I know I know, research studies and articles are oftentimes difficult to wade through and understand the relevance to our no thyroid situation, especially if you have brain fog or the attention span of a fruit fly, like me lately. But, this is an important research article that breaks down what is known and unknown in regards to combination therapy for thyroid replacement treatment. As I’ve mentioned before, T4/T3 therapy is fairly new and there isn’t a lot of reliable science backed information and long term studies available yet. I’m going to do my best to pick out the important parts of this article and hopefully you will find it useful in understanding the viability of combination thyroid treatment. I have attached the complete study at the bottom of this summary.
Combination Thyroid Hormone Replacement; Knowns and Unknowns
Frontiers in Endocrinology
Peter N. Taylor, Vinay Eligar, Ilaria Muller, Anna Scholz, Colin Dayan and Onyebuchi Okosieme
Hypothyroidism is common throughout the world and readily diagnosed with thyroid function tests. Management should be straightforward but appears not to be the case. Thyroid hormone replacement with levothyroxine monotherapy is the standard treatment which is effective in the majority of cases. However, 10–15% of patients established on levothyroxine do not feel their health is entirely restored and some patients prefer the addition of liothyronine (T3).
Proponents of liothyronine argue that the ratio of T3 and T4 hormones is substantially altered on T4 monotherapy and therefore both hormones may be needed for optimal health. This remains controversial as clinical trials have not demonstrated superiority of combination therapy (levothyroxine and liothyronine) over levothyroxine monotherapy.
This review summarizes the evidence where there is established knowledge and agreement (knowns) and areas where research is lacking (unknowns).
THE KNOWNS
Serum T4, Not Serum T3 Is the MainSource of T3 Within Cells
In mammals, the majority of active thyroid hormone (T3) within cells is derived not directly from T3 in the circulation, but indirectly from T4, via the action of the D2 deiodinase. The concentration of circulating T4 is about five times higher than T3 and it is the circulating T4 rather than T3 that serves as the main source of thyroid hormone for the body.
There Is Dissatisfaction in Individuals With Hypothyroidism Who Are on LT4 Monotherapy
Even with normalization of TSH, patients may still complain of symptoms overlapping with overt hypothyroidism such as lethargy, sleepiness, memory problems, inability to concentrate, and process information (brain fog), feeling cold and weight gain.
It is a consistent finding that patients on LT4 replacement even with a normal TSH display significant impairment in psychological well-being compared to controls of similar age and sex. It has been hypothesized that LT4 monotherapy may not restore intracellular T3 levels in the brain in all patients and this may explain the dissatisfaction some patients have on LT4.
Patients Who Have Their Thyroid Function Tested Are Growing in Number, but Are Not Entirely Representative of the General Population
There has been a steady increase in thyroid function testing in the last two decades. Individuals who have their thyroid function checked are more likely to be female, aged over 60, have higher psychological morbidity, but do not appear to have increased rates of hypothyroidism compared to the general population. Importantly, these potential selection biases will need to be taken into account in cohort studies. Symptoms at initial levothyroxine prescription may need to be considered by selection criteria or minimization depending on the outcome measure used.
Patient Characteristics Influence Current Prescribing Practice and Treatment Course
Individuals with only borderline abnormalities in TSH are increasingly being started on LT4.
It appears that thresholds for levothyroxine initiation differ according to patient symptoms at presentation. For example, individuals with tiredness or depression had levothyroxine initiated at lower TSH thresholds than those who had their thyroid function checked as part of general screening. Future trials of combination thyroid hormone replacement need to have inclusion criteria which take into account the patient’s thyroid status at initiation of levothyroxine.
Patients on Levothyroxine Replacement Do Not Have “Normal” Thyroid Function
Patients treated with levothyroxine to achieve normal serum TSH values typically have serum triiodothyronine (T3) concentrations in the reference range but with increased levels of T4 resulting in a significantly increased T4/T3 ratio. Studies of patients established on levothyroxine also reveal that the relationship between TSH and FT3 disassociates on LT4 monotherapy particularly in athyreotic (no thyroid) individuals. Supra-physiological levels of FT4 are actually required to normalize serum FT3 levels.
In support of this hypothesis, a recent large cohort study confirmed that individuals on LT4 had 15–20% lower T3:T4 ratios on LT4 than healthy or matched controls. Prolonged exposure to this different ratio appeared to have adverse health outcomes as, LT4 treated individuals had higher a body mass index despite lower calorie consumption, reported less physical activity and were more likely to be taking antidepressants.
Reliance on TSH Alone May Be Problematic
Due to small changes in thyroid hormone levels resulting in large TSH modifications, TSH has been the preferred diagnostic test for hypothyroidism. However, this approach has been challenged. Key issues include that its reference-interval is not universally agreed and it is not usually adjusted for other factors such as ethnicity and iodine status. This is important as it is perhaps unlikely therefore that TSH accurately reflects thyroid hormone concentrations in all tissues and organs on T4 alone. By contrast, combination LT3:LT4 therapy was able to normalize thyroid hormone dependent biological parameters in the brain, liver, and skeletal muscle. Restoring TSH to the reference-range has been adopted as the goal of thyroid hormone replacement. However, TSH may not be corrected to an individual’s own reference range.
Genetic variation in PDE8B is robustly associated with TSH levels but this relationship is lost in individuals on LT4, thus indicating that whilst TSH is normalized on LT4 therapy this may not be to an individual’s genetic set-point. Given an individual has a narrow genetically determined set point of thyroid function the long-term health consequences are unclear and merit further study.
Current LT3 Dosing Strategies Do Not Replicate T3 Levels in Euthyroid Individuals
FT3 levels show a substantial peak 2–4 hours after a dose and wear off after 12 hour in individuals on a single daily dose of LT3. These profiles are markedly different from euthyroid individuals not on thyroid medications. In particular the peak FT3 level after dose is often substantially above the reference-range. Long-acting T3 preparations are in development and may be the key here. Long-acting preparations make it easier to monitor dosing. The ratio of LT3:LT4 is also of paramount importance. Given the majority of circulating T3 comes from peripheral conversion of FT4 to FT3, a secretion ratio of FT4:FT3 in healthy individuals is ∼14:1. ETA guidelines suggested three possible methods for calculating LT3 and LT4 doses to give a T4:T3 ratio between 13:1 and 20:1 which is close to normal thyroid hormone secretion, however this ratio is generally lower than those used in clinical trials to date. Using these recommended ratios a patient on 100 mcg of LT4 would require between 4 and 6 mcg of LT3 which would be impractical to deliver in split doses with current LT3 formulations.
Combination LT3:LT4 Therapy Has Not Demonstrated Clear Superiority Over LT4 Monotherapy in Clinical Trials
To date there have been at least 13 randomized controlled trials comparing efficacy of combination LT4:LT3 therapy vs. LT4 monotherapy. Four systematic reviews/meta-analyses of these trials of combination LT3:LT4 replacement found no clear benefit over LT4 monotherapy in terms of mood, health-related quality of life or cognitive function. This data has been taken to suggest that at the population level there is no benefit of using combination therapy over monotherapy. However, in no study to date has physiological replacement been achieved. Overall, it seems reasonable to assume that combination therapy cannot be assumed to have no advantages over monotherapy until a well-designed long-term trial of physiological combination treatment with a sustained release preparation or three times daily dosing of FT3 has been conducted.
THE UNKNOWNS
Serum TSH May Be Determined Predominantly by Circulating T4, Not T3
While the complex inverse relationship between the thyroid hormones and TSH is well-established, the relative contribution of FT4 and FT3 in regulating TSH levels is less clear. FT4 may have a greater effect on TSH than FT3. As a result, feedback on serum TSH and its production may be predominantly determined by circulating T4, not T3. This becomes highly relevant when the balance between T4and T3 in circulation is perturbed by replacement with T4 monotherapy, as is standard in endocrine practice. TSH levels may appear to be suppressed more easily on LT4 monotherapy. More research is needed to clarify the relative contributions of LT4 and LT3 therapy on TSH levels.
The Effect of Short Acting LT3 May Have a Disproportionate Effect on TSH
T4 is slowly metabolized with a serum half-life of several days. As a result, once daily dosing results in <20% variation in T3 levels over 24 hours. In contrast, T3 has a shorter half-life, and even 2–3 times a day dosing results in substantial fluctuation in T3 levels over 24 hours. This variation increases with the proportion of T3 in the replacement formulation when combination T3/T4 therapy is used. The effect of this is unclear, but one potential consequence is that spikes of T3 may have a greater suppressive effect on TSH than for the same area under the curve for T3.
The Role of Circulating T3 Is Unclear
Circulating T3 appears to have a different role in physiology than circulating T4. First, even during profound hypothyroidism (e.g., T4 < 5.0 pmol/L, TSH>20 mU/L), T3 is almost always maintained in the reference range. Second, by contrast, during acute illness T3 falls rapidly whereas T4 is maintained, or may even rise. Taken together, these observations suggest that circulating T3 levels have a role in signaling nutritional or health status to the brain, perhaps more so than being a major source of T3 to tissues.
The Usefulness of SNPS in Predicting Who Will Benefit From Combination Therapy Is Unclear
Genetic variation in the deiodinases is associated with altered thyroid function and adverse health outcomes. However, effects have been modest and not consistently replicated. Individuals with genetic variants in DIO2 (rs225014) and MCT10 (rs12885300) have shown preference for combination LT3:LT4 therapy with an additive effect. However, these studies had limitations due to multiple testing and small sample size. Individual SNPs may have poor discriminatory power in determining who might benefit from LT3:LT4 combination therapy.
There Is Limited Data About the Safety Profile of Long-Term LT3 Therapy
An important argument against the widespread use of LT3 is the lack of data on the safety of long-term use. Given the relatively small number of patients using combination LT3:LT4 therapy this is unlikely to be resolved soon. Most of the studies have been of short duration and only one lasted a full year. An increased risk of anti-psychotic medication prescription was noted in T3 users, which may reflect biases in individuals who receive LT3.
CONCLUSION
It has proved challenging when treating a proportion of patients with hypothyroidism to ensure they are restored to optimal health. This is perhaps surprising considering the high global prevalence of this chronic condition. Although current management practices may satisfy the majority of patients, they remain sub-optimal. Key issues affect all stages of management and include excessive thyroid function testing, variation in threshold for treatment by presenting symptoms, wide spread over-replacement on LT4 as evidenced by suppressed TSH, and inequality in access to LT3. Given the importance of thyroid status for health and the substantial dissatisfaction with LT4 replacement further research is urgently needed.
So there it is, NOBODY has all the answers in regards to T4/T3 combination therapy and it’s effect on our body or it’s ability to return us to our pre-thyroid loss health. When bossy Brenda on your favorite thyroid Facebook group eagerly spreads her internet BS about how much T3 you should be taking with your T4 or where your levels should be, I assure you, SHE doesn’t know either. But, now you’re informed, because you read this study and understand the advantages and limitations of combination therapy in it’s current state. Hopefully soon there will be more answers and treatment options available to give our bodies the exact replacement hormones that were lost when our thyroid was removed or destroyed.
Please remember, Darcey and I try to keep our content on this website in line with what is safe, effective and recommended by medical professionals, researchers and leading scientists in Endocrinology.
Here is a link to the study in it’s entirety.
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