OR32-3 Kisspeptin- a Novel Clinical Test of Hypothalamic Function in Men with Hypogonadotrophic Hypogonadism

Abstract

Background: Hypogonadotrophic Hypogonadism is characterised by hypogonadism in the context of low / inappropriately normal gonadotrophin levels. Congenital HH (CHH) occurs due to defective hypothalamic GnRH neuronal migration (e.g. Kallman’s syndrome), or secretion. However, no direct test of hypothalamic GnRH neuronal function currently exists. Kisspeptin is a neuropeptide that stimulates endogenous hypothalamic GnRH release. Thus, we investigated whether kisspeptin could be used to interrogate hypothalamic function in men with CHH. Methods: Men with CHH (low testosterone, low LH/FSH, normal MRI pituitary / baseline pituitary function, absent puberty, unprimed by pulsatile GnRH; n=4) and healthy eugonadal men (n=20) received an intravenous bolus of GnRH (100mcg), or kisspeptin-54 (6.4nmol/kg), on two study visits ≥1 week apart. Serum gonadotrophins were measured every 15mins for 6hrs following injection. Increases in serum gonadotrophins from baseline following GnRH / kisspeptin in eugonadal men and CHH were compared by unpaired t test. Results: Mean increase in serum LH from baseline was 8.2±3.8iU/L in eugonadal men and 0.12±0.13iU/L in CHH (P=0.0003) following kisspeptin administration. All eugonadal men had an LH increase >1.5iU/L, whereas all men with CHH had an LH increase <1.5iU/L following kisspeptin. In contrast, mean increase in serum LH from baseline following GnRH was 6.2±3.2iU/L in eugonadal men and 2.2±3.8iU/L in CHH (P=0.062). Therefore, whilst the kisspeptin-induced LH increase effectively discriminated men with HH from eugonadal men (area under ROC 1.0), GnRH-induced LH increase was less discriminatory (area under ROC 0.82). In eugonadal men, the maximal increase in LH following kisspeptin significantly predicted the maximal increase in LH following GnRH (univariate linear regression, r2=0.45; P=0.0013), however this relationship was lost in men with HH (r2=0.03; P=0.83). Conclusion: Collectively, these data confirm that a novel kisspeptin test of hypothalamic GnRH function can better discriminate men with CHH from eugonadal men than currently available investigations (such as GnRH test). Therefore, a kisspeptin test could offer significant clinical benefit for the accurate diagnosis and management of patients with hypogonadism.