Effects of insulin-like growth factor on linear growth, head circumference, and body fat in patients with Laron-type dwarfism

doi:10.1016/0140-6736(92)91594-X

The Lancet

Volume 339, Issue 8804, 23 May 1992, Pages 1258-1261

https://doi.org/10.1016/0140-6736(92)91594-X Get rights and content

Abstract

Patients with Laron-type dwarfism are clinically indistinguishable from those with isolated growth hormone (GH) deficiency, yet have high circulating GH concentrations associated with an inability to generate endogenous insulin-like growth factor I (IGF-l). Biosynthetic IGF-l was administered subcutaneously once daily for 3 to 10 months to 5 children with Laron-type dwarfism aged 3·3 to 14·5 years. There was a rapid stimulation of linear growth in body limbs, with a striking increase in head circumference, increased body weight, and a reduction in subcutaneous fat. Administration of IGF-l to patients with Laron-type dwarfism seems to have a beneficial effect on growth similar to that observed with long-term administration of GH in children with GH deficiency.

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Normal linear growth in humans requires GH and IGF-I. Diminished GH action resulting in reduced availability of IGF-I and IGF-binding proteins is the hallmarks of GH Insensitivity Syndromes (GHIS). The deficiencies are the perceived mechanisms for the growth failure of affected patients and the therapeutic targets for the restoration of normal growth. Early treatment attempts with pituitary-derived GH had limited effects in GHIS patients. Recombinant human insulin-like growth factor-I (rhIGF-I) treatment initially provides accelerated growth to GHIS children and provides substantial benefit. But, in general, catch up growth is less substantial with rhIGF-I treatment of GHIS than with rhGH treatment of GH Deficiency. Few classic GHIS patients have reached heights in the normal range (height SD score between − 2.0 SD and + 2.0 SD) with rhIGF-I monotherapy. A potential explanation is that while rhIGF-I treatment increases circulating concentrations of IGF-1 and IGFBP-3, such treatment reduces endogenous GH levels by negative feedback inhibition of pituitary GH release. In as much as both GH and IGF-I are required for good catch up growth, the loss of any residual GH signaling during IGF-I monotherapy in GHIS patients may attenuate possible catch up growth. Consistent with this explanation is the finding that, as predicted by the preclinical studies by Ross Clark, combination of rhGH & rhIGF-1 provides better growth responses than rhIGF-1 monotherapy in prepubertal children with short stature and low IGF-I levels despite normal stimulated GH responses. In the future, rhGH and rhIGF-I combination therapy can potentially improve growth outcomes over that seen with rhIGF-I monotherapy in all GHIS patients except in those with a total lack of functional GH signaling. Future alternative treatments for GHIS subjects may also include the use of post-growth hormone receptor signaling agonists which restore both GH signaling and IGF-I exposures or the addition of long-acting rhGH species to rhIGF-I. Additional etiologic factors for the growth failure in GHIS should be considered if the growth deficits of GHIS do not resolve with treatment.
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A growth hormone (GH) dependent substance responsible for sulfate uptake by costal cartilage of hypophysectomized rats, labeled sulfation factor, was reported in 1957. In 1962 the radioimmunoassay for GH was described. The clinical picture of severe GH deficiency but with high serum concentrations of GH was reported in 3 siblings in 1966 and followed by a 1968 report of 22 patients belonging to 14 consanguineous oriental Jewish families in Israel. Defective sulfation factor generation was demonstrated in 15 of these individuals and in a 1971 report; FFA response to IV GH and growth response to GH injections suggested competitive saturation of peripheral tissue receptors by an abnormal GH. However, studies published in 1973 demonstrated normal fractionation of their circulating GH, and normal binding of GH from 22 patients to various antisera used for radioimmunoassay. In 1976, the Israeli investigators reported that circulating GH from 7 patients reacted normally in the recently developed radioreceptor assay for GH. In 1984, using hepatic microsome pellets, they demonstrated that the defect was a failure of GH binding to receptors. Characterization of the human GH receptor (GHR) gene, reported in 1989, included the initial description of a genetic defect of the GHR in 2 of 9 Israeli patients. At about the same time began the identification in Ecuador of what was to become the largest population of GH insensitivity in the world, ~ 100 individuals, and the only substantial population with a common mutation of the GH receptor. Treatment studies with recombinant IGF-I began in 1990. Growth response was modest compared to that of GH treated GH deficient subjects. The spectrum of GH insensitivity has expanded beyond GH receptor deficiency to include postreceptor abnormalities: IGF-I gene mutation (1996); IGF-I receptor mutation (2003); signal transducer and activator of transcription 5b mutation (2003); and mutation of the GH-dependent acid labile subunit (2004).
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Citation Excerpt :
Laron syndrome patients (OMIM# 262500) lacking GH activity and IGF-1 deficient, become progressively obese [15,16]. Short term IGF-1 replacement therapy was shown to decrease the subcutaneous fat both in children and adult patients [17,18]. In the present report we show that long term administration of hGH or IGF-1 to three distinct diagnostic entities of congenital hGH/IGF-1 deficient children results in a biphasic effect on the subcutaneous adipose tissue depending on the length of the hormone administration.
To evaluate changes in adiposity in congenital GH/IGF-1 deficient children during hGH or IGF-1 treatment.
27 children with congenital isolated growth hormone deficiency (cIGHD) treated with hGH for 2.5–15.2 years (mean 10.0 ± 3.4), 18 children with congenital multiple pituitary hormone deficiency (cMPHD), treated with hGH for 2.3–17.9 years (mean 6.1 ± 4.3), and 14 children with Laron syndrome (LS) treated with IGF-1 for 1.2–12 years (mean 5.5 ± 3.7) were studied. Changes in the degree of adiposity were evaluated by subscapular skinfold thickness (SSFT), before, during and up to 2 years after treatment. All the children had various degrees of obesity.
During the pretreatment period, cIGHD patients showed little changes in SSFT (P = 0.45), cMPHD and LS patients showed an increase in SSFT (P = 0.01, P = 0.06 respectively). During the initial 0.6–1.1 years of hGH/IGF-1 treatment, the SSFT decreased in all 3 groups (P < 0.001), while during subsequent years a significant increase in SSFT (P < 0.001) was observed, in all types of patients, notably in females. Only the cIGHD patients demonstrated a significant correlation between the degree of SSFT decrease and height SDS gain (R = −0.56, P = 0.002) in the first period of treatment.
Short term replacement therapy of 0.6–1.1 years with either hGH or IGF-1, induced a reduction in subscapular subcutaneous fat whereas prolongation of therapy led to an increase in the subcutaneous fat.

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ORIGINAL ARTICLESEffects of insulin-like growth factor on linear growth, head circumference, and body fat in patients with Laron-type dwarfism

Abstract

Lancet

Lancet

Genetic pituitary dwarfism with high serum concentration of growth hormone. A new inborn error of metabolism?

Isr J Med Sci

Laron type dwarfism (hereditary somatomedin deficiency): a review

Administration of growth hormone in patients with familial dwarfism with high plasma immunoreactive growth hormone. Measurement of sulfation factor, metabolic and linear growth responses

J Clin Endocrinol Metab

Defect of human growth hormone receptors in the liver of two patients with Laron type drawfism

Isr J Med Sci

Characterization of the human growth hormone receptor gene and demonstration of a partial gene deletion in 2 patients with Laron type dwarfism

Proc Natl Acad Sci USA

Heterogeneity of molecular defects causing Laron type dwarfism

Laron dwarfism and mutation of the growth hormone receptor gene

N Engl J Med

Absence of the plasma growth hormone binding protein in Laron type dwarfism

J Clin Endocrinol Metab

Serum GH binding protein activities identifies the heterozygous carriers for Laron type dwarfism

Acta Endocrinol

Intravenous administration of rIGF-I lowers serum GHRH and TSH

Acta Endocrinol

ORIGINAL ARTICLES
Effects of insulin-like growth factor on linear growth, head circumference, and body fat in patients with Laron-type dwarfism