Male hypogonadism resulting from mutations in the genes for the gonadotropin subunits and their receptors

Abstract

Mutations in the genes of gonadotropin subunits (CGA, LHB, FSHB, and CGB) and receptors (LHCGR and FSHR) are extremely rare causes of male hypogonadism. No germ line mutations of CGA have been reported, apparently because of the incompatibility of pregnancy maintenance in the absence of hGG. Five inactivating LHB mutations have been described in men with normal prenatal masculinization but arrested pubertal development. The three men so far described with FSHB mutation were azoospermic. Constitutively activating mutations of the LHCGR gene give rise to very early onset familial male-limited precocious puberty (FMPP) also termed testotoxicosis. Inactivating LHCGR mutation results in an array of male phenotypes ranging from micropenis and hypospadias to complete sex reversal (XY, disorder of sexual development), depending on the completeness of receptor inactivation. Inactivating FSHR mutations in men cause a decrease in testicular size and suppressed quality and quantity of spermatogenesis but not azoospermia, and some affected men may be fertile. Only two cases of activating FSHR mutations have been detected, and they suggest that the mutation does not have phenotype in men with otherwise normal endocrine function. The discrepancy between the phenotypes of men with inactivating FSHB (azoospermia) and FSHR (no azoospermia) mutations must be clarified with additional subjects. Information about the genotypic effects of common polymorphisms in gonadotropin and gonadotropin receptor genes is gradually mounting. A common polymorphism in LHB affects bioactivity of the hormone and has multiple mild phenotypic effects, including slow tempo of puberty in boys and is enriched in post-term boys with cryptorchidism. Some FSHB and FSHR polymorphisms have been shown to affect spermatogenesis and the response of oligozoospermic men to FSH therapy. Such polymorphisms may represent important targets for the pharmacogenetic evaluation of gonadotropin treatment in infertility.