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Leidet Ihr Patient unter Stimmungsschwankungen und sexueller Unlust? Und ist bei ihm zusatzlich ein metabolisches Syndrom bekannt? Dann sollten Sie einen Hypogonadismus abklaren und eine Testosteronsubsti­tution ins Auge fassen. Einer aktuellen Metaana­lyse zufolge profitieren adipose Manner mit metabolischen Storungen von Testosteron im Hinblick auf ihr kardiovaskulares Risiko.

Study objectives Recent evidence suggests that certain antidepressants are associated with an increase of periodic leg movements (PLMS) that may disturb sleep. So far, this has been shown in patients clinically treated for depression and in cross-sectional studies for various substances, but not mirtazapine. It is unclear whether antidepressants induce the new onset of PLMS or only increase preexisting PLMS, and whether this is a general property of the antidepressant or only seen in depressed patients. We report here the effect of mirtazapine on PLMS in young healthy men. Design Open-labeled clinical trial (NCT00878540) including a 3-week preparatory phase with standardized food, physical activity, and sleep-wake behavior, and a 10-day experimental inpatient phase with an adaptation day, 2 baseline days, and 7 days with mirtazapine. Setting Research institute. Participants Twelve healthy young (20-25 years) men. Interventions Seven days of nightly intake (22:00) of 30 mg mirtazapine. Measurements and results Sleep was recorded on 2 drug-free baseline nights, the first 2 drug nights, and the last 2 drug nights. Eight of the 12 subjects showed increased PLMS after the first dose of mirtazapine. Frequency of PLMS was highest on the first drug night and attenuated over the course of the next 6 days. Three subjects reported transient restless legs symptoms. Conclusions Mirtazapine provoked PLMS in 67% of young healthy males. The effect was most pronounced in the first days. The possible role of serotonergic, noradrenergic and histaminergic mechanisms in mirtazapine-induced PLMS is discussed.

Background: Multiple-endocrine-neoplasia-type-1 (MEN1) is an autosomal-dominant inherited disorder characterized by the combined occurrence of primary hyperparathyroidism (pHPT), gastroenteropancreatic neuroendocrine tumors (GEP), adenomas of the pituitary gland (APA), adrenal cortical tumors (ADR) and other tumors. As the tumors appear in an unpredictable schedule, uncertainty about screening programs is persisting. Objective: To optimize screening and to analyze possible differences in sporadic versus familial cases. Methods: We analyzed data of 419 individuals including 306 MEN-1 patients (138 isolated and168 familial cases out of 102 unrelated families). Results: A total of 683 tumors occurred consisting of 273 pHPT, 138 APA, 166 GEP, 57 ADR, 24 thymic- and bronchial-carcinoids as well as 25 neoplasms of other tissues. The age-related penetrance was determined as 10%, 35%, 67%, 81% and 100% at 20, 30, 40, 50 and 65 years respectively. Although pHPT being the most frequent first manifestation (41%), also GEP (22%) or APA (21 %) were found to be the first presentation. APA occurred significantly more frequent (p

Introduction: The association of thyroid disorders (TDs) and mood disorders is a well-investigated empirical finding. Although TDs are highly prevalent in patients with major depression (MD), the impact of TDs on treatment outcome has been sparsely investigated. Methods: Treatment Response was analyzed in 704 in-patients with MD participating in the Munich Antidepressant Response Signature (MARS) project, a large observational naturalistic psychopharmacological treatment study. TD was defined by thyroid hormone substitution, morphological thyroid gland abnormalities, or thyroid autoimmunity. Treatment response was measured by weekly Hamilton Depression Rating Scale (HDRS) assessments during 6 weeks. All patients were euthyroid at baseline. TSH levels were analyzed for potential prediction of treatment outcome. Results: MD patients with TD (n = 172) displayed a significantly impaired treatment outcome compared to MD patients without TD (n = 532) in response rates after 6 weeks (p = 7.4E-04), remission rate at discharge (p = 0.018) as well as in mean HDRS change after 6 weeks (p = 0.019). These differences were most pronounced under treatment with Serotonin Reuptake Inhibitors (SSRIs). TSH levels were not associated with treatment outcome. Discussion: Our results suggest that MD patients with comorbid TD may be at risk for impaired treatment outcome. Replication and substantiation of these findings could inform differential antidepressant therapy for these patients.

Objective: For patients in whom acromegaly persists despite pituitary surgery or drug treatment, gamma-knife surgery represents an additional treatment option. Considering carefully the different reported biochemical outcomes, the central point is whether gamma-knife radiosurgery has advantages compared to conventional radiotherapy or, furthermore, to newer medical therapies, such as long-acting somatostatin analogues or growth hormone receptor antagonists. Design and Methods: We report the outcome of 44 patients with acromegaly, who received gamma-knife surgery with the Leksell gamma knife. The median follow-up time was 1.9 years (0.5-4.3 years) post-radiosurgery. 43 of 44 patients had previously undergone pituitary surgery. Results: Immediately prior to gamma-knife surgery, median xULN of patients' serum IGF-I was 1.9 times above upper limit of normal (range: 0.5-8.9 xULN [multiple of upper limit of normal range]). There was a significant decline of serum IGF-I at patients' final follow-up. We found a normal age-adjusted IGF-I in 21/44 patients (xULN of IGF-I < 1). Furthermore, as the number of treated patients increased, we found an improvement in remission rate, which let us assume that there was a learning effect for the gamma-knife performing team over time. In addition, the median adenoma size decreased from 1.5ml (0.1-6.9 ml) prior to gamma-knife therapy to 0.3 ml (no rest vol. detectable -2.4 ml) at patients' last visit. Conclusion: We have shown that pituitary gamma-knife surgery is effective in lowering serum IGF-I levels. At the end of the follow-up period, 48% of our cohort had normal age-adjusted IGF-I levels.

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

Profound alterations of the hypothalamic-pituitary-thyroid (HPT) and the hypothalamic-pituitary-adrenal (HPA) systems at the hypophyseal level have been described in affective disorder. To precisely characterize the basal alterations of both axes during sleep, we simultaneously investigated sleep EEG and the secretion of thyrotropin, ACTH and cortisol in nine drug-free male patients with depression in comparison to 10 healthy age and sex matched controls. In depressed patients the nearly diametrical nocturnal secretion of thyrotropin and ACTH was disturbed by significantly blunted thyrotropin values (TSH AUC 51.96+/-5.68 vs. 87.23+/-13.63, P

OBJECTIVES: The case presented here describes the clinical evolution of a malignant prolactinoma with occurrence of intra- and extra-cranial metastases. In this case, the presence of dopamine 2 receptor (D2R) was studied at the mRNA and protein level, in order to understand the pathological background of the resistance to treatment with different dopamine agonists. DESIGN: Together with an extensive description of the clinical history of this case, a combination of in vitro and in vivo techniques was performed to provide the basis of the dopamine resistance developed in the course of the disease. METHOD: A comparison of the D2R was performed in specimens obtained at presentation of the disease compared with autoptic specimens derived from local invasion and metastasis using in situ hybridization and immunohistochemical techniques. RESULTS: Intact D2R mRNA was found in the primitive tumor and metastatic tissues, whereas protein for the same receptor was present only in the tissues derived from neurosurgical operations and not in the metastases obtained post-mortem. CONCLUSION: This is the first report of the absence of D2R protein despite the retention of the transcript in an advanced stage of a malignant prolactinoma. The findings of this single case suggest the hypothesis that postranscriptional mechanisms may contribute to the development of dopamine resistance in prolactinomas.

Impaired glucose tolerance and diabetes have been associated with depression, and antidepressant treatment is assumed to improve impaired glucose tolerance. However, antidepressant treatment is also considered as a risk factor for the development of diabetes. Reports about glucose tolerance under antidepressant treatment frequently lack appropriate control groups. We conducted the oral glucose tolerance test (OGTT) in 10 healthy controls selected from an epidemiological sample with a negative lifetime history of mental Axis I disorder. Controls were carefully matched to a sample of inpatients with major depression that participated in an OGTT before and after antidepressant treatment with mirtazapine. All participants underwent a standard OGTT protocol. In patients, a second (after 2 weeks) and a third (after 4-6 weeks) OGTT was performed under treatment with mirtazapine. Compared to healthy controls, we observed significantly impaired glucose tolerance in acutely depressed patients. Effect size calculation indicated a moderate to large effects on glucose and insulin concentrations in response to an OGTT. Although glucose tolerance improved under mirtazapine treatment, insulin sensitivity was still impaired and remained significantly lower in patients compared to controls.

Enhanced sialylation of thyrotropin (TSH) prolongs its metabolic clearance rate and thus increases the hormone's in vivo bioactivity. This has been shown for hypothyroid rats and for recombinant human TSH, but there are few data on the sialylation of human serum TSH. The aim of this work was to further study sialylated human serum TSH, its precursors bearing terminal galactose residues, and the role of pharmacological doses of thyrotropin-releasing hormone (TRH) on their secretion under different degrees of primary hypothyroidism. We analyzed serum TSH in patients with subclinical (n = 9) and overt primary hypothyroidism (n = 13) compared with euthyroid individuals (n = 12) and human standard pituitary TSH (IRP 80/558). Blood was drawn before and 30 min after intravenous administration of 200 micrograms TRH, and TSH was purified by immunoaffinity concentration. The content of sialylated (sialo-) TSH and isoforms bearing terminal galactose (Gal-TSH, asialo-Gal-TSH) was measured by Ricinus communis (RCA 120) affinity chromatography in combination with enzymatic cleavage of sialic acid residues. TSH immunoreactivity was measured by an automated second generation TSH immunoassay. Pituitary TSH contained 16.5 +/- 0.8% Gal-TSH. In euthyroid individuals the proportion of Gal-TSH was 14.6 +/- 1.9%, whereas TSH in patients with subclinical and overt primary hypothyroidism contained 23.9 +/- 3.5% (P < 0.05 vs euthyroid individuals) and 21.1 +/- 1.7% Gal-TSH respectively. The mean ratio of asialo-Gal TSH was 23.8 +/- 0.6% for pituitary TSH, 35.7 +/- 4.2% in euthyroid individuals, 48.0 +/- 3.3% in patients with subclinical, and 61.5 +/- 3.8% (P < 0.001 vs euthyroid individuals) in patients with overt primary hypothyroidism. For pituitary TSH the calculated proportion of sialo-TSH was 6.5 +/- 0.2%, for euthyroid individuals 20.3 +/- 2.8%, for patients with subclinical hypothyroidism 24.1 +/- 3.0%, and for patients with overt primary hypothyroidism 40.7 +/- 3.0% (P < 0.001 vs euthyroid individuals). The proportions of Gal-TSH, asialo-Gal-TSH, and sialo-TSH did not differ significantly before and after TRH administration in the individuals studied. Our data show that patients with subclinical and overt primary hypothyroidism have a markedly increased proportion of serum TSH isoforms bearing terminal galactose and sialic acid residues, which may represent a mechanism for the further stimulation of thyroid function. Pharmacological doses of TRH cause an increased quantity of TSH to be released, but do not significantly alter the proportion of sialylated or terminally galactosylated TSH isoforms.

The purpose of this study was to assess, in relation to metabolic control, the cognitive, depressive, and anxiety symptoms among 40 adult patients (age: 18-60 years) with either type 1 (n = 28) or type 2 (n = 12) diabetes mellitus (DM1, DM2). Nineteen healthy subjects matched for age, gender, and education served as the control group. For most cognitive domains, no significant performance differences were found between subjects from the diabetic groups and control subjects. However, diabetes patients demonstrated reduced information processing accuracy along with impaired visual and verbal working memory performance. In addition, psychopathology scores were significantly elevated but did not reach the clinical criteria for depression or anxiety. Overall, there were no significant differences between diabetic subgroups, and no significant correlation was found between cognitive performance, psychopathology scores, and HbA1c values for either subgroup. Thus, patients with DM1 or DM2 may show mild-to-moderate cognitive impairment as well as subtle psychopathological symptoms. While cognitive impairments may be understood in terms of diabetes-associated cognitive dysfunction, psychopathological symptoms may also result from unsuccessful coping with high task demands in everyday life activities. The outcome of the current study underscores the importance of early clinical neuropsychological standardized assessment as well as the diagnosis of cognitive and psychopathological symptoms in adult patients with diabetes.

Objective In multiple endocrine neoplasia type 1 (MEN1), age-related tumour penetrance according to the type of MEN1 germline mutation has not been investigated in-depth. This study was conducted to examine whether carriers of out-of-frame/truncating and in-frame MEN1 mutations differ in age-related tumour penetrance. Design A multicentre study with biochemical, hormonal and radiological screening for MEN1-associated tumours. Patients A total of 258 MEN1 carriers from six major German tertiary referral centres averaging 43 years of age at last follow-up. Measurements Main outcome measure was time to first diagnosis of MEN1-associated tumours. Results Independent of the year of birth and observation period, time to first tumour diagnosis did not vary much by the type of MEN1 germline mutation or endocrine organ system, and perhaps not even by the type of endocrine tumour when the amount of time was considered by which the diagnosis probably has been advanced through the manifestation of hormonal symptoms. Parathyroid hyperplasia and adenomas developed almost twice as often as enteropancreatic and pituitary tumours (77% vs. 49-32%), and more than five to sevenfold as often as adrenal cortical tumours and carcinoids (77% vs. 15-10%), reaching penetrance rates of up to 90%, 60%, 40%, 26% and 17%, respectively. The heterogeneity of tumour penetrance was marked, ranging from 9 years to 25 years for the earliest, and from 68 years to 77 years for the latest tumour manifestation. Conclusions Because of our inability of predicting tumour penetrance and malignant transformation individually, life-long follow-up of MEN1 carriers is warranted to prevent tumour morbidity.

Objective: Patients with traumatic brain injury (TBI) are at moderate risk of GH deficiency (GHD), requiring a diagnostic test with high specificity. The GHRH + arginine (GHRH + ARG) test has been recommended as a reliable alternative to the insulin-tolerance test (ITT) as a standard test with a cutoff level of 9 ng/ml. However, it has recently been questioned for its low specificity in obese subjects, and now BMI-dependent cut-off levels are available. In this study, we compared the ITT and GHRH + ARG test in patients with TBI. Design: A cross-sectional study Methods: We performed an ITT and a GHRH + ARG test in 21 patients with TBI (6 women, 15 men; mean age 40.2 ± 12.1 years; BMI 30.7 ± 6.2). The number of patients classified discordantly as GH deficient by the ITT and the GHRH + ARG test with both classical and BMI-dependent cut-off levels was assessed. Results: Using the GHRH + ARG test with the classical cut-off (≤ 9 ng/ml), we identified 12 patients as GH deficient who had a normal GH response to ITT (> 3 ng/ml), and one patient as GH sufficient who had a blunted GH response to ITT (discordance rate 61.9%). All patients discordantly classified as GH deficient by the GHRH + ARG test had a BMI of ≥ 28. With the BMI-dependent cut-offs (4.2, 8.0, and 11.5 ng/ml in obese, overweight, and lean subjects respectively), only 3 of the 21 patients were discordantly classified (discordance rate 14.3%). Conclusions: Our results discourage the use of a cut-off level of 9 ng/ml for the GHRH + ARG test in obese subjects. The diagnostic reliability of this test is improved with the BMI-dependent cut-offs.

Members of the Toll receptor (Tlr) family have a crucial role in the innate immune response following bacterial infection. The effects of Gram-negative bacteria-derived endotoxins (lipopolysaccharide, LPS) are predominantly mediated by Tlr4, and we have recently shown that pituitary folliculostellate cells express functional Tlr4. In the present study, we investigated whether Tlr4 is also present in normal and transformed endocrine epithelial pituitary cell types. By reverse transcriptase-polymerase chain reaction, Tlr4 mRNA expression was found in some pituitary epithelial tumour cell lines (AtT20, HP75), whereas others were negative (GH3, αT3-1). Tlr4 protein was detected by immunohistochemistry in a few epithelial cells in normal human anterior pituitaries and in 26 out of 67 human pituitary tumours analysed. LPS had no effect on adrenocorticotropic hormone secretion in Tlr4-positive AtT20 cells, but it suppressed the growth of these cells in a dose-dependent manner. As expected, neither hormone secretion, nor growth of Tlr4-negative GH3 cells was affected by LPS. In cell cultures of Tlr4-positive pituitary adenomas, LPS dose-dependently stimulated the production of interleukin (IL)-6, which is known to induce growth and hormone production in pituitary tumours. The LPS-induced IL-6 production was blocked by the specific p38αMAP kinase inhibitor, SB203580, and by the synthetic glucocorticoid, dexamethasone. The data suggest that, during Gram-negative bacteria-induced infections or inflammatory processes, LPS could affect pituitary tumour pathophysiology and progression in the subset of Tlr4-expressing pituitary adenomas. © 2005 Blackwell Publishing Ltd.

The oncogenic effects of epidermal growth factor (EGF) have long been established. EGF receptor (EGFr) is overexpressed in many types of tumors and constitutes a target for cancer treatment. The pituitary gland is a target of EGF action and it is very likely that EGFr plays a role in pituitary tumor formation and progression. However, there is a controversy in the literature concerning EGFr expression in the different types of pituitary adenomas. In the present study we investigated the expression pattern of the wild type EGFr (EGFrWT) and the constitutively active variant III (EGFrvIII) at the mRNA and protein levels in a large series of pituitary tumors. EGFrWT was found in a high percentage of hormone-secreting tumors, but only in a small fraction of non-functioning pituitary adenomas, while no expression of the EGFrvIII could be detected by nested RT-PCR in any tumor. Among the hormone-secreting adenomas, the highest incidence of EGFr expression was found in Cushing’s pituitary adenomas. Furthermore, immunohistochemistry for the phosphorylated EGFr revealed the presence of activated EGFr in most Cushing’s adenomas, compared with most pituitary adenomas. Taking into account that downregulation of p27/Kip1 plays a significant role in corticotrope tumorigenesis and that EGFr mitogenic signaling results in decreased p27/Kip1, we searched for a correlation between EGFr expression and p27/Kip1 levels in corticotropinomas. Low p27/Kip1 immunoreactivity was observed in corticotropinomas expressing EGFr. On the other hand, somatotropinomas expressing EGFr had high p27/Kip1 immunoreactivity. These data suggest a corticotrope-specific phenomenon and indicate that EGFr may have a role in the unbalanced growth of corticotrope tumoral cells.

It is well established that depressed patients show a blunted TSH response in the TRH-stimulation test. However, it has not been investigated so far whether pre-treatment with 3,5,3'-triiodothyronine (T3) is able to further suppress the TRH-induced TSH response in depressed patients or whether it may cause an escape-phenomenon with paradoxically enhanced TSH stimulation in a subsequent TRH test. In 20 drug-free depressed patients (eight men, 12 women) suffering from a major depressive episode according to DSM-IV criteria and in 20 age- and sex-matched healthy controls, the single TRH-stimulation test (administration of 200 microg TRH at 09:00 h) was carried out followed by a combined T3/TRH test (pre-treatment with 40 microg T3 at 23:00 h the night before; administration of 200 microg TRH at 09:00 h the next day). Compared to the controls, the depressed patients showed a significantly blunted TSH response in the single TRH test. However, the percentage suppression of TRH-induced TSH stimulation after pre-treatment with 40 microg T3 was comparable in the depressive patients (61.07%) and the healthy volunteers (64.20%). Prolactin secretion did not differ between patients and controls either in the single TRH test or in the combined T3/TRH test. Apparently, in contrast to the hypothalamo-pituitary-adrenocortical (HPA) system, no disturbance of feedback control in regulation of the hypothalamo-pituitary-thyroid (HPT) axis secretion can be demonstrated in depressed patients when using the combined T3/TRH test.

Estrogens are considered to be critically involved in lactotroph and lactosomatotroph pituitary tumor development. In addition to direct effects, estradiol-induced tumor formation may involve alterations in growth factor and cytokine production. We have studied whether estradiol stimulates the production of the angiogenic vascular endothelial growth factor and the potential tumor progression factor interleukin-6 in 5 lactotroph (LA) and 5 lactosomatotroph (LSA) human pituitary adenoma cell cultures. All tumors secreted heterogenous basal amounts of VEGF (18.0 +/- 1.4 to 425 +/- 26 pg/ml per 24 h) and IL-6 (18.1 +/- 1.5 to 604 +/- 17 pg/ml per 24 h). Estradiol (100 nM) significantly enhanced VEGF release in all LA and LSA cell cultures (47 to 168 % above basal). IL-6 secretion was stimulated in 3 out of 5 LA and in all LSA cell cultures (31 to 287 % above basal). In cell cultures obtained from tumors from which sufficient cells could be isolated, a dose-dependent effect of estradiol (1 to 100 nM) on VEGF and IL-6 production was observed. Stimulation of IL-6 and/or VEGF secretion by estradiol in the majority of human lactotroph and lactosomatotroph adenoma cell cultures studied, suggests that estrogens may contribute to adenoma expansion through the stimulation of these auto-/paracrine-acting adenoma progression factors.

TGF-beta isoforms are expressed in the anterior pituitary and modulate the growth and function of endocrine pituitary cells. Recently, TGF-beta has been shown to stimulate growth and basic fibroblast growth factor secretion in nonendocrine folliculostellate (FS) pituitary cells. We therefore studied whether the production of FS cell-derived vascular endothelial growth factor (VEGF), the most important regulator of vascular permeability and angiogenesis, is affected by TGF-beta. We observed by RT-PCR that TtT/GF cells, which are FS mouse pituitary tumor cells, synthesize TGF-beta1, -beta2, and -beta3. They also express TGF-beta receptors types 1 and 2, as well as Smad2, Smad3, and Smad4 proteins, which are essential for TGF-betabinding and signaling. Stimulation of TtT/GF cells with either TGF-beta1 or TGF-beta3 induced a rapid translocation of Smad2 into the cell nuclei. Both TGF-beta isoforms dose dependently stimulated VEGF production in TtT/GF cells, but not in lactosomatotroph GH3 cells. Time-course studies and suppression of TGF-beta-induced VEGF production by cycloheximide suggest that TGF-beta induces de novo synthesis of VEGF in folliculostellate cells, which is completely blocked by dexamethasone. In primary rat pituitary cell cultures, TGF-beta1 and -beta3 stimulated VEGF production. TGF-beta stimulation of VEGF production by folliculostellate cells could modulate intrapituitary vascular permeability and integrity as well as angiogenesis in an auto-/paracrine manner.

The recent identification of MEN1 gene mutations as the molecular cause of familial multiple endocrine neoplasia type 1 syndrome (MEN1) has had a significant impact on clinical patient care. In the following consensus statement we will present recommendations for clinical screening and follow-up in patients and relatives with suspected or established MENI syndrome. MENI mutational analysis should be performed in individuals with newly diagnosed MEN1-typical endocrine neoplasia (e.g., primary hyperparathyroidism, gastroenteropancreatic tumor, pituitary adenoma) if additional diagnostic criteria are met (e.g., age

Thyrotropin (TSH) is secreted not as one distinct hormone, but rather as a group of isohormones which differ in their oligosaccharide composition. Although the mechanisms regulating TSH glycosylation are not fully understood, there is strong evidence that TRH plays an important role. The aim of our study was to determine the dynamic influence of TRH on TSH microheterogeneity. Sera were obtained from euthyroid volunteers (n=20) before and 30, 60, 120, 180 and 240 min after intravenous, nasal and oral administration of TRH in three independent runs (randomized order, at a time-interval of 3 weeks between each run). TSH was immuno-concentrated and analysed by isoelectric focusing (IEF) and lentil lectin affinity chromatography. TSH immunoreactivity was measured by an automated second-generation TSH immunoassay. Overall, serum TSH concentrations reached maximal values 30 min after intravenous, 60 min after nasal and 180 min after oral TRH stimulation. IEF analysis revealed 63.3+/-3.3% of pituitary standard TSH (IRP 80/558) in the neutral pH range (8>pH>6). In contrast, 30 min after TRH stimulation 80.8+/-3.7% (P

NGF has anti-proliferative and anti-invasive effects in neuroendocrine tumors. In the present work we examined the effects of NGF and retinoic acid on cell proliferation and invasion in thyroid carcinoma cells. We found that NGF and retinoic acid do not affect cell proliferation on their own but in combination they produce a strong inhibition. We also found that retinoic acid regulates the matrix metalloproteinase 2 activity and invasion. In contrast, NGF inhibited invasion and reverted the effect of retinoic acid. This effect of NGF is likely mediated by an increase in adhesion to laminin and collagen IV and the inhibition of cell migration. NGF also induced the expression of the p75 NGF receptor. In conclusion, NGF and retinoic acid in combination inhibit proliferation and invasion of thyroid papillary carcinoma cells. These data open the possibility of a potential combined therapy for thyroid papillary carcinomas.

We investigated whether subclinical hyperthyroidism [subnormal basal thyroid-stimulating hormone (TSH) level, attenuated TSH response to thyrotropin-releasing hormone (TRH) stimulation, peripheral thyroid hormones within normal range] is accompanied by physical and mental changes. Thirty-five subclinically hyperthyroid patients (27 female, 8 male) were compared with 60 overtly hyperthyroid patients (51 female, 9 male) and with 28 euthyroid control patients (18 female, 10 male) with respect to physical symptoms, affective state, short-term memory, ability to concentrate and psychomotor performance. Patients with subclinical hyperthyroidism ranged between the other two groups. The major difference between controls and subclinically hyperthyroid patients was an increase in frequency of nervous symptoms and symptoms due to an increase of metabolic rate and thermal regulation changes. The major differences between subclinically hyperthyroid and overtly hyperthyroid patients were psychomotor impairment and symptoms of increased metabolic rate. Self-ratings of affective state tended to be similar in patients with subclinical and overt hyperthyroidism. The ability to concentrate and short-term memory were not impaired in any group. Symptoms in patients with subclinical hyperthyroidism probably result from central changes which lead to attenuated TSH responses to TRH, or from elevated but still normal thyroxine levels, which possibly enhance the effect of catecholamines.

The significance of intrathyroidal lymphocytic infiltration is not known. However, several indirect lines of evidence suggest that interstitial or intraepithelial lymphocytes are the effector or thyroid autoantibodyproducing lymphocytes in Graves' disease. This has not been investigated in vivo. Changes of nuclear volume of endocrine cells have previously been shown to be a reliable parameter of functional stimulation of endocrine glands. Therefore we investigated this parameter near and off lymphocytic aggregates, loosely distributed plasma cells and memory T cells in paraffine sections of Graves' disease thyroid glands. In 21 Graves' disease thyroid glands we found significant increases of thyroid epithelial cell nuclear volume near plasma cells (198.4 μm3) as well as near lymphocytic aggregates (219.1 μm3) compared with thyroid epithelial cell nuclear volume one microscopic field away (160.1 and 137.7 μm3 respectively). Similar nuclear volume differences were observed after propanolol and thiourelene antithyroid drug treatment. These nuclear volume differences could not be observed in 10 control thyroid glands and around CD45R0-positive memory T cells in Graves' disease thyroid glands. These direct in vivo investigations of regional functional stimulation of thyroid epithelial cells in Graves' disease show local stimulation near lymphocytic aggregates and diffusely distributed plasma cells. Therefore our in vivo data do not permit to identify stimulatory lymphocytes only interstitially or intraepithelially as previously suggested.

Impaired glucose tolerance is observed in depressed patients, and patients suffering from depression have an increased risk to develop diabetes mellitus. In depressed and diabetic patients, studies have shown both a beneficial effect of antidepressants on glucose homeostasis and the opposite. This review aims to structure the conflicting data and focuses on the question, which effect specific antidepressants have on glucose homeostasis. We therefore performed a systematic review of all available studies referenced in Medline from 1960 to 2011. We included antidepressant agents indexed in the Anatomical Therapeutic Chemical (ATC) classification system of the WHO in 2011 and searched for studies investigating their effects on glucose metabolism in clinical samples as well as in healthy subjects. Of 876 studies screened we included 66. Most studies had small sample sizes and lacked a placebo group limiting conclusions about antidepressant effects on glucose tolerance. However, some evidence points to beneficial effects on glucose homeostasis of hydrazine-type monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors (SSRIs). In case of SSRIs, the effect is more pronounced in diabetic patients or patients with comorbid depression and diabetes mellitus. Noradrenegic substances (and possibly also dualacting antidepressants), in contrast, may deteriorate glucose tolerance. They can be used in depressed patients when favorable effects on mood outweigh adverse metabolic effects, but in depressed diabetics this can be at the expense of worsening of glycemic control. The effects of other antidepressants, like bupropione, mirtazapine or newer agents, require further investigation before reliable conclusions can be made. The synthesis of the findings is discussed in light of the specific pharmacodynamic properties of the antidepressants as well as the pathophysiological changes in depression and impaired glucose homeostasis, including animal studies.