We conclude that in the formation of male gender identity, normal T exposures of the brain in utero and at puberty are major contributing factors. Thus, in normal males the formation of gender identity is at least partially androgen induced.