Does chronic undernutrition or low energy availability alter HPA-axis function and diurnal cortisol patterns?

Chronic undernutrition and low energy availability (LEA) are well-established metabolic stressors that fundamentally alter the function of the hypothalamic-pituitary-adrenal (HPA) axis. Research across clinical populations, including those with Relative Energy Deficiency in Sport (RED-S) and functional hypothalamic amenorrhea (FHA), demonstrates that the body prioritizes survival by activating the stress response to mobilize energy stores.

Clinical evidence and cortisol patterns

Clinical studies consistently show that individuals in a chronic state of negative energy balance exhibit significant deviations in cortisol production compared to energy-replete individuals.

• Elevated Basal Levels: Meta-analyses indicate that women with LEA frequently present with significantly higher morning cortisol levels. In cases of clinical undernutrition, integrated 24-hour cortisol secretion can be 50% to 100% higher than in healthy controls.
• Diurnal Rhythm Shifts: While the general circadian shape is often preserved, the entire curve is shifted upward. This is characterized by a "flattening" of the diurnal slope, where cortisol fails to decline to normal nadir levels in the evening and night.
• Response Metrics: Studies on the Cortisol Awakening Response (CAR) show mixed results; while some experimental models show an amplified morning surge, chronic cases may eventually lead to a blunted CAR, suggesting HPA axis exhaustion or habituation over time.

Mechanistic explanations

The alteration of the HPA axis in response to undernutrition is driven by a complex neuroendocrine survival mechanism.

• Leptin and CRH Signaling: Low energy availability leads to a decrease in the adipokine leptin. Under normal conditions, leptin suppresses the release of Corticotropin-Releasing Hormone (CRH). When leptin levels drop, this inhibition is removed, leading to increased CRH and subsequent ACTH/cortisol secretion.
• Feedback Resistance: Chronic undernutrition induces a state of central resistance to the negative feedback of cortisol. Normally, high cortisol would signal the hypothalamus to slow production; however, in energy-deprived states, the axis remains "locked" in an active position to ensure continued gluconeogenesis (blood sugar production) and proteolysis (muscle breakdown for fuel).
• HPA-HPG Interplay: In females, high CRH levels directly inhibit the hypothalamic-pituitary-gonadal (HPG) axis. This suppression of reproductive hormones—often occurring alongside the transition toward perimenopause—can exacerbate bone density loss and metabolic dysfunction.

Bottom line

Chronic undernutrition is a potent trigger for HPA axis dysregulation, typically manifesting as functional hypercortisolism and an upward shift in the diurnal cortisol rhythm. These changes represent a metabolic survival mode that prioritizes immediate energy mobilization at the long-term expense of reproductive, bone, and immune health.