Theophylline blunts the GH-response to growth hormone releasing hormone in normal subjects

Theophylline enhances GH-secretion in vitro, whereas in vivo a slight decrease of basal GH-levels has been observed. In the present study the effect of theophylline on the GH-responsiveness to acute and continuous administration of growth hormone releasing hormone (GHRH) was investigated. The following protocol was performed. 1) GHRH study. Fifty μg GHRH was given as an iv bolus followed by constant GHRH-infusion (100 μg/h) over 2 h after which another GHRH bolus of 50 μg was given. 2) GHRH plus theophylline study. GHRH was administered as in the first study and theophylline was infused at a constant rate of 3.56 mg/min over 3 h, starting one h before the GHRH bolus. 3) Theophylline study. Only saline and theophylline were infused. GHRH alone led to a GH-rise within 30 min with a maximum of 22.8 ± 7.2 ng/ml (mean ± SE) after which GH-levels decreased despite continuous GHRH-infusion to a nadir of 12.1 ± 4.4 ng/ml at 105 min. The second GHRH bolus led to a minimal GH-increase (13.3 ± 6.4 ng/ml at 135 min). Theophylline administration resulted in blunting of the GH-response to GHRH in all volunteers, with GH levels fluctuating between 4-6 ng/ml throughout GHRH-administration. Theophylline alone did not affect GH-levels in three subjects studied, whereas in the other one a GH secretory episode 90 min after administration of the drug was observed. Prl showed a minimal increase only after the second GHRH bolus (from 254.2 ± 7.7 μU/ml to 317.3 ± 96.0 μU/ml in study 1, and from 139.3 ± 26.9 μU/ml to 193.0 ± 32.6 μU/ml in study 2), TSH-levels did not change during any of the test-procedures and GHRH-levels were comparable in both study 1 and 2. Free fatty acids (FFA) rose progressively after theophylline administration (from 0.68 ± 0.10 mEq/l to 1.06 ± 0.08 mEq/l in study 2, and from 0.64 ± 0.12 mEq/l to 1.09 ± 0.05 mEq/l in study 3), but also after GHRH alone (from 0.50 ± 0.05 mEq/l to 0.78 ± 0.11 mEq/l). This shows that therapeutical doses of theophylline blunt the GH-response to GHRH in normal subjects. The mechanisms involved may be a competition for the adenosine receptor at the pituitary, or an indirect effect mediated by the rise of FFA levels.