As predicted by the complexity of this cellular network, several reports have suggested that no isolated pathway or cellular subset is solely responsible for the neuroendocrine control of puberty 10–12. Instead, initiation of this process may require regulatory gene networks controlled by a handful of “upstream” genes 10. Some of these central nodes have been identified, including the POU-domain gene Oct2, the homeodomain gene Ttf1/Nkx2.1, and a novel Zinc finger-containing gene termed EAP1 (Enhanced At Puberty1) 13. Although monogenic mutations, such as those affecting GNRHR 14, GPR54 15, 16, KiSS1 17, TAC3 and TACR3 18, result in pubertal failure, it does not appear that these are the only puberty-relevant genes as genome-wide association studies have shown that variants of more than 30 genes are associated with the age of menarche in humans 19.
