# Adrenal steroid hormone responses to exercise under thermal stress: Potential role for nonclassic congenital adrenal hyperplasia in heat illness susceptibility

## TL;DR

The study explores how adrenal hormone responses during exercise in heat may be linked to a genetic condition called nonclassic congenital adrenal hyperplasia, potentially increasing susceptibility to heat illness.

## Contribution

The paper introduces a novel link between nonclassic congenital adrenal hyperplasia and heat illness susceptibility through genetic and physiological findings.

## Key findings

- Hyponatremic heat illness patients showed blunted cortisol and aldosterone responses compared to controls.
- Elevated precursor product levels in hyponatremic cases suggest 21 hydroxylase deficiency.
- One normonatremic heat illness case also exhibited elevated precursor product, indicating potential 21OHD involvement.

## Abstract

We queried whether adrenal insufficiency attributable to non‐classic congenital adrenal hyperplasia (21 hydroxylase deficiency, 21OHD) might contribute to heat illness susceptibility. Patients referred to a specialist heat illness clinic (n = 2 with prior hyponatremia; n = 16 lacking documentary evidence) and controls (n = 16) underwent laboratory Heat Tolerance Assessment (HTA: 60–90 min walking, 60% relative intensity, 34°C heat), synthetic adrenocorticotrophic hormone stimulation (heat illness only) and CYP21A2 genotyping (hyponatremic heat illness only). Copeptin, cortisol, 17‐hydroxyprogesterone, and 21 deoxycortisol were assayed from blood at baseline and post‐HTA, with precursor product [17‐hydroxyprogesterone +21 deoxycortisol] expressed relative to cortisol. Saliva and urine were assayed for free cortisol (one hyponatremic case, controls). Versus controls, normonatremic heat illness exhibited greater (p < 0.05) serum cortisol across HTA, while hyponatremic heat illness showed blunted responses in aldosterone and free cortisol (salivary cortisol 1.6 and 1.6 vs. 6.0 [4.2, 19.4] and 4.2 [3.8, 19.2] nmol.L‐1; urine cortisol 19 vs. 117 +/− 71 nmol.L‐1). Hyponatremic heat illness demonstrated elevated precursor product consistent with 21OHD and multiple CYP21A2 mutations. One normonatremic case of heat illness also showed elevated precursor product. These data support the potential for 21OHD to precipitate heat illness under sustained physical stress and advance a case for targeted genetic screening.