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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-2298
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 5 1872-1875
Copyright © 2006 by The Endocrine Society

BRIEF REPORT

Improvement in Cardiac Systolic Function and Reduced Prevalence of Metabolic Syndrome after Two Years of Growth Hormone (GH) Treatment in GH-Deficient Adult Survivors of Childhood-Onset Acute Lymphoblastic Leukemia

Cecilia Follin, Ulf Thilén, Bo Ahrén and Eva Marie Erfurth

Departments of Endocrinology (C.F., B.A., E.M.E.) and Cardiology (U.T.), Lund University Hospital, SE 221 85 Lund, Sweden

Address all correspondence and requests for reprints to: Eva Marie Erfurth, Department of Endocrinology, Lund University Hospital, SE-221 85 Lund, Sweden. E-mail: eva_marie.erfurth{at}med.lu.se.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Survivors of childhood-onset (CO) acute lymphoblastic leukemia (ALL) treated with prophylactic cranial radiotherapy often exhibit GH deficiency (GHD), which is associated with increased prevalence of cardiovascular risk factors and cardiac dysfunction.

Objective: The objective of the study was to evaluate the effect of GH replacement on cardiovascular risk factors and cardiac function in former CO ALL patients.

Design: Eighteen former CO ALL patients (aged 19–32 yr) treated with cranial radiotherapy (18–24 Gy) and chemotherapy and with confirmed GHD were studied at baseline and after 12 (n = 18) and 24 months (n = 13) of GH treatment (median 0.5 mg/d). A group of 18 age- and sex-matched subjects served as controls.

Results: After 12 months of GH treatment, a significant decrease in serum leptin (P = 0.002), leptin per kilogram fat mass (FM) (P = 0.01), plasma glucose (P = 0.004), FM (P = 0.002), and hip (P = 0.04) and waist (P = 0.02) circumference and increased muscle mass (P = 0.004) were recorded in the patients. Before GH treatment six patients had a metabolic syndrome, but after 12 months only one had it and after 24 months none. After 24 months of GH treatment, an increase in left ventricular mass index (P = 0.06) and significant improvements in cardiac systolic function, measured as fractional shortening (P = 0.03) and ejection fraction (P = 0.03), were recorded.

Conclusions: Improvement in cardiac systolic function and reduced prevalence of metabolic syndrome were recorded after 2 yr of GH replacement in former CO ALL patients with GHD. Long-term follow-up is highly warranted.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
SURVIVAL RATES HAVE improved dramatically in certain childhood malignancies, e.g. acute lymphoblastic leukemia (ALL) (1). As a consequence of such remarkable cure rates, significant detrimental effects of the endocrine system have been recognized (1), and recently we showed an increased prevalence of cardiovascular risk factors and a marked reduction in cardiac dimensions and function among adult ALL with GH deficiency (GHD) (2). However, only minor improvements in body composition and lipid profiles were observed after 12–18 months of GH replacement, suggesting that GHD may not be the major etiological factor behind these risk factors (3). Cardiac function is commonly affected after anthracycline treatment in former childhood-onset (CO) ALL patients (4), and we recently suggested that GHD might have an additive effect to this dysfunction (2). However, the role of GHD for the increased cardiovascular risk in these patients and the beneficial potential of GH treatment is still not established. The aim of this study was to evaluate the effect of 24-month GH treatment on the prevalence of cardiovascular risk factors and metabolic syndrome and cardiac function in a group of GHD survivors of CO ALL.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Eighteen young adults with confirmed GHD (12 females), with a median age of 26 yr (range 22–31 yr) treated with chemotherapy and cranial radiotherapy (CRT) for CO ALL were studied. These 18 patients were no. 9, 12, 14, 15, 20, 24–28, and 32–39 in Table 2Go in a previous publication (2). The median age at diagnosis was 4 yr (1–17), all patients were treated with CRT, median dose 24 Gy (18–24), and the median time since CRT was 22 yr (13ndash;27). Only one patient was treated previously with GH, from age 12 to 14 yr. Chemotherapy had been given according to common protocols in the Nordic countries (5, 6) and according to the protocols of the Swedish Child Leukemia Group (7); details are presented elsewhere (2). The median dose of anthracycline was 120 mg/m2 body surface area (40–540). All patients were in first remission. Median time between maintenance therapy and the present investigation was 20 yr (13–22). Two of the male patients had received irradiation to the testis and were properly substituted with testosterone. All females had spontaneous and regular menstrual cycles. For the female patients, the expected median final height was 167 cm (based on parental height), and the actual median final height was 156 cm [–1.6 SD score (SDS)]. The corresponding figures for the male patients were 181 and 174 cm (SDS –1.3), respectively. For each of the 18 patients, one age- and sex-matched control subject was randomly selected from a computerized population register, the details of which are presented elsewhere (2). All participants gave written informed consent, and the study was approved by the Ethics Committee of Lund University.


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  		TABLE 2. Doppler echocardiography data in 13 former ALL patients at baseline and at 24 months of GH treatment and in 13 sex- and age-matched controls at baseline

 
Data are presented as median and range. Comparison of data before and after GH treatment and between patients and controls was made with Wilcoxon signed-rank test for matched pairs. The level of significance was set at P < 0.05.

Study design

All baseline investigations in the patients were repeated after 12 and 24 months of GH therapy, except the Doppler echocardiography, which was performed only after 24 months. The controls were investigated only at baseline. All 18 patients completed 12 months of GH therapy. Due to pregnancy, four females discontinued the GH treatment after 12 months, and one male declined to participate in the study during the second year. Thus, 13 patients were left for the last 12 months of the study. Patients were treated with human GH (Humatrope; Eli Lilly and Co., Indianapolis, IN) by sc injections, and the aim was a serum IGF-I in the middle of the reference range. After 12 months the median GH dose was 0.5 mg/d (0.2–0.6), and after 24 months the median GH dose was still 0.5 mg/d (0.2–0.5).

Test procedure for GH secretion and biochemical assays

GHD was diagnosed with two stimulation tests: GHRH-arginine test according to the method of Ghigo et al. (8) and a standard insulin tolerance test. GHD was defined as a GH peak less than 3 µg/liter to an insulin tolerance test and a GH peak less than 9 µg/liter during the GHRH-arginine test.

All blood samples were obtained in the morning after an overnight fast. Details of assay procedures for serum IGF-I, GH, TSH, free T4, free T3, cortisol, testosterone, estradiol, leptin, and plasma glucose are presented elsewhere (2). Fasting serum total, low-density (LDL) and high-density (HDL) lipoprotein cholesterol, triglycerides (TG), and plasma fibrinogen were measured with standard procedures.

Body mass index (BMI), waist and hip circumferences, body composition [bioelectrical impedance assay (BIA) and dual-energy x-ray absorptiometry (DXA)], Doppler echocardiogram, and physical exercise

All details regarding BMI, waist and hip circumferences, BIA, DXA, Doppler echocardiogram measurements, and physical exercise are presented elsewhere (2). Left atrial and ventricular (LV) dimensions (left atrial area and LV area), LV mass, and LV inner dimension in diastole were calculated from body surface area. LV fractional shortening (FS) and ejection fraction (EF) were used as indices of LV systolic function and the ratio of early filling velocity E wave to atrial filling velocity A wave as indices of left diastolic function (see Table 2Go).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Lipoproteins, leptin, and anthropometric measures

Significantly higher serum levels of LDL-cholesterol (P = 0.03) and leptin per kilogram fat mass (FM) (P = 0.05) were recorded among former CO ALL patients at baseline, compared with controls (Table 1Go). In comparison with baseline, 12 and 24 months of GH therapy did not result in significant changes in serum levels of insulin, total cholesterol, and LDL- and HDL-cholesterol. After 12 months of GH treatment, serum leptin (P = 0.002) and leptin per kilogram FM (P = 0.01) were significantly lower. When stratified for gender serum leptin in both men and women were significantly lower after 12 months of therapy (P = 0.03 and P = 0.02, respectively). At 12 and 24 months of GH replacement, a significant decrease in plasma glucose levels was recorded. A significant increase in serum TG was recorded after 12 and 24 months of GH treatment.


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  		TABLE 1. Biochemical and body composition characteristics in 18 former ALL patients at baseline and at 12 and 24 months of GH treatment and in 18 sex- and age-matched controls at baseline

 
After 24 months of GH therapy, the median weight of the patients had increased significantly (P = 0.04). At baseline, patients had higher percentage FM (P = 0.03) and lower percentage muscle mass (MM) (P = 0.07) and lean mass (LM) (P = 0.01), compared with controls. After 12 months of GH therapy, percentage FM had decreased significantly (P = 0.002), and percentage MM and LM had increased significantly (P = 0.004 and P = 0.002, respectively). After 24 months of GH treatment, LM was still significantly increased (P = 0.005). GH treatment caused a decrease in hip (P = 0.04) and waist (P = 0.02) circumferences during the first 12 months, and at 24 months hip (P = 0.06) and waist circumferences (P = 0.1) had decreased further. When using the International Diabetes Federation definition of the metabolic syndrome (9), which considers central obesity as a key issue, together with at least two of four possible risk factors (raised TG, reduced HDL-cholesterol, raised blood pressure, raised fasting plasma glucose), six patients (four women and two men) and one control fulfilled the definition at baseline. After 12 and 24 months of GH treatment, one male patient and none, respectively, had a metabolic syndrome. In detail, 55% of the patients and 6% of the controls had impaired fasting plasma glucose at baseline. After 12 and 24 months of GH treatment, none of the patients had an increase in plasma glucose.

Hormone levels, Doppler echocardiography, and physical exercise

There was no difference in median levels of serum TSH, free T4, free T3, cortisol, estradiol, or testosterone between patients and the controls at baseline (data not shown). At baseline, serum levels of IGF-I were significantly lower in patients than controls (Table 1Go). After 12 and 24 months of GH therapy, the serum IGF-I level increased significantly. Expressed as SDS IGF-I, the median value for the patients was at baseline –1.6 (range –3.5, 1.0), 12 months 0.2 (–3.4, 1.2), and 24 months 0.3 (–0.5, 1.4).

Doppler echocardiography data are shown in Table 2Go. Twenty-four months of GH treatment gave a small increase in LV mass index and improved systolic function, measured as FS (P = 0.03) and EF (P = 0.03).

There were no significant differences in physical exercise during spare time or working time between the patients at baseline and after the two GH treatment periods (all P > 0.3).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We present novel information of beneficial effects of GH therapy on cardiac systolic function in former CO ALL patients with confirmed GHD. These findings are in agreement with the results from studies in patients with CO GHD of other causes (10, 11). Thus, either GH therapy may counteract anthracycline-induced cardiac dysfunction (4) in former CO ALL patients or cardiac dysfunction was induced by GHD and reversed by GH therapy.

In a recent study of GH therapy in children with ALL, an increase in LV wall thickness, corresponding to LV mass index in the present study, was recorded (12). But the effect was lost after discontinuation of GH therapy. No effect of GH therapy on the progressive LV dysfunction, i.e. corresponding to FS or EF in the present study, was found (12). It has to be pointed out, however, that the total dose of anthracycline in the present study was rather low, which reduces the risk of late cardiac damage. Only one patient received GH during childhood, and the patients’ final height was only somewhat reduced, which probably reflects the impact of partial and not severe GHD during puberty and adolescence.

In the present study, the patients had significantly higher LDL-cholesterol compared with the controls at baseline. After GH treatment, no improvement was observed in the lipid profile among the patients, which accords with only minor improvements in other studies (3). On the other hand, it was striking that GH therapy resulted in a decrease in the prevalence of the metabolic syndrome.

Hyperleptinemia has previously been reported in patients treated with CRT for ALL (13, 14), and hypothalamic damage induced by CRT resulting in leptin resistance has been suggested (14). We recorded a decrease in both FM and leptin levels after 12 months of GH treatment, which was maintained at 24 months. This is in contrast to a recent study (15) in which we reported maintained insulin resistance and no decrease in serum leptin levels after 1 yr of GH treatment in 11 patients with CO ALL. The differing results might be due to a lesser degree of FM reduction together with no significant effect on waist and hip circumferences in the previous study. A decrease in leptin might be due to indirect effects by GH decreasing FM (16) or directly by affecting leptin gene expression in adipose tissue (17). Because the degree of physical exercise was not changed during the study period, this could not explain the beneficial effects on body composition.

In summary, 24 months of GH replacement showed improvement in cardiac systolic function and reduced prevalence of metabolic syndrome in adult GHD survivors of CO ALL. This suggests that 2 yr of GH treatment reverses some but not all cardiovascular risk factors in former CO ALL patients with GHD.


   Acknowledgments
 
The authors are grateful to Ann-Sofie Nilsson and Lilian Bengtsson for technical assistance.


   Footnotes
 
This work was supported by the Swedish Research Council (Grant K 1999-27X013074-01A), the Swedish Children’s Cancer Foundation, and the Medical Faculty, Lund University, Sweden.

The authors have nothing to declare.

First Published Online March 7, 2006

Abbreviations: ALL, Acute lymphoblastic leukemia; BIA, bioelectrical impedance assay; BMI, body mass index; CO, childhood onset; CRT, cranial radiotherapy; DXA, dual-energy x-ray absorptiometry; EF, ejection fraction; FM, fat mass; FS, fractional shortening; GHD, GH deficiency; HDL, high-density lipoprotein; LA, left atrial; LDL, low-density lipoprotein; LM, lean mass; LV, left ventricular; MM, muscle mass; SDS, SD score; TG, triglycerides.

Received October 18, 2005.

Accepted February 27, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Oeffinger KC, Eshelman DA, Tomlinson GE, Tolle M, Schneider GW 2000 Providing primary care for long-term survivors of childhood acute lymphoblastic leukemia. J Fam Pract 49:1133–1146[Medline]
  2. Link K, Moëll C, Garwicz S, Cavallin-Ståhl E, Björk J, Thilén U, Ahrén B, Erfurth EM 2004 Growth hormone deficiency predicts cardiovascular risk in young adults treated for acute lymphoblastic leukaemia in childhood. J Clin Endocrinol Metab 89:5005–5012
  3. Murray RD, Darzy KH, Gleeson HK, Shalet SM 2002 GH-deficient survivors of childhood cancer: GH replacement during adult life. J Clin Endocrinol Metab 87:129–135[Abstract/Free Full Text]
  4. Nysom K, Colan SD, Lipshultz SE 1998 Late cardiotoxicity following anthracycline therapy for childhood cancer. Progress in Pediatr Cardiol 8:121–138[CrossRef]
  5. Gustafsson G, Garwicz S, Hertz H, Johanesson G, Jonmundsson G, Moe PJ, Salmi T, Seip M, Siimes MA, Yssing M, Åhström L 1987 A population-based study of childhood acute lymphoblastic leukemia diagnosed from July 1981 through June 1985 in the five Nordic countries. Acta Paediatr Scand 76:781–787[Medline]
  6. Gustafsson G, Kreuger A, Clausen N, Garwicz S, Kristinson J, Lie SO, Moe PJ, Perkkiö M, Yssing M, Saarinen-Pihkala UM 1998 Intensified treatment of acute childhood lymphoblastic leukaemia has improved prognosis, especially in non-high risk patients: the Nordic experience of 2,648 patients diagnosed between 1981 and 1996. Acta Paediatr 87:1151–1161[CrossRef][Medline]
  7. Gustafsson G, Kreuger A, Dohlwitz A 1981 Acute lymphoblastic leukemia in Swedish children 1973–1978. Acta Paediatr Scand 70:609–614[Medline]
  8. Ghigo E, Aimaretti G, Arvatr E, Camanni F 2001 Growth hormone-releasing hormone combined with arginine or growth hormone secretagogues for the diagnosis of growth hormone deficiency in adults. Endocrine 15:29–38[CrossRef][Medline]
  9. Alberti KG, Zimmet P, Shaw J; the IDF Epidemiology Task Force Concensus Group 2005 The metabolic syndrome: a new worldwide definition. Lancet 366:1059–1062[CrossRef][Medline]
  10. Amato G, Carella C, Fazio S, La Montagna G, Cittadini A, Sabatini D, Marciano-Mone C, Sacca L, Bellastella A 1993 Body composition, bone metabolism, and heart structure and function in growth hormone (GH) deficient adults before and after GH replacement therapy at low doses. J Clin Endocrinol Metab 77:1671–1676[Abstract]
  11. Merola B, Cittadini A, Colao A, Longobardi S, Fazio S, Sabatini D, Sacca L, Lombardi G 1993 Cardiac structural and functional abnormalities in adult patients with growth hormone deficiency. J Clin Endocrinol Metab 77:1658–1661[Abstract]
  12. Lipshultz S, Vlach S, Lipsitz S, Sallan S, Marcy L 2005 Cardiac changes associated with growth hormone therapy among children treated with antracyclines. Pediatrics 115:1613–1622[Abstract/Free Full Text]
  13. Birkebæk NH, Fisker S, Clausen N, Tuovinen V, Sindet-Pedersen S, Christiansen J S 1998 Growth and endocrinological disorders up to 21 years after treatment for acute lymphoblastic leukaemia in childhood. Med Pediatr Oncol 30:351–356[CrossRef][Medline]
  14. Brennan BMD, Rahim A, Blum WF, Adams JA, Eden OB, Shalet SM 1999 Hyperleptinaemia in young adults following cranial irradiation in childhood: growth hormone deficiency or leptin insensitivity? Clin Endocrinol (Oxf) 50:163–169[CrossRef][Medline]
  15. Bülow B, Link K, Ahrén B, Nilsson AS, Erfurth EM 2004 Survivors of childhood acute lymphoblastic leukaemia, with radiation-induced GH deficiency, exhibit hyperleptinaemia and impaired insulin sensitivity, unaffected by 12 months of GH treatment. Clin Endocrinol (Oxf) 61:683–691[Medline]
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  17. Wang J, Liu R, Liu L, Chowdhury R, Barzilai N, Tan J, Rossetti L 1999 The effect of leptin on Lep expression is tissue-specific and nutritionally regulated. Nat Med 8:895–899




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