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Brief Reports

Indian Pediatrics 2001; 38: 534-539  

Evaluation of Growth Hormone Secretion and Insulin-like Growth Factor I in Children with Thalassemia


Alp Φzkan*
Ilknur Arslanoglu
Asim Yoruk
Cetin Timur

From the *Departments of Pediatric Hematology-Oncology, Cerrahpasa Medical Faculty, University of Istanbul, Turkey, and Social Security Gφztepe Training Hospital, Department of Pediatric Hemotology, Gφztepe, Istanbul, Turkey.
Correspondence to: Alp Φzkan, 7900 Cambridge St. Apt # 4-1A, Houston TX 77054, USA.
E-mail: alpozkan74@hotmail.com

Manuscript received: June 23, 2000;
Initial review completed: August 28, 2000;
Revision accepted: November 6, 2000.

Growth retardation has been reported to occur in most patients with thalassemia major(1-4). This is believed to be due, at least in part, to a direct effect of iron overload on the endocrine mechanisms of puberty. Growth Hormone (GH) impairment at different levels (hypothalamic or pituitary) and/or reduced insulin like growth factor 1 (IGF-1) synthesis have been suggested to be the main causes of stunned growth in these patients. We, therefore evaluated the relationship between GH, IGF-I and growth parameters in beta-thalassemia patients.

Subjects and Methods

Twenty children with beta-thalassemia major (12 girls and 8 boys), ranging in age from 2 months to 14 years were studied. Height and weight were measured and stand-ard deviation scores (SDS) were calculated according to local standards(5). Bone ages were assessed from hand X-rays according to the Greulich and Pyle Atlas(6). GH stimulation test with oral L-dopa (patients over 22.5 kg, 500 mg; 11 to 22.5 kg., 250 mg; below 11 kg, 125 mg) was performed in every subject and a second test, insulin induced hypoglycemia (ITT: regular insulin, 0.1 U/kg IV) was performed in the subjects whose GH values were below 10 ΅g/L. GH was measured by RIA (ICN Biomedicals Diagnostics Division, Inc. RSL 124 I Growth Hormone, U.S.). IGF-I was measured in morning serum samples after acid ethanol extraction by RIA (Fa. Nichols, Cal., USA). Reference for normal standards was used from literature(7). IGF-I SDS values were calculated using the formula (IGF-I–1 - mean IGF-I–1)/SD–1 for prepubertal patients and the correction formula (b ΄ age + a) was used instead of IGF-I–1 for pubertal children(7). Results were expressed as mean ±SEM and correlation analysis was used as statistical method.

Results

The physical characteristics and the laboratory data of the patients are shown in Tables I and II. The bone age was signi- ficantly lower than the chronological age (p <0.01). We found no significant correlation between height SDS and mean pretransfusion Hb (r = –0.34, p >0.05) or height SDS and mean ferritin levels (r = 0.32, p >0.25). All patients but two responded to L-dopa stimulation test with normal or high GH peaks. ITT stimulation of two nonresponders (Pts No. 17 and 18) also resulted in subnormal GH values (Table II). We found no correlation between ferritin levels and peak GH responses (r = –0.06, p >0.25), but height SDS was strongly correlated with peak GH (r = 0.59, p <0.01).

IGF-I levels of the patients were generally below mean of age and sex matched normal children(7). There was no correlation between IGF-I and ferritin (r = 0.08, p >0.25), IGF-I and duration of chelation therapy (r = 0.21, p >0.05) or IGF-I and height SDS (r = 0.22, p >0.05). We found a weak correlation between IGF-I and Hb (r = 0.41, p = 0.05). Most of the patients (90%) had negative scores for IGH-I SDS values, with 40% below –2 SDS (Table II). IGF-I SDS correlated negatively with ferritin (r = –0.46, p <0.05). Cranial MRI scanning of the two patients with GH insufficiency (Pts. No. 17 and 18) revealed ferritin deposition in basal ganglia (Fig.1). Their LH and FSH levels were in the normal range [LH: 6 and 8 mIU/ml, FSH:8 and 9 mIU/ml respectively; normal: 2-12 mIU/ml].

The serologic tests of our patients revealed that, at diagnosis only two patients (10%) were seropositive for both anti-HbC and anti-HbS; none of the patients was positive for anti-HCV. Following the therapy, one patient was found to be positive for anti-HCV (Pt 20). Liver biopsy was performed in these three children and they were followed up.

Table I__Patient Characteristics

Pt. No.
Sex
Age*
Bone age*
Height SDS
Weight for
height %
Pubertal
stage
Age at
1 transfusion
Age at
1 chelation*
1
M
1.2
0.5
–0.59
102
1
0.4
–
2.
F
1.9
1.8
–1.48
103
1
1.5
–
3.
F
2.8
2.3
–0.31
99
1
1.4
2.0
4.
F
3.1
2.5
–0.72
89
1
0.3
0.5
5
M
3.6
3.5
0.24
100
1
1.0
2.6
6.
F
3.6
3.5
–1.23
112
1
1.8
2.5
7.
M
3.8
3.0
–0.62
114
1
0.9
2.9
8.
M
4.0
3.3
–0.51
88
1
2.4
3.0
9.
M
5.3
4.0
–1.25
88
1
0.3
3.1
10.
F
6.4
4.6
0.35
90
1
1.4
3.3
11.
M
6.5
4.5
–2.11
105
1
5.0
6.3
12.
F
7.3
6.8
–1.16
93
1
0.3
5.1
13.
M
8.6
8.5
0.98
99
1
3.0
3.5
14.
F
9.6
7.4
–1.16
87
1
2.5
7.4
15.
F
10.1
9.4
–0.35
80
2
6.1
6.2
16.
F
11.0
10.0
–1.34
89
2
5.1
   –
17.
F
11.3
10.5
–1.18
85
2
1.5
2.1
18.
F
11.5
8.4
–4.04
93
2
2.7
9.0
19.
M
12.4
10.5
–2.15
87
2
1.5
6.0
20.
F
14.1
10.5
–4.13
94
2
0.3
6.1
Mean
 
6.8
5.7
–1.14
95
 
1.9
3.9
SEM
 
0.7
0.7
0.27
2
 
1.6
2.3

*Decimal year.

Table II__Laboratory Data of the Patients

Pt. No.
Serum ferritin
(ng/ml)
Pretransfusion
mean Hb (g/dl)
Peak GH to
L-dopa(΅g/L)
Peak GH to
ITT (΅g/L)
IGF-I
(΅g/L)
IGF-I
SDS
1
715
8.8
26.0
–
60.8
–0.61
2.
968
9.2
18.0
–
115.9
0.6
3.
1439
10.0
26.0
–
74.1
–0.42
4.
2900
11.0
16.0
–
91.2
–0.28
5.
2800
9.0
17.0
–
47.5
–1.43
6.
3800
9.2
32.0
–
85.5
–0.41
7.
3600
9.0
12.0
–
47.5
–1.43
8.
1530
10.7
12.0
–
70.3
–1.13
9.
2980
8.6
11.0
–
57.0
–1.75
10.
3200
8.4
17.0
–
123.5
–1.34
11.
1800
11.2
14.0
–
380.0
2.44
12.
2000
10.0
21.0
–
95.0
–2.15
13.
4600
8.8
32.0
–
98.8
–1.4
14.
1887
9.6
20.0
–
74.1
–2.46
15.
1400
10.1
24.0
–
–85.5
–2.51
16.
5900
8.8
10.8
–
102.6
–2.39
17.
5300
11.6
6.8
6.8
102.6
–2.45
18.
5800
10.3
0.1
3.5
70.3
–2.97
19.
2500
8.9
15.0
–
76.0
–3.18
20.
4680
10.4
11.0
–
121.6
–2.62
Mean
2990
9.7
17.0
 
 
–1.39
SEM
348
0.2
1.8
 
 
0.78
Discussion

Growth retardation has been reported to occur in most patients with beta-thalassemia major(1-4). Several mechanisms may be involved, including chronic anemia, iron overload, and endocrine abnormalities. Apart from hypogonadotrophism, defective IGF-I activity has been suggested as one of the causes of this growth failure, as significant suppression of GH is usually not seen(3,4). In our population, though transfusions were regular, pretransfusion Hb levels were suboptimal and some children were receiving only short time iron chelation therapy. Height SDS were negative, but only four patients (Pts. No. 11,18,19,20) had serious growth retardation. However, the height SDS values of our patients showed no statistically signifi-cant correlation with mean pretransfusion Hb, and serum ferritin levels.

All patients but two had normal GH response to L-dopa stimulation, with peak GH response strongly correlated with height SDS. Most studies reported similar findings(1-4). Pintor et al. investigating an older population, found low GH responses to growth hormone releasing hormone (GHRH) and glucagon and held iron deposition in the hypothalamus and hypophysis responsible for GH insuffi-ciency(2). Martin et al. reported that the GH secretion increased in mice when ventro-medical hypothalamic nuclei were stimulated with electrical current(8). Through MRI scanning of our two GH insufficient patients, iron deposition was documented in basal ganglia. Whether these deposits interact with GHRH secretion remains to be established.

Interestingly, some patients (Pts. No. 3,6,19) had supranormal basal GH levels. This was also reported elsewhere and was related to diminished somatostatin secretion(9,10). In general we found a tendency to low IGF-I levels and this was more striking in older patients. One of our patients (Pt. No. 20) was found to be positive for anti-HCV and chronic hepatitis and siderosis seen in the liver biopsy. Liver dysfunction could be contributing to her growth retardation.

In our study population we did not found glucose intolerance or hypothyroidism (11, 12). We could document a relationship between IGF-I SDS and ferritin despite the limited number of our patients. This suggests that poor clinical control may be responsible for growth retardation. Its pathogenesis seems to be related to diminished IGF-I production, and in long standing cases, to diminished GH secretion. Better clinical control would possibly minimize growth retardation in these children.

Contributors: AO and IA co-ordinated the study (design and interpretation) and drafted the paper. AY and CT participated in the data collection and drafting.

Funding: None.

Competing interests: None stated.

Fig. 1. MRI showing ferritin deposition in the basal ganglia.

Key Messages

  • Growth retardation has been reported to occur in most patients with thalassemia major, and may be due to several endocrine and non-endocrine causes.

  • GH insufficiency is seen in older ages while IGF generation is diminished earlier.

  • GH insufficiency detected in the prepubertal period, may be the result of hypothalamic-pituitary dysfunction.

  • Cranial MRI scanning of our two patients with GH insufficiency, revealed ferritin deposition in the basal ganglia.
References
  1. Masala A, Meloni T, Gallisai D, Alagna S, Ravasio PP, Rassu S, et al. Endocrine function-ing in multitransfused prepubertal patients with homozygous beta-thalassemia. J Clin Endo-crinol Metab 1984; 58: 667-670.

  2. Pintor C, Cella SG, Manso P, Corda R, Dessi C, Locatelli V, et al. Impaired growth hormone response to GH-releasing hormone in thalas-semia major. J Clin Endocrinol Metab 1986; 62: 263-267.

  3. Leger J, Girot R, Crosnier H, Postel-Vinay MC, Rappaport R. Normal growth hormone (GH) response to G releasing Hormone in children with thalassemia major before puberty: A possible age-related effect. J Clin Endocrinol Metab 1989; 69: 453-456.

  4. Theodoridis C, Ladis V, Papatheodorou A, Berdousi H, Palamidou F, Evagelopoulou C, et al. Growth and management of short stature in thalassemia major. J Pediatr Endocrinol Metab 1998; 11: 835-844.

  5. Neyzi O. Buyume ve gelisme bozukluklar. In: Pediatri Eds. Neyzi O, Ertugrul T. Istanbul, Nobel Tp Kitabevi, 1993; p 69.

  6. Greulich WW, Pyle Sl. Radiographic Atlas of Skeletal Development of the Hand and Wrist, 6th edn. New York, Standford University Press, 1970.

  7. Juul A, Bang P, Hertel NT, Main K, Dalgaard P, Jorgensen K, et al. Serum insulin-like growth factor I in 1030 healthy children, adoles- cents, and adults: Relation to age, sex, stage of puberty, testiculer size, and body mass index. J Clin Endocrinol Metab 1994; 78: 744-752.

  8. Martin JB, Renaud LP, Brazeau JR, Pulsatile growth hormone secretion: Suppression by hypothalamic ventromedical lesions and by long-acting somatostatin. Science 1974; 186: 538-540.

  9. Bercu BB, Schulman D, Root AW, Spiliotis BE. Growth hormone provicative testing fre-quently does not reflect endogenous GH secretion. J Clin Endocrinol Metab 1986; 63: 709-711.

  10. Bronspiegel-Weintrob N, Olivieri NF, Tyler B, Andres DF, Freedman MH, Holland FJ. Effect of age at the start of iron chelation therapy on gonadal function in beta-thalassemia major. N Engl J Med 1990; 323: 713-719.

  11. Dedeoglu S, Timur C, Isik K. Iron deposition in the B Cells of the pancreas in thalassemia major. In: Abstract Book XXIV National Hematology Congress, Ed. Tangun Y, Istanbul, 1999, p 159.

  12. Arslanoglu I, Demir H, Isik K. Pituitary-thyroid interaction in Thalassemia major. Clin Impr 1996; 9: 4200-4203.

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