Abstract
The current guideline-based management of hypothyroidism recommends monotherapy with levothyroxine (LT4), titrated to maintain the level of thyrotropin within a euthyroid reference range. This has been successful for most people with hypothyroidism, but a substantial minority still report symptoms of hypothyroidism unexplained by a comorbid medical condition. LT4 is essentially a prodrug for triiodothyronine (T3), the thyroid hormone that acts on target tissues in the brain and the periphery. Thyroid hormone replacement with LT4 alone does not restore physiological tissue levels of thyroid hormones, particularly T3. During the last two decades, much interest has focussed on the potential of combinations of LT4 and T3 to provide a superior outcome to LT4 monotherapy for people with hypothyroidism, especially those with residual symptoms despite thyrotropin-optimized LT4. This review seeks to provide an overview of currently available evidence on combination (LT4 + T3) therapy to be used for personalized medicine in patients with hypothyroidism. A number of randomized, controlled trials (RCTs) have failed to demonstrate superiority for the combination therapy approach, largely due to non-physiological T3 doses. However, patients with hypothyroidism are highly heterogeneous in terms of their residual thyroid function, individual set points for optimal thyroid homeostasis and for the presence or absence of polymorphisms in deiodinase enzymes in tissues that activate and deactivate circulating thyroid hormones. Accordingly, these RCTs may have failed to demonstrate benefits of combination therapy in individual hypothyroid phenotypes. The pharmacokinetics of LT4 and T3 also differ, which is a barrier to their co-administration. Future clinical trials using LT4 + T3 tablets better suited for combination therapy will resolve the outstanding research questions relating to the place of LT4 + T3 combination therapy in the management of hypothyroidism.
Introduction
About 80% of the thyroid hormone secreted by the thyroid is in the form of thyroxine (T4), with the rest secreted as triiodothyronine (T3)Citation1. In principle, therefore, co-administering a mixture of T4 and T3 might provide a strategy to mimic the physiological euthyroid state for someone with hypothyroidism. This approach has not been demonstrated to provide a clear benefit, compared with monotherapy with levothyroxine (LT4), although numerous anecdotal reports and a vocal community of patient advocates support itCitation2. In this article, we review the existing clinical and pathologic evidence for and against the therapeutic use of combinations of LT4 and T3 and consider the potential for the increased use of this therapeutic approach in future.
About this review
This is a narrative review, focussing on the current limitations of LT4 + T3 combinations as a long-term means of thyroid hormone replacement, with the authors’ views as to if and how these might be overcome in future. The review is based mainly on randomized studies in English, identified by a structured PubMed search: “(hypothyroid* OR athyreotic) AND (triiodothyronine [ti] OR liothyronine [ti] OR tri-iodothyronine [ti])”, limited to “Clinical Trial”, and “Randomized Clinical Trial”. Reference lists of identified studies, authoritative management guidelines for hypothyroidism, expert review articles, and the literature collections of the authors provided further source material.
Successes and limitations of the current management of hypothyroidism
Physiology and current management approach
The physiology of thyroid hormones is extremely complex and a detailed description of it is beyond the scope of this review and has been reviewed elsewhereCitation2,Citation3. Briefly, thyrotropin-releasing hormone (TRH) released from neurones in the hypothalamus reaches the anterior pituitary through the pituitary portal circulation, where it stimulates release of thyrotropin (thyroid stimulating hormone; TSH) into the general circulation. TRH is also able to regulate the bioactivity of TSH. The secreted TSH then acts on the thyroid to elicit increased release of thyroid hormones.
Up to about four-fifths of thyroid hormone secretion is in the form of T4, which is chemically identical to administered LT4, with T3 accounting for almost all of the remainderCitation2. The kinetics of thyroid hormones vary by thyroid status and the terminal elimination half-life in hypothyroid subjects has been described as 7.5 days for T4 and 1.4 days for T3Citation4,Citation5. T3 is the active thyroid hormone in the peripheryCitation1,Citation2. T4 (endogenous or via LT4 treatment) and T3 enter cells via a membrane transporter, following which T4 is converted to T3 by intracellular deiodinases mainly in the liver, especially by Deiodinase 2 (DIO2); these enzymes can also deactivate thyroid hormonesCitation2,Citation6,Citation7. Furthermore, these enzymes may provide another layer of regulation of thyroid homeostasis, at the tissue levelCitation8. Intracellular T3 then binds to one of several thyroid hormone receptors and translocates to the nucleus, where it exerts its biological actions by altering the transcription of numerous genes in target organs, including the brain, liver, muscle, heart and circulation, pancreas, bone, and fat, among othersCitation9,Citation10.
Thyroid hormone homeostasis is based on complex feedback loops: for example, thyroid hormone levels feed back to inhibit TSH release, and there is evidence that TSH itself regulates its own secretion (autocrine action) and that of TRH (paracrine action)Citation11. Importantly, the action of thyroid hormones on TSH release is not linear and has been described as inverse log-linear (although the true relationship is probably more complex and may vary importantly between individuals)Citation12. As a result, even a small fall in circulating T4 leads to much larger change in circulating TSH. Indeed, a 50% reduction in the level of T4 can stimulate TSH levels by as much as 100-fold; similarly, increases in T4 in the setting of hyperthyroidism can be detected readily as substantial reductions in the level of circulating TSHCitation2,Citation12,Citation13. This relationship has identified TSH as a sensitive and easily measured surrogate for overall thyroid status, as large changes in TSH can be measured more reliably than small changes in individual thyroid hormonesCitation12,Citation13.
The current management of hypothyroidism is based on monotherapy with LT4Citation14–16. The dosage of LT4 is titrated until TSH falls to within a predetermined range that has been defined previously using a reference population of (ideally local) people without known thyroid dysfunction. There is a consensus that all people with overt hypothyroidism require treatment with LT4, while this treatment is recommended for a subgroup of people with subclinical hypothyroidism, particularly in younger patients with TSH >10 mU/L and free T4 (FT4) in the normal rangeCitation14–16. This LT4-based approach has been largely successful in controlling the symptoms of overt hypothyroidism, and in preserving long-term outcomes and quality of life (QoL), to the point where LT4 has become the most widely prescribed medication in the USACitation17. Potential limitations to this approach exist however, and these are summarized below
Limitations: potential for abnormal T3 homeostasis
LT4 is essentially a prodrug for T3, the thyroid hormone that acts on target tissues in the brain and the periphery, as described aboveCitation1. It has been shown in one study that TSH-driven treatment of thyroidectomized patients with LT4 was able to produce normal T3 levels, although the level of FT4 was elevatedCitation18. Conversely a prospective study of 133 subjects following total thyroidectomy showed that mildly-suppressed levels of TSH (0.03–0.3 mU/L) were required to stabilize other thyroid hormone levels to their preoperative levelsCitation19. Elsewhere, the conversion of LT4 to T3 in athyreotic patients was highly variable, with reduced FT3, suggesting that the deiodinases in peripheral tissues were unable to normalize the level of FT3 in the absence of physiological T3 secretion from the thyroidCitation20,Citation21.
Limitations: residual symptoms despite optimized LT4 therapy
A substantial minority of LT4-treated people with hypothyroidism still report symptoms typical of this condition (e.g. fatigue, weakness, feeling cold, gastrointestinal disturbances, among others), despite successful normalization of TSH to within its laboratory reference rangeCitation22–24. These symptoms also tend to occur commonly in the euthyroid population, and provide poor discrimination between people with or without genuine thyroid dysfunction. Expert recommendations on the management of these patients stress the need to exclude other possible causes of these symptoms, before considering a thyroid-related aetiologyCitation23,Citation25. Chronic fatigue, anaemia, stress, or overweight/obesity can induce symptoms reminiscent of hypothyroidism; excluding such conditions commonly resolves the issues presented by the patient, but may be difficult in practice for someCitation23,Citation25.
A systematic review and meta-analysis of 58 studies of the associations between TSH levels, other thyroid hormones and symptoms of thyroid dysfunction found a weaker association between TSH and clinical findings compared with other thyroid hormones, especially FT4Citation26. In addition, thyroid hormone homeostasis varies between individuals: a given patient may have an individual “set point” for thyroid hormones, which reflects their optimal thyroid balance, even if levels of some thyroid hormones fall outside the reference range defined by measurements in a cohort believed to have “normal” thyroid functionCitation2,Citation12,Citation27. In addition, polymorphisms in thyroid hormone deiodinases (especially DIO2) have been implicated as a possible reason for the failure of TSH-guided LT4 monotherapy to abolish symptoms of hypothyroidism in some patientsCitation28. Thyroid hormone homeostasis may vary between individual tissues, for example in the heart where cardiac disease may precipitate a low myocardial T3 syndrome that has been associated with adverse cardiovascular outcomesCitation29,Citation30. A polymorphism in DIO2 (Thr92Ala) has been associated significantly with low FT3 in athyreotic patients on TSH-optimized LT4 therapyCitation31. Finally, a mechanism for TSH receptor-driven increased production of T3 in thyrocytes, independently of deiodination of T4, has been described, adding a further level of complexityCitation32. These observations all add support to the concept of an individualized approach to thyroid hormone management, beyond management based solely on the TSH level.
The TSH result itself is subject to a number of confounding factors. For example, diurnal variations, body weight, gender, age, and several drugs (including metformin, steroids, neuroleptics) influence the TSH level, certain supplements of foodstuffs (e.g. calcium, iron or soya) can affect the absorption of LT4, and certain circulating factors (autoantibodies to LT4, rhesus factor, heterophile antibodies or macro-TSH can interfere directly with the operation of the TSH testCitation12.
Current status of LT4 + T3 combinations in people with hypothyroidism
Guidelines
Influential guidelines for the management of hypothyroidism do not support the routine use of LT4 + T3 combinations, citing a lack of evidence to support this approachCitation14,Citation15,Citation22,Citation33. This is especially true for the American Thyroid Association (ATA) guideline, which provides no recommendations for the application of LT4 + T3 combination therapyCitation14.
A guideline from the European Thyroid Association (ETA) supports a trial of LT4 + T3 for people with overt hypothyroidism and persistent symptoms despite complying well with their optimized LT4 treatmentCitation22. This support is given somewhat reluctantly: the guideline acknowledges the frequent use of LT4 + T3 combinations (see also below), and seeks to “enhance its safety and to counter its indiscriminate use”. summarizes its main recommendations. A 3-month trial of combination treatment is regarded as an experimental approach (the patient must be counselled on this) to be administered by a suitably qualified specialist physician. The recommended ratios of LT4:T3 excluded all available fixed combination treatments available when the guideline was written, so that LT4 and T3 must be given as separate tablets. A choice of algorithms of varying complexity is provided to estimate the starting dose of each hormone. The goal of therapy is to normalize TSH as well as FT4 and FT3, and the FT4:FT3 ratio. Importantly, the guideline recommends avoidance of LT4 + T3 combination therapy for pregnant women, as we have insufficient data on the safety of this approach for the growing foetus.
Table 1. Overview of recommendations regarding the application of combinations of levothyroxine (LT4) + triiodothyronine (T3) in a guideline for the management of hypothyroidism issued by the European Thyroid AssociationCitation22.
Neither the ATA guidelineCitation14 nor the ETA guidelineCitation22 provided support for the use of genotyping to identify patients with polymorphisms of DIO2 that might identify them as suitable candidates for LT4 + T3 combination therapy.
Randomized trials
provides an overview of randomized comparisons of LT4 monotherapy with LT4 + T3 combinations in people with primary hypothyroidism, or following thyroid surgeryCitation21,Citation34–48. Some studies demonstrated benefits for the LT4 + T3 combination, vs. LT4 monotherapy, usually greater patient preference or improvements in psychological scores or QoLCitation35,Citation39,Citation42,Citation43,Citation48. One of the larger studies to date found that this benefit for two dose levels of T3 appeared to be driven by weight loss on the combination, with no significant influence of changes in hypothyroid symptoms or preferenceCitation35. The weight loss in turn appeared to be driven by over treatment, as the final serum TSH level was 0.35 mU/L and 0.07 mU/L, respectively, in the combination therapy groups. Other studies demonstrated little, no or transient benefits for the combination vs. LT4 alone, including the largest and longest study to dateCitation21,Citation34,Citation36–38,Citation40,Citation41,Citation45–47. Additionally, a “quasi-randomized”, single-blind study in 37 women with symptoms of hypothyroidism despite optimized LT4 therapy reported that some aspects of female sexual functioning were improved in women who received LT4 + T3, compared with those who continued on LT4 alone, and that this improvement paralleled increases in FT3Citation49.
Table 2. Randomized trials that have compared monotherapy with levothyroxine (LT4) with combinations of LT4 and triiodothyronine (T3) in patients with hypothyroidism.
Overall, these trials did not demonstrate a clear or consistent benefit from adding T3 to LT4 therapy, for example based on evaluations of cognition, mood, or QoL. Moreover, no particular ratio of LT4:T3 was more or less successful. Although patients preferred the combination in some studies, this was not explained necessarily by improvements in symptoms related to hypothyroidism, as described above. Recent (2018Citation50 and 2021Citation51 systematic review/meta-analyses concluded that the addition of T3 to LT4 therapy had little benefit in terms of objective improvements in such outcomes (the more recent review also concluded that LT4 + T3 and LT4 monotherapy were tolerated similarly). However, these trials were conducted in relatively broad populations of patients with hypothyroidism, did not consistently use disease-specific instruments for measuring patient-reported outcomes, and therefore cannot exclude a potential benefit in subgroups of patients with hypothyroidism: these issues are discussed in greater detail below.
Real world evidence
The largest and longest observational study of LT4 + T3 combination therapy was conducted in Tayside, UKCitation52. Here, patients who had received thyroid hormone replacement were divided into those who had only ever received LT4 (n = 33,955) and those who had received at least one additional prescription of T3 (n = 400) and were followed retrospectively for a total of 17 years. There was no excess risk of side effects associated with over-treatment of hypothyroidism, i.e. cardiovascular disease (hazard ratio [HR] 1.0 [0.7, 1.5]), atrial fibrillation (HR 0.9: [0.5, 1.8]), or fractures (HR 0.8: [0.5, 1.3]), and no increased use of medications for cardiovascular disease or osteoporosis (statins, bisphosphonates). An increased use of antipsychotic medications that was proportional to exposure to T3 provided a note of caution.
A recent (2018) large survey of 12,146 people with hypothyroidism (free of comorbidities) demonstrated a low level of satisfaction with the management of this condition: the average rating of satisfaction on a scale of 10 was 5 for LT4-managed patients, with higher scores (6–7) for patients who were taking T3 either in the form of pharmaceutical supplements or desiccated animal thyroid preparationsCitation24. Patients taking T3 also reported fewer problems with weight management, tiredness, mood or memory. One of the randomized studies cited in suggested that weight loss on combination therapy with LT4 + T3 might have been a more important driver of patient preference for this regimen (vs. LT4 monotherapy) than changes in thyroid hormones or symptomsCitation35. A 1-year observational study in which LT4 monotherapy was switched to LT4 + T3 (ratio 17:1) found that QoL (measured using the validated Thyroid-Related Quality of Life Measure [ThyPRO] questionnaire) increased steadily during the observation period, with no change in average bodyweight and no significant correlation between changes in weight and changes in QoL, suggesting that other mechanisms are at playCitation53.
Retrospective data from 42 patients with hypothyroid-like symptoms despite normal TSH and a lack of potential comorbidities to explain these symptoms found that changes in FT3 did not relate to the persistence or abolition of symptomsCitation54. An epidemiological analysis of the population at baseline of the largest randomized trial in this area to date showed that FT4 and TSH levels correlated significantly with QoL (measured using the General Health Questionnaire [GHQ], a generic QoL instrument) while FT3 or FT3:FT4 ratio did notCitation34,Citation55. On the other hand, another survey identified a subpopulation of 7% of 200 athyreotic patients, for whom LT4 therapy failed to normalize TSH, even when FT4 reached levels associated with hyperthyroidism. Observational data from these patients suggested that the addition of T3 reduced TSH and FT4 and increased FT3Citation56.
Real world evidence is used increasingly by regulators and other clinical experts to evaluate the effects of therapeutic interventions in the routine clinical setting outside the restrictions of randomized clinical trials. Such studies are inherently prone to bias, however, and their results should be interpreted with caution. They are also subject to some of the methodological and design limitations of trials in this area, which we discuss further below.
Future prospects for LT4 + T3 combinations for hypothyroidism
Are attitudes to LT4 + T3 therapy changing?
A survey of 363 physicians managing patients with hypothyroidism in the USA in 2017 found almost unanimous support (98%) for the use of LT4 monotherapy for an uncomplicated hypothyroid patient without continuing symptomsCitation57. However, the likelihood of prescribing additional therapy was increased by 26-fold, if continuing symptoms were present. Low serum T3, relatively high serum TSH, the presence of a mutation in DIO2 (which deiodinates T4 to generate T3), and patient requests or preference for additional therapies increased this likelihood by about 2–3-fold. A further report from this survey demonstrated that doctors in North America were about twice as likely to prescribe T3 preparations in addition to LT4Citation58.
Many patients with thyroid disorders are avid consumers of social media, and there is no doubt that exposure to these sources influences their perceptions of hypothyroid management, including the use of non-evidence-based approachesCitation59,Citation60. A feeling of not being listened to by physicians, and persistence of symptoms, have been identified as important drivers of the use of desiccated thyroid extract among social media users with hypothyroidism, although about half of this sample claimed to have derived their initial interest in this approach from their physicianCitation59. Self-adjustment of these medications by patients, driven by symptoms, is also commonCitation61. Given the interest in the use of T3 preparations within thyroid disease management from both physicians and patients, it is perhaps unsurprising that their use in routine practice is widespread and increasingCitation61.
Need for new T3 preparations
The differing pharmacokinetics of LT4 and T3 derived from available preparations (described above) has proved to be an important limitation of its use. LT4 is given once daily, and administration of a fixed-dose combination LT4 + T3 tablet has been associated with peak concentrations of T3 that go above its reference range. It was shown almost 20 years ago that administration of a slow-release formulation of T3 alongside LT4 to people with hypothyroidism provided better normalization of FT4 and FT3, compared with LT4 aloneCitation62. No such preparation is currently available for routine clinical use, however. Co-administration of any two medications with such different half-lives would inevitably lead to more pronounced peaks and troughs in the serum concentration of the shorter acting agent (T3 in this case)Citation63. It has been reported that twice-daily administration of a combination of LT4 and T3 to patients with hypothyroidism produced a pharmacokinetic profile “without significant peaks above the reference range” for T3Citation64. Another study demonstrated physiological effects of a single dose of T3 that outlasted the period of raised circulating T3 concentration, with a transient increase in heart rate following administrationCitation65. While these studies are described as supporting the design of future trials of LT4 + T3 combinations, preparations with smoother, more sustained delivery of thyroid hormones in a physiological ratio would be preferableCitation65.
Need for new clinical trial designs
Clinical expert commentators are responding increasingly to the perceived needs of patients dissatisfied with their current management of hypothyroidism. One recent review, from 2019, focuses on the highly individualized nature of thyroid homeostasis, and argues that population-derived approaches to management, including the use of TSH cut-offs set by reference populations as a one-size-fits-all approach, inevitably lead to sub-optimal management of a substantial proportion of people with hypothyroidism in the routine day-to-day care settingCitation66. These authors call for an individualized biochemical approach to thyroid disease management, though they accept that more research needs to be done to provide an evidence-based foundation for applying this approach.
Similar caveats are applied to data from randomized clinical trials, such as those summarized in , and improved trial designs are neededCitation66–68. Briefly, new trials in this area should use validated, thyroid-specific instruments for measuring QoL, and should be adequately powered to detect clinically meaningful difference in their outcomes (as well as for biochemical outcomes related to thyroid function) that are determined a prioriCitation67,Citation68. In addition, the level of residual thyroid function appears to be an important determinant of T3 homeostasis during LT4 replacement therapyCitation69. Accordingly, the benefits of additional T3 are likely to vary according to patients’ residual thyroid function and their endogenous capacity for generating T3. Combining a heterogeneous collection of patients into a randomized trial is likely to lead to amalgamation bias, where important benefits in particular subgroups of patients are lostCitation67. Future clinical trials must support the application of individualized thyroid care, including consideration of pre-treatment thyroid function and the presence of polymorphisms in DIO2, and be of sufficient duration (at least 1 year) to provide support for long-term routine management outside the clinical trial settingCitation68. Achieving a physiological FT4:FT3 ratio should be a key objectiveCitation68.
Future perspectives
The current management of hypothyroidism (TSH-directed monotherapy with LT4) leaves a substantial minority of patients with residual hypothyroid symptoms. A consensus is emerging among experts in thyroid management that the potential benefits of combination LT4 + T3 preparations has not been studied adequately in randomized clinical trials. One solution to this unmet medical need, in the opinion of the authors, could be administration of a free combination of T4 and T3, as this is more flexible than a fixed-dose combination. LT4 could be given once-daily, with T3 given twice (ideally, if serum T3 can be kept within normal limits) or three times daily. The ETA guideline provides several algorithms for switching from LT4 monotherapy (that has normalized TSH) to LT4 + T3 combination therapyCitation22. These assume an optimal LT4:T3 dose ratio of between 13:1 and 20:1, although future clinical trials will be needed to confirm this. A range of T3 dosage strengths would be needed for this, e.g. 2.5 µg, 5 µg, 7.5 µg; in practice, the calculated dose of T3 would be rounded to the nearest available tablet strength for T3Citation22. One example from the ETA guideline, based on a patient originally receiving LT4 at a TSH-optimized dose of 100 µg, 150 µg or 200 µg, involves switching of LT4/T3 doses of 87.5 µg/5 µg, 125 µg/7.5 µg, and 175 µg/10 µg, respectivelyCitation22.
TSH and FT4 might remain the mainstay of monitoring while FT3 monitoring is more usually used in hyperthyroidism currentlyCitation70, and FT3 is a less stable laboratory parameter over time than TSH and FT4, due to its relatively short half-life, as described above. Nevertheless, better-standardized FT3 assays, with measurements made before ingestion of the day’s thyroid medication may provide a useful adjunct to thyroid care for patients without concomitant, non-thyroidal disease (such as many of the large population of younger patients with hypothyroidism)Citation71,Citation72. Looking further ahead, improved clinical study designs that support a more individualized approach, and improved LT4 + T3 free or fixed-dose combination treatments with appropriate dosing regimens, will clarify the place of LT4 + T3 combination therapy in the future management of hypothyroidism.
Transparency
Declaration of funding
Merck Healthcare KGaA funded medical writing services (see below) and Fast Track review for this article. No other funding applied.
Declaration of financial/other relationships
UH is an employee of Merck Healthcare KGaA. GJK has acted as a consultant for Merck Healthcare KGaA.
Acknowledgements
A medical writer (Dr Mike Gwilt, GT Communications) provided editorial assistance, funded by Merck Healthcare KGaA, Darmstadt, Germany.
References
- Pirahanchi Y, Toro F, Jialal I. Physiology, thyroid stimulating hormone. StatPearls [Internet]; 2021 [cited 2021 Sep]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK499850/.
- Hennessey JV. Pharmacodynamic and therapeutic actions of levothyroxine. In Kahaly GJ, editor. 70 Years of levothyroxine. Cham, Switzerland: Springer; 2021. pp. 23–45.
- Mariotti S, and, Beck-Peccoz P. Physiology of the hypothalamic-pituitary-thyroid axis. Endotext [Internet]; 2021 [cited 2021 Jul]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK278958/.
- Lipp H-P. Administration and pharmacokinetics of levothyroxine. In Kahaly GJ, editor. 70 Years of levothyroxine. Cham, Switzerland: Springer; 2021. pp. 13–22.
- Colucci P, Yue CS, Ducharme M, et al. A review of the pharmacokinetics of levothyroxine for the treatment of hypothyroidism. Eur Endocrinol. 2013;9(1):40–47.
- Luongo C, Dentice M, Salvatore D. Deiodinases and their intricate role in thyroid hormone homeostasis. Nat Rev Endocrinol. 2019;15(8):479–488.
- Visser TJ. Cellular uptake of thyroid hormones. Endotext [Internet] [cited 2021 Jul]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK285565/.
- Werneck de Castro JP, Fonseca TL, Ueta CB, et al. Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine. J Clin Invest. 2015;125(2):769–781.
- Sinha R, Yen PM. Cellular action of thyroid hormone. Endotext [Internet]; 2018 [cited 2021 Jul]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK285568/.
- Kahaly GJ. Therapeutic use of levothyroxine: a historical perspective. In Kahaly GJ, editor. 70 Years of levothyroxine. Cham, Switzerland: Springer; 2021. pp. 1–11.
- Prummel MF, Brokken LJ, Wiersinga WM. Ultra short-loop feedback control of thyrotropin secretion. Thyroid. 2004;14(10):825–829.
- Razvi S, Bhana S, Mrabeti S. Challenges in interpreting thyroid stimulating hormone results in the diagnosis of thyroid dysfunction. J Thyroid Res. 2019;2019:4106816.
- Sheehan MT. Biochemical testing of the thyroid: TSH is the best and, oftentimes, only test needed – a review for primary care. Clin Med Res. 2016;14(2):83–92.
- Jonklaas J, ., Bianco AC, Bauer AJ, American Thyroid Association Task Force on Thyroid Hormone Replacement, et al. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on thyroid hormone replacement. Thyroid. 2014;24(12):1670–1751.
- Thyroid disease: assessment and management. NICE guideline [NG145]; November 2019 [cited 2020 May]. Available from: https://www.nice.org.uk/guidance/ng145/chapter/Recommendations.
- Pearce SH, Brabant G, Duntas LH, et al. 2013 ETA guideline: management of subclinical hypothyroidism. Eur Thyroid J. 2013;2(4):215–228.
- Rodriguez-Gutierrez R, Maraka S, Ospina NS, et al. Levothyroxine overuse: time for an about face? Lancet Diabetes Endocrinol. 2017;5(4):246–248.
- Jonklaas J, Davidson B, Bhagat S, et al. Triiodothyronine levels in athyreotic individuals during levothyroxine therapy. Jama. 2008;299(7):769–777.
- Ito M, Miyauchi A, Hisakado M, et al. Biochemical markers reflecting thyroid function in athyreotic patients on levothyroxine monotherapy. Thyroid. 2017;27(4):484–490.
- Gullo D, Latina A, Frasca F, et al. Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients. PLoS One. 2011;6(8):e22552.
- Fadeyev VV, Morgunova TB, Sytch JP, et al. TSH and thyroid hormones concentrations in patients with hypothyroidism receiving replacement therapy with L-thyroxine alone or in combination with L-triiodothyronine. Hormones (Athens). 2005;4:101–107.
- Wiersinga WM, Duntas L, Fadeyev V, et al. 2012 ETA guidelines: the use of L-T4 + L-T3 in the treatment of hypothyroidism. Eur Thyroid J. 2012;1(2):55–71.
- Razvi S, Mrabeti S, Luster M. Managing symptoms in hypothyroid patients on adequate levothyroxine: a narrative review. Endocr Connect. 2020;9(11):R241–50.
- Peterson SJ, Cappola AR, Castro MR, et al. An online survey of hypothyroid patients demonstrates prominent dissatisfaction. Thyroid. 2018;28(6):707–721.
- Centanni M, Benvenga S, Sachmechi I. Diagnosis and management of treatment-refractory hypothyroidism: an expert consensus report. J Endocrinol Invest. 2017;40(12):1289–1301.
- Fitzgerald SP, Bean NG, Falhammar H, et al. Clinical parameters are more likely to be associated with thyroid hormone levels than with thyrotropin levels: a systematic review and meta-analysis. Thyroid. 2020;30(12):1695–1709.
- Andersen S, Pedersen KM, Bruun NH, et al. Narrow individual variations in serum T(4) and T(3) in normal subjects: a clue to the understanding of subclinical thyroid disease. J Clin Endocrinol Metab. 2002;87(3):1068–1072.
- Paragliola RM, Corsello A, Concolino P, et al. Iodothyronine deiodinases and reduced sensitivity to thyroid hormones. Front Biosci. 2020;25:201–228.
- Razvi S, Jabbar A, Pingitore A, et al. Thyroid hormones and cardiovascular function and diseases. J Am Coll Cardiol. 2018;71(16):1781–1796.
- Biondi B. The management of thyroid abnormalities in chronic heart failure. Heart Fail Clin. 2019;15(3):393–398.
- Castagna MG, Dentice M, Cantara S, et al. DIO2 Thr92Ala reduces deiodinase-2 activity and serum-T3 levels in thyroid-deficient patients. J Clin Endocrinol Metab. 2017;102(5):1623–1630.
- Citterio CE, Veluswamy B, Morgan SJ, et al. De novo triiodothyronine formation from thyrocytes activated by thyroid-stimulating hormone. J Biol Chem. 2017;292(37):15434–15444.
- Okosieme O, Gilbert J, Abraham P, et al. Management of primary hypothyroidism: statement by the British Thyroid Association Executive Committee. Clin Endocrinol. 2016;84(6):799–808.
- Saravanan P, Simmons DJ, Greenwood R, et al. Partial substitution of thyroxine (T4) with tri-iodothyronine in patients on T4 replacement therapy: results of a large community-based randomized controlled trial. J Clin Endocrinol Metab. 2005;90(2):805–812.
- Appelhof BC, Fliers E, Wekking EM, et al. Combined therapy with levothyroxine and liothyronine in two ratios, compared with levothyroxine monotherapy in primary hypothyroidism: a double-blind, randomized, controlled clinical trial. J Clin Endocrinol Metab. 2005;90(5):2666–2674.
- Walsh JP, Shiels L, Lim EM, et al. Combined thyroxine/liothyronine treatment does not improve well-being, quality of life, or cognitive function compared to thyroxine alone: a randomized controlled trial in patients with primary hypothyroidism. J Clin Endocrinol Metab. 2003;88(10):4543–4550.
- Smith RN, Taylor SA, Massey JC. Controlled clinical trial of combined triiodothyronine and thyroxine in the treatment of hypothyroidism. Br Med J. 1970;4(5728):145–148.
- Valizadeh M, Seyyed-Majidi MR, Hajibeigloo H, et al. Efficacy of combined levothyroxine and liothyronine as compared with levothyroxine monotherapy in primary hypothyroidism: a randomized controlled trial. Endocr Res. 2009;34(3):80–89.
- Nygaard B, Jensen EW, Kvetny J, et al. Effect of combination therapy with thyroxine (T4) and 3,5,3'-triiodothyronine versus T4 monotherapy in patients with hypothyroidism, a double-blind, randomised cross-over study. Eur J Endocrinol. 2009;161(6):895–902.
- Clyde PW, Harari AE, Getka EJ, et al. Combined levothyroxine plus liothyronine compared with levothyroxine alone in primary hypothyroidism: a randomized controlled trial. JAMA. 2003;290(22):2952–2958.
- Sawka AM, Gerstein HC, Marriott MJ, et al. Does a combination regimen of thyroxine (T4) and 3,5,3'-triiodothyronine improve depressive symptoms better than T4 alone in patients with hypothyroidism? Results of a double-blind, randomized, controlled trial. J Clin Endocrinol Metab. 2003;88(10):4551–4555.
- Bunevicius R, Kazanavicius G, Zalinkevicius R, et al. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med. 1999;340(6):424–429.
- Bunevicius R, Prange AJ. Mental improvement after replacement therapy with thyroxine plus triiodothyronine: relationship to cause of hypothyroidism. Int J Neuropsychopharmacol. 2000;3(2):167–174.
- Escobar-Morreale HF, Botella-Carretero JI, Gómez-Bueno M, et al. Thyroid hormone replacement therapy in primary hypothyroidism: a randomized trial comparing L-thyroxine plus liothyronine with L-thyroxine alone. Ann Intern Med. 2005;142(6):412–424.
- Kaminski J, Miasaki FY, Paz-Filho G, et al. Treatment of hypothyroidism with levothyroxine plus liothyronine: a randomized, double-blind, crossover study. Arch Endocrinol Metab. 2016;60(6):562–572.
- Rodriguez T, Lavis VR, Meininger JC, et al. Substitution of liothyronine at a 1:5 ratio for a portion of levothyroxine: effect on fatigue, symptoms of depression, and working memory versus treatment with levothyroxine alone. Endocr Pract. 2005;11(4):223–233.
- Siegmund W, Spieker K, Weike AI, et al. Replacement therapy with levothyroxine plus triiodothyronine (bioavailable molar ratio 14: 1) is not superior to thyroxine alone to improve well-being and cognitive performance in hypothyroidism. Clin Endocrinol. 2004;60(6):750–757.
- Bunevicius R, Jakuboniene N, Jurkevicius R, et al. Thyroxine vs thyroxine plus triiodothyronine in treatment of hypothyroidism after thyroidectomy for Graves' disease. Endocrine. 2002;18(2):129–133.
- Krysiak R, Szkróbka W, Okopień B. Sexual function and depressive symptoms in young women with hypothyroidism receiving levothyroxine/liothyronine combination therapy: a pilot study. Curr Med Res Opin. 2018;34(9):1579–1586.
- Fischman A, Domínguez JM. Combined therapy with levothyroxine and liothyronine for hypothyroidism. Medwave. 2018;18(8):e7376.
- Millan-Alanis JM, Gonzalez-Gonzalez JG, Flores-Rodríguez A, et al. Benefits and harms of levothyroxine/liothyronine vs. levothyroxine monotherapy for adult patients with hypothyroidism: systematic review and meta-analysis. Thyroid. 2021. DOI:https://doi.org/10.1089/thy.2021.0270
- Leese GP, Soto-Pedre E, Donnelly LA. Liothyronine use in a 17 year observational population-based study - the tears study. Clin Endocrinol. 2016;85(6):918–925.
- Michaelsson LF, la Cour JL, Medici BB, et al. Levothyroxine/liothyronine combination therapy and quality of life: is it all about weight loss? Eur Thyroid J. 2018;7(5):243–250.
- Medici BB, la Cour JL, Michaelsson LF, et al. Neither baseline nor changes in serum triiodothyronine during levothyroxine/liothyronine combination therapy predict a positive response to this treatment modality in hypothyroid patients with persistent symptoms. Eur Thyroid J. 2017;6(2):89–93.
- Saravanan P, Visser TJ, Dayan CM. Psychological well-being correlates with free thyroxine but not free 3,5,3'-triiodothyronine levels in patients on thyroid hormone replacement. J Clin Endocrinol Metab. 2006;91(9):3389–3393.
- Solter D, Solter M. Benefit of combined triiodothyronine (LT(3)) and thyroxine (LT(4)) treatment in athyreotic patients unresponsive to LT(4) alone. Exp Clin Endocrinol Diabetes. 2012;120(02):121–123.
- Jonklaas J, Tefera E, Shara N. Physician choice of hypothyroidism therapy: influence of patient characteristics. Thyroid. 2018;28(11):1416–1424.
- Jonklaas J, Tefera E, Shara N. Prescribing therapy for hypothyroidism: influence of physician characteristics. Thyroid. 2019;29(1):44–52.
- Toloza FJK, Espinoza Suarez NR, El Kawkgi O, et al. Patient experiences and perceptions associated with the use of desiccated thyroid extract. Medicina. 2020;56:161.
- Haskins C. Bogus hypothyroid cures are rampant across social media. Buzzfeed article [cited 2021 Jul]. Available from: https://www.buzzfeednews.com/article/carolinehaskins1/sea-moss-does-not-cure-thyroid-disease-but-people-sell-it.
- Michaelsson LF, Medici BB, la Cour JL, et al. Treating hypothyroidism with thyroxine/triiodothyronine combination therapy in Denmark: following guidelines or following trends? Eur Thyroid J. 2015;4(3):174–180.
- Hennemann G, Docter R, Visser TJ, et al. Thyroxine plus low-dose, slow-release triiodothyronine replacement in hypothyroidism: proof of principle. Thyroid. 2004;14(4):271–275.
- Jonklaas J. Risks and safety of combination therapy for hypothyroidism. Expert Rev Clin Pharmacol. 2016;9(8):1057–1067.
- Van Tassell B, Wohlford GF, 4th, Linderman JD, et al. Pharmacokinetics of L-triiodothyronine in patients undergoing thyroid hormone therapy withdrawal. Thyroid. 2019;29(10):1371–1379.
- Jonklaas J, Burman KD, Wang H, et al. Single-dose T3 administration: kinetics and effects on biochemical and physiological parameters. Ther Drug Monit. 2015;37(1):110–118.
- Midgley JEM, Toft AD, Larisch R, et al. Time for a reassessment of the treatment of hypothyroidism. BMC Endocr Disord. 2019;19(1):37.
- Hoermann R, Midgley JEM, Larisch R, et al. Lessons from randomised clinical trials for triiodothyronine treatment of hypothyroidism: have they achieved their objectives? J Thyroid Res. 2018;2018:3239197.
- Jonklaas J, Bianco AC, Cappola AR, et al. Evidence-based use of levothyroxine/liothyronine combinations in treating hypothyroidism: a consensus document. Eur Thyroid J. 2021;10(1):10–38.
- DiStefano J, 3rd, Jonklaas J. Predicting optimal combination lt4 + lt3 therapy for hypothyroidism based on residual thyroid function. Front Endocrinol. 2019;10:746.
- National Institute for Health and Care Excellence. Thyroid disease: assessment and management. NICE guideline [NG145]; 2019 [cited 2021 Jul]. Available from: https://www.nice.org.uk/guidance/ng145/chapter/recommendations.
- Thienpont LM, Van Uytfanghe K, Beastall G, et al. Report of the IFCC working group for standardization of thyroid function tests; part 2: free thyroxine and free triiodothyronine. Clin Chem. 2010;56:91.
- Midgley JE. Global FT4 immunoassay standardization. Response to: Kratzsch J et al. Global FT4 immunoassay standardization: an expert opinion review. Clin Chem Lab Med. 2021;59(6):e223–e224.