A 34 year old female with a history of Hashimoto’s thyroiditis presents to the clinic with complaints of persistent fatigue, difficulty concentrating, and weight gain over the past several months. She has been compliant with her prescribed levothyroxine and recent labs show normal TSH levels. She denies anemia or other systemic symptoms. Despite reassurance that her thyroid levels are within range, she reports frustration with her symptoms, asking if there is another treatment option that could help. Her provider considers whether combination therapy with levothyroxine and liothyronine would provide additional benefit.
Search Question:
In adults with Hashimoto’s disease already treated with levothyroxine, does the addition of T3 (liothyronine) lead to reduced fatigue and improved quality of life compared to continuing levothyroxine monotherapy alone?
Question Type: What kind of question is this? (boxes now checkable in Word)
| Prevalence | Screening | Diagnosis |
| Prognosis | Treatment | Harms |
PICO search terms:
| P | I | C | O |
| Adults with Hashimoto’s disease | Levothyroxine + T3 | Levothyroxine | Fatigue |
| Hashimoto’s disease | Levothyroxine and liothyronine | Levothryxoine alone | Symptom improvement |
| Hypothyroidism | Combination therapy | Monotherapy | Quality of life |
Search tools and strategy used:
I used PubMed, ScienceDirect, and Google Scholar and used different filters, such as age, date within the last 10 years, the type of study, such as systematic reviews, meta-analysis or RCT, and the country which the study was conducted in, which would be the United States. I originally had 36 articles in PubMed, 25 articles in Science Direct, and 90 articles in Google Scholar. I narrowed it down to four articles by reading the abstracts of each article and making sure it was relevant to my focused clinical question. I included studies that involved adults with hypothyroidism or Hashimoto’s disease, directly compared levothyroxine monotherapy to combination therapy with liothyronine, and evaluated outcomes such as fatigue and quality of life. I excluded studies that focused only on biochemical outcomes, such as TSH levels without assessing patient reported symptoms and articles that did not specifically evaluate combination therapy.
| Database | Search Terms Used | Filters Applied | Number of Results |
| PubMed | ((Hashimoto’s disease) OR (hypothyroidism) AND (levothyroxine monotherapy)) AND (LT4 and LT3 therapy) AND (fatigue) OR (quality of life)) | In the last 10 years, United States, systematic review, meta-analysis, randomized controlled trial, Free full text | 36 |
| Science Direct | ((adults with Hashimoto’s disease) OR (hypothyroidism) AND (LT4 monotherapy)) AND (LT4 and LT3 therapy)) AND (fatigue) OR (quality of life)) | In the last 10 years, systematic review, meta-analysis, review articles, English, Open access | 25 |
| Google Scholar | ((Hashimoto’s disease) OR (hypothyroidism) AND (levothyroxine monotherapy)) AND (LT4 + LT3 therapy)) AND (fatigue) OR (quality of life) | In the last 10 years (sorted by date), review articles, systematic reviews, include citations, | 90 |
Articles Chosen:
- Combination therapy with levothyroxine and liothyronine in hypothyroid patients with persistent symptoms: A case series
Peterman, K., Naraval Tacata, R. H., Cerezo, N., & Casimiro, I. (2025). Combination therapy with levothyroxine and liothyronine in hypothyroid patients with persistent symptoms: A case series. Journal of Clinical and Translational Endocrinology: Case Reports, 38, 100201. https://doi.org/10.1016/j.jecr.2025.100201
Article Type: Case series
Abstract
Background
Levothyroxine (LT4) monotherapy remains the standard treatment for hypothyroidism in current clinical practice. However, a subset of patients on LT4 continue to experience fatigue and other hypothyroid symptoms despite normal thyroid-stimulating hormone (TSH) and free T4 (FT4) levels.
Methods
Three patients with symptomatic hypothyroidism on LT4 monotherapy were transitioned to combination therapy with liothyronine (LT3) by reducing LT4 dosage and adding LT3 5 μg daily. All had a normal TSH and low total triiodothyronine T3 levels. LT3 was administered in the morning alongside LT4, with one patient requiring an additional afternoon dose (3:00 and 5:00 p.m.) for symptom control. Laboratory values and clinical symptoms were reassessed after initiating combination thyroid hormone therapy.
Results
A 67-year-old woman with idiopathic bradycardia and fatigue experienced marked improvement in energy and bradycardia, accompanied by normalization of T3 levels and improved heart rate at clinic visits. A 58-year-old woman with post-ablative hypothyroidism reported improved fatigue and modest weight loss. A 40-year-old man post-thyroidectomy for papillary thyroid carcinoma noted improvement of fatigue, daytime sleepiness and serum T3 concentrations. Across all three cases, total T3 levels increased, and symptom burden decreased following LT4 + LT3 therapy.
Conclusion
In select hypothyroid patients with persistent symptoms and low total T3 despite normal TSH, addition of liothyronine to levothyroxine may improve both biochemical and clinical outcomes. These findings highlight the potential benefit of individualized thyroid hormone replacement strategies in optimizing thyroid hormone status.
I chose this article because it directly addresses the PICO question by evaluating the addition of liothyronine (T3) in patients with hypothyroidism who continue to experience persistent symptoms despite appropriate levothyroxine therapy and normal TSH levels. In this case series, the patients had persistent fatigue and other symptoms consistent with hypothyroidism. After initiation of combination therapy, each patient demonstrated meaningful improvement in fatigue, energy levels and overall symptom burden along with increased total T3 levels. These findings support the intervention in my PICO question. Although the study design is limited, as it is a case series with only three patients, it provides clinical evidence that aligns with the PICO question, that combination therapy may offer symptomatic benefit.
- Interventions to improve symptomatology in patients with hypothyroidism and persistent symptoms: A systematic review
Hidalgo, J., Lincango, E.P., Cordova-Madera, S. et al. Interventions to improve symptomatology in patients with hypothyroidism and persistent symptoms: A systematic review. Endocrine 84, 864–873 (2024). https://doi.org/10.1007/s12020-024-03816-1
Article Type: Randomized controlled trial
Abstract
Background
Levothyroxine (LT4) monotherapy is the standard treatment for hypothyroidism; however, 10–15% of patients have persistent hypothyroid symptoms despite normalizing thyroid hormone levels with LT4. This study aims to summarize the best available evidence on interventions to improve symptomatology in patients with hypothyroidism and persistent symptoms.
Methods
A systematic search was conducted in March 2022 for randomized controlled trials and observational studies on interventions for adult patients with persistent hypothyroid symptoms despite biochemical euthyroidism on thyroid hormone replacement.
Results
A total of 277 articles were reviewed and seven fulfilled the inclusion criteria. 455 participants were included. Most intervention participants were female (78.6%) with a mean age of 47.5 (±2.8) years. Five clinical trials evaluating ginger (vs. starch), L-carnitine (vs. placebo), combination LT4 and liothyronine (LT3) (vs. LT4 or placebo), and surgery for patients with serum antithyroid peroxidase (TPO Ab) titers greater than 1000 IU/ml (vs. LT4) found inconsistent improvement in hypothyroidism related symptoms and general health. The two clinical trials with the largest improvement in fatigue scores were the use of ginger and surgery. One observational study comparing thyroidectomy vs observation found no significant difference on general health. Lastly, another observational study evaluating combination LT4/LT3 (vs. LT4 monotherapy) found improvement in fatigue and quality of life. There were 31 (12%) adverse events in the intervention group and 18 (10.8%) in the comparator group.
Conclusions
There is no high-quality evidence supporting any intervention for persistent symptoms in hypothyroidism. Available evidence, limited by the risk of bias, inconsistency, and heterogeneity, suggests that some persistent symptoms, particularly fatigue, could improve with ginger and thyroidectomy.
I selected this article because it is a systematic review, which represents a higher level of evidence and directly evaluates intervention for patients with hypothyroidism, specifically Hashimoto’s thyroidists, who continue to experience symptoms despite adequate levothyroxine therapy. The findings from the reviews demonstrated improvements in overall quality of life and mental health when using combination therapy with liothyronine. However, there was no significant difference in fatigue, depression, or cognitive symptoms when compared to levothyroxine alone. This inconsistency directly addresses my clinical question by showing that while combination therapy may provide benefit in certain patients, it does not consistently outperform monotherapy.
- Benefits and Harms of Levothyroxine/L-Triiodothyronine Versus Levothyroxine Monotherapy for Adult Patients with Hypothyroidism: Systematic Review and Meta-Analysis
Millan-Alanis, J. M., González-González, J. G., Flores-Rodríguez, A., Singh Ospina, N., Maraka, S., Moreno-Peña, P. J., Brito, J. P., González-Velázquez, C., & Rodríguez-Gutiérrez, R. (2021). Benefits and harms of Levothyroxine/L-triiodothyronine versus Levothyroxine monotherapy for adult patients with hypothyroidism: Systematic review and meta-analysis. Thyroid®, 31(11), 1613-1625. https://doi.org/10.1089/thy.2021.0270
Article Type: Systematic review and meta-analysis
Abstract
Background:
Combined therapy with levothyroxine (LT4)/L-triiodothyronine (LT3) has garnered attention among clinicians and patients as a potential treatment alternative to LT4 monotherapy. The objective of this study was to compare the benefits and harms of LT4/LT3 combined therapy and LT4 monotherapy for patients with hypothyroidism.
Methods:
A systematic search in MEDLINE, Scopus, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials was performed by a librarian from inception date until September 2020. Randomized clinical trials and quasiexperimental studies comparing combined therapy (LT4/LT3) versus monotherapy (LT4) for adult patients with hypothyroidism were considered for inclusion. Independent data extraction was performed by paired reviewers. A meta-analysis comparing standardized mean differences of the effect of each therapy was performed on clinical outcomes and patient preferences. Proportions of adverse events and reactions were assessed narratively.
Results:
A total of 1398 references were retrieved, from which 18 fulfilled the inclusion criteria. Results supported by evidence at low-to-moderate certainty evidence did not display a difference in treatment effect between therapies on clinical status, quality of life, psychological distress, depressive symptoms, and fatigue; all measured with standardized questionnaires. Furthermore, meta-analysis of patient preferences revealed higher proportions of choice for combined therapy (43%) when compared with monotherapy (23%) or having no preference (30%). When evaluating treatment adverse events or adverse reactions, similar proportions were observed between treatment groups; meta-analysis was not possible.
Conclusions:
The available evidence at low-to-moderate certainty demonstrates that there is no difference in clinical outcomes between LT4/LT3 combined therapy and LT4 monotherapy for treating hypothyroidism in adults, except for a higher proportion of patients preferring combined therapy. Adverse events and reactions appear to be similar across both groups, however, this observation is only narrative. These results could inform shared decision-making conversations between patients with hypothyroidism and their clinicians.
I selected this article because it is a systematic review and meta analysis of 18 trials over 1,500 patients, providing a high level of evidence and allows for a comprehensive evaluation of both benefits and harms of combination therapy. The results do not support a significant clinical advantage of combination therapy over monotherapy. There were no statistically significant differences between the two treatment groups in improving quality of life, fatigue, depression, psychological distress, and overall clinical outcomes. Additionally adverse events were found to be similar between therapies, suggesting no clear safety benefit to combination therapy either. However, patient preference favored combination therapy, suggesting that the only favorable outcome of this treatment method is improved perceived well being.
- Sexual function and depressive symptoms in young women with hypothyroidism receiving levothyroxine/liothyronine combination therapy: a pilot study
Krysiak, R., Szkróbka, W., & Okopień, B. (2018). Sexual function and depressive symptoms in young women with hypothyroidism receiving levothyroxine/liothyronine combination therapy: A pilot study. Current Medical Research and Opinion, 34(9), 1579-1586. https://doi.org/10.1080/03007995.2018.1448771
Article Type: Systematic review and meta-analysis
Abstract
Objective Even mild hypothyroidism in pre-menopausal women is accompanied by impaired sexual functioning. The study was aimed at comparing the effect of levothyroxine, administered alone or in combination with liothyronine, on sexual function and depressive symptoms in pre-menopausal women treated because of hypothyroidism.
Methods This quasi-randomized, single-blind study included 39 young women receiving levothyroxine treatment who, despite thyrotropin and thyroid hormone levels within normal limits, still experienced clinical symptoms of hypothyroidism. These patients were divided into two groups: group A (n = 20) continued levothyroxine treatment, while group B (n = 19) received levothyroxine/liothyronine combination therapy. At the beginning of the study, and 6 months later, all participants of the study filled in questionnaires evaluating female sexual functioning (Female Sexual Function Index; FSFI) and the presence and severity of depressive symptoms (Beck Depression Inventory-Second Edition; BDI-II).
Results The study was completed by 37 women. Baseline sexual functioning and depressive symptoms did not differ between the study groups. Neither the total FSFI score nor the domain scores changed throughout the study in women who continued levothyroxine treatment. Compared to levothyroxine administered alone, levothyroxine/liothyronine combination therapy increased scores for two domains: sexual desire and arousal, tended to increase the total FSFI score, as well as tended to decrease the overall BDI-II score. The effect of the combination therapy on sexual function correlated with a treatment-induced increase in serum levels of free triiodothyronine and testosterone.
Conclusions The obtained results suggest that levothyroxine administered together with liothyronine is superior to levothyroxine administered alone in affecting female sexual functioning.
I selected this article because it addresses my PICO question in other aspects. The study focuses on premenopausal women who are already treated with levothyroxine but remain symptomatic. While the primary outcomes assessed were sexual function and depressive symptoms rather than fatigue, these outcomes are strongly related to quality of life and commonly overlap with persistent hypothyroid symptoms such as low energy, mood disturbances, and decreased well being. This article is relevant because it provides insight into whether combination therapy may improve patient centered outcomes when standard levothyroxine treatment is insufficient. Even though it does not directly measure fatigue, its findings on mood and functional well being contribute to the broader understanding of quality of life improvements, helping inform clinical decision making for patients.
| Author (Date) | Level of Evidence | Sample/Setting (# of subjects/studies, cohort definitions etc.) | Outcome(s) studies | Key Findings | Limitations and Biases |
| (Peterman et al., 2025) | Level IV- Case series | – 3 adult patients with hypothyroidism, all patients on levothyroxine monotherapy, had persistent symptoms (fatigue, low energy), and had normal TSH and free T4- Patients included were a 67 year old female, 58 year old female, and 40 year old male | – Symptom improvement (fatigue, energy levels, cognition) – Total T3 levels, TSH, FT4- Heart rate, weight changes | – Each patient showed improved fatigue, energy levels, and cognitive function after starting LT4 and LT3 combination therapy. – There was an increase in total T3 levels- Additional findings: improvement in bradycardia in one patient (Case 1). | – Very small sample size- No control group- High risk of bias- Short follow up duration |
| (Hidalgo et al., 2024) | Level I – Systematic review | – 7 studies included (5 randomized controlled trials and 2 comparative observation studies) – Total sample size: 455 adults patients – Follow up duration: 1-18 months – Adults with hypothyroidism on levothyroxine who have persistent symptoms despite normal thyroid levels (biochemical euthyroidism) | – Quality of life- Hypothyroid symptoms improvement (fatigue, cognitive dysfunction, weight gain)- Depression and mental health- Adverse events/complications | – Combination therapy with LT4 and LT3 daily at a ratio of 5:1 for 6 weeks did not lead to significant differences in fatigue, depression, slow thinking and attention problems when compared to LT4 monotherapy. – However, they showed that overall ThyPRO-39 scores significantly decreased on combined LT4/LT3 therapy despite stable TSH, showing improvement across several domains, including emotional susceptibility, impaired social and daily life, and cognitive complaints. | – High risk of bias- Small sample sizes- Heterogeneity in interventions- Short follow up durations |
| (Millan-Alanis et al., 2021) | Level I – Systematic review and meta-analysis | – 18 studies- Around 1563 adult patients with hypothyroidism (Hashimoto’s thyroiditis included)- Included RCTs and quasi experimental studies comparing the efficacy of LT4/LT3 synthetic combined therapy or desiccated thyroid extracts versus LT4 monotherapy on adult patients | – Clinical status, quality of life, psychological distress, fatigue, patient preference, adverse events | – There was no significant difference between LT4/L3 combined therapy versus L4 monotherapy in clinical scores, quality of life, psychological distress, depression,and fatigue. – There was a statistically significant effect favoring LT4/L3 therapy on depressive symptoms among studies where the dose of LT3 was higher than 10 μg.- The incidence of adverse events among participants on combined therapy did not tend to differ substantially from those on monotherapy. | – Heterogeneity in dosing, duration, and outcome measures- Many short duration studies (< 12 weeks)- Some studies with risk of bias – Limited data on long-term outcomes – Some studies were excluded from meta-analysis due to missing information |
| (Krysiak et al., 2018) | Level II – Quasi-experimental | – 39 premenopausal women (37 completed the study)- Women with hypothyroidism post thyroidectomy on levothyroxine but still symptomatic | – Sexual function – Depressive symptoms- Hormone levels (T3, testosterone, TSH) | – Group A had normal levothyroxine treatment. Group B had combined levothyroxine and liothyronine treatment. -7.5 ± 12.8 μg in group A and 88.2 ± 12.9 μg in group B. The mean daily dose of levothyroxine at the end of the study in group A was the same as at the beginning of the study. In group B, the mean daily doses were 44.1 ± 6.4 μg for levothyroxine and 8.8 ± 1.7 μg for liothyronine.- In group A, serum levels of thyrotropin, free thyroid hormone levels, testosterone, and prolactin remained at a similar level throughout the study. At the end, free triiodothyronine levels were higher ,while free thyroxine was insignificantly lower in group B than in group A. – Levothyroxine, administered together with liothyronine improved sexual desires and increased the total FSFI score. – Replacing levothyroxine with levothyroxine/liothyronine tended to reduce the overall BDI-II score but did not affect the percentage of patients with total, mild, moderate, and severe depressive symptoms. | – Small sample size- Quasi-randomization (selection bias)- Single-blind design – Subjective self-reported outcomes- Limited generalizability – Some adverse effects in combination group |
Conclusions:
- This case series demonstrates that select patients with persistent symptoms and low T3 levels despite normal TSH may experience symptomatic improvement after adding LT3. All three patients showed improvements in fatigue, energy levels, and biochemical markers. However, the findings are limited by the small sample size, lack of control group and inability to determine causation. While the results are clinically relevant, they primarily serve to create hypotheses rather than guide definitive practice. Therefore, combination therapy may benefit only select patients with persistent symptoms with Hashimoto’s thyroiditis/hypothyroidism.
- This systematic review highlights the complexity of managing patients with hypothyroidism who continue to experience symptoms despite being on levothyroxine. Unfortunately, even combination therapy of LT4 and LT3 daily at a ratio of 5:1 for 6 weeks did not lead to significant differences in fatigue, depression, slow thinking and attention problems when compared to LT4 monotherapy. However, the ThyPRO-39, a questionnaire completed by the participants to measure quality of life in patients with thyroid disease, decreases, indicating improvement in certain aspects of life, such as emotional susceptibility, and cognitive complaints. This shows that combination therapy may only be successful in limited patient groups, and may not be able to be used as a generalized standard treatment option. Further research is necessary to understand the mechanism behind the clinical manifestations behind hypothyroidism and ultimately look for more specific therapeutic targets.
- This systematic review and meta analysis demonstrates that levothyroxine monotherapy and LT4/LT3 combination therapy provides equivalent clinical outcomes across multiple domains, including quality of life, psychological distress, depression, and fatigue. WHile no clinical superiority was identified, a significant proportion of patients preferred combination therapy, suggesting a subjective benefit that is not captured by standardized outcome measures. Adverse events appeared similar between groups, although reporting was heterogeneous. Overall, this study reinforces LT4 monotherapy as standard of care, while highlighting the importance of shared decision making.
- This smaller, single blind study suggests that LT4.LT3 combination therapy may provide targeted symptomatic benefits, particularly in sexual desires. While this is not a significant aspect of my PICO question, it still addresses quality of life and depressive symptoms as a factor. The benefits noted were modest, limited to specific domains and accompanied by potential adverse effects, such as tachycardia in some patients. Although questionnaires that were given showed improvement after taking combination therapy in depressive and sexual symptoms, there were no significant differences between both therapies. Overall, combination therapy may be utilized specifically in female patients whose sexual functioning is being affected by hypothyroidism.
Overall, the current evidence collected is moderate in quality but inconsistent in findings. A major strength of all of these studies is that they directly address patient centered outcomes, such as fatigue and quality of life, relevant aspects to my PICO question. However, the limitations of the studies makes it difficult to rely on the new treatment option as a potential option. From the results of these studies, levothyroxine monotherapy still remains the standard of care for hypothyroidism/Hashimoto’s thyroiditis. Combination levothyroxine and liothyronine therapy should not be used routinely, given the lack of consistent high-quality evidence. However, in select patients with persistent symptoms despite normal TSH and particularly those with low T3 levels, a carefully monitored trial of combination therapy may be reasonable. From the above studies, certain aspects of quality of life did improve in select patients when on combination therapy. With that being said, more research should be done to find out a definitive approach to better manage these persistent symptoms if levothyroxine alone is insufficient. In such situations, shared decision making is essential, weighing potential benefits, such as symptomatic improvement, against risks, including overtreatment and lack of long term data.
Clinical bottom line:
Weight of the evidence:
The overall weight of the evidence suggests that levothyroxine monotherapy remains the standard treatment for hypothyroidism and Hashimoto’s thyroiditis, even in patients with persistent symptoms despite normal TSH levels. The strongest evidence comes from the systematic review and meta-analysis by Millan-Alanis et al. This evidence demonstrated no significant difference between LT4/LT3 combination therapy and LT4 monotherapy in fatigue, depression, psychological distress, or overall quality of life. Similarly, the review by Hidalgo et al., also found inconsistent improvements in persistent hypothyroid symptoms. Combination therapy introduces shorter acting T3, which can lead to increased risk of symptoms, such as palpitations, anxiety or even arrhythmias in some patients. Although overall adverse event rates were similar across the studies, the lack of standardized reporting and long term safety data remains a limitation.
The case series and experimental studies demonstrated subjective symptomatic improvements in select patients receiving combination therapy. However, these studies were limited by small sample sizes, lack of randomization or control groups, short follow-up periods, and higher risk of bias. Therefore, while some evidence suggests potential benefit in carefully selected individuals, the overall weight of evidence does not support routine use of LT4/LT3 combination therapy in most patients.
Magnitude of effects:
The magnitude of benefit associated with combination therapy was modest and inconsistent. In the review by Hidalgo et al., combination therapy using an LT4:LT3 ratio of 5:1 for six weeks did not significantly improve fatigue, depression, attention problems, or slow thinking compared to LT4 monotherapy. However, patients demonstrated improvement in the ThyPRO-39 quality of life scores, particularly in emotional aspects, cognitive complaints, and impairment in social/daily functioning. In these patients, the evidence suggests that while combination therapy may not significantly improve objective outcomes, it may provide subjective benefits that matter to patients, such as improved well being or symptom perceptions. The study done by Millan-Alanis et al. similarly found no statistically significant improvement in fatigue or depression scores overall, although subgroup analysis showed that studies using LT3 doses greater than 10 μg demonstrated some improvement in depressive symptoms. Importantly, patient preference favored combination therapy, with 43% preferring LT4 and LT3 therapy compared to 23% favoring LT4 alone. This suggests that although clinical outcomes may not differ substantially, some patients perceive meaningful symptomatic improvement. The case series by Peterman et al., reported improvements in fatigue, daytime sleepiness, energy levels and cognition in all three patients after starting combination therapy. However, these findings are only relevant to these three patients and the true magnitude of effect cannot be generalized reliably.
Clinical Significance:
The evidence suggests that normal TSH alone may not fully address all of the symptoms of patients with hypothyroidism. Persistent fatigue, cognitive complaints, mood changes, and reduced quality of life remain important concerns despite biochemical euthyroidism. Although combination therapy has not consistently demonstrated superiority in objective outcomes, the subjective improvements reported by patients may still hold clinical significance for several patients. This is particularly relevant because fatigue and impaired quality of life are highly patient centered outcomes. For some patients, even small improvements in energy, mood, or daily functioning may substantially improve overall wellbeing and satisfaction with treatment. Additionally, the consistent finding that many patients prefer combination therapy suggests that current objective outcome measures may not fully capture patient experiences. However, the lack of consistent clinical benefit across high quality studies prevents combination therapy from replacing LT4 monotherapy as standard treatment. Therefore, its clinical significance is dependent on individualized symptoms management rather than a standardized treatment option.
Other considerations in using this evidence to guide clinical practice:
There are several important considerations that should guide clinical decision making when evaluating combination therapy. Combination therapy may be most appropriate for carefully selected patients who continue to experience persistent symptoms with normal TSH levels that are significantly affecting their quality of life. In such situations, shared decision making is important, as patients should understand that current evidence does not favor combination therapy over monotherapy. Additionally, long term safety data on LT4/LT3 therapy remain limited, especially regarding cardiovascular outcomes. Many of the available studies were limited by differences in dosing regimens, treatment duration, outcome measures, and patient populations, making direct comparison difficult. Most of the trials were short in duration as well, which may not adequately assess long term symptom improvements. Ultimately, it is important to engage in patient conversation about what they want, discussing risks and potential long term outcomes. Overall, the approach to managing symptomatic patients despite being on levothyroxine monotherapy is complex, requiring more research and data on the effects of combination therapy.
