bluuebunny/crossref_metadata_2025 huggingface dataset:
Thyroid structure and size and two-year follow-up of solitary cold thyroid nodules in an unselected population with borderline iodine deficiency
Authors: Knudsen N , Perrild H , Christiansen E , Rasmussen S , Dige-Petersen H , Jorgensen T
Published: January 2005

OBJECTIVE: Multinodular goitre has been found with a high prevalence in iodine-deficient areas, but less frequently in iodine-replete areas; the iodine intake sufficient to prevent goitre has not been established, however. METHODS: We report data from an ultrasonic investigation of the thyroid glands of 2656 randomly selected subjects aged 41 to 71 years in an area with borderline iodine deficiency. RESULTS: Median iodine concentration in spot urine samples was 70microg/l. Multinodular thyroid structure was found in 23% of the population, increasing in women from 20 to 46% with increasing age, and in men from 7 to 23%. Solitary, scintigraphically cold, thyroid nodules >10mm were found in 2.4% of the population with the same prevalence in the different age and sex groups. Two years of follow-up of these cold nodules revealed no signs of malignancies. Median thyroid volume was 11.0ml. Thyroid enlargement (>18ml for women and >25ml for men) was found among 13. 1% of the women and 6.2% of the men, and the prevalence increased with age. The presence of thyroid nodules was related to positive anti-thyroperoxidase antibody (TPO Ab) titres, whereas thyroid enlargement was associated with iodine excretion <50microg/day. CONCLUSIONS: Thyroid enlargement was associated with low iodine excretion and median thyroid volume was slightly increased compared with iodine-replete areas. Multinodular thyroid structure was found with a high prevalence and was associated with TPO Ab >200kU/l. Cold thyroid nodules were moderately prevalent, with no cases of detected malignancies during 2 years of follow-up.
The effect of thyrotoxicosis on adrenocortical reserve
Authors: Tsatsoulis A , Johnson EO , Kalogera CH , Seferiadis K , Tsolas O
Published: January 2005

OBJECTIVE: Variations in thyroid function are known to be associated with changes in adrenocortical activity. Previous studies in animals have suggested that long-standing hyperthyroidism may be associated with diminished adrenal functional reserve despite a continuing hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. In humans, there has been no direct assessment of adrenal secretory reserve in clinical thyrotoxicosis. This study aimed to assess adrenocortical reserve in response to low-dose ACTH, following dexamethasone suppression, in patients with severe thyrotoxicosis. DESIGN AND METHODS: Ten patients (four men and six women, 30-45 years) with severe long-standing thyrotoxicosis due to Graves' disease (n=6) or toxic nodular goitre (n=4) were studied at diagnosis and again when in a stable euthyroid state following drug therapy for 8-12 months. All patients underwent ACTH stimulation tests at 0800h with ACTH(1-24) (Cortrosyn; 0.1microg/kg body weight, i.v.) following overnight suppression of the HPA axis with dexamethasone (1mg per os at 2300h). Serum cortisol was assayed at -15, 0, 15, 30, 60 and 90min after the administration of ACTH. RESULTS: The mean (+/-s.d.) peak and delta cortisol responses to ACTH (634.5+/-164nmol/l and 618+/- 196nmol/l respectively), as well as the net area under the response curve (36769+/-12188nmol/lx min) in the hyperthyroid patients were significantly lower compared with the values when the same patients were euthyroid (911+/-157nmol/l, 905+/-160nmol/l and 57652+/-10128nmol/lxmin respectively; P<0.005). Subnormal peak cortisol responses (<500nmol/l) were observed in two severely toxic patients. The findings were independent of the cause of thyrotoxicosis. CONCLUSION: In patients with severe thyrotoxicosis, cortisol secretion in response to low-dose ACTH stimulation, following dexamethasone suppression, is lower in the hyperthyroid than in the euthyroid state. It appears that thyrotoxicosis is associated with subtle impairment of adrenocortical reserve.
The role of cytokines and cortisol in the non-thyroidal illness syndrome following acute myocardial infarction
Authors: Karga H , Papaioannou P , Venetsanou K , Papandroulaki F , Karaloizos L , Papaioannou G , Papapetrou P
Published: January 2005

OBJECTIVE: A number of different hormone changes have been described during the acute myocardial infarction (AMI), including those of the non-thyroidal illness syndrome (NTIS). DESIGN AND METHODS: We assessed the alterations of serum thyroid hormones, cytokines and cortisol levels in 30 patients with a first episode of AMI 4, 24, 48h and 10 days (240h) after the onset of the chest pain and we investigated the possible relationship of these alterations with the severity of AMI. RESULTS: Fifteen patients had left ventricular ejection fraction (LVEF) </=50% (group I) and 15 patients had LVEF >50% (group II). A transient decrease of total tri-iodothyronine (T(3)), more prominent in group I (P<0.05, t-test) with a concomitant rise of reverse T(3 )(rT(3)) occurred at 24h. Total thyroxine (T(4)), free T(4) (FT(4)) and free T(4) index did not change significantly, but tended to be higher in group I patients, whereas TSH significantly increased in group II at 48h. Interleukin-6 (IL-6) increased significantly at 24h only in group I and declined thereafter (24 vs 240h, P<0.001) and this temporal change of IL-6 was associated with similar changes of creatine phosphokinase and creatine kinase isoenzyme MB (CK-MB). Tumor necrosis factor-alpha and IL-1beta remained low in both groups. Cortisol was higher at 4h and in 12 patients was above the normal values. Negative correlation was found between LVEF and IL-6 (P<0. 001), whereas T(3), T(4) or cortisol levels were not correlated with the LVEF. CONCLUSIONS: Our data indicate that NTIS, in association with increase of IL-6, occurs in the early post-infarction period. In the NTIS following AMI the high level of IL-6 is the best predictor, among several parameters, of the severity of AMI as assessed by the LVEF and the rise of CK-MB.
The effect of GH replacement therapy on endothelial function and oxidative stress in adult growth hormone deficiency
Authors: Evans LM , Davies JS , Anderson RA , Ellis GR , Jackson SK , Lewis MJ , Frenneaux MP , Rees A , Scanlon MF
Published: January 2005

OBJECTIVES: Controversy persists with regard to the atherogenic risk associated with adult growth hormone deficiency (GHD). Endothelial dysfunction and enhanced oxidative stress are early features of atherogenesis. Therefore, we have studied the effect of three months of low dose GH replacement therapy (0.03IU/kg/day) on these parameters in GHD adults. SUBJECTS AND METHODS: Eight hypopituitary GHD adults (4 male, 4 female), who were receiving conventional hormone replacement therapy, were studied before and after 3 months of GH replacement (0.03IU/kg/day). All observations obtained were compared with similar measurements made in 8 matched control subjects. All study subjects were non-smokers, normotensive and gave no personal or family history of premature vascular disease. Endothelial function was assessed using a specialised vessel wall tracking system to measure endothelium-dependent, flow-mediated, brachial artery dilatation (FMD). Measurements were repeated following glyceryl-trinitrate (GTN) (endothelium-independent dilatation). Oxidative stress was assessed by directly measuring lipid-derived free radicals in venous blood by electron paramagnetic resonance spectroscopy. Fasting lipids, insulin, plasma glucose and IGF-I were also measured at baseline and following GH replacement. RESULTS: FMD, expressed as a percentage change from resting base-line diameter, was significantly impaired in the pre-treatment GHD patients compared with controls (3.1+/-2.1% vs 6.1+/-0.9%, P<0. 001; means+/-s.d.) indicating endothelial dysfunction. Significant increase in FMD was noted following GH therapy (3.1+/-2.1% vs 6. 5+/-1.9%, P<0.001). Free radicals (arbitrary units) were elevated in the pre-treatment GHD patients compared with controls (0.36+/-0.09 vs 0.11+/-0.12, P<0.05) and fell significantly following GH therapy (0.23+/-0.03 vs 0.36+/-0.09, P<0.05), although they remained elevated compared with controls. Fasting insulin was significantly higher (25.9+/-18.8 vs 13.9+/-6.7mu/l, P<0.05) and IGF-I concentrations lower (10.8+/-4.7 vs 20.2+/-6.3nmol/l, P<0.05) in the pre-treatment GHD subjects. After treatment there were no changes in insulin concentration, although IGF-I levels were normalised (10. 8+/-2.3 vs 23.6+/-11.4nmol/l, P<0.05). CONCLUSIONS: Endothelial dysfunction and enhanced oxidative stress are features of adult GHD. This study suggests plausible mechanisms underlying any proatherogenic tendency in adult GHD and demonstrates improvement of these factors following GH replacement.
Serum leptin and habitual fatty acid dietary intake in patients with type 1 diabetes mellitus
Authors: Rojo-Martinez G , Soriguer FJ , Gonzalez-Romero S , Tinahones F , Moreno F , de Adana SR , Garriga MJ , Esteva I , Garcia-Arnes J , Gomez-Zumaquero JM , Garcia-Almeida JM
Published: January 2005

OBJECTIVE: To study the contribution of a normal intake of nutrients to the variability of serum leptin concentrations in persons with type 1 diabetes mellitus. DESIGN: We studied the relation between serum leptin and nutrient intake in a cross-sectional study. METHODS: Serum leptin measured by radioimmunoassay, nutritional data determined by a self-administered 7-day nutritional questionnaire, and the fatty acid composition of the serum phospholipids (measured by thin layer chromatography and gas chromatography) were determined in 60 patients with type 1 diabetes mellitus. Correlation and regression analyses were performed between serum leptin and dietary fatty acids and serum phospholipid fatty acids. RESULTS: In the prediction models for the concentrations of serum leptin in men with type 1 diabetes mellitus, the dietary fatty acids displaced the anthropometric variables, and were independent of the serum testosterone concentrations. This fact remained when the prediction was made on the basis of indirect markers of the intake, such as the serum phospholipid fatty acids. In the women, the fatty acids from the diet or from the serum phospholipids also partly explained the variation in serum leptin, although not displacing the anthropometric variables. CONCLUSIONS: Our data suggest that, in non-experimental conditions, the concentrations of serum leptin in men with type 1 diabetes mellitus and, to a lesser extent, those in women with diabetes, may be influenced by the composition of the habitual diet, especially the type of dietary fat.
Allopregnanolone concentrations and premenstrual syndrome
Authors: Monteleone P , Luisi S , Tonetti A , Bernardi F , Genazzani AD , Luisi M , Petraglia F , Genazzani AR
Published: January 2005

OBJECTIVE: To evaluate basal allopregnanolone and progesterone in both phases of the menstrual cycle in women suffering from premenstrual syndrome (PMS) and their response to a GnRH test. DESIGN: We selected 56 women (28 patients with PMS and 28 controls) aged between 18 and 32 years. Blood samples were drawn in both follicular and phases. Twenty-eight women (14 patients with PMS and 14 controls) underwent a GnRH test in the luteal phase. METHODS: We evaluated allopregnanolone by RIA, using a specific antibody. Serum progesterone and oestradiol were determined using a commercially available RIA kit. RESULTS: Luteal phase allopregnanolone concentrations were significantly lower in patients with PMS than in controls. Progesterone concentrations were significantly lower in patients with PMS in both the follicular and the luteal phase. Serum oestradiol concentrations were in the normal range in both groups of women, although slightly greater in those with PMS. Allopregnanolone and progesterone responses to a GnRH test were significantly blunted in women with PMS. CONCLUSIONS: Diminished concentrations of allopregnanolone and progesterone, its precursor, and a blunted response to the GnRH test lead us to hypothesise that patients with PMS may suffer from an inadequate production of ovarian neuroactive steroids, especially in the luteal phase. This would lead to an impaired anxiolytic GABA(A)-mediated response in stressful physiological and psychological conditions, and may in part explain various psychoneuroendocrine symptoms that arise during PMS.
Mechanism for the development of ovarian cysts in patients with congenital lipoid adrenal hyperplasia
Authors: Shima M , Tanae A , Miki K , Katsumata N , Matsumoto S , Nakajima S , Harada T , Shinagawa T , Tanaka T , Okada S
Published: January 2005

OBJECTIVE: Although ovarian cysts commonly occur in patients with congenital lipoid adrenal hyperplasia (CLAH), the mechanism of development remains to be determined. To clarify the pathogenesis of the ovarian cysts, endocrinological examinations were performed in patients with CLAH. METHODS: The subjects were three Japanese CLAH patients. Basal body temperature, serum and urinary gonadotropin levels, serum and/or urinary ovarian hormones and mutations of the steroidogenic acute regulatory protein (StAR) gene were examined. RESULTS: The basal body temperature was not biphasic in any patient. Basal LH levels were high in all CLAH patients and markedly responded to LH-releasing hormone in two patients. Urinary gonadotropin analysis revealed repetitive LH surges in the menstrual cycles of the CLAH patients. No increase in the urinary pregnanediol suggested anovulation in all patients, and bilateral ovarian cysts were found in two of the subjects. Examination of the StAR gene revealed a frameshift mutation 840delA at codon 238, a nonsense mutation Q258X at codon 258, a homozygotic mutation at Q258X, and a compound heterozygotic mutation with 251insG and Q258X. CONCLUSIONS: We concluded that the development of ovarian cysts may be derived from continued anovulation in CLAH patients. Elevated LH levels may be explained by increased sensitivity of the anterior pituitary to circulating estrogen.
Association between the expression of E1A oncogene and increased sensitivity to growth inhibition induced by sustained levels of cAMP in rat thyroid cells
Authors: Villone G , De Vita G , Chieffi P , Picascia A , Stanzione R , Santoro M , Fusco A , Tramontano D
Published: January 2005

OBJECTIVE: The aim of this study was to investigate: (i) whether a persistent increase of cAMP interferes with the proliferation of transformed thyroid cells, and (ii) whether the degree of malignancy is correlated with the sensitivity to a transient and/or sustained increase in intracellular cAMP levels. DESIGN AND METHODS: To address these questions we used thyroid cell lines transformed with E1A oncogene from adenoviruses 5 (PC E1A cell line) or 2 (PC HE4 cell line), or infected with the polyoma murine leukemia virus (PC PyMLV cell line) carrying the middle T gene of the polyoma virus, or, finally, expressing both E1A and PyMLV. These cell lines present various degrees of malignancy: PC EIA and PC HE4 cells are not tumorigenic; PC PyMLV cells induce non-invasive tumors after a long latency period; and PC EIA+PyMLV cells are highly tumorigenic. RESULTS AND CONCLUSIONS: Thyroid cell proliferation required the transient increase of intracellular cAMP levels, while persistent elevation of cAMP blocked the proliferation of normal thyroid PC Cl 3 cells and of PC Cl 3 cells transformed by a variety of different oncogenes. In addition, sustained levels of cAMP induced apoptosis in cells carrying the adenovirus EIA oncogene, but not in cells transformed with other oncogenes or in the wild-type PC Cl 3 cells. Furthermore, middle T gene of the polyoma virus seemed to afford protection only from apoptosis induced by cAMP when middle T is present in thyroid cells along with the E1A gene.
Steroidogenic acute regulatory protein mRNA expression in adrenal tumours
Authors: Zenkert S , Schubert B , Fassnacht M , Beuschlein F , Allolio B , Reincke M
Published: January 2005

The rate limiting step in steroidogenesis is cholesterol transport through the outer to the inner mitochondrial membrane and the cytochrome P450 side chain cleavage (P450scc) complex. The protein factor responsible for this transport, and as such necessary for regulating the acute production of steroids, has been identified and named the steroidogenic acute regulatory protein (StAR). We investigated the expression of StAR in functional and non-functional adrenal neoplasms and compared the expression with that of P450scc. Poly A RNA was extracted from normal adrenal glands (NAG, n=5), aldosterone producing adenomas (APA, n=4), cortisol producing adenomas (CPA, n=5), adrenocortical carcinomas (ACC, n=6) and non-functional adenomas (NFA, n=3), electrophoresed through a 1% agarose gel, blotted and hybridised with a PCR-generated cDNA labelled with [(32)P]CTP. The blots were stripped and re-hybridised with a P450scc cDNA and a mouse beta-actin probe. Compared with P450scc, StAR mRNA expression showed little variability in the magnitude of expression and did not correlate with the endocrine profiles (NAG: StAR 100+/-16%, P450scc 100+/-14%; APA: StAR 80+/-3%, P450scc 94+/-13%; CPA: StAR 71+/-10%, P450scc 109+/-15%; NFA: StAR 64+/-9.5%, P450scc 18+/-5%; means+/-s.e.m.). ACC expressed low levels of both genes probably as a result of dedifferentiation (StAR 29+/-9%, P450scc 46+/-18%). Incubation of the NCI-h295 tumour cell line with 10nmol ACTH and 10micromol forskolin induced an increase in the abundance of StAR and P450scc mRNA, demonstrating gene regulation by the cAMP protein kinase A pathway. Furthermore, we incubated the NCI-h295 tumour cell line with the adrenostatic compounds, aminoglutethimide and metyrapone. We could not detect an effect on the expression of StAR mRNA, whereas the expression of P450scc mRNA was significantly reduced. We conclude that, in contrast to P450scc, StAR seems to be evenly expressed in adrenocortical adenomas. Therefore, the endocrine activity of a given tumour cannot be explained by the abundance of StAR expression. In ACC, both StAR and P450scc expression is low, explaining the relatively inefficient steroid production of these tumours.
Effect of long-term ovariectomy and estrogen replacement on the expression of estrogen receptor gene in female rats
Authors: Mohamed MK , Abdel-Rahman AA
Published: January 2005

OBJECTIVE: Estrogen exerts a wide variety of actions involving many target tissues. We studied the effects of long-term ovariectomy (OVX) and OVX with 17beta-estradiol treatment (OVXE2) on the level of estrogen receptor (ER) gene expression in target tissues of female rats. DESIGN: Three groups of Sprague-Dawley female rats were utilized in this study: sham operated (SO), OVX and OVXE2. METHODS: SO and OVX were performed 2 weeks before starting the 17beta-estradiol treatment. All groups were maintained on liquid diet for 12 weeks from the time of estradiol treatment. Total RNA was prepared from the tissues of the rats and relative quantitative reverse transcription PCR was utilized to compare the ER alpha-subtype (ERalpha) mRNA level in the three groups for each target tissue. RESULTS: Following long-term OVX, the levels of ERalpha expression showed a significant increase in the uterus, kidney and cerebral cortex and no significant change in the liver, cerebellum, brainstem, heart and thoracic and abdominal aorta compared with their SO levels. On the other hand, a 12-week treatment of OVX rats with 17beta-estradiol restored the previously upregulated ERalpha mRNA to near SO levels except for the liver where the 17beta-estradiol treatment resulted in a significant increase in the ERalpha mRNA level compared with that in SO rats. CONCLUSIONS: We conclude that the regulation of ERs by its ligand is tissue specific.
Defective nitric oxide synthesis: a link between metabolic insulin resistance, sympathetic overactivity and cardiovascular morbidity
Authors: Scherrer U , Sartori C
Published: January 2005

Epidemiological studies demonstrate an association between insulin resistance, hypertension and cardiovascular morbidity. In addition to its metabolic effects, insulin also has important cardiovascular actions. The sympathetic nervous system and the nitric oxide-l-arginine pathway have emerged as central players in the mediation of these actions. Over the past decade, the underlying mechanisms and the factors that may govern the interaction between insulin and these two major cardiovascular regulatory systems have been studied extensively in healthy people and insulin-resistant individuals. Here we summarize the current understanding and gaps in knowledge on these interactions. We propose that a genetic and/or acquired defect of nitric oxide synthesis could represent a central defect triggering many of the metabolic, vascular and sympathetic abnormalities characteristic of insulin-resistant states, all of which may predispose to cardiovascular disease.
Inhibin A, B and pro-alphaC in serum and peritoneal fluid in postmenopausal patients with ovarian tumors
Authors: Ala-Fossi SL , Maenpaa J , Blauer M , Tuohimaa P , Punnonen R
Published: January 2005

OBJECTIVE: To compare serum and peritoneal fluid concentrations of inhibin A, B, and pro-alphaC in women with ovarian tumors. METHODS: Serum and peritoneal fluid samples were taken from 41 postmenopausal women operated on for an ovarian tumor. Twenty-one patients with endometrial cancer formed a control group. Serum and peritoneal fluid inhibin A, B, and pro-alphaC concentrations, and serum FSH and tumor marker CA 125 (study group only) concentrations were analyzed. RESULTS: Inhibin A was found in low concentrations (median 4.1pg/ml, range <2-29pg/ml) in serum in most postmenopausal patients with epithelial ovarian carcinoma, whereas inhibin B was not measurable. Inhibin pro-alphaC circulated in high concentrations (median 125pg/ml, range 37->1000pg/ml). All inhibins were found in clearly greater concentrations in the peritoneal fluid than in serum. International Federation of Gynecology and Obstetrics (FIGO) stage III-IV and poor differentiation grade were associated with significantly lower concentrations of inhibin A and pro-alphaC in the peritoneal fluid compared with stages I-II or low grade. This correlation was not found in the serum concentrations of inhibin A or pro-alphaC. In the control group, no dimeric inhibins were found in serum, and pro-alphaC circulated in median concentrations of 47pg/ml (range 12-174pg/ml). CONCLUSIONS: Postmenopausal patients with epithelial ovarian tumors had low concentrations of inhibin A and relatively high concentrations of inhibin pro-alphaC in serum. The peritoneal fluid concentrations of all inhibins far exceeded those in the serum. Relatively low concentrations of inhibin A and pro-alphaC in the peritoneal fluid of patients with ovarian cancer seem to be associated with high stage and grade and, to a lesser degree, with positive peritoneal cytology.
Semi-quantitative comparison of the differentiation markers and sodium iodide symporter messenger ribonucleic acids in papillary thyroid carcinomas using RT-PCR
Authors: Tanaka K , Otsuki T , Sonoo H , Yamamoto Y , Udagawa K , Kunisue H , Arime I , Yamamoto S , Kurebayashi J , Shimozuma K
Published: January 2005

OBJECTIVE: To investigate the levels of expression of the sodium iodide symporter (NIS) and three differentiation markers (thyroglobulin (Tg), thyroid peroxidase (TPO) and thyrotrophin receptor (TSH-R)) in 35 patients with primary (n=31) or recurrent (n=4) papillary thyroid carcinoma, and to compare the findings with clinical data. METHODS: We performed a multiplex semi-quantitative RT-PCR to analyse the relative levels of expression of Tg, TPO and TSH-R mRNAs, and a separate semi-quantitative RT-PCR for NIS mRNA. RESULTS: Tg, TPO and TSH-R mRNAs were expressed in all the patients, whereas NIS mRNA was expressed in all but eight. Analysis of the expression of the differentiation markers in all patients showed a significant correlation among Tg, TPO and NIS. With regard to the relationship between the expression of each gene and the MACIS score, there was significant correlation only for the Tg gene (P<0.05). CONCLUSIONS: The levels of expression of NIS mRNA correlated significantly with those of Tg and TPO mRNAs, but not with those of TSH-R mRNA. The relationship with clinical stage and prognostic score, however, varied among these differentiation markers.
Comparisons among old and new provocative tests of GH secretion in 178 normal adults
Authors: Aimaretti G , Baffoni C , DiVito L , Bellone S , Grottoli S , Maccario M , Arvat E , Camanni F , Ghigo E
Published: January 2005

Classical provocative stimuli of GH secretion such as insulin-induced hypoglycaemia, arginine, clonidine, glucagon and levodopa have been widely used in clinical practice for approximately 30 years. On the other hand, in the last 10 years new potent stimuli of GH secretion have been proposed, but an extensive comparison with the classical ones has rarely been performed, at least in adults. In order to compare the GH-releasing activity of old and new provocative stimuli of GH secretion, and to define the normative values of the GH response, in 178 normal adults (95 males, 83 females; age range: 20-50 years, all within +/-15% of their ideal body weight), we studied the GH response to: insulin-induced hypoglycaemia (ITT, 0.1IU/kg i.v.), arginine (ARG, 0.5g/kg i.v.), clonidine (CLO, 300 microg/kg p.o.), glucagon (GLU, 1mg i.m.), pyridostigmine (PD, 120mg p.o.), galanin (GAL, 80pmol/kg per min), GH-releasing hormone (GHRH, 1 microg/kg i.v.), GHRH+ARG, GHRH+PD, hexarelin, a GH-releasing protein (HEX, 2 microg/kg i.v.) and GHRH+HEX (0.25 microg/kg i.v.). The mean (+/-s.e.m.) peak GH response to ITT (21.8+/-2.8, range: 3.0-84.0 microg/l) was similar to those to ARG (18.0+/-1.6, range: 2.9-39.5 microg/l) or GLU (20. 5+/-2.2, range: 10.6-36.9 microg/l) which, in turn, were higher (P<0. 001) than those to CLO (8.2+/-1.6, range: 0.3-21.5 microg/l), PD (9. 6+/-1.1, range: 2.2-33.0 microg/l) and GAL (9.3+/-1.1, range: 3.9-18. 3 microg/l). The GH response to GHRH (19.1+/-1.5, range: 2.7-55.0 microg/l) was similar to those after ITT, ARG or GLU but clearly lower than those after GHRH+ARG (65.9+/-5.5, range: 13.8-171.0 microg/l) and GHRH+PD (50.2+/-4.6, range: 17.7-134.5 microg/l) which, in turn, were similar. The GH response to HEX (55.3+/-5.5, range: 13.9-163.5 microg/l) was similar to those after GHRH+ARG and GHRH+PD but lower (P<0.001) than that after GHRH+HEX (86.0+/-4.3, range: 49. 0-125.0 microg/l) which was the most potent stimulus of GH secretion. In this adult population the third centile limits of peak GH response to various stimuli were the following: ITT: 5.3; ARG: 2.9; CLO: 1.5; GLU: 7.6; PD: 2.2; GAL: 4.0; GHRH: 5.0; GHRH+ARG: 17.8; GHRH+PD: 17.9; HEX: 21.6; GHRH+HEX: 57.1. These results confirm that, among classical provocative tests of GH secretion, ITT followed by ARG and GLU are the most potent ones and possess clear limits of normality. GHRH+ARG or PD and HEX are strong stimuli of GH secretion which, however, is maximally stimulated by a combination of GHRH and a low dose of HEX. It is recommended that each test is used with appropriate cut-off limits.
The GH response to low-dose bolus growth hormone-releasing hormone (GHRH(1-29)NH2) is attenuated in patients with longstanding post-irradiation GH insufficiency
Authors: Achermann JC , Brook CG , Hindmarsh PC
Published: January 2005

OBJECTIVE: Previous studies have suggested that post-irradiation GH insufficiency results from a loss of GHRH secretion, since many patients were able to release GH following exogenous GHRH stimulation. However, supramaximal doses of GHRH were used and the response may decline with time after radiotherapy. We re-evaluated the GHRH dose-response curve in patients post cranial irradiation and in controls. DESIGN: Randomized controlled study. METHODS: Five adult male long-term survivors of childhood brain tumours (median age 21.8 years (18.4-26.7); 13.7 years (11.4-15.7) post-radiotherapy, >30Gy) and five matched controls were studied. An intravenous bolus of GHRH(1-29)NH(2) was administered in doses at the lower (0.05 microg/kg) and upper (0.15 microg/kg) range of the dose-response curves for young males, as well as the standard supramaximal dose (1. 0 microg/kg). GH was measured before stimulation, every 2min for the first hour and every 5min for the second hour. All studies were conducted in a random fashion. RESULTS: Significantly lower peak and area under the curve (AUC) GH concentrations occurred in the irradiated group using 0.15 microg/kg (median peak Irradiated, 4. 5mU/l vs median Controls, 37.4mU/l; P<0.01) and 1.0 microg/kg (median peak Irradiated, 4.8mU/l vs median Controls, 15.2mU/l; P<0. 05) GHRH(1-29)NH(2). In irradiated subjects there was an incremental rise in GH output with increasing doses of GHRH(1-29)NH(2 )(median AUC: 122mU/l.min vs 179mU/l.min vs 268mU/l.min; P=0.007) reflecting altered pituitary sensitivity and reduced responsiveness. CONCLUSION: The GH response to bolus GHRH(1-29)NH(2) is attenuated in adult long-term survivors of childhood brain tumours. This may reflect direct pituitary damage and/or the loss of the tropic effects of chronic GHRH deficiency.
Five cases with central diabetes insipidus and hypogonadism as first presentation of neurosarcoidosis
Authors: Bullmann C , Faust M , Hoffmann A , Heppner C , Jockenhovel F , Muller-Wieland D , Krone W
Published: January 2005

OBJECTIVES: We retrospectively reviewed 5 patients with neurosarcoidosis, who all presented with central diabetes insipidus and hypogonadism. DESIGN: This was a single-centre, retrospective analysis of 5 cases with a minimum follow-up of 2 years. METHODS: Case analysis included clinical, biochemical, and endocrinological evaluation and frequent CT/MRI scans of involved organs as primary evaluation and in response to immunosuppressive therapy. RESULT: Neurosarcoidosis was diagnosed in all patients. Two patients had no proven extracerebral manifestation and had a stable disease over 3 and 5 years. One patient showed deterioration with corticosteroids alone but partial remission after additional cyclophosphamide. Pituitary dysfunction remained unchanged in all patients, despite total clinical and radiological remission in two patients. However, one of these patients died of acute granulomatous meningoencephalitis after two years of follow-up. CONCLUSION: Although the presenting symptoms of neurosarcoidosis may vary, the occurrence of central diabetes insipidus associated with typical radiological features is suggestive of neurosarcoidosis. However, there is an increasing number of case reports on lymphocytic hypophysitis. Without the bioptic diagnosis, the differentiation between potentially lethal isolated neurosarcoidosis and lymphocytic hypophysitis is difficult. These cases demonstrate the difficulties in diagnosing neurosarcoidosis and reflect experiences with follow-up parameters.
Genetic and clinical characterisation of maturity-onset diabetes of the young in Spanish families
Authors: Costa A , Bescos M , Velho G , Chevre J , Vidal J , Sesmilo G , Bellanne-Chantelot C , Froguel P , Casamitjana R , Rivera-Fillat F , Gomis R , Conget I
Published: January 2005

OBJECTIVE: To investigate the frequencies of the major maturity-onset diabetes of the young (MODY) subtypes in a panel of Spanish families and to assess phenotypic differences in patients with the different subtypes of MODY. METHODS: Forty-eight subjects from twenty families with clinical diagnosis of MODY were studied. They underwent a standardised clinical examination and a 75-g oral glucose tolerance test (OGTT) was performed. Estimations of insulin sensitivity (%S) and insulin secretion capacity (%B) were calculated by the computer-solved homeostasis model assessment (HOMA). Mutations in the coding regions of hepatocyte nuclear factor (HNF)-4alpha/MODY1, glucokinase (GCK/MODY2) and HNF-1alpha/MODY3 genes were investigated by single strand comformation polymorphism and sequencing analysis. RESULTS: Mutations in the GCK and HNF-1alpha genes were observed in 5 (25%) and 7 (35%) families respectively. Novel mutations included R385X, M238fsdelT, V226fsdelTinsAA and S418-7del11 in the GCK gene, and S121fsdelC, V133M, R159Q and V259D in the HNF-1alpha gene. No MODY1 families were found. Subjects which were neither MODY2 nor MODY3 (MODY-X) had a higher fasting glucose than subjects in the other groups. Insulin secretion capacity was similar in the three groups and the insulin sensitivity was decreased in MODY-X subjects. Glucose levels were significantly higher and insulin levels significantly lower, throughout the OGTT, in MODY3 compared with MODY2 subjects. CONCLUSIONS: Mutations in the GCK/MODY2 and HNF-1alpha/MODY3 genes account for the majority of cases in a panel of Spanish MODY families, with MODY3 being the most frequent subtype. The relative frequencies and the clinical characteristics of these MODY subtypes are in agreement with data previously reported in other European populations. MODY-X patients seem to present a heterogeneous clinical profile.
Regulation of UT-OC-3 ovarian carcinoma cells by cytokines: inhibitory effects on cell proliferation and activation of transcription factors AP-1 and NF-kappaB
Authors: Seppanen M , Lin L , Punnonen J , Grenman S , Punnonen R , Vihko KK
Published: January 2005

The present study was designed to investigate the growth regulatory effects of cytokines in UT-OC-3 ovarian cystadenocarcinoma cells in vitro. The effects of interleukin-6 (IL-6), interferons alpha (IFN-alpha) and gamma (IFN-gamma), granulocyte-macrophage colony-stimulating factor (GM-CSF), tumour necrosis factor alpha (TNF-alpha), and transforming growth factor beta1 (TGF-beta1) were investigated by (125)I-deoxyuridine ((125)IUdR) incorporation assay. In order to understand better the molecular mechanisms of the observed effects, the activation of DNA-binding proteins was studied by electrophoretic mobility shift assay. In addition, cellular DNA was tested by fragmentation analysis to determine if the most growth inhibitory cytokines are able to induce programmed cell death (apoptosis). After 48h in culture, TGF-beta1, TNF-alpha, IFN-alpha and IL-6 showed a clear inhibitory effect on (125)IUdR incorporation (P<0.005), and IFN-gamma and GM-CSF caused even more significant inhibition (P<0.001). IFN-alpha and IFN-gamma were both growth inhibitory after 72h in culture (P<0.005). Similarly, GM-CSF induced a slight inhibition (P<0.05), whereas TGF-beta1 and TNF-alpha almost blocked DNA synthesis (P<0.001) after 72h. IL-6 had no statistically significant effect on cell proliferation after 72h. Transcription factors AP-1 and NF-kappaB were both constitutively expressed in UT-OC-3 cells. The binding activity of AP-1 was found to be stimulated by the growth inhibitory cytokines, TGF-beta1 and TNF-alpha, and the binding of NF-kappaB was stimulated by TNF-alpha. Apoptosis does not seem to be induced by any of these cytokines in the UT-OC-3 ovarian cancer cell model.
Human chorionic gonadotropin with C-elongated alpha-subunit retains full receptor binding and partial agonist activity
Authors: Marichatou H , Martinat N , Guillou F , Combarnous Y
Published: January 2005

OBJECTIVE: To test whether extension of the C-terminus of human chorionic gonadotropin (hCG) alpha-subunit (halpha) alters the bioactivity of the recombined alphabeta heterodimer. DESIGN: The stop codon of halpha was mutated to produce a 24 amino acid extension. METHODS: The extended halpha (alpha(+24)) was co-expressed with hCGbeta in COS-7 cells and the receptor binding and in vivo bioactivity of the secreted hormone was compared with its wild-type counterpart. RESULTS: This extension did not impair the binding of hCG to rat LH/CG receptors and provoked a sixfold reduction in its stimulatory activity of testosterone secretion in rat Leydig cells. CONCLUSIONS: The extension of alpha by itself does not lead to inhibition of the alphabeta heterodimer to LH receptors but the structure of the extension appears to play an important role. It is thus possible that one-chain hCG chimeras with the beta N-terminus fused to the alpha C-terminus might be active.
In vitro pituitary and testicular effects of the leptin-related synthetic peptide leptin(116-130) amide involve actions both similar to and distinct from those of the native leptin molecule in the adult rat
Authors: Tena-Sempere M , Pinilla L , Gonzalez LC , Navarro J , Dieguez C , Casanueva FF , Aguilar E
Published: January 2005

The obese gene (ob) product, leptin, has recently emerged as a key element in body weight homeostasis, neuroendocrine function and fertility. Identification of biologically active, readily synthesized fragments of the leptin molecule has drawn considerable attention, as they may provide a powerful tool for detailed characterization of the biological actions of leptin in different experimental settings. Recently, a fragment of mouse leptin protein comprising amino acids 116-130, termed leptin(116-130) amide, was shown to mimic the effects of the native molecule in terms of body weight gain and food intake, and to elicit LH and prolactin (PRL) secretion in vivo. As a continuation of our previous experimental work, the present study reports on the effects of leptin(116-130) amide on basal and stimulated testosterone secretion by adult rat testis in vitro. In addition, a comparison of the effects of human recombinant leptin and leptin(116-130) amide at the pituitary level on the patterns of LH, FSH, PRL and GH secretion is presented. As reported previously by our group, human recombinant leptin(10(-9)-10(-7)M) significantly inhibited both basal and human chorionic gonadotrophin (hCG)-stimulated testosterone secretion in vitro. Similarly, incubation of testicular tissue in the presence of increasing concentrations of leptin(116-130) amide (10(-9)-10(-5)M) resulted in a dose-dependent inhibition of basal and hCG-stimulated testosterone secretion; a reduction that was significant from a dose of 10(-7)M upwards. In addition, leptin(116-130) amide, at all doses tested (10(-9)-10(-5)M), significantly decreased LH and FSH secretion by incubated hemi-pituitaries from adult male rats. In contrast, in the same experimental protocol, recombinant leptin(10(-9)-10(-7)M) was ineffective in modulating LH and FSH release. Finally, neither recombinant leptin nor leptin(116-130) amide were able to change basal PRL and GH secretion in vitro. Our results confirm the ability of leptin, acting at the testicular level, to inhibit testosterone secretion, and map the effect to a domain of the leptin molecule that lies between amino acid residues 116 and 130. In addition, we provide evidence for a direct inhibitory action of leptin(116-130) amide on pituitary LH and FSH secretion, a phenomenon not observed for the native leptin molecule, in the adult male rat.
The role of Y chromosome deletions in male infertility
Authors: Ma K , Mallidis C , Bhasin S
Published: January 2005

Male infertility affects approximately 2-7% of couples around the world. Over one in ten men who seek help at infertility clinics are diagnosed as severely oligospermic or azoospermic. Recent extensive molecular studies have revealed that deletions in the azoospermia factor region of the long arm of the Y chromosome are associated with severe spermatogenic impairment (absent or severely reduced germ cell development). Genetic research into male infertility, in the last 7 years, has resulted in the isolation of a great number of genes or gene families on the Y chromosome, some of which are believed to influence spermatogenesis.
Virologic factors related to interferon-alpha-induced thyroid dysfunction in patients with chronic hepatitis C
Authors: Hsieh MC , Yu ML , Chuang WL , Shin SJ , Dai CY , Chen SC , Lin ZY , Hsieh MY , Liu JF , Wang LY , Chang WY
Published: January 2005

OBJECTIVE: Hepatitis C virus (HCV), being reported to be associated with a high prevalence of serological markers of autoimmunity in HCV-infected patients, and possibly sharing partial sequences in amino acid segments with thyroid tissue antigens, may be associated with interferon-alpha (IFN-alpha)-induced thyroid dysfunction in chronic hepatitis C patients. We conducted this study to clarify the issue. DESIGN AND METHODS: One hundred and fifty chronic hepatitis C patients with normal baseline thyroid function were treated with IFN-alpha 2a, 2b and n1 (3-6 million Units three times weekly for 24 weeks). Pretreatment sera were tested for HCV genotype and HCV RNA levels. Serum thyrotropin, total thyroxine and free thyroxine index were performed every 4 weeks for 24 weeks followed by every 8 weeks for another 24 weeks. RESULTS: Twenty-one (14.0%) patients developed early thyroid dysfunction (abnormal thyroid function during the first 3 months of therapy). Female gender, lower HCV RNA levels, IFN-alpha n1 and a lower IFN-alpha dose were significantly associated with early thyroid dysfunction. On multivariate analysis, gender, IFN-alpha preparation and HCV RNA levels were the significant factors associated with early thyroid dysfunction. Seven (4.7%) patients developed thyroid dysfunction during the second 3 months of IFN-alpha therapy. Taken together, 18.7% patients developed thyroid dysfunction. Female, mixed HCV genotype infection and lower HCV RNA levels were significantly associated with thyroid dysfunction. However, only gender remained significantly associated with IFN-alpha-induced thyroid dysfunction in multivariate analysis. CONCLUSIONS: The virologic features of HCV may be associated with thyroid dysfunction in chronic hepatitis C patients treated with IFN-alpha. Nevertheless, gender still plays the most important role in IFN-alpha-induced thyroid dysfunction.
Psychoses associated with thyrotoxicosis - 'thyrotoxic psychosis.' A report of 18 cases, with statistical analysis of incidence
Authors: Brownlie BE , Rae AM , Walshe JW , Wells JE
Published: January 2005

OBJECTIVE: To report a series of newly diagnosed thyrotoxic patients with concurrent acute psychosis, and to assess the association between the two disorders. DESIGN: Retrospective study of thyrotoxic patients with associated psychosis ('thyrotoxic psychosis'; TP) requiring inpatient psychiatric care. New Zealand thyrotoxicosis annual incidence figures and first psychiatric admission rates for affective psychosis were utilised to statistically assess the co-occurrence of thyrotoxicosis and affective psychosis. PATIENTS AND METHODS: During the 20-year study period, 18 inpatients (16 women and 2 men), mean age 54 years, with TP were identified. No patient had a past history of thyrotoxicosis, but four had required psychiatric inpatient care many years earlier. Thyrotoxicosis was documented by radioimmunoassay of thyroid hormone levels, and thyroid scintiscan. Psychiatric manifestations were classified using ICD9 criteria. RESULTS: Thyroid hormone levels were markedly elevated in more than half of our TP patients. All younger patients had Graves' disease, and most older patients toxic nodular goitre. All patients were treated with antithyroid drugs, and all but one subsequently received (131)I therapy. Two patients were not mentally ill when thyrotoxicosis was diagnosed, but suffered major mood swings when thyroid hormone levels were falling. There was no specific psychiatric clinical picture but affective psychoses were commonest - seven depression, seven mania. The other diagnoses were two schizophreniform, one paranoid, and one delirium. Initially, neuroleptic medication was used in all but one patient, and during long-term follow-up (median 11 years) more than half our series had remained well with no further psychiatric problems. Statistical analysis was restricted to thyrotoxic patients with first psychiatric hospital admission for affective psychosis. During the 20-year period, there were nine thyrotoxic patients (95% confidence interval 4.5-17.1) with concurrent affective psychosis requiring first admission, and the calculated expected number was only 0.36. These findings indicate a clear association well above chance co-occurrence. CONCLUSION: TP is not a specific clinical picture, but affective psychoses are commonest. Statistical analysis of thyrotoxic patients with concurrent affective psychoses showed an incidence well above chance co-occurrence. It appears that thyrotoxicosis may be a precipitant of acute affective psychosis.
The effect of long-term, non-suppressive levothyroxine treatment on quantitative ultrasonometry of bone in women
Authors: Hadji P , Hars O , Sturm G , Bauer T , Emons G , Schulz KD
Published: January 2005

OBJECTIVE: To evaluate the impact of long-term, non-suppressive levothyroxine (L-T(4)) treatment on quantitative ultrasonometry in women. DESIGN: This was a case-control study. SUBJECTS AND METHODS: Altogether 667 women (mean age+/-s.d., 49.5+/-13.1 years) were studied. Of these, 156 (23%) had non-toxic goitre or hypothyroidism and had been taking L-T(4) (75-100 microg/day) for at least 5 years (mean+/-s.d., 12.5+/-7.5 years); the remaining 511 (77%) women were not receiving L-T(4). All women had completed a questionnaire on risk factors for thyroid dysfunction and osteoporosis, and those with diseases or treatments known to effect bone metabolism - other than thyroxine or hormone replacement therapy (HRT) - were excluded. Women underwent quantitative ultrasonometry (QUS) at the heel. Speed of sound (SOS), broadband ultrasound attenuation (BUA) and the stiffness index (SI) were compared, first, in all women taking L-T(4) and controls and, secondly, in women taking L-T(4) and controls pair-matched for age, weight, body mass index (BMI), menopausal status and HRT use. RESULTS: Even after matching for age, weight, BMI, menopausal and HRT status, women taking L-T(4) had significantly lower values for SOS and SI (P<0.05), but not for BUA. However, absolute T- and Z-scores for SI were not low in either the study or control groups. Lower values were associated, but not significantly so, with years since the menopause and duration of L-T(4) treatment. CONCLUSIONS: Long-term, non-suppressive L-T(4) treatment in women with goitre or hypothyroidism was associated with a slight reduction in QUS values, which was more pronounced in postmenopausal women. This group could be at higher risk for osteoporotic fracture.
Birth weight influences long-term catch-up growth and height prognosis of GH-deficient children treated before the age of 2 years
Authors: Wasniewska M , Arrigo T , Cisternino M , De Luca F , Ghizzoni L , Maghnie M , Valenzise M
Published: January 2005

OBJECTIVE: To investigate which pretreatment variables most significantly affect long-term growth response to GH therapy in children with apparently idiopathic GH deficiency (GHD) treated from a similar and very young age (less than 2 years), for the same period (7 years) and with the same therapeutic protocol. DESIGN AND METHODS: Twelve children with either isolated GHD or multiple pituitary hormone deficiency were treated with biosynthetic human GH (0.7IU/kg per week) and were examined every 6 months. Height measurements were performed by Harpenden stadiometers. Bone age was evaluated every 12 months. RESULTS: The onset of therapy was followed in all patients by an important height gain, which attained its zenith during the first year of treatment and became progressively less evident during the next 4 years. Cumulative height gain was 3.0+/-1.7SDS. Thanks to the therapy, at the end of the 7-year treatment period, average height in the entire series was not significantly far from mean target height (TH) (-0.7+/-1.3 vs -0. 3+/-0.4SDS) and average predicted height (PH) (-0.2+/-1.4SDS) was very close to TH. A stepwise regression analysis showed that both catch-up growth under therapy and PH at the end of the 7-year treatment period were positively influenced by birth weight (BW). CONCLUSIONS: a) Our 7-year prospective study on GHD infants treated with GH from less than 2 years of age confirmed the importance of early diagnosis and treatment of GHD in childhood. b) The influence of BW on growth response to GH therapy in GHD children persists over time, at least when treatment is begun from less than 2 years of age.