What Is the HPA Axis: Function and Dysfunction

9.11.2025 0 comments

Author: Trisha Houghton, CNS, ASIST

Your physiological response to stress involves both the sympathetic-adrenal-medullary (SAM) system, which drives the immediate, fight-or-flight reaction, and the hypothalamic pituitary adrenal axis (HPA axis). The HPA axis governs the slower cortisol response. The activation of this axis towards short-term stressors determines your survival during a life-threatening situation. Biologically, the first law of nature is self-preservation, and the HPA axis plays a central role in enforcing this by mobilising the body’s resources when in danger or when there is an anticipated threat.

Sometimes you wonder why some people thrive under pressure while others struggle. One key reason lies in the HPA axis. Whenever it functions properly, it strengthens our ability to cope with stress, but when it becomes dysregulated, it undermines those coping mechanisms.

Let us dive into the article to have a firm understanding of your HPA axis health, uncover how it shapes your responses to stress, why its balance matters for both mental and physical health, and what you can do to keep it working in your favor.

Introduction to the HPA Axis: What It Is and Why It Matters

The HPA axis is a complex neuroendocrine system that integrates the central nervous system with peripheral tissues to regulate adrenal gland hormones. These hormones, such as glucocorticoids, help conserve or restore balance in the body during stressful conditions. The stimulation of this axis causes the secretion of cortisol, a glucocorticoid steroid hormone, which redirects energy sources from different parts of the body to manage stress and meet its demands.

The HPA axis relies on the coordinated activities of different brain regions. The hippocampus in the limbic system inhibits anticipatory activation of the axis, while the amygdala drives the stress response. The prefrontal cortex helps suppress stress responses that depend on specific situations. Together, this neural network regulates glucocorticoid secretion and determines the intensity of the stress response.

Cortisol, the primary output of the HPA axis during stress, acts through glucocorticoid receptors found in almost all the cells of the body. The widespread receptor presence underscores its powerful influence on the overall health of the body, especially when regulation is disrupted. Even minor imbalances can trigger diverse symptoms, affecting multiple organs and systems. Beyond physical health, a dysfunctional HPA axis can also disrupt mood, energy levels, and immune function-highlighting its far-reaching impact on general well-being.

How the Hypothalamus, Pituitary, and Adrenal Glands Work Together

The chemistry between the hypothalamus, pituitary gland, and adrenal gland involves a dynamic interplay of signaling molecules such as corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and cortisol. Together, these regulate stress responses, energy metabolism, and overall homeostasis. Like we previously noted, the end product of the HPA axis is the cortisol hormone, but how does that happen?

The series of activities that leads to the production of the cortisol hormone usually begins when the HPA axis is stimulated by stress. Stressors trigger the release of CRH from the hypothalamus via specialised blood vessels that connect it to the pituitary gland. Within the pituitary gland, corticotroph cells are activated to secrete ACTH into the systemic circulation. ACTH then stimulates the adrenal glands to synthesise and release glucocorticoids, which circulate throughout the body and bind to specific receptors to exert their biological effect.

An essential aspect of the HPA axis communication is its feedback loop system. Cortisol provides negative feedback to the hypothalamus, pituitary gland, and higher brain centers such as the hippocampus, reducing further CRH and ACTH release. This regulatory mechanism ensures that cortisol levels remain within a healthy range, protecting the body from the harmful effects of prolonged stress.

In essence, the HPA axis is a back-and-forth system that functions as a finely tuned chain reaction, which starts in the brain and ends with the release of cortisol, which also provides a negative feedback for its regulation.

The HPA Axis and the Stress Response: A Biological Breakdown

The physiology of stress response is regulated by two components: a fast response, which is controlled by the sympathetic-adrenal-medullary (SAM) system. This is often seen in the fight or flight response and the slow response, and is controlled by the HPA axis. Our focus in this article is on the slow release.

Stress activates the HPA axis, prompting the hypothalamus to release CRH. The CRH has two receptors: CRH-R1 and CRH-R2. CRH-R1 is the main receptor in the brain which drives ACTH release from the anterior pituitary gland. About half of the circulating CRH is bound by CRH-biding protein, which reduces its availability for receptor binding. Cortisol itself drives the negative feedback on CRH and ACTH.

In the pituitary gland, CRH stimulates the release of ACTH, and then ACTH triggers cortisol secretion. Most circulating cortisol is bound to proteins like CBG and albumin, with only 5-10% free and active. The rest is stored as cortisone to be converted to the active form by 11beta-HSD enzyme.

What Happens When the HPA Axis Becomes Dysregulated

The negative feedback mechanism, which ensures that cortisol is produced just in the right amount, is essential for maintaining the body’s homeostasis and survival. However, in certain conditions, the HPA axis becomes dysfunctional and cortisol is chronically produced, which can lead to a range of problems.

Chronic stress can lead to the dysregulation of the HPA axis, leading to alterations in the levels of cortisol and potentially contributing to some psychiatric disorders. HPA axis dysfunction usually manifests in the following ways:

• Hypocortisolism;

• Hypercortisolism;

• Distorted cortisol rhythm;

Chronic stress often begins by driving prolonged elevations in cortisol, which over time dulls the body’s responsiveness and worsens HPA axis imbalance, heightening the risk for:

• Cardiovascular;
• Metabolic;
• Immune;
• Mental health disorders;
• And cognitive impairments;

Ultimately, maintaining HPA axis regulation is crucial for maintaining both physical and mental well-being. When this system is reactive for so long, chronic stress may cause either persistent cortisol elevation or a blunted cortisol response, both disrupting the balance and worsens health outcomes.

Symptoms of HPA Axis Dysfunction You Shouldn’t Ignore

Since the HPA axis function affects virtually all the major organs and systems in the body, symptoms of dysregulation can be classified based on physical, psychological, and metabolic or hormonal symptoms.

• Physical Symptoms: fatigue, frequent infections, headaches, poor sleep, weight changes, etc.
• Psychological symptoms: anxiety, depression, brain fog, mood swings, low stress tolerance, etc.
• Metabolic/hormonal symptoms: unstable blood sugar, cravings, reduced libido, menstrual irregularities, low testosterone, etc.

Put together, HPA axis dysfunction amplifies the stress effects on both mind and body, influencing everything from mood to metabolism. Because cortisol plays a key role in regulating the immune response, both too much and too little can leave the body more vulnerable to illnesses.

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Common Causes of HPA Axis Imbalance

The HPA axis is highly sensitive to both internal and external influences, and its balance can be disrupted by a variety of factors. This increases your vulnerability to stress-related disorders. Some key contributors include:

• Psychosocial stress: Chronic emotional stress, early-life trauma and insufficient social support can overactivate the HPA axis, impairing adaptive coping mechanisms.
• Genetic and epigenetic changes: Mutations in genes such as NR3C1, FKBP5, and HSD11β2, or epigenetic changes like DNA methylation, can alter glucocorticoid receptor sensitivity and overall axis function.
• Dietary Influences: Diets high in sugar and fat, nutrient deficiencies, (e.g., omega-3s, whereas antioxidant-rich food may help maintain balance.
• Toxin: Exposure to alcohol, smoking, illicit drugs, heavy metals and endocrine-disrupting chemicals can interfere with hormone production, receptor sensitivity and signaling pathways.
• Hormonal Factors: sex hormones influence HPA activity; estrogen tends to amplify cortisol responses under stress, while testosterone generally reduces axis reactivity.

It is important to understand these factors because they highlight areas where interventions and modification is necessary. In stress management, dietary improvements and lifestyle changes can help restore HPA axis balance and support overall physical and mental health.

The Link Between Chronic Stress and HPA Axis Dysfunction

Chronic, not acute, stress is responsible for the dysfunction of the HPA axis. HPA axis research has shown that during chronic stress, the adrenal cortisol-secreting cells undergo both hyperplasia and hypertrophy, especially in the zona fasciculata (where cortisol is made). This means that the adrenal gland may develop an enhanced capacity to produce cortisol. This structural change can cause HPA axis dysfunction in the following ways:

Sustained hypercortisolism: Enlarged adrenal glands produce more cortisol than normal, even without proportional ACTH stimulation.

• Negative feedback disruption: Normally, high cortisol feedback to the hypothalamus and pituitary to reduce CRH/ACTH. With adrenal hypertrophy, cortisol output may stay high despite negative feedback.
• Feedback desensitization: The hypothalamus and pituitary become less sensitive to cortisol’s inhibitory signals. This is often seen in stress-related disorders where cortisol levels become elevated or erratic.
• Cycle of dysregulation: Over time, this maladaptive state can lead to a blunted or paradoxical cortisol rhythm.

This shows that sometimes the HPA axis dysfunction may involve both signaling changes and in some cases, a structural adrenal changes.

How HPA Dysfunction Affects Sleep, Mood, and Metabolism

The HPA axis plays a central role in regulating the body’s daily rhythms, emotional balance, and energy metabolism. When this system becomes dysregulated, it can disrupt sleep patterns, alter mood and impair metabolic processes, creating a series of effects that impact both physical and mental health. Understanding these connections helps explain why chronic stress often leads to insomnia, mood disorders and metabolic imbalances.

SLEEP

Deep sleep suppresses the HPA axis, which is why cortisol levels are usually lowest at night. However, the relationship is two-way: lack of sleep keeps the HPA axis overactive, while HPA dysfunction can disrupt sleep. This cycle is evident in insomnia, where cortisol remains high in the evening instead of dropping. Elevated cortisol is often observed in insomnia and reflects overactive stress pathways, like CRH, that are overactive at night. Overall, excessive HPA activity fragments sleep, and fragmented sleep further drives cortisol release.

MOOD

The HPA axis is closely involved in several neuropsychiatric disorders. Its hyperactivity is strongly linked to major depressive disorder, contributing to cognitive impairment and mood disturbances. It also has a significant connection with the gut microbiome, which plays an important role in depression. A dysregulated HPA axis can reduce microbial diversity and negatively affect mood, while gut microbiome disruptions can, in turn, impair HPA axis function. This bidirectional relationship highlights the complex interplay between brain health, gut physiology, and stress adaptation.

METABOLISM

There is a causal relationship between high cortisol levels and its promotion of visceral adipose cells and visceral obesity. Additionally, cortisol, acting through different mechanisms, stimulates gluconeogenesis, glycogenolysis, and lipolysis in subcutaneous fat tissues, and over time, this can cause diabetes, hyperlipidemia, and insulin resistance. Furthermore, overexpression of the 11ß-HSD1 enzyme has been linked to obesity and insulin resistance, features of metabolic syndrome.

Natural Ways to Support a Healthy HPA Axis

Understanding the causes of HPA axis dysfunction is essential for maintaining the body’s homeostasis. Fortunately, there are natural strategies you can adopt to support healthy HPA axis function, including:

• Mindfulness, meditation, breathwork, CBT, and stress management
• Social support and emotional resilience techniques
• Balanced diet rich in omega-3s, fiber, micronutrients, and fermented foods
• Adequate sleep and moderate physical activity
• Some adaptogens (ask your medical doctor if ashwagandha, rhodiola, ginseng, licorice root would be healthy for you)

By caring for your stress response system through regulating your nervous system through these lifestyle and nutritional strategies, you can restore balance to your HPA axis, and in turn, support energy, mood, and overall health.

Medical Approaches and Testing for HPA Axis Disorders

Medical approaches to HPA Axis Disorder involve evaluating symptoms, performing hormonal tests like a 4-point salivary cortisol and low dose ACTH stimulation tests (SST). Sometimes Insulin Tolerance Tests are also used to check adrenal function. Dexamethasone Suppression Tests (DSTs) are used to assess cortisol regulation. HPA axis treatment is tailored to the underlying disorder (adrenal insufficiency, Cushing’s) and may include medications, supplementation, hormone replacement, or surgery alongside managing underlying issues such as chronic stress, inflammation, sleep disorders and trauma.

This also forms the basis of testing for HPA axis disorders. Tests could be non-stimulated (basal serum cortisol, 4-point salivary cortisol testing, DHEA-S) or stimulated (low-dose ACTH stimulation test, ITT etc.).

Additionally, it must be noted that some of these tests are contraindicated in some patients, so be sure to check with your medical doctor before embarking on one. Comprehensive testing and informed medical approaches enable doctors to identify whether the HPA axis is overactive, underactive or dysregulated and to tailor treatment that restores hormonal balance and supports overall health.

Long-Term Strategies for Restoring Balance to the HPA Axis

While medical treatments can be effective, they can carry potential side effects. That’s why it may be beneficial to incorporate supportive, non-medical strategies alongside your prescribed care. These approaches aren’t quick fixes, nor appropriate for everyone so please ask your medical provider. That said,and over time, these may help support the underlying causes of HPA axis dysfunction and promote lasting balance. Some of these strategies include:

• Psychological, spiritual, stress, and social interventions: Because chronic stress is heavily tied to HPA axis dysfunction, addressing the psychological, spiritual, and social components of the stressor is key to a lasting balance of the HPA axis. To assess this, a 2024 meta-analysis on the Effectiveness of stress management interventions to change cortisol levels was carried out. 58 of the studies were conducted to determine if psychological stress management interventions can change cortisol levels. This study had over 3500 participants. Their findings revealed that stress management can significantly reduce cortisol levels in non-patients.
• Lifestyle approaches: Sleep, physical activity and diet are key factors that can balance or disrupt the HPA axis. 

• Herbal medicine/adaptogens: Adaptogens are natural substances that are being studied. They are basically herbs and roots that help the body cope with stress. Common examples are ashwagandha, rhodiola, panax ginseng, and licorice root. They have stress regulating effects and evidence is still being gathered. Massage: Massages of various types can help regulate the HPA axis, with some studies showing that five weeks of twice-weekly sessions reduce salivary cortisol levels and ease stress-related physiological responses.

Quality sleep is one of the most powerful—and overlooked—ways to restore a healthy HPA rhythm. Deep, consistent sleep helps recalibrate cortisol’s daily curve, steadies mood and energy, and reinforces the “rest-and-digest” pathways that keep stress in check. If you’re looking to gently support that reset alongside your lifestyle changes, a targeted, bedtime-friendly magnesium blend can be a simple next step.

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Frequently Asked Questions

What hormones are involved in the HPA axis?

The main hormones involved in the HPA axis are corticotropin-releasing hormone (CRH) from the hypothalamus, adrenocorticotropic hormone (ACTH) from the pituitary gland, and cortisol (the primary glucocorticoid) from the adrenal cortex, all of which work in a tightly regulated feedback loop to control the body’s stress response.

What role does the HPA axis play in anxiety disorders?

In anxiety disorder, the HPA axis becomes overactive, raising cortisol levels and stress sensitivity, which disrupts brain regions that regulate fear and emotion. This in turn intensifies anxiety symptoms.

What tests assess HPA axis activity and dysfunction?

The test that assess HPA axis activity and dysfunction include, ACTH stimulation, dexamethasone suppression, metyrapone, CRH stimulation, and insulin tolerance tests.

What are the neurological pathways linked to the HPA axis?

The main neurological pathways linked to the HPA axis are the amygdala, which activates the stress response, the hippocampus, which inhibits it, and the prefrontal cortex, which regulates the balance.

How does cortisol dysregulation affect mood disorders?

Excess cortisol disrupts brain regions that regulate mood and memory, leading to impaired cognition, heightened stress sensitivity and depressive symptoms. Conversely, low cortisol levels contribute to fatigue, low motivation and reduced emotional resilience often seen in mood disorders.

REFERENCE

1. Hypothalamic–pituitary–adrenal axis and stress
2. Hypothalamic-Pituitary-Adrenal Axis
3. Limbic Pathways to Stress Control: Regulation of the HPA Axis
4. An Integrative Approach to HPA Axis Dysfunction: From Recognition to Recovery
5. Regulation of the hypothalamic-pituitary-adrenocortical stress response
6. Stress, hypothalamic-pituitary-adrenal axis, hypothalamic-pituitary-gonadal axis, and aggression
7. An Integrative Approach to HPA Axis Dysfunction: From Recognition to Recovery
8. Symptoms & Causes of Adrenal Insufficiency & Addison’s Disease
9. Adrenal Fatigue or HPA Axis Dysfunction?
10. A new model for the HPA axis explains dysregulation of stress hormones on the timescale of weeks
11. HPA axis and Sleep
12. Interactions between sleep, stress, and metabolism: From physiological to pathological conditions
13. HPA Axis in the Pathomechanism of Depression and Schizophrenia: New Therapeutic Strategies Based on Its Participation
14. HPA axis abnormalities and metabolic syndrome
15. Pharmacological Treatment of Anxiety Disorders: The Role of the HPA Axis
16. Mifepristone for management of Cushing’s syndrome
17. Endocrine Testing Protocols: Hypothalamic Pituitary Adrenal Axis
18. Effectiveness of stress management interventions to change cortisol levels: a systematic review and meta-analysis
19. Physiological adjustments to stress measures following massage therapy: a review of the literature
20. Cortisol and shiftwork: A scoping review
21. Sleep loss results in an elevation of cortisol levels the next evening
22. Gut microbiota’s effect on mental health: The gut-brain axis
23. Pharmacological Treatment of Anxiety Disorders: The Role of the HPA Axis

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