bluuebunny/crossref_metadata_2025 huggingface dataset:
Follow-up of low-risk patients with differentiated thyroid carcinoma: a European perspective
Authors: Schlumberger M , Berg G , Cohen O , Duntas L , Jamar F , Jarzab B , Limbert E , Lind P , Pacini F , Reiners C , Sanchez Franco F , Toft A , Wiersinga WM
Published: January 2005

OBJECTIVE: Because differentiated (follicular and papillary) thyroid cancer (DTC) may recur years after initial treatment, the follow-up of patients with DTC is long term. However, this population has changed, with more individuals being discovered at an earlier stage of the disease, so that previous follow-up protocols based mostly on data from high-risk patients no longer apply. We sought to develop an improved protocol for the follow-up of low-risk patients with DTC based on the findings of recent studies. METHODS: We analysed recent literature on the follow-up of DTC. RESULTS: Recent large studies have produced three important findings: (i) in patients with low-risk DTC with no evidence of disease up to the 6- to 12-month follow-up, diagnostic whole-body scan adds no information when serum thyroglobulin (Tg) is undetectable and interference from anti-Tg antibodies is absent; (ii) use of recombinant human thyroid-stimulating hormone to aid Tg measurement is effective and provides greater safety, quality-of-life and work productivity than does levothyroxine withdrawal with its attendant hypothyroidism; and (iii) ultrasonography performed by an experienced operator is the most sensitive means of detecting neck recurrences of DTC. CONCLUSIONS: We present a revised follow-up protocol for low-risk patients taking into account the above findings. This protocol should help clinicians enter a new era of monitoring characterized by greater safety, simplicity, convenience and cost savings.
Advances in diagnostic practices affect thyroid cancer incidence in France
Authors: Leenhardt L , Bernier MO , Boin-Pineau MH , Conte Devolx B , Marechaud R , Niccoli-Sire P , Nocaudie M , Orgiazzi J , Schlumberger M , Wemeau JL , Cherie-Challine L , De Vathaire F
Published: January 2005

OBJECTIVE: To analyse trends in diagnostic practices of thyroid diseases and to relate them to the increase in thyroid cancer incidence in France over time. DESIGN: From 1980 to 2000, a French retrospective multicentric (three endocrinology and three nuclear medicine centres) study of thyroid diseases was conducted on 20 consecutive unselected patients' records, sampled every 5 years in each centre. METHODS: Characteristics of the population and diagnosis procedures (thyroid ultrasonography (US), radionuclide scan, cytology and hormonal measurements) were described over time. Changing trends in operated patients and in cancer prevalence were analysed as well as the impact of practices on cancer incidence. RESULTS: The study included 471 patients (82% female, mean age 46.7, range 9-84 years), referred for nodular thyroid diseases (66.7%) or thyroid dysfunctions (33.3%). A significant increase in US (3 to 84.8%) and cytological practices (4.5 to 23%), and a decrease (89.4 to 49.6%) in radionuclide scan procedures were observed over time. Although the proportion of patients undergoing surgery remained constant (24.8%), the prevalence of cancer increased among operated patients from 12.5 to 37% (P=0.006). In a Cox's proportional hazard model stratified on the clinical characteristics of patients, only the cytological practice, regardless of its results, was significantly associated with the occurrence of cancer: relative risk (RR)=4.4 (95% confidence interval (CI): 1.1-16; P=0.04). CONCLUSIONS: From 1980 to 2000, a major evolution in clinical practices has led to the increase in thyroid cancer reported in France. Such changes in medical, as well as in surgical and pathological, practices must be taken into account in incidence measurement.
Video-assisted thoracoscopic surgery as a first-line treatment for mediastinal parathyroid adenomas: strategic value of imaging
Authors: Amar L , Guignat L , Tissier F , Richard B , Vignaux O , Fulla Y , Legmann P , Bertagna X , Bonnichon P
Published: January 2005

OBJECTIVE: To present first-line thoracic surgery made possible by localization studies in three patients with ectopic parathyroid adenomas. DESIGN AND METHODS: Three patients with ectopic parathyroid tissue in the mediastinum were examined by ultrasound, technetium-99m sestamibi scintigraphy, computed tomography (CT), and venous catheterization with measurement of parathyroid hormone. Without previous cervical exploration, video-assisted thoracic surgery (VATS) was used in all cases to avoid the need for thoracic open surgical procedures. RESULTS AND CONCLUSIONS: The mediastinal parathyroid glands were all detected at scintigraphy, and CT and venous catheterization were helpful in anatomic and functioning characterization. All pathologic glands were successfully resected, with only one minor complication. VATS can safely remove a deep mediastinal parathyroid adenoma and avoid more aggressive open approaches. In an experienced referral center, systematic and sophisticated imaging studies may accurately identify and localize rare ectopic parathyroid adenomas, and avoid cervical surgery.
Utility of P300 auditory event related potential latency in detecting cognitive dysfunction in growth hormone (GH) deficient patients with Sheehan's syndrome and effects of GH replacement therapy
Authors: Golgeli A , Tanriverdi F , Suer C , Gokce C , Ozesmi C , Bayram F , Kelestimur F
Published: January 2005

OBJECTIVE: Impaired cognitive function has been demonstrated in adults with growth hormone (GH) deficiency (GHD) by using different neuropsychological tests. Despite several studies, present knowledge about the impact of GHD and GH replacement therapy (GHRT) on cognitive function is limited. P300 event-related potential (ERP) application is a well-established neurophysiological approach in the assessment of cognitive functions including the updating of working memory content and the speed of stimulus evaluation. GHD is a well-known feature of Sheehan's syndrome and cognitive changes due to GHD and the effects of GHRT remain to be clarified. The present study was designed to investigate the effects of GHD and 6 months of GHRT on cognitive function in patients with Sheehan's syndrome by using P300 latency. DESIGN AND METHODS: The study comprised 14 patients with Sheehan's syndrome (mean age, 49.5+/-7.8 years) and 10 age-, education- and sex-matched healthy controls. With hormone replacement therapy, basal hormone levels other than GH were stable before enrollment and throughout the GHRT. The diagnosis of GH deficiency was established by insulin-tolerance test (ITT), and mean peak level of GH in response to insulin hypoglycemia was 0.77+/-0.35 mIU/l. Treatment with GH was started at a dose of 0.45 IU (0.15 mg)/day in month 1, was increased to 0.9 IU (0.30 mg)/day in month 2 and was maintained at 2 IU (0.66 mg)/day. Initially baseline auditory ERPs in patients and controls were recorded at frontal (Fz), central (Cz), and parietal (P3 and P4) electrode sites. In the patient group, ERPs were re-evaluated after 6 months of GH replacement therapy. During each session P300 amplitude and latency were measured. RESULTS: Mean serum insulin-like growth factor-I (IGF-I) concentration in the patient group before GHRT was 23+/-13 ng/ml. After 6 months of GH therapy mean IGF-I significantly increased to an acceptable level, 234+/-71 ng/ml (P<0.05). The mean latencies (at all electrode sites) of the patients before GHRT were found to be significantly prolonged when compared with those of normal controls (P<0.05). After 6 months of GHRT mean P300 latencies (at all electrode sites) were decreased significantly when compared with latencies before treatment (P<0.05). CONCLUSIONS: The present study, using P300 ERP latencies, therefore suggests an impairment of cognitive abilities due to severe GHD in patients with Sheehan's syndrome and an improvement of cognitive function after 6 months of physiological GHRT. Moreover, this was a novel application of P300 ERP latencies in cognitive function detection in patients with GHD. Further studies with different patient groups need to be done to assess the clinical use of this electrophysiological method in the diagnosis of cognitive dysfunction due to GHD.
Central reassessment of GH concentrations measured at local treatment centers in children with impaired growth: consequences for patient management
Authors: Hauffa BP , Lehmann N , Bettendorf M , Mehls O , Dorr HG , Partsch CJ , Schwarz HP , Stahnke N , Steinkamp H , Said E , Sander S , Ranke MB
Published: January 2005

OBJECTIVE: GH deficiency is diagnosed in children if serum GH fails to rise above a predefined cutoff value in response to at least two stimuli. Diagnostic decisions based on this testing are highly variable between centers and depend on the GH assays used. Considering the large spectrum of commercially available GH assays, we wanted to evaluate the agreement between assays, and to test whether assay-related variability of diagnostic decisions could be reduced by reassessment of peak GH concentrations in a reference center. DESIGN: We reanalysed 699 peak GH serum samples obtained after GH testing of 382 children and adolescents from 19 centers using three reference assays and compared these results with those obtained with the local assays. A subgroup of 132 patients tested with the combination of insulin hypoglycemia test and arginine test was evaluated for changes in the assignment to the diagnostic group of GH deficiency. RESULTS: The mean difference between methods ranged from 5.4 to 10.3 mU/l, slopes of the regression lines from 1.28 to 1.65. Significant non-linearity was detected in five of six assay comparisons, indicating that most assay results cannot be interconverted by the use of a factor. Overall agreement between reference and local assays was only moderate. Significant changes in diagnostic assignment occurred when different assays were used on the same patient (P<0.0001-P<0.0023). Based on GH remeasurement by one reference assay, 36 of 132 patients were categorized differently, with 35 patients changing into the GH-deficient group. Similar findings were obtained with the other reference assays. CONCLUSIONS: To decrease variability in GH testing related to assays and cutoff values, we recommend nationwide reassessment of GH peak sera in reference centers. Decisions to treat GH deficiency should incorporate the reference center results.
Genetic variation in the human vitamin D receptor is associated with muscle strength, fat mass and body weight in Swedish women
Authors: Grundberg E , Brandstrom H , Ribom EL , Ljunggren O , Mallmin H , Kindmark A
Published: January 2005

OBJECTIVE: Bone mineral density (BMD) is under strong genetic control and a number of candidate genes have been associated with BMD. Both muscle strength and body weight are considered to be important predictors of BMD but far less is known about the genes affecting muscle strength and fat mass. The purpose of this study was to investigate the poly adenosine (A) repeat and the BsmI SNP in the vitamin D receptor (VDR) in relation to muscle strength and body composition in healthy women. DESIGN: A population-based study of 175 healthy women aged 20-39 years was used. METHODS: The polymorphic regions in the VDR gene (the poly A repeat and the BsmI SNP) were amplified by PCR. Body mass measurements (fat mass, lean mass, body weight and body mass index) and muscle strength (quadriceps, hamstring and grip strength) were evaluated. RESULTS: Individuals with shorter poly A repeat, ss and/or absence of the linked BsmI restriction site (BB) have higher hamstring strength (ss vs LL, P=0.02), body weight (ss vs LL, P=0.049) and fat mass (ss vs LL, P=0.04) compared with women with a longer poly A repeat (LL) and/or the presence of the linked BsmI restriction site (bb). CONCLUSIONS: Genetic variation in the VDR is correlated with muscle strength, fat mass and body weight in premenopausal women. Further functional studies on the poly A microsatellite are needed to elucidate whether this is the functionally relevant locus or if the polymorphism is in linkage disequilibrium with a functional variant in a closely situated gene further downstream of the VDR 3'UTR.
A comparison between spironolactone and spironolactone plus finasteride in the treatment of hirsutism
Authors: Kelestimur F , Everest H , Unluhizarci K , Bayram F , Sahin Y
Published: January 2005

OBJECTIVE: To compare the clinical efficacy and safety of the combination of spironolactone (100 mg/day) plus finasteride (5 mg/day) and spironolactone (100 mg/day) alone in the treatment of hirsutism. PATIENTS AND MEASUREMENTS: Sixty-five hirsute women were randomly assigned to one of these two treatment groups. Hirsutism score was measured according to the modified Ferriman-Gallwey scoring system. Baseline and post-treatment assessments were carried out in each subject by an investigator blinded to the therapy. Both groups had similar demographic properties at baseline. The serum levels of total and free testosterone, dehydroepiandrosterone sulphate and sex hormone-binding globulin were measured at the beginning and after 1 year of therapy. Blood chemistry and side-effects were evaluated during the study. Hirsutism scores were decreased significantly in both groups at the end of the year. RESULTS: The mean percentage change in hirsutism scores from baseline in the spironolactone plus finasteride-treated group (51.3%) was significantly (P<0.005) higher than in the group treated with spironolactone alone (36.6%). Patients from both treatment groups experienced similar side-effects. CONCLUSIONS: We have concluded that a combination of spironolactone plus finasteride is a safe and effective therapy in the treatment of hirsutism.
The effects of GH and hormone replacement therapy on serum concentrations of mannan-binding lectin, surfactant protein D and vitamin D binding protein in Turner syndrome
Authors: Gravholt CH , Leth-Larsen R , Lauridsen AL , Thiel S , Hansen TK , Holmskov U , Naeraa RW , Christiansen JS
Published: January 2005

OBJECTIVE: Studies in animals and humans indicate that growth hormone (GH) and insulin-like growth factor-I (IGF-I) modulate immune function. Recently, it was reported that GH therapy increased the level of mannan-binding lectin (MBL) in normal patients, and that treatment of acromegalics with pegvisomant decreased the levels of MBL. The effect on MBL was thought to be due to a specific action of GH, since IGF-I treatment did not affect MBL. Whether it is advantageous or not to have high or low levels of MBL is not known. Likewise, it is not clear how the modifications induced by GH affect immune function. In the present study we examined whether GH or hormone replacement therapy (HRT) in Turner syndrome (TS) influence the serum concentrations of MBL and two other proteins partaking in the innate immune defence, surfactant protein D (SP-D) and vitamin D binding protein (DBP). DESIGN: Study 1: a double-blind crossover study of 12 healthy TS adolescents examined during treatment with either placebo or GH for 2 months, and compared with a control group. Study 2: triple-blind crossover study of 9 healthy TS adolescents randomized to treatment with placebo, GH or GH+17beta-estradiol. Study 3: 60 adult TS patients (55 received HRT) compared with 59 age-matched controls. Study 4: 27 patients with TS were examined before and during sex hormone replacement with 17beta-estradiol and norethisterone and compared with age-matched controls (n=24). METHODS: Measurement of MBL, SP-D, DBP, and other inflammation markers. RESULTS: Study 1: the levels of MBL (P=0.002) and SP-D (P=0.012) increased during GH treatment, whereas no changes were observed in comparison with controls. DBP was unchanged by GH, but was significantly higher in TS compared with controls (P=0.017). Study 2: treatment with GH increased MBL (P=0.045) and SP-D (P=0.05) concentrations in TS, while treatment with GH+17beta-estradiol did not increase levels further. DBP was unchanged by treatment. Study 3: levels of MBL, SP-D, and DBP were similar in adult TS and control subjects. Study 4: DBP levels decreased in response to HRT, while MBL and SPD levels were unchanged. Levels of all three plasma proteins were similar to controls. CONCLUSION: We show that treatment with GH significantly increases MBL and SP-D concentrations in TS, while HRT marginally decreases DBP. Whether the present findings, suggesting a link between the endocrine and the immune system, have clinical consequences needs to be studied further.
Pharmacokinetics, safety, and endocrine and appetite effects of ghrelin administration in young healthy subjects
Authors: Akamizu T , Takaya K , Irako T , Hosoda H , Teramukai S , Matsuyama A , Tada H , Miura K , Shimizu A , Fukushima M , Yokode M , Tanaka K , Kangawa K
Published: January 2005

OBJECTIVE: It has been demonstrated that ghrelin plays a major role in the regulation of GH secretion and food intake. These actions make ghrelin a strong candidate for the treatment of GH deficiency, anorexia and cachexia. However, only preliminary studies have been performed to assess ghrelin administration in humans. In this study, we have conducted a double-blind, randomized, placebo-controlled trial to investigate the pharmacokinetics, safety, and endocrine and appetite effects of ghrelin in young healthy volunteers. DESIGN: Eighteen male volunteers were randomly assigned into three groups of six subjects: low- and high-dose ghrelin groups, who received intravenous injections of 1 and 5 microg/kg ghrelin (acylated form) respectively, and a placebo group who were injected with mannitol instead of ghrelin. RESULTS: Acylated ghrelin disappeared more rapidly from plasma than total ghrelin, with elimination half life (t(1/2)) of 9-13 and 27-31 min respectively. The number of subjects that experienced adverse effects did not significantly differ among the three groups, and all adverse effects were transient and well tolerated. Both the low and high doses of ghrelin strongly stimulated GH release (peak plasma concentration (C(max,0-90 min)): 124.2+/-63.9 and 153.2+/-52.2 ng/ml for 1 and 5 microg/kg ghrelin respectively). Slight alterations of blood glucose and insulin levels after the injection were observed. Although not statistically significant, ghrelin administration tended to increase hunger sensation in a dose-dependent manner. CONCLUSIONS: These results suggest that ghrelin is safe, and that clinical trials may be started to assess the usefulness of ghrelin for the treatment of disorders related to GH secretion and appetite.
Raloxifene decreases serum IGF-I in male patients with active acromegaly
Authors: Dimaraki EV , Symons KV , Barkan AL
Published: January 2005

OBJECTIVE: Most patients with acromegaly require additional treatments after trans-sphenoidal surgery. Although traditional methods of treatment aim at suppressing GH hypersecretion from the pituitary tumor, recent studies on the use of the GH receptor antagonist have shown that targeting the action of GH on peripheral tissues may be more effective. Estrogens and the selective estrogen receptor modulator tamoxifen have been used previously to suppress circulating IGF-I levels in patients with acromegaly. Positive effects of raloxifene in women with active acromegaly have been reported recently. This study was designed to examine the potential role of raloxifene in the treatment of acromegaly in male patients. DESIGN: We studied eight men with active acromegaly despite the fact that they were receiving traditional treatments. All subjects were treated with raloxifene (60 mg twice a day) for a median of 5 weeks. METHODS: The effects of raloxifene on GH secretion were assessed by obtaining 24-h GH profiles and studying the response of GH to various stimuli before and after treatment with raloxifene. Serum IGF-I was measured before and after raloxifene treatment. RESULTS: Raloxifene did not affect basal GH secretion or response of GH to TRH, GHRH or glucose, but it decreased circulating IGF-I by 16+/-4% (P=0.001), and normalized plasma IGF-I in two patients. No changes in clinical parameters were observed. Prolactin levels, the prolactin response to TRH and free testosterone levels remained unchanged. Raloxifene was well tolerated. CONCLUSION: Raloxifene might be useful in the treatment of male patients with active acromegaly, but longer term studies are clearly needed.
Inhibition of prostate cell growth by BXL-628, a calcitriol analogue selected for a phase II clinical trial in patients with benign prostate hyperplasia
Authors: Crescioli C , Ferruzzi P , Caporali A , Scaltriti M , Bettuzzi S , Mancina R , Gelmini S , Serio M , Villari D , Vannelli GB , Colli E , Adorini L , Maggi M
Published: January 2005

OBJECTIVE: Calcitriol analogues might represent an interesting new therapy for benign prostate hyperplasia (BPH). We here report the preclinical characterization of BXL-628, an analogue selected for an ongoing double-blind, randomized, placebo-controlled phase II trial in BPH. DESIGN: Experiments with BXL-628 were carried out in human BPH cells and in the ventral prostate of intact and castrated rats. METHODS: BPH cell and rat prostate growth were evaluated along with morphological and biochemical hallmarks of apoptosis. RESULTS: BXL-628 inhibited human BPH cell proliferation and induced apoptosis even in the presence of androgens or growth factors. It also decreased prostate growth to an extent similar to finasteride, inducing DNA fragmentation and apoptosis, both in intact and in testosterone-supplemented castrated rats. Accordingly, BXL-628, like finasteride, increased the expression of clusterin, a prostatic atrophy marker. However, BXL-628 did not inhibit 5 alpha-reductase 1 and 2, did not bind to the androgen receptor (AR) in BPH homogenates and did not affect AR-coupled luciferase activity. In addition, BXL-628 did not affect rat pituitary and testis activity or calcemia. CONCLUSIONS: BXL-628 inhibited in vitro and in vivo prostate cell proliferation, and therefore might represent a novel, interesting option for the treatment of BPH.
The environment and autoimmune thyroid diseases
Authors: Prummel MF , Strieder T , Wiersinga WM
Published: January 2005

Genetic factors play an important role in the pathogenesis of autoimmune thyroid disease (AITD) and it has been calculated that 80% of the susceptibility to develop Graves' disease is attributable to genes. The concordance rate for AITD among monozygotic twins is, however, well below 1 and environmental factors thus must play an important role. We have attempted to carry out a comprehensive review of all the environmental and hormonal risk factors thought to bring about AITD in genetically predisposed individuals. Low birth weight, iodine excess and deficiency, selenium deficiency, parity, oral contraceptive use, reproductive span, fetal microchimerism, stress, seasonal variation, allergy, smoking, radiation damage to the thyroid gland, viral and bacterial infections all play a role in the development of autoimmune thyroid disorders. The use of certain drugs (lithium, interferon-alpha, Campath-1H) also increases the risk of the development of autoimmunity against the thyroid gland. Further research is warranted into the importance of fetal microchimerism and of viral infections capable of mounting an endogenous interferon-alpha response.
The emerging role of the CTLA-4 gene in autoimmune endocrinopathies
Authors: Vaidya B , Pearce S
Published: January 2005

It is thought that the majority of autoimmune endocrinopathies, including Graves' disease, autoimmune hypothyroidism, type 1 diabetes mellitus and autoimmune Addison's disease (sporadic and as well as autoimmune polyendocrinopathy syndrome type 2) are inherited as complex genetic traits. Multiple genetic and environmental factors interact with each other to confer susceptibility to these disorders. In recent years there have been considerable efforts towards defining susceptibility genes for complex traits. These investigations have shown, with increasing evidence, that the cytotoxic T lymphocyte antigen-4 (CTLA-4) gene is an important susceptibility locus for autoimmune endocrinopathies and other autoimmune disorders. Here we review the genetic and functional analyses of the CTLA-4 locus in autoimmune endocrinopathies, and discuss the recent efforts in fine-mapping this locus.
A meiotic recombination in a new isolated familial somatotropinoma kindred
Authors: Luccio-Camelo DC , Une KN , Ferreira RE , Khoo SK , Nickolov R , Bronstein MD , Vaisman M , Teh BT , Frohman LA , Mendonca BB , Gadelha MR
Published: January 2005

We report here the genetic findings of a new isolated familial somatotropinoma (IFS) kindred in which the mother (subject I:2) and one daughter (subject II:2) are affected; their ages at diagnosis were 25 and 14 years respectively. Additionally, patient I:2 developed virilization due to an androgen-secreting adrenocortical mass, presenting clinical and molecular features of sporadic adrenal carcinoma. To genotype this family and to narrow down the candidate interval of the putative IFS gene at 11q13, we performed haplotyping on the DNA from all five members of the family and allelotyping of one available somatotropinoma using polymorphic microsatellite markers from chromosome region 11q12.1-11q13.5. Results indicated that the disease haplotype, between markers D11S956 and D11S527, was transmitted from subject I:2 only to subject II:2. A meiotic recombination event was detected in the fraternal twin sister of II:2 (subject II:1), but her disease status is unknown. Since she is only 18 years old this genetic event cannot yet narrow down the area involved in the pathogenesis of IFS. Allelotyping of the somatotropinoma from II:2 revealed loss of the chromosome carrying the wild-type copy of the putative IFS gene inherited from her father. These results support the involvement of a tumor suppressor gene at 11q13.1-q13.3 in the pathogenesis of IFS.
Effects of TSH-suppressive therapy on cardiac morphology and function: beneficial effects of the addition of beta-blockade on diastolic dysfunction
Authors: Gullu S , Altuntas F , Dincer I , Erol C , Kamel N
Published: January 2005

OBJECTIVE: To investigate the effects of long-term levothyroxine (LT4) suppressive therapy on the heart and the effects of beta-blockade on cardiac functions. DESIGN: Twelve female patients receiving LT4, selected from a group of patients with TSH levels of 0.1-0.4 microU/ml, were evaluated. The control group consisted of 11 healthy subjects and 12 patients with TSH levels <0.05 microU/ml. METHODS: Cardiac evaluation consisted of a 12-lead electrocardiogram and an echocardiographic study. Left ventricular mass index (LVMI), isovolumetric relaxation time (IVR), left ventricular end systolic (LVESD) and diastolic diameters, early (VE) and late (VA) diastolic flow velocities and fractional shortening were evaluated. Exercise capacity was assessed with a bicycle ergometer. Both work load and maximal exercise time were measured. Atenolol was given to the patient group at a dosage of 50 mg/day for 3 months and evaluations were repeated. RESULTS: On basal evaluations, LVMI (96+/-17 vs 78+/-21 g/m(2)) and IVR (101+/-9 vs 91+/-4 ms) were found to be increased in the patients taking LT4 (P<0.01). LVESD was also lower than controls (P<0.05). A decrease in VE and an increase in VA were also observed in the patients (P<0.01). IVR decreased after atenolol (92+/-10 vs 101+/-9 ms, P<0.05). LVMI decreased and VE and VA improved but did not reach statistical significance after beta-blockade. Baseline work load and maximal exercise duration were significantly lower in the patients and improvements were observed after atenolol treatment. CONCLUSIONS: These results indicated that cardiac dysfunction may occur even when TSH is suppressed to 0.1-0.4 microU/ml with LT4. beta-blockade improved the cardiac functions.
Circulating adiponectin levels and cardiovascular risk factors in acromegalic patients
Authors: Ronchi CL , Corbetta S , Cappiello V , Morpurgo PS , Giavoli C , Beck-Peccoz P , Arosio M , Spada A
Published: January 2005

OBJECTIVE: Adiponectin (ApN) is an adipocytokine expressed in human adipose cells with anti-atherogenic and anti-inflammatory properties that plays a role in the pathophysiology of insulin resistance, metabolic syndrome and coronary artery disease. The aim of the study was to evaluate ApN secretion in patients with acromegaly, a chronic disease associated with insulin resistance and increased cardiovascular mortality, and to correlate ApN levels with hormonal, metabolic and cardiovascular parameters. DESIGN AND METHODS: The study included 32 patients with active acromegaly (11 male and 21 female, aged 48+/-11 years, duration of disease: 8+/-6 years, GH: 9.2+/-9.8 microg/l, IGF-I: 80+/-33 nmol/l (means+/-s.d.)) and 38 control subjects sex- and body mass index (BMI)-matched. In all subjects, serum ApN, leptin and ghrelin levels, BMI, waist circumference, insulin resistance (assessed by homeostasis model assessment and the quantitative insulin check index), lipid profile and blood pressure values were evaluated. RESULTS: Acromegalic patients and control subjects had similar ApN levels (9.4+/-3.5 vs 9.5+/-4.0 mg/l, NS), while when considering obese subjects acromegalic patients had ApN levels significantly higher than controls (10.2+/-4 vs 7.5+/-3 mg/l, P<0.05). No significant correlation between ApN and GH/IGF-I levels or duration of disease was found. ApN concentrations negatively correlated with BMI, waist circumference, glucose and diastolic blood pressure and positively with high-density lipoprotein cholesterol and ghrelin in controls, while all these correlations were lost in acromegalic patients. CONCLUSIONS: We provide evidence that, although metabolic and cardiovascular abnormalities are present in most acromegalic patients, in these subjects ApN levels are not reduced and, contrary to what is found in BMI-matched controls, do not correlate with cardiovascular risk factors. These data support the view that atherosclerosis is not the main determinant of cardiovascular mortality in acromegaly and suggest a permissive action of GH and/or IGF-I excess on ApN secretion.
Circumstances of discovery of phaeochromocytoma: a retrospective study of 41 consecutive patients
Authors: Baguet JP , Hammer L , Mazzuco TL , Chabre O , Mallion JM , Sturm N , Chaffanjon P
Published: January 2005

OBJECTIVE:Phaeochromocytoma is a rare tumour of the chromaffin cells, the diagnosis of which is based on an assay of metanephrines and treatment is surgical excision of the tumour. It is usually discovered due to a rich and varied symptomatology or classic paroxysmal hypertension. The main purpose of this study was to specify the exact circumstances of discovery of the phaeochromocytomas operated on in our university hospital between 1990 and 2002. DESIGN AND METHODS: Forty-one consecutive and complete case reports of patients who had surgery for phaeochromocytoma were analysed retrospectively. This series includes 10 patients with a genetic disorder predisposing to phaeochromocytoma. RESULTS: The association of headaches and palpitations with sweating was found in only 24% of cases (10/41). Blood pressure anomalies led to the discovery of phaeochromocytoma in only 51% of cases (21/41) and 59% (24/41) of all the patients suffered from hypertension. In almost half the cases (20/41), the tumour was discovered by an imaging method (ultrasonography, CT scan or MRI) which had been performed for reasons unrelated to a blood pressure abnormality. CONCLUSIONS: Phaeochromocytoma, the symptoms of which are not very specific and during which hypertension is present in only half the patients, is a disease that remains rare. Its incidence could be increasing because of changes in the method of detection. Indeed, in our study, different imaging techniques led to its incidental discovery in half of the cases.
Association of leptin receptor polymorphism with insulin resistance
Authors: Chiu KC , Chu A , Chuang LM , Saad MF
Published: January 2005

OBJECTIVE: Although the role of the leptin receptor (LEPR) in obesity is well recognized, its role in insulin sensitivity remains unknown. DESIGN: This was a cross-sectional study to investigate the impact of the Q223R polymorphism of the LEPR gene on insulin sensitivity. METHODS: Sixty-seven glucose-tolerant Caucasians were enrolled. The insulin sensitivity index and glucose clearance were measured using a hyperglycemic clamp. Genomic DNA was extracted for genotyping. RESULTS: We identified 20 QQ, 31 QR, and 16 RR subjects. The three genotypic groups were similar in age, gender distribution, body mass index, waist-hip ratio, and blood pressure, but differed in the insulin sensitivity index (P=0.0180) and in glucose clearance (P=0.0220). Multivariate analyses showed that the Q223R polymorphism was independently associated with the insulin sensitivity index (P=0.0317) and glucose clearance (P=0.0436). A trend of increasing low density lipoprotein cholesterol concentration was also observed (P=0.0447). CONCLUSION: We have reported the first association of the Q223R polymorphism of the LEPR gene with insulin resistance.
Orexin A suppresses in vivo GH secretion
Authors: Seoane LM , Tovar SA , Perez D , Mallo F , Lopez M , Senaris R , Casanueva FF , Dieguez C
Published: January 2005

BACKGROUND/AIMS: Orexins (OXs) are a newly described family of hypothalamic neuropeptides. Based on the distribution of OX neurons and their receptors in the brain, it has been postulated that they could play a role in the regulation of neuroendocrine function. GH secretion is markedly influenced by nutritional status and body weight. To investigate the role OX-A plays in the neuroregulation of GH secretion we have studied its effect on spontaneous GH secretion as well as GH responses to GHRH and ghrelin in freely moving rats. Finally, we also assessed the effect of OX-A on in vitro GH secretion. METHODS: We administered OX-A (10 microg, i.c.v.) or vehicle (10 microl, i.c.v.) to freely moving rats. Spontaneous GH secretion was assessed over 6 h with blood samples taken every 15 min. RESULTS: Administration of OX-A led to a decrease in spontaneous GH secretion in comparison with vehicle-treated rats, as assessed by mean GH levels (means+/-s.e.m. 4.2+/-1.7 ng/ml vs 9.4+/-2.2 ng/ml; P<0.05), mean GH amplitude (3.6+/-0.5 ng/ml vs 20.8+/-5.6 ng/ml; P<0.01) and area under the curve (848+/-379 ng/ml per 4 h vs 1957+/-458 ng/ml per 4 h; P<0.05). In contrast, OX-A failed to modify in vivo GH responses to GHRH (10 microg/kg, i.v.) although it markedly blunted GH responses to ghrelin (40 microg/kg, i.v.) (mean peak GH levels: 331+/-71 ng/ml, vehicle, vs 43+/-11 ng/ml in OX-A-treated rats; P<0.01). Finally, OX-A infusion (10(-7), 10(-8) or 10(-9) M) failed to modify in vitro basal GH secretion or GH responses to GHRH, ghrelin and KCl. CONCLUSIONS: These data indicate that OX-A plays an inhibitory role in GH secretion and may act as a bridge among the regulatory signals that are involved in the control of growth, nutritional status and sleep regulation.
Quantitave and qualitative changes in vascular endothelial growth factor gene expression in glomeruli of patients with type 2 diabetes
Authors: Bortoloso E , Del Prete D , Dalla Vestra M , Gambaro G , Saller A , Antonucci F , Baggio B , Anglani F , Fioretto P
Published: January 2005

OBJECTIVE: Vascular endothelial growth factor (VEGF) exists in three main splice variants, characterized by 121, 165 and 189 amino acids (VEGF 121, VEGF 165 and VEGF 189) and acts via two specific receptors: VEGF-R1 or Flt-1 and VEGF-R2 or KDR. VEGF plays an important role in the pathogenesis of diabetic retinopathy. This study examined the relationship between VEGF and its isoforms and the severity of diabetic nephropathy in type 2 diabetes. DESIGN: We evaluated the glomerular gene expression of VEGF and its receptors and studied the relationships with renal functional and structural parameters in type 2 diabetic patients. METHODS: Glomeruli from 17 kidney biopsies were microdissected; 14 out of 17 biopsies were also subjected to electron microscopic morphometric analysis to estimate glomerular structural parameters. VEGF mRNA was studied by comparative kinetic RT-PCR and real-time RT-PCR in order to identify the three different isoforms and to quantify VEGF, VEGF-R1 and VEGF-R2 mRNA levels. RESULTS: (i) Glomerular VEGF mRNA levels were inversely related to albumin excretion rate (r=-0.66, P=0.004); (ii) both the degree of mesangial and mesangial matrix expansion were inversely related to VEGF 165 mRNA levels (r=-0.73, P=0.005 and r=-0.64, P=0.017), and directly to VEGF 121 mRNA levels (r=0.74, P=0.003 and r=0.73, P=0.004); and (iii) VEGF and VEGF-R2 mRNA levels were directly related (r=0.62, P=0.033). CONCLUSIONS: These findings suggested that quantitative and qualitative changes in VEGF expression are present in type 2 diabetic patients with nephropathy and might be involved in the pathogenesis and progression of diabetic glomerulopathy.
PPARgamma inhibits GH synthesis and secretion and increases apoptosis of pituitary GH-secreting adenomas
Authors: Bogazzi F , Ultimieri F , Raggi F , Russo D , Vanacore R , Guida C , Viacava P , Cecchetti D , Acerbi G , Brogioni S , Cosci C , Gasperi M , Bartalena L , Martino E
Published: January 2005

OBJECTIVE: The objective of the study was to evaluate the expression and functional activity of Peroxisome proliferator-activated receptor (PPAR) gamma in pituitary adenomas from 14 consecutive acromegalic patients and to establish its role in apoptosis. SUBJECTS AND METHODS: Fourteen consecutive acromegalic patients were enrolled in the study. Wistar-Furth rats were used for in vivo studies. Expression of PPARgamma was evaluated by RT-PCR and Western blot. Apoptosis and cell cycle were assessed by FACS analysis. The effects of PPARgamma ligands on transcriptional regulation of GH gene were evaluated by RT-PCR and electromobility shift assay. RESULTS: PPARgamma was expressed in all human GH-secreting adenoma (GH-oma), in normal pituitary tissue samples (39+/-24% and 78+/-5% of immunostained nuclei respectively; P<0.0002; ANOVA), and in rat GH-secreting (GH3) cells. A PPRE-containing reporter plasmid transfected into GH3 cells was activated by ciglitazone or rosiglitazone (TZDs), indicating that PPARgamma was functionally active. Treatment of GH3 cells with TZDs increased apoptosis in a dose-dependent manner (P=0.0003) and arrested cell proliferation, reducing the number of cells in the S-phase (P<0.0001 vs untreated cells). TZDs increased the expression of TRAIL, leaving unaffected that of p53 and Bax. TZDs reduced GH concentrations in the culture media from 43.7+/-5.4 ng/ml to 2.1+/-0.3 ng/ml (P<0.0001) and in cell extracts (P<0.004). PPARgamma-RXRalpha heterodimers bound to GH promoter, inhibiting its activity and reducing GH mRNA levels (1.8 x 10(6) vs 5.7 x 10(6) transcripts respectively vs untreated cells; P<0.002). Subcutaneous GH-oma developed in rats injected with GH3 cells; tumor growth increased in placebo-treated rats and to a lesser extent in TZDs-treated animals (24.1+/-2.0 g, and 14.8+/-4.2 g respectively, P<0.03). Serum GH concentrations were lower in TZDs-treated rats than in controls (871+/-67 ng/ml vs 1.309+/-238 ng/ml; P<0.05). CONCLUSIONS: The results of this study indicate that PPARgamma controls GH transcription and secretion as well as apoptosis and growth of GH-oma; thus, TZDs have the potential of a useful tool in the complex therapeutic management of acromegalic patients.
Adipogenic and orexigenic effects of the ghrelin-receptor ligand tabimorelin are diminished in leptin-signalling-deficient ZDF rats
Authors: Holm AM , Johansen PB , Ahnfelt-Ronne I , Romer J
Published: January 2005

OBJECTIVE: The aim was to investigate the possible interactions of the two peripheral hormones, leptin and ghrelin, that regulate the energy balance in opposite directions. METHODS: Leptin-receptor mutated Zucker diabetic fatty (ZDF) and lean control rats were treated with the ghrelin-receptor ligand, tabimorelin (50 mg/kg p.o.) for 18 days, and the effects on body weight, food intake and body composition were investigated. The level of expression of anabolic and catabolic neuropeptides and their receptors in the hypothalamic area were analysed by in situ hybridization. RESULTS: Tabimorelin treatment induced hyperphagia and adiposity (increased total fat mass and gain in body weight) in lean control rats, while these parameters were not increased in ZDF rats. Treatment with tabimorelin of lean control rats increased hypothalamic mRNA expression of the anabolic neuropeptide Y (NPY) mRNA and decreased hypothalamic expression of the catabolic peptide pro-opiomelanocortin (POMC) mRNA. In ZDF rats, the expression of POMC mRNA was not affected by treatment with tabimorelin, whereas NPY mRNA expression was increased in the hypothalamic arcuate nucleus. CONCLUSION: This shows that tabimorelin-induced adiposity and hyperphagia in lean control rats are correlated with increased hypothalamic NPY mRNA and decreased POMC mRNA expression. The elimination of tabimorelin-induced adiposity and hyperphagia in ZDF rats may be due to lack of POMC mRNA downregulation. In conclusion, we suggest that ghrelin-receptor ligands exert their adipogenic and orexigenic effects via hypothalamic mechanisms that are dependent on intact leptin-receptor signalling.
Glucocorticoid-dependent stimulation of adiposity and appetite by a ghrelin mimetic in the rat
Authors: Tung YL , Hewson AK , Dickson SL
Published: January 2005

OBJECTIVE: Chronic administration of GH secretagogues (GHSs) induces a state of positive energy balance in rodents by a GH-independent mechanism. Here we sought to determine to what extent the GHS effects to increase food intake and increase fat accumulation are glucocorticoid-dependent. DESIGN: The effects of twice-daily s.c. injections of GH-releasing peptide-6 (GHRP-6) (250 microg/kg) for 2 weeks on body weight, food intake and fat pad weight were determined in both adrenalectomised (ADX) rats (with or without basal corticosterone replacement) and adrenal-intact rats. RESULTS: All GHS-injected rats had a significantly increased body weight at the end of 2 weeks of treatment compared with saline controls. However, increased fat accumulation was only seen in adrenal-intact rats, with a 15% increase in s.c. inguinal (P<0.05 vs saline controls) and 20% increase in visceral mesenteric (P<0.05) fat pad weights following GHS treatment. The increased body weight observed in ADX rats following GHS treatment was not due to increased fat mass or increased weight of other organs measured. Food intake was increased for up to 7 h following a single injection of GHRP-6 in both the adrenal-intact (P<0.01) and corticosterone-replacement groups (P<0.05). This stimulating effect on food intake was not observed at any time point in the ADX rats without corticosterone replacement. CONCLUSION: These data suggest that GHS-induced body weight gain is glucocorticoid-independent. However, basal levels of glucocorticoids are permissive for the GHS-induced increase in food intake whilst activation of the hypothalamo-pituitary-adrenal axis appears to contribute to the GHS-induced accumulation of fat mass.
Recent advances in radiological and radionuclide imaging and therapy of neuroendocrine tumours
Authors: Kaltsas G , Rockall A , Papadogias D , Reznek R , Grossman AB
Published: January 2005

Neuroendocrine tumours (NETs) constitute a heterogeneous group of tumours that are able to express cell membrane neuroamine uptake mechanisms and/or specific receptors, such as somatostatin receptors, which can be of great value in the localization and treatment of these tumours. Scintigraphy with (111)In-pentetreotide has become one of the most important imaging investigations in the initial identification and staging of gastro-enteropancreatic (GEP) tumours, whereas helical computed tomography (CT), magnetic resonance imaging (MRI), endoscopic and/or peri-operative ultrasonography are used for the precise localization of GEPs and in monitoring their response to treatment. Scintigraphy with (123)I-MIBG (meta-iodobenzylguanidine) is sensitive in the identification of chromaffin cell tumours, although scintigraphy with (111)In-pentetreotide may also have a role in the localization of malignant chromaffin cell tumours and medullary thyroid carcinoma; for further localization and monitoring of the response to treatment both CT and MRI are used with high diagnostic accuracy. More recently, positron emission tomography (PET) scanning is being increasingly used for the localization of NETs, particularly when other imaging modalities have failed, although its precise role and utility remain to be defined. Surgery is still the usual initial therapeutic, and only curative, modality of choice; however, the majority of NETs will require further treatment with somatostatin analogues and/or interferon; chemotherapy may be used for progressive and highly aggressive NETs, but its role has not been clearly defined. For those NETs that demonstrate uptake to a diagnostic scan with (123)I-MIBG or (111)In-octreotide, therapy with radionuclides such as (131)I-MIBG or (111)In/(90)Y-octreotide or other isotopes, presents a further evolving therapeutic modality.
Short-term low-dose growth hormone administration in subjects with impaired glucose tolerance and the metabolic syndrome: effects on beta-cell function and post-load glucose tolerance
Authors: Yuen K , Wareham N , Frystyk J , Hennings S , Mitchell J , Fryklund L , Dunger D
Published: January 2005

OBJECTIVE: Modest elevations in circulating IGF-I levels have been suggested to protect against the development of glucose intolerance in insulin-resistant subjects. To further understand the interactions of GH and IGF-I on beta-cell function and post-load glucose tolerance in glucose-intolerant subjects predisposed to diabetes, we performed a pilot study in 12 subjects with impaired glucose tolerance and the metabolic syndrome using a low GH dose (1.7 microg/kg per day) known to increase endogenous IGF-I production. DESIGN: Fourteen daily GH or placebo injections in a double-blind cross-over study. METHODS: Baseline and post-treatment oral glucose tolerance tests were performed. The homeostasis model assessment and the insulinogenic index was used to estimate fasting insulin sensitivity (S(I)) and beta-cell function respectively, whereas changes in the incremental area under the curve were used to estimate post-load glucose tolerance (DeltaAUC(glu)) and post-load insulin levels (DeltaAUC(ins)). RESULTS: GH increased total IGF-I (P<0.02), free IGF-I (P<0.04) and fasting insulin (P<0.04) levels, but did not modify plasma IGF-binding proteins (IGFBPs)-1 and -3, fasting glucose, non-esterified fatty acid and C-peptide levels, and fasting S(I). After oral glucose intake, glucose tolerance improved (P<0.03), but post-load insulin levels and beta-cell function remained unchanged. CONCLUSION: Short-term low-dose GH administration induced fasting hyperinsulinaemia possibly by reducing insulin clearance but improved post-load glucose tolerance, suggesting that increased bioavailable IGF-I enhanced post-load S(I) without altering beta-cell function. Longer-term studies are required to ascertain whether these positive effects on post-load glucose tolerance and the preservation of beta-cell function can be sustained by this GH dose in these high-risk subjects.