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Thyroid function after assisted reproductive technology in women free of thyroid disease.

OBJECTIVE: To evaluate thyroid function in women undergoing a first assisted reproductive technology (ART) procedure and to compare women with ongoing pregnancy or miscarriage. DESIGN: Prospective cohort study. SETTING: Tertiary referral center. PATIENT(S): Seventy-seven women free of thyroid disease. INTERVENTION(S): Serum TSH and FT4 were determined before and 2, 4, and 6 weeks after ET. All women received the same ART protocol. MAIN OUTCOME MEASURE(S): Thyroid function. RESULT(S): Forty-five women had ongoing pregnancies, and 32 suffered a miscarriage after 6.7 weeks (range 5-11). Mean age and number of ET were similar in both groups. Compared with baseline values, TSH and FT4 increased significantly 2 weeks after ET (ongoing pregnancies group: TSH 2.5 +/- 1.3 vs. 1.6 +/- 0.8 mU/L and FT4 13.8 +/- 1.4 vs. 12.4 +/- 1.8 ng/L; miscarriage group: TSH 2.1 +/- 1.0 vs. 1.5 +/- 0.7 mU/L and FT4 14.2 +/- 2.0 vs. 12.4 +/- 1.9 ng/L). Pregnancy outcome did not affect thyroid function and its evolution over time. CONCLUSION(S): In women free of thyroid diseases, thyroid function changed significantly after ART, but these changes were not different between women with ongoing pregnancy and miscarriage.

Abortion, Spontaneous↗

Characterization of novel non-clonal intrachromosomal rearrangements between the H4 and PTEN genes (H4/PTEN) in human thyroid cell lines and papillary thyroid cancer specimens.

The two main forms of RET rearrangement in papillary thyroid carcinomas (PTC) arise from intrachromosomal inversions fusing the tyrosine kinase domain of RET with either the H4 (RET/PTC1) or the ELE1/RFG genes (RET/PTC3). PTEN codes for a dual-specificity phosphatase and maps to chromosome 10q22-23. Germline mutations confer susceptibility to Cowden syndrome whereas somatic mutations or deletions are common in several sporadic human tumors. Decreased PTEN expression has been implicated in thyroid cancer development. We report the characterization of a new chromosome 10 rearrangement involving H4 and PTEN. The initial H4/PTEN rearrangement was discovered as a non-specific product of RT-PCR for RET/PTC1 in irradiated thyroid cell lines. Sequencing revealed a transcript consisting of exon 1 and 2 of H4 fused with exons 3-6 of PTEN. Nested RT-PCR with specific primers bracketing the breakpoints confirmed the H4/PTEN rearrangements in irradiated KAT-1 and KAT-50 cells. Additional H4/PTEN variants, generated by recombination of either exon 1 or exon 2 of H4 with exon 6 of PTEN, were found in non-irradiated KAK-1, KAT-50, ARO and NPA cells. Their origin through chromosomal recombination was confirmed by detection of the reciprocal PTEN/H4 product. H4/PTEN recombination was not a clonal event in any of the cell lines, as Southern blots with appropriate probes failed to demonstrate aberrant bands, and multicolor FISH of KAK1 cells with BAC probes for H4 and PTEN did not show a signal overlap in all cells. Based on PCR of serially diluted samples, the minimal frequency of spontaneous recombination between these loci was estimated to be approximately 1/10(6) cells. H4/PTEN products were found by nested RT-PCR in 4/14 normal thyroid tissues (28%) and 14/18 PTC (78%) (P<0.01). H4/PTEN is another example of recombination involving the H4 locus, and points to the high susceptibility of thyroid cells to intrachromosomal gene rearrangements. As this also represents a plausible mechanism for loss-of-function of PTEN, other thyroid neoplastic phenotypes and eventually other cancer types need to be screened for clonal H4/PTEN rearrangements.

Chromosome Mapping↗

Thyroid autoimmune disease: demonstration of thyroid antigen-specific B cells and recombination-activating gene expression in chemokine-containing active intrathyroidal germinal centers.

Autoimmune thyroid disease--Hashimoto thyroiditis and Graves' disease--patients produce high levels of thyroid autoantibodies and contain lymphoid tissue that resembles secondary lymphoid follicles (LFs). We compared the specificity, structure, and function of tonsil and lymph node LFs with those of the intrathyroidal LFs to assess the latter's capability to contribute to autoimmune response. Thyroglobulin and thyroperoxidase binding to LFs indicated that most intrathyroidal LFs were committed to response to thyroid self-antigens and were associated to higher levels of antibodies to thyroglobulin, thyroperoxidase, and thyroid-stimulating hormone receptor. Intrathyroidal LFs were microanatomically very similar to canonical LFs, ie, they had well-developed germinal centers with mantle, light, and dark zones and each of these zones contained B and T lymphocytes, follicular dendritic and interdigitating dendritic cells with typical phenotypes. Careful assessment of proliferation (Ki67) and apoptosis (terminal dUTP nick-end labeling) indicators and of the occurrence of secondary immunoglobulin gene rearrangements (RAG1 and RAG2) confirmed the parallelism. Unexpected high levels of RAG expression suggested that receptor revision occurs in intrathyroidal LFs and may contribute to generate high-affinity thyroid autoantibodies. Well-formed high endothelial venules and a congruent pattern of adhesion molecules and chemokine expression in intrathyroidal LFs were also detected. These data suggest that ectopic intrathyroidal LFs contain all of the elements needed to drive the autoimmune response and also that their microenvironment may favor the expansion and perpetuation of autoimmune response.

Adult↗

Dimethylsulfoxide maintains human thyroid cells in suspension culture, facilitating synthesis and release of thyroid hormone.

Usually, human thyrocytes in primary culture rapidly lose their thyroid function and fail to synthesize or release thyroid hormone after 3-5 days of culture. By culturing thyroid follicles obtained from patients with Graves' disease in medium supplemented with TSH and a low concentration of fetal calf serum (1%), thyrocytes can maintain thyroid function for several days. We have found that the addition of dimethylsulfoxide to culture medium (1.7%) furthermore enhanced and maintained thyroid function (de novo synthesis and release of [125I] thyroxine) for more than 13 days, probably by inhibiting dedifferentiation of thyrocytes. The present bioassay will be also useful for detecting thyroid stimulating immunoglobulin in patients with Graves' disease.

Cell Survival↗

Sarcoidosis of the thyroid gland manifested initially as thyroid tumor.

A rare case of a patients with sarcoidosis of the thyroid gland, who was preoperatively diagnosed as having thyroid carcinoma and who had no other clinical features of sarcoidosis, is reported. Thyroidectomy specimen revealed numerous noncaseating, epithelioid granulomas in the thyroid tissue. Mycobacteria, fungi and foreign body material were not identified. Similar granulomas were also found in the lymph nodes and muscular tissue adjacent to the thyroid gland and parathyroid gland After the diagnosis of sarcoidosis of the thyroid, systemic examination failed to reveal any involvement in other sites, including lung, eye and skin. This case demonstrated that sarcoidosis can manifest initially as a thyroid tumor with no other evidence of disease.

Aged↗

Productivity of thyroglobulin and thyroid hormone on human thyroid cell in collagen gel culture.

Thyroid cells obtained from 21 normal human thyroid tissue samples and 17 tissue samples from diseased thyroid, including one of Graves disease, 4 with follicular adenoma, 11 with papillary carcinoma, and 1 with follicular carcinoma, were cultured in collagen gel, and ability to produce thyroglobulin (Tg), triiodothyronine (T3) and thyroxine (T4) was determined. Changes in morphological characteristics and production of Tg, T3, and T4 induced by addition of thyroid stimulating hormone (TSH) to medium in collagen gel culture were also determined. Twenty of all cases exhibited positive reaction for Tg. No relationship was found between rate of positivity for Tg and pathologic diagnosis. Three with carcinoma showed positive reaction for T3, and 4 with carcinoma showed positive reaction for T4. Only for normal thyroid cells did addition of TSH to medium induce increase the percentage of colonies producing Tg or T4 and morphological changes including an enlarged follicular lumen and increase in the height of columnar epithelium. These findings suggest that thyroid cells in collagen culture develop in an in vivo-like fashion. In conclusion, collagen has important effects on cellular differentiation when included in extracellular matrix.

Adenoma↗

Thyroid cell apoptosis. A new understanding of thyroid autoimmunity.

Apoptosis is a highly regulated mechanism of cell death involved in normal development, immune regulation, and homeostasis. Abnormal apoptotic activity has been implicated in a variety of diseases including cancer, autoimmunity, and degenerative disorders. In the thyroid, altered cell death may play a role in the pathogenesis of autoimmune disorders such as Hashimoto's thyroiditis and Graves' disease. Apoptosis-signaling pathways can be initiated through activation of death receptors or in response to cellular damage, such as in gamma irradiation. It has been demonstrated that Fas, tumor necrosis factor, and tumor necrosis factor-related apoptosis-inducing ligand pathways are present and functional in the thyroid, although the expression of these molecules and their roles in thyroid autoimmunity have been debated. Thyroid apoptosis is regulated at multiple levels, including receptor and ligand expression, and the expression of antiapoptotic proteins, such as FAP-1 and Bcl-2. These factors may provide potential mechanisms for modifying the pathogenesis of autoimmune thyroid disease.

Animals↗

Effect of thyroid hormone on growth. Lessons from the syndrome of resistance to thyroid hormone.

Thyroid hormone deprivation results in deleterious effects on bone growth. The delayed bone development is mediated by a direct effect of thyroid hormone on bone and an indirect effect of the hormone on GH release and IGF-1 action. Both TR alpha and TR beta are expressed in bone cells. To examine the role of TR beta on bone, we have reviewed the growth abnormalities in the human syndrome of RTH caused by mutations in the TR beta gene. The mutant TR beta reduces the tissue responsiveness to thyroid hormone, producing in some tissues variable degrees of thyroid hormone deprivation. With regard to bone, relative thyroid hormone deficiency caused by the mutant TR beta produces short stature and delayed bone growth but does not attenuate growth to the extent that absolute thyroid hormone deficiency does. These observations indicate that an intact TR beta is required for normal bone development and growth.

Bone and Bones↗

Effect of coenzymes and thyroid hormones on the dual activities of Xenopus cytosolic thyroid-hormone-binding protein (xCTBP) with aldehyde dehydrogenase activity.

A cytosolic thyroid-hormone-binding protein (xCTBP), predominantly responsible for the major binding activity of T3 in the cytosol of Xenopus liver, has been shown to be identical to aldehyde dehydrogenase class 1 (ALDH1) [Yamauchi, K., Nakajima, J., Hayashi, H., Horiuchi, R. & Tata, J.R. (1999) J. Biol. Chem. 274, 8460-8469]. Within this paper we surveyed which signaling, and other, compounds affect the thyroid hormone binding activity and aldehyde dehydrogenase activity of recombinant Xenopus ALDH1 (xCTBP/xALDH1) while examining the relationship between these two activities. NAD+ and NADH (each 200 microm), and two steroids (20 microm), inhibit significantly the T3-binding activity, while NADH and NADPH (each 200 microm), and iodothyronines (1 microm), inhibit the ALDH activity. Scatchard analysis and kinetic studies of xCTBP/xALDH1 indicate that NAD+ and T3 are noncompetitive inhibitors of thyroid-hormone-binding and ALDH activities, respectively. These results indicate the formation of a ternary complex consisting of the protein, NAD+ and thyroid hormone. Although the in vitro studies indicate that NAD+ and NADH markedly decrease T3-binding to xCTBP/xALDH1 at approximately 10-4 m, a concentration equal to the NAD content in various Xenopus tissues, photoaffinity-labeling of [125I]T3 using cultured Xenopus cells demonstrates xCTBP/xALDH1 bound T3 within living cells. These results raise the possibility that an unknown factor(s) besides NAD+ and NADH may modulate the thyroid-hormone-binding activity of xCTBP/xALDH1. In comparison, thyroid hormone, at its physiological concentration, would poorly modulate the enzyme activity of xCTBP/xALDH1.

Aldehyde Dehydrogenase↗

What should we do? Papillary thyroid carcinoma in a lymph node but normal thyroid tissue--how should we proceed?

Papillary cell carcinoma of the thyroid is a relatively indolent disease, usually presenting as an asymptomatic mass in the thyroid gland that is either noted by the patient or diagnosed at routine clinical examination. Although the prognosis is generally good there are a number of controversies in the management of this condition. The significance of age at presentation, size of the tumour and the presence of lymph node metastasis are still disputed. We present the unusual case of a woman found to have papillary cell thyroid carcinoma within a lymph node during a cosmetic thyroid lobectomy. The thyroid tissue removed was not found to contain tumour. We describe the evidence behind the decision to proceed to total thyroidectomy and the finding of a tiny focus of papillary cell thyroid carcinoma within the contralateral lobe.

Adult↗

Recombinant thyrotropin versus thyroid hormone withdrawal in evaluating patients with thyroid carcinoma.

Patients with previously treated thyroid carcinoma require lifelong monitoring for recurrent disease. Two diagnostic tests that play a central role in follow-up of these patients--radioiodine whole body scanning and serum thyroglobulin measurement--are most accurate during thyroid-stimulating hormone (TSH) stimulation. Temporary discontinuation of thyroid hormone therapy was previously the sole effective approach for TSH-stimulated testing. However, hormone withdrawal was associated with the morbidity of hypothyroidism and occasional tumor progression. The introduction of recombinant TSH (rTSH)-stimulated testing offers an alternative therapy. Recent clinical trials have shown that the sensitivity of combined rTSH-stimulated radioiodine scanning and serum thyroglobulin measurement has equivalent sensitivity to testing after thyroid hormone withdrawal. Furthermore, measurement of the rTSH-stimulated thyroglobulin concentration is a more sensitive way to detect residual thyroid cancer or normal tissue than thyroglobulin measurement on thyroid hormone therapy alone. The results of these trials are reviewed and strategies for implementing rTSH-mediated testing are presented.

Hormone Replacement Therapy↗

[Ultrasound for differentiated carcinoma of the thyroid, autonomous adenoma and thyroiditis (author's transl)].

The article deals with a number of thyroid abnormalities which produce similar sonographic patterns, characterised by a paucity of echos of low amplitude. It concerns three more or less circumscribed changes (differentiated carcinoma of the thyroid, autonomous adenoma and focal thyroiditis) and two diffuse thyroid conditions (sub-acute and lymphocytic diffuse thyroiditis, hyperthyroidism). Carcinoma of the thyroid is of particular interest. The distinguishing features and differential diagnosis are discussed.

Diagnosis, Differential↗

Role of the thyroid-stimulating hormone receptor signaling in development and differentiation of the thyroid gland.

The thyroid-stimulating hormone/thyrotropin (TSH) is the most relevant hormone in the control of thyroid gland physiology in adulthood. TSH effects on the thyroid gland are mediated by the interaction with a specific TSH receptor (TSHR). We studied the role of TSHTSHR signaling on gland morphogenesis and differentiation in the mouse embryo using mouse lines deprived either of TSH (pit(dw)pit(dw)) or of a functional TSHR (tshr(hyt)tshr(hyt) and TSHR-knockout lines). The results reported here show that in the absence of either TSH or a functional TSHR, the thyroid gland develops to a normal size, whereas the expression of thyroperoxidase and the sodium/iodide symporter are reduced greatly. Conversely, no relevant changes are detected in the amounts of thyroglobulin and the thyroid-enriched transcription factors TTF-1, TTF-2, and Pax8. These data suggest that the major role of the TSH/TSHR pathway is in controlling genes involved in iodide metabolism such as sodium/iodide symporter and thyroperoxidase. Furthermore, our data indicate that in embryonic life TSH does not play an equivalent role in controlling gland growth as in the adult thyroid.

Animals↗

Thyroid-stimulating antibodies and thyroid stimulation-blocking antibodies during the pregnancy and postpartum period: a case report.

This report describes a unique pattern of changes in thyroid function and thyroid antibodies in a woman during the course of two pregnancies and two postpartum periods. A 25-year-old woman developed hypothyroidism in the postpartum period after the delivery of her first child. She was found to have potent thyroid stimulation-blocking antibodies (TSBAb) in the serum. One year later, she became pregnant again, and during the pregnancy, TSBAb had decreased to an undetectable level. She gave birth to the second healthy child and developed postpartum thyrotoxicosis, probably due to destruction of the thyroid gland, which gradually resolved. In this postpartum period, serum TSBAb levels increased. Eight months postpartum, she developed what appeared to be Graves' disease with an elevated 123I-thyroid uptake. Serum thyroid-stimulating antibodies (TSAb) were found at that time, and the TSBAb had disappeared from her serum.

Adult↗

Thyroid evaluation of hospitalized psychiatric patients: the role of TSH screening for thyroid dysfunction.

The incidence and pattern of changes in thyroid function tests were studied in acutely hospitalized psychiatric patients and the cost effectiveness of a systematic screening program for thyroid dysfunction was estimated. Thyroid testing was performed on 1275 of 1424 (90%) admissions to the psychiatric wing of Strong Memorial Hospital between April 1, 1993 and March 30, 1994. Discharge samples were obtained in 232 patients who were hospitalized at least 2 days; 163 patients were admitted multiple times. Psychiatric diagnosis was coded using DSM-III-R criteria. TSH, T4, free T4, and T3 levels were measured within 48 h of admission. TSH values were most frequently abnormal (7.8%) and free T4 the least (1.3%). Admission and discharge thyroid tests were similar. Significant differences in the four parameters of thyroid function were present among the psychiatric groups. By analysis of variance every 1 microU/mL increase in TSH levels was associated with a 2.5% increase in length of stay (LOS) (95% confidence intervals: 0.21%, 4.75%), holding psychiatric diagnosis, age, and gender constant. For patients with elevated TSH levels, the average LOS was increased by 10.7 days (95% confidence intervals: 2.8, 18.7 days). It is concluded that patients hospitalized for psychiatric illness have an incidence of thyroid dysfunction at or slightly higher than the general population. However, patients with elevated TSH levels are hospitalized longer than those with normal or suppressed values.

Adolescent↗

An improved assay method for thyroid peroxidase applicable for a few milligrams of abnormal human thyroid tissues.

A peroxidase assay method (Mini assay method) which is applicable for a minute amount (as small as a few mg) of thyroid tissue was developed, employing guaiacol or iodide as the second substrate. This method is a modification of the previous one (Ordinary assay method): the volume of the reaction mixture was reduced to about one-tenth with prior solubilization of the enzyme. The correlation between the Mini assay and Ordinary assay methods, and between the guaiacol and iodide assays by both methods were satisfactorily good, but the iodine content of thyroglobulin was found to be not directly correlated to the peroxidase activities. Protein-based specific activities of peroxidase from normal human thyroid tissue were about 0.030 guaiacol units/mg protein and 0.0066 iodide units/mg protein, which were slightly higher than those of porcine thyroid tissue. The Mini assay method developed in the present study was used for the determination of peroxidase activity in a small amount (1-8 mg) of thyroid tissue obtained by means of a needle biopsy from patients with thyroid disorders. One specimen (goitrous cretinism) showed no peroxidase activity in both the guaiacol and iodide assays, and three specimens (two chronic thyroiditis, one familial nontoxic goiter) possessed no ability to catalyze the oxidation of iodide in spite of the high reactivity towards guaiacol, suggesting the presence of an abnormal peroxidase in these tissues.

Animals↗

Tall cell papillary thyroid carcinoma metastatic to femur: evidence for thyroid hormone synthesis within the femur.

A 67-year old man with a 3-month history of left hip pain had a history of Graves disease, treated with 131I 20 years before admission, and papillary thyroid carcinoma, treated with cervical lymphadenopathy 9 years before admission. Removal of a 3.5- x 5-cm mass from the left femur revealed it to be a tall cell variant of papillary thyroid carcinoma. Removal of this mass resulted in his thyrotropin level increasing from 2 (presurgery) to 23 mIU/mL, whereas his thyroxine level simultaneously decreased from 5.79 (presurgery) to 2.29 microg/dL 12 days after surgery despite continuation of levothyroxine of 0.137 mg/day. On histological examination, the tall cell variant in the femur was producing abundant thyroglobulin. This first case of a metastatic papillary thyroid carcinoma in bone producing thyroid hormone to the extent that the patient became hypothyroid after removal of this metastasis illustrates that metastatic thyroid lesion(s) may produce significant amounts of thyroid hormone.

Aged↗

Individual thyroid dose estimation for a case-control study of Chernobyl-related thyroid cancer among children of Belarus-part I: 131I, short-lived radioiodines (132I, 133I, 135I), and short-lived radiotelluriums (131MTe and 132Te).

Large amounts of radioiodines were released into the atmosphere during the accident at the Chernobyl nuclear power plant on 26 April 1986. In order to investigate whether the thyroid cancers observed among children in Belarus could have been caused by radiation exposures from the Chernobyl accident, a team of Belarusian, Russian, and American scientists conducted a case-control study to compare cases and controls according to estimated thyroid dose. The primary purpose of this paper is to present detailed information on the estimated thyroid doses, due to intakes of 131I, that were used in the case-control study. The range of the 131I thyroid doses among the 107 cases and the 214 controls was found to extend from 0.00002 to 4.3 Gy, with medians of approximately 0.2 Gy for the cases and 0.07 Gy for the controls. In addition, the thyroid doses resulting from the intakes of short-lived radioiodines (132I, 133I, and 135I) and radiotelluriums (131mTe and 132Te) were estimated and compared to the doses from 131I. The ratios of the estimated thyroid doses from the short-lived radionuclides and from I for the cases and the controls range from 0.003 to 0.1, with median values of approximately 0.02 for both cases and controls.

Body Burden↗