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

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.

Research Highlights
► Stress or CRF inhibits the GnRH pulse generator.
► Specific roles for CRF receptor type 1 and 2 in different stressors.
► Stress and CRF downregulate kisspeptin and its receptor in the hypothalamus.
► Activation of GABA in the preoptic area by stress is correlated to suppression of LH.
► CRF in the limbic system and locus coeruleus is involved in LH pulse suppression.