• Asif Ali
  • Rizwan Hashim
  • Farooq Ahmad Khan
  • Abdus Sattar
  • Aamir Ijaz
  • Syed Mohsin Manzoor
  • Muhammad Younas


Background: Growth Hormone Deficiency (GHD) is conventionally diagnosed and confirmed bydiminished peak Growth Hormone (GH) levels to provocative testing. Serum Insulin-like growthfactor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) are under the influence ofGH and reflect the spontaneous endogenous GH secretion. Owing to the absence of a circadian rhythm,it is possible to take individual measurements of IGF-1 and IGFBP-3 at any time of the day forevaluation of GH status instead of subjecting the individual to cumbersome provocative tests.Objectives of this study were to compare IGF-1 and IGFBP-3 assays with Exercise and L-Dopastimulation tests in the diagnosis of growth hormone deficiency in short stature children using ITT asgold standard. Methods: This validation study was conducted at Department of Chemical Pathologyand Endocrinology, AFIP, Rawalpindi, from November 2005 to October 2006. Fifty-two short staturechildren were included in the study. Basal samples for GH levels and simultaneous IGF-1 and IGFBP-3measurements were obtained and afterwards all children were subjected to sequential exercise and LDopa stimulation tests. Insulin Tolerance Test (ITT) was performed one week later with all thenecessary precautionary measures. On the basis of ITT results, children were divided into two groups,i.e., 31 growth hormone deficient and 21 Normal Variant Short Stature (NVSS). Results: Thediagnostic value of exercise stimulation test remained highest with sensitivity 90.3%, specificity 76.0%,Positive Predictive Value (PPV) 84.84%, Negative Predictive Value (NPV) 84.2% and accuracy84.6%. The conventional L-Dopa stimulation had sensitivity 96.7%, specificity 38.0%, PPV 69.7%,NPV 88.8 % and accuracy 73.0%. The serum IGF-1 and IGFBP-3 levels were positively correlatedwith post ITT peak GH levels (r= 0.527, r=0.464 respectively, both p<0.001). The diagnostic value ofIGF-1 had sensitivity 83.87%, specificity 76.2%, PPV 83.87%, NPV 76.2% and accuracy 80.76%. Thediagnostic value of IGFBP-3 had sensitivity 54.83%, specificity 90.47%, PPV 89.47%, NPV 57.57%and accuracy 69.23%. With combined use of IGF-1 and IGFBP-3 diagnostic value had sensitivity69.35%, specificity 83.33% PPV 86%, NPV 64.81% and accuracy 75%. Conclusion GrowthHormones provocative tests still remain the most useful investigations for the diagnosis of GHD.Measurements of IGF-1 and IGFBP-3 have shown comparable diagnostic performance with growthhormone stimulation tests and are valuable for patients’ convenience and ease of performance and canbe useful in the initial workup of short stature.Keywords: Growth Hormone Deficiency, Insulin-like Growth Factor-1, IGF-1, Insulin-like GrowthFactor Binding Protein-3, Normal Variant Short Stature


Agarwal YP, Lewandrowski K. Laboratory evaluation of

pituitary disorders, adrenal cortex and medulla and selected

neuroendocrine tumours. In: Lewandrowski K. Clinical

chemistry; Laboratory management and clinical correlations.

Philadelphia: Lippincot Williams and Wilkins; 2002. p. 607–8.

Styne DM. Growth. In: Greenspoon FS, Gardener DG. Basic

and clinical endocrinology. 7th ed. New york: Mc Graw Hill;

p. 177–213.

Awan TM, Sattar A, Khattak EG. Frequency of growth

hormone deficiency in short stature children. J Coll

Physicians Surg Pak 2005;15:295–8.

Styne DM. Growth disorders. In: Fitzgerald PA. Handbook

of clinical endocrinology. 2nd ed. London: Prentice-Hall Int;


Shah A, Stanhope R, Mathew D. Hazards of pharmacological

tests of growth hormone secretion in childhood. BMJ


Ranke MB, Schweizer R, Lindberg A, Price DA, Reiter EO,

Albertson-Wikland K, et al. Insulin-like growth factors as

diagnostic tools in growth hormone deficiency during

childhood and adolescence: the KIGS experience. Horm Res

;62(suppl 1):17–25.

Dehiya RK, Bhartiya D, Kapadia C, Desai MP. Insulin-like

growth factor-1, insulin-like growth factor binding protein-3

and acid labile subunit levels in healthy children and

adolescents residing in Mumbai Suburbs. Indian Pediatr


Rosen JC. Serum insulin-like growth factors and insulin-like

growth factor binding proteins: clinical implications. Clin

Chem 1999;45:1384–90.

Blum WF, Albertson-Wikland K, Rosberg S, Ranke MB.

Insulin like growth factor-1 (IGF-1) and IGF binding protein-

(IGFBP-3) reflect spontaneous growth hormone (GH)

secretion. J Clin Endocrinol Metab 1993;76:1610–6.

Jaruratanasirikul S. The usefulness of serum insulin-like

growth factor-1 (IGF-1) and insulin-like growth factor

binding pritein-3 (IGFBP-3) for evaluation of children with

short stature. J Med Assoc Thai 2000;83:619–26.

Elmlinger MW, Zwimer, Kuhnel W. Stability of Insulin-Like

Growth Factor (IGF)-I and IGF Binding Protein-3 (IGFBP)-3

measured by the Immulite® automated Chemi-Luminescence

assay system in different blood specimens. Clin Lab


IMMULITE Growth Hormone (hGH), Technical Instructions

for use on Immulite 1000 systems. Diagnostic Products

Corporation (DPC), Los Angeles, USA 2005:1–6.

IMMULITE IGF-1, Technical Instructions for use on

Immulite 1000 systems. Diagnostic Products Corporation

(DPC), Los Angeles, USA 2005:1–7.

IMMULITE IGFBP-3, Technical Instructions for use on

Immulite1000 systems. Diagnostic Products Corporation

(DPC), Los Angeles, USA 2005:1–7.

Nicoll AG, Smail PJ, Forsyth CC. Exercise test for growth

hormone deficiency. Arch Dis Child 1984;59:1177–8.

Liberman B, Cesar FP, Wajchenberg BL. Human growth

hormone (hGH) stimulation tests: the sequential exercise and

L-dopa procedure. Clin Endocrinol (Oxf) 1979;10:649–54.

Demers LM, Vance ML. Pituitary function. In: Burtis CA,

Ashwood ER, Burns DE. Tietz Textbook of Clinical

Chemistry and Molecular Diagnostics. 4th ed. Missouri:

Saunders; 2006.p. 1967–2002.

Eddy RL, Jones AL, Chakmakjian ZH, Silverthorne MC.

Effects of levodopa (L-Dopa) on human hypophyseal tropic

hormone release. J Clin Endocrinol Metab 1971;33:709–12.

Biller Beverly MK, Samuels MH, Zagar A, Cook DM,

Arafah BM, Bonert V, et al. Sensitivity and specificity of six

tests for the diagnosis of adult GH Deficiency. J Clin

Endocrinol Metab 2002;87:2067–79.

Blum WF, Ranke MB. Use of insulin-like growth factorbinding protein-3 for the evaluation of growth disorders.

Horm Res 1990;33(Suppl 4):31–7.

Blum WF, Ranke MB. Insulin-like growth factor binding

proteins (IGFBPs) with special reference to IGFBP-3. Acta

Pediatr Scand 1990;367(Suppl):55–62.

Hasegawa Y, Hasegawa T, Tadaka M, Tsuchiya Y. Plasma

free insulin-like growth factor-1 concentrations in growth

hormone deficiency in children and adolescents. Eur J

Endocrinol 1996;134:184–9.

Granada ML, Murillo J, Lucas A, Salinas I, Lopis MA,

Castells I, et al. Diagnostic efficiency of serum IGF-1, IGFbinding protein-3 (IGFBP-3), IGF-1/IGFBP-3 molar ratio

and urinary GH measurements in the diagnosis of adult GH

deficiency: importance of an appropriate reference

population. Eur J Endocrinol 2000;142:243–53.

Juul A, Kastrup KW, Pederson SA, Skakkebaek NE. Growth

hormone (GH) provocative retesting of 108 young adults

with childhood-onset GH deficiency and the diagnostic value

of insulin-like growth factor-1 and IGF-binding protein-3. J

Clin Endocrinol Metab 1997;82:1195–201.

Cianfarani S, Liguori A, Boemi S, Maghnie M, Iughetti L,

Wasniewska M, et al. Inaccuracy of insulin-like growth

factor binding protein-3 (IGFBP-3) assessment in the

diagnosis of growth hormone deficiency from childhood to

young adulthood: association to low GH dependency of IGFII and presence of circulating IGFBP-3 18- kilodalton

fragment. J Clin Endocrinol Metab 2005;90:6028–34.

Milani D, Carmichael JD, Welkowitz J, Ferris S, Reitz RE,

Danoff A, et al. Variability and reliability of single serum

IGF-I measurements: impact on determining predictability of

risk ratios in disease development. J Clin Endocrinol Metab


Harrela M, Koistinen H, Kaprio J, Lehtovirta M, Tuomilehto J,

Eriksson J, et al. Genetic and environmental components of

inter-individual variation in circulating levels of IGF-I, IGF-II,

IGFBP-1, and IGFBP-3. J Clin Invest 1996;98:2612–5.

Cianfarani S, Boemi S, Spagnoli A, Cappa M, Argirò G,

Vaccaro F, et al. Is IGF binding protein-3 assessment helpful

for the diagnosis of GH deficiency? Clin Endocrinol


Cianfarani S, Tondinelli T, Spadoni GL, Scirè G, Boemi S,

Boscherinia B. Height velocity and IGF-1 assessment in the

diagnosis of childhood-onset GH insufficiency: do we still

need second GH stimulation test? Clin Endocrinol


Boquete HR, Sobrado PGV, Fideleff HL, Sequera AM,

Giaccio AV, et al. Evaluation of diagnostic accuracy of

insulin-like growth factor-1 and IGF-binding protein-3 in

growth hormone-deficient children and adults using ROC

plot analysis. J Clin Endocrinol Metab 2003;88:4702–8.

Blum WF, Ranke MB, Kietzmann K, Gauggel E, Zeisel HJ,

Bierich JR. A specific radioimmunoassay for the growth

hormone (GH)-dependent somatomedin binding protein: its

use for diagnosis of GH deficiency. J Clin Endocrinol Metab


J Ayub Med Coll Abbottabad 2009;21(3)

http://www.ayubmed.edu.pk/JAMC/PAST/21-3/Asif.pdf 45

Hasegawa Y, Hasegawa T, Aso T, Kotoh S, Nose O, Ohyama

Y, et al. Clinical utility of insulin-like growth factor binding

protein-3 in the evaluation and treatment of short children

with suspected growth hormone deficiency. Eur J Endocrinol


Nunez AB, Municchi G, Barnes KM, Rose SR. Insulin-like

growth factor-1 and IGF-binding protein-3 concentrations

compared to stimulated and night growth hormone in the

evaluation of short children- a clinical research centre study.

J Clin Endocrinol Metab 1996;81:1927–32.

Juul A, Skakkebaek NE. Prediction of the outcome of growth

hormone provocative testing in short children by

measurement of serum levels of insulin-like growth factor-1

and insulin-like growth factor binding protein 3. J Pediatr


Tillman V, Buckler JMH, Kibirige MS, Price DA, Shalet

SM, Wales JKH, et al. Biochemical tests in the diagnosis of

childhood growth hormone deficiency. J Clin Endocrinol

Metab 1997;82:531–35.

Rikken B, van Doorn J, Ringeling A, van den Brande JL,

Massa G, Wit JM. Plasma levels of insulin-like growth factor

(IGF)-I, IGF-II and IGF-binding protein-3 in the evaluation

of childhood growth hormone deficiency. Horm Res


Baxter RC. Circulating binding proteins for the insulin-like

growth factors. Trends Endocrinol Metab 1993;4:91–6.

Rosenfeld RG, Wilson DM, Lee PDK, Hintz RL. Insulin-like

growth factors I and II in evaluation of growth retardation. J

Pediatr 1986;109:428–33.

Hossenlopp P, Sergovia B, Lassarre C, Roghani M, Bredon

M, Binoux M. Evidence of enzymatic degradation of insulinlike growth factor binding proteins (IGFBPs) in the 150 K

complex during pregnancy. J Clin Endocrinol Metab


Mitchell H, Dattani MT, Nanduri V, Hindmarsh PC, Preece MA,

Brook CGD. Failure of IGF-I and IGFBP-3 to diagnose growth

hormone insufficiency. Arch Dis Child 1999;80:443–7.

Thissen JP, Ketelslegers JM. Underwood LE. Nutritional

regulation of the insulin-like growth factors. Endocr Rev


Miell JP, Taylor AM. Zini M. Maheshwari HG. Ross RJM,

Valcavi R. Effects of hypothyroidism and hyperthyroidism

on insulin-like growth factors and growth hormone and IGFbinding protein. J Clin Endocrinol Metab 1993:76:950–5.

Tonshoff B, Blum WF, Wingren AM, Mehls O. Serum

insulin-like growth factors and IGF binding protein 1, 2 and

in children with chronic renal failure: relationship to height

and glomerular filtration rate. J Clin Endocrinol Metab





Most read articles by the same author(s)

1 2 > >>