Male pseudohermaphroditism due to inactivating luteinizing hormone receptor mutations.

Human male sexual development is regulated by chorionic gonadotropin (CG) and luteinizing hormone (LH), the action of both mediated by the LH receptor (LHR). Mutations that inactivate the LHR cause Leydig cell hypoplasia (LCH), an autosomal recessive disorder. In its mild form, LCH patients present with male hypogonadism. In its severe form, patients present with male pseudohermaphroditism, with female external genitalia, and cryptorchid testis. Mullerian derivatives are absent. Histological examination of the testis shows absence of mature Leydig cells. LCH patients have elevated plasma levels of LH, normal-to-elevated levels of follicle stimulating hormone (FSH), and low levels of testosterone that do not respond to CG stimulation. Missense mutations, nonsense mutations, deletion mutations, and in-frame insertion mutation of the LHR have been identified in patients with LCH. These mutations are not localized in any particular region of the gene and cause variable degrees of receptor-activity loss. The clinical manifestation of patients with LCH with homozygous or compound heterozygous mutations can be correlated with the residual activity of their respective mutated LHRs. Homozygous inactivating mutations of the LHR in the female cause hypergonadotrophic hypogonadism with primary amenorrhea or oligoamenorrhea, cystic ovaries, and infertility.