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

2. 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.

3. 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.

4. 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.

5. 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:

6. 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.

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

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. 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.

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.

15. 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.