Reversible Isolated Hypogonadotropic Hypogonadism due to Mutations in the Neurokinin B Regulation of Gonadotropin-Releasing Hormone Release

Abstract

In this commentary, congenital isolated hypogonadotropic hypogonadism (IHH) is defined as absent, incomplete, or arrested isosexual development when both chronological and bone ages are at least 18 yr, together with low concentrations of gonadotropins and sex hormones in the absence of systemic disease, syndromic malformations, nutritional deprivation, and other functional or anatomic pituitary abnormalities. To date, the identified forms of IHH are primarily due to inactivating mutations in the genes whose products control: 1) the differentiation and development (NROB1 or DAX1, CHD7, FGFR1, FGF8); 2) the subsequent migration of neurons that synthesize and secrete GnRH from their embryological site of origin in the nasal (olfactory) placode to their network in the hypothalamic arcuate nucleus (infundibulum); 3) the synthesis, release, and action of GnRH; and 4) the synthesis and secretion of the gonadotropins (LH, FSH) (Table 1) (1, 2). The migration of GnRH-synthesizing nerve cells requires the coordinated activity of the products encoded by KAL1, FGFR1, FGF8, NELF, PROK2, PROKR2, and likely many other factors yet to be identified. Inasmuch as loss-of-function mutations in these genes are often associated with abnormalities of olfaction (anosmia, hyposmia), they constitute the defined forms of Kallmann syndrome. Disrupted expression of factors (LEP, LEPR, KISS1R) that regulate the synthesis of GnRH (GNRH1), its storage in the median eminence, its release into the hypophyseal-portal vasculature, its action upon the pituitary gonadotrope (GHAHR), or the expression and synthesis of the gonadotropins (LH , FSH , PCSK1) themselves also leads to IHH (3). To the list of modulators of GnRH synthesis and secretion have recently been added the products of TAC3 (tachykinin 3 or neurokinin B) and TACR3 (the G proteincoupled receptor for tachykinin 3) (4, 5). Gianetti et al. (6) have now genotyped TAC3 and TACR3 in 345 patients (247 males) with IHH and have identified both nonsense and missense nonsynonymous and synonymous mutations in TACR3 in 19 patients (four females) (5.5%) as well as a frameshift mutation in TAC3 in one woman (0.3%). In nine subjects, the TACR3 mutation was biallelic and in eight of nine homozygotic, whereas in 10 patients the mutations in TACR3 were monoallelic. Both recessive and dominant modes of IHH transmission were present in patients with mutations in TACR3. Patients with heterozygous mutations in TACR3 were clinically similar to the subjects with homozygous mutations. In none of the patients with heterozygous mutations in TACR3 were mutations in other examined IHH genes identified, suggesting that digenic transmission of IHH was less likely in these subjects (7). Functional characterization of several of the missense mutations in TACR3 revealed that the DNA base changes inactivated the product except for two monoallelic mutations (Gly18Asp and Ile249Val) in which in vitro bioactivity was normal, leaving unexplained the mechanism by which these mutations resulted in IHH in their carriers. Clinically, 14 of 15 males with IHH due to mutations in TACR3 had phallic lengths that were less than 10.5 cm and were classified as micropenis. As anticipated, at diagnosis of IHH, most affected males had very small testes, but in some patients testicular volumes were a bit larger than prepubertal, a size increase attributable to endogenous mechanisms. After discontinuation of sex hormone replacement therapy, testicular volume and/or gonadotropin and/or testosterone secretion increasedspontaneously infivemales, twoofwhomreported