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Reproduction under Siege: How Chronic Stress Hijacks the HPG Axis?
Duo Xu1, Xu Zhao1, Wanxin Chen1
1School of Public Health, Southern Medical University, Guangzhou, China.
Background:
Chronic stress profoundly disrupts homeostasis, with the hypothalamic-pituitary-gonadal (HPG) axis emerging as an active integrator rather than a passive target in stress pathophysiology.
Summary:
This review synthesizes evidence that chronic stress acts on the HPG axis at multiple levels: hypothalamic-pituitary-adrenal (HPA)-derived corticotropin-releasing hormone and glucocorticoids suppress the gonadotropin-releasing hormone (GnRH) pulse generator through kisspeptin/KNDy and gonadotropin-inhibitory hormone pathways; sympathetic overdrive impairs gonadal steroidogenesis while parasympathetic tone declines; and metabolic-inflammatory crosstalk amplifies suppression. The resulting decline in sex steroids - estradiol, progesterone, and testosterone - creates sex-specific vicious cycles that further dysregulate stress and immune circuits, contributing to affective, reproductive, and neurodegenerative disorders.
Key Messages:
The HPG axis serves as a critical hub integrating stress signals, and its suppression is an active, regulated process with distinct sex differences. Hormone-based interventions, including estrogen, neurosteroid analogs, and testosterone, show therapeutic promise for stress-related conditions, and future research should focus on the neural circuits and molecular switches that govern HPA-HPG crosstalk to enable personalized, neuroendocrine-informed therapies.
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