Inadequate control of thyroid hormones sensitizes to hepatocarcinogenesis and unhealthy aging.
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ABSTRACT:
SUBMITTER: Lopez-Noriega L
PROVIDER: S-EPMC6781991 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Thyroid function is central in the control of physiological and pathophysiological processes. Studies in animal models and human research have determined that thyroid hormones modulate cellular processes relevant for aging and for the majority of age-related diseases. While several studies have associated mild reductions on thyroid hormone function with exceptional longevity in animals and humans, alterations in thyroid hormones are serious medical conditions associated with unhealthy aging and premature death. Moreover, both hyperthyroidism and hypothyroidism have been associated with the development of certain types of diabetes and cancers, indicating a great complexity of the molecular mechanisms controlled by thyroid hormones. In this review, we describe the latest findings in thyroid hormone research in the field of aging, diabetes, and cancer, with a special focus on hepatocellular carcinomas. While aging studies indicate that the direct modulation of thyroid hormones is not a viable strategy to promote healthy aging or longevity and the development of thyromimetics is challenging due to inefficacy and potential toxicity, we argue that interventions based on the use of modulators of thyroid hormone function might provide therapeutic benefit in certain types of diabetes and cancers.
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Project description:Background: The effects of thyroid-stimulating hormone (TSH) and thyroid hormones on the development of human papillary thyroid cancer (PTC) remain poorly understood.Methods: The study population consisted of 741 (341 women, 400 men) histologically confirmed PTC cases and 741 matched controls with prediagnostic serum samples stored in the Department of Defense Serum Repository. Concentrations of TSH, total T3, total T4, and free T4 were measured in serum samples. Conditional logistic regression models were used to calculate ORs and 95% confidence intervals (CI).Results: The median time between blood draw and PTC diagnosis was 1,454 days. Compared with the middle tertile of TSH levels within the normal range, serum TSH levels below the normal range were associated with an elevated risk of PTC among women (OR, 3.74; 95% CI, 1.53-9.19) but not men. TSH levels above the normal range were associated with an increased risk of PTC among men (OR, 1.96; 95% CI, 1.04-3.66) but not women. The risk of PTC decreased with increasing TSH levels within the normal range among both men and women (Ptrend = 0.0005 and 0.041, respectively).Conclusions: We found a significantly increased risk of PTC associated with TSH levels below the normal range among women and with TSH levels above the normal range among men. An inverse association between PTC and TSH levels within the normal range was observed among both men and women.Impact: These results could have significant clinical implications for physicians who are managing patients with abnormal thyroid functions and those with thyroidectomy. Cancer Epidemiol Biomarkers Prev; 26(8); 1209-18. ©2017 AACR.
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Project description:Normal thyroid hormone level is essential to maintain the normal physiologic function of the human body. Disturbances of these hormone levels have variable clinical manifestations ranging from asymptomatic to severe illness. Resistance to thyroid hormone (RTH) is a syndrome characterized by reduced intracellular action of T3, the active thyroid hormone. It is a rare autosomal dominant condition and occurs mostly due to heterogeneous mutations in the thyroid hormone receptor. Other causes of RTH include thyroid hormone cell membrane transport defect and thyroid hormone metabolism defect. Affected individuals present with symptoms of both increased and decreased thyroid hormone action, depending on the tissue's predominant receptor isoform expression, the magnitude of hormonal resistance, and the effectiveness of compensatory mechanisms. Here, we share our experience in diagnosing a case of RTH confirmed with a genetic test and found to have sequence variant mutation that is not well described in the literature previously due to the absence of genetic conclusive evidence.
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Project description:Endometriosis is characterized by the presence of ectopic endometrial cells outside the uterine cavity. Thyroid autoimmunity has been associated with endometriosis. This work investigated the potential pathophysiological link between endometriosis and thyroid disorders. Transcripts and proteins involved in thyroid metabolism are dysregulated in eutopic and ectopic endometrium of endometriotic patients, leading to resistance of ectopic endometrium to triiodothyronine (T3) action and local accumulation of thyroxine (T4). Thyroid-stimulating hormone (TSH) acts as a proliferative and prooxidative hormone on all endometria of endometriosis patients and controls, whereas T3 and T4 act to specifically increase ectopic endometrial cell proliferation and reactive oxygen species (ROS) production. Mouse studies confirmed the data gained in vitro since endometriotic implants were found to be bigger when thyroid hormones increased. A retrospective analysis of endometriosis patients with or without a thyroid disorder revealed an increased chronic pelvic pain and disease score in endometriotic patients with a thyroid disorder.
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Project description:The aim of this study was to evaluate the association between persistent organic pollutants (POPs) and thyroid hormones in an aging population. Forty-eight women and 66 men, aged 55-74 years and living in upper Hudson River communities completed a questionnaire and provided blood specimens. Serum was analyzed for thyrotropin (thyroid stimulating hormone, TSH), free (fT4) and total thyroxine (T4), total triiodothyronine (T3), and for POPs. POPs included 39 polychlorinated biphenyls (PCBs), dichlorodiphenyltrichloroethane (DDT) and dichlorodiphenyldichloroethylene (DDE) determined by gas chromatography with electron capture detection (GC-ECD), and nine polybrominated diphenyl ethers (PBDEs) determined by high-resolution gas chromatography with high-resolution mass spectrometry detection (HRGC-HRMS). Multivariable linear regression analysis was used to evaluate associations between thyroid hormones and sums of POPs, adjusted for covariates and stratified by sex. Effects were expressed as differences in thyroid hormone levels associated with a doubling in the level of exposure. Among women, DDT+DDE increased T4 by 0.34?g/dL (P=0.04) and T3 by 2.78ng/dL (P=0.05). Also in women, sums of PCBs in conjunction with PBDEs elicited increases of 24.39-80.85ng/dL T3 (P<0.05), and sums of PCBs in conjunction with DDT+DDE elicited increases of 0.18-0.31?g/dL T4 (P<0.05). For men estrogenic PCBs were associated with a 19.82ng/dL T3 decrease (P=0.003), and the sum of estrogenic PCBs in conjunction with DDT+DDE elicited an 18.02ng/dL T3 decrease (P=0.04). Given age-related declines in physiologic reserve, the influence of POPs on thyroid hormones in aging populations may have clinical implications and merits further investigation.
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Project description:BackgroundInternal quality control (IQC) plays a key role in the evaluation of precision performance in clinical laboratories. This report aims to present precision status of thyroid hormones immunoassays from 2011 to 2016 in China.MethodsThrough Clinet-EQA reporting system, IQC information of Triiodothyronine and Thyroxine in the form of free and total (FT3, TT3, FT4, TT4), as well as Thyroid Stimulating Hormone (TSH) were collected from participant laboratories submitting IQC data in February, 2011-2016. For each analyte, current CVs were compared among different years and measurement systems. Percentages of laboratories meeting five allowable imprecision specifications (pass rates) were also calculated. Analysis of IQC practice was conducted to constitute a complete report.ResultsCurrent CVs were decreasing significantly but pass rates increasing only for FT3 during 6 years. FT3, TT3, FT4, and TT4 had the highest pass rates comparing with 1/3TEa imprecision specification but TSH had this comparing with minimum imprecision specification derived from biological variation. Constituent ratios of four mainstream measurement systems changed insignificantly. In 2016, precision performance of Abbott and Roche systems were better than Beckman and Siemens systems for all analytes except FT3 had Siemens also better than Beckman. Analysis of IQC practice demonstrated wide variation and great progress in aspects of IQC rules and control frequency.ConclusionWith change of IQC practice, only FT3 had precision performance improved in 6 years. However, precision status of five analytes in China was still unsatisfying. Ongoing investigation and improvement of IQC have yet to be achieved.
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Project description:The canonical view about the effect of thyroid hormones (THs) on thermogenesis assumes that the hypothalamus acts merely as a modulator of the sympathetic outflow on brown adipose tissue (BAT). Recent data have challenged that vision by demonstrating that THs act on the ventromedial nucleus of the hypothalamus (VMH) to inhibit AMP-activated protein kinase (AMPK), which regulates the thermogenic program in BAT, leading to increased thermogenesis and weight loss. Current data have shown that in addition to activation of brown fat, the browning of white adipose tissue (WAT) might also be an important thermogenic mechanism. However, the possible central effects of THs on the browning of white fat remain unclear. Here, we show that 3,3',5,5' tetraiodothyroxyne (T4)-induced hyperthyroidism promotes a marked browning of WAT. Of note, central or VMH-specific administration of 3,3',5-triiodothyronine (T3) recapitulates that effect. The specific genetic activation of hypothalamic AMPK in the VMH reversed the central effect of T3 on browning. Finally, we also showed that the expression of browning genes in human WAT correlates with serum T4 Overall, these data indicate that THs induce browning of WAT and that this mechanism is mediated via the central effects of THs on energy balance.
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Project description:Exemplifying the long-pursued thyroid hormones (TH)-cancer association, the TH-lung cancer association is a compelling, yet elusive, issue. The present narrative review provides background knowledge on the molecular aspects of TH actions, with focus on the contribution of TH to hallmarks of cancer. Then, it provides a comprehensive overview of data pertinent to the TH-lung cancer association garnered over the last three decades and identifies obstacles that need to be overcome to enable harnessing this association in the clinical setting. TH contribute to all hallmarks of cancer through integration of diverse actions, currently classified according to molecular background. Despite the increasingly recognized implication of TH in lung cancer, three pending queries need to be resolved to empower a tailored approach: (1) How to stratify patients with TH-sensitive lung tumors? (2) How is determined whether TH promote or inhibit lung cancer progression? (3) How to mimic the antitumor and/or abrogate the tumor-promoting TH actions in lung cancer? To address these queries, research should prioritize the elucidation of the crosstalk between TH signaling and oncogenic signaling implicated in lung cancer initiation and progression, and the development of efficient, safe, and feasible strategies leveraging this crosstalk in therapeutics.
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Project description:Loss of function mutations in the gene encoding the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to severe neurodevelopmental defects in humans associated with a specific thyroid hormone phenotype manifesting high serum 3,5,3'-triiodothyronine (T3) and low thyroxine (T4) levels. Patients present a paradoxical state of peripheral hyperthyroidism and brain hypothyroidism, this last one most likely arising from impaired thyroid hormone transport across the brain barriers. The administration of thyroid hormones by delivery pathways that bypass the brain barriers, such as the intranasal delivery route, offers the possibility to improve the neurological defects of MCT8-deficient patients. In this study, the thyroid hormones T4 and T3 were administrated intranasally in different mouse models of MCT8 deficiency. We have found that, under the present formulation, intranasal administration of thyroid hormones does not increase the content of thyroid hormones in the brain and further raises the peripheral thyroid hormone levels. Our data suggests intranasal delivery of thyroid hormones is not a suitable therapeutic strategy for MCT8 deficiency, although alternative formulations could be considered in the future to improve the nose-to-brain transport.
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Project description:Parkinson's disease (PD) was reported to be connected with thyroid diseases clinically, which might be a critical clew to immune pathogenesis of PD. However, there was no further research to study the pathogenesis correlation between PD and thyroid diseases. In this study, except for investigating the difference in thyroid hormone between PD and the control group, we explored genetic correlation between thyroid and PD. We tried to find their shared molecular pathway by analyzing the effect of PD risk genes on thyroid function. Interestingly, most of those 12 meaningful SNPs we found could affect PD and thyroid function through immune mechanism, which is consistent with our original conjecture and provides significant evidence for the immune pathogenesis of PD.
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