Hypothalamic KISS 1 Expression, Gonadotrophin‐Releasing Hormone and Neurotransmitter Innervation Vary with Stress and Sensitivity in Macaques

The present study examined the effect of short‐term psychosocial and metabolic stress in a monkey model of stress‐induced amenorrhaea on the hypothalamic‐pituitary‐gonadal axis. KISS 1 expression was determined by in situ hybridisation in the infundibular arcuate nucleus. Downstream of KISS 1, gonadotrophin‐releasing hormone ( G n RH) axons in lateral areas rostral to the infundibular recess, serum luteinising hormone (LH) and serum oestradiol were measured by immunohistochemistry and radioimmunoassay . Upstream of KISS 1, norepinephrine axons in the rostral arcuate nucleus and serotonin axons in the anterior hypothalamus and periaqueductal grey were measured by immunohistochemistry . Female cynomolgus macaques ( M acaca fascicularis ) characterised as highly stress resilient ( HSR ) or stress sensitive ( SS ) were examined. After characterisation of stress sensitivity, monkeys were either not stressed, or mildly stressed for 5 days before euthanasia in the early follicular phase. Stress consisted of 5 days of 20% food reduction in a novel room with unfamiliar conspecifics. There was a significant increase in KISS 1 expression in HSR and SS animals in the presence versus absence of stress (P = 0.005). G n RH axon density increased with stress in HSR and SS animals (P = 0.015), whereas LH showed a gradual but nonsignificant increase with stress. Oestradiol trended higher in HSR animals and there was no effect of stress (P = 0.83). Norepinephrine axon density (marked with dopamine β‐hydroxylase) increased with stress in both HSR and SS groups (P ≤ 0.002), whereas serotonin axon density was higher in HSR compared to SS animals and there was no effect of stress (P = 0.03). The ratio of dopamine β‐hydroxylase / oestradiol correlated with KISS 1 (P = 0.052) and G n RH correlated with serum LH (P = 0.039). In conclusion, oestradiol inhibited KISS 1 in the absence of stress, although stress increased norepinephrine , which may over‐ride oestradiol inhibition of KISS 1 expression. We speculate that neural pathways transduce stress to KISS 1 neurones, which changes their sensitivity to oestradiol .