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 Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 39  |  Issue : 4  |  Page : 238-245

Evaluation of growth hormone and insulin-like growth factor-1 in children during and after therapy for acute lymphoblastic leukemia


1 Department of Medical Biochemistry, Faculty of Medicine, Al-Mustansiriya University, Baghdad, Iraq
2 Department of Medical Biochemistry, Faculty of Medicine, Menoufia University, Menoufia, Egypt
3 Department of Oncology, Child's Central Teaching Hospital, Baghdad, Iraq

Date of Submission25-Mar-2015
Date of Acceptance25-Mar-2015
Date of Web Publication25-Mar-2015

Correspondence Address:
Ibrahim Elmadbouh
Private Clinic, 8 El Amin St., Sharaf Square, Shebin El-Kom, Menoufia 32111-18
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-1067.153967

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  Abstract 

Background Higher levels of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) stimulate the growth of myeloid and lymphoid cells and may contribute to leukemogenesis.
Aim The aim of this study was to evaluate serum GH and IGF-1 levels in children with acute lymphoblastic leukemia (ALL) during active disease and after achieving clinical remission.
Patients and methods Forty children with newly diagnosed ALL on the basis of history, physical examination, and blood and bone marrow analysis were included in the study. Patients were treated with vincristine, prednisolone, intrathecal methotrexate, l-asparaginase, and adriamycin and followed up for 6 weeks, in order to achieve clinical remission. Twenty healthy children of the same age group were used as the control group. Serum GH and IGF-1 levels of both controls and patients before and after therapy were measured.
Results After the diagnosis of ALL and before therapy, GH was found to be nonsignificantly higher compared with healthy controls (8.80 ± 6.80 vs. 5.76 ± 2.77 ng/ml, P = 0.061), but IGF-1 was significantly higher in patients than in controls (233.50 ± 100.1 vs. 179.70 ± 77.94 ng/ml, P = 0.040). After achieving remission with 6 weeks of therapy, GH was found to be highly significantly decreased (2.04 ± 1.31 ng/ml) in patients compared with the level before treatment and compared with the control group (P = 0.0001). Also, IGF-1 was reduced significantly (192.93 ± 81.15 ng/ml) compared with the level before treatment (P = 0.0001) but was nonsignificantly higher compared with the level of the control group (P = 0.569). There was significant correlation between GH and IGF-1 levels in ALL patients before therapy and after achieving remission (P < 0.05).
Conclusion The higher levels of GH and IGF-1 during active ALL and their reduction after treatment may be helpful in assessing the disease activity and predicting the response to chemotherapy.

Keywords: Acute lymphoblastic leukemia, growth hormone, insulin-like growth factor-1


How to cite this article:
Al-Azzawi MA, Elmadbouh I, Al-Azzawi TN, Humood TA, Ghanayem NM. Evaluation of growth hormone and insulin-like growth factor-1 in children during and after therapy for acute lymphoblastic leukemia. Egypt J Haematol 2014;39:238-45

How to cite this URL:
Al-Azzawi MA, Elmadbouh I, Al-Azzawi TN, Humood TA, Ghanayem NM. Evaluation of growth hormone and insulin-like growth factor-1 in children during and after therapy for acute lymphoblastic leukemia. Egypt J Haematol [serial online] 2014 [cited 2019 Dec 14];39:238-45. Available from: http://www.ehj.eg.net/text.asp?2014/39/4/238/153967


  Introduction Top


Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. It accounts for one-fourth of all childhood cancers and ~75% of childhood leukemia cases every year. ALL has a striking peak incidence at 5-7 years of age and occurs more frequently in boys than in girls at less than 15 years of age [1].

The majority of childhood ALL cases have tumor cells that appear to be of thymic origin, and patients may have mediastinal masses. Patients usually present with recent onset of signs of marrow failure (pallor, fatigue, bleeding, fever, infection). Hepatosplenomegaly and adenopathy are common. Male patients may have testicular enlargement reflecting leukemic involvement. Meningeal involvement may be present at diagnosis or may develop later. Elevated lactic dehdrogenas (LDH), hyponatremia, and hypokalemia may be present, in addition to anemia, thrombocytopenia, and high peripheral blood blast counts [1],[2].

The etiology of ALL is unknown, although several genetic and environmental factors are associated with childhood leukemia. Exposure to medical diagnostic radiation both in utero and in childhood has been associated with an increased incidence of ALL in the USA. In certain developing countries, there has been an association between B-cell ALL and Epstein - Barr viral infections [3].

Cytogenetic translocation associated with specific molecular genetic abnormalities in ALL, t(12; 21), is the most common translocation and portends a good prognosis, whereas t(4; 11) is the most common in children under 12 months and portends a poor prognosis. Infants with ALL, along with patients who present with specific chromosomal abnormalities, such as t(9; 22) or t(4; 11), have an even higher risk of relapse despite intensive therapy [1,2]. Chromosomal abnormalities, including hypodiploidy, the Philadelphia chromosome, and MLL gene rearrangements, and certain mutations, including deletion of the IKZF1 gene, portend a poorer outcome. More favorable characteristics include a rapid response to therapy, hyperdiploidy, trisomy of specific chromosomes, and rearrangements of the TEL/AML1 genes [3],[4]. Prognosis is adversely affected by high presenting white count, age more than 35 years, and the presence of t(9; 22), t(1; 19), and t(4; 11) translocations. HOX11 expression identifies a more favorable subset of T-cell ALL [1],[2],[5].

Several studies have hypothesized a potential role for growth hormone (GH) and insulin-like growth factor-1 (IGF-1 or somatomedin C) in malignancy. In humans, elevated levels of GH and IGF-1 are associated with an increased risk for breast, gastric, large bowel, lung, and prostatic cancer [6],[7],[8]. The relationship between GH and IGF-1 is complex and not fully understood. The ability of GH, through its mediated peptide IGF-1, to influence the regulation of cell growth has been the focus of much interest in recent years [9]. Available experimental data support the suggestion that GH/IGF-1 status may influence neoplastic tissue growth [9], enhance the proliferation of human leukemic blasts in vitro [10], and accelerate fetal growth [7],[11], which may be a risk factor for childhood ALL.

IGF-1 does not fluctuate greatly throughout the day for an individual and is used by physicians as a screening test for GH deficiency and excess [1],[12],[13]. The IGF system is known to be involved in the regulation of cell proliferation and apoptosis of a variety of normal and malignant cell types [14]. It has been shown that normal lymphocytes and lymphoblast cell lines express and secrete IGFs and insulin-like growth factor binding proteins (IGFBPs) [13],[15]. IGF-1 is produced throughout life and the highest rates of production occur during the pubertal growth sprout, whereas the lowest levels occur during infancy and old age [1],[13],[16]. The debate about the direct or indirect relationship of GH and IGF-1 to the occurrence or recurrence of malignancy, especially in the case of GH therapy in patients with leukemia, is still unresolved [17],[18]. Childhood ALL is the first disseminated cancer shown to be curable and consequently represents the model malignancy for cancer diagnosis, prognosis, and treatment [1],[2].

Therefore, our study aimed to evaluate serum levels of GH and IGF-1 in children with ALL during active disease and after achieving clinical remission.


  Patients and methods Top


Patients were selected from the oncology unit in Al-Mansour Teaching Hospital and Child's Central Teaching Hospital in Iraq. Patients were diagnosed with ALL on the basis of history, physical examination, and blood and bone marrow analysis. Blast cells are seen on blood smears in the majority of cases of childhood ALL (blast cells are precursors to all immune cell lines). A bone marrow biopsy is conclusive confirmation of ALL.

All patients were newly diagnosed and did not receive any treatment affecting our study. All patients were selected after diagnosis by a specialist through history and physical examination. Forty patients were selected: 25 boys with ages ranging from 1.5 to 12 years and 15 girls with ages ranging from 2 to 12 years. Patients were followed up after treatment with vincristine, prednisolone, intrathecal methotrexate, l-asparaginase, and adriamycin for a period of 6 weeks to achieve clinical remission. The goal of the study was to achieve remission, which means that the patients are clinically normal, with acceptable blood picture and bone marrow with fewer than 5% blast cells [1]. Thirty out of the 40 patients had remission episodes within 6 weeks after treatment (three patients died during induction and seven were missed). A comparable group of 20 normal healthy children (10 boys and 10 girls with age range of 3-11 years) were selected as controls.

Height and weight of the patients were measured and evaluated on the basis of the official 2000 Centers for Disease Control (CDC) growth charts, created by the National Center for Health Statistics [9]. Height and weight values below the fifth centile were considered short stature and low weight for age, respectively, and height and weight values above the 95th centile were considered tall stature and high weight for age, respectively.

As ALL is not a solid tumor, the TNM classification as used in solid cancers is of little use. The French-American-British (FAB) classification system refers to a series of classifications of hematologic diseases [19]. L1 lymphoblasts are usually smaller, with scant cytoplasm and inconspicuous nucleoli. Cells of the L2 variety are larger, considerably heterogenous in size, and have prominent nucleoli and more abundant cytoplasm. Lymphoblasts of the L3 type, notable for their deep cytoplasmic basophilia, are large, frequently display prominent cytoplasmic vacuolation, and are morphologically identical to Burkitt's lymphoma cells.

The venous blood samples were obtained under two occasions from patients with ALL and from controls in the following order: before starting treatment (initial) and after achieving first remission. The venous blood sample was taken in a plain tube using plastic disposable syringes, left to clot, and was centrifuged; the serum obtained was stored at −20°C as aliquots until measurement of serum human GH and IGF-1 concentration. The human GH was measured with ELISA assay using the quantitative test kit supplied by BioCheck, Inc. (Foster City, CA, USA). IGF-1 was measured by ELISA assay using kit supplied by DRG International Inc. (Springfield, New Jersey, USA).

Statistical analysis

Variables are presented as numbers, percentage, or mean ± SD as indicated. Student's t-test, the c2 -test, or Fisher's exact test and one-way ANOVA and the unpaired t-test were used to compare means values between the treatment groups and controls, as indicated. The Bonferroni procedure was applied to the raw two-sided P value. Adjusted P values less than 0.05 were considered statistically significant. Results were analyzed using statistical software package SPSS (version 11; SPSS Inc., Chicago, Illinois, USA) for Windows.


  Results Top


The prevalence of ALL was higher in children between 5 and 10 years. The number of male patients (62.5%) was higher than the number of female patients (37.55%). There was no significant correlation between ALL patients and the control group regarding age and sex (P = 0.737 and 0.355, respectively). After treatment, the hemoglobin level improved significantly versus before or during active disease stage (10.71 ± 1.35 vs. 7.40 ± 1.57 g/dl, P = 0.0001). This finding mostly related to repeated blood transfusions and improved bone marrow cellularity during induction of remission in ALL patients [Table 1].

GH level increased nonsignificantly in ALL patients before chemotherapy compared with the control group (P > 0.05). After treatment and remission, GH decreased significantly from that before remission (P = 0.0001). The level of GH after treatment also decreased significantly compared with that of the control group (P = 0.0001). IGF-1 was significantly higher in ALL patients at baseline compared with the control group (P = 0.040). IGF-1 was highly significantly decreased in ALL patients after treatment versus baseline before treatment (P = 0.0001) [Table 2].
Table 2: Growth hormone and insulin-like growth factor-1 were measured in controls and patients with acute lymphoblastic leukemia before and after treatment

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GH was highly significantly correlated with different IGF-1 levels both before and after patients' treatment (P = 0.0001). GH levels (low, normal, and high) before treatment had a significant relationship with IGF-1 after treatment (P = 0.0001), which became nonsignificant after treatment (P > 0.05). IGF-1 was also highly significantly correlated with different GH levels before patients' treatment (P = 0.0001), and this relation became nonsignificant after treatment (P>0.05). Patients who died during chemotherapy induction had higher GH and IGF-1 levels compared with those who survived [Table 3] and [Table 4].
Table 3: Relation of the growth hormone level to different insulin-like growth factor levels was evaluated before and after treatment in acute lymphoblastic leukemia patients

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Table 4: Relation of the insulin-like growth factor level to different growth hormone levels was evaluated before and after treatment in acute lymphoblastic leukemia patients

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There was a significant correlation between GH and IGF-1 levels and the presence of fever before therapy and after achieving remission in ALL patients; however, there was no significant correlation with other clinical signs and symptoms (bruising, joint pain, weakness/pallor). There was a significantly higher level of both GH and IGF-1 before treatment in ALL patients who had leukocytosis and numerous blast cells in blood and a hypercellular bone marrow with many blast cells compared with those with pancytopenia and hypocellular bone marrow with few blast cells [Table 5].
Table 5: Relation of serum growth hormone and insulin-like growth factor was evaluated with clinical and laboratory assay in patients with acute lymphoblastic leukemia

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  Discussion Top


GH is a peptide hormone that stimulates growth and cell reproduction in humans and other animals. It is a 191-amino acid, single-chain polypeptide hormone that is synthesized, stored, and secreted by somatotropic cells within the lateral wings of the anterior pituitary gland [7]. Also, IGF-1 comprises polypeptides with high sequence similarity to insulin. IGF-1 has a molecular weight of 7649 Da. IGFs are part of a complex system that cells use to communicate with their physiologic environment. This complex system (IGF 'axis') consists of two cell-surface receptors (IGF1R and IGF2R), two ligands (IGF-1 and IGF-2), a family of six high-affinity IGFBP 1-6, as well as associated IGFBP degrading protease enzymes [20],[21]. The signal is transduced by intracellular events. IGF-1 is one of the most potent natural activators of the protein kinase B signaling pathway, a stimulator of cell growth and multiplication and a potent inhibitor of programmed cell death [13],[21]. In addition, IGF-1 is mainly secreted by the liver as a result of stimulation by the GH [17],[22]. The direct relationship between GH/IGF-1 axis and leukemogenicity and their level during activity and after clinical remission with chemotherapy are still unclear.

The aim of this study was to evaluate the state of GH and IGF-1 in hospitalized patients diagnosed with ALL, before therapy and after achieving clinical remission with many regular courses of chemotherapy.

In this study, GH level before treatment was nonsignificantly increased compared with that of healthy controls. After achieving remission, GH was reduced significantly from the level before treatment. The level of GH after treatment was also significantly lower than that in controls. The serum level of IGF-1 before treatment was found to be significantly higher than that of the healthy control group. In addition, IGF-1 level after treatment was highly significantly decreased from the level before treatment. These results were in agreement with other studies that showed that GH and IGF-1 concentrations appeared to be higher at the time of onset of the disease and decreased while on therapy [14],[18],[20],[23]. These results may indicate that childhood ALL is associated with elevated serum IGF-1, which may explain its important role in the mitogenicity of the hematopoietic cell system of ALL. The presence of significant pretreatment higher IGF-1 levels and nonsignificant GH elevation may indicate that there is another mechanism (other than GH hormone liver stimulation for IGF-1 secretion [17],[22]) that plays a role in increasing IGF-1 level in ALL patients.

However, our results were not in agreement with those of other studies, which found that IGF-1 levels were lower in ALL patients at the time of diagnosis [22],[24],[25],[26]. Other investigators [22] suggested that there may be another alternative explanation for elevated IGF-1 in patients with malignancy. First, an effect of IGF-1 causing symptomatic tissue hyperplasia may result in an ascertainment bias leading to an initiation of procedures resulting in the diagnosis of asymptomatic cancers. Second, elevated serum IGF-1 in cancer patients may have origins within the tumor. Third, serum IGF-1 may actually be a surrogate factor, which is not under GH control and may be involved in cancer initiation.

This study showed the correlation between IGF-1 and GH levels before and after treatment. Our results can be explained by the fact that IGF-1 concentration is dependent on the amount of GH available in the circulation, but a high level of GH was not recorded in patients after remission. This can be explained as the effect of chemotherapy on GH and IGF-1. GH deficiency and growth velocity reduction have been reported in children treated for ALL [7],[14],[27].

Lymphoblasts in ALL - that is, immature (stage I) and mature (stage II) T-cell ALL, as well as pre-B ALL cell lines, express a high number of IGF-1 receptors [28]. Another study reported that IGF-1 overexpression can induce leukomogenesis through action on specific IGF-1 receptors of lymphoblasts. Detecting a high level of IGF-1 in ALL patients before treatment may suggest its role in lymphocyte differentiation and metabolism, which was in agreement with our patient results.

Lee et al. [29] reported that specific receptors for IGF-1 and insulin are present on T-lymphoblasts and B-lymphoblasts isolated from patients with lymphoid malignancies. In addition, they studied the influence of antibodies against IGF-1 or IGF-1 receptors on the proliferation of human ALL cell lines, suggesting that insulin through the IGF-1 receptors or insulin receptors can function as an autocrine or paracrine growth factor in ALL [28]. Recent studies have found increases in the serum level of IGF-1 in patients who had, or who eventually developed, solid tumors. As there was an association of higher GH with increased IGF-1 level, concern has been raised regarding its potential role as a cancer initiation factor [22]. Therefore, IGFs may be significantly involved in the mechanism that controls the proliferation and/or differentiation of many types of cells.

Our results showed that GH and IGF-1 have a significant relationship with peripheral blood cellularity and bone marrow, whereas higher levels of GH and IGF-1 were related to hypercellular marrow and leukocytotic blood film with many blast cells. This is explained by the direct relationship between GH/IGF-1 axis and leukemogenicity [30],[31]. Lymphoblasts can secrete IGF-1 [8],[13] and reduction of these blasts in bone marrow will decrease IGF-1; therefore, the net result will be a low level of IGF-1 in both hypocellular and hypercellular peripheral blood with no significant difference after induction of remission with chemotherapy. Our finding that increased level of IGF-1 in ALL patients during the active disease process may give information about the presence of abnormal leukemic blood and bone marrow proliferating cells (qualitative criteria) first, and about the 'mass' of these abnormal cells (quantitative criteria).

Our febrile patients tended to have higher GH and IGF-1 levels both before and after treatment. Numerous factors serve as a stimulus for GH release, including hypoglycemia, moderate to severe exercise, emotional stress, illness, and fever [16],[30]. Factors that are known to cause variation in the levels of GH and IGF-1 in the circulation include an individual's genetic makeup, the time of day, age, sex, exercise status, stress levels, nutrition level and BMI, disease state, race, and estrogen status [32].

Chemotherapy has considerably improved the outcome of children with ALL. However, a number of patients still die from relapse and others suffer from the side effects of treatment. Therefore, reliable prognostic factors at the time of diagnosis are required to select patients for appropriate therapeutic strategies [33]. In childhood ALL, the prognosis for infants and adolescents is worse than that for toddlers and school-aged children (age 1-10 years) [34]. Thus, GH and IGF-1 biomarkers may be helpful in assessing the activity of ALL and in predicting the response to chemotherapy.


  Conclusion Top


There was a higher level of IGF-1 in patients with ALL before treatment (newly diagnosed) and to a less extent of GH. Both GH and IGF-1 were decreased after achieving first remission. Elevated IGF-1 can be one of the etiological factors for ALL (mitogenicity of hematopoietic cells). GH and/or IGF-1 could be used as a biomarker for diagnosis, remission, and relapse (prognostic factor) in patients with ALL on treatment. GH replacement therapy is suitable for pediatric patients with ALL after achieving remission [35],[36]. More follow-up studies are needed on patients who achieved remission from ALL with GH and/or IGF-1 to evaluate the possibility of relapse and for prognosis.


  Acknowledgements Top


Conflicts of interest

There are no conflicts.

 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]


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