Disorders linked to insufficient androgen action in male children

Virilization of the external genitalia in the male fetus requires testoster one and dihydrotestosterone (DHT), which is formed from testosterone by the action of the enzyme, 5 alpha -reductase type 2 (5 alphaR-2). Mediation of the effects of both testosterone and DHT requires a functional androgen re ceptor (AR) located in the cytoplasmic compartment of target cells. DHT (or testosterone) binding induces a conformational change which facilitates AR nuclear transport, phosphorylation and dimerization, ultimately regulating of the rate of transcription of androgen-dependent genes. Any event which impairs DHT formation (mutation within the 5 alphaR-2 gene or 5 alphaR-2 in hibitors) or normal function of the AR (mutation in the AR gene, antiandrog ens) may result in insufficient androgen action in the male fetus and in su bsequent undervirilization in the newborn. Hypospadias may be due to a defe ct in androgen action due to mutation of the 5 alphaR-2 or of the AR gene. Mutation of unidentified genes is likely to underlie this displacement of t he urethral meatus from the tip to the ventral side of the phallus. An aeti ological role for environmental chemical products has been postulated, sinc e ethnic as well as geographical differences in the incidence of hypospadia s have been noted. Increasing evidence has been gathered indicating that wi dely used industrial and agricultural chemicals have deleterious effects on normal male sexual differentiation. Cryptorchidism and micropenis may repr esent an intersex phenotype, even if they are isolated. Aetiological factor s include 5 alphaR-2 gene mutation, AR gene mutation or environmental hormo nal disruptors. In conclusion, several phenotypes have been attributed to i nsufficient androgen action during fetal life. Whereas mutations in the 5 a lphaR-2 gene and AR gene are natural, attention should be focused on enviro nmental endocrine disruptors that are able to mimic steroid 5 alpha -reduct ase deficiency or partial androgen insensitivity syndrome.