April 1976
The Journal o f P E D l A T R I C S
565
Provocative tests for growth hormone release Subnormal growth hormone responses to both insulin-induced hypoglycemia and arginine infusion (peak response < 5 ng/ml) were found in five male subjects (aged 10 to 14 years) with short stature but with normal interval growth rates and normal bone ages (in 4 cases). They demonstrated one or more normal GH responses to subsequent provocation by glucagon stimulation, tolbutamide-induced hypoglycemia, and repeat insulin and arginine testing following pretreatment with sex steroids. Two subjects had reeeived exogenous GH therapy for six months prior to the subsequent assessment; eaeh one failed to demonstrate the growth response characteristic of GH deficiency. These studies indicate the need for multiple provoeative human GH testing to exclude children whose growth would not be enhanced by GH therapy despite a subnormal response to provocative tests with insulin and arginine.
Wah Jun Tze, M.D., F.R.C.P. (C),* Harvey J. Guyda, M.D., F.R.C.P.(C), and Peter Hoy, B.Sc., V a n c o u v e r , B. C., C a n a d a
O N L Y A SMALL F R A C T I O N o f c h i l d r e n w i t h growth failure, those with growth hormone deficiency, can benefit from specific hormone supplementation. Therefore, it is important to identify those whose stunting is caused by this deficiency, and all the more critical because of the shortage of human growth hormone. Insulin-inducedhypoglycemia and arginine infusion,1, -~ as provocative tests for GH release, show no such response in children with GH deficiency. Many other agents :' have provoked GH release; these include tolbutamide, ~ glucagon, 5 vasopressin,'~ metyrapone, 7 and L-dihydroxyphenylalanine (L-dopa). 8 The more recent test procedures ~-11 have involved insulin-inducedhypoglycemia and arginine infusion in subjects primed with sex hormones. The use of sleep and exercise has also been suggested as a screen for GH deficiency.1~.... So far, gIucagon has been the only stimulus with more effect than insulin-induced hypoglycemia or arginine infusion? However, there has been little information by which to compare responses to the various tests. The present report describes five children with short stature who had had a normal interval growth rate. They responded subnormally to insulin-induced hypoglycemia and to arginine infusion.'They were sujbected to other
From the Department of Pediatrics, University of British Columbia, and MeGill University. *Reprint address: Children's Hospital, 250 West 59th A re., Vancouver, B. C., V5X 1X2.
provocative tests for GH release, and the results were compared with those of the two standard test procedures. The possible influence of exogenous GH therapy for six months in two of these children was also studied.
Abbreviations used HGH: human growth hormone IRGH: immunoreactive growth hormone
SUBJECTS AND METHODS The five subjects were boys with short stature who had had a normal interval growth rate. The GH responses to insulin-induced hypoglycemia and to arginine infusion were subnormal. Their physical measurements were made by one of us (W.J.T,) with a Harpenden stadiometer. The height was plotted on the anthropometric chart of the Children's Hospital Medical Center, Boston, and bone age was determined from Greulich and Pyle 1~ standards using hand and wrist radiography. GH secretion was assessed by serum immunoreactive growth hormone responses to stimuli such as arginine, insulin-induced hypoglycemia, glucagon, tolbutamide, and to arginine or insulin after priming with stilbestrol or testosterone. Prior to each provocative test, the subjects fasted for 12&ours overnight; an indwelling venous catheter was inserted at 0800 hours. Blood was sampled for serum 1RGH and
Vol. 88, No. 4, part 1, pp. 565-568
56 6
Tze, Guyda, and Hoy
The Journal of Pediatrics April 1976
Table I. Clinical data
Genital development
Patient
Chronologic age
B.B. D.F. D.O. R.S. G.S.
14 0/12 13 4/12 10 2/12 12 9/12 13 3/12
3.3 3.0 3.1 4.1 3.9
Head circumference (cm)
Upper~lower segment
53.0 51.0 52.5 53.0 52.0
0.95 0.90 0.96 1.06 0.97
t ,estes
Size of penis
(cm) 6.0 x 4.5 • 6.5 x 4.5. • 5.0 x
(era)
2.0 2.3 1.6 2.0 2.0
2.8 3.6 2.0 2.6 2.2
x • x x x
1.4 1.7 t.0 2.2 1.2
l
Sexual hair
Family history of short stature
Present None None None Present
No No Yes Yes No
Size of
Table II. G r o w t h hormone responses to provocative tests I R G H (ng/ml): peak/baseline levels
(after sex hormones) Patient
Insulin
A rginine
Tolbutamide
Glucagon
Insulin
B.B. D.F. D.O. R.S. G.S.
5.0/1.7 4.1/0.5 3.3/0.5 3.6/2.0 2.3/0.5
1.5/0.5 0.5 / 1.2 0.7/0.5 2.9/1.0 2.6/0.5
7.7/0.5 20.0/0.5 2.6/0.5 1.8/2.2 1.6/0.5
16.0/1.4 1.6/5.6 7.8/1.4 21.0/0.5 1.4/0.5
5.6/5.5 11.0/5.5 9.3/4.4 -
I
Arginine 23.5/0.5 22.2/2.5 30.0/2.9 11.0/2.9
Table HI. Selected endocrine data
"11 uptake Patient
T4 ~g/dl
Urinary 17&etosteroids
4-hours
24-hours
(%)
(%)
B.B.
9.4
-
D.F. D.O. R.S. G.S.
8.5 7.2 8.4 8.1
5 -8 8
-
9 14 18
glucose assay at timed intervals after the stimulus had been given. Insulin (crystalline), 0.1 U / k g , was given and blood samples were taken at 0, 15, 30, 45, 60, 90, a n d 120 minutes. The same timing was used after the intramuscular administration of glucagon, 0.03 mg/kg, to a maxim u m dosage of 1 mg. Arginine, 0.5 gm/kg, was infused for 30 minutes; and blood samples were obtained at 0, 30, and 60 minutes. Tolbutamide, 25 mg/kg, was given intravenously with a m a x i m u m dosage of 1 gm; blood sampling was at 0, 1, 3, 5, 10, 15, 30, 45, 60, 90, and 120 minutes. In the sex h o r m o n e - p r i m e d insulin and arginine tests, the subject was given stilbestrol, 2.5 mg orally twice daily, or proprionate, 50 nag intramuscularly daily for 3 days. Insulin was always followed by 50% or greater reduction of fasting blood glucose level at 15 to 30 minutes. Serum GH was assayed by the double antibody i m m u -
Bone age
Chronologic age
(yr) 12 6/12 12 6/12 6 3/12 12 0/12 13 0/12
(14 (13 ( 9 (12 (13
1/12) 4/12) 7/12) 9/12) 3/12)
l Baseline 6.5 5.4 5.0 7.2 12.6
Postmetyrapone 12.2 10.2 20.0 29.5
noassay method 1~ and serum glucose, by the glucose oxidase method. The criterion of G H response in all provocative tests was a m i n i m u m serum level above 5 ng/ml. Because of their earlier subnormal responses to arginine infusion and to insulin-induced hypoglycemia, two children (Patients B.B. and G.C.) received two units of human growth hormone three times weekly for a period of six months prior to the additional tests. (Program sponsored by the Medical Research Council of Canada.) The linear growth rates during and after H G H administration were compared. R E S U L T S
The clinical dat~i (Table I) show that there had been a family history of short stature in two of the five subjects.
Volume 88 Number 4, part 1
The birth weights were between the twenty-fifth and seventy-fifth percentiles for gestational age. The head circumference and body proportions were normal. Three subjects had early pubertal development judged by testicular size and the appearance of sexual hair. The GH responses (Table II) to both insulin and arginine were subnormal in all except Patient B.B. whose peak reached 5 ng/ml at 120 minutes following insulin. However, the responses were normal on repetition o f these two tests after priming with stilbestrol and/or testosterone. Thus in three subjects given insulin after administration of stilbestrol, the GH levels were 5.6, 11.0, and 8.6 ng/ml, respectively, and in those stimulated by arginine after stilbestrol, the GH levels rose much higher, to 23.5, 22.2, 30.0, and 11.0 ng/ml, respectively, with an average peak at 21.7 ng/ml. Normal GH responses occurred in two of the five subjects following administration of tolbutamide and in three of the five after glucagon. Linear growth increments of 2.8 and 2.6 cm in Patients B.B. and G.S., respectively, were achieved during the sixmonth period after which time the HGH administration was discontinued, but with no actual growth rate increase during the period of exogenous HGH therapy.
Tests for growth hormone release
BOYS Cm.
170 160 150 140 130 120 kg.
110
65
100
6O
90
80
55
70
50
Age 45
year
4O 35 3O 25 2O
DISCUSSION Failure of an adequate GH response to insulin-induced hypoglycemia and arginine infusion has been accepted as a demonstration of its deficiency. The present study, however, shows that a subsequent provocation with a variety of other agents can induce a normal response even after these first two agents had been ineffectual. Nine postoperative patients with craniopharyngioma reported by Hohnes and colleagues 16 in the postoperative period had a normal or superior growth rate in spite of a subnormal GH response to insulin stimulation and after exercise. Joss and Zuppinger 17 have emphasized that 5 to 10% of normal people who are not GH deficient may exhibit blunted responses to one or more provocative tests. It is not clear why these five subjects had shown a subnormal GH response to the two standard tests and then reacted normally to other provocative agents. It is unlikely to have been a chance finding, as suggested by Joss and Zuppinger, but a partial GH deficiency should be considered. Because GH secretion is regulated by multiple independent pathways, TM variability of the GH response in these subjects may be an expression of a defect in a particular pathway. It may be necessary to conclude that more than two standard tests are required for the diagnosis of GH deficiency. All of these subjects showed adequate GH response when primed with sex hormone, and this would suggest
567
15 10
Fig. 1. Growth curves of the five patients.
an important relationship between GH and the sex hormones. Greater and more consistent GH responses to arginine have been found in normal adult females and also in normal adult males primed with stilbestrolY Similar findings have been seen in prepubertal males given testosterone proprionate and then subjected to insulin-induced hypoglycemia and arginine infusionY A sex hormone dependency in the GH response is suggested by the report by Penny and Blizzard 1"~of three males with subnormal GH responses to insulin and arginine who demonstrated normal results while sexual development was progressing. The two subjects who received a six-month course of exogenous HGH therapy without any acceleration of growth rate would support the previous observation that HGH therapy is not effective in promoting growth in the absence o f a GH deficiency. There is an occasional growth response, however, to large doses of HGH in low-birthweight dwarfsY ~ This study suggests that more than two standard tes~ts (insulin-induced hypoglycemia and infusion of arginine) may be needed to diagnose GH deficiency, particularly in
568
Tze, Guyda, and Hoe
subjects with n o r m a l interval growth rates. O t h e r provocative tests are n o w readily available a n d s h o u l d b e used in conjunction w i t h the two cited above to m a k e the definitive diagnosis of G H deficiency, which is particularly essential because o f the very short supply o f H G H . The authors are indebted to Dr. D. Hardwick for laboratory assistance and to Dr. S. Segal for reviewing the manuscript and providing uSeful suggestions. REFERENCES
1. Raiti S, Davis WT, and Blizzard RM: A comparison of the effects of insulin hypoglycemia and arginine infusion on release of human growth hormone, Lancet 2:1182, 1967. 2. Youlton R, Kaplan SL, and Grumbach MM: Growth and growth hormone. IV. Limitations of the growth hormone response to arginine in the assessment of growth hormone deficiency in children, Pediatrics 43:989, 1969. 3. Frasier SD: A review of growth hormone stimulation tests in children, Pediatrics 53:929, 1974. 4. Boden G, and Soeldner JS: A sensitive double antibody radio-immunoassay for human growth hormone (HGH): levels of serum HGH following rapid tolbutamide infusion, Diabetologia 3:413, 1967. 5. Cain JP, Williams GH, and Dluhy RG: Glucagon-initiated human growth hormone release: a comparative study, Can Med Assoc J 107:617, 1972. 6. Gagliardino JJ, Bailey JD, and Martin MM: Effect of vasopressin on serum levels of human growth hormone, Lancet 1:1357, 1967. 7. Kunita H, Takebe K, Nanagawa K , Sawano S, and Horinchi Y: Effect o f metyrapone on secretion of growth hormone in man, J Clin Endocrinol 31:301, 1970. 8. Hayek A, and Crawford JD: L-Dopa and pituitary secretion, J Clin Endocrinol 34:765, 1972. 9. Merimee JT, Burgess JA, and Rabinowitz D: Sex-determined variation in serum insulin and growth hormone
The Journal of Pediatrics April 1976
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
response to amino acid stimulation, J Clin Endocrinol 26:791, 1966. Martin LG, Clark JW, and Connor TB: Growth hormone secretion enhanced by androgens, J Clin Endocrino128:425, 1968. Lippe B, Wong S-LR, and Kaplan SA: Simultaneous assessment of growth hormone and ACTH reserve in children pretreated with diethylstilbesterol, J Clin Endocrinol 33:949, 1971. Cain JP, Williams GH, and Dluhy RG: Glucagon stimulation of human growth hormone, J Clin Endocrinol 31:222, 1970. Keenan BS, Kilmer LB, and Sode J: .Growth hormone response to exercise: a test of pituitary function in children, Pediatrics 50:760, 1972. Greulich WW, and Pyle SI: Radiographic atlas 0f skeletal development of the hand and wrist, ed 2, Standford, Calif, 1959, Standford University Press. Friesen H, Guyda H, and Hardy J: Biosynthesis of human growth hormone and prolactin, J Clin Endocrinol Metab 31:611 1970. Holmes LB, Frants AG, Rabkin MT, Soeldner JS, and Crawford JD: Normal growth with subnormal growth hormone levels, N Engl J Med 279:559, !968. Joss EE, and Zuppinger KA: The significance of intermediate plasma growth hormone levels in growth-retarded children, J PEDIATR 81:1092, 1972. Glick SM: Regulation of growth hormone secretion, p 141. in Martini L, and Ganong WF, editors: Frontiers in neuroendocrinology, London, 1973, Oxford University Press. Penny R, and Blizzard RM: The possible influence of puberty on the release of growth hormone in three males with apparent isolated growth hormone deficiency, J Clin Endocrinol 24:82, 1972. Foley TP Jr, Thompson RG, Shaw M, Baghdassarian A, Nissley SP, and Blizzard RM: Growth responses to human growth hormone in patients with intrauterine growth retardation, J PEDIATR 84:635, 1974.
The Journal o f P E D l A T R I C S
565
Provocative tests for growth hormone release Subnormal growth hormone responses to both insulin-induced hypoglycemia and arginine infusion (peak response < 5 ng/ml) were found in five male subjects (aged 10 to 14 years) with short stature but with normal interval growth rates and normal bone ages (in 4 cases). They demonstrated one or more normal GH responses to subsequent provocation by glucagon stimulation, tolbutamide-induced hypoglycemia, and repeat insulin and arginine testing following pretreatment with sex steroids. Two subjects had reeeived exogenous GH therapy for six months prior to the subsequent assessment; eaeh one failed to demonstrate the growth response characteristic of GH deficiency. These studies indicate the need for multiple provoeative human GH testing to exclude children whose growth would not be enhanced by GH therapy despite a subnormal response to provocative tests with insulin and arginine.
Wah Jun Tze, M.D., F.R.C.P. (C),* Harvey J. Guyda, M.D., F.R.C.P.(C), and Peter Hoy, B.Sc., V a n c o u v e r , B. C., C a n a d a
O N L Y A SMALL F R A C T I O N o f c h i l d r e n w i t h growth failure, those with growth hormone deficiency, can benefit from specific hormone supplementation. Therefore, it is important to identify those whose stunting is caused by this deficiency, and all the more critical because of the shortage of human growth hormone. Insulin-inducedhypoglycemia and arginine infusion,1, -~ as provocative tests for GH release, show no such response in children with GH deficiency. Many other agents :' have provoked GH release; these include tolbutamide, ~ glucagon, 5 vasopressin,'~ metyrapone, 7 and L-dihydroxyphenylalanine (L-dopa). 8 The more recent test procedures ~-11 have involved insulin-inducedhypoglycemia and arginine infusion in subjects primed with sex hormones. The use of sleep and exercise has also been suggested as a screen for GH deficiency.1~.... So far, gIucagon has been the only stimulus with more effect than insulin-induced hypoglycemia or arginine infusion? However, there has been little information by which to compare responses to the various tests. The present report describes five children with short stature who had had a normal interval growth rate. They responded subnormally to insulin-induced hypoglycemia and to arginine infusion.'They were sujbected to other
From the Department of Pediatrics, University of British Columbia, and MeGill University. *Reprint address: Children's Hospital, 250 West 59th A re., Vancouver, B. C., V5X 1X2.
provocative tests for GH release, and the results were compared with those of the two standard test procedures. The possible influence of exogenous GH therapy for six months in two of these children was also studied.
Abbreviations used HGH: human growth hormone IRGH: immunoreactive growth hormone
SUBJECTS AND METHODS The five subjects were boys with short stature who had had a normal interval growth rate. The GH responses to insulin-induced hypoglycemia and to arginine infusion were subnormal. Their physical measurements were made by one of us (W.J.T,) with a Harpenden stadiometer. The height was plotted on the anthropometric chart of the Children's Hospital Medical Center, Boston, and bone age was determined from Greulich and Pyle 1~ standards using hand and wrist radiography. GH secretion was assessed by serum immunoreactive growth hormone responses to stimuli such as arginine, insulin-induced hypoglycemia, glucagon, tolbutamide, and to arginine or insulin after priming with stilbestrol or testosterone. Prior to each provocative test, the subjects fasted for 12&ours overnight; an indwelling venous catheter was inserted at 0800 hours. Blood was sampled for serum 1RGH and
Vol. 88, No. 4, part 1, pp. 565-568
56 6
Tze, Guyda, and Hoy
The Journal of Pediatrics April 1976
Table I. Clinical data
Genital development
Patient
Chronologic age
B.B. D.F. D.O. R.S. G.S.
14 0/12 13 4/12 10 2/12 12 9/12 13 3/12
3.3 3.0 3.1 4.1 3.9
Head circumference (cm)
Upper~lower segment
53.0 51.0 52.5 53.0 52.0
0.95 0.90 0.96 1.06 0.97
t ,estes
Size of penis
(cm) 6.0 x 4.5 • 6.5 x 4.5. • 5.0 x
(era)
2.0 2.3 1.6 2.0 2.0
2.8 3.6 2.0 2.6 2.2
x • x x x
1.4 1.7 t.0 2.2 1.2
l
Sexual hair
Family history of short stature
Present None None None Present
No No Yes Yes No
Size of
Table II. G r o w t h hormone responses to provocative tests I R G H (ng/ml): peak/baseline levels
(after sex hormones) Patient
Insulin
A rginine
Tolbutamide
Glucagon
Insulin
B.B. D.F. D.O. R.S. G.S.
5.0/1.7 4.1/0.5 3.3/0.5 3.6/2.0 2.3/0.5
1.5/0.5 0.5 / 1.2 0.7/0.5 2.9/1.0 2.6/0.5
7.7/0.5 20.0/0.5 2.6/0.5 1.8/2.2 1.6/0.5
16.0/1.4 1.6/5.6 7.8/1.4 21.0/0.5 1.4/0.5
5.6/5.5 11.0/5.5 9.3/4.4 -
I
Arginine 23.5/0.5 22.2/2.5 30.0/2.9 11.0/2.9
Table HI. Selected endocrine data
"11 uptake Patient
T4 ~g/dl
Urinary 17&etosteroids
4-hours
24-hours
(%)
(%)
B.B.
9.4
-
D.F. D.O. R.S. G.S.
8.5 7.2 8.4 8.1
5 -8 8
-
9 14 18
glucose assay at timed intervals after the stimulus had been given. Insulin (crystalline), 0.1 U / k g , was given and blood samples were taken at 0, 15, 30, 45, 60, 90, a n d 120 minutes. The same timing was used after the intramuscular administration of glucagon, 0.03 mg/kg, to a maxim u m dosage of 1 mg. Arginine, 0.5 gm/kg, was infused for 30 minutes; and blood samples were obtained at 0, 30, and 60 minutes. Tolbutamide, 25 mg/kg, was given intravenously with a m a x i m u m dosage of 1 gm; blood sampling was at 0, 1, 3, 5, 10, 15, 30, 45, 60, 90, and 120 minutes. In the sex h o r m o n e - p r i m e d insulin and arginine tests, the subject was given stilbestrol, 2.5 mg orally twice daily, or proprionate, 50 nag intramuscularly daily for 3 days. Insulin was always followed by 50% or greater reduction of fasting blood glucose level at 15 to 30 minutes. Serum GH was assayed by the double antibody i m m u -
Bone age
Chronologic age
(yr) 12 6/12 12 6/12 6 3/12 12 0/12 13 0/12
(14 (13 ( 9 (12 (13
1/12) 4/12) 7/12) 9/12) 3/12)
l Baseline 6.5 5.4 5.0 7.2 12.6
Postmetyrapone 12.2 10.2 20.0 29.5
noassay method 1~ and serum glucose, by the glucose oxidase method. The criterion of G H response in all provocative tests was a m i n i m u m serum level above 5 ng/ml. Because of their earlier subnormal responses to arginine infusion and to insulin-induced hypoglycemia, two children (Patients B.B. and G.C.) received two units of human growth hormone three times weekly for a period of six months prior to the additional tests. (Program sponsored by the Medical Research Council of Canada.) The linear growth rates during and after H G H administration were compared. R E S U L T S
The clinical dat~i (Table I) show that there had been a family history of short stature in two of the five subjects.
Volume 88 Number 4, part 1
The birth weights were between the twenty-fifth and seventy-fifth percentiles for gestational age. The head circumference and body proportions were normal. Three subjects had early pubertal development judged by testicular size and the appearance of sexual hair. The GH responses (Table II) to both insulin and arginine were subnormal in all except Patient B.B. whose peak reached 5 ng/ml at 120 minutes following insulin. However, the responses were normal on repetition o f these two tests after priming with stilbestrol and/or testosterone. Thus in three subjects given insulin after administration of stilbestrol, the GH levels were 5.6, 11.0, and 8.6 ng/ml, respectively, and in those stimulated by arginine after stilbestrol, the GH levels rose much higher, to 23.5, 22.2, 30.0, and 11.0 ng/ml, respectively, with an average peak at 21.7 ng/ml. Normal GH responses occurred in two of the five subjects following administration of tolbutamide and in three of the five after glucagon. Linear growth increments of 2.8 and 2.6 cm in Patients B.B. and G.S., respectively, were achieved during the sixmonth period after which time the HGH administration was discontinued, but with no actual growth rate increase during the period of exogenous HGH therapy.
Tests for growth hormone release
BOYS Cm.
170 160 150 140 130 120 kg.
110
65
100
6O
90
80
55
70
50
Age 45
year
4O 35 3O 25 2O
DISCUSSION Failure of an adequate GH response to insulin-induced hypoglycemia and arginine infusion has been accepted as a demonstration of its deficiency. The present study, however, shows that a subsequent provocation with a variety of other agents can induce a normal response even after these first two agents had been ineffectual. Nine postoperative patients with craniopharyngioma reported by Hohnes and colleagues 16 in the postoperative period had a normal or superior growth rate in spite of a subnormal GH response to insulin stimulation and after exercise. Joss and Zuppinger 17 have emphasized that 5 to 10% of normal people who are not GH deficient may exhibit blunted responses to one or more provocative tests. It is not clear why these five subjects had shown a subnormal GH response to the two standard tests and then reacted normally to other provocative agents. It is unlikely to have been a chance finding, as suggested by Joss and Zuppinger, but a partial GH deficiency should be considered. Because GH secretion is regulated by multiple independent pathways, TM variability of the GH response in these subjects may be an expression of a defect in a particular pathway. It may be necessary to conclude that more than two standard tests are required for the diagnosis of GH deficiency. All of these subjects showed adequate GH response when primed with sex hormone, and this would suggest
567
15 10
Fig. 1. Growth curves of the five patients.
an important relationship between GH and the sex hormones. Greater and more consistent GH responses to arginine have been found in normal adult females and also in normal adult males primed with stilbestrolY Similar findings have been seen in prepubertal males given testosterone proprionate and then subjected to insulin-induced hypoglycemia and arginine infusionY A sex hormone dependency in the GH response is suggested by the report by Penny and Blizzard 1"~of three males with subnormal GH responses to insulin and arginine who demonstrated normal results while sexual development was progressing. The two subjects who received a six-month course of exogenous HGH therapy without any acceleration of growth rate would support the previous observation that HGH therapy is not effective in promoting growth in the absence o f a GH deficiency. There is an occasional growth response, however, to large doses of HGH in low-birthweight dwarfsY ~ This study suggests that more than two standard tes~ts (insulin-induced hypoglycemia and infusion of arginine) may be needed to diagnose GH deficiency, particularly in
568
Tze, Guyda, and Hoe
subjects with n o r m a l interval growth rates. O t h e r provocative tests are n o w readily available a n d s h o u l d b e used in conjunction w i t h the two cited above to m a k e the definitive diagnosis of G H deficiency, which is particularly essential because o f the very short supply o f H G H . The authors are indebted to Dr. D. Hardwick for laboratory assistance and to Dr. S. Segal for reviewing the manuscript and providing uSeful suggestions. REFERENCES
1. Raiti S, Davis WT, and Blizzard RM: A comparison of the effects of insulin hypoglycemia and arginine infusion on release of human growth hormone, Lancet 2:1182, 1967. 2. Youlton R, Kaplan SL, and Grumbach MM: Growth and growth hormone. IV. Limitations of the growth hormone response to arginine in the assessment of growth hormone deficiency in children, Pediatrics 43:989, 1969. 3. Frasier SD: A review of growth hormone stimulation tests in children, Pediatrics 53:929, 1974. 4. Boden G, and Soeldner JS: A sensitive double antibody radio-immunoassay for human growth hormone (HGH): levels of serum HGH following rapid tolbutamide infusion, Diabetologia 3:413, 1967. 5. Cain JP, Williams GH, and Dluhy RG: Glucagon-initiated human growth hormone release: a comparative study, Can Med Assoc J 107:617, 1972. 6. Gagliardino JJ, Bailey JD, and Martin MM: Effect of vasopressin on serum levels of human growth hormone, Lancet 1:1357, 1967. 7. Kunita H, Takebe K, Nanagawa K , Sawano S, and Horinchi Y: Effect o f metyrapone on secretion of growth hormone in man, J Clin Endocrinol 31:301, 1970. 8. Hayek A, and Crawford JD: L-Dopa and pituitary secretion, J Clin Endocrinol 34:765, 1972. 9. Merimee JT, Burgess JA, and Rabinowitz D: Sex-determined variation in serum insulin and growth hormone
The Journal of Pediatrics April 1976
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
response to amino acid stimulation, J Clin Endocrinol 26:791, 1966. Martin LG, Clark JW, and Connor TB: Growth hormone secretion enhanced by androgens, J Clin Endocrino128:425, 1968. Lippe B, Wong S-LR, and Kaplan SA: Simultaneous assessment of growth hormone and ACTH reserve in children pretreated with diethylstilbesterol, J Clin Endocrinol 33:949, 1971. Cain JP, Williams GH, and Dluhy RG: Glucagon stimulation of human growth hormone, J Clin Endocrinol 31:222, 1970. Keenan BS, Kilmer LB, and Sode J: .Growth hormone response to exercise: a test of pituitary function in children, Pediatrics 50:760, 1972. Greulich WW, and Pyle SI: Radiographic atlas 0f skeletal development of the hand and wrist, ed 2, Standford, Calif, 1959, Standford University Press. Friesen H, Guyda H, and Hardy J: Biosynthesis of human growth hormone and prolactin, J Clin Endocrinol Metab 31:611 1970. Holmes LB, Frants AG, Rabkin MT, Soeldner JS, and Crawford JD: Normal growth with subnormal growth hormone levels, N Engl J Med 279:559, !968. Joss EE, and Zuppinger KA: The significance of intermediate plasma growth hormone levels in growth-retarded children, J PEDIATR 81:1092, 1972. Glick SM: Regulation of growth hormone secretion, p 141. in Martini L, and Ganong WF, editors: Frontiers in neuroendocrinology, London, 1973, Oxford University Press. Penny R, and Blizzard RM: The possible influence of puberty on the release of growth hormone in three males with apparent isolated growth hormone deficiency, J Clin Endocrinol 24:82, 1972. Foley TP Jr, Thompson RG, Shaw M, Baghdassarian A, Nissley SP, and Blizzard RM: Growth responses to human growth hormone in patients with intrauterine growth retardation, J PEDIATR 84:635, 1974.
