Stress as a Neuroendocrine Modulator of the Reproductive Axis: Roles of Glucocorticoids, Kisspeptin, and Serotonergic...

Reproductive dysfunction is a major health concern affecting men and women globally, mediated by the activation of the hypothalamic-pituitary-adrenal axis as well as strongly influenced by exposure to stress. Consequently, this results in suppression of the hypothalamic-pituitary-gonadal (HPG) axis, facilitated by glucocorticoid signalling. Although we have a clear understanding of glucocorticoids as the main mediators of stress-induced reproductive suppression, evidence indicates that monoaminergic pathways, particularly serotonin (5-HT) and its receptors, play pivotal roles in linking stress to reproductive regulation. Kisspeptin neurons have emerged as crucial integrators of both glucocorticoid and serotonergic signals.

Current evidence from animal studies demonstrates that stress dysregulates reproductive function at multiple levels of the HPG axis. Glucocorticoids interact through combined genomic and non-genomic pathways to suppress the secretion of kisspeptin, gonadotropin-releasing hormone (GnRH), gonadotropins, as well as gonadal steroidogenesis. In addition to the well-established glucocorticoid mechanisms, monoamines such as 5-HT play a crucial role in mediating the link between stress and reproduction. Recent molecular, electrophysiological, and transcriptomic studies have highlighted the importance of the 5-HT7 receptor, which is highly expressed in kisspeptin neurons of the arcuate nucleus (ARC), where it acts as a critical excitatory driver of GnRH/luteinising hormone (LH) pulse generation. Stress, however, suppresses serotonergic signalling by lowering 5-HT levels and suppressing serotonin receptor expression, including 5-HT7 receptor, thereby reducing kisspeptin and GnRH neuronal excitation. Glucocorticoid-mediated suppression of kisspeptin signalling might be a key underexplored pathway contributing to stress-mediated reproductive dysfunction, particularly when combined with stress-induced reductions in 5-HT and 5-HT receptor expression, suggesting a dual suppressive mechanism.

Stress suppresses reproductive function through the coordinated actions of glucocorticoids and monoaminergic, particularly serotonergic, signalling. Kisspeptin neurons situated in the ARC of the hypothalamus act as crucial integrators of glucocorticoid and serotonergic inputs and are particularly susceptible to stress-induced alterations. Normally, serotonin-mediated excitation via the 5-HT7 receptors plays an important role in promoting both kisspeptin and GnRH secretion, which are indispensable for reproductive function. However, stress downregulates 5-HT7 receptor expression in the kisspeptin-producing neurons in the arcuate, leading to the subsequent suppression of GnRH and LH pulsatility. This disruption ultimately results in reproductive dysfunction.