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Isolated growth hormone deficiency (IGHD) represents conditions of GH deficiency that are not necessarily associated with other pituitary hormone deficiencies or with an organic lesion. Three sub-categories of IGHD have been clinically identified (IGHD types 1-3), and IGHD type 1 has been further separated into IGHD types 1a and b. However, this clinical sub-categorization of IGHD may need reconsideration due to the recent identification of molecular heterogeneity within each sub-type of IGHD. In a small number of children with IGHD, defects in the GH, GH-releasing hormone receptor (GHRH-R), and GH1 genes have been identified.
In most cases, no cause for IGHD can be identified; however, the proportion of idiopathic IGHD cases may be decreasing due to identification of causative factors. The phenotype of IGHD is variable depending in part on the underlying genetic disorders in the affected individuals. Several studies have focused on the usefulness of MRI findings in patients with GHD but anatomic abnormalities of the pituitary gland are variable. We review current studies and the clinical, biochemical, and molecular features described for different groups of affected individuals with IGHD.
Recombinant hGH (rhGH) therapy may unmask central hypoadrenalism in adults with organic GH deficiency (GHD), likely by normalizing 11beta-hydroxysteroid dehydrogenase type 1 isoenzyme (11betaHSD1) activity and reducing cortisone to cortisol conversion. . . . According to the diagnostic criteria, no child became hypoadrenal on rhGH, contrary to what observed in patients with organic GHD, further supporting the view that only in patients with organic multiple pituitary hormone deficiency GHD masks the presence of a hidden central hypoadrenalism.
Assessment of growth hormone (GH) secretion is based on stimulation tests. Low GH peaks in stimulation tests, together with decreased insulin-like growth factor-I (IGF-I) secretion, confirm a diagnosis of GH deficiency (GHD). However, limitations in interpreting the test results and discrepancies between GH and IGF-I secretion in particular patients have both been reported. GH therapy should improve the prognosis of adult height (PAH). The aim of the study was to compare the deficit of height at diagnosis, IGF-I secretion and PAH in children with either decreased (in varying degrees of severity) or normal GH secretion in stimulation tests.
The analysis comprised 540 short children (373 boys, 167 girls), aged 11.7 +/- 3.2 years. In all the patients two GH stimulation tests were performed, IGF-I serum concentration was measured, bone age was assessed and PAH was calculated. According to the GH peak in the two stimulation tests, the patients were classified into the following groups: severe GHD (sGHD)--GH peak < 5 ng/mL (n = 44), partial GHD (pGHD)--GH peak 5-10 ng/mL (n = 190), idiopathic short stature (ISS)--GH peak at least 10 ng/mL (n = 306).
A significantly greater deficit of height, lower IGF-I secretion and worse PAH were observed in sGHD than in both remaining groups, while all the differences between pGHD and ISS in the parameters analysed were insignificant. The results obtained indicate the necessity of applying other methods of qualifying short children for GH therapy other than GH stimulation tests with a cut-off value at a level of 10 ng/mL.
Circulating baseline free IGF-1 and IGFBP-3 were better predictors for adult height in GH-treated SGA children than total IGF-I, or total IGF-I to IGFBP-3 ratio. This suggests a possible role for free IGF-I measurement in predicting the effect of GH therapy in for free IGF-I measurement in predicting the effect of GH therapy in short SGA children.
Very young SGA children without spontaneous catch-up growth could benefit from GR treatment because growth was accelerated and no negative side effects were observed.
Alterations in the GH-IGF-I axis in short small-for-gestational-age (SGA) children might be associated with abnormalities in bone mineral density (BMD) and body composition. In addition, birth weight has been inversely associated with diabetes and cardiovascular disease in adult life. Data on detailed body composition in short SGA children and long-term effects of GH treatment are very scarce. . . . During long-term GH treatment in short SGA children, fat percentage SDS decreased and BMAD(LS) SDS increased. These effects of GH treatment were most prominent in children who started treatment at a younger age and in those with greater height gain during GH treatment. LBM SDS(height )remained around 0 SDS in GH-treated children, but declined to low normal values in untreated controls.
Turner syndrome (TS) affects more than 50,000 girls and women in the United States. The National Cooperative Growth Study (NCGS) has collected efficacy and safety data for 5220 TS children treated with recombinant human growth hormone (rhGH) during the last 20 years. Objective: To determine frequencies of specific targeted adverse events (AEs) and additional AEs of interest in TS patients. Corresponding safety data in non-TS patients or normal populations were compared for selected AEs.
Children with TS who were treated with rhGH exhibit an increased underlying risk for selected AEs associated with rhGH and for type 1 diabetes, which is likely unrelated to rhGH. The aortic dissection/rupture incidence reflects the higher baseline risk for these events in TS, was consistent with current epidemiologic data in smaller TS populations, and is likely unrelated to rhGH. It is not known if the reported malignancies represent an inherently increased risk in TS patients. Twenty years of experience in 5220 patients indicates no new rhGH-related safety signals in the TS population. The NCGS and similar registries, although focused on the years during rhGH treatment, may also be a window into the natural history of TS in childhood.
Metabolic Effects of Oral Versus Transdermal Estrogen in Growth Hormone-Treated Girls with Turner Syndrome.
In GH-treated girls with Turner syndrome, neither oral nor TD estrogen adversely affected rates of protein turnover, lipolysis, and lipid oxidation rates or plasma lipids, fibrinogen, or fasting insulin concentrations. There was no clinically significant change in IGF-I concentrations after either form of estrogen. In aggregate, these data suggest that the route of delivery of estrogen does not adversely affect these metabolic effects of GH in young gi:ls with Turner syndrome.
[Metabolic control and insulin administration in a girl with Turner syndrome and type 1 diabetes during long-term growth hormone therapy.] Pankowska E, Szalecki M, Romer TE. Endokrynol Diabetol Chor Przemiany Materii Wieku Rozw. 2007 13(4):213-5. [Article in Polish].
Many surveys have indicated that short stature affects at least 95% of all patients with Turner syndrome (TS). It is also clear that growth hormone (GH) therapy can accelerate the physical development in girls with TS. According to some clinical experience diabetes type 1 may be considered as a contraindication for GH therapy leading to low efficacy and high risk of late complications due to hyperglycaemia and elevated IGF-1 level. We present the results of growth hormone therapy on the metabolic control in a girl with TS and type 1 diabetes treated with continuous subcutaneous insulin infusion. The parameters of metabolic control and insulin doses were compared before and after introducing GH therapy. The correct diurnal glycemia profile was obtained after 4-fold increase of basal insulin and 2-fold increase of the total daily dose. The acceleration of growth was observed during 3.5-year therapy and average linear growth velocity was 7 cm/year. Growth hormone administration in children with Turner syndrome and type 1 diabetes can be efficacious and safe.
Metabolic effects of oral versus transdermal estrogen in growth hormone-treated girls with turner syndrome. Mauras N, Shulman D, Hsiang HY, Balagopal P, Welch S. J Clin Endocrinol Metab. 2007 Nov 92(11):4154-60. Epub 2007 Aug 21. Nemours Children's Clinic, 807 Childrens Way, Jacksonville, Florida 32207, USA. email@example.com
Transdermal (TD) estrogen is often preferred over the oral route in postmenopausal and GH-deficient women taking estrogen, but this has not been studied in detail in girls. OBJECTIVE: Our objective was to study the metabolic effects of oral vs. TD estrogen in GH-treated girls with Turner syndrome. . . . In GH-treated girls with Turner syndrome, neither oral nor TD estrogen adversely affected rates of protein turnover, lipolysis, and lipid oxidation rates or plasma lipids, fibrinogen, or fasting insulin concentrations. There was no clinically significant change in IGF-I concentrations after either form of estrogen. In aggregate, these data suggest that the route of delivery of estrogen does not adversely affect these metabolic effects of GH in young girls with Turner syndrome.
Does growth hormone therapy before 4 years of age enhance the linear growth of girls with Turner's syndrome? Backeljauw P. Nat Clin Pract Endocrinol Metab. 2007 Oct 30; [Epub ahead of print] P Backeljauw is Professor of Pediatrics, University of Cincinnati College of Medicine and a member of the Division of Pediatric Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA (Presently, no abstract is available.).
Age at Growth Hormone Therapy Start and First-Year Responsiveness to Growth Hormone Are Major Determinants of Height Outcome in Idiopathic Short Stature.
Prepubertal children with ISS who show an appropriate first-year response to GH are likely to benefit from long-term treatment, even on low GH dosages.
Progressive Reduction of Relative Height in Childhood Predicts Adult Stature below Target Height in Boys with Constitutional Delav of Growth and Puberty. Horm Res 2007;68:99-104.
Subjects with early height SD reduction do not attain final height consistent with their genetic height potential, whereas those without such reduction do. Treatment with low doses of testosterone do not adversely affect final height.
The arginine-clonidine growth hormone (GH) stimulation test causes hypotension, requiring intravenous fluids to stabilize blood pressure (BP) and delaying departure from clinic. We hypothesized that oral hydration during the stimulation test would decrease need for intravenous fluids and shorten clinic stay. Children drank a diet electrolyte drink (10 ml/kg) on arrival to the test, which was repeated after clonidine. Fifteen children (7 girls) were tested without oral hydration, and 23 (6 girls) were tested with oral hydration (age range, 2-15 years). Compared with no oral hydration, intake of >13 ml/kg rarely required intravenous fluids, improved diastolic BP, and permitted discharge at the end of the GH test, with a higher BP.
Cut-off limits of the GH response to GHRH plus arginine test and IGF-I levels for the diagnosis of GH deficiency in late adolescents and young adults. Corneli G, Di Somma C, Prodam F, Bellone J, Bellone S, Gasco V, Baldelli R, Rovere S, Schneider HJ, Gargantini L, Gastaldi R, Ghizzoni L, Valle D, Salerno M, Colao A, Bona G, Ghigo E, Maghnie M, Aimaretti G. Eur J Endocrinol. 2007 Dec;157(6):701-8.
Endocrinology, Department of Clinical and Experimental Medicine, Amedeo Avogadro University of Novara, Via Solaroli, 17, 28100 Novara, Italy.
iIn late adolescent and early adulthood patients, a GH cut-off limit using the GHRH+ARG test lower than 19.0 microg/l is able to discriminate patients with a suspicion of GHD and does not vary from infancy to early adulthood.
Insulin Growth Factor I Based Dosing of Growth Hormone Therapy in Children: A Randomized, Controlled Study. Cohen P, Rogol AD, Howard CP, Bright GM, Kappelgaard AM, Rosenfeld RG; American Norditropin Study Group. J Clin Endocrinol Metab 2007 92: 2480-2486. Department of Pediatric Endocrinology, Mattel Children's Hospital at UCLA, 10833 Le Conte Avenue, MDCC 22-315, Los Angeles, California 90095, USA. firstname.lastname@example.orgComment in: J Clin Endocrinol Metab. 2007 Jul;92(7):2436-8; Nat Clin Pract Endocrinol Metab. 2007 Oct;3(10):682-3.
IGF-I-based GR dosing is clinically feasible and allows maintaining serum IGF-I concentrations within the desired target range. Titrating the GH dose to achieve higher 1GF –I targets results lU Improved growth responses, although at higher average GH doses.
Growth hormone replacement improves thyroxine biological effects: implications for management of central hypothyroidism. Martins MR, Doin FC, Komatsu WR, Barros-Neto TL, Moises VA, Abucham J. J Clin Endocrinol Metab. 2007 Nov;92(11):4144-53. Epub 2007 Sep 4. Division of Endocrinology, da Escola Paulista de Medicina-Universidade Federal de São Paulo, Rua Pedro de Toledo 910, São Paulo, Brazil 04039-002.
The biological significance of GH-induced changes in serum TH concentrations is unknown. It has been suggested that serum free T(4) (FT(4)) should be targeted at the high-normal range during GH replacement. OBJECTIVE: Our objective was to evaluate the effects of GH replacement on T(4) biological effects. HYPOTHESIS: If GH modulates thyroxine biological effects, serum FT(4) should be targeted accordingly. . . . GH replacement improves the biological effects of T(4). Serum FT(4) should be targeted at the high-normal range in GH-deficient patients only off GH replacement.
Growth rates and the prevalence and progression of scoliosis in short-statured children on Australian growth hormone treatment programmes. Day GA, McPhee IB, Batch J, Tomlinson FH. Scoliosis. 2007 Feb 22;2:3.;Print Department of Surgery, University of Queensland, Brisbane, Australia. email@example.com
This was a longitudinal chart review of a diverse group (cohort) of patients undergoing HGH (Human Growth Hormone) treatment. Clinical and radiological examinations were performed with the aim to identify the presence and progression of scoliosis. . . . In this study, there was no evidence of HGH treatment being responsible for progression of scoliosis in a small number of non-syndromic patients (four). An incidental finding was that scoliosis, similar to the idiopathic type, appears to be more prevalent in Turner syndrome than previously believed.
Growth hormone treatment in prepubertal children with celiac disease and growth hormone deficiency. Giovenale D, Meazza C, Cardinale GM, Farinelli E, Mastrangelo C, Messini B, Citro G, Del Vecchio M, Di Maio S, Possenti I, Bozzola M. J Pediatr Gastroenterol Nutr. 2007 Oct;45(4):433-7. Department of Pediatric Science, Università degli Studi di Pavia, Fondazione IRCCS San Matteo, Pavia, Italy.
In patients with CD with GH deficiency confirmed after >/=12 [more than or equal to 12] months of gluten-free diet, GH replacement therapy should be started to allow complete catch-up growth in children. In addition, the effect of GH treatment in patients who comply with a gluten-free diet seems to be comparable to that observed in children with IGHD.
Serum IGF-1, IGFBP-3 and growth hormone levels in children with congenital heart disease: relationship with nutritional status, cyanosis and left ventricular functions. Dinleyici EC, Kilic Z, Buyukkaragoz B, Ucar B, Alatas O, Aydogdu SD, Dogruel N. Neuro Endocrinol Lett. 2007 Jun;28(3):279-83. Department of Pediatrics, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey. firstname.lastname@example.org
In this study we aimed to evaluate serum insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3) and growth hormone (GH) levels in children with congenital heart disease (CHD) and to determine if these parameters have any relationship to the cyanosis, nutritional status and the left ventricular systolic function. . . . In conclusion, we determined that the most important factor on serum IGF-1 levels is cyanosis. Reduced IGF1 levels and decreased left ventricular mass with an elevated GH levels in CHD patients and these findings are prominent in the cases with cyanosis and malnutrition. For this reason we believe that chronic hypoxia plays a significant role in the pathogenesis of malnutrition and also we believe that IGF-1 deficiency seen in CHD patients may be responsible in the etiology of the decrease in left ventricular mass independently from GH.
Growth Hormone Increases Final Height in Patients With Juvenile Idiopathic Arthritis: Data from a Randomized Controlled Study. J Clin Endocrinol Metab 2007 92: 3013-3018.
Our data suggest that long-term GH therapy has a beneficial effect on growth and final height in the majority of growth retarded children with severe forms of JIA
Early Recombinant Human Growth Hormone Treatment in Glucocorticoid-Treated Children with Juvenile Idiooathic Arthritis: A 3·Year Randomized Study. J Clin Endocrinol Metab 2007 92: 2567-2578.
rhGH started early in the course of JIA preserved normal growth velocity and height. Although rhGH was well tolerlated, carbohydrate metabolism should be monitored closely.