Overtraining, Undereating & Self-Inflicted Hypothyrodism: Thresholds for Low T3 and High Reverse T3 Levels at 8% & 15% Reduced Energy Intake + Exercise After Only 4 Days!

This is not a "woman thing" only and your T3 levels are not the only thing that's going to "fall flat" if you starve yourself through your workouts! Yep, low libido => low total testosterone => low free testosterone => hypogonadism, that's what we are talking about, guys.

While I did promise to summarize some of the things, I said about creatine kinase, ALT, AST & Co on the last installment of the SuppVersity Science Round-Up on the Super Human Radio Network (I will do that in a future blogpost), today's SuppVersity article will focus on a single and in my experience often misinterpreted and / or overlooked symptom of overtraining that I personally have encountered numerous times in both male and female trainees: Self-induced hypothyrodism, low T3- or the euthyroid sick syndrome are just a couple of names that have been used in the science and laypress to describe this peculiar result of the way trainees deliberately ruin their metabolism by training for hours day in and day out, while following a diet that would hardly nourish a sedentary person, let alone the athlete or fitness model whose physique they are aspiring to achieve.

Pertinent studies are scarce, but they exist

I don't know if the shortage of scientific evidence is a result of the general ignorance of professional athletes, trainers and above all the "average gymrat" that he or she has an organically  healthy thyroid that's just shut off by your body in order not to waste precious muscle and organ weight in a state of constant catabolism.

Despite the scarcity of research, there are two pertinent studies from the Department  of  Biological  Sciences at the College  of  Osteopathic  Medicine of the Ohio  University. Both studies were published in the early 1990s and deal - as you would expect it with female subjects (with no recent history of dieting or weight loss were recruited from the university and surrounding community) who were randomly assigned to a 3x2 experimental design of aerobic exercise and energy availability treatments. The subjects had kept detailed food logs (including weighing and measuring all their foods) before the intervention to have a baseline reading for their energy intake and their heart rates and VO2 max were established during testing seasons before the first workout day.

• 

  Table 1: Detailed information about the participants in the 1993 (Study A) and 1994 (Study B) studies by Loucks et al. (Loucks. 1993 & 1994)

  participants in study A (Loucks. 1993): 51 volunteers 18-29 years of age
• participants in study B (Loucks. 1994): 28 volunteers 18-29 years of age 
• none of the participant was using medication including oral contraceptives, no history of heart, liver, or renal disease, diabetes, menstrual or thyroid disorders, or a history of severe dieting; all had  at least 3 mo of documented menstrual cycles 26-32 days in length and had exercised for only ~60 min per week in the previous 3 months 

Since the basic design of the studies did vary, we are now going to look at the studies separately and in the order in which they've been conducted. This does obviously mean that we'll start with study A the subjects were randomized to groups

• exercising not at all (Z; zero exercise group), 
• expending 1,300kcal/day on low (40% VO2max) intensity exercise (LO)
• expending 1,300kcal/day on high (70% VO2max) intensity exercise (HI)

The exercise was performed under continuous supervision on treadmill and cycle ergometers in 30min and 60min bouts for the high and low intensity groups, respectively.

"So what did happen? Did they drop dead?" Not exactly, no...

Figure 1: Experimental design: dietary energy intake (I), energy expenditure during exercise (E), and net energy availability (A) in the 3 x 2 (exercise X energy availability) experimental design; note: B indicates adequate energy intake, D indicated reduced energy intake (Loucks, 1993)

On the 4 subsequent treatment days the women consumed a liquid clinical dietary product (Ensure, Ross Laboratories, Columbus, OH) was consumed by all subjects as their only food source. The latter contained either

• 30kcal/kg body weight per day (~1,750kcal/day of available energy) in the normal energy group (B) and
• 8kcal/kg body weight per day (~500kcal/day of available energy) in the low energy group (D)

According to the protocol of study A, no effort was made to compensate for the daily energy expenditure and other than the liquid meal replacement Ensure (250 kcal/can, 15% protein, 30% fat, and 55% carbohydrate) the subjects were allowed to consume only plain water.

The blood was sampled for 8 days beginning on the day before the intervention began, in order to track (a) the time course of the development and (b) the persistence of the hormonal changes in the subjects.

Figure 2: Thyroid hormones at the end of the 4-day intervention expressed relative to baseline (Loucks. 1993)

Now, while there were no differences in baseline thyroid status for the participants a brief glance at the data in figure 2 will suffice to see that those were present during and after the intervention. And while the scientists state that ...

"[w]hen dietary energy intake was increased in exact compensation for the energy cost of exercise (LB, HB) [...] even the large volume of exercise performed in this study (similar to running a half marathon each day) had no effect on T3 levels." (Loucks. 1993)

I have my doubts whether "training in the zone" for hours everyday will not shut down the thyroid after 3 weeks and thus 5x the duration of the study. I mean -10% T3 & 5%+ increase in reverse T3 are certainly boding ill (see my comment in figure 2). The data from the two-way ANOVA plotted in figure 3, on the other hand, confirm that the scarcity of energy and thus your bodies' desire to conserve energy is the main factor, here. 

"You're thyroid function is fine - rather high than low!", says the Dr. to the patient

The experiment Loucks et al. conducted does also shows why most patients don't receive adequate counseling (there is no need for treatment) by their doctors and statements like the one above are rather the rule than the exception.

Figure 3: Treatment effects on the changes of total T3 (in nmol/l) in the study particpants of study A (Loucks. 1993)

With normal or low TSH levels (not measured in the study at hand; generally indicating normal or even high thyroid function) and normal or increased T4 levels (this is an exclusive feature of the earlier stages of the overtraining + undereating syndrome) usually being the only additional value you may be able to convince your medical practitioners to measure this appears like an adequate diagnosis. The lowered T3 and even more so the increasing rT3 levels, on the other hand, will go unnoticed by the majority of GPs whose text-book tells them that even a mere TSH test should suffice to determine your thyroid health (in fact that's true, because your thyroid is perfectly healthy).

In a way this is yet better than a Dr. prescribing T4 in these situations. The latter will only be converted to rT3 and can aggrevate the sluggishness and apathy that comes with the low metabolic function due to "low T3 syndrome".

We need more data: Study B (Loucks. 1994)

"How did I let this happen again?", asks Oprah in her own magazine  - the answer is simple, Oprah! Your "diet" programmed the YoYo effect! It happened not after, but right while you were starving... ah, pardon "dieting"! Learn more about the benefits of dieting down slowly.

It goes without saying that the results of study A (Loucks. 1993) of which the scientists themselves point out that it had a "limited purpose" which was to determine (Study B; Loucks. 1994)

1. whether exercise training is capable of altering thyroid metabolism in women, and, if so, 
2. whether this alteration can be wholly explained by the impact of exercise on energy availability, with all other physiological processes occurring during exercise training (i.e., “exercise stress”) having no influence on thyroid metabolism. 

are of low practical relevance, as I would hope that even the most notorious masochists out there won't try to cut on a "8kcal/kg per day" diet... well, I got to qualify this statement, I suppose. In the obese "diets" like that are actually common practice - the "biggest loser" diets often contain 800kcal per day, as does the HCG diet and if you take into account that almost all obese men and a significant amount of obese women weigh more than 100kg, the protocol does no longer seem to be that unrealistic.

Still, I and I would guess, you, as well, will appreciate that Loucks & Heath conducted a follow up study, in the course of which they wanted to elucidate how important the dietary compensation of the exercise induced energy expenditure is, if you want to keep your thyroid hormone metabolism intact. To this ends the subjects were randomly allocated to four groups (ordered from lowest to highest energy intake):

• 10.8kcal/kg LBM available energy -- this is what's left from a baseline intake of 39.5kcal/kg LBM, after the energy expended during the workouts is subtracted from a diet with a caloric deficit of ~23% below the participants' habitual intake
• 19.0kcal/kg LBM available energy -- this is what's left from a baseline intake of 48.6kcal/kg LBM, after the energy expended during the workouts is subtracted from a diet with a caloric deficit of ~6% below the participants' habitual intake
• 25.0kcal/kg LBM available energy -- this is what's left from a baseline intake of 53.4kcal/kg LBM, after the energy expended during the workouts is subtracted from a diet that had an identical energy content as the participant's habitual diets
• 40.4kcal/kg LBM available energy -- this is what's left from a baseline intake of 68.4kcal/kg LBM, after the energy expended during the workouts is subtracted from a diet with a caloric content that was ~32% above the participants' habitual diets (typo in kcal values corrected)
  

All subjects performed the high intensity protocol of the previous study (70% VO2max) and expended 30 kcal kg LBM of energy in daily exercise for four consecutive days beginning on day 2, 3,4, or 5 of the menstrual cycle (this is important, because the energy expenditure during the workouts was obviously not compensated for in the habitual diet). Just as in the previous study the exercise sessions were performed on treadmill or cycle ergomenter, and in 30 min bouts with 10min breaks in between (obviously until the target calorie expenditure was met).

Figure 4: Effects of training at 70% VO2max aiming for a total energy expenditure of 30kcal/kg LBM at different levels of available energy (intake - expenditure in kcal/LBM) on thyroid hormones; values expressed rel. to baseline (Loucks. 1994)

As the literal "blind man" should see, the combination of what most people would not even necessarily call overtraining (after all it's just 4 days and "only" 70% VO2max) reduces the T3 reserves (total T3) to zero and reduce the purportedly active T3 levels by 28% - a reduction that will have a significant impact on how you feel and how your metabolism will function.

Figure 5: The changes in thyroid hormones come "stepwise" with thresholds at 22.5kcal/LBM body weight for FT3 and  ~14kcal/LBM available energy for FT4 and rT3 (Loucks. 1994)

As the text boxes in figure 5 already tell you, we are dealing with a general 2-step mechanism, here, and it it is fully dependent on the extent of the calorie deficit. For a ~8% reduced total energy intake that corresponds to an available energy level of  ~22kcal/LBM, we see "nothing" but a drop in active thyroid hormones FT3, when the energy deficit increases (and I assume when it persists for longer than 4 days), this reduction is no longer enough to minimize the energy expenditure so that your body resorts to what you may term an STRM, a selective thyroid hormone receptor modulator that goes by the telling name reverse T3. Since rT3 is produced from T4 and the other metabolic pathway, the conversion of T4 to T3 is already shutting down, we see an increase in free T4 levels, which will serve as a substrate for the production of rT3 to further slow down the metabolism (in the days/weeks to come TSH will probably go further down so that you will end up with all levels being suppressed and only rT3 high - if anything).

---

As you can see, your body is smarter the average starvation dieter thinks he is. So the bottom line is easily formulated: Don't starve yourself if you don't want do feel and look like miserable, hold water, get fat from whatever you eat and end up as a physiological and psychological wrack.

References:

• Loucks AB, Callister R. Induction and prevention of low-T3 syndrome in exercising women. Am J Physiol. 1993 May;264(5 Pt 2):R924-30.
• Loucks AB, Heath EM. Induction of low-T3 syndrome in exercising women occurs at a threshold of energy availability. Am J Physiol. 1994 Mar;266(3 Pt 2):R817-23.

Science Round-Up Seconds: Vitamin E Succinate, How It's Extracted from Barley Leaves, Kills Cancer, Ramps up Growth Hormone & Spikes Prolactin. Plus: Testostosterone & Thyroid Hormone Decline Due To Plyometrics & HIIT

Regardless of all the hypocritical hoopla around his persona, Lance Armstrong has always been able to push himself like no one else. No wonder that intense plyometrics were part of his regimen.

If the SuppVersity Science Round Up was a meal, I guess you could say that Carl Lanore and I were sort of gluttonous, yesterday (click here to download the podcast, if you have not already done so). We almost raced from one topic to another and therefore all the good stuff from the list is gone already and I am a bit pressed on time to get some "private life" in, so that I am not psyched about the idea of writing about auxiliary stuff.

Against that background and in view of the fact that I felt that the pace of yesterday's show did not really leave enough room for some important details, I will stick to rehashing and expanding on the stories about Vitamin E succcinate and the detrimental effects of beating the crap out of yourself doing plyometrics or crazy HIIT workouts (too regularly), in today's installment of the SuppVersity Science Round-Up Seconds.

Let's see. Why don't we start at the end of yesterday's show?

• Vitamin E succinate the most potent anti-cancer tocopherol known to man. As you have heard on the show, vitamin E succinate attaches directly to a protein that's preferentially expressed in carcinogenic or pre-carcinogenic cells. It goes by the name α-Tocopherol-associated protein (TAP) and was found to be one of the major α-tocopherol binding proteins in serum, liver, brain and prostate. What has as of yet not been so clear, though, is that the expression of this protein increases with the malignancy of (breast) cancer (Tam. 2012). 
  
  

  

  Figure 1: Effects of alpha tocoperyl succinate alone (TOS), doxorubicin alone (DOX) or both (DOX + TOS) on cell viability in human MB231 breast cancer cells (my edits, original from Tam. 2012) - note: The effect was less pronounced in other cancer cells, so that it is reasonable to assume that the efficacy of the therapy will depend on the exact genotype of the cancer (for those tested in the study it was MB231 > SKBR3 > MCF 10A)

  When alpha tocopherol succinate binds to the protein on the cancer cells, this will either alone, or in combination with chemotherapy trigger apoptosis and cell death. It is as of yet not fully elucidated why vitamin E succinate is highly cancer-specific and leaves the healthy cells intact, but this could be related to the high metabolic rate and exuberant ROS production of cancer cells. There is however some research that would suggest that the cancer cells literally suffocate in their own radical oxygen specimen (ROS), which can no longer be cleared from the cell, due to the alpha-tocopheryl succinate induced displacement of ubiquinone from CII and the subsequent blockade of succinate dehydrogenase (SDH) activity (Dong. 2012).  If this hypothesis holds true it would therefore appear that long-term chronic supplementation with vitamin E succinate cannot be recommended until future studies on its general safety have been undertaken. As an adjuvant to chemotherapy, on the other hand, it could drastically reduce the dosage requirements during chemotherapy in specific types of cancer (see figure 1) and thus minimize side effects.
  
  You see, there is more to it than you can say in two minutes on the radio and this is why I will make sure we don't rush through the items that fast, in the next show. Ah,... of course the dietary source. I had almost forgotten about that one. As mentioned on the show, alpha tocopheryl succinate was originally extracted from Barley leaves. An while this may not be the first paper dealing with this "natural vitamin E analog", the one by Badamchian et al. is probably the one you will be most interested in.
  
  Published in the Journal of Nutritional Biochemistry the paper does not only describe the isolation of vitamin E succinate from green barley leaf extract (BLE)...
  

  "BLE [barley leaf extract] powder (50 mg/mL) was suspended in water and stirred for 1 hr at room temperature. The mixture was then centrifuged at 3000g for 30 minutes using a bench-top centrifuge. The pellet was discarded and the supernatant was pre-filtered through a Millipore DEPTH filter. The filtrate was then filtered through 0.45 I.tM mem- brane and stored at -20 ° C for HPLC or biological assays." (Badamchian. 1999)

  ... it does also shine another spotlight on its potential biological effects, as far as it's ability to increase growth hormone, but (unfortunately?) also prolactin in isolated anterior pituitary cells from female rodents:
  

  

  Figure 2: Prolactin and growth hormone release in anterior pituitary cells of female rodents after incubation with different amounts of green barley extract in which vitamin E succinate had been deterimed as the main ingredient before (based on Badamchian. 1999)

  It's really hard to estimate whether or not one of these effects would translate from a rodent cell in the petri dish to you or me popping a cap with vitamin E succinate everyday. That's particularly true in view of the fact that the underlying mechanism of the increase in GH and the imho more concerning increase in prolactin is neither mediated by increases in intracellular C-AMP, as it would be the case for GRF (old acronym for growth hormone releasing hormone), nor is it induced by the hydrolysis of polyhoshpoinositide, which is the underlying mechanism of the stimulative effect of TRH (thyrotropin releasing hormone). So basically we neither know how it works, nor do we know, whether the oral ingestion of vitamin E-succinate would be sufficient to produce serum concentrations in the pituitary that would be high enough concentrations to make any difference at all (note: the scientists excluded the influence of other components of the extract by testing alpha tocopherol succinate on its own in a separate trial)
  
  Bottom line: Based on roughly one dozen of in-vitro studies there is simply still to little evidence to decide who, outside of people with a history of cancer or someone who is just undergoing chemotherapy would benefit. Therefore, I suggest you wait before you add vitamin E succinate to your list of 'must have' supplements. Is it promising? Sure! Is it exciting, yeah! Is it save for a healthy being to be taken chronically??? I can't tell.
• The detrimental hormonal effects of pushing yourself beyond the tolerable threshold - Hardcore plyometrics and heavy HIIT and their impact on testosterone, cortisol, thyroid hormone and co: I guess you did already get the main message when you listened to the show, but just to give you an idea about the actual quantities, I thought it would be nice to provide you with two graphs as a reference.
  

  

  Figure 3: Comparison of the hormonal responses measured in the plyometrics (left) and the HIIT vs. LISS (right) study (based on Ozen. 2012 and Hackney. 2012)

  If you focus mainly on the differential cortisol responses in the two studies, it would appear likely that we are dealing with two very different forms of 'overtraining' here. While the HIIT protocol (90s at 100-110%, 90s active recovery at 40% matched for workload with steady state jogging at 60-65% of the VO2 max) probably wouldn't be a problem, if the athletes would get adequate rest and nutrition in the days after the session, the 6-weeks of plyometrics (15 session, increasing density, 90-195 reps per session) were enough to send the participants right into the vicious circle of the Athlete's Triad (if you have not done so already, I suggest you read up on that in the eponymous SuppVersity series).
  
  And you know what? Despite, or I should probably rather say due to their compromised hormone levels the guys in the plyometrics study did not lose a single gram of body weight. Good for their muscle, bad for the fat which was likewise preserved by the hormonal shut down, which affected both cortisol and testosterone in a similar way. So is that good or bad news? Well, let me say it this way:. Usually I see people training for a purpose and while the outcome often is stagnation and chronic fatigue, I would suspect that only few of you will have that on their mind, when they are hitting the gym, right?

Apropos viscous circle, and overtraining in order to avoid "overblogging" I will call it a day for today. Come back tomorrow for a couple of wholly new studies from the realms of exercise and nutrition sciences and in case you are planning to drink this evening, I highly suggest you check out the SuppVersity Facebook newspost on the effects of green tea extract on the uptake of alcohol. It may well be that those old fatburner caps of yours can be put to a way better use ;-)

References:

• Badamchian M, Spangelo BL, Bao Y et al. Isolation of a vitamin E analog from green barley leaf extract that stimulates the release of prolactin and growth hormone from rat anterior pituitary cells in vitro. Journal of Nutritional Biochemestry. 1994; 5: 145-150.
• Dong LF, Low P, Dyason JC, Wang XF, Prochazka L, Witting PK, Freeman R, Swettenham E, Valis K, Liu J, Zobalova R, Turanek J, Spitz DR, Domann FE, Scheffler IE, Ralph SJ, Neuzil J. Alpha-tocopheryl succinate induces apoptosis by targeting ubiquinone-binding sites in mitochondrial respiratory complex II. Oncogene. 2008 Jul 17;27(31):4324-35. Epub 2008 Mar 31.
• Hackney AC, Kallman A, Hosick KP, Rubin DA, Battaglini CL. Thyroid hormonal responses to intensive interval versus steady-state endurance exercise sessions. Hormones (Athens). 2012 Jan-Mar;11(1):54-60.
• Ozen, SV. Reproductive hormones and cortisol responses to plyometric training in males. Biol Sport.2012; 29 (3).
• Tam KW, Ho CT, Lee WJ, Tu SH, Huang CS, Chen CS, Lee CH, Wu CH, Ho YS. Alteration of α-tocopherol-associated protein (TAP) expression in human breast epithelial cells during breast cancer development. Food Chemistry. 2012 [ahead of print]

Hypothyroid, Cold, Tired & Depressed? Try Replacing 50µg of T4 With 12.5µg of T3 - Study Shows, 65% of Patients Would not Want to Go Back to Synthyroid (T4), Only!

Image 1: Are you taking copious amounts of synthyroid (levothyroxin, T4), already, and feel as if your hypothyroidism became rather worse than better? Does Your Dr tell you that your TSH is fine and you should just exercise more and eat less to stop gaining weight like mad? Than this post is for you!

The issue of optimal thyroid medication resurfaced as of late on the SuppVersity facebook wall, when I posted the link to a recently conducted retrospect study in patients who had undergone total thyroidectomy and were now receiving postoperative levothyroxin only hormone therapy by Ito et al. Not to my personal, but obviously to the researchers surprise, the textbook prescription of the "metabolically inactive"  T4 (essentially that is as almost 90% of "general knowledge about thyroid hormone metabolism incorrect as T4 can very well interact with thyroid receptors, it is though TR-alpha specific and has little metabolically activating effects, cf.  Koury. 2009) did not suffice to restore the circulating levels of the active thyroid hormone T3 to the preoperative levels (Ito. 2012). Only when so much T4 was administered that the thyroid stimulating hormone (TSH, also known as thyrotropin) were "suppressed" (as per textbook definition) the circulating T3 levels got back within the physiological normal range.

"Nurse, send the patient home and show me his lab report!"

The real-life consequences of treating lab values instead of patients and going by textbook prescriptions instead of the often debilitating symptoms of hypothyroidism which range from

• physical problems such as weight gain, constipation, constant cold, feeling of cold, blurred vision, nausea, sleepiness, low blood pressure, high cholesterol and blood glucose levels, etc. to
• psychological issues such as general cognitive decline, inability to concentrate, mental fatigue, anger, confusion and depression

and often become rather worse than better, when patients who still have their thyroid gland are going on "partial replacement" or start taking a "supportive" dose of synthyroid (levothyroxin, T4) to help a sluggish thyroid along.

Image 2: Ladies, you are lucky you got all that subcutaneous fat to absorb those lubricants and PCB laden cosmetics you are using and stash it away ... a pity it's all going to haunt you, when you want to get rid of those fatty, unaesthetic dumping grounds.

Weight loss and thyroid function: Beyond overdieting and undereating While those two, i.e. training like mad and eating like too little or only protein are unquestionably the main culprits, when it comes to diet-induced thyroid malfunction (in this cases thyroid medication is by the way counter-indicated; T4 would not work, T3 would simply burn away even more muscle mass), there is another interesting phenomenon you maybe have not heard about: Self-intoxication! Well, at least this is how I would call the sudden drop of thyroid function that is only one of the nasty effects the release of organochlorines, which have accumulated in the fat tissue of the dieters over years and are now liberated within months, in morbidly obese patients on "zero calorie" diets often weeks, has on the whole endocrine system of formerly big losers (Pelletier. 2002; Tremblay. 2004; Hue. 2006). Pelletier et al. for example found statistically significant negative correlations between the circulating levels of active thyroid hormone T3 and the amount of ...

• hexachlorobenzene (HCB), which was used as a pesticide until 1965 and was also used in the production of rubber, aluminum, and dyes and in wood preservation and is currently formed as a byproduct during the manufacture of other chemicals, mainly solvents and pesticides, and 
• PCB 156, one of the members of the olychlorinated biphenyl (PCB) family of chemicals that has now been banned from industrial insulators and lubricants, because of substantial evidence of its carcinogenic and neurotoxic effects.

... And you bet that this is only the tip of an iceberg. After all, fat is not just a storage site for useful energy, it is also the dumping ground for everything fat soluble you better lock away so that it cannot harm important organs; now, when you think about that, it stands to reason why the fat of animals that have been fed corn or whatever else that's been exposed to one or another of these compounds probably actually is, as common "wisdom" says, associated with an increased cancer risk and all sorts of other ailments.

What most doctors either don't know or simply ignore is the fact that the thyroid produces T3 and T4 at a very specific natural ratio of about 100/6 (I deliberately did not cancel the fraction, and wrote 50/3, instead, because 100/6 is the thyroid's daily production of T4/T3 in mcg, the rest of the approximately 20mcg of T3 come from local deiodinase processes at in other organs). Now, if we simply add say 50µg of T4, the corresponding decline in TSH will reduce the overall thyroid hormone output from the gland; and though the exact degree of "suppression" will depend on absorption kinetics, inter-individual differences, the presence / absence of inflammation and the specific activity of deiodinase enzymes which convert T4 to either T3 or reverse T3 (rT3) in the peripheral organs (esp. the liver and the kidneys), we will at this point simply assume that corresponding to the daily T4 output of 100µg the 50µg dose will suppress the total (T4+T3) output of thyroid hormones by ~50%:

Figure 1: Illustrative "calculation" of the effects of partial thyroid hormone replacement with 50mcg T4 only.

As my example calculation in figure 1 shows, this would equal a reduction of roughly -10% in terms of thyroid hormone activity and that despite the fact that the textbook will tell you that it would not make a difference. That I write "roughly" and not "definitively" is yet quite important, here, as there are too many confounding factors, such as the...

• possible increase in conversion of T4 to rT3 and thus "anti-thyroid" activity; the latter is especially prominent in insulin resistant individuals (Ruhla. 2011) and those receiving high doses of T4 (Clur. 1986)
  Note: this renders the recommendation to simply up the doses of T4 to levels with partially suppressed TSH levels Ito et al. make in the initially cited study pretty much nonsensical
• lack of enzymatic conversion at the level of the target tissue and consequently even lower thyroid activity; something that is often seen in patients who have a "sluggish thyroid metabolism" anyways and receive only a partial substitution

... which will eventually determine both, the hormone production, as well as its metabolic effects to make any clearcut statement. Unfortunately, the same is true, but rarely appreciated for the success of the standard (T4 only) treatment for hypothyroidism, the efficiacy of which will likewise vary from person to person and is even highly susceptible to fluctuations and changes in body weight, inflammation, macro- and micronutrient content of the diet etc.

Against this background, it stands to reason that the argument "but it works for most of my clients" you will often hear from your Dr. is of little significance for you as an individual and even a statement like "but didn't you feel better, when we initiated the treatment 2 months ago" could not just be missing the boat, altogether, but brings another commonly overlooked problem to mind: If you have been suffering from symptoms of hypothyroidism for a couple of years, you would probably feel "major improvements" if you went from a "1" as in "very bad" to a "3" as in "bad", without knowing that you may, just as the majority of the subjects in a study that's been published in The New England Journal of Medicine in 1999, feel even better if you received 12.5mcg of T3 instead of 50mcg of the T4 your Dr. has prescribed.

T4 + T3 therapy makes subjects feel better, 20/32 don't want to go back on monotherapy

The 31 hypothyroid patients who took part in the 10-week study during which the participants received in random order either their regular "T4 only" thyroid medication (e.g. 200mcg of T4) or an identically looking combination preparation in which 50mcg of the original T4 dosage had been replaced with 12.5mcg of T3 (e.g. 150mcg T4 + 12.5mcg T3). The patients, 31 women and 2 men with a mean age of 46 years and either autoimmune thyroiditis or thyroid cancer that was treated with baseline doses of 75±53 µg T4 per day  (range 100-300 µg), were closely monitored during the both of the 5-week interventions and biochemical, physiologic, and psychological tests were performed at the end of each treatment period.

Figure 2: Cognitive performance and psychological well-being of the 32 subjects of the Bunevicius study assessed by standardized tests on either regular T4 only or T4 and T3 combination protocols (based on Bunevicius. 1999)

A cursory glance at the subjects' "objectively" measured cognitive performance (figure 2, left) and pyschological well-being (figure 2, right) does already reveal that there were statistically improvements in a host of parameters that are of unquestionably greater importance to your daily life than an "optimal" level of thyroid stimulating hormone.

Figure 3: Mood and physical symptoms in the 32 subjects of the Bunevicius study assessed by straight forward questionnaires with visual analogue scales - this is the "how do yo actually feel" data (based on Bunevicius. 1999)

If you combine that with the information the patients provided on a visual analogue scale questionnaire on their perceived psychological and physiological well-being, where every single test result spoke in favor of the combination therapy(!), it is thus not very surprising that

[w]hen asked at the end of the study whether they preferred the first or second treatment, 20 patients preferred thyroxine plus triiodothyronine, 11 had no preference, and 2 preferred thyroxine alone (P=0.001).

These results were unrelated to the order of treatment and the two patients who preferred the T4 only treatment had probably ended up slightly hyperthyroid as they were complaining of feeling "slightly nervous during combined treatment" (Bunevicius. 1999). The others however emphasized that they "noticed that they were more energetic, had better concentration, and simply felt better" (ibid.) than on T4 alone.

The Bunevicius study in nuce

Protocol Reduce T4 intake by 4mcg per 1mcg of T3 you introduce; optimally reduce T4 intake by 50mcg and att 12.5mcg of T3 in.

Results Thyroid hormone levels staid in range (see table above), the +3beat/min increase in pulse rate is harmless and the non-significant drop of 6 and 2pts in systolic and diastolic blood pressure is nothing to speak of.

	T4	T4+T3
TSH (µU/ml)	0.8	0.5
TSH = 0*	7	5
T4 (µg/dl)	15.2	11.3
T3 (ng/dl)	87	117

Table 1: Serum levels of selected hormones and *# of patients with serum TSH <0.05µU/ml

Side Effects Two subjects felt slightly agitated on T4 + T3, no other side effect were reported

Useful for people who are taking high (>>50mcg) doses of T4 (only under supervision of your Dr!)

Not useful for people who don't need thyroid medication and simply suffer from low thyroid hormone due to overtraining, undereating or both (see links below).

Suggested reads

• (Over-)Motivational Orthorexia,
• Overtraining, Inflammation,
• Dietary Thyroid Treatment
• more on overtraining
• more on thyroid

Implications: Especially the usually overlooked effects on mood, cognitive function and "subjective" well-being, or rather the negative effects T4 only treatment has on these parameters, do speak in favor of putting the unwarranted prejudice against the "myotoxic" (=heart damaging) T3 overboard. We are, after all, not talking about the induction of full-blown hyperthyroidism, the detrimental effects of which on the hearts of rodents are essentially what brought the myth of the "dangerous T3" to live; we are just talking about doing our best to emulate the natural balance, which is not adequately and reliably measurable by taking the thyroid stimulating hormone (TSH) levels in the blood of a patient as your only reference.

Moreover, the notion of "just throwing in T4 and waiting for the target tissue to produce as much T3 from it as needed" is intrinsically flawed as it negates the established exogenous T3 requirements of the mammalian brain (~20% of the T3; cf. Silva. 1984), as well as the local downregulation of the T4 => T3 conversion in the brain upon exposure to elevated serum thyroxine (T4) levels (Silva. 1985), as they will occur whenever you simply "up the dosage" of levothyroxine in the false belief that this would help you to get rid of persistent symptoms of hypothyroidism. Against that background it appears to be rather the exception than the norm that you would be optimally functioning on T4 only and not end up

1. still systemically hypothyroid with even lower serum T3 levels (or T3-to-rT3 ratios), than before, or
2. now centrally (in the brain) hypothyroid despite "normal" or even suppressed TSH levels and adequate or high circulating thyroid hormone levels

Against that background, the researchers conclusion that the "ideal replacement regimen [especially] when thyroid-gland function is absent or nearly absent might consist of 10 µg of triiodothyronine daily in sustained-release form (because the hormone is rapidly absorbed and metabolized), along with enough thyroxine to ensure euthyroidism" (Bunevicius. 1999) does appear reasonable, although the necessity and value of "sustained" release formulas is certainly debatable, esp. for lower doses of T3.

References:

• Bunevicius R, Kazanavicius G, Zalinkevicius R, Prange AJ Jr. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med. 1999 Feb 11;340(6):424-9.
• Clur A. Reverse tri-iodothyronine as part of alpha 2 adrenergic receptors. Med Hypotheses. 1986 Nov;21(3):281-92.
• Hue O, Marcotte J, Berrigan F, Simoneau M, Doré J, Marceau P, Marceau S, Tremblay A, Teasdale N. Increased plasma levels of toxic pollutants accompanying weight loss induced by hypocaloric diet or by bariatric surgery. Obes Surg. 2006 Sep;16(9):1145-54. 
• Ito M, Miyauchi A, Morita S, Kudo T, Nishihara E, Kihara M, Takamura Y, Ito Y, Kobayashi K, Miya A, Kubota S, Amino N. TSH-suppressive doses of levothyroxine are required to achieve preoperative native serum triiodothyronine levels in patients who have undergone total thyroidectomy. Eur J Endocrinol. 2012 Jun 18.
• Koury EJ, Pawlyk AC, Berrodin TJ, Smolenski CL, Nagpal S, Deecher DC. Characterization of ligands for thyroid receptor subtypes and their interactions with co-regulators. Steroids. 2009 Feb;74(2):270-6. 
• Ruhla S, Arafat AM, Weickert MO, Osterhoff M, Isken F, Spranger J, Schöfl C, Pfeiffer AF, Möhlig M. T3/rT3-ratio is associated with insulin resistance independent of TSH. Horm Metab Res. 2011 Feb;43(2):130-4. 
• Silva JE, Matthews PS. Production rates and turnover of triiodothyronine in rat-developing cerebral cortex and cerebellum: responses to hypothyroidism. J Clin Invest 1984;74:1035-49.
• Silva JE, Leonard JL. Regulation of rat cerebrocortical and adenohypophyseal type II 5'-deiodinase by thyroxine, triiodothyronine, and reverse triiodothyronine. Endocrinology 1985;116:1627-35.
• Tremblay A, Pelletier C, Doucet E, Imbeault P. Thermogenesis and weight loss in obese individuals: a primary association with organochlorine pollution. Int J Obes Relat Metab Disord. 2004 Jul;28(7):936-9.