Molecular evaluation of the gonadotropin-releasing hormone receptor

The gonadotropin-releasing hormone receptor (GnRHR) is a guanine nucleotide-binding protein-coupled receptor with a characteristic seven transmembrane domain motif. It transduces the hypothalamic message carried by the decapeptide gonadotropin-releasing hormone. At the gonadotrope cell surface the hormone binds to the receptor, leading to pituitary synthesis and secretion of gonadotropins. These glycoprotein hormones, in turn, modulate folliculogenesis and ovulation in the ovary. Failure of the GnRHR to respond appropriately to its cognate ligand has been demonstrated in humans. These patients have genomic mutations in the gene for the GnRHR and represent the first individuals with hypogonadotropic hypogonadism of autosomal inheritance. The mutant receptors are poorly expressed at the cell surface and have a diminished capacity to transduce the hypothalamic message efficiently. To date, no mutations have been identified that lead to constitutively active receptors and autonomous gonadotropin function. This article identifies the mutations in the GnRHR reported to date and reviews how these abnormal receptors help us to better understand the biology of this interesting molecule.