HPA Axis Support

HPA Axis Support: A Nutritional and Natural-Health Reference

1. Definition and Overview

The hypothalamic–pituitary–adrenal (HPA) axis is a complex set of direct influences and feedback interactions among three components: the hypothalamus (a part of the brain located below the thalamus), the pituitary gland (a pea-shaped structure located below the hypothalamus), and the adrenal glands (small, conical organs on top of the kidneys). The HPA axis is a major neuroendocrine system that controls reactions to stress and regulates many body processes, including digestion, immune responses, mood and emotions, sexual activity, and energy storage and expenditure.

The hypothalamic-pituitary-adrenal axis is a complex system of neuroendocrine pathways and feedback loops that function to maintain physiological homeostasis. By regulating the plasma levels of corticosteroids secreted from adrenal glands, it also controls many bodily processes, including mood and emotions, digestion, sexuality, the immune system, energy storage and expenditure.

In the nutrition and natural-health context, the term HPA axis support refers to dietary, lifestyle, and supplemental strategies aimed at maintaining or restoring the balanced function of this neuroendocrine system, particularly when it has been altered by chronic stress or other modifiable factors. Dysfunction of the HPA axis can manifest as abnormal cortisol rhythms, impaired stress resilience, mood disturbances, immune dysregulation, and chronic fatigue.

2. Physiology of the HPA Axis

2.1 The Hormonal Cascade

The HPA axis is a major neuroendocrine system that regulates responses to physical, emotional, and metabolic stress. It links the hypothalamus, anterior pituitary, and adrenal cortex through a coordinated series of hormonal signals. The cascade proceeds as follows:

• Corticotropin-releasing hormone (CRH) travels to the anterior pituitary gland, triggering it to release adrenocorticotropic hormone (ACTH) into the bloodstream.
• ACTH reaches the adrenal glands and binds to the outer layer (adrenal cortex), specifically the zona fasciculata region, which then produces and releases cortisol into the bloodstream.
• ACTH activation stimulates the synthesis and release of glucocorticoids such as cortisol and adrenal androgens from the zona fasciculata and zona reticularis of the adrenal cortex, respectively.

2.2 Negative Feedback and Circadian Rhythm

The HPA axis uses a negative feedback loop to maintain homeostasis. When cortisol levels rise, receptors in the hypothalamus and hippocampus detect the increase and signal the system to stop producing more, preventing overstimulation and helping the body return to a steady state after stress.

The HPA axis can be activated in three ways: activation due to the internal biological clock located in the hypothalamic suprachiasmatic nucleus (SCN), which maintains a rhythmic activity in the HPA system, creating a circadian rhythm; the pulsatile release of hormones and the negative feedback loops within the HPA axis; and stressful situations, which can activate the HPA axis, leading to an additional release of cortisol superimposed on the circadian and ultradian rhythms.

Diurnal cortisol declines from waking to evening in response to circadian modulation from the suprachiasmatic nucleus (SCN) of the hypothalamus; a declining slope is an indicator of a healthy, intact system.

2.3 Body Systems Involved

The HPA axis describes a complex set of positive and negative feedback influences between the hypothalamus, pituitary gland, and adrenal gland. These mechanisms work in a neuroendocrine manner to modulate a number of physiological processes such as immunity, fertility, and the body's response to stress.

The stress response orchestrated by the HPA axis is a well-choreographed multi-system response, involving behavioral, physiological, and metabolic responses, with tightly regulated components that need to become active at the appropriate times and in the appropriate contexts. ACTH is produced via enzymatic processing of pro-opiomelanocortin (POMC); cleavage of POMC generates not just ACTH, but also melanocyte-stimulating hormone (MSH), endorphins, and enkephalins, which regulate pain and mood.

3. HPA Axis Dysfunction: How It Presents

3.1 Overactivation and Underactivation

Experiencing frequent or intense stress and other issues can cause dysfunction with the HPA axis. The HPA axis can become overactive (typically called HPA axis dysfunction) or underactive (HPA axis suppression). Chronic stress leads to reduced sensitivity of the negative feedback system that governs the HPA axis. The loss of this negative feedback system is due to an increased level of circulating glucocorticoids.

Importantly, dysregulation of the HPA axis can occur both during exposure to chronic stress as well as for weeks to months after the cessation of the chronic stress. HPA axis dysregulation can typically be characterized by distinct phases as a result of dissociation between the output of ACTH from pituitary corticotrophs and glucocorticoids from the adrenal fasciculata cells.

3.2 Signs and Functional Presentations

Dysfunction in this system—often caused by chronic stress or trauma—can lead to fatigue, anxiety, depression, and immune issues. More specifically:

• Cognitive: Cognitive and mood changes are frequently observed due to the direct impact of altered cortisol levels on the brain. Sustained high cortisol exposure is detrimental to the hippocampus, a region important for memory and emotional regulation, potentially leading to reduced volume and synaptic dysfunction. These neurobiological changes are associated with persistent fatigue, difficulty concentrating ("brain fog"), anxiety, and depressive symptoms.
• Sleep: Individuals may experience sleep disturbances, including difficulty falling asleep, staying asleep, or waking up feeling unrefreshed.
• Metabolic and physical: Physical symptoms may include unexplained weight changes, particularly around the abdominal area, and digestive issues like irritable bowel syndrome (IBS)-like symptoms. A weakened immune function and altered pain perception are also possible.
• Mood: Adults may experience a more pronounced impact of chronic stress on the HPA axis, leading to persistent dysregulation of cortisol levels, which can contribute to a range of psychiatric symptoms including an increased risk for anxiety and depressive disorders.

3.3 Downstream Disease Risk

HPA axis dysregulation results in downstream physiological consequences, increasing risk for immune system dysfunction, mood disorders, metabolic disease, and cardiovascular disease. Disorders related to disrupted HPA function include depression, post-traumatic stress disorder (PTSD), metabolic dysfunction, and anxiety disorders.

Chronic stress leads to impaired HPA axis feedback, glucocorticoid receptor resistance, and paradoxical cortisol dysregulation, fostering a pro-inflammatory state. The chronic stress-induced HPA axis dysfunction interacts with inflammatory pathways and generates oxidative stress, contributing to cellular damage and neuroinflammation that further aggravates depressive symptoms. These processes result in structural and functional alterations in the hippocampus, which is essential for emotional regulation and cognitive function.

4. Contributing and Associated Factors

4.1 Chronic Psychological Stress

Chronic psychological stress, such as demanding work environments or unstable relationships, is a common initiating factor. This persistent perception of threat keeps the HPA axis constantly engaged, preventing necessary rest and recovery. Chronic psychological stress, adverse childhood experiences, and a lack of social support are significant contributors to HPA axis dysfunction. These factors can lead to persistent activation of the HPA axis, resulting in maladaptive stress responses and an increased risk of stress-related diseases.

4.2 Early Life Stress and Trauma

Traumatic experiences, especially those occurring in early life, can profoundly influence the set point and sensitivity of the HPA axis for decades. Early-life trauma causes lasting structural and regulatory changes, predisposing an individual to an over- or under-reactive stress response later in life.

Emerging epidemiological evidence demonstrates that adverse early-life stress-induced dysregulation of the HPA axis increases vulnerability for metabolic disorders. In particular, exposure to an adverse environment during prenatal and postnatal periods — including lack of nutrition, traumatic experiences such as childhood physical or sexual abuse, neglect, or medical trauma — has been demonstrated to be one of the major risk factors contributing to the development of metabolic disorders including insulin resistance, type 2 diabetes mellitus, and hyperlipidemia.

Components of the HPA axis negative-feedback loop may be more plastic during infancy than at any other point in childhood, and exposure to trauma during this time may result in poor HPA axis recovery from acute stress that extends at least until adolescence.

4.3 Inflammation

Biological stressors like chronic inflammation also trigger HPA axis activation. Pro-inflammatory cytokines, signaling molecules released during infection or autoimmune conditions, can pass the blood-brain barrier and directly stimulate the hypothalamus — treating the body's internal inflammatory state as a persistent external stressor.

4.4 Sleep Disruption

Poor sleep quality, sleep deprivation, and sleep disorders can lead to HPA axis dysregulation, characterized by elevated cortisol levels and altered stress responses. HPA axis dysregulation is commonly seen in obesity, sleep deprivation, and sleep disorders such as obstructive sleep apnea (OSA) and insomnia. Many studies have shown an increase in cortisol levels during the nighttime period of total sleep deprivation and in the prolonged wakefulness of the following day.

4.5 Dietary Imbalances

Western-like, high-fat diets elicit deregulation of the HPA axis and glucocorticoid release and lower hippocampal volumes, besides inducing a plethora of other effects including insulin resistance, inflammation, microglia activation, and cognitive impairments. Micronutrient deficiencies — including deficiencies in omega-3 fatty acids, B vitamins, magnesium, and zinc — can impair HPA axis function.

4.6 Genetic and Epigenetic Factors

Abnormal development of the HPA axis can result in long-term alterations in neuropeptide and neurotransmitter synthesis in the central nervous system, as well as glucocorticoid hormone synthesis in the periphery. Together, these changes can potentially lead to a disruption in neuroendocrine, behavioral, autonomic, and metabolic functions in adulthood. The literature reviewed in the American Journal of Medicine (2025) notes that sources on HPA axis dysfunction include studies on genetic and epigenetic influences, and evidence supports the role of early life stress, trauma, coping styles, and social environments in modulating HPA activity and stress-related outcomes.

4.7 Circadian Misalignment

In an observational study, night workers had attenuated cortisol secretion during work hours and more pronounced social jet lag than day workers, indicating HPA-axis dysregulation. Dietary timing also matters, as irregular meal patterns (e.g., late-night eating or prolonged fasting) can disrupt cortisol, and HPA axis dysfunction is influenced by a complex interplay of internal and external stressors, including chronic psychological stress, dietary imbalances, and disrupted circadian rhythms.

5. Nutrients, Herbs, and Natural Ingredients

The following substances have been studied or used in relation to HPA axis function. Traditional use and scientific evidence are presented separately for each, with honest characterization of evidence strength.

5.1 Ashwagandha (Withania somnifera)

Traditional Use

Ashwagandha (Withania somnifera), a well-established herb in Ayurvedic medicine, is increasingly researched for its adaptogenic properties and regulatory roles in neuroimmune processes. Adaptogens such as Withania somnifera are commonly used in Ayurvedic medicine for stress relief and ameliorating HPA axis dysfunction. In Ayurveda, the root was used as a rasayana (rejuvenating tonic), prepared as a root powder (churna) taken with milk or ghee, and was traditionally indicated for fatigue, debility, and nervous exhaustion.

Scientific Evidence

Research integrates mechanistic, preclinical, and clinical evidence on ashwagandha's immunomodulatory, neuroprotective, psychiatric, sleep-regulating, and anti-inflammatory activities, with emphasis on its bioactive compounds such as withanolides, sitoindosides, and alkaloids. Such compounds modulate the HPA axis, inhibit NF-κB, induce Nrf2 activation, and affect GABAergic signaling, collectively contributing to its anti-inflammatory, antioxidant, and anxiolytic actions.

Clinical trials with standardized ashwagandha extracts have shown reductions in stress-related biomarkers, along with improvements in cognitive performance, sleep quality, and mood parameters.

A 2020 double-blind, randomized, placebo-controlled clinical study (published on PubMed, PMID 32021735) found that serum cortisol levels were reduced with both ashwagandha 250 mg/day and 600 mg/day (p < 0.05 and p < 0.0001, respectively), and participants receiving ashwagandha had significant improvement in sleep quality compared to the placebo group. A significant reduction in Perceived Stress Scale (PSS) scores was also observed with both doses.

A 2024 randomized, double-blinded, placebo-controlled study examined three doses of a water-extracted ashwagandha (WS): an 8-week comparison of WS doses of 125, 250, and 500 mg was performed, with 131 adults enrolled and 98 included in the final analysis. A review demonstrated that supplementation with 250–500 mg of ashwagandha extract daily for 4 to 13 weeks significantly decreased morning cortisol levels in adults experiencing higher stress levels.

A 2025 systematic review and meta-analysis (PMC12242034) concluded that ashwagandha supplementation is safe and effective in reducing stress and anxiety in adult patients, resulting in a statistically significant reduction of cortisol levels, PSS scale, and Hamilton Anxiety Rating (HAM-A) scale scores.

Evidence strength: Among the strongest in the adaptogen literature for cortisol-related outcomes. Multiple RCTs support modest-to-meaningful reductions in salivary and serum cortisol in stressed populations. Limitations include variable extract standardization across trials and relatively small sample sizes. A 2026 case report (PMC12824993) noted that while short-term clinical trials with standardized ashwagandha extracts have shown modest cortisol-lowering effects and subjective stress benefit, the long-term endocrine consequences of chronic, high-dose consumption remain incompletely characterized, and data regarding dose thresholds and duration beyond which HPA-axis modulation becomes clinically relevant are especially limited.

5.2 Rhodiola rosea

Traditional Use

Rhodiola rosea L. has a long history of use in traditional medicine to stimulate the nervous system, treat stress-induced fatigue and depression, enhance physical performance and work productivity, and treat gastrointestinal ailments and impotence. It has been used in Siberian, Scandinavian, and Russian folk medicine for centuries, and was historically employed by Viking warriors and Russian cosmonauts to enhance physical endurance and mental performance.

Active Constituents

Salidroside (rhodioloside), the trans-cinnamyl alcohol glycoside compounds (rhodiolin, rosin, rosavin, rosarin, and rosiridin), and tyrosol are thought to be the most critical plant constituents needed for therapeutic activity. A characteristic of R. rosea is its unique presence and relatively high rosavins content, which have not been detected in other Rhodiola species, and are now an accepted marker for genetically pure R. rosea. Extracts are generally standardized to a minimum of 3.0% rosavins and 1.0% salidroside.

Scientific Evidence

A pivotal randomized, double-blind, placebo-controlled trial (Olsson et al., 2009; PubMed PMID 19016404) enrolled 60 participants meeting criteria for stress-related fatigue syndrome: a total of 60 individuals were randomised, one group receiving four tablets daily of SHR-5 extract (576 mg extract/day), while a second received four placebo tablets daily. Effects with respect to quality of life, symptoms of fatigue, depression, attention, and saliva cortisol response to awakening were assessed on day 1 and after 28 days. It was concluded that repeated administration of R. rosea extract SHR-5 exerts an anti-fatigue effect that increases mental performance, particularly the ability to concentrate, and decreases cortisol response to awakening stress in burnout patients with fatigue syndrome.

Apart from its well-established traditional use, a significant number of publications on the clinical efficacy of various R. rosea preparations can be found in the literature. The majority of these studies are related to the efficacy of R. rosea in terms of cognitive functions and mental performance, including various symptoms of life-stress, fatigue and burnout. Even though most evidence originates from pre-clinical trials, several clinical studies have additionally demonstrated the remediating effects of R. rosea on cardiovascular and reproductive health by addressing non-specific stress damage. Overall, the results provide an encouraging basis for the clinical efficacy of R. rosea preparations in managing various aspects of stress-induced conditions.

Evidence strength: Moderate. Multiple RCTs, primarily using the standardized SHR-5 extract, support anti-fatigue effects and modulation of the cortisol awakening response. Most trials are small in sample size, and not all preparations are equivalent. Evidence is strongest for burnout and stress-related fatigue; less robust for direct cortisol endpoint outcomes compared to ashwagandha.

5.3 Phosphatidylserine (PS)

Traditional Use

Phosphatidylserine is not a traditional herbal remedy. It is a phospholipid naturally present in cell membranes throughout the body. PS can be obtained from the diet primarily from animal sources, with some plant-based foods providing small amounts. The average Western diet provides an estimated 130–180 mg of PS per day. Organ meats and fatty fish provide the highest concentrations. Modern Western diets have moved away from organ meat consumption, reducing dietary PS intake.

Scientific Evidence

The most consistently demonstrated mechanism of supplemental PS is its modulation of the hypothalamic-pituitary-adrenal (HPA) axis. Activation of the HPA axis has been proposed as the mechanism by which PS blunts cortisol production. The current theories assert that this may be accomplished by possibly altering receptor ligand interactions or corticotropin-releasing factor (CRF) receptor interactions. By decreasing CRF there would be a decrease in ACTH, thereby decreasing cortisol secretion. It has been proposed that chronic treatment with PS alters CRF receptor interactions resulting in reduced activation of the HPA axis after stress.

A double-blind, placebo-controlled randomized study (PMC4237891, published in Lipids in Health and Disease, 2014) enrolled 75 healthy male volunteers: the study examined effects of oral supplementation with 400 mg PS & 400 mg PA (PAS 400) per day on ACTH, salivary, and serum cortisol response to a psychosocial stressor. Supplementation was administered for 42 days. Acute stress resulted in a hyper-responsivity of the HPA axis in chronically stressed subjects. Compared to placebo, a supplementation with PAS 400 was effective in normalizing the ACTH (p=0.010), salivary (p=0.043), and serum cortisol responses (p=0.035) in chronically high but not in low stressed subjects. PAS 200 did not result in any significant differences.

An earlier controlled study (PMC2503954) demonstrated that supplementation with 600 mg of soy-derived PS per day for 10 days blunted cortisol response before and during exercise-induced stress.

Evidence strength: Moderate for exercise- and psychosocial stress-induced cortisol blunting in chronically stressed individuals. Effect appears dose-dependent and most pronounced at 400–600 mg/day. The evidence base is smaller than that for ashwagandha, and most trials involve exercise or laboratory stress paradigms rather than naturalistic chronic stress.

5.4 Panax Ginseng (Panax ginseng)

Traditional Use

Panax ginseng has been used for over 2,000 years in Traditional Chinese Medicine (TCM) as an adaptogenic tonic (qi tonic) for fatigue, debility, and enhancement of vitality. It was prepared as a decoction of dried root, often combined with other tonic herbs.

Scientific Evidence

Panax ginseng contains ginsenosides that modulate stress hormone release and enhance neural adaptability. The clinical evidence for ginseng's effects specifically on HPA axis biomarkers (cortisol, ACTH) in humans is more limited than for ashwagandha or rhodiola; most available data addresses mental performance, fatigue, and immune function. Evidence is preliminary for direct HPA axis endpoints and is characterized as promising but requiring larger, well-designed trials.

5.5 Holy Basil (Ocimum tenuiflorum, Tulsi)

Traditional Use

Holy basil has been used for millennia in Ayurvedic medicine as a rasayana and adaptogen, indicated for stress, fever, respiratory disorders, and metabolic conditions. It was consumed as a tea (infusion of fresh or dried leaves) or as a powder. It holds sacred status in Hindu culture and has been grown in Indian households for religious and medicinal purposes.

Scientific Evidence

The clinical evidence for holy basil's direct effects on HPA axis endpoints (cortisol, ACTH) remains preliminary. Available human trials have studied outcomes including cognitive function, anxiety, and metabolic parameters, but are generally small, heterogeneous in design, and have not consistently measured cortisol as a primary endpoint. More robust evidence is needed before direct HPA axis modulation can be confirmed in humans.

5.6 Magnesium

Traditional and Dietary Context

Magnesium is an essential mineral found in green leafy vegetables, legumes, nuts, seeds, and whole grains. Its role in over 300 enzymatic reactions includes processes fundamental to neuromuscular and adrenal function.

Scientific Evidence

Nutritional interventions should address common micronutrient insufficiencies, including magnesium, B vitamins, zinc, and vitamin C, that impair adrenal and neuroendocrine function. Animal and human research indicates that magnesium deficiency is associated with enhanced HPA axis reactivity. A 2012 review summarized evidence that adequate magnesium helps moderate the HPA axis stress response and reduces cortisol reactivity (Cuciureanu and Vink, "Magnesium in the Central Nervous System"). The American Journal of Medicine review (2025) cites studies on magnesium and vitamin B6 supplementation demonstrating improvements in severe stress outcomes in individuals with low magnesemia.

Evidence strength: The link between magnesium deficiency and heightened HPA axis reactivity is supported by animal models and observational human data. Intervention trials specifically targeting cortisol as a primary endpoint are limited, and most human data relies on indirect stress and anxiety outcomes. Correction of deficiency is better supported than supplementation above adequate intake.

5.7 Vitamin C (Ascorbic Acid)

Traditional and Dietary Context

Vitamin C is found at high concentrations in the adrenal glands and is released during ACTH-stimulated cortisol synthesis.

Scientific Evidence

Vitamin C is required for several adrenal functions and offers a modulatory effect on the HPA axis. Vitamin C is necessary for cortisol synthesis since it is a co-factor for enzymes present in the adrenal glands. Vitamin C may indirectly assist in minimizing oxidative stress associated with chronic stress by maintaining adrenal health and normalizing cortisol levels. Vitamins with strong antioxidant properties, such as vitamins C and E, can mitigate oxidative stress, which is known to lead to increased secretion of glucocorticoids, thereby disrupting the normal cortisol pattern.

In clinical trials, supplementation with vitamin C was effective in reducing anxiety, decreasing stress levels, improving recovery from mental stress, boosting mood, and improving blood pressure levels in stressed participants. However, most such trials are modest in scale, and direct measurement of HPA axis endpoint changes (cortisol, ACTH) is not universal.

Evidence strength: Preliminary to moderate. Evidence from animal models is mechanistically plausible; human trial data generally supports stress and anxiety symptom reduction but is inconsistent in measuring cortisol as a direct endpoint. Deficiency correction is the most evidence-supported use.

5.8 B Vitamins (Particularly B5 and B6)

Traditional and Dietary Context

B vitamins are essential cofactors in energy metabolism and neurotransmitter synthesis. Pantothenic acid (vitamin B5) is required for the synthesis of coenzyme A, which is central to the production of steroid hormones including cortisol in the adrenal cortex.

Scientific Evidence

Deficiencies in essential vitamins and minerals, including omega-3 fatty acids, B vitamins, magnesium, and zinc, can impair HPA axis function. The mechanism by which combining magnesium and vitamin B6 leads to reduced stress remains to be defined, but vitamin B6 may offer direct and indirect effects on stress and the function of the HPA axis. The 2025 American Journal of Medicine review cites a clinical trial demonstrating the superiority of magnesium combined with vitamin B6 over magnesium alone on severe stress outcomes in individuals with low magnesemia. Human clinical evidence for B5 specifically as a direct HPA axis modulator is limited largely to animal studies and mechanistic inference.

Evidence strength: Weak to preliminary for direct HPA axis modulation; moderate for supporting adrenal enzymatic function when deficiency is present.

5.9 Zinc

Traditional and Dietary Context

Zinc is an essential trace element widely distributed in animal proteins, legumes, and seeds.

Scientific Evidence

Zinc is also required to make several neurotransmitters and hormones, including serotonin and melatonin; therefore, a zinc deficiency could affect the circadian rhythm and sleep-wake cycle. Prolonged stress depletes zinc concentrations in the blood. Animal studies (cited in the International Journal of Molecular Sciences, 2016) have demonstrated that dietary zinc deficiency leads to behavioral abnormalities consistent with enhanced HPA axis activity, supporting a physiological role for zinc in stress regulation. Direct clinical trial evidence for zinc supplementation effects on cortisol in humans is limited.

Evidence strength: Preliminary; primarily animal and mechanistic data. Deficiency correction is more supported than supranormal supplementation.

5.10 Omega-3 Fatty Acids (EPA/DHA)

Dietary Context

Omega-3 fatty acids are found primarily in fatty fish (salmon, mackerel, sardines), as well as in flaxseed and walnuts as the precursor alpha-linolenic acid (ALA).

Scientific Evidence

Omega-3 fatty acids are crucial for maintaining neuronal membrane integrity and function, which is essential for proper HPA axis signaling. A PubMed-indexed trial (PMID 22575036) found that treatment with omega-3 phosphatidylserine seemed to restore the cortisol response in a subgroup of low responders, and subgroups characterized by high chronic stress and/or a dysfunctional response of the HPA axis may profit from omega-3 PS supplementation.

Evidence strength: Preliminary to moderate for HPA axis endpoints specifically; stronger evidence exists for anti-inflammatory and mood-related outcomes. Most HPA-specific data comes from combination preparations (omega-3 + PS) rather than omega-3 alone.

5.11 Selenium

Scientific Evidence

Selenium has the potential to facilitate the functioning of the HPA axis through its ability to induce a mechanism of downregulation of TLR4 miRNA, thereby promoting the synthesis of adrenal steroids. Reduced corticosterone secretion due to selenium deficiency can be attributed to the blunting of the adrenal response to ACTH. The involvement of selenoproteins in the development of the HPA axis represents a captivating correlation between selenium and the physiological reaction to stress.

Evidence strength: Primarily mechanistic and animal-model data. Direct human clinical evidence is lacking. Noted here as an area of active research interest.

6. Dietary and Lifestyle Factors

6.1 Overall Dietary Pattern

Diets high in refined carbohydrates and saturated fats increase HPA activity and inflammatory mediators. In contrast, a whole-food, anti-inflammatory diet rich in polyphenols, fiber, omega-3 fatty acids, and antioxidants appears to downregulate stress reactivity. Nutrients and overall dietary patterns play a significant role in modulating cortisol secretion, interacting with both central and peripheral components of the HPA axis.

6.2 Macronutrient Considerations

Both undernutrition and overnutrition can impact HPA axis function. Undernutrition, as seen in conditions like anorexia nervosa, is associated with hypercortisolism and increased central CRH levels. Several anthropometric and metabolic parameters, including BMI and visceral adiposity, are associated with alterations in cortisol secretion. Irregular meal timing is also a recognized perturbant; dietary timing matters, as irregular meal patterns (e.g., late-night eating or prolonged fasting) can disrupt cortisol patterns.

6.3 Micronutrient Sufficiency

Nutritional interventions should address common micronutrient insufficiencies, including magnesium, B vitamins, zinc, and vitamin C, that impair adrenal and neuroendocrine function. These insufficiencies are prevalent in modern populations, particularly in individuals consuming processed, nutrient-poor diets.

6.4 Sleep

Poor sleep quality, sleep deprivation, and sleep disorders can lead to HPA axis dysregulation, characterized by elevated cortisol levels and altered stress responses. Good sleep quality achieved through sleep hygiene and treatment of sleep disorders, in addition to nutritional education with regular meal frequency and circadian alignment of food intake, are considered strategies for preventing metabolic disorders associated with HPA dysfunction.

6.5 Physical Activity

Exercise influences circadian rhythms through temperature regulation, hormonal effects, and gene expression. Physical activity increases core body temperature, which subsequently drops post-exercise, facilitating sleep onset. Exercise also affects hormones like cortisol and melatonin and modulates the expression of clock genes in peripheral tissues.

The 2025 American Journal of Medicine review notes that yoga may improve stress resilience, normalize cortisol rhythms, and enhance mood and cognitive function. Tai Chi has also demonstrated benefits in reducing cortisol levels and improving psychobiological stress markers, although findings vary across studies.

6.6 Mind-Body and Psychosocial Interventions

Because chronic stress heavily influences HPA axis dysregulation, addressing psychological, spiritual, and social stressors is central to therapeutic success. Evidence-based interventions include meditative practices, Cognitive-Behavioral Therapy, and Emotional Freedom Techniques.

Addressing this complex dysregulation requires a comprehensive, integrative approach that reflects the multifactorial nature of stress-related illness. A bio-psycho-social-spiritual model is particularly well suited to this task, as it considers the interconnected biological, psychological, social, and spiritual factors that influence HPA axis function.

6.7 Gut Microbiota

The gut microbiota plays an important role in regulating behavior and is associated with depression, and the translocation and change of gut microbiota composition caused by early stress may be a contributing reason for altered HPA function. The gut-brain-HPA axis connection is an emerging area of active research, but clinical intervention trials linking specific microbiome modifications to HPA axis endpoints remain preliminary.

7. Relationship to "Adrenal Fatigue"

It is important to note that the term "adrenal fatigue" — which suggests that the adrenal glands themselves become exhausted and underproductive — is distinct from, and less scientifically supported than, HPA axis dysregulation. HPA axis dysfunction is not the same as "adrenal fatigue." The concept of adrenal fatigue suggests the adrenal glands are "worn out" and produce insufficient cortisol, but a systematic review found no consistent evidence supporting this model (Cadegiani & Kater, 2016). The concept of HPA axis dysfunction has growing support from psychoneuroendocrine literature and is considered a more accurate descriptor of the impact of chronic stress on the body than the term "adrenal fatigue."

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