Modulation of cortisol metabolism by low-dose growth hormone replacement in elderly hypopituitary patients

II P-hydroxysteroid dehydrogenase type 1(11 beta-HSD1) functions as a net r eductase converting cortisone to cortisol. GH inhibits 11 beta-HSD1, result ing in a shift in cortisol metabolism favoring cortisone, an observation th at may have significance in patients with ACTH deficiency who are unable to compensate for such changes. We have studied the effect of three doses of GH replacement (0.17, 0.33, and 0.5 mg each given for 12 weeks in ascending order) on cortisol metabolism in nine patients, aged 62-70 yr, with hypopi tuitarism who were receiving fixed doses of oral hydrocortisone. Serum insulin-like growth factor I levels rose in a dose-dependent manner o ver the course of the study. Fat mass decreased significantly at 24 weeks ( P = 0.02), a change that was maintained at 36 weeks. Fasting serum insulin levels did not change significantly over the course of the study. The ratio of urine cortisol to cortisone metabolites (Fm/Em) fell significa ntly at 12 weeks (GH dose, 0.17 mg/day) from 1.32 (0.91-2.20) at baseline t o 1.08 (0.89-2.11) (P < 0.05). Although it did not fall further as the dose of GH was increased, the reduction in the Fm/Em ratio persisted at 24 week s (GH dose, 0.33 mg/day), 1.09 (0.8-2.11) (P < 0.05 vs. baseline), and 36 w eeks (GH dose, 0.5 mg/day), 1.19 (0.82-2.31) (P < 0.05 vs, baseline). The F m/Em ratio did not correlate with serum insulin-like growth factor I, fat m ass, or fasting insulin levels at any time during the study. This study confirms the inhibitory effect of GH on 11 beta-HSD1 but has sho wn that the effect occurs maximally at very low GH doses and is not mediate d indirectly by change in circulating insulin. Patients with partial or tot al ACTH deficiency, in whom cortisol replacement is suboptimal, may be at r isk of the clinical manifestations of cortisol deficiency when they are com menced on GH therapy.