bluuebunny/crossref_metadata_2025_split huggingface dataset:
Parathyroid hormone‐related protein in the aetiology of fibrous dysplasia of bone in the McCune Albright syndrome
Authors: Fraser William D. , Walsh Cathy A. , Birch Mark A. , Durham Brian , Dillon Jane P. , McCreavy David , Gallagher James A. 
Published: March 2003

OBJECTIVEFibrous dysplasia, observed in bone lesions in the McCune Albright syndrome (MAS), is thought to result from abnormalities in cells of the osteogenic lineage associated with over‐activation of the cAMP signalling pathway in affected cells. The aim of this study was to investigate the role of parathyroid hormone‐related protein (PTHrP) in the aetiology of MAS, and to determine a possible therapeutic role for 1,25‐dihydroxy vitamin D3 (1,25(OH)2D3).DESIGNThe effects of 1,25(OH)2D3 on PTHrP production and mRNA expression were determined in vitro. 1,25(OH)2D3 therapy was administered to three patients with MAS.PATIENTSClinical data from four MAS patients (MAS1, 2, 3 and 4), and in vitro studies using bone from three MAS patients (MAS1, 2, and 3), are presented.MEASUREMENTSImmunoradiometric assay and low‐cycle number reverse transcriptase‐linked PCR were used to determine PTHrP production and mRNA expression in vitro. Standard clinical biochemistry was recorded pre and post commencement of 1,25(OH)2D3 treatment.RESULTSWe report the elevated secretion of PTHrP, and a concomitant rise in PTHrP mRNA expression, in cultured osteoblasts from three MAS patients. Treatment with 1,25(OH)2D3 produced a dose‐dependent decrease in PTHrP protein secretion and mRNA expression. Marked improvement in bone biochemistry in MAS1, 2 and 3 post treatment with 1,25(OH)2 D3 is documented.CONCLUSIONThis study provides the first evidence suggesting that PTHrP may contribute to the aetiology of fibrous dysplasia in MAS. In addition, the therapeutic administration of 1,25(OH)2D3 may provide clinicians with an important new regime for symptomatic relief of bone pain and fracture in some patients with MAS.
Adrenal hyperandrogenism in adolescent girls with a history of low birthweight and precocious pubarche
Authors: Ibáñez Lourdes , Potau Neus , Marcos Maria Victoria , De Zegher Francis 
Published: March 2003

OBJECTIVEGirls with precocious pubarche (PP) are at increased risk for ovarian dysfunction, hyperinsulinism and dyslipidaemia in adolescence, in particular when PP is preceded by reduced fetal growth. However, it is not known whether PP girls still have adrenal hyperandrogenism after puberty and if so, which fraction of PP girls develops so‐called functional adrenal hyperandrogenism (FAH), an entity characterized by ACTH‐dependent 17‐ketosteroid excess.PATIENTS AND DESIGNData were longitudinally collected from 47 girls with PP: at birth (weight for gestational age), at diagnosis of PP (age 6.7 ± 1.1 years) and in adolescence (age 15.0 ± 1.9 years).MEASUREMENTSSerum dehydroepiandrosterone sulphate (DHEAS) and androstenedione were measured at PP diagnosis, as well as the 17‐hydroxyprogesterone (17‐OHP) response to ACTH; postpubertal evaluation included assessment of adrenal and ovarian function, and of insulin responses to a glucose load. PP girls were considered to have FAH in adolescence if both DHEA and androstenedione responses to ACTH were excessive (> 1500 ng/dl and > 350 ng/dl, respectively).RESULTSAt diagnosis of PP, girls had high DHEAS and androstenedione levels, as well as high 17‐OHP responses to ACTH. In adolescence, PP girls had a normal BMI, presented with mild hirsutism and had high baseline and post‐ACTH concentrations of most adrenal androgens, low SHBG levels and tended to have hyperinsulinemia and to present biological signs of ovarian hyperandrogenism. More than a third of the PP cohort developed FAH in adolescence. Neither baseline DHEAS, androstenedione, nor post‐ACTH 17‐OHP values at diagnosis of PP predicted the development of FAH in adolescence. In PP girls, only a low weight at birth was found to be significantly associated with subsequent FAH.CONCLUSIONSThese longitudinal findings in girls with PP point to the possibility of an endocrine sequence of prenatal onset: low weight at birth, PP in childhood and adrenal hyperandrogenism in adolescence. The pathophysiological mechanisms underpinning this newly recognized sequence remain to be identified.
The effect of distinct activating mutations of the luteinizing hormone receptor gene on the pituitary–gonadal axis in both sexes
Authors: Latronico Ana Claudia , Lins Teresa Selma S. , Brito Vinicius Nahime , Arnhold Ivo Jorge P. , Mendonca Berenice B. 
Published: March 2003

OBJECTIVEFamilial or sporadic male‐limited precocious puberty is a distinct and unusual gonadotrophin‐independent form of sexual precocity caused by constitutively activating mutations of the luteinizing hormone receptor (LHR). In the present study, we evaluated the effect of known activating mutations at different sites of the LHR gene on the pituitary–gonadal axis in both sexes.PATIENTSFour unrelated Brazilian boys (I‐IV) with gonadotrophin‐independent precocious puberty and two asymptomatic females (V‐VI), a sister and mother of two of the affected boys, were studied. Patients I, II and V carried the Ala568Val mutation located at the third intracellular loop of the LHR. Patient III carried the Leu457Arg mutation at the third transmembrane helix, and patients IV and VI carried the Thr577Ile mutation at the sixth transmembrane helix of the LHR.MEASUREMENTSSerum levels of LH, FSH, testosterone, and oestradiol under basal and GnRH‐stimulated conditions were determined in all patients. Testosterone levels were also measured after a hCG stimulation test in patient III.RESULTSBasal LH and FSH levels were prepubertal in all boys studied. The GnRH‐stimulated serum LH and FSH levels were prepubertal in three boys (I, II and IV), whereas patient III showed totally suppressed LH and FSH levels at ages 2 and 7 years (bone ages 6 and 14 years, respectively). Serum testosterone levels ranged from 3.8 to 69.5 nmol/l in the four boys. Patient III had the highest testosterone levels that did not respond to hCG stimulation. The 4 year‐old girl (patient V) was phenotypically normal and the acute response to GnRH was indicative of prepubertal status. Patient VI had normal menstrual cycles and fertility.CONCLUSIONSThese findings indicate variable effects of LHR activating mutations on the pituitary–gonadal axis in boys that can result in lack of normal LH and FSH release. In contrast, prepubertal and adult females were asymptomatic and had normal basal and GnRH‐stimulated LH and FSH levels.
Construction and field validation of a self‐administered screener for testosterone deficiency (hypogonadism) in ageing men
Authors: Smith Kevin W. , Feldman Henry A. , McKinlay John B. 
Published: March 2003

To design a self‐administered screening questionnaire to inform men about their risk for testosterone deficiency.The screener was developed in two phases. First was a construction phase in which relevant risk factors and a scoring algorithm were defined from multiple logistic regression analyses of survey data. In the second phase, the screener's accuracy (based on sensitivity, specificity, and Receiver Operating Characteristic (ROC) curves) was tested using patients from a primary care clinic. All subjects provided blood samples for endocrine testing.Survey data from 1660 men aged 40–79 years participating in the Massachusetts Male Ageing Study (MMAS) were analysed in the first phase. The clinic sample consisted of 304 men aged 40–79 years presenting at a large Massachusetts primary health care clinic for routine check‐ups or minor medical problems.The primary outcome was testosterone deficiency, defined as serum total testosterone below 12·1 nmol/l. Self‐reported variables considered as potential risk factors included age, obesity, chronic diseases, health behaviour, the Jackson dominance scale, and symptoms of stress.The prevalence of testosterone deficiency was 20·4% in the MMAS and 42·1% in the clinic sample. An eight‐item screener was developed based on age, body mass index, diabetes, asthma, headaches, sleep patterns, dominance preferences, and smoking status. The screener performed significantly better than chance in identifying men with low testosterone levels; the area under the ROC curve was 0·66 in the MMAS sample and 0·67 in the clinic sample.The self‐scored screener developed in this study reliably detects men at risk of hypogonadism. The screener encourages at risk men to seek professional evaluation of their testosterone levels.
Toxic multinodular goitre in a patient with generalized resistance to thyroid hormone who harbours the R429Q mutation in the thyroid hormone receptor β gene
Authors: Taniyama Matsuo , Ishikawa Naofumi , Momotani Naoko , Ito Koichi , Ban Yoshio 
Published: March 2003

The association of resistance to thyroid hormone (RTH) due to a receptor defect with toxic multinodular goitre or with carcinoma of the thyroid has not been previously reported. Previous histopathological studies of the thyroid gland in patients with RTH have revealed changes similar to multinodular goitre, probably due to continuous stimulation by TSH. We report here a case of generalized resistance to thyroid hormone associated with a multinodular goitre, which became toxic. The patient was a 46‐year‐old Japanese woman who noticed a goitre although she had no symptoms of thyrotoxicosis. Initial examination revealed elevated serum thyroid hormone levels and a normal TSH level. Ultrasonography disclosed a multinodular goitre with cystic lesions. Three years later, the patient complained that the goitre had become larger and that she had developed symptoms of thyrotoxicosis such as palpitation and hyperhydrosis. Progressive hyperthyroxinaemia with relatively suppressed TSH, increased radioiodine uptake and negative anti‐TSH receptor antibodies led to the diagnosis of toxic multinodular goitre. Subtotal thyroidectomy was performed, and pathological examination revealed a micropapillary carcinoma within the multinodular goitre. Occurrence of thyroid carcinoma should be considered in RTH because its incidence is high in multinodular goitre. Molecular examination revealed the R429Q mutation in the thyroid hormone receptor β gene, which is one of the mutations usually manifesting as the pituitary resistance phenotype. That thyrotoxic manifestations appeared only during toxic stage of multinodular goitre in this case suggests that the phenotype of this type of mutation can be dependent on the amount of thyroid hormone.
Carbohydrate metabolism during long‐term growth hormone treatment in children with short stature born small for gestational age
Authors: Sas Theo , Mulder Paul , Aanstoot Henk Jan , Houdijk Mieke , Jansen Maarten , Reeser Maarten , Hokken‐Koelega Anita 
Published: March 2003

OBJECTIVETo assess possible side‐effects of long‐term continuous growth hormone (GH) treatment on carbohydrate (CH) metabolism in children with short stature born small for gestational age.DESIGNIn a prospective, randomised double‐blind, dose–response multicentre trial, the effect of GH treatment on CH metabolism was evaluated, comparing two GH dosages [3 vs. 6 IU/(m2 body surface·day)].PATIENTSSeventy‐eight children with short stature (height SD‐score < − 1·88) born small for gestational age (birth length SD‐score < − 1·88) being all prepubertal with a mean (SD) chronological age of 7·3 (2·2) years before start of treatment.MEASUREMENTSGlucose and insulin concentrations during oral glucose tolerance tests (OGTTs) and glycosylated haemoglobin (HbA1c) were measured before and during 6 years of GH treatment.RESULTSBefore treatment, the glucose response to oral glucose after 120 min was in six of the 78 children (8%) above 7·8 mmol/l but below 11·1 mmol/l, indicating impaired glucose tolerance (IGT), whereas after 6 years of GH treatment, IGT was found in 4% of the children. None of the children developed diabetes mellitus. Mean fasting glucose levels had increased significantly by 0·5 mmol/l after 1 year of GH treatment, without a further increase thereafter. The 2‐h area under the curve adjusted for fasting levels (AUCab) for glucose and the HbA1c levels were lower after 6 years of GH treatment compared to baseline. During GH treatment, all HbA1c levels were in the normal range. In contrast to the effects on glucose levels, GH treatment induced considerably higher fasting insulin levels and glucose‐stimulated insulin levels. The increase in AUCab for insulin occurred particularly during the first year of treatment, whereas the fasting insulin levels showed a further increase from one to six years. As a result, the 30‐ and 120‐min ratios of insulin to glucose were higher during GH treatment compared to the start of treatment. The children who remained prepubertal during the entire study period showed similar patterns in glucose and insulin levels compared to the children who entered puberty. None of the observed changes were different between the GH dosage groups.CONCLUSIONSContinuous GH treatment during 6 years in children with short stature born small for gestational age has no adverse effects on glucose levels, even with dosages up to 6 IU/(m2 d). However, as has been reported in other patient groups, GH treatment induces higher fasting insulin levels and glucose‐stimulated insulin levels, indicating relative insulin resistance. Since the consequences of long‐term hyperinsulinism during childhood are unknown, careful follow‐up of these GH‐treated children born small for gestational age is required.
Growth hormone (GH) secretion in children with Noonan syndrome: frequently abnormal without consequences for growth or response to GH treatment
Authors: Noordam C. , Van Der Burgt I. , Sweep C. G. J. , Delemarre‐van de Waal H. A. , Sengers R. C. A. , Otten B. J. 
Published: March 2003

The role of GH insufficiency in the pathogenesis of short stature in Noonan syndrome is unclear.Cross‐sectional study.Seventeen patients with Noonan syn‐drome (13 boys, 4 girls; aged 4·8–13·3 (mean 9·2) years) and short stature before start of GH treatment.Spontaneous 12‐h overnight GH secretion by continuous sampling analysed using Pulsar, plasma IGF‐I and IGFBP‐3 levels, and 24‐h urinary GH excretion were measured at start of GH treatment. A glucagon stimulation test was performed. Height and height velocity were monitored before and after 1 year of GH treatment. IGF‐I and IGFBP‐3 were remeasured after 1 year of GH treatment.Nine of the 17 children had a mean overnight GH concentration below the lower limit of the normal range. In six of the 17 patients, overnight GH profiles showed high trough GH concentrations. Glucagon stimulation tests were normal in 16 of the 17 patients. Mean IGF‐I level was below normal (−0·4 SD). None of the parameters regarding GH secretion obtained from the overnight profile or provocative test was related to height or height velocity, nor to first year response to GH treatment. IGF‐I and IGFBP‐3 did not correlate with any of the GH secretion data. IGF‐I and IGFBP‐3 were related to height and height velocity at the start of GH treatment (r = 0·53 (P < 0·01) and r = 0·61 (P < 0·03) respectively). Rises in IGF‐I and IGFBP‐3 under GH treatment were related to the increment in height velocity (r = 0·70 (P < 0·01) and r = 0·71 (P < 0·02) respectively).Abnormalities in GH secretion are frequent in patients with Noonan syndrome and short stature. These abnormalities were not related to auxology at start of or response to GH treatment. Clinically GH insufficiency is not important in Noonan syndrome and monitoring spontaneous GH secretion is not necessary before the start of GH treatment.
Influence of melatonin administration on glucose tolerance and insulin sensitivity of postmenopausal women
Authors: Cagnacci Angelo , Arangino Serenella , Renzi Antonietta , Paoletti Anna Maria , Melis Gian Benedetto , Cagnacci Paolo , Volpe Annibale 
Published: March 2003

The effect of melatonin on human carbohydrate metabolism is not yet clear. We investigated whether melatonin influences glucose tolerance and insulin sensitivity in aged women.Twenty‐two postmenopausal women of whom 14 were on hormone replacement therapy.After an overnight fast, at 0800 hours on two nonconsecutive days, placebo or melatonin (1 mg) were administered randomly and in a double blind fashion. Forty‐five minutes later, an oral glucose tolerance test (75 g; OGTT) was performed in 13 women. In another nine women insulin‐dependent (Si) and ‐independent (Sg) glucose utilization was tested by a frequently sampled intravenous glucose tolerance test (FSIGT).Areas under the response curve to OGTT (AUC) for glucose (1420 ± 59vs.1250 ± 55 mmol × min/l;P < 0·01), and C‐peptide (420980 ± 45320vs.33528 ± 15779 pmol × min/l;P < 0·02) were higher following melatonin than placebo, while Si values were lower (2·6 ± 0·28 unitsvs.3·49 ± 0·4 units;P < 0·03). Si modifications induced by melatonin were inversely related to Si values of the placebo day (r2 = 0·538;P < 0·025).The present results indicate that in aged women administration of 1 mg of melatonin reduces glucose tolerance and insulin sensitivity. The present data may have both physiological and clinical implications.
The expression of thyrotrophin‐releasing hormone receptor 1 messenger ribonucleic acid in human pituitary adenomas
Authors: Kim Kyongsong , Arai Keiko , Sanno Naoko , Teramoto Akira , Shibasaki Tamotsu 
Published: March 2003

Thyrotrophin‐releasing hormone (TRH) paradoxically induces the release of growth hormone (GH) when injected intravenously into acromegalic patients, although the mechanism of this action is unknown at present. Several research groups have reported that the level of TRH receptor‐1 (TRHR‐1) mRNA expression is variable in pituitary adenomas, and does not correlate with the degree of paradoxical GH response to TRH administration in a limited number of acromegalic patients. We aimed to compare the expression levels of TRHR‐1 mRNA among various types of pituitary adenoma and to clarify whether these levels correlate with the degree of pituitary hormone response to TRH.Pituitary adenoma tissue was obtained by surgery from 14 patients with acromegaly, four with prolactinomas, nine with nonfunctioning adenomas and one with a TSH‐producing adenoma.The level of human TRHR‐1 mRNA expression in each adenoma was quantified using the competitive reverse transcription polymerase chain reaction (RT‐PCR) method. For amplification of a TRHR‐1 cDNA fragment, a sense primer was designed according to the sequence in exon 2 and an antisense primer designed according to the sequence located at the region in exon 3 that does not encode for the alternative splicing‐generated short form of TRHR‐1 mRNA.TRHR‐1 mRNA was detected in all pituitary adenomas examined and did not correlate with their size. The mean level of TRHR‐1 mRNA expression was significantly lower in GH‐producing adenomas than in prolactinomas and nonfunctioning adenomas (1·4 ± 0·4 × 10−2 attomol/μg total RNA, 10·7 3·4 × 10−2 attomol/μg total RNA, and 7·2 ± 3·3 × 10−2 attomol/g total RNA, respectively). The ratio of plasma peak GH induced by TRH administration to the basal level of plasma GH in the patients with acromegaly correlated positively with the level of TRHR‐1 mRNA expression in their GH‐producing adenomas (r = 0·620, P = 0·0179). The responsiveness of plasma PRL and gonadotrophin to TRH in the patients with prolactinoma and nonfunctioning pituitary adenoma did not significantly correlate with the levels of TRHR‐1 mRNA expression in their pituitary adenomas, respectively.The findings of the present study suggest that the level of TRHR‐1 mRNA expression varies among different types of pituitary adenoma. Furthermore, in acromegaly, the responsiveness of plasma GH to TRH administration appears to at least partially depend on the level of TRHR‐1 mRNA expression in the GH‐producing pituitary adenoma.
Angiotensin II type 1 receptor and ACTH receptor expression in human adrenocortical neoplasms
Authors: Schubert Barbara , Fassnacht Martin , Beuschlein Felix , Zenkert Simone , Allolio Bruno , Reincke Martin 
Published: March 2003

OBJECTIVE Type 1 angiotensin II (Ang II) receptors transduce most of the known actions of Ang II, including steroidogenesis and trophic actions on the adrenal cortex. We investigated the type 1 Ang II receptor expression in adrenocortical tissues to define its regulation in adrenocortical neoplasms and to compare its expression with that of the ACTH receptor (ACTH‐R).PATIENTS AND MEASUREMENTS Poly A RNA was extracted from tumour tissue and electrophoresed through a 1·0% agarose gel, blotted and hybridized with α32P‐CTP labelled PCR generated type 1 Ang II receptor cDNA probe. Receptor autoradiography was performed on slices from normal adrenals and tumour tissue by incubation with 125I‐Sar1, Ile8‐Ang II with and without pretreatment with cold Ang II or with the selective type 1 receptor antagonist losartan.RESULTS Ang II type 1 receptor mRNA was high in cortisol producing (CPA; n = 5) and aldosterone producing (APA; n = 4) adenomas (normal adrenals 100 ± 12% vs. 180 ± 16% in CPA and 154 ± 26% in APA, mean ± SEM), but was low in nonfunctioning adenomas (NFA; n = 2; 2 ± 1%). ACTH receptor mRNA followed a similar pattern (CPA 178 ± 17, APA 196 ± 30, NFA 0%, carcinomas 56 ± 11%) with a good correlation between Ang II type 1 receptor and ACTH‐R mRNA of r = 0·692, P = 0·0019. Receptor autoradiography in normal adrenals demonstrated Ang II type 1 receptors predominantly in the zona glomerulosa. In tumour tissue, mainly type 1 receptor expression was found confirming the Northern blot data.CONCLUSIONS Angiotensin II type 1 receptor and ACTH receptor expression seems to be correlated with the functional status of adrenocortical tumours, suggesting regulation by similar factors. The predominant receptor expressed in adrenocortical tumours is the Angiotensin II type 1 receptor whereas type 2 receptor expression is minimal.
Polymorphic differences from normal in the aldosterone synthase gene (CYP11B2) in patients with primary hyperaldosteronism and adrenal tumour (Conn's syndrome)
Authors: Inglis Gordon C. , Plouin Pierre F. , Friel Elaine C. , Davies Eleanor , Fraser Robert , Connell John MC. 
Published: March 2003

OBJECTIVE The hypertension of Conn's syndrome is due to autonomous aldosterone production by a unilateral adrenocortical adenoma. The source of tumour initiation and the reasons for excess aldosterone production as opposed to cortisol are not known, although variations in the promoter region of the gene coding for aldosterone synthase (CYP11B2) might account for the altered rate of aldosterone secretion.DESIGN In a series (n = 27) of well–characterized Conn's syndrome cases, the aldosterone synthase gene (CYP11B2) was screened by single‐strand conformational polymorphism (SSCP) for differences from the consensus sequence.RESULTS No new mutations were found. The frequencies of two previously described linked polymorphisms, one a change of −344C to T in a putative steroidogenic factor‐1 (SF‐1) binding site and the other an exchange of intron 2 for that of CYP11B1 (conversion) were measured in tumour and genomic DNA. The frequency of the SF‐1 T allele (P < 0·0001) and the conversion allele (P < 0·001) were markedly different between the Conn's syndrome group and the normal controls. However, the frequency did not differ between tumour and genomic DNA in the patient group.CONCLUSION While it is unlikely that this difference from normal is related to tumour growth, these genotypes may predispose the tumour to aldosterone production.