Nitric Oxide Thyroid Study - NOTHYS

Thyroid diseases display a wide variety of different disorders and moreover, dysfunction of the thyroid gland varies dependent on the stage of the disease. Nitric oxide (NO) has been implicated in numerous pathophysiological mechanisms, including thyroid dysfunction. However, the impact of NO on thyroidal dysfunction, especially regarding the different causes and stages of thyroid disease remains elusive to date. Thyroid dysfunction is also discussed to be associated with the metabolic syndrome (MeS). NO may be involved in thyroid related MeS as it has been shown that NO is involved in various concomitant pathophysiological mechanisms. We here hypothesise that the nitric oxide pathway is implicated in thyroid diseases and related MeS. The aim of the present study is to investigate the impact of the nitric oxide pathway on thyroid diseases and related MeS. This is achieved by investigating the NO pathway in the clinical trial pilot study NOTHYS, in cell culture systems as well as in a rodent model. The clinical trail pilot study NOTHYS is designed to investigate various metabolites and biomarkers, lipometry and oral glucose tolerance test in pre and post treated patients with thyroid dysfunctions and healthy controls. The in vitro part of the proposed project is designed to investigate the pathophysiological mechanisms of NO and thyroid hormones by using cell culture models in thyroid derived cells and in insulin sensitive skeletal muscle cells and adipocytes. Moreover, to investigate the underlying pathophysiological mechanisms rats with thyroidal dysfunctions will be used. The investigation of the nitric oxide pathway in the thyroid diseases as well as in various cell culture systems and rodent models would make it possible to determine the impact of NO in a holistic approach. The understanding of the role of NO in thyroid dysfunction and related disorders, like MeS, would give the opportunity to develop NO as a specific therapeutic target.

The various thyroid diseases represent a complex network, depending on the functional behaviour of the thyroid gland which is the basis for diagnosis and therapy. Classification guidelines define these diseases upon functional aspects into hyper-, eu-, or hypothyroidism reflecting excessive, normal or defective levels of thyroid hormones. The thyroid hormones thyroxine (T4) and triiodothyronine (T3) are involved in a wide variety of physiological functions including metabolism, growth and other hormone systems. Nitric oxide (NOX) is a reactive labile molecule and has been implicated in various pathophysiological situations like inflammation, oxidative stress, endothelial dysfunction, atherogenesis, cardiovascular disease (CVD) and the metabolic syndrome (MeS). There is also evidence for an involvement of the NO pathway in various thyroidal dysfunctions. However, results are limited and in part conflicting. The aim of the present study is to investigate the impact of the nitric oxide pathway on thyroid diseases. Firstly, analyses of nitric oxide (NOX), its endogenous inhibitor asymmetric dimethylarginine (ADMA) and thyroid hormone levels in hypo- and hyperthyroid Sprague Dawley rats revelaed significantly reduced serum NOX levels in hypothyroid rats. Analyses of the endogenous NO synthase inhibitor ADMA revealed declining levels in hypothyroid groups and increased levels in hyperthyroid rats. Additionally administration of the nitric oxide donor compensated the decrease of thyroid hormones. Moreover administration of nitric oxide markedly increased T3 levels in all groups, independent of the underlying thyroid dysfunction. Subsequent cell culture experiments identified adipocytes as a target of thyroid hormones by altering activation of transcription factor kappa B and induction of inflammatory cytokines like IL-6 due to various thyroid hormone treatments. Moreover, we also found an association of the nitric oxide pathway with thyroid dysfunctions in a clinical pilot study. Taken together, our results indicate that the NO pathway is implicated in thyroid dysfunctions, which may be of clinical relevance.