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  • Research
  • Open Access

Effect of zinc supplementation on growth Hormone Insulin growth factor axis in short Egyptian children with zinc deficiency

  • †1Email author,
  • †2 and
  • †3
†Contributed equally
Italian Journal of Pediatrics201238:21

https://doi.org/10.1186/1824-7288-38-21

©  Hamza et al.; licensee BioMed Central Ltd. 2012

  • Received: 28 September 2011
  • Accepted: 24 May 2012
  • Published:

Abstract

Background

The relationship between zinc (Zn) and growth hormone-insulin growth factor (GH-IGF) system and how Zn therapy stimulates growth in children has not been clearly defined in humans. Thus, we aimed to assess GH-IGF axis in short children with Zn deficiency and to investigate the effect of Zn supplementation on these parameters.

Methods

Fifty pre-pubertal Egyptian children with short stature and Zn deficiency were compared to 50 age-, sex-, and pubertal stage- matched controls. All subjects were subjected to history, auxological assessment and measurement of serum Zn, IGF-1, insulin growth factor binding protein-3 (IGFBP-3); and basal and stimulated GH before and 3 months after Zn supplementation (50 mg/day).

Results

After 3 months of Zn supplementation in Zn-deficient patients, there were significant increases in height standard deviation score (SDS, P = 0.033), serum Zn (P < 0.001), IGF-1 (P < 0.01), IGF-1 standard deviation score (SDS,P < 0.01) and IGFBP-3 (P = 0.042). Zn rose in all patients but reached normal ranges in 64 %, IGF-1 levels rose in 60 % but reached normal ranges in 40 % and IGFBP-3 levels rose in 40 % but reached reference ranges in 22 %. Growth velocity (GV) SDS did not differ between cases and controls (p = 0.15) but was higher in GH-deficient patients than non-deficient ones, both having Zn deficiency (p = 0.03).

Conclusion

Serum IGF-1 and IGFBP-3 levels were low in short children with Zn deficiency, and increased after Zn supplementation for 3 months but their levels were still lower than the normal reference ranges in most children; therefore, Zn supplementation may be necessary for longer periods.

Keywords

  • Egyptian
  • Growth hormone
  • Insulin growth factor-1
  • Zinc

Introduction

Although Zn deficiency is a common nutritional problem around the world, especially in children in developing countries where diets have less Zn available, it is difficult to identify this problem. Zn is important for the metabolic activity of more than two hundred enzymes. It is essential for cell replication, and deoxyribonucleic acid (DNA) and protein synthesis. Zn deficiency is reported to be associated with impairment of growth, testicular functions, appetite, and sense of taste, delay in wound healing, immune resistance and memory. Zn deficiency interferes with the metabolism of thyroid hormones, androgens and growth hormone (GH). It is not known what mechanism is responsible for growth retardation in Zn deficiency and how Zn therapy stimulates growth in children [1].

The principal regulator of growth in the body is the GH-IGF system [2]. It appears that Zn supplementation has positive effects on growth and IGF-1 levels in various groups of Zn-deficient children. However, the exact mechanism of Zn deficiency and the mechanism by which Zn supplementation affects GH secretion and IGF-1 levels is not well delineated. Furthermore, the effect of Zn supplementation on the GH-IGF axis in non Zn-deficient short children is not known [3]. Some studies have reported positive effects of Zn supplementation on growth in various groups of Zn-deficient children [3–5]. However, in some studies, this effect was not observed [6, 7].

With this background, we were stimulated to assess GH-IGF axis in short children with Zn deficiency and to investigate the effect of Zn supplementation on these parameters.

Subjects and methods

Study population

This prospective case control study was conducted on 50 pre-pubertal Egyptian children with short stature and Zn deficiency [27 males (54 %), 23 females (46 %)] whose ages ranged between 3.2 and 10.9 years (mean age: 6.5 ± 3.05 years). All patients were shorter than expected for their chronological age and sex (height SDS < −2) [8]. Patients were recruited from Nile Hospital, Egyptian Health Insurance (n = 32) and the Pediatrics Outpatient Clinic, Children's hospital, Faculty of Medicine, Ain Shams University, Cairo, Egypt (n = 18) during the period from the beginning of April 2010 to the end of August 2011. Cases were compared to 50 healthy age-, sex- and pubertal stage- matched children serving as controls who had normal serum Zn levels. They were 28 males (56 %) and 22 females (44 %) whose ages ranged between 3.5 and 10.8 years (mean age: 6.7 ± 2.05 years). They were recruited from the Pediatrics Outpatient clinic, Children`s hospital, Faculty of Medicine, Ain shams University, Cairo, Egypt.

Children with chronic systemic diseases, bone dysplasias, dysmorphic syndromes, chronic malabsorption, other nutritional deficiencies, short stature with normal serum Zn levels (>109 μg/dl), other endocrine problems e.g hypothyroidism and history of long-term medications that might influence the GH-IGF axis were excluded from the study. In addition, all patients were not on GH therapy during the time of the study.

An informed written consent of participation in the study was signed by the parents or legal guardians of the studied subjects. This study was approved by the Bioethical Research Committee, Faculty of Medicine, Ain Shams University hospitals, Cairo, Egypt.

Study measurements

All studied children were subjected to:

  • Medical history and clinical assessment: laying stress on therapeutic history, systemic examination and dysmorphic features.

  • Auxological parameters: Height was measured to the nearest 1.0 mm with a Harpenden wall mounted stadiometer and weight to the nearest 0.1 kg on electronic scales together with calculation of height for age, weight for height and height velocity Standard Deviation Scores (SDSs) [8]. Body Mass Index (BMI) was calculated using the formula weight (in kg)/height2 (in meters) together with calculation of BMI SDS calculated from the age- and sex-specific reference values [9].

  • Tanner pubertal staging: for assessment of pubertal status according to the standards of Tanner and Whitehouse (1976) [10]

  • Laboratory assays: All blood samples were taken in the morning after an overnight fast for measurement of the following:

    • Serum Zn which was measured by a spectrophotometric method after deproteinization of samples. The normal reference range ranged from109-167 ng/dl while serum Zn values below 109 μg/dl indicated Zn deficiency [11].

    • Serum IGF-1 and IGFBP-3 that were measured using a solid phase, enzyme labeled chemiluminescent immunometric assay. Values were expressed as absolute values (ng/ml) and were also expressed as SDS for age and sex according to normal reference ranges of Elmlinger et al., 2004 [12]

    • Basal and stimulated serum GH levels after insulin induced hypoglycemia, in which baseline GH and glucose samples were withdrawn and regular insulin was administered in a dose of 0.1 unit/kg intravenously and samples for measurement of GH and glucose were withdrawn at 30, 60, 90 and 120 minutes. Blood glucose must decrease by 50 % of the initial value or to <40 mg%. In addition, GH provocation test by clonidine was done to confirm the diagnosis of growth hormone deficiency (GHD) in which a baseline GH sample was withdrawn and clonidine was administered in a dose of 5 μg/kg orally and samples for measurement of GH were withdrawn at 30, 60, 90 and 120 minutes. Normally, GH should rise to a peak of ≥10 ng/ml at any of the post-stimulatory samples. Patients with peak GH levels <10 ng/ml by the 2 stimulatory tests were considered GH-deficient [13]. Serum GH concentrations were measured using commercial reagents (Pharmacia Diagnostics, Uppsala, Sweden) by a solid-phase, enzyme-labeled chemiluminiscent immunometric assay (by the Immulite, 2000 Analyzer, Siemens).

  • Bone age (BA) was done by performing plain X ray left hand and wrist together with calculation of bone age SDS according to the standards of Greulich and Pyle [14].

  • Oral Zn sulfate (50 mg/day elemental Zn) was given to all subjects for 3 months after which auxological assessment was repeated and serum samples were withdrawn to repeat all laboratory assays. In addition, growth velocity (GV) after 3 months of Zn therapy was calculated. GV is the variable that describes the patient's one year or 6 months or 3 months height velocity. GV SDS was calculated according to the norms of Tanner etal, 1966 [8].

Statistical analysis

The results were analyzed using the Statistical Package for the Social Science (SPSS) version number 10, Echosoft corp; USA, 2005. Description of quantitative variables was in the form of mean ± standard deviation and range while that of qualitative variables was in the form of frequency and percentage. Student’s t-test of 2 independent samples was used to compare 2 quantitative variables while Wilcoxon Signed Rank test was used to compare 2 dependent groups before and after Zn supplementation. Spearman correlation coefficient test (r-test) was used to rank different variables against each other either directly or indirectly. A p-value of <0.05 was considered significant.

Results

Characteristics of studied cases

Descriptive clinical, laboratory and radiological data of studied cases are presented in Table 1. Of the 50 studied cases, serum IGF-1 levels were below the normal age- matched reference ranges in 47(94 %) while serum IGFBP-3 concentrations were below the normal age- matched reference ranges in all children (100 %). In addition, GHD was diagnosed in 25 cases (50 %), that is, a peak GH of < 10 ng/ml by 2 GH provocation tests. The mean GV of all studied cases after 3 months of Zn supplementation was 0.55 ± 0.1 (range:0.1-2.23) with a GV SDS of +1.01 ± 0.2 (range: -0.5 - +2.11, Table 1).
Table 1

Descriptive clinical, laboratory and radiological data of studied cases (n = 50)

 

Mean ± SD

Range

Age (years)

6.5 ± 3.05

3.20-10.90

Height SDS

-3.12 ± 0.2

-2.15- -4.21

-GV after Zn (cm/3 months)

0.55 ± 0.1

0.1-2.23

-GV SDS after Zn

+1.01 ± 0.2

-0.5 - +2.11

- Weight SDS

-1.88 ± 0.62

-2.01- +0.55

- BMI SDS

-1.77 ± 0.41

-2.10- -0.78

- Serum Zn (μg/dl)

56.76 ± 7.90

37.52-93.11

-Peak GH after insulin stimulation (ng/ml)

10.65 ± 2.01

7.61-13.20

-Peak GH after clonidine stimulation (ng/ml)

11.14 ± 1.41

6.92-14.11

- IGF-1 (ng/ml)

96.72 ± 11.5

36.52-115.69

-IGF-1 SDS

-2.46 ± 0.11

-3.22- +0.55

- IGFBP-3 (ng/ml)

2436.12 ± 392

1195.45-3898.15

-BA (years)

3.7 ± 1.05

1.81-9.25

-BA SDS

-1.75 ± 1.14

-2.44 - +0.22

Results are expressed as mean ± SD and range, Zn: zinc, SDS: Standard deviation score, GV: Growth velocity, BMI: Body mass index, GH: Growth hormone, IGF-1: Insulin like growth factor-1, IGFBP-3: Insulin like growth factor binding protein-3, BA: bone age.

Cases versus controls

Height SDS (p < 0.001), serum Zn (p < 0.001), peak GH after insulin (P = 0.04) and clonidine stimulation (P = 0.041), IGF-1 (P < 0.001), IGF-1 SDS (p < 0.001), IGFBP-3 (P < 0.001), BA (p = 0.02) and BA SDS (p < 0.001) were significantly lower among cases than controls. On the other hand, other clinical parameters and; GV and GV SDS did not differ between both groups (p > 0.05, Table 2).
Table 2

Comparison of clinical, laboratory and radiological data among cases and controls

 

Cases

Controls

t

p

 

(N = 50)

(N = 50)

  

Age (years)

6.5 ± 3.05

6.7 ± 2.05

1.2

0.11

 

(3.2 -10.9)

(3.5-10.8)

  

Sex , n(%)

    

Males

27(54 %)

28 (56 %)

1.11

0.23

Females

23(46 %)

22(44 %)

  

Height SDS

-3.12 ± 0.2

+1.04 ± 0.5

19.88

 <0.001***

(-2.15- -4.21)

(+0.99 - +1.65)

  

GV after Zn (cm/3 months)

0.55 ± 0.1

0.61 ± 0.1

0.82

0.11

(0.1-2.23)

(0.2-3.13)

  

GV SDS

+1.01 ± 0.2

+1.21 ± 0.1

1.3

0.15

(-0.5 - +2.11)

(-0.3 - +2.31)

  

Weight SDS

-1.88 ± 0.62

-1.02 ± 0.71

1.7

0.2

(-2.01 - +0.55)

(-1.20 - +1.45)

  

BMI (kg/m2)

16.41 ± 1.56

17.51 ± 0.52

1.0

0.3

(14.33-20.12)

(14.33-20.12)

  

BMI SDS

-1.77 ± 0.41

-1.02 ± 0.31

1.99

0.082

(-2.10- -0.78)

(-1.30 - +0.23)

  

Serum Zn (μg/dl)

56.76 ± 7.90

136.70 ± 8.10

22.5

<0.001***

(37.52-93.11)

(123.17-149.50)

  

Peak GH after insulin stimulation (ng/ml)

10.65 ± 2.01

14.25 ± 3.01

6.50

0.04*

(7.61-13.20)

(10.91-18.30)

  

Peak GH after clonidine stimulation (ng/ml)

11.14 ± 1.41

15.24 ± 2.11

6.81

0.041*

(6.92-14.11)

(11.12-19.21)

  

IGF-1 (ng/ml)

96.72 ± 11.5

286.62 ± 12.5

12.86 

<0.001***

(36.52-115.69)

(198.72-325.19)

  

IGF-1 SDS

-2.46 ± 0.11

+1.46 ± 0.21

17.66

<0.001***

(-3.22- +0.55)

(+0.89 - +1.85)

  

IGFBP-3 (ng/ml)

2436.12 ± 392

3936.22 ± 194

15.12

<0.001***

(1195.45-3898.15)

(3721.45-4498.15)

  

-BA (years)

3.7 ± 1.05

6.8 ± 1.6

6.11

0.020*

(1.81-9.25)

(3.31-11.25)

  

-BA SDS

-1.75 ± 1.14

+0.85 ± 1.20

13.24

<0.001***

(-2.44 - +0.22)

(+1.04 - +0.22)

  

Results are expressed as mean ± SD and range frequency and percentage, *p < 0.05, **p < 0.01, ***p < 0.001, GHD: growth hormone deficiency, SDS: Standard deviation score, GV: growth velocity, Zn: zinc, BMI: Body mass index, Zn: zinc, GH: Growth hormone, IGF-1: Insulin like growth factor-1, IGFBP-3: Insulin like growth factor binding protein-3, BA: bone age.

Cases with GHD versus cases without GHD

Height SDS (p = 0.043), serum Zn (p < 0.001), peak GH after insulin (P = 0.021) and clonidine stimulation (P = 0.01), IGF-1 (P < 0.001), IGF-1 SDS (p < 0.001), IGFBP-3 (P = 0.01), BA (p = 0.03) and BA SDS (p = 0.01) were significantly lower among cases with GHD when compared to those without GHD. On the other hand, cases with GHD had significantly higher GV (p = 0.041) and GV SDS (p = 0.03) when compared to those without GHD (Table 3).
Table 3

Comparison of clinical, laboratory and radiological data of studied cases with and without GHD

 

With GHD

Without GHD

t

p

 

(N = 25)

(N = 25)

  

Height SDS

−3.52 ± 0.3

−2.56 ± 0.1

6.11

0.043*

(−2.85- -4.21)

(−2.15- -2.91)

  

GV (cm/3 months)

1.21 ± 0.2

0.85 ± 0.1

5.99

0.041*

(0.7-2.23)

(0.1-1.83)

  

GV SDS

+1.56 ± 0.5

+0.91 ± 0.2

7.12

0.030*

(+0.72 - +2.11)

(-0.5 - +1.86)

  

Weight SDS

-1.68 ± 0.12

-1.58 ± 0.52

1.9

0.5

(-1.99 - +0.55)

(-2.01- +0.25)

  

BMI (kg/m2)

16.91 ± 0.25

17.31 ± 0.46

1.8

0.3

(15.56-18.12)

(14.53-17.92)

  

BMI SDS

-1.81 ± 0.10

-1.72 ± 0.32

2.1

0.5

(-1.9- -0.78)

(-2.10- -0.82)

  

Serum Zn (μg/dl)

45.71 ± 2.9

76.16 ± 5.9

18.12

<0.001***

(37.52-61.55)

(39.12 - 93.11)

  

Peak GH after insulin stimulation(ng/ml)

7.81 ± 0.1

11.61 ± 1.01

9.11

0.021*

(7.61-8.91)

(10.55-13.20)

  

Peak GH after clonidine stimulation (ng/ml)

7.14 ± 0.12

12.54 ± 1.21

10.16

0.01*

(6.92-8.53)

(10.88-14.11)

  

IGF-1 (ng/ml)

46.78 ± 6.5

100.12 ± 12.5

16.22

<0.001***

(36.52-59.11)

(72.55-115.69)

  

IGF-1 SDS

-2.72 ± 0.10

+0.38 ± 0.21

19.01

<0.001***

(-3.22- -2.11)

(-1.20- +0.55)

  

IGFBP-3 (ng/ml)

2006.22 ± 92

3445.11 ± 292

9.88

0.01*

(1195.45 - 2111.26)

(3124.45 - 3898.15)

  

-BA (years)

2.8 ± 1.0

5.7 ± 1.26

8.15

0.03*

(1.81-5.9)

(4.-9.25)

  

-BA SDS

-1.7 ± 0.12

-0.7 ± 0.14

11.22

0.01*

(-2.44 - +0.01)

(-1.14 - +0.22)

  

Results are expressed as mean ± SD and range, *p < 0.05, **p < 0.01, ***p < 0.001, GHD: growth hormone deficiency, SDS: Standard deviation score, GV: growth velocity, BMI: Body mass index, Zn: zinc, GH: Growth hormone, IGF-1: Insulin like growth factor-1, IGFBP-3: Insulin like growth factor binding protein-3, BA: bone age.

Characteristics of cases before and 3 months after Zn supplementation

On comparing clinical, laboratory and radiological parameters among all studied patients before and 3 months after Zn supplementation, there were significant increases in height SDS (P = 0.033), serum Zn (P < 0.001), IGF-1 (P < 0.01), IGF-1 SDS (p < 0.01) and IGFBP-3 (P = 0.042) while other clinical and laboratory parameters did not differ 3 months after Zn supplementation (P > 0.05, Table 4).
Table 4

Comparison of clinical, laboratory and radiological data of studied cases (n = 50) before and 3 months after Zn supplementation

 

Before Zn

After Zn

z

p

Height SDS

−3.12 ± 0.2

−1.87 ± 0.1

6.76

0.033*

(−2.15- -4.21)

(−2.0- -3.11)

  

Weight SDS

-1.88 ± 0.62

-1.72 ± 0.51

1.83

0.21

(-2.01- +0.55)

(-2.05- + 0.66)

  

BMI (kg/m2)

16.41 ± 0.56

16.58 ± 0.22

1.59

0.11

(14.33-18.12)

(14.91-18.42)

  

BMI SDS

-1.77 ± 0.41

-1.58 ± 0.32

1.80

0.26

(-2.10- -0.78)

(-0.91- -1.95)

  

Serum Zn (μg/dl)

56.76 ± 7.9

148.25 ± 15.4

8.29

 <0.001***

(37.52-93.11)

(77.55-226.13)

  

Peak GH after insulin stimulation (ng/ml)

10.65 ± 2.01

12.10 ± 1.13

2.10

0.081

(7.61-13.20)

(8.90-14.82)

  

Peak GH after clonidine stimulation (ng/ml)

11.14 ± 1.41

12.99 ± 1.22

1.15

0.090

(6.92-14.11)

(8.90-14.82)

  

IGF-1 (ng/ml)

96.72 ± 11.5

177.50 ± 9.06

7.12

<0.010**

(36.52-115.69)

(42.65-213.66)

  

IGF-1 SDS

-2.46 ± 0.11

-0.91 ± 0.43

9.16

<0.010**

(-3.22- +0.55)

(-2.95 - +1.10)

  

IGFBP-3 (ng/ml)

2436.12 ± 392

2856.30 ± 411

5.90

0.042*

(1195.45-3898.15)

(1341.10-3912.51)

  

-BA (years)

3.7 ± 1.05

4.12 ± 1.32

1.25

0.081

(1.81-9.25)

(2.13-9.81)

  

-BA SDS

-1.7 ± 1.14

-1.5 ± 1.21

0.13

0.35

(-2.44 - +0.22)

(-2.10- + 0.65)

  

Results are expressed as mean ± SD and range, *p < 0.05, **p < 0.01, ***p < 0.001, Zn: zinc, SDS: Standard deviation score, BMI: Body mass index, GH: Growth hormone, IGF-1: Insulin like growth factor-1, IGFBP-3: Insulin like growth factor binding protein-3, BA: bone age.

Serum Zn levels rose in all patients but reached normal reference ranges in 32 cases (64 %), serum IGF-1 levels rose in 30 cases (60 %) but reached normal reference ranges in 20 cases (40 %) and serum IGFBP-3 levels rose in 20 cases (40 %) but reached normal reference ranges in 11 cases (22 %). There were no adverse effects other than mild nausea in some patients during the Zn supplementation period.

Relation between serum Zn and each of laboratory and radiological parameters among studied cases

There were significant positive correlations between serum Zn level and each of serum IGF-1 (r = 0.938, p < 0.0001, Figure 1A), IGF-1 SDS (r = 0.81, p < 0.001) and IGFBP-3 levels (p = 0.910, p < 0.0001, Figure 1B) before Zn supplementation. On the other hand, serum Zn did not correlate significantly with peak stimulated GH after insulin induced hypoglycemia (r = 0.17, p = 0.31) and clonidine stimulation (r = 0.13, p = 0.23), BA (r = 0.15, p = 0.13) and BA SDS (r = 0.11, p = 0.22).
Figure 1
Figure 1

Correlations between serum zinc and each of serum IGF-1 (Figure 1A) and serum IGFBP-3 (Figure 1B).

Discussion

Zn deficiency in humans is widespread throughout the world especially in developing countries. In Egypt, growth retardation and short stature due to Zn deficiency are commonly observed. This could be explained by the fact that intakes of animal products and animal protein are very low due to low socio-economic status of the population. In addition, Zn intake is not only low, but its bioavailability is poor because of the high phytate, fiber and tea content of the diet among Egyptian population [15]. Zn deficiency during the period of growth results in growth failure and lack of gonadal development, especially in males. Other effects of Zn deficiency include skin changes, poor appetite, mental lethargy, delayed wound healing, neurosensory disorders and cell-mediated immune disorders [1].

Cesur et al, 2009 [16] found that serum IGF-1 and IGFBP-3 were below normal reference ranges in 96.6 % and 100 % of their short children with Zn deficiency which is close to our findings (94 % and 100 % respectively). It is not known what mechanism is responsible for growth retardation in Zn deficiency and how Zn therapy stimulates growth in children [1]. Moreover, the exact mechanism of the effects of Zn deficiency and Zn supplementation on GH secretion, serum IGF-1 levels, and growth is not well delineated [3].

The current study revealed significant increases in height SDS, GV and its SDS; serum Zn, IGF-1 and IGFBP-3 after 3 months of Zn therapy with no difference in GV between Zn deficient cases and non Zn-deficient controls. Our findings were supported by other studies [3–5, 17, 18] who reported that Zn supplementation was effective for inducing growth in short children with Zn deficiency in a rate similar to that in healthy children. However, in some studies, this effect was not observed [6, 7]. Ninh et al [19] showed that Zn supplementation increased both weight and height after five months compared with placebo treatment but this was not the case in our study concerning the weight. According to these findings, some studies [19–21] suggested that the growth- stimulating effect of Zn might be mediated through changes in circulating IGF-1 levels.

On the other hand, an experimental study in rats [22] showed that restoration of normal circulating levels of IGF-1 and IGFBP-3 by recombinant IGF-1 infusion failed to reverse the growth retardation induced by Zn deficiency. They suggested that growth retardation related to Zn deficiency is caused not only by low serum IGF-1 concentrations, but also by inhibition of the anabolic actions of IGF-1. Moreover, it has been shown that Zn deficiency also leads to alterations in the distribution of serum IGFBPs, in addition to lower circulating IGF-1 concentrations [21]. This theory was further supported by the strong positive correlations between serum Zn and each of IGF-1, IGF-1 SDS and IGFBP-3 levels reported in our study. In addition, other studies [20, 21] suggested a state of GH resistance rather than GHD in case of Zn deficiency.

In addition, Imamoglu et al [23] reported that Zn supplementation increased IGF-1 and IGFBP-3 in non-Zn-deficient children with idiopathic short stature. They suggested several explanations for this observation. First, Zn supplementation may have increased the sensitivity to endogenous GH. Secondly, Zn supplementation may have increased the physiological GH secretion (i.e. sleep associated) without altering GH response to pharmacological stimulation. Alternatively, Zn may have non-GH mediated (direct) effects on the synthesis of IGF-1 and IGFBP-3. Support for the first hypothesis comes from animal studies in which ionic Zn exerted a dose dependent stimulation of hGH specific binding to isolated rat adipocytes [24]. Furthermore, Zn ion was found to induce dimerization of human GH [25] and to enhance the bioactivity of hGH [26]. In vivo studies demonstrated that Zn deficiency markedly decreased expression of IGF-1 and GH receptor genes in the liver of growing rats [27]. Support for the third hypothesis comes from the observation that Zn deficiency causes a post-receptor defect in GH action, and a decrease in IGF-1 gene expression which is reversed by Zn supplementation but not by GH administration [28]. This hypothesis was further supported in our study by the finding of higher GV after 3 months of Zn supplementation in GH-deficient than non GH-deficient, both having Zn deficiency.

On the other hand, some reports found increased GH response to pharmacological stimulation after Zn supplementation in Zn-deficient children [5, 21, 29, 30] which was not the case in our study. Siklar et al [30] suggested that during GH treatment in GH deficient children, Zn status should be evaluated, as severe Zn deficiency could decrease the response to GH treatment which is improved with correction of Zn deficiency [30].

In the current study, after 3 months of Zn supplementation, serum Zn levels rose in all patients but reached normal reference ranges in 32 cases (64 %), serum IGF-1 levels rose in 30 cases (60 %) but reached normal reference ranges in 20 cases (40 %) and serum IGFBP-3 levels rose in 20 cases (40 %) but reached normal reference ranges in 11 cases (22 %). Similar results were obtained by Cesur et al, 2009 [16] who confirmed the fact that Zn supplementation affects serum IGF-1 and IGFBP-3 levels in children with Zn deficiency but due to the fact that Zn supplementation was given for only two months, the increases in serum IGF-1 and IGFBP-3 levels were still lower than the normal range in most of their children; therefore, they suggested that Zn supplementation may be necessary for longer periods.

Conclusions

In conclusion, serum IGF-1 and IGFBP-3 levels were found to be low in short children with Zn deficiency, and increased after Zn supplementation for 3 months but their levels were still lower than the normal reference ranges in most children; therefore, Zn supplementation may be necessary for longer periods. In addition, GV did not differ between Zn-deficient and healthy children with a better GV observed in GH-deficient children. Further studies on larger population scales and for longer periods are warranted to explore the mechanism by which Zn deficiency affects GH- IGF axis and to assess the effect of Zn supplementation on it.

Authors' information

- RTH: Assistant Professor of Pediatrics and Pediatric Endocrinology, Ain Shams University, Cairo, Egypt.

- AIH: Lecturer of Clinical Pathology, Ain Shams University, Cairo, Egypt.

-MTS: Lecturer of Clinical and Chemical Pathology, National Research Center, Cairo, Egypt.

Notes

Declarations

Authors’ Affiliations

(1)
Department of Pediatrics, Ain Shams University, 36 Hisham Labib street, off Makram Ebeid street, Nasr City, Cairo, Egypt
(2)
Department of Clinical Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
(3)
Department of Clinical and Chemical Pathology, National Research Center, Cairo, Egypt

References

  1. Prasad AS: Zinc: an overview. Nutrition. 1995, 11: 93-99.PubMedGoogle Scholar
  2. Underwood LE, Thissen JP, Lemozy S, Ketelslegers JM, Clemmons DR: Hormonal and nutritional regulation of IGF-I and its binding proteins. Horm Res. 1994, 42: 145-151. 10.1159/000184187.View ArticlePubMedGoogle Scholar
  3. Nakamura T, Nishijama S, Futagoishi Y, Matsuda I, Higashi A: Mild to moderate zinc deficiency in short children: effect of zinc supplementation on linear growth velocity. J Pediatr. 1993, 123: 65-69. 10.1016/S0022-3476(05)81538-0.View ArticlePubMedGoogle Scholar
  4. Walravens PA, Hambidge KM, Koepfer DM: Zinc supplementation in infants with a nutritional pattern of failure to thrive: a double-blind, controlled study. Pediatrics. 1989, 83: 532-538.PubMedGoogle Scholar
  5. Nishi Y, Hatano S, Aihara K, Fujie A, Kihara M: Transient partial GH deficiency due to zinc deficiency. Am Coll Nutr. 1989, 8: 93-97.View ArticleGoogle Scholar
  6. Friis H, Ndhlovu P, Mduluza T, Kaondera K, Sandstrom β, Michaelsen KF, Vennervald BJ, Christensen NO: The impact of zinc supplementation on growth and body composition: a randomised, controlled trial among rural Zimbabwean school children. Eur J Clin Nutr. 1997, 51: 38-45. 10.1038/sj.ejcn.1600358.View ArticlePubMedGoogle Scholar
  7. Hershkowitz E, Printzman L, Segev Y, Levy J, Philip M: Zinc supplementation increases the level of serum IGF-I but does not promote growth in infants with nonorganic failure to thrive. Horm Res. 1999, 52: 200-204. 10.1159/000023461.View ArticleGoogle Scholar
  8. Tanner JM, Whitehouse RH, Takaishi M: Standards from birth to maturity for height, weight, height velocity, and weight velocity: British children, 1965. Arch Dis Child. 1966, 41: 454-613. 10.1136/adc.41.219.454.PubMed CentralView ArticlePubMedGoogle Scholar
  9. Cole TJ: A chart to link child centiles of body mass index, weight and height. Eur J Clin Nutr. 2002, 56: 1194-1199. 10.1038/sj.ejcn.1601473.View ArticlePubMedGoogle Scholar
  10. Tanner JM, Whitehouse RH: Clinical longitudinal standards for height, weight, height velocity, weight velocity and stages of puberty. Arch Dis Child. 1976, 51: 170-179. 10.1136/adc.51.3.170.PubMed CentralView ArticlePubMedGoogle Scholar
  11. Lampugnani L, Maccheroni M, Rotunno T: A simple colorimetric method for the zinc assay in blood. Anal Lett. 1990, 23: 1665-1683. 10.1080/00032719008052517.View ArticleGoogle Scholar
  12. Elmlinger MW, Kühnel W, Weber MM, Ranke MB: Reference ranges for two automated chemiluminescent assays for serum insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3). Clin Chem Lab Med. 2004, 42: 654-664.View ArticlePubMedGoogle Scholar
  13. Greenwood FC, Landon J, Stamp TCB: The plasma sugar, free fatty acid, cortisol, and growth hormone response to insulin in control subjects. J Clin Invest. 1966, 45: 429-436. 10.1172/JCI105357.PubMed CentralView ArticlePubMedGoogle Scholar
  14. Greulich WW, Pyle SI: Radiographic atlas of skeletal development of the hand and wrist. 1959, Stanford University Press, Stanford, CaliforniaGoogle Scholar
  15. Neumannn CG, Harrison GG: Onset and evolution of stunting in infants and children. Examples from the Human Nutrition Collaborative Research Support Program. Kenya and Egypt studies. Eur J Clin Nutr. 1994, suppl 1: s90-s102.Google Scholar
  16. Cesur Y, Yordam N, Dogan M: Serum Insulin-like Growth Factor-I and Insulin-like Growth Factor Binding Protein-3 Levels in Children with Zinc Deficiency and the Effect of Zinc Supplementation on these Parameters. J Pediatr Endocrinol Metab. 2009, 22: 1137-1143.View ArticlePubMedGoogle Scholar
  17. Sayeg Porto MA, Oliveira HP, Cunha AJ, Miranda G, Guimaraes MM, Oliveira WA, Dos Santos DM: Linear growth and zinc supplementation in children with short stature. J Pediatr Endocrinol Metab. 2000, 13: 1121-1128.View ArticlePubMedGoogle Scholar
  18. Ghavami-Maibodi SZ, Collipp PJ, Castro-Magana M, Stewart C, Chen SY: Effect of oral zinc supplements on growth, hormonal levels, and zinc in healthy short children. Ann Nutr Metab. 1983, 27: 214-219. 10.1159/000176660.View ArticlePubMedGoogle Scholar
  19. Ninh NX, Thissen JP, Collette L, Gerard G, Khoi HH, Ketelslegers JM: Zinc supplementation increases growth and circulating insulin-like growth factor I (IGF-I) in growth-retarded Vietnamese children. Am J Clin Nutr. 1996, 63: 514-519.PubMedGoogle Scholar
  20. Oner G, Bhaumick B, Bala RM: Effect of zinc deficiency on serum somatomedin levels and skeletal growth in young rats. Endocrinology. 1984, 114: 1860-1863. 10.1210/endo-114-5-1860.View ArticlePubMedGoogle Scholar
  21. Clegg MS, Keen CL, Donovan SM: Zinc deficiency induced anorexia influences the distribution of serum insulin-like growth factor-binding proteins in the rat. Metabolism. 1995, 44: 1495-1501. 10.1016/0026-0495(95)90152-3.View ArticlePubMedGoogle Scholar
  22. Ninh NX, Mailer D, Verniers J, Lause P, Ketelslegers JM, Thissen JP: Failure of exogenous IGF-I to restore normal growth in rats submitted to dietary zinc deprivation. J Endocrinol. 1998, 159: 211-217. 10.1677/joe.0.1590211.View ArticlePubMedGoogle Scholar
  23. Imamoglu S, Bereket A, Turan S, Taga Y, Haklar G: Effect of zinc supplementation on growth hormone secretion, IGF-I, IGFBP-3, somatomedin generation, alkaline phosphatase, osteocalcin and growth in prepubertal children with idiopathic short stature. J Pediatr Endocrinol Metab. 2005, 18: 69-74.View ArticlePubMedGoogle Scholar
  24. Herington AC: Effect of zinc on the binding and action of GH in isolated rat adipocytes. Biochem Int. 1985, 11: 853-862.PubMedGoogle Scholar
  25. Cunningham BC, Mulkerrin MG, Wells JA: Dimerization of human growth hormone by zinc. Science. 1991, 253: 545-548. 10.1126/science.1907025.View ArticlePubMedGoogle Scholar
  26. Dattani MT, Hindmarsh PC, Brook CG, Robinson IC, Weir T, Marshall NJ: Enhancement of GH bioactivity by zinc in the eluted stain assay system. Endocrinology. 1993, 133: 2803-2808. 10.1210/en.133.6.2803.PubMedGoogle Scholar
  27. McNall AD: The impaired growth induced by zinc deficiency in rats is associated with decreased expression of the hepatic IGF-I and GH receptor genes. J Nutr. 1995, 125: 874-879.PubMedGoogle Scholar
  28. Ninh NX, Thissen JP, Maiter D, Adam E, Mulumba K, Ketelslegers JM: Reduced liver IGF-I gene expression in young zinc deprived rats is associated with a decrease in liver GH receptors and serum GHBP. J Endocrinol. 1995, 144: 449-456. 10.1677/joe.0.1440449.View ArticlePubMedGoogle Scholar
  29. Collip PJ, Castro Magana PJ, Petroviz μ, Thomas J, Cheruvanky T, Chen SY, Sussman H: Zinc deficiency: improvement in growth and growth hormone levels with oral zinc therapy. Ann Nutr Metab. 1982, 26: 287-290. 10.1159/000176575.View ArticleGoogle Scholar
  30. Siklar Z, Tuna C, Dallar Y, Tanyer G: Zinc deficiency: a contributing factor of short stature in growth hormone deficient children. J Trop Pediatr. 2003, 49: 187-188. 10.1093/tropej/49.3.187.View ArticlePubMedGoogle Scholar

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© Hamza et al.; licensee BioMed Central Ltd. 2012

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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