Mitochondrial reserve capacity constrains the HPA, thyroid, and gonadal systems simultaneously, determining whether stress responses stay adaptive or consolidate into chronic dysfunction.

When a patient presents with a dysregulated cortisol rhythm, suppressed free T3 despite normal TSH, and declining sex hormones alongside rising inflammatory markers, the conventional approach is to evaluate each axis independently. A new framework published in the International Journal of Molecular Sciences argues that these findings represent a single coordinated response to one underlying problem: the body is running low on cellular energy and making trade-offs. The Energy Allocation System (EAS), developed by a six-author team led by Corey Schuler, Director of Medical Affairs at Allergy Research Group and faculty at Augsburg University, proposes that the HPA, thyroid, and gonadal axes function as a unified energy governance network constrained by mitochondrial reserve capacity.

The Body Prioritizes Survival Over Repair When Mitochondrial Energy Runs Short

The logic of the framework follows a straightforward biological principle. The HPA axis mobilizes fuel through cortisol-driven gluconeogenesis, lipolysis, and proteolysis. The HPT axis sets the metabolic pace by regulating mitochondrial output through triiodothyronine (T3). The HPG axis funds long-term, energy-expensive processes including tissue repair, reproductive function, and immune tolerance through estrogen, progesterone, and testosterone. All three depend on the same mitochondrial ATP supply.

When that supply is sufficient, all three systems run in parallel. When mitochondrial reserve capacity contracts, whether from chronic stress, inflammation, circadian disruption, or nutrient depletion, the body begins rationing. Cortisol-driven mobilization holds priority because immediate survival depends on it. Thyroid-mediated metabolic pacing slows to conserve ATP. Sex hormone production drops because reproduction and tissue rebuilding can be deferred. These are three expressions of one adaptive reallocation driven by insufficient energy at the mitochondrial level.

The Pattern Maps to Four Recognizable Clinical Profiles

These reallocation patterns produce four recognizable clinical profiles. In the mobilization-biased profile, the HPA axis dominates while thyroid throughput and gonadal output begin to decline. The patient is still functional but running on cortisol and depleting reserves. In the throughput-constrained profile, T3 activation drops and reverse T3 (rT3) climbs even though TSH remains in range. The metabolic pace has slowed to conserve energy, and fatigue becomes persistent. In the conservation-dominant profile, all three axes are broadly suppressed and the immune system shifts toward tolerance as its default operating mode. Recovery stalls because the body has deprioritized repair. In the resilient profile, all three axes engage proportionately, activation is transient and scaled to demand, and recovery is efficient. The difference between these profiles is mitochondrial reserve capacity.

These are dynamic states that shift as energy supply and demand change, which means they are reversible when the underlying constraint is addressed.

Inflammation and Nutrient Deficiency Tighten the Constraint Further

Two factors compress the energy margin independent of stress exposure itself. Low-grade chronic inflammation driven by cytokines including IL-6 and TNF-alpha impairs mitochondrial substrate switching, reduces oxidative phosphorylation efficiency, and shifts cells toward glycolysis. Every unit of ATP the immune system consumes for inflammatory signaling is a unit unavailable for endocrine function, neural processing, and tissue repair. The more inflammation a patient carries, the less mitochondrial reserve remains for the three axes to draw from.

Micronutrient status has a parallel effect. Iron, selenium, iodine, folate, cholecalciferol, and cobalamin are required cofactors for mitochondrial electron transport, thyroid hormone conversion, antioxidant defense, and immune regulation. A deficiency in any one of these compresses the available energy margin and can drive the same pattern of hormonal trade-offs seen in chronic stress, even in the absence of a primary endocrine diagnosis.

Four Testable Predictions Give the Framework Scientific Accountability

Four falsifiable hypotheses give the framework scientific accountability. First, reductions in the free T3:T4 ratio under metabolic stress will correlate more strongly with skeletal muscle mitochondrial capacity than with circulating TSH. Second, individuals with preserved mitochondrial reserve will show proportionate, transient cortisol activation and rapid recovery, while those with depleted reserves will show prolonged or erratic cortisol patterns under the same stress load. Third, gonadal suppression will track inflammatory load and metabolic inflexibility more closely than stress exposure itself. Fourth, restoring bioenergetic reserve will normalize endocrine signaling across all three axes before individual hormone levels correct on their own.

The Practical Shift Is in How Practitioners Read the Labs They Already Order

Practitioners already order the relevant markers. A suppressed free T3:T4 ratio with normal TSH, when read through this lens, reflects the body conserving metabolic pace to preserve ATP. Suppressed sex hormones during chronic stress reflect active energy conservation at the gonadal level. A flattened cortisol awakening response reflects impaired energy scheduling across the day. These lab findings are coordinated signals of one shared energy constraint.

Validated questionnaires add a functional layer. The Thyroid Symptom Questionnaire (TSQ-36) captures metabolic pacing. The Pittsburgh Sleep Quality Index reflects circadian restoration. The Perceived Stress Scale measures HPA mobilization burden. The Brief Resilience Scale tracks recovery capacity. Read together, these instruments map to the clinical profiles described above and shift dynamically as energy supply changes.

The clinical implication is that supporting the upstream energy supply, specifically mitochondrial reserve and the nutrient cofactors that feed it, may resolve the coordinated endocrine pattern more effectively than adjusting any single hormone.

Full Reference:

Schuler CB, Sayre AB, Zakaria L, Tassone S, Rinehart A, Harris R. Energy Allocation System (EAS): A Bioenergetic Framework for Resilience Across Endocrine, Immune, and Metabolic Domains. Int. J. Mol. Sci. 2026;27(3):1345. doi:10.3390/ijms27031345

Further Reading

“Optimizing the HPA Axis,” NDNR.com: https://ndnr.com/optimizing-the-hpa-axis/

“CVD and the HPA Axis: How Adrenal Dysfunction Contributes to CV Disease,” NDNR.com: https://ndnr.com/cardiopulmonary-medicine/cvd-the-hpa-axis-how-adrenal-dysfunction-contributes-to-cv-disease/

“Cortisol and Depression: Identifying Pattern Differences,” NDNR.com: https://ndnr.com/cortisol-depression-identifying-pattern-differences/

“Adrenal Fatigue: Environmentally Induced Adrenal Hypofunction?” NDNR.com: https://ndnr.com/endocrinology/adrenal-fatigue-environmentally-induced-adrenal-hypofunction/