Although obstructive sleep apnea (OSA) occurs commonly in acromegaly, we have recently reported an unexpectedly high prevalence of central sleep apnea (CSA) in these patients. Acromegalic patients with CSA have increased growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels compared with their counterparts with OSA. Studies in animals, normal humans, and patients with sleep apnea have suggested that CSA is associated with increased gain of the respiratory control system. To examine the relationship between sleep apnea, respiratory control, and hormonal activity in acromegaly, we performed sleep studies and examined ventilatory responses to hypoxia at resting CO2 (HVR) and 8 mm Hg above resting CO2 (HHVR) and hypercapnia (HCVR) in 54 patients with acromegaly who also underwent detailed endocrine evaluation. Patients with CSA (n = 11) had higher HCVR (3.47 +/- 0.57 L/min/mm Hg) than did patients with obstructive sleep apnea (OSA) (1.86 +/- 0.19, n = 33) and patients without sleep apnea (1.77 +/- 0.21, n = 10). Measures of ventilatory control were all correlated with the mean of 12 hourly GH concentrations, but only HCVR was correlated with IGF-1 levels. Multiple linear regression analysis revealed that HCVR, HHVR, and IGF-1 could explain 39% of the variability in the degree of CSA in acromegalic patients with sleep apnea. We conclude that increased ventilatory responsiveness and elevated hormonal parameters of disease activity both contribute to the pathogenesis of central sleep apnea in acromegaly.