Does growth hormone (GH) enhance growth in GH-deficient children with myelomeningocele?

GH deficiency (GHD) in patients with myelomeningocele leads to the question of whether these disabled patients should be treated with human GH. To date, only a few short-term reports of GH therapy are available in the literature, and long-term data for final height are lacking. We report auxological and laboratory data for seven prepubertal myelomeningocele patients with proven GHD (idiopathic GHD or neurosecretory dysfunction) during GH treatment. All patients (five males and two females; median chronological age, 6.6 yr) had shunted hydrocephalus and were treated with GH (0.5 IU/kg x week; 0.15 mg/kg x week; daily sc injections) over a median period of 38 months (range, 35-49 months). GH secretion was analyzed by measurement of spontaneous overnight GH secretion and two standard stimulation tests. Auxological parameters, bone age, serum levels of insulin-like growth factor I and insulin-like growth factor-binding protein-3, and neurological and orthopedic status were documented regularly. Median growth velocity of supine length improved during treatment (at start, 3.7 cm/yr; after 36 months, 5.7 cm/yr; P < 0.05), with highest levels 6 months after the start of therapy (8.1 cm/yr). The growth velocity of arm span was greater than these values. Supine length SD score for chronological age increased from -4.71 (at start) to -3.35 (after 36 months; P = NS), length SD score for bone age increased from -2.70 to -2.23 (P = NS), and arm span SD score increased from -2.98 to -1.75 (P < 0.05). The growth velocities of length and arm span remained significantly above the pretreatment values (P < 0.05). Symptomatic tethered cord associated with progression of scoliosis developed in two of seven children. GH treatment significantly improved the growth velocities of body length and arm span. However, the increase in length SD score was not significant, whereas arm span SD scores significantly improved over the study period.     

Can growth hormone (GH) accelerate aging? Evidence from GH-transgenic mice

Overexpression of heterologous growth hormone (GH) in transgenic mice results in numerous phenotypic effects, including a drastically shortened life span. Early onset of pathological changes in the kidneys, glomerulosclerosis and glomerulonephritis, undoubtedly contributes to and perhaps accounts for reduced longevity of these animals. However, GH-transgenic mice exhibit various symptoms of accelerated aging, including increased astrogliosis, shortened reproductive life span, and early onset of age-related changes in cognitive function, hypothalamic neurotransmitter turnover, and plasma corticosterone levels. The hypothesis that supraphysiological levels of GH can accelerate aging derives indirect support from findings in GH-deficient and GH-resistant mutant mice in which aging is delayed and the life-span is increased and from the reciprocal relationship of body size and longevity within species.     

Vitamin D and growth hormone regulate growth hormone/insulin-like growth factor (GH–IGF) axis gene expression in human fetal epiphyseal chondrocytes

ObjectiveCell proliferation and gene expression regulation were studied in human fetal epiphyseal chondrocytes to ascertain the involvement of GH–IGF axis components in human fetal growth regulation by 1,25-dihydroxyvitamin D₃ (VitD) and growth hormone (GH).DesignChondrocytes from primary cultures were plated in serum-free medium for 48 h and incubated for a further 48 h with VitD (10^?11 to 10^?6 M) and/or IGF-I (100 ng/ml) and/or GH (500 ng/ml). We analyzed ³H-thymidine incorporation into DNA and IGF-I, IGFBP-3, GHR, SOX9, COL2A1, aggrecan and COMP gene expression by real-time quantitative PCR.ResultsVitD dose-dependently and significantly inhibited ³H-thymidine incorporation whereas GH had no effect on proliferation and, when combined with VitD, the same inhibition was observed as with VitD alone. IGF-I (100 ng/ml) significantly stimulated proliferation and opposed inhibition by VitD. VitD dose-dependently stimulated IGF-I (11.1 ± 19.8 at VitD 10^?6 M), IGFBP-3 (2.6 ± 0.9), GHR (3.8 ± 2.8) and COMP (1.5 ± 0.6) expression whereas it inhibited SOX9 (0.7 ± 0.2), COL2A1 (0.6 ± 0.3) and aggrecan (0.6 ± 0.2) expression and had no significant effect on IGF-II. IGF-I stimulated IGF-I, IGFBP-3, SOX9, COL2A1 and aggrecan expression and opposed COL2A1 and aggrecan gene expression inhibition by VitD. GH alone had no effect on gene expression whereas, in the presence of VitD, significantly-increased IGF-I expression stimulation was observed above values obtained with VitD alone (17.5 ± 7.4).ConclusionsOur results suggest that VitD regulation of fetal growth cartilage could have consisted of parallel enhancing of cell differentiation and conditioning to a phenotype more sensitive to regulation by other hormones such as GH as shown by increased GHR and IGF-I expression, but not by IGF-II expression which was not regulated.     

Therapeutic potential of Takeda‐G‐protein‐receptor‐5 (TGR5) agonists. Hope or hype?

The gastrointestinal tract regulates glucose and energy metabolism, and there is increasing recognition that bile acids function as key signalling molecules in these processes. For example, bile acid changes that occur after bariatric surgery have been implicated in the effects on satiety, lipid and cholesterol regulation, glucose and energy metabolism, and the gut microbiome. In recent years, Takeda‐G‐protein‐receptor‐5 (TGR5), a bile acid receptor found in widely dispersed tissues, has been the target of significant drug discovery efforts in the hope of identifying effective treatments for metabolic diseases including type 2 diabetes, obesity, atherosclerosis, fatty liver disease and cancer. Although the benefits of targeting the TGR5 receptor are potentially great, drug development work to date has identified risks that include histopathological changes, tumorigenesis, gender differences, and questions about the translation of animal data to humans. The present article reviews the noteworthy challenges that must be addressed along the path of development of a safe and effective TGR5 agonist therapy.     

How many tests are required to diagnose growth hormone (GH) deficiency in adults?

OBJECTIVE: The diagnosis of GH deficiency in adults relies on the results of GH provocative testing. Whilst in some patients the testing strategy is clear, this is not the case in all patients. The objective of this study was to further examine the concordance between the GH responses to two different provocative stimuli, to correlate this with the number of additional pituitary hormone deficits, and to produce guidelines as to which patients require two GH provocative tests and which require only one. STUDY DESIGN AND PATIENTS: The results of GH provocative tests were reviewed in 103 patients (mean age 28 years, 48 male), with documented or potential hypothalamic-pituitary disease and 35 normal volunteers (mean age 21 years, 18 male). All patients and normal volunteers underwent an insulin tolerance test (ITT) and an arginine stimulation test (AST). Severe GH deficiency was defined as a GH response to an ITT of < 5 mU/l and a GH response to an AST of < 2 mU/l, utilizing data from previous studies in this unit. Patients were divided into four groups according to the number of anterior pituitary hormone deficits present other than possible GH deficiency: no other pituitary hormone deficits (GHD0) or one, two or three other hormone deficits (GHD1, GHD2 or GHD3). RESULTS: The 103 patients were divided between the four groups as follows: 69 (67%) in GHD0, 15 (14. 6%) in GHD1, six (5.8%) in GHD2, and 13 (12.6%) in GHD3. There was a significant decline in the median GH peak to both the ITT and the AST with increasing numbers of other pituitary hormone deficits (P < 0.0001). If the magnitude of the difference between each individual's GH response to the ITT and AST is plotted against the mean GH value a clear trend is seen (Spearmans rank correlation = 0. 88, P < 0.0001) indicating that the magnitude of the difference between the GH responses to an ITT and AST increases with the underlying mean GH value. These data allow the estimation of the median ITT/AST ratio as 1.17 (CI 0.98, 1.39). None of the control subjects and 14.1% (10), 26.7% (four), 83% (five) and 92.3% (12) of groups GHD0, 1, 2 and 3, respectively, had severe GHD. The concordance between the AST and ITT (percent of patients in whom both tests confirmed or refuted the biochemical diagnosis of severe GHD) was 100%, 76.8%, 66.6%, 83.3%, and 92.3% in the controls, GHD0, 1, 2, and 3, respectively. Thus, 16/69 GHD0, 5/15 GHD1, 1/6 GHD2 and 1/13 GHD3 patients were misclassified by one or other test. CONCLUSION: We have demonstrated that a constant ratio links the GH response to an ITT and AST in an individual, rather than a constant difference, and that the difference between the GH responses to two provocative stimuli is greater in those patients with milder degrees of GH deficiency or insufficiency. These patients tend to have one or no additional pituitary hormone deficits and may be misclassified if a single GH provocative test is performed. We suggest that whilst a single GH provocative test can be used with confidence in patients with two or three additional pituitary hormone deficits, in patients with suspected isolated GH deficiency or with only one additional pituitary hormone deficit, two GH provocative tests should be performed.     

131I治疗Graves甲亢专家共识(2010年)

甲状腺功能亢进症(hyperthyroidism,简称甲亢)以Graves甲亢最多见,我国人群患病率约1.2％[1].Graves甲亢的主要治疗方法为抗甲状腺药物和131I治疗.近年来,用131I治疗Graves甲亢的患者呈增多趋势,为了进一步规范131I治疗,由多位核医学专家经多次共同商讨,数易其稿,历时2年,就有关131I治疗Graves甲亢临床相关问题形成此共识.     

Height velocity and IGF‐I assessment in the diagnosis of childhood onset GH insufficiency: do we still need a second GH stimulation test?

OBJECTIVE: The diagnosis of GH insufficiency (GHI) in childhood is not straightforward. Our aim was to test the sensitivity and specificity of height velocity (HV), IGF-I, IGFBP-3 and GH stimulation tests alone or in combination in the diagnosis of GHI. DESIGN: A retrospective review of patients with GHI and idiopathic short stature (ISS) diagnosed in our centre and followed up to the completion of linear growth. PATIENTS: Thirty-three GHI children and 56 children with ISS were evaluated. GHI diagnosis was based on fulfilment of anthropometric, endocrine and neuroradiological criteria: stature < or = -2 z-score, delayed bone age (at least 1 year), GH peak response to at least two different provocative tests < 10 micro g/l (20 mU/l), brain MRI positive for hypothalamus-pituitary abnormalities, catch-up growth during the first year of GH replacement therapy > or = 75th centile, peak GH response to a third provocative test after growth completion < 10 micro g/l (20 mU/l). Children with anthropometry resembling that of GHI but with peak GH responses > 10 micro g/l (20 mU/l) were diagnosed as ISS. MEASUREMENTS: All subjects underwent standard anthropometry. GH secretory status was assessed by clonidine, arginine and GHRH plus arginine stimulation tests. IGF-I and IGFBP-3 circulating levels were measured by immunoradiometric assay (IRMA). The following cut-off values were chosen to discriminate between GHI and nonGHI short children: HV < 25th centile over the 6-12 months prior to the initiation of GH therapy, peak GH responses < 10 or < 7 micro g/l (< 20 or < 14 mU/l) and IGF-I and IGFBP-3-values < -1.9 z-score. Sensitivity (true positive ratio) and specificity (true negative ratio) were evaluated. RESULTS: Taking 10 micro g/l (20 mU/l) as the cut-off value, sensitivity was 100% and specificity 57% for GH provocative tests, whereas taking 7 as the cut-off value, sensitivity was 66% and specificity rose to 78%. Sensitivity was 73% for IGF-I and 30% for IGFBP-3 measurement, whilst specificity was 95% for IGF-I and 98% for IGFBP-3 evaluation. HV assessment revealed a sensitivity of 82% and a specificity of 43%. When HV and IGF-I evaluations were used in combination, sensitivity reached 95% and specificity 96%. When both HV and IGF-I are normal (26% of our subjects) GHI may be ruled out, whereas when both the indices are subnormal (23%) GHI is so highly likely that the child may undergo only one GH provocative test and brain MRI and, thereafter, may begin GH therapy without any further test. In case of discrepancy, when IGF-I is normal and HV < 25th centile (44% of children), due to the relatively low sensitivity of IGF-I assessment and low specificity of HV, the patient should undergo GH tests and brain MRI. Finally, in the rare case of HV > 25th centile and subnormal IGF-I-values (7%), due to the high specificity of IGF-I measurement, the child should undergo one provocative test and brain MRI for the high suspicion of GHI. CONCLUSIONS: Our results suggest that a simple assessment of HV and basal IGF-I may exclude or, in association with only one stimulation test, confirm the diagnosis of GH insufficiency in more than half of patients with short stature.     

尿生长激素(GH)排泄物作为GH缺乏的筛选试验

垂体前叶分泌GH呈脉冲式,且在睡眠慢波期达最大量。当前常用的GH缺乏症筛选试验就是根据这个观察而定的,因此需要整夜进行试验;白天试验则GH分泌易受药物等刺激所影响。无论是白天或夜间试验都需反复插管取血标本,故费时,耗资,占据病床,且使病人自觉不适和有一定危险     

Measuring self‐report obsessionality in anorexia nervosa: Maudsley obsessive–compulsive inventory (MOCI) or obsessive–compulsive inventory‐revised (OCI‐R)?

Self-report measures are often used in research and clinical practise as they efficiently gather a large amount of information. With growing numbers of self-report measures available to target single constructs, it is important to revisit one's choice of instrument to be sure that the most valid and reliable measure is employed. The Maudsley Obsessive-Compulsive Inventory (MOCI) and the Obsessive-Compulsive Inventory-Revised (OCI-R) were administered to 223 female participants: 30 inpatients with anorexia nervosa (AN), 62 community cases with AN, 69 community cases weight restored from AN and 62 healthy controls. Both measures distinguished between clinical and healthy groups; however, the OCI-R showed superior internal reliability. Additionally, the OCI-R measures six (to the MOCI's four) obsessive-compulsive constructs, and uses a more sensitive response format (likert scale vs. categorical). It is recommended that the OCI-R be employed as the self-report instrument of choice for assessing obsessive-compulsive pathology in those with AN.     

Can some growth hormone (GH)-deficient children benefit from combined therapy with gonadotropin-releasing hormone analogs and GH? Results of a retrospective study

Recombinant GH (rGH) treatment does not invariably correct height deficits in GH-deficient children once puberty has begun. The addition of GnRH analogs (GnRHa) to delay puberty has been advocated, but published results are few and sometimes conflicting. We retrospectively compared GH-deficient children treated with rGH and GnRHa for at least 1 yr after entering puberty and having attained their final height (n = 23) with a matched control group treated only with rGH. Overall, combined therapy did not significantly increase final height relative to rGH alone. However, the shortest girls at the onset of puberty (<25th percentile) benefited more than the tallest (>75th percentile) in both final height relative to predicted height and pubertal catch-up growth. In the control group, patients having experienced intrauterine growth retardation (IUGR) attained a lower mean final height than patients without IUGR (difference significant in boys, but not in girls). In the combined therapy group, IUGR did not affect the final height of either sex. Our results suggest that two populations might benefit most from combined GnRHa and rGH therapy: girls particularly short at the onset of puberty and patients who had experienced IUGR. Further prospective studies are required to confirm these preliminary hypothesis.     

Transforming growth factor (TGF)‐β1 inversely related to vascular cell adhesion molecule‐1 in postmenopausal women with coronary artery disease. A possible mechanism for the putative cardioprotective role of TGF‐β1?

OBJECTIVE AND DESIGN: Transforming growth factor beta (TGF-beta1) is involved in a variety of physiological processes as well as in many diseases. Both in vitro and in vivo evidence suggest that TGF-beta1 may influence atherogenesis and a dominant protective role of TGF-beta1 on coronary arteries has been proposed. On the other hand, increased levels of soluble adhesion molecules have been found in patients with atherosclerosis, and adhesion of monocytes to the endothelium followed by migration to the intima, has been proved to be an early event in atherosclerosis. The purpose of the present investigation was to look at a possible relationship between circulating active TGF-beta1 and adhesion molecules in postmenopausal women with angiographically verified coronary heart disease (CHD) (n=118). RESULTS: Serum levels of the active form of TGF-beta1 showed a tendency to be lower in patients with increasing number of vessels with more than 50% stenosis (P=0.058), and there was higher TGF-beta1 in the group with one vessel disease compared with those with two or more vessels affected (P=0.041). Additionally, negative association between TGF-beta1 and VCAM-1 was found (r=-0.26, P=0.023). However, no associations were observed between TGF-beta1 and intercellular adhesion molecule-1 (ICAM-1) or E-selectin in the present study. CONCLUSION: We observed an inverse correlation between the active form of TGF-beta1 and VCAM-1 in postmenopausal women with verified CHD. These results may suggest a role of TGF-beta1 in CHD.