Search

The homeodomain transcription factor Six1 and its modulator, the protein phosphatase Eya1, cooperate to promote cell differentiation and survival during mouse organ development. Here, we studied the effects caused by loss of eya1 and six1 function on pituitary development in zebrafish. eya1 and six1 are co-expressed in all adenohypophyseal cells. Nevertheless, eya1 (aal, dog) mutants show lineage-specific defects, defining corticotropes, melanotropes, and gonadotropes as an Eya1-dependent lineage, which is complementary to the Pit1 lineage. Furthermore, eya1 is required for maintenance of pit1 expression, leading to subsequent loss of cognate hormone gene expression in thyrotropes and somatotropes of mutant embryos, whereas prolactin expression in lactotropes persists. In contrast to other organs, adenohypophyseal cells of eya1 mutants do not become apoptotic, and the adenohypophysis remains at rather normal size. Also, cells do not trans-differentiate, as in the case of pit1 mutants, but display morphological features characteristic for nonsecretory cells. Some of the adenohypophyseal defects of eya1 mutants are moderately enhanced in combination with antisense-mediated loss of Six1 function, which per se does not affect pituitary cell differentiation. In conclusion, this is the first report of an essential role of Eya1 during pituitary development in vertebrates. Eya1 is required for lineage-specific differentiation of adenohypophyseal cells, but not for their survival, thereby uncoupling the differentiation-promoting and anti-apoptotic effects of Eya proteins seen in other tissues.

It has been known for decades that the neuroendocrine system can both directly and indirectly influence the developmental and functional activity of the immune system. In contrast, far less is known about the extent to which the immune system collaborates in the regulation of endocrine activity. This is particularly true for immune-endocrine interactions of the hypothalamus-pituitary-thyroid axis. Although thyroid-stimulating hormone (TSH) can be produced by many types of extra-pituitary cells--including T cells, B cells, splenic dendritic cells, bone marrow hematopoietic cells, intestinal epithelial cells, and lymphocytes--the functional significance of those TSH pathways remains elusive and historically has been largely ignored from a research perspective. There is now, however, evidence linking cells of the immune system to the regulation of thyroid hormone activity in normal physiological conditions as well as during times of immunological stress. Although the mechanisms behind this are poorly understood, they appear to reflect a process of local intrathyroidal synthesis of TSH mediated by a population of bone marrow cells that traffic to the thyroid. This hitherto undescribed cell population has the potential to microregulate thyroid hormone secretion leading to critical alterations in metabolic activity independent of pituitary TSH output, and it has expansive implications for understanding mechanisms by which the immune system may act to modulate neuroendocrine function during times of host stress. In this article, the basic underpinnings of the hematopoietic-thyroid connection are described, and a model is presented in which the immune system participates in the regulation of thyroid hormone activity during acute infection.

The goal of this study was to express and purify recombinant feline TSH as a possible immunoassay standard or pharmaceutical agent. Previously cloned feline common glycoprotein alpha (CGA) and beta subunits were ligated into the mammalian expression vector pEAK10. The feline CGA-FLAG and beta subunits were cloned separately into the pEAK10 expression vector, and transiently co-transfected into PEAK cells. Similarly, previously cloned and sequenced yoked (single chain) fTSH (yfTSH) and the CGA-FLAG sequences were ligated into the same vector, and stable cell lines selected by puromycin resistance. Expression levels of at least 1 microg/ml were achieved for both heterodimeric and yoked fTSH forms. The glycoproteins were purified in one step using anti-FLAG immunoaffinity column chromatography to high purity. The molecular weights of feline CGA-FLAG subunit, beta subunit and yfTSH were 20.4, 17, and 45 kDa, respectively. Both heterodimeric and yoked glycoproteins were recognized with approximately 40% detection by both a commercial canine TSH immunoassay and an in-house canine TSH ELISA. The yoked glycoprotein exhibited parallelism with the heterodimeric form in the in-house ELISA, supporting their possible use as immunoassay standards. In bioactivity assays, the heterodimeric and yoked forms of fTSH were 12.5 and 3.4% as potent as pituitary source bovine TSH at displacing (125)I-bTSH and 45 and 24% as potent in stimulating adenylate cyclase activity in human TSH receptor-expressing JP09 cells. However, in addition to reduced receptor binding affinity, the recombinant glycohormones produced a reduced maximal effect at maximal concentration (E(max)) suggesting the possibility of the recombinant glycohormone constructs acting as partial agonists at the human TSH receptor.

Introduction: The study summarizes the results of an audit evaluating the realization of the suppressive TSH therapy in patients with differentiated thyroid cancer., Material and Methods: The evaluation was performed in 500 consecutive patients., Results: In patients in whom remission was diagnosed < 5 years ago, in 70% subcomplete suppression was stated (TSH 0.1-0.3 mU/L) and complete suppression (TSH < 0.1 mU/L) was observed in 20%. Unexpectedly in patients in whom remission lasted > 5 years, complete suppression was observed in 60%. However, this last group was less numerous, thus, the majority of no evidence of disease patients exhibited subcomplete TSH suppression, while only 40% of patients with active disease had this goal realized., Conclusions: 1. Iatrogenous hypothyroidism was well controlled in nearly all differentiated thyroid cancer patients. 2. The goal of L-thyroxine treatment, defined as TSH serum level < 0.4 mU/L was achieved in 90% of them without a significant risk of iatrogenous thyrotoxicosis. 3. Some overdosage of L-thyroxine was observed, especially in patients in whom remission lasted > 5 years. It this group of patients there is no reason to induce full suppression of TSH by L-thyroxine treatment.

The immune and neuroendocrine systems have been shown to work conjointly in a number of ways. One aspect of this has to do with a potential role for thyroid stimulating hormone (TSH) in the regulation of the mucosal immune system, although the mechanisms by which this occurs remain vague. To more thoroughly understand how TSH participates in intestinal intraepithelial lymphocyte (IEL) development and immunity, experiments have been conducted to define local sites of intestinal TSH production, and to characterize changes that occur in the synthesis of TSH during acute enteric virus infection. Here, we demonstrate that TSH in the small intestine is specifically localized to regions below villus crypts as seen by immunocytochemical staining, which revealed high-level TSH staining in lower crypts in the absence of IL-7 staining, and TSH and IL-7 co-staining in upper crypt regions. Additionally, prominent TSH staining was evident in TSH 'hotblocks' sparsely dispersed throughout the epithelial layer. In rotavirus-infected mice, the TSH staining pattern differed significantly from that of non-infected animals. Notably, at 2 and 3 days post-infection, TSH expression was high in and near apical villi where virus infection was greatest. These findings lend credence to the notion that TSH plays a role both in the development of intestinal T cells, and in the process of local immunity during enteric virus infection.

Many types of evidence support a role of the sympathetic nervous system in the regulation of thyroid function, although there is no general consensus on the type of influence that catecholamines exert. Depending on the experimental approach, epinephrine and norepinephrine (NE) can stimulate, inhibit, or fail to act on thyroid function. The aim of this study was to determine the effect of NE on thyroglobulin (Tg) synthesis and gene expression in FRTL-5 cells. Tg content, measured by immunoprecipitation with a specific antibody, showed that NE caused a 45% inhibition of thyrotropin (TSH) effect. The content of Tg mRNA was analyzed by Northern blot, the relative inhibition in total Tg mRNA levels from NE-treated cells, compared to TSH alone, ran parallel with inhibition in Tg content, while total RNA did not change after incubation with NE. There was no alteration in Tg mRNA stability by NE. When plasmids harboring different sequences of Tg promoter fused to the CAT reporter gene were transfected into FRTL-5 cells, TSH treatment stimulated promoter activity while NE diminished this effect by 43%-55%. Northern blots were performed to analyze mRNA for thyroid transcription factors (TTF1, TTF2, Pax8), and no significant changes were observed with the different treatments. In conclusion these results suggest that NE inhibits Tg synthesis at the transcriptional level.

Objectives: The examination of potential associations between Graves' disease and thyrotropin-producing pituitary adenoma (TSHoma) after treatment using octreotide, and of the expression of peroxisome proliferator-activated receptor gamma (PPAR gamma)., Design and Methods: A specimen of resected TSHoma tissue from our case was immunohistochemically examined for expression of somatostatin receptor 2A (SSTR2A) and PPAR gamma. Specimens of thyroid tissue from two cases with Hashimoto's thyroiditis were immunohistochemically examined for expression of SSTR2A., Results: Expression of SSTR2A and PPAR gamma was identified in TSHoma cells. SSTR2A was also expressed in lymphocytes that had infiltrated thyroid tissue in Hashimoto's thyroiditis. In previous reports, three of four patients with TSHoma displayed Graves' disease after tumor resection, and TSH is also known to play a major role in regulating immunomodulatory gene expression in thyrocytes., Conclusions: Both the immunomodulatory effects of octreotide on intrathyroidal lymphocytes and rapid reductions in TSH may contribute to the onset of Graves' disease. Patients with TSHoma-associated autoimmune thyroiditis should undergo careful follow-up for development of Graves' disease after treatment. Both octreotide and the PPAR gamma receptor-activating ligands, thiazolidinediones, may be effective for patients with TSHoma.

We reported a rare case of pleomorphic TSH-producing pituitary adenoma with calcification and reviewed the literature. A 25-year-old female was admitted to our hospital with a complaint of anterior neck swelling. An endocrinological examination demonstrated elevated serum levels of free triiodothyronine (FT3: 5.6 pg/ml), free thyroxin (FT4: 2.2 ng/dl), TSH (5.85 microIU/ml), and TSH a-subunit (5.9 ng/ml), whereas a physical examination revealed no goiter. CT scan showed a suprasellar isodensity mass with dense calcification. Contrast-enhanced T1-weighted images revealed a less enhancing tumor extending from the left upper portion of pituitary fossa into suprasellar cistern. The patient underwent gross total removal of the tumor via the right pterional approach. Microscopically, medium-sized to enlarged tumor cells with marked pleomorphism and prominent calcification were observed. The tumor cells displayed positive reaction for TSH (beta-subunit). The MIB-1 index averaged 2.9%. The histological diagnosis was a pleomorphic TSH-producing pituitary adenoma. Postoperatively, the serum levels of FT3, FT4, TSH, and TSH alpha-subunit decreased to normal range. Follow-up MR images showed no evidence of recurrent tumor 3 years after the resection. All of six patients with densely calcified TSH-producing pituitary adenoma, previously reported in the literature, remained well without tumor recurrence. We suggest that this type of TSH-producing pituitary adenoma may be associated with favorable prognosis despite histologically pleomorphic appearance.

Background & Objectives: Di (2-ethyl hexyl) phthalate (DEHP), a plasticizer commonly used in PVC blood storage bags leaches out in significant amounts into blood during storage. In view of many reports on the toxicity of this compound, it was considered necessary to investigate the effect of DEHP at the low level solubilized in blood on some important hormones in rats and in human blood stored in DEHP plasticized blood bags., Methods: Rats were administered DEHP at a low level of 750 microg/100 g body weight on alternate days for 14 days. Changes in the serum insulin, blood glucose, liver glycogen level and T3, T4 and thyroid stimulating hormone (TSH) as well as cortisol in the serum were studied. Changes in the hormones were also studied in blood stored in DEHP plasticized PVC bags., Results: The results indicated decrease in serum insulin, cortisol and liver glycogen, and increase in blood glucose, serum T3 and T4 in rats receiving DEHP. These changes were reversed when administration of DEHP was stopped. Similar changes in hormones were also observed in the blood stored in DEHP plasticized blood bags., Interpretation & Conclusion: The results indicated that administration of DEHP at low levels to rats caused symptoms of diabetes, thyroid and adrenocortical dysfunction. Though the results obtained in rats cannnot be extrapolated to human, the fact that similar hormonal changes seen in human blood stored in DEHP plasticized blood bags may suggest possibility of DEHP causing similar changes in human. The fact that these changes were reversed in rats when DEHP administration was stopped, indicates that transfusion of a few units of blood to a recipient may not be harmful, but it may pose a problem during repeated transfusions such as in thalassaemia patients.

The set point of thyrotropin (TSH) secretion is determined by the balance of a positive regulation of thyrotropin releasing hormone (TRH) and the strong negative regulation exerted by thyroid hormones. In addition, there are other regulators superimposed on this main axis such as somatostatin and dopamine, which act as inhibitors of TSH secretion, and central alpha-adrenergic pathways that are predominantly stimulatory and involved in the cold-induced thyroid activation. Nutritional status and leptin also regulate TSH by stimulating TRH neurons through direct and indirect mechanisms. Stress is also involved in lowering TRH/TSH secretion possibly through glucocorticoids, cytokines and opioids. Recently, a new regulatory pathway has been proposed, via peptides produced in pituitary, acting in an autocrine/paracrine manner. Among those, more consistent data are available on neuromedin B, gastrin-releasing peptide and pituitary leptin, which act as local inhibitors of TSH release. Neonatal programming of TSH secretion set point is also discussed.

Aim: To assess thyrotropin (thyroid-stimulating hormone; TSH) suppression and serum thyroxine (T(4)) concentrations in infants with congenital hypothyroidism in relation to T(4) dose and pretreatment parameters., Method: A retrospective study of all cases treated in a single centre since neonatal screening began was performed., Results: In 54 infants treated with a mean daily T(4) dose of 9.8 microg/kg, the TSH concentration was suppressed (<6 mU/l) in 65% of the cases by 6 months with the serum T(4) level at the upper end of the infant reference range. Infants who suppressed their TSH later did not differ in pretreatment serum TSH or T(4) concentration. T(4) dose and serum T(4) level were lower in infants whose TSH was not suppressed., Conclusions: TSH suppression in congenital hypothyroidism is significantly related to serum levels and dosage of T(4). We suggest that a delay in TSH suppression is mainly due to undertreatment., (Copyright 2003 S. Karger AG, Basel)

Objective: A clinicopathological and clonal study of a pituitary tumor was made in a 26-year-old woman with chronic thyroiditis to differentiate TSH-producing adenoma from TSH hyperplasia., Methods: Tumor specimens were subjected to histopathological study and clonal analysis (HUMARA)., Results: Immunohistochemical examination disclosed TSH-beta, PRL, GH, ACTH, FSH-beta, LH-beta, and alpha-subunit production in the adenoma cells. These heterogeneous phenotypes are characteristic of both thyrotroph hyperplasia and plurihormonal TSH-producing adenoma. However, the HUMARA method demonstrated monoclonality of the tumor cells., Conclusion: Monoclonality of the tumor cells proved that the pituitary tumor was plurihormonal TSH-producing adenoma, not TSH hyperplasia., (Copyright 2003 S. Karger AG, Basel)

Oxyntomodulin (OXM) is a product of proglucagon processing in the intestine and the central nervous system. We reported that intracerebroventricular (ICV) and intranuclear administration of OXM caused an inhibition of food intake in rats (Dakin CL, Gunn I, Small CJ, Edwards CM, Hay DL, Smith DM, Ghatei MA, and Bloom SR. Endocrinology 142: 4244-4250, 2001). In this study, we investigated the effect of twice-daily ICV administration of OXM, 1 nmol, for 7 days. A pair-fed control was included. These animals were restricted to the food intake of the OXM group but injected twice daily with saline. OXM-treated animals gained significantly less weight than either control group (day 8: OXM, 12.2 +/- 1.9 g vs. pair fed, 21.0 +/- 2.1 g; P < 0.005). OXM treatment caused a reduction in epididymal white adipose tissue (OXM, 1.13 +/- 0.03 g vs. pair fed, 1.29 +/- 0.04 g; P < 0.05) and interscapular brown adipose tissue (OXM, 0.15 +/- 0.01 g vs. pair fed, 0.18 +/- 0.01 g; P < 0.05) and increased core temperature compared with saline control, suggestive of enhanced energy expenditure. The food restriction-induced suppression in plasma TSH, seen in the pair-fed group, was prevented by OXM, potentially via increased release of hypothalamic TRH. In summary, ICV OXM causes reduced body weight gain and body adiposity following chronic administration.

Objective: Local 5'-deiodination of l-thyroxine (T(4)) to active thyroid hormone 3,3',5-tri-iodothyronine (T(3)) catalyzed by the two 5'-deiodinase enzymes (D1 and D2) regulates various T(3)-dependent functions in the anterior pituitary and has been well studied in rodents. Only limited information about deiodinase expression and its cellular distribution in human anterior pituitaries is available., Design: We examined 5'-deiodinase enzyme activities in pituitary adenomas (18 non-functioning, seven TSH-producing, one GH- and TSH-producing, five GH-producing, eight prolactin (PRL)-producing, two adenomas each from patients with Cushing's disease and Nelson's syndrome) and three normal anterior pituitaries., Methods: Activities were measured as release of (125)I(-) from tyrosyl-ring labeled reverse T(3) with or without propylthiouracil, a potent inhibitor of D1 which does not influence D2 activities., Results: Most of the adenomas and normal tissues expressed both isoenzymes, with D2 activity higher than D1. In a few tissues D1 activity was higher than D2 and some tissues did not express D1 activity at all. Highest activities of both enzymes were found in TSH- and PRL-producing adenomas but absolute activities and the D1/D2 ratio were variable in the same kind of tumor in different patients., Conclusion: The finding that all examined tissues expressed 5'-deiodinase activity, most of them expressing both isoenzymes, implies that both enzymes are still active in tumors and that local deiodination is important for the function and feedback regulation of human anterior pituitary.

We have previously characterized the structure of the murine somatostatin receptor type 5 gene (sst5). Initial transient transfection studies in pituitary somatolactotropes (GH(3)) mapped the promoter activity of this gene to a region 290 bp upstream of the transcription start site. The current study identifies the sst5 promoter region critical for basal activity. A series of deletions was generated, and promoter activity was localized to a region between -83 and -19. Similar promoter deletion patterns were evident in five pituitary cell types. Seven 10-bp transversion mutations encompassing the region between -83 and -19 were generated, and functional activity was assessed. Promoter activity was reduced by the mutations spanning -67 to -47 compared with the wild-type construct. Another mutation between -26 and -17 resulted in promoter activity reduction in GH(3) cells, but not TtT-97 thyrotropes. Deoxyribonuclease I protection analysis of the sst5 promoter region between -208/+47 was performed using GH(3) and TtT-97 nuclear extracts. The most striking protected regions, located between -61 and -41 and -25 and -3, correlated with functionally important regions identified by transfection studies. In summary, the mouse sst5 gene promoter has been characterized, and functional activity and nuclear factor interactions were mapped to two specific promoter regions. The region between -67 and -47 appears to contain a nucleotide sequence critical for basal transcriptional regulation of the mouse sst5 gene in pituitary cells.

Thyroid hormone exerts its biological effect by binding to a TR. Both liganded and unliganded TRs regulate the transcription of T(3)-responsive genes. Cofactors with activating or repressing function modulate the transcriptional regulation by TRs. We showed that steroid receptor coactivator 1 (SRC-1)-deficient mice (SRC-1(-/-)) exhibit partial resistance to thyroid hormone at the level of the pituitary thyrotrophs. To determine whether SRC-1 deficiency affects globally T(3)-dependent transcriptional regulation, we studied the effects of thyroid hormone deprivation and replacement on the expression of several genes in different tissues of SRC-1(-/-) and wild-type mice (SRC-1(+/+)). Thyroid hormone deficiency was induced by a low iodine diet (LoI) supplemented with propylthiouracil (PTU) for 2 wk. L-T(3) was injected ip for the last 4 d in one group (PTU+T(3) group), and another group (PTU group) received only vehicle. Levels of mRNAs for T(3)-responsive genes were determined by Northern blotting: GH and TSH beta in pituitary; type 1 iodothyronine 5'-deiodinase, spot 14 (S14), and malic enzyme in liver; and sarcoplasmic reticulum calcium adenosine triphosphatase 2 and myosin heavy chain alpha and beta in heart. Serum parameters, TSH, total cholesterol, creatine kinase, and alkaline phosphatase (AP), were also measured. Hypothyroidism produced a comparable increase in TSH beta mRNA in both genotypes, but its suppression by L-T(3) was attenuated in SRC-1(-/-) mice. In contrast, hypothyroidism failed to reduce S14 mRNA levels in SRC-1(-/-) mice. As a consequence, the response to L-T(3) was not observed in these mice. SRC-1 deficiency had no effect on the expression of the rest of the T(3)-responsive genes examined. Of the four serum parameters, the T(3)-mediated decrease in TSH and changes in AP were attenuated in SRC-1(-/-) mice. We conclude that SRC-1 deficiency altered the expression of only some of the T(3)-responsive genes. SRC-1 appears to be involved not only in transcriptional activation by liganded TRs, but also in the suppression by liganded or unliganded TRs. Some of the effects of SRC-1 may be TR isoform specific.

We have investigated how a low dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) affects thyroid hormone regulation, especially in relation to the localization of thyroid stimulating hormone (TSH) in the pituitary and that of thyroxin (T4) of the thyroid in the rat. Female Sprague-Dawley rats were given a single oral administration of TCDD ranging from 1.0 to 4.0 microg/kg body weight (bw), and then tissue specimens were removed on day 7 post-administration. Thyroid hormone concentrations were measured in serum, and the expression of the TCDD-responsive genes, UDP-glucuronosyltransferase-1 (UGT1) and cytochrome P4501A1 (CYP1A1) were examined in the liver. TCDD administration resulted in an increase in both immunostaining intensity and the number of TSH-positive cells in the anterior pituitary. T4 was found to localize only in the follicular lumen of the thyroid in vehicle-treated control rats, while TCDD administration caused a foamy change in the colloid of some follicles, an indication of accelerating the biosynthesis of T4 in the thyroid. By morphometrical analysis, the ratio of parenchymal/lumenal area of the thyroid was found to increase in response to TCDD. TCDD treatment as low as 2.0 microg TCDD/kg bw induced a significant decrease in both serum total T4 (TT4) and free T4 (FT4) concentrations in the rats, with a significant increase in serum TSH levels in the 4.0 microg TCDD/kg bw rats. Serum total triiodothyronine (TT3) level was unchanged in all groups. The UGT1 gene was significantly induced at a TCDD dose as low as 1.0 microg/kg bw in a dose-dependent manner. TCDD concentrations in the serum, liver and adipose tissues were detected in a dose-related fashion. The present immunohistochemical results clearly support the earlier biochemical findings on the perturbation of the thyroid-pituitary axis by TCDD and suggest that UGT1 is an immediate target of a low TCDD exposure that triggers the perturbation.

We report a very rare case of thyrotropin (thyroxin stimulating hormone, TSH)-producing pituitary adenoma coexisting with a papillary adenocarcinoma of the thyroid. A 45-year-old woman presented with hyperhidrosis and a nodule in the left thyroid that was first noticed one year earlier. An endocrinological examination showed elevated serum levels of free triiodothyronine (T3) and free throxin (T4) without inhibition of TSH, suggesting the presence of syndromes of inappropriate secretion of TSH. A specimen obtained by needle aspiration of the thyroid nodule revealed the presence of papillary adenocarcinoma. Magnetic resonance images demonstrated a pituitary macroadenoma. The patient was diagnosed as having a TSH-producing pituitary adenoma coexisting with a papillary adenocarcinoma of the thyroid. The patient underwent a total thyroidectomy with resection of the neighboring lymph nodes. Two weeks after this surgery, the pituitary adenoma was totally removed via a pterional approach. Histological and immunohistochemical examinations of the surgical specimens confirmed the lesion as a papillary adenocarcinoma of the thyroid and a TSH-producing pituitary adenoma. Serum TSH levels decreased to undetectable levels immediately after the surgery for the pituitary adenoma. Prolonged stimulation of the thyroid gland by TSH may be involved in the growth of thyroid carcinoma. In cases with a TSH-producing pituitary adenoma, the possible coexistence of thyroid carcinoma should be carefully ruled out. In such cases, a total thyroidectomy followed by TSH level normalization should be performed. Incomplete removal of the thyroid might enable the carcinoma to re-grow if TSH level can not be normalized after the pituitary adenomectomy.

We report on 7 patients referred for treatment of hepatic hemangioendothelioma with increased thyrotropin levels. The serum thyroxine level was decreased in 4 and increased in 2. Immunohistochemistry showed positive staining of tumor, but not of normal liver tissue, for thyrotropin. We propose secretion by the tumor of a thyrotropin-like factor.

We investigated propofol pharmacokinetics in a patient with secondary hyperthyroidism caused by thyroid stimulating hormone (TSH) producing pituitary adenoma. Laboratory data indicated thyrotoxic state with elevated TSH, FT3 and FT4 levels. General anesthesia was maintained with a doubled propofol infusion rate (8-10 mg.kg-1.hr-1) compared to our standard procedure. During 370 min of infusion, propofol concentrations in arterial blood were kept within optimal ranges (2-4 micrograms.ml-1). Although the clearance of propofol was high (2.8 l.min-1) because of the thyrotoxic state, the patient showed delayed recovery from anesthesia. The half-life of blood propofol after the termination of infusion exceeded 30 minutes (normal: 10-15 minutes). We conclude that the delayed recovery was due to the accumulation of propofol in the adipose tissue during long-term infusion in spite of the increased propofol clearance.

A 27-year-old woman who presented with a left thyroid nodule was found to have hyperthyroidism caused by a syndrome of inappropriate secretion of TSH. The levels of free T3, free T4 and TSH were 9.50 pg/mL, 4.05 ng/dL and 2.16 microU/mL, respectively. Magnetic resonance imaging of the head revealed a pituitary macroadenoma. The TSH response to TRH stimulation was normal and responses of other anterior pituitary hormones to stimulation tests were also normally preserved. Administration of octreotide with iodine successfully reversed hyperthyroidism prior to total resection of pituitary adenoma, which was followed by hemithyroidectomy of the left thyroid five months later. Histologically, the resected pituitary adenoma was a TSH-producing adenoma (TSH-oma) and the thyroid nodule was a papillary adenocarcinoma. Serum TSH diminished to undetectable levels immediately following pituitary adenomectomy but gradually normalized over nine months. Coexistence of a TSH-oma with thyroid cancer is very rare and only two similar cases have previously been documented. This combination raises the possibility that TSH may be involved in tumorigenesis in the thyroid gland.

Advances related to thyrotropin during 1999 included better understanding of the genetic basis of pituitary development and genetic advances in identifying clinical entities and their mechanisms and enabling new therapies. Initial clinical use of recombinant thyrotropin in evaluation of thyroid cancer recurrence was described. The importance of glycosylation pattern was clarified including the role of thyrotropin-releasing hormone in synthesis of thyrotropin molecules with mature glycosylation, and the impact of abnormal glycosylation in loss-of-function and gain-of-function mutations of the thyrotropin receptor. Causes of excessive thyrotropin secretion were evaluated, including pituitary thyrotropin-secreting adenomas. The fairly common causes of central hypothyroidism including ischemic injury, cranial irradiation, psychiatric conditions, or medical illness were assessed. The action of thyrotropin at the thyroid cell was assessed as a growth factor and as an influence on tyrosine sulfate content of thyroglobulin. Such basic and clinical science advances are rapidly affecting clinical care.

Thyroid hormone inhibits thyrotropin (TSH) production and thyrotrope growth. Somatostatin has been implicated as a synergistic factor in the inhibition of thyrotrope function. We have previously shown that pharmacological doses of thyroid hormone (levothyroxine [LT4]) inhibit growth of murine TtT-97 thyrotropic tumors in association with upregulation of somatostatin receptor type 5 (sst5) mRNA and somatostatin receptor binding. In the current study, we examined the effect of physiological thyroid hormone replacement alone or in combination with the long-acting somatostatin analogue, Sandostatin LAR, on thyrotropic tumor growth, thyrotropin growth factor-beta (TSH-beta), and sst5 mRNA expression, as well as somatostatin receptor binding sites. Physiological LT4 replacement therapy resulted in tumor shrinkage in association with increased sst5 mRNA levels, reduced TSH-beta mRNA levels and enhanced somatostatin receptor binding. Sandostatin LAR alone had no effect on any parameter measured. However, Sandostatin LAR combined with LT4 synergistically inhibited TSH-beta mRNA production and reduced final tumor weights to a greater degree. In this paradigm, Sandostatin LAR required a euthyroid status to alter thyrotrope parameters. These data suggest an important interaction between the somatostatinergic system and thyroid hormone in the regulation of thyrotrope cell structure and function.

The diagnostic algorithm of thyroid diseases, the most frequent dysendocrine condition, can be today integrated by the newly developed molecular methodologies. From the early diagnostic approaches, centered on the assessment of thyroid function, either by in vivo radioisotopic techniques, or by in vitro radioimmunological measurement of hormone plasma concentrations, it is nowadays possible to precisely define the molecular events triggered by the iodothyronine signal at the level of target tissues. In this brief review will be discussed the recent progresses on cloning and characterization of several genes involved in the regulation of thyroid differentiation, ability to trap iodine, synthesis and secretion of iodothyronines, regulation of thyroid function by TSH, transduction of the hormonal signal to subcellular structures involved in the translation of the hormone message in specific biological, effects such as those on metabolic homeostasis, cell proliferation and differentiation. It will be also discussed the most recent advancements on the genetics of thyroid diseases which have allowed to characterize the molecular basis of several thyropathies such as congenital hypothyroidism, thyroid hormone resistance syndrome, hyperthyroidism or hypothyroidism caused by TSH-receptor alterations, molecular abnormalities of oncogenes or tumor suppressor genes which are associated with benign or malignant thyroid cell transformation. The most recent developments of the diagnostic procedures of thyroid diseases, also in their pre-clinical stage, will be also reviewed together with a brief highlight on the most recent treatment options, centered on prophylactic therapeutic intervention or on the development of gene therapy strategies which will be possibly applied in a near future.

Many malignancies may present with metastases to the pituitary gland. The association of thyroid carcinoma with pituitary metastases is, however, very rare. This report describes two patients in whom metastases from a papillary thyroid carcinoma to the pituitary gland resulted in panhypopituitarism with blunted endogenous thyrotropin (TSH) production following withdrawal of levothyroxine. Both required the use of recombinant human TSH prior to radioiodine therapy. Symptoms of hypopituitarism may be difficult to distinguish clinically from those of hypothyroidism in the setting of levothyroxine withdrawal. Clinicians should be aware of the clinical and biochemical manifestations of this rare association.

In addition to regulating anterior pituitary function by being released from the median eminence, mammalian neurotensin (NT) may also exert an autocrine or a paracrine action within the anterior pituitary. In this study, using double immunostaining with elution restaining, we identified the specific anterior pituitary cells which express NT immunoreactivity (NT-IR) during the rat oestrous cycle. In the normal cycling rat, NT-IR was present in both gonadotrophs and thyrotrophs and displayed plastic changes along the oestrous cycle. Both the number of TSH-NT positive cells and the intensity of immunological reaction were elevated during dioestrus, and decreased through pro-oestrus and early oestrus. NT-IR was also high in both follicle stimulating hormone (FSH)- or luteinizing hormone (LH)-positive cells during early pro-oestrus, and decreased during late pro-oestrus. Treatment of intact rats with either the anti-oestrogens Tamoxifen or LY117018, or the anti-progestagen RU486 prevented the normal expression of NT-IR in thyroid-stimulating hormone (TSH)-, FSH-, and LH-positive cells during pro-oestrus. Bilateral ovariectomy induced a dramatic reduction in the number of NT-IR cells. This effect was completely prevented by treatment of ovariectomized rats with oestradiol and progesterone, and was unaffected by the concurrent administration of a GnRH antagonist. Furthermore, administration of an anti-oestrogen together with an anti-progestagen to ovariectomized-oestrogen, progesterone-treated rats, blocked the stimulatory effect of ovarian hormones on NT-IR in anterior pituitary cells. These findings demonstrate that, in female rats, NT is specifically localized in gonadotrophs or thyrotrophs. In addition, they strongly suggest that changes in circulating concentrations of ovarian steroids may control both NT synthesis in, and release from, these cells.

We present the case of a 7-month-old baby with Cushing's disease due to an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma combined with cells producing thyreotropin-secreting hormone (TSH). In MRI scans, a contrast-enhancing lesion was seen inside the pituitary fossa, and it extended into the suprasellar region. On the assumption of a pituitary adenoma, surgery was performed. Corresponding with biochemical findings, histopathological evaluation revealed an ACTH- and TSH-producing tumor. Genetic analysis did not demonstrate an alteration at codon 201 (Arg) and 227 (Glu). To our knowledge, this is the first case described in a child of this age.

The stable transfectants of wild-type (W25) and mutant thyrotropin-receptor (TSH-R) allow detection of the bioactivities of TSH-R antibodies in Graves' patients. A mutant Chinese hamster ovary (CHO) cell line (Mc1+2) transfected with a chimeric construct, where residues 8 to 165 of the TSH-R are replaced with residues 10 to 166 of the lutropin/choriogonadotropin (LH/CGR) receptor, lacks the cyclic adenosine monophosphate (cAMP) response to most thyrotropin stimulating antibodies (TSAb), yet retains the response to TSH and acquires the response to LH/CG. We compared Mc1+2 cells with wild-type W25 cells for their ability to detect TSAb as well as thyrotropin-blocking antibodies (TBAb) in Graves' sera. Eighteen normal and 39 Graves' sera were tested for TSAb and TBAb levels by in vitro bioassays using W25 and Mc1+2 cells. In addition, these sera were also tested for thyrotropin-binding inhibitory activity (TBII) by a radioreceptor assay. Eighteen (47%) Graves' sera had TBAb activity measured with W25 cells but not with Mc1+2 cells. These TBAbs were, therefore, a population of antibodies with functional epitopes on the N-terminus of the extracellular domain. This TBAb activity by W25 cells exhibited a high degree of correlation with TBII levels by a radioreceptor assay (r = 0.70, p = 0.001). Ten (25.6%) Graves' sera had positive TBAb activity in both W25 and Mc1+2 cells; moreover, their activity in both assays was similar (r = 0.83, p < 0.001). The TBAb activity in these sera, however, did not correlate with TBII activity. Eleven (28%) Graves' sera had no TBAb activity. Overall, thyroid-stimulating antibodies were detected in 87% and 28% of the 39 Graves' sera by W25 and Mc1 +2 cells, respectively. Thus, using the 2 cell lines, at least 2 distinct populations of TBAbs were detected. One is detected in a similar fashion by both W25 and Mc1+2 cell lines and likely interacts with the epitopes residing in the unaltered C-terminus of the TSH-R. The other is reactive in W25 cells only, indicating the loss of TBAb epitope in the chimeric receptor located in the N-terminus of the TSH-R. Furthermore, our results indicate that the TBAb binding epitope in 8-165 residues of the native TSH-R is highly associated with TBII activity in Graves' disease. These results indicate that patients with Graves' disease harbor TBAbs with epitope heterogeneity and favor the notion that there are different sites and mechanisms by which TBAbs act in Graves' patients. It remains to be determined whether or not TBAb subtyping will have a useful predictive role in the management of patients with Graves' disease.

Comprehensive article summarizing more than 25 years of experience with pituitary hyperplasia in surgical material. Morphologic forms of hyperplasia--diffuse and nodular--are defined and, for comparison, the normal morphology, frequency and intraglandular distribution of cell types are briefly reviewed. All cell types can give rise to hyperplasia, although their frequency, extent and clinical importance widely vary. Somatotroph hyperplasia is rare; it is limited to cases of GHRH overproduction by extrapituitary endocrine neoplasms and sporadic examples of gigantism. Prolactin cells display the highest propensity for non-neoplastic proliferation. Physiologic hyperplasia occurs in pregnancy and lactation. Pathological hyperplasia is mostly secondary to other, neoplastic or non-neoplastic, space occupying processes. Idiopathic lactotroph hyperplasia is very rare. The much-disputed corticotroph hyperplasia is infrequent cause of pituitary dependent Cushing's disease. Despite difficulties of diagnosis in fragmented biopsies, several well-documented cases prove the existence of corticotroph hyperplasia which is nearly always nodular. Thyrotroph hyperplasia, secondary to hypothyroidism, a treatable condition, is not expected to occur in surgical material, yet several cases have been identified. Operated lesions are massive nodular leading to significant pituitary enlargement thereby mimicking TSH- or PRL-producing adenoma. Hyperprolactinemia is a frequent concomitant of severe thyrotroph hyperplasia. Gonadotroph hyperplasia and proliferation of pars intermedia derived POMC cells are not likely to occur in surgical material and have no clinical significance. Adenoma formation may rarely be associated with any type of pituitary hyperplasia.

Two of 420 patients with pituitary adenoma who underwent operation from 1989 to 1997 had thyroid stimulating hormone (TSH) producing adenoma. We investigated these TSH cell adenomas with immunohistochemical and ultrastructural methods and compared their ultrastructural features with brefeldin A (BFA, 0.5 mg/ml) treated pituitary adenoma cells. BFA-treated pituitary adenomas include a prolactin (PRL) cell adenoma, a growth hormone (GH) cell adenoma, an adrenocorticotropic hormone (ACTH) cell adenoma, a gonadotroph adenoma, and a plurihormonal adenoma. Immunohistochemical staining disclosed that one of the TSH cell adenomas produced only TSH-beta and that another produces both TSH-beta and FSH-beta. Ultrastructural analysis showed the abundance of oval-shaped dilated rough endoplasmic reticulum (rER). Within the dilated rER, the mistlike deposit or deposit along the inner margin of the rER membrane was observed. On the other hand, BFA-treated cultured pituitary adenoma cells showed the opening of the cavity of the rER cisterna and they enlarged to an oval form with time and revealed an accumulation of electron-dense deposits within the dilated rER. These ultrastructural similarities between TSH cell adenoma and BFA-treated pituitary adenoma cells indicate the functional disturbances in the secretory passage through the Golgi apparatus in TSH cell adenoma cells.

Thyroid diseases include forms amenable to alterations in genes involved in functional regulatory processes, morphofunctional development, hormogenesis and hormone functional expression. A number of genetic diseases are consequent of a point mutation, the cause of the replacement of a single nucleotide which may alter the chromosome number structure and morphology. Among structural anomalies there is deletion, duplication, inversion, translocation and isochromosome formation. Among thyroid diseases, the underlying cause of some of them is represented by alterations in genes regulating the thyroid function, alterations in genes of thyroid differentiation. Less common are the alterations in genes connected with the synthesis of proteins involved in hormone transport while alteration in genes encoding thyroid hormone receptors and in genes involved in thyroid neoplastic transformation are extensively described in literature. The studies of molecular biology will allow in-dept knowledge of the pathogenesis of thyroid disease associated to genetic alterations.

The pathologist plays an important role in the distinction of pituitary adenomas from other tumors and tumor-like lesions of the sellar region, and in the accurate morphologic characterization of pitutiary adenomas. A clinicopathologic classification of pituitary adenomas is based on cell differentiation correlated with clinical evidence of hormone secretion; this classification emphasizes clinically relevant features that can offer guidance for patient management. The application of a rational approach to the immunohistochemical analysis of these lesions can be used to evaluate pathogenetic and prognostic markers and to predict responses to specific therapeutic modalities.

Seasonal changes in the mRNA levels of glycoprotein alpha, gonadotropin (GTH) Ibeta and IIbeta, and thyrotropin (thyroid-stimulating hormone (TSH)) beta subunits in the pituitary of goldfish were quantified by Northern blot analysis and laser densitometry. Reproductive development and thyroid activity were monitored by measuring gonadosomatic index, plasma GTH II, testosterone (T), estradiol, 11-ketotestosterone, and thyroid hormones (T4 and T3). Plasma GTH II and steroids showed characteristic increases, while plasma thyroid hormones levels, in general, decreased in association with the reproductive period. In females, the mRNA levels of the alpha, GTH Ibeta, and GTH IIbeta subunits increased synchronously during early spawning period (April) and then decreased during ovarian regression (August). In males, the levels of the alpha and GTH IIbeta subunits showed changes similar to those in females, but the GTH Ibeta mRNA levels showed only a small increase during the late spawning period (May). In both sexes, TSHbeta mRNA levels were high during winter to early spring (February and April) and low during late spring to summer (May and August). These results suggest that in goldfish the gonadotropins may be synthesized synchronously in order for asynchronous gametogenesis to take place. Additionally, the data suggest a negative feedback relationship between synthesis of the TSHbeta subunit and the thyroid hormones., (Copyright 1999 Academic Press.)

The biological activities of thyroid hormones are thought to be mediated by receptors generated by the TRalpha and TRbeta loci. The existence of several receptor isoforms suggests that different functions are mediated by specific isoforms and raises the possibility of functional redundancies. We have inactivated both TRalpha and TRbeta genes by homologous recombination in the mouse and compared the phenotypes of wild-type, and single and double mutant mice. We show by this method that the TRbeta receptors are the most potent regulators of the production of thyroid stimulating hormone (TSH). However, in the absence of TRbeta, the products of the TRalpha gene can fulfill this function as, in the absence of any receptors, TSH and thyroid hormone concentrations reach very high levels. We also show that TRbeta, in contrast to TRalpha, is dispensable for the normal development of bone and intestine. In bone, the disruption of both TRalpha and TRbeta genes does not modify the maturation delay observed in TRalpha -/- mice. In the ileum, the absence of any receptor results in a much more severe impairment than that observed in TRalpha -/- animals. We conclude that each of the two families of proteins mediate specific functions of triiodothyronin (T3), and that redundancy is only partial and concerns a limited number of functions.

Elevated levels of free triiodothyronine (fT3) of 8.8 ng/dl (normal range 2.0 to 4.2) and free thyroxin (fT4) of 3.5 pg/ml (0.8 to 1.7) were found in the course of an examination of a 53-year old patient due to a planned hysterectomy. As thyrotropin (TSH) also was elevated with 5.8 mU/l (0.4 to 4.5), these findings corresponded to an inappropriate secretion of TSH (IST). Additional examinations revealed a blunted rise of TSH secretion after i.v. injection of 200 micrograms thyrotropin releasing hormone (TRH) as well as lacking suppression of TSH secretion after oral doses of 75 micrograms T3 during one week. alpha-TSH levels with 3.7 micrograms/l were elevated in comparison to a matched normal sample just as the molar ratio alpha-TSH/TSH with 6.95 and sex hormone-binding globulin (SHBG) with 175 nmol/l and showed an absence of inhibition in the T3 suppression test. These results were suggestive of neoplastic inappropriate secretion of TSH (nIST) due to a TSH-secreting pituitary adenoma. In concordance, the magnetic resonance imaging (MRI) showed a 1 cm tumor in the sella. The adenoma could also be visualized by 111In-octreotide and 123I-epidepride scintigraphies of the pituitary gland. After transsphenoidal resection, histological examination of the tumor resulted in the finding of a TSH-secreting adenoma. Postoperative TSH levels were not detectable, indicating the complete removal of the adenoma. Levels of fT3 and fT4 were slightly below normal with 1.9 pg/ml and 0.7 ng/dl, respectively. A control scintigraphy with 111In-octreotide following an equivocal MRI showed no uptake in the pituitary.

Central hypothyroidism (thyrotropic deficiency) is due to a defect in TSH secretion by thyrotrophs (or alternatively to an altered bioactivity of TSH). Central hypothyroidism is rare and is often associated with other pituitary deficiencies as it is generally encountered in case of hypothalamo-pituitary tumoral process. Clinical symptoms are milder than those of primary thyroid failure. Diagnosis is based on free T4 measurement whose level is decreased while TSH concentration is normal or minimally increased, reflecting an alteration in the bioactivity of TSH. Replacement therapy is monitored by T4 level measurement: the objective is to obtain normal T4 levels. TSH concentration must not be taken into account for the adjustment of the thyroxine doses.

The aim of this study was to determine the causes of the high heterogeneity, in the number and the length, of the thyrotropin (TSH) beta mRNA in the European eel. Northern blot analysis showed that removal of the poly(A) tail did not affect this heterogeneity. PCR amplification on reverse-transcribed pituitary RNAs (RT) showed the main source of heterogeneity to be a highly variable region in the 3' untranslated region (UTR). PCR amplification of the 3' UTR from RTs and genomic DNAs demonstrated that the high variability reflected polymorphism within the eel TSH beta gene. Isolation and sequencing of 3' UTR amplification fragments showed that the variable region comprised more or less exact repetitions of a 26-42-bp fragment. The number of repetitions varied from one allele to another. This variable region could be characterized as a minisatellite. In conclusion, instability of a minisatellite in the 3' UTR of the TSH beta gene generated the multiple and widely differing TSH beta mRNAs.

Central hyperthyroidism is a rare condition in which thyrotoxicosis results from primary overproduction of TSH by the pituitary gland with subsequent thyroid enlargement and hyperfunction. The two known causes of central hyperthyroidism are TSH-producing pituitary tumors (TSHomas) and the syndrome of PRTH. Both of these entities are characterized by clinical thyrotoxicosis, diffuse goiters, elevated circulating levels of free T4 and T3, and a nonsuppressed serum TSH. It is critical to distinguish central hyperthyroidism from the much more common types of primary hyperthyroidism, all of which have undetectable TSH values. TSHomas and PRTH can usually be differentiated from one another by measuring the serum alpha-subunit and the TSH response to intravenous TRH or exogenous thyroid hormone, and by pituitary imaging studies. TSHomas are usually benign adenomas arising from the monoclonal expansion of neoplastic thyrotropes. Causative oncogenes have not yet been convincingly identified. PRTH is a nonneoplastic disorder caused by inherited mutations in the gene for the thyroid hormone receptor beta; it is a poorly understood variant of GRTH. For unclear reasons, in PRTH, the pituitary gland is resistant to the feedback inhibitory effects of circulating thyroid hormones while peripheral tissues respond normally, causing patients to experience the toxic peripheral effects of thyroid hormone excess. TSHomas are best treated by transphenoidal surgical removal. Radiotherapy is indicated for inoperable or incompletely resected tumors. Octreotide administration is a useful adjunct for preoperatively reducing tumor size and for the medical management of surgical treatment failures. PRTH is ideally treated by chronically suppressing TSH secretion with medications such as D-thyroxine, TRIAC, octreotide, or bromocriptine. If such therapy is ineffective or unavailable, thyroid ablation with radioiodine or surgery may be employed with subsequent close monitoring of both thyroid hormone status and pituitary gland size.

Thyrotropin (TSH)-secreting pituitary adenomas cause hyperthyroxinemia in the presence of "inappropriately" elevated concentrations of TSH. TSH production under these circumstances escapes the normal negative feedback effect of thyroid hormone. We propose that this defective negative feedback is mediated by an abnormality of thyroid hormone receptor (TR) expression. Two TSH-secreting pituitary adenomas were analyzed by immunocytochemistry for TR isoform protein expression and by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) for TR isoform mRNA expression. The results obtained from these tumors were compared with the findings from six normal human pituitaries. Neither tumor examined expressed detectable levels of nuclear TRalpha or TRbeta proteins, in contrast to the normal pituitaries studied, which expressed all TR isoforms. Application of RT-PCR, however, revealed mRNAs encoding each TR isoform in all tumorous and normal tissues examined. Semiquantitative RT-PCR revealed similar levels of expression of TRalpha and TRbeta isoform mRNAs in tumors and normal tissue, in contrast to the observed difference in TR proteins. Absent TRalpha and TRbeta protein expression, in association with normal mRNA levels, implies a post-transcriptional defect in TR mRNA processing in TSH-secreting adenomas. Reduced TR expression in these tumors may explain defective negative feedback of thyroid hormone on TSH production, and may also contribute to uncontrolled tumor growth.

The GH4C1 pituitary cell line, an excellent model for a thyroid hormone action study, was used for determination of the relationship between thyroid hormone receptor occupancy and intensity of cell proliferation, prolactin (PRL) production, thyrotropin (TSH) inhibition and 3,5,3,-L-triiodothyronine (T3) receptor down-regulation. Nuclear receptor population was progressively occupied by T3 in concentrations ranging from 0.025 to 10.0 nM T3. Bmax ranged from 0.029 fmol/10(6) cells at the lowest T3 concentration to Bmax = 12.51 fmol/10(6) cells at the highest concentration. Each of the observed biological events is operative within distinct dose-response ranges in cultured GH4C1 cells. The maximal biological response (except the TSH inhibition and T3 receptor down-regulation) does not require the occupation of the whole nuclear receptor population by T3 and the intensity of none of the responses studied was directly proportional to thyroid hormone receptor occupancy.

Glucose-6-phosphatase is generally accepted as a functional component of rough endoplasmic reticulum and has been histochemically examined in many organs. The aim of this study is to know the ultracytochemical localization of glucose-6-phosphatase in each type of hormone-producing cell constituting the anterior pituitary gland in the rat. Pituitaries of male Sprague-Dawley rats were perfused with 1.5% glutaraldehyde from the left ventricles. After buffer washing 40 microns sections were incubated in the medium of Hugon et al. for 60 min at 37 degrees C. The sections were then postfixed with 1% osmium tetroxide, embedded in epoxy resin and observed under an electron microscope. The reaction product for glucose-6-phosphatase was observed in the lumen of rough endoplasmic reticulum and nuclear envelope of all anterior pituitary cells. The enzyme activities in thyroid-stimulating hormone-producing cells and luteinizing hormone/follicle-stimulating hormone-producing cells (LH/FSH cells) were stronger than those in growth hormone-producing cells and prolactin-producing cells; adrenocorticotropic hormone-producing cells and folliculo-stellate cells presented intermediate activity. In LH/FSH cells, the activity in dilated cisternae of endoplasmic reticulum had weaker density than that in flattened cisternae. In addition, substantial reaction product was also frequently observed in the cis saccules of the Golgi apparatus. These findings suggest that glucose-6-phosphatase may play different functional roles in hormone synthesis within different types of anterior pituitary cells.

Background: Cigarette smoking has been linked to thyroid disease, although studies of this problem have not shown consistent affects, with some studies linking smoking to increased thyroid hormone levels, and others to decreased thyroid hormone levels., Methods: We performed a secondary analysis of information collected from 4462 Vietnam-era male US Army veterans aged 31-49 years who participated in the Vietnam Experience Study in 1985-1986. The study group consisted of 1962 current smokers and 2406 current non-smokers who had no thyroid abnormalities on physical examination, no current use of thyroid medicine, and no history of thyroid disease., Results: We found that current smokers have higher thyroxine levels and lower thyroid stimulating hormone levels than never smokers and former smokers. The higher thyroxine levels that we detected in smokers, compared to non-smokers, diminished when we controlled for thyroxine-binding globulin and testosterone. We also found that heavy smokers had a smaller increase in thyroxine levels than did light smokers, when compared to non-smokers., Conclusions: Our findings suggest at least two distinct mechanisms for the effect of tobacco smoke on thyroid function; one related to higher levels of thyroxine-binding globulin and testosterone among smokers compared to non-smokers and another related to higher levels of thyrotoxins in tobacco smoke in heavy smokers compared to light and moderate smokers.

The iodine is indispensable element for life that is also fundamental substract for thyroid hormone synthesis which make very important influence on protein's lipid's, carbohydrate's and highly caloric substances metabolism and are a requisite of proper man development. The pregnant women are one of population group which is the most sensitive on iodine's deficiency. The results of researches indicate on insufficient iodine intake in pregnant women diet, whose take food even according to diet's recommendation given by physician. The wide iodine's prophylaxis which was provided as yet is insufficient in case of pregnant and nursing women. It is confirmed the necessity of additional iodine supplementation. A set of control tests should be done in requires cases that inform physician about changes in function and size of thyroid gland and make possible the individualization of treatment. The supplementation doses of iodine about 150 micrograms are safe and there was not observed any side effects during their taking.