The 2021 European Group on Graves' orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves' orbitopathy.

Graves' orbitopathy (GO) is the main extrathyroidal manifestation of Graves' disease (GD). Choice of treatment should be based on the assessment of clinical activity and severity of GO. Early referral to specialized centers is fundamental for most patients with GO. Risk factors include smoking, thyroid dysfunction, high serum level of thyrotropin receptor antibodies, radioactive iodine (RAI) treatment, and hypercholesterolemia. In mild and active GO, control of risk factors, local treatments, and selenium (selenium-deficient areas) are usually sufficient; if RAI treatment is selected to manage GD, low-dose oral prednisone prophylaxis is needed, especially if risk factors coexist. For both active moderate-to-severe and sight-threatening GO, antithyroid drugs are preferred when managing Graves' hyperthyroidism. In moderate-to-severe and active GO i.v. glucocorticoids are more effective and better tolerated than oral glucocorticoids. Based on current evidence and efficacy/safety profile, costs and reimbursement, drug availability, long-term effectiveness, and patient choice after extensive counseling, a combination of i.v. methylprednisolone and mycophenolate sodium is recommended as first-line treatment. A cumulative dose of 4.5 g of i.v. methylprednisolone in 12 weekly infusions is the optimal regimen. Alternatively, higher cumulative doses not exceeding 8 g can be used as monotherapy in most severe cases and constant/inconstant diplopia. Second-line treatments for moderate-to-severe and active GO include (a) the second course of i.v. methylprednisolone (7.5 g) subsequent to careful ophthalmic and biochemical evaluation, (b) oral prednisone/prednisolone combined with either cyclosporine or azathioprine; (c) orbital radiotherapy combined with oral or i.v. glucocorticoids, (d) teprotumumab; (e) rituximab and (f) tocilizumab. Sight-threatening GO is treated with several high single doses of i.v. methylprednisolone per week and, if unresponsive, with urgent orbital decompression. Rehabilitative surgery (orbital decompression, squint, and eyelid surgery) is indicated for inactive residual GO manifestations.

Does early response to intravenous glucocorticoids predict the final outcome in patients with moderate-to-severe and active Graves' orbitopathy?

PURPOSE: Intravenous glucocorticoids (ivGCs) given as 12-weekly infusions are the first-line treatment for moderate-to-severe and active Graves' orbitopathy (GO), but they are not always effective. In this study, we evaluated whether response at 6 weeks correlated with outcomes at 12 (end of intervention) and 24 (follow-up) weeks, particularly in patients initially unresponsive. METHODS: Our database (Bartalena et al. J Clin Endocrinol Metab 97:4454-4463, 10), comprising 159 patients given three different cumulative doses of methylprednisolone (2.25, 4.98, 7.47 g) was analyzed, pooling data for analyses. Responses at 6 weeks were compared with those at 12 and 24 weeks using three outcomes: overall ophthalmic involvement [composite index (CI)]; quality of life (QoL); Clinical Activity Score (CAS). Responses were classified as "Improved", "Unchanged", "Deteriorated", compared to baseline. RESULTS: Deteriorated patients at 6 weeks for CI (n = 8) remained in the same category at 12 weeks and 7/8 at 24 weeks. Improved patients at 6 weeks for CI (n = 51) remained in the same category in 63% and 53% of cases at 12 and 24 weeks, respectively. Unchanged patients at 6 weeks (n = 100) eventually improved in 28% of cases (CI), 58% (CAS), 32% (QoL). There was no glucocorticoid dose-dependent difference in the influence of early response on later outcomes. CONCLUSIONS: Patients who deteriorate at 6 weeks after ivGCs are unlikely to benefit from continuing ivGCs. Patients unresponsive at 6 weeks still have a significant possibility of improvement later. Accordingly, they may continue ivGC treatment, or, alternatively, possibly stop ivGCs and be switched to a second-line treatment.

No causal relationship between Yersinia enterocolitica infection and autoimmune thyroid disease: evidence from a prospective study.

The objective of this study was to evaluate prospectively the relationship between Yersinia enterocolitica (YE) infection and the development of overt autoimmune hypo- or hyperthyroidism (study A) and the de novo occurrence of thyroid antibodies (study B). This was a prospective cohort study of 790 euthyroid women who were first- or second-degree relatives of autoimmune thyroid disease (AITD) patients. Follow-up was 5 years, with annual assessments. Study A was a nested case-control study in which YE serological status was measured between cases {subjects who developed overt hypothyroidism [thyroid stimulating hormone (TSH) > 5·7 mU/l and free T4 (FT4) < 9·3 pmol/l] or overt hyperthyroidism (TSH < 0·4 mU/l and FT4 > 20·1 pmol/l)} and matched controls. For study B, 388 euthyroid women without thyroid antibodies at baseline were enrolled. The YE serological status was compared between subjects who developed thyroid peroxidase (TPO)-antibodies and/or thyroglobulin (Tg)-antibodies at 4-year follow-up and those who remained negative. For study A, the proportion of subjects positive for Yersinia enterocolitica outer membrane protein (YOP) immunoglobulin (Ig)G or YOP IgA did not differ between cases and controls at baseline. One year before the development of overt hypo- or hyperthyroidism, the proportion of subjects with YOP IgG was not different between cases and controls, but YOP IgA were less prevalent in cases. For study B, de novo occurrence of TPO (or TPO-antibodies and/or Tg-antibodies) did not differ between subjects in whom YOP IgG were positive or negative at baseline. Neither persistence nor emergence of YOP IgG at 4-year follow-up was associated with the occurrence of TPO-antibodies or Tg-antibodies. Similar results were observed with respect to YOP IgA. YE infection does not contribute to an increased risk of thyroid autoimmunity.

Acute inflammation increases pituitary and hypothalamic glycoprotein hormone subunit B5 mRNA expression in association with decreased thyrotrophin receptor mRNA expression in mice.

The biological function of thyrostimulin, consisting of the GPA2 and GPB5 subunit, is currently poorly understood. The recent observation that pro-inflammatory cytokines up-regulate the transcription of GPB5 in vitro suggested a role for thyrostimulin in the nonthyroidal illness syndrome, a state of altered thyroid hormone metabolism occurring during illness. In the present study, we used GPB5 knockout (GPB5(-/-) ) and wild-type (WT) mice to evaluate the role of GPB5 in the pituitary and hypothalamus during acute inflammation induced by lipopolysaccharide (LPS, bacterial endotoxin) administration. We evaluated serum thyroid hormones and mRNA expression of genes involved in thyroid hormone metabolism in the pituitary and in two hypothalamic regions; the periventricular region (PE) and the arcuate nucleus/median eminence region. As expected, LPS administration increased deiodinase type 2 mRNA in the PE, at the same time as decreasing pituitary thyrotrophin (TSH)ß mRNA and serum thyroxine and triiodothyronine both in GPB5(-/-) and WT mice. GPB5 mRNA, but not GPA2 mRNA, markedly increased after LPS in the pituitary (200-fold) and hypothalamus of WT mice. In addition, we found large (>50%) suppression of TSH receptor (TSHR) mRNA in the pituitary and hypothalamus of WT mice but not in GPB5(-/-) mice. In conclusion, our results demonstrate in vivo regulation of central GPB5 transcription during acute illness. The observed differences between GPB5(-/-) and WT mice point to a distinct role for GPB5 in pituitary and hypothalamic TSHR suppression during acute illness.

Glucocorticoid administration for Graves' hyperthyroidism treated by radioiodine. A questionnaire survey among members of the European Thyroid Association.

BACKGROUND: Glucocorticoid prophylaxis is required in some instances after radioiodine (RAI) treatment for Graves' hyperthyroidism to prevent progression of Graves' orbitopathy (GO). However, no randomized clinical trial has been performed to ascertain the optimum glucocorticoid therapy. AIM AND METHODS: Aim of this study was to perform a questionnaire-based survey of glucocorticoid prophylaxis among European thyroidologist members of the European Thyroid Association. RESULTS: Eighty-two responses from 25 European Countries were received. Two respondents did not prescribe steroids in any clinical scenario, while 8 gave the drug to all patients receiving RAI therapy. The majority of respondents only gave glucocorticoids to patients showing some degree of ocular involvement or if risk factors for the progression of GO after RAI were present (e.g., cigarette smoking); 24% of responses indicated that clinicians would not give glucocorticoids if patients were thought to have no GO or inactive GO. Ninety-one percent of clinicians used prednisone (53%) or prednisolone (38%). The mean starting dose [given for 16 days (range 2-60 days)] was 37.6 mg prednisone or prednisone-equivalent (range 15-80 mg). Overall, the results of this survey showed a wide diversity in the regimens used, in terms of timing of initiation of treatment, duration of treatment, cumulative doses of administered glucocorticoids and monitoring of side-effects of glucocorticoid treatment. CONCLUSIONS: The results of this study underscore the need for randomized clinical trials to ascertain the optimum regimen of prophylactic glucocorticoid therapy.

Skeletal muscle deiodinase type 2 regulation during illness in mice.

We have previously shown that skeletal muscle deiodinase type 2 (D2) mRNA (listed as Dio2 in MGI Database) is upregulated in an animal model of acute illness. However, human studies on the expression of muscle D2 during illness report conflicting data. Therefore, we evaluated the expression of skeletal muscle D2 and D2-regulating factors in two mouse models of illness that differ in timing and severity of illness: 1) turpentine-induced inflammation, and 2) Streptococcus pneumoniae infection. During turpentine-induced inflammation, D2 mRNA and activity increased compared to pair-fed controls, most prominently at day 1 and 2, whereas after S. pneumoniae infection D2 mRNA decreased. We evaluated the association of D2 expression with serum thyroid hormones, (de-)ubiquitinating enzymes ubiquitin-specific peptidase 33 and WD repeat and SOCS box-containing 1 (Wsb1), cytokine expression and activation of inflammatory pathways and cAMP pathway. During chronic inflammation the increased muscle D2 expression is associated with the activation of the cAMP pathway. The normalization of D2 5 days after turpentine injection coincides with increased Wsb1 and tumor necrosis factor alpha expression. Muscle interleukin-1beta (Il1b) expression correlated with decreased D2 mRNA expression after S. pneumoniae infection. In conclusion, muscle D2 expression is differentially regulated during illness, probably related to differences in the inflammatory response and type of pathology. D2 mRNA and activity increases in skeletal muscle during the acute phase of chronic inflammation compared to pair-fed controls probably due to activation of the cAMP pathway. In contrast, muscle D2 mRNA decreases 48 h after a severe bacterial infection, which is associated with local Il1b mRNA expression and might also be due to diminished food-intake.

Evaluation of endocrine tests. D: the prolonged fasting test for insulinoma.

OBJECTIVE: To establish the diagnostic performance of the prolonged fasting test in patients suspected of insulinoma. METHODS: We included all patients who were referred to our department between August 1995 and August 2006 with a clinical suspicion of insulinoma. Insulinoma was diagnosed by a positive Whipple's triad during the prolonged fast in combination with an insulin/C-peptide ratio below 1. The presence of insulinoma was confirmed by histopathological data, which was considered the golden standard. If the prolonged fast was negative, long-term follow-up was obtained. RESULTS: Ten patients had a positive Whipple's triad during the prolonged fast: eight had a histologically proven insulinoma, and two had factitious hypoglycaemia (insulin/C-peptide ratio >1.0) One additional patient likely had an insulinoma, but the Whipple's triad remained absent at up to 56 hours of fasting. Follow-up (median 53 months (3 to 142) in 76% of patients with a negative fasting test revealed no missed cases of insulinoma. During the prolonged fast the glucose, insulin and C-peptide concentrations overlapped in patients with and without insulinoma. CONCLUSION: In our centre, the prolonged fasting test defined as a positive Whipple's triad in combination with an insulin/C-peptide ratio <1 had a sensitivity of 88.9% and a specificity of 100% for the diagnosis of insulinoma.

Graves' orbitopathy in a patient with adrenoleukodystrophy after bone marrow transplantation.

OBJECTIVE: For many years, the treatment of X-linked childhood cerebral adrenoleukodystrophy (XALD) consisted of hydrocortisone replacement and a mixture of short chain-fatty acids, known as 'Lorenzo's oil'. Recently, bone marrow transplantation (BMT) has also been used. CASE REPORT: We report the case of a patient affected by XALD who developed Graves' hyperthyroidism (GH) and Graves' orbitopathy (GO) after BMT and who we could follow-up for 6.5 years afterwards. EVIDENCE SYNTHESIS: A boy affected by XALD was treated at the age of 6 years, with a whole BMT from his sister. One year after BMT, the transplanted patient presented TSH at the lower normal value and 3 years later he developed thyrotoxicosis. After a further 2 years, the patient developed GO, which showed clinical evidence of reactivation 5 years after its onset as a consequence of an attempt to treat thyrotoxicosis by means of I(131) (300 MBq). Seven years after BMT, the donor showed alterations of thyroid autoimmunity and 1 year thereafter she developed GH. She never presented GO during a subsequent 5 year follow-up. CONCLUSIONS: This case illustrates that autoimmunity originating from a pre-symptomatic donor can be transferred into the host during allogeneic stem cell transplantation. In cases where autoimmune phenomena are recognized in the donor prior to donation, alternative donors or T-cell manipulation of the graft might be considered.

Higher maternal TSH levels in pregnancy are associated with increased risk for miscarriage, fetal or neonatal death.

BACKGROUND: To examine the relationship between maternal TSH and free thyroxine (FT(4)) concentrations in early pregnancy and the risk of miscarriage, fetal or neonatal death. METHOD: Cohort study of 2497 Dutch women. TSH, FT(4), and thyroid peroxidase antibodies concentrations were determined at first booking. Child loss was operationalized as miscarriage, fetal or neonatal death. Women with overt thyroid dysfunction were excluded. RESULTS: Twenty-seven cases of child loss were observed. The mean TSH and FT(4) level in the women with child loss was 1.48 mU/l and 9.82 pmol/l compared with 1.11 mU/l and 9.58 pmol/l in women without child loss. The incidence of child loss increased by 60% (OR=1.60 (95% confidence interval (CI): 1.04-2.47)) for every doubling in TSH concentration. This association remained after adjustment for smoking, age, parity, diabetes mellitus, hypertension, previous preterm deliveries, and previous preterm stillbirth/miscarriage (adjusted odds ratio=1.80 (95% CI: 1.07-3.03)). This was not true for FT(4) concentrations (OR=1.41 (95% CI: 0.21-9.40); P=0.724). CONCLUSION: In a cohort of pregnant women without overt thyroid dysfunction, the risk of child loss increased with higher levels of maternal TSH. Maternal FT(4) concentrations and child loss were not associated.

Evaluation of Endocrine Tests. C: glucagon and clonidine test in phaeochromocytoma.

BACKGROUND: The diagnosis of phaeochromocytoma is based on the demonstration of catecholamine excess. Urine and plasma metanephrine measurements are highly sensitive tests for the diagnosis of phaeochromocytoma, but moderate elevations in metanephrines lack optimal specificity. In this study we aimed to evaluate the diagnostic value of additional tests, i.e. glucagon stimulation and clonidine suppression test, in patients with moderately elevated catecholamines and/or metanephrines. METHODS: Patients with suspected phaeochromocytoma with moderately elevated catecholamines and/or metanephrines in plasma or urine were subjected to the glucagon stimulation and clonidine suppression test. The presence of phaeochromocytoma was confirmed by histology and the absence by a disease-free extended follow-up. RESULTS: Fifty-five patients were included. Phaeochromocytoma was diagnosed in 11 patients. The follow-up period in patients without phaeochromocytoma was 56 (19 to 154) months. The sensitivity of the glucagon test was 30% and the specificity 100%. The clonidine test had no discriminative power, because the area under the ROC curve was not significantly different from 0.5. CONCLUSION: The clonidine suppression test without normetanephrine measurements and the glucagon stimulation test are not sensitive enough to safely exclude phaeochromocytoma in patients with mildly elevated plasma or urine catecholamines.

Outcome of orbital decompression for disfiguring proptosis in patients with Graves' orbitopathy using various surgical procedures.

AIM: To compare the outcome of various surgical approaches of orbital decompression in patients with Graves' orbitopathy (GO) receiving surgery for disfiguring proptosis. METHOD: Data forms and questionnaires from consecutive, euthyroid patients with inactive GO who had undergone orbital decompression for disfiguring proptosis in 11 European centres were analysed. RESULTS: Eighteen different (combinations of) approaches were used, the swinging eyelid approach being the most popular followed by the coronal and transconjunctival approaches. The average proptosis reduction for all decompressions was 5.0 (SD 2.1) mm. After three-wall decompression the proptosis reduction was significantly greater than after two-wall decompression. Additional fat removal resulted in greater proptosis reduction. Complications were rare, the most frequent being worsening of motility, occurring more frequently after coronal decompression. The average change in quality of life (QOL) in the appearance arm of the GO-QOL questionnaire was 20.5 (SD 24.8) points. CONCLUSIONS: In Europe, a wide range of surgical approaches is used to reduce disfiguring proptosis in patients with GO. The extent of proptosis reduction depends on the number of walls removed and whether or not fat is removed. Serious complications are infrequent. Worsening of ocular motility is still a major complication, but was rare in this series after the swinging eyelid approach.

Thr92Ala polymorphism in the type 2 deiodinase is not associated with T4 dose in athyroid patients or patients with Hashimoto thyroiditis.

OBJECTIVE: The type 2 deiodinase (D2)-Thr92Ala polymorphism has been associated with decreased D2 activity in some in vitro experiments but not in others. So far no association between the D2-Thr92Ala polymorphism and serum thyroid hormone levels has been observed in humans, but in a recent study in athyroid patients, it was suggested that patients homozygous for the Ala(92) allele needed higher T4 doses to achieve TSH suppression. We studied the association between the D2-Thr92Ala polymorphism with thyroid hormone levels and T4 dosage, in patients treated for differentiated thyroid carcinoma (DTC) and in a group of patients treated for Hashimoto thyroiditis. DESIGN: Cross-sectional study. PATIENTS: We studied 154 patients with DTC treated with TSH suppressive thyroid hormone replacement therapy for longer than 3 years and 141 patients with Hashimoto thyroiditis treated for at least 6 months with T4. MEASUREMENTS: In all patients, serum levels of TSH, free T4, T3 and reverse T3 were measured and genotypes of the D2-Thr92Ala polymorphism were determined by Taqman assay. Univariate regression analysis was performed to determine the relation between T4 dosages and the D2-Thr92Ala polymorphism corrected for age, gender, BMI and serum TSH levels. RESULTS: Both in DTC patients and Hashimoto patients, no association was observed between serum thyroid hormone levels or T4 dosages in presence of the D2-Thr92Ala polymorphism. Categorization of DTC patients according to degree of TSH suppression did not change these results. CONCLUSION: The D2-Thr92Ala polymorphism is not associated with thyroid hormone levels or T4 dose in patients treated for DTC or Hashimoto thyroiditis.

Goserelin-induced transient thyrotoxicosis in a hypothyroid woman on L-thyroxine replacement.

An increase in free thyroxine (fT4) and a decrease in thyroid-stimulating hormone (TSH) was observed in a hypothyroid woman on levothyroxine treatment after implantation of goserelin, a gonadotropin-releasing hormone (GnRH) analogue. In the literature no data are available that describe a drug interaction between GnRH analogues and thyroid hormone replacement. Our hypothesis to explain this observation is that goserelin decreased serum thyroxine-binding-globulin (TBG), resulting in an increase in fT4 and thereby a decrease in serum TSH.

Thyroid function disorders--Guidelines of the Netherlands Association of Internal Medicine.

Thyroid function disorders are common with a female to male ratio of 4 to 1. In adult women primary hypothyroidism and thyrotoxicosis have a prevalence of 3.5/1000 and 0.8/1000, respectively. This guideline is aimed at secondary care providers especially internists, but also contains relevant information for interested general practitioners and gynaecologists. A multidisciplinary working group, containing delegates of professional and patient organisations, prepared the guideline. According to principles of 'evidence-based medicine' available literature was studied and discussed. Considering the availability and quality of published studies a practical advice was formulated. For a full overview of the literature and considerations the reader is referred to the original version of the guideline (accessible through NIV-net). In this manuscript we have aimed to provide the practicing internist with practical and 'as evidence-based as possible' treatment guidelines with respect to thyroid function disorders.

Hypermetabolism in Gaucher disease type I is not associated with altered thyroid hormone levels.

Type I Gaucher disease (OMIM 231000) is an inherited storage disorder in which deficiency of the enzyme glucocerebrosidase (EC 32145) leads to accumulation of glucocerebroside in lysosomes of macrophages. These storage cells are present in liver, spleen and bone marrow resulting in hepatosplenomegaly, cytopenia and bone complications. Metabolic abnormalities in Gaucher patients include hypermetabolism, possibly caused by elevated levels of pro-inflammatory cytokines. Nonthyroidal illness (NTI) is a combination of changes in circulating thyroid hormone levels (decreased T(3), elevated rT(3), normal or mildly depressed TSH) present in different illnesses and might be an adaptation to protect the organism from harmful catabolic effects of hypermetabolism. The hypermetabolism and the elevated cytokine levels in Gaucher disease led us to hypothesize that the alterations in thyroid hormone levels as seen in NTI might also occur in Gaucher patients. We studied thyroid hormone levels before and during treatment in 22 adult type I Gaucher patients and resting energy expenditure (REE) and correlations with thyroid hormone levels in 12 patients. Baseline thyroid hormone levels were normal in the majority (17) of patients. No cases of nonthyroidal illness were detected. Baseline REE (kcal/kg per 24 h) was not correlated with circulating levels of T(3), rT(3) or fT(4). Treatment of Gaucher disease with enzyme replacement therapy for several years resulted in a decrease in circulating fT(4) levels. After several months of treatment most patients showed a decrease in REE. There was no correlation between the changes in REE and changes in fT(4) and T(3).

Interleukin-1beta modulates endogenous thyroid hormone receptor alpha gene transcription in liver cells.

One of the main characteristics of nonthyroidal illness (NTI) is a decrease in serum triiodothyronine, partly caused by a decrease in liver deiodinase type 1 (D1) mRNA and activity. Proinflammatory cytokines have been associated with NTI in view of their capability to decrease D1 and thyroid hormone receptor (TR)beta1 mRNA expression in hepatoma cells. Proinflammatory cytokine induction leads to activation of the inflammatory pathways nuclear factor (NF)kappaB and activator protein (AP)-1. The proinflammatory cytokine interleukin (IL)-1beta decreases thyroid hormone receptor (TR)beta1 mRNA in an NFkappaB-dependent way. The aim of this study was to unravel the effects of IL-1beta on endogenous TRalpha gene expression in an animal model and in a liver cell line. The TRalpha gene product is alternatively spliced in TRalpha1 and TRalpha2, TRalpha2 is capable of inhibiting TRalpha1-induced gene transcription. We showed that both TRalpha1 and TRalpha2 mRNA decreased not only after lipopolysaccharide administration in liver of mice, but also after IL-1beta stimulation of hepatoma cells (HepG2). Using the NFkappaB inhibitor sulfasalazine and the AP-1 inhibitor SP600125, it became clear that the IL-1beta-induced decrease in TRalpha mRNA expression in HepG2 cells can only be abolished by simultaneous inhibition of NFkappaB and AP-1. The IL-1beta-induced TRalpha1 and TRalpha2 mRNA decrease in HepG2 cells is the result of decreased TRalpha gene promoter activity, as evident from actinomycin D experiments. Cycloheximide experiments showed that the decreased promoter activity is independent of de novo protein synthesis and therefore most likely due to posttranslational modifications such as phosphorylation or subcellular relocalization.

Effect of amiodarone and dronedarone administration in rats on thyroid hormone-dependent gene expression in different cardiac components.

OBJECTIVE: In view of their different actions on thyroid hormone receptor (TR) isoforms we set out to investigate whether amiodarone (AM) and dronedarone (Dron) have different and/or component-specific effects on cardiac gene expression. DESIGN: Rats were treated with AM or Dron and the expression of TRalpha 1, TRalpha 2, TRbeta 1 and several tri-iodothyronine (T3)-regulated genes was studied in different parts of the heart, namely the right atrium (RA), left ventricular wall (LVW) and apex. METHODS: Rats were treated for 14 days with 100 mg/kg body weight AM or Dron. The expression of TRalpha 1, TRalpha 2, TRbeta 1 and T3-regulated genes was studied using real-time PCR and non-radioactive in situ hybridisation. RESULTS: AM and Dron affected TR expression in the RA similarly by decreasing TRalpha 1 and beta 1 expression by about 50%. In the LVW, AM and Dron decreased TRbeta 1 and, interestingly, AM increased TRalpha 1. In the apex, AM also increased TRalpha 2. The changes seen in T3-dependent gene expression are reminiscent of foetal reprogramming. CONCLUSION: Taken together, our results indicate that AM and Dron have similar effects on the expression of TR isoforms in the RA, which could partly contribute to their ability to decrease heart rate. On the other hand, the more profound effect of AM appears on TR- and T3-dependent gene expression in the left ventricle suggests foetal reprogramming.

Ethnic differences in TSH but not in free T4 concentrations or TPO antibodies during pregnancy.

OBJECTIVE: To describe the TSH, free T4 and thyroid peroxidase antibody (TPO-Ab) concentrations during pregnancy among four ethnic groups and to determine reference values for these parameters during normal pregnancy. METHODS: Cross-sectional study of a cohort of 3270 pregnant women living in the city of Amsterdam. Blood samples were drawn at first booking in the first or second trimester. TSH, free T4 and TPO-Ab concentrations were determined. Four ethnic groups were studied: Dutch, Surinam, Turkish and Moroccan. RESULTS: Plasma TSH increased and free T4 decreased from the first to the second trimester of pregnancy for all the ethnic groups. Ethnic differences were observed in TSH concentrations, with Dutch females having the highest TSH levels compared to the other three ethnic groups. The median TSH difference was 0.16 mU/l between the Dutch and Moroccan women, 0.15 mU/l between the Dutch and Surinam women and 0.10 mU/l between the Dutch and Turkish women. These could not be explained by differences in age, parity and current smoking status. No differences were seen in free T4 concentrations between the four ethnic groups. The prevalence of TPO-Ab was comparable across the ethnic groups (about 6% in each); the concentration of TPO-Ab was also comparable among the ethnic groups. The Dutch women had a higher lower-limit (2.5 percentile) of the TSH reference range than the Surinam, Turkish and Moroccan women, ranging from 0.14 mU/l for the Surinam and Moroccan to 0.27 mU/l for the Dutch women. CONCLUSION: The increase in TSH and decrease in free T4 values during pregnancy correspond to previous reported studies. Pregnant Dutch women had consistently higher TSH values than the ethnic group, but corresponding free T4 levels and TPO-Ab did not differ between these ethnic groups.

PGC-1alpha regulates the isoform mRNA ratio of the alternatively spliced thyroid hormone receptor alpha transcript.

Transcripts derived from the thyroid hormone receptor alpha (TRalpha) gene are alternatively spliced resulting in a functional receptor TRalpha1 and a non-T3-binding variant TRalpha2 that can exert a dominant negative effect on the transactivation functions of other TRs. There is evidence that the ratio of TRalpha isoform transcripts can be modulated and here, we investigate whether the PPARgamma co-activator alpha (PGC-1alpha) has an effect on this splicing process. PGC-1alpha was discovered not only as a transcriptional co-activator, but also has certain motifs characteristic of splicing factors. We demonstrate that PGC-1alpha alters the ratio of endogenously expressed TRalpha isoform transcripts in HepG2 cells, by decreasing TRalpha1 mRNA levels twofold. This change in isoform ratio is accompanied by a decrease in 5'-deiodinase expression, whereas no differences were found in TRbeta1 expression. Deletion of the RNA-processing domain of PGC-1alpha abrogated the effect on the TRalpha splicing, whereas expression of only the RNA-processing domain favored TRalpha1 expression. PGC-1alpha showed a similar effect on the splicing of a TRalpha minigene containing only the last four exons and introns of the TRalpha gene. These data suggest that PGC-1alpha is involved in the RNA processing of TRalpha transcripts.