GnRH and its receptor GnRHR are key regulators of the hypothalamo-pituitary axis. They modulate the secretion of LH and FSH gonadotropins and therefore, the development and maturation of gonads in fetal life as well as after birth. Congenital functional defect of this axis results in isolated hypogonadotropic hypogonadism (IHH). Several natural mutations causing IHH without anosmia have now been identified in GnRHR or GnRH genes. These mutations inactivate GnRHR or its ligand function and cause highly variable phenotypes, ranging from partial to complete gonadotropic deficiencies. The present review describes the published natural GnRHR mutations and tries to correlate them with the corresponding phenotypes according to the different steps of the GnRH system development.
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