Deciphering the Contributions of CRH Receptors in the Brain and Pituitary to Stress-Induced Inhibition of the Reproductive Axis.

Androniki Raftogianni,Claudia Kühne,Daniel J Spergel,Diego García-González,Lena C Roth,Jan M Deussing,Thorsten Bus,Hannah Monyer,Valery Grinevich

doi:10.3389/fnmol.2018.00305

Abstract

Based on pharmacological studies, corticotropin-releasing hormone (CRH) and its receptors play a leading role in the inhibition of the hypothalamic–pituitary–gonadal (HPG) axis during acute stress. To further study the effects of CRH receptor signaling on the HPG axis, we generated and/or employed male mice lacking CRH receptor type 1 (CRHR1) or type 2 (CRHR2) in gonadotropin-releasing hormone neurons, GABAergic neurons, or in all central neurons and glia. The deletion of CRHRs revealed a preserved decrease of plasma luteinizing hormone (LH) in response to either psychophysical or immunological stress. However, under basal conditions, central infusion of CRH into mice lacking CRHR1 in all central neurons and glia, or application of CRH to pituitary cultures from mice lacking CRHR2, failed to suppress LH release, unlike in controls. Our results, taken together with those of the earlier pharmacological studies, suggest that inhibition of the male HPG axis during acute stress is mediated by other factors along with CRH, and that CRH suppresses the HPG axis at the central and pituitary levels via CRHR1 and CRHR2, respectively.

Highlights

It is well accepted that stress has a negative impact on reproductive function (Lovejoy and Barsyte, 2011)
Male Gonadotropin-releasing hormone (GnRH)-green fluorescent protein (GFP) transgenic mice (Table 1) ranging in age from postnatal day (P) 28, which is around the time at which the HPG axis becomes active (Bell, 2018), to P44 were used for ex vivo electrophysiology experiments, whereas male transgenic and wild type (WT) mice ranging in age from P90 to P180 were used for stress, infusion, and cell culture experiments
After verifying the fidelity of Cre expression in GnRH neurons and the efficiency of Cre recombination induced by tamoxifen injection, these mice were bred with CRH receptor type 1 (CRHR1)-2LoxP mice (Muller et al, 2003) to generate GnRH-CRHR1 conditional knockout (GnRHCRHR1 CKO) mice

Summary

Introduction

It is well accepted that stress has a negative impact on reproductive function (Lovejoy and Barsyte, 2011). It was demonstrated that the central neuropeptide of the hypothalamic–pituitary–adrenocortical (HPA) axis, corticotropin-releasing hormone (CRH), profoundly suppresses the activity of the hypothalamic– pituitary–gonadal (HPG) axis mainly at the central level Studies showed that central infusion of CRH receptor antagonists reverses acute stress-induced inhibition of luteinizing hormone (LH) levels in rats (Rivier et al, 1986; Maeda et al, 1994; Rivest and Rivier, 1995), suggesting that CRH receptor signaling is required for stress-induced suppression of the HPG axis. GnRH reaches the pituitary via the hypophyseal portal circulation (Levine and Ramirez, 1982), binds to GnRH receptors on gonadotropes, and stimulates the release of LH and FSH into the bloodstream (Gharib et al, 1990; Lopez et al, 1998; Bliss et al, 2010; Gongrich et al, 2016)

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