ESPE Abstracts (2014) 82 S6.2

New Syndromes Resulting in Secretory Pathway and Gonadotropic Axis Regulation Defects

N de Roux


Paris Diderot University, Paris, France


Puberty is defined by the appearance of secondary sexual characteristics and the maturation of reproductive function. It is driven by an increase in sexual steroid hormone synthesis under the control of the gonadotropic axis. The key event in puberty initiation is an increase in the pulsatile release of the GnRH by hypothalamic neurons, triggering the release of LH and FSH. This pubertal increase in GnRH secretion is associated with increases in glutamatergic inputs and decreases in GABAergic inputs to GnRH neurons. It is also facilitated by hypothalamic glial cells, which interact directly or indirectly with GnRH neurons. Kisspeptins are currently thought to be the principal hypothalamic neuropeptides controlling GnRH secretion, not only at puberty, but also during adulthood. The activation of the kisspeptins signaling pathway in the hypothalamus is seen as the major hallmark of puberty onset, and its control is partly epigenetic.

Characterization of the genetic defects underlying the isolated form of congenital hypogonadotropic hypogonadism (CHH) has proved crucial, not only for elucidating the fundamental role of kisspeptins in the central regulation of the gonadotropic axis and puberty, but also for determining the role played by Neurokinin B. CHH may be associated with anosmia, due to olfactory bulb agenesis, in Kallmann syndrome. CHH has also been associated with complex neurodevelopmental disorders caused by loss-of-function mutations in genes encoding proteins involved in diverse cellular pathways. This association indicates that the same etiopathogenic mechanism may be responsible for a specific neuroendocrine deficiency and common neurological dysfunctions. Here, I will review genetic causes of these syndromic CHH without anosmia and presented our recent data on a new syndrome which associates GnRH deficiency with complex neurological and endocrine phenotypes.

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