Clinical Endocrinology (1991) 35,491498
Effects of pyridostigmine on spontaneous and growth hormone-releasing hormone stimulated growth hormone secretion in children on daily glucocorticoid therapy after liver transplantation Andrea Glustlna, Angela Glrelll, Danlele Albertl’, Slmonetta Bossoni, Fabio Buzit, Mauro Doga, Maurlzlo Schettlno and William B. WehrenbergS Clinica Medica, Chirurgia Pediatrica and TCIinica Pediatrica, University of Brescia, Italy; $Department of Health Sciences, University of Wisconsin, Milwaukee, USA
(Received 2 April 1991; returned for revision 16 June finally revised 5 July 1991; accepted 30 July 1991)
1991;
Summary OBJECTIVES We aimed to investigate both nocturnal spontaneous and morning growth hormone (GH)-releasIng hormone (GHRH)-InducedGH secretion In children on dally glucocortlcold treatment after liver transplantatlon and to evaluatethe effect of pyrldostlgmlne(an acetylchollnesterase lnhlbltor thought to reduce hypothalamic somatostatin tone) on GH secretion In these patlents. DESIGN We performed a randomlzed, slngle-bllnd, crossover study. PATIENTS We studied three male and three female juvenile patients, within a year of orthotopic liver transplantation and under immunosuppressiveglucocorticoid therapy (mean dose*SEM, 592&0.63 mglday) and five normal children (four males, one female). MEASUREMENTS Both nocturnal spontaneous and mornIng GHRH-Induced OH secretion were evaluated after admlnlstration of placebo, 1 tablet P.o., or pyrldostigmine, 2 mglkg p.0. RESULTS Spontaneous GH. Placebo: In liver transplanted children nocturnal GH secretion (mean GH level 10.8f2.0 mU/I) was not slgnlflcantly different wlth respect to normal children (mean GH level 12.8f1.2mU/I); pyrldostlgmlne: nocturnal OH secretion was signlflcantly Increased as comparedto placebo In subjects wlth liver transplantatlon but not In normal chlldren. GHRH test. Placebo: llver transplanted patients showed a blunted OH response to GHRH wlth respect to normal children; pyrldostlgmlne: the OH responses to GHRH (P< 0.05) increased as compared to placebo and dld not differ slgnlflcantly In the two groups.
Correspondence: Dr Andrea Giustina, Cattedra di Clinica Medica, Universita’ di Brescia, c/o 2a Medicina-Spedali Civili, 25125 Brescia, Italy
CONCLUSIONS Our data suggest a steroid-mediated increase in hypothalamic somatostatin tone in llver transplanted children.
Glucocorticoids have long been known to interfere with normal somatic growth in laboratory animals (Hodges & Vernikos, 1958) and in man. Children receiving high-dose glucocorticoid treatment (Blodgett et al., 1956) or with Cushing’s disease (Solomon & Shoen, 1976)exhibit impaired growth. It has been hypothesized that glucocorticoids may reduce insulin-like growth factor-I (IGF-I) levels or activity (Phillips et al. 1975). On the other hand, numerous studies have also demonstrated that normal subjects after administration of supraphysiological doses of glucocorticoids and patients with Cushing’s disease have blunted G H responses to various pharmacological stimuli (Hartog et al., 1964; Nakagawa et al., 1969; Hotta et al., 1988; Giustina et al., 1990b). However, the precise mechanisms of glucocorticoidinduced inhibition of G H secretion have not yet been identified. GH synthesis and secretion are regulated by the hypothalamic peptides GH-releasing hormone (GHRH), which has an excitatory role, and somatostatin, which has an inhibitory role (Wehrenberg et al., 1982). Recently, studies performed in the rat and in man have suggested that the effects of glucocorticoids on GH secretion may be due to the enhancement of hypothalamic somatostatin release by glucocorticoids in uiuo (Giustina el al., 1990c;Wehrenberg et al., 1990b). There is increasing evidence for an important stimulatory role of cholinergic neurotransmission in the regulation of G H secretion in normal man (Dieguez et al., 1988). Pyridostigmine (PD), an acetylcholinesterase inhibitor, is able to elicit G H secretion when given alone (Giustina et al., 1990~) and to enhance the G H response to GHRH in normal subjects (Giustina et al., 1990a). Experimental studies suggest that the action of PD may be mediated by a decrease in the hypothalamic somatostatin secretion (Richardson et a[., 1980; Locatelli et al., 1986). In the literature a few studies of spontaneous nocturnal G H secretion in adult (Krieger & Click, 1974; Motson et al., 1978) and paediatric (Pennisi et al., 1979) patients undergoing chronic glucocorticoid treatment have been performed. These studies have given conflicting results showing that
491
Clinical Endocrinology (1991) 35
492 A. Giustina et a/.
Table 1 Clinical data of six paediatric liver transplant recipients and five normal control subjects
Patient 1 2 3 4 5
6 Meanf SEM Control 1 2 3 4 5 Mean f SEM
9.5/M 8.O/F 2.5/F 12.O/M 5O/F 13.O/M
1
1 1 1 1 1
8.3 1.6
1 1
8.1/M 8.9/M 7.4/F 9.O/M lO.l/M
1
I 1
8.7 0.5
127.0/18 118.5/10 85.0131 126.51< 3 102.0/50 136.015
1.5/
Effects of pyridostigmine on spontaneous and growth hormone-releasing hormone stimulated growth hormone secretion in children on daily glucocorticoid therapy after liver transplantation Andrea Glustlna, Angela Glrelll, Danlele Albertl’, Slmonetta Bossoni, Fabio Buzit, Mauro Doga, Maurlzlo Schettlno and William B. WehrenbergS Clinica Medica, Chirurgia Pediatrica and TCIinica Pediatrica, University of Brescia, Italy; $Department of Health Sciences, University of Wisconsin, Milwaukee, USA
(Received 2 April 1991; returned for revision 16 June finally revised 5 July 1991; accepted 30 July 1991)
1991;
Summary OBJECTIVES We aimed to investigate both nocturnal spontaneous and morning growth hormone (GH)-releasIng hormone (GHRH)-InducedGH secretion In children on dally glucocortlcold treatment after liver transplantatlon and to evaluatethe effect of pyrldostlgmlne(an acetylchollnesterase lnhlbltor thought to reduce hypothalamic somatostatin tone) on GH secretion In these patlents. DESIGN We performed a randomlzed, slngle-bllnd, crossover study. PATIENTS We studied three male and three female juvenile patients, within a year of orthotopic liver transplantation and under immunosuppressiveglucocorticoid therapy (mean dose*SEM, 592&0.63 mglday) and five normal children (four males, one female). MEASUREMENTS Both nocturnal spontaneous and mornIng GHRH-Induced OH secretion were evaluated after admlnlstration of placebo, 1 tablet P.o., or pyrldostigmine, 2 mglkg p.0. RESULTS Spontaneous GH. Placebo: In liver transplanted children nocturnal GH secretion (mean GH level 10.8f2.0 mU/I) was not slgnlflcantly different wlth respect to normal children (mean GH level 12.8f1.2mU/I); pyrldostlgmlne: nocturnal OH secretion was signlflcantly Increased as comparedto placebo In subjects wlth liver transplantatlon but not In normal chlldren. GHRH test. Placebo: llver transplanted patients showed a blunted OH response to GHRH wlth respect to normal children; pyrldostlgmlne: the OH responses to GHRH (P< 0.05) increased as compared to placebo and dld not differ slgnlflcantly In the two groups.
Correspondence: Dr Andrea Giustina, Cattedra di Clinica Medica, Universita’ di Brescia, c/o 2a Medicina-Spedali Civili, 25125 Brescia, Italy
CONCLUSIONS Our data suggest a steroid-mediated increase in hypothalamic somatostatin tone in llver transplanted children.
Glucocorticoids have long been known to interfere with normal somatic growth in laboratory animals (Hodges & Vernikos, 1958) and in man. Children receiving high-dose glucocorticoid treatment (Blodgett et al., 1956) or with Cushing’s disease (Solomon & Shoen, 1976)exhibit impaired growth. It has been hypothesized that glucocorticoids may reduce insulin-like growth factor-I (IGF-I) levels or activity (Phillips et al. 1975). On the other hand, numerous studies have also demonstrated that normal subjects after administration of supraphysiological doses of glucocorticoids and patients with Cushing’s disease have blunted G H responses to various pharmacological stimuli (Hartog et al., 1964; Nakagawa et al., 1969; Hotta et al., 1988; Giustina et al., 1990b). However, the precise mechanisms of glucocorticoidinduced inhibition of G H secretion have not yet been identified. GH synthesis and secretion are regulated by the hypothalamic peptides GH-releasing hormone (GHRH), which has an excitatory role, and somatostatin, which has an inhibitory role (Wehrenberg et al., 1982). Recently, studies performed in the rat and in man have suggested that the effects of glucocorticoids on GH secretion may be due to the enhancement of hypothalamic somatostatin release by glucocorticoids in uiuo (Giustina el al., 1990c;Wehrenberg et al., 1990b). There is increasing evidence for an important stimulatory role of cholinergic neurotransmission in the regulation of G H secretion in normal man (Dieguez et al., 1988). Pyridostigmine (PD), an acetylcholinesterase inhibitor, is able to elicit G H secretion when given alone (Giustina et al., 1990~) and to enhance the G H response to GHRH in normal subjects (Giustina et al., 1990a). Experimental studies suggest that the action of PD may be mediated by a decrease in the hypothalamic somatostatin secretion (Richardson et a[., 1980; Locatelli et al., 1986). In the literature a few studies of spontaneous nocturnal G H secretion in adult (Krieger & Click, 1974; Motson et al., 1978) and paediatric (Pennisi et al., 1979) patients undergoing chronic glucocorticoid treatment have been performed. These studies have given conflicting results showing that
491
Clinical Endocrinology (1991) 35
492 A. Giustina et a/.
Table 1 Clinical data of six paediatric liver transplant recipients and five normal control subjects
Patient 1 2 3 4 5
6 Meanf SEM Control 1 2 3 4 5 Mean f SEM
9.5/M 8.O/F 2.5/F 12.O/M 5O/F 13.O/M
1
1 1 1 1 1
8.3 1.6
1 1
8.1/M 8.9/M 7.4/F 9.O/M lO.l/M
1
I 1
8.7 0.5
127.0/18 118.5/10 85.0131 126.51< 3 102.0/50 136.015
1.5/
