bluuebunny/crossref_metadata_2025 huggingface dataset:
The investigation of galectin-3 in diseases of the thyroid gland
Authors: Kovacs RB , Foldes J , Winkler G , Bodo M , Sapi Z
Published: January 2005

OBJECTIVE: Malignant tumors of the thyroid gland exhibit a variety of histopathologies and clinical behavior. Immune markers are gaining more and more importance in diagnostic pathology, especially in the differential diagnostics and in the grading of thyroid gland tumors. DESIGN: The Authors investigated the immunohistochemical reaction of galectin-3 (gal3) in patients with various thyroid gland diseases. They tested the diagnostic value of gal3 in determining the benign or malignant nature of various lesions, especially in lesions of follicular origin, because previous results have indicated nearly 100% specificity and sensitivity in this regard. METHODS: Gal3 immunoperoxidase reaction was carried out on 91 sections of thyroid gland samples fixed in formalin and embedded in paraffin. RESULTS: While gal3 expressed itself strongly and diffusely in papillary carcinomas (19 of 20 cases), in other malignant lesions it showed weaker, focal or variable positivity. Focal positivity was found in four of 19 follicular adenomas, and negativity was found in three of 10 follicular carcinomas. In all cases of inflammation a focal positivity was observed (eight of eight cases). All nodular goiter and normal thyroid tIssue were negative (25 of 25 cases). CONCLUSIONS: Based on our results, the gal3 immunohistochemical reaction seems to be reliable in the diagnosis of papillary carcinomas. However, in the case of solitary thyroid nodules and follicular lesions, although it is still a useful supplementary marker, it is not of absolute value (as stated in previous studies) in determining whether a tumor is benign or malignant.
Functional in vitro studies on the role and regulation of interleukin-6 in human somatotroph pituitary adenomas
Authors: Thiele JO , Lohrer P , Schaaf L , Feirer M , Stummer W , Losa M , Lange M , Tichomirowa M , Arzt E , Stalla GK , Renner U
Published: January 2005

OBJECTIVE: Interleukin-6 (IL-6), a member of the gp130 cytokine family, is considered to be an important modulator of function and growth in endocrine anterior pituitary cells. In pituitary adenomas, where IL-6 is often produced by the tumour cells, it is thought to be involved in pituitary adenoma pathophysiology via autocrine/paracrine mechanisms. METHODS: We have studied in primary cell cultures of human somatotroph adenomas whether IL-6 stimulates growth hormone secretion and whether intratumoral IL-6 is affected by various IL-6-regulating factors. RESULTS: Interleukin-6 stimulated GH secretion in 10 out of 11 somatotroph adenoma cultures (1.4- to 6.5-fold above basal levels). In comparative studies the GH-stimulatory potency of IL-6 was identical, or even stronger, than that of GHRH. In eight out of 11 adenoma cell cultures, IL-6 production was observed. This suggests that GH production might be stimulated by IL-6 in an autocrine/paracrine manner in these tumours. Dexamethasone strongly inhibited basal IL-6 secretion in all IL-6-producing adenoma cell cultures, whereas the IL-6 inhibitory or stimulatory action of other factors (octreotide, transforming growth factor-beta1, insulin-like growth factor-I, pituitary adenylate cyclase-activating peptide and oestradiol) were heterogeneous in the different adenomas. Only transforming growth factor-alpha consistently stimulated IL-6 secretion in all of the adenomas studied. CONCLUSIONS: Intratumoral IL-6, which is differently regulated by various factors, might contribute to excessive GH production in the majority of somatotroph adenomas.
Molecular epidemiology of prostate cancer: androgens and polymorphisms in androgen-related genes
Authors: Ntais C , Polycarpou A , Tsatsoulis A
Published: January 2005

In most western countries prostate cancer is the most commonly diagnosed non-skin cancer in men. Despite its high morbidity and mortality the etiology of prostate cancer remains obscure. The involvement of androgens has been examined extensively in prostate carcinogenesis but the results of most epidemiological studies remain inconclusive. This review focuses on current perspectives of androgen levels and polymorphisms in androgen-related genes. Racial differences in genetic polymorphisms that have a role in the biosynthesis and metabolism of androgens may partly account for racial differences in prostate cancer risk. Reasons are also given for inconsistent results in molecular epidemiological studies and insights and directions for future research are discussed. The development of a polygenic model for prostate cancer, incorporating multiple loci from the individual genes, may maximize the chance of identifying individuals with high-risk genotypes, resulting in better preventive, diagnostic, and therapeutic strategies.
Effective treatment of bone metastases from a neuroendocrine tumour of the pancreas with high activities of Indium-111-pentetreotide
Authors: van der Hiel B , Stokkel MP , Chiti A , Lucignani G , Bajetta E , Pauwels EK , Bombardieri E
Published: January 2005

OBJECTIVE: To evaluate therapy with high doses of (111)Indium pentetreotide in a patient with bone metastases from a carcinoid of the pancreas. CASE REPORT: A 55-Year-old male presented in November 1990 with stomach ache with dorsal irradiation. Ultrasonography and computed tomography (CT-) scans of the abdomen revealed a tumour of the tail of the pancreas and liver metastases. Histological examination revealed a neuroendocrine tumour. Surgery and polychemotherapy were initiated and after seven cycles a tumour regression of 30% was achieved. During follow-up multiple metastases were seen upon bone scintigraphy for which treatment with high doses Indium-111-octreotide was initiated. MATERIALS AND METHODS: The patient underwent eight cycles, with one cycle every 5 weeks. Each treatment consisted of an i.v. injection of 6 GBq Indium-111-pentetreotide. Comparing the results of the first and the last post-treatment scintigraphy, a regression of the number and intensity of uptake in the lesions was found. Bone scintigraphy showed a regression of the skeletal lesions as well, while X-ray, CT-scan and chromogranin-A levels showed stable disease. CONCLUSION: Results from the treatment of our patient indicate that the use of high dose radiolabelled somatostatin analogues could be of significant use, even in the case of bone metastases. To our knowledge, this is the first report describing therapeutic effects on bone metastases from a neuroendocrine tumour.
Resumption of methimazole after 131I therapy of hyperthyroid diseases: effect on thyroid function and volume evaluated by a randomized clinical trial
Authors: Bonnema SJ , Bennedbaek FN , Gram J , Veje A , Marving J , Hegedus L
Published: January 2005

OBJECTIVE: Retrospective studies have indicated that anti-thyroid drugs (ATD) might possess a radioprotective effect, leading to a higher rate of recurrence of hyperthyroidism after iodine-131 ((131)I) therapy. DESIGN: A randomized clinical trial was performed to clarify whether resumption of methimazole after (131)I influences the final outcome of this treatment. METHODS: We assigned 149 patients with Graves' disease or a toxic nodular goitre to groups either to resume (+ATD) or not to resume (-ATD) methimazole 7 days after (131)I. Before (131)I therapy, all patients were rendered euthyroid by methimazole, which was discontinued 4 days before the (131)I therapy. RESULTS: During the follow-up period of 12 Months, 13 patients developed hypothyroidism, 42 were euthyroid, and 18 had recurrence of hyperthyroidism in the +ATD group; the respective numbers in the -ATD group were 16, 42 and 18 (P=0.88). At 3 weeks after (131)I therapy, the serum free-thyroxine index was slightly decreased (by 5.7%; 95% confidence interval (CI) -15.5 to 5.4%) in the +ATD group, in contrast to an increase of 35.9% (95% CI 18.8 to 55.5%) in the -ATD group (P<0.001 between groups). In the subgroup that remained euthyroid during follow-up, thyroid Volume reduction, assessed by ultrasonography, was smaller in the +ATD group [38.7% (95% CI 33.3 to 44.1%)] than in the -ATD group [48.6% (95% CI: 41.5-55.6%)] (P<0.05). CONCLUSION: No radioprotective effect could be demonstrated, with regard to final thyroid function, for the resumpton of methimazole 7 days after (131)I therapy. Although resumption of methimazole slightly reduced the magnitude of shrinkage of the goitre obtained by (131)I, the prevention of a temporary thyrotoxicosis in the early period after radiation favours this regimen.
Circulating IGF-I levels in monitoring and predicting efficacy during long-term GH treatment of GH-deficient adults
Authors: Ezzat S , Fear S , Gaillard RC , Gayle C , Marcovitz S , Mattioni T , Nussey S , Rees A , Svanberg E
Published: January 2005

OBJECTIVE: To investigate the effects of long-term GH in GH-deficient adults, as predicted by IGF-I levels. METHODS: Patients received GH, 5 microg/kg per day for 1 Month and 10 microg/kg per day for another 12-30 Months. Changes in body composition, cardiac structure/function, serum lipids and quality of life were measured. RESULTS: There was a significant increase in lean body mass (LBM) (2.21 kg; P<0.0001) after 6 Months, which was sustained throughout treatment. A larger increase occurred in males than females (2.97 vs 1.19 kg; P<0.0001). Total fat mass was reduced (2.56 kg; P<0.0001 (3.26 kg males, 1.63 kg females)). Responsiveness to GH varied greatly, but LBM changes correlated with IGF-I changes (P<0.004). Furthermore, thinner patients experienced greater and progressive LBM increases. There was an increase in ejection fraction (3.85+/-9.95%; P=0.0002) after 6 Months, sustained to 18 Months. These cardiac effects were equal for males and females, and did not correlate with IGF-I levels. Serum low-density lipoprotein/high-density lipoprotein ratios decreased within 6 Months, and were sustained thereafter. Quality of life improved significantly after 6 Months, an effect that was sustained/enhanced as treatment continued. No major adverse events were identified. CONCLUSIONS: Improved body composition is both reflected by IGF-I changes and predicted inversely by baseline adiposity. Other effects of GH replacement on cardiac function, dyslipidaemia and quality of life, however, do not correlate with circulating IGF-I concentrations. Our findings validate the importance of sustained GH therapy, but caution on the interpretation of IGF-I levels in monitoring the long-term effects of GH treatment.
Impaired adrenocortical function in very low birth weight infants after multiple pregnancies
Authors: Eskola V , Lenko HL , Tammela O
Published: January 2005

OBJECTIVE: To evaluate the differences in adrenal function between very low birth weight (VLBW) infants from singleton and multiple pregnancies. DESIGN AND METHODS: Forty infants of birth weights less than 1500 g underwent an ACTH test. Thirty infants born from singleton pregnancies (singleton group) and ten born from multiple pregnancies (multiple group) were enrolled. A baseline blood sample was drawn for cortisol measurement and thereafter serum cortisol was measured 1 and 2 h after an i.v. injection of ACTH. RESULTS: In multiple pregnancies, the median basal cortisol level of the infants was significantly lower than that in the singletons. The median cortisol level at 1 and 2 h after administration of ACTH was significantly lower in infants from multiple gestations than in singletons. Of infants from the multiple gestation group six, and of the singleton infants 12, had baseline cortisol levels lower than the reference values (P=0.48). One hour after ACTH stimulation all multiple and 53% of the singleton group infants showed a subnormal (<500 nmol/l, P=0.007) cortisol response. Two hours after ACTH, nine multiple group patients and 43% of the singletons had subnormal (<500 nmol/l, P=0.01) stimulated cortisol levels. CONCLUSIONS: We have concluded that VLBW infants from multiple gestations seem to be at an increased risk of insufficient postnatal adrenocortical function. In the future, specific attention should be paid to evaluate further newborn infants from multiple pregnancies with regard to a possible benefit of hydrocortisone substitution in stressful clinical situations.
Is the plasma ACTH concentration a reliable parameter in the insulin tolerance test?
Authors: Borm K , Slawik M , Seiler L , Flohr F , Petrick M , Honegger J , Reincke M
Published: January 2005

OBJECTIVE: The insulin tolerance test (ITT) is an established standardized test for the evaluation of the hypothalamic-pituitary-adrenal axis. While a peak cortisol value of >18 microg/dl is usually interpreted as a sufficient response to the ITT, the plasma ACTH response has not yet been standardized. METHODS: We evaluated retrospectively the peak plasma ACTH concentrations during 140 ITTs in 125 patients with suspected pituitary insufficiency and prospectively in 15 healthy subjects. RESULTS: All healthy subjects had a peak cortisol concentration >/=18 microg/dl; 32 of 125 tests in the patients showed an insufficient cortisol response (peak cortisol concentration <18 microg/dl). The peak stimulated ACTH concentration in patients with secondary adrenal insufficiency (SAI) was 49.2+/-37.2 pg/ml (mean+/-s.d.) vs 130.9+/-89.3 pg/ml in patients without SAI, and 110.9+/-55.4 pg/ml in normal subjects (P<0.001). There was a weak, but significantly positive correlation between the peak ACTH and peak cortisol concentrations (rho=0.446, P<0.001), but there was also a very wide spread of the values. Defining a cut-off value for the peak plasma ACTH concentration with a sufficient sensitivity and specificity to identify patients with an impaired hypothalamic-pituitary-adrenal (HPA) axis was not possible. A peak plasma ACTH <20 pg/ml as a cut-off value had a sensitivity of 25% and a specificity of 98% for SAI. A cut-off value of a peak plasma ACTH <140 pg/ml had a sensitivity of 97% but a low specificity of 39%. CONCLUSIONS: Although there is a significant positive correlation between the peak ACTH and the peak cortisol concentrations, we conclude that there is no additional benefit in determining the ACTH concentrations during an ITT. Because of the strong variations of the values, the peak ACTH concentration is a poor parameter for the evaluation of the HPA axis.
Hepatic steatosis in Cushing's syndrome: a radiological assessment using computed tomography
Authors: Rockall AG , Sohaib SA , Evans D , Kaltsas G , Isidori AM , Monson JP , Besser GM , Grossman AB , Reznek RH
Published: January 2005

OBJECTIVE: Hepatic steatosis may occur in association with insulin resistance and obesity, two features commonly seen in Cushing's syndrome (CS). The aim of this report is to assess the prevalence of hepatic steatosis in patients with active CS using computed tomography (CT) and to identify any associations between hepatic steatosis, endocrine and biochemical variables and body fat distribution. PATIENTS AND MEASUREMENTS: We identified 50 patients with active CS in whom appropriate CT was available to allow measurement of liver and spleen attenuation. In 26 patients, abdominal fat measurements were also available. Serum markers of CS and liver function tests were recorded. RESULTS: Ten of 50 patients had a liver-to-spleen CT attenuation ratio (L/S) of less than 1, indicating hepatic steatosis. There was a significant negative correlation between both liver attenuation and L/S ratio with total abdominal fat area, visceral fat area, the percentage of visceral fat and the visceral to subcutaneous fat ratio; the strongest negative correlation was found between visceral fat area and L/S ratio (r=-0.638, P<0.001, n=26). L/S ratio positively correlated with alkaline phosphatase levels (r=+0.423, P=0.044, n=23) but with no other serum marker of CS activity or liver enzyme. CONCLUSIONS: We have demonstrated hepatic steatosis on CT in 20% of patients with active CS. The presence of hepatic steatosis was significantly correlated with total abdominal fat area and visceral fat area.
Birthsize, gestational age and adrenal function in adult life: studies of dexamethasone suppression and ACTH1-24 stimulation
Authors: Kajantie E , Eriksson J , Barker DJ , Forsen T , Osmond C , Wood PJ , Andersson S , Dunkel L , Phillips DI
Published: January 2005

OBJECTIVE: Several studies show that low birthweight is associated with long-term alterations in the function of the hypothalamic-pituitary-adrenal axis (HPAA). We recently reported that the relationship between birthweight and fasting serum cortisol concentrations differed according to the gestational age of the babies, suggesting that both hypercortisolism and hypocortisolism could be a consequence of impaired fetal growth. We have now extended these findings by examining the relationship between birthweight, gestational age and tests of adrenal suppression and stimulation. DESIGN: Prospective birth cohort study. SUBJECTS AND METHODS: We studied 165 women (mean age 71.3 Years) born at term in Helsinki, Finland, between 1924 and 1933, whose body size and gestational age at birth were recorded. These women underwent an overnight 0.25 mg dexamethasone suppression test followed by a 1 microg ACTH(1-24) stimulation test. RESULTS: In all women combined, low birthweight was associated with lower total (P=0.03) and free (P=0.02) cortisol concentrations following dexamethasone. However, these relationships were dependent on gestational age at birth, interactions between the effects of birth size and gestational age on dexamethasone responsiveness being statistically significant. To demonstrate these interactions, we divided the study population into two groups according to gestational age. In subjects born at 40 weeks of gestation or more, low birthweight was strongly associated with enhanced dexamethasone suppression (P=0.003 for total and P=0.0004 for free cortisol), while in subjects born before 40 weeks of gestation there was no association. There was, however, no correlation between birth size and the adrenal response to ACTH(1-24). CONCLUSIONS: These findings reinforce our suggestions that events during prenatal life may lead to both up-regulation and down-regulation of the HPAA.
Vitamin D receptor polymorphisms: no association with type 1 diabetes in the Finnish population
Authors: Turpeinen H , Hermann R , Vaara S , Laine AP , Simell O , Knip M , Veijola R , Ilonen J
Published: January 2005

OBJECTIVE: The effect of polymorphisms of the vitamin D receptor (VDR) gene on susceptibility to type 1 diabetes has recently been investigated extensively. Several findings on positive disease associations have been observed and, in addition, a protective effect of vitamin D supplementation has been reported. DESIGN: We studied the effect of three vitamin D receptor gene polymorphisms (VDRA, VDRB, VDRF) on susceptibility to type 1 diabetes in a large case-control series (more than 2000 controls and about 1000 patients) from the Finnish population. METHODS: A combination of case-control and affected-family based approaches was used. Subjects were genotyped for VDRA (ApaI), VDRB (BsmI) and VDRF (FokI) single nucleotide polymorphisms using a minisequencing reaction. RESULTS: A few borderline significant associations were observed with both approaches used. In the case-control association analyses we found significant differences between cases and controls in frequencies of VDRB (P=0.024, all subjects and P=0.016, HLA DQB1*0302-positive subjects) and VDRF (P=0.0063, Turku cohort). In the total family set a decreased (39.3%) transmission of the VDRA-VDRB-VDRF haplotype 1-1-2 and an increased (60.3%) transmission of haplotype 2-1-2 to sons was seen (P=0.0059 and P=0.024 respectively). Transmission of the haplotype 2-2-1 to daughters was decreased (37.6%, P=0.022). Interestingly, we also observed significant differences in allele frequencies of the polymorphisms studied between populations from three different regions in Finland. CONCLUSIONS: All these differences disappeared after correction for multiple testing. We conclude that the single nucleotide polymorphisms analysed are unlikely to be associated with type 1 diabetes in the Finnish population.
Androgen receptor gene exon 1 CAG repeat polymorphism in Finnish patients with childhood-onset type 1 diabetes
Authors: Gombos Z , Hermann R , Veijola R , Knip M , Simell O , Pollanen P , Ilonen J
Published: January 2005

OBJECTIVE: Animal models suggest that androgen receptor gene polymorphisms might affect disease predisposition in human immune-mediated diabetes. The aim of this study was to investigate the effect of the human androgen receptor gene exon 1 CAG repeat polymorphisms on type 1 diabetes (T1D) susceptibility. DESIGN AND METHODS: A combined strategy of case-control and family-based approaches was used. Affected sibling pair families (n=120), nuclear families (n=645) and cohorts of sporadic cases (n=208) and controls (n=1381) were genotyped for androgen receptor gene exon 1 CAG repeat polymorphism. An automated fluorescence-based DNA fragment-sizing method was used. RESULTS: The distribution of CAG repeat alleles did not differ significantly between patients and controls. However, short repeat alleles (7-14) were more prevalent among cases in girls compared with controls (8.77% vs 5.91%; P=0.03). Long repeat alleles (19-28) were less frequent among HLA DR3-positive diseased boys than in DR3-positive control boys (32.6% vs 40.6%; P=0.011). The differences were not significant after adjustment for multiple comparisons. Transmission of CAG repeat alleles was not different from expected in the total material. However, transmissions to girls deviated from the expected value significantly (extended transmission disequilibrium test (ETDT) 37.82; P=0.0016). A decreased transmission of the alleles with 13, 20 and 26 repeats to girls was observed (T%0, P=0.046; T%25.5, P=0.0003, T%0, P=0.025). CONCLUSION: The results do not support a common role for the androgen receptor gene exon 1 CAG repeat in T1D susceptibility; however, an effect of a disease variant in linkage disequilibrium could be detected.
Sex hormones, inflammation and the metabolic syndrome: a population-based study
Authors: Laaksonen DE , Niskanen L , Punnonen K , Nyyssonen K , Tuomainen TP , Salonen R , Rauramaa R , Salonen JT
Published: January 2005

OBJECTIVE: Mild hypoandrogenism in men is associated with features of the metabolic syndrome, but the association with the metabolic syndrome itself using an accepted definition has not been described. DESIGN: Men with the metabolic syndrome were identified and testosterone and sex hormone-binding globulin (SHBG) levels were determined in a population-based cohort of 1896 non-diabetic middle-aged Finnish men. RESULTS: Calculated free testosterone and SHBG were 11% and 18% lower (P<0.001) in men with the metabolic syndrome (n=345, World Health Organisation definition). After categorisation by tertiles and adjusting for age and body mass index, total and free testosterone and SHBG were inversely associated with concentrations of insulin, glucose, triglycerides, C-reactive protein (CRP) and CRP-adjusted ferritin and positively associated with high-density lipoprotein cholesterol. Men with free testosterone levels in the lowest third were 2.7 (95% confidence interval (CI) 2.0-3.7) times more likely to have the metabolic syndrome in age-adjusted analyses, and 1.7 (95% CI 1.2-2.4) times more likely even after further adjusting for body mass index. Exclusion of men with cardiovascular disease did not alter the association. The inverse association of SHBG with the metabolic syndrome was somewhat stronger. CONCLUSIONS: Low testosterone and SHBG levels were strongly associated not only with components of the metabolic syndrome, but also with the metabolic syndrome itself, independently of body mass index. Furthermore, sex hormones were associated with inflammation and body iron stores. Even in the absence of late-stage consequences such as diabetes and cardiovascular disease, subtle derangements in sex hormones are present in the metabolic syndrome, and may contribute to its pathogenesis.
Plasma levels of active form of ghrelin during oral glucose tolerance test in patients with anorexia nervosa
Authors: Nakai Y , Hosoda H , Nin K , Ooya C , Hayashi H , Akamizu T , Kangawa K
Published: January 2005

OBJECTIVE: Ghrelin is an acylated peptide, whose octanoyl modification is essential for its biological activities. Previous studies demonstrated that fasting plasma ghrelin levels were high in anorectic patients, suggesting ghrelin may play an important role in the pathophysiology of anorexia nervosa. However, antibodies used in previous work to measure ghrelin concentrations in human blood do not distinguish between the active form of ghrelin (active ghrelin) and desacyl ghrelin with no biological activities. Therefore, we studied plasma levels of active ghrelin during oral glucose tolerance test (OGTT) in anorectic patients, using a radioimmunoassay (RIA) specific for active ghrelin. METHODS: Active ghrelin response to OGTT was evaluated in five female anorectic patients and seven age-matched control females. All subjects were given a 75 g/225 ml glucose solution orally after overnight fasting. For RIA of active ghrelin, 1 N hydrogen chloride was added to the samples at final concentration of 0.1 N immediately after separation of plasma. RESULTS: Plasma basal levels of active ghrelin were significantly higher in anorectic patients than in controls (52.1+/-10.5 vs 21.2+/-3.1 fmol/ml, P<0.01). They were significantly decreased during OGTT in anorectic patients and in controls, reaching a nadir of 49.0+/-7.7% and 57.3+/-4.5% of the basal levels, respectively. CONCLUSION: These results suggest that hyperghrelinemia in anorectic patients is caused at least partly by increased secretion of active ghrelin and that glucose ingestion suppresses active ghrelin release in these patients.
Ghrelin administration affects circulating pituitary and gastro-entero-pancreatic hormones in acromegaly
Authors: Arosio M , Ronchi CL , Gebbia C , Pizzinelli S , Conte D , Cappiello V , Epaminonda P , Cesana BM , Beck-Peccoz P , Peracchi M
Published: January 2005

OBJECTIVE: Ghrelin, a gut-brain peptide involved in the control of energy homeostasis, affects antero-pituitary and gastro-entero-pancreatic (GEP) hormone secretion in healthy subjects. We aimed to verify whether such hormonal responses are retained in acromegaly, a disease characterized by high GH, subnormal ghrelin and abnormal GEP hormone levels. DESIGN AND METHODS: The effect of ghrelin (3.3 microg/kg given after overnight fasting as an i.v. bolus) on GH, prolactin (PRL), adrenocorticotropin (ACTH), cortisol, insulin, glucose, total somatostatin (SS) and pancreatic polypeptide (PP) circulating levels were evaluated in seven non-diabetic patients with newly diagnosed acromegaly and in nine healthy controls. RESULTS: Ghrelin elicited a prompt, marked increase of serum GH and PRL levels in all normal (from 1.6+/-0.6 to 52.9+/-7.8 and from 9.7+/-0.8 to 24.2+/-4.8 microg/l (means+/-S.E.M.), respectively) and acromegalic subjects (from 11.2+/-4.9 to 91.6+/-21.0 and from 42.9+/-26.1 to 113.8+/-79.0 microg/l, respectively). Both plasma ACTH and serum cortisol levels rose significantly in the controls, whereas the cortisol response was blunted in the acromegalic patients. Glucose levels rose earlier and insulin levels fell later in all subjects, with a significantly greater net insulin decrease in acromegalic than in healthy subjects (-80+/-21 vs -17+/-4 pmol/l, P<0.01). A prompt PP rise and a biphasic SS response occurred in all controls, whereas in the acromegalic group the PP response (from 26.1+/-5.0 to 92.2+/-39.0 pmol/l) and the SS response (from 11.9+/-3.0 to 19.7+/-4.0 ng/l) were quite variable. CONCLUSIONS: Ghrelin affects both pituitary and GEP hormones in acromegalic patients as in normal subjects. These findings suggest that ghrelin actions on the energy balance are mediated by complex interactive endocrine loops that involve also the gut and pancreas.
A comparison of in vitro bioassays to determine cellular glucocorticoid sensitivity
Authors: Vermeer H , Hendriks-Stegeman BI , Verrijn Stuart AA , van Buul-Offers SC , Jansen M
Published: January 2005

An altered cellular glucocorticoid (GC) sensitivity is associated with several pathophysiological conditions such as asthma, diabetes, or rheumatoid arthritis. Several bioassays have been developed and employed to assess cellular GC sensitivity of peripheral blood mononuclear cells (PBMC), but correlations between these have rarely been investigated. We have compared four mitogen-based assays and an FK506 binding protein 51 (FKBP51) mRNA induction assay, using ten controls and a GC-resistant patient. The mitogen-based assays were performed using either diluted whole blood or isolated PBMC, and showed relatively large assay variations for the parameters maximal effect and half-maximal effect concentration. The FKBP51 assay showed smaller intra-assay and within-individual variation compared with the mitogen-based assays. The whole blood-based mitogen assays and the FKBP51 assay clearly discriminated the GC-resistant patient from the controls but, in contrast to expectations, both PBMC-based mitogen assays did not. The GC-induced FKBP51 mRNA increase in PBMC may be an alternative to determine an altered individual GC sensitivity with several advantages as compared with mitogen-based assays, such as the use of unstimulated PBMC, and a better intra- and inter-individual reproducibility.
Pharmacokinetics and tolerability of a bioadhesive buccal testosterone tablet in hypogonadal men
Authors: Ross RJ , Jabbar A , Jones TH , Roberts B , Dunkley K , Hall J , Long A , Levine H , Cullen DR
Published: January 2005

OBJECTIVE: A phase I single centre, open label study of the pharmacokinetics and tolerability of a buccal testosterone tablet (COL 1621) was carried out. DESIGN: Twelve testosterone-deficient males were treated with the buccal tablet twice daily for 7 consecutive days. Multiple blood samples were drawn for testosterone, dihydrotestosterone (DHT), bioavailable testosterone and sex hormone-binding globulin (SHBG). RESULTS: After COL 1621, means+/-S.D. serum testosterone level increased to a peak concentration of 26.6+/-5.8 nmol/l (7.7+/-1.7 ng/ml) at 4.8+/-5.8 h and stayed in the eugonadal range. Steady state was achieved within the first 24 h and was maintained in the normal range. The bioavailable testosterone, DHT and free testosterone index followed a pattern very similar to that of testosterone. The mean serum testosterone to DHT ratio was within the normal male range throughout treatment. There was only one treatment-related adverse event (headache). Two-thirds of patients indicated that treatment with COL 1621 was acceptable and that the tablet was convenient to use. Six patients (50.0%) preferred COL 1621 to their previous testosterone replacement therapy, two patients gave preference to their previous treatment and three patients found both treatments to be equally acceptable. Data for one patient was not available. CONCLUSION: We conclude that COL 1621 can efficiently elevate serum testosterone and DHT levels in hypogonadal men within the first day of application, achieve a steady state within 24 h and maintain serum testosterone in the normal range with a twice-daily treatment regimen. COL 1621 provides an effective alternative oral testosterone replacement therapy that gives physiological levels of testosterone and is well tolerated by the patients.
Association of endogenous testosterone with blood pressure and left ventricular mass in men. The Tromso Study
Authors: Svartberg J , von Muhlen D , Schirmer H , Barrett-Connor E , Sundfjord J , Jorde R
Published: January 2005

OBJECTIVE: To test the hypothesis that lower endogenous testosterone levels are associated with higher blood pressure, left ventricular mass, and left ventricular hypertrophy. DESIGN: Population-based cross-sectional study. METHODS: Sex hormone levels, measured by immunoassay, anthropometric measurements and resting blood pressure were studied in 1548 men aged 25-84 Years; echocardiography was completed in 1264 of these men. Partial correlations and multiple regressions were used to estimate the associations between sex hormones, blood pressure and left ventricular mass by height. Analyses of variance and covariance were used to compare men with categorical hypertension and left ventricular hypertrophy. RESULTS: In age-adjusted partial correlations, total testosterone and sex hormone-binding globulin (SHBG) were each inversely associated with systolic blood pressure (SBP) (P<0.001). Men with categorical hypertension (SBP> or =140 or diastolic blood pressure (DBP)> or =90 mmHg) had lower levels of total and free testosterone and SHBG before (P<0.001, P=0.011 and P<0.001, respectively) and after (P<0.001, P=0.035 and P=0.002, respectively) adjusting for body mass index (BMI). Total testosterone and SHBG were each inversely associated with left ventricular mass (P<0.001), and men with left ventricular hypertrophy had significantly lower levels of total testosterone (P=0.042) and SHBG (P=0.006); these associations were no longer significant after adjusting for BMI. CONCLUSION: The results of the present study are consistent with the hypothesis that lower levels of testosterone in men are associated with higher blood pressure, left ventricular mass, and left ventricular hypertrophy. The reduced associations after adjusting for BMI suggest that the association of low testosterone levels with blood pressure and left ventricular mass is mediated by obesity.
Evidence for processing of compact insoluble thyroglobulin globules in relation with follicular cell functional activity in the human and the mouse thyroid
Authors: Gerard AC , Denef JF , Colin IM , van den Hove MF
Published: January 2005

OBJECTIVE: Thyroglobulin (Tg) is stored within the follicular lumen mainly in a soluble form, but globules made of insoluble multimers are also present and considered to be a mechanism to store prohormone at high concentration. We investigated the immunohistochemical properties of these intrafollicular globules and their possible processing by thyroid cells upon stimulation in the human and in the mouse. DESIGN: Human thyroids (normal, Graves' disease and hot adenomas) and thyroids from old ICR mice without or with goitrogenic treatment were processed for light microscopy. METHODS: Immunohistochemistry for Tg with a polyclonal antibody and two monoclonal antibodies, one specific for thyroxine-rich-iodinated Tg and the other recognizing Tg independently of its iodine level, staining with periodic-acid-schiff, and binding of lectins specific for mannose and sialic acid were performed on all tIssue sections. Intrafollicular globules were quantified, with distinction between 'active' or 'hot' and 'hypofunctioning' or 'cold' follicles. RESULTS: In normal human and old mouse thyroids, the intrafollicular globules were strongly stained with PAS, but negative for the three anti-Tg antibodies and the two lectin-binding assays, while the surrounding soluble Tg was positive. In normal human tIssue, globules were more frequent in 'hypofunctioning' than in 'active' follicles. They were exceptional in Graves' disease and hot adenomas. In old mice, Tg globules were more frequent in 'cold' than in 'hot' follicles. Along with the goitrogen treatment, they became fewer, fragmented and more often present in follicles with a 'hot' aspect. CONCLUSIONS: Upon TSH stimulation, thyrocytes become able to process colloid globules suggesting that this stock of Tg can be used in vivo for thyroid hormone synthesis.
Importance of quantifying insulin secretion in relation to insulin sensitivity to accurately assess beta cell function in clinical studies
Authors: Ahren B , Pacini G
Published: January 2005

Insulin sensitivity and insulin secretion are mutually related such that insulin resistance is compensated by increased insulin secretion. A correct judgement of insulin secretion therefore requires validation in relation to the insulin sensitivity in the same subject. Mathematical analyses of the relationship between insulin sensitivity and insulin secretion has revealed a hyperbolic function, such that the product of the two variables is constant. This product is usually called the disposition index. Several techniques may be used for its estimation such as data derived from the frequently sampled i.v. glucose tolerance test, the oral glucose tolerance test or the glucose-dependent arginine stimulation test or the euglycemic hyperinsulinemic clamp technique in combination with a test on insulin secretion. Using these techniques the compensatory increase in beta cell function in insulin resistance has been verified in obesity, in pregnancy and after glucocorticoid administration as has the defective beta cell function as the underlying cause of impaired glucose tolerance and type 2 diabetes. Similarly, combined analysis of insulin sensitivity and insulin secretion has shown a down-regulation of beta cell function in increased insulin sensitivity accompanying weight reduction in obesity and following exercise. Acknowledging this inverse relationship between insulin secretion and insulin sensitivity therefore requires estimation of both variables for correct assessment in any individual.
Estrogens and atherosclerosis
Authors: Arnal JF , Gourdy P , Elhage R , Garmy-Susini B , Delmas E , Brouchet L , Castano C , Barreira Y , Couloumiers JC , Prats H , Prats AC , Bayard F
Published: January 2005

Numerous epidemiological as well as experimental studies have suggested that estradiol (E2) prevents atherosclerosis development. However two controlled prospective and randomized studies in women using hormone replacement therapy (HRT) did not confirm this beneficial effect. We then decided to use mouse models of atherosclerosis to define the possible mechanisms involved and the reasons for the discrepancy. We have shown that, although serum cholesterol decreases, this influence on lipid metabolism is negligible. Surprisingly, E2 induces an inflammatory-immune response towards a T helper cell (Th1) profile with increasing interferon-gamma production that could destabilize atheromatous plaques, and could account for the increase in the frequency of cardiovascular events in women undergoing HRT. At the level of the endothelium, E2 induces an increase in nitric oxide (NO) biodisponibility, but this phenomenon does not concern the development of fatty streaks. Nevertheless, the atheroprotective effect is apparently mediated at the level of the endothelium by a mechanism that has still to be characterized in molecular terms. These new acquisitions constitute a basis for new pharmacological developments allowing the prevention of deleterious effects and preserving the beneficial ones.
Precocious puberty secondary to massive ovarian oedema in a 6-month-old girl
Authors: Natarajan A , Wales JK , Marven SS , Wright NP
Published: January 2005

A 6-month-old girl was referred with breast and pubic hair development. Investigations excluded an adrenal or central cause for her precocity. Ovarian ultrasound scans showed bilaterally enlarged ovaries with both solid and cystic changes. A follow-up examination suggested progression of the precocity and in view of the young age of the child, and concerns regarding underlying malignancy, she underwent laparotomy. Histology showed no evidence of neoplasia but there was stromal oedema consistent with a diagnosis of massive ovarian oedema. This entity is poorly recognised in the paediatric literature as a cause of sexual precocity, and has never previously been described in such a young patient. This is an unusual cause of precocity in a young child and its recognition and management are reviewed.
Change in von Willebrand factor and carotid intima-media thickness in hypothyroid patients with normal thyroid function after levothyroxine replacement therapy
Authors: Nagasaki T , Inaba M , Henmi Y , Kumeda Y , Ueda M , Tahara H , Ishimura E , Onoda N , Ishikawa T , Nishizawa Y
Published: January 2005

OBJECTIVE: This study examined whether levothyroxine (L-T4) replacement might affect serum markers of endothelium injury, including von Willebrand factor (vWF), factor VIII activity and thrombomodulin (TM), during normalization of increased intima-media thickness (IMT) in the common carotid artery (CCA) in hypothyroid patients after L-T4 replacement therapy. PATIENTS AND METHODS: Thirty-three hypothyroid patients were examined for vWF, factor VIII, TM and CCA IMT before and after 1 year of normalization of thyroid function by L-T4 replacement. CCA IMT was measured from digitized still images taken during scanning by high-resolution ultrasonography as an indicator of early atherosclerosis. RESULTS: Serum factor VIII and vWF increased significantly during 1 year of normalization of thyroid function (from 122.7+/-9.4 to 151.3+/-18.8% (P<0.05) and from 109.9+/-9.6 to 135.2+/-12.4% (P<0.005) respectively), although these values all fell within the respective normal range. Serum TM, in contrast, did not change appreciably in response to L-T4 treatment, moving from 2.57+/-0.15 to 2.74+/-0.18 ng/ml (P=0.086). During 1 year of a euthyroid state, all patients showed a significant decrease in CCA IMT (P<0.0001). Change in serum vWF, but not in factor VIII or TM, showed a positive correlation with that of CCA IMT during L-T4 replacement therapy. Furthermore, the change in serum vWF was significantly and independently associated with change in CCA IMT (r=0.490, P=0.0038). CONCLUSIONS: The present study demonstrated that the improvement of CCA IMT during L-T4 treatment might have the potential to attenuate an elevation of vWF and to attenuate vascular injury by the cardiovascular effects of thyroid hormone in hypothyroid patients.
Direct causes of death in Japanese patients with hypopituitarism as analyzed from a nation-wide autopsy database
Authors: Kaji H , Chihara K
Published: January 2005

OBJECTIVES: The direct causes of death in Japanese patients with hypopituitarism remain unclear. In this study, the direct causes of death were investigated and compared between Japanese patients with hypopituitarism from a nation-wide autopsy database and an age- and gender-matched control population from national reports. SUBJECTS: Three hundred and ninety-one subjects with hypopituitarism who had died were selected from a nation-wide autopsy database (1984-1993). The ratios of each cause of death among the age- and gender-matched control population were derived from national reports. RESULTS: In subjects with hypopituitarism, an increased relative frequency of death from cerebrovascular diseases (male; 2.02 (95% confidence interval (CI) 1.45-2.82), female; 1.73 (95% CI 1.18-2.52)) was found. In particular, the relative frequency of death from cerebral hemorrhage was 4.60 (95% CI 2.95-7.17) in male and 4.80 (95% CI 2.90-7.94) in female subjects with hypopituitarism. Unexpectedly, a decreased relative frequency of death from all heart diseases (male; 0.439 (95% CI 0.277-0.696), female; 0.267 (95% CI 0.149-0.478)) was found in subjects with hypopituitarism, although there was no difference between subjects with hypopituitarism and controls in the frequency of death from ischemic heart disease. CONCLUSIONS: These results provide useful information for the long-term care of Japanese patients with hypopituitarism.
Body mass index, circulating levels of sex-steroid hormones, IGF-I and IGF-binding protein-3: a cross-sectional study in healthy women
Authors: Lukanova A , Lundin E , Zeleniuch-Jacquotte A , Muti P , Mure A , Rinaldi S , Dossus L , Micheli A , Arslan A , Lenner P , Shore RE , Krogh V , Koenig KL , Riboli E , Berrino F , Hallmans G , Stattin P , Toniolo P , Kaaks R
Published: January 2005

OBJECTIVE: Excess weight has been associated with increased risk of cancer at several organ sites. In part, this effect may be modulated through alterations in the metabolism of sex steroids and IGF-I related peptides. The objectives of the study were to examine the association of body mass index (BMI) with circulating androgens (testosterone, androstenedione and dehydroepiandrosterone sulfate (DHEAS)), estrogens (estrone and estradiol), sex hormone-binding globulin (SHBG), IGF-I and IGF-binding protein (IGFBP)-3, and the relationship between sex steroids, IGF-I and IGFBP-3. DESIGN AND METHODS: A cross-sectional analysis was performed using hormonal and questionnaire data of 620 healthy women (177 pre- and 443 post-menopausal). The laboratory measurements of the hormones of interest were available from two previous case-control studies on endogenous hormones and cancer risk. RESULTS: In the pre-menopausal group, BMI was not related to androgens and IGF-I. In the post-menopausal group, estrogens, testosterone and androstenedione increased with increasing BMI. The association with IGF-I was non-linear, with the highest mean concentrations observed in women with BMI between 24 and 25. In both pre- and post-menopausal subjects, IGFBP-3 did not vary across BMI categories and SHBG decreased with increasing BMI. As for the correlations between peptide and steroid hormones, in the post-menopausal group, IGF-I was positively related to androgens, inversely correlated with SHBG, and not correlated with estrogens. In the pre-menopausal group, similar but weaker correlations between IGF-I and androgens were observed. CONCLUSIONS: These observations offer evidence that obesity may influence the levels of endogenous sex-steroid and IGF-related hormones in the circulation, especially after menopause. Circulating IGF-I, androgens and SHBG appear to be related to each other in post-menopausal women.
Expression of ghrelin and biological activity of specific receptors for ghrelin and des-acyl ghrelin in human prostate neoplasms and related cell lines
Authors: Cassoni P , Ghe C , Marrocco T , Tarabra E , Allia E , Catapano F , Deghenghi R , Ghigo E , Papotti M , Muccioli G
Published: January 2005

BACKGROUND: Ghrelin, a natural growth hormone secretagogue (GHS), has been identified in prostate carcinoma cell lines. OBJECTIVES: To investigate the presence of ghrelin and its receptors in human prostate tumours and in DU-145, PC-3 and LNCaP prostate carcinoma cell lines, and to assess the effects of ghrelin and its more abundant circulating form, des-octanoyl ghrelin, on cell proliferation. METHODS: Ghrelin and types 1a and 1b GHS receptor (GHS-R) were determined at the mRNA and protein levels by RT-PCR, in situ hybridization, immunohistochemistry and enzyme immunoassay in tissues, cell lines and culture medium. Ghrelin binding was determined by radioreceptor assay. The effects on cell proliferation were evaluated by growth curves. RESULTS: Ghrelin mRNA was found in prostatic carcinomas and benign hyperplasias, but immunohistochemistry was negative. GHS-R1a and 1b mRNAs were absent from carcinomas, but GHS-R1b mRNA was present in 50% of hyperplasias. Ghrelin peptide and mRNA were present in PC-3 cells exclusively, whereas GHS-R1a and 1b mRNAs were expressed in DU-145 cells only. Specific [125I]Tyr4-ghrelin binding was detected in prostate tumour, DU-145 and PC-3 cell membranes and the binding was displaced by ghrelin, synthetic GHS and des-octanoyl ghrelin, which is devoid of GHS-R1a binding affinity and GH-releasing activity. Ghrelin and des-acyl ghrelin inhibited DU-145 cell proliferation, displayed a biphasic effect in PC-3 cells and were ineffective in LNCaP cells. CONCLUSIONS: Specific GHS binding sites, other than GHS-R1a and 1b, are present in human prostatic neoplasms. Ghrelin, in addition to des-acyl ghrelin, exerts different effects on cell proliferation in prostate carcinoma cell lines.