Acta P(l'diatr Scand [Suppl] 377: 92-95, 1991
Regulation of Growth Hormone Secretion in Patients with Growth Hormone Insensitivity A.M. COTTERILL'. J.M.P. HOLLY 1, G.A.I. SNODGRASS 2 and M.O. SAVAGE' From 1the Departments of Endocrinology. St Bartholomew's Hospiflll and 2the Academic Department of Child Health, The Royal London Hospital. London. UK
ABSTRACT. Cotterill, A.M., Holly, J,M.P., Snodgrass, G.A.I., Savage, M.O. (Departments of Endocrinology, St Bartholomew's Hospital and the Academic Department of Child Health, The Royal London Hospital, London, UK.) Regulation of growth hormone secretion in patients with growth hormone in.wnsitivity. Acta Paediatr Scand [Suppl)377: 92-95, 1991. Two subjects with growth hormone (GH) insensitivity were studied using standard methods of examining GH regulation: overnight GH sampling, stimulation of GH secretion with two sequential intravenous injections of GH-relea.o;ing hormone (GHRH), and suppression with somatostatin. Subject I was a girl, aged 14 years (height, 103 em; -8.3 SDS for chronological age). Subject 2 was a boy, aged 11.5 years (height, 103.6 em; -5.9 SDS for chronological age). The overnight pattern of GH secretion was similar In both subjects and appeared pulsatile with three pulses overnight, the major peaks of 203 mUll and 206 mUll In subjects I and 2 occurring at 00.00 hours and 00.20 hours, respectively. Serum GH levels were detectable throughout and the mean overnight serum GH levels were 65 mUll and 53 mUll for subjects I and 2 respectively. The pattern of GH response to GHRH stimulation was similar In both subjects, with a large rise in GH after the first injection, to a peak of 512 mUll and 216 mUll in subjects I and 2 respectively. The response to the second GHRH injection was less than the first, with peaks of 486 mUll and ISO mUll. During somatostatin infusion, GH levels fell to 7 mUll and were undetectable in the two subjects respectively, with a rebound following the cessation of infusion. High resolution computerized tomography (CT) scans of both subjects confirmed normal anatomy of the hypothalamus and pituitary with a small gland at the base of the fossa. In conclusion, GH secretion in GH insensitivity Is pulsatile and the pituitary is responsive to exogenous GHRH and somatostatin. This suggests that GH feedback does not Influence the dual control or the pulsatile release of GH by GHRH and somatostatin, but that GH feedback is necessary for the control of the absolute amounts of GH released during each pulse. Key words: Growth hormone insensitivity, growth hormone secretion, somatostatin, growth hormone-releasing hormone.
The syndrome of growth hormone (GH) insensitivity (Laron-type) is caused by defects in the GH receptor gene (1-3). This paper reports the regulation of GH secretion in two subjects with GH insensitivity. The syndrome of GH insensitivity is a unique model for the further investigation of the control mechanisms of GH secretion. In rendering GH completely inactive, it allows the examination of the hypothalamic control of GH secretion by GHRH and somatostatin in isolation (4). Few studies have reported the detailed secretory profiles of GH, in both the normal physiological state and during dynamic studies in patients with GH insensitivity (5). In this study, standard methods were used to assess GH secretion and its control, namely, overnight GH sampling, stimulation of GH secretion with GHRH, and suppression with somatostatin. High resolution computerized tomography (CT) of the sella turcica was also carried out to examine the possible effects of presumed continuous GHRH stimulation of the pituitary.
PATIENTS AND METHODS PmientJ. Two unrelated prepubertal Asian subjects with GH insensitivity were studied. Both children had been to be unresponsive to short term exogenous GH therapy (0.1 Ulkg/day s.c. for 4 days), with no increase in serum insulin-like growth factor CIGF-1) levels. The children were admitted to hospital between May and October 1989 for investigation of GH secretion, and informed parental consent was obtained. Subject 1 was a girl aged 14 years. originally from Pakistan (height. 103 em: -8.3 SDS for chronological age). Subject 2 was a boy aged 11.5 years originally from Bangladesh (height 103.6 em: -5.9 SDS for chronological age). Methoci.f. Both children underwent investigation of GH secretion by overnight blood sampling. A light meal was taken at 19.30 hours, and blood samples (2 ml) were taken every 20 minutes from 20.00 to 08.00 hours via an indwelling cannula. The children slept and were disturbed as little as possible. ~hown
Acta Paediatr Scand [Suppl) 377
Regulation of GH secretion in GH insensitivity
GHRH stimulation testing was carried out following an overnight fast. A cannula was inserted into a forearm vein 30 minutes before the start of the study. Two sequential GHRH(l- 29)NH 2 injections, IOOpg i.v., were given 180 minutes apart. Blood samples were taken at 15-30-minute intervals for 300 minutes. Somatostatin suppression testing was carried out following an overnight fast. A cannula was inserted into a forearm vein 30 minutes before the stan of the study. Somatostatin, I pg/minute. was infused for 120 minutes. Blood samples were taken at 30-minute intervals for 240 minutes. A standard oral glucose tolerance test (50 g) was carried out on a separate occasion. Blood samples were again taken at 30-minute intervals. GH was measured by radioimmunoassay (RIA), using reagents supplied by NETRIA (North East Thames Radioimmunoassay Service), St Bartholomew's Hospital, London (6). The working range for the assay was 1-50 mU/1 (I mU/1 = 0.5 pg/1) and dilutions were made as necessary so that samples fell within this range.
RESULTS The night-time pattern of GH secretion appeared pulsatile, with three pulses overnight and the major peaks of 203 mUll and 206 mUll in subjects I and 2 occurring at 00.00 hours and 00.20 hours, respectively, soon after the children went to sleep (Fig. Ia and b, panel 1). Serum GH level were detectable throughout the sampling period and the mean overnight serum GH levels was 65 mUll and 53 mU/1 for subjects 1 and 2, respectively. The pattern of GH response to GHRH stimulation was similar in both subjects, with an immediate and large rise in GH levels after the first GHRH injection, to a peak of 512 mU/1 and 216 mU/1 in subjects 1 and 2 respectively, occurring 30 minutes after the first GHRH injection (Figs. Ia and b, panel 2). The response to the second GHRH injection was less than the first, with a peak of 486 mU/1, and 150 mU/1 in subjects 1 and 2 respectively, again occurring at 30 minutes after GHRH injection. In both subjects serum GH levels fell during somatostatin infusion and there was a rebound following cessation of infusion. In subject 2, GH levels became undetectaj>le after 120 minutes of somatostatin infusion and in subject 1 levels fell to 7 mU/1. The latter subject was studied on a further occasion when the long-acting somatostatin analogue octreotide (Sandoz Pharma, Basel, Switzerland) was infused, 0.5 ~tglminute for 120 minutes, and during this study GH became undetectable (data not shown). There was some suppression of serum GH levels after the glucose tolerance test, but in contrast to normal subjects, GH remained detectable throughout (data not shown). High resolution CT scans of both subjects confirmed normal anatomy of the hypothalamus and pituitary, with a small gland at the base of the fossa. DISCUSSION The overnight pattern of GH secretion was pulsatile with, as is seen in normal subjects, three major pulses overnight. The pulsatility was entrained with sleep, with the main pulse occurring soon after the onset of sleep. The pattern was otherwise abnormal, with detectable levels of GH in serum throughout the night and following a glucose tolerance test (5). The absolute values of GH detected and the failure to suppress these levels after a glucose meal would in other circumstances be diagnostic of acromegaly. However, the pattern of pulsatile release of GH overnight in GH insensitivity is similar to that seen in normal subjects, which is in contrast to the findings in acromegaly, in which negative feedback control of GH secretion is also lost but pulsatile secretion of GH is significantly disrupted (7). These findings suggest that the normal dual hypothalamic control mechanisms of GHRH and somatostatin are preserved in GH insensitivity and that their episodic release is not influenced by the lack of GH feedback control. The failure of GH levels to fall to undetectable values at any time overnight could be due either to a prolonged half-life of GH, perhaps because of impaired clearance due to the GH receptor defect, or to the failure of endogenous somatostatin to completely suppress GH secretion between GHRH stimulated pulses. The extremely high values detected during the pulses appear to be due to a failure of GH feedback inhibition on its own release. The site of this feedback is likely to be at the pituitary level, as a lack of effect at the hypothalamic level would have been expected to disrupt the pulse pattern.
93
A.M. Cotterill et a/.
94
(a)
Acta Paediatr Scand [Suppl) 377
1 . Overnight pulsatility
250! 200
3
.s J:
(!)
150 100 50 1
Regulation of Growth Hormone Secretion in Patients with Growth Hormone Insensitivity A.M. COTTERILL'. J.M.P. HOLLY 1, G.A.I. SNODGRASS 2 and M.O. SAVAGE' From 1the Departments of Endocrinology. St Bartholomew's Hospiflll and 2the Academic Department of Child Health, The Royal London Hospital. London. UK
ABSTRACT. Cotterill, A.M., Holly, J,M.P., Snodgrass, G.A.I., Savage, M.O. (Departments of Endocrinology, St Bartholomew's Hospital and the Academic Department of Child Health, The Royal London Hospital, London, UK.) Regulation of growth hormone secretion in patients with growth hormone in.wnsitivity. Acta Paediatr Scand [Suppl)377: 92-95, 1991. Two subjects with growth hormone (GH) insensitivity were studied using standard methods of examining GH regulation: overnight GH sampling, stimulation of GH secretion with two sequential intravenous injections of GH-relea.o;ing hormone (GHRH), and suppression with somatostatin. Subject I was a girl, aged 14 years (height, 103 em; -8.3 SDS for chronological age). Subject 2 was a boy, aged 11.5 years (height, 103.6 em; -5.9 SDS for chronological age). The overnight pattern of GH secretion was similar In both subjects and appeared pulsatile with three pulses overnight, the major peaks of 203 mUll and 206 mUll In subjects I and 2 occurring at 00.00 hours and 00.20 hours, respectively. Serum GH levels were detectable throughout and the mean overnight serum GH levels were 65 mUll and 53 mUll for subjects I and 2 respectively. The pattern of GH response to GHRH stimulation was similar In both subjects, with a large rise in GH after the first injection, to a peak of 512 mUll and 216 mUll in subjects I and 2 respectively. The response to the second GHRH injection was less than the first, with peaks of 486 mUll and ISO mUll. During somatostatin infusion, GH levels fell to 7 mUll and were undetectable in the two subjects respectively, with a rebound following the cessation of infusion. High resolution computerized tomography (CT) scans of both subjects confirmed normal anatomy of the hypothalamus and pituitary with a small gland at the base of the fossa. In conclusion, GH secretion in GH insensitivity Is pulsatile and the pituitary is responsive to exogenous GHRH and somatostatin. This suggests that GH feedback does not Influence the dual control or the pulsatile release of GH by GHRH and somatostatin, but that GH feedback is necessary for the control of the absolute amounts of GH released during each pulse. Key words: Growth hormone insensitivity, growth hormone secretion, somatostatin, growth hormone-releasing hormone.
The syndrome of growth hormone (GH) insensitivity (Laron-type) is caused by defects in the GH receptor gene (1-3). This paper reports the regulation of GH secretion in two subjects with GH insensitivity. The syndrome of GH insensitivity is a unique model for the further investigation of the control mechanisms of GH secretion. In rendering GH completely inactive, it allows the examination of the hypothalamic control of GH secretion by GHRH and somatostatin in isolation (4). Few studies have reported the detailed secretory profiles of GH, in both the normal physiological state and during dynamic studies in patients with GH insensitivity (5). In this study, standard methods were used to assess GH secretion and its control, namely, overnight GH sampling, stimulation of GH secretion with GHRH, and suppression with somatostatin. High resolution computerized tomography (CT) of the sella turcica was also carried out to examine the possible effects of presumed continuous GHRH stimulation of the pituitary.
PATIENTS AND METHODS PmientJ. Two unrelated prepubertal Asian subjects with GH insensitivity were studied. Both children had been to be unresponsive to short term exogenous GH therapy (0.1 Ulkg/day s.c. for 4 days), with no increase in serum insulin-like growth factor CIGF-1) levels. The children were admitted to hospital between May and October 1989 for investigation of GH secretion, and informed parental consent was obtained. Subject 1 was a girl aged 14 years. originally from Pakistan (height. 103 em: -8.3 SDS for chronological age). Subject 2 was a boy aged 11.5 years originally from Bangladesh (height 103.6 em: -5.9 SDS for chronological age). Methoci.f. Both children underwent investigation of GH secretion by overnight blood sampling. A light meal was taken at 19.30 hours, and blood samples (2 ml) were taken every 20 minutes from 20.00 to 08.00 hours via an indwelling cannula. The children slept and were disturbed as little as possible. ~hown
Acta Paediatr Scand [Suppl) 377
Regulation of GH secretion in GH insensitivity
GHRH stimulation testing was carried out following an overnight fast. A cannula was inserted into a forearm vein 30 minutes before the start of the study. Two sequential GHRH(l- 29)NH 2 injections, IOOpg i.v., were given 180 minutes apart. Blood samples were taken at 15-30-minute intervals for 300 minutes. Somatostatin suppression testing was carried out following an overnight fast. A cannula was inserted into a forearm vein 30 minutes before the stan of the study. Somatostatin, I pg/minute. was infused for 120 minutes. Blood samples were taken at 30-minute intervals for 240 minutes. A standard oral glucose tolerance test (50 g) was carried out on a separate occasion. Blood samples were again taken at 30-minute intervals. GH was measured by radioimmunoassay (RIA), using reagents supplied by NETRIA (North East Thames Radioimmunoassay Service), St Bartholomew's Hospital, London (6). The working range for the assay was 1-50 mU/1 (I mU/1 = 0.5 pg/1) and dilutions were made as necessary so that samples fell within this range.
RESULTS The night-time pattern of GH secretion appeared pulsatile, with three pulses overnight and the major peaks of 203 mUll and 206 mUll in subjects I and 2 occurring at 00.00 hours and 00.20 hours, respectively, soon after the children went to sleep (Fig. Ia and b, panel 1). Serum GH level were detectable throughout the sampling period and the mean overnight serum GH levels was 65 mUll and 53 mU/1 for subjects 1 and 2, respectively. The pattern of GH response to GHRH stimulation was similar in both subjects, with an immediate and large rise in GH levels after the first GHRH injection, to a peak of 512 mU/1 and 216 mU/1 in subjects 1 and 2 respectively, occurring 30 minutes after the first GHRH injection (Figs. Ia and b, panel 2). The response to the second GHRH injection was less than the first, with a peak of 486 mU/1, and 150 mU/1 in subjects 1 and 2 respectively, again occurring at 30 minutes after GHRH injection. In both subjects serum GH levels fell during somatostatin infusion and there was a rebound following cessation of infusion. In subject 2, GH levels became undetectaj>le after 120 minutes of somatostatin infusion and in subject 1 levels fell to 7 mU/1. The latter subject was studied on a further occasion when the long-acting somatostatin analogue octreotide (Sandoz Pharma, Basel, Switzerland) was infused, 0.5 ~tglminute for 120 minutes, and during this study GH became undetectable (data not shown). There was some suppression of serum GH levels after the glucose tolerance test, but in contrast to normal subjects, GH remained detectable throughout (data not shown). High resolution CT scans of both subjects confirmed normal anatomy of the hypothalamus and pituitary, with a small gland at the base of the fossa. DISCUSSION The overnight pattern of GH secretion was pulsatile with, as is seen in normal subjects, three major pulses overnight. The pulsatility was entrained with sleep, with the main pulse occurring soon after the onset of sleep. The pattern was otherwise abnormal, with detectable levels of GH in serum throughout the night and following a glucose tolerance test (5). The absolute values of GH detected and the failure to suppress these levels after a glucose meal would in other circumstances be diagnostic of acromegaly. However, the pattern of pulsatile release of GH overnight in GH insensitivity is similar to that seen in normal subjects, which is in contrast to the findings in acromegaly, in which negative feedback control of GH secretion is also lost but pulsatile secretion of GH is significantly disrupted (7). These findings suggest that the normal dual hypothalamic control mechanisms of GHRH and somatostatin are preserved in GH insensitivity and that their episodic release is not influenced by the lack of GH feedback control. The failure of GH levels to fall to undetectable values at any time overnight could be due either to a prolonged half-life of GH, perhaps because of impaired clearance due to the GH receptor defect, or to the failure of endogenous somatostatin to completely suppress GH secretion between GHRH stimulated pulses. The extremely high values detected during the pulses appear to be due to a failure of GH feedback inhibition on its own release. The site of this feedback is likely to be at the pituitary level, as a lack of effect at the hypothalamic level would have been expected to disrupt the pulse pattern.
93
A.M. Cotterill et a/.
94
(a)
Acta Paediatr Scand [Suppl) 377
1 . Overnight pulsatility
250! 200
3
.s J:
(!)
150 100 50 1
![[Regulation of growth hormone-releasing hormone gene expression and secretion].](/assets/img/hold.png)
