bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel modalities of somatostatin actions
Authors: Krantic S , Goddard I , Saveanu A , Giannetti N , Fombonne J , Cardoso A , Jaquet P , Enjalbert A
Published: January 2005

The first part of this contribution reviews the current knowledge about endocrine and neuromodulatory actions of somatostatin. These biological actions are exerted according to endocrine, paracrine and autocrine modes of action and involve five distinct types of membrane receptors belonging to the 'super-family' of G-protein-coupled receptors.A new concept concerning a juxtacrine mode of action has recently been introduced to refer to the intervention of cytokines and growth factors in direct, cell-to-cell communication. The evidence in favor of juxtacrine actions of somatostatin will be presented in the second part of this review and illustrated by our own results on macrophage-lymphocyte T interactions in the immune system and spermatogonia-Sertoli cell interactions in mammalian testis. Another phenomenon such as ligand-induced somatostatin receptor homo- and hetero-dimerization resulting in 'poly'-receptors (with characteristics different from those of each of the two receptors forming the complex) is also at the origin of a novel mode of somatostatin action. The latter will be illustrated by the data obtained on human pituitary adenomas with somatostatin analogs specific for either 'poly'-receptor or relevant individual receptors.The arguments in favor of the analogous mode of actions among different families of chemical messengers such as peptides, cytokines and growth factors are discussed in the concluding section. The emerging unifying concepts on such functional analogies might provide a useful basis for the development of synthetic analogs not only for bioactive peptides but also for other types of chemical messengers.
Epidemiological, endocrine and metabolic features in Turner syndrome
Authors: Gravholt CH
Published: January 2005

Turner syndrome is one of the more common genetic disorders, associated with abnormalities of the X chromosome, and occurring in about 50 per 100 000 liveborn girls. Turner syndrome is usually associated with reduced adult height, gonadal dysgenesis and thus insufficient circulating levels of female sex steroids, and infertility. A number of other signs and symptoms are seen more frequently with the syndrome. Morbidity and mortality are increased. The average intellectual performance is within the normal range. A number of recent studies have provided new insights with respect to epidemiology, cardiology, endocrinology and metabolism. Treatment with GH during childhood and adolescence allows a considerable gain in adult height, although very-long-term consequences of this treatment are not clear. Puberty has to be induced in most cases, and female sex hormone replacement therapy is given during the adult years. The proper dose of hormone replacement therapy (HRT) has not been established, and, likewise, benefits and/or drawbacks from HRT have not been thoroughly evaluated. Since the risk of cardiovascular and endocrinological disease is clearly elevated, proper care during adulthood is emphasized. In summary, Turner syndrome is a condition associated with a number of diseases and conditions which are reviewed in the present paper.
Effect of long-term l-thyroxine treatment on bone mineral density in young adults with congenital hypothyroidism
Authors: Salerno M , Lettiero T , Esposito-Del Puente A , Esposito V , Capalbo D , Carpinelli A , Padula S , Del Puente A
Published: January 2005

OBJECTIVE: To evaluate whether long-term l-thyroxine therapy in young adults with congenital hypothyroidism may affect bone mineral density (BMD). DESIGN: Thirty-seven subjects with congenital hypothyroidism, detected by neonatal screening and longitudinally followed from the time of diagnosis and treatment (26+/-4 days) up to the age of 17.8+/-1.0 years, were studied. METHODS: Spinal (L2-L4) BMD, measured by dual-energy X-ray densitometry, and bone quality, measured as amplitude-dependent speed of sound (Ad-SoS) by quantitative ultrasound, were evaluated. RESULTS: Z-score mean values (+/-s.d.) of BMD (-0.3+/-0.7) and Ad-SoS (-0.7+/-1. 1) were slightly below the average but within the normal range. Ad-SoS resulted in a z-score below -1 in 38% of patients as compared with BMD which resulted in a z-score below -1 in only 13.5% of subject. No significant differences were observed between males (BMD, -0.3+/-0.7; Ad-SoS, -0.9+/-1.0) and females (BMD, -0.3+/-0.7; Ad-SoS, -0.5+/-1.2) or when dividing patients on the basis of aetiological defects; ectopic gland (BMD, -0.3+/-0.6; Ad-SoS, -0.8+/-0.9), athyreosis (BMD, -0.3+/-0.9; Ad-SoS, -0.8+/-1.0) and eutopic gland (BMD, -0.3+/-0.8; Ad-SoS, -0.4+/-1.3). No significant relationships were observed between BMD or Ad-SoS z-score and hormonal status or l-thyroxine dosages at the time of the study or during the pubertal period. CONCLUSIONS: The careful monitoring of serum thyroid-stimulating hormone and adjustment of l-thyroxine dosage avoided the significant deleterious effects of prolonged l-thyroxine replacement therapy on bone tissue in adolescents and young adults with congenital hypothyroidism treated from the neonatal period.
Effects of morning cortisol replacement on glucose and lipid metabolism in GH-treated subjects
Authors: Segerlantz M , Bramnert M , Thomasson R , Manhem P , Laurila E , Groop LC
Published: January 2005

OBJECTIVE: Insulin resistance is a frequent consequence of GH replacement therapy but patients on GH replacement therapy often also have replacement of other hormone deficiencies which theoretically could modify the metabolic effects of GH. In particular, cortisol replacement if given in supra physiologic doses immediately before the evaluation of insulin sensitivity could influence insulin sensitivity. The aim of this study was thus to evaluate the effect of morning cortisol replacement given prior to a euglycaemic clamp combined with infusion of [3-(3)H]glucose and indirect calorimetry on glucose and lipid metabolism. METHODS: Ten GH/ACTH-deficient adults received, in a double-blind manner, either cortisol (A) or placebo (B) before the clamp whereas five GH-deficient-ACTH-sufficient adults participated in a control (C) clamp experiment. All subjects received GH replacement therapy. RESULTS: Serum cortisol levels were significantly higher after cortisol than after placebo (324+/-156 vs 132+/-136 mmol/l; P=0.006) and similar to controls (177+/-104 mmol/l). As a measure of the biological effect of cortisol, eosinophil leukocyte counts in peripheral blood decreased (164+/-91x10(9)/l vs 216+/-94x10(9)/l; P=0.04). Cortisol replacement had no significant effect on insulin-stimulated glucose uptake (11.8+/-1.8 vs 13.2+/-3.9 mumol/kg min), either on glucose oxidation or on glucose storage. There was also no significant effect of cortisol on fasting endogenous glucose production and no effect was seen on serum free fatty acid concentrations. CONCLUSION: Administration of cortisol in the morning before a clamp cannot explain the insulin resistance seen with GH replacement therapy.
Cushing's disease in childhood as the first manifestationof multiple endocrine neoplasia syndrome type 1
Authors: Rix M , Hertel NT , Nielsen FC , Jacobsen BB , Hoejberg AS , Brixen K , Hangaard J , Kroustrup JP
Published: January 2005

OBJECTIVE: To describe three cases of Cushing's disease in children with multiple endocrine neoplasia type 1 (MEN1), as clinical manifestations of MEN1 are very rare in childhood. DESIGN AND METHODS: A retrospective review of three cases of Cushing's disease diagnosed between 1997 and 1999. Genetic screening for MEN1 gene mutation was performed in each patient. RESULTS: An ACTH-secreting microadenoma was diagnosed in three children, aged 11-13 years, presenting with growth retardation and weight gain over a period of 3-4 years. All patients had successful transsphenoidal adenomectomies. Primary hyperparathyroidism was subsequently diagnosed in two of the patients, and in the monozygotic twin of one of the patients. A new mutation in the MEN1 gene (Tyr351His) was identified in two of the patients and the affected members of their families. In the third patient a de novo MEN1 gene mutation (Leu444Pro) was found. CONCLUSIONS: MEN1 has to be considered in all children with tumours of the pituitary gland, and in those presenting with primary hyperparathyroidism. The children and their families should be advised to seek genetic counselling. We suggest that careful growth records be kept for children at risk of developing inherited MEN1 and, in the event of a decelerating growth rate, further diagnostic evaluation be undertaken with regards to ACTH-secreting pituitary tumours.
The desmopressin test as a predictive factor of outcome after pituitary surgery for Cushing's disease
Authors: Valero R , Vallette-Kasic S , Conte-Devolx B , Jaquet P , Brue T
Published: January 2005

OBJECTIVE: Taking advantage of the over-expression of V3 receptors in adenomatous corticotroph cells, we evaluated the response to the vasopressin agonist desmopressin in 22 patients operated on for Cushing's disease, with a mean follow-up of 4.5 years. SUBJECTS AND METHODS: Twenty-two patients (17 women) operated on for Cushing's disease with a follow-up >2 years (median, 48; range, 24-141 months) underwent one desmopressin test (10 mug i.v. bolus) 3-6 months postoperatively. Twelve were in remission (R group), five had immediate failure (IF) after surgery and five had late recurrence (LR). RESULTS: Both ACTH and cortisol peaks after desmopressin were significantly lower in the R group than in the LR group (P=0.003 and P=0.013 respectively). The receiver operator characteristic curve method defined an ACTH peak threshold >/=22 pg/ml or ACTH rise >/=35%; cortisol peak >/=350 nmol/l or cortisol rise >/=14%. None of twelve patients in remission had ACTH or cortisol peaks above these thresholds vs three of five patients from the LR group and five of five in the IF group. DISCUSSION: On the basis of ACTH or cortisol peaks respectively, the desmopressin test was predictive of a later recurrence with a positive predictive value of 100% or 80% respectively, and a negative predictive value of 92%. Sensitivity and specificity were 80% and 100% respectively based on ACTH peak, and 80% and 92% respectively based on cortisol peak. CONCLUSION: In this first long-term study, a marked response of ACTH or cortisol to desmopressin was predictive of a later recurrence with good specificity and sensitivity.
Gender diversity in developing overweight over 35 years of Westernization in an Inuit hunter cohort and ethno-specific body mass index for evaluation of body-weight abnormalities
Authors: Andersen S , Mulvad G , Pedersen HS , Laurberg P
Published: January 2005

OBJECTIVE: To establish an Inuit body mass index (BMI) norm from a healthy, not malnourished, pure Inuit population and to investigate the development of overweight in the Inuit in Greenland. DESIGN:Longitudinal study with 35 years follow-up on overweight among Inuit in Greenland. METHODS: The heights and weights of 97% of all inhabitants in Eastgreenland in 1963 (n=1852) were recovered recently and BMI calculated. We obtained similar data in 96% of the 50-69-year-old population in Eastgreenland in 1998 and in a random sample of 25% of individuals aged 50-69 years in the capital Nuuk (n=535). RESULTS: Overweight or obesity, as defined by the World Health Organization (WHO), was found in 30% of all men and 22% of all women in Eastgreenland in 1963, and in 31% of young Inuit hunters in 1963. Such high rates were incompatible with a hunter's way of living. Inuit-specific BMI norms from data on healthy Inuit aged 20-29 years in 1963 were computed: men, 20.2-27.9; women, 17.9-27.7. These differed from the WHO classification (P<0.001). Using the Inuit-specific BMI norm for the classification of 50-69-year-old Inuit in 1963 and 1998, the fraction of overweight men increased by over six times (4.0 to 25.6%; P<0.001), and overweight increased with Westernization (P=0.001). The fraction of overweight women by the Inuit BMI norm doubled from 1963 to 1998 (14.0 to 30.7%; P<0.001) while median BMI remained unaltered (P=0.22) because the fraction of slim women more than doubled (3.5 to 9.0%; P<0.001). CONCLUSION: A steep increase in the fraction of overweight Inuit men and women calls for intervention. Westernization predicted increased BMI. In women the increased number of obese people was accompanied by an increased fraction of slim people. This illustrates that transition can be modified and indicates that monitoring of populations in transition should observe gender differences. Finally, the historical data argue against the global applicability of the WHO delineation of normal BMI.
Serum adiponectin concentrations in relation to maternaland perinatal characteristics in newborns
Authors: Mantzoros C , Petridou E , Alexe DM , Skalkidou A , Dessypris N , Papathoma E , Salvanos H , Shetty G , Gavrila A , Kedikoglou S , Chrousos G , Trichopoulos D
Published: January 2005

OBJECTIVE: To assess serum adiponectin levels of neonates in relation to ponderal index and birth length with and without adjustment for potential confounding factors including maternal factors and perinatal characteristics. DESIGN: A cross-sectional study. METHODS: Three hundred and three newborns (Caucasian, singleton, full term, with a birth weight of >/=2500 g, and apparently healthy) were included in the study. Blood samples were collected from the newborns no later than the fifth day of life for measurements of adiponectin and major IGF system components (IGF-I, IGF-II, IGF binding protein-3 (IGFBP-3)). The data were analyzed using simple and multiple regression analyses. RESULTS: Adiponectin is substantially higher in neonates than in adults, with no evidence of the gender dimorphism observed among adults. We found an inverse association between neonatal adiponectin levels and newborn ponderal index and a positive association with newborn length by univariate analysis. We also found a statistically significant inverse association of adiponectin with jaundice/bilirubin, and a marginally significant positive association of this hormone with IGFBP-3 but no significant association with any maternal factors. In multivariate analysis, the inverse association between serum adiponectin and ponderal index does not remain significant after adjustment for potential confounding factors. In contrast, neonatal adiponectin levels correlate inversely significantly and independently with liver maturity and IGF-II and tend to remain positively associated with IGFBP-3 and increased birth length. CONCLUSIONS: An inverse association of adiponectin with ponderal index by univariate analysis is not independent from confounding factors. In contrast, the positive association between serum adiponectin and birth length may reflect either a direct effect of adiponectin or an adiponectin-mediated increase in the sensitivity of tissues to insulin and components of the IGF system, and needs to be explored further.
Changes of diurnal rhythm and levels of total and free testosterone secretion from pre to late puberty in boys: testis size of 3 ml is a transition stage to puberty
Authors: Ankarberg-Lindgren C , Norjavaara E
Published: January 2005

OBJECTIVE: To establish levels for comparison for 24-h total and free serum testosterone in prepubertal boys and throughout pubertal development. DESIGN: The study subjects were 55 healthy boys, aged 5.0-18.6 years, who underwent serial sampling one or more times during their pubertal development. METHODS: Testicular volumes were determined by orchidometer. Serum testosterone was measured by a modified RIA (detection limit, 0.03 nmol/l). Free testosterone was calculated (calc-FT) using a formula derived from the law of mass action. RESULTS: Significant increases in testosterone and calc-FT concentrations in boys were found between testis volumes of 1 ml to 2 ml, 2 ml to 3 ml, 6 ml to 8 ml, and 10 ml to 15 ml. No differences were found between testis volumes of 3, 4, 5 and 6 ml neither were there differences between 8 and 10 ml, or between 15, 20 and 25 ml. Boys who had reached their final height had higher calc-FT values than boys who had the same pubertal development but had not reached their final height. Based on the results, puberty was classified into six stages: pre1 (testis, 1 ml), pre2 (testis, 2 ml), early (testis, 3-6 ml), mid (testis, 8-12 ml), late1 (testis,15-25 ml, not reached final height) and late2 (testis, 15-25 ml, reached final height). Serum testosterone was secreted with a diurnal variation in prepuberty and during puberty. The increase of testosterone in the morning hours started earlier in pubertal than in pre-pubertal boys. The most pronounced diurnal rhythm was found in early and in mid puberty. CONCLUSION: Using a sensitive method, and a pubertal reclassification, we have established levels for comparison of testosterone and calc-FT in prepubertal and pubertal boys. The existence of data for comparison forms the basis for future studies on pubertal disorders.
Does the response of bone mass to calcium supplements depend on calcium absorption efficiency?
Authors: Smith E , Need AG , Schultz CG , Horowitz M
Published: January 2005

OBJECTIVE: Calcium supplements can reduce bone resorption and slow bone loss after the menopause, but these effects may be limited by poor intestinal absorption. Since the increase in blood ionised calcium and decrease in serum parathyroid hormone after a calcium load are diminished in patients with poor calcium absorption, we aimed to see whether the response of bone mineral content (BMC) to calcium is related to initial calcium absorption. DESIGN: We retrospectively examined the changes in forearm BMC in 164 patients (139 women and 25 men) receiving calcium therapy alone for low bone density in a university hospital. METHODS:BMC was measured in a Molsgaard single energy absorptiometer and calcium absorption in a single blood sample 1 h after a dose of 5 muCi (45)Ca in 20 mg calcium carrier. Results were analysed by simple and multiple regression analysis. RESULTS: Mean forearm BMC did not change significantly over the mean 43 (s.D., 33) months of treatment (1.023 (0.247) to 1.017 (0.246) g/cm). The annual percentage of change was positively related to both body weight (r=0.180; P=0.020) and radiocalcium absorption (r=0.185; P=0.017). Multiple linear regression confirmed that both variables contributed to the change in BMC (P=0.023 and 0.019 respectively). The mean annual percentage of change in BMC on calcium therapy was not related to age, initial BMC, serum 1,25-dihydroxyvitamin D or fasting urinary calcium/creatinine ratio. CONCLUSIONS: These results support our earlier studies which suggest that poor calcium absorption limits the response of bone to calcium supplements.
Thyroid follicular adenomas may display features of follicular carcinoma and follicular variant of papillary carcinoma
Authors: Vasko VV , Gaudart J , Allasia C , Savchenko V , Di Cristofaro J , Saji M , Ringel MD , De Micco C
Published: January 2005

Thyroid follicular adenomas (FA) are encapsulated tumors lacking vascular, capsular or lymphatic invasion and the typical nuclear features of papillary carcinoma (PC). However, some FA demonstrate nuclear atypia reminiscent of either follicular carcinomas (FC) or follicular variant of papillary carcinomas (FVPC), suggesting they may represent precursors of malignant transformation. We hypothesized that an objective evaluation of nuclear chromatin patterns could be used to define atypical follicular tumors (AFT) that are likely to be premalignant. To test this hypothesis, we used a computer-aided image analysis system to define the chromatin pattern of nuclei from thyroid tumors. To validate the system, we analyzed 3000 nuclei from 10 FA, 10 FC, and 10 FVPC samples and accurately distinguished between these classes of tumors. Then, we analyzed nine AFT and, in parallel, we analyzed the tumors for activating mutations of N2-RAS and over-expression of RET. The predominant chromatin pattern of AFT was of FA type in two cases, FC type in two cases, and PC type in three cases. One case contained similar numbers of FC and PC nuclei and one was comprised of a mixture of the three nuclear types. Neither RAS mutation nor RET overexpression were detected in FA. N2-RAS mutations were found in 33% of AFT, 20% of FC and 20% of FVPC without correlation with chromatin pattern. Over-expression of RET was detected in 45% of AFT, 20% of FC and 50% of FVPC and was correlated with PC nuclei. These results show that AFT are a heterogenous group of tumors, containing genuine benign tumors and tumors that share morphological and molecular features with follicular and papillary carcinomas that might be precursors of both types of thyroid carcinomas.
Urotensin-II is present in pancreatic extracts and inhibits insulin release in the perfused rat pancreas
Authors: Silvestre RA , Egido EM , Hernandez R , Leprince J , Chatenet D , Tollemer H , Chartrel N , Vaudry H , Marco J
Published: January 2005

OBJECTIVE: Previous work from our laboratory has demonstrated that frog urotensin-II (UII), at a high concentration, inhibits glucose-induced insulin release in the rat pancreas. We have investigated the effect of rat UII and two structural analogs on insulin secretion and searched for the presence of UII-immunoreactivity in rat pancreatic extracts. METHODS: The study was performed in the perfused rat pancreas. UII as well as its analogs were synthesized by solid phase methodology. Pancreatic extracts were analyzed for UII by reversed-phase HPLC combined with a sensitive UII RIA. RESULTS: Infusion of synthetic rat UII inhibited glucose-induced insulin release in a dose-dependent manner (IC(50): 0.12 nmol/l). UII (1 nmol/l) also inhibited the insulin responses induced by carbachol, glucagon-like peptide-1, and a calcium channel agonist (BAY K 8644). The inhibitory effect of UII was mimicked by the potent G protein-coupled receptor (GPR14) agonist [3-iodo-Tyr(6)]UII(4-11). In contrast, [Ala(8)]UII(4-11), a UII analog devoid of contractile activity on rat aortic rings, did not affect glucose-induced insulin secretion. Analysis of rat pancreatic extracts revealed the presence of an immunoreactive peptide exhibiting the same retention time as synthetic rat UII. CONCLUSIONS: Our results demonstrate that UII is a potent insulinostatic peptide. The observation that UII is actually present in the pancreas suggests that this peptide may play a physiological role in the control of insulin secretion. Concerning the two UII analogs tested, only [3-iodo-Tyr(6)]UII(4-11), reportedly possessing GPR14-mediated contractile activity, mimics the insulinostatic effect of UII. This finding would support the view that UII acts on the pancreatic beta cell through the GPR14 receptor.
Genetic defects in GH synthesis and secretion
Authors: Bona G , Paracchini R , Giordano M , Momigliano-Richiardi P
Published: January 2005

Growth hormone (GH) is a multifunctional hormone produced in the anterior pituitary that promotes postnatal growth of skeletal and soft tissues. GH secretion and release are complex phenomena depending on several intrinsic and extrinsic factors modulating the release of two hypothalamic hormones, GH releasing hormone and somatostatin. Any genetic or acquired disorder that impairs GH secretion or action causes a pathological phenotype characterized by harmonic short stature with isolated GH deficiency (IGHD) or combined pituitary hormone deficiency (CPHD). In this article we report current knowledge about the genetic basis of IGHD and CPHD.
New molecular mechanisms of GH resistance
Authors: Rosenfeld RG , Hwa V
Published: January 2005

Primary growth hormone (GH) resistance describes growth failure in the presence of normal, or even elevated, GH secretion. In its classic form, the phenotype is identical to that of GH deficiency, and was originally described in association with defects of the GH receptor. With increasing understanding of the GH-insulin-like growth factor (IGF) axis, it has become apparent that GH resistance can result from either primary IGF deficiency (IGFD) or IGF resistance. Primary IGFD may be due to: (i) defects of the GH receptor, (ii) defects of post-GH receptor signaling or (iii) primary defects of IGF-I synthesis. IGF resistance may result from: (i) defects of the IGF receptor, (ii) defects of post-IGF receptor signaling, (iii) defects of IGF binding proteins or (iv) defects of the epiphyseal growth plate or of regulatory proteins involved in epiphyseal growth.
Evidence for a link between IGF-I and cancer
Authors: Jenkins PJ , Bustin SA
Published: January 2005

Cancer risk is determined by a combination of environmental factors and genetic predisposition. Recent evidence suggests that dietary and related factors such as physical activity and body size may influence cancer risk through their effects on the serum concentration of IGF-I and its binding proteins. The growth hormone (GH)/IGF-I axis is involved in both human development as well as the maintenance of normal function and homeostasis in most cells of the body. In addition to their classical role as endocrine hormones, its members regulate a wide range of biological functions such as cell proliferation, differentiation and apoptosis through paracrine and autocrine mechanisms. During cancer development this complex network regulating tissue homeostasis breaks down, with inappropriate expression of the GH/IGF-I axis making an important contribution. The increased understanding of the molecular mechanisms and signalling pathways regulated by the GH/IGF-I axis has started to provide significant insights into the aetiology, prevention and therapy for a number of common cancers.
The GH/IGF-I axis and longevity
Authors: Holzenberger M
Published: January 2005

Several converging lines of evidence obtained over the last years in a wide variety of experimental model organisms suggest that the ageing process is regulated by genes that encode proteins from the somatotroph axis: longevity genes like daf-2, which were identified using mutant Caenorhabditis elegans strains, turned out to be orthologues of the mammalian genes encoding insulin-like signalling cascade proteins. Transgenic flies with mutations in the corresponding insect genes showed a similar pattern of increased lifespan. Finally, mice with spontaneous mutations leading to pituitary hormone deficiency significantly outlived controls. While these and other genetic models suggest that the downregulation of the somatotroph axis can slow the ageing process, other results from studies using pharmacological administration of growth hormone suggest that such stimulating treatment can restore some of the phenotypic traits associated with youth. To better understand the role of the insulin-like receptors in mammalian lifespan regulation and ageing, we explored the phenotype of heterozygous IGF-I receptor (IGF1R) knockout mice. Compared with control littermates these mutants live longer without any obvious impairment of their health and physiology, except a reduced glucose tolerance that we observed in males. These IGF1R(+/-) mutants were also more resistant to oxidative stress in vivo, and we identified a possible molecular pathway linking underphosphorylation of IGF-I receptors to the lack of activation of p66Shc, a protein capable of increasing resistance to oxidative stress through regulation of a set of downstream genes. These and other results suggest that in mammals too, lifespan can be increased by continuous, long-term downregulation of IGF signalling. Since growth hormone administration normally stimulates IGF production in tissues, the question arises whether the beneficial effects of GH, as reported by others, could be IGF independent. This hypothesis can be addressed, for example, by adequately combining existing transgenic mouse models.
The psychological burden of short stature: evidence against
Authors: Voss LD , Sandberg DE
Published: January 2005

Short stature, per se, is clearly not a disease, but is commonly perceived to be associated with social and psychological disadvantage. The assumption, widely held by pediatricians that short children are likely to be significantly affected by their stature, has been founded largely on older, poorly designed clinic-based studies and laboratory investigations of beliefs about the association between stature and individual characteristics. In contrast, data from more recent and better designed clinic- and community-based studies show that, in terms of psychosocial functioning, individuals with short stature are largely indistinguishable from their peers, whether in childhood, adolescence or adulthood. Parents and children alike should be reassured by these findings. In the absence of clear pathology, physical or psychological, GH therapy for the short but otherwise normal child raises ethical concerns about so-called 'cosmetic endocrinology'.
Why do some children of short stature develop psychologically well while others have problems?
Authors: Erling A
Published: January 2005

The present paper addresses the question: why do some children of short stature develop psychologically well while others have problems? Based on the work of Wallander and Varni, a model is presented to illustrate risk as well as resistance factors that are important for children of short stature.It is suggested that important risk factors for the psychological adjustment of children of short stature are the child's satisfaction with its height and the aetiology of the short stature. Another possible risk factor is the tendency for people in the child's environment to treat the child as if he or she were younger than is actually the case. The most important risk factor, however, seems to be the psychosocial stress related to being teased or bullied due to the short stature. Important resistance factors for children of short stature might be the child's temperament, familial support and coping strategies.It is concluded that an important aim for future research is, in a multi-disciplinary setting, to empirically test models of risk and resistance factors that are relevant for children of short stature.
Benefit of postponing normal puberty for improving final height
Authors: Wit JM , Balen HV , Kamp GA , Oostdijk W
Published: January 2005

Experiments of nature and clinical observations have provided indications that postponing puberty may increase final height in short children. In children with central precocious puberty, a GnRH analog (GnRHa) alone is efficacious in increasing final height, but in other conditions a combination of growth hormone (GH) and GnRHa is needed. In GH-deficient children with early onset of puberty and poor height prediction, the combination of GH and GnRHa increases final height by 1.0-1.3 s.d. In children with idiopathic short stature and persistent short stature after intrauterine growth retardation, the combination also appears to be beneficial. Potential side effects include weight gain, a negative effect on bone mineralization, and psychosocial consequences. More data on long-term safety have to be collected before the combination of GH and GnRHa in children with idiopathic short stature should be considered for clinical use outside clinical trials.
Lessons from the national cooperative growth study
Authors: Wyatt D
Published: January 2005

OBJECTIVE: To review the National Cooperative Growth Study (NCGS), a national post-marketing surveillance program for children treated with biosynthetic growth hormone (GH) products from Genentech. METHODS: Representative data are presented to summarize the extensive experience of the NCGS. This study is a multicenter, observational surveillance registry begun in 1985 in coordination with the release of the first recombinant DNA biosynthetic GH. RESULTS: After almost 20 years, data from over 47 000 patients representing 165 000 patient years have been collected. There are over 12 000 active subjects (estimated to be approximately 75% of all current patients treated with a Genentech GH product) at 435 centers, providing extensive efficacy and safety data. The GrowTrak program is a secure, user-friendly database which encourages a high level of participation by the pediatric endocrine community in the USA. Efficacy has been shown in a variety of clinical diagnoses, including isolated (IGHD) and organic growth hormone deficiency (OGHD), idiopathic short stature (ISS), and Turner syndrome. Safety monitoring of this large population has provided reassuring evidence that leukemia (de novo or relapse), extracranial nonleukemic neoplasms and central nervous system (CNS) tumor recurrence are not associated with GH therapy. A small risk of intracranial hypertension and slipped capital femoral epiphyses has been suggested, especially in children with renal disease or Turner syndrome. NCGS substudies have also provided important insights into actual clinical practice. For example, screening for renal, cardiac, or auditory comorbidities in Turner syndrome is often done less than is recommended by national guidelines (NCGS 9). Furthermore, almost 65% of children referred for short stature may be lost to follow-up before an evaluation is completed (NCGS 8). CONCLUSIONS: The NCGS has proven to be a valuable method of monitoring the safety and efficacy of biosynthetic GH. The study has attracted wide physician participation due to the data collection software used and the extensive sharing of the analyses of that data with the providers.
Ghrelin: update on a novel hormonal system
Authors: Korbonits M , Grossman AB
Published: January 2005

Ghrelin is a peptide hormone secreted into the circulation from the stomach but also synthesised in a number of tissues, suggesting both endocrine and paracrine effects. These include: stimulation of GH, prolactin and ACTH secretion; an increase in appetite; a diabetogenic effect on carbohydrate metabolism; positive inotropic effects on heart; vasodilatation; and effects on cell proliferation. The possibility of chronic manipulation of the ghrelin system on body weight, growth and appetite remains an exciting new field of exploration.
Novel analogs of ghrelin: physiological and clinical implications
Authors: Halem HA , Taylor JE , Dong JZ , Shen Y , Datta R , Abizaid A , Diano S , Horvath T , Zizzari P , Bluet-Pajot MT , Epelbaum J , Culler MD
Published: January 2005

Ghrelin, the 28 amino acid peptide recently identified as the natural ligand for the growth hormone (GH) secretagogue (GHS) receptor, has multiple activities in addition to stimulation of GH secretion, including stimulation of feeding and weight gain. To utilize these actions for potential therapeutic benefit, we have produced analogs of human ghrelin with enhanced metabolic stability, affinity for the GHS receptor, and efficacy in stimulating weight gain. We have also discovered an analog of ghrelin, BIM-28163, that is an antagonist at the GHS receptor and that fully inhibits GHS receptor activation induced by native ghrelin. In vivo, BIM-28163 does not increase GH secretion but fully blocks ghrelin-induced GH secretion. In contrast, BIM-28163 acts as a full agonist with regard to the ghrelin actions of stimulating weight gain and food intake. These results suggest that a receptor other than the GHS receptor mediates the actions of ghrelin on feeding and weight gain. This concept is strengthened by our observation that at certain hypothalamic sites, BIM-28163 acts as an antagonist of ghrelin-induced neuronal activation, while at other sites, both ghrelin and BIM-28163 induce neuronal activation via the same receptor. Collectively, these results indicate the existence of a novel ghrelin receptor that may regulate the feeding activity of ghrelin. Using BIM-28163 as a tool to define the endogenous role of ghrelin in normal GH secretion, we have demonstrated that antagonism of the GHS receptor in normal rats does not impair the pulsatility of GH secretion but lowers the pulse amplitude and mean GH level. These results demonstrate that endogenous ghrelin acts to amplify the basic pattern of GH secretion established by the interplay of hypothalamic GH-releasing hormone and somatostatin. These studies demonstrate the feasibility of creating ghrelin analogs that are selective for specific activities, as well as their utility in dissecting the role of ghrelin in both normal physiology and specific pathologies.
Cystic fibrosis -- therapeutic challenge in cystic fibrosis children
Authors: Staab D
Published: January 2005

Cystic fibrosis (CF) is the most common autosomal recessive disease with fatal outcome in Caucasians with a frequency of 1 in 2500 life births. It is caused by mutations in a single gene on the long arm of chromosome 7 encoding a protein called the cystic fibrosis transmembrane regulator (CFTR). The defect in CFTR leads to pathological changes in all organs with mucus-secretory glands, e.g. airways, pancreas, gut, biliary tract, vas deferens and sweat glands. Despite impressive advances in understanding the molecular basis of the disease, life expectancy is still limited in CF and chronic infection of the lung resulting in fibrosis and bronchiectasis followed by respiratory insufficiency is still the main factor in morbidity and the leading cause of death. Poor nutritional status is one of the major problems in the vicious cycle of chronic inflammation and lung destruction and its impact on outcome in lung function has been demonstrated. The possible role of growth hormone treatment in this context will be discussed.
The heart: an end-organ of GH action
Authors: Colao A , Vitale G , Pivonello R , Ciccarelli A , Di Somma C , Lombardi G
Published: January 2005

Several experimental and clinical studies have indicate that the heart is an end-organ of GH action. Patients with either childhood- or adulthood-onset GH deficiency (GHD) have abnormalities of cardiac structure and function, such as reduced cardiac mass, impaired diastolic filling and reduced left ventricular response at peak exercise. These cardiovascular abnormalities can be reversed, at least partially, after GH replacement therapy. On the other hand, the chronic overproduction of GH and IGF-I in acromegaly leads to the development of a specific cardiomyopathy. Concentric cardiac hypertrophy occurs in more than two-thirds of patients at diagnosis and is commonly associated with diastolic dysfunction. In later stages, impaired systolic function ending in heart failure can occur if GH/IGF-I excess is not controlled. Additionally, acromegalic cardiomyopathy is complicated by abnormalities of cardiac rhythm and cardiac valves. Successful control of acromegaly is accompanied by a decrease of the left ventricular mass and improvement of cardiac function. These beneficial effects appear earlier in young patients with short disease duration than in elderly patients. In conclusion, GH and IGF-I play a main role in the regulation of cardiac development and performance.
Treating to goal: challenges of current management
Authors: Barnett AH
Published: January 2005

Extensive evidence supports the benefits of treating to glycated haemoglobin (HbA1c) goal, both in terms of health and economic outcomes. As shown by the UK Prospective Diabetes Study (UKPDS) and the Diabetes Control and Complications Trial (DCCT), the risk of patients with type 2 diabetes developing vascular complications is strongly correlated with HbA1c levels and the duration of poor glycaemic control. Moreover, good glycaemic control significantly reduces the risk of complications. In controlled clinical trials, a number of pharmacological agents have been shown to significantly reduce HbA1c levels in patients with type 2 diabetes. However, the reality is that most patients with type 2 diabetes have HbA1c levels above the recommended target levels. Although there are regional differences in the average HbA1c level, poor glycaemic control is a universal problem that will continue to grow in line with the rapidly increasing prevalence of type 2 diabetes. Barriers to good blood glucose control are present in almost every aspect of diabetes care. Furthermore, in patients with type 2 diabetes, therapy-, patient- and/or healthcare system-related barriers are compounded by an ongoing decline in beta-cell function that is characteristic of the progressive nature of the disease. Therapy-related barriers include reduced long-term efficacy with oral agents, fear of hypoglycaemia and a variety of issues related to flexibility and convenience that encourage poor compliance with therapy. From the patient perspective, issues relating to lifestyle, education, psychology and the environment can prevent optimum diabetes self-management. Poor access to and/or use of specialist healthcare resources also has a negative effect on treatment outcomes. These barriers to glycaemic control need to be overcome so that the established benefits of reducing glucose to normal or near-normal levels can be experienced by more people with type 2 diabetes.
Resourcing issues
Authors: Gagliardino JJ
Published: January 2005

Diabetes is a chronic, progressive disease and achieving appropriate control of glycaemia and the other associated cardiovascular risk factors is essential to prevent its long-term complications. Currently, recovery and rehabilitation from the cardiovascular complications of diabetes are the major focus of diabetes care rather than primary and secondary prevention of diabetes and its complications. This focus, coupled with limited funding and other resource issues, means that diabetes care and outcomes are generally suboptimal. More efficient and effective management strategies, primarily based upon a broad educational approach including both those with diabetes and their care-givers will be essential in reducing the cost of diabetes and diabetes-related complications. Continuous education of patients and providers increases the quality of care and improves clinical and metabolic outcomes as well as reducing the cost of care and optimising human and financial resources. Thus, education will be a key strategy in minimising the growing burden of diabetes on society. Making these changes will require the co-operation of patients, their families, the community, healthcare policy makers, national governments and the pharmaceutical industry. Medical schools must also place more emphasis on educating doctors about chronic disease management using not only recovery and rehabilitation, but also prevention strategies, emphasising the importance of helping patients to participate in the control of their disease.
Psychological barriers
Authors: Skinner TC
Published: January 2005

Type 2 diabetes treatment outcomes ultimately depend on patients and their ability to make long-term behavioural changes that support good self-care and metabolic control. Patients' perceptions about diabetes and diabetes-related complications can have a strong influence on their emotional well-being, as well as day-to-day self-care and the quality of metabolic control. The gravity of diabetes is often underestimated, and many patients do not understand the link between poor glycaemic control and long-term complications of the disease. Similarly, people with diabetes commonly undervalue the role of lifestyle changes and pharmacological therapy in preventing future complications. Negative emotions and preconceptions about treatment can also discourage adherence to treatment plans. 'Psychological insulin resistance' caused by fear and concerns about insulin and daily insulin injections can discourage many patients from starting insulin therapy, even if oral agents have failed. Depression, stress and anxiety represent further obstacles to optimum self-care and the attainment of glucose goals. Healthcare professionals should endeavour to understand and accommodate these issues when setting personal treatment goals and developing plans to achieve them. Importantly, the advice and support they provide should be tailored to the unique needs of each patient. There is scope to improve outpatient consultations to ensure agreement between patients and professionals concerning issues discussed and decisions made, and this may help to improve recall and motivation to manage diabetes. Engaging patients in the goal-setting process can help to overcome potential barriers to good self-care and may increase the probability that treatment goals are achieved.
Overcoming obstacles: collaboration for change
Authors: Funnell MM
Published: January 2005

Effective diabetes care requires a partnership between prepared, proactive practice teams and informed, activated patients. Diabetes education helps to overcome many of the barriers to effective self-management by enabling people with diabetes to make informed decisions about their day-to-day self-care. Both psychosocial and health outcomes have been improved through a variety of training programmes; however, education must be coupled with ongoing self-management support if these benefits are to be sustained. The principal goal of diabetes education has undergone a major shift over the past few years--evolving from primarily didactic interventions, focused on encouraging patients to adhere to the prescribed therapy, towards more interactive learning that supports people in making informed, self-directed decisions.
Overcoming obstacles: new management options
Authors: Heinemann L
Published: January 2005

The outlook for patients with type 2 diabetes looks set to improve with the availability of new diabetes management options that provide more comprehensive control of blood glucose levels and/or encourage better patient compliance than previous alternatives. New insulin analogues, such as insulin lispro, aspart and glargine, allow more physiological insulin replacement and greater freedom in the timing and content of meals, compared with regular insulin preparations. The development of novel non-invasive routes of insulin administration promises to further improve diabetes management. Many barriers to initiating insulin relate to the need for frequent insulin injections, fears that insulin injections will be painful and difficult to administer, and concerns about hypoglycaemia and weight gain. Thus, each measure that reduces these barriers will help to prevent inappropriate delays in starting insulin therapy as well as to promote better compliance with therapy. The output from continuous glucose monitoring devices will assist accurate insulin replacement, which is difficult using point-estimates of blood glucose. Such devices will hopefully also circumvent the need for finger stick tests. There are several novel therapies in development that will further expand the portfolio of treatment options for patients with type 2 diabetes. Improved quality and choice of diabetes management options will provide doctors with the tools they require to develop tailored treatment plans, increase the probability that treatment goals are achieved and thereby reduce the risk of patients developing late-stage diabetes-related complications.
A perspective on stem cells by a clinician
Authors: Hughes IA
Published: January 2005

Stem cell terminology has entered the lexicon of medical practitioners even though the application of harvesting stem cells to treat diseases other than haematological disorders is not yet a reality in clinical practice. All branches of medicine will be affected by the new technology, more so those related to regenerative cell-based therapy for disorders such as Parkinson's disease, Alzheimer's disease, multiple sclerosis and traumatic injuries to the nervous system. Endocrinology is not a branch of medicine that carries a burden of disease that merits priority for the early application of stem cell therapy once the technique becomes safe and practical to do so. However, the allied disorder of diabetes is, sine qua non, an ideal example of how stem cell therapy has the potential to cure a chronic disabling condition. It is logical therefore to have included a number of articles on stem cells in this special issue of this journal, publishing papers on a range of endocrine-related topics.