Thyroid Resistance Syndrome and Reverse T3

Thyroid Resistance Syndrome-RT3

Thyroid resistance syndrome is a result of the body converting T4 (Thyroxine) to a form of T3 (liothyronine)  know as reverse T3. This can occur on its own or if a person has been on T4 containing medication like Synthroid or even one of the porcine glandular medications such as Armour thyroid. As long as T4 is coming into the body there is the ability for it to be converted to reverse T3 if the correct conditions exist.

Reverse T3  is completely inactive. The body has a built-in mechanism for the balance of T3 and RT3. Under various conditions, the body can shift the ratio of T3 to reverse T3 and an imbalance can occur. You can calculate the ratio of FT3 to RT3.  A healthy ratio is greater than 20.


What happens if I make too much RT3? It will become an issue. It binds to the T3 receptor sites. This, in turn, blocks the beneficial effects of T3 and the result is that you remain functionally hypothyroid and have many of the lingering symptoms even if your labs look normal. This can be very frustrating for many patients and they can suffer if this situation is not found and corrected. Many people who seem to chase their dosing of thyroid medication have thyroid resistance. The typical story I hear is " I began on one dose and have had to continually increase the dosing because I feel good for a few weeks and then the symptoms return." This continual need for dose increases is a sure sign of thyroid resistance syndrome.


As you can see T3 and rT3 look alike except for the fact that one iodine (I) molecule has been switched creating a mirror (isomer) image of T3. This form is completely inactive and also blocks receptors from being able to use circulating T3.

Reverse T3 is the best measurement of tissue thyroid levels 

The Journal of Clinical Endocrinology & Metabolism 2005; 90(12):6403–6409

Thyroid Hormone Concentrations, Disease, Physical Function and Mortality in Elderly Men
Annewieke W. van den Beld, Theo J. Visser, Richard A. Feelders, Diederick E. Grobbee, and Steven W. J. Lamberts Department of Internal

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 is euthyroid (normal thyroid levels) at the tissue level. In fact, T4 levels had a negative correlation with tissue thyroid levels (higher T4 levels were associ­ated with a decreased peripheral conversion of T4, low T3 levels, and high rT3). 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 physical func­tioning and the presence of a catabolic state (breakdown of the body). This study adds to the mounting evidence that giving T4 preparations such as Synthroid and Levoxyl are inadequate for restoring tissue euthyroidism and that a normal TSH cannot be relied upon as an indication of euthyroidism, as it has a very low sensitivity and specificity for hypothyroidism. This poor sensitivity and specificity are further decreased with the presence of one or more systemic illnesses, including diabetes, heart disease, hypertension, systemic inflammation, asthma, CFS, fibro­myalgia, rheumatoid arthritis, lupus, insulin resistance, obesity, chronic stress, and almost any other systemic illness.

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 rT3 and the T3/rT3 ratio.


Reverse T3 Suppresses T4 to T3 Conversion 

Endocrinology 101(2):453-63

A study of extrathyroidal conversion of thyroxine (T4)to 3,3’,5-triiodothyronine (T3) in vitro
Chopra IJ

Most endocrinologists believe that reverse T3 (rT3) is just and inactive metabolite with no physiologic effect, which is not the case, however. This study and subsequent others demonstrate that rT3 is a more potent inhibitor of T4 to T3 conversion than PTU (propylthio­uracil), 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, rT3 not just an inactive metabolite. 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…

Low Normal Thyroid Levels Cause Weight Gain 

The Journal of Clinical Endocrinology & Metabolism 90(7):4019–4024

Small Differences in Thyroid Function May Be Important for Body Mass Index and the Occurrence of Obesity in the Population
Nils Knudsen, Peter Laurberg, Lone B. Rasmussen, Inge Bu¨ low, Hans Perrild, Lars Ovesen, and Torben Jørgensen

This study demonstrates that low normal thyroid levels are associated with an inability to lose weight and obesity.


Tissue levels of T3 with T4 only preparations

Tissue and pituitary levels of T3 with T4 only preparations 
Journal of Clinical Investigation 96:2828-2838

Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues…

Escobar-Morreale HF, Obregon MJ, Escobar del Rey F, Morreale de Escobar G

Only the combined treatment with thyroxine and triiodothryoidine ensures euthyroidism in all tissue…

Escobar-Morreale HF, Escobar del Rey F, Obregon MJ, Morreale de Escobar G

Levothyroxine (T4) only replacement with products such as Synthroid and Levoxyl are the most widely accepted forms of thyroid replacement. This is based on a widely held assumption that the body will convert what it needs to the biologically active form T3. Based on this assumption, most physicians and endocrinologists believe that the normalization of TSH with a T4 preparation demonstrates adequate tissue levels of thyroid. This assumption, however, had never been directly tested until these studies were published. The first study investigated whether or not giving T4 only preparations will provide adequate T3 levels in varying tissues. Plasma TSH, T4 and T3 levels and 10 different tissue levels of T4 and T3 were measured after the infusion of 12-13 days of thyroxine. The second study compared the plasma TSH, T4 and T3 levels and 13 different tissues levels of T4 and T3 when T4 or T4/T3 preparations were utilized.

These studies demonstrate that the normalization of plasma TSH and T4 levels with T4 only preparations provide adequate tissue T3 levels to only a few tissues including the pituitary (hence the normal TSH) but almost every other tissue will be deficient. They show that it is impossible to achieve normal tissue levels of T3 by giving T4 only preparations unless supra-physiological levels of T4 are given. The authors conclude, “The current replacement therapy of hypothyroidism should no longer be considered adequate…”

The second study found that a combination of T4/T3 is required to normalize tissue levels of T3. The study found that the pituitary was able to maintain normal levels of T3 despite the rest of the body being hypothyroid on T4 only preparations. Under normal conditions, it was shown that the pituitary will have 7 to 60 times the concentration of T3 of other tissues of the body and when thyroid levels drop, the pituitary was shown to have 40 to 650 times the concentration of T3 of other tissues. Thus, the pituitary is unique in its ability to concentrate T3 in the presence of diminished thyroid levels that is not present in other tissues. Consequently, the pituitary levels of T3 and the subsequent level of TSH is a poor measurement of tissue hypothyroidism as almost the entire body can be severely hypothyroid despite a normal TSH level.

These studies add to the large amount of studies that demonstrate that pituitary thyroid levels are not indicative of other tissues in the body and demonstrate why the TSH level is a poor indicator of a proper thyroid dose. They also demonstrate that it is impossible to achieve normal tissue thyroid levels with T4 preparations such as Synthroid and Levoxyl. It is no surprise that the majority of patients on T4 preparations will continue to suffer from symptoms of hypothyroidism despite being told their levels are “normal”. Patients on T4 only preparations should seek out a physician who is well-versed in the medical literature and understands the physiologic limitations and inadequacy of commonly used thyroid preparations.

Additional Studies 

  1. Low normal thyroid levels result in a higher risk of heart disease than if you have high cholesterol, high blood pressure, if you smoke or even have diabetes. Individuals with low normal thyroid levels are 2.5 times more likely to suffer a heart attack. This is greater than if you have high cholesterol (2.4 times risk), high blood pressure (1.6 times risk), if you smoke (2 times risk) or have diabetes (2.4 times risk). Doctors and patients are well aware of these risk factors for heart disease but fail to correct the more important low normal thyroid levels. Many patients needlessly suffer heart attacks because their physician tells them their thyroid is fine because it is in the normal range instead of optimizing to more optimal levels.
    Risk Factor Age Adjusted Relative Risk
    Low normal thyroid
    Diabetes Mellitus

    Annals of Internal Med, 2000

  2. Many physicians have realized that patients can be profoundly hypothyroid and still have normal values of TSH and Free T4. In the British Medical Journal several physicians noted this by stating, “We wish to question present medical practice, which considers abnormal serum concentrations of free thyroxin and thyroid stimulation hormone-those outside the 95% reference interval-to indicate hypothyroidism but incorrectly considers “normal” free thyroxin and thyroid stimulation hormone concentrations to negate this diagnosis. It is unusual for doctors to start thyroxin replacement in clinically hypothyroid but biochemical euthyroid patients.” They note that of 80 patients who were diagnosed as hypothyroid on established clinical (signs and symptoms), only 5 patients had abnormally low T4 levels and only 4 had abnormal high TSH levels. The averaged TSH concentration was below the middle of the reference range. They state that these people deserve treatment otherwise they are condemned to many years of hypothyroidism with its complications and poor quality of life.
    British Medical Journal
  3. In a published article in the British Medical Journal, the authors state, “For over 80 years, before the advent of TSH testing, physicians with outstanding ability have regularly treated thyroid patients with enough thyroid to clinically normalize their patients regardless of dose. The maxim of the day before TSH arrived was to give enough thyroid until the patient felt better. Medical students are still repeatedly told to treat the patient and not the lab values, but this quickly gets forgotten and disregarded when it comes to thyroid. The 80 years of experience with thyroid hormone treatment demonstrated that people would normally need 200-400 micrograms of T4, such as Synthroid, or 3 to 5 grains of desiccated thyroid. The long-term studies of over 40 years show no side effects from such doses and thyroid is probably the safest long-term drug of the Century. When TSH testing came into use in 1973, the average doses dropped to 1/3 of the doses previously used.”
    British Medical Journal
  4. 4. In a study published in the Journal of Endocrinology and Metabolism, clinical signs were compared to blood tests. The authors demonstrated that individuals have varying degrees of thyroid resistance in different tissues. The authors describe this as a metabolic hypothyroidism in different tissues. They state “…tissue hypothyroidism at the peripheral target organs must be different in the individual patient.” The authors summarize their findings by stating that they agree with the statement in an endocrinology text book stating, "The ultimate test of whether a patient is experiencing the effects of too much or to little thyroid hormone is not the measurement of hormone concentration in the blood but the effect of thyroid hormones on the peripheral tissues"
    The Journal of Clinical Endocrinology & Metabolism
    Basic and clinical endocrinology, 3rd ed. London: Appleton
  5. Low thyroid is associated with an increased risk of coronary artery disease, heart attack, heart enlargement, stroke, infections, and cancer.
    Numerous studies

  6. In a study published in the Journal of Clinical Endocrinology and Metabolism, it was shown that T4 preparations such a Levoxyl and Synthroid resulted in very minimal increase in metabolism while supplementation with T3 was shown to increase metabolism by an average of 18%. For a person consuming a 2000 calorie diet, 18% is equivalent to burning an extra 360 calories per day. Thus giving T3 would equate to approximately a 40 pound weight loss in a year. This is equivalent to approximately jogging on a treadmill for 1 hour per day. If we would simply optimize everyone’s thyroid, we would no longer have the obesity crises in this country. This could easily be remedied and drastically cut he incidence of diabetes, heart disease, hypertension, stroke and cancer. Thyroid should never be given as a weight loss medication but appropriate replacement with the proper preparations often elevates a number of symptoms, often including continued weight gain.
    The Journal of Clinical Endocrinology & Metabolism
  7. Reverse T3 blocks T3 action and lowers metabolism
    Research Experimental Medicine
  8. Thyroid hormones improve blood flow to heart and prevent heart attacks
  9. There is an increased risk of arrhythmias if your T3 levels are low and/or your reverse T3 levels are high. This is opposite of what most doctors think.
    Journal of Cardiology
  10. Flame retardants are building up in people's bodies and blocking the thyroid effect resulting in a diminished thyroid effect despite having normal thyroid levels.
    Toxilogical Sciences
  11. Organochlorine compounds (pesticides) are well known to alter the thyroid hormone system by decreasing serum thyroid hormone levels in several species including humans.
    Environmental Health Perspectives
  12. The higher the level of polychlorinated biphenyls (PCB’s) in children the lower the thyroid and the higher the level of cadmium in children the lower the thyroid levels (not picked up on standard blood test)
    Environmental Health Perspectives
  13. “In an ambitious review of the literature from laboratory experiments, wildlife observations and human epidemiology, Françoise Brucker-Davis concludes that wildlife data clearly demonstrate thyroid disruption by synthetic chemicals.”
  14. “Synthetic chemicals are released into the environment by design (pesticides) or as a result of industrial activity. It is well known that natural environmental chemicals can cause goiter or thyroid imbalance. However, the effects of synthetic chemicals on thyroid function have received little attention.”