Androgens and male physiology the syndrome of 5α-reductase-2 deficiency

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Abstract

Dihydrotestosterone (DHT), a potent androgen, is converted from testosterone by 5α-reductase isozymes. There are two 5α-reductase isozymes, type 1 and type 2 in humans and animals. These two isozymes have differential biochemical and molecular features. Mutations in type 2 isozyme cause male pseudohermaphroditism, and many mutations have been reported from various ethnic groups. The affected 46XY individuals have high normal to elevated plasma testosterone levels with decreased DHT levels and elevated testosterone/DHT ratios. They have ambiguous external genitalia at birth so that they are believed to be girls and are often raised as such. However, Wolffian differentiation occurs normally and they have epididymides, vas deferens and seminal vescles. Virilization occurs at puberty frequently with a gender role change. The prostate in adulthood is small and rudimentary, and facial and body hair is absent or decreased. Balding has not been reported. Spermatogenesis is normal if the testes are descended. The clinical, biochemical and molecular genetic analyses of 5α-reductase-2 deficiency highlight the significance of DHT in male sexual differentiation and male pathophysiology.

Introduction

Male sexual development in the mammalian system involves three sequential processes. The first step is establishment of genetic sex by the presence of 46XY sex chromosomes, a process completed at the time of fertilization of the ovum. The second step is differentiation of the indifferent gonad to a testis. The process of testicular differentiation involves the SRY gene located on the Y chromosome as well as multiple genes located on autosomal chromosomes. The third step is translation of the gonadal sex to phenotypic sex, i.e. the formation of internal and external genitalia. Both testosterone and its 5α reduced metabolite, DHT, play critical roles in this process.

The importance of both androgens in male sexual differentiation and development, and in determining male gender identity will be discussed by reviewing the clinical syndrome of 5α-reductase-2 deficiency.

Section snippets

5α-Reductase isozymes

Steroid 5α-reductase isozymes are located in the microsomes of the cell. These isozymes convert testosterone to DHT, a more potent androgen. They are NADPH-dependent enzymes that reduce the double bond at the four to five position in C19 steroids as well as C21 steroids. Both testosterone and DHT bind to the same intracellular androgen receptor, which is a member of the nuclear steroid/thyroid hormone receptor superfamily, to regulate target gene expression (Beato, 1989). Although testosterone

Clinical presentation

The clinical syndrome of 5α-reductase deficiency was first described, clinically and biochemically, in studies of 24 affected subjects from a large Dominican kindred (Imperato-McGinley et al., 1974), and in two siblings from Dallas (Walsh et al., 1974). Subsequently a large cohort in New Guinea (Imperato-McGinley et al., 1991) and another in Turkey were described (Akgun et al., 1986, Can et al., 1998, Imperato-McGinley et al., 1987) as well as many other cases worldwide [see recent review (Zhu

Biochemical features of 5α-reductase-2 deficiency

Over the years, the biochemical features of this syndrome have been well defined (see recent reviews Imperato-McGinley, 1996, Zhu et al., 1998). These include: (a) normal to elevated levels of plasma testosterone; (b) decreased levels of plasma DHT; (c) an increased testosterone to DHT ratio at baseline and/or following hCG stimulation; (d) decreased conversion of testosterone to dihydrotestosterone (DHT) in vivo; (e) normal metabolic clearance rates of testosterone and DHT; (f) decreased

Defects in the 5α-reductase-2 gene

The first identified genetic defect of 5α-reductase deficiency was carried out in male pseudohermaphrodites from our New Guinean kindred (Andersson et al., 1991). To date, over 33 mutations in the 5α-reductase-2 gene (Wilson et al., 1993, Nordenskjold et al., 1998, Vilchis et al., 2000, Zhu et al., 1998 and our unpublished data) have been identified, including mutations in the three largest kindreds of male pseudohermaphrodites with 5α-reductase-2 deficiency in the world—the Dominican, New

Gender identity change

Gender identity change from female to male has been demonstrated in subjects with 5α-reductase-2 deficiency from different areas of the world (see recent review Imperato-McGinley and Zhu, 2002). These subjects demonstrate that exposure of the brain to androgen (testosterone) in utero, during the early postnatal period, and at puberty, appears to have a greater impact in determining male gender identity than does sex of rearing and sociocultural influences. Normally the sex of rearing and

Acknowledgements

The studies were supported in part by NIH Grant M01-RR-00047 (General Clinical Research Center) and HD-09421-15.

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