We investigated the mechanisms of the beneficial effect derived from progesterone therapy for sleep apnea syndrome (SAS). Nine patients with SAS were treated for 7 days with chlormadinone acetate (CMA), a respiratory stimulant known to increase not only CO2 and hypoxic chemosensitivity but also respiratory drive response for ventilatory loading. They were examined as to sleep events and ventilatory control during wakefulness before and during CMA treatment. Apnea-hypopnea index was significantly reduced from 51.1 +/- 5.7 to 43.6 +/- 8.1 episodes/h (p less than 0.05). The ratio of desaturation time with more than 4% SaO2 fall to total sleep time was diminished in seven of nine patients, and its mean value decreased from 44.9 +/- 8.6 to 28.7 +/- 8.1% (p less than 0.05). Both hypercapnic ventilatory response (HCVR) and load response during wakefulness were significantly increased, although isocapnic hypoxic ventilatory response (HVR) was not significantly enhanced by CMA. The degree of augmentation in awake load response as well as in HCVR was positively correlated with that of improvement in sleep-disordered breathing. Moreover, patients who did not show amelioration in oxygen desaturation were found to be incapable of increasing load response despite increased HCVR. We conclude that CMA therapy for sleep apnea syndrome is effective in the patients whose load response as well as respiratory control activity are augmented during wakefulness.