Common misconceptions about the HPA axis

The hypothalamic-pituitary-adrenal (HPA) axis is the neuroendocrine system comprising the paraventricular nucleus (PVN) of the hypothalamus, the anterior pituitary, and the adrenal cortex, linked by corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and glucocorticoids such as cortisol. It is a pathway, not a gland and not a single hormone; the term is sometimes written as the hypothalamic-pituitary-adrenal axis or HPA axis, and it is classified as a neuroendocrine feedback loop rather than a compound. The evidence block for this page does not supply a sequence, formula, or molecular weight for the axis as a whole, and none is asserted here.

The work summarised below centres on the CRH/ACTH/cortisol signalling cascade and its regulation by noradrenergic input from the locus coeruleus, together with the cytokine and neuropeptide networks that intersect with it [1][2][3].

Research Studies

HPA axis activation and sleep restriction in older men and postmenopausal women

A study in older men and postmenopausal women was designed to determine how HPA axis activation occurs with sleep restriction and to evaluate how hypothalamic-pituitary-gonadal (HPG) axis deactivation occurs with the same intervention. Cognitive function, food intake, and food cravings were also examined [6].

HPA axis activation and sleep restriction in a general adult population

A parallel study addressed the same two questions — how HPA axis activation occurs with sleep restriction and how HPG axis deactivation occurs with sleep restriction — and likewise examined cognitive function, food intake, and food cravings [7].

Noradrenergic drive, CRF release, and nocturnal cortisol in PTSD

In post-traumatic stress disorder, the literature describes a complex noradrenergic dysregulation in which the amygdala activates the hypothalamus to release excessive corticotropin releasing factor (CRF), which in turn activates the HPA axis and leads to high nocturnal cortisol levels with EEG changes and increased arousals. Concurrently, the locus coeruleus releases excess norepinephrine, which interferes with the transition to non-REM sleep and suppresses the stability of REM sleep [1].

Stellate ganglion block and stress biomarkers in PTSD

A registered study in patients with PTSD examined physiological sleep indices that reflect clinical improvement and reduction in stress biomarkers after stellate ganglion block [1].

HPA axis regulation and polyphenol intake in humans

A study in humans 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].

HPA axis dysregulation in chronic prostatitis/chronic pelvic pain syndrome

A comprehensive review synthesised five years of evidence on neuroendocrine pathways in chronic prostatitis/chronic pelvic pain syndrome. The analysis focused on neuropeptide functions, HPA axis dysregulation, sympathetic nervous system signalling, and glial cell involvement, noting that traditional models emphasising infection and local inflammation have limited explanatory power for the condition [3].

Cytokine signalling and psychiatric disorders in cancer patients

A study in cancer patients addressed the multifactorial pathophysiology of cancer-related psychiatric disorders, describing contributions from several neuropsychological and neurobiological factors and specifically the production of cytokines [2].

Cortisol and BDNF in cervicogenic headache among smartphone users

A study in smartphone users with cervicogenic headache examined the effect of isometric neck exercises on headache symptoms together with cortisol and BDNF levels. The condition was described as a secondary headache arising from referred pain in the cervical spine, associated with decreased cervical range of motion, decreased sleep quality, increased stress, disturbed mood, and altered physiologic chemicals [4].

Adrenocorticotropic hormone and cortisol responses to exercise in Thoroughbred racehorses

In Thoroughbred racehorses, exercise is described as a physiological challenge that induces intensity-dependent HPA axis responses. The study assessed whether different exercise sessions — training and racing — affect equine adrenal output differently [10].

α7 nicotinic acetylcholine receptor signalling and CRH neurons in the PVN

In an animal model, activation of the α7 nicotinic acetylcholine receptor was reported to promote anxiety- and depressive-like behaviours associated with CREB/CRH signalling in the hypothalamic paraventricular nucleus. CRH neurons in the PVN are described as initiating neuroendocrine stress responses, and HPA axis dysregulation is characterised as a central feature of stress-related affective disorders [11].

Schisandrin B and anxiety-like behaviour in rats

In rats exhibiting anxiety-like behaviours, Schisandrin B was examined for anxiolytic effects and for mechanisms involving hippocampal synaptic plasticity and restoration of the intestinal barrier. Behavioural assessment used the elevated plus-maze test and the open field test, and the reported dose was 10 mg/kg [9].

Phyto adaptogens and stress management

A narrative review summarised 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 diseases, inflammation, and ageing [8].

If you are reading this for personal health reasons

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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/