Mutations of gonadotropins and gonadotropin receptors: Elucidating the physiology and pathophysiology of pituitary-gonadal function

The recent unraveling of structures of genes for the gonadotropin subunits and gonadotropin receptors has provided reproductive endocrinologists with new tools to study normal and pathological functions of the hypothalamic-pi tuitary-gonadal axis. Rare inactivating mutations that produce distinctive phenotypes of isolated LH or FSH deficiency have been discovered in gonadot ropin subunit genes. In addition, there is a common polymorphism in the LH beta subunit gene with possible clinical significance as a contributing fac tor to pathologies of LH-dependent gonadal functions. Both activating and i nactivating mutations have been detected in the gonadotropin receptor genes , a larger number in the LH receptor gene, but so far only a few in the gen e for the FSH receptor. These mutations corroborate and extend our knowledg e of clinical consequences of gonadotropin resistance and inappropriate gon adotropin action. The information obtained from human mutations has been co mplemented by animal models with disrupted or inappropriately activated gon adotropin ligand or receptor genes. These clinical and experimental genetic disease models form a powerful tool for exploring the physiology and patho physiology of gonadotropin function and provide an excellent example of the power of molecular biological approaches in the study of pathogenesis of d iseases.