Journal September 25, 2026 6 min read

How does the HPA axis work?

The hypothalamic-pituitary-adrenal (HPA) axis is the neuroendocrine stress-response cascade linking hypothalamic corticotropin-releasing hormone release to pituitary adrenocorticotropic hormone secretion and adrenal gluc

peptides-pro Editorial

The hypothalamic-pituitary-adrenal (HPA) axis is the neuroendocrine cascade that converts central stress signalling into peripheral glucocorticoid output. It is also written as the hypothalamic-pituitary-adrenal axis, and its terminal effector hormones are the glucocorticoids, principally cortisol in humans and corticosterone in rodents. The axis is not a single molecule but a three-tier relay: hypothalamic corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN) drive pituitary adrenocorticotropic hormone (ACTH) release, which in turn drives adrenal steroidogenesis. The evidence summarised here does not supply a sequence, formula or molecular weight for the axis as a whole, because the axis is a system rather than a compound; where individual peptides are named, they are named as signalling components.

The work collected below centres on CRH/CRH-receptor signalling originating in the hypothalamic paraventricular nucleus, together with the glucocorticoid feedback that terminates the response, and on the parallel noradrenergic and sympathetic arms that interact with it.

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 under sleep restriction, and in parallel to evaluate deactivation of the hypothalamic-pituitary-gonadal (HPG) axis under the same condition [6]. Cognitive function associated with sleep restriction, including food intake and food cravings, was also examined [6]. The design therefore treats HPA activation and HPG deactivation as coupled responses to a single imposed stressor rather than as independent variables.

HPA axis activation and sleep restriction in a general adult cohort

A companion protocol applied the same two questions — how HPA axis activation occurs with sleep restriction, and how HPG axis deactivation occurs with sleep restriction — and again extended the assessment to cognitive function, food intake and food cravings [7]. The pairing of the two protocols indicates that the sleep-restriction model has been run across more than one population, which matters when comparing hormonal responses between age and sex groups.

CRH-driven HPA activation and noradrenergic signalling in PTSD

In post-traumatic stress disorder, the described pathophysiology is a complex noradrenergic dysregulation in which the amygdala activates the hypothalamus to release excessive corticotropin-releasing factor (CRF), which activates the HPA axis and leads to high nocturnal cortisol levels with EEG changes and increased arousals [1]. In the same account, the locus coeruleus releases excess norepinephrine, which interferes with the transition to non-REM sleep and suppresses the stability of REM sleep [1]. This is a clinical population — patients with PTSD — and the CRF/HPA and locus coeruleus/norepinephrine arms are presented as concurrent rather than sequential.

HPA axis dysregulation and neuroendocrine signalling in chronic prostatitis/chronic pelvic pain syndrome

A review of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) notes that traditional pathophysiological models emphasise infection and local inflammation, and that the limited efficacy of conventional therapies suggests deeper regulatory mechanisms are involved [3]. Synthesising five years of literature, the review focused on neuropeptide functions, HPA axis dysregulation, sympathetic nervous system signalling and glial cell contributions [3]. The population here is patients with CP/CPPS; the HPA axis appears as one of several interacting neuroendocrine pathways rather than as a standalone cause.

Cortisol as an HPA axis readout in cervicogenic headache among smartphone users

A study of cervicogenic headache — a secondary headache attributed to referred pain arising from the cervical spine, felt in the forehead and sometimes the temporal region — measured cortisol alongside BDNF in smartphone users [4]. The condition is described as affecting daily activities through decreased cervical range of motion, decreased sleep quality, increased stress, disturbed mood and altered physiologic chemicals, and as more prevalent in females [4]. Cortisol is used here as an index of HPA axis output in a musculoskeletal pain model.

HPA axis regulation as a proposed mechanism for muscadine wine polyphenols

A study of muscadine wine nutraceuticals hypothesised that 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]. The hypothesis is stated as a mechanism to be tested; the HPA axis is one of several proposed routes, not an established one.

HPA axis and cytokine signalling in cancer-related psychiatric disorders

A study in oncological psychiatry frames psychiatric disorders in cancer patients as frequently observed but underdiagnosed, and as potentially contributing to poor oncological outcomes rather than being merely secondary complications [2]. The pathophysiology is described as multifactorial and related to several neuropsychological and neurobiological factors, specifically including cytokine production [2]. The population is cancer patients; the HPA axis is situated within a broader neuroimmune account.

Exercise intensity and HPA axis response in Thoroughbred racehorses

Exercise is described as a physiological challenge that induces intensity-dependent HPA axis responses, and a study in Thoroughbred racehorses tested the hypothesis that training and racing sessions induce different degrees of HPA axis activation [10]. The work assessed whether different exercise sessions affect adrenal output in that species [10]. This is an animal model, and the findings should not be read across to human endocrine responses without separate human data.

α7 nicotinic receptor activation and CRH signalling in the hypothalamic paraventricular nucleus

Dysregulation of the HPA axis is described as a central feature of stress-related affective disorders, with corticotropin-releasing hormone neurons in the hypothalamic paraventricular nucleus initiating neuroendocrine stress responses [11]. A study examined α7 nicotinic acetylcholine receptor activation and its association with CREB/CRH signalling in the PVN, reporting that activation promoted anxiety- and depressive-like behaviours [11]. This is a mechanistic animal study of the CRH neuron as the initiating node of the axis.

Adaptogens and stress-resistance mechanisms

A narrative review describes adaptogens as primarily plant-derived bioactive compounds that enhance resistance to physical, chemical and biological stressors, with proposed relevance to stress-related disorders, neurodegenerative disease, inflammation and ageing [8]. The review is a synthesis rather than a primary dataset, and it is cited here for the framing of stress-resistance mechanisms, not for any specific HPA axis measurement.

Schisandrin B and hippocampal synaptic plasticity in an anxiety model

A rat study examined the anxiolytic effects of Schisandrin B in animals exhibiting anxiety-like behaviours, using the elevated plus-maze and open field tests, and reported effects at a dose of 10 mg/kg alongside investigation of hippocampal synaptic plasticity and intestinal barrier restoration [9]. This is an animal study; the dose is a laboratory administration in rats and is not a human dose.

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