Clinical Endocrinology (1991), 35,485-490
Corticosteroid-induced growth hormone secretion in normal and obese subjects Covadonga Muruais', Fernando Cordldot, Marla J. Moralest, Fellpe F. Casanuevat and Carlos Dieguez' t Department of Medicine and Endocrine Section, Hospital General Galicia and *Department of Physiology, Faculty of Medicine Santiago University, Santiago de Compostela, Spain (Received 17 September 1990; returned for revision 5 November 1990; finally revised 5 April 1991; accepted 30 July 7991)
Summary OBJECTIVE In normal subjects, cortlcosterolds stimulate growth hormone (GH) secretion at 3 hours. Obesity Is associated with blunted GH secretion. In order to clarify both the deranged mechanism of GH secretlon In obesity and the corticosterold mechanism of action we have assessed In normal and obese subjects the effects of dexamethasone, pyridostigmine (a drug capable of suppressing somatostatin release) and GHRH. We also compared in normal subjects the stimulatory effect of three different cortlcosterolds on plasma OH levels. DESIGN In both normal and obese subjects the following tests were carrled out: placebo: dexamethasone alone (4 mg I.v. at 0 mlnutes); and dexamethasone plus pyrldostigmlne (120 mg p.0. at 60 minutes). In normal subjects we also studied the effects of hydrocortisone (100 mg f.v. at 0 minutes) and deflazacort (a cortlcosteroidthat does not cross the blood-brain barrier) (60 mg i.v. at 0 minutes). In obese subjects we also assessed the effect of dexamethasone plus GHRH (100 pg i.v. at 150 minutes) on plasma GH levels. PATIENTS f e n normal subjects and 22 obese subjects were studied. Normal controls were wlthln 10% of their Ideal body welght. Obese subjects had a body mass Index of 37.1f 1.1 (mean SEM). MEASUREMENTS Plasma GH levels were measured by radlolmmunoassay. RESULTS Dexamethasone-induced GH secretlon In normal subjects (28.6 i7.8 mpil, P < 0.05). Cortlcosterolds dld not alter GH levels In obese subjects. Pretreatment with pyridostlgmlne Increased dexamethasone-induced GH release in normal subjects (40.8 f 6.8 mpll) but this dld not achieve statisticalslgnificance. Dexamethasoneplus pyrl-
*
Correspondence: Dr C. Dieguez, PO Box 563, 15780 Santiago de Compostela, Spain.
dostigmine did not alter OH levels In obese subjects (&Of 1.6 mull). In some subjects, dexamethasone pretreatment potentiated GHRH-stimulated GH secretion, while In half the subjects the basal GH levels were not altered. In control subjects, hydrocortisone and deflazacort caused GH release slmllar to dexamethasone. CONCLUSIONS Corticosteroids are a new and selective stimulus of GH secretion. They do not cause GH release in obese subjects. Their relative Independence from chollnerglc control suggest that they act by reducing somatostatin secretion.
Corticosteroids inhibit somatic growth and growth hormone (GH) secretion in patients (Boldgett et al.. 1956; Hartog et a[., 1964; Krieger & Glick, 1972). In particular, chronic hypercortisolism is associated with reduced G H secretion, while short-term corticosteroid administration in normal volunteers leads to the blockade of G H release elicited by stimuli such as hypoglycaemia, arginine, physical exercise (van Werder el al. 1971; Takeda et al., 1974; Nakagawa & Mashimo, 1973) and GHRH (Smals rt al., 1986; Casanueva rt al., 1988; Leal-Cerro et al., 1990). Our group has recently communicated that corticosteroids also have a dual effect on GH secretion in man: 12 hours after administration they consistently block GH release (Burguera et al., 1990), while shortly after administration corticosteroids have the opposite effect, releasing G H (Casanueva et al., 1988). This stimulatory action of corticosteroid presents a peculiar timecourse pattern because only 3 hours after administration do the stimulatory effects become evident (Casanueva et al., 1990). On the other hand, obesity is a pathological state associated with blunted G H secretion in light of all the stimuli so far tested (Dieguez et al., 1988; Bell et a/., 1970; Finer et al., 1987; Williams et al., 1984; Kopelman et al., 1985, 1986; Cordido et al., 1989, 1990; Castro et al., 1990). Given that obese subjects usually show an alteration in glucocorticoid metabolism, and that such compounds are involved in the regulation of food intake in obese rats (Dieguez et al., 1988), the present study was designed to assess the acute action of corticosteroids on G H release in normal and obese subjects, with two main purposes. We wished firstIy, to clarify the altered mechanism of GH secretion in obesity in addition to 485
486
Clinical Endocrinology (1991) 35
C.Muruais et al.
the corticosteroid mechanism of action and secondly, to study the dose and type-dependency of corticosteroids on GH secretion in normal volunteers. Subjects and methods
Ten normal subjects and 22 obese subjects were studied. Normal controls were within 10% of their ideal body weight and obese subjects weighed about 140%of ideal body weight as determined by the Fogarty Center Conference on obesity (Bray, 1979), and had a body mass index (BMI kg/m2) of 37.1 1.1. The women had normal ovarian cycles and were tested in the follicular phase. All volunteers led normal life styles and none had diabetes mellitus or other medical problems or were taking any drugs. Approval for this study was obtained from the Hospital Ethics Committee and all subjects provided informed consent. Nine obese subjects (eight women and one man, mean kSEM age 33 k2.4 years, body mass index BMI 37.9 _+ 0.7, range 32.9-41.6, and per cent ideal body weight 167k4.5) and eight control volunteers (six women and two men, age 28f2.2 years) were tested twice. On one day they were administered dexamethasone (4 mg i.v., Fortecortin, Merck, Spain), and on the second day they received isovolumetric saline. A different group of six obese women (mean+SEM, age 39k3.8 years, BMI 37.2f 1.8, range 31.3-43, and per cent ideal body weight 168+76) was also tested twice. On day 1 they received 4 rng i.v. of dexamethasone at 0 minutes followed by the administration of pyridostigmine, 120 mg p.0. (Mestinon, Roche, Spain) 60 minutes after the corticosteroid. As a control for this group the normal volunteers of the previous experiment were tested for a third time with dexamethasone at 0 minutes and pyridostigmine at 60 minutes. A third group of seven obese subjects (six women and one man, meankSEM, age 36.2h4.8 years, BMI 38-3 5 2 . 7 , per cent ideal body weight 1725 11-8) underwent two tests each on a different day. One day they received dexamethasone (4 mg i.v.) at 0 minutes, and in the second test the same dose of corticosteroid was administered at 0 minutes, followed by GHRH (100 pg i.v. at 150 minutes, GHRH (1-29) NH2, Geref, Serono, Spain). In the last group, five normal volunteers (two women and three men, mean+SEM age 33+2 years) underwent three tests each on a separate day; on one day they received 1 mg dex i.v. at 0 minutes; on another day they received 100 mg i.v. of hydrocortisone at 0 minutes; and on the third day 60 mg of deflazacort (Dezacort, Merrel Dow, Spain) was administered at time 0 minutes. Each subject's tests were performed in random order by a single-blind protocol, so each subject served as her/his own control. After an overnight fast, testing started at 0900 h with
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Fig. 1 Mean ASEM of GH secretion in a, normal and b, obese subjects after administrationof A, 0,dexarnethasone (4 mg i.v.) or A, 0 , saline at time 0.
the subjects recumbent. An indwelling catheter was placed in a forearm vein and kept patent with a slow infusion of 0.9% NaCI. Blood samples were obtained at appropriate intervals throughout the next 5 hours. Determinations of human plasma hormones were carried out with a commercial kit: G H from Sorin, Spain, with 7% intra-assay coefficient of variation, and a sensitivity of 1.0 mU/1. All the samples from each subject were analysed in the same assay. The statistical evaluation was carried out by non-parametric Wilcoxon rank test. The areas under the curve were calculated by a trapezoidal method. The statistical level of significance was set at Pc0.05. Results
Dexamethasone (4 rng i.v.) administration to normal volunteers induced a mean peak of G H discharge at 210 minutes of 28.6k7.8 mU/1 (Fig. 1). On an individual basis GH peaks occurred between 165 and 210 minutes. Differences with respect to the saline test were significant both when analysed as mean GH peak, and on comparing the areas under the
Corticosteroid-induced GH secretion
Clinical Endocrinology (1991) 35
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Fig. 2 Mean SEM of GH secretion in normal and obese subjects after administration at time 0 of dexamethasone (4 mg i.v.), followed at 60 minutes by either A , 0,placebo or A , 0 , pyridostigmine.
secretory curve (P
Corticosteroid-induced growth hormone secretion in normal and obese subjects Covadonga Muruais', Fernando Cordldot, Marla J. Moralest, Fellpe F. Casanuevat and Carlos Dieguez' t Department of Medicine and Endocrine Section, Hospital General Galicia and *Department of Physiology, Faculty of Medicine Santiago University, Santiago de Compostela, Spain (Received 17 September 1990; returned for revision 5 November 1990; finally revised 5 April 1991; accepted 30 July 7991)
Summary OBJECTIVE In normal subjects, cortlcosterolds stimulate growth hormone (GH) secretion at 3 hours. Obesity Is associated with blunted GH secretion. In order to clarify both the deranged mechanism of GH secretlon In obesity and the corticosterold mechanism of action we have assessed In normal and obese subjects the effects of dexamethasone, pyridostigmine (a drug capable of suppressing somatostatin release) and GHRH. We also compared in normal subjects the stimulatory effect of three different cortlcosterolds on plasma OH levels. DESIGN In both normal and obese subjects the following tests were carrled out: placebo: dexamethasone alone (4 mg I.v. at 0 mlnutes); and dexamethasone plus pyrldostigmlne (120 mg p.0. at 60 minutes). In normal subjects we also studied the effects of hydrocortisone (100 mg f.v. at 0 minutes) and deflazacort (a cortlcosteroidthat does not cross the blood-brain barrier) (60 mg i.v. at 0 minutes). In obese subjects we also assessed the effect of dexamethasone plus GHRH (100 pg i.v. at 150 minutes) on plasma GH levels. PATIENTS f e n normal subjects and 22 obese subjects were studied. Normal controls were wlthln 10% of their Ideal body welght. Obese subjects had a body mass Index of 37.1f 1.1 (mean SEM). MEASUREMENTS Plasma GH levels were measured by radlolmmunoassay. RESULTS Dexamethasone-induced GH secretlon In normal subjects (28.6 i7.8 mpil, P < 0.05). Cortlcosterolds dld not alter GH levels In obese subjects. Pretreatment with pyridostlgmlne Increased dexamethasone-induced GH release in normal subjects (40.8 f 6.8 mpll) but this dld not achieve statisticalslgnificance. Dexamethasoneplus pyrl-
*
Correspondence: Dr C. Dieguez, PO Box 563, 15780 Santiago de Compostela, Spain.
dostigmine did not alter OH levels In obese subjects (&Of 1.6 mull). In some subjects, dexamethasone pretreatment potentiated GHRH-stimulated GH secretion, while In half the subjects the basal GH levels were not altered. In control subjects, hydrocortisone and deflazacort caused GH release slmllar to dexamethasone. CONCLUSIONS Corticosteroids are a new and selective stimulus of GH secretion. They do not cause GH release in obese subjects. Their relative Independence from chollnerglc control suggest that they act by reducing somatostatin secretion.
Corticosteroids inhibit somatic growth and growth hormone (GH) secretion in patients (Boldgett et al.. 1956; Hartog et a[., 1964; Krieger & Glick, 1972). In particular, chronic hypercortisolism is associated with reduced G H secretion, while short-term corticosteroid administration in normal volunteers leads to the blockade of G H release elicited by stimuli such as hypoglycaemia, arginine, physical exercise (van Werder el al. 1971; Takeda et al., 1974; Nakagawa & Mashimo, 1973) and GHRH (Smals rt al., 1986; Casanueva rt al., 1988; Leal-Cerro et al., 1990). Our group has recently communicated that corticosteroids also have a dual effect on GH secretion in man: 12 hours after administration they consistently block GH release (Burguera et al., 1990), while shortly after administration corticosteroids have the opposite effect, releasing G H (Casanueva et al., 1988). This stimulatory action of corticosteroid presents a peculiar timecourse pattern because only 3 hours after administration do the stimulatory effects become evident (Casanueva et al., 1990). On the other hand, obesity is a pathological state associated with blunted G H secretion in light of all the stimuli so far tested (Dieguez et al., 1988; Bell et a/., 1970; Finer et al., 1987; Williams et al., 1984; Kopelman et al., 1985, 1986; Cordido et al., 1989, 1990; Castro et al., 1990). Given that obese subjects usually show an alteration in glucocorticoid metabolism, and that such compounds are involved in the regulation of food intake in obese rats (Dieguez et al., 1988), the present study was designed to assess the acute action of corticosteroids on G H release in normal and obese subjects, with two main purposes. We wished firstIy, to clarify the altered mechanism of GH secretion in obesity in addition to 485
486
Clinical Endocrinology (1991) 35
C.Muruais et al.
the corticosteroid mechanism of action and secondly, to study the dose and type-dependency of corticosteroids on GH secretion in normal volunteers. Subjects and methods
Ten normal subjects and 22 obese subjects were studied. Normal controls were within 10% of their ideal body weight and obese subjects weighed about 140%of ideal body weight as determined by the Fogarty Center Conference on obesity (Bray, 1979), and had a body mass index (BMI kg/m2) of 37.1 1.1. The women had normal ovarian cycles and were tested in the follicular phase. All volunteers led normal life styles and none had diabetes mellitus or other medical problems or were taking any drugs. Approval for this study was obtained from the Hospital Ethics Committee and all subjects provided informed consent. Nine obese subjects (eight women and one man, mean kSEM age 33 k2.4 years, body mass index BMI 37.9 _+ 0.7, range 32.9-41.6, and per cent ideal body weight 167k4.5) and eight control volunteers (six women and two men, age 28f2.2 years) were tested twice. On one day they were administered dexamethasone (4 mg i.v., Fortecortin, Merck, Spain), and on the second day they received isovolumetric saline. A different group of six obese women (mean+SEM, age 39k3.8 years, BMI 37.2f 1.8, range 31.3-43, and per cent ideal body weight 168+76) was also tested twice. On day 1 they received 4 rng i.v. of dexamethasone at 0 minutes followed by the administration of pyridostigmine, 120 mg p.0. (Mestinon, Roche, Spain) 60 minutes after the corticosteroid. As a control for this group the normal volunteers of the previous experiment were tested for a third time with dexamethasone at 0 minutes and pyridostigmine at 60 minutes. A third group of seven obese subjects (six women and one man, meankSEM, age 36.2h4.8 years, BMI 38-3 5 2 . 7 , per cent ideal body weight 1725 11-8) underwent two tests each on a different day. One day they received dexamethasone (4 mg i.v.) at 0 minutes, and in the second test the same dose of corticosteroid was administered at 0 minutes, followed by GHRH (100 pg i.v. at 150 minutes, GHRH (1-29) NH2, Geref, Serono, Spain). In the last group, five normal volunteers (two women and three men, mean+SEM age 33+2 years) underwent three tests each on a separate day; on one day they received 1 mg dex i.v. at 0 minutes; on another day they received 100 mg i.v. of hydrocortisone at 0 minutes; and on the third day 60 mg of deflazacort (Dezacort, Merrel Dow, Spain) was administered at time 0 minutes. Each subject's tests were performed in random order by a single-blind protocol, so each subject served as her/his own control. After an overnight fast, testing started at 0900 h with
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Fig. 1 Mean ASEM of GH secretion in a, normal and b, obese subjects after administrationof A, 0,dexarnethasone (4 mg i.v.) or A, 0 , saline at time 0.
the subjects recumbent. An indwelling catheter was placed in a forearm vein and kept patent with a slow infusion of 0.9% NaCI. Blood samples were obtained at appropriate intervals throughout the next 5 hours. Determinations of human plasma hormones were carried out with a commercial kit: G H from Sorin, Spain, with 7% intra-assay coefficient of variation, and a sensitivity of 1.0 mU/1. All the samples from each subject were analysed in the same assay. The statistical evaluation was carried out by non-parametric Wilcoxon rank test. The areas under the curve were calculated by a trapezoidal method. The statistical level of significance was set at Pc0.05. Results
Dexamethasone (4 rng i.v.) administration to normal volunteers induced a mean peak of G H discharge at 210 minutes of 28.6k7.8 mU/1 (Fig. 1). On an individual basis GH peaks occurred between 165 and 210 minutes. Differences with respect to the saline test were significant both when analysed as mean GH peak, and on comparing the areas under the
Corticosteroid-induced GH secretion
Clinical Endocrinology (1991) 35
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Fig. 2 Mean SEM of GH secretion in normal and obese subjects after administration at time 0 of dexamethasone (4 mg i.v.), followed at 60 minutes by either A , 0,placebo or A , 0 , pyridostigmine.
secretory curve (P
