The control of the onset of human puberty remains an enigma. According to current understanding, the GnRH pulse generator, a functionally interconnected and synchronized network of GnRH neurons, is inhibited throughout childhood following a period of pubertal level activity during fetal life. Release of this inhibition at the early second decade of life signifies the reawakening of the pulse generator.
Recently, we have identified loss-of-function mutations TAC3 or TACR3 (encoding neurokinin B and its receptor, NK3R, respectively) in 11 patients from five multiplex families affected by normosmic idiopathic hypogonadotropic hypogonadism. These findings provide compelling evidence for the involvement of Neurokinin B (NKB) signaling in puberty. Recent studies suggest that a network of sex-steroid responsive neurons in the infindubular (arcuate) nucleus in the hypothalamus coexpress NKB, kisspeptin, Dynorphin and ERalfa and probably communicating via NKB-NKR3 signaling these neurons project to ipsi- and contralaterally to the infindubular (arcuate) nucleus as well as to GnRH terminals in the median eminence to put out a synchronized intermittent secretion of GnRH.
The facts that the discovery of both kisspeptin and NKB signaling in puberty was thanks to multiplex human families and that in the great majority of such families, the genetic causes are still waiting to be unraveled imply that there are more single genes to be discovered, which will help understand the elusive developmental process of puberty.
24 - 28 Apr 2010
European Society of Endocrinology