What is the HPA Axis?

The hypothalamic-pituitary-adrenal (HPA) axis is the neuroendocrine signalling circuit that runs from the hypothalamus through the anterior pituitary to the adrenal cortex, and it is the principal endocrine system governing the glucocorticoid response to stress. It is also referred to in the literature as the hypothalamic-pituitary-adrenal axis, the HPA axis, and the stress axis; the related hypothalamic-pituitary-gonadal (HPG) axis is a separate but frequently co-measured system. The evidence block for this page does not supply a sequence, molecular formula or molecular weight for the axis as a whole, because the HPA axis is a multi-tissue regulatory pathway rather than a single molecular entity.

The work summarised here centres on corticotropin-releasing factor (CRF) and corticotropin-releasing hormone (CRH) signalling from the hypothalamic paraventricular nucleus, downstream adrenocorticotropic hormone (ACTH) output, and the resulting adrenal cortisol response, together with the noradrenergic and cytokine inputs that modulate the axis.

Research Studies

HPA axis activation and noradrenergic dysregulation in PTSD

A registered study of stellate ganglion block in patients with post-traumatic stress disorder describes PTSD as a chronic disorder developing after trauma exposure and characterised by intrusive experiences, avoidance, cognitive-emotional changes and hyperarousal, resting on complex noradrenergic dysregulation. In that model, the amygdala activates the hypothalamus to release excessive CRF, which activates the HPA axis and leads to high nocturnal cortisol levels with EEG changes and increased arousals. In parallel, the locus coeruleus releases excess norepinephrine, which interferes with the transition to non-REM sleep and suppresses REM sleep stability [1].

HPA axis dysregulation in chronic prostatitis / chronic pelvic pain syndrome

A comprehensive review synthesised evidence from the previous five years on neuroendocrine pathways in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). The authors note that traditional pathophysiological models emphasise infection and local inflammation, but that the limited efficacy of conventional therapies suggests deeper regulatory mechanisms. Their analysis focused on neuropeptide function, HPA axis dysregulation, sympathetic nervous system signalling and glial cell involvement [3].

Sleep restriction and HPA axis activation in older adults

A registered study in older men and postmenopausal women was designed to determine how HPA axis activation occurs with sleep restriction, and to evaluate how HPG axis deactivation occurs with the same intervention. Cognitive function associated with sleep restriction, including food intake and food cravings, was also examined [6]. A companion registered study with the same objectives was conducted in a broader participant group [7].

HPA axis and HPG axis responses compared across sleep restriction protocols

Cytokine signalling and psychiatric disorders in cancer patients

A registered study in oncological psychiatry notes that psychiatric disorders are frequently observed in cancer patients and are underdiagnosed, undermining possible interventions, and that such disorders are not merely secondary complications but may actively contribute to poor oncological outcomes. The pathophysiology is described as multifactorial and related to several neuropsychological and neurobiological factors, specifically including cytokine production [2].

Polyphenol intake, cognition and HPA axis regulation

A registered study of muscadine wine nutraceuticals notes that previous studies have shown polyphenol-rich foods can positively affect cognitive functions, memory and mood in humans. The investigators hypothesised that both acute and chronic intake of muscadine wine polyphenols would improve cognitive performance and mood through regulating the HPA axis, alleviating inflammation and oxidative stress, and/or inhibiting monoamine oxidase activities [5].

Cervicogenic headache, cortisol and BDNF in smartphone users

A registered study of isometric neck exercises in smartphone users describes cervicogenic headache as a secondary headache caused by referred pain arising from the cervical spine, with impact on daily activities, decreased cervical range of motion, decreased sleep quality, increased stress, disturbed mood and altered physiologic chemicals. The condition is reported as more prevalent in females and is experimentally diagnosed using the Cervical Flexion-Rotation Test, with the upper trapezius midpoint (2 cm lateral to C2) commonly acting as a pressure point [4].

Exercise-induced HPA axis responses in Thoroughbred racehorses

A study in Thoroughbred racehorses assessed whether different exercise sessions affect equine adrenal output. The authors frame exercise as a physiological challenge inducing intensity-dependent HPA axis responses, and hypothesised that training and racing sessions induce different degrees of HPA axis activation [10]. This finding is animal-only.

α7 nicotinic receptor signalling and CRH neurons in the paraventricular nucleus

A study reports that dysregulation of the HPA axis is a central feature of stress-related affective disorders, and that CRH neurons in the hypothalamic paraventricular nucleus initiate neuroendocrine stress responses. The work examined α7 nicotinic acetylcholine receptor activation and its association with CREB/CRH signalling in the paraventricular nucleus in relation to anxiety- and depressive-like behaviours [11].

Adaptogens and stress-related disorders

A narrative review summarises adaptogens as primarily plant-derived bioactive compounds reported to enhance resistance to physical, chemical and biological stressors, with proposed relevance to stress-related disorders, neurodegenerative disease, inflammation and ageing [8].

Schisandrin B and anxiety-like behaviour in rats

A study examined the anxiolytic effects of Schisandrin B in rats exhibiting anxiety-like behaviours, using the elevated plus-maze test and the open field test, and investigated enhancement of hippocampal synaptic plasticity and restoration of the intestinal barrier as mechanisms. Schisandrin B was administered at 10 mg/kg in that model [9]. This finding is animal-only.

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Sources

• [1] Identification of Physiological Sleep Indices That Reflect Clinical Improvement and Reduction in Stress Biomarkers After Stellate Ganglion Block in Patients With Posttraumatic Stress Disorder (PTSD) — https://clinicaltrials.gov/study/NCT07618611
• [2] MEOP - Multidimensional Evaluations in Oncological Psychiatry — https://clinicaltrials.gov/study/NCT07406113
• [3] Current research hotspots and difficulties of chronic prostatitis/chronic pelvic pain syndrome: neuroendocrine mechanism — https://europepmc.org/article/PMC/PMC12821347
• [4] Effect of Isometric Neck Exercises on Cervicogenic Headache Symptoms, Cortisol and BDNF Levels Among Smart Phone Users — https://clinicaltrials.gov/study/NCT07354776
• [5] Use Muscadine Wine Nutraceuticals to Improve Brain Health, Cognition, and Mental Health — https://clinicaltrials.gov/study/NCT05541887
• [6] Hormonal Mechanisms of Sleep Restriction - Axis Study in Older Men and Postmenopausal Women — https://clinicaltrials.gov/study/NCT04037605
• [7] Hormonal Mechanisms of Sleep Restriction - Axis Study — https://clinicaltrials.gov/study/NCT03142893
• [8] Phyto adaptogens in stress management and health optimization: Current understanding and future perspectives — https://pubmed.ncbi.nlm.nih.gov/42721096/
• [9] Mechanistic Study of Schisandrin B in Alleviating Anxiety-Like Behaviors in Rats via Enhancement of Hippocampal Synaptic Plasticity and Restoration of the Intestinal Barrier — https://pubmed.ncbi.nlm.nih.gov/42718869/
• [10] Training- and competition-related changes on circulating adrenocorticotropic hormone and cortisol response in Thoroughbred Racehorses — https://pubmed.ncbi.nlm.nih.gov/42697342/
• [11] α7 nicotinic acetylcholine receptor activation promotes anxiety- and depressive-like behaviors associated with CREB/CRH signaling in the hypothalamic paraventricular nucleus — https://pubmed.ncbi.nlm.nih.gov/42685894/