The effect of growth hormone replacement on cortisol metabolism and glucocorticoid sensitivity in hypopituitary adults
Authors: Weaver Jolanta U. , Theventhiran Lakshmi , Noonan Kate , Burrin Jacqueline M. , Taylor Norman F. , Norman Michael R. , Monson John P. 
Published: March 2008

OBJECTIVE Growth hormone (GH) replacement therapy in hypopituitary adults is associated with sodium and water retention. The underlying mechanisms are incompletely understood and a possible contribution of altered cortisol metabolism or action has not been evaluated. We have investigated the effect of GH replacement therapy on cortisol metabolism, cortisol binding globulin and In‐vitro glucocorticold sensitivity in a group of adult hypopituitary patients.

DESIGN AND PATIENTS We studied 19 adult hypopituitary patients (18 adult onset, Y:F, 6:13), who were receiving conventional hydrocortisone (16 patients), thyroxine (14 patients), triiodothyronine (1 patient), sex steroid (9 patients), human chorionic gonadotrophin (1 patient) or desmopressin (6 patients) replacement 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 dose: 0·2 IU/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/ll‐oxo CoM (F/E) and ratio 5α/β tetrahydrocortisol were measured at 6 months, 12 months and after the 6 week washout phase. Serum cortisol binding globulin was measured basally, at 6 months, 12 months and after washout. Glucocorticold sensitivity was determined in lymphocyte preparations from 8 patients, during GH therapy and after washout, using an In‐vitro technique dependent on dexamethasone suppression of phytohaemagglutinin‐stimulated thymidine Incorporation into DNA. Plasma renin activity and aidosterone were measured after 6‐12 months GH therapy and after washout.

RESULTS After 6 months of GH, In patients on hydrocortisone (n= 9), there were significant decreases in CoM (mean decrement 21%, P < 0·01), F/E (mean decreased from 1·27to 1·0, P= 0·04; reference range0·33‐1·29) and 5α/5β tetrahydrocortisol (mean decreased from 0·67 to 0·48, P= 0·01) and a subsequent increase after washout. Patients not on hydrocortisone (n= 2) demonstrated a normal basal F/E falling by 25% on GH therapy but no change in CoM. During 12 months of OH therapy, patients on hydrocortisone (n= 7) demonstrated a further trend to decrement in CoM (P= 0·09) which reversed after washout (P= 0·04). Urine free cortisol tended to fall during OH therapy and Increased significantly following washout after 12 months treatment (P < 0·02). Serum cortisol binding globulin decreased by 20% (P < 0·05) during 12 months GH treatment but remained within the reference range. In‐vitro studies demonstrated a trend to reduced giucocorticoid sensitivity on GH therapy; the maximum inhibition of phytohaemaggiutinin by dexamethasone tended to be less on OH therapy (P= 0·052) and 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 aidosterone in recumbent patients (P= 0·04) during the open phase of GH therapy in the placebo arm.

CONCLUSIONS GH therapy in hypopltuitary adults is associated with an apparent reduction in availability of administered hydrocortisone as measured by urine cortisol metabolites and urine free cortisol. This effect is unlikely to be clinically significant except possibly in ACTH deficient subjects on suboptimal hydrocortisone replacement. The changes in F/E suggest that GH may directly or indirectly modulate the activity of 11β‐hydroxysteroid dehydrogenase. The apparent decrease in giucocorticoid sensitivity during GH therapy, demonstrated in vitro, merits further investigation.