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.

(Mis-)Managing Hypothyroidism: 7% Reduction in Energy Expenditure & Fat Oxidation in Patients on Levothyroxin (T4) Mono Therapy. Plus: Alternative Dessicated Thyroid?

The thyroid is a real diva. You better treat her with utmost care (learn more)

I guess, ... no, I know that a couple of you have to deal with all sorts of thyroid problems. I know you won't like to hear that, but if you read the SuppVersity Athlete's Triad Series you should know that there is more than just the remote possibility, that food and rest would be everything to "heal" your underactive ductless gland (=thyroid). Good indicators are you train everyday, (1) you eat a high protein, low carb, low to at best medium fat diet with a constant caloric deficit, and (b) your TSH level is low to normal, your free T4 level is low to normal but your free T3 level is sub-par. In consequence you will feel sluggish, look sluggish, train sluggish and won't achieve either your fat loss, performance or muscle building goals.

If that's you, there is need for meditation, not medication, for stress management, not pills. In fact, throwing the "inactive" precursor T4, the textbook treatment for hypothyroidism into the equation, could make things even worse, as your body is going to convert the lion's share of it to the metabolic emergency break rT3, to avoid that increasing levels of the active metabolite T3 start gnawing away on your undernourished muscle and exacerbate the chronic stress you are exposing yourself to.

Is being "euthyroid" really the same as having normal TSH levels?

Data from the The Colorado Thyroid Disease Prevalence Study indicates the risk of suboptimal thyroid function & hypothyroidism is more pronounced in women (Canaris. 2000); associations w/ certain contraception meds, pregnancy & menopause in other studies point towards estrogen / progesteron issues as confounding factors.

Interestingly enough, a recent study from Division of Endocrinology and Metabolic Medicine, Policlinico di Monza and the Department of Biomedical Sciences for Health at the Università degli Studi di Milano, both obviously in Italy, did now reveal that it does note necessarily take overtraining + undereating to end up in a 'metabolically and mentally sluggish euthyroid state'. This became evident, when the Italian researchers compared the body composition and resting energy expenditures of 30 hypothyroid women with an average BMI >25 kg/m² and normal serum TSH levels (<3.5 μU/ml; text-book says: "Your patient has optimal thyroid function, doctor!") who had been on the "gold standard" (*rofl*) replacement therapy with L-T4 (levothyroxin = synthyroid; mean dose: 73±34 μg/d) for at least 2 years to the same parameters in a control group with matched age, BMI, menopausal state and life-style habits (P>0.3 for all).

While neither the average TSH levels, which were 1.92±1.06 µU/ml in the T4 and 1.87±0.89 μU/ml in the control group (P=0.91), nor the body composition (body fat: 41.4±7.4 vs 42.1±8.3%; LBM 58.6±7.4 vs 57.8±8.3%; P>0.7 for all) revealed a statistically significant inter-group difference, the resting energy expenditure of the the hypo- / after medication "euthyroid" women on levothyroxin did:

• 

  Click on the image to learn how to calculate (I should rather say estimate) your resting energy expenditure using different scientifically verified formulas and why it is important not to go below a certain threshold (learn more)

  In absolute terms, the women in the T4 group had a -7% lower REE than the controls (1347±171 vs 1447±154 kcal/d; P<0.05).
• The -7% difference remained the same and had an even higher statistical significance (P<0.02 vs. P<0.05), when the resting energy expenditure was expressed relative to the the subjects lean body mass (28.3±2.6 vs 30.5±3.0 kcal/kg LBM die; P<0.02).
• A smaller yet still significant difference was observed when the actual resting energy expenditure was compared to the "supposed" resting energy expenditure calculated by the means of the Harris-Benedict Equation (91±7 vs 95±7%; P<0.05).

The most significant difference (P<0.01) was yet observed, when the scientists analyzed the respiratory quotient (also respiratory exchange rate, short: RER) of their subjects. The latter is a direct measure of the ratio of glucose to fat your body is using a substrate to fulfill its energy requirements, in particular,...

• 

  Suggested read: Maximal Intra- & Post- Workout Fat Oxidation With Pause or 90min LISS Between 2x40min Incremental Exercise Bouts? (read more)

  higher RER levels indicate a greater contribution of glucose, while
• lower RER levels indicate a greater contribution of fats
• A RER of ~1.0 would be observed in healthy individuals, only, when they are engaging in highly glycolytic + brief exercise bouts like sprinting.
• Many "fat burners" work in part by decreasing the RER. When you are in a caloric deficit (and only then) this is an advantage because you will spare glucose and burn fat. 
• Other supplements like creatine, for example,  gear your metabolism towards an increase in glucose expenditure, which can be beneficial in all sorts of activities that rely heavily on short sprints / brief muscle contraction

In fact, the women on T4 (only) had a 11% higher respiratory exchange ratio (0.92±0.07 vs 0.86±0.06; P<0.01), of which even the scientists have to admit that it's clearly suggesting an "impaired fasting lipid oxidation in hypothyroid women" and would thus support "the view that additional interventions may be necessary to fully revert the entire set of hypothyroidism-related metabolic alterations." (Martucci. 2013)

Aren't there better alternatives? T4+T3 or dessicated thyroid?

In a way it is funny - or should I say tragic(?) - that this is the first study in years that bothers with the metabolic and often psychological downsides of T4 only regimen in a way that goes beyond the analysis of TSH levels. After all, the Internet and the waiting rooms of medical practitioners all over the world are full of (mostly female) patients complaining about the non-existent benefits and / or side effects of levothyroxin, only, therapies.

It should be obvious that some of those patients may belong to the initially referred to group of people who suffer from self-induced hypothyrodism in response to undereating and/or overtraining, while others may have confounding, often undetected pathologies that are responsible for their compromised metabolism, their inability to lose weight, their sluggishness, brain fog etc.

Suggested read: "Dietary Thyroid Treatment: Beef, Green Vegetables, Full-Fat Milk & Butter Normalize TSH in Subclinical Hypothyroidism " (read more)

If you do however put the results of the study at hand in perspective with previous studies comparing "T4 only" vs. "T4+T3" treatments and the overall patient-preference of the latter, and combine that with the results of a very recent comparison of levothyroxin vs. natural dissicated thyroid treatment, in the course of which researchers from the Department of Endocrinology at the Walter Reed National Military Medical Center and the University of Health Sciences in Bethesda observed significant weight (I highly suspect fat) loss in the 70 18–65 year-old patients with primary hypothyroidism who had been on a stable dose of T4 for 6 months, when the subjects were given desiccated thyroid extract (DTE) instead of levothyroxin (1 mg DTE ~ 1.667 g L-T4; cf. Hoang. 2013).

Interestingly, the patients had significantly lower rT3 levels, higher total T3 levels, lower otal and free T4 levels and that in the presence of higher, but normal TSH levels (inter-group difference p=0.032) during the DTR part of the 2x16 week cross-over trial. A health hazard, as it is often argued that it would be the result of depressed TSH levels is thus a weak argument against using an alternative treatment strategy, of which I would highly suspect that it could resolve part of the metabolic dysadvantages arising in the context of T4 monotherapy and which was preffered by 34 of the patients in the Hoang study.

---

Bottom line: Whether using T4 + T3 or natural dessicated thyroid as the treatment method of choice is necessary or the best strategy for everyone is something that remains to be seen. Something that stands out of question, though, is that the stubborn adherence to the textbook standards, the blind reliance on TSH tests and the ignorance doctors display towards the complaints of their patients is not going to solve an increasingly prevalent problem (+3% increase in congenital hypothyrodism per year in the US, esp. in white and hispanic newborns; cf. Hintnon. 2010)

References

• Canaris GJ, Manowitz NR, Mayor G, Ridgway E. The Colorado Thyroid Disease Prevalence Study. Arch Intern Med. 2000;160(4):526-534.
• Hinton CF, Harris KB, Borgfeld L, Drummond-Borg M, Eaton R, Lorey F, Therrell BL, Wallace J, Pass KA. Trends in incidence rates of congenital hypothyroidism related to select demographic factors: data from the United States, California, Massachusetts, New York, and Texas. Pediatrics. 2010 May;125 Suppl 2:S37-47.
• Hoang TD, Olsen CH, Mai VQ, Clyde PW, Shakir MK. Desiccated Thyroid Extract Compared With Levothyroxine in the Treatment of Hypothyroidism: A Randomized, Double-Blind, Crossover Study. J Clin Endocrinol Metab. 2013 Mar 28.
• Martucci F, Manzoni G, Lattuada G, Perseghin G. Overweight/obese women with primary acquired hypothyroidism in appropriate levothyroxine replacement therapy are characterized by impaired whole body energy metabolism. Endocrine Abstracts (2013) 32 P1004 | DOI:10.1530/endoabs.32.P1004 Share on facebook Share on twitter Share on digg Share on stumbleupon Share on delicious Share on linkedin | Share on email Share on print