Missense loss-of-function mutations in TAC3 and TACR3, the genes encoding neurokinin B (NKB) and its receptor NK3R, respectively, were recently discovered in kindreds with non syndromic normosmic congenital hypogonadotropic hypogonadism (nCHH), thus identifying a fundamental role of this pathway in the human gonadotrope axis.
We investigated the consequences on gonadotrope axis of TAC3 and TACR3 invalidations in adult patients with complete nCHH.
We identified 3 unrelated patients with the same homozygous substitution in the TAC3 intron 3 acceptor splicing site (c.209-1G>C) and 3 siblings who bore a homozygous mutation in the TACR3 intron 2 acceptor splicing site (c.738-1G>A). We demonstrated that these 2 mutations invalidate respectively neurokinin B and its receptor NK3R. We found in three patients with TAC3 mutation originating from Congo and Haiti, a founding event in a more distant ancestor by means of haplotype analysis. We calculated that time to this common ancestor was ~600 years.
In several patients, we observed a dissociation between the very low LH and normal or nearly normal FSH levels, this gonadotropin responding excessively to the GnRH challenge test. This particular hormonal profile, suggest the possibility of a specific neuroendocrine impairement in patients with alteration of neurokinin B signaling.
Finally, in these patients, pulsatile GnRH administration normalized circulating sex steroids, LH release and restored fertility.
In conclusion, our data demonstrate the hypothalamic origin of the gonadotropin deficiency in these genetic forms of nCHH. Neurokinin B and NK3R therefore both play a crucial role in hypothalamic GnRH release in humans.
Prague, Czech Republic
24 - 28 Apr 2010
European Society of Endocrinology