bluuebunny/crossref_metadata_2025 huggingface dataset:
Growth hormone replacement does not increase serum prostate-specific antigen in hypopituitary men over 50 years
Authors: le Roux CW , Jenkins PJ , Chew SL , Camacho-Hubner C , Grossman AB , Besser GM , Monson JP
Published: January 2005

OBJECTIVE: Epidemiological studies have shown an increased risk for prostate carcinoma in men with serum IGF-I in the upper part of the age-related reference range. Recombinant human GH (rhGH) is widely used in patients with GH deficiency, usually raising the serum IGF-I levels into the normal range: safety surveillance is therefore mandatory, with particular regard to neoplasia. The aim was to examine whether rhGH replacement in hypopituitary adults is associated with changes in serum prostate-specific antigen (PSA) as a surrogate marker of changes in prostatic growth. DESIGN AND METHODS: A prospective longitudinal study was used with a median follow-up of 22 (range 2.5-32) months, in which 41 men aged over 50 years with adult onset hypopituitarism and GH deficiency during rhGH replacement were examined. Serum PSA and IGF-I were measured at baseline and at latest follow-up. RESULTS: Mean serum PSA remained unchanged during rhGH replacement, with a median follow-up of 2 years. No correlation was found between the individual changes in serum IGF-I and changes in serum PSA. CONCLUSIONS: These data are reassuring thus far regarding the safety of GH replacement in relation to the prostate in this patient group.
Dopaminergic tone and obesity: an insight from prolactinomas treated with bromocriptine
Authors: Doknic M , Pekic S , Zarkovic M , Medic-Stojanoska M , Dieguez C , Casanueva F , Popovic V
Published: January 2005

OBJECTIVE: It has recently been shown that increased body weight is associated with prolactinomas and that weight loss occurs with normalization of prolactin levels. On the other hand, decreased dopaminergic tone in humans is well correlated with obesity. The objective of this study was to correlate changes in prolactin levels with leptin and body mass index (BMI) in patients with prolactinomas treated with the long-acting dopamine agonist bromocriptine (BC). METHODS: Eleven female and twelve male patients, aged 36.7+/-2.6 years with BMI in males of 30.4+/-1.7 kg/m(2) and in females of 24.4+/-1.2 kg/m(2), were evaluated after 1 and 6 months and 11 patients were further evaluated after 2 years of BC therapy. Plasma prolactin is presented as the mean of four samples taken daily. Serum leptin was determined in the pooled serum from three samples taken at 15-min intervals at 0800 h after an overnight fast. Multivariate linear regression and repeated measures analysis of covariance were used. RESULTS: In males, pretreatment prolactin levels were 71 362+/-29 912 mU/l while leptin levels were 14.9+/-1.8 microg/l. In females, pretreatment prolactin levels were 11 395+/-5839 mU/l and leptin levels were 16.7+/-2.5 microg/l. The sexual dimorphism of serum leptin levels at initial presentation was preserved after adjusting for BMI and prolactin-induced hypogonadism. After 1 month of therapy, prolactin levels significantly decreased (males: 17 618+/-8736 mU/l, females: 3686+/-2231; P<0.05), BMI did not change (males: 30.2+/-1.7 kg/m(2), females: 24.1+/-1.2 kg/m(2); P>0.05), while serum leptin levels decreased (males: 12.5+/-1.5 microg/l, females: 13.6+/-2.1 microg/l; P<0.05). After 6 months of treatment, prolactin further decreased (males: 3456+/-2101 mU/l, females: 677+/-360 mU/l; P<0.05) as did BMI (males: 28.6+/-1.6 kg/m(2), females 23.1+/-1.0 kg/m(2); P<0.05). The difference was more pronounced in male patients. Leptin levels were 12.8+/-2.8 microg/l in males and 12.9+/-1.8 microg/l in females (P<0.05). After 2 years of BC treatment, prolactin levels were near normal (males: 665+/-439 mU/l, females 447+/-130 mU/l; P<0.05) and BMI remained 26.5+/-1.9 kg/m(2) for males and 23.6+/-0.8 kg/m(2) for females (P<0.05). Leptin levels were 9.5+/-2.2 microg/l in males and 18.7+/-3.1 microg/l in females (P<0.05). There was a gradual increase in the gender difference in serum leptin levels over time. Changes in serum leptin levels significantly correlated with changes in BMI (r=0.844, P<0.001) but did not correlate with changes in plasma prolactin levels after 1 month (r=0.166), 6 months (r=0.313) and 2 years (r=0.234, P>0.05). CONCLUSION: The long-acting dopamine agonist BC, by increasing dopaminergic tone, may influence body weight and likely body composition by mechanisms in addition to reducing hyperprolactinemia in patients with prolactinomas.
Expression of G(alpha)(s) proteins and TSH receptor signalling in hyperfunctioning thyroid nodules with TSH receptor mutations
Authors: Holzapfel HP , Bergner B , Wonerow P , Paschke R
Published: January 2005

OBJECTIVE: Constitutively activating mutations of the thyrotrophin receptor (TSHR) are the main molecular cause of hyperfunctioning thyroid nodules (HTNs). The G protein coupling is an important and critical step in the TSHR signalling which mainly includes G(alpha)(s), G(alpha)(i) and G(alpha)(q)/11 proteins. DESIGN: We investigated the in vitro consequences of overexpressing G(alpha) proteins on signalling of the wild-type (WT) or mutated TSHR. Moreover, we investigated whether changes in G(alpha) protein expression are pathophysiologically relevant in HTNs or cold thyroid nodules (CTNs). METHODS: Wild-type TSH receptor and mutated TSH receptors were coexpressed with G(alpha)(s), G(alpha)(i) or G(alpha)(q)/11, and cAMP and inositol phosphate (IP) production was measured after stimulation with TSH. The expression of G(alpha)(s), G(alpha)(i) and G(alpha)(q)/11 proteins was examined by Western blotting in 28 HTNs and 14 CTNs. RESULTS: Coexpression of G(alpha)(s) with the WT TSH receptor in COS 7 cells significantly increased the basal and TSH-stimulated cAMP accumulation while coexpression of the G(alpha)(q) or G(alpha)11 protein significantly increased the production of cAMP and inositol triphosphate (IP(3)). The coexpression of the TSH receptor mutants (I486F, DEL613-621), known to couple constitutively to G(alpha)(s) and G(alpha)(q) with G(alpha)(s) and G(alpha)(q)/11, significantly increased the basal and stimulated cAMP and IP(3) accumulation. Coexpression of the TSH receptor mutant V556F with G(alpha)(s) only increased the basal and stimulated cAMP production while its coexpression with G(alpha)(q)/11 increased the basal and stimulated IP(3) signalling. The expression of G(alpha)(s) protein subunits determined by Western blotting was significantly decreased in 14 HTNs with a constitutively activating TSH receptor mutation in comparison with the corresponding surrounding tissue, while in 14 HTNs without TSH receptor or G(alpha)(s) protein mutation and in 14 CTNs the expression of G(alpha)(s) protein was not different compared with the surrounding tissue. The expression of G(alpha)(i) and G(alpha)(q)/11 proteins in HTNs or CTNs was not significantly different compared with the surrounding tissue. CONCLUSIONS: The reduced expression of G(alpha)(s) protein subunits in HTNs with TSHR mutations could act as a feedback mechanism to desensitise the chronically stimulated cAMP cascade. As G(alpha) protein expression was not significantly increased in the majority of CTNs and HTNs an influence of G(alpha) overexpression on TSH signalling could be excluded in these nodules.
Origin of parathyroid hormone (PTH) fragments detected by intact-PTH assays
Authors: Nguyen-Yamamoto L , Rousseau L , Brossard JH , Lepage R , Gao P , Cantor T , D'Amour P
Published: January 2005

BACKGROUND: Intact parathyroid hormone (I-PTH) assays react with non-(1-84)PTH, large carboxyl-terminal (C) fragments with a partially preserved amino-terminal (N) structure. They account for up to 50% of I-PTH in renal failure and may be implicated in PTH resistance. We wanted to know if they were secreted by the parathyroid glands and generated by peripheral metabolism of PTH(1-84). METHODS: Anesthetized normal and nephrectomized (NPX) rats were injected i.v. with 1.5 microg human (h) PTH(1-84). Blood was obtained from 8 rats at 2, 4, 6, 8, 12, 24, 48 and 96 min. I-PTH (Allegro I-PTH) was measured in all samples. Pools of serum were fractionated by HPLC at each time point and the fractions assayed to quantitate hPTH(1-84) and non-(1-84)PTH. Secretion studies were performed with dispersed cells from 5 parathyroid adenomas. The serum of 10 patients with primary hyperparathyroidism and cell supernatants were fractionated by HPLC and were analyzed as described. RESULTS: hPTH(1-84) disappeared from serum biexponentially. The half-life of the first exponential was similar in normal (2.08 min) and NPX (1.94 min) rats, while that of the second was longer in NPX rats (32.4 vs 20.9 min). The residual quantity of hPTH(1-84) under the curve was greater in NPX (6964+/-2392 pmol) than in normal rats (3229+/-561 pmol; P<0.001). Non-(1-84)PTH concentration was maximal at 8 min in both groups and was higher in NPX (92.8+/-13.8 pmol/l) than in normal rats (38.8+/-7.2 pmol/l; P<0.01). The area under the curve of non-(1-84)PTH was also greater in NPX (1904+/-405 pmol) than in normal rats (664+/-168 pmol; P<0.001). All parathyroid adenomas secreted non-(1-84)PTH. It represented 21.1+/-3.9% of secreted and 32.5+/-1.3% of circulating I-PTH in primary hyperparathyroidism. CONCLUSIONS: Non-(1-84)PTH, like other C-PTH fragments, originates from both the peripheral metabolism of hPTH(1-84) and from parathyroid gland secretion. Renal failure influences its concentration by increasing the amount of substrate available and by reducing non-(1-84)PTH clearance. Its higher proportion in serum relative to cell supernatants in primary hyperparathyroidism reflects the added role of peripheral metabolism and the longer half-life of fragments.
Effect of the GH secretagogue L-163,255 and restricted feeding time on GH pulsatility in the rat
Authors: Moulas AN ,   Krieg RJ, Veldhuis JD , Chan JC
Published: January 2005

OBJECTIVE: To determine the effect of repeated treatments with the growth hormone secretagogue (GHS) L-163,255 on the pulsatile release of GH when administered in meal-fed rats before and after feeding. DESIGN: The first group of rats (AL, n=6) had food available ad libitum. The second (restricted, R, n=6), third (GHSB, n=6), and fourth (GHSA, n=6) groups were fed from 1100 to 1400 h. Groups GHSB and GHSA were given GHS by gavage, 3.0 mg/kg L-163,255, at 1000 h (before feeding, B) and at 1500 h (after feeding, A) respectively. Three weeks after the initiation of the treatment, blood samples were collected at 10-min intervals over 6 h, and GH levels were determined. RESULTS: In group R, the concentrations of GH were higher before feeding (17.6+/-2.4 ng/ml) than during feeding (11.2+/-1.2 ng/ml), P<0.05. The average concentrations of the peak in response to GHS were higher when GHS was administered before (121.70+/-33.68 ng/ml) than after (49.67+/-17.87 ng/ml) feeding. The mass of GH, as calculated by deconvolution analysis was also higher in the GHSB group than in the GHSA group (251.6+/-64.1 ng/ml per min vs 85.3+/-22.9 ng/ml per min respectively, P<0.05). CONCLUSION: L-163,255 is effective in inducing GH release after repeated oral administration in rats. The effectiveness is greater when GHS is administered before rather than after feeding in meal-fed animals.
Endurance training improves responsiveness to insulin and modulates insulin signal transduction through the phosphatidylinositol 3-kinase/Akt-1 pathway
Authors: Luciano E , Carneiro EM , Carvalho CR , Carvalheira JB , Peres SB , Reis MA , Saad MJ , Boschero AC , Velloso LA
Published: January 2005

BACKGROUND: Endurance training increases insulin-stimulated muscle glucose transport and leads to improved metabolic control in diabetic patients. OBJECTIVE: To analyze the effects of endurance training on the early steps of insulin action in muscle of rats. DESIGN: Male rats submitted to daily swimming for 6 weeks were compared with sedentary controls. At the end of the training period, anesthetized animals received an intravenous (i.v.) injection of insulin and had a fragment of their gastrocnemius muscle excised for the experiments. METHODS: Associations between insulin receptor, insulin receptor substrates (IRS)-1 and -2 and phosphatidylinositol 3-kinase (PI3-kinase) were analyzed by immunoprecipitation and immunoblotting. Akt-1 serine phosphorylation and specific protein quantification were detected by immunoblotting of total extracts, and IRS-1/IRS-2-associated PI3-kinase activity were determined by thin-layer chromatography. RESULTS: Insulin-induced phosphorylation of IRS-1 and IRS-2 increased respectively by 1.8-fold (P<0.05) and 1.5-fold (P<0.05), whereas their association with PI3-kinase increased by 2.3-fold (P<0.05) and 1.9-fold (P<0.05) in trained rats as compared with sedentary controls, respectively. The activity of PI3-kinase associated with IRS-1 and IRS-2 increased by 1.8-fold (P<0.05) and 1.7-fold (P<0.05) respectively, in trained rats as compared with their untrained counterparts. Serine phosphorylation of Akt-1/PKB increased 1.7-fold (P<0.05) in trained rats in response to insulin. These findings were accompanied by increased responsiveness to insulin as demonstrated by a reduced area under the curve for insulin during an i.v. glucose tolerance test, by increased glucose disappearance rate during an insulin tolerance test, and by increased expression of glucose transporter-4. CONCLUSIONS: The increased responsiveness to insulin induced by chronic exercise in rat skeletal muscle may result, at least in part, from the modulation of the insulin signaling pathway at different molecular levels.
Growth hormone deficiency in pituitary disease: relationship to depression, apathy and somatic complaints
Authors: Zenker S , Haverkamp F , Klingmuller D
Published: January 2005

OBJECTIVE: Adults with GH deficiency (GHD) have been reported to suffer from increased levels of depression and apathy, which are thought to contribute to the reduced quality of life observed in these patients when compared with healthy controls. Recent studies, however, cast doubt on the attribution of these impairments to GHD as opposed to an unspecific stress response to the chronic medical condition. DESIGN: To further clarify this relationship, we used psychometric tests to quantify depression, apathy and typical psychosomatic complaints in patients with different types of pituitary disease and compared the results with measurements of the patients' widely varying GH status. SUBJECTS AND METHODS: In 98 patients, serum IGF-I was measured and at least one provocative test of the somatotrope pituitary axis was performed (GH-releasing hormone test (GHRHT) and/or insulin tolerance test (ITT)). All patients completed a set of well-established psychometric instruments (Beck Depression Inventory (BDI), Apathy Evaluation Scale (AS) and List of Somatic Complaints (LSC)). In addition, AS was administered in an informant report version for completion by a close relative or friend to verify the validity of the patient's self assessment. RESULTS: No relationship between measures of GHD (IGF-I, GHRHT and ITT) and psychometrically measured depression, apathy or psychosomatic well-being was found. A highly significant linear correlation between scores of all psychometric instruments (BDI, AS and LSC) was found. CONCLUSIONS: The absence of any relationship between the severity of GHD and the level of depression/apathy/psychosomatic complaints suggests that these impairments are not specific symptoms of GHD. The reported improvement of these symptoms under GH substitution therapy might thus be interpreted as a secondary effect of somatic effects of GH substitution. Consequently, indication for GH substitution therapy should not be based on psychological impairments alone without the presence of somatic symptoms of GHD.
Meal timing, fasting and glucocorticoids interplay in serum leptin concentrations and diurnal profile
Authors: Elimam A , Marcus C
Published: January 2005

BACKGROUND: In a previous study, we reported a 4-fold increase in serum leptin following total parenteral nutrition given after surgery. We hypothesised that the perioperative fasting and stress contributed to this, possibly mediated by increased serum insulin and cortisol. OBJECTIVE: To test the hypothesis that fasting, in combination with glucocorticoids, sensitises the leptin response to subsequent energy intake. DESIGN: Healthy volunteers were randomised into two groups, one group received dexamethasone (DEX), 0.1 mg twice daily for 3 days, while the other group served as a control. Each group was then subdivided into two feeding protocols. Protocol 1, where a standard meal was given at 0, 24, 36 and 48 h and protocol 2 where the same meal was given at 0 and 48 h. Blood samples were drawn before, as well as every other hour during the study period for determination of serum leptin, insulin, glucose and cortisol concentrations. RESULTS: In all groups serum leptin increased significantly following each meal (P<0.01). The rise in serum leptin in response to the standard meal was higher when the meal was taken in the evening (P<0.001) or following longer duration of fasting (P<0.02). In those fasting for 48 h, leptin decreased by 60% and showed no diurnal variation. DEX intake increased leptin concentrations in those fasting for short periods (P<0.02) but not for 48 h. CONCLUSIONS: Long durations of fasting sensitise the response of leptin to subsequent energy intake and abolish the DEX-induced upregulation of leptin. Meal timing is an important factor determining the leptin diurnal rhythm, but other factors must contribute since the leptin response to a standard meal taken in the evening was greater than to the same meal taken in the morning.
Amplified and orderly growth hormone secretion characterizes lean adolescents with polycystic ovary syndrome
Authors: Garcia-Rudaz MC , Ropelato MG , Escobar ME , Veldhuis JD , Barontini M
Published: January 2005

OBJECTIVE: The present study evaluated the hypothesis that pulsatile GH secretion is altered in adolescents with polycystic ovary syndrome (PCOS). DESIGN AND PATIENTS: Thirteen adolescent girls with PCOS (ages 13-19 years) and ten eumenorrheic controls (ages 14-19 years) matched for a range of body mass index (BMI) values underwent blood sampling every 20 min for 12 h overnight. METHODS: Serum concentrations of GH and LH were measured by specific immunofluorometric assays (IFMA). Pulsatile secretion was quantitated by deconvolution analysis and pattern orderliness by the approximate entropy (ApEn) statistic. Fasting serum androstenedione, testosterone, 17-hydroxyprogesterone, estrone, estradiol, insulin and IGF-I concentrations were measured by RIA, GH-binding protein (GHBP) by IFMA and IGF-binding protein (IGFBP)-1 and IGFBP-3 by IRMA. RESULTS: Twelve-hour mean and integrated GH concentrations, the mass of GH secreted per burst, and the GH pulse frequency were not distinguishable in patients with PCOS and controls as a whole. Subanalysis of non-obese (BMI<25 kg/m(2)) PCOS and healthy volunteers disclosed elevated 12-h GH production rates (P=0.03) and integrated serum GH concentrations (P=0.04) in (lean) patients with PCOS. ApEn analysis of the orderliness of GH release showed remarkably more regular GH secretion patterns (lower ApEn of GH release) in girls with PCOS compared with controls (P=0.02). Serum GHBP, IGF-I and IGFBP-3 concentrations were similar in both groups, whether lean or obese. However, IGFBP-1 levels were lower in the combined group of PCOS subjects compared with BMI-matched controls (P<0.05). In volunteers with PCOS, mean (12-h) serum GH concentrations correlated positively with mean serum LH levels (P=0.006). Based on deconvolution analysis, the 12-h production rate and the mass of GH secreted per burst also correlated strongly with the cognate LH measure (both predicted) (P=0.004) in PCOS. Androstenedione levels were also related to the 12-h GH secretion rate (P=0.02). CONCLUSIONS: This study shows that non-obese adolescents with PCOS secrete GH at a higher rate and with more orderly patterns, resembling a male profile. Determining whether this pattern reflects an intrinsic hypothalamic abnormality or is secondary to androgen excess in PCOS will require further studies.
FSH response-dose can be predicted in ovulation induction for normogonadotropic anovulatory infertility
Authors: van Santbrink EJ , Eijkemans MJ , Macklon NS , Fauser BC
Published: January 2005

OBJECTIVE: To evaluate the ability of a prediction model to identify the individual starting dose of FSH for ovulation induction using a step-down regimen. DESIGN: Retrospective analysis of clinical data in an academic fertility unit. Fifty-six normogonadotropic anovulatory infertile patients who failed to ovulate or conceive with clomiphene citrate were included. They were treated with exogenous gonadotropins with a flexible starting dose for ovulation induction using a step-down regimen. The clinically applied starting dose of exogenous gonadotropins was compared with the calculated response-dose using a previously published prediction model. RESULTS: Patients were arbitrarily divided into three groups according to the day of the first decrease in gonadotropin dose: (a) early step-down (day 3 or earlier); (b) standard step-down (day 4 or later); (c) no step-down. These groups had average starting doses of 28.5 IU (group a) and 13 IU (group b) above the calculated response-dose, and 43 IU (group c) under the calculated response-dose. A significant correlation between day of first step-down and the difference between clinically applied and calculated response-dose was observed (P<0.0001, F-test for ANOVA). CONCLUSIONS: The patient group with the best step-down profile for ovulation induction exhibited the closest match between the clinically applied and calculated starting dose of gonadotropins. Therefore, this study provides support for the concept that the individual effective FSH starting dose for gonadotropin induction of ovulation in anovulatory infertile patients can be predicted on the basis of initial screening characteristics, such as body mass index, clomiphene resistance or failure, free IGF-I and FSH. This may result in more effective patient treatment protocols, reduced complication rates and health-economic benefits.
Correlation of maternal serum fetuin/alpha2-HS-glycoprotein concentration with maternal insulin resistance and anthropometric parameters of neonates in normal pregnancy and gestational diabetes
Authors: Kalabay L , Cseh K , Pajor A , Baranyi E , Csakany GM , Melczer Z , Speer G , Kovacs M , Siller G , Karadi I , Winkler G
Published: January 2005

OBJECTIVE: Human fetuin/alpha(2)-HS-glycoprotein (AHSG) is a 49 kDa serum and tissue protein which is a natural inhibitor of insulin receptor signaling. We investigated serum AHSG levels during pregnancy and whether the protein is involved in insulin resistance observed in healthy pregnant women and patients with gestational diabetes. DESIGN: One hundred and four healthy pregnant women and 23 of their neonates, 30 patients with gestational diabetes and their neonates and 30 healthy age-matched non-pregnant females as a control group were investigated in a case-control cross-sectional study. METHODS: Serum AHSG was determined by radial immunodiffusion. RESULTS: We observed an increase of serum AHSG concentration in the second and third trimesters. Gestational diabetes patients had significantly higher AHSG levels than healthy pregnant women and non-pregnant controls. There was a highly significant positive correlation between serum AHSG concentration and indirect parameters of insulin resistance, i.e. tumor necrosis factor-alpha (TNF-alpha), leptin, C-peptide and C-peptide/blood glucose ratio. There was also a negative correlation between maternal AHSG, TNF-alpha, leptin levels and head circumference, body length and body weight of newborns. CONCLUSION: AHSG, TNF-alpha and leptin may contribute to insulin resistance during normal pregnancy and gestational diabetes. AHSG along with these cytokines may also negatively regulate neonatal skeletal development.
Evidence for functional CB1 cannabinoid receptor expressed in the rat thyroid
Authors: Porcella A , Marchese G , Casu MA , Rocchitta A , Lai ML , Gessa GL , Pani L
Published: January 2005

OBJECTIVE: Previous reports have shown that the Delta(9)-tetrahydrocannabinol (Delta(9)TCH), the major psychoactive cannabinoid components of marijuana, is able [corrected] to inhibit thyroid hormonal activity. The aim of this study was to characterize the CB1 functional expression in the rat thyroid by a multi-methods approach. METHODS AND RESULTS: RT-PCR was used to detect the mRNA expression of the CB1 cannabinoid receptor (17.8+/-4.0% of the normalizing reference gene beta(2) microglobulin), as well as the expression of the endocannabinoid hydrolyzing enzyme, fatty acid amide hydrolase (46.9+/-4.3% of beta(2) microglobulin), in the rat thyroid gland. The CB1-encoded protein was detected in its glycosylated form (63 kDa) by Western blot, employing a polyclonal antibody, while CB1 immunohistochemical localization showed an intracellular positive staining in both follicular and parafollicular cells. In addition, a 30% decrease in serum levels of both 3,5,3' tri-iodothyronine (T(3)) and thyroxine (T(4)) was detected 4 h after the administration of the synthetic cannabinoid receptor agonist, WIN 55,212-2 (10 mg/kg i.p.). These effects were antagonized by pretreatment with the CB1 antagonist SR 141716A (3 mg/kg i.p.); thyrotrophin levels were unaffected by both treatments. CONCLUSION: These data indicate that functional CB1 receptors which are able to modulate the release of T(3) and T(4) are expressed in the rat thyroid, and suggest a possible role of cannabinoids in the regulation of rat thyroid hormonal activity.
Anorexia nervosa in female adolescents: endocrine and bone mineral density disturbances
Authors: Munoz MT , Argente J
Published: January 2005

Anorexia nervosa (AN) is a chronic childhood psychiatric illness that involves a reduction in caloric intake, loss of weight and amenorrhea, either primary or secondary. The diagnostic criteria for AN have been established by the American Psychiatric Association. The prevalence of this disease amongst adolescents and young adults is between 0.5 and 1% and the incidence of new cases per year is approximately 5-10/100,000 between 15 and 19 years of age.A number of endocrine and metabolic disturbances have been described in patients with AN including amenorrhea-oligomenorrhea, delayed puberty, hypothyroidism, hypercortisolism, IGF-I deficiency, electrolyte abnormalities, hypoglycemia and hypophosphatemia, among others. In addition to prolonged amenorrhea, osteopenia and osteoporosis are the most frequent complications leading to clinically relevant fractures and increased fracture risk throughout life. Patients exhibit an alteration in the hypothalamic-pituitary-gonadal axis, which is responsible for the menstrual disorders. The increase in gonadotropin secretion that can be observed after ponderal recuperation suggests that malnutrition could be the most important mechanism involved in the decrease in gonadotropin secretion.The loss of fat tissue as a consequence of nutrient restriction has been associated with hypoleptinemia and abnormal secretion of peptides implicated in food control (neuropeptide Y, melanocortins and corticotropin-releasing factor, among others).A review of the endocrine abnormalities, disturbances in neurotransmitters, as well as a detailed analysis of bone markers and bone mineral density in patients with AN is described.
Oncogenic mutations in the thyrotropin receptor of autonomously functioning thyroid nodules in the Japanese population
Authors: Vanvooren V , Uchino S , Duprez L , Costa MJ , Vandekerckhove J , Parma J , Vassart G , Dumont JE , Van Sande J , Noguchi S
Published: January 2005

OBJECTIVE: Constitutively activating mutations of the thyrotropin receptor (TSHR) have been found in the majority of autonomously functioning thyroid nodules (AFTNs) in European patients. The reported frequency of these mutations varies among reports but amounts to 50-80%. To date, only one such mutation responsible for AFTNs has been identified in the Japanese population and the pathogenic role of such mutations in Japanese AFTNs has been questioned. In the present study, we evaluated the frequency of activating mutations in the TSHR and G(alpha)s in 10 Japanese AFTNs. DESIGN: Genomic DNA was extracted from fresh frozen tissue. The TSHR and the almost entire sequence of the gene coding for the alpha subunit of Gs have been amplified and sequenced. RESULTS: In sequence analysis, four mutations in the TSHR (T632A, I486M, M453T and L512R) were found. To complete our analysis, we searched mutations in the gene coding for the alpha subunit of Gs, in the samples negative for TSHR mutations. In one case a mutation (R201H) affecting GTPase activity was found. CONCLUSIONS: If we focus on the solitary nodules, we obtain the same mutation proportion as in European patients (70%). The absence of TSHR and G(alpha)s mutations in a significant proportion of autonomous adenomas in multinodular goiters suggests that other causes may also play a role in the genesis of these lesions.
Effect of iodine or iopanoic acid on thyroid Ca2+/NADPH-dependent H2O2-generating activity and thyroperoxidase in toxic diffuse goiters
Authors: Cardoso LC , Martins DC , Campos DV , Santos LM , Correa da Costa VM , Rosenthal D , Vaisman M , Violante AH , Carvalho DP
Published: January 2005

OBJECTIVE: The aim of the present study was to compare the effects of iopanoic acid (IOP) or a saturated solution of potassium iodide (SSKI) administration to patients with toxic diffuse goiters (TDG). DESIGN: Patients with TDG are treated with thionamides and high doses of iodine preoperatively. In this study, two types of preoperative drug regimens were used: propylthiouracil or methimazole plus SSKI for 10-15 days (n=8) or IOP for 7 days (n=6). METHODS: Serum thyroid hormones (total and free thyroxine (T(4)), total tri-iodothyronine (T(3)) and reverse T(3) (rT(3)), were evaluated after 7 days of either SSKI or IOP treatment, and after 10-15 days of SSKI administration. During thyroidectomy, samples of thyroid gland were obtained to evaluate thyroperoxidase and thyroid H(2)O(2)-generating activities. RESULTS: Serum total T(3) was significantly decreased after 7 days of either treatment, and serum rT(3) was significantly increased in IOP-treated patients. Serum total and free T(4) were unaffected by 7 days of IOP treatment, but decreased after 7 days of SSKI treatment, although significantly diminished levels were only reached after a further 3-8 days of SSKI administration. During both drug regimens, serum TSH remained low (SSKI: 0.159+/-0.122; IOP: 0.400+/-0.109 microU/ml). Thyroperoxidase activity was significantly lower in thyroid samples from patients treated with SSKI for 10-15 days than in the thyroid glands from IOP-treated patients. However, thyroid H(2)O(2) generation was inhibited in samples from patients treated with either IOP or SSKI. CONCLUSIONS: We show herein that IOP treatment can be effective in the management of hyperthyroidism and that this drug inhibits thyroid NADPH oxidase activity, just as previously described for SSKI, probably due to its iodine content.
Prevalence of diaphragmatic muscle weakness and dyspnoea in Graves' disease and their reversibility with carbimazole therapy
Authors: Goswami R , Guleria R , Gupta AK , Gupta N , Marwaha RK , Pande JN , Kochupillai N
Published: January 2005

OBJECTIVES: Dyspnoea is a common complaint among patients with thyrotoxicosis. However, its causative mechanisms have not been identified. We assessed the role of thoracic diaphragmatic muscle weakness in dyspnoea among patients with active Graves' disease. METHODS: Twenty-seven patients (19 female, 8 male) with active Graves' disease were assessed for the clinical severity of dyspnoea, functional (pressure generating capacity) and anatomical aspects (thickness and excursion) of the diaphragm at presentation. The severity of dyspnoea was assessed using a visual analogue scale (VAS) and the 6 min walk test. Lung function tests, diaphragmatic strength (sniff oesophageal pressure, SniffP(oeso)), maximum inspiratory and expiratory pressures, diaphragmatic thickness and movements on real time ultrasonography were evaluated during normal and deep respiration. Twenty of the 27 patients were reassessed after achieving euthyroidism with carbimazole therapy at a mean interval of 5+/-2 months. RESULTS: Reevaluation after carbimazole therapy revealed a significant reduction in dyspnoea on the VAS (59+/-26 to 23+/-13%). Patients covered a similar distance during the 6 min walk before and after euthyroidism. Significant improvement was observed in the vital capacity (2.57+/-0.62 to 2.94+/-0.60 l), forced expiratory volume in the first second (2.21+/-0.49 to 2.45+/-0.47 l), total lung capacity (3.57+/-1.19 to 4.1+/-1.12 l), diaphragmatic movement during deep respiration (5.5+/-1.0 to 6.6+/-1.1 cm) and SniffP(oeso) (68.7+/-23 to 93.1+/-25.2 cmH(2)O). There was no significant change in the distance walked in 6 min, tidal volume, lung diffusion capacity and diaphragmatic thickness. There was no significant correlation between the net change in dyspnoea score and net change in lung function tests, diaphragmatic movement and SniffP(oeso). CONCLUSIONS: Significant functional weakness of diaphragm muscle is present in patients with active Graves' disease. This weakness is more marked during a maximal respiratory manoeuvre, indicating a diminished diaphragmatic reserve which could be the cause of dyspnoea observed on exertion among patients with thyrotoxicosis.
An endocrinopathy characterized by dysfunction of the pituitary-adrenal axis and alopecia universalis: supporting the entity of a triple H syndrome
Authors: Ichiki K , Nakamura T , Fujita N , Honda K , Hiraga T , Ishibashi S , Ishikawa S
Published: January 2005

We demonstrate the rare disorder of triple H syndrome in a 25-year-old man. He was pointed out as having short stature, at -5.9 s.d., and diagnosed as GH deficient at 6 years old. Approximately a year ago, he noticed systematic hair loss. He lost body weight by 7 kg during the last half year. He was admitted to Jichi Medical School Hospital because of unconsciousness. Physical findings showed disturbance of consciousness with Japan Coma Scale I-3. He had emaciation and alopecia universalis. Laboratory findings showed plasma glucose was as low as 1.11 mmol/l. GH and ACTH deficiency with hypoadrenocorticism were clarified. His intelligence was in the low normal range with a WAIS IQ of 70, and anterograde amnesia was suggested in the presence of a little, but not significant, morphological change in the hippocampus on a magnetic resonance imaging scan. Replacement by a physiological dose of hydrocortisone normalized plasma glucose, and restored body weight and growth of hair during the 7 month therapeutic period. The present finding strongly supports a clinical entity of triple H syndrome, including ACTH deficiency, alopecia universalis and anterograde amnesia, and that there may be some variation of the triad among the subjects.
Nerve growth factor and retinoic acid interactions in the control of small cell lung cancer proliferation
Authors: Fiorentini C , Facchetti M , Finardi A , Sigala S , Paez-Pereda M , Sher E , Spano P , Missale C
Published: January 2005

OBJECTIVE: Nerve growth factor (NGF) has antiproliferative and differentiating effects in neuroendocrine tumors. In cell lines derived from small cell lung cancer (SCLC), NGF treatment stimulates NGF receptor expression, activates NGF secretion, inhibits proliferation and abrogates invasion. Since these effects are lost upon NGF withdrawal, it is relevant to identify other differentiation factors that may co-operate with the NGF system to control SCLC growth and differentiation. DESIGN: Retinoic acid (RA), which has been shown to inhibit cell transformation and proliferation, modulates the expression of NGF receptors and the sensitivity to NGF in different cell models. In the present study, we have investigated whether NGF and RA may interact to control the proliferation of SCLC cell lines. METHODS: SCLC cells were exposed to 50 ng/ml NGF or 1 microM all-trans RA for different times. Cell proliferation was measured by the [(3)H]thymidine incorporation test and NGF receptor expression was evaluated by immunofluorescence. RESULTS: We found that RA increased the expression of both trkA and p75 NGF receptors in NCI-N-592 and GLC8 cell lines and prevented the loss of both NGF production and NGF receptor expression occurring when NGF treatment was discontinued. As a result, RA, which did not inhibit the proliferation of untreated cells, abolished NGF withdrawal-related increase in cell proliferation both in vitro and in vivo, thus making permanent the antiproliferative effects of NGF. CONCLUSIONS: These data suggest that combined treatments with NGF and RA or mimicking drugs may represent a strategy to be further investigated for the treatment of SCLC.
Expression of growth hormone-releasing hormone in human primary endometrial carcinomas
Authors: Chatzistamou I , Schally AV , Pafiti A , Kiaris H , Koutselini H
Published: January 2005

BACKGROUND: Hypothalamic GH-releasing hormone (GHRH) regulates GH release from the pituitary, but an ectopic production of GHRH has been detected in various non-hypothalamic tissues, especially cancers. OBJECTIVE: To investigate whether endometrial tumors produce GHRH. METHODS: Twenty-four endometrioid, three serous papillary (SP), three mixed type endometrioid/serous papillary adenocarcinomas and one malignant mixed Mullerian tumor (MMMT) were assessed for GHRH immunoreactivity by the polyclonal anti-rabbit antibody SV95 and for the expression of GHRH mRNA by in situ hybridization using an oligonucleotide probe. RESULTS: Increased GHRH immunoreactivity was detected in 15 out of 24 (63%) of the endometrioid tumors, including two out of three (66%) of the mixed type endometrioid/serous adenocarcinomas but not in the three SP or the MMMT tumor. Cytoplasmic staining was detected in all positive cases, while in three of them strong nuclear localization of GHRH was also revealed. In situ hybridization indicated the presence of GHRH mRNA in six cases, all characterized as positive for GHRH immunoreactivity. CONCLUSION: GHRH is expressed in a subset of endometrial tumors, of the endometrioid type in particular. A paracrine/autocrine role for GHRH in the development of the disease should be considered.
Interaction between malnutrition and ovarian hormones on the systemic IGF-I axis
Authors: Goya L , Garcia-Segura LM , Ramos S , Pascual-Leone AM , Argente J , Martin MA , Chowen JA
Published: January 2005

OBJECTIVE: In malnutrition both the GH-IGF and reproductive axes are greatly affected. Because the actions of IGF and sex steroids are inter-dependent in many tissues, we have examined how ovariectomy modulates the response of the systemic IGF system to undernutrition. DESIGN AND METHODS: Peripubertal (30 days of age) female rats were either sham operated or ovariectomized. Five days later half of each group was submitted to a protein-caloric restriction diet. All rats were killed at 60 days of age. RESULTS: Growth was decreased in all rats submitted to calorie restriction and this was consistent with a decrease in circulating IGF-I concentrations and liver IGF-I mRNA expression. While in normally fed rats ovariectomy had no significant effect on serum IGF-I concentrations, ovariectomized and underfed rats had significantly higher levels than intact underfed rats. In undernourished rats, serum IGF-binding proteins (IGFBP)-1, -2 and -3 concentrations were significantly reduced and this was not modified by ovariectomy. In contrast, liver mRNA concentrations of IGFBP-1 and -2 were increased and IGFBP-3 unchanged in intact undernourished animals, suggesting that undernutrition could be affecting the proteolysis of these binding proteins, and this response was significantly modulated by ovariectomy. CONCLUSION: These results indicate that the presence of circulating ovarian hormones significantly affects the response of the IGF system to undernutrition.
Rapid signal transduction in Sertoli cells
Authors: Silva FR , Leite LD , Wassermann GF
Published: January 2005

The importance of non-genomic signaling as a complementary route for cell regulation has recently become evident. This rapid mechanism is utilized not just by peptide hormones, but also by steroids and other lipid-related substances, resulting in amplification and fine-tuning of the signals. The Sertoli cell is the principal target for hormone action in the seminiferous tubules. The involvement of FSH, testosterone and tri-iodothyronine (T(3)) in the spermatogenetic process is widely known. This paper discusses some rapid responses to FSH, retinol, testosterone and T(3) in the control of Sertoli cell function. Studies employing various methodologies and techniques are described and several hypotheses are considered in an attempt to explain the interactions of hormones with plasma membrane receptors. Recent knowledge about these new signaling mechanisms and cross-talk between them opens new fields of research on the communication and integration of the multiple hormonal signaling systems.
Effects of long-lasting raloxifene treatment on serum prolactin and gonadotropin levels in postmenopausal women
Authors: Lasco A , Cannavo S , Gaudio A , Morabito N , Basile G , Nicita-Mauro V , Frisina N
Published: January 2005

OBJECTIVE: To evaluate the effects of a 6 month administration of raloxifene hydrochloride, a selective estrogen receptor modulator which was recently approved for the prevention of osteoporosis, on serum gonadotropin and prolactin (PRL) levels and on TRH-stimulated PRL responsiveness in postmenopausal women who have not undergone estrogen replacement therapy. DESIGN AND METHODS: Sixteen healthy postmenopausal women were divided into two groups on the basis of their bone status, evaluated by dual energy X-ray absorptiometry at the lumbar level. Eight women (chronological age 52.4+/-4.1 (s.d.) years, menopausal age 42.4+/-3.9 years), in whom T-score L2-L4 was less than -2.5 s.d., were treated with raloxifene (60 mg p.o.) administered daily for 6 months (group 1), while the other eight women (chronological age 52.6+/-2.5 years, menopausal age 42.1+/-3.6 years), in whom the T-score L2-L4 ranged between -1 and -2.5 s.d., were used as a control group (group 2). Serum PRL, FSH, LH and 17beta-estradiol (E2) levels were evaluated at baseline and after 3 and 6 months of treatment. In all subjects, PRL responsiveness to TRH (200 microg i.v.) administration was evaluated at baseline and at the end of the study. RESULTS: At baseline, mean PRL, LH and FSH levels were not significantly different in the two groups (PRL 133.6+/-21.7 vs 136.7+/-28.1 mIU/l (NS), LH 25.1+/-6.8 vs 24.4+/-6.7 mIU/ml (NS), FSH 74.4+/-25.0 vs 71.1+/-24.1 mIU/ml (NS), in group 1 and group 2 respectively). No significant variations in serum FSH and LH values, in either group, or in serum PRL levels in group 2, were observed at the 3 and 6 month examinations. On the contrary, serum PRL values decreased significantly in group 1 after 3 months (100.1+/-47.7 mIU/l, P<0.05) and 6 months (81.5+/-30.2 mIU/l, P<0.001). At baseline, no significant differences were observed in the TRH-stimulated serum PRL peak between the groups (1015.4+/-30.5 vs 1030.2+/-25.7 mIU/l in group 1 and in group 2 respectively), while it decreased significantly at the 6 month examination in group 1 (770.5+/-47.4 mIU/l, P<0.001) and it was significantly lower than in group 2 (1068.1+/-301.8 mIU/l, P=0.02). Serum E2 was not detected at baseline and at each examination, in all patients. CONCLUSIONS: The decrease of PRL values induced by long-term raloxifene administration in postmenopausal women could be explained by a direct antiestrogenic effect of raloxifene on lactotrope cells or by the recently suggested increase of opiatergic tone on the hypothalamic-pituitary region.
Comparison of high-dose finasteride (5 mg/day) versus low-dose finasteride (2.5 mg/day) in the treatment of hirsutism
Authors: Bayram F ,   Muderris, Guven M , Kelestimur F
Published: January 2005

OBJECTIVE: To compare the clinical efficacy and safety of high-dose (5 mg/day) and low-dose (2.5 mg/day) finasteride in the treatment of hirsutism in women. DESIGN: A prospective, randomized and controlled clinical trial. METHODS: Fifty-six hirsute women with moderate to severe hirsutism were prospectively evaluated to see the effects of low-dose (2.5 mg/day) and high-dose (5 mg/day) finasteride. Patients were randomly divided into two treatment groups. Group I (n=29) received 2.5 mg finasteride/day and group II (n=27) received 5 mg finasteride/day orally for 1 year. Hirsutism score, body mass index and hormonal parameters (FSH, LH, estradiol, androstenedione, testosterone, free testosterone, 17alpha-hydroxyprogesterone, dehydroepiandrosterone sulfate and sex hormone-binding globulin) were measured in all the patients before treatment and repeated at six-monthly intervals. RESULTS: The hirsutism scores decreased significantly at months 6 and 12 from a mean+/-s.d. of 18.4+/-4.6 to 13.3+/-5.2 (P<0.001) and 18.4+/-4.6 to 8.6+/-4.2 (P<0.001) in group I and from 18.7+/-5.2 to 13.9+/-5.3 (P<0.001) and 18.7+/-5.2 to 10.3+/-5.0 (P<0.001) in group II respectively. No significant changes in the blood chemistry and hormonal parameters except estradiol levels were observed. No serious side-effects were seen in the two groups. In group II, estradiol levels increased significantly at 6 and 12 months. CONCLUSIONS: In this study, hirsutism scores decreased significantly at 6 and 12 months in both groups I and II. Low-dose (2.5 mg/day) finasteride is safe and cost effective in the treatment of hirsutism and may be used instead of high-dose finasteride (5 mg/day) therapy.
Impact of constitutional genetic variation in androgen/oestrogen-regulating genes on age-related changes in human prostate
Authors: Azzouzi AR , Cochand-Priollet B , Mangin P , Fournier G , Berthon P , Latil A , Cussenot O
Published: January 2005

OBJECTIVE: Benign prostatic hyperplasia (BPH) is the most common benign tumour in ageing men. While the etiopathology remains unsolved, a disruption in the endocrine/autocrine-paracrine prostatic homeostasis, involving steroid hormones, contributes to the pathogenesis of BPH. DNA polymorphisms in genes involved in hormone synthesis, signalling and metabolism may, therefore, be responsible for these changes. We have evaluated the correlation between specific genotypes in androgen- and oestrogen-regulating genes (AR, SRD5A2, CYP17 and CYP19), and age-related prostatic changes. METHODS: We have tested genetic susceptibility to morphological and pathological criteria in 195 French Caucasians, using allelic variants for candidate genes involved in androgen/oestrogen prostatic activity: androgen receptor (CAG repeats), 5alpha-reductase type 2 (TA repeats, V89L and A49T mutations), A2 variant of the 17alpha-hydroxylase (CYP17) and the simple tandem repeat polymorphism (STRP) aromatase (CYP19) polymorphisms. RESULTS: The A2 variant of 17alpha-hydroxylase (CYP17) and allele 191 of STRP aromatase (CYP19) showed an opposite effect on age-related prostate hyperplasia: CYP17 being associated with increased risk of prostate enlargement and CYP19 with reduced risk. The 5alpha-reductase type II variants studied did not show links with prostate hyperplasia. The androgen receptor gene CAG repeat length showed a low correlation with the increase of prostate weight, suggesting some effect on age-related prostate growth. CONCLUSION: These results suggested that common variants of the CYP17 gene are associated with prostate enlargement and therefore may increase the risk of development of BPH in this population, while infrequent variants of the aromatase gene (CYP19) could be of a protective nature.