RF9 Rescues Cortisol-Induced Repression of Testosterone Levels in Adult Male Macaques.

Rahim Ullah,Aalia Batool,Muhammad Shahab,Madiha Wazir,Fazal Wahab,Ghulam Nabi,Rabia Naz,Tanzil Ur Rahman,Junfen Fu

doi:10.3389/fphys.2021.630796

Abstract

Cortisol inhibits hypothalamic-pituitary-gonadal (HPG) axis whereas RF9, a potent agonist of kisspeptin receptor (GPR54) activates HPG-axis during fasting-induced stress and under normal physiological conditions. However, the effect of RF9 on the cortisol-induced repressed HPG-axis is not studied yet. This study investigated whether exogenous cortisol-induced repression of the HPG-axis can be rescued by RF9. Six intact adult male rhesus monkeys (Macaca mulatta) habituated to chair-restraint were administered hydrocortisone sodium succinate at a rate of 20 mg/kg of body weight (BW) per day for 12 days. Single blood sample was taken by venipuncture from each animal on alternate days for hormones analyses. On experimental day 12, hydrocortisone treated monkeys received a single intravenous bolus of RF9 (n = 3) and vehicle (n = 3). The animals were bled for a period of 4 h at 60 min intervals from an indwelling cannula in the saphenous vein. RF9 was administered intravenously at the dose of 0.1 mg/kg BW immediately after taking 0 min sample. Plasma cortisol and testosterone concentrations were measured by using specific enzyme immunoassays. Hydrocortisone treatment increased plasma cortisol levels (P ≤ 0.0001) and decreased plasma testosterone (P ≤ 0.0127) levels. Interestingly, compared to vehicle, RF9 treatment significantly increased plasma testosterone levels at 120 min (P ≤ 0.0037), 180 min (P ≤ 0.0016), and 240 min (P ≤ 0.0001) intervals in the hydrocortisone treated monkeys. From these results, we concluded that RF9 administration relieves the suppressed HPG-axis in term of plasma testosterone levels in the cortisol treated monkeys.

Highlights

Successful reproduction is the result of a dynamic balance between the stimulatory and inhibitory signals of the central nervous system (CNS) (Wahab et al, 2015; Ullah et al, 2016)
Gonadotropin-releasing hormone is centrally regulated by various neuropeptides including agouti-related protein (AgRP), neuropeptide Y (NPY), corticotrophin-releasing hormone (CRH), alpha-melanocyte-stimulating hormone (α-MSH), kisspeptin, and gamma-aminobutyric acid (GABA) (Wahab et al, 2015; Ullah et al, 2016)
One-way ANOVA indicated that plasma cortisol levels were raised acutely (P ≤ 0.0001) on all post-treatment days compared to pre-treatment concentrations (Supplementary Figure 1A)

Summary

Introduction

Successful reproduction is the result of a dynamic balance between the stimulatory and inhibitory signals of the central nervous system (CNS) (Wahab et al, 2015; Ullah et al, 2016). Gonadotropin-releasing hormone is centrally regulated by various neuropeptides including agouti-related protein (AgRP), neuropeptide Y (NPY), corticotrophin-releasing hormone (CRH), alpha-melanocyte-stimulating hormone (α-MSH), kisspeptin, and gamma-aminobutyric acid (GABA) (Wahab et al, 2015; Ullah et al, 2016). Likewise, peripheral hormones such as leptin, ghrelin, insulin, cortisol, etc., regulate GnRH neurons (Wahab et al, 2015; Ullah et al, 2016). These studies reported that RF9 failed to activate GnRH neurons and gonadotropin secretions in GPR54 knock-out set up (Liu and Herbison, 2014; Min et al, 2015)

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Conclusion