Reverse T3 and Reverse T3 Dominance
The thyroid gland is located in the lower part of the neck near your Adam's Apple. It secretes two essential thyroid hormones: triiodothyronine (T3) and thyroxine (T4) which are responsible for regulating cell metabolism in every cell in your body. They promote optimal growth, development, function and maintenance of all body tissues. They are also critical for nervous, skeletal and reproductive tissue as well as regulating body temperature, heart rate, body weight and cholesterol.
In a healthy patient a normal thyroid gland secretes all of the circulating T4 (about 90 to 100mcg daily) and about 20% of the circulating T3. The T4 made by the thyroid gland circulates throughout the body and is converted by the 5-deiodinase enzymes Type 1 & 2 into T3 or via the 5-deiodinase Type 3 enzymes into reverse T3 in roughly equal amounts of T3. Most of the biological activity of thyroid hormones is due to T3. It has a higher affinity for thyroid receptors and is approximately 4 times more potent than T4. Because 80% of serum T3 is derived from T4 in tissues such as the liver and kidney, T4 is considered a pro-hormone. No receptors have ever been identified for T4. Normal physiological production ratio of T4 to T3 is 3.3:1.
Reverse T3 (rT3) is virtually inactive having only 1% the activity of T3 and being a T3 antagonist binds to T3 receptors blocking the action of T3 and thus acting as a metabolic break. Normal metabolism of T4 requires the production of the appropriate ratio, or balance, of T3 to rT3. If the proportion of rT3 dominates then it will antagonize T3 thus producing hypothyroid symptoms despite sufficient circulating levels of T4 and T3. Reverse T3 has the same molecular structure as T3 however its three dimensional arrangement (stereochemistry) of atoms is a mirror image of T3 and thus fits into the receptor upside down without causing a thyroid response and thus preventing or antagonizing the active T3 from binding to the receptor acting as a metabolic break.
Reverse T3 dominance, also known as Wilson's Syndrome, is a condition that exhibits most hypothyroid symptoms although circulating levels of T3 and T4 are within normal test limits. The metabolism of T4 into rT3 is in excess when compared to T3 therefore it is a T4 metabolism malfunction rather than a straight forward thyroid deficiency. Periods of prolonged stress may cause an increase in cortisol levels as the adrenal glands respond to the stress. The high cortisol levels inhibit the 5-deiodinase enzyme Type 1 and thus the conversion of T4 into T3 thus reducing active T3 levels. The conversion of T4 is then shunted towards the production of the inactive rT3 via the 5-deiodinase enzyme Type 3. This rT3 dominance may persist even after the stress passes and cortisol levels have returned to normal as the rT3:T3 imbalance itself may also inhibit the 5-deiodinase enzyme Type 1 thus perpetuating the production of the inactive rT3 isomer. There is some argument to this last point with some research indicating that the elevated rT3 is only temporary and not a permanent condition and in most healthy people this may well be the case. We have however found that in many patients suffering from a range of hypothyroid symptoms do indeed have prolonged elevated rT3 levels which respond favorably to this treatment. Many medical practitioners do not accept rT3 dominance theory and thus many doctors will refuse to treat this condition despite the fact many suffers have been successfully treated. See below for the evidence in the references.
Other causes of reverse T3 dominance include: leptin resistance, inflammation (NF kappa-B), dieting, nutrient difficiencies such as low iron, selenium, zinc, chromium, Vit B6 and B12, Vit D and iodine, Low testosterone, low human growth hormone, Insulin dependent Diabetes, Pain, Stress, environmental toxins, Free radical load, Hemorrhagic shock, Liver disease, Kidney disease, Severe or systemic illness, severe injury, Surgery, Toxic metal exposure.
In addition to considering T3 levels we also need to consider rT3 because if it is too high it will block the effects of T3 thus producing hypothyroid symptoms. If this is the case the TSH, T4 and T3 tests alone will give a false impression of true thyroid function and therefore you must also measure rT3 in order to diagnose this condition. Ideally the ratio of T3/rT3 multiplied by 100 should be between 1.06 to 2.2 - preferably towards the upper end of this range. If this ratio is at the low end of this range or below then rT3 dominance is present and slow release T3 therapy needs to be initiated once adrenal exhaustion, hypoglycemia, nutritional deficiencies and/or low sex hormone levels have been ruled out and/or treated as they can all inhibit 5-deiodinase Type 1 activity. In addition nutrients such as selenium, zinc, Vit B6, B12 and E, iron and iodine should be supplemented as they are necessary cofactors for this enzyme to function correctly and thus ensure appropriate T3 production.
It is also very important that if elevated levels of cortisol are found (stage 1 adrenal exhaustion) it should be treated first because if it remains elevated it will only continue to inhibit the 5-deiodinase enzyme and thus continue rT3 production reducing the effectiveness of this treatment. Low cortisol levels should also be treated because low cortisol will reduce the number of T3 receptors and also prevent T3 transport within the cell, again impeding improvement while on this treatment. In addition some patients respond poorly to thyroid medication if adrenal fatigue is present. Therefore we recommend you test adrenal function and correct it before commencing this treatment.
In summary you should have the following tested: DHEA, cortisol, TSH, T3, T4 and reverse T3.
It is important that no T4 (thyroxine), including Armour Thyroid, is used for this condition as a portion of the supplemented T4 will only be converted into rT3 and perpetuate the viscous cycle. The idea is to use slow release T3 to provide the active thyroid hormone to alleviate hypothyroid symptoms and to rebalance the T3/rT3 ratio without the risk of increasing rT3 production. This will allow rT3 levels to diminish over time and thus for T3 to be able to bind to its receptors and thus be effective. It is critical that rT3 levels are reduced in order to achieve a positive therapeutic outcome.
Dr Wilson developed a protocol using cycled doses of slow release T3 based on body temperature. A major problem with this protocol is that in many cases very high non physiological doses of T3 are required (90 to 120mcg daily) before a normal body temperature is obtained. In addition it does not necessarily address all the underlying problems of what caused the inhibition of the 5-deiodinase enzyme to begin with such as hormone deficiencies, leptin and insulin resistance and nutritional deficiencies. It is also a complicated protocol that many patients find confusing. The assumption with this protocol is that high dose T3 will suppress TSH causing a reduction in T4 production. With little or no T4 left in the system reverse T3 can no longer be produced and eventually whatever is already present in the body will be eliminated thus reducing overall reverse T3 levels. The 5-deiodinase enzyme Type 1 will then no longer be inhibited by the rT3 allowing the appropriate activation of T4 into the active T3 form to occur once the dose of T3 has ceased and thyroid production has recommenced. Unfortunately the risk of high dose T3 causing hyperthyroid symptoms is high and should be avoided if possible.
Our preference is to supplement with a combination capsule (thyroid conversion capsules) which contains selenium, zinc, chromium, Vit B6 and B12, iron, Vit D and iodine as they are all required by the 5-deiodinase Type 1 enzyme responsible for proper T3 production while the chromium helps control insulin resistance which can also inhibit conversion. Adrenals are also addressed to make sure both DHEA and cortisol levels are within the optimal range to ensure they are not affecting conversion. Testosterone and hGH levels may also need adjusting. Finally slow release T3 capsules are also used to obtain an appropriate T3:rT3 balance. Slow release capsules work best as they prevent peak concentrations of T3 after 1 to 2hrs often observed with tablets which are responsible for the side effects associated with T3. Begin by taking 10mcg T3 SR daily and adjust from there. Symptoms should be monitored for improvement in energy levels and an increase in body temperature (ideally underarm temperature above 36.5C). The dose should be gradually adjusted until levels are adequate and balanced.
Symptoms for hyperthyroid such as sweating, anxiety, palpitations, etc must also be monitored for and doses reduced at the first sign of these symptoms appearing. Care should be taken not to allow the pulse rate to remain above 100 beats / minute, or more than about 20 beats / minute faster than before treatment.
We have found that by using a consistent low dose of T3 over two to three months without the need of cycling the dose, as described by Dr Wilson, in addition to addressing the causes of improper T4 metabolism, many patients have responded favorably with improved symptoms and a reduction in reverse T3 levels.
Peripheral Metabolism of Thyroid Hormones: A Review. Alternative Medicine Review, August, 2000 by Greg Kelly
Under normal conditions, 45-50 percent of the daily production of T4 is transformed into rT3. Substantial individual variation in these percentages can be found secondary to a range of environmental, lifestyle, and physiological influences Although an adequate understanding of the metabolic role of rT3 is somewhat limited, it is thought to be devoid of hormonal activity and to act as the major competitive inhibitor of T3 activity at the cellular level. Experimental data also suggests rT3 has inhibitory activity on 5'-deiodinase, suggesting it might also directly interfere with the generation of T3 from T4.
[1.] Chopra IJ. An assessment of daily production and significance of thyroidal secretion of 3,3',5' triiodithyronine (reverse T3) in man. J Clin Invest 1976:58:32-40.
[2.] Robbins J. Factors altering thyroid hormone metabolism. Environ Health Perspect 1981;38:65-70.
[3.] Kohrle J, Spanka M, Irmscher K, Hesch RD. Flavonoid effects on transport, metabolism and action of thyroid hormones. Prog Clin Biol Res 1988;280:323-340.
A study of extrathyroidal conversion of thyroxine (T4) to 3,3’,5-triiodothyronine (T3) in vitro. Endocrinology;101(2):453-63. Chopra IJ
Many endocrinologists believe that reverse T3 (3,3’,5-triodothyronine) is only an inactive metabolite with no physiologic effect. This is an erroneous belief as this and other studies demonstrate that reverse T3 (rT3) is a more potent inhibitor of T4 to T3 conversion than propylthiouracil (PTU) which is a medication used to decrease thyroid function in hyperthyroidism. In fact, rT3 is 100 times more potent than PTU at reducing T4 to T3 conversion. Clearly demonstrating that rT3 not just an inactive metabolite, but rather a potent inhibitor of tissue thyroid levels. The authors conclude, “Reverse t3 appeared to inhibit the conversion of t4 to T3 with a potency which is about 100 times more than PTU…”
Thyroid Hormone Concentrations, Disease, Physical Function and Mortality in Elderly Men. The Journal of Clinical Endocrinology & Metabolism 2005; 90(12):6403–6409.
Annewieke W. van den Beld, Theo J. Visser, Richard A. Feelders, Diederick E. Grobbee, and Steven W. J. Lamberts Department of Internal Medicine , University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands
This study of 403 men investigated the association between TSH, T4, free T4, T3, TBG and reverse T3 (rT3) and parameters of physical functioning. This study demonstrates that TSH and/or T4 levels are poor indicators of tissue thyroid levels and thus, in a large percentage of patients, cannot be used to determine whether a person has normal thyroid levels at the tissue level. This study demonstrates that rT3 inversely correlates with physical performance scores and that the T3/rT3 ratio is currently the best indicator of tissue levels of thyroid.
This study showed that increased T4 and RT3 levels and decreased T3 levels are associated with hypothyroidism at the tissue level with diminished physicial functioning and the presence of a catabolic state (breakdown of the body). Low T3 syndrome, with low T3 and high reverse T3, is almost always missed when using standard thyroid function tests, as the T3 level is often in the low normal range and reverse T3 is the high normal range, again making the T3/rT3 ratio the most useful marker for tissue hypothyroidism and as a marker of diminished cellular functioning. The authors of this study conclude, “Subjects with low T3 and high reverse T3 had the lowest PPS [PPS is a scoring system that takes into account normal activities of daily living and is a measure of physical and mental functioning]…Furthermore, subjects with high reverse T3 concentrations had worse physical performance scores and lower grip strength. These high rT3 levels were accompanied by high FT4 levels (within the normal range)…These changes in thyroid hormone concentrations may be explained by a decrease in peripheral thyroid hormone metabolism… Increasing rT3 levels could then represent a catabolic state, eventually proceeding an overt low T3 syndrome.”
This study demonstrates that TSH and T4 levels are poor measures of tissue thyroid levels, TSH and T4 levels should not be relied upon to determine the tissue thyroid levels and that the best estimate of the tissue thyroid effect is the rT3 level and the T3/rT3 ratio.
“Elevation in reverse triiodothyronine level is also seen as a consequence of diminished use of thyroxine, diminished thyroxine-to-triiodothyronine conversion, and diminished tissue levels of triiodothyronine. And “obtaining free triiodothyronine, reverse triiodothyronine, and triiodothyronine/reverse-triiodothyronine ratios may help obtain a more accurate evaluation of tissue thyroid status and may be useful to predict those who may respond favorably to triiodothyronine supplementation”
Erika T. Schwartz, MD, Kent Holtorf, MD, Hormones in Wellness and Disease Prevention: Common Practices, Current State of the Evidence, and Questions for the Future. Prim Care Clin Office Pract 35 (2008) 669–705