Effect of theophylline on cortisol secretion

Theophylline is thought to improve asthma by increasing intracellular cyclic adenosine 3'-5'-monophosphate (cAMP) levels. It has been demonstrated in experimental animals that elevation of intracellular cAMP in the adrenal cortex causes an increased secretion of cortisol. We studied whether therapeutic doses of theophylline given intravenously and orally to human subjects over 3 days would increase cortisol secretion. A single-blind, 6-day protocol was employed in five normal and five asthmatic volunteers. Adrenal function was monitored by 8 A.M. and 4 P.M. serum cortisol and adrenocorticotropic hormone (ACTH) levels; daily 24-hr urine for urinary-free cortisol (UFF), 17-hydroxysteroids (17-OH), and 17-ketosteroids (17-KS); and alternate-day cortisol secretory rates (FSR) measured by isotope dilution after intravenous 14C-cortisol. Serum theophylline concentration also was monitored. Results in normal and asthmatic subjects were similar. Theophylline caused a significant but transient increase in UFF and 17-OH excretion. Urine volumes also increased significantly, suggesting that the renal effect of theophylline accounted for the increased UFF and 17-OH excretion. FSR increased during the first 24 hr after theophylline in eight of nine cases (p < 0.05 by sign test), mean values increasing from 14.2 to 19.3 mg, but this effect had dissipated by day 3 of theophylline administration. In contrast to these findings, theophylline had no effect on serum cortisol or ACTH or urinary 17-KS. It is likely that serum cortisol and ACTH remained unchanged because the increase in cortisol secretion was offset by a concomitant increase in cortisol clearance. It is concluded that theophylline produces a small, transient increase in cortisol secretion and clearance, and this effect is similar in asthmatic and normal subjects.