Hypothalamic-Pituitary-Adrenal Axis Activation in Obstructive Sleep Apnea: The Effect of Continuous Positive Airway Pressure Therapy

Context: Obstructive sleep apnea (OSA) is a common condition with significant cardiovascular and metabolic comorbidity. We hypothesized that these may result from OSA-induced perturbations of endogenous ultradian hypothalamic-pituitary-adrenal axis activity. Objective: The aim of the study was to investigate ACTH and cortisol ultradian patterns using an automated, repetitive blood sampling technique. Design: Samples for ACTH and cortisol were collected from 10 patients with moderate to severe OSA under basal conditions, at 10-min intervals over 24 h, at diagnosis and 3 months after compliant continuous positive airway pressure (CPAP) therapy. Multiple-parameter deconvolution estimated specific measures of ACTH and cortisol pulsatile secretion from blood hormone concentrations. Results: Mean total ACTH and cortisol production were elevated pre-CPAP compared to post-CPAP (ACTH, 1459.8 ± 123.0 vs. 808.1 ± 97.9 pg/ml, P < 0.001; cortisol, 5748.9 ± 364.9 vs. 3817.7 ± 351.7 nmol/liter, P < 0.001) as were mean total pulsatile production (ACTH, 764.1 ± 86.3 vs. 383.5 ± 50.0 pg/ml, P = 0.002; cortisol, 4715.9 ± 253.3 vs. 3227.7 ± 258.8 nmol/liter, P < 0.001). ACTH and cortisol secretory burst mean half-duration were higher at diagnosis (12.3 ± 0.7 and 13.5 ± 0.7 vs. 7.8 ± 0.4 and 8.4 ± 0.6 min, respectively, P < 0.001); thus, 95% of each ACTH secretion occurred in 21.0 ± 1.2 vs. 12.9 ± 0.8 min post-CPAP (P < 0.001) and for cortisol in 23.0 ± 1.2 vs. 14.2 ± 1.1 min post-CPAP (P < 0.001). Approximate entropy (ApEn) revealed greater disorderliness in both ACTH (P = 0.03) and cortisol (P = 0.001) time series pre-CPAP. Forward and reverse cross-ApEn suggested nodal disruption at central and adrenal levels pre-CPAP (P = 0.01). Significantly elevated cortisol responses to a single breath of 35% CO2 occurred pre-CPAP (P = 0.006). Conclusions: Untreated compared to treated OSA is associated with marked disturbances in ACTH and cortisol secretory dynamics, resulting in prolonged tissue exposure to disordered, elevated hormone levels. Untreated obstructive sleep apnea (OSA), compared to treated OSA, is associated with disturbances in hypothalamic-pituitary-adrenal axis functioning including altered ACTH and cortisol secretory dynamics, resulting in prolonged tissue exposure to disordered, elevated hormone levels which are ameliorated by 3 months compliant continuous positive airway pressure therapy.