bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hexarelin as a test of pituitary reserve in patients with pituitary disease
Authors: Korbonits Márta , Kaltsas Gregory , Perry Leslie A. , Grossman Ashley B. , Monson John P. , Besser G. Michael , Trainer Peter J. 
Published: March 2003

BACKGROUNDThe insulin tolerance test (ITT) is the reference standard for the diagnosis of cortisol and growth hormone (GH) deficiency, but problems have occurred in small children in inexperienced hands and it is contraindicated in patients with cardiac disease and epilepsy. Hexarelin is a growth hormone‐releasing peptide with GH‐, ACTH/cortisol‐ and prolactin‐releasing effects which involve both hypothalamic and direct pituitary mechanisms. We therefore investigated whether it could be used to test GH and ACTH/cortisol reserve in patients with pituitary disease.METHODS AND SUBJECTSThe changes in GH and cortisol in response to insulin‐induced hypoglycaemia (intravenous human Actrapid 0.15 IU/kg) and hexarelin (2 μg/kg) in 19 patients with possible pituitary disease (5 males, mean age 39 years, range 21–70) were compared. The patients' responses during the hexarelin test were also compared to normal ranges of GH and cortisol responses established in healthy volunteers following hexarelin administration.RESULTS AND DISCUSSIONGH peak levels were significantly higher after hexarelin than after hypoglycaemia (mean ± SEM; 67.1 ± 16 vs. 26.9 ± 6.8 mU/l respectively; P < 0.001), while cortisol levels were significantly lower (420 ± 34 vs. 605 ± 50 nmol/l; P < 0.001). The peak responses of both hormones correlated significantly between the hexarelin and insulin‐induced hypoglycaemia tests (r = 0.80, P < 0.001 for cortisol). Peak GH levels after hexarelin and ITT showed a significant positive correlation with IGF‐I levels (r = 0.84 and r = 0.77, P < 0.001 for both). All patients with a subnormal GH response to hexarelin (<41.4 mU/l) had a peak GH response to ITT of <9 mU/l, and only one patient had a normal (although borderline) response to hexarelin with a subnormal GH response to the ITT. Although 17 of the 19 patients had corresponding cortisol responses to hexarelin and the ITT test (either failing or passing both), two patients had normal cortisol responses to hexarelin but subnormal responses to the ITT. A peak serum cortisol level following hypoglycaemia of >580 nmol/l is indicative of normal cortisol reserve, as established in patients undergoing surgery; only five of the normal volunteers and one of the thirteen patients with a normal ACTH/cortisol reserve on ITT had a peak cortisol >580 nmol/l in response to hexarelin.CONCLUSIONAdult patients who have a subnormal peak GH response to hexarelin are likely to be GH deficient on an insulin tolerance test. However, our data suggest that the hexarelin test is not a useful test of ACTH/cortisol reserve. The hexarelin test could be a useful first/screening test to diagnose adult GH deficiency, particularly in patients in whom an insulin tolerance test is contraindicated or who are already ACTH deficient and in whom the GH reserve alone is of interest.
Increased urinary albumin excretion in Cushing's syndrome: remission after correction of hypercortisolaemia
Authors: Koh  , Kim  , Chung  , Park  , Shong  , Hong  , Kim  , Lee  
Published: March 2003

OBJECTIVESIncreased urinary albumin excretion (UAE) in diabetic and nondiabetic subjects is frequently associated with insulin resistance syndrome and central obesity. Cushing's syndrome is also characterized by central obesity and insulin resistance. This study was undertaken to see whether increased UAE is found in Cushing's syndrome.DESIGNCross‐sectional study.PATIENTSThirteen consecutive patients with Cushing's syndrome.MEASUREMENTSPatients collected three overnight urine samples for the measurement of UAE by radioimmunoassay. UAE was also measured in 479 nondiabetic subjects who comprised the control population for this study. In the patients who had initial microalbuminuria, UAE was remeasured 2 months after successful removal of pituitary or adrenal tumours. Kidney biopsy was performed in three patients during adrenalectomy.RESULTSEleven out of 13 patients (84.6%) had increased UAE (> 9.6 μg/min), and eight patients (61.5%) had microalbuminuria or overt proteinuria (> 20 μg/min). Kidney biopsy revealed apparently normal glomerular structures without evidence of diabetic nephropathy. After correction of hypercortisolaemia, UAE declined profoundly in all of the patients.CONCLUSIONSMore than 80% of patients with Cushing's syndrome had increased UAE. This was almost completely reversed after successful treatment of hypercortisolaemia. These results indicate that endogenous hypercortisolaemia increases UAE by a mechanism that is presently unknown.
A novel mutation in the pendrin gene associated with Pendred's syndrome
Authors: Bogazzi Fausto , Raggi Francesco , Ultimieri Federica , Campomori Alberto , Cosci Chiara , Berrettini Stefano , Neri Emanuele , La Rocca Roberto , Ronca Giovanni , Martino Enio , Bartalena Luigi 
Published: March 2003

OBJECTIVEPendred's syndrome is an autosomal recessive disorder characterized by goitre, sensorineural deafness and iodide organification defect. It is one of the most frequent causes of congenital deafness, accounting for about 10% of hereditary hearing loss. It is caused by mutations in the pendrin (PDS) gene, a 21 exon gene located on chromosome 7. The aim of this study was to examine an Italian family affected with Pendred's syndrome at the molecular level.PATIENTSThirteen subjects belonging to a family from Southern Italy were evaluated for the clinical and genetic features of Pendred's syndrome.MEASUREMENTSExons 2–21 of the PDS gene were amplified from peripheral leucocytes by the polymerase chain reaction; mutation analysis was performed by single strand conformation polymorphism, direct sequencing and restriction analysis.RESULTSThe index patient had the classical triad of the syndrome and harboured two mutations in the PDS gene in the form of compound heterozygosity. He was found to be heterozygous for a cytosine to adenosine mutation at nucleotide 1523 in exon 13 and for a IVS 1001 + 1G → A mutation. The former is a novel mutation which results in a change of 508 threonine to asparagine in the putative eleventh transmembrane domain. The latter mutation in the donor splice site has already been described in other patients and is thought to lead to aberrant splicing and premature protein truncation. Three subjects who were heterozygous for one mutation had normal phenotypes. Two subjects had sensorineural deafness and were heterozygous for a single mutation. Goitre was found only in patients with Pendred's syndrome and was absent in all other individuals, albeit residing in an iodine‐deficient area.CONCLUSIONSWe have identified a novel mutation in the pendrin gene causing Pendred's syndrome, and confirm that molecular analysis is a useful tool for a definitive diagnosis. This is particularly relevant in cases such as in the subjects of our family in which the clinical features might be misleading and other genetics factors might be responsible for deafness.
The negative association between serum free testosterone and leptin is dependent on insulin‐like growth factor‐binding protein 1 in healthy young and middle‐aged men
Authors: Marie Erturth Eva , Ahrén Bo 
Published: March 2003

SummaryOBJECTIVE Previous studies have shown that serum levels of testosterone correlate negatively with leptin and positively with insulin‐like growth factor binding protein 1 (IGFBP‐1). The present study examined whether these associations are linked. DESIGN AND PATIENTS The association between serum levels of IGFBP‐1, free testosterone and insulin on one hand and leptin on the other hand were investigated in 38 healthy men with a medlan age of 48 years (range 23‐62 years). RESULTS Univariate analyses revealed that serum levels of leptin correlated negatively with serum free testosterone (r=−0.42, P=0.008) and with serum IGFBP‐1 (r=‐0.45, P= 0.005) and positively with body mass index (BMI; r=0.46, P=0.003) and serum insulin (r=0.45, P=0.004). Serum free testosterone correlated with IGFBP‐1 (r=0.42, P=0.008) but not with serum insulin (r=‐0.08, ns). The correlations between leptin and free testosterone and between leptin and IGFBP‐1 remained significant after adjustement for the influences of BMI and insulin. Forward stepwise multiple regression when BMI, insulin, testosterone and IGFBP‐1 were entered in a model as independent variables and leptin as the dependent variable showed that BMI and IGFBP‐1 were independent predictors of circulating leptin. These two parameters yielded an r2 of 0.38, thereby together explaining approximately 40% of serum leptin. CONCLUSION Serum levels of free testosterone and IGFBP‐1 correlate negatively with serum leptin in healthy nonobese men but this influence is dependent on the influence of IGFBP‐1. The study therefore suggests an important impact of IGFBP‐1 on the regulation of circulating leptin in young and middle‐aged men.
Abnormal LH pulsatility in women with hyperprolactinaemic amenorrhoea normalizes after bromocriptine treatment: deconvolution‐based assessment
Authors: Sartorio  , Pizzocaro  , Liberati  , De Nicolao  , Veldhuis  , Faglia  
Published: March 2003

OBJECTIVEThe present study examines the LH secretory process in hyperprolactinaemic women before, during and after bromocriptine therapy, using restrictive clinical selection criteria as well as improved methodological tools.PATIENTS AND DESIGNSix women (aged 20–40 years) with microprolactinomas (mean ± SE prolactin, PRL: 2478 ± 427 mU/l, range: 1370–3800 mU/l) and four age‐ and sex‐matched healthy controls were admitted to the study. After an overnight fast, all patients and controls had blood samples withdrawn at 10 minute intervals for 6 h (during saline infusion) from 0800 h to 1400 h to determine serum LH and PRL concentrations. After baseline evaluation, patients were treated with bromocriptine, which was started at a daily dose of 1.25 mg for 7 days; the dose was then increased to 2.5 mg daily for the next 7 days and subsequently to 2.5 mg twice daily. PRL levels were evaluated at weekly intervals after the beginning of bromocriptine therapy for the duration of the study. The 6 h pulsatility study was repeated on four patients during treatment at a time when PRL levels were decreased, although not normalized (PRL range: 450–1350 mU/l) and, on four patients, with the attainment of normal serum PRL levels (PRL < 450 mU/l) in the early follicular phase of the menstrual cycle (days 2–5). The LH instantaneous secretion rate was reconstructed by a nonparametric deconvolution method. In addition to pulse analysis made using the program DETECT, the evaluation of the secretion rate yielded the pulse frequency as well as the pulse amplitude distribution.RESULTSEach time series was submitted to deconvolution analysis using a nonparametric method in order to estimate the instantaneous secretion rate (ISR). Hyperprolactinaemic patients had very few high‐amplitude LH pulses above 0.2 IU/(l minutes) before treatment (average frequency: 0.83 ± 0.40 pulses/6 h) and at the intermediate evaluation (0.25 ± 0.25 pulses/6 h). In both cases, the pulse frequency was significantly lower than in controls (P < 0.05 and P < 0.01, respectively). When PRL was normalized, the number of high‐amplitude LH pulses (4.25 ± 1.03 pulses/6 h), became statistically different from the pulse number before (P < 0.01) and during (P < 0.01) therapy; in particular the pulse frequency after therapy rose to a level not statistically different from that in controls.CONCLUSIONThe present study shows the presence of reduced LH pulsatility in hyperprolactinaemic women that recovers completely to within the physiological distribution when PRL levels are normalized by bromocriptine therapy.
Loss of heterozygosity in sporadic parathyroid tumours: involvement of chromosome 1 and the MEN1 gene locus in 11q13.
Authors: Dwight Trisha , Twigg Stephen , Delbridge Leigh , Wong Fung‐Ki , Farnebo Filip , Richardson Anne Louise , Nelson Anne , Zedenius Jan , Philips Jeanette , Larsson Catharina , Teh Bin Tean , Robinson Bruce 
Published: March 2003

OBJECTIVEHyperparathyroidism (HPT) is a common endocrine disorder. Several loci of genetic interest have been identified in parathyroid tumours, including the MEN1 gene locus at 11q13; the HPT‐JT region at 1q21‐q32; and a putative tumour suppressor gene on 1p. We analysed these intervals, which harbour known genes or putative loci associated with familial hyperparathyroidism, in order to clarify the involvement of the respective regions in parathyroid tumourigenesis.DESIGNWe performed loss of heterozygosity (LOH) studies on 33 sporadic parathyroid tumours using a PCR based technique. A total of 22 microsatellite markers were used to analyse loci at 11q13, 1q21‐q32 and 1p. Ten markers located distal on 1p, eight markers encompassed the HPT‐JT region at 1q21‐q32 and four markers surrounded the MEN1 gene locus at 11q13. MEN1 mutations were screened for using Single Strand Conformation Polymorphism analysis (SSCP) and automated sequencing of SSCP variants.PATIENTSThirty‐three parathyroid glands and the corresponding blood samples were obtained from 33 patients (26 females and seven males) who underwent parathyroidectomy for primary hyperparathyroidism.RESULTSLoss of heterozygosity was detected in 13 of 33 (39%) cases at 11q13, 6 of 33 (18%) cases at 1p, and in three of 33 (9%) cases at 1q (in conjunction with 1p loss). Only one of the 18 tumours in which LOH was detected, showed LOH at both chromosome 1 and chromosome 11. Additionally, those tumours found to exhibit LOH at 11q13 were screened for MEN1 mutations using single strand conformation polymorphism analysis (SSCP) and automated sequencing. Nine novel somatic mutations were found on the remaining allele in 13 (69%) tumours.CONCLUSIONSThis study consolidates the role of multiple loci in the pathogenesis of sporadic parathyroid tumours. The results indicate that there are at least two genetic loci involved in sporadic parathyroid tumourigenesis on chromosome 1, one of which has been linked to the distinct familial parathyroid condition, hyperparathyroidism‐jaw tumour (HPT‐JT) syndrome. The high frequency of loss of heterozygosity at 1p suggests the presence of a tumour suppressor at this locus.
A polymorphism of the 5′ flanking region of tumour necrosis factor α gene is associated with thyroid‐associated ophthalmopathy in Japanese
Authors: Kamizono Shintaro , Hiromatsu Yuji , Seki Naoko , Bednarczuk Tomasz , Matsumoto Hajime , Kimura Akinori , Itoh Kyogo 
Published: March 2003

OBJECTIVEWe have studied the polymorphism of the 5′ flanking region of the tumour necrosis factor (TNF)‐α gene in order to better understand the genetic background of autoimmune thyroid disorders and thyroid‐associated ophthalmopathy.PATIENTS AND METHODSWe studied the polymorphism of the 5′ flanking region of the TNF‐α gene at positions − 1031 (T to C change, termed as − 1031C), − 863 (C to A, − 863 A), − 857 (C to T, − 857T), − 308 (G to A, − 308 A) and − 238 (G to A, − 238 A) in Japanese patients with Graves' disease [n = 173, 62 of whom had associated ophthalmopathy (American Thyroid Association (ATA) class III or greater)] and healthy control subjects (n = 575), using a polymerase chain reaction sequence‐specific oligonucleotide probe method.RESULTSThe allele frequency of − 857T in the Graves' disease patients (22.5% vs. 17.7%, OR  = 1.35, P  = 0.045, corrected P  = 0.23) was slightly greater than in the Japanese healthy subjects, respectively. However, the difference was not statistically significant. In Graves' disease patients with evident ophthalmopathy (ATA class III or greater), the allele frequencies of − 1031C and − 863 A were significantly greater than those with no or mild ophthalmopathy (ATA class 0–II) (31.5% vs. 13.5%, OR =2.94, P < 0.0001, corrected P < 0.0005; 23.4% vs. 11.7%, OR =2.30, P  = 0.0044, corrected P  = 0.022, respectively) and in control subjects. The strength of the association of the polymorphism − 1031C increased with the severity of ophthalmopathy, with odds ratios of 2.36 for ATA class III, and 5.43 for ATA class IV–VI, respectively, compared with Graves' disease with no or mild ophthalmopathy (ATA class 0–II). Although the phenotype frequency of DRB1*0901 was not different among Graves' disease patients with or without ophthalmopathy and control subjects, the phenotype frequency of DRB1*0901(−)/−1031C(+) was significantly increased in Graves' disease patients with ophthalmopathy compared to those with no or mild ophthalmopathy (OR = 4.91, P  = 0.0005) or control subjects (OR = 4.59, P < 0.0001).CONCLUSIONSThese results suggest that the − 1031C or − 863 A alleles, or a gene in linkage disequilibrium with the TNF‐α gene, predispose to the development of ophthalmopathy in Japanese patients with Graves' disease.
The somatotrophic system in patients with dilated cardiomyopathy: Relation of insulin‐like growth factor‐1 and its alterations during growth hormone therapy to cardiac function
Authors: Osterziel Karl Josef , Ranke Michael B. , Strohm Oliver , Dietz Rainer 
Published: March 2003

OBJECTIVETreatment with human recombinant growth hormone has yielded conflicting results in patients with congestive heart failure. In addition, growth hormone resistance has been reported in severe heart failure. Therefore, the purpose of this study was to evaluate the somatotrophic axis and effects of growth hormone on haemodynamics in patients with heart failure due to dilated cardiomyopathy.DESIGNRandomized, double‐blind, placebo‐controlled trial.PATIENTSFifty clinically‐stable patients with moderate heart failure (mean left ventricular ejection fraction = 26 ± 2%) due to dilated cardiomyopthy were examined.MEASUREMENTSPatients were randomly assigned to treatment with placebo or 2 IU/d sc human recombinant growth hormone for a mean of 14 weeks. Cardiac size and function were evaluated by magnetic resonance imaging. Central haemodynamics were obtained by right heart catheterization. Measurements of plasma noradrenaline, serum insulin‐like growth factor‐1, and insulin‐like growth factor binding protein‐3 were performed by standard assays at baseline and at the end of the treatment period.RESULTSThe severity of heart failure as determined by stroke volume, left ventricular end diastolic diameter and plasma noradrenaline concentrations correlated significantly to baseline serum insulin‐like growth factor‐1 levels (each P < 0.05). The growth hormone‐induced increase of insulin‐like growth factor‐1 predicted the changes in ejection fraction (P < 0.05). A significant increase in ejection fraction of 7% was observed in patients whose insulin‐like growth factor‐1 increased by more than the median increase in comparison to the patients with an increase below the median (+ 4.0 ± 2.3% vs. − 3.0 ± 1.8%; P = 0.03).CONCLUSIONSSerum levels of insulin‐like growth factor‐1, reflecting growth hormone secretion, are diminished in relation to the severity of heart failure in patients with dilated cardiomyopathy. Growth hormone induced increases of insulin‐like growth factor–1 of more than 77 ng/l caused significant improvement of ejection fraction.
Cranial radiotherapy of childhood brain tumours: Growth hormone deficiency and its relation to the biological effective dose of irradiation in a large population based study
Authors: Schmiegelow  , Lassen  , Poulsen  , Feldt‐Rasmussen  , Schmiegelow  , Hertz  , Müller  
Published: March 2003

OBJECTIVEThe study was to determine the incidence of GH deficiency (GHD) following cranial radiotherapy (RT) for a childhood brain tumour in a large population based study and analyse the biological effective dose (BED) to the hypothalamus/pituitary (HP) region as a risk factor.DESIGNBED was assessed by use of the linear‐quadratic (LQ) model, which gives a means of expressing the biological effect of various treatment schedules in a uniform way. In patients aged ≥ 18 years (n = 53) GH status was assessed by an insulin‐tolerance test (ITT) (n = 34), however, in patients with seizure disorders (n = 19), and in 20 children aged < 18 years GH status was assessed by an arginine test. Cut‐off levels for GHD, indicating GH substitution, were defined by a peak GH response of < 9 mU/l and < 15 mU/l for patients ≥ 18 and < 18 years, respectively.PATIENTSNinety‐one children aged < 15 years eligible for the study, diagnosed between 1970 and 1997 in the Eastern part of Denmark, the Faroe Islands and Greenland, with a primary brain tumour not directly involving the HP axis. 84% (n = 76) agreed to participate. Three patients were excluded due to hypothyroidism detected at time of testing.MEASUREMENTSSerum GH and levels of serum insulin‐like growth factor‐I (s‐IGF‐I) and serum insulin‐like growth factor binding protein‐3 (s‐IGFBP‐3) were measured. BED was assessed to the HP region.RESULTSThe median age at the time of RT was 8.7 years (range: 0.8–14.9 years) and the median time of follow‐up was 15 years (range: 2–28 years). Fifty‐eight patients (80%) had GHD and they had received a median BED of 77.5 Gy to the HP region, whereas the median BED was 54.5 Gy for 15 patients without GHD (P = 0.002). Peak GH and BED were correlated (rs = −0.53, P < 0001). Median IGF‐I SDS and IGFBP‐3 SDS were −2.5 (−5.2–0.7 SDS) and −1.7 (−5.8–0.9 SDS), respectively, and IGF‐I SDS was correlated to peak GH (rs = 0.45, P < 0.001). Peak GH and length of follow‐up were related (rs = −0.28, P = 0.018). Stepwise backward multiple linear regression analysis showed that the best‐fit model to predict the peak GH release following ITT/arginine stimulation included BED (P < 0.0001) and length of follow‐up (P = 0.05).CONCLUSIONSThe data of this study suggest that the majority of long‐term survivors of brain tumours develop GH deficiency following radiotherapy in childhood and that the adverse effects of radiotherapy may be directly related to the biologically effective dose. With longer follow‐up fewer patients might respond normally to GH stimulation tests.
Serum levels of free insulin‐like growth factor (IGF)‐I and IGF‐binding protein‐1 in prepubertal children with idiopathic short stature
Authors: Kamoda Tomohiro , Saitoh Hisako , Hirano Takeki , Matsui Akira 
Published: March 2003

The study was performed to evaluate the relationships among serum free and total insulin‐like growth factor (IGF)‐I, IGF‐binding protein‐1 (IGFBP‐1), IGFBP‐3, and insulin concentrations in prepubertal children with idiopathic short stature (ISS).Eighteen children with ISS and 15 age‐matched controls were included in the study. All short children had a height standard deviation score of more than 2 below the mean, and maximum stimulated GH levels greater than 10 µg/l after two standard provocation tests.The serum levels of free IGF‐I were significantly lower in short children (1·6 ± 0·3 µg/l) than in the controls (2·8 ± 0·6 µg/l, P < 0·05), while total IGF‐I levels were slightly, but not significantly, lower in short children than in controls. The serum levels of IGFBP‐1 were significantly higher in the ISS group (124·6 ± 5·6 µg/l) than in controls (80·0 ± 8·7 µg/l, P < 0·0001). The fasting insulin and IGFBP‐3 levels were similar in both groups. A stepwise regression analysis for all subjects revealed that IGFBP‐1 is the only independent predictor of log free IGF‐I (R2 = 0·23, P < 0·01).The present study shows that the serum levels of free IGF‐1 are significantly lower and insulin‐like growth factor‐binding protein‐1 levels are higher in prepubertal children with idiopathic short stature, as compared with age‐matched controls. The high IGFBP‐1 may contribute to growth retardation in a subgroup of idiopathic short stature through a decrease in free IGF‐1.