bluuebunny/crossref_metadata_2025 huggingface dataset:
Twelve months of treatment with octreotide-LAR reduces joint thickness in acromegaly
Authors: Colao A , Cannavo S , Marzullo P , Pivonello R , Squadrito S , Vallone G , Almoto B , Bichisao E , Trimarchi F , Lombardi G
Published: January 2005

OBJECTIVE: To evaluate the role of age, gender, duration and control of acromegaly on the reversibility of arthropathy. PATIENTS AND DESIGN: 30 de novo patients with active acromegaly, 30 cured patients and 30 healthy subjects were studied in a tranverse and an open longitudinal study design. METHODS: Shoulder, wrist and knee thickening was measured by ultrasonography at study entry in all 90 subjects and after 12 Months of treatment with octreotide-LAR (OCT-LAR) at a dose of 10-40 mg every 28 days in the 30 de novo patients. RESULTS: Thickness at all joint sites was greater in the active than in the cured patients and controls (P<0.001), and was greater in the cured patients than in the controls (P<0.001). There was no gender difference, but joint thickness was less in the patients with disease duration >10 Years. Age significantly correlated with wrist (r=-0.55; P<0.001), right knee (r=-0.45; P=0.01), and left knee thickness (r=-0.42; P=0.02) in patients with active disease, and with wrist thickness (r=0.88; P<0.0001) in controls. Twelve Months of OCT-LAR treatment led to disease control in 18 patients (60%). There was a decrease in the thickness of the shoulder (15.1+/-3.2%), wrist (20.5+/-3.1%), right knee (22.2+/-3.4%) and left knee (18.2+/-2.8%) in all patients but the reduction in joint thickness at all sites was greater in the patients with controlled disease after OCT-LAR treatment than in the uncontrolled patients (P<0.01). Shoulder and right knee thickening normalized in respectively 11 (61.1%) and 16 (88.9%) well-controlled patients. CONCLUSIONS: Growth hormone and insulin-like growth factor-I (IGF-I) suppression by 12 Months' OCT-LAR treatment is accompanied by a significant decrease in the thickness of both weight-bearing and non-weight-bearing joints (mainly in patients whose disease is controlled) regardless of disease duration. These findings suggest that tIssue hypertrophy in the context of the acromegalic arthropathy can be improved by suppressing IGF-I levels.
Plasma chromogranin A in patients with sporadic gastro-entero-pancreatic neuroendocrine tumors or multiple endocrine neoplasia type 1
Authors: Peracchi M , Conte D , Gebbia C , Penati C , Pizzinelli S , Arosio M , Corbetta S , Spada A
Published: January 2005

OBJECTIVE: As circulating chromogranin A (CgA) has been claimed to be the best general neuroendocrine marker so far available, we evaluated the usefulness of CgA determination in the clinical assessment of patients with sporadic gastro-entero-pancreatic neuroendocrine tumors (GEP NETs) or multiple endocrine neoplasia type 1 (MEN 1). DESIGN AND METHODS: Plasma CgA levels were measured using a commercial enzyme-linked immunosorbent assay in 61 patients with sporadic GEP NET and in 25 with MEN 1 including 16 with GEP NET. Controls were 50 healthy volunteers, 46 patients with pituitary adenoma and 35 patients with primary hyperparathyroidism. RESULTS: The cutoff value for CgA established in our healthy subjects (as mean+2 s.d.) was 20 U/l. CgA levels were above the normal range in 71/77 patients with sporadic or MEN 1-related GEP NETs (92%), in four out of nine MEN 1 patients without GEP NETs (44%), and only in 22/81 control patients with pituitary or parathyroid disease (27%). Furthermore, CgA levels of over 100 U/l occurred in 36/77 patients with GEP NETs (47%) and only in one patient with a non-functioning pituitary adenoma. In the patients with GEP NETs, both tumor burden and secretory activity affected CgA levels, and successful surgical resection was associated with markedly decreased CgA values. CONCLUSIONS: Plasma CgA was confirmed to be a reliable marker for GEP NETs. Moreover, in MEN 1 patients the finding of very high CgA levels strongly suggests the presence of a GEP NET, as both primary hyperparathyroidism and pituitary adenomas rarely cause marked CgA increases.
During a corticotropin-releasing hormone test in healthy subjects, administration of a beta-adrenergic antagonist induced secretion of cortisol and dehydroepiandrosterone sulfate and inhibited secretion of ACTH
Authors: Kizildere S , Gluck T , Zietz B , Scholmerich J , Straub RH
Published: January 2005

OBJECTIVE: In chronic inflammatory diseases, serum levels of dehydroepiandrosterone (DHEA) sulfate (DHEAS) are low. Interestingly, several non-inflammatory diseases display similarly low levels of DHEAS which points to other inhibitory factors such as an activated sympathetic nervous system (SNS) (e.g. in patients with heart failure, fibromyalgia, or cancer cachexia). We aimed to identify the influence of the SNS tone on stimulated adrenal steroid secretion in 16 male and 12 female healthy subjects. METHODS: One group were given oral propranolol 2 h before a corticotropin-releasing hormone (CRH) test, and levels of adrenocorticotropin (ACTH), cortisol, 17-hydroxyprogesterone (17OHP), androstenedione, DHEA, and DHEAS were measured. RESULTS: Propranolol treatment decreased heart rate (by 20%), diastolic blood pressure (by 20%), and plasma ACTH, and increased serum cortisol, serum DHEAS, and the molar ratio of cortisol/17OHP, cortisol/DHEA, and DHEAS/DHEA similarly in female and male subjects. CONCLUSIONS: A beta-adrenergic influence seems to decrease CRH-stimulated cortisol in relation to ACTH and 17OHP, and decreases DHEAS in relation to DHEA. Although other workers have found beta-adrenergic stimulation of steroid secretion in cultured adrenocortical cells, the overall systemic influence of the SNS via beta-adrenoceptors seems to inhibit adrenal steroids under unstimulated and stimulated conditions. Sympathetic hyperactivity may be a common denominator for low levels of DHEAS in inflammatory and non-inflammatory diseases.
Do reproductive hormones modify insulin sensitivity and metabolism in older men? A randomized, placebo-controlled clinical trial of recombinant human chorionic gonadotropin
Authors: Liu PY , Wishart SM , Celermajer DS , Jimenez M , Pierro ID , Conway AJ , Handelsman DJ
Published: January 2005

OBJECTIVE: In order to assess the hormonal determinants of insulin sensitivity and related components of the metabolic syndrome, we evaluated the effect of subcutaneous recombinant human chorionic gonadotropin (r-hCG; Ovidrel) on insulin sensitivity, vascular reactivity, leptin, insulin-like growth factor-I (IGF-I) and lipids in ambulant, community dwelling men >60 Years of age with serum testosterone <or= 15 nmol/l on two occasions. DESIGN: Forty eligible men were randomized to receive 250 microg (5000 IU) r-hCG subcutaneously twice each week (n=20) or placebo (n=20) injections for 3 Months, and all subjects (mean age 67 (range 60-85) Years) completed the study. METHODS AND RESULTS: Groups were well matched for height, weight, anthropometry and insulin sensitivity. Insulin sensitivity was assessed by homeostasis model (HOMA) and euglycemic hyperinsulinemic clamp at baseline and at the end of the treatment period in the first 30 men who did not have diabetes mellitus. Insulin sensitivity (HOMA and euglycemic clamp) or beta cell function (HOMA) were not significantly changed by r-hCG despite a significant increase in lean body mass (approximately 2 kg, P<0.001) and reduced fat mass (approximately 1 kg, P<0.05). Subcutaneous fat (skinfold measurements), abdominal girth and serum leptin all decreased and IGF-I tended to increase, but these changes were not significant. Recombinant hCG significantly reduced total and low density lipoprotein cholesterol, and triglycerides, but did not significantly alter high density lipoprotein cholesterol. Endothelial function (vascular reactivity) was not significantly worsened. We conclude that three-Months of treatment with r-hCG demonstrates expected hormonal effects, improved lipids and did not worsen vascular endothelial function. Insulin sensitivity was not altered despite suggestive changes in body composition. CONCLUSIONS: These findings suggest short-term metabolic and cardiovascular safety and argue against an important role for androgens in the hormonal control of insulin sensitivity in older men.
Measuring serum oestradiol in women with Alzheimer's disease: the importance of the sensitivity of the assay method
Authors: Hogervorst E , Williams J , Combrinck M , David Smith A
Published: January 2005

OBJECTIVE: Oestrogens could be protective against the development of Alzheimer's disease (AD) but reports on oestrogen levels in AD have been conflicting. DESIGN AND METHODS: A meta-analysis using robust regression was carried out to assess whether the sensitivity of the assays of past studies had affected the reported level of total oestradiol. We had also measured total oestradiol in women with AD (n=66) and controls (n=62) not using hormone replacement therapy. We used two assays for total oestradiol to assess the difference between sensitive (radioimmunoassay with a specific rabbit antibody: 3 pmol/l) and relatively insensitive (immunoassay: 37 pmol/l) assays. RESULTS: Meta-analysis using robust regression indicated that insensitive assays gave higher levels of total oestradiol when many samples fall below the level of sensitivity of the method. Earlier reports of low levels of total oestradiol in AD might be explained by this phenomenon, since total oestradiol levels (using the sensitive assay) in our controls were one third of those reported in the earlier studies. Using the sensitive assay we found that women with AD had significantly (P<0.01) higher levels (26+/-13 pmol/l) of total oestradiol than controls (21+/-13 pmol/l). Using the insensitive assay, there was no significant difference in the levels of total oestradiol. CONCLUSIONS: The sensitivity of the assay determines the reported value of the oestradiol levels. Studies using a sensitive assay do not report significantly lower levels of total oestradiol in women with AD. This weighs against the hypothesis that low levels of total oestradiol are a risk factor for AD.
Nitric oxide decreases the production of inositol phosphates stimulated by angiotensin II and thyrotropin-releasing hormone in anterior pituitary cells
Authors: Velardez MO , Benitez AH , Cabilla JP , Bodo CC , Duvilanski BH
Published: January 2005

OBJECTIVE: Nitric oxide (NO) affects the synthesis of several second messengers, such as cyclic nucleotides, arachidonic acid metabolites and the intracellular calcium concentration, involved in the anterior pituitary hormone release. The present study was performed to investigate the effect of NO on phosphoinositide metabolism. METHODS: The synthesis of inositol phosphates (IPs) was studied in primary cultures of anterior pituitary cells from Wistar male rats. IPs (mono, bis and tris phosphates) were determined by ionic exchange chromatography. RESULTS: Sodium nitroprusside and DETA NONOate (DETA/NO) significantly decreased IP synthesis and prolactin release stimulated by angiotensin II (AngII) and thyrotropin-releasing hormone (TRH). These effects were not observed with decayed DETA NONOate (unable to release NO). LY-83583, a guanylyl cyclase inhibitor, completely reversed the inhibitory effect of DETA/NO on AngII-induced IP production. However, BAY 41-2272, a novel stimulator of the soluble guanylyl cyclase, did not mimic the effect of NO donors. Likewise, neither 8-Bromine-cyclic GMP (8-Br-cGMP), an analog of cGMP, nor Sp-8-pCPT-cGMPS triethylamine, a cGMP-dependent protein kinase (PKG) stimulator, decreased IP synthesis stimulated by AngII. In addition, Rp-8-pCPT-cGMPS triethylamine, a PKG inhibitor, did not block the effect of NO. The decrease of IPs induced by DETA/NO was fully reversed by guanosine 5'-O-(3-thiotriphosphate) tetralithium salt, a non-hydrolyzable analog of GTP. CONCLUSIONS: The present work indicated that NO decreases IP synthesis stimulated by Ang II and TRH in anterior pituitary cells by a soluble guanylyl cyclase/cGMP/PKG-independent pathway, and suggested that NO affects some regulatory factor located between the plasma membrane receptor and G-protein.
A yeast-based functional assay for the detection of the mutant androgen receptor in prostate cancer
Authors: Ceraline J , Erdmann E , Erbs P , Deslandres-Cruchant M , Jacqmin D , Duclos B , Klein-Soyer C , Dufour P , Bergerat JP
Published: January 2005

OBJECTIVE: Mutations in the ligand-binding domain of the human androgen receptor (AR) figure among the ways used by prostate adenocarcinoma (PCa) cells to escape androgen dependence. These mutations may broaden the specificity and/or affinity of the AR to other hormones, resulting in inappropriate receptor activation and thus affecting the PCa response to physiological stimuli and hormonal therapies. DESIGN: In order to clarify the impact of these mutations on disease progression and treatment, we have developed a yeast-based functional assay that allows the detection of mutant ARs and the analysis of their transactivation capacities in response to different ligands. METHODS: AR cDNA was directly cloned into an expression vector in a yeast strain that carries a reporter gene (ADE2) linked to an androgen-dependent promoter. The expression of the ADE2 gene and consequently the yeast cell growth in a selective medium depleted in adenine depends on the specificity of the AR for the ligand added to the medium. RESULTS: By analysing the transactivation capacities of different AR molecules in response to a broad range of steroid and non-steroid ligands, we have demonstrated that this assay can discriminate among wild-type AR, T877A, C685Y and L701H mutant ARs and that at least 1% of mutant ARs could be detected when mutant and wild-type ARs were mixed at the cDNA level. CONCLUSIONS: The data presented here show that this simple AR assay is convenient for the routine detection of mutant ARs in PCa and is also suitable to evaluate the antagonist activities of anti-androgen molecules.
Altered circulating hormone levels, endothelial function and vascular reactivity in the testicular feminised mouse
Authors: Jones RD , Pugh PJ , Hall J , Channer KS , Jones TH
Published: January 2005

OBJECTIVE: Testicular feminised (Tfm) mice express a non-functional androgen receptor, and also have reduced levels of circulating testosterone. Recent studies support a cardio-protective role for testosterone since it elicits systemic and pulmonary vasodilatation. The aim of the present study was to determine whether androgen insensitivity and hypotestosteronaemia in the Tfm mouse are associated with abnormal vascular reactivity or hormone status. METHODS: Adult male Tfm and littermate control mice were killed and the blood collected. Femoral (diameter range = 183-508 microm) and pulmonary (diameter range = 320-816 microm) arteries were dissected and loaded in either a wire or pressure myograph, at 100 mmHg or 17.5 mmHg respectively. Pharmacological assessment of the vasoreactivity to potassium chloride (KCl, 80 mmol/l) and either noradrenaline (NA, 1 nmol/l-100 micromol/l) and acetylcholine (ACh, 0.1-100 micromol/l) or testosterone (1 nmol/l-100 micromol/l) was then made. RESULTS: Tfm mice had reduced levels of testosterone (1.8+/-0.3 nmol/l) compared with controls (9.3+/-2.0 nmol/l, P<0.001) and elevated levels of cholesterol (3.6+0.1 mmol/l) compared with controls (3.2+0.1 mmol/l, P<0.05). Femoral arteries from Tfm mice exhibited reduced vasoconstriction to 80 mmol/l KCl (3.27+/-0.23 mN/mm) compared with vessels from controls (4.44+/-0.41 mN/mm, P<0.05), and reduced endothelial-dependent vasodilatation to 0.1-100 micromol/l ACh (23.3+/-3.6% relaxation) compared with vessels from controls (41.6+/-5.4% relaxation, P<0.05). Vasoconstriction to NA (1 nmol/l-100 micromol/l) and vasodilatation to testosterone were unaffected. CONCLUSIONS: Androgen receptor deficiency and hypotestosteronaemia in the Tfm mouse reduced endothelial function and impaired voltage-operated calcium channel activity, which may pre-dispose to cardiovascular disease. Testosterone-induced vasodilatation was unaffected, demonstrating no involvement of the androgen receptor in this response.
5-HT1 and 5-HT2 receptor activation reduces N-methyl-D-aspartate (NMDA)-stimulated LH secretion in prepubertal male and female rats
Authors: Pinilla L , Gonzalez LC , Tena-Sempere M , Aguilar E
Published: January 2005

OBJECTIVE: Excitatory amino acids and serotonin are involved in the control of gonadotropin secretion. The actions of these neurotransmitters are interconnected and recently we have reported that 5-HT(1) and 5-HT(2) receptor agonists blunted (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-stimulated GH secretion in prepubertal rats. The present experiments were carried out to analyze the effects of activation of different 5-hydroxytryptamine (5-HT) receptor subtypes on gonadotropin secretion and their role in the N-methyl-d-aspartate (NMDA)-stimulated LH release. DESIGN AND METHODS: We analyzed the gonadotropin secretion after manipulation of serotoninergic and aminoacidergic systems and their interactions in 5-, 16- and 23-day-old male and female rats. To this end, serum LH and FSH concentrations were measured in rats treated with 5-hydroxytryptophan methyl ester (5-HTP) (a precursor of 5-HT synthesis) plus Fluoxetine (Fx, a blocker of 5-HT reuptake), d,l-p-chlorophenyl-alanine methyl ester (PCPA, a blocker of 5-HT synthesis), R-(+)-8-hydroxydipropylaminotetralin hydrobromide (8-OH-DPAT, an agonist of 5-HT(1A) receptors), (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) and alpha-methyl-5-hydroxytryptamine (alpha-Me-5-HT, agonists of 5-HT(2) receptors), and 1-Phenylbiguanide (1-PHE an agonist of 5-HT(3) receptors). In addition, the effects of 8-OH-DPAT and DOI on NMDA-stimulated LH secretion were analyzed. RESULTS: Neither the activation nor blockade of the serotoninergic system modified LH secretion. Basal gonadotropin secretion remained unchanged in 23-day-old male and female rats after activation of 5-HT(1A), 5-HT(2) and 5-HT(3) receptors. The stimulatory effect of NMDA on LH secretion was blocked in both sexes after activation of the serotoninergic system, through specific 5-HT(1) and 5-HT(2) receptor agonists. CONCLUSIONS: Activation of serotoninergic receptors decreased the stimulatory effect of NMDA on LH secretion in prepubertal male and female rats.
Differential production of adrenal steroids by purified cells of the human adrenal cortex is relative rather than absolute
Authors: Young LS , Murphy G , Kelly SN , Smith TP , Cunningham SK , Joseph McKenna T
Published: January 2005

OBJECTIVES: The adrenal cortex produces aldosterone, cortisol and androgens in response to ACTH and angiotensin II. To define the differential response of morphologically distinct cells of the adrenal cortex, we examined the phenotypical and functional characteristics of human adrenocortical cells. RESULTS: Tumour growth factor-beta receptor-1 (TGFbeta-R1) and CYP-11 were found to be expressed predominantly in the zona fasciculata, whereas human leukocyte antigen (HLA-DR) and CYP-17 were localised to the zona reticularis. The angiotensin II receptor, AT-1, was found to be predominantly expressed in the zona glomerulosa. Adrenocortical cells, separated by density, yielded two distinct fractions which displayed differential growth patterns. Lipid-rich cells of fraction I expressed TGFbeta-R1 and produced significantly more cortisol relative to androstenedione than unseparated or fraction II cells, whereas lipid-poor cells of fraction II expressed HLA-DR and produced more androstenedione relative to cortisol in the presence of ACTH. Aldosterone production by fraction II was significantly greater than fraction I or unseparated cells. TGFbeta-R1-positive fasciculata-type cells separated into fraction I and HLA-DR-positive cells consistent with reticularis cells separated into fraction II. Aldosterone-producing cells indicative of glomerulosa cells separated into fraction II. CONCLUSIONS: Our findings are consistent with the concept that all adrenocortical cells are capable of producing a range of steroids, but the relative production of cortisol, androgen and aldosterone differs.
Insulin can block apoptosis by decreasing oxidative stress via phosphatidylinositol 3-kinase- and extracellular signal-regulated protein kinase-dependent signaling pathways in HepG2 cells
Authors: Kang S , Song J , Kang H , Kim S , Lee Y , Park D
Published: January 2005

OBJECTIVE: Insulin has well-known activities in controlling energy metabolism, cellular proliferation and biosynthesis of functional molecules to maintain a biological homeostasis. Recently, several studies have suggested that insulin may protect cells from apoptosis in different cell lines; however, little is known about the nature of its anti-apoptotic activity. In many clinical disorders, including type 2 diabetes mellitus, oxidative stress and the production of reactive oxygen species (ROS) is increased. With these facts as a background, we examined here whether insulin protects HepG2 cells from apoptosis by decreasing oxidative stress and, if so, which signaling steps are involved in this process. METHODS: Intracellular DNA content, the degree of nuclear condensation or poly(ADP-ribose) polymerase hydrolysis was measured to verify the occurrence of apoptotic events. Caspase-3 activity and ROS accumulation within cells were also measured. Western blot analysis was performed to identify signaling molecules activated in response to insulin. RESULTS: Serum starvation resulted in a marked accumulation of ROS, activation of caspase-3, and subsequent apoptotic cell death which were, in turn, markedly blocked by the addition of insulin. The anti-apoptotic activity of insulin was sensitive to blockade of two different signaling steps, activations of phosphatidylinositol 3-kinase (PI3 kinase) and extracellular signal-regulated protein kinase (ERK). CONCLUSION: Insulin exerts an anti-apoptotic activity by suppressing the excessive accumulation of ROS within cells through signaling pathways including stimulation of PI3 kinase and ERK in HepG2 cells.
Augmented serum levels of the IGF-I/IGF-binding protein-3 ratio in pre-menopausal patients with type I breast cysts
Authors: Enriori PJ , Fischer CR ,   Gori, Etkin AE , Calandra RS , Luthy IA
Published: January 2005

OBJECTIVE: Gross cystic disease (GCD) is the most common benign breast pathology. Although breast cysts are not considered pre-malignant lesions, an increased risk of breast cancer has been reported for patients with type I cysts (Na(+)/K(+)<3). Furthermore, an augmented IGF-I/IGF-binding protein-3 (IGFBP-3) ratio has been described in breast cancer patients. The objective was to evaluate serum IGF-I and binding protein concentrations of type I and type II cyst patients as compared with healthy women. METHODS: Twenty-four patients with type I cysts, 17 with type II cysts and 25 healthy women were evaluated. Serum IGF-I, IGFBP-3 and IGFBP-1 concentrations were measured by IRMA. RESULTS: IGF-I concentrations were significantly higher in sera from patients with type I cysts than in patients with type II cysts. A highly significant decrease of IGFBP-3, the major IGFBP, was found in patients with type I cysts with respect to healthy women, whereas no significant difference was evident between the different cyst types. The IGF-I/IGFBP-3 ratio, an estimate of biologically active IGF-I, was very significantly higher in patients with type I cysts than in both type II patients and healthy women. IGFBP-1 levels were significantly lower in patients with type I than in controls and type II cysts. The IGF-I/IGFBP-1 ratio was significantly higher in patients with type I cysts than in type II bearers and healthy women. Estrogen levels correlated with IGF-I in patients and controls. CONCLUSIONS: The enhanced levels of IGF-I/IGFBP-3 found in patients with type I cysts could eventually be associated with the increased risk of breast cancer described for this group.
GH replacement therapy increases plasma osteoprotegerin levels in GH-deficient adults
Authors: Lanzi R , Losa M , Villa I , Gatti E , Sirtori M , Dal Fiume C , Rubinacci A
Published: January 2005

OBJECTIVE: Osteoprotegerin (OPG), a glycoprotein belonging to the tumor necrosis factor receptor family, is an endogenous inhibitor of osteoclastogenesis produced by cells of the osteoblast lineage. OPG is a key cytokine involved in the regulation of osteoblast/osteoclast cross-talk. Since GH replacement therapy in GH deficiency (GHD) activates bone remodeling and increases bone mass, we investigated if short-term GH replacement therapy affects plasma OPG levels. DESIGN AND METHODS: Eighteen adults with GHD, ranging from 17 to 51 Years (nine childhood-onset and nine adult-onset) were enrolled in the study. All subjects were on stable replacement therapy, especially sex hormones. The starting dose of GH replacement therapy was 4 microg/kg per day x 7 days/week, and was progressively increased according to the serum IGF-I values. Biochemical parameters of bone and mineral metabolism were measured before and after 6 Months of GH replacement therapy. Bone mass density (BMD) was monitored at three skeletal sites (lumbar vertebrae, femur, radius) by dual-energy X-ray absorptiometry. RESULTS: After 6 Months of therapy, ionized calcium, parathyroid hormone and 25-OH vitamin D did not change, whereas total serum calcium and urinary calcium excretion increased significantly (P<0.01). Also osteocalcin and urinary deoxypyridinoline/24 h increased significantly (P<0.02, P<0.05 respectively). Mean basal T-scores of BMD values showed an osteopenic state, which remained unchanged after GH therapy. Plasma OPG increased significantly after 6 Months of therapy (P<0.02) and this increase was significantly correlated with the increase of osteocalcin (r=-0.52; P=0.04) and deoxypyridinoline values (r=-0.64; P=0.011). CONCLUSIONS: Our results suggest that the bone anabolic effect of GH replacement therapy could in part be mediated by a positive bone balance at each remodeling unit due to the inhibitory action of OPG on osteoclastogenesis.
Impact of successful transsphenoidal surgery on cardiovascular risk factors in acromegaly
Authors: Jaffrain-Rea ML , Minniti G , Moroni C , Esposito V , Ferretti E , Santoro A , Infusino T , Tamburrano G , Cantore G , Cassone R
Published: January 2005

BACKGROUND: Cardiac abnormalities develop in patients with acromegaly as a consequence of effects of GH/IGF-I on the heart and related cardiovascular risk factors. OBJECTIVE: To evaluate the possible contribution of postoperative variations in blood pressure (BP), glucose tolerance and insulin sensitivity to the cardiac improvement reported in patients who have been cured of acromegaly. DESIGN: Thirty-one patients with acromegaly were studied before and 6 Months after successful transsphenoidal surgery, defined by normal age-related IGF-I concentrations and glucose-suppressed GH concentrations <1 microg/l. METHODS: Cardiovascular parameters were assessed by Doppler echocardiography and 24-h ambulatory blood pressure monitoring. Insulin sensitivity indexes were calculated on the basis of fasting and post-load glycaemia and insulinaemia and referred to as HOMA(ISI) and OGTT(ISI), respectively. RESULTS: Successful surgery was confirmed to improve left ventricular mass index (LVMI) and diastolic filling significantly. Mean 24-h systolic BP values decreased (P=0.009) and BP rhythm was restored in 12 of 15 patients with a blunted preoperative profile. Glucose tolerance normalized in patients with preoperative glucose intolerance (n=7) or diabetes mellitus (n=3). HOMA(ISI) and OGTT(ISI) increased (P=0.0001 for each parameter), indicating a marked improvement in insulin sensitivity. The postoperative reduction in LVMI correlated with increased insulin sensitivity (P<0.001 for both indexes), but not with other parameters. Improved diastolic filling correlated with the reduction in LVMI. CONCLUSIONS: Successful surgery in patients with acromegaly induces a significant improvement in haemodynamic and metabolic risk factors. This study suggests a direct link between insulin resistance and acromegalic cardiomyopathy.
The relationship between pituitary tumour transforming gene (PTTG) expression and in vitro hormone and vascular endothelial growth factor (VEGF) secretion from human pituitary adenomas
Authors: Hunter JA , Skelly RH , Aylwin SJ , Geddes JF , Evanson J , Besser GM , Monson JP , Burrin JM
Published: January 2005

OBJECTIVE: Pituitary tumour transforming gene (PTTG) is a recently identified protooncogene, ubiquitously expressed in pituitary tumours at levels higher than those detected in normal pituitary. Although the precise function of PTTG protein is unknown, in vitro experiments have shown that it induces angiogenesis. In this study, we have examined the potential relationship between the level of PTTG expression and tumour phenotype, tumour size, in vitro pituitary hormone secretion and release of vascular endothelial growth factor (VEGF), a potent angiogenic factor. METHODS: Pituitary tumours (12 somatotroph, five lactotroph, five corticotroph and 18 non-functioning) were studied by cell culture, measuring the basal secretion of anterior pituitary hormones and VEGF in vitro. Immunocytochemistry was used to confirm the clinical diagnosis and tumour phenotype. PTTG mRNA expression was investigated by comparative RT-PCR. Tumour Volume was quantitated from pre-operative MRI scans. RESULTS: PTTG expression was significantly increased 2.7-fold in somatotroph tumours compared with non-functioning adenomas (P<0.01, ANOVA). A positive correlation was demonstrated between PTTG expression and in vitro GH secretion (r=0.41, P<0.01, Spearman) but no correlations were found for any of the other pituitary hormones. In 16 out of 40 pituitary tumours, we were able to determine the in vitro secretion of VEGF and relate this to PTTG expression. All of the adenomas tested secreted measurable VEGF but there was no correlation between the amount of VEGF secreted and either the tumour phenotype or PTTG expression. Neither PTTG expression nor VEGF secretion correlated with tumour Volume. CONCLUSIONS: Our studies have confirmed the presence of PTTG in pituitary adenomas and demonstrated a higher level of expression in somatotroph tumours and a significant correlation with GH secretion. We failed to demonstrate a relationship between PTTG expression and production of the angiogenic factor, VEGF, or tumour Volume. Thus, although PTTG induces angiogenesis experimentally, it seems unlikely that a VEGF-mediated angiogenic mechanism occurs during pituitary tumour progression.
Anthropometric, haemodynamic, humoral and hormonal evaluation in patients with incidental adrenocortical adenomas before and after surgery
Authors: Bernini G , Moretti A , Iacconi P , Miccoli P , Nami R , Lucani B , Salvetti A
Published: January 2005

OBJECTIVE: To compare clinical and humoral parameters before and after surgery in patients with incidental adrenocortical adenomas. DESIGN: Six patients with subclinical Cushing's syndrome and nine with non-functioning adenomas were investigated before and 12 Months after removal of the mass. METHODS: Anthropometric (body weight, body mass index and waist to hip ratio), haemodynamic (blood pressure and heart rate), metabolic (lipids and oral glucose tolerance test (OGTT)), hormonal (cortisol, plasma renin activity, aldosterone, androgens and catecholamines) and bone metabolism (hydroxyproline, parathyroid hormone, osteocalcin and ostase) parameters were evaluated. RESULTS: In the whole group, a significant decrease in body weight (69.7+/-3.5 vs 70.8+/-3.5 kg, P<0.03), in systolic (135.3+/-5.1 vs 145.6+/-4.9 mmHg, P<0.009) and diastolic (83.7+/-1.9 vs 91.0+/-3.5 mmHg, P<0.03) blood pressure and in glucose levels in response to OGTT (106.4+/-9.6 vs 127.5+/-6.5 mg/dl, P<0.05) was observed after surgery. All other parameters examined did not change significantly. This trend was also found in both groups separately. Analytical data showed a high frequency of overweight/obesity (66.6%), hypertension (66.6%) and impaired glucose profile (26.6%) in our patients, with a greater prevalence of these cardiovascular risk factors in the subclinical Cushing's syndrome group. After surgery, values normalized or improved in eight out of ten hypertensive patients and in three out of four patients with impaired glucose profile. CONCLUSIONS: Solid adrenocortical incidentalomas are associated with some cardiovascular risk factors which may be corrected after removal of the mass. Therefore, surgery may be an appropriate choice in patients with subclinical Cushing's syndrome but also in those with solid non-functioning adenomas and coexistent cardiovascular risk factors.
Close association of severe hyponatremia with exaggerated release of arginine vasopressin in elderly subjects with secondary adrenal insufficiency
Authors: Yatagai T , Kusaka I , Nakamura T , Nagasaka S , Honda K , Ishibashi S , Ishikawa SE
Published: January 2005

OBJECTIVE: Hyponatremia occurs not infrequently in hypopituitarism. Arginine vasopressin (AVP)-induced impaired water excretion is found in patients with hypopituitarism and experimental models of glucocorticoid deficiency. DESIGN: The present study was undertaken to determine whether augmented release of AVP is involved in the development of hyponatremia in elderly subjects with secondary adrenal insufficiency. METHODS: Forty patients with ACTH-deficient, secondary adrenal insufficiency were examined. They were divided into three groups according to the age at which diagnosis was ascertained (group A <20 Years, group B 20-64 Years, and group C>or=65 Years). RESULTS: Hyponatremia was more manifest in the elderly group than in the other two groups, serum sodium (Na) levels being 124.7 mmol/l in the elderly group, a value significantly less than 141.5 and 133.5 mmol/l in groups A and B. Plasma AVP levels seemed likely to be high compared with the respective hypo-osmolality in plasma in the elderly group, as plasma AVP levels were 1.7 pmol/l despite a mean plasma osmolality of 259 mmol/kg. Such an alteration was less clear in group B and was not found in group A. Therefore, elevation of plasma AVP was apparent in the elderly patients. Hydrocortisone replacement promptly normalized serum Na levels from 125 to 142 mmol/l (P<0.01) and reduced plasma AVP levels from 1.7 to 0.9 pmol/l (P<0.05), which were comparable to the respective plasma osmolality in the elderly patients. CONCLUSION: These results indicate that non-suppressible release of AVP is crucially involved in the impaired water excretion and hyponatremia seen in elderly patients with secondary adrenal insufficiency compared with the younger patients, and that exaggerated release of AVP becomes manifest as the subjects grow older.
Maternal serum inhibin A levels are a marker of a viable trophoblast in incomplete and complete miscarriage
Authors: Luisi S , Florio P , D'Antona D , Severi FM , Sanseverino F , Danero S , Petraglia F
Published: January 2005

OBJECTIVE: From early gestation the human trophoblast secretes large amounts of inhibin A and activin A, and their measurement provides a value for predicting the outcome in women who become pregnant after assisted reproductive techniques. The aim of the study was to investigate the putative role of maternal serum inhibin A and activin A levels as markers of a viable trophoblast in women who miscarry. DESIGN: Controlled cross-sectional study. METHODS: One group consisted of 65 healthy pregnant women (controls), progressing to deliver a healthy singleton baby and another group consisted of 54 miscarriages (38 incomplete (27 non-viable, 11 anembryonic pregnancies) and 16 complete). Maternal blood samples were collected between 5 and 12 weeks of gestation. RESULTS: Serum human chorionic gonadotrophin concentrations in women with incomplete or complete miscarriages were significantly (both P<0.001) lower than in controls; activin A levels being lowest only in women with a complete miscarriage (P<0.001). On the other hand, inhibin A levels were significantly lower in incomplete or complete miscarriage than in controls (both P<0.0001). CONCLUSIONS: Maternal serum inhibin A, but not activin A, determination reflects the lack of a viable trophoblast in complete miscarriage.
Cell-specific expression of NADPH-dependent cytosolic 3,5,3'-triiodo-L-thyronine-binding protein (p38CTBP)
Authors: Suzuki S , Mori J , Kobayashi M , Inagaki T , Inaba H , Komatsu A , Yamashita K , Takeda T , Miyamoto T , Ichikawa K , Hashizume K
Published: January 2005

We have previously shown that cytosolic 3,5,3'-triiodo-L-thyronine (T3)-binding protein (CTBP) possesses a high affinity for T3 binding in the presence of nicotinamide adenine dinucleotide phosphate in vitro, and that p38CTBP increases intracellular content of T3, and suppresses T3-mediated transactivity. Screening of mRNA expression in 73 different human tIssues has demonstrated that p38CTBP mRNA is expressed at high levels in brain and heart. We have examined the intracellular localization and tissue-specific distribution of this protein by using a specific antibody against human p38CTBP. Western blotting and immunoprecipitation studies have shown that the antibody recognizes human p38CTBP. Interaction of p38CTBP with the antibody did not affect the T3-binding activity of p38CTBP, and its dimer formation in vitro. Western blotting analysis has shown that p38CTBP is expressed in brain and heart predominantly, similar to the distribution of mRNA. Immunohistochemical studies have demonstrated p38CTBP in neural cells and cardiac muscle cells. p38CTBP localizes in cytoplasm rather than in nuclei in neural cells. The evidence for the presence of tIssue-specific localization of p38CTBP has indicated that p38CTBP has a tIssue-specific function, such as the regulation of T3 delivery from cytoplasm to nuclei.
Non-genomic actions of sex steroid hormones
Authors: Simoncini T , Genazzani AR
Published: January 2005

Steroid hormone receptors have been traditionally considered to act via the regulation of transcriptional processes, involving nuclear translocation and binding to specific response elements, and ultimately leading to regulation of gene expression. However, novel non-transcriptional mechanisms of signal transduction through steroid hormone receptors have been identified. These so-called 'non-genomic' effects do not depend on gene transcription or protein synthesis and involve steroid-induced modulation of cytoplasmic or cell membrane-bound regulatory proteins. Several relevant biological actions of steroids have been associated with this kind of signaling. Ubiquitous regulatory cascades such as mitogen-activated protein kinases, the phosphatidylinositol 3-OH kinase and tyrosine kinases are modulated through non-transcriptional mechanisms by steroid hormones. Furthermore, steroid hormone receptor modulation of cell membrane-associated molecules such as ion channels and G-protein-coupled receptors has been shown. TIssues traditionally considered as 'non-targets' for classical steroid actions are instead found to be vividly regulated by non-genomic mechanisms. To this aim, the cardiovascular and the central nervous system provide excellent examples, where steroid hormones induce rapid vasodilatation and neuronal survival via non-genomic mechanisms, leading to relevant pathophysiological consequences. The evidence collected in the past Years indicates that target cells and organs are regulated by a complex interplay of genomic and non-genomic signaling mechanisms of steroid hormones, and the integrated action of these machineries has important functional roles in a variety of pathophysiological processes. The understanding of the molecular basis of the rapid effects of steroids is therefore important, and may in the future turn out to be of relevance for clinical purposes.
Association of selenium with thyroid volume and echostructure in 35- to 60-year-old French adults
Authors: Derumeaux H , Valeix P , Castetbon K , Bensimon M , Boutron-Ruault MC , Arnaud J , Hercberg S
Published: January 2005

OBJECTIVE: To investigate the relationship between selenium status, thyroid Volume and gland echostructure. DESIGN: Cross-sectional. METHODS: In 792 men (45-60 Years) and 1108 women (35-60 Years) from the SU.VI.MAX study, thyroid Volume and gland echostructure were determined ultrasonographically. At baseline, thyrotropin, free thyroxine, selenium, zinc, alpha-tocopherol, beta-carotene, retinol, urinary iodine and thiocyanate concentrations were measured. Alcohol consumption, smoking, and menopausal status were assessed by a questionnaire. A stepwise linear and a logistic regression model were used, adjusting for antioxidant vitamins, trace elements status and age. RESULTS: In women, there was an inverse association between selenium status and thyroid Volume (P=0.003). A protective effect of selenium against goiter (odds ratio (OR)=0.07, 95% confidence interval (CI)=0.008-0.6) and thyroid tIssue damage (OR=0.2, 95% CI=0.06-0.7) was observed. There was no evidence of an association between menopausal status and other antioxidant elements, thyroid Volume or thyroid hypoechogenicity. Smoking, but not alcohol consumption, was associated with an increased risk of thyroid enlargement in women (OR=3.94, 95% CI=1.64-9.48). No association between thyroid Volume, thyroid structure or selenium was found in men. CONCLUSION: Our findings suggest that selenium may protect against goiter. Selenium was related to thyroid echostructure, suggesting it may also protect against autoimmune thyroid disease.
Association between the GH receptor/exon 3 genotype and the level of exon 3-positive GH-binding protein in human serum
Authors: Seidel B , Glasow A , Schutt M , Kiess W , Wu Z , Strasburger CJ , Kratzsch J
Published: January 2005

OBJECTIVE: The human GH-binding protein (GHBP) is derived from the GH receptor (GHR) through proteolytic cleavage of its extracellular domain. Two isoforms of the GHBP exist, differing in the retention or exclusion of exon 3: E3(+)GHBP and E3(-)GHBP. Our study aimed to answer the questions whether the level of E3(+)GHBP in the serum correlates with the GHR exon 3 expression and whether or not the E3 genotype matches the mRNA expression pattern. METHODS: Since exon 3 retention/deletion can be detected at the protein level using epitope-specific antibodies, we were able to quantify the two isoforms by means of specific immunoassays in a total of 37 individuals. Additionally, these persons were also genotyped for exon 3 by genomic PCR and tested for GHR exon 3 mRNA expression by RT-PCR. RESULTS: We found a significant correlation between GHR exon 3 genotype and the ratio of E3(+)GHBP and E3(-)GHBP in the serum. Moreover, the genotype matched exactly the mRNA expression in fibroblasts and/or blood leukocytes in all samples investigated. The levels of E3(+)GHBP are more strongly correlated with body mass index, proinsulin and C-peptide than the levels of the E3(-) isoform. CONCLUSIONS: Our results show that the GHR exon 3 genotype is in accord with the type of GHBP isoforms found in the serum. Our data thus support the idea that the presence of exon 3-retaining and -excluding GHR/GHBP isoforms results from a genomic deletion rather than from alternative splicing.
Gender differences in the prevalence, clinical features and response to cabergoline in hyperprolactinemia
Authors: Colao A , Sarno AD , Cappabianca P , Briganti F , Pivonello R , Somma CD , Faggiano A , Biondi B , Lombardi G
Published: January 2005

BACKGROUND: Gender differences in tumor size are supposed to exist in hyperprolactinemia since microadenomas are more commonly found in women and macroadenomas in men. Whether this reflects only a delay in diagnosis in men or a true gender difference in tumor pathogenesis is still unclear. OBJECTIVE: To prospectively analyze gender differences in the presentation and response to cabergoline treatment in 219 consecutive newly diagnosed patients with hyperprolactinemia. DESIGN: An open prospective design. SUBJECTS: Of the 219 patients of which 145 were women; 107 patients had macroprolactinoma, 97 had microprolactinoma, and 15 had non-tumoral hyperprolactinemia. METHODS: Presenting clinical symptoms, prolactin levels and tumor size at magnetic resonance imaging were measured before and 3-6 Months after cabergoline therapy. RESULTS: Prevalence of microprolactinomas (56% vs 22%, P=<0.0001) and non-tumoral hyperprolactinemia (10% vs 0%, P=0.01) was higher in women than in men. Men and women were of similar age (median 32 vs 29 Years; P=0.2) and a similar number had gonadal/sexual dysfunction (85 vs 83%, P=0.6); weight gain (70 vs 46%; P=<0.0001) and galactorrhea (52 vs 19%; P=<0.0001) were more common in women. Prolactin levels were higher in men than in women, whether exhibiting macro- (2848+/-2954 vs 1132+/-2351 microg/l, P=<0.0001) or microadenomas (187.8+/-51.8 vs 135.4+/-60.5 microg/l, P=0.009) and the size of the adenoma was larger in men than in women irrespective of macro- (25.8+/-12.4 vs 17.2+/-7.2 mm, P=<0.0001) or microadenoma diagnosis (8.0+/-1.4 vs 7.1+/-1.6 mm, P=0.04). After treatment, prolactin levels decreased by 89.2-96.4% in all groups, and normalized more frequently in micro- than in macroadenoma patients (86 vs 64%, P<0.0001), regardless of gender (70% vs 69%, P=0.9). Menses resumed in 82% of women, libido disturbances improved in 57% of men. Tumor size was reduced by 45+/-25% and 52+/-24% in macroprolactinoma patients and by 44+/-31 and 38+/-29% in microprolactinoma patients in women and men respectively. Visual field defects disappeared in 61% of women and in 71% of men (P=0.6). CONCLUSIONS: Prevalence of macroprolactinomas was similar in men and women; microprolactinomas and non-tumoral hyperprolactinemia were more frequent in women. Clinical symptoms at presentation differed according to gender, with galactorrhea and weight gain more frequent in women. The successful response to cabergoline treatment for 6 Months was higher in micro- than in macroprolactinoma patients and was similar in women and men.
A study of carotid intima-media thickness in GH-deficient Japanese adults during onset among adults and children
Authors: Murata M , Kaji H , Mizuno I , Sakurai T , Iida K , Okimura Y , Chihara K
Published: January 2005

OBJECTIVES: Increased carotid intima-media thickness (IMT) has been reported among Caucasian adult GH-deficient (AGHD) patients, but not Japanese. Also, it is known that the clinical and biochemical characteristics of AGHD patients are somewhat different based on the onset of the disease in either childhood or adult life. Nevertheless, there has been no study comparing the magnitude of the deviation of their IMT from normal subjects between child-onset (CO) and adult-onset (AO) patients in terms of Z score. The aim of this study, therefore, was first to examine whether Japanese AGHD patients have a risk of early development of atherosclerosis similar to Caucasian patients and secondly to assess the difference in the onset and in progression of atherosclerosis. DESIGN AND SUBJECTS: Thirty-four patients (17 CO-AGHD, age 29+/-7 Years, body mass index (BMI) 24+/-3.8 kg/m(2) and 17 AO-AGHD, age 48+/-12 Years, BMI 23+/-3.6 kg/m(2)) and 34 age- and sex-matched healthy controls (17 CO controls and 17 AO controls) were enrolled in the present study. Blood samples were taken for measurements of lipids, lipoproteins and IGF-I. Subsequently, patients underwent IMT assessment. RESULTS: CO patients were significantly younger than AO patients. The duration of GH-deficiency in CO patients was significantly longer than that in AO patients. Serum triglyceride (TG) was significantly higher in CO patients than in CO controls (P<0.05). Serum total cholesterol and TG were significantly higher in AO patients than in AO controls (P<0.01). The IMT was significantly greater in CO and AO patients (0.82+/-0.08 and 0.79+/-0.03 mm) than in CO and AO controls (0.59+/-0.02 and 0.68+/-0.03 mm, P<0.01 and P<0.01 respectively). There was no significant difference in raw values of IMT between CO and AO patients. However, the Z score of IMT calculated using normal Japanese IMT values was significantly higher in CO than in AO patients (2.07+/-0.68 vs 0.35+/-0.48, P<0.05). CONCLUSIONS: These findings suggest that GH deficiency appears to increase an atherosclerotic risk in Japanese AGHD patients, as with Caucasians, and to cause more extensive IMT thickening in CO-AGHD than AO-AGHD patients.