Variation in Hypothalamic GnIH Expression and Its Association with GnRH and Kiss1 during Pubertal Progression in Male Rhesus Monkeys (Macaca mulatta)

SIMPLE SUMMARY: An increase in the pulsatile release of gonadotropin-releasing hormone (GnRH) is essential for the onset of puberty. However, the mechanisms controlling pubertal increases in GnRH release are still unclear. In primates the GnRH neurosecretory system is active during the neonatal period but subsequently enters a dormant state in the juvenile period. The present study examined developmental changes in the gonadotropin inhibitory hormone (GnIH) neuronal system, an inhibitory neuropeptidergic system upstream of GnRH neurons, and the relationship among changes that were observed in GnRH and kisspeptin (Kiss1) gene expression during puberty. A significant inverse age-related relationship between GnRH, Kiss1, and GnIH was observed, suggesting GnIH’s potential role in reproductive suppression prior to puberty, with this theoretical ‘brake’ during the pubertal transition. These findings underscore the need for further research on the role that is played by GnIH in reproductive transition to aid in the development of potential GnIH-based drugs to treat pubertal disorders and adult fertility. ABSTRACT: Modulation of pulsatile gonadotropin-releasing hormone (GnRH) secretion across postnatal development in higher primates is not fully understood. While gonadotropin-inhibitory hormone (GnIH) is reported to suppress reproductive axis activity in birds and rodents, little is known about the developmental trajectory of GnIH expression in rhesus monkeys throughout the pubertal transition. This study was aimed at examining the variation in GnIH immunoreactivity (-ir) and associated changes among GnIH, GnRH, and Kiss1 mRNA expression in the hypothalamus of infant, juvenile, prepubertal, and adult male rhesus monkeys. The brains from rhesus macaques were collected from infancy until adulthood and were examined using immunofluorescence and RT-qPCR. The mean GnIH-ir was found to be significantly higher in prepubertal animals (p < 0.01) compared to infants, and significantly reduced in adults (p < 0.001). Significantly higher (p < 0.001) GnRH and Kiss1 mRNA expression was noted in adults while GnIH mRNA expression was the highest at the prepubertal stage (p < 0.001). Significant negative correlations were seen between GnIH-GnRH (p < 0.01) and GnIH-Kiss1 (p < 0.001) expression. Our findings suggest a role for GnIH in the prepubertal suppression of the reproductive axis, with disinhibition of the adult reproductive axis occurring through decreases in GnIH. This pattern of expression suggests that GnIH may be a viable target for the development of novel therapeutics and contraceptives for humans.