defining insulin-like growth factor-i deficiency michael b. ranke
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Defining Insulin-Like Growth Factor-I Deficiency
Michael B. Ranke
Defining Insulin-Like Growth Factor-I Deficiency
• 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
Background
Ranke MB. Horm Res 2006;65(suppl 1):9–14.
Defining Insulin-Like Growth Factor-I Deficiency
• 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
Background
Ranke MB. Horm Res 2006;65(suppl 1):9–14.
Defining Insulin-Like Growth Factor-I Deficiency
• 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
Background
Ranke MB. Horm Res 2006;65(suppl 1):9–14.
Mean Serum IGF-I Concentrations in Normal Subjects
Le Roith D. N Engl J Med 1997;336:633-40.
Age (years)
IGF
-I (
ng
/ml)
1000
800
600
400
200
0<5 6-8 9-11 12-15 16-24 25-39 40-54
Female subjectsMale subjects
Defining Insulin-Like Growth Factor-I Deficiency
• 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)
Background
Ranke MB. Horm Res 2006;65(suppl 1):9–14.
The GH–IGF-I Axis
Adapted from Le Roith D. N Engl J Med 1997;336:633-40.
GHIGF-I
Defining Insulin-Like Growth Factor-I Deficiency
• 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
Definitions
Ranke MB. Horm Res 2006;65(suppl 1):9–14.
Classification of Causes of IGF-I Deficiencies
Ranke MB. Horm Res 2006;65(suppl 1):9–14.
Secondary IGF-I deficiency
Defects in GH production
with impaired GH levels
Primary IGF-I deficiency
Defects in GH action
without impaired GH levels
Primary IGF-I deficiency
Defect in IGF production
without impaired GH levels
Functional IGF-I deficiency
Defect in IGF action
without impaired GH levels
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
Defining Insulin-Like Growth Factor-I Deficiency
• 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
Diagnosis
Ranke MB. Horm Res 2006;65(suppl 1):9–14.
Defining Insulin-Like Growth Factor-I Deficiency
• 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
Diagnosis
Ranke MB. Horm Res 2006;65(suppl 1):9–14.
Defining Insulin-Like Growth Factor-I Deficiency
• 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
Diagnosis
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
0.0
0.5
1.0
1.5
2.0
2.5
3.0
0 10 20 30 40 50 60 70
Ranke MB. Horm Res 2006;65(suppl 1):9–14.
0.0
0.5
1.0
1.5
2.0
2.5
3.0
0 10 20 30 40 50 60 70rhGH [μg/kg/d]
ΔIG
F-I
[S
DS
]
ΔIG
FB
P-3
[S
DS
]
rhGH [μg/kg/d]
Growth Hormone Deficient (GHD)Small for Gestational Age (SGA)
Defining Insulin-Like Growth Factor-I Deficiency
• 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
Diagnosis
Ranke MB. Horm Res 2006;65(suppl 1):9–14.
Defining Insulin-Like Growth Factor-I Deficiency
• 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
Conclusions
Ranke MB. Horm Res 2006;65(suppl 1):9–14.