KISS1 and hypogonadotropic hypogonadism: Later, hypogonadotropic hypogonadism was also observed in Kiss1 knockout mice (12), while precocious puberty onset occurred in humans with either gpr54-activating mutation leading to prolonged in vitro activation of intracellular signaling pathways in response to kisspeptin (13) or Kiss1 mutations leading to higher in vitro kisspeptin resistance to degradation (14).