THE EFFECT OF GROWTH-HORMONE REPLACEMENT THERAPY ON CORTISOL-CORTISONE INTERCONVERSION IN HYPOPITUITARY ADULTS - EVIDENCE FOR GROWTH-HORMONE MODULATION OF EXTRARENAL 11-BETA-HYDROXYSTEROID DEHYDROGENASE-ACTIVITY

OBJECTIVE Growth hormone (GH) replacement therapy in hypopituitary adu lts has been associated with a decreased urinary ratio of 11-hydroxy/1 1-oxo-cortisol metabolites (CoM). This could result from GH regulation of the activity of hepatic or renal 11 beta-hydroxysteroid dehydrogen ase (11 beta-HSD1 and 2), the enzymes responsible for cortisol-cortiso ne interconversion, or alternatively it might reflect decreased cortis ol availability. To elucidate this, we examined the effect of GH on ur inary cortisol, cortisone and cortisol metabolites in hypopituitary ad ults at increasing doses of hydrocortisone replacement. DESIGN Patient s received increasing twice daily doses of hydrocortisone (HC) (10/10, 20/10, 40/20 mg) each week, before and during 2 months of GH replacem ent (0.25 U/kg/week). PATIENTS Seven hypopituitary adults (three men a nd four women, age range 47-64 years) with combined GH and ACTH defici ency. Three additional patients with GH deficiency, but intact ACTH re serve, were also studied. MEASUREMENTS Urine steroid metabolite profil es were measured in 24-hour urine collections by gas chromatography af ter each week of treatment. Urinary free cortisol and free cortisone w ere measured by radioimmunoassay as a measure of renal 11 beta-HSD-2 a ctivity. RESULTS Total urinary CoM increased with rising doses of HC, but at each particular HC dose, were unchanged after GH (before versus after GH, median (range): 9.67 (7.86-12.59) versus 9.93 (8.31-14.08); 15.87 (12.37-31.39) versus 17.07 (12.64-23.81); 26.68 (19.07-42.14) v ersus 26.77 (8.01-37.62) mg/24 hours). The urine ratio 11-hydroxy/11-o xo-CoM decreased significantly with GH treatment, at each HC dose sche dule (1.22 (1.02-1.96) versus 0.92 (0.83-1.63) P=0.018; 1.53 (1.30-2.2 3) versus 1.23 (0.93-1.46) P=0.018; 1.87 (1.45-2.70) versus 1.56 (1.22 -1.79) P=0.018). The urinary ratio tetrahydrocortisols/tetrahydrocorti sone, an alternative index of 11 beta-HSD activity, also fell with GH therapy at each HC dose (P=0.049; P=0.018; P=0.043). In contrast, the urinary 20-hydroxy/20-oxo-CoM ratio exhibited a small increase with GH , suggesting that the changes observed above were not simply due to ch anges in redox status. The patients with GH deficiency, but intact ACT H reserve, demonstrated changes in urine steroid profiles similar to t he group receiving hydrocortisone replacement. Urinary free cortisone and urinary free cortisol/free cortisone ratios did not change with GH therapy, but the serum cortisol/cortisone ratio fell significantly wi th GH therapy at each hydrocortisone dose. CONCLUSIONS GH therapy decr eases the urinary ratios 11-hydroxy/11-oxo-cortisol metabolites and te trahydrocortisols/tetrahydrocortisone, but not urinary free cortisone or the urinary free cortisol/free cortisone ratio. This effect is not secondary to reduced cortisol availability. These findings provide fur ther evidence for direct or indirect modulation of cortisol metabolism by growth hormone and suggest that this occurs at hepatic or an alter native site of 11 beta-hydroxysteroid dehydrogenase-l activity.