Chronic Stress Exposure

 

Chronic exposure to psychological stress is one of the most validated and dominant causes of HPA axis dysfunction. When the brain perceives a stressor, whether emotional, occupational, caregiving , even noise pollution, it activates corticotropin-releasing hormone (CRH) secretion from the hypothalamus, initiating a cascade that stimulates ACTH release from the pituitary and cortisol production from the adrenal glands. 

 

In the early stages, cortisol output may be elevated. However, repeated exposure to stress reduces the responsiveness of the HPA axis, a phenomenon referred to as ‘adaptive blunting’ or ‘functional exhaustion’. In adaptive blunting, ACTH levels decrease and cortisol levels show diminished changes even after repeated stress sessions. 

 

This reduction is attributed to neural adaptation from prior exposure, and is linked to reduced sensitivity of the HPA axis to the same or similar stressors, a finding consistent with patterns seen in post-traumatic stress disorder (PTSD) and other chronic stress conditions [6][20][28].

 

Chronic stress also increases extracellular glutamate, particularly in the prefrontal cortex, leading to excitotoxicity and neuronal dysfunction. The prefrontal cortex plays a regulatory role over the hypothalamus, especially in modulating CRH release. Prolonged glutamate elevation may impair this regulatory feedback, ultimately disturbing HPA axis signaling and contributing to a blunted response [31].

 

Furthermore chronic stress disrupts the serotonin (5-HT) system. In the early stages of stress, increased serotonin activity can stimulate CRH release from the hypothalamus, enhancing cortisol production. However, with ongoing stress, serotonin receptors become desensitized or downregulated, reducing their influence over cortisol production [31].

 

Chronic Inflammation and Oxidative Stress

 

Chronic inflammation both contributes to and results from HPA axis hypofunction. Under normal conditions, cortisol acts as a potent anti-inflammatory hormone. However, sustained immune activation, common in autoimmunity and chronic infections can lead to cortisol resistance, diminishing its effect on the body [6][22].

 

Further, inflammatory cytokines such as TNF-α, IL-1β, and IL-6 initially activate the HPA axis to control immune responses. Yet with ongoing inflammation, this activation causes the axis to gradually lose sensitivity to cytokine signaling, leading to reduced cortisol output, perpetuating a cycle of unresolved inflammation [32].

 

Moreover, oxidative stress can directly impair hypothalamic neurons and pituitary corticotrophs, reducing their ability to synthesize and release CRH and ACTH. Over time, this leads to decreased stimulation of the adrenal cortex and diminished cortisol production, reinforcing a state of HPA hypofunction [6][22].

 

Childhood Trauma 

 

Adverse childhood experiences, including neglect, abuse, or loss, produce lasting epigenetic alterations in HPA axis regulation. Early exposure to trauma sensitizes the amygdala and paraventricular nucleus (PVN) to overrespond to stress, while simultaneously impairing hippocampal glucocorticoid receptor expression, reducing negative feedback capacity and excessive cortisol production. 

 

Over time, this leads to a paradoxical downregulation of cortisol output in adulthood, often presenting as diminished ACTH response. These developmental changes set the stage for lifelong HPA axis hypofunction. [19][34].

 

Autoimmune disorders

 

A blunted HPA axis can is often observed in autoimmune diseases due to its ongoing activation to  suppress autoimmune activation via cortisol synthesis and activity. This on-going process eventually leads to HPA blunting, subsequently allowing persistent inflammation and autoreactivity. 

 

Evidence of HPA blunting has been observed in autoimmune conditions such as
 

• Rheumatoid arthritis

• Fibromyalgia

• Chronic fatigue syndrome

• Systemic lupus erythematosus (SLE)

• Sjögren’s syndrome (SS)

• Systemic sclerosis (SSc) [38]

 

Chronic Opioid Use

 

The opioid system and the hypothalamic-pituitary-adrenal (HPA) axis are closely interconnected, working together to regulate stress, mood, and pain responses. Under normal conditions, when the body encounters stress or pain, the HPA axis is activated. 

 

Simultaneously, the body releases endogenous opioids, such as endorphins, which help modulate the stress response and reduce pain perception. These opioids also act as a regulatory brake by inhibiting CRH neurons, ensuring the HPA axis doesn't overreact.

 

However, chronic opioid exposure, which includes cigarette smoking, activates the brain’s opioid pathways repeatedly, leading to overstimulation of opioid receptors. Over time, this persistent stimulation causes the receptors to become desensitized. Desensitised opioid receptors then lead to short-term HPA overdrive, driving further addiction but also driving towards a blunted HPA response [33][41].

 

Shift Work and Prolonged Sleep Deprivation

 

Disruption of the body's internal clock is a well-recognized contributor to HPA axis hypofunction, particularly in individuals experiencing chronic sleep disturbances, shift work, or circadian misalignment. 

 

Under normal conditions, cortisol levels rise sharply after waking, a phenomenon known as the cortisol awakening response (CAR), and then decline gradually throughout the day. However, persistent disruption of the light–dark cycle or sleep quality has been shown to flatten the CAR, impair pituitary responsiveness to corticotropin-releasing hormone (CRH), and reduce ACTH secretion, ultimately leading to dampened adrenal output and a blunted overall HPA axis response [23][28]

 

Metabolic Syndrome and Obesity

 

Although cortisol is often elevated in the early stages of metabolic syndrome, the long-term consequence of this chronic metabolic burden is often HPA axis hypofunction. Persistent inflammation, insulin resistance, and adipokine dysregulation desensitize the hypothalamic-pituitary-adrenal loop. 

 

As visceral fat accumulates, inflammatory signaling interferes with glucocorticoid feedback sensitivity, eventually dampening cortisol output and flattening its circadian rhythm. Many obese individuals present with normal or low total cortisol, but exhibit signs of reduced cortisol responsiveness and adrenal exhaustion, indicating an underactive stress-adaptation system despite high physiological demand [20].

 

Chronic Alcohol Consumption

 

Chronic alcohol consumption profoundly disrupts the HPA axis and impairs adrenal function. Over time, it suppresses hypothalamic CRH production, diminishes pituitary responsiveness to CRH, and reduces adrenal cortisol output, even in the presence of ACTH. Notably, after alcohol withdrawal, ACTH responses can remain blunted for months, suggesting a persistent desensitization of the neuroendocrine system [6].

 

PTSD and Burnout 

 

Both post-traumatic stress disorder (PTSD) and occupational burnout exemplify advanced stages of HPA axis exhaustion. In PTSD, baseline cortisol levels are typically low, yet the body maintains exaggerated autonomic nervous system responses, indicating an inability to mount a cortisol-mediated stress resolution. 

 

Similarly, chronic occupational stress without adequate recovery leads to flattened diurnal cortisol patterns, ACTH desensitization, and reduced adrenal capacity. In both conditions, this hypocortisolemic state impairs immune regulation, emotional resilience, and neurocognitive function, contributing to persistent symptoms and poor recovery from stress [9][21].

 

Chronic Infections and Immune Triggers

 

Acute infections typically activate the HPA axis to raise cortisol and control inflammation. However, chronic infections, particularly latent viruses such as Herpes Simplex, Epstein Barr, Cytomegalovirus, cause persistent immune activation may deplete adrenal reserves and induce cortisol resistance in immune cells. Over time, this leads to a blunted HPA response and insufficient cortisol to modulate systemic inflammation [6][22].

 

Nutritional Deficiencies

 

Micronutrient deficiencies critically impair HPA axis function, particularly when the body is under chronic stress. Vitamin C is essential for cortisol synthesis in the adrenal cortex, Vitamin B5 supports coenzyme A production needed for steroidogenesis, and zinc modulates ACTH receptor sensitivity. 

 

In the absence of these nutrients, adrenal hormone production becomes inefficient, and the axis progressively loses its ability to respond to ACTH signaling. This leads to functional hypoadrenia, a key feature of HPA hypofunction, manifesting as fatigue, poor stress tolerance, and flattened cortisol rhythms [4].

 

Dysbiosis

 

Although not traditionally linked to endocrinology, the gut-brain axis plays a direct role in HPA regulation. Imbalances in the gut microbiota, known as dysbiosis, trigger chronic low-grade inflammation and influence the central nervous system via microbial metabolites (e.g., SCFAs), vagal nerve stimulation, and cytokine release. Persistent dysbiosis upregulates hypothalamic CRH output initially, but over time, contributes to HPA exhaustion and feedback failure. 

 

This can also result in blunted cortisol responses, impaired ACTH signaling, and poor stress recovery. Gut-originated inflammation and neurochemical imbalance are now recognized as common pathways leading to HPA axis hypofunction [7][12].

 

Long COVID

Studies have demonstrated patients with long-covid consistently display low morning cortisol levels,
with ACTH responses blunted, and flattened diurnal cortisol rhythms, suggesting disrupted HPA axis function [42].