THE EFFECT OF GROWTH-HORMONE REPLACEMENT ON CORTISOL METABOLISM AND GLUCOCORTICOID SENSITIVITY IN HYPOPITUITARY ADULTS

OBJECTIVE Growth hormone (GH) replacement therapy in hypopituitary adu lts is associated with sodium and water retention. The underlying mech anisms are incompletely understood and a possible contribution of alte red cortisol metabolism or action has not been evaluated. We have inve stigated the effect of GH replacement therapy on cortisol metabolism, cortisol binding globulin and in-vitro glucocorticoid sensitivity in a group of adult hypopituitary patients. DESIGN AND PATIENTS We studied 19 adult hypopituitary patients (18 adult onset, M:F, 6:13), who were receiving conventional hydrocortisone (16 patients), thyroxine (14 pa tients), triiodothyronine (1 patient), sex steroid (9 patients), human chorionic gonadotrophin (1 patient) or desmopressin (6 patients) repl acement during a 6-month, double blind controlled trial of GH therapy (active:placebo, 8:11) followed by a 6-month open phase of GH (mean do se: 0.2IU/kg/week, range 0.051-0.27) and after a 6-week washout phase following discontinuation of GH therapy. MEASUREMENTS Twenty-four-hour urine free cortisol, cortisol metabolites (CoM), ratio 11-hydroxy/11- oxo CoM (F/E) and ratio 5 alpha/beta tetrahydrocortisol were measured at 6 months, 12 months and after the 6 week washout phase. Serum corti sol binding globulin was measured basally, at 6 months, 12 months and after washout. Glucocorticoid sensitivity was determined in lymphocyte preparations from 8 patients, during GH therapy and after washout, us ing an in-vitro technique dependent on dexamethasone suppression of ph ytohaemagglutinin-stimulated thymidine incorporation into DNA. Plasma renin activity and aldosterone were measured after 6-12 months GH ther apy and after washout. RESULTS After 6 months of GH, in patients on hy drocortisone (n = 9), there were significant decreases in CoM (mean de crement 21%, P < 0.01), F/E (mean decreased from 1.27 to 1.0, P = 0.04 ; reference range 0.33-1.29) and 5 alpha/5 beta tetrahydrocortisol (me an decreased from 0.67 to 0.48, P = 0.01) and a subsequent increase af ter washout. Patients not on hydrocortisone (n = 2) demonstrated a nor mal basal F/E falling by 25% on GH therapy but no change in CoM. Durin g 12 months of GH therapy, patients on hydrocortisone (n = 7) demonstr ated a further trend to decrement in CoM (P = 0.09) which reversed aft er washout (P = 0.04). Urine free cortisol tended to fall during GH th erapy and increased significantly following washout after 12 months tr eatment (P < 0.02). Serum cortisol binding globulin decreased by 20% ( P < 0.05) during 12 months GH treatment but remained within the refere nce range. In-vitro studies demonstrated a trend to reduced glucocorti coid sensitivity on GH therapy; the maximum inhibition of phytohaemagg lutinin by dexamethasone tended to be less on GH therapy (P = 0.052) a nd was also lower than in 29 normal volunteers (P < 0.05). There were no significant changes in plasma renin but there was a small increment in aldosterone in recumbent patients (P = 0.04) during the open phase of GH therapy in the placebo arm. CONCLUSIONS GH therapy in hypopitui tary adults is associated with an apparent reduction in availability o f administered hydrocortisone as measured by urine cortisol metabolite s and urine free cortisol. This effect is unlikely to be clinically si gnificant except possibly in ACTH deficient subjects on suboptimal hyd rocortisone replacement. The changes In F/E suggest that GH may direct ly or indirectly modulate the activity of 11 beta-hydroxy-steroid dehy drogenase. The apparent decrease in glucocorticoid sensitivity during GH therapy, demonstrated in vitro, merits further investigation.