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Thyroid autoimmunity (TAI) appears to play a crucial role in female infertility, recurrent pregnancy loss and IVF failure. Thyroid autoantibodies against thyroid peroxidase and thyroglobulin have been shown to represent an independent risk factor for infertility and miscarriage. Moreover, thyroxin hormone administration reduces the risk of obstetrical complications in TAI positive women. The aim of our present study was to investigate the immunological background of female infertility and recurrent pregnancy loss in euthyroid and subclinical hypothyroid women with TAI focusing on innate immunity. Phenotypic and functional analysis was carried out on peripheral blood mononuclear cells from healthy donors and TAI patients by flow cytometry. Our findings show Th1 oriented changes of innate immunity in the peripheral blood of women suffering from thyroid autoimmunity. Elevated NK and NKT-like cells ratios and enhanced natural cytotoxicity of TAI positive women reveal an altered immune status with possible negative impact on pregnancy outcome. It is important to notice that immune alterations are already established in the euthyroid phase of autoimmune thyroiditis before endocrine dysfunction develops and only the presence of thyroid autoantibodies indicate TAI condition. For this reason, screening of healthy women of reproductive age for the presence of thyroid autoantibodies would be beneficial not only from the endocrinological aspect but from the reproductive point of view since, although yet unexplained, thyroid hormone administration may improve pregnancy outcome.

Background: Metyrapone is a steroidogenesis inhibitor approved in Europe for the treatment of endogenous Cushing’s syndrome (CS) based on observational retrospective studies published over more than 50 years. We present data from the first prospective study designed to confirm metyrapone efficacy and good tolerance in patients with CS. Methods: This single arm, open-label, multicenter, international trial enrolled 50 patients with CS who had three baseline 24 hours urine free cortisol (UFC) values at least 50% above the upper limit of normal (ULN=165 nmol/24h). Metyrapone was titrated over 12 weeks (W12) to achieve normal urine (mean of 3 values, mUFC) and serum cortisol levels. Patients whose mUFC did not exceed 2-fold the ULN could enter a 6-month extension period. The primary efficacy endpoint was the proportion of patients with mUFC ≤ ULN at W12 assessed in a central laboratory using LC-MS/MS. The most important secondary endpoint was mUFC decrease of ≥ 50% at W12. Results: At baseline: mean age was 47 years, median mUFC (range) was 570 (291 - 8476) nmol/24h (3.5 x ULN). Hypercortisolism was in 96% of patients either moderate (mUFC ≥ 2xULN; < 5x ULN) in 63% or severe (≥5 x ULN) in 33%. Hypertension (69%) and diabetes mellitus (47%) were the most common comorbidities. At W12: 47% (23/ 49) met primary endpoint. Another 40% (19 / 49) had mUFC ≤ 2xULN. Median percentage decrease in mUFC from baseline to W12 was -74%. Secondary endpoint was met by 80% of patients who had a mUFC decrease of 50%. Final median metyrapone dose was 1500 (250; 5500) mg/day. Physical signs and symptoms were normalized or improved in 66% of patients. Circulating cholesterol, HbA1C and fasting glucose and insulin improved with median decrease of 12%, 3%, 5% and 9% respectively and median systolic and diastolic blood pressure also decreased by 4 and 5mmHg respectively. Among patients with antihypertensive treatments, 10 (31%) had a decrease in number of drugs and 5 (16%) had an increase in number of drugs during the study. Median ACTH increased by 11 % from baseline. Twenty six (52%) patients experienced mild to moderate study drug related adverse events (AEs). One patient discontinued before W12 because of an unrelated SAE on day 2 (pneumonia with septic shock). The most common AEs were nausea (24%), decreased appetite (18%), fatigue (14%), headache (10%), peripheral edema (6.0%), hypokalemia (6.0%) and hypertension (6.0%). Reversible adrenal insufficiency occurred in 6 (12%) patients. Few patients 14% (7/50) experienced at least one AE that led to a dose interruption or dose adjustment. Cushing Quality of Life Questionnaire increased of 10 points from baseline which is close to minimal clinically important difference = 10.1. Conclusions: This prospective study in patients with CS confirms that metyrapone effectively lowers UFC levels with a tolerability profile similar to the previously reported safety profile and improves QoL, at Week 12.

Post-traumatic hypopituitarism is a major complication after severe head trauma. The aim of our study was to evaluate the possible role of early clinical parameters in the development of endocrine deficits. Data on endocrine function, on-admission clinical-, laboratory-, and ICU-monitored parameters were available in 63 patients of the surviving 86 severe head injury patients (post-resuscitation GCS under 8) treated at one neurosurgical center during a 10-year period. Hypopituitarism was diagnosed in 68.3 % of the patients. The most frequently affected pituitary axis was the growth hormone (GH): GH deficiency or insufficiency was present in 50.8 %. Central hypogonadism affected 23.8 % of male patients; hypothyroidism and secondary adrenal failure were found in 22.2 and 9.5 % of the investigated population, respectively. Early onset (within 1 year of brain injury) hypopituitarism was found in 24 patients. No connection was found between the development of hypopituitarism and any of the clinical parameters assessed on-admission or at ICU. Significant correlations were found between early endocrine dysfunctions and surgical intervention (OR: 4.64) and the diagnosis of subdural hematoma (OR: 12). In our population, after road traffic accidents, the development of late-onset hypopituitarism was less prevalent (OR: 0.22). Since our results do not indicate any reliable predictive parameter for the development of endocrine dysfunction in a cohort of patients with severe traumatic brain injury, regular endocrine screening of this specific patient population seems obligatory.

Thyroglobulin (Tg) is the most important tumor marker in differentiated thyroid cancer (DTC). The aim of this study was to assess the diagnostic and prognostic roles of postoperative stimulated and postablative lowest, highest, and one-year non-stimulated Tg values obtained during the follow-up of patients with DTC. In this retrospective study, 222 radioiodine-treated, anti-thyroglobulin antibody (TgAb)-negative DTC patients having at least 9 months&rsquo, follow-up time were included (172 papillary and 50 follicular cancers, median age: 48 (from 15 to 91) years, female&ndash, male ratio: 158/64, median (quartiles) follow-up time: 54 (22&ndash, 97) months). The 2015 American Thyroid Association guidelines were applied as criteria of the therapeutic response. Postoperative stimulated Tg values had significantly lower diagnostic accuracy than any of the non-stimulated postablative Tg values. One-year non-stimulated Tg had excellent prognostic value for structural disease: a cut-off value of 0.85 ng/mL had an 88.1% diagnostic accuracy. If the Tg value did not decrease below 0.75 ng/mL at any time during follow-up, the risk of residual disease was 25 times higher. The highest non-stimulated Tg during follow-up was the best predictor of residual disease (e.g., a Tg value exceeding 7.7 ng/mL indicated a 30-fold increase in risk). Non-stimulated Tg values measured during follow-up have excellent diagnostic accuracy to predict structural disease in DTC patients. The risk classification of a patient can safely be modified based on even a single Tg measurement.

Acromegaly is a rare disease with typical clinical manifestations. Untreated acromegaly carries a 2-4-fold increase in mortality in long-term outcome. The goal of treatment is double, including biochemical control of the disease (normalization of serum IGF1 levels compared to age and gender matched controls, GH levels below 1 ng/ml after oral glucose load, or random GH below 2.5 ng/ml) and control of the tumor mass. The therapeutic modalities currently available for the treatment of acromegaly are: surgery, medical therapy, radiation therapy and their combinations. The cornerstones of medical therapy in acromegaly are the somatostatin receptor ligands due to their effectiveness in controlling GH excess in 60-70 % of patients and their beneficial effects on tumor volume. Somatostatin analogues have an established role as adjuvant therapy after non-curative surgery, and evidence suggests their use as primary treatment for selected patients. The long-term use of somatostatin receptor ligands is safe and they are well tolerated. Future medical therapy consists of pasireotide, a novel, universal somatostatin receptor agonist, and a new class of drugs named dopastatins. The latter so-called chimeric molecules have strong affinity for somatostatin receptors and dopamine-2 receptors, resulting in a more effective blocking of GH secretion, according to preliminary data. The authors of this paper review the current medical therapy of acromegaly, focusing on the role of somatostatin receptor ligands. Orv. Hetil., 2011, 152, 715–721.

The oxidative processes (oxygen consumption, superoxoid anion generation, arachidonic acid cascade) of human polymorphonuclear granulocytes (PMNs) obtained from patients suffering from thyroid disorders of autoimmune origin (Graves' disease and Hashimoto's thyroiditis), and non autoimmune origin (toxic adenoma) were investigated. All Graves' and toxic adenoma patients were hyperthyroid. Hashimoto's thyroiditis patients were euthyroid. Healthy age and sex matched volunteers served as controls. The results are as follows: 1) In PMNs from both hyperthyroid groups (Graves' disease and toxic adenoma), independently from the autoimmune origin of the disease, a significantly increased Antimycin A sensitive mitochondrial oxygen consumption and a slightly increased superoxide anion generation were detected. 2) In both autoimmune thyroid disease groups (Graves' disease and Hashimoto's thyroiditis)--depending on the functional state of the thyroid gland--a significantly altered intracellular killing activity was measured. 3) An increased arachidonic acid cascade--triggered by opsonized zymozan (OZ)--was detected in both autoimmune thyroid diseases. The increased arachidonic acid cascade was sensitive to phospholipase A2 inhibiting Mepacrin treatment. 4) The PMNs from both autoimmune thyroid diseases produced large amount of leukotriens (LTs)--LTC4 and LTB4--after stimulation through their Fc receptors but the synthesis of prostagalandins (PGs) has not changed. There are no data indicating local, specific effects of circulating leukotriens in the thyroid gland itself, but based on authors' data, their general, regulating role on both the endocrine-- as well as on the immune system--seems to be plausible.

In Graves' ophthalmopathy (GO), only patients with immunologically active disease respond to immunosuppressive therapy. Previous studies and theoretical considerations suggest that elevated orbital (99m)Tc-diethylenetriamine-pentaacetic-acid (DTPA) single photon emission computed tomography (SPECT) reflects inflammatory disease activity. We studied whether corticosteroid treatment causes a substantial decrease in DTPA uptake in GO, a result consistent with successful immunosuppressive treatment of GO and referred to as a favorable treatment outcome.One hundred fourteen orbits in 57 patients with active GO (CASor= 4) were entered into the study. All patients received corticosteroid treatment. Orbital DTPA uptakes were numerically quantified for the entire orbit as well as the anterior and posterior segments separately. DTPA SPECT was performed before, and 2 to 9 months after the initiation of immunosuppressive treatment. The normal range for DTPA uptake was established in 34 orbits of 17 patients who were being worked up for Raynaud's phenomenon and had no thyroid disease.The mean DTPA uptake of the 114 orbits of GO patients was higher prior to corticosteroid therapy than after this treatment (11.03 +/- 4.26 MBq/cm(3) and 9.84 +/- 3.51 MBq/cm(3), respectively, p0.001) but a substantial decline in DTPA uptake was seen in only 39.5% of GO patients. The positive predictive value of an initial DTPA12.28 MBq/cm(3) for a substantial decline in DTPA uptake (favorable treatment outcome) was 76%, while a negative predictive value of a pretreatment DTPAor=12.28 MBq/cm(3) was 78%.Corticosteriod treatment is associated with a decline in DTPA uptake in a fraction of GO patients. GO patients with a DTPA uptake above 12.28 MBq/cm(3) are more likely to have a favorable response to corticosteroid therapy while patients with lower values are less likely to have this potentially favorable response. An elevated DTPA uptake may identify patients who are most likely to benefit from immunosuppressive treatment.

UNLABELLED: The relationship between resistin, one of the adipokines, and metabolic syndrome is not fully elucidated. Altered activity of the HDL-associated antioxidant enzyme paraoxonase 1 (PON1) that participates in the antioxidant defense mechanisms of HDL may have an important role in the obesity-related accelerated atherosclerosis. Inverse associations of PON1 with obesity and serum levels of leptin have been demonstrated. Our aim was to investigate the association of serum levels of resistin with (i) PON1 activity, and (ii) parameters of metabolic syndrome, including some that are additional for research. A total of 74 Caucasian subjects were recruited into the study and divided into 3 age and sex-matched groups. Group 1, 25 non-diabetic overweight/obese subjects with BMI of 28-39.9 kg/m (2); group 2, 25 non-diabetic obese patients with BMI >or=40 kg/m (2); and the control group 3, 24 healthy, normal-weight control subjects. Serum levels of resistin were correlated negatively with BMI (r=-0.27, P

Background: A novel oral octreotide formulation was tested for efficacy and safety in a phase III, multicenter, open-label, dose-titration, baseline-controlled study in patients with acromegaly. Methods: We enrolled 155 complete or partially controlled patients (IGF-1 Results: Of 151 evaluable subjects initiating OOCs, 65% maintained response and achieved the primary endpoint of IGF-1 Conclusions: OOC, an oral therapeutic peptide, achieves efficacy in controlling IGF-1 and GH after switching from injectable SRLs for up to 13 months, with a safety profile consistent with approved SRLs. OOC appears to be effective and safe as an acromegaly monotherapy.

There is increasing awareness among physicians of the risks of traumatic brain injury (TBI)-induced hypopituitarism. We have assessed the prevalence and risk factors of post-traumatic hypopituitarism by analyzing the TBI database of the University of Pecs.This consecutive analysis of 126 TBI survivors (mean age: 42.4 years, average follow-up time: 48 months) revealed that 60.3% had severe and 39.7% moderately severe trauma based on GCS score. Subdural hemorrhage (29.3%) and diffuse injury (27%) were the most common types of injury; 17.5% of patients suffered basal skull fractures.The prevalence of major anterior pituitary failure was 57.1%. Occurrence of total and partial growth hormone deficiency (GHD/GHI) was 39.7%, while LH/FSH, TSH and ACTH deficiencies were less frequent, namely 23.0%, 16.7% and 10.3%, respectively. Of the 82 patients with multiple endocrine evaluations, 31.7% presented significant changes in hormonal deficiencies during the follow-up period: new hormone deficiencies developed in 16 patients, while hormonal disturbances resolved in 10 subjects. Looking for factors influencing the prevalence of pituitary dysfunction, endocrine results were analyzed in relation to age, gender, GCS scores, injury types, basal skull fracture, ventricular drain insertion and necessity of neurosurgical intervention. All hormonal disturbances were more prevalent after severe trauma (OR: 3.25, p=0.002), while the need for surgery proved to be an independent determinant of multiple and GH deficits (OR: 3.72 (p=0.004) and 9.33 (p=0.001)).Post-traumatic hypopituitarism is common and may evolve or resolve over time. Victims of severe TBI and/or patients who have undergone neurosurgical intervention for head injury are the most prone to post-traumatic hypopituitarism.

Traumatic brain injury (TBI) is the leading cause of death and disability in the young, active population and expected to be the third leading cause of death in the whole world until 2020. The disease is frequently referred to as the silent epidemic, and many authors highlight the "unmet medical need" associated with TBI.The term traumatically evoked brain injury covers a heterogeneous group ranging from mild/minor/minimal to severe/non-salvageable damages. Severe TBI has long been recognized to be a major socioeconomical health-care issue as saving young lives and sometimes entirely restituting health with a timely intervention can indeed be extremely cost efficient.Recently it has been recognized that mild or minor TBI should be considered similarly important because of the magnitude of the patient population affected. Other reasons behind this recognition are the association of mild head injury with transient cognitive disturbances as well as long-term sequelae primarily linked to repeat (sport-related) injuries.The incidence of TBI in developed countries can be as high as 2-300/100,000 inhabitants; however, if we consider the injury pyramid, it turns out that severe and moderate TBI represents only 25-30 % of all cases, while the overwhelming majority of TBI cases consists of mild head injury. On top of that, or at the base of the pyramid, are the cases that never show up at the ER - the unreported injuries.Special attention is turned to mild TBI as in recent military conflicts it is recognized as "signature injury."This chapter aims to summarize the most important features of mild and repetitive traumatic brain injury providing definitions, stratifications, and triage options while also focusing on contemporary knowledge gathered by imaging and biomarker research.Mild traumatic brain injury is an enigmatic lesion; the classification, significance, and its consequences are all far less defined and explored than in more severe forms of brain injury.Understanding the pathobiology and pathomechanisms may aid a more targeted approach in triage as well as selection of cases with possible late complications while also identifying the target patient population where preventive measures and therapeutic tools should be applied in an attempt to avoid secondary brain injury and late complications.

Traumatic brain injury (TBI) is the leading cause of death and disability in the young, active population and expected to be the third leading cause of death in the whole world until 2020. The disease is frequently referred to as the silent epidemic, and many authors highlight the "unmet medical need" associated with TBI.The term traumatically evoked brain injury covers a heterogeneous group ranging from mild/minor/minimal to severe/non-salvageable damages. Severe TBI has long been recognized to be a major socioeconomical health-care issue as saving young lives and sometimes entirely restituting health with a timely intervention can indeed be extremely cost efficient.Recently it has been recognized that mild or minor TBI should be considered similarly important because of the magnitude of the patient population affected. Other reasons behind this recognition are the association of mild head injury with transient cognitive disturbances as well as long-term sequelae primarily linked to repeat (sport-related) injuries.The incidence of TBI in developed countries can be as high as 2-300/100,000 inhabitants; however, if we consider the injury pyramid, it turns out that severe and moderate TBI represents only 25-30 % of all cases, while the overwhelming majority of TBI cases consists of mild head injury. On top of that, or at the base of the pyramid, are the cases that never show up at the ER - the unreported injuries.Special attention is turned to mild TBI as in recent military conflicts it is recognized as "signature injury."This chapter aims to summarize the most important features of mild and repetitive traumatic brain injury providing definitions, stratifications, and triage options while also focusing on contemporary knowledge gathered by imaging and biomarker research.Mild traumatic brain injury is an enigmatic lesion; the classification, significance, and its consequences are all far less defined and explored than in more severe forms of brain injury.Understanding the pathobiology and pathomechanisms may aid a more targeted approach in triage as well as selection of cases with possible late complications while also identifying the target patient population where preventive measures and therapeutic tools should be applied in an attempt to avoid secondary brain injury and late complications.

New experimental models of human neoplastic diseases attempt to mimic the human environment that fostered the development of disease in cancer patients. The aim of the present study was to establish a human lymphocyte-engrafted, severe combined immunodeficient (hu-PBL-SCID) mouse model to investigate thyroid cancer and to evaluate the potential use of this model for cancer immunotherapy. Thyroid neoplastic tissues were obtained from ten patients (one follicular adenoma, five papillary, one follicular, one anaplastic and two medullary cancers). One 8 x 4 x 3 millimeter sample from each tumor was cut into two pieces of identical size and transplanted into two SCID mice. In each case, one of the two mice was injected intraperitoneally with lymphocytes from the same tumor patient for the reconstitution of the human immune system (Group A), while the other animal received no lymphocytes (Group B). The engraftment of the tumors was successful in all cases. The growth rate was highly dependent on the histological type. When histologies were compared before implantation and after the removal of the implants, the characters of the tumors proved to be unchanged, except one case where an anaplastic cancer arose from a papillary tumor. Macrophages were present in all but one papillary cancer. All differentiated thyroid cancers were infiltrated by T and B lymphocytes. Lymphocytes and macrophages disappeared from 19/20 grafts by week 16. However, in one case from group A lymphocytes were detected four months after the transplantation. In another case from group A, one papillary cancer spontaneously decreased in size and disappeared. Before implantation, HLA-DR expression was detected in every papillary cancer. HLA-DR expression in the grafts was not seen in 3/5 cases by week 16. In conclusion, an animal model has been established for the investigation of human thyroid cancer, by which the analysis of anti-tumor immunity, as a postulate of immune therapy, may be possible.

TRAIL preferentially induces apoptosis in tumor cells and virus-infected cells. Unlike other tumor necrosis factor family members, TRAIL does not kill cells from most normal tissues and has thus been proposed as a promising new cancer treatment. Our study demonstrated that IFNgamma combined with TRAIL can trigger apoptosis in vitro in several resistant thyroid tumor cell lines, such as thyroid anaplastic carcinoma cells (ARO cells), while either agent alone exerts only a minimal effect. We further tested this effect on a mouse thyroid tumor model, when in vivo tumor growth was also significantly inhibited by this combination. The mechanism of how IFNgamma sensitized thyroid carcinoma cells to TRAIL-induced apoptosis was investigated by screening global gene alterations in ARO cells treated with IFNgamma. Microarray data revealed that a proapoptotic gene, Bak, is markedly upregulated by IFNgamma, and this was confirmed by RNase protection assay. Western blot analysis also showed a significant increase in Bak at the protein level. Upregulation of Bak and sensitization for apoptosis by IFNgamma was blocked by overexpression of antisense Bak in ARO cells. Furthermore, overexpression of Bak sensitized ARO cell to TRAIL-induced apoptosis without the need for IFNgamma pretreatment. This suggests that Bak is a regulatory molecule involved in IFNgamma-facilitated TRAIL-mediated apoptosis in thyroid cancer cells.

The specific pathogenesis of nodular goiter and the role of apoptosis in goitrogenesis are not known. We sought to examine the regulation of the TNF-related apoptosis-inducing ligand (TRAIL) and Fas ligand (FasL)-induced apoptosis pathways in primary thyroid cells from 17 patients with nodular goiter, using 10 normal thyroids as controls. Both goitrous and normal thyroid cells were resistant to recombinant human TRAIL and an agonist anti-Fas antibody under basal conditions. However, all normal thyrocytes could be sensitized by TNF/IL-1 or interferon /IL-1 to undergo apoptosis in response to TRAIL or FasL, respectively. In contrast, the majority of goiter-derived cells remained resistant to TRAIL (12 of 17 samples) or FasL (9 of 17 samples) after cytokine pretreatment; 14 of 17 goiter nodules were resistant to at least one death ligand. Goiter size was inversely correlated with the sensitivity to TRAIL-mediated apoptosis. The resistance of goiter cells to TRAIL did not appear to be due to transcriptional regulation or cell surface expression of death and decoy receptors. However, increased proteasome activity was found in a subset of goiter cells resistant to both death ligands, and proteasome inhibitors could sensitize these goiter cells to TRAIL-mediated apoptosis. In conclusion, goiter-derived thyroid cells are resistant to TRAIL and/or Fas-induced apoptosis in vitro, and this may represent a new aspect of aberrant growth regulation in goiter nodules. The increased proteasome activity associated with this resistance suggests that the proteasome may be an important regulator of apoptosis in nodular goiter. (J Clin Endocrinol Metab 87: 4264 – 4272, 2002)

Treatment of cultured primary human thyroid cells with IFN-γ and TNF-α uniquely allows the induction of Fas-mediated apoptosis. To investigate the role of this cytokine combination in vivo, CBA/J mice were immunized with thyroglobulin and then injected with IFN-γ and TNF-α. Compared with control animals, mice treated with IFN-γ and TNF-α showed significantly sustained lymphocytic infiltration in the thyroid, which was associated with the destruction of portions of the follicular architecture at wk 6 after initial immunization. Furthermore, the number of apoptotic thyroid follicular cells was increased only in the thyroids from mice treated with the IFN-γ and TNF-α. We also analyzed the function of the Fas pathway in vivo in cytokine-treated mice by using an agonist anti-Fas Ab injected directly into the thyroid. Minimal apoptosis of thyroid epithelial cells was observed unless the mice were pretreated with IFN-γ and TNF-α. These data demonstrate that this unique combination of inflammatory cytokines facilitates the apoptotic destruction of thyroid follicular cells in experimental autoimmune thyroiditis, in a manner similar to what is observed in Hashimoto’s thyroiditis in humans.

OBJECTIVE: To assess the iodine nutritional status and the prevalence of goitre during pregnancy in a region of Hungary that appeared to be iodine sufficient in previous studies. DESIGN: A cross-sectional voluntary screening study was organized in which 313 pregnant women participated. METHODS: Urine iodine concentration and the volume of the thyroid gland were measured in every woman. In the presence of low urinary iodine concentrations, goitre, or both, thyroid function tests were performed. RESULTS: Iodine deficiency was found in 57.1% of the pregnant women, and was severe in 15.6%. The volume of the thyroid gland was enlarged in 19.2% of individuals. Nodular goitre was found in 17 women (5.4%). The frequency of goitre and the mean thyroid volume were increased in the group of iodine-deficient women. In the 89 cases of iodine deficiency or goitre, thyrotrophin concentrations were in the normal range; however, the free triiodothyronine:free throxine ratio was increased in 97% of them, indicating that the thyroid gland was in a stimulated state in these individuals. CONCLUSIONS: Iodine deficiency with high prevalence of goitre was recognized among pregnant women in an area that previously appeared to be iodine sufficient. An unexpected mild iodine deficiency was also noted in the non-pregnant control group. Reassessment and continuous monitoring of iodine nutritional status is warranted even in populations that are apparently considered to be 'at no risk' of iodine deficiency, especially in pregnant women. Regular administration of iodine, starting at preconception or in early pregnancy and continuing during the period of nursing, is recommended in these regions.

Objective: We compared different signal transduction pathways through thyroid stimulating hormone receptor (TSH-R) in porcine thyroid cells (PTC) following stimulation with thyroid stimulating hormone (TSH) and 11 thyroid stimulating immunoglobulin samples (TSI) obtained from patients with Graves’ disease. Design: Following stimulation with TSI, the level of inositol trisphosphate (IP3) and [Ca 2˛ ]i, as well as the membrane bound protein kinase C (PKC) activity and the intensity of the arachidonic acid (AA) cascade, were determined in PTC. Results: Seven out of eleven TSI samples activated PTC through IP3 generation, elevated [Ca 2˛ ]i from the intracellular pools, exhibited verapamil-insensitive membrane-bound PKC activation, and enhanced release of [ 14 C]AA derivates (however, one of the samples was also able to take up Ca 2˛ from the extracellular space). Four out of eleven TSI samples did not activate the phospholipase C (PLC) system in which case the Ca 2˛ signal occurred only in the presence of extracellular Ca 2˛ , the membrane bound PKC activation was verapamil sensitive, and in two of these four TSI samples, the AA release was extremely high. Conclusions: The simultaneous examination of the majority of the known signal pathways using TSI samples showed that TSI samples from different patients activate thyroid cells through different pathways. Their effects differ from that of TSH and, to a certain extent, from each other. The results give a certain new insight into the intracellular mechanisms exerted by TSI.

BACKGROUND Acetylsalicylic acid (ASA) plays an important role in the treatment and prevention of cardiovascular diseases. Metamizole (MET) is an analgesic and antipyretic medicine, it is not used as an antiplatelet drug. OBJECTIVES We aimed to examine the antiplatelet effect of MET and the possible interactions between the drugs. METHODS In our in vitro investigations different concentrations of ASA and MET solutions were added to blood. To examine the interactions MET and ASA were added together. In our in vivo crossover study intravenous MET, oral ASA or both drugs together were administered. Epinephrine and adenosine-diphosphate induced platelet aggregation was determined by optical aggregometry. RESULTS Epinephrine-induced aggregation was completely inhibited in all ASA and MET concentrations in vitro. Lower, ineffective concentration of MET prevented the antiplatelet effect of ASA. The inhibition was completely restored when higher concentration of ASA was used or when ASA was added first. Our in vivo study showed that in the MET group rapid onset of inhibition was developed and there was no inhibition after one day. In the ASA group platelet aggregation decreased slowly but still had significant inhibitory effect after 72 hours. Combined therapy showed similar changes to the MET group. CONCLUSION Antiplatelet effect of MET and ASA did not differ significantly in vitro. The observations may indicate a competitive interaction between the two drugs. The in vivo experiments showed that intravenously administered MET is an effective antiplatelet drug and can be considered as a therapeutic alternative, when ASA cannot be used in oral form.

Acromegaly is a rare disease with typical clinical manifestations. Untreated acromegaly carries a 2-4-fold increase in mortality in long-term outcome. The goal of treatment is double, including biochemical control of the disease (normalization of serum IGF1 levels compared to age and gender matched controls, GH levels below 1 ng/ml after oral glucose load, or random GH below 2.5 ng/ml) and control of the tumor mass. The therapeutic modalities currently available for the treatment of acromegaly are: surgery, medical therapy, radiation therapy and their combinations. The cornerstones of medical therapy in acromegaly are the somatostatin receptor ligands due to their effectiveness in controlling GH excess in 60-70 % of patients and their beneficial effects on tumor volume. Somatostatin analogues have an established role as adjuvant therapy after non-curative surgery, and evidence suggests their use as primary treatment for selected patients. The long-term use of somatostatin receptor ligands is safe and they are well tolerated. Future medical therapy consists of pasireotide, a novel, universal somatostatin receptor agonist, and a new class of drugs named dopastatins. The latter so-called chimeric molecules have strong affinity for somatostatin receptors and dopamine-2 receptors, resulting in a more effective blocking of GH secretion, according to preliminary data. The authors of this paper review the current medical therapy of acromegaly, focusing on the role of somatostatin receptor ligands.

According to epidemiological studies, the prevalence of pituitary adenomas is 16.5% and the majority of them are "incidentalomas". The symptoms of pituitary disorders are often non-specific; disturbances of pituitary function, compression symptoms, hypophysis apoplexy or accidental findings may help the diagnosis. The hormonal evaluation of pituitary adenomas is different from the algorithm used in the disorders of peripheral endocrine organs. The first-line therapy of prolactinomas are the dopamine agonists, and the aims of the treatment are to normalize the prolactin level, restore fertility in child-bearing age, decrease tumor mass, save or improve the residual pituitary function and inhibit the relapse of the disease. The available dopamine agonists in Hungary are bromocriptine and quinagolide. In case of tumors with good therapeutic response, medical therapy can be withdrawn after 3-5 years; hyperprolactinemia will not recur in 2/3 of these patients. Neurosurgery is the primary therapy of GH-, ACTH-, TSH-producing and inactive adenomas. In the last decades, significant improvement has been reached in surgical procedures, resulting in low mortality rates. Acromegalic patients with unresectable tumors have a great benefit from somatostatin analog treatment. The growth hormone receptor antagonist pegvisomant is the newest modality for the treatment of acromegaly. The medical therapy of Cushing's disease is still based on the inhibition of steroid production. A new, promising somatostatin analog, pasireotide is evaluated in clinical trials. The rare TSH-producing tumor can respond to both dopamine agonist and somatostatin analog therapy. The application of conventional radiotherapy has decreased; radiotherapy is mainly used in the treatment of invasive, incurable or malignant tumors. Further studies are needed to elucidate the exact role of radiosurgery and fractionated stereotaxic irradiation in the treatment of pituitary tumors.