Corticotrophin-releasing factor and stress-induced inhibition of the gonadotrophin-releasing hormone pulse generator in the female

Abstract

It is well established that stress activates the hypothalamo–pituitary–adrenal (HPA) axis and suppresses the hypothalamo–pituitary–gonadal (HPG) axis. A large literature dealing with various stressors that regulate gonadotrophin-releasing hormone (GnRH) secretion in a variety of species (including nonhuman primates, sheep, and rats) provides evidence that stress modulates GnRH secretion by activating the corticotrophin-releasing factor (CRF) system and sympathoadrenal pathways, as well as the limbic brain. Different stressors may suppress the HPG axis by activating or inhibiting various pathways in the CNS. In addition to CRF being the principal hypophysiotropic factor driving the HPA axis, it is a potent inhibitor of the GnRH pulse generator. The suppression of the GnRH pulse generator by a variety of stressful stimuli can be blocked by CRF antagonists, suggesting a pivotal role for endogenous CRF. The differential roles for CRF receptor type 1 (CRF-R1) and CRF-R2 in stress-induced suppression of the GnRH pulse generator add to the complexity of CRF regulation of the HPG axis. Although the precise sites and mechanisms of action remain to be elucidated, noradrenergic and gamma-amino-butyric acid (GABA) neurones are implicated in the system's regulation, and opioids and kisspeptin in the medial preoptic area (mPOA) and hypothalamic arcuate nucleus (ARC) may operate downstream of the CRF neuronal system.

Introduction

There is overwhelming evidence that a myriad of stressors suppress the activity of the hypothalamo–pituitary–gonadal (HPG) axis, specially its central regulator, the gonadotrophin-releasing hormone (GnRH) pulse generator, resulting in reproductive dysfunction. The GnRH pulse generator is defined as the neural construct that eventuates in the pulsatile discharge of luteinizing hormone (LH) into the peripheral circulation. The activity of the GnRH pulse generator can be assessed by the monitoring of pulsatile LH secretion and/or any antecedent or associated events such as GnRH release, the electrophysiological manifestations of associated neurosecretory processes or other cognate phenomena (Chen et al., 1992). The hypothalamic multiunit electrical activity (MUA) volleys invariably associated with LH pulses, which provide the most robust electrophysiological correlate of GnRH pulse generator activity, have been recorded solely from the arcuate nucleus (ARC) of rats, goats, and primates (O'Byrne and Knobil, 1993, Kinsey-Jones et al., 2008, Ohkura et al., 2009). Although the frequency of LH pulses directly correlates to the activity of the GnRH pulse generator, with each pulse of LH resulting directly from a secretory episode of GnRH from the hypothalamus (Clarke, 1992), the amplitude of LH pulses more likely reflects pituitary responsiveness to GnRH. However, there is a growing appreciation of modulation of GnRH pulse amplitude (Wagenmaker et al., 2009).

The stress models most frequently used to investigate the mechanism of stress-induced suppression of the GnRH pulse generator have been immunological challenge (e.g., endotoxin or cytokines), psychological restraint or isolation, and metabolic perturbation (insulin-induced hypoglycaemia, fasting, or exercise). Hypoglycaemic stress in monkeys (Fig. 1) (Chen et al., 1992) and lipopolysaccharide (LPS) immunological stress in goats (Takeuchi et al., 1997) and rats (Yoo et al., 1997) have been shown to decrease the frequency of MUA volleys. Endotoxins inhibit pulsatile GnRH secretion in the pituitary portal blood of sheep (Williams et al., 2001). Numerous studies have demonstrated that hypoglycaemia, LPS, or restraint/confinement stress result in suppression of pulsatile LH secretion in rats (Li et al., 2006, Matsuwaki et al., 2006), sheep (Clarke et al., 1990, Dobson et al., 1999, Tilbrook et al., 1999, Wagenmaker et al., 2009), and monkeys (Chen et al., 1996). Although activation of the hypothalamo–pituitary–adrenal (HPA) axis during stress commonly coincides with suppression of the HPG axis, for example, functional hypothalamic amenorrhoea is associated with hypercortisolism in which a disruption of pulsatile LH secretion is observed (Suh et al., 1988), causality is undetermined. CRF in the hypothalamic paraventricular nucleus (PVN) is the principal factor driving the HPA axis, but CRF is also highly expressed in other brain regions including the amygdala and the bed nucleus of the stria terminalis (BNST) where it increases in response to stress (Chalmers et al., 1995). Intracerebroventricular (ICV) administration of CRF inhibited MUA volleys in monkeys (Williams et al., 1990) and LH pulses in rats (Cates et al., 2004), and CRF antagonists can reverse stress-induced suppression of the GnRH pulse generator in these species (Chen et al., 1996, Cates et al., 2004, Li et al., 2006). In contrast, in the ewe ICV administration of CRF either dramatically increased (Naylor et al., 1990, Caraty et al., 1997) or had no effect (Clarke et al., 1990, Caraty et al., 1997) on LH pulse frequency, suggesting a major species difference in the action of CRF on GnRH pulse generator activity. In addition, CRF antagonist was unable to prevent the inhibitory effect of hypoglycaemic stress on LH pulses in the sheep (Clarke et al., 1990). The role of vasopressin (AVP) (which synergises with CRF in the HPA axis) in the regulation of the GnRH pulse generator during stress remains controversial; although AVP antagonists are able to block the suppressive effects of hypoglycaemia on pulsatile LH secretion in some studies (Heisler et al., 1994, Xiao et al., 1996) other investigations did not find corroborating evidence (Cates et al., 1999, Chen et al., 1996). The sympathetic nervous system responds rapidly to stressors, involving noradrenaline (NA) neurones in the locus coeruleus (LC) that provides one of the major sources of NA to the PVN, which is involved in stress-induced suppression of LH pulses (Maeda et al., 1994). There is substantial evidence for a role for endogenous opioid peptides (EOPs) and GABA in the regulation of GnRH pulse generator activity during stress and their involvement as downstream effectors of CRF.

Although stress can potentially influence the reproductive system at any level of the HPG axis, and stress also affects LH pulse amplitude and the preovulatory LH surge (for extensive review, see Ferin, 2006), this review focuses on the central neuroendocrine mechanisms, and in particular the role of CRF, in the suppression of pulsatile LH secretion in the female.