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Hypothesis and Theory ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Endocrinol. | doi: 10.3389/fendo.2019.00787

3,5-T2 – A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine And Intracrine Hepatic Action

  • 1Institut für Experimentelle Endokrinologie, Charité Medical University of Berlin, Germany
  • 2Institute of Experimental Endocrinology, Charity University Medicine Berlin, Germany
  • 3Institute for Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Germany
  • 4Institute of Metabolic Science, MRC Epidemiology Unit, University of Cambridge, United Kingdom
  • 5Endocrinology Department, Hospital do Divino Espírito Santo, Portugal
  • 6Georgetown University, United States

Over the last decades, thyroid hormone metabolites received marked attention as it has been demonstrated that they are bioactive compounds. Among those metabolites, 3,5-diiodothyronine occurs at low nanomolar concentrations in human serum, but might reach tissue concentrations similar to those of T4 and T3. However, the immunoassay-based measurements revealed remarkable variations depending on antibodies used in the assays and thus need to be interpreted with caution. In clinical experimental approaches in euthyroid volunteers and hypothyroid patients using immunoassay analytics no evidence of formation of 3,5-T2 from its putative precursors T4 or T3 was found, nor was any support found for the assumption that 3,5-T2 might represent a direct precursor for serum 3-T1-AM generated by combined deiodination and decarboxylation from 3,5-T2, as previously documented for mouse intestinal mucosa. We hypothesized that lowered endogenous production of 3,5-T2 in patients requiring T4 replacement therapy after thyroidectomy or for treatment of autoimmune thyroid disease, compared to production of 3,5-T2 in individuals with intact thyroid glands might contribute to the discontent seen in a subset of patients with this therapeutic regimen. So far, our observations do not support this assumption. However, the unexpected association between high serum 3,5-T2 and elevated urinary concentrations of metabolites related to coffee consumption requires further studies for an explanation. Elevated 3,5-T2 serum concentrations were found in several situations including impaired renal function, chronic dialysis, sepsis, non-survival in the ICU as well as post-operative atrial fibrillation in studies using a monoclonal antibody-based chemoluminescense immunoassay. Pilot analysis of human sera using LC-linear-ion-trap-mass-spectrometry yielded 3,5-T2 concentrations below the limit of quantification in the majority of cases, thus the divergent results of both methods need to be reconciliated by further studies. Although positive anti-steatotic effects have been observed in rodent models, use of 3,5-T2 as a muscle anabolic, slimming or fitness drug, easily obtained without medical prescription, must be advised against, considering its potency in suppressing the HPT axis and causing adverse cardiac side effects. 3,5-T2 escapes regular detection by commercially available clinical routine assays used for thyroid function tests, which may be seriously disrupted by in individuals self-administering 3,5-T2 obtained over-the counter.

Keywords: iodothyronine, 3,5-Diiodo-L-Thyronine, Hypothyroidism, Metabolome, Thyroid hormone, antisteatotic action, Coffee metabolites, deiodinase, Dialysis, chemoluminescence immunoassay, thyromimetic actions

Received: 22 Jul 2019; Accepted: 29 Oct 2019.

Copyright: © 2019 Köhrle, Lehmphul, Pietzner, Renko, Rijntjes, Richards, Anselmo, Danielsen and Jonklaas. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Josef Köhrle, Charité Medical University of Berlin, Institut für Experimentelle Endokrinologie, Berlin, D-13353, Germany,