In 2019, I published a post called Is TSH the Best Test? If you’re a fan of the blog — or even if you hate-read Hormones Demystified — you almost certainly know that I advocated strongly for the use of TSH in the clinical care of hypothyroidism. I also debunked several of alternative medicine’s claims regarding the supposed deficiencies of using TSH to diagnose thyroid hormone deficiency and guide thyroid hormone replacement. And I did this all by using science to show how alt med corrupts actual medical evidence, twisting it in ways that — in the absence of sufficient inspection — appear to bolster alt med’s claims.
One thing I didn’t adequately explore in that post, however, is whether TSH is specifically less reliable in guiding thyroid hormone dosing when the thyroid preparation in question contains a sizable proportion of T3 (such as any desiccated thyroid medication, or pig thyroid, as I prefer to call it). I didn’t realize the extent to which this assertion is promoted in the alt med world, until it was brought to my attention by an astute reader (thanks, Tayshia1).
In Search of the (Pseudo) Science
As y’all are aware, I love diving down alt med rabbit holes to unearth the perversions of real science to be found there.2 Regarding the influence of exogenous T33 on TSH production, however, I found surprisingly little internet fodder that was more substantive than stereotypical alt med word salad. That said, I was able to find one well-researched, intelligently-written, and ultimately misguided piece on the web that cited legitimate articles from legitimate medical journals.
So, in this post, I will endeavor to explain why I think the author of that well-intentioned piece drew the wrong conclusions. As always, if you can point me in the direction of other proposed mechanisms that you’ve found on the internet, I’m happy to vet them.
If you don’t spend much of your time marinating in this stuff, you may want to first re-read just this section of Is TSH the Best Test? which goes over the relevant aspects of how T4 and T3 interact with/feed back to the pituitary.
The “Evidence” for T3-containing Medication Making TSH Unreliable is Weak — Very, Very Weak
The first argument made by the author derives from an old study in which the researcher gave some people with and without hypothyroidism a few different doses of a combination T4/T3 medication, for 3-4 weeks at a time. Then, the investigator did what’s called a TRH stimulation test. In this test, a synthetic version of a natural hormone produced by the hypothalamus — thyrotropin-releasing hormone — is infused into the subject, and then TSH levels are serially measured at intervals after the infusion. Because TRH’s purpose is to tell the pituitary to release TSH, the hope here is that one can learn something useful by observing the TSH response to an infusion of TRH — more on this in a minute.
In this particular study, the investigator wanted to “quantitate the degree to which small quantities of triiodothyronine (T3) and thyroxine (T4) can inhibit the release of thyrotropin (TSH)….” He seems to be postulating that, if a given dose of T4/T3 medication does not push serum T4 and T3 levels above the normal range, then any subsequent blunting of the expected TSH rise after an infusion of TRH should be interpreted as the TSH being overly sensitive to suppression by even “small” doses of thyroid medication. Taking this line of reasoning a step further, if the TSH can potentially be suppressed by even small doses of thyroid hormone, then TSH might not be the most accurate reflection of one’s thyroid status during thyroid hormone replacement therapy.
I have multiple criticisms of this study’s design, as well as the extrapolation of its findings to suggest that exogenous T3 suppresses TSH out of proportion to what an equivalent amount of exogenous T4 does to TSH.
But I don’t think any of my complaints are more important than the fact that TRH stimulation tests yield results that lack both reliability and reproducibility, they never caught on as a useful clinical tool, TRH hasn’t been available in the US for decades, and the rare clinician who gets her hands on some TRH usually doesn’t understand the test characteristics or what to make of the results.4
Before the advent of third and fourth generation TSH blood tests that were sensitive enough to detect lower levels of TSH, the TRH stimulation test was mainly used to attempt to diagnose central hypothyroidism, a rare condition in which the pituitary does not release enough TSH to stimulate the thyroid to produce adequate amounts of thyroid hormone. TRH testing fell out of favor a long time ago, so we simply don’t have enough cumulative experience with the test to know what to make of the way in which it was used in the particular study I mentioned above.
Next, it is critical to note that the pituitary’s response to an artificially-induced stimulus like exogenous TRH cannot be extrapolated to interpret how the pituitary would respond to a normal physiologic stimulus. What I mean to say is: walloping someone’s pituitary with a big dose of TRH should not be thought to reflect the normal cross-talk between the hypothalamus and pituitary when responding to changes in ambient T4 and T3 levels.
Quite honestly, I feel like I’ve said all I need to say about why I find the citing of this particular study uncompelling. I realize, though, that some of you want more — good on you for being curious. But there’s another reason why I’m not going to dive into the results of the TRH stimulation testing from that study, and that’s because the study was not designed in a way that could even address whether T3 suppresses TSH production more than an equivalent dose of T4. Let me explain.
The author of the study said he wanted to see what “small doses” of T4 and T3 would do to TSH, and the three medication combinations he used were: 15mcg T3 + 60mcg T4, 22.5mcg T3 + 90mcg T4, and 30mcg T3 + 120mcg T4.5
How can you possibly draw any conclusions about T3 suppressing TSH out of proportion to what an equivalent dose of T4 would do when you’re giving both T3 and T4 in escalating doses? Why not give only T3 to the subject and then do your fancy TRH testing, followed by giving only an equivalent dose of T4, followed by more TRH testing?6 Or how about giving three different combination products that all have the same effective dose of thyroid hormone, just increasing the amount of T3 and decreasing the T4 in products two and three? Even these two suggested study designs wouldn’t be perfect, since T3 and T4 have different pharmacokinetics and dynamics, but they’d be better if you’re trying to prove that the TSH becomes unreliable in the presence of exogenous T3.
In defense of the clinical investigator, he wasn’t trying to prove that T3 medication acts differently on the pituitary than does T4 medication. But the author of the piece I found on the internet seems to be hanging her hat on this study, as if it’s earth-shattering evidence. I don’t mean to sound overly dismissive of her article, as she does approach the topic with intellectual rigor, but I think the author has completely missed the mark in trying to apply this study to her hypothesis.
And finally, for what it’s worth, not a single subject in the study — control or intervention group — demonstrated suppression of the TSH to below the normal range with any of the medication doses. Frankly, it makes me wonder if some of the subjects were skipping doses or taking the T4 with food or other substances known to interfere with absorption, as I’m surprised that non-hypothyroid people taking 30mcg T3 + 120mcg T4 didn’t exhibit suppressed TSHs. But whatever, all it does is make me even less certain that this study reveals any important secrets about thyroid hormone economy. What this study does do — and all it really does — is show how healthy controls and hypothyroid people react to infusions of TRH while under the influence of different doses of thyroid hormone. Full stop.
More Evidence, Same Problem — Irrelevant and Weak
The author of the internet article then turns her attention to another study by the same clinical investigator. In this study, the researcher looked at what happens to T3, T4, and TSH levels in healthy subjects without hypothyroidism, during overfeeding vs taking exogenous T3. What did he find? In overfeeding, T3 went up a bit, while T4 and TSH remained about the same. While taking T3, T3 went up a bit, while T4 and TSH went down a bit.
I will allow for the possibility that I may be missing something here, but while these findings may have been interesting when the study was published in the 1980s, they’re eliciting barely a yawn from me today.7
The regulation of thyroid hormone economy in healthy people is a complex process that involves but is not limited to: thyroid hormone synthesis and release; transport in the bloodstream; transport into the cell; transport into the nucleus; binding to nuclear receptors; conversion to active and inactive forms by deiodinase enzymes; local regulation of thyroid hormone activity by deiodinase enzymes; macronutrient composition of the diet and fasting; metabolic requirements; etc.8
My point is that comparing what happens to thyroid function tests during a physiologic stimulus like overfeeding and an exogenous therapy like giving T3 pills is apples to oranges. It’s not that we can’t learn interesting things about the hypothalamic-pituitary-thyroid axis by stressing the body in different ways — we totally can. In fact, if you follow the link in the prior paragraph, you’ll get to read about how ketogenic diets produce some interesting derangements of thyroid function testing that appear to have absolutely no clinical significance (to the best of my knowledge).
The fact that giving 10mcg or 20mcg of T3 (doses used in the above study) caused the TSH to go down a bit does not mean that T3 pills have a suppressive effect on TSH secretion that is out of proportion to the effect of endogenous T3 on TSH secretion. Think about it this way: when you give T3 to someone, you are intervening at one of the final steps in the normal pathway of thyroid hormone metabolism. In other words, the body’s deiodinase enzymes normally convert T4 to T3 within the body’s tissues. When you give T3, you’re jumping all the way to that step, fairly late in the process. Because of normal feedback, this T3 is going to have some sort of suppressive effect on TSH secretion, which will in turn lead to lower T4 secretion by the thyroid.
But when you overfeed someone, you are sending all sorts of signals to the body: there’s an overabundance of available energy, there’s an acute need to increase metabolic rate, etc. Because the hypothalamic-pituitary-thyroid axis is involved in this sort of stuff, you will see a response by the hypothalamus and pituitary that will ultimately be manifested by some changes in thyroid hormone synthesis and action — some of which can be measured and many of which can’t. Note that the overfeeding stimulus is proximal to the whole pathway of thyroid hormone synthesis. It’s a totally different kind of intervention, so it simply can’t be used to tell you how the pituitary should respond to a dose of exogenous T3.
Given that I couldn’t find a single study that was actually designed to determine whether exogenous T3 has an outsized suppressive effect on TSH when compared to an equivalent dose of T4, I have to say that we simply don’t know the answer to this question. And given that the alternative medicine community promotes the idea that pig thyroid should be titrated to relief of symptoms, even if that means suppressing the TSH to very low or undetectable levels, I would like to know the answer to the question. Unfortunately, from what I’ve seen so far on the internet, no one has offered a compelling argument in support of the concept that hypothyroid people on pig thyroid are more likely to have suppressed TSHs while being adequately replaced, when compared to their counterparts on T4 monotherapy.
If you have a scientific reference that you believe supports this concept, please note it in the Comments section below.
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Image credit: Photo by Volkan Kaçmaz on Unsplash
- Not her real name, but bonus points to the first person who gets this reference and notes it in the Comments.
- IMHO one of my greatest feats of debunkery is Everything You Never Needed to Know About Reverse T3. For an extra chuckle, go to that post and read Samantha’s comment. It was low-hanging fruit, but it was just too delicious to not take a bite.
- In this circumstance, exogenous refers to T3 hormone that you ingest, as opposed to endogenous T3 that your body produces on its own.
- I will allow for the possibility that there may be physicians in other countries who have more experience with TRH testing, but given the lack of well-standardized guidelines for interpreting the results, I would still question the utility of the test.
- The first medication combination is close in equivalency to a 90mg dose of Armour thyroid, for your reference. Let’s table the fact that I wouldn’t really call any of these medication combinations “small doses,” especially if giving them to control subjects without hypothyroidism.
- While different sources will give different estimates for how to convert a T3 dose to a T4 dose, one rule of thumb is a roughly 1:4 conversion. Therefore, 15mcg of T3 should have similar strength to about 60mcg of T4, meaning that the first medication combination should be equivalent to roughly 120mcg of levothyroxine (T4). I can tell you, however, that in real life, these conversions often/usually don’t play out consistently. Sometimes I see more of a 1:3 relationship between T3:T4, sometimes 1:5. It depends a lot on dose preparations, dose timing in relation to meals, number of doses per day, etc.
- Again, I don’t mean to denigrate the author of the internet article; rather, I’m trying to point out that the research she has cited cannot be used to support her thesis.
- In the clinical investigator’s defense, the discovery of deiodinase enzymes came after he published this study, so there was a whole lot he didn’t know at the time of his research.