T3 Controversies: Can Impaired Thyroid Hormone Action be Treated with T3?

Evidence-Based: written by a Board-Certified Endocrinologist

In Comments and Controversies on Hormones Demystified, I laid out the case for why I needed to write this series of posts about T3. In this and future articles about the topic, I will address the myriad claims and questions that have come up over the years in the Comments section of T3 Or Not T3 – Exploring The Controversy. Per my current Comment policy, I will aggressively moderate reader-generated content that doesn’t meet the standard. I would also ask you to restrict your thoughts, questions, and theories about T3 to the narrow subject of each post in the T3 Controversies Series. I believe this will make the reader experience better for everyone, allowing people to more easily find the information they need. Let’s get started!

Claim: There are acquired forms of impaired thyroid hormone action (also called tissue resistance to thyroid hormone) that require abnormally high levels of T3 and, therefore, high doses of T3 medication to alleviate symptoms1. This situation can exist in the presence of normal thyroid function tests (TFTs, e.g. TSH, FT4, FT3). The appropriate way to treat many of these patients with biochemical euthyroidism but persistent “hypothyroid” symptoms is to increase the T3 dose until symptoms are improved or signs/symptoms of thyrotoxicosis develop.

HD: Mostly False. The non-physician commenter making this claim seems to have a sophisticated understanding of the physiology of thyroid hormone metabolism and action (based on comments he’s left on this blog). However, his strident advocacy for high-dose T3 therapy appears to be primarily based on his personal experience with taking T3. Working backward from his firm belief in the validity of his treatment strategy, he weaves a mechanistic explanation of why it works. He presents his position as fact, while simultaneously sowing mistrust of mainstream medicine by claiming that endocrinologists have a dismal understanding of thyroid hormone physiology. In the second half of this post, I will explain why his argument suffers from the same fatal flaw as many similar positions offered by alternative medicine practitioners.

The commenter also seems to believe that Endocrinologists like me suffer from a slavish adherence to dogma, such that the idea that a normal TSH might not indicate clinical euthyroidism makes us uncomfortable. He has called for better science than what we have currently to guide the treatment of hypothyroidism, given that there is a sizable minority of hypothyroid people with symptoms that persist despite standard treatment.

I don’t totally disagree with his position, as summarized in the preceding paragraph, although I think that TSH is – more often than not – an accurate reflection of thyroid status. The problem I have with his claim that T3 (or T4, for that matter) should be initiated/titrated in the setting of normal thyroid function tests but hypothyroid symptoms is: these symptoms are nonspecific and overlap with symptoms of myriad illnesses, but they can also simply be a downstream effect of a busy life. Quite often, there is no discernible “diagnosis” for these symptoms, but they could be addressed by better attention to diet, exercise, sleep, stress management, and mental health. Sadly, my years of clinical experience have taught me that these symptoms are frequently “medicalized” by alternative medicine practitioners who prescribe thyroid hormone, adrenal extract, and a host of supplements – none of which provides lasting relief. I have taken hundreds of these people off of thyroid hormone – including high doses of T3 – that was initially prescribed in the setting of normal TFTs. It has been extraordinarily uncommon to see someone get any worse off of thyroid hormone, suggesting that thyroid dysfunction in the setting of normal TFTs is rare.

For someone who seems genuinely interested in applying better science to the treatment of hypothyroidism, the commenter’s recommendation to titrate T3 to clinical effect – with no objective evidence that the patient has impaired thyroid hormone production, conversion, transport, or action – seems incongruent. While it is possible to see a constellation of nonspecific symptoms improve on T3, it is also possible to see the same set of symptoms improve on prednisone, testosterone, and a number of other drugs, illicit or not. Remember that almost any hormone ingested when not actually needed has the potential to act as a stimulant, rather than as a replacement therapy. The improvement in such symptoms with T3 therapy does not prove that the patient has hypothyroidism of any sort and, therefore, does not contribute much to advancing our understanding of hypothyroidism.

One could argue that, if a patient has no objective evidence for hypothyroidism but feels better on T3, isn’t that important? While I agree that making people feel better is important, we should endeavor to do that without causing harm. Giving escalating doses of a thyroid hormone that may not be addressing a deficiency or impairment of action could have negative short and long-term consequences, such as muscle wasting, arrhythmias and osteoporosis. In addition, I would be remiss in not pointing out the irony that most seekers of alternative medicine want to address the root cause of their symptoms; in fact, they bitterly complain that mainstream medicine simply wants to give them a pill without fixing the underlying problem. In that case, they should be more interested in doing the deep dive into diet, exercise, sleep, stress management, and mental health – as opposed to simply taking T3 pills from alt med, of course.

The reason why I have graded this claim about T3 usage as “mostly” false instead of entirely false is due, in part, to the subject of the next claim.

Claim: Endocrine-disrupting chemicals (EDCs) can interfere with all aspects of thyroid hormone metabolism and action. Because exposure to EDCs is widespread, and because such chemicals can cause impaired thyroid hormone action without causing abnormal TFTs, doses of T4 and T3 medications should be adjusted to resolution of symptomsnot to normalization of TFTs.

HD: Partly True. I’m happy that the commenter brought up the subject of EDCs; I agree with him that EDC exposure is widespread and that they deserve more mainstream press than they get. The Endocrine Society has published multiple papers about EDCs, summarizing what they are, why we should care, what we can do, and the current state of the research.

Despite scientists’ valiant efforts, the trouble with the research on EDCs and the thyroid is that it shows effects that are all over the map. In the animal and limited human data that exist, EDCs can:

  • raise, lower, or have no effect on TFTs.
  • increase, decrease, or have no effect on deiodinase activity (which is responsible for T4 to T3 conversion as well as local action of thyroid hormone).
  • increase, decrease, or have no effect on the transport of thyroid hormone into cells.
  • increase, decrease, or have no effect on intracellular thyroid hormone action.

Not only that, but the effect of combinations of different EDCs is unknown. “Safe” levels of exposure are also unknown. Blood and urine testing for certain EDCs is not necessarily accurate; and, the testing may reflect recent exposure more than whole body stores, in the case of compounds that have short elimination half-lives.

Because it is extremely difficult to avoid all EDCs, and because we don’t have a good way to test for EDC-impact in our bodies, it is tempting to stick our heads in the sand and simply ignore them. The commenter implies – and I agree – that this is not a sound strategy.

So what should we do? The commenter argues that, because some EDCs are known to interfere with thyroid hormone action by competing for binding to thyroid hormone receptors, the best strategy would be to titrate doses of T3 (and perhaps T4) to compete with the EDCs for binding to receptors. Again, symptom resolution would have to be the endpoint, as biochemical parameters may be unreliable.

On its surface, this logic appears to be sound. In people with a high burden of EDCs – though we can’t identify who they are – it may even be correct. Earlier in this post, however, I promised you that I would explain why this type of mechanistic argument is fatally flawed. Well, here it is: like numerous other metabolic pathways, the system of thyroid hormone production, conversion, transport, and action is complex and well-known to be geared towards maintaining homeostasis. Based on an understanding of human physiology, should one or two steps in the thyroid hormone metabolic pathway be negatively impacted, other components of the pathway will attempt to compensate in the opposite direction of the insult. For example, if thyroid hormone action is impaired at the cellular level2, it is conceivable that transport of thyroid hormone into the cell would be up-regulated in an attempt to flood the intracellular receptors with more thyroid hormone to out-compete the EDCs and “get the job done.” It is also likely that, at some level in the pathway, deiodinase activity would be up-regulated, leading to increased production and availability of T3. Also remember that deiodinase enzymes regulate local thyroid hormone action, so up-regulation of enzyme activity may increase local thyroid hormone action.

To restate the above concept in another way, you simply cannot invoke a “block” at a single point in the thyroid hormone metabolic pathway as the sine qua non of needing to give large doses of T3. Even multiple blocks in the pathway by different types of EDCs might not cause enough of an effect to be clinically apparent. The human clinical data in this space is thin, so I will have to explain my opinion on this matter using a combination of my clinical experience and knowledge of physiology.

In my opinion, here are the necessary conditions that would need to exist in order to see EDCs cause clinically meaningful hypothyroidism:

  • The person has hypothyroidism, making them unable to ramp up production of thyroid hormone if required.
  • The person has a high burden of EDCs with constant or recurrent exposure.
  • Multiple different EDCs present in high concentrations will cause multiple blocks at different steps in the synthesis, conversion, transport, and intracellular action of thyroid hormone.
  • These blocks will – at least at some of the steps – be complete or near-complete blocks, likely due to the high blood EDC concentration.
  • Compensatory actions taken by the body will be inadequate due to the number and completeness of the blocks, thereby failing to increase thyroid hormone action at the cellular level.

Look, I’m clearly not saying it’s impossible for a scenario to exist in which EDCs cause clinically meaningful hypothyroidism without causing detectable biochemical hypothyroidism. The mechanistic research shows it is, indeed, possible. Unfortunately, to the best of my knowledge we have no clinical research proving this happens with any regularity and no way to confidently make this diagnosis. It is my opinion, based on my understanding of human physiology and years of clinical experience, that the number needed to treat (NNT) to ameliorate one instance of the aforementioned hypothetical scenario will be extremely high. In other words, I believe that a huge number of people would embark on a quixotic quest of ever-increasing T3 doses, only to find after months or years that their primary problem has not been solved. And of course, they would endure both short and long-term side effects secondary to the adventure. If you disagree with my assessment, please peruse internet thyroid forums, which are filled with people trying and failing to nail down a T3 protocol that will work for them.

Again, in my opinion, it would be better to do an overhaul of the part of the environment under your control, ridding your home of as many EDCs as possible3, than to take huge doses of T3 to combat presumed EDC impact. For people like many of my readers, who profess to be more interested in curing and addressing the underlying cause of disease, reducing EDC exposure makes a heck of a lot more sense than combating their effects. It bears repeating – even though I just said it in the last paragraph – if there really were that many people with poor T3 conversion or impaired T3 action, then those people should have been “cured” long ago by one of the many “T3 protocols” advocated by alternative medicine. Based on the volume of hypothyroid patients continuing to seek answers on the internet, I don’t think that’s the case.

By reading this site and interacting with me and others in the Comments, you agree to abide by my Disclaimer. As a reminder, please restrict your comments and questions to the narrow topic at hand. There will be plenty of opportunities to discuss other claims and controversies in future posts.

Image Credit: Photo by Toa Heftiba on Unsplash

  1. This claim should not be confused with genetic forms of thyroid hormone resistance, such as those caused by mutations in the TR alpha or beta genes. Nor should it be confused with the even rarer situation of a mutation in the MCT8 gene, which causes a defect in thyroid hormone transport into cells. []
  2. For example, binding of thyroid hormone to its receptor could be reduced by EDCs competing for the same binding sites. []
  3. There are entire websites dedicated to helping you do this. []

12 Replies to “T3 Controversies: Can Impaired Thyroid Hormone Action be Treated with T3?”

  1. I’m looking forward to the rest of the series.

    Are you going to cover TSH suppression at some point? One of the things that surprised me about alt-med in this context is the variety of excuses of why it supposedly OK to leave the TSH in a suppressed state.

  2. Thank you for writing this series. I agree that it’s a sore point that needs further elucidation. I’ll just add that my wife tried combo therapy and slowly felt worse over time. We just reduced her T3 does by half to see if there was an improvement and she’s feeling so much better!

  3. Thank you for taking the time to write this series. I have given up responding to people who advocate T3 as the ultimate magic pill, especially in the scenarios you have illustrated. I see people diagnosing others as hypothyroid because their FT3 is not in the upper normal range and their reverse T3 is slightly elevated. As a radiation survivor that has lost almost all thyroid function, I feel remarkably well on T4 (Tirosint). My brief experience with T3 was horrible – palpitations and increased blood pressure. I do know many people who feel well on a low dose T3 taken with T4, but it was not for me.

  4. I am a 65 yr old f. After 5 + yrs of t4 and feeling worse, getting fatter, more depression even with a low TSH. I WAS FINALLY given small amounts of t3 added to a lowered t4. I slept like a baby for the first time in years and my husband said I was a calmer person. Now I’m on t3 only at a medium dose. ( for the last yr) I don’t feel sped up. I also am eating gluten free, wheat free, sugar free most of the time…( a little very dark chocolate) low on animal products…eggs, fish only. Mostly veggies and wild rice. Taking walks and now that I have a new puppy I’m tired all the time but am getting more exercise. Don’t eat fast foods.
    Also take supplements but don’t mind if I skip a day because my diet is very clean…as clean as it can be today.

    1. I do think Vicki’s experience is not unusual. I have a feeling it can be a bit hard for folks to process T4 only meds. So many people share similar experiences. Either certain people just don’t convert consistently, or other issues are causing them to have low T3 levels (nutrient deficiencies such as Iron, Vitamin D, selenium, zinc, etc). It is possible to work on these, but some people don’t appear to be able to fix it. So people try taking some T3 and it is a game changer. I’m still holding out, and have been doing better once I fixed my nutrient issues. So I ask, why are nutrients such as Iron, Vitamin D, selenium, zinc, etc not checked by doctors more? And not just getting them into range and saying they are OK. My Iron levels were technically in range but at the bottom and I really do feel that is why I had high FT4 and low FT3. After getting my Iron back to normal, FT4 went down and FT3 went up. This is where at least testing TSH and FT4 is useful (even from an endo perspective I would think). I know you guys don’t trust FT3, but FT4 would let you know if someone isn’t processing the T4 medication correctly.

      1. FT4 levels won’t tell you if someone is not converting/processing T4 appropriately. A FT4 – at best – might tell you if someone is absorbing levothyroxine appropriately from the gut or not. But then again, the FT4 is going to vary a bit depending on when you check it in relation to a T4 dose, and the TSH should be elevated if you’re not absorbing it well. As for vitamins/mineralsand thyroid hormone metabolism, I’d be interested in seeing data that show anything other than extremely low levels can have a major impact on thyroid hormone metabolism. As far as I know, the idea that “normal” levels of these things can be “not normal enough” for thyroid hormone metabolism is unsupported. But I’m certainly open to the possibility of being wrong if you’ve seen literature that proves otherwise.

        1. I always take my tests early in the morning before taking my dose. I agree it’s important to understand when you take it. I believe it’s very important to be consistent with the tests (same time same lab). I’ll see if I can find some data on Iron and other nutrients. Certainly zinc, selenium and Iodine are important to thyroid processes. I do believe FT4 was a sign for me. For instance, when I was on Levo 100, my TSH went to .7 and my FT4 was high (and low FT3, but I know that’s not focused on with Endos). I had all kinds of problems occurring similar to over-medication except not a high heart rate. My heart rate was still super low. But I had tremors, diarrhea , night sweats, uncontrollable anxiety, etc. Cut my dose to .88 and things calmed down tremendously. However, then I got quite hypo again, TSH varied from 5 to 3 (still in range but obviously not correct by symptoms). I switched to Synthroid and it’s taken awhile to dial in. But my Iron studies last time were perfect (optimal). Before they were pretty poor but technically still in range (barely). Now my dose is 112 and my FT4 is a bit more toward the middle to 3/4th range. My FT3 has risen also and I’m feeling my best (last TSH was 2.09). I will admit reading FT4 and FT3 is likely difficult to see patterns. But I think there are benefits to seeing all 3 tests. I also think this issue is more complicated than people realize and each person is unique.

  5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166193/
    “In summary, IDA decreases serum T4 and T3 concentrations, reduces peripheral conversion of T4 to T3, decreases T3 metabolism (turn over), decreases hepatic T4-5’-deiodinase and may increase circulating TSH activities”

    So a key here is reduction of the conversion of T4 to T3…which would explain higher FT4 and lower FT3. Other things reduce conversion such as lack of exercise, liver problems, etc.

    Here’s the thing. Nutrient levels don’t have to be completely deficient to have impact. Just like TSH actually. I had all kinds of weird symptoms with a TSH of 4.7 (barely in range). We all know the range for TSH is hotly debated. I think most people would agree it’s a bit high and .5-3 is more reasonable for normal healthy individuals. Sure there could be people who’s set point is above and below that, but not many I would guess.
    More Iron info below:
    https://pubmed.ncbi.nlm.nih.gov/12097675/
    https://pubmed.ncbi.nlm.nih.gov/22200582/

    I didn’t supplement Iron since I know that’s tricky. So I just try to have calf liver once a week. It’s copper heavy so I supplement with Zinc on those days. Focus on nutrition is actually one thing that really helped me turn things around (I believe at least). Sometimes it’s a vicious cycle with hypothyroidism. It causes issues which further cause issues and that cycle keeps going until corrected.

    1. The first citation is a nice summary of the relationship between iron status and the thyroid, but it doesn’t support the assertion that subtle decreases of iron within the normal range will cause clinically meaningful changes to thyroid hormone metabolism. I think that’s important to note, given the propensity of alt med practitioners to recommend a host of vitamins, minerals, and nutraceuticals to “optimize” levels that don’t need optimizing. Now, if one has a tendency to develop iron deficiency anemia for some reason, I am all for eating iron rich foods to be proactive. But if one has a normal hemoglobin and hematocrit, with no history of anemia, and low-normal iron levels, I would say it is highly unlikely that boosting iron levels would cause a clinically meaningful improvement in thyroid levels.

      1. That’s a fair point on the has to be “optimal” to work claims. Another possibility is hypothyroidism itself (which for me was uncontrolled for a long time since I didn’t know I had it ) creates these deficiencies. But over time with thyroid hormone help, some of those start to go away. You maybe able to help that process with nutrition though. Something that can be hard to understand is it can take a long time to turn things around. I think many folks (myself included) thought in a few weeks I’d be back to normal. Probably also proportional to how much damage has been done.

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