Insulin Like Growth Factor 1 (IGF-1) Explained: Everything You Should Know
Das Portal für seltene Krankheiten und Orphan DrugsThe growth hormone-IGF insulin-like growth factor system plays a central role in hormonal growth regulation. Recombinant igf 1 gh axis rh growth hormone GH has been available since the late s for replacement therapy in GH-deficient patients and for the stimulation of growth in patients with acis stature of various causes. In children with severe primary IGF-1 deficiency a rare condition whose prevalence is less than 1: There is no alternative treatment at present. There is, however, a risk of hypoglycemia, as IGF-1 has an insulin-like effect. As treatment testosterone endurance training wheels IGF-1 igf 1 gh axis complex, this new medication should only be prescribed, for the time being, by experienced pediatric endocrinologists and diabetologists.
The growth hormone-IGF insulin-like growth factor system plays a central role in hormonal growth regulation. Recombinant human rh growth hormone GH has been available since the late s for replacement therapy in GH-deficient patients and for the stimulation of growth in patients with short stature of various causes. In children with severe primary IGF-1 deficiency a rare condition whose prevalence is less than 1: There is no alternative treatment at present.
There is, however, a risk of hypoglycemia, as IGF-1 has an insulin-like effect. As treatment with IGF-1 is complex, this new medication should only be prescribed, for the time being, by experienced pediatric endocrinologists and diabetologists. In the past 50 years, a trend has developed in the understanding of growth regulation that is based on the so-called somatomedin hypothesis e1.
This has led to an understanding of the insulin-like growth factor IGF system and its different components and multiple effects 1. At the center of the system is IGF-1, an insulin-like peptide that vitally affects the metabolism and diverse cell functions.
After IGF-1 had been cloned and became biosynthetically produced subsequently, initial clinical studies aimed to investigate its growth promoting and insulin-like effects 2. The neuroprotective potential of IGF-1 has been investigated experimentally and in clinical studies only recently 3 — 5.
Table 1 lists the possible therapeutic roles for IGF For most indications, however, these will require further extensive, controlled studies. The appearance resembles that found in severe growth hormone deficiency, even if growth hormone secretion is normal. Treatment with IGF-1 is the only effective therapeutic option in such cases.
Since IGF-1 has only just been licensed for the treatment of primary IGF-1 deficiency, a discussion of the substance with its complex mechanisms of action is of general interest. In Salmon and Daughaday found a growth hormone GH dependent factor that had growth promoting effects on the epiphyseal cartilage. These circumstances provide the basis for the insulin-like effects of the IGFs, which affect cellular uptake of glucose and amino acids, glycogen synthesis, lipogenesis, and cellular reproduction e5 , e6.
Effects that are more specific for the IGFs, however, are effects of cell differentiation, cell proliferation, and apoptosis. These are all structurally similar but can be changed in terms of their binding behavior for IGFs by means of chemical modifications such as phosphorylation, glycosylation, or proteolysis. The secretion of growth hormone, insulin, and sexual steroids, as well as liver function and nutritional status are the main determinants of their synthesis e9. Through association to binding proteins and the acid-labile subunit ALS , the breakdown of IGFs is inhibited and their biological half life is prolonged from a few minutes to several hours e10 , e Mediated by binding protein cascades, circulating IGF is transported to different peripheral target organs.
Growth hormone GH is a peptide hormone that is produced in the somatotropic cells of the frontal lobe of the pituitary gland. They are released in a pulsatile manner e GH as well as IGF-1 are thus prerequisites for the optimal longitudinal growth of the bones. IGF-1 and GH synergistically affect growth and the anabolic metabolism. They have antagonistic effects on the glucose and fat metabolisms, since GH has anti-insulin effects e14 whereas IGF-1 has insulin-like effects e The concentrations of IGF-1 in the circulation and the release of GH are quantitatively linked to one another in a typical endocrine regulatory circuit e If the synthesis of IGF-1 is inhibited while hypophyseal function is normal, growth is also inhibited but GH secretion remains normal or is even raised.
In such cases, the result is pronounced dwarfism with a phenotype that corresponds to that of severe GH deficiency figure 1.
A lack of circulating IGF-1 can also be caused by disorders that affect the formation of IGF-1, such as malnutrition, hypothyreosis, renal failure, or hepatic failure. The terminology with regard to such situations is currently not consistent e19 , e A boy aged 4 years and 4 months with Laron syndrome compound heterozygote mutation in Exon 4 [C38X8] and Exon 3 [W16X] of the growth receptor gene.
Further, the recommendation is to confirm the diagnosis by means of an IGF-1 generation test. In such a test, the change in IGF-1 concentration in the blood is quantified after short term administration of recombinant growth hormone, so as to confirm sensitivity to growth hormone. This test also investigates the responsiveness to exogenous administration of GH normally 3—7 days at the level of the IGF-1 synthesis.
The assumption is that this reflects the improvement in growth achieved by long term GH treatment. However, the discussion about the standardization and significance of the test has by no means reached its conclusion 6 — Often, cases of a gene defect in the GH receptor or in components of the post-receptor signaling cascade can also be verified by molecular genetic methods 12 , 13 figure 2.
After binding to the IGF-1 receptor, circulating IGF-1 exerts its effects on proliferation and growth as well as its metabolic and anti-apoptotic effects in a tissue dependent manner The pathology described by Laron, with comprehensive phenocopy of severe GH deficiency, normal GH secretion, and GH resistance, has been identified as a GH receptor defect e As rhIGF-1 became available, such patients received treatment and, in lower numbers, also patients with traditional GH deficiency who developed neutralizing GH antibodies during treatment with GH.
Laron and colleagues were the first to report results in 5 children with severe IGF-1 deficiency Laron syndrome. The children were aged 3. In the first year of treatment, their growth velocity increased from 2. Four study groups have reported further experiences regarding this treatment from Israel e21 , 14 , Ecuador 15 , Europe 7 , 16 , 17 , and the US 18 — Altogether, some children and adolescents were treated with rhIGF-1 from several manufacturers. The results with regard to growth in the short term and long term 4—7 years are remarkably consistent table 3.
This is particularly notable when taking into account the heterogeneity of the studies ethnic origins of patients, geography, preparations table 3. Short term studies 15 have shown a positive relation between dose and growth rate. Long term studies 17 , 20 have shown an increase in body height by 10—17 cm table 3. On comparing the results of treatment for severe primary IGF-1 deficiency with IGF-1 and severe GH deficiency with GH with regard to the resulting final height of the participants, the latter has yielded better results.
The following reasons are responsible:. Relevant studies were listed; the few individual case reports were not included. During therapy with IGF-1, a range of typical side effects have been noted 15 , 16 , These include hypoglycemia, proliferation of lymphatic tissues, and others, as listed in Table 4. Children with primary and secondary IGF-1 deficiency a priori tend to develop hypoglycemia.
This is to do with the genuine insulin-like effects of IGF-1, as a result of which the peripheral glucose uptake is increased and hepatic glucose formation is reduced. In a study reported by Chernausek et al.
In the European study, relevant hypoglycemia ceased only once meals were administered before the injections. Further adverse effects include headaches and benign intracranial hypertension as well as papillary edema, which was mostly caused by IGF-1 mediated fluid retention and mostly limited to the early stages of treatment.
Proliferation of the lymphatic tissues tonsils, adenoids, spleen, thymus is a characteristic side effect of IGF-1 and GH. Especially during puberty, facial features coarsened 7. The importance of such treatment is obvious from the fact that those affected reach a final height of only cm without treatment.
The growth gain of 2—2. It should be borne in mind, however, that patients with a congenital disorder have initially received treatment at inappropriately late stages.
By exclusive administration of IGF-1, not all components of the IGF systems can be normalized that are not GH dependent and that may be of importance for the effectiveness of circulating IGFs in the target organ. This underlines the pathophysiological complexities in severe primary IGF-1 deficiency.
The risk can be reduced successfully by food intake directly before IGF-1 is administered 16 , The treatment has been found to be relatively safe for patients, even though they have to be treated over many years. The importance of the IGF system and especially of concentrations of IGF-1 in the blood in the development and promotion of malignancies is currently unknown e For this reason, raised blood concentrations of IGF-1 owing to exogenous administration should be avoided in the longer term.
In any case, the complexity associated with the treatment means that the treatment should be given exclusively by experienced pediatric endocrinologists and pediatric diabetologists.
The treatment is a novel therapeutic option, and comprehensive control examinations and detailed documentation are of the essence.
In our opinion, dose adjustments, for example, should be made stepwise while monitoring any associated metabolic effects with a great deal of precision. Bearing in mind the multiple potential effects of IGF-1 in addition to its effect on growth, the treatment has to be accompanied by examinations that seek to identify possible changes to the function and composition of the body.
The background to this therapeutic option will continue to be the discussion of the role of growth factors in the development and therapy of malignancies 22 , Conflict of interest statement. Dr Schnabel is a consultant for Ipsen.
He is in receipt of financial study support from Pfizer. National Center for Biotechnology Information , U. Journal List Dtsch Arztebl Int v. Published online Oct Received Sep 10; Accepted Mar This article has been cited by other articles in PMC.
Abstract Background The growth hormone-IGF insulin-like growth factor system plays a central role in hormonal growth regulation. Results and conclusion In children with severe primary IGF-1 deficiency a rare condition whose prevalence is less than 1: Table 1 The therapeutic potential of IGF Open in a separate window.
IGF-1 deficiency The concentrations of IGF-1 in the circulation and the release of GH are quantitatively linked to one another in a typical endocrine regulatory circuit e Table 2 Classification of the causes of IGF-1 deficiency, from e Lack of binding protein: Excess of binding proteins: The following reasons are responsible: Adverse effects During therapy with IGF-1, a range of typical side effects have been noted 15 , 16 , Study Ranke et al.
Recombinant human IGF-1 mecasermin now enables causal replacement therapy of primary IGF-1 deficiency, for which no alternative exists. On the basis of the data, which are still limited in terms of long term results, an improvement in the final height can be assumed for primary IGF-1 deficiency.
Treatment of Dwarfism With Recombinant Human Insulin-Like Growth Factor-1
Der schwere primäre IGFMangel mit Mutationen im GH-Rezeptor (GHR), mit Mutationen im Post-GHR-Signalweg und mit IGFGendefekten ist sehr selten. Phase IV Study: Status of the growth hormone/ insulin-like growth factor-1 axis in relation to growth failure, body weight and neuroprotection in children with. The growth hormone (GH)/Insulin-like growth factor (IGF)-system is highly controls of diseases involving the GH/IGF-axis (e.g. acromegaly, dwarfism).