Insulin like Growth Factors Axis and Growth Disorders

67 Symposium on Growth and Its Disorders-II Insulin like Growth Factors Axis and Growth Disorders Anurag Bajpai 1 and P.S.N. Menon 1 Department of Endocrinology and Diabetes, Center for Hormone Research, Royal Children s Hospital, Melbourne, Victoria, Australia and Department of Pediatrics, Armed Forces Hospital, Kuwait Abstract. The growth hormone-insulin like growth factor (GH-IGF) axis plays a crucial role in the regulation of growth. Initially considered to be a mediator of growth hormone actions, IGF axis has been established as an independent endocrine system with wide array of actions. Recent advances have led to tremendous increase in the clinical utility of the IGF axis. IGF-based investigations (IGF1 and IGF binding protein 3) are now replacing GH-based investigations for evaluation and monitoring of disorders of the GH-IGF axis. IGF therapy has been successfully utilized in growth hormone insensitivity syndrome and GHD type 1B. The possibility of IGF axis as therapeutic options is being explored in wide variety of disorders like hypoxic-ischemic encephalopathy, Alzheimer s disease and psoriasis. [Indian J Pediatr 2006; 73 (1) : 67-71] Email: psnmenon@hotmail.com Key words : Growth disorders; Insulin like growth factor binding proteins (IGFBP); Insulin like growth factors (IGF) Regulation of growth is a complex process involving interaction of a wide variety of systems. The growth hormone and insulin like growth factors (GH-IGF) axis plays a vital role in the regulation of growth. 1 Initially considered to be mediators of GH action, insulin like growth factors have been found to be independent endocrine factors influencing a wide array of biological processes. 2 HISTORICAL PERSPECTIVE The existence of a GH-dependent growth regulating system was first identified by experiments on the effect of GH on sulfation of rat chondrocytes. 3 In vitro addition of GH failed to induce sulfation of chondrocytes cultured in serum of hypophysectomized rats. Interestingly, serum from GH-treated hypophysectomized rats promoted the process suggesting the role of an intermediary factor (named Sulfation factor) for the growth-promoting effects of GH. Studies on insulin activity in rat muscle and adipocytes conducted at the same time led to the identification of insulin like activity in serum that was not suppressed by insulin antibodies (non-suppressible insulin like activity, NSILA). 4 The chemical structure for this factor was later found to be similar to the sulfation factors. Considering their role in mediation of growth- Correspondence and Reprint requests : Dr. P.S.N. Menon, Consultant and Head, Department of Pediatrics, Armed Forces Hospital, Kuwait. promoting effects of GH, these substances were renamed somatomedins. Subsequent research showed structural similarity of somatomedins and insulin resulting in the modern nomenclature of insulin like growth factors (IGF). 5 PHYSIOLOGY The GH-IGF axis includes the hypothalamic-pituitary axis (responsible for production of GH), GH receptors (responsible for IGF production), IGF binding proteins (IGFBP) (responsible for transport of IGF) and IGF receptors (responsible for IGF action). The axis and its disorders affecting growth have been illustrated in fig. 1. Insulin like growth factors (IGF): IGF1 and 2 are low molecular weight peptides (7 kilodaltons) produced by hepatocytes under the influence of GH. They resemble insulin in sharing 50% of the amino acid sequence and having similar A and B chains. They differ from insulin in having additional C and D chains. IGF are GH-dependent with IGF1 being more influenced by GH than IGF2. Factors other than GH (age, pubertal status, nutritional status and liver functions) also affect IGF production. 6 Age is, in particular, an important factor influencing IGF levels with greater effects on IGF1 than IGF2. IGF1 levels are 50% of adult levels at birth and increase gradually to adult levels at the onset of puberty. 7 There is an exponential increase in IGF1 levels during puberty (up to two to three times the adult levels) followed by a gradual decline. IGF2 levels are also 50% of adult levels at birth but show a rapid postnatal increase so as to achieve adult values by one year of age. IGF receptors : Most growth-promoting effects of IGF are mediated by the type 1 IGF receptor. IGF binding to the 67

68 Anurag Bajpai and P.S.N. Menon DEFICIENCY Hypothalamic Genetic Malformation Tumor Radiation GHRH Hypothalamus Somatostatin EXCESS Hypothalamic Tumor Pituitary Malformations Tumors Genetic Trauma Pituitary GH Pituitary Microadenoma GH Receptor Laron syndrome Post receptor defect IGF gene deletion GHR Liver, peripheral tissue GH Receptor Activating mutation IGF1, 2 IGF receptor IGF insensitivity IGF Receptor IGF receptor Activating mutation Short stature Growth and differentiation Gigantism Fig. 1. Disorders of the GH-IFG1 axis receptor results in the activation of the tyrosine kinase system and regulation of cellular growth, differentiation and apoptosis. The type 1 IGF receptor has been identified in most body systems including brain, testes, liver and bones suggesting important paracrine and endocrine roles of IGF. 6 Insulin binds to the type 1 IGF receptor (although with lower potency compared to IGF1 and 2), a fact that explains growth promoting effect of the hormone. IGF on the other hand binds the insulin receptor and shares its hypoglycemic effect. The type 2 IGF receptors almost exclusively bind IGF 2 and play a minor role in the growth promoting effect of IGF. 68 IGF binding proteins (IGFBP): IGF differs from insulin in having large circulatory binding proteins. These proteins are involved in regulation of delivery and metabolism of IGF. The IGFBP system (comprising of six proteins IGFBP 1-6) is widely distributed in the body and controls paracrine actions of IGF. Individual IGFBPs differ in molecular structure as well as their pattern of distribution. IGFBP1 is the most abundant IGFBP in the amniotic fluid while the levels of IGFBP2 are highest in the cerebrospinal fluid. GH dependency and high circulating levels make IGFBP3 the ideal candidate marker for the GH-IGF axis. IGFBP3 levels are age-independent and reflect blood levels of IGF1 and IGF2. 8

69 Insulin like Growth Factors Axis and Growth Disorders IGF axis and growth : The central role of the IGF axis in regulation of pre and postnatal growth has been proved by gene knockout mice models. 9 The GH and GH receptor gene knocked out mice have normal birth weight confirming the long held belief that GH is not an important regulator of pre-natal growth. The IGF1 gene deleted mice on the other hand has a birth weight of 60% of normal and has severe postnatal growth failure. The synergistic effect of IGF1 and IGF2 on growth has been proven by the observation that mice deleted for both IGF1 and IGF2 genes have a birth weight of only 30% of normal. These findings have been corroborated by the observation of severe growth retardation in patients with deletions of IGF1 gene. 10 IGF AXIS IN CLINICAL PRACTICE Considering the significant role of the IGF axis in the regulation of growth, it is not surprising that it is becoming increasingly relevant in the management of growth disorders. Besides having assumed a critical role in the assessment and monitoring of disorders of the GH- IGF axis, the IGF system has been increasingly utilized in their treatment. ROLE IN EVALUATION OF THE GH-IGF AXIS IGF system has been widely used for evaluation of the GH and IGF axis. There has been a gradual shift from GHbased approaches to that utilizing IGF for assessment of the GH-IGF axis. 1 Growth hormone deficiency (GHD): Growth hormone provocation tests have long been considered gold standard for the diagnosis of GHD. Arbitrary cut-off values combined with lack of reproducibility and nonphysiological nature of these tests have raised doubts on the validity of these tests. Tests utilizing the IGF axis have the advantage of being more reproducible and not requiring repeated sampling and un-physiological stress. It is however important to note that IGF levels are influenced by age, pubertal status, nutritional status and liver functions, factors that should be considered while interpreting their results. Levels of IGF1, IGF2 and IGFBP3 correlate best with spontaneous GH secretion making them potential candidates for markers of GH status. Their features have been compared in table 1. IGF1 is by far the most GHdependent and thus considered the best indicator of GH status. IGF1 levels are however age-dependent, and normal levels may overlap with those observed in GHD during early childhood. IGF2 is age-independent but has the disadvantage of being the least GH-dependent. IGFBP3 has the advantage of being age-independent on Table 1. Comparison of IGF1, IGF2 and IGFBP3 As Markers of GH status Feature IGF1 IGF2 IGFBP3 GH dependence Highest Lowest Intermediate Age dependence Highest Lowest Intermediate Difficulty of validating assay High High Low Diagnostic accuracy High Low High Recommendations as an > 2 years No < 2 years individual marker one hand and being a good indicator of GH status on the other. Age independence of IGFBP3 makes it particularly useful marker of GH-IGF axis during infancy. The sensitivity and specificity of IGF1 for diagnosing GHD (with GH provocation tests being gold standard) is 80% and 65% respectively. 11 Combination of IGF2 to IGF1 increases the diagnostic accuracy to as much as 95%. The best diagnostic accuracy (sensitivity of 97% and specificity of 95%) is however achieved by combining IGF1 and IGFBP3 assays. 12 Under ideal circumstances, investigations for evaluation of the GH-IGF axis should include both IGF1 and IGFBP3; if economical constraints preclude both the investigations, performing IGFBP3 in children younger than two years and IGF1, thereafter, is a reasonable alternative. IGF1 and IGFBP3 levels lower than -2 standard deviation score (SDS) for age are highly suggestive of GHD, while those above -1 SDS for age exclude the condition. Approach to a child with suspected GH-IGF axis disorder is presented in fig. 2. > 1 SDS Re-evaluate for other causes Low GH provocation test GH < 10 ng/ml MRI head Insulin tolerance test Prolactin Urine osmolality Free T 4, TSH IGF1, IGFBP3 < 1 SDS Basal GH High GHIS GH > 10 ng/ml Idiopathic short stature Partial GHD Partial GHIS Fig. 2. Approach to a child with suspected disorder of GH- IGF 1 axis GH- Growth hormone; GHD- Growth hormone deficiency; GHIS-Growth hormone insensitivity syndrome; SDS- standard deviation score 69

70 Anurag Bajpai and P.S.N. Menon TABLE 2. Studies on IGF1 Therapy in Growth Hormone Insensitivity Syndrome Study Year N Dose µg/kg/day Duration Finding Guevara-Aguirre et al 18 15 240 2 years Increase in growth velocity 1997 7 160 No difference in the two groups Azcona et al 19 1999 11 160 1 years Increase in growth velocity Response dependent on age at treatment and IGFBP3 levels Backeljauw et al 20 2001 8 160-240 5 years Sustained effect Lower than that for GH in GHD Ranke et al 21 1999 17 80-240 4 years Increase in HSDS 1.7 ± 1.2 Sustained effect Growth hormone insensitivity syndrome (GHIS): Children with the GHIS have phenotypic features of GHD in the wake of elevated GH levels. GH provocation tests are of no value in these settings, and IGF-based tests are clearly the investigations of choice. GHIS is diagnosed in the presence of growth retardation (height < -3 SDS for age), low IGF1 and IGFBP3 (<- 3 SDS for age), elevated basal GH (> 5 ng/ml) and lack of increase in IGF1 following administration of GH (peak levels < 15 ng/ ml). 13 IGF generation test, the assessment of increase in IGF 1 following administration of GH, is considered the gold standard for the diagnosis of GHIS. Growth hormone excess: Elevated GH levels in the presence of hyperglycemia have been traditionally used for the diagnosis of GH excess. IGF1 and IGFBP3 levels are good indicators of GH excess and should be employed as screening tests for the diagnosis of the condition. High IGF1 levels and IGFBP3 should be followed up with glucose suppression test. FOLLOW-UP OF INDIVIDUALS WITH DISORDERS OF GH-IGF AXIS IGF-based tests have emerged as the ideal investigations for monitoring therapy of subjects with GH-IGF axis disorders. Growth hormone deficiency: Conventional GH treatment involves using dose adjusted to body mass or surface area with monitoring of growth parameters. The advent of IGF-based assays has provided another approach for monitoring these patients. 14 Adjusting GH doses to achieve IGF1 and IGFBP3 levels in the high normal range (+1.5-2.5 SDS for age) is associated with better response compared to maintaining them in the normal range (-0.5 to + 0.5 SDS for age). 15 Association of high IGF1 and low IGFBP3 levels with breast, colo-rectal and prostate cancer also emphasizes the need of regular monitoring of these levels during GH treatment. 16 GH excess : IGF1 levels fall significantly following treatment of GH excess. They have emerged as investigations of choice for monitoring efficacy of treatment for the condition. 70 ROLE IN TREATMENT IGF1, being the final mediator of growth, theoretically has potential role in the treatment of disorders of the GH-IGF axis. IGF1 has however not been shown to be superior to GH in GHD, the commonest disorder of the GH-IGF axis. Considering the side effects of IGF1 (hypoglycemia, benign intracranial hypertension and lipohypertrophy), GH remains the treatment of choice in GHD. IGF1 is however the only treatment option in GHIS where GH is ineffective. Successful induction of hypoglycemia with IGF1 in individuals with GHIS not only demonstrated preserved responsiveness to the peptide in GHIS but also provided an option for treatment of the condition. 17 Sustained growth promoting effects of IGF1 in GHIS have been demonstrated in subsequent studies (Table 2). 18-21 In a dose finding randomized controlled trial of IGF1 therapy in GHIS, a dose of 160 µg/kg/day (in two divided doses given 12 hours apart) was found to be appropriate for treatment. 18 The benefits of IGF1 therapy in GHIS are not restricted to growth but also include improvement in bone mineral density, body composition and insulin resistance. 22-24 Growth response to IGF1 in GHIS is however lower than that following GH treatment in GHD. This relative IGF1 insensitivity may be caused by low IGFBP3 levels in GHIS resulting in faster metabolism of IGF1. The pleiotrophic effects of IGF axis have led to the exploration of its use in conditions like hypoxic ischemic encephalopathy, psoriasis, Alzheimer s disease and hypoglycemic brain damage. 25-27 Key Messages 1. GH-IGF axis plays a crucial role in regulation of growth period. 2. IGF1 and IGFBP3 are ideal screening tools for disorders of the GH and IGF axis. 3. IGF1 and IGFBP3 levels should be monitored during follow-up of individuals with disorders of the GH- IGF axis. 4. IGF therapy is being explored in a variety of endocrine and non-endocrine conditions. REFERENCES 1. Rosenfield GR, Cohen P. Disorders of growth hormone/

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72 IJP TRAVEL GRANT FOR MEDICAL CONFERENCES 1. Six grants are available. Only Postgraduate students are eligible to apply. 2. Grant will cover train journey to and fro, registration fee and limited local expenses. Total expenditure not to exceed Rs. 5000 per candidate. 3. Applicant should submit a copy of the research paper to be presented at the conference along with the letter of acceptance by the conference organizers. 4. The application should be forwarded through the Head of the Department along with a letter certifying that the applicant is not being supported by any other source. 5. Applicant should explain in 200 words why he/she would like to be considered for the grant. For information please write to : Editor-in-Chief, The Indian Journal of Pediatrics, 125 (2nd Floor), Gautam Nagar, New Delhi-110049. Post Box No. 3875, New Delhi - 110 049. Phone : 26568098. Telefax : 26857587 E-mail : ijp.journal.vsnl.net@vsnl.net; ijp@vsnl.net 72