Chemical Hybridization of Glucagon and Thyroid Hormone Optimizes Therapeutic Impact for Metabolic Disease.

Glucagon and thyroid hormone (T3) exhibit therapeutic potential for metabolic disease but also exhibit undesired effects. We achieved synergistic effects of these two hormones and mitigation of their adverse effects by engineering chemical conjugates enabling delivery of both activities within one precisely targeted molecule. Coordinated glucagon and T3 actions synergize to correct hyperlipidemia, steatohepatitis, atherosclerosis, glucose intolerance, and obesity in metabolically compromised mice. We demonstrate that each hormonal constituent mutually enriches cellular processes in hepatocytes and adipocytes via enhanced hepatic cholesterol metabolism and white fat browning. Synchronized signaling driven by glucagon and T3 reciprocally minimizes the inherent harmful effects of each hormone. Liver-directed T3 action offsets the diabetogenic liability of glucagon, and glucagon-mediated delivery spares the cardiovascular system from adverse T3 action. Our findings support the therapeutic utility of integrating these hormones into a single molecular entity that offers unique potential for treatment of obesity, type 2 diabetes, and cardiovascular disease.

Screening for drugs potentially interfering with MCT8-mediated T3 transport in vitro identifies dexamethasone and some commonly used drugs as inhibitors of MCT8 activity.

BACKGROUND: Monocarboxylate transporter 8 (MCT8) is the first thyroid hormone transporter that has been linked to a human disease. Besides genetic alterations other factors might impair MCT8 activity. AIM: This study aimed at investigating whether some common drugs having a structural similarity with TH and/or whose treatment is associated with thyroid function test abnormalities, or which behave as antagonists of TH action can inhibit MCT8-mediated T3 transport. METHODS: [125I]T3 uptake and efflux were measured in COS-7 cells transiently transfected with hMCT8 before and after exposure to increasing concentrations of hydrocortisone, dexamethasone, prednisone, prednisolone, amiodarone, desethylamiodarone, dronedarone, buspirone, carbamazepine, valproic acid, and L-carnitine. The mode of inhibition was also determined. RESULTS: Dexamethasone significantly inhibited T3 uptake at 10 µM; hydrocortisone reduced T3 uptake only at high concentrations, i.e. at 500 and 1000 µM; prednisone and prednisolone were devoid of inhibitory potential. Amiodarone caused a reduction of T3 uptake by MCT8 only at the highest concentrations used (44% at 50 µM and 68% at 100 µM), and this effect was weaker than that produced by desethylamiodarone and dronedarone; buspirone resulted a potent inhibitor, reducing T3 uptake at 0.1-10 µM. L-Carnitine inhibited T3 uptake only at 500 mM and 1 M. Kinetic experiments revealed a noncompetitive mode of inhibition for all compounds. All drugs inhibiting T3 uptake did not affect T3 release. CONCLUSION: This study shows a novel effect of some common drugs, which is inhibition of T3 transport mediated by MCT8. Specifically, dexamethasone, buspirone, desethylamiodarone, and dronedarone behave as potent inhibitors of MCT8.

Effects of treatment with haloperidol and clozapine on the plasma concentrations of thyroid hormones in rats.

OBJECTIVES: Psychoactive drugs are group of compounds used to treat severe mental problems, including psychosis, as well as other conditions. This study assessed clinically relevant side effects of haloperidol and clozapine on the thyroid hormones. METHODS: Haloperidol (0.05 and 2 mg/kg) or clozapine (0.5 and 20 mg/kg) was intraperitoneally injected to male Wistar rats for 28 days. The control group received 2 ml of physiological saline. A chemiluminescent immunoassay was used to measure the plasma levels of thyroid hormones. RESULTS: Plasma concentrations of thyroxine (T4) in rats treated with high-dose (2 mg/kg) of haloperidol decreased significantly compared to the control group (p=0.001). However, both low (0.5 mg/kg) and high clozapine (20 mg/kg) doses did not have a significant effect on the plasma concentrations of T4 and triiodothyronine (T3) (p>0.05). Neither of the compound had a significant effect on T3 plasma concentration levels (p>0.05). CONCLUSIONS: Haloperidol and clozapine act via different mechanisms and may have dissociable effects on thyroid hormones. Following treatment with haloperidol, significant changes in T4, but not in T3, serum levels were observed. Haloperidol and clozapine had different effects on the thyroid hormone levels. These results indicate that antipsychotic treatment can contribute to the thyroid dysfunction. Therefore, greater caution should be applied to the antipsychotics use. The thyroid function of the patients should be closely monitored, while using these drugs.

The Joint Effects of Bisphenols and Iodine Exposure on Thyroid during Pregnancy.

The aim of this research was to study the combined effects of bisphenols and iodine exposure on the thyroid gland during pregnancy. We included 162 pregnant women from a cohort established in Shanghai. Urinary concentrations of bisphenol A, bisphenol B(BPB), bisphenol C(BPC), bisphenol F, bisphenol S, and bisphenol AF(BPAF) were examined. Bayesian kernel machine regression (BKMR) and quantile g-computation models were used. The geometric means of BPA, BPB, BPC, BPF, BPS, BPAF, and ΣBPs levels in urine were 3.03, 0.24, 2.66, 0.36, 0.26, 0.72, and 7.55 µg/g creatinine, respectively. We observed a positive trend in the cumulative effects of BPs and iodine on serum triiodothyronine (FT3) and free thyroxine (FT4), as well as a U-shaped dose-response relationship between BPs and the probability of occurrence of thyroperoxidase autoantibody positivity in women with low urinary iodine concentration. In addition, a synergistic effect on the probability of occurrence of thyroid autoantibody positivity was observed between BPF and BPB, as well as between BPC and BPAF in this study. There were adverse health effects on the thyroid after co-exposure to BPs and iodine. Even if pregnant women were exposed to lower levels of BPs, women with iodine deficiency remained vulnerable to thyroid autoimmune disease.

[Effect of selenium on serum TGAb, TMAb, FT3, FT4 and TSH of rats with excessive intake of iodine].

OBJECTIVE: To investigate the effect of selenium on the TGAb, TMAb, FT3, FT4 and TSH level of rats with excessive intake of iodine. METHODS: Wistar rats were divided into three groups by random:normal control, high iodine group and high iodine plus selenium group. Rats in the high iodine plus selenium group were lavaged with sodium selenite for 10 weeks. The levels of serum TGAb, TMAb, FT3, FT4 and TSH were tested at different time of the experiment. RESULTS: There were no significant change on levels of FT3, FT4 and TSH (P > 0.05). The levels of TGAb and TMAb in the high iodine group were increased slowly (P < 0.05), but no significant change was observed in the high iodine plus selenium group. CONCLUSION: Excessive intake of iodine might induce goiter, and selenium might have antagonistic effect on it.

Assessment of biotin interference in thyroid function tests.

The aim of the study was to systematically characterize the interference of biotin on thyroid function tests and biotin washout periods.Ten healthy adults were recruited with administration of 5 and 10 mg/d biotin for 7 days. Analyte concentrations of thyroid function tests were measured at baseline prior to starting biotin and from 2 hours to 2 days after withdrawal of 5 and 10 mg/d biotin. The outcomes were compared the baseline with the several points after taking biotin at Roche cobas e602, Beckman UniCel DxI 800, and Abbott Architect 2000 immunoassay platforms, respectively.Ingesting 5 or 10 mg/d of biotin for 7 days could produce positive or negative interference among the thyroid function tests at Roche cobas e602 and Beckman UniCel DxI 800 systems, but no interference on Abbott Architect 2000. Interference duration of 5 mg/d biotin for Roche cobas e602 and Beckman UniCel DxI 800 of thyroid function tests lasted for 8 hours, while 10 mg/d biotin interfered with Roche cobas e602 or Beckman UniCel DxI 800 for 1 day or 2 days.This study provides valuable guidance on biotin washout periods at doses common in over-the-counter supplements necessary to avoid false assay results.Trial registration: ChiCTR1800020472.

Bisphenol A and thyroid hormones: Bibliometric analysis of scientific publications.

Bisphenol A (BPA) is a well-known endocrine-disrupting chemical which can cause potential health risks and interfere with thyroid hormones through multiple avenues. This study aimed to evaluate the hotspots and emerging trends on BPA and thyroid hormones by using a bibliometric method.Publications related on BPA and thyroid hormones were downloaded from Science Citation Index-Expanded database. Annual outputs, high yield journals, countries, institutions, authors and their cited times were summarized. In addition, keywords co-occurrence, burst references and citation networks were bibliometric analyzed.From 2000 to 2019, 418 articles were published. Both of the Environment International and Environmental Health Perspectives, United States, Chinese Academy of Sciences and Antonia M. Calafat were the most recorded journals, countries, institutions and authors, respectively. The main research area was Toxicology. In addition of the retrieve term "bisphenol-a" and "thyroid-hormone", "in-vitro", "exposure" and "endocrine disruptors", were the hotspot keywords and "triclosan", "oxidative stress" and "united-states" were the most recent trends keywords. "Thyroid hormone action is disrupted by Bisphenol A as an antagonist" published on The Journal of Clinical Endocrinology & Metabolism by Kenji Moriyama in 2002 got both the highest burst score and citation score. Six groups were clustered and the mechanism of BPA's effect on thyroid hormones, and the exposure of BPA and potential risks in children and pregnant women were the two main large fields.The number of publications in the field of BPA and thyroid hormones has increased tremendously since 2000. The research hotspot ranged from mechanism researches in animal models to epidemiological studies. "Thyroid hormone action is disrupted by bisphenol A as an antagonist" of Kenji Moriyama provided important building blocks in the field. The impact of BPA on thyroid hormones, especially pregnant women and children, was the latest research frontiers and might be the future direction of this filed in the following years.

In vivo identification of promoter elements and transcription factors mediating activation of hepatic HMG-CoA reductase by T3.

The promoter elements and transcription factors necessary for triiodothyronine (T3) induction of hepatic HMG-CoA reductase (HMGR) were investigated by transfecting rat livers with wild type and mutant HMGR promoter-luciferase constructs using in vivo electroporation. Mutations in the sterol response element (SRE), nuclear factor-y (NF-Y) site, and the newly identified upstream transcription factor-2 (USF-2) site essentially abolished the T3 response. Chromatin immunoprecipitation (ChIP) analysis demonstrated that T(3) treatment caused a 4-fold increase in in vivo binding of USF-2 to the HMGR promoter. Co-transfection of the wild type HMGR promoter with siRNAs to USF-2, SREBP-2, or NF-Y nearly abolished the T3 induction, as measured by promoter activity. These data provide in vivo evidence for functional roles for USF-2, SREBP-2, and NF-Y in mediating the T3-induction of hepatic HMGR transcription.

Thyroid hormone homeostasis in brain: possible involvement of adrenergic phenomenon in adult rat.

BACKGROUND: Imbalance in thyroid hormone concentrations has been linked with profound neurobehavioral alterations in the adult. Peripheral hypothyroidism is associated with a phenomenon of central thyroid hormone homeostasis in adult rat. This central homeostasis mechanism could be maintained by adrenergic interplay due to close physiological association between sympathetic nervous system activity and thyroid hormones. The central homeostasis is characterized by increased cerebrocortical synaptosomal T(3) content, deiodinase type II (DII) activity, and cAMP content. METHODS: We injected specific alpha- and beta-adrenergic receptor (AR) agonists and antagonists along with an anti-thyroid drug to find out any AR-mediated action on central homeostasis. RESULTS: The alpha(2)-AR agonist did not alter the onset of central homeostasis, but prolonged its duration. Similar prolongation was observed with alpha(2)-AR antagonist and beta-AR agonist, but these compounds amplified the normal anti-thyroid drug-induced rise in cerebrocortical T(3) content on the day of onset of central homeostasis. Injections of the beta-AR antagonist did not cause any perturbations. All these observations have been supported by parallel changes in cerebrocortical DII activity, cAMP and [Ca(2+)](i) content. CONCLUSION: There emerges a close correlation between cerebral T(3) content, DII activity, cAMP and [Ca(2+)](i) content that are regulated by the AR system. Thus, thyroid hormone homeostasis in the adult mammalian brain is maintained primarily by the beta-adrenergic pathway along with an unexpected pharmacological involvement of the alpha-ARs.

Effect of difluoromethylornithine on thyroid function in rats.

BACKGROUND: A variety of stimuli cause a rapid increase in polyamine synthesis by increasing an enzyme ornithine decarboxylase required for the biosynthetic pathway of protein synthesis. Difluoromethyl ornithine is a selective inhibitor of this enzyme and hence arrests cell replication strikingly. Its effects on thyroid gland are studied with respect to change in animal's weight and levels of Triiodothyronine, Thyroxine and Thyroid stimulating hormone. The study was conducted to evaluate the inhibitory effects of Di-fluoromethyl ornithine (DFMO) administration on polyamine metabolism of thyroid gland in rats. METHODS: The study was conducted on rats weighing 248 to 320 grams, divided into control and DFMO treated group. A dose of 50 mg/rat was administered subcutaneously to the treated group for 5 consecutive days and placebo (normal saline) injections to control group. On sixth day, blood was collected by cardiac puncture and serum was separated. Serum T3, T4 and TSH were analyzed with the help of radioimmunoassay in both groups. RESULTS: In treated group there was a fall in T3, T4 concentration with significant rise in TSH concentration as compared to control group. CONCLUSION: DFMO (Difluoro methyl ornithine) decreases cellular proliferation of thyroid gland as is assessed by decrease in thyroid hormone levels. The hypothalamo pituitary thyroid axis however remains intact as is shown by a feedback rise in TSH concentration. DFMO can thus be employed for anti-neoplastic clinical trials on account of interference with activity of ODC (Ornithine Decarboxylase) fundamental for polyamine biosynthesis.

Comparison of thyroid hormone disruption potentials by bisphenols A, S, F, and Z in embryo-larval zebrafish.

Several structural analogues of bisphenol A (BPA), e.g., bisphenol F (BPF), bisphenol S (BPS), and bisphenol Z (BPZ), have been used as its substitutes in many applications and consequently detected in the environment, and human specimen such as urine and serum. While BPA has been frequently reported for thyroid hormone disruption in both experimental and epidemiological studies, less is known for the BPA analogues. In the present study, thyroid hormone disrupting effects of BPF, BPS and BPZ, were investigated, and compared with those of BPA, using embryo-larval zebrafish (Danio rerio). At 120 hpf, significant increases in T3 and/or T4 were observed in the larval fish following exposure to BPA, BPF, or BPS. Moreover, transcriptional changes of the genes related to thyroid development (hhex and tg), thyroid hormone transport (ttr) and metabolism (ugt1ab) were observed as well. Thyroid hormone (T4) disruption by BPF was observed even at the concentration (2.0 mg/L) lower than the effective concentration determined for BPA (>2.0 mg/L). Delayed hatching was observed by all tested bisphenols. Our results clearly show that these BPA analogues can disrupt thyroid function of the larval fish, and their thyroid hormone disruption potencies could be even greater than that of BPA. The concentrations which disrupt thyroid function of the larval fish were orders of magnitude higher than those occurring in the ambient environment. However, thyroid hormone disruption by longer term exposure and its consequences in the fish population, deserve further investigation.

Propranolol inhibits myocardial infarction-induced brown adipose tissue D2 activation and maintains a low thyroid hormone state in rats.

Considering the recognized role of thyroid hormones on the cardiovascular system during health and disease, we hypothesized that type 2 deiodinase (D2) activity, the main activation pathway of thyroxine (T4)-to-triiodothyronine (T3), could be an important site to modulate thyroid hormone status, which would then constitute a possible target for ß-adrenergic blocking agents in a myocardial infarction (MI) model induced by left coronary occlusion in rats. Despite a sustained and dramatic fall in serum T4 concentrations (60-70%), the serum T3 concentration fell only transiently in the first week post-infarction (53%) and returned to control levels at 8 and 12 weeks after surgery compared to the Sham group (P<0.05). Brown adipose tissue (BAT) D2 activity (fmol T4·min-1·mg ptn-1) was significantly increased by approximately 77% in the 8th week and approximately 100% in the 12th week in the MI group compared to that of the Sham group (P<0.05). Beta-blocker treatment (0.5 g/L propranolol given in the drinking water) maintained a low T3 state in MI animals, dampening both BAT D2 activity (44% reduction) and serum T3 (66% reduction in serum T3) compared to that of the non-treated MI group 12 weeks after surgery (P<0.05). Propranolol improved cardiac function (assessed by echocardiogram) in the MI group compared to the non-treated MI group by 40 and 57%, 1 and 12 weeks after treatment, respectively (P<0.05). Our data suggested that the beta-adrenergic pathway may contribute to BAT D2 hyperactivity and T3 normalization after MI in rats. Propranolol treatment maintained low T3 state and improved cardiac function additionally.

Cleavage Region Thyrotropin Receptor Antibodies Influence Thyroid Cell Survival In Vivo.

Background: Graves' disease is associated with thyrotropin receptor (TSHR) antibodies of variable bioactivity. Recently, antibodies have been characterized that bind to the cleavage region of the TSHR ectodomain (C-TSHR-Ab), and their ability to induce thyroid cell apoptosis in vitro via excessive cell stress involving multiple organelles was demonstrated. Methods: To investigate the in vivo effects of C-TSHR-Ab, first a murine monoclonal antibody (mAb) directed against residues 337 to 356 of the TSHR cleavage region was developed, and then it was injected into mice. Results: These injections caused reduced serum total triiodothyronine and thyroxine and increased TSH levels compared to control mAb-injected mice. The C-TSHR-mAb induced histological evidence of endoplasmic reticulum stress, mitochondrial stress, and apoptosis in the thyroid glands. C-TSHR-mAb-mediated apoptosis was associated with cellular infiltrates consisting mostly of macrophages, dendritic cells, and neutrophils, while T- and B-lymphocytes were scarce. In addition, in the treated mouse thyroid tissue, hyper-citrullination of histone H3 was also found. This is known to occur via peptidylarginine deiminase 4 and plays an important role in the formation of neutrophil extracellular traps, which are likely to be partly responsible for thyroid infiltration, as seen in many autoimmune diseases. Examination of thyroid tissue from patients with Graves' disease also showed increased stress and some thyrocyte apoptosis compared to normal thyroid tissues. Conclusions: The fact that the C-TSHR-mAb induced accumulation of macrophages, neutrophils, and dendritic cells indicates that innate immunity plays a central role in shaping the adaptive immune response to the TSHR. In addition, this study provides further evidence that the hinge region of the TSHR ectodomain is intimately involved in the immune response in autoimmune thyroid disease.

Effects of in utero exposure to 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153) on somatic growth and endocrine status in rat offspring.

Exposure to polychlorobiphenyl (PCB) mixtures at an early stage of development has been reported to affect endocrine glands; however, little is known about the precise toxicological properties of individual PCB. The present study was undertaken to determine whether prenatal exposure to 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153), a di-ortho-substituted non-coplanar congener, affects postnatal development in rat offspring. Pregnant Sprague-Dawley rats (Crj: CD (SD) IGS) were given PCB 153 (0, 16, or 64 mg/kg/day) orally from gestational day (GD) 10 through GD 16, and developmental parameters in the male and female offspring were examined. We found no dose-dependent changes in body weight, body length (nose-anus length), tail length, or the weights of kidneys, testes, ovaries and uterus in offspring at 1 or 3 weeks of age. Liver weights were increased in the PCB 153-treated groups, although we observed a significant difference only in males. Anogenital distance was unaffected in the PCB 153-treated groups. We observed a significant dose-dependent decrease in the plasma concentrations of thyroxine and tri-iodothyronine, whereas those of thyroid-stimulating hormone were not significantly changed. In addition, there were no dose-dependent changes in plasma concentrations of growth hormone and insulin-like growth factor-I in any dose group. These findings suggest that prenatal exposure to PCB 153 (GD 10-16, 16-64 mg/kg/day) may alter the thyroid status in rat offspring to some extent without affecting somatic growth or its related hormonal parameters.

Safety of topical methimazole for the treatment of melasma. Transdermal absorption, the effect on thyroid function and cutaneous adverse effects.

Methimazole is an oral antithyroid compound that exhibits a skin-depigmenting effect when used topically. However, the effect of topical methimazole on thyroid function has not been reported. This study was aimed at assessing the safety of topical methimazole used to treat pigmented lesions, without affecting thyroid hormones due to systemic delivery. The pharmacokinetics of methimazole, either applied in the form of a 5% topical formulation to facial skin or taken orally in the form of a 5-mg tablet by 6 volunteers, were determined. In addition, the effect of long-term topical applications of 5% methimazole on the function of the thyroid gland in 20 patients with epidermal melasma was determined following 6 weeks of once-daily application. Cutaneous adverse effects of topical methimazole were determined. From 15 min up to 24 h after application, methimazole was undetectable in the serum of the individuals receiving single topical methimazole dosing. Methimazole, however, was detected in serum after 15 min of oral administration and remained detectable in serum up to 24 h after administration. Long-term topical methimazole applications in melasma patients did not induce any significant changes in serum TSH, free thyroxine and free triiodothyronine levels. Topical methimazole was well tolerated by the patients and did not induce any significant cutaneous side effects. Present data together with the previously shown non-cytotoxic and non-mutagenic characteristics of methimazole indicate that this agent could be considered as a safe skin-depigmenting compound for topical treatment of skin hyperpigmentary disorders in humans.

Impact of Drinking Water Fluoride on Human Thyroid Hormones: A Case- Control Study.

The elevated fluoride from drinking water impacts on T3, T4 and TSH hormones. The aim was study impacts of drinking water fluoride on T3, T4 and TSH hormones inYGA (Yazd Greater Area). In this case- control study 198 cases and 213 controls were selected. Fluoride was determined by the SPADNS Colorimetric Method. T3, T4 and TSH hormones tested in the Yazd central laboratory by RIA (Radio Immuno Assay) method. The average amount of TSH and T3 hormones based on the levels of fluoride in two concentration levels 0-0.29 and 0.3-0.5 (mg/L) was statistically significant (P = 0.001 for controls and P = 0.001 for cases). In multivariate regression logistic analysis, independent variable associated with Hypothyroidism were: gender (odds ratio: 2.5, CI 95%: 1.6-3.9), family history of thyroid disease (odds ratio: 2.7, CI 95%: 1.6-4.6), exercise (odds ratio: 5.34, CI 95%: 3.2-9), Diabetes (odds ratio: 3.7, CI 95%: 1.7-8), Hypertension (odds ratio: 3.2, CI 95%: 1.3-8.2), water consumption (odds ratio: 4, CI 95%: 1.2-14). It was found that fluoride has impacts on TSH, T3 hormones even in the standard concentration of less than 0.5 mg/L. Application of standard household water purification devices was recommended for hypothyroidism.

Possible protective effect of curcumin on the thyroid gland changes induced by sodium fluoride in albino rats: light and electron microscopic study.

OBJECTIVES: Thyroid gland regulates the body's metabolic rate and plays an exquisitely important role in the human health. Fluoride exposure can affect thyroid function. Curcumin is a potent antioxidant that works through several mechanisms. The aim of the present study was to demonstrate the hormonal, histological, and ultrastructural changes occurred in the thyroid gland induced by exposure to sodium fluoride (NaF) and study the possible protective effect of curcumin on the NaF-induced effects. METHODS: Thirty male albino rats were randomly divided into 3 equal groups (10 rats each): the control group, NaF group, and NaF+Curcumin (NaF+Cur) group. Thyroid-stimulating hormone (TSH), triiodothyronine (T3) and thyroxine (T4) levels were assayed and thyroid tissues processed for light and transmission electron microscopic study. RESULTS: In NaF group, serum T3 and T4 levels were significantly decreased whereas TSH level was significantly increased compared to the control group. Thyroid tissues showed flattening of the epithelial lining with several follicular cell degenerations, hyperplasia, decreased colloid, disrupted basement membrane, cytoplasmic vacuolations, degenerated mitochondria, widening of rough endoplasmic reticulum cisternae, and vascular congestion compared to the control group. In the NaF+Cur group, serum TSH levels were significantly decreased in comparison with NaF group and no significant difference in comparison with the control group. Thyroid sections appeared apparently normal compared to the control group and NaF group. CONCLUSIONS: Sodium fluoride affected both the function and structure of the thyroid gland while curcumin was protective against these toxic effects.

Influence of female sex hormones on thyroid parameters determined in a thyroid screening.

This is a cross-sectional study with a non-randomly selected population to ascertain the influence of female sex hormones on thyroid function. TSH, TT4, FT4, TT3 and FT3 were determined in 251 women using either oral hormonal contraceptives or hormone replacement treatment, 255 women not taking either, and a control group of 900 men. Women with normal thyroid morphology using oral hormonal contraceptives in the pre-menopausal group had a significantly higher TT4 and TT3, and lower FT3, respectively, than both non-users and men. FT4 and TSH remained unchanged. In the peri-/post-menopausal group, thyroid function of women using hormone replacement treatment was not significantly different from non-users, but either women still had a significantly lower FT3 than men. We conclude that oral hormonal contraceptives and hormone replacement treatment increase TT4 and TT3 and do not influence FT4 and TSH. They decrease FT3 which is in contrast to what would be expected theoretically and what has been observed in earlier studies.

Apigenin (4',5,7-trihydroxyflavone) regulates hyperglycaemia, thyroid dysfunction and lipid peroxidation in alloxan-induced diabetic mice.

The potential of apigenin (4',5,7-trihydroxyflavone) in regulating hyperglycaemia, thyroid dysfunction and lipid peroxidation (LPO) has been revealed. While in alloxan-treated diabetic animals, a significant decrease in the concentrations of serum insulin, thyroxine (T(4)) and triiodothyronine (T(3)), with a parallel increase in serum glucose and hepatic glucose-6-phospatase (G-6-Pase) activity, was observed, administration of 0.78 mg kg(-1) of apigenin for 10 consecutive days increased the levels of serum insulin and thyroid hormones with a parallel decrease in glucose concentration and hepatic G-6-Pase activity. Alloxan-induced elevation in serum cholesterol was also reduced by the compound. With respect to LPO, while in alloxan-treated animals an increase in hepatic LPO and a decrease in the activity of cellular antioxidants, such as catalase (CAT) and superoxide dismutase (SOD), and in glutathione (GSH) content was observed, administration of apigenin to alloxan-treated mice reversed all these changes, suggesting its hepatoprotective potential. Similar effects of apigenin were also observed in most of the parameters in normoglycaemic animals. It appears that apigenin has a potential to regulate diabetes mellitus, as well as disease-induced thyroid dysfunction and lipid peroxidation.

Sorafenib-Induced Changes in Thyroid Hormone Levels in Patients Treated for Hepatocellular Carcinoma.

Context: The pathogenesis of tyrosine kinase inhibitor-induced thyroid hormone (TH) alterations are still a matter of debate. Objective: The objective of this study was to determine the effects of sorafenib on TH levels in patients with hepatocellular carcinoma (HCC) and to evaluate possible mechanisms. Design: We performed a prospective cohort study between 2009 and 2016. Setting: This study was conducted at a tertiary referral center. Patients: This study included 57 consecutive patients with HCC who were treated with sorafenib. Main Outcome Measure: Thyroid-stimulating hormone (TSH) and free thyroxine (FT4) levels were measured every 6 weeks, and extensive thyroid function tests (TFTs) were measured before treatment (t0), after 6 weeks (t6), and at the end of therapy. The effect of sorafenib on TH transport by monocarboxylate transporter (MCT)8 or MCT10 was tested in transfected COS1 cells. Results: Four patients (7%) developed thyroiditis. Among the other patients, 30% had elevation of TSH or FT4 above the normal range. Overall, between t0 and t6, mean TSH increased from 1.28 to 1.57 mU/L (P < 0.001) and mean FT4 from 18.4 to 21.2 pmol/L (P < 0.001). Simultaneously, the serum triiodothyronine (T3)/reverse triiodothyronine ratio and the (T3/thyroxine) ×100 ratio decreased. Sorafenib decreased cellular T3 uptake by MCT8 and to a lesser extent by MCT10. Conclusions: These in vivo data suggest that sorafenib affects TFTs on multiple levels. Our in vitro experiments suggest a possible role of sorafenib-induced inhibition of T3 transport into the cell by MCT8 and MCT10.