Premium
The effect of growth hormone replacement therapy on cortisol–cortisone interconversion in hypopituitary adults: evidence for growth hormone modulation of extrarenal 11β‐hydroxysteroid dehydrogenase activity
Author(s) -
Gelding S. V.,
Taylor N. F.,
Wood P. J.,
Noonan K.,
Weaver J. U.,
Wood D. F.,
Monson J. P.
Publication year - 1998
Publication title -
clinical endocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.055
H-Index - 147
eISSN - 1365-2265
pISSN - 0300-0664
DOI - 10.1046/j.1365-2265.1998.00364.x
Subject(s) - endocrinology , medicine , cortisone , growth hormone , hormone , hypopituitarism , hydrocortisone , 11β hydroxysteroid dehydrogenase type 1 , dehydrogenase , hydroxysteroid , biology , enzyme , biochemistry
OBJECTIVE Growth hormone (GH) replacement therapy in hypopituitary adults has been associated with a decreased urinary ratio of 11‐hydroxy/11‐oxo‐cortisol metabolites (CoM). This could result from GH regulation of the activity of hepatic or renal 11β‐hydroxysteroid dehydrogenase (11β‐HSD1 and 2), the enzymes responsible for cortisol–cortisone interconversion, or alternatively it might reflect decreased cortisol availability. To elucidate this, we examined the effect of GH on urinary cortisol, cortisone and cortisol metabolites in hypopituitary adults at increasing doses of hydrocortisone replacement. DESIGN Patients received increasing twice daily doses of hydrocortisone (HC) (10/10, 20/10, 40/20 mg) each week, before and during 2 months of GH replacement (0.25 U/kg/week). PATIENTS Seven hypopituitary adults (three men and four women, age range 47–64 years) with combined GH and ACTH deficiency. Three additional patients with GH deficiency, but intact ACTH reserve, were also studied. MEASUREMENTS Urine steroid metabolite profiles were measured in 24‐hour urine collections by gas chromatography after each week of treatment. Urinary free cortisol and free cortisone were measured by radioimmunoassay as a measure of renal 11β‐HSD‐2 activity. 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) versus 26.77 (8.01–37.62) mg/24 hours). The urine ratio 11‐hydroxy/11‐oxo‐CoM decreased significantly with GH treatment, at each HC dose schedule (1.22 (1.02–1.96) versus 0.92 (0.83–1.63) P = 0.018; 1.53 (1.30–2.23) 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/tetrahydrocortisone, an alternative index of 11β‐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 changes in redox status. The patients with GH deficiency, but intact ACTH reserve, demonstrated changes in urine steroid profiles similar to the 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 with GH therapy at each hydrocortisone dose. CONCLUSIONS GH therapy decreases the urinary ratios 11‐hydroxy/11‐oxo‐cortisol metabolites and tetrahydrocortisols/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 further evidence for direct or indirect modulation of cortisol metabolism by growth hormone and suggest that this occurs at hepatic or an alternative site of 11β‐hydroxysteroid dehydrogenase‐1 activity.