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Although hypogonadotrophism appears to be sustained in KISS1/KISS1R-deficient individuals, hypogonadotrophism may not be permanent in patients with TAC3/TACR3 pathway mutations. The majority of IHH patients bearing disabling Alectinib purchase mutations in the NKB pathway (assessed long term) exhibit evidence of spontaneous partial or complete recovery of their reproductive axis as determined by the following changes: (i) increases in LH pulsatility; (ii) increases in testosterone; (iii) increases in testicular volume; (iv) the presence of withdrawal bleeding; (v) spontaneous menstrual cycles; and/or (vi) spontaneous pregnancy (Gianetti et al. 2010). The observed rate of reversal in IHH patients with NKB pathway mutations and long term follow-up is estimated to be 80% (Gianetti et al. 2010); however, the rate of reversal is much lower, 10%, in a diverse IHH population unselected for genotype (Raivio et al. 2007). While mutations in KISS1 and KISS1R are rarer than those GPX4 in TAC3/TACR3, to date, no individuals with kisspeptin pathway mutations have been documented with reversal. Thus, the role of the NKB pathway in GnRH secretion may be less critical in adult life compared with that of kisspeptin. In fact, kisspeptin signalling may be able to overcome NKB pathway mutations as evidenced by an increase in LH pulsatility in patients with TAC3 or TACR3 mutations receiving Osimertinib supplier exogenous pharmacological doses of kisspeptin (Young et al. 2012). Additionally, it is possible that in the absence of either NKB or its receptor there is compensation by other tachykinin ligands and/or receptors, as suggested by recent animal studies (see next section; Fig. 1). Utilization of mouse models deficient in kisspeptin and NKB allows for a more in-depth probing of the mechanism by which these neuropeptides regulate the hypothalamic control of reproduction. Kiss1r?/? mice demonstrate a profound reproductive phenotype of absent sexual maturation and infertility (Funes et al. 2003; Seminara et al. 2003); a phenotype that is largely echoed in Kiss1?/? mice (d��Anglemont de Tassigny et al. 2007; Lapatto et al. 2007). However, both Kiss1?/? and Kiss1r?/? mutant mice demonstrate kisspeptin-independent GnRH release as evidenced by measurable gonadotrophin levels (Chan et al. 2009), harkening back to the enfeebled GnRH secretion observed in human patients bearing mutations in this pathway. In the NKB pathway, Tacr3?/? mice were reported initially to be fertile, leading to a puzzling discordance between mouse and human genetic models (Kung et al. 2004). However, upon more detailed phenotyping, Tacr3?/? mice were found to have reproductive defects, including impaired oestrous cyclicity, decreased ovulatory events and subfertility (Yang et al. 2012).