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Four years of growth hormone replacement in adults with growth hormone deficiency: further increase in bone mineral density
1 9 4 Poster abstracts
Growth hormone inhibits renal and hepatic 1 lJ3.hydroxysteroid dehydrogenases in man B. R. Walker, R. Best, S. Stewart, K. M. McLeod, P. L. Padfield Department of Medicine, Western General Hospital, Edinburgh, UK
Growth hormone (GH)-induced retention of sodium could be due to cortisol-dependent mineralocorticoid receptor activation if GH impairs the conversion of cortisol to cortisone by renal ll~-hydroxysteroid dehydrogenase-2 (ll-HSD2). However, in hypopituitary patients, GH has been shown to reduce the ratio of urinary cortisol:cortisone metabolites, suggesting either enhanced renal 11-HSD2 or impaired conversion of cortisone to cortisol by hepatic 11-HSD1. In rats, GH inhibits both 11-HSD2 and l l-HSD1. The aim of this study was to discriminate between the effects of GH on these two enzymes in man. Patients with GH deficiency (14 men, 17 women, aged 22-60 years) took part in a 6-month, randomized, double-blind trial to compare the effects of GH, 0.04-0.08 mg/kg/week (0.125-0.25 IU/kg/week), with those of placebo. Plasma (sampled at 09.00 hours) and urine (after overnight collection) were taken at baseline and after 6 months of treatment for the measurement of cortisol metabolites by gas chromatography-mass spectrometry. The only change in the ratios of plasma or urinary cortisol
metabolites after GH treatment was in patients receiving hydrocortisone. These patients had a substantial increase in the urinary free cortisol:cortisone ratio - a novel assay which reflects renal ll-HSD2 independently of hepatic ll-HSD1 from 0.88 + 0.11 to 2.56 +_0.85 for patients on hydrocortisone vs 0.54 + 0.15 to 0.57 _+ 0.11 for patients not on hydrocortisone). However, this was not associated with higher blood pressure, increased plasma sodium or lower plasma potassium. As in rats, GH replacement in patients with adrenocorticotrophin deficiency inhibits renal 11-HSD2, but this is only apparent when the ratio of urinary free cortisol:cortisone is measured and is not detected by urinary A-ring-reduced cortisol metabolites or the plasma cortisol:cortisone ratio. This biochemical pattern suggests that GH inhibits both the renal conversion of cortisol to cortisone (11-HSD2) and the hepatic conversion of cortisone to cortisol (11-HSD1). It may therefore be important to adjust replacement doses of hydrocortisone in patients receiving GH therapy.
Four years of growth hormone r e p l a c e m e n t in adults with growth hormone deficiency: further increase in bone mineral density o
G. Johannsson, T. Rosdn, B.-A. Bengtsson Research Center for Endocrinology and Metabolism (RCEM), Sahlgrenska University Hospital, G6teborg, Sweden
The aim of this study was to investigate the effects of 4 years of growth hormone (GH) treatment on bone mineral content (BMC) and bone mineral density (BMD) in adults with adultonset GH deficiency (AO-GHD). Fifty-two adults (31 men, 21 women; mean age, 49.8 years; range, 20-67 years) with AO-GHD participated in a 4-year open-treatment trial with GH. Total body BMC and BMD in the lumbar spine and the proximal femur were assessed by dual-energy X-ray absorptiometry. At the end of the treatment period, BMD increased in the lumbar spine (L2-L4) by 5.5% (95% confidence interval [CI], 3.4-7.7%), in the femoral neck by 7.2% (95% CI, 3.1-11.3%) and in the femoral trochanter by 7.1% (95% CI,
3.6-9.1%) compared with baseline. Total body BMC increased by 3.4% (95% CI, 1.4-5.4%). The increase in BMD in the lumbar spine and proximal femur was highly significant (P < 0.001) after between 2 and 4 years of GH treatment. In conclusion, 4 years of GH treatment induced a sustained increase in total body BMC and BMD in the lumbar spine and proximal femur in patients with AO-GHD, with a marked increase in BMD in weight-bearing skeletal locations after between 2 and 4 years of treatment. Patients with the lowest pretreatment BMD had the best response to GH treatment. Normalization of BMD may therefore be achieved by prolonging GH replacement in patients with AO-GHD.
Growth hormone inhibits renal and hepatic 1 lJ3.hydroxysteroid dehydrogenases in man B. R. Walker, R. Best, S. Stewart, K. M. McLeod, P. L. Padfield Department of Medicine, Western General Hospital, Edinburgh, UK
Growth hormone (GH)-induced retention of sodium could be due to cortisol-dependent mineralocorticoid receptor activation if GH impairs the conversion of cortisol to cortisone by renal ll~-hydroxysteroid dehydrogenase-2 (ll-HSD2). However, in hypopituitary patients, GH has been shown to reduce the ratio of urinary cortisol:cortisone metabolites, suggesting either enhanced renal 11-HSD2 or impaired conversion of cortisone to cortisol by hepatic 11-HSD1. In rats, GH inhibits both 11-HSD2 and l l-HSD1. The aim of this study was to discriminate between the effects of GH on these two enzymes in man. Patients with GH deficiency (14 men, 17 women, aged 22-60 years) took part in a 6-month, randomized, double-blind trial to compare the effects of GH, 0.04-0.08 mg/kg/week (0.125-0.25 IU/kg/week), with those of placebo. Plasma (sampled at 09.00 hours) and urine (after overnight collection) were taken at baseline and after 6 months of treatment for the measurement of cortisol metabolites by gas chromatography-mass spectrometry. The only change in the ratios of plasma or urinary cortisol
metabolites after GH treatment was in patients receiving hydrocortisone. These patients had a substantial increase in the urinary free cortisol:cortisone ratio - a novel assay which reflects renal ll-HSD2 independently of hepatic ll-HSD1 from 0.88 + 0.11 to 2.56 +_0.85 for patients on hydrocortisone vs 0.54 + 0.15 to 0.57 _+ 0.11 for patients not on hydrocortisone). However, this was not associated with higher blood pressure, increased plasma sodium or lower plasma potassium. As in rats, GH replacement in patients with adrenocorticotrophin deficiency inhibits renal 11-HSD2, but this is only apparent when the ratio of urinary free cortisol:cortisone is measured and is not detected by urinary A-ring-reduced cortisol metabolites or the plasma cortisol:cortisone ratio. This biochemical pattern suggests that GH inhibits both the renal conversion of cortisol to cortisone (11-HSD2) and the hepatic conversion of cortisone to cortisol (11-HSD1). It may therefore be important to adjust replacement doses of hydrocortisone in patients receiving GH therapy.
Four years of growth hormone r e p l a c e m e n t in adults with growth hormone deficiency: further increase in bone mineral density o
G. Johannsson, T. Rosdn, B.-A. Bengtsson Research Center for Endocrinology and Metabolism (RCEM), Sahlgrenska University Hospital, G6teborg, Sweden
The aim of this study was to investigate the effects of 4 years of growth hormone (GH) treatment on bone mineral content (BMC) and bone mineral density (BMD) in adults with adultonset GH deficiency (AO-GHD). Fifty-two adults (31 men, 21 women; mean age, 49.8 years; range, 20-67 years) with AO-GHD participated in a 4-year open-treatment trial with GH. Total body BMC and BMD in the lumbar spine and the proximal femur were assessed by dual-energy X-ray absorptiometry. At the end of the treatment period, BMD increased in the lumbar spine (L2-L4) by 5.5% (95% confidence interval [CI], 3.4-7.7%), in the femoral neck by 7.2% (95% CI, 3.1-11.3%) and in the femoral trochanter by 7.1% (95% CI,
3.6-9.1%) compared with baseline. Total body BMC increased by 3.4% (95% CI, 1.4-5.4%). The increase in BMD in the lumbar spine and proximal femur was highly significant (P < 0.001) after between 2 and 4 years of GH treatment. In conclusion, 4 years of GH treatment induced a sustained increase in total body BMC and BMD in the lumbar spine and proximal femur in patients with AO-GHD, with a marked increase in BMD in weight-bearing skeletal locations after between 2 and 4 years of treatment. Patients with the lowest pretreatment BMD had the best response to GH treatment. Normalization of BMD may therefore be achieved by prolonging GH replacement in patients with AO-GHD.