Mutations of gonadotropins and their receptors [Mutationen der gonadotropine und gonadotropinrezeptoren]

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The gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are fundamental for reproduction. They exert their action through specific receptors located exclusively in gonadal somatic cells. Mutations of the gonadotropins and their receptors are very rare but help to elucidate the mechanism of gonadotropin action. To date, only one missense mutation of the LH β-subunit and two missense mutations and one deletion of the FSH β-subunit gene have been described. These mutations lead to loss of gonadotropin function and hypogonadism. Selective loss of FSH in men caused by mutations in the β-chain result in azoospermia. For gonadotropin receptors, about two dozen loss-of-function (inactivating) and gain-of-function (activating) mutations are known. Inactivating mutations of the LH receptor cause Leydig cell hypoplasia with various degrees of hypoandrogenization up to male pseudohermaphroditism, while in females they result in primary amenorrhea. Activating mutations of the LH receptor are responsible for familial male-limited pseudoprecocious puberty (testotoxicosis) but do not cause phenotypic alterations in females. Inactivating mutations of the FSH receptor result in primary or early secondary amenorrhea in females and reduced spermatogenesis in males. Only one activating mutation of the FSH receptor has been described so far, in a hypophysectomized man with normal spermatogenesis in the absence of gonadotropins and very low endogenous testosterone levels. In addition, several polymorphisms in both gonadotropins and gonadotropin receptor genes have been identified, and their impact on gonadal pathophysiology is currently being investigated.