Frequently Asked Questions

The most commonly used medication in the treatment of hypothyroidism is thyroxine or T4, with Synthroid being the most recognized brand name of T4. T4 is typically used as a standalone treatment, which is referred to as T4 monotherapy. T3/T4 combination therapy as I prescribe it involves the use of a small dosage of T3 alongside T4. 

The primary hormone produced by the thyroid gland is tetraiodothyronine (T4), so-named because it contains four iodine atoms. A much smaller amount of triiodothyronine (T3), containing three iodine atoms, is produced by the thyroid gland. Both T3 and T4 circulate in the bloodstream bound to transport proteins, with only a very small fraction of each left unbound and biologically active. When these transport proteins arrive at their final destination – a cell in need of thyroid hormone – T4 dissociates from its transport protein and is transported across the cell membrane and into the cell. T4 is converted to T3 by an enzyme called a deiodinase. T3 then binds to a thyroid hormone receptor to regulate gene expression. While T4 may have some direct actions of its own, mediated by binding of T4 to receptors within the cell membrane, it is widely accepted on the basis of abundant evidence that T3 is responsible for most, if not all, of the physiological effects of thyroid hormone, and that T4 acts primarily as a pro-hormone. In other words, T4 serves as a precursor and all or nearly all of its beneficial effects are dependent on it being converted to T3. 

As noted above, the most commonly used medication in the treatment of hypothyroidism is thyroxine or T4. While most patients with hypothyroidism do well on T4 monotherapy, others continue to experience signs and symptoms potentially consistent with inadequately controlled hypothyroidism. Some of these patients feel better and experience a resolution of these signs and symptoms with the use of T3/T4 combination therapy. It is possible that these patients do not adequately convert exogenously administered T4 to T3, which explains why they feel better on combination therapy. This is not mere supposition on my part as there are a number of studies demonstrating that patients on T4 monotherapy have lower T3 levels (including free T3 levels) and/or T3:T4 ratios than individuals with normal thyroid function not on thyroid hormone replacement and that some of these patients have T3 levels that are below the lower limit of normal. 

Although definite figures are hard to come by, studies suggest that between 5 and 10 percent of patients on T4 monotherapy with normal TSH values have signs and symptoms potentially consistent with inadequately controlled hypothyroidism. Dr Antonio Bianco, an esteemed endocrinologist and former president of the American Thyroid Association, estimates that 10-20 percent of patients with hypothyroidism do not benefit fully from T4 monotherapy and might therefore benefit from a trial of T3/T4 combination therapy1. 

Not necessarily. The signs and symptoms of hypothyroidism are very non-specific, which means that a wide variety of causes can be responsible for each of these signs and symptoms. While inadequately controlled hypothyroidism may certainly contribute to such non-specific symptoms, it’s important to acknowledge that other factors, such as poor diet and chronic stress, may be contributory if not causative. Before jumping to the conclusion that inadequately controlled hypothyroidism is the culprit, it’s important to assess for other factors that may be contributing to the patient’s signs and symptoms. I’d like to provide a few examples to make this point crystal clear. 

Jane is a 40-year-old woman who was diagnosed with overt hypothyroidism two years ago and has been on Synthroid ever since. Her dosage has been stable at 100 mcg once daily for a year and a half. Although she feels better than she did pre-treatment, she feels much more fatigued than she thinks she should and is having tremendous difficulty losing the 20 pounds that she put on prior to her diagnosis despite having diligently adhered to a well thought out weight loss regimen for the past six months. Her thinking isn’t as sharp as it once, which is making it increasingly difficult for her to keep up at work. She also feels mildly depressed, seemingly without cause, which isn’t like her. In other words, Jane is endorsing multiple symptoms potentially consistent with inadequately controlled hypothyroidism. Her lifestyle is really quite exemplary – she eats a healthy diet at a moderate but not excessive caloric deficit, gets enough but not too much exercise, sleeps 8 hours a day, and does an excellent job of managing her stress. Her last TSH level came back at 1.5 mIU/L (i.e., in the optimal range) but her T3 level is at the very low end of the normal range on repeated measurements. On reviewing her medical history and bloodwork, there are no clear potential causes for the signs and symptoms she is reporting other than inadequately controlled hypothyroidism. In this case, it would be reasonable to consider a trial of T3/T4 combination therapy. 

Emily is also 40 years old and, like Jane, has been on a stable dosage of Synthroid for overt hypothyroidism for several years. Also like Jane, Emily feels more tired than she thinks she should and is having difficulty losing weight. It’s here that the similarities end. Emily doesn’t report any other symptoms potentially consistent with inadequately controlled hypothyroidism. She’s been eating a low-calorie diet in an effort to lose weight on an on again/off again basis. She has difficulty sticking to an exercise regimen. She’s very stressed, which she attributes to a demanding job and an unhappy marriage. She has difficulty getting to sleep and wakes up several times throughout the night. Given all this, are you surprised that Emily is tired and is having difficulty losing weight? I’m not! Her last TSH level came back at 1.5 mIU/L (i.e., in the optimal range) and her T3 level is at the upper end of the normal range on repeated measurements. In this case, it would not be reasonable to consider a trial of T3/T4 combination therapy. 

Not necessarily. This is because there is evidence that numerous factors – inflammation, oxidative stress, stress/cortisol, negative energy balance, the use of select medications, etc – might decrease T3 levels and/or action, in part by inhibiting the conversion of T4 to T3. Prior to considering a trial of T3/T4 combination therapy, it would be reasonable to attempt to optimize the metabolism of exogenously administered T4 by assessing for and addressing these factors. 

In recent years there have been strident calls from a segment of the ‘hypothyroidism community’ for the wholesale abandonment of TSH as the test of choice not only for diagnosing hypothyroidism but for gauging the adequacy of thyroid hormone replacement. This view has been promulgated in books such as Stop the Thyroid Madness. Within this community the view is often expressed that a suppressed TSH level in a patient on thyroid hormone replacement, which would be indicative to a conventionally trained medical doctor of excessive thyroid hormone dosing, is no cause for concern, and that what matters most is how the patient feels. 

While I agree that careful attention should be paid to a patient’s self report, the fact that a patient feels best on a dosage of thyroid hormone (no matter whether this is in the form of T3 alone, T4 alone, or a combination of the two) that results in a suppressed TSH level doesn’t necessarily mean that this is acceptable or ideal, particularly from the point of view of long-term health outcomes. 

There is some validity to the argument that TSH might not be a perfect test for gauging the adequacy of thyroid hormone replacement. For example, there is evidence that T4 monotherapy resulting in normal TSH levels may not fully correct metabolic alterations related to hypothyroidism. For example, studies have found that patients on T4 monotherapy have lower resting metabolic rates and higher total cholesterol and LDL levels than individuals with normal thyroid function not on thyroid hormone replacement. In addition, studies have found that in patients on T4 monotherapy, tissues are closest to euthyroidism (i.e., a state in which thyroid hormone levels and signaling are adequate) at a TSH of 0.03-0.3 mIU/L. In other words, tissue euthyroidism is only achieved with TSH-suppressive dosages of T4. 

Nevertheless, the fact of the matter is that there is considerable evidence that suppressed TSH levels, including those that fall within the subclinical hyperthyroidism range, and especially if accompanied by supraphysiologic T3 and/or T4 levels, are associated with an increased risk of negative health outcomes. 

There’s nothing that will get a medical doctor’s hackles up more quickly than a patient requesting a reverse T3 test on the recommendation of their naturopathic doctor. There’s something about the reverse T3 test that generates particularly strong reactions from both sides – with proponents of reverse T3 testing stating or at least insinuating that not ordering a reverse T3 is indicative of a lackadaisical approach to managing hypothyroidism and detractors of reverse T3 testing steadfastly refusing to order the test because it’s ‘useless.’ 

I do not order reverse T3 testing for the simple reason that the test result will not meaningfully inform my treatment approach. The same situations that result in an elevated rT3 level also result in a low T3 level. For example, a pronounced negative energy balance will favour the production of rT3 over T3. Therefore, any compromise in thyroid hormone metabolism is already being captured by the low T3 level. 

While T4 monotherapy is now the standard of care, most if not all family doctors have at least a few patients with hypothyroidism on desiccated thyroid extract. I inherited half a dozen such patients when I started my family practice, all of whom insisted on remaining on desiccated thyroid extract and essentially refused to switch to T4. I have no reason to suspect that my practice was somehow unique in this regard. A study that looked at insurance claims for prescriptions estimated that between the late 2010s and early 2020s there were about 1.5 million patients on desiccated thyroid extract in the United States1. Therefore, although T3/T4 combination therapy is employed much less often than T4 monotherapy in the treatment of hypothyroidism, it is hardly uncommon. 

If T3/T4 combination therapy is appropriately administered in appropriately selected patients, then the answer is yes. 

Several large observational studies bear this out. A Scottish study identified about thirty-four thousand patients taking T4 and compared them with about four hundred patients taking T3 and T4, or T3 alone. Over a follow-up period of close to a decade, no differences in mortality or morbidity risk due to cardiovascular disease, atrial fibrillation, or fractures were seen. 

A subsequent Swedish study of adults who used thyroid hormone between 2005 and 2017 concluded that the use of T3 by approximately eleven thousand individuals during a median follow-up of about eight years did not increase all-cause mortality compared with T4 use.

Ultimately, the safety of T3/T4 combination therapy comes down to 1) only employing this therapy in appropriately selected patients; 2) administering appropriate/safe dosages of T3 while avoiding thyrotoxicosis. Let’s review each of these points in turn. 

T3/T4 combination therapy should only be used in appropriately selected patients. 

There are a variety of medical conditions that could be exacerbated by the use of T3. For example, the use of T3 would be inappropriate in a patient with inadequately controlled atrial fibrillation or decompensated heart failure. 

T3 must be administered in appropriate/safe dosages while avoiding thyrotoxicosis. 

I generally prescribe a low dosage of synthetic T3 alongside synthetic T4 with the aim of achieving optimal and safe TSH, T4, and T3 levels. I should note that the dosage of T3 that I generally prescribe is less than that found in 1 grain of desiccated thyroid extract and therefore cannot be considered a dosage that poses a significant risk of harm. 

There are multiple forms of T3 on the market: 1) synthetic T3; 2) desiccated thyroid extract; and 3) compounded slow-release T3. Each of these forms of T3 has distinct advantages and disadvantages. 

Synthetic instant-release T3 (hereby referred to simply as synthetic T3 for the sake of brevity) is manufactured by pharmaceutical companies and so you know exactly what you’re getting. When you’re talking about a hormone administered not in milligrams but in micrograms, dosing accuracy is of paramount importance and so this is a considerable advantage. The disadvantage of synthetic T3 is that it is metabolized much more rapidly and has a much shorter half-life than T4. If anything more than a low dose is administered at a time, supraphysiologic (i.e., higher than normal) T3 levels are likely to result. Therefore, in order to minimize excursions in T3 levels, synthetic T3 should be administered in divided doses (i.e., multiple times daily), which can be inconvenient for patients, especially given that T3 is ideally taken on an empty stomach.  

Desiccated thyroid extract contains primarily T4 and T3, with lesser quantities of T2 and T1. One of the primary disadvantages of desiccated thyroid extract is that you cannot manipulate T3 and T4 doses independently of one another as they are present in desiccated thyroid extract in a fixed ratio of ~ 1:4. In addition, it has been my experience and the experience of many other medical doctors that if desiccated thyroid extract is being used as the exclusive form of thyroid hormone replacement, and especially if it is being used in higher dosages (> 1 grain per day, which is considered the equivalent of 100 mcg of T4 and which contains ~ 9 mcg of T3), you often see suppressed TSH and/or supraphysiologic T3 levels. Another potential disadvantage, admittedly theoretical, is that the administration of porcine thyroid tissue, which from the immune system’s point of view is very much a foreign substance, might exacerbate the autoimmune attack on the thyroid gland that is responsible for the majority of cases of hypothyroidism. Anecdotally, it is said that the administration of desiccated thyroid extract results in a slower rise in serum T3 levels than the administration of synthetic T3. Nevertheless, desiccated thyroid extract cannot be regarded as a slow-release form of T3 and therefore, as is the case with synthetic T3, it is prudent to administer desiccated thyroid extract in divided doses. And, if you’re going to do this, why not use synthetic T3 instead, which doesn’t have the same disadvantages as desiccated thyroid extract? 

At first glance, compounded slow-release T3 would appear to the ideal form of T3. Administering T3 in a slow-release form should minimize peaks and valleys in T3 levels and allow for once daily administration. However, the issue of quality control looms large as compounded medications are not subject to rigorous testing. This is a particular concern when it comes to T3 prescribed in larger doses. Consider a patient taking 225 mcg of T4 daily who is switched over to an equivalent dosage of T3 of 75 mcg once daily in slow-release form. (Note: a meticulously conducted study by Celi et al. suggests that T3 should be substituted for T4 at a 1:3 ratio). What if the pharmacist makes a mistake in the preparation of the compounded medication and it behaves more like an instant-release than slow-release medication? Or what if the medication is slow release as intended but dosed incorrectly and each capsule contains 50% more T3 than prescribed? In both cases, we’d be looking at supraphysiologic T3 levels which could increase the risk of a variety of negative short- and long-term health outcomes. The potential for negative outcomes resulting from a compounding error is obviously much reduced with lower doses of T3, which is why I only prescribe low doses of compounded slow-release T3, which is more physiologic in any case. However, this does not eliminate the possibility of a gross dosing error, which is why it is important to employ the services of a pharmacy that specializes in compounding and whose pharmacists have a great deal of experience in compounding hormonal preparations. For this purpose, I employ the services of Smith’s Pharmacy in Toronto exclusively as Smith’s has an in-house quality control team to ensure compliance with NAPRA and USP standards. 

When employed as part of T3/T4 combination therapy, T3 is generally prescribed at 1.5 to 5 percent of the T4 dosage. Dr Kenneth Blanchard, endocrinologist and author of The Functional Approach to Hypothyroidism, recommends the lower end of the dosage range as a starting point and ideally in the form of compounded slow-release T31. So, for example, a patient who is taking 100 mcg of T4 would be prescribed a T3 dosage of 1.5 mcg once daily. Dr Wilmar Wiersinga, a clinician-scientist at the University of Amsterdam, recommends the higher end of the dosage range and in the form of synthetic T32, a method of administration endorsed by Dr Antonio Bianco. So, for example, a patient who is taking 100 mcg of T4 would be prescribed a T3 dosage of 5 mcg daily in divided doses. 

In a patient who is older and/or who has comorbid medical conditions that could theoretically be aggravated by the use of T3, I generally prescribe compounded slow-release T3 dosed at 1.5 percent of the T4 dosage (as a starting point). In a younger patient, I generally prescribe synthetic T3 dosed multiple times daily at 5 percent of the T4 dosage (as a starting point). 

This will depend on the dosage of T3 being administered. For example, if 0.75 mcg of compounded slow-release T3 is being used in a patient taking 50 mcg of T4, adjustment of the T4 dosage is not required. On the other hand, if 10 mcg of synthetic T3 in divided doses is being used in a patient taking 200 mcg of T4, the T4 dosage should be decreased. The question then becomes ‘by what amount?’ Dr Wilmar Wiersinga recommends reducing the dosage of T4 by 2.5 times the T3 dosage1. So, using the example above, the patient would end up taking 175 mcg of T4 once daily (10 mcg x 2.5 = 25 mcg; 200 mcg – 25 mcg = 175 mcg) alongside 5 mcg T3 twice daily. 

On the surface, the rationale underlying T3 monotherapy is quite compelling – if T4 is simply acting as a prohormone or precursor to T3, why not ‘cut out the middleman’ so to speak and administer T3 directly? Although the potential advantage of this approach is clear – no need to worry about whether inflammation, high cortisol levels, genetic variants affecting deiodinase function, etc are decreasing T3 levels and/or action – one difficulty lies in how to safely accomplish this. 

Recall that we have two T3-only treatment options: synthetic T3 and compounded slow-release T3. Say that a patient on 150 mcg/day of T4 wants to switch over to T3. Although this is a matter of considerable debate, a meticulously conducted study by Celi et al. suggests that T3 should be substituted for T4 at a 1:3 ratio i.e., 50 mcg of T3 = 150 mcg T4. If we were to prescribe synthetic T3, we obviously couldn’t administer this as a single morning dose of 50 mcg as this would result in a rapid upswing in T3 levels followed by an equally dramatic crash. The dosage would have to be administered in divided doses. However, twice daily dosing would also be problematic, as 25 mcg doses would also result in supraphysiologic T3 levels. Dosing T3 four or more times per day would be required. Compounded slow-release T3 would certainly be more convenient, but here we run into concerns related to quality control (see the answer to the question ‘How do you prescribe T3?’ for more information on this). A slow-release T3 preparation with well-characterized pharmacokinetic properties manufactured by a pharmaceutical company would make T3 monotherapy much more feasible. Unfortunately, such a product is unlikely to ever come to market. 

There’s another, and perhaps more important reason, to avoid T3 monotherapy, and this relates to the desirability of replicating normal physiology to the greatest extent possible. Recall that the thyroid gland secretes much more T4 than T3. There must be a reason for this. Under most conditions, serum T3 levels are relatively stable. However, if T3 levels are stable, how can T3 modify the different bodily functions that are sensitive to it? The answer is that some organs can accelerate the local conversion of T4 to T3. For example, during exercise, T4 is activated to T3 at a faster pace in the muscles being exercised. The resulting local buildup of T3 increases the muscle’s capacity to produce energy. This takes place without an increase in serum T3 levels. If a systemic increase in T3 levels were to occur, all organs in the body would be stimulated by T3 during exercise, which would not be desirable. The ability to accelerate T4-to-T3 conversion on demand and in an organ-specific fashion gives the system a great deal of flexibility. This would not be possible if the thyroid gland secreted only T3. An excellent example of the wisdom of the body. 

Due to the inadequacy of the T3 treatment options that are available and the desirability of replicating normal physiology to the greatest extent possible, I’m not in favour of T3 monotherapy. 

Dr Ridha Arem, a board-certified endocrinologist who specializes in the treatment of autoimmune thyroid diseases, spoke to this issue in his book The Thyroid Solution:

“…no research so far has been conducted adequately enough to provide evidence that the T4/T3 combination is not beneficial for patients with lingering symptoms. The quality of the published research is so poor that it should not have been published to start with. Most of the studies suffered from a wide range of flaws in their design. The number of patients was in general too small, and the selection of patients studied was often inappropriate…The other major problem with the published research has to do with the dose of T3 used. Most studies used a fixed amount of T3 for all patients irrespective of the total amount of thyroid hormone needed and irrespective of their symptoms.”

One of the biggest flaws in the design of the studies that have compared T4 monotherapy to T3/T4 combination therapy is that they did not specifically recruit subjects who were symptomatic on T4 monotherapy1. The implications of this very obvious design flaw (so obvious that it really makes me wonder whether this was done purposefully) are tremendous. Let’s say I wanted to study whether a given supplement reduces joint pain. Would it make sense for me to recruit subjects who aren’t experiencing any joint pain whatsoever? Of course not. The same rationale applies here. T3/T4 combination therapy cannot lead to a noticeable symptomatic improvement in a subject who has no symptoms. 

It is important to note that the interventional studies that have compared the efficacy of T4 monotherapy to T3/T4 combination therapy have found, virtually without exception, that T3/T4 combination therapy is either equal or superior to T4 monotherapy. As far as I am aware there is only a single study (by Clyde et al.) that has demonstrated the superiority of T4 monotherapy over T3/T4 combination therapy in any respect. 

I suspect that what’s occurring in most such cases is that excessive thyroid hormone dosing results in a certain degree of thyroid hormone receptor desensitization, such that a switch to a safer and more physiologic regimen results in a return of signs and symptoms of hypothyroidism. This is admittedly conjectural but there’s a great deal of precedence in the realm of endocrinology to support this view. Consider the example of a man who takes up competitive bodybuilding and starts using high dosages of anabolic steroids, resulting in sky-high testosterone levels. The body will attempt to protect itself from this onslaught of androgens by downregulating the number and/or sensitivity of androgen receptors. If circumstances, often health-related, compel the man to stop using high dosages of anabolic steroids, and he switches over to a replacement dosage of testosterone, he will undoubtedly feel unwell for a prolonged period of time. Depression and sexual dysfunction are likely to occur. This is because his body has become adapted to very high testosterone levels and a normal level of testosterone will not adequately activate the now downregulated androgen receptors. The only solution for this is time, which will allow the hypothalamic-pituitary-gonadal axis to recalibrate and the androgen receptors to regain their sensitivity.

I suspect that an analogous scenario is responsible for the return of symptoms of hypothyroidism that is sometimes seen when a patient is switched from desiccated thyroid extract or T3 monotherapy to T3/T4 combination therapy. Does this mean that the patient should switch back to desiccated thyroid extract or T3 monotherapy? On balance, I think the answer is no. After all, in the example above, we wouldn’t encourage the patient to return to using high dosages of anabolic steroids simply because he feels unwell on a replacement dosage of testosterone. I believe the most prudent approach in these situations is to be patient (I know this is easy for me to say!) in the hopes that any signs and symptoms of hypothyroidism will resolve with continued use of a safer and more physiologic T3/T4 regimen.  

If your family doctor has the knowledge base to prescribe T3/T4 combination therapy safely and effectively and is willing to do so, then by all means see your family doctor. There is evidence that medical doctors are generally reluctant to prescribe T3/T4 combination therapy. A series of surveys of over four hundred doctors1-3 found that if a patient on T4 presented with persistent signs and symptoms potentially consistent with inadequately controlled hypothyroidism, only 20 percent of doctors would consider prescribing T3/T4 combination therapy. If such a patient were to request the addition of T3 to their regimen, only 35 percent of doctors would prescribe it.

It’s important to keep in mind that I’m not only prescribing T3/T4 combination therapy but attempting to comprehensively address the root cause(s) of whatever symptoms are troubling you. Patients who are seeking a second opinion regarding thyroid hormone replacement are generally doing so because of the presence of non-specific signs and symptoms such as fatigue, which they attribute to inadequately controlled hypothyroidism. While inadequately controlled hypothyroidism may certainly contribute to such non-specific signs and symptoms, other factors, such as poor diet and chronic stress, may be contributory if not causative. In addition, factors such as inflammation and stress/HPA axis dysregulation might decrease T3 levels and/or action. Finally, the inflammation that is part and parcel of Hashimoto’s thyroiditis, the most common cause of hypothyroidism, can also contribute to non-specific signs and symptoms. For all of these reasons an integrative treatment plan is included as part of every thyroid hormone replacement consultation.