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Background: The paradox of normal growth despite a lack of growth hormone (GH) is an unexplained phenomenon described in some pathological (sellar, suprasellar, and hypothalamic disorders) and overgrowth syndromes. It has been suggested that the paradoxical growth is due to other GH variants, GH-like moieties, prolactin, insulin, insulin-like growth factors (IGFs), and unidentified serum factors or growth mechanisms. The objective of this study was to determine the mechanism underlying this normal growth without GH. Case Description: We describe here growth, hormonal, and genetic analyses for an adolescent boy with panhypopituitarism who achieved an adult height above his genetic potential. Results: Normal growth was observed despite low serum GH, IGF-I, IGF-II, IGF binding protein 3 (IGFBP-3) and acid labile subunit (ALS) concentrations, but the IGF-II/IGFBP-3 molar ratio was slightly high. Panhypopituitarism was associated with a heterozygous missense mutation of HESX1, with variable penetrance in heterozygous relatives. Exome analysis detected heterozygous missense mutations of various genes involved in intracellular signaling pathways. The growth-promoting activity of the patient's serum was unable to induce AKT phosphorylation in the MCF-7 cell line. Conclusion: The high IGF-II/IGFBP-3 molar ratio was not the cause of the sustained high growth velocity, due to the low affinity of IGF-II for IGF type 1 receptor. The key finding was the HESX1 mutation, as similar cases have been described before, suggesting a common mechanism for growth without GH. However, the variable penetrance of this variant in heterozygous relatives suggests that modifier genes or mechanisms involving combinations with mutations of other genes involved in intracellular signaling pathways might be responsible. [ABSTRACT FROM AUTHOR]

Background/Aims: Insulin-like growth factor (IGF)-I is related to cardiometabolic risk in adults, whereas the metabolic role of IGF-II is unclear. The aim of this study was to assess IGFs in obese children and correlate them with metabolic syndrome (MetS) components. Methods: This is a retrospective study including 574 obese children (11.34 ± 3.16 years). All subjects underwent complete anthropometry and biochemical assessment. In a subgroup of 136 subjects, body composition was evaluated. IGF-I was measured in 300 obese subjects and IGF-II in 77 obese and 15 lean children. 177 subjects were divided according to the presence of 1 or more MetS criteria: group 1, subjects with 1 MetS criterion; group 2, subjects with 2 components; and group 3, subjects with MetS diagnosis. Results: IGF-I, IGF-II, and IGF-I/insulinlike growth factor-binding protein-3 ratio were not different among subjects with an increasing number of MetS criteria and were not associated with single components of MetS as well as with body composition parameters. In children younger than 10 years, IGF-I directly correlated with highdensity lipoprotein cholesterol (p < 0.005) even after controlling for confounders. IGF-II was significantly higher in obese children and correlated with parameters of insulin sensitivity (p < 0.05). Conclusion: IGFs were neither related to MetS nor to body composition parameters in obese children. Further studies are needed to clarify the mechanisms underlying the relationship between IGF-II and insulin sensitivity. [ABSTRACT FROM AUTHOR]

This mini review presents a personal view about the past, the present and the future of the relationship between growth retardation and the IGF system. Looking back, it is pertinent to include a brief look at the evolution of the somatomedin hypothesis, the use of IGF-I determinations in the clinic, and a review of the literature beginning in the late 1980s with the description of mutations in the Growth Hormone Receptor (GHR) gene. The present possibly started in the mid-1990s with the description of mutations in the IGFI gene, followed in 2003 by reports of mutations in the genes coding for the IGF-I receptor and in the signal transducer and activator of transcription 5b (STAT5b). Finally, in 2004, mutations in the IGFALS gene were described. A diffuse limit between the present and the future might have been reached (the author's arbitrary decision) with the clinical applications of whole exome sequencing, which rapidly showed mutations in genes coding for STAT3, PAPP-A2 (pregnancy-associated plasma protein A2), and IGF-II. [ABSTRACT FROM AUTHOR]

Background: Our objective was to assess the relative bioavailability of the first somatropin produced in transgenic cloned cows that carry the human growth hormone (GH) gene (Biohormon®) and somatropin produced in Escherichia coli culture (HHT®), the procedure most frequently used for the commercial production of the hormone. Methods: Upon approval by an independent ethics committee and the National Regulatory Agency of Argentina, we compared the time-concentration profiles of somatropin in 24 healthy volunteers, in a randomized, 2-period, 2-sequence crossover design after inhibition of endogenous GH secretion with lanreotide, a long-acting somastostatin analogue. After the subcutaneous administration of 1.33 mg of each formulation, serum somatropin was analyzed by chemiluminescent immunoassay and IGF-I by immunoradiometric assay. Safety was assessed by clinical and laboratory parameters. Pharmacokinetic parameters were calculated with Win Nonlin® 5.2 using a non-compartmental model and bioequivalence was assessed. Results: The test/reference ratios of AUC, AUClast and Cmax were 106.4 (90% CI = 100.2-112.9), 105.3 (90% CI = 99.1-111.8) and 105.49 (90% CI = 92.6-120.1), respectively. No serious adverse events were reported and no GH antibodies were detected. Conclusion: This study demonstrates that a single dose of Biohormon, the first product with somatropin obtained from milk of transgenic mammals, is bioequivalent to the reference product HHT according to standard criteria. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Mutations of numerous genes encoding proteins that affect multiple pathways responsible for regulation of cell proliferation can cause growth disturbances in humans. Genes such as HESX1, PROP1, PIT1/POU1F1 and GLI2 have been shown to cause pituitary hormone deficiency. In addition, heterozygous mutations or gene deletions in the growth hormone-insulin-like growth factor (GH-IGF) axis such as the GH, GH-releasing hormone receptor, GH receptor, STAT5b, IGF-I, IGF-I receptor and the acid labile subunit have also been observed in children with growth failure and short stature. More recently, mutations of genes encoding regulators of cell proliferation and division, i.e., the pericentrin gene, have also resulted in severe growth disturbances. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]