The Parkes lecture. Mutations of gonadotrophin and gonadotrophin receptor genes: what do they teach us about reproductive physiology?

Although mutations in human gonadotrophin and gonadotrophin receptor genes are rare, they have greatly elucidated the physiology and pathophysiology of gonadotrophin action. These 'nature's transgenics' have been corroborated by mouse transgenic and knock-out models. An inactivating mutation of the human LHbeta chain and knock-out of the mouse common alpha-chain show that pituitary LH is not needed to stimulate fetal testicular steroidogenesis and male sexual differentiation. In mice, early testicular steroidogenesis is apparently gonadotrophin-independent and, in humans, it is regulated by placental hCG. Pituitary LH becomes necessary only after birth. Inactivating LH receptor mutations block prenatal hCG action, thus inhibiting male-type sexual differentiation. In females, this process is autonomous, and LH becomes important only at puberty; inactivation of LH receptor causes anovulatory infertility. Activating LH receptor mutations cause male-limited gonadotrophin-independent precocious puberty in males, but no apparent phenotype in females. Animal models for LH or LH receptor inactivation are not yet available. Inactivating FSH ligand and receptor mutations cause infertility because of a lack of follicular maturation in women. Findings in men are controversial, since FSHbeta inactivation is related to azoospermia, whereas the cognate receptor inactivation only suppresses spermatogenesis without causing absolute infertility. The FSHbeta and FSH receptor knock-out mice display phenocopies of the human FSH receptor mutation. Information about activating FSH receptor mutations is still insufficient. Hence, the above human mutations have brought important new information about the role of gonadotrophins in reproductive functions. The genetically modified animal models provide useful tools to explore the pathogenesis and new treatment modalities of infertility, and to develop new contraceptive strategies.