<p>Levothyroxine is a synthetically produced form of thyroxine, a major endogenous hormone secreted by the thyroid gland.<sup class="text-reference-group"><a class="reference-popover-link" data-content="FDA Label - levothyroxine" href="#reference-F4633">14</a></sup> Also known as L-thyroxine or the brand name product Synthroid, levothyroxine is used primarily to treat hypothyroidism, a condition where the thyroid gland is no longer able to produce sufficient quantities of the thyroid hormones T<sub>4</sub> (tetraiodothyronine or thyroxine) and T<sub>3</sub> (triiodothyronine or <a href="https://go.drugbank.com/drugs/DB00279">Liothyronine</a>), resulting in diminished down-stream effects of these hormones. Without sufficient quantities of circulating thyroid hormones, symptoms of hypothyroidism begin to develop such as fatigue, increased heart rate, depression<sup class="text-reference-group"><a class="reference-popover-link" data-content="Tang R, Wang J, Yang L, Ding X, Zhong Y, Pan J, Yang H, Mu L, Chen X, Chen Z: Subclinical Hypothyroidism and Depression: A Systematic Review and Meta-Analysis. Front Endocrinol (Lausanne). 2019 Jun 4;10:340. doi: 10.3389/fendo.2019.00340. eCollection 2019. (PubMed ID 31214119)" href="#reference-A179620">4</a></sup>, dry skin and hair, muscle cramps, constipation, weight gain, memory impairment, and poor tolerance to cold temperatures.<sup class="text-reference-group"><a class="reference-popover-link" data-content="American Association of Clinical Endocrinologists (AACE): Clinical Practice Guidelines for Hypothyroidism in Adults" href="#reference-F4636">15</a>,<a class="reference-popover-link" data-content="Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, Cooper DS, Kim BW, Peeters RP, Rosenthal MS, Sawka AM: Guidelines for the treatment of hypothyroidism: prepared by the american thyroid association task force on thyroid hormone replacement. Thyroid. 2014 Dec;24(12):1670-751. doi: 10.1089/thy.2014.0028. (PubMed ID 25266247)" href="#reference-A35722">10</a></sup></p><p>In response to Thyroid Stimulating Hormone (TSH) release by the pituitary gland, a normally functioning thyroid gland will produce and secrete T<sub>4</sub>, which is then converted through deiodination (by type I or type II 5′-deiodinases)<sup class="text-reference-group"><a class="reference-popover-link" data-content="Kaplan MM, Breitbart R: Conversion of thyroxine to triiodothyronine in the anterior pituitary gland and the influence of this process on thyroid status. Horm Metab Res Suppl. 1984;14:79-85. (PubMed ID 6595194)" href="#reference-A179941">8</a></sup> into its active metabolite T<sub>3</sub>. While T<sub>4</sub> is the major product secreted by the thyroid gland, T<sub>3</sub> exerts the majority of the physiological effects of the thyroid hormones; T<sub>4</sub> and T<sub>3</sub> have a relative potency of ~1:4 (T4:T3).<sup class="text-reference-group"><a class="reference-popover-link" data-content="FDA Label - levothyroxine" href="#reference-F4633">14</a></sup> T<sub>4</sub> and T<sub>3</sub> act on nearly every cell of the body, but have a particularly strong effect on the cardiac system.<sup class="text-reference-group"><a class="reference-popover-link" data-content="Osmak-Tizon L, Poussier M, Cottin Y, Rochette L: Non-genomic actions of thyroid hormones: Molecular aspects. Arch Cardiovasc Dis. 2014 Apr;107(4):207-11. doi: 10.1016/j.acvd.2014.02.001. Epub 2014 Mar 26. (PubMed ID 24680385)" href="#reference-A179935">6</a></sup> As a result, many cardiac functions including heart rate, cardiac output, and systemic vascular resistance are closely linked to thyroid status.<sup class="text-reference-group"><a class="reference-popover-link" data-content="Klein I, Ojamaa K: Thyroid hormone and the cardiovascular system. N Engl J Med. 2001 Feb 15;344(7):501-9. doi: 10.1056/NEJM200102153440707. (PubMed ID 11172193)" href="#reference-A179938">7</a></sup></p><p>Prior to the development of levothyroxine, <a href="https://go.drugbank.com/drugs/DB09100">Thyroid, porcine</a> or desiccated thyroid, used to be the mainstay of treatment for hypothyroidism. However, this is no longer recommended for the majority of patients due to several clinical concerns including limited controlled trials supporting its use. Desiccated thyroid products contain a ratio of T4 to T3 of 4.2:1, which is significantly lower than the 14:1 ratio of secretion by the human thyroid gland. This higher proportion of T3 in desiccated thyroid products can lead to supraphysiologic levels of T3 which may put patients at risk of thyrotoxicosis if thyroid extract therapy is not adjusted according to the serum TSH.<sup class="text-reference-group"><a class="reference-popover-link" data-content="Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, Cooper DS, Kim BW, Peeters RP, Rosenthal MS, Sawka AM: Guidelines for the treatment of hypothyroidism: prepared by the american thyroid association task force on thyroid hormone replacement. Thyroid. 2014 Dec;24(12):1670-751. doi: 10.1089/thy.2014.0028. (PubMed ID 25266247)" href="#reference-A35722">10</a>,<a class="reference-popover-link" data-content="American Association of Clinical Endocrinologists (AACE): Clinical Practice Guidelines for Hypothyroidism in Adults" href="#reference-F4636">15</a></sup></p>