bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression of tumor necrosis factor (TNF)-alpha protein in the subcutaneous and visceral adipose tissue in correlation with adipocyte cell volume, serum TNF-alpha, soluble serum TNF-receptor-2 concentrations and C-peptide level
Authors: Winkler G , Kiss S , Keszthelyi L , Sapi Z , Ory I , Salamon F , Kovacs M , Vargha P , Szekeres O , Speer G , Karadi I , Sikter M , Kaszas E , Dworak O , Gero G , Cseh K
Published: January 2005

OBJECTIVE: The aim of the study was to evaluate the expression of tumor necrosis factor (TNF)-alpha protein in the subcutaneous and visceral adipose tIssue in correlation with adipocyte cell Volume, serum TNF-alpha, soluble TNF-receptor-2 (sTNFR-2) and indirect parameters of insulin resistance in overweight/obese and lean healthy persons. DESIGN: A cross-sectional case-control study was used. PATIENTS: Twenty-eight overweight/obese probands with normal glucose tolerance (BMI>27 kg/m(2)) and 15 lean people (BMI<25 kg/m(2)), all of them undergoing planned surgical operation, participated in the study. METHODS: Two to four grams of subcutaneous and visceral adipose tIssue were removed and studied using semi-quantitative immunohistochemical staining of the TNF-alpha protein. Serum TNF-alpha, sTNFR-2 (ELISA) and fasting C-peptide (RIA) were measured. RESULTS: TNF-alpha protein was expressed in adipocytes of both depots. The expression was evaluated visually and found to be greater in the obese patients. Significantly higher serum TNF-alpha (5.58+/-0.87 pg/ml vs 4.21+/-0.55, mean+/-s.d., P<0.01, Mann-Whitney) and sTNFR-2 levels (7.84+/-3.56 ng/ml vs 4.59+/-1.35, P=0.005) were found in the obese subgroup in correlation with the fasting C-peptide level (r=0.49, P=0.003; and r=0.74, P=0.001) and the C-peptide/ blood glucose ratio (r=0.47, Spearman, P=0.005; and r=0.70, P=0.001). The cell Volume of both adipocyte depots was found to have a significant positive correlation with serum TNF-alpha and sTNFR-2 levels in the total group of patients (subcutaneous: r=0.52, P=0.0003; r=0.69, P<0.0001; visceral: r=0.65, P<0.0001; r=0.63, P<0.0001) and in both subgroups. CONCLUSIONS: Adipocyte cell Volume of both the subcutaneous and visceral fat depots may be determinants of TNF-alpha, sTNFR-2 production and obesity-linked insulin resistance.
Endothelial function, insulin sensitivity and inflammatory markers in hyperprolactinemic pre-menopausal women
Authors: Yavuz D , Deyneli O , Akpinar I , Yildiz E , Gozu H , Sezgin O , Haklar G , Akalin S
Published: January 2005

BACKGROUND: Hyperprolactinemia has been reported to be associated with abnormalities of carbohydrate metabolism. The aim of this study was to evaluate the effects of hyperprolactinemia and bromocriptine (Brc) treatment on endothelial function, insulin sensitivity and inflammatory markers in pre-menopausal women. METHODS: Sixteen hyperprolactinemic pre-menopausal women with pituitary adenomas were recruited and 20 healthy subjects were included as controls. Patients were given Brc in doses of 2.5-20 mg/dl until normal levels of prolactin were reached. Prior to treatment and 2 months after prolactin levels were normalized, the following tests were performed. Insulin sensitivity was determined by an oral glucose tolerance test based on a formula named the insulin sensitivity index (ISI composite). Endothelial function was measured as flow-mediated dilatation (FMD) on a brachial artery using high resolution ultrasound. RESULTS: Serum glucose, insulin, estrogen, highly sensitive C-reactive protein (hsCRP), fibrinogen, homocysteine and uric acid levels were measured. Calculated ISI composite and FMD were significantly lower in the hyperprolactinemic group in comparison with the controls and improved after Brc treatment. Serum homocysteine, hsCRP and uric acid levels were significantly higher in hyperprolactinemic patients than in the controls and returned to normal levels with Brc treatment. Serum prolactin concentrations were inversely correlated with FMD measurements (r=-0.68; P<0.0001), ISI composite (r=-0.48; P<0.005) and serum estrogen (r=-0.54; P<0.005), and positively correlated with serum homocysteine concentrations (r=0.55; P<0.0001) in the hyperprolactinemic group. CONCLUSIONS: The hyperprolactinemic state is associated with impaired endothelial function and decreased insulin sensitivity, which are early markers of atherosclerosis. These alterations may predispose to the development of atherosclerosis in non-treated cases. Correction of the hyperprolactinemic state is associated with improved endothelial function and insulin sensitivity.
Hypercalciuria is a common and important finding in postmenopausal women with osteoporosis
Authors: Giannini S , Nobile M , Dalle Carbonare L , Lodetti MG , Sella S , Vittadello G , Minicuci N , Crepaldi G
Published: January 2005

OBJECTIVE AND DESIGN: The prevalence and the effects of hypercalciuria on bone in patients with primary osteoporosis are poorly defined. We therefore retrospectively analyzed the data of 241 otherwise healthy women. They were 45-88 years of age and had been referred for their first visit to our Unit for Metabolic Bone Diseases over a 2-year period because of primary osteoporosis (bone density T-score < -2.5). METHODS: The main parameters of calcium and skeletal metabolism had been analyzed in all subjects. This population was then divided into two groups, according to the presence (HC+) or absence (HC-) of hypercalciuria. RESULTS: Elevated urinary calcium was present in 19% of the subjects. Due to the selection criteria, spinal and femoral bone loss was similar in the two groups. Urinary calcium, phosphate and fractional calcium excretion were higher in hypercalciuric patients. In a logistic regression model, the higher the Tm of phosphate, the lower the risk of hypercalciuria (odds ratio 0.33, confidence interval 0.18-0.62). On the contrary, hypercalciuria was the most important predictor of low bone mass in HC+ (accounting for more than 50% of the variance in spinal bone density). CONCLUSIONS: Hypercalciuria is a common feature in postmenopausal bone loss. Since increased urinary calcium excretion and low bone mass appear to be linked, hypercalciuria seems to be an important determinant of reduced bone density in this setting as well.
Differential expression of adrenomedullin and resistin in 3T3-L1 adipocytes treated with tumor necrosis factor-alpha
Authors: Li Y , Totsune K , Takeda K , Furuyama K , Shibahara S , Takahashi K
Published: January 2005

DESIGN: It has recently been shown that deficiency of adrenomedullin (AM), a potent vasodilator peptide, leads to insulin resistance. We studied expression of AM in NIH 3T3-L1 adipocytes and compared it with expression of resistin, an adipocyte-derived peptide hormone that is proposed to cause insulin resistance. Moreover, we studied the effects of tumor necrosis factor-alpha (TNF-alpha), a known mediator of insulin resistance, on the expression of AM and resistin in 3T3-L1 adipocytes. METHODS: 3T3-L1 cells were induced to differentiate to adipocytes by insulin, dexamethasone and 3-isobutyl-1-methylxanthine. Expression of AM mRNA and resistin mRNA was examined by Northern blot analysis. Immunoreactive AM in the medium was measured by RIA. RESULTS: AM mRNA was expressed in preadipocytes, but barely detectable in adipocytes. Immunoreactive AM was detected in the medium of both preadipocytes and adipocytes, with about 2.5 times higher levels found in preadipocytes. In contrast, resistin mRNA was expressed in adipocytes, whereas it was not detected in preadipocytes. Treatment with TNF-alpha increased AM expression in both adipocytes and preadipocytes, whereas it decreased resistin mRNA levels in adipocytes. CONCLUSIONS: The present study has shown that AM expression was down-regulated and resistin expression was up-regulated during adipocyte differentiation of 3T3-L1 cells. TNF-alpha acted as a potent negative regulator of resistin expression and a potent positive regulator of AM expression in adipocytes, raising the possibility that in addition to its known actions in causing insulin resistance, TNF-alpha may also have actions against insulin resistance through AM and resistin.
Large carboxy-terminal parathyroid hormone (PTH) fragment with a relatively longer half-life than 1-84 PTH is secreted directly from the parathyroid gland in humans
Authors: Yamashita H , Gao P , Cantor T , Futata T , Murakami T , Uchino S , Watanabe S , Kawamoto H , Fukagawa M , Noguchi S
Published: January 2005

OBJECTIVE: It was discovered that an immunoreactive large carboxy-terminal parathyroid hormone (PTH) fragment (large C-PTH), likely 7-84 PTH, is present in the circulation. However, very little is known about the production and metabolism of this large C-PTH. Combining a whole molecule PTH (whole PTH) immunoradiometric assay (IRMA) specifically for 1-84 PTH and an intact PTH (iPTH) IRMA for the sum of 1-84 PTH and large C-PTH, we were able to assess the circulating level of this large C-PTH as well as the glandular secretion and metabolism of this large C-PTH in primary hyperparathyroidism (pHPT). METHODS: This study consisted of two patient groups consisting of 77 pHPT patients with a single adenoma. Of these, 43 comprised the venous sampling study group and 70 comprised the intra-operative PTH study group. (Seven patients belonged only to the former group, 34 patients to only the latter group, and 36 patients to both groups.) Preoperatively, blood samples were drawn from the bilateral internal jugular vein by ultrasonographic guidance and from the peripheral vein (n=43). During surgery, blood samples were drawn after anesthesia (basal level), before excision (pre-excision level) of one enlarged parathyroid gland, and at 5, 10, and 15 min post-excision (n=70). RESULTS: There were 26 patients whose iPTH assay levels differed by more than 10% between the right and left internal jugular. In 24 of the 26 patients, the large C-PTH levels obtained from the adenoma side were significantly higher than those from the contralateral side (117+/-135 vs 43+/-33 pg/ml, P<0.001). The plasma whole PTH values decreased more rapidly than the iPTH values after parathyroidectomy (P<0.001). CONCLUSIONS: Our study has demonstrated that the large C-PTH, likely 7-84 PTH, is directly released from the parathyroid gland in humans. Since the half-life of 1-84 PTH is much shorter than large C-PTH, likely 7-84 PTH, it would be advantageous to use an assay that specifically measures 1-84 PTH for intra-operative monitoring of parathyroidectomy.
Quantitative ultrasound for the assessment of osteopenia in preterm infants
Authors: Rubinacci A , Moro GE , Boehm G , De Terlizzi F , Moro GL , Cadossi R
Published: January 2005

OBJECTIVE: To evaluate the potential role of quantitative ultrasound (QUS) investigation in assessing the osteopenia of prematurity. DESIGN: QUS parameters measured at the time of discharge were related to the anthropometric characteristics and age (postnatal and gestational) of 51 (34 female and 17 male) preterm infants fed fortified human milk. METHODS: QUS evaluation was performed at the humerus (h) by measuring two parameters: ultrasound velocity (hSOS, in m/s) and bone transmission time (hBTT, in micros). A group of 43 term infants (29 female and 14 male) was also evaluated. RESULTS: In preterm infants, significant correlations were found for hSOS and hBTT vs gestational age (r=0.504, 0.477, P<0.0001), length (r=0.641, 0.594, P<0.0001) and weight (r=0.580, 0.562, P<0.0001) at birth, and length (r=0.341, 0.332, P<0.05) and weight (r=0.331, r=0.362, P<0.05) at QUS measurement. In preterm infants, both QUS parameters were negatively correlated with age (r=-0.536, P<0.0001, r=-0.443, P<0.001) and were significantly lower than in the term infants (hSOS: 1664+/-42 m/s vs 1734+/-28 m/s, P<0.0001; hBTT: 0.58+/-0.24 micros vs 1.06+/-0.15 micros, P<0.0001) even when adjusted for body length (P<0.05). In preterm infants, hSOS was also negatively correlated with postconceptional age (r=-0.322, P<0.05). CONCLUSIONS: This study suggests that bone mineral accrual is mainly determined by the development in utero, and that prematurity induces a halt in the bone development process in the early postnatal period. QUS parameters are correlated with the severity of prematurity and might therefore have clinical applications when bone maturation in early life needs to be determined.
Insulin levels measured with an insulin-specific assay in patients with fasting hypoglycaemia related to endogenous hyperinsulinism
Authors: Vezzosi D , Bennet A , Fauvel J , Boulanger C , Tazi O , Louvet JP , Caron P
Published: January 2005

OBJECTIVE: The finding of insulin levels above a minimum threshold at the time of symptomatic hypoglycaemia is crucial in the diagnosis of endogenous hyperinsulinism. The aim of this study was to evaluate insulin levels at the time of hypoglycaemia with an insulin-specific assay in such patients. DESIGN AND METHODS: We measured insulin levels in 15 patients with fasting hypoglycaemia related to endogenous hyperinsulinism using an insulin-specific immunoradiometric assay (IRMA) without any significant cross-reaction with intact proinsulin. RESULTS: Insulin levels were below 6 mIU/l in all the samples taken at the time of symptomatic hypoglycaemia in 6/15 patients, and in some of the samples in three patients; insulin levels were below 3 mIU/l in samples from 5 patients. C-peptide levels were above 0.6 ng/ml in all these samples. The lowest proinsulin level was 35 pmol/l. Insulin levels were measured with a less specific RIA (40% cross-reaction with proinsulin) in 8/15 patients and were above 6 mIU/l in all samples in seven patients, and all but one sample in the 8th patient. Mean concomitant C-peptide and insulinoma size were lower in those patients with insulin-IRMA levels below 6 mIU/l. CONCLUSION: Symptomatic hypoglycaemia below 0.45 g/l can result from insulin levels below 6 or even 3 mIU/l; lower insulin levels and secretion could be observed preferentially in small insulinomas. If an insulin assay devoid of any significant cross-reaction with intact proinsulin is employed, measuring C-peptide (and/or proinsulin) levels at the time of symptomatic hypoglycaemia is mandatory to make the diagnosis of endogenous hyperinsulinism.
Prevalence of polycystic ovaries in women with androgenic alopecia
Authors: Cela E , Robertson C , Rush K , Kousta E , White DM , Wilson H , Lyons G , Kingsley P , McCarthy MI , Franks S
Published: January 2005

OBJECTIVE: Although androgenic alopecia is recognised to be a symptom of polycystic ovary syndrome (PCOS), it is not known whether polycystic ovaries (PCO) and associated endocrine abnormalities are present in patients who present with alopecia as a primary complaint. We therefore set out to determine the strength of the association between androgenic alopecia and PCO. We examined the prevalence of ultrasound-based polycystic ovarian morphology and associated clinical and biochemical features in a large multiethnic group of women whose presenting complaint was of alopecia, and in a control group. SUBJECTS AND METHODS: We studied 89 women of mixed ethnic origin with androgenic alopecia and compared them to 73 control women. A detailed history was taken, anthropometry was performed and assessment of body-hair distribution was made. The presence of PCO was established by pelvic ultrasound scan. Serum gonadotrophins, testosterone, androstenedione, dihydrotestosterone and sex hormone binding globulin concentrations were measured. RESULTS: Women with alopecia had a higher prevalence of PCO and hirsutism than the control population (PCO: 67% vs 27%, P<0.00001; hirsutism: 21% vs 4%, P=0.003). Women with alopecia (with or without PCO) had higher testosterone, androstenedione and free androgen index than controls, even though few had frankly abnormal androgens. CONCLUSIONS: These findings confirm an association between androgenic alopecia and PCO, and other symptoms of hyperandrogenaemia. Thus most women who present with androgenic alopecia as their primary complaint also have PCO and have indices of abnormal androgen production. Since PCO is a well known risk factor for development of type 2 diabetes, this association has important implications for long-term management.
Thyroid over-expression of type 1 and type 2 deiodinase may account for the syndrome of low thyroxine and increasing triiodothyronine during propylthiouracil treatment
Authors: Weetman AP , Shepherdley CA , Mansell P , Ubhi CS , Visser TJ
Published: January 2005

Although propylthiouracil inhibits type 1 deiodinase, leading to a more rapid fall in triiodothyronine (T(3)) than thyroxine (T(4)) levels in patients treated for hyperthyroidism, we report a patient with Graves' disease whose free T(3) paradoxically rose during such treatment, despite low free T(4) levels and increasing doses of propylthiouracil. A similar response has previously been associated with high levels of thyroid stimulating antibodies, but it has been unclear why there should be a dichotomy in the circulating thyroid hormone profile. Thyroid tIssue from our patient contained very high levels of type 1 and, especially, type 2 deiodinase, in contrast to other patients treated with Graves' disease, which were most likely secondary to high levels of thyroid stimulating antibodies. This unusual response to propylthiouracil is important to recognise therapeutically, and represents a further situation in which abnormal expression of deiodinase enzymes has clinical significance.
The usefulness of 99mTc-SestaMIBI scan in the diagnostic evaluation of thyroid nodules with oncocytic cytology
Authors: Boi F , Lai ML , Deias C , Piga M , Serra A , Uccheddu A , Faa G , Mariotti S
Published: January 2005

OBJECTIVE: To assess the relevance of (99m)Tc-SestaMIBI (MIBI) scan in the diagnostic evaluation of thyroid nodules with oncocytic cytology. SUBJECTS AND METHODS: Twenty-four patients with a single (or prevalent) 'cold' solid nodule with Hurthle cells (HC) at fine needle aspiration cytology (FNAC) were studied. Cytological diagnosis of oncocytic metaplasia (OM) or HC tumor (HCT) was made when HC on the smear were comprised 10-75%, or >75%. Nodules concentrating MIBI at early and late (2 h after washout) stages were considered MIBI-positive. In all cases histological findings were obtained after total thyroidectomy. RESULTS: FNAC was malignant or suspect for malignancy in 16 cases (six HCT and 10 OM) and not suspect in eight (two HCT and six OM). Histological examination revealed 14 malignant tumors (11 HCT and three OM), and 10 benign thyroid lesions (three HCT and seven OM). Sensitivity of FNAC for malignancy was 92.8% and specificity was 70.0%; HCT were identified by FNAC in only 35.7% and OM in 70.0% of cases. No significant difference in MIBI positivity was found between malignant and benign thyroid nodules. The highest percentage of MIBI positivity was found in HCT (78.5%), but MIBI-positive nodules were also observed in thyroid lesions with HC metaplasia (40.0%). CONCLUSIONS: MIBI scintiscan has no value in differentiating malignant from benign HC thyroid neoplasias. Most HCT are MIBI-positive, but this scan is not sufficiently specific to differentiate true HC neoplasias from other thyroid lesions showing HC at FNAC, although an MIBI-negative scan strongly supports the absence of true HCT.
Inhibition of lipolysis during acute GH exposure increases insulin sensitivity in previously untreated GH-deficient adults
Authors: Segerlantz M , Bramnert M , Manhem P , Laurila E , Groop LC
Published: January 2005

OBJECTIVE: Previous studies evaluating the lipolytic effect of GH have in general been performed in subjects on chronic GH therapy. In this study we assessed the lipolytic effect of GH in previously untreated patients and examined whether the negative effect of enhanced lipolysis on glucose metabolism could be counteracted by acute antilipolysis achieved with acipimox. METHODS: Ten GH-deficient (GHD) adults participated in four experiments each, during which they received in a double-blind manner: placebo (A); GH (0.88+/-0.13 mg) (B); GH+acipimox 250 mg b.i.d. (C); and acipimox b.i.d. (no GH) (D), where GH was given the night before a 2 h euglycemic, hyperinsulinemic clamp combined with infusion of [3-(3)H]glucose and indirect calorimetry. RESULTS: GH increased basal free fatty acid (FFA) levels by 74% (P=0.0051) and insulin levels by 93% (P=0.0051). This resulted in a non-significant decrease in insulin-stimulated glucose uptakes (16.61+/-8.03 vs 12.74+/-5.50 micromol/kg per min (s.d.), P=0.07 for A vs B). The rates of insulin-stimulated glucose uptake correlated negatively with the FFA concentrations (r=-0.638, P<0.0001). However, acipimox caused a significant improvement in insulin-stimulated glucose uptake in the GH-treated patients (17.35+/-5.65 vs 12.74+/-5.50 micromol/kg per min, P=0.012 for C vs B). The acipimox-induced enhancement of insulin-stimulated glucose uptake was mainly due to an enhanced rate of glucose oxidation (8.32+/-3.00 vs 5.88+/-2.39 micromol/kg per min, P=0.07 for C vs B). The enhanced rates of glucose oxidation induced by acipimox correlated negatively with the rate of lipid oxidation in GH-treated subjects both in basal (r=-0.867, P=0.0093) and during insulin-stimulated (r=-0.927, P=0.0054) conditions. GH did not significantly impair non-oxidative glucose metabolism (6.86+/-5.22 vs 8.67+/-6.65 micromol/kg per min, P=NS for B vs A). The fasting rate of endogenous glucose production was unaffected by GH and acipimox administration (10.99+/-1.98 vs 11.73+/-2.38 micromol/kg per min, P=NS for B vs A and 11.55+/-2.7 vs 10.99+/-1.98 micromol/kg per min, P=NS for C vs B). On the other hand, acipimox alone improved glucose uptake in the untreated GHD patients (24.14+/-8.74 vs 16.61+/-8.03 micromol/kg per min, P=0.0077 for D vs A) and this was again due to enhanced fasting (7.90+/-2.68 vs 5.16+/-2.28 micromol/kg per min, P=0.01 for D vs A) and insulin-stimulated (9.78+/-3.68 vs 7.95+/-2.64 micromol/kg per min, P=0.07 for D vs A) glucose oxidation. CONCLUSION: The study of acute administration of GH to previously untreated GHD patients provides compelling evidence that (i) GH-induced insulin resistance is mainly due to induction of lipolysis by GH; and (ii) inhibition of lipolysis can prevent the deterioration of insulin sensitivity. The question remains whether GH replacement therapy should, at least at the beginning of therapy, be combined with means to prevent an excessive stimulation of lipolysis by GH.
Insulin sensitivity and glucose tolerance improve in patients with acromegaly converted from depot octreotide to pegvisomant
Authors: Drake WM , Rowles SV , Roberts ME , Fode FK , Besser GM , Monson JP , Trainer PJ
Published: January 2005

AIM AND METHOD: Insulin resistance leading, in some cases, to glucose intolerance is an important contributory factor to the cardiovascular morbidity and mortality associated with acromegaly. The aim of this study was to document changes in insulin sensitivity (IS) in a group of seven patients with acromegaly (three male, four female, mean+/-s.d. age 59+/-13 Years) treated initially with a stable dose of depot octreotide (OT; median dose 30 mg four times weekly, range 10-30 mg) for a median of 18 Months (range 16-19 Months) and who were then transferred to treatment with pegvisomant (median dose 15 mg daily, range 10-20 mg) for a median of 8 Months (range 7-9 Months). IS was assessed by homeostatic model assessment (HOMA) using fasting glucose and insulin concentrations and by a short insulin tolerance test (sITT). Body composition was assessed by dual energy X-ray absorptiometry. RESULTS: Mean+/-s.d. serum IGF-I concentrations during therapy with OT and with pegvisomant were not statistically different (283+/-119 ng/ml on OT vs 191+/-39 ng/ml on pegvisomant (P=0.4)). However, mean+/-s.d. fasting plasma glucose fell from 6.2+/-1.0 mmol/l on OT to 5.2+/-0.6 mmol/l on pegvisomant (P=0.017) and was lower on pegvisomant in all seven patients. In four patients, fasting plasma glucose fell from values diagnostic of diabetes mellitus or impaired fasting glucose on OT to within the normal range on pegvisomant. Mean+/-s.d. peripheral IS (by sITT) increased from 139+/-39 micromol/l per min on OT to 169+/-59 micromol/l per min on pegvisomant (P=0.037). Mean+/-s.d. IS (by HOMA %S) was unchanged over the course of the study (149.1+/-43.7% on OT vs 139.9+/-76.6% on pegvisomant, P=0.28). Mean+/-s.d. pancreatic beta-cell secretory function (HOMA %B) improved significantly on pegvisomant compared with OT (49.4+/-19.2% vs 82.4+/-43.5%, P=0.01). No statistically significant change in total fat (P=0.3), % fat (P=0.28) or circulating non-esterified fatty acids (P=0.35) was observed. CONCLUSIONS: IS and glucose tolerance improved in patients converted from OT therapy to pegvisomant, without a change in body composition and even when serum IGF-I concentrations remained equally well controlled. This may be an important factor in the choice of medical therapy for patients with acromegaly.
Elevated plasma endothelin as an additional cardiovascular risk factor in patients with Cushing's syndrome
Authors: Kirilov G , Tomova A , Dakovska L , Kumanov P , Shinkov A , Alexandrov AS
Published: January 2005

BACKGROUND: Recently the pathophysiological role of endothelin (ET) has been presumed in a number of adrenal disorders such as primary hyperaldosteronism, pheochromocytoma and adrenocortical insufficiency. AIM: The aim of the present study was to evaluate circulating ET-1 levels in patients with endogenous Cushing's syndrome. METHODS AND RESULTS: Plasma ET-1 levels were determined by highly sensitive RIA. Thirteen untreated subjects with Cushing's syndrome were studied: eight women and five men of mean age 44.2+/-9.5 Years (s.d.). In ten of them, Cushing's disease had been diagnosed and three had adrenal adenomas. ET-1 was 3-fold higher in the patient group than in age-matched healthy controls (n=13): 1.59+/-0.78 vs 0.46+/-0.20 pmol/l respectively, P<0.001. In adrenal adenoma patients, ET-1 was not significantly higher than in the Cushing's disease subjects (1.84+/-0.67 vs 1.51+/-0.83 pmol/l respectively, P>0.05). In three patients who died of severe cardiovascular complications, plasma ET-1 was significantly higher than in the remaining patients (2.34+/-0.35 pmol/l, P<0.05). A positive correlation was found between the total cholesterol (6.94+/-1.75 mmol/l) and ET-1 levels in the patients with Cushing's syndrome: r=+0.73, P<0.02. No correlation was observed, however, between the levels of ET-1 and blood pressure (183+/-37/106+/-18 mmHg), plasma cortisol levels (455.2+/-74.5 nmol/l) or urinary cortisol excretion (1463+/-726 nmol/24 h). The successful treatment and correction of hypercortisolism in seven patients led to insignificant reduction in plasma ET from 1.34+/-0.69 to 0.73+/-0.53 pmol/l, P>0.05. CONCLUSION: Our results clearly demonstrate that the ET system is activated in Cushing's syndrome. Elevated plasma ET-1 levels probably play a role in the pathogenesis of accelerated and early atherosclerosis development in this disorder.
Increases in plasma levels of atrial and brain natriuretic peptides after running a marathon: are their effects partly counterbalanced by adrenocortical steroids?
Authors: Niessner A , Ziegler S , Slany J , Billensteiner E , Woloszczuk W , Geyer G
Published: January 2005

OBJECTIVE: Long-distance running results in considerable stress. Little evidence exists about the role of the atrial and brain natriuretic peptides, ANP and BNP, deriving from the myocardium. The aim of our study was to investigate the influence of running 42.195 km on changes in circulating natriuretic propeptides and adrenocortical steroids. DESIGN AND METHODS: We studied 17 male and 2 female runners (age: 28-62 Years) participating in a marathon. Blood samples were obtained before and immediately after the competition. proANP(1-98) and proANP(1-30) as well as Nt-proBNP(8-29) were determined by enzyme immunoassays. RESULTS: Runners finished the competition between 2 h 58 min and 4 h 25 min. We observed a more pronounced increase in proANP(1-98) (+58%) and proANP(1-30) (+99%, both P<0.001) compared with Nt-proBNP(8-29) (+6%; P=0.005). Increases in proANP(1-30) positively correlated with runners' age (r=0.53; P=0.02). We also observed a marked increase in cortisol (+73%) and especially in aldosterone (+431%, both P<0.001). CONCLUSIONS: Cardiac strain during long-distance running may explain the pronounced increase in proANP. Other explanations for the observed rise in plasma levels might be a change in the permeability of myocardial cells and an impaired clearance. A rise in adrenocortical steroids may compensate for the negative influence of ANP on natriuresis and blood pressure. Positive effects of ANP during a marathon could be the regulation of body temperature by influencing sweat glands as well as the stimulation of lipolysis compensating for the enormous energy demand.
Computed tomography assessment of fat distribution in male and female patients with Cushing's syndrome
Authors: Rockall AG , Sohaib SA , Evans D , Kaltsas G , Isidori AM , Monson JP , Besser GM , Grossman AB , Reznek RH
Published: January 2005

OBJECTIVE: Our aims were to describe the abdominal fat distribution in male patients with Cushing's syndrome (CS) on computerised tomography (CT), to compare our findings with non-cushingoid patients, to validate previous reports of increased visceral fat in female patients with CS and to identify any correlations between fat distribution and biochemical findings. DESIGN: Retrospective and observational. PATIENTS: Appropriate CT scans were identified in 31 patients (seven male) with active CS. MEASUREMENTS: Total, visceral and subcutaneous fat areas were obtained. The percentage of visceral fat and the visceral to subcutaneous fat ratio (V:S ratio) were calculated. Biochemical data were recorded. Control data of fat distribution were obtained from the literature. RESULTS: There was a significant increase in the V:S ratio in male patients with CS when compared with non-cushingoid controls (1.175+/-0.59 vs 0.77+/-0.39, 95% confidence interval (CI) 0.0817-0.728). There was a significant increase in the V:S ratio in female patients with CS (0.845+/-0.53 vs 0.38+/-0.19, 95% CI 0.269-0.661). There was no difference in the V:S ratio between male and female patients with CS (1.175+/-0.59 vs 0.845+/-0.53, 95% CI -0.144-0.804). No significant correlations between fat distribution and glucose levels, circulating cortisol, ACTH or lipids were found. CONCLUSIONS: Our data demonstrate an increase in visceral fat distribution in both male and female patients with CS, with the abolition of the normal male to female difference in visceral fat. Increased visceral fat may increase the risk of the metabolic syndrome in this group of patients.
Do patients with multiple endocrine neoplasia syndrome type 1 benefit from periodical screening?
Authors: Geerdink EA , Van der Luijt RB , Lips CJ
Published: January 2005

OBJECTIVE: To determine the benefit of periodical clinical screening of carriers of a mutation in the multiple endocrine neoplasia type 1 (MEN-1) gene, because any useful discussion requires more concrete data. DESIGN AND METHODS: Our study population consisted of all the patients with MEN-1 (n=58) who were treated at the University Medical Centre Utrecht, The Netherlands, during the period 1975-2003, and their affected relatives (n=29). Records of affected individuals who died were analysed for morbidity, cause of death and age at death. We discuss our results in the light of the literature on MEN-1 regarding the benefit of screening. RESULTS: Over a period of 28 Years, we identified 87 individuals affected with MEN-1, from 16 families. A mutation in the MEN-1 gene was detected in 57%, 18% were obligate carriers, and in 24% the diagnosis was only clinically confirmed. Thirty individuals died, 17 from MEN-1-related causes, including malignancies (n=12: pancreatic islet cell tumours n=6 and carcinoid tumours n=6), the Zollinger-Ellison syndrome (n=4) and Cushing's disease (n=1). The remaining patients died of causes probably related to MEN-1 (n=3), unrelated to MEN-1 (n=7) or of unknown causes. Mean ages at death from MEN-1 were 55.4 Years for men and 46.8 Years for women, in both cases significantly lower than the mean age at death in the average Dutch population (P<0.05). CONCLUSIONS: We feel that the significantly increased risk of premature death found in patients with MEN-1 justifies the periodical clinical screening of carriers of the MEN-1 gene mutation. Early detection and treatment of abnormalities will probably reduce this risk.
Endogenous sex hormones in men aged 40-80 years
Authors: Muller M , den Tonkelaar I , Thijssen JH , Grobbee DE , van der Schouw YT
Published: January 2005

OBJECTIVE: To determine the relationship between aging, life-style factors and health-related factors and endogenous sex hormone levels. DESIGN: Cross-sectional study of 400 independently living men between 40 and 80 Years of age. METHODS: After exclusion of subjects who were not physically or mentally able to visit the study center, 400 men were randomly selected from a population-based sample. Total testosterone (TT), bioavailable testosterone (BT) (i.e. not bound to sex hormone-binding globulin (SHBG)), SHBG, estradiol (E(2)) and dehydroepiandrosterone-sulfate (DHEA-S) were investigated for their relationship with age, body mass index (BMI), waist circumference, smoking, physical activity and general health status. Multivariate models using ANCOVA analyses were used to examine the contribution of life-style factors to sex hormone variability. RESULTS: TT, BT and DHEA-S decreased with age; 0.2, 0.7 and 1.2%/Year respectively. SHBG showed an increase with age of 1.1%/Year. No changes with age were found for E(2). General health status modified the association of TT and SHBG with age (P interaction 0.10 and 0.002 respectively). Increased BMI and waist circumference were associated with decreased TT, BT, SHBG and DHEA-S and increased E(2) (all P<0.01). Current smoking, lower alcohol intake and a higher physical activity score were associated with higher TT and SHBG levels. CONCLUSION: This study showed the important determinants of sex hormones were age, BMI, waist circumference, smoking, general health status and physical activity. Furthermore, it can be concluded that general health status modified the effect between sex hormones and age. For future observational studies it should be taken into account that the above-mentioned determinants may alter the association between sex hormones and diseases and related conditions.
Clinical and hormonal characteristics of central hypothyroidism at diagnosis and during follow-up in adult patients
Authors: Alexopoulou O , Beguin C , De Nayer P , Maiter D
Published: January 2005

OBJECTIVE: We studied the clinical and hormonal profiles of patients with central hypothyroidism (CH), the adequacy of levothyroxine (L-T4) treatment and the influence of other pituitary hormone replacement therapies. METHODS: We reviewed medical records of 108 adult patients with child-onset (CO; n=26) or adult-onset (AO; n=82) CH. RESULTS: At diagnosis, the most frequently reported symptoms were fatigue and headaches in AO patients, and growth retardation in CO patients. Serum TSH was normal in a majority of CH patients, low in 8% and elevated in 8%. Serum free thyroxine (fT(4)) was usually reduced, but remained within the low normal range in 28% of the study population (mostly CO patients). Similarly, serum total T(4) (tT(4)), total triiodothyronine (tT(3)) and free T(3) (fT(3)) were found to be within the normal range in significant subsets of patients. Interestingly, the clinical and biochemical characteristics of CH patients with normal f/t T(4) levels were not different from those of the patients with low fT(4) values. The thyroid hormonal profile was not influenced by gender, etiology or by the number of hormone deficiencies. At last evaluation, the mean dose of L-T(4) was 1.6+/-0.5 microg/kg/day and was negatively correlated to current age (P<0.001) but positively correlated to the number of hormone deficiencies (P<0.05). Treatment suppressed TSH in 75% of the patients, induced normal fT(4) in 94%, but normal fT(3) in only 49% of them. Male GH-treated patients and estrogen-treated females needed a higher L-T(4) dose compared with non-treated patients. CONCLUSIONS: fT(4) is clearly the best indicator of CH, but remains in the low normal range in a significant subset of patients, especially in those with CO disease. Adequacy of therapy is mostly reflected by the combination of upper normal fT(4) and low normal fT(3) levels. Pituitary hormone replacement therapy may require an adjustment of T(4) treatment, as female patients under estrogen treatment and male patients under GH treatment will need a higher T(4) dose in order to remain in the euthyroid range.
Prevalence of calcium sensing receptor autoantibodies in patients with sporadic idiopathic hypoparathyroidism
Authors: Goswami R , Brown EM , Kochupillai N , Gupta N , Rani R , Kifor O , Chattopadhyay N
Published: January 2005

OBJECTIVE: The pathogenesis of sporadic idiopathic hypoparathyroidism is unclear. The calcium sensing receptor (CaSR) plays a pivotal role in extracellular calcium homeostasis and is the candidate autoantigen in hypoparathyroidism associated with autoimmune polyglandular endocrinopathy syndrome. We therefore looked for antibodies (Ab) against the CaSR in patients with sporadic idiopathic hypoparathyroidism and their association, if any, with the major histocompatibility complex (MHC) class II human leukocyte antigen (HLA)-DR haplotypes. METHODS: The subjects included 51 patients with sporadic idiopathic hypoparathyroidism and 45 healthy controls. Investigations included computerised tomography, serum calcium, phosphorus, thyroxine, TSH, cortisol, intact parathyroid hormone (iPTH), ACTH and thyroid peroxidase (TPO) and adrenal antibodies. The CaSRAb were assayed in patients' sera by Western blot. Genotyping of the HLA-DR locus was performed using PCR and sequence-specific oligonucleotide probes. RESULTS: Intracranial calcification and cataract were present in 76.5% and 41.1% of the patients respectively and 62.7% had convulsions. Autoantibodies against the 168 kDa CaSR protein were demonstrated in the serum of 49.0% of the patients and in 13.3% of the controls (P<0.001). Pre-incubating serum samples from the CaSRAb-positive patients with parathyroid membrane produced a 90% decrease in the band intensity. HLA-DRB1*01 and DRB1*09 alleles were significantly associated with idiopathic hypoparathyroidism (relative risk of 7.8, P=0.001). The frequency of HLA-DRB1*09 and DRB1*10 alleles tended to be higher in patients positive for the CaSRAb. There was no significant difference in the frequency of occurrence of convulsions, cataract, intracranial calcification, calcium:phosphorus ratio, and iPTH levels between patients with and without CaSRAb. CONCLUSION: 49.0% of the patients studied had serological evidence of organ-specific autoimmunity against the CaSR protein. The occurrence of CaSRAb and the HLA-DR associations imply an autoimmune component to the disease, but the primary role of the CaSRAb in the pathogenesis of the disease needs to be assessed further.
Persistent disease after surgery for primary hyperparathyroidism: the long-term outcome
Authors: Hedback G , Oden A
Published: January 2005

OBJECTIVE: Nineteen patients with persistent primary hyperparathyroidism were investigated to evaluate their clinical and laboratory status a long time after treatment was ended. The risk of persistent disease and need for extensive surgery for cure, i.e. more than two neck operations, or mediastinal exploration, was also evaluated. DESIGN: The medical records of 896 consecutive patients operated on for primary hyperparathyroidism were scrutinised at follow-up, a mean of 10.3 Years after surgery. Data on state of health, medication, bone fractures and other diagnoses were collected by use of a questionnaire. There were 600 patients still alive, among whom 13 had persistent disease and they were compared with 509 patients who were cured and without any suspicion of recurrent disease, according to laboratory examination. RESULTS: Serum calcium and creatinine values had with few exceptions remained stable over the Years. In five patients, serum calcium levels were within the normal range at follow-up. Still, all 19 patients were considered hyperparathyroid. They had substantial cardiovascular morbidity, and their state of health was not as good as that of the patients who were surgically cured. After one operation, 5.5% (95% confidence interval (CI) 4.0-7.2%) had persistent disease, and 2.1% after reoperation. Extensive surgery for cure was performed in 2% of the patients (95% CI 1.1-3.2%). CONCLUSIONS: We found that the state of health was significantly better for patients with cured primary hyperparathyroidism than for patients with persistent disease, but serious deterioration of laboratory values was uncommon. The result of the present study supports surgical treatment.
Oleic acid from cooking oils is associated with lower insulin resistance in the general population (Pizarra study)
Authors: Soriguer F , Esteva I , Rojo-Martinez G , Ruiz de Adana MS , Dobarganes MC , Garcia-Almeida JM , Tinahones F , Beltran M , Gonzalez-Romero S , Olveira G , Gomez-Zumaquero JM
Published: January 2005

AIM: To evaluate the relation between type of dietary fatty acid and degree of insulin resistance. DESIGN: A cross-sectional study. METHODS: Anthropometrical data were measured in 538 subjects, aged 18-65 Years, selected randomly from the municipal census of Pizarra (Spain). An oral glucose tolerance test (OGTT) was given to all subjects and measurements were made of glycemia, insulinemia and the proportion of fatty acids in plasma phospholipids. Insulin resistance (IR) was estimated by homeostasis model assessment. Samples of cooking oil being used were obtained from the kitchens. The strength of association between variables was measured by calculating the odds ratio (OR) from logistic models, and the relationships were measured by linear correlation coefficients. RESULTS: Insulin resistance was significantly less in people who used olive oil compared with those who used sunflower oil or a mixture. Statistical significance remained in the group of people with normal OGTT after adjusting for obesity. In the whole sample, IR correlated negatively with the concentration of oleic acid (r=-0.11; P=0.02) and positively with that of linoleic acid (r=0.10; P=0.02) from the cooking oil. In subjects with normal OGTT, IR correlated negatively with oleic acid from cooking oil (r=-0.17; P=0.004) and from plasma phospholipids (r=-0.11; P=0.01) and positively with the concentration of linoleic acid in cooking oil (r=0.18; P=0.004) and plasma phospholipids (r=0.12; P=0.005). The risk (OR) of having raised IR was significantly lower in people who consumed olive oil, either alone (OR=0.50) or mixed (OR=0.52) compared with those who consumed only sunflower oil. CONCLUSION: There is an association between the intake of oleic acid, the composition of oleic acid in plasma phospholipids and peripheral insulin action.
Autoantibodies against 21-hydroxylase and side-chain cleavage enzyme in autoimmune Addison's disease are mainly immunoglobulin G1
Authors: Boe AS , Bredholt G , Knappskog PM , Hjelmervik TO , Mellgren G , Winqvist O , Kampe O , Husebye ES
Published: January 2005

OBJECTIVE: Immunoglobulin G (IgG) antibodies to the steroidogenic enzymes 21-hydroxylase (21OH) and side-chain cleavage enzyme (SCC) are important diagnostic markers for autoimmune Addison's disease and autoimmune polyendocrine syndromes (APS) types I and II. The characterization of autoantibody (IgG) subclasses may reveal information on how tIssue destruction takes place; therefore, IgG subtypes of anti-21OH and anti-SCC antibodies from sera of patients with Addison's disease, APS I and APS II were determined using recombinant 21OH and SCC. METHODS: SCC(51-521) and his-SCC(51-521) were expressed by pET-scc in the Escherichia coli strain BL21 Star (DE3) and inclusion bodies were purified. Full-length, human 21OH fused to an N-terminal 6x histidine affinity tag was expressed in insect cells by using the baculovirus expression system bac-to-bac. Western blots were used to investigate the IgG subtype(s) of the autoantibodies against 21OH and SCC in patients and healthy blood donors. RESULTS: All anti-SCC positive sera (n=10) contained autoantibodies of the IgG1 subclass, while four out of ten also contained IgG3. All anti-21OH positive sera (n=16) had autoantibodies exclusively against IgG1. Sera from 20 healthy subjects did not show any reactivity against 21OH or SCC. CONCLUSIONS: The finding of a predominating IgG1 response against 21OH and SCC may suggest that T helper (Th) cells of the Th1 subclass are involved in destruction of the adrenal cortex in patients with autoimmune Addison's disease.
Influence of fluor salts, hormone replacement therapy and calcitonin on the concentration of insulin-like growth factor (IGF)-I, IGF-II and transforming growth factor-beta 1 in human iliac crest bone matrix from patients with primary osteoporosis
Authors: Pepene CE , Seck T , Diel I , Minne HW , Ziegler R , Pfeilschifter J
Published: January 2005

OBJECTIVE: Data from cell culture experiments suggest that local growth factors (GFs) may mediate the effects of estrogens, calcitonin or fluor ions on the skeleton. To assess the in vivo relevance of the in vitro reports, the effect of fluor salts, hormone replacement therapy (HRT) and calcitonin on the concentrations of IGF-I, IGF-II and transforming growth factor (TGF)-beta 1 in bone matrix extracts from osteoporotic patients was evaluated. DESIGN: Iliac crest bone biopsies were obtained from 170 patients (76 men and 94 women) with primary osteoporosis aged 55.5+/-0.8 Years. METHODS: Bone matrix extraction was performed based on a guanidine-HCl/ethylendiamine-tetra-acetic acid method. RESULTS: In comparison with age- and body mass index (BMI)-matched controls, no influence of long-term therapy with fluor ions (n=41) or calcitonin (n=16) on the bone matrix concentration of GFs was noticed. Postmenopausal women with osteoporosis on HRT (n=39) had lower skeletal IGF-I but not IGF-II levels as compared with age- and BMI-matched non-users. However, the lower rate of bone turnover in women with HRT may account for this difference, since the significance was lost after adjustment for alkaline phosphatase. Likewise, a tendency for lower TGF-beta 1 levels was observed in HRT users as compared with non-users but was lost after adjustment for bone turnover. None of the therapies influenced the serum levels of GFs when patients receiving continuous therapy for at least 1 Year before bone biopsy were considered. CONCLUSIONS: Our data suggest no direct effect of fluor therapy on skeletal GFs levels. At the concentrations used, neither HRT nor calcitonin appeared to exert any significant influence on serum or bone matrix GF levels.