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Growth and somatomedin-C responses to growth hormone in dwarfed children
868
December 1981 TheJournalofPEDIATRICS
Growth and somatomedin-C responses to growth hormone in dwarfed children Nineteen children were studied because o f short stature. The)' had in common abnormally low Sm-C values for age, and each received a ten-day course of exogenous GH therapy. Based on their endogenous GH concentrations and the response to GH therapy, in terms of Sm-C and height increments, they were classified into three groups. Group I included patients with GH insufficiency who had blunted GH responses to stimulation, but responded to therapy by normalizing the Sm-C concentration and velocity of growth. Group H patients all had normal GH responses to stimulation, but their responses to exogenous GH were similar to those observed in the GH deficient subjects. In the two children in Group I I I who had normal release o f endogenous GH, Sm-C values and growth rate did not increase in response to GH. Group H patients may represent children with biologically inactive but immunoreactive GH, whereas the children in Group I I I are examples of the Laron type of dwarfism. Thus, rather than the plasma GH response to provocative stimuli, the Sm-C and growth increment responses to short-term exogenous GH therapy may more precisely identify children that wit/benefit from long-term GH therapy.
Alberto Hayek, M.D.,* and Glenn T. Peake, M.D., Albuquerque, N.M.
GENERALLY ACCEPTED CRITERIA for treatment of dwarfed children with exogenous growth hormone have been based on the demonstration of a failure of plasma growth hormone concentration to rise following appropriate stimulation. These criteria include the demonstration of low plasma GH values after at least two provocative stimuli, significant delay in height age and bone age compared to chronologic age, a growth rate of < 4.0 cm/year, and the lack of an intercurrent organic or emotional problem which could interfere with normal growth. Following the discovery that the effects of growth hormone on cartilage proliferation were dependent upon another substance or substances/ it was suspected that a deficiency of these growth hormone-dependent substances, now termed somatomedins, could account for growth failure. The association of low Sm-C values with growth hormone deficiency has been amply demonFrom the Departments o f Pediatrics and Medicine, University of New Mexico Medical School. Supported by grants from the National Institute of Health i RO1 05794-08, the Judithe G. Douglffs Fund, and from the General Clinical Research Centers Program, DRR, N I H 5 MO1 RR00997-05. *Reprint address: Department of Pediatrics, University of New Mexico, School of Medicine, Albuquerque, NM 87131.
VoL 99, No. 6, pp. 868-872
strated, ~ " and a clinical syndrome in which GH secretion is normal, but somatomedin is not produced, even with exogenous GH treatment, has been described? A few dwarfed children with normal circulating GH and diminished plasma somatomedin values, in whom treatment with exogenous GH produced a rise in somatomedin concentrations and an enhanced growth rate, have also been described. ~ On the basis of preliminary observations,7 we suspected that there might exist a larger population of dwarfed children with normal circulating immunoassayable GH and diminished Sm-C values who might benefit from GH treatment. Abbreviations used GH: growthhormone Sm-C somatomedin-C T4: thyroxine METHODS Patient populatiom Children referred to the pediatric endocrine clinic for evaluation of short stature were investigated for possible inclusion in this study. Children who were > 3 SD below the mean for height, had a documented yearly growth rate of < 4 cm/year, significantly delayed bone age, and two baseline Sm-C concen-
0022-3476/8t/120868+05500.50/0 9 1981 The C. V. Mosby Co.
Volume 99 Number 6
Growth and Sm-C responses to GH in dwarfed children
869
Table, Clinical and laboratory data on p a t i e n t p o p u l a t i o n
CA* Patient
HAt
Diagnosis
Peak GH concentration (ng/ml)
3%2 10 12%~ 0.5 8 4 7 c'/1~
Histiocytosis Craniopharyngioma Isolated GILl deficiency Septo-optic dysplasia Isolated GH deficiency Craniopharyngioma Isolated GH deficiency
< 2 < 2 5 5 4 < 2 2
0.17 0.12 0.20 0.13 0. I 0.16 0.15
Short Short Short Short Short Short Short Short Short Short
stature stature stature stature stature stature stature stature stature stature
36 12 23 33 14 10 35 10 15 29
0.12 0.21 0.25 0.24 0.32 0.28 0.24 0.15 0.24 0.15
Short stature Short stature
18 20
0.19 < 0A
BAJ;
Sex
Sm-C (U/ml) ~
]
,Peak
Group I 1
2 3 4 5 6 7 Group I1
M
6
3Y,~
M M M M M F
14%2 15"/12 3 1O~A~ 6 11%2
44/1~ 9%_, t 6~/,~ 3~'/,~ 6'>/~x
M
14~%2
9~/,~
M M M M M M M F M
9'~ 5%~ 11%_~ 8HA= 3 8%~ 571~ 57/12 3~/~
6~/~ 3 7s/l~ 63A2 1 5 3 3 27,_~
12 6%~ 2~/,~ 6 4 1%~ 4 3 3 2
I
M
3%~
1%2
1%~
2
M
3%~
1~/,~
1%~
1
2 3 4 5 6 7 8 9 I0 Group III
0.99 5.2 3.5 0.27 0.49 0A6 2.6 0.85 0.37 0.39 1.3 1.3 0.94 0.4 1.3 0.48
< 0.1 < 0A
*Chronologic age. ~Height age. ~:Bone age. trations i n a p p r o p r i a t e l y below those of a g e - m a t c h e d controls were included, after i n f o r m e d consent was obtained. N i n e t e e n such children form the basis of this report. All of the children were healthy, lived in h o m e e n v i r o n m e n t s that were emotionally supportive, had no evidence of active chronic disease, h a d n o r m a l blood counts, urinalysis, and m u l t i c h a n n e l blood chemistry determinations, had n o r m a l body proportions, a n d were receiving p r o p e r h o r m o n a l m a i n t e n a n c e t h e r a p y if a n established h o r m o n al deficiency h a d b e e n identified. Each child was followed without t r e a t m e n t for a period o f at least three m o n t h s to establish p r e t r e a t m e n t growth rates. Subjects were classified as b e i n g G H deficient if they failed to have a n o r m a l rise in p l a s m a G H c o n c e n t r a t i o n lollowing either a c o m b i n e d L-dopa a n d arginine ~ or arginine-insulin challenge2 Subjects were classified as having n o r m a l growth h o r m o n e secretion if plasma G H concentration exceeded 10 n g / m l following stimulation. In addition to a group of children with p r o v e n G H deficiency, we studied a n u m b e r of children with height age and b o n e age delay a n d a n t h r o p o m o r p h i c features similar to those of GH-deficient children, b u t w h o h a d n o r m a l p l a s m a G H responses to p r o v o c a t N e stimuli. In order to d e t e r m i n e w h e t h e r some of these children with n o r m a l circulating levels of G H would r e s p o n d to exoge-
nous G H therapy, we m e a s u r e d Sm-C c o n c e n t r a t i o n s in them; those w h o h a d Sm-C c o n c e n t r a t i o n s below n o r m a l were given a ten-day course o f exogenous G H to ascertain their p l a s m a Sm-C values a n d their growth i n c r e m e n t over the s u b s e q u e n t 12 weeks. H e i g h t m e a s u r e m e n t s were recorded prior to exogenous G H therapy a n d eight to t2 weeks following treatment. G r o w t h increments were calculated on a per m o n t h basis a n d c o m p a r e d to rates observed prior to exogenous a d m i n i s t r a t i o n of GH. Each child was m e a s u r e d on a p e r m a n e n t l y w a l l - m o u n t e d stadiometer by one o f the authors and the average of at least three readings was taken as the child's height. In no case did repeated m e a s u r e m e n t s vary by more t h a n 0.16 cm. To eliminate investigator bias, previous heights a n d the p h a s e of the study that the child was participating in at the time were not revealed until after each m e a s u r e m e n t was made. H o r m o n e assays. Plasma G H was m e a s u r e d as previously described? ~>Blood was collected in E D T A tubes prior to exogenous a d m i n i s t r a t i o n of GH, and o n days one, five, and ten of treatment, centrifuged at 4~ and the p l a s m a frozen a n d shipped to Nichols Institute in Los Angeles, for the s o m a t o m e d i n assay. 1~ G r o w t h h o r m o n e treatment. Growth h o r m o n e was o b t a i n e d from the N a t i o n a l Pituitary Agency, dissolved in
870
Hayek and Peake
The Journal of Pediatrics December 1981
GROUP I CONTROL
GH T H E R A P Y
GROUP Z
GROUP
AH
T
l-Z
2
O E
? a
,4 ,3 .I
p L
<,OOI
~ 3
e-rrr
II I
Fig. 1. Growth increments in centimeters per month for the three groups (l, II, and III) of patients before and after GH therapy. Bars indicate mean + SEM. *Difference in growth increments between control and GH therapy periods for each group. sterile distilled water, and injected intramuscularly for ten consecutive days. The dose chosen was 0.168 IU/ kg x 0.75, which is an intermediate dose that produced measurable growth increments in dwarfed children and was predictive of the response to long-term GH therapy, as previously demonstrated by Rudman et al. 1~ Because some of the distributions were not bell shaped, we used the Wilcoxon Signed Rank test for paired data in the analysis of the growth and Sm-C responses to therapY. RESULTS Individual data for each patient are shown in the Table. On the basis of plasma growth hormone values, the Sm-C concentrations and the observed growth increments, the patients could be divided into three groups, as follows: Group I. Growth hormone deficiency. Each child had a maximum plasma GH response of less than 5 ng/ml and the peak growth hormone concentrations were significantly less than those observed in Groups II and III. Baseline Sm-C values were diminished in all subjects and none had a value in excess of 0.25 U/ml. Normal children, older than 3 years, have values above 0.4 U/ml. Age-related normal values compared with abnormal values are available from the Nichols Institute on request. All the children had clinical features of GH deficiency, with retarded height ages, and bone ages which were similar to the height age (Table). Seven children, six boys and one girl, with ages between 3 and 15 #12 years, were classified into this group. Treatment with exogenous GH significantly enhanced the growth rate in these children (Fig. 1). Growth rates were increased above 4.0 cm/year as predicted from the
,25 DAYS 0 1 5 <.05
<,05
I0
0
5 I0
01510
<.00 <,01
Fig. 2. Sm-C responses to GH therapy in the three groups of
patients. Day 0 is the average of two baseline samples. Bars indicate mean +_ SEM. Peak values on day 5 are not statistically different between Groups I and II.
eight- to 12-week posttreatment period in each child given exogenous GH, whereas predicted growth rates had been less than 4.0 cm/year in each child when calculated on the basis of the three-month observation period prior to therapy. Plasma Sm-C values increased with GH treat~ ment in each child, with a mean peak of 1.75 _+ 0.74 U/ml attained at day 5 (Fig. 2). The highest individual somatomedin-C values of 5.2 and 3.1 U/ml, respectively, were observed in the two older children (ages 14 and 15 5/1~ years) who were in Stage II and Stage III puberty; the lowest, 0.27 U/ml, was found in the 3-year-old child with septo-optic dysplasia who also had the poorest growth response (0.35 cm/month) to the administered GH. Group II. Normal growth hormone with low Sm-C. Each child in this group had a maximal plasma GH exceeding 10 ng/ml on provocative testing. All subjects had low basal somatomedin-C values with none exceeding 0.4 U/ml (Table). Clinically, the patients were not clearly distinguishable from subjects in Group I, as they also had retarded height ages with bone ages comparable to their height age. No hepatic, renal, or hematologic disease was detected by routine testing in any of these subjects. Radiographs of the skull showed no evidence of sella or parasellar tumor. Ten children could be classified into this group of patients, nine boys and one girl, with ages ranging from 3 to 15 7/1~years. Treatment with growth hormone significantly increased the growth rate in this group of children (Fig. 1) and
Volume 99 Number 6
posttreatment growth increments were indistinguishable from those observed in the subjects in Group I. Plasma Sm-C concentrations rose in all subjects treated with growth hormone, and the mean peak value of Sm-C was observed on the fifth day of treatment, as in the subjects in Group I (Fig. 2). The elevations of somatomedin-C were sustained throughout the ten-day treatment with exogenous GH, paralleling the results observed in the growth hormone deficient subjects. Group IIL Laron type dwarfs. The two subjects in this group, a set of twins, had normal plasma GH responses to provocative stimuli and low basal Sm-C values. Height ages and bone ages were delayed comparably, and clinically the subjects were not different from the subjects in Groups I or II. Following treatment with exogenous GH, no changes in growth rate (Fig. 1) or in Sm-C concentrations (Fig. 2) were observed. D][SCUSSION The studies reported here have delineated a group of children with short stature, delayed skeletal maturation, and normal GH values who had an enhanced growth rate following short-term treatment with growth hormone. Each of these children was observed to have a low basal Sm-C concentration and a substantial rise in plasma Sm-C in response to exogenous GH therapy. Similar findings have been reported by Kowarski et al, 6 and we have presented a brief report on one of the children included in this study. 7 We chose to determine the response to GH using a short-term course of growth hormone therapy since this is an established method to determine the growth promoting effect of GH '~ and conserves the limited supplies of GH. The rise in Sm-C values following treatment with growth hormone in each of the children indicated that the potential existed for a positive growth response, which in fact did occur in each of the children we studied. Our studies in the GH-deficient children have confirmed the original observation of Rudman et al 1~regarding the linear height increments following short-term exogenous GH therapy. A similar rise in plasma Sm-C values following growth hormone therapy was observed in our GH-deficient subjects, as documented by other investigators. ~ 4 Two of the children with GH deficiency had very high Sm-C elevations with GH therapy. Since both of these children were in early to midpuberty, it is possible that increased endogenous androgens facilitated this response to exogenous administration of GH. Some studies have shown that administration of anabolic steroids with GH results in a greater growth increment than when GH is given alone? ~, H Perhaps this augmentation of growth is mediated by a greater rise in Sm-C concen-
Growth and S m - C responses to G H in dwarfed children
87 |
trations when GH and anabolic steroids are given together. On the other hand, the lowest Sm-C response observed in this group of children coincided with the lowest growth increment, as seen in the child with septo-optic dysplasia (Table). Copeland et al 1~ have shown that some hypopituitary dwarfs, when given GH, grow at normal rates but fail to increase their Sm-C values. Their patients, like ours, were undernourished, and the apparent resistance to GH disappeared following a substantial weight gain. They have theorized that the low Sm-C levels may result from failure to generate a binding protein for at least one of the molecular complexes of Sm-C; this situation is analogous to T4-binding globulin deficiency, in which the individual is euthyroid in the face of low total T4 but normal free T~ concentrations. Recent reports with the radioreceptor assay for Sm-C following GH administration to GHdeficient children have shown consistently higher values than those observed by radioimmunoassay, suggesting the generation of other GH-dependent growth factors in addition to Sm-C. 1~ The two children in Group III appear to represent examples of the type of dwarfism first described by Laron,; in which there is an inability to generate somatomedin in the presence of endogenous or exogenous GH. Our patients, like those reported by Laron, did not have a growth response to the short-term course of exogenous GH. The lack of a rise in Sm-C values during the ten-day course of therapy in these children demonstrates the association between the Sm-C response and the subsequent growth response. Thus, children who do not have a rise in Sm-C values during the ten-day course of exogenous GH may not be expected to respond to exogenous GH with an increased growth rate. Administration of growth hormone over more extended periods of time to children with Laron type dwarfism has not caused an enhanced growth rate'7; thus, it is not surprising that our patients did not respond to the short course of GH therapy. Very recent studies have indicated that the Laron-type dwarf lacks a biologic response to exogenous GH, perhaps because of a deficiency in cellular GH receptors? s In the children who have normal growth hormone values with low Sm-C concentrations, and who respond to growth hormone treatment, there is no clearly established pathophysiologic basis for their problem. They may have a growth hormone molecule which is altered structurally in such a way that it has little or no biologic activity. ' ~ Thus, when the subject is given normal GH exogenously, normal somatomedin and growth responses occur. Another potential explanation is that their diurnal rhythm of GH secretion is diminished, ~ 20 and as a result there is insufficient GH produced over a day to sustain normal
872
Hayek and Peake
p l a s m a s o m a t o m e d i n concentrations. T h e n o r m a l rise in G H to provocative stimuli in these children m a y not reflect the diurnal physiologically stimulated h o r m o n e secretion; thus, studies o f G H reserve m a y be s o m e w h a t misleading? .... T h e clinical relevance o f the observations in the patients in G r o u p II is that they constitute a group o f dwarfed children in w h o m the n o r m a l p l a s m a G H values are not helpful in the e v a l u a t i o n of their growth problem, in the absence of c o n c o m i t a n t Sm-C d e t e r m i n a tions. W h e t h e r these children will have a sustained increase in growth rates with chronic exogenous G H therapy is currently u n d e r investigation. Thus, it may be feasible to identify which child will potentially benefit from exogenous G H therapy by assessing their growth a n d Sm-C responses to a short course o f G H treatment. REFERENCES
1. Salmon WD, and Daughaday WH: A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro, J Lab Clin Med 49:825, 1957. 2. D'Ercole JA, Underwood LE, and Van Wyk J J: Serum somatomedin C in hypopituitarism and in other disorders of growth, J PEDIATR 90:375, 1977. 3. Kemp SF, Rosenfeld RG, Liu F, Gaspich S, and Hintz RL: Acute somatomedin response to growth hormone: radioreceptor assay versus radioimmunoassay, J Clin Endocrinol Metab 52:616, 1981. 4. Rudman D, Moffitt SD, Fernhoff PM, McKenzie W J, Kenny JM, and Bain RP: The relation between growth velocity and serum somatomedin C concentration, J Clin Endocrinol Metabol 52:622, 1981. 5. Laron Z: Syndrome of familial dwarfism and high plasma immunoreactive growth hormone, Isr J Med Sci 10:1247, 1974. 6. Kowarski AA, Schneider J, Ben-Galim E, Weldon VV, and Daughaday WH: Growth failure with normal serum RIAGH and low somatomedin activity: somatomedin restoration and growth acceleration after exogenous GH, J Clin Endocrinol Metab 47:461, 1978. 7. Hayek A, Peake GT, and Greenberg RE: A new syndrome of short stature due to biologically inactive but immunoreactive growth hormone, Pediatr Res 12:413, 1978. 8. Weldon VV, Gupta SK, Klingensmith G, Clarke WL, Duck SC, Haymond MW, and Pagiiara AS: Evaluation of growth hormone release in children using arginine and L-dopa in combination, J PEDIATR 87:540, 1975. 9. Penny R, Blizzard RM, and Davis WT: Sequential-arginine and insulin tolerance test on the same day, J Clin Endocrinol Metab 29:1499, 1969.
The Journal of Pediatrics December 1981
10. Peake GT, Morris J, and Buckman MT: Growth hormone, in Jaffe B, and Berhman HR, editors: Methods of hormone radioimmunoassay, ed 2, New York, 1979, Academic Press, Inc., pp 223-243. 12. Furlanetto RW, Underwood JE, Van Wyk J J, and D'Ercole AJ: Estimation of somatomedin-c levels in normals and patients with pituitary disease by radioimmanoassay, J Clin Invest 60:648, 1977. 12. Rudman D, Kutner MH, Fleming GA, Harris RC, Kennedy EE, Bethel RA, and Priest JH: Effect of 10-day courses of human growth hormone on height of short children, J Clin Endocrinol Metab 46:28, 1978. 13. MacGillivray MH, Kolotkin M, and Munschaver RW: Enhanced linear growth responses in hypopituitary dwarfs treated with growth hormone plus androgens versus growth hormone alone, Pediatr Res 8:103, 1974. 14. Romshe CA, and Sotos JF: The combined effect of growth hormone and oxandrolone in patients with growth hormone deficiency, J PEDIATR 96:127, 1980. 15. Copeland KC, Underwood LE, and Van Wyk J: Induction of immunoreactive somatomedin-C in human serum by growth hormone: Dose response relationships and effect on chromatographic profiles, J Clin Endocrinol Metab 50:690, 1980. i6. Kemp SF, Rosenfeld RG, Liu F, Gaspich S, and Hintz RL: Acute somatomedin response to growth hormone: radioreceptor assay versus radioimmunoassay, J Clin Endocrinol Metab 52:616, 1981. 17. Laron Z, Pertzelan A; Karp M, Kowaldo A, and Daughaday WH: Administration of growth hormone to patients with familial dwarfism with high plasma immunoreactive growth hormone: measurement of sulfation factor, meta~ bolic and linear growth responses, J Clin Endocrinol Metab 33:332, 1971. 18. Golde DW, Bersch N, Kaplan SA, Rimoin DL, and Li CH: Peripheral unresponsiveness to human growth hormone in Laron dwarfism, N Engl J Med 303:1156, 1980. 19. Plotnick LP, Thompson RG, Kowarski A, deLucerda L, Migeon CF and Blizzard RM: Circadian variation of integrated concentration of growth hormone in children and adults, J Clin Endocrinol Metab 40:240, 1975. 20. Plotnick LP, Lee PA, Migeon CJ, and Kowarski A: Normal integrated concentrations of growth hormone (GH) in certain patients wish subnormal GH responses to stimulation: A subgroup of apparent GH deficient patients. Pro~ gram and Abstracts of The 59th Annual Meeting of the Endocrine Society, 1977, p 209. 21. Wise PH, Burner RB, Geary TD, and Berriman H: Selective impairment of growth hormone response to physiological stimuli, Arch Dis Child 50:210, 1975.
December 1981 TheJournalofPEDIATRICS
Growth and somatomedin-C responses to growth hormone in dwarfed children Nineteen children were studied because o f short stature. The)' had in common abnormally low Sm-C values for age, and each received a ten-day course of exogenous GH therapy. Based on their endogenous GH concentrations and the response to GH therapy, in terms of Sm-C and height increments, they were classified into three groups. Group I included patients with GH insufficiency who had blunted GH responses to stimulation, but responded to therapy by normalizing the Sm-C concentration and velocity of growth. Group H patients all had normal GH responses to stimulation, but their responses to exogenous GH were similar to those observed in the GH deficient subjects. In the two children in Group I I I who had normal release o f endogenous GH, Sm-C values and growth rate did not increase in response to GH. Group H patients may represent children with biologically inactive but immunoreactive GH, whereas the children in Group I I I are examples of the Laron type of dwarfism. Thus, rather than the plasma GH response to provocative stimuli, the Sm-C and growth increment responses to short-term exogenous GH therapy may more precisely identify children that wit/benefit from long-term GH therapy.
Alberto Hayek, M.D.,* and Glenn T. Peake, M.D., Albuquerque, N.M.
GENERALLY ACCEPTED CRITERIA for treatment of dwarfed children with exogenous growth hormone have been based on the demonstration of a failure of plasma growth hormone concentration to rise following appropriate stimulation. These criteria include the demonstration of low plasma GH values after at least two provocative stimuli, significant delay in height age and bone age compared to chronologic age, a growth rate of < 4.0 cm/year, and the lack of an intercurrent organic or emotional problem which could interfere with normal growth. Following the discovery that the effects of growth hormone on cartilage proliferation were dependent upon another substance or substances/ it was suspected that a deficiency of these growth hormone-dependent substances, now termed somatomedins, could account for growth failure. The association of low Sm-C values with growth hormone deficiency has been amply demonFrom the Departments o f Pediatrics and Medicine, University of New Mexico Medical School. Supported by grants from the National Institute of Health i RO1 05794-08, the Judithe G. Douglffs Fund, and from the General Clinical Research Centers Program, DRR, N I H 5 MO1 RR00997-05. *Reprint address: Department of Pediatrics, University of New Mexico, School of Medicine, Albuquerque, NM 87131.
VoL 99, No. 6, pp. 868-872
strated, ~ " and a clinical syndrome in which GH secretion is normal, but somatomedin is not produced, even with exogenous GH treatment, has been described? A few dwarfed children with normal circulating GH and diminished plasma somatomedin values, in whom treatment with exogenous GH produced a rise in somatomedin concentrations and an enhanced growth rate, have also been described. ~ On the basis of preliminary observations,7 we suspected that there might exist a larger population of dwarfed children with normal circulating immunoassayable GH and diminished Sm-C values who might benefit from GH treatment. Abbreviations used GH: growthhormone Sm-C somatomedin-C T4: thyroxine METHODS Patient populatiom Children referred to the pediatric endocrine clinic for evaluation of short stature were investigated for possible inclusion in this study. Children who were > 3 SD below the mean for height, had a documented yearly growth rate of < 4 cm/year, significantly delayed bone age, and two baseline Sm-C concen-
0022-3476/8t/120868+05500.50/0 9 1981 The C. V. Mosby Co.
Volume 99 Number 6
Growth and Sm-C responses to GH in dwarfed children
869
Table, Clinical and laboratory data on p a t i e n t p o p u l a t i o n
CA* Patient
HAt
Diagnosis
Peak GH concentration (ng/ml)
3%2 10 12%~ 0.5 8 4 7 c'/1~
Histiocytosis Craniopharyngioma Isolated GILl deficiency Septo-optic dysplasia Isolated GH deficiency Craniopharyngioma Isolated GH deficiency
< 2 < 2 5 5 4 < 2 2
0.17 0.12 0.20 0.13 0. I 0.16 0.15
Short Short Short Short Short Short Short Short Short Short
stature stature stature stature stature stature stature stature stature stature
36 12 23 33 14 10 35 10 15 29
0.12 0.21 0.25 0.24 0.32 0.28 0.24 0.15 0.24 0.15
Short stature Short stature
18 20
0.19 < 0A
BAJ;
Sex
Sm-C (U/ml) ~
]
,Peak
Group I 1
2 3 4 5 6 7 Group I1
M
6
3Y,~
M M M M M F
14%2 15"/12 3 1O~A~ 6 11%2
44/1~ 9%_, t 6~/,~ 3~'/,~ 6'>/~x
M
14~%2
9~/,~
M M M M M M M F M
9'~ 5%~ 11%_~ 8HA= 3 8%~ 571~ 57/12 3~/~
6~/~ 3 7s/l~ 63A2 1 5 3 3 27,_~
12 6%~ 2~/,~ 6 4 1%~ 4 3 3 2
I
M
3%~
1%2
1%~
2
M
3%~
1~/,~
1%~
1
2 3 4 5 6 7 8 9 I0 Group III
0.99 5.2 3.5 0.27 0.49 0A6 2.6 0.85 0.37 0.39 1.3 1.3 0.94 0.4 1.3 0.48
< 0.1 < 0A
*Chronologic age. ~Height age. ~:Bone age. trations i n a p p r o p r i a t e l y below those of a g e - m a t c h e d controls were included, after i n f o r m e d consent was obtained. N i n e t e e n such children form the basis of this report. All of the children were healthy, lived in h o m e e n v i r o n m e n t s that were emotionally supportive, had no evidence of active chronic disease, h a d n o r m a l blood counts, urinalysis, and m u l t i c h a n n e l blood chemistry determinations, had n o r m a l body proportions, a n d were receiving p r o p e r h o r m o n a l m a i n t e n a n c e t h e r a p y if a n established h o r m o n al deficiency h a d b e e n identified. Each child was followed without t r e a t m e n t for a period o f at least three m o n t h s to establish p r e t r e a t m e n t growth rates. Subjects were classified as b e i n g G H deficient if they failed to have a n o r m a l rise in p l a s m a G H c o n c e n t r a t i o n lollowing either a c o m b i n e d L-dopa a n d arginine ~ or arginine-insulin challenge2 Subjects were classified as having n o r m a l growth h o r m o n e secretion if plasma G H concentration exceeded 10 n g / m l following stimulation. In addition to a group of children with p r o v e n G H deficiency, we studied a n u m b e r of children with height age and b o n e age delay a n d a n t h r o p o m o r p h i c features similar to those of GH-deficient children, b u t w h o h a d n o r m a l p l a s m a G H responses to p r o v o c a t N e stimuli. In order to d e t e r m i n e w h e t h e r some of these children with n o r m a l circulating levels of G H would r e s p o n d to exoge-
nous G H therapy, we m e a s u r e d Sm-C c o n c e n t r a t i o n s in them; those w h o h a d Sm-C c o n c e n t r a t i o n s below n o r m a l were given a ten-day course o f exogenous G H to ascertain their p l a s m a Sm-C values a n d their growth i n c r e m e n t over the s u b s e q u e n t 12 weeks. H e i g h t m e a s u r e m e n t s were recorded prior to exogenous G H therapy a n d eight to t2 weeks following treatment. G r o w t h increments were calculated on a per m o n t h basis a n d c o m p a r e d to rates observed prior to exogenous a d m i n i s t r a t i o n of GH. Each child was m e a s u r e d on a p e r m a n e n t l y w a l l - m o u n t e d stadiometer by one o f the authors and the average of at least three readings was taken as the child's height. In no case did repeated m e a s u r e m e n t s vary by more t h a n 0.16 cm. To eliminate investigator bias, previous heights a n d the p h a s e of the study that the child was participating in at the time were not revealed until after each m e a s u r e m e n t was made. H o r m o n e assays. Plasma G H was m e a s u r e d as previously described? ~>Blood was collected in E D T A tubes prior to exogenous a d m i n i s t r a t i o n of GH, and o n days one, five, and ten of treatment, centrifuged at 4~ and the p l a s m a frozen a n d shipped to Nichols Institute in Los Angeles, for the s o m a t o m e d i n assay. 1~ G r o w t h h o r m o n e treatment. Growth h o r m o n e was o b t a i n e d from the N a t i o n a l Pituitary Agency, dissolved in
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The Journal of Pediatrics December 1981
GROUP I CONTROL
GH T H E R A P Y
GROUP Z
GROUP
AH
T
l-Z
2
O E
? a
,4 ,3 .I
p L
<,OOI
~ 3
e-rrr
II I
Fig. 1. Growth increments in centimeters per month for the three groups (l, II, and III) of patients before and after GH therapy. Bars indicate mean + SEM. *Difference in growth increments between control and GH therapy periods for each group. sterile distilled water, and injected intramuscularly for ten consecutive days. The dose chosen was 0.168 IU/ kg x 0.75, which is an intermediate dose that produced measurable growth increments in dwarfed children and was predictive of the response to long-term GH therapy, as previously demonstrated by Rudman et al. 1~ Because some of the distributions were not bell shaped, we used the Wilcoxon Signed Rank test for paired data in the analysis of the growth and Sm-C responses to therapY. RESULTS Individual data for each patient are shown in the Table. On the basis of plasma growth hormone values, the Sm-C concentrations and the observed growth increments, the patients could be divided into three groups, as follows: Group I. Growth hormone deficiency. Each child had a maximum plasma GH response of less than 5 ng/ml and the peak growth hormone concentrations were significantly less than those observed in Groups II and III. Baseline Sm-C values were diminished in all subjects and none had a value in excess of 0.25 U/ml. Normal children, older than 3 years, have values above 0.4 U/ml. Age-related normal values compared with abnormal values are available from the Nichols Institute on request. All the children had clinical features of GH deficiency, with retarded height ages, and bone ages which were similar to the height age (Table). Seven children, six boys and one girl, with ages between 3 and 15 #12 years, were classified into this group. Treatment with exogenous GH significantly enhanced the growth rate in these children (Fig. 1). Growth rates were increased above 4.0 cm/year as predicted from the
,25 DAYS 0 1 5 <.05
<,05
I0
0
5 I0
01510
<.00 <,01
Fig. 2. Sm-C responses to GH therapy in the three groups of
patients. Day 0 is the average of two baseline samples. Bars indicate mean +_ SEM. Peak values on day 5 are not statistically different between Groups I and II.
eight- to 12-week posttreatment period in each child given exogenous GH, whereas predicted growth rates had been less than 4.0 cm/year in each child when calculated on the basis of the three-month observation period prior to therapy. Plasma Sm-C values increased with GH treat~ ment in each child, with a mean peak of 1.75 _+ 0.74 U/ml attained at day 5 (Fig. 2). The highest individual somatomedin-C values of 5.2 and 3.1 U/ml, respectively, were observed in the two older children (ages 14 and 15 5/1~ years) who were in Stage II and Stage III puberty; the lowest, 0.27 U/ml, was found in the 3-year-old child with septo-optic dysplasia who also had the poorest growth response (0.35 cm/month) to the administered GH. Group II. Normal growth hormone with low Sm-C. Each child in this group had a maximal plasma GH exceeding 10 ng/ml on provocative testing. All subjects had low basal somatomedin-C values with none exceeding 0.4 U/ml (Table). Clinically, the patients were not clearly distinguishable from subjects in Group I, as they also had retarded height ages with bone ages comparable to their height age. No hepatic, renal, or hematologic disease was detected by routine testing in any of these subjects. Radiographs of the skull showed no evidence of sella or parasellar tumor. Ten children could be classified into this group of patients, nine boys and one girl, with ages ranging from 3 to 15 7/1~years. Treatment with growth hormone significantly increased the growth rate in this group of children (Fig. 1) and
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posttreatment growth increments were indistinguishable from those observed in the subjects in Group I. Plasma Sm-C concentrations rose in all subjects treated with growth hormone, and the mean peak value of Sm-C was observed on the fifth day of treatment, as in the subjects in Group I (Fig. 2). The elevations of somatomedin-C were sustained throughout the ten-day treatment with exogenous GH, paralleling the results observed in the growth hormone deficient subjects. Group IIL Laron type dwarfs. The two subjects in this group, a set of twins, had normal plasma GH responses to provocative stimuli and low basal Sm-C values. Height ages and bone ages were delayed comparably, and clinically the subjects were not different from the subjects in Groups I or II. Following treatment with exogenous GH, no changes in growth rate (Fig. 1) or in Sm-C concentrations (Fig. 2) were observed. D][SCUSSION The studies reported here have delineated a group of children with short stature, delayed skeletal maturation, and normal GH values who had an enhanced growth rate following short-term treatment with growth hormone. Each of these children was observed to have a low basal Sm-C concentration and a substantial rise in plasma Sm-C in response to exogenous GH therapy. Similar findings have been reported by Kowarski et al, 6 and we have presented a brief report on one of the children included in this study. 7 We chose to determine the response to GH using a short-term course of growth hormone therapy since this is an established method to determine the growth promoting effect of GH '~ and conserves the limited supplies of GH. The rise in Sm-C values following treatment with growth hormone in each of the children indicated that the potential existed for a positive growth response, which in fact did occur in each of the children we studied. Our studies in the GH-deficient children have confirmed the original observation of Rudman et al 1~regarding the linear height increments following short-term exogenous GH therapy. A similar rise in plasma Sm-C values following growth hormone therapy was observed in our GH-deficient subjects, as documented by other investigators. ~ 4 Two of the children with GH deficiency had very high Sm-C elevations with GH therapy. Since both of these children were in early to midpuberty, it is possible that increased endogenous androgens facilitated this response to exogenous administration of GH. Some studies have shown that administration of anabolic steroids with GH results in a greater growth increment than when GH is given alone? ~, H Perhaps this augmentation of growth is mediated by a greater rise in Sm-C concen-
Growth and S m - C responses to G H in dwarfed children
87 |
trations when GH and anabolic steroids are given together. On the other hand, the lowest Sm-C response observed in this group of children coincided with the lowest growth increment, as seen in the child with septo-optic dysplasia (Table). Copeland et al 1~ have shown that some hypopituitary dwarfs, when given GH, grow at normal rates but fail to increase their Sm-C values. Their patients, like ours, were undernourished, and the apparent resistance to GH disappeared following a substantial weight gain. They have theorized that the low Sm-C levels may result from failure to generate a binding protein for at least one of the molecular complexes of Sm-C; this situation is analogous to T4-binding globulin deficiency, in which the individual is euthyroid in the face of low total T4 but normal free T~ concentrations. Recent reports with the radioreceptor assay for Sm-C following GH administration to GHdeficient children have shown consistently higher values than those observed by radioimmunoassay, suggesting the generation of other GH-dependent growth factors in addition to Sm-C. 1~ The two children in Group III appear to represent examples of the type of dwarfism first described by Laron,; in which there is an inability to generate somatomedin in the presence of endogenous or exogenous GH. Our patients, like those reported by Laron, did not have a growth response to the short-term course of exogenous GH. The lack of a rise in Sm-C values during the ten-day course of therapy in these children demonstrates the association between the Sm-C response and the subsequent growth response. Thus, children who do not have a rise in Sm-C values during the ten-day course of exogenous GH may not be expected to respond to exogenous GH with an increased growth rate. Administration of growth hormone over more extended periods of time to children with Laron type dwarfism has not caused an enhanced growth rate'7; thus, it is not surprising that our patients did not respond to the short course of GH therapy. Very recent studies have indicated that the Laron-type dwarf lacks a biologic response to exogenous GH, perhaps because of a deficiency in cellular GH receptors? s In the children who have normal growth hormone values with low Sm-C concentrations, and who respond to growth hormone treatment, there is no clearly established pathophysiologic basis for their problem. They may have a growth hormone molecule which is altered structurally in such a way that it has little or no biologic activity. ' ~ Thus, when the subject is given normal GH exogenously, normal somatomedin and growth responses occur. Another potential explanation is that their diurnal rhythm of GH secretion is diminished, ~ 20 and as a result there is insufficient GH produced over a day to sustain normal
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p l a s m a s o m a t o m e d i n concentrations. T h e n o r m a l rise in G H to provocative stimuli in these children m a y not reflect the diurnal physiologically stimulated h o r m o n e secretion; thus, studies o f G H reserve m a y be s o m e w h a t misleading? .... T h e clinical relevance o f the observations in the patients in G r o u p II is that they constitute a group o f dwarfed children in w h o m the n o r m a l p l a s m a G H values are not helpful in the e v a l u a t i o n of their growth problem, in the absence of c o n c o m i t a n t Sm-C d e t e r m i n a tions. W h e t h e r these children will have a sustained increase in growth rates with chronic exogenous G H therapy is currently u n d e r investigation. Thus, it may be feasible to identify which child will potentially benefit from exogenous G H therapy by assessing their growth a n d Sm-C responses to a short course o f G H treatment. REFERENCES
1. Salmon WD, and Daughaday WH: A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro, J Lab Clin Med 49:825, 1957. 2. D'Ercole JA, Underwood LE, and Van Wyk J J: Serum somatomedin C in hypopituitarism and in other disorders of growth, J PEDIATR 90:375, 1977. 3. Kemp SF, Rosenfeld RG, Liu F, Gaspich S, and Hintz RL: Acute somatomedin response to growth hormone: radioreceptor assay versus radioimmunoassay, J Clin Endocrinol Metab 52:616, 1981. 4. Rudman D, Moffitt SD, Fernhoff PM, McKenzie W J, Kenny JM, and Bain RP: The relation between growth velocity and serum somatomedin C concentration, J Clin Endocrinol Metabol 52:622, 1981. 5. Laron Z: Syndrome of familial dwarfism and high plasma immunoreactive growth hormone, Isr J Med Sci 10:1247, 1974. 6. Kowarski AA, Schneider J, Ben-Galim E, Weldon VV, and Daughaday WH: Growth failure with normal serum RIAGH and low somatomedin activity: somatomedin restoration and growth acceleration after exogenous GH, J Clin Endocrinol Metab 47:461, 1978. 7. Hayek A, Peake GT, and Greenberg RE: A new syndrome of short stature due to biologically inactive but immunoreactive growth hormone, Pediatr Res 12:413, 1978. 8. Weldon VV, Gupta SK, Klingensmith G, Clarke WL, Duck SC, Haymond MW, and Pagiiara AS: Evaluation of growth hormone release in children using arginine and L-dopa in combination, J PEDIATR 87:540, 1975. 9. Penny R, Blizzard RM, and Davis WT: Sequential-arginine and insulin tolerance test on the same day, J Clin Endocrinol Metab 29:1499, 1969.
The Journal of Pediatrics December 1981
10. Peake GT, Morris J, and Buckman MT: Growth hormone, in Jaffe B, and Berhman HR, editors: Methods of hormone radioimmunoassay, ed 2, New York, 1979, Academic Press, Inc., pp 223-243. 12. Furlanetto RW, Underwood JE, Van Wyk J J, and D'Ercole AJ: Estimation of somatomedin-c levels in normals and patients with pituitary disease by radioimmanoassay, J Clin Invest 60:648, 1977. 12. Rudman D, Kutner MH, Fleming GA, Harris RC, Kennedy EE, Bethel RA, and Priest JH: Effect of 10-day courses of human growth hormone on height of short children, J Clin Endocrinol Metab 46:28, 1978. 13. MacGillivray MH, Kolotkin M, and Munschaver RW: Enhanced linear growth responses in hypopituitary dwarfs treated with growth hormone plus androgens versus growth hormone alone, Pediatr Res 8:103, 1974. 14. Romshe CA, and Sotos JF: The combined effect of growth hormone and oxandrolone in patients with growth hormone deficiency, J PEDIATR 96:127, 1980. 15. Copeland KC, Underwood LE, and Van Wyk J: Induction of immunoreactive somatomedin-C in human serum by growth hormone: Dose response relationships and effect on chromatographic profiles, J Clin Endocrinol Metab 50:690, 1980. i6. Kemp SF, Rosenfeld RG, Liu F, Gaspich S, and Hintz RL: Acute somatomedin response to growth hormone: radioreceptor assay versus radioimmunoassay, J Clin Endocrinol Metab 52:616, 1981. 17. Laron Z, Pertzelan A; Karp M, Kowaldo A, and Daughaday WH: Administration of growth hormone to patients with familial dwarfism with high plasma immunoreactive growth hormone: measurement of sulfation factor, meta~ bolic and linear growth responses, J Clin Endocrinol Metab 33:332, 1971. 18. Golde DW, Bersch N, Kaplan SA, Rimoin DL, and Li CH: Peripheral unresponsiveness to human growth hormone in Laron dwarfism, N Engl J Med 303:1156, 1980. 19. Plotnick LP, Thompson RG, Kowarski A, deLucerda L, Migeon CF and Blizzard RM: Circadian variation of integrated concentration of growth hormone in children and adults, J Clin Endocrinol Metab 40:240, 1975. 20. Plotnick LP, Lee PA, Migeon CJ, and Kowarski A: Normal integrated concentrations of growth hormone (GH) in certain patients wish subnormal GH responses to stimulation: A subgroup of apparent GH deficient patients. Pro~ gram and Abstracts of The 59th Annual Meeting of the Endocrine Society, 1977, p 209. 21. Wise PH, Burner RB, Geary TD, and Berriman H: Selective impairment of growth hormone response to physiological stimuli, Arch Dis Child 50:210, 1975.