Defining Insulin-Like Growth Factor-I Deficiency Michael B. Ranke

Defining Insulin-Like Growth Factor-I Deficiency Background An important breakthrough in the understanding of the mechanisms of GH action came with the discovery of IGF-I and its role as the key mediator of GH at various sites and during different developmental phases The IGF-I system is now considered to be part of the foundation on which growth and functional differentiation of the body are based Ranke MB. Horm Res 2006;65(suppl 1):9–14.

Defining Insulin-Like Growth Factor-I Deficiency Background Certain proteins specifically bind IGFs and are thus called “IGF binding proteins” The complex formation between IGF-I and its binding proteins prevents its degradation and plays a role in its targeting to tissues Ranke MB. Horm Res 2006;65(suppl 1):9–14.

Defining Insulin-Like Growth Factor-I Deficiency Background Changes in the concentration of IGF-I mark specific stages of human development For example, IGF-I levels are low at birth, peak during puberty and then gradually decline during adult life, essentially reflecting the changes in GH secretion during development Ranke MB. Horm Res 2006;65(suppl 1):9–14.

Mean Serum IGF-I Concentrations in Normal Subjects Age (years) IGF-I (ng/ml) 1000 800 600 400 200 <5 6-8 9-11 12-15 16-24 25-39 40-54 Female subjects Male subjects Mean Serum IGF-I Concentrations in Normal Subjects from Birth to Adulthood. The numbers of subjects in each group ranged from 40 to 195. Le Roith D. N Engl J Med 1997;336:633-40.

Defining Insulin-Like Growth Factor-I Deficiency Background A feedback relationship exists between GH and IGF-I: Impaired GH secretion results in decreased IGF-I levels and, conversely, impaired IGF production leads to an increase in GH secretion The GH-IGF system can be viewed as being similar to other endocrine systems, with a central, trophic hormone (GH) and a peripherally active hormone (IGF-I) Ranke MB. Horm Res 2006;65(suppl 1):9–14.

The GH–IGF-I Axis GH IGF-I Adapted from Le Roith D. N Engl J Med 1997;336:633-40.

Defining Insulin-Like Growth Factor-I Deficiency Definitions Secondary IGF-I deficiency: Any impairment in IGF-I levels resulting from diminished GH secretion Primary IGF-I deficiency: A decrease in IGF-I production without a concomitant impairment in GH secretion Growth Hormone Insensitivity Syndrome (GHIS): A type of Primary IGF-I deficiency in which the body is unresponsive to GH; can be treated using rhIGF-I Ranke MB. Horm Res 2006;65(suppl 1):9–14.

Classification of Causes of IGF-I Deficiencies Secondary IGF-I deficiency Defects in GH production with impaired GH levels Primary IGF-I deficiency Defects in GH action without impaired GH levels Defect in IGF production Functional IGF-I deficiency Defect in IGF action Defects in GH production Neocortical/psychological Defect of GHRH GHRH receptor defect GH gene defects Inhibition of GH binding to GHR GH antibodies Excess GHBP GH post-receptor defects JAK/STAT signaling defects Other defects Inhibition of IGF-I binding to IGFR Excess of IGFBPs IGF antibodies Developmental defects of pituitary Hormone-producing cells Other structural defects GH receptor defects Reduced GHR number GHR antibodies GHR gene defects IGF-I gene defects Gene deletion Bioinactive IGF-I IGF resistance IGF-I receptor defect IGF-I post receptor defect Other causes Destruction of hypothalamus and/or pituitary Aging Defects in IGF production Liver diseases Malnutrition Hormone deficits (e.g. insulin) ALS gene mutations Ranke MB. Horm Res 2006;65(suppl 1):9–14.

Defining Insulin-Like Growth Factor-I Deficiency Diagnosis GH, IGF-I and IGFBP-3 measurements can help determine whether there is a defect in the GH-IGF axis The normal ranges for these measurements vary based on age, sex, pubertal status, height, and body composition Ranke MB. Horm Res 2006;65(suppl 1):9–14.

Defining Insulin-Like Growth Factor-I Deficiency Diagnosis Another important tool in the diagnosis of growth disorders is the IGF Generation Test This test measures the short-term rise in IGF-I/IGFBP-3 after standardized exposure to GH A useful definition for an insufficient response to exogenous GH is IGF-I levels less than 15 ng/ml IGFBP-3 levels less than 400 ng/ml Ranke MB. Horm Res 2006;65(suppl 1):9–14.

Defining Insulin-Like Growth Factor-I Deficiency Diagnosis The IGF Generation Test has been useful in identifying patients with GHIS Since impaired sensitivity to GH can occur in varying degrees, this test may also be useful in identifying ISS patients that have reduced GH responsiveness Ranke MB. Horm Res 2006;65(suppl 1):9–14.

Comparison of the Dose-Dependent Changes of IGF-I SDS and IGFBP-3 SDS in Patients with GHD and SGA to rhGH Growth Hormone Deficient (GHD) Small for Gestational Age (SGA) ΔIGF-I [SDS] ΔIGFBP-3 [SDS] Comparison of the dose-dependent changes of IGF-I SDS and IGFBP-3 SDS in GHD (n = 31; green circles) and SGA (n = 23; blue squares) to rhGH indicates a shift towards the right and an earlier saturation in SGA. rhGH [μg/kg/d] rhGH [μg/kg/d] Ranke MB. Horm Res 2006;65(suppl 1):9–14.

Defining Insulin-Like Growth Factor-I Deficiency Diagnosis Functional tests other than IGF-I testing procedures may also be necessary to ascertain the pathogenic abnormalities which may cause short stature Additional tests include: determination of body composition measurement of GHBP, IGFBPs, and ALS genetic analyses These abnormalities may be subtle or present in combination Ranke MB. Horm Res 2006;65(suppl 1):9–14.

Defining Insulin-Like Growth Factor-I Deficiency Conclusions Accurate identification and treatment of growth disorders in children remains a complex issue due to inherent pathogenetic heterogeneity Insight of the GH–IGF-I axis and its role in growth and development can aid in the understanding of growth disorders Hormone levels and functional tests can help identify defects in the GH–IGF-I axis which may aid in appropriate diagnosis and therapy Ranke MB. Horm Res 2006;65(suppl 1):9–14.