An open letter to anyone who believes that triiodothyronine is dangerous.
The protective role of thyroid hormones is well-known, yet often dangerous parallels are made with supra-physiological doses applied in rodent studies, and inappropriate comparisons of hyperthyroidism, increased bone loss and osteoporosis as just some of the examples. There are many perpetuated myths about thyroid hormone assessment and treatment. Many of these are still maintained in medical school, and it’s not been uncommon to hear from clients that some doctors have said that triiodothyronine (T3) is dangerous and that Levothyroxine (synthetic thyroxine or LT4) should only be used to treat hypothyroidism.
One of the most common, erroneous ideas around thyroid hormone use, is Levothyroxine is standardised and reliable, whilst natural desiccated thyroid is not, and promotes dangerous levels of T3. This statement although disproven through research showing that a grain of natural desiccated thyroid is simply more potent, requiring less than a higher dose of LT4, is still promoted ((Lowe, 2009). One of the earliest mistakes made by those treating hypothyroidism, was the assumption that 100 mcg of LT4 was equivalent to 100 mcg of desiccated thyroid extract (NDT). Yet NDT due to its additional constituent of T3 had a more realistic equivalency of 60 mcgs (a grain of NDT) compared to LT4s 100 mcgs.
Treatment with LT4 is often incomplete for a number of reasons in many. Most notably that a reduction in thyroxine or T4 will often just serve to lower pituitary TSH production, without necessarily restoring conversion of T4 to T3 (Jonklaas et al., 2021).
T3 has both rapid nongenomic and slower genomic effects and adequate values are essential for optimal cardiovascular function and a consideration in post coronary artery bypass surgery CABGS). T3 use post CABGS has been shown for decades to improve cardiac output and decrease need for further lifesaving interventions (Mullis-Jansson et al., 1999). T3 promotes oxidative metabolism (oxidative phosphorylation or OP) ensuring adequate production of both adenosine triphosphate (ATP) and oxidative rate enhancing levels of carbon dioxide, through the oxidation of both glucose (pyruvate) and fatty acids. Adequate OP is essential for decreasing lactate production that could be the fate between cellular death and necrosis or maintenance of sensitive living tissue of CABGS patients.
Adequate thyroid hormones are essential for decreasing the likelihood of cardiovascular disease (CV) and even subclinical states of hypothyroidism are associated with increased CV/arterial disease states (Sun et al., 2017). Additionally preoperative thyroid hormone values are predictive of ICU length of stay in both paediatric and adult surgery patients (Yu et al., 2021). Of course, the excess administration of thyroid hormone (and in particular T3) might be problematic for those who are at imminent risk of a myocardial infarction (MI or heart attack). However, this can generally be avoided by even the most fragile of cardiovascular systems by a very low dose of T3 and using the simplest of cardiac evaluations, the resting heart rate and beats per minute.
Combination therapy of either synthetic combination therapy of T4 and T3 or natural desiccated thyroid have been shown to improve hypothyroid symptoms more effectively than standard monotherapy with LT4 and are often preferred by many patients seeking euthyroid status (Shakir et al., 2021)(Hoang, Olsen, Mai, Clyde, & Shakir, 2013). There may be a number of reasons why a combination therapy or indeed mono T3 therapy might be more beneficial than chronic LT4 therapy.
Paul Robinson, author of Recovering with T3 ( an excellent resource on treating hypothyroidism with T3 monotherapy), alerted me to the associations between cancer and chronic LT4 therapy, which showed a 50% increased risk from cancers at most sites, (AOR: 1.50, 95% CI: 1.46-1.54; P < .0001) (Wu et al., 2021). T4 has a nongenomic effect via activation of the integrin αvβ3 receptor (Davis, Goglia, & Leonard, 2016). Perpetual elevations of T4 therefore may stimulate fibrosis through interactions with the protein F actin and be related to proliferation and unrestrained proliferation and angiogenesis is the hallmark of tumour formation and metastasis. It’s also quite plausible to suggest that adequate T3 may be especially important particularly in females when increased estrogens in the form of estradiol and exogenous estrogen like chemicals have a variety of thyroid inhibiting capacities. Estradiol can decrease thyroid hormone availability by inhibiting T4 and its availability in free form (FT4).
Evaluating the impact of estrogen like pollutants in humans is challenging but the idea that pollutants alter thyroid hormone production is not a novel idea (Gore et al., 2015). Recently I have been working on a meta-analysis assessing the effects of a variety of pollutants and their capacity to lower thyroid hormones. Whilst this data is in rodents, it’s interesting to note that the modest yet significant reductions occur in both T3 (total and free) and T4 (effect size -3.96 (CI -6.05 to - 1.81) and -2.10 (CI -3.92 to 0.28). However thyroid stimulating hormone (TSH) only increases slightly with an effect size of 1.48 (CI -3.03 to 5.99).
TSH
T4/FT4 combined
T3/FT3 combined
These obvious decreases in both T4 and T3 and the less obvious, subtle changes to TSH could be a useful window to perceive how pollution could muddy the waters of thyroid hormone evaluation. Also adding to the decade’s old contentious idea that the TSH is the gold standard for evaluating thyroid hormone function.
T3 is dangerous in supraphysiologic amounts but then so are six pints of water, seventy-three espressos, and other chemical formulas in excess. If anything, adequate T3 even in the form of monotherapy might be offering more protection in an environment where thyroid hormones are either being degraded or failing to be converted and assimilated at an appropriate rate for maintaining biological organisation.
References
Davis, P. J., Goglia, F., & Leonard, J. L. (2016). Nongenomic actions of thyroid hormone. Nature Reviews Endocrinology. https://doi.org/10.1038/nrendo.2015.205
Gore, A. C., Chappell, V. A., Fenton, S. E., Flaws, J. A., Nadal, A., Prins, G. S., … Zoeller, R. T. (2015). Executive Summary to EDC-2: The Endocrine Society’s second Scientific Statement on endocrine-disrupting chemicals. Endocrine Reviews. https://doi.org/10.1210/er.2015-1093
Hoang, T. D., Olsen, C. H., Mai, V. Q., Clyde, P. W., & Shakir, M. K. M. (2013). Desiccated thyroid extract compared with levothyroxine in the treatment of hypothyroidism: A randomized, double-blind, crossover study. Journal of Clinical Endocrinology and Metabolism, 98(5), 1982–1990. https://doi.org/10.1210/jc.2012-4107
Jonklaas, J., Bianco, A. C., Cappola, A. R., Celi, F. S., Fliers, E., Heuer, H., … Dayan, C. M. (2021). Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document. Thyroid, 31(2). https://doi.org/10.1089/thy.2020.0720
Lowe, J. C. (2009). Stability, Effectiveness, and Safety of Desiccated Thyroid vs Levothyroxine: A Rebuttal to the British Thyroid Association. Thyroid Science (Vol. 4).
Mullis-Jansson, S. L., Argenziano, M., Corwin, S., Homma, S., Weinberg, A. D., Williams, M., … Ergina, P. L. (1999). A randomized double-blind study of the effect of triiodothyronine on cardiac function and morbidity after coronary bypass surgery. Journal of Thoracic and Cardiovascular Surgery, 117(6). https://doi.org/10.1016/S0022-5223(99)70249-7
Robinson, P. Recovering with T3: My Journey from Hypothyroidism to Good Health using the T3 Thyroid Hormone (1) (Recovering from Hypothyroidism Series) 2018.
Shakir, M. K. M., Brooks, D. I., Mcaninch, E. A., Fonseca, T. L., Mai, V. Q., Bianco, A. C., & Hoang, T. D. (2021). Comparative Effectiveness of Levothyroxine, Desiccated Thyroid Extract, and Levothyroxine+Liothyronine in Hypothyroidism. Journal of Clinical Endocrinology and Metabolism, 106(11). https://doi.org/10.1210/clinem/dgab478
Sun, J., Yao, L., Fang, Y., Yang, R., Chen, Y., Yang, K., & Limin, T. (2017). The relationship between subclinical thyroid dysfunction and the risk of cardiovascular outcomes: a systematic review and meta-analysis of prospective cohort studies. International Journal of Endocrinology, 2017(2017). https://doi.org/10.1007/s00774-017-0828-5
Wu, C. C., Islam, M. M., Nguyen, P. A., Poly, T. N., Wang, C. H., Iqbal, U., … Yang, H. C. (2021). Risk of cancer in long-term levothyroxine users: Retrospective population-based study. Cancer Science, 112(6). https://doi.org/10.1111/cas.14908
Yu, D., Zou, L., Cun, Y., Li, Y., Wang, Q., Shu, Y., & Mo, X. (2021). Preoperative thyroid hormone levels predict ICU mortality after cardiopulmonary bypass in congenital heart disease patients younger than 3 months old. BMC Pediatrics, 21(1). https://doi.org/10.1186/s12887-021-02513-6