Cortisol Signaling in Stress-Induced Pathophysiology: Molecular Mechanism and Therapeutic Implication

Abstract

Cortisol is a glucocorticoid hormone essential for the physiological stress response. Its secretion is controlled by the hypothalamic-pituitary-adrenal (HPA) axis, which coordinates the body's adaptive behaviour to internal and external stressors. Cortisol has extensive effects on metabolic control, the immune system, and the heart. Although brief increases are necessary to sustain homeostasis in response to acute stress, persistent hypercortisolemia impairs normal circadian rhythmicity and also contributes to insulin resistance, visceral adiposity, and increased neuronal degeneration. Together, these perturbations result in a continuum of stress-related pathologies, such as major depressive disorder, anxiety disorders, metabolic syndrome, cardiovascular disease, and neurodegenerative pathologies such as Alzheimer-type dementia. This review incorporates recent molecular understanding of the genomic and non-genomic processes involved in cortisol activity, circadian disruption, and pro-inflammatory pathways, thereby explaining the mechanistic connections between chronic stress and the development of disease. New treatment options, such as selective glucocorticoid receptor modulators (SEGRMs), aim at repairing HPA axis homeostasis with as few adverse effects on the system as possible. Moreover, biosensor platforms, monitoring and detection systems based on proteolytic enzymes, and modern imaging techniques, including functional magnetic resonance imaging and positron emission tomography, can be used to monitor real-time metabolic and neurophysiological changes. Knowledge of the impact of adrenal signalling pathways on systemic physiology underpins personalised intervention measures that have the potential to reduce maladaptive stress responses and prevent the development of chronic pathology.