Effect of synthetic beta1–24 corticotropin on growth hormone release in children

Volume 78 Number 4

9. Gorlin, R. J., Meskin, L. H., and St. Geme, J. W.: Oculodentodigital dysplasia, J. PEDIAT. 63: 69, 1963.

Effect of synthetic beta 1-24 corticotropin on growth hormone release in children Maria Jos~ Del Guerclo, M.D., Margherita Carnelutti, M.D., Anna Caccamo, B.S., and Giuseppe Chiumello, M.D. ~" M I L A N O , ITALY

I N 1969, Zahnd and associates 1 demonstrated that the intravenous administration of 1 rag. of synthetic fi>~4-corticotropin stimulated the release of growth hormone in 5 out of 6 adult subjects; the growth hormone secretion was similar to that obtained with insulin-induced hypoglycemia. From these results they suggest that growth hormone secretion in stress situations may be mediated by corticotropin. Zahnd and associates '1 observations explain in part the clinical observation of an accelerated growth rate in children treated with adrenocorticotropic hormone as compared with subjects treated with corticosteroids. 2 In fact growth hormone secretion after insulin-induced hypoglycemia is reduced in subjects treated with corticosteroids, -~ whereas it is increased in children treated with adrenocorticotropic hormone. 3 The aim of the present investigation was to evaluate the release of growth hormone in children after administration of synthetic fll-24-corticotropin. From the Department o[ Pediatrics and Child Health, University o/ Milano. ~Address: Clinica Pediatrica, Via Commenda 9, Milano 20122, ltaly.

Brie[ clinical and laboratory observations

6 89

10. Buran, D. J., and Duvall, A. J., III: The oto-palatal-digital (OPD) syndrome, Arch. Otolaryng. 85: 394, 1967.

MATERIAL AND METHODS Twenty children (14 girls and 6 boys) aged 4 to 10 years, of normal weight and height, who were admitted to the hospital for mild respiratory diseases, were examined shortly before their discharge. Growth hormone release was measured after insulin-induced hypoglycemia, arginine infusion, and synthetic fl>24-corticotropin administration, respectively. The 3 tests were performed 48 hours apart, at random; they were performed after" an overnight fast and after one additional hour of bed rest after the night's sleep. Heparinized venous blood was obtained through an indwelling scalp vein needle (first sample); then isotonic saline solution was infused for 30 minutes, and another sample was collected (time 0 minutes) just before the administration of insulin, arginine, or synthetic fi>24-corticotropin. Insulin was administered by rapid intravenous injection in the amount of 0.1 U. per kilogram of body weight, diluted in 2 ml. of isotonic saline solution; blood samples were obtained at 20, 40, 60, and 120 minutes after insulin administration. L-Arginine monochloride was given by intravenous infusion at 30 minutes, in the amount of 0.5 Gm. per kilogram, diluted in hypotonic Ringer's solution. ~ Blood samples were obtained at 30, 60, 90, and 120 minutes after the start of arginine infusion. Synthetic fll-2*-corticotropin (Synacthen, Ciba Pharm. Co., Summit, N. J.) was rapidly administered intravenously in the following amounts: to 6 children, 0.25 mg.; to 6 children, 0.50 mg.; and to 8 children, 1 rag. Blood samples were obtained at 1, 3, 7, 10, 15, 30, 45, 60, and 90 minutes after the administration of Synacthen. Plasma levels of immunoreactive growth hormone were assessed by a modification of

690

Brie[ clinical and laboratory observations

The ]ournal o/ Pediatrics April 1971

T a b l e I. Plasma growth h o r m o n e (nanograms p e r milliliter) in n o r m a l children after synthetic arginine infusion ( A T T )

Time

Case I Age No. Sex (yr.) Synacthen 0.25 rag. 1

F

9

2 3 4 5 6

F F F M M

9 10 4 8 7

Synacthen 7 8 9 10 I1 12

0.50 rag. M F M F M F

6 9 7 6 6 9

Synacthen 13 14 15 I6 17 18 19 20

I rag. F F F

9 9 4

F

i0

M F

9 9

F

8

F

8

-so

I

<1 <1 <1
<1 <1 <1 <1 3

<1

1

1.5
AND

I

1 <1 <1

E

3 <1

<1

7 <1

2 1

2

I

<1

1 <1 <1

1

l

1

2

1

2

1

1

1

2

1

2

2

1 2

1

2

1

<1 <1

<1


<1

<1

3

4

2

2

1

1

1

1

2

1

<1

<1 1

<1

<1 2

<1 2 4

DISCUSSION

G r o w t h h o r m o n e values o b t a i n e d in the 3 tests are presented in T a b l e I. All the subjects e x a m i n e d h a d a n o r m a l increase of growth h o r m o n e after insulin-induced hypoglycemia a n d after arginine infusion similar to our previous resultsC; only the m a x i m u m i n c r e m e n t of growth h o r m o n e increase is shown in the table. T h e synthetic fi~-24-corticotropin was injected in increasingly larger doses. I n only 2 subjects was there a significant increase of growth h o r m o n e : Case 4 h a d an increase of 8 ng. over the basal value and Case 7 h a d a n increase of 18 ng. I n Case 7, the increase in growth h o r m o n e can be explained by the

<1 1 1

2

<1

3 2

1

<1 <1

Herbert's radioimmunoassay charcoai-dextran technique .5 RESULTS

o

2

<1

1.5

<1

<1

2 < 1

1 < 1

2

I

<1 < 1

<1 < 1

fact that the needle h a d to be replaced before blood w i t h d r a w a l ; in Case 4 no a p p a r e n t reason could be found for the increase. I n contrast to the observations of Z a h n d and associates a in adults, with the exception of the changes in Cases 4 a n d 7, none of our subjects responded to synthetic fil-2~_ corticotropin stimulation by an increase in the p l a s m a concentration of growth hormone. The antiserum (N.2-5-19) was prepared by Drs. R. S. Yatow and S. A. Berson and supplied through the kindness of the National Pituitary Agency and Endocrinology Study Section; the most satisfactory standard curves in our assay were obtained with final dilution of 1/1,000,000. The human pituitary growth hormone was supplied through the generosity of the National Pituitary Agency and the Endocrinology Study Section.

Volume 78 Number 4

Brief clinical and laboratory observations

fil24-corticotropin and maximum

(minutes) 10 < 1 1 1 1

I

15 < 1 < 1. < 1 3.2

< < < <

30 <

1 1 < 1 8

I

45 < 1 1.2 < 1 -

I

60

I

90

< 1 < 1 < 1 < 1

< 1 < 1 < I < 1

1

1

1

I

1

2

2

1

1

1

3

1

1 1

<

1 1

i

<

1

<

I

<

1

1

<

1

<

1

<

1

1 1

<1

1 2 1 1 1 1 1 1

<

< 1 < 1 <

I

increment after insulin-induced hypoglycemia (ITT)

1 2 1 1 1 1 1 1

< <

2 1 <

1 2 < 1 2 1 2 < 1 < 1

< <

< < <

1 1

1 1

18 I

i

19 14 18 20 35 12

13

20 10 13 13 24 15 19 13 10 25 18 14 19

1

<

1

1

~

1 I

<

1 I

1 1 < 1 < 1 < 1 <1 < 1 < 1

<

1 1 1 < 1 < 1 <1 < 1 < 1

18 10 12 9 15 25 22 23

REFERENCES

I. Zahnd, G. R., Nadeau, A., and yon Miihlendahl, K.: Effect of corticotrophin on plasma levels of human growth hormone, Lancet 2: 1278, 1969. 2. Friedman, M., and Strang, L. B.: Effect of long-term corticosteroid and corticotrophin on the growth of children, Lancet 2: 568, 1966. 3. Hartog, M., Gaafar, M. A., and Fraser, R.: Effect of corticosteroids on serum growth hormone, Lancet 2: 376, 1964.

<

3

< < < < < <

1 2 1 1 1 1 I 1

2

<

25 20 23 40 21 16

15

<

<

and

ITT ATT (maximum (maximum increment) increment..)

30 19 18 7 12

<

691

4. Parker, M. L., Hammond, J. M., and Daughaday, W. H.: The arginine provocative test, J. Clin. Endocr. 27: 1129, 1967. 5. Herbert, V., Lau, K. S., Gottlieb, C. W., and Bleicher, S. J.: The coated charcoal immunoassay of insulin, J. Clin. Endocr. 25: 1375, 1965. 6. Carnelutti, M., del Guercio, IV[. J., and Chiumello, G.: Influence of growth hormone on the pathogenesis of obesity in children, J. PEDIAT. 77: 285, 1970.