Pig Thyroid is Best?

Evidence-Based: Written by a Board-Certified Endocrinologist

In response to the presentation of a new clinical trial abstract at ENDO 2021, one of my readers (thanks, Mike) commented:

I think A LOT of patients are saying I told you so here. But this is very interesting. Especially because it was presented at Endo 2021. I haven’t read the study yet, but I can tell you what’s been written up in the news articles I’ve heard over and over again. So maybe it should get A LOT more research and consideration.

So what’s all the excitement about?  If you guessed it’s regarding the age-old controversy of T3 or not T3, bingo.  Dr. Thanh D. Hoang conducted a randomized, double-blind trial of desiccated thyroid extract (DTE) vs combination levothyroxine + liothyronine (T4/T3) vs levothyroxine (T4).  Each group of hypothyroid subjects was treated for three, 3-month periods, without knowing which therapy they were receiving during each 3-month period.  While the results of the trial, in aggregate, showed no statistically significant differences among the groups in symptom scores, 45% of people preferred DTE, 32% preferred T4/T3, and 23% preferred T4 alone.

Let’s pause here for a second and note a couple of things.  First, the above information is from third-party summaries of the presentation of the abstract of this study at one of our best, yearly, national endocrine conferences, ENDO 2021.  I did not attend this presentation and, as far as I can tell, the full paper has not yet been published, so I know about as much as you do regarding the details of the trial.  Second, how awesome is it that Dr. Hoang decided to perform such a study?  As I think both supporters and critics of my blog can agree, we need more clarity regarding the use of T3 in hypothyroidism.  Studying this topic is really, really hard, in part due to the sheer number of confounding variables that can influence how people with hypothyroidism feel during any predefined treatment period.  So, Dr. Hoang, good on you!

Symptom Scores the Same, People Prefer Pig Thyroid

I love the above newspaper headline I invented, because it portends the tribal divide we’re going to see as this article gets discussed on the internet and dissected by the medical community.  The pro-T4/anti-T3 contingent is going to point out that there was no difference in symptom scores among the three groups, and they will seek to explain away the preference for DTE and T4/T3 over T4 alone.  And they will make some good points.  On the other hand, the pro-T3/anti-T4-alone tribe will say – as Mike pointed out – “I told you so!”  And they will have some ammunition to back up their contention.

Let’s start with what I expect will be the major criticisms of the study.  First, it was fairly small – just 75 people.  I do not fault Dr. Hoang for this; I’m sure he had a statistician determine how many subjects would be needed for appropriate power to detect a significant difference in the primary outcomes.  And, for those of you who don’t know, doing clinical trials with humans is incredibly hard.  People have their own agendas coming into this sort of endeavor; they can be flaky, non-compliant with the protocol, or drop out completely; and any primary outcome that relies on people’s subjective sense of how they feel is inherently less reliable than objective measures.

Nonetheless, it appears that there was no statistically significant difference among the three groups with respect to the primary outcome of symptom scores.  BUT, upon performing a subgroup analysis, Dr. Hoang says that individual subjects who weren’t feeling great on T4 alone were the ones who tended to report feeling much better on DTE and/or T4/T3 combination therapy.  This squares with both selected studies that have already been done on this topic – including Dr. Hoang’s similar 2013 study – as well as with the experience of many patients across the internet and a smaller number of patients in my practice.

Critics of the subgroup analysis will say that such an analysis is not powered to detect meaningful differences, and I assume that this statement will be correct, if we restrict the scope to evaluating the statistical validity of the subgroup analysis.  My complaint about this criticism is that it gets me nowhere, with respect to deciding what to do with the symptomatic, T4-treated hypothyroid patient sitting in my office, who has otherwise “perfect” lab results.  I’m not sure if there are other studies of this nature in the pipeline, but my sense is that we are unlikely to gain further clarity by insisting that aggregate study results should always trump using an individual as his/her own control.  While regular readers know that I am a big fan of using trial data to inform clinical decision making, I think we need to take the entire corpus of research on the T4 vs T3 issue into account. Even before this study, I believe that we had enough data to argue in favor of a trial of T3 add-on therapy to T4, under certain circumstances.

My sentiment in the preceding paragraph should not be construed to mean that I endorse DTE, nor that I think the preferences of people for DTE over T4/T3 over T4 are ipso facto evidence for the blanket superiority of those treatments.  In fact, I am not at all surprised that a larger percentage of people expressed a preference for DTE and T4/T3.  Let we walk you through my reasoning.

I can surmise that there was selection bias in the study participants, simply due to the fact that people who enter these types of trials usually have their own agendas.  In this case, it would be hypothyroid people who were at least somewhat dissatisfied with their current care and looking for something “new.”  I suspect (but do not know) that the average, pre-intervention symptom score for the study participants was higher than the average symptom score for the larger population of hypothyroid people in the U.S.  We already know that patients who feel unwell (or less well) on T4 alone are the very patients for whom we are most likely to try T3.  Therefore, any clinical trial of this nature should have a bias toward seeing improvement on T3 when using the study subject as his/her own control.

In addition – and this is crucial – we also know that the addition of T3 to T4 often results in transient clinical improvement, presumably due to the stimulant effect of T3 in people who don’t really “need” it as a replacement therapy.  This improvement in such individuals typically lasts for weeks to a few months, rarely persisting beyond 6 months if due to the placebo or stimulant effect of T3.  It is only the people who continue to feel well on T3, beyond 6 months, who I would consider to truly need that therapy.

Unfortunately, Dr. Hoang’s trial used relatively short, 3-month periods for each therapy, making it impossible to know if the subjects on DTE or T4/T3 would have continued to feel better with continuation beyond 6 months.  It is quite possible that some of the people who preferred having some T3 on board would have regressed to their normal (worse) baseline 6 months down the road on that therapy, making the preference percentages for each therapy relatively equal.

Back to First Principles: What About Normal Physiology?

In my T3 Controversies Series, I have written extensively about why pig thyroid (DTE) makes no sense as a thyroid replacement therapy.  Notice that I said, “makes no sense,” which should be differentiated from asking whether it works.  It makes no sense because the ratio of T4:T3 in most DTE preparations is around 4:1, while the ratio of T4:T3 in the human body is somewhere between 15-20:1.  Therefore, a dose of DTE will expose the body to much higher amounts of T3 – a short half-life hormone – than it is accustomed to seeing.  Any hormone that reaches a peak within a few hours and then dissipates fairly quickly has the potential to act as a stimulant.

Why should we care, as long as it makes people feel better?  Well, I’ve discussed these reasons before, so let’s restrict today’s focus to the fact that DTE has the potential to improve symptoms that may not be due to inadequately treated hypothyroidism.  Remember, it has stimulant potential, so people with depression or fatigue, for example, may feel better.  They may not always feel better long-term, but they can at least feel better over a 3-month time period.

When DTE is not Treating Hypothyroidism

Let’s consider – more deeply – these patients with “hypothyroid” symptoms that may be due to something other than hypothyroidism.  As a thought experiment, consider a person with hypothyroidism who has tried T4 as well as T4/T3, with beautiful labs on paper throughout, but not enough clinical improvement.  Assume that a thorough workup has revealed no other explanation for his/her persistent symptoms.  Instead of saying “It’s not your thyroid,” and referring the patient back to their primary doctor, should we consider a trial of DTE?  Such a trial would not be conducted in the name of thyroid hormone replacement therapy; rather, we would be doing a simultaneous diagnostic and therapeutic maneuver to see if the patient has “DTE-responsive malaise.”

I realize this sounds terribly unscientific and, quite frankly, I need to sit with this idea I just came up with a lot longer, in order to determine how I really feel about it.  I hesitate to invent another waste-can diagnosis that has the potential to medicalize something that shouldn’t be.  But there is precedent, I think.  Consider “steroid-responsive encephalopathy,” which denotes an acute brain condition in people with elevated thyroperoxidase antibodies.  Some have called this Hashimoto’s encephalopathy, but most experts agree that the presence of Hashimoto’s has nothing to do with this brain problem, which gets better with steroids.  So, without really knowing what the problem is, these patients are treated with steroids and get better, never to discover what caused the problem in the first place.

I suppose I can make another argument in favor of using DTE to bring a patient out of their doldrums, based on my clinical experience.  Although I don’t prescribe pig thyroid, I have seen a few people over the years who felt poorly with conventional treatment, got better on DTE, and then were able to transition back to T4/T3 or T4 alone.  So perhaps there is a role for DTE as a last-ditch effort to get someone feeling better, regardless of the cause of their symptoms, with the intention to eventually transition them back to a more physiologic and natural replacement regimen with T4/T3 or T4 alone.  Again, for a physician-scientist, it is unsatisfying to initiate a treatment without a diagnosis, but if the patient gets better…perhaps that should be our north star.

Conclusion

A reader of mine (thanks, Arthur) recently pointed out that one of the larger Facebook thyroid groups deleted some of his comments questioning their recommendation for more T3 to be given to a woman who already seemed overmedicated.  Ultimately, he was banned from the group and told that people like him just “didn’t believe,” and the group has tens of thousands of patient-reported case studies to prove the success of their methods.  He rightly expressed concern that this is the behavior typical of a cult.

Just as these online support groups can be heavy on dogma, dismissive of cases that don’t fit their ideology, and light on tolerating the liberal exchange of ideas, physicians can also be stubbornly adherent to old ideas that would benefit from nuanced reexamination.  While I do not believe that Dr. Hoang’s new study constitutes a celebratory “I told you so” moment for dissatisfied thyroid patients, I do think it re-raises the important question of when to try T3, what kind of preparation to try, and what dose to use.

By using this site and interacting in the Comments, you agree to abide by my Disclaimer.  Please keep your comments respectful and refrain from ad hominem attacks.  In the past, I’ve been permissive – no longer.  The social and political discourse in our country has become so toxic that I cannot, in good conscience, allow my blog to provide a space for those who simply want to express outrage.  If you disagree with something I’ve written, or something written by a fellow reader, fabulous.  Make your argument in as dispassionate a way as you can, and we’ll all get along just fine.

Image Credit: Photo by Benjamin Wedemeyer on Unsplash

 

27 Replies to “Pig Thyroid is Best?”

  1. Desiccated thyroid saved my life. Everyday I reflect on how awful I felt before and how amazing I now feel. I’ve been on desiccated thyroid for almost 2 years. Before I was so fatigued that I couldn’t exercise, I could barely work or get through the day. I gained 40 pounds (which is now gone) and developed several secondary diseases which are all done now as well. I thought I was going to have to quit my job as a college professor. My doctor wanted to diagnose me with chronic fatigue syndrome as opposed to getting my ft3 up. My ft3 was 2.6 (reference range 2.7-5.8), now it’s 4.8, I feel amazing and I’m contributing positively to society. I’m so grateful I found a dr who was willing to try something else and I’m so grateful for researchers like Dr. Hoang. It’s time we question the current thyroid paradigm.

    1. [Redacted. Unnecessarily antagonistic toward Tara, who did not post enough information to draw the conclusion made by Anon.]

  2. Dear Demystified, I was unfamiliar with the percentages you quoted on the ratios of T4 to T3 you quoted. I always presumed Pig thyroid , was more physiological than Cow thyroid for example. I have witnessed the stimulating effect of T3 in a multitude of people and often feel a minority amongst my colleagues when I am recommending T3 as an acceptable treatment option. The overstimulating potential you referenced is, I believe in part (and the varied responsiveness an individual has to ingesting T3) is due to the unknowable distribution of T3 receptors in different tissues. Unhinge this with the idea that T3 receptor agonists might be developed to lower LDL (if designed to only bind to the T3 receptors in the liver, for example) and the fact that many persons will have tachycardia on T3 (these individuals likely have an abundance of T3 receptors in the sinus node (Heart pacemaker) perhaps) and not tolerate the hormone, despite the energizing impact it could have on their other tissues. For sure Kudos to Dr. Hoang, and grateful for the update (I was unable to attend this year).

    1. As far as I am aware, most of the desiccated animal extracts will have similar T4:T3 ratios to each other, but not so similar to humans. Pig thyroid is, indeed, 4:1. Although some of the mechanisms you mention can be at play, I think the primary problem with DTE is simply that the amount of ingested T3 is too high to be consistent with what the human body is used to seeing.

  3. Those Facebook groups are the worst! I was having lots of hypo symptoms and was desperate to feel better. I found information about iodine and Brownstein’s method that was really convincing (I was young and dumb). I tried high doses of iodine and it did made me feel better for a while. I joined Iodine Facebook group where people were sharing their “amazing” experiences and that’s what keep me going even though after some time on iodine I started to feel that something was off with my body. I was so into that group that I didn’t want to believe that it was iodine wrecking my health. I was so so stupid. I ended up with severe thyrotoxicosis and almost died. I never told anyone about iodine and that Facebook group… Im so ashamed I believed in that crap. It took me a lot of time to recover… I’m on T4 meds now and doing fine. I learned a lot from this experience. I’m not on Facebook anymore, obviously.

    1. Thank you for sharing your horrifying experience. It is incredibly sad and disturbing to see these support groups functioning as cults giving often dangerous medical advice.

    2. Yes, I got banned from one of them because I questioned the high Iodine dose someone was taking. I’m in a much better group now that’s science based.

  4. We see a lot of patients on combination therapy, also desiccated stuff who do seek help because they complain exactly about what you pointed out: when they started the regime, most of them experienced major improvements of fatigue etc , but in the long run feel sh…ty again. Lab shows the typical profile of combination therapy: suppressed TSH and really bad/low T4, with normal or slightly elevated T3. Suppressed TSH because T3 is unphysiologically high, which inhibits T4 conversion, esp in the respective organs. Due to the short half time of T3, there is also no sense in taking it once daily, what most of the patients do though.
    In our experience, we do not see an advantage in combination therapy and rarely recommend it. If lab is normal, thyroid looks good we search for other causes of the persistent complaints.
    PS : we doubt that the author of the abstract will be able to publish his study in a journal like Endos JCEM etc because the results are well-known and have been widely discussed in numerous meetings of the Endocrine Society, AACE etc…

    1. I became very symptomatic on T4 only. T4+T3 combo wasn’t great. Desiccated thyroid improved my situation although didn’t resolve it completely. And I felt better on NDT alone than NDT + T4. I wish more of us felt better on T4 only, and I know that you guys do too. We just want to feel normal again.

      What other tests do you run for persistent complaints?
      What do you do if you can’t find the cause?

      1. That’s a fairly broad question, but I am going to try to tackle that within my next post or two. Spoiler alert: I likely have no unique insight, but I will give my take on it.

        1. We all waiting for ya

          What other websites are good to seek for advice and more deep thought?

          I’m an admin of a 12k group of hypothyroidism on Facebook so I filter all the non sense people try to put it in. (Supplements, fake therapy, quacks etc)

          When I first got diagnosed I fell for the bs and now I’m doing good. But have been a long road

          And the last one, I really like these research review, can you do a similar to this tsh suppression study on total thyroidectomy individuals?

          https://eje.bioscientifica.com/view/journals/eje/167/3/373.xml

          I’m all for it if you open a patreon, we need more docs stepping the nets

          1. What other websites are good to seek for advice and more deep thought?

            Erick, that’s a great question and a really tough one for me to answer. I haven’t come across many patient-focused sites that I would recommend without reservation. I think that starting with the professional association websites for ATA, AACE, Endocrine Society, or any of their European counterparts is always a good idea. I know that Mike, a regular blog commenter, has a few sites he likes. He steered me towards thyroidpatients.ca, and I’ve read some stuff on that patient-centered site. Although I don’t always (or even often) agree with the conclusions the writers draw, I appreciate their scientific approach. A lot of the science they present is factually accurate and very well-referenced, though there are times when I think they overplay the clinical significance of some of the accurate, underlying facts.

            As for what I work on with my writing, I’m always open to suggestions. If you send me something that stimulates my intellectual curiosity, I will work on it. I won’t say never, but I’d like to avoid charging for what I do, so probably no Patreon…

          2. Frontiers in Endocrinology has recently posted a grouping of twenty-some articles covering combination therapy.

  5. I wish that these studies were large enough to group people by the cause of their hypothyroidism. I am a member of some thyroid groups and notice that people with hypothyroidism due to a throidectomy for cancer seem to have better outcomes with t4 than people with other causes. But there is too much bias in who joins to draw real conclusions.

    1. Agree about the bias. In my practice, I find that people with thyroidectomies are the ones who may benefit from T3 add-on therapy, though I have the occasional person with Hashimoto’s who also benefits.

      1. HD, Probably a Hashimoto’s patient with the majority of their thyroid destroyed. And therefore not helping out at all. It think this is an important concept as people with Hashimoto’s (most of those that have hypothyroidism in developed countries) have varying levels of damage to the thyroid. Which is why some people say, hey, what’s the big deal and others are struggling. Of course there can be other factors going on. But, it really is something for people to consider.

  6. HD. So glad to see you back in the saddle. While I don’t always agree with you on every topic, it’s really good to get different takes on these discussions. More dialog like this is needed to help solve these mysteries. One thing I think that should be discussed (that currently is not) are lab tests and where people feel best. And this has to do with all the different types of combination therapy and T4 only. I’ve heard time and time again, that the majority of people feel best with a FT4 and FT3 mid to 3/4 range and TSH below 2.5. The discussed that in the article as well. I’m finally feeling somewhat normal and I’m at those levels finally. This could be a missing factor to current treatments by thyroid doctors. Actually, the dosing of combination medication is why I have not taken the offer from my Endocrinologist to add some T3. I’m just not sure managing combination therapy has been researched enough. Hence why I’d like to see A LOT more of these types of studies and see strategies for combination therapy. We know the strategy for T4 only is mostly to use TSH by doctors. But on combination therapy I don’t believe (based on what I’ve seen) that TSH is enough (but still can be important). Taking into account TSH, FT4 and FT3 seems to be a better way of evaluating it for combo. Actually, I feel like it’s relevant for T4 only as well, but it has to be tracked over time. I feel that’s something important with thyroid hormones (as you have also stated), you have to give this stuff a long time for things to settle. 3 months is not enough time for things to settle and the body to adjust. I feel like all 3 tests should be tracked over a long timeframe no matter what type of hormone you are on. I also feel more comfortable with synthetic T4 and T3 (over desiccated) because you have more control over the ratios. Not to mention there have been a lot of recall issues with desiccated thyroid recently. Even the hardcore desiccated thyroid folks were admitting these issues and recommending people consider using synthetic alternatives.

    1. I think my next post will be about the nuances of how to use thyroid function tests in combination with what the patient is telling me to adjust the thyroid hormone dose.

      It is somewhat important to know about the diurnal rhythm of TSH, the relationship of dose timing to blood draw timing, and so on. I’ll get to work on that soon.

      1. Thank you…this is exactly what I have been waiting for. I am on combo T4+T3 therapy for very long standing Hashimotos. I need to get my levels tested at this time but am uncertain as to timing. I take 5mcg. Of T3 at 7:00 AM and 3:00 PM. I usually aim for 4 hours after a dose of T3 but that limits me to 11:00 AM exclusively. As T3 has such a short half life…I do not know what this level tells me about the rest of my day. I look forward to this information.

  7. When I add T3 to my T4 dose, I don’t get symptoms of hyperthyroidism but hypothyroidism, getting more tired, slower and sleepy. This happens with both small and large doses, that is, if I add to my dose of 88 mcg of t4, 2.5 or 10 mcg of t3 I get more tired, not faster and with a fast beating heart, etc.
    Why does it happen? Why I don’t have hyperthyroid symptoms when taking t3?
    Thank you.

    1. Lucas, I can’t speak to your situation, but I can say that too much thyroid hormone from any source can cause fatigue. It is widely appreciated that not all over- or under-replaced people will have the classic symptoms.

    2. Same for me, and making it difficult to distinguish symptoms between hyper and hypo.

      Also even small slivers of a 5mcg Cytomel LT3 tablet pack a punch for me. I had to go the compounding route to get consistent small doses.

  8. I am one of those patients who started with T4 and developed significant symptoms immediately. Since then, I’ve tried T4+T3, DTE(NDT)+T4, and then DTE alone for a number of years. On DTE alone, labs were stable, my health improved, and although not perfect, I felt the best. Thanks (sarcastically) to the DTE supply issues, I went back on T4. I became severely symptomatic again, to the point that other drugs (which will have side effects) have been recommended to manage my symptoms. Frankly, I could scream. It’s utter nonsense. I’ve been at this for decades, have no functioning thyroid gland and I’m tired of advocating for myself. While the endocrine field battles and the pharmaceutical companies do their maneuvering , I am losing out on my life and my family loses too. Evidence-based is important but each of us are individuals, and it’s those individual differences that become problematic in the research. “It’s not a good thing to be outside of normal in medicine”, I’ve been told.

    HD, would you be willing to reach out to Dr. Theodore Friedman and have a dialogue with him about DTE, RT3, etc. and possibly do a write-up about your thoughts? He’s an endocrine professor researcher, and similar to the late Dr. Leslie DeGroot, believes T3 levels are important. (Dr. DeGroot, btw, told me NDT was acceptable….yes his opinion and not evidence-based at the time. 🙂 )

    1. I don’t know anything about Dr. Friedman, and if I’m being perfectly honest, I’m not going to watch that youtube link. I will grant that it is possible for someone to say something I haven’t heard before about why T3 levels are important and how to use them, but I kind of doubt it. That said, if you think there’s a nugget of gold in that youtube link, give me a time marker range to watch (hopefully < 5 minutes). I will say some more about T3 and T3 levels in my next post (although I think I covered T3 levels adequately in T3 Controversies: Should T3 Levels Be Normal When Treating Hypothyroidism?).

  9. Dr. Kenneth Blanchard’s short book, The Functional Approach to Hypothyroidism, covers this topic quite well. He was a clinical endocrinologist and Phd chemist, with degrees from MIT, Princeton, and Cornell.

    His book is an interesting read for anyone who wants to explore combination therapy from a credible source.

    While he acknowledged he didn’t have all the answers, he did conclude after decades in practice that adding very small amounts of porcine DTE (or synthetic LT3) to the normal LT4 regimen had great benefit to some of his patients. His belief also was that most people on DTE monotherapy or on LT4/LT3 combination therapy were ingesting way too much LT3; they had the initial great improvement then a crash shortly thereafter.

    I’m curious why his work isn’t referenced more often. In the copious amount of reading I’ve done I don’t think I’ve ever seen him mentioned. My wife stumbled across his book several years ago on Amazon.

    Blanchard passed away about five years ago, but the small compounding pharmacy he used in Massachusetts is still providing the type of combination therapy scripts he recommends in his book. I mail order from there.

    1. DaveinDenver, the part of your post I find interesting is the part talking about people getting too much T3 and having initial improvement, then it failing. I think there needs to be A LOT more studies on the use of combination therapy or DTE and how to dose it. Maybe more of these studies will get that ball rolling. But I think the fact that doctors tend to think of it as a bad thing is what’s holding it back. My guess is 20% of people with hypothyroidism would benefit from it. I’m thinking I would benefit but I’m too chicken to try it. And I worry that doctors won’t know how to dose it and read the labs properly. It’s kind of crazy that it’s not more common. While I think many online thyroid patients think HD is on the conservative side of things. HD does think some patients should use T3 in addition to T4. Of the 5 endocrinologists I went to, only my current one was open to it and had some patients on T3. And both of my PCPs I had were against it. What people don’t consider is how much thyroid has been destroyed (or people without a thyroid). Meanwhile there is a lot of unnecessary suffering and sub-optimal living. I can tell I’m still not where I should be. But I’m doing at least OK nowadays.

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