New Studies Refute old T3 objections

  1. Post New Studies Refute old T3 objections

    New Studies Refute an
    Old Objection to T3 Therapy

    Dr. John C. Lowe
    August 17, 2005

    In 2002, a Portuguese molecular biologist, Dr. Joana Palha, reported study findings that, although not intended to, show that an argument for using T4 alone is false. The findings should change the beliefs and clinical practice of many doctors, enabling more hypothyroid patients to get effective treatment.

    Since the 1950s, some thyroid researchers believed there was only one way thyroid hormone got from the blood into the brain: by binding to a protein called "transthyretin" (trans’-th§-r‘’-tin). Transthyretin is one of three proteins that bind and transport thyroid hormone. The main protein is "thyroxine-binding globulin" and the other is "albumin."

    Cell membranes have sites that strongly bind transthyretin. The binding sites are probably transthyretin receptors that are instrumental in delivering thyroid hormone into cells.[4]

    The transthyretin that transports thyroid hormone in the blood is manufactured by the liver. Transthyretin that transports thyroid hormone from the blood into the brain is produced in a brain structure called the "choroid plexus." The choroid plexus is a complex outgrowth of blood vessels. It’s situated just above the brain stem and below the brain’s fluid containing cavities called "ventricles." The plexus produces and secretes the fluid, called "cerebrospinal fluid," that the brain and spinal cord float in.

    Thyroid hormone travels to the choroid plexus through the blood. When the hormone encounters the transthyretin the plexus has produced, the hormone binds to it. Then the protein transports the hormone into the brain.

    T3-Binding to Transthyretin. In the 1950s, limited information led some researchers to conclude that transthyretin only transports T4 into the brain. Based on this conclusion, they believed that brain cells get their T3 only by converting T4 to T3. Some doctors adopted these two beliefs. And based on the beliefs, they wouldn’t let their patients use T3 alone. These false beliefs probably contributed to conventional doctors’ rigid use of T4-replacement (patients’ use of T4 alone with their dosages adjusted by their TSH levels). All of this happened despite studies in the 1950s and early 1960 that showed T3 alone was highly effective for patients who failed to benefit from T4 alone or T4/T3 therapy.

    Let me illustrate the types of problems that resulted from doctors holding these false beliefs. I used to co-treat patients with a neuropsychiatrist in Houston, Texas. More than once, he expressed frustration at an experience he occasionally had. After he prescribed T3 for depressed and cognitively-impaired hypothyroid patients, endocrinologists would switch them to T4-replacement. The endocrinologists would argue that without taking T4, the patients’ brain cells wouldn’t have enough T3. But soon after being switched to T4, their depression and cognitive dysfunction returned. So, when the patients went back to the neuropsychiatist to complain, he switched them back to T3. Quickly, their depression and cognitive dysfunction cleared up again.

    At that time, it appeared to the neuropsychiatrist and me that transthyretin must transport T3 as well as T4 into the brain. We assumed this because we trusted that the researchers were right about thyroid hormone getting into the brain only by piggybacking on transthyretin.

    Dr. Pilha, author of the Portuguese studies I cite here, appears to agree with the researchers and doctors who believe that transthyretin delivers only T4 into the brain. She recently wrote that transthyretin "binds virtually no T3."[3,p.1293] She then went further, stating that transthyretin "is not a T3 carrier."[3,p.1296]

    But other researchers contend that transthyretin binds and transports both T4 and T3.[1][2] Some of these investigators have measured how readily T4, T3, and T2 bind to transthyretin. By far, T4 binds most strongly to the protein. T3 binds to it but with 10-times lower affinity than T4. T2 also binds to transthyretin, although with 100-times less affinity than T4.[6] (An enzyme converts T3 to T2 when it removes one of T3's three iodine atoms.)

    The conclusion that T3 binds to transthyretin is consistent with findings of other studies. Researchers have documented that T3 passes the blood-brain barrier and enters the brain.[9][10][11]

    One study showed that how readily T3 enters the brain depends on the shape of its molecule. The molecule comes in two shapes, right and left. We call the right-handed molecule dextro-T3 or DT3, and the left-handed molecule levo-T3 or LT3. LT3 enters the brain about three times more readily than DT3.[7]

    The T3 in products such as Cytomel and Cynomel is LT3.[8] Even in the absence of transthyretin, LT3 (along with less DT3) still readily passes the blood-brain barrier and enters the brain.

    New Studies. Some doctors, as I wrote above, long denied patients the use of T3 alone because they thought that transthyretin only carries T4 into the brain. But whether the protein carries only T4 or both T4 and T3 into the brain has become an irrelevant question in view of the new studies cited by Dr. Pilha.

    The researchers who conducted the studies found that transthyretin isn’t essential for T4 or T3 to get into the brain, at least not in mice. Nor is transthyretin necessary for a normal T3 concentration in brain cells. Dr. Pilha wrote that this is now shown "conclusively" by studies of mice whose cells produce no transthyretin at all.[3,p.1292] Despite the mice having no transthyretin, they have normal amounts of T3 in their brain cells.[3][12][13]

    Proteins that transport thyroid hormone through the blood also aren’t essential for T4 and T3 to enter tissues other than the brain. Nor are the proteins necessary to having a normal concentration of thyroid hormone in the cells. For example, humans who have no "thyroxine-binding globulin" (the major transport protein in humans) still have normal thyroid hormone regulation. The same is true of rats that have no albumin, which is their major thyroid hormone binding protein.

    Some researchers used to disagree with the "free hormone hypothesis," which states that it’s the free thyroid hormone in the blood that’s important to normal biological function. These new findings, however, show that the free hormone hypothesis is correct.[3]

    Conclusion. In a critique I wrote in 2004,[5] I documented some disturbing findings about T4-replacement: in five studies, it left hypothyroid patients suffering from hypothyroid symptoms.[14][15][16][17][18] And in one study, patients on T4-replacement used more drugs and had an increased incidence of potentially fatal diseases.[18]

    Our long line of research shows that some patients with too little thyroid hormone regulation don’t benefit at all from T4-replacement or from T4/T3 combination therapy. Virtually all these patients, however, improve or recover with high enough doses of T3 alone.

    On such patients’ behalf, we need to get word of these studies out to their doctors. I hope that doctors who’ve falsely believed that the brain gets T3 solely from T4 will consider the treatment implications of the study results. If so, perhaps they’ll then allow their patients who respond poorly to T4-replacement or T4/T3 therapy to switch to T3 alone, the only approach likely to work for them.


    1. Robbins, J. and Rall, J.E.: The iodine containing hormones. In Hormones in Blood, Vol. 1, 3rd edtion, edited by C.H. Gray and V.H.T. James, London, Academic Press, 1979, p. 576.

    2. Robbins, J.: Thyroid hormone transport proteins and the physiology of hormone binding. In Werner and Ingbar’s The Thyroid: A Fundamental and Clinical Text, 6th edition. Edited by L.E. Braverman and R.D. Utiger, New York, J.B. Lippincott Co., 1991, pp.111-125.

    3. Palha, J.A.: Transthyretin as a thyroid hormone carrier: function revisited. Clin.. Chem. Lab. Med., 40(12):1292-1300, 2002.

    4. Schussler, G.C.: The thyroxine-binding proteins. Thyroid, 10(2):141-149, 2000.

    5. Lowe, J.C.:

    6. Wojtczak, A., Luft, J., and Cody, V.: Mechanism of molecular recognition. Structural aspects of 3,3'-diiodo-L-thyronine binding to human serum transthyretin. J. Biol. Chem., 267(1):353-357, 1992.

    7. Terasaki, T. and Pardridge, W.M.: Stereospecificity of triiodothyronine transport into brain, liver, and salivary gland: role of carrier- and plasma protein-mediated transport. Endocrinology, 121(3):1185-1191, 1987.


    9. Mooradian, A.D.: Blood-brain transport of triiodothyronine is reduced in aged rats. Mech. Ageing Dev., 52(2-3):141-147, 1990.

    10. Cheng, L.Y., Outterbridge, L.V., Covatta, N.D., et al.: Film autoradiography identifies unique features of [125I]3,3'5'-(reverse) triiodothyronine transport from blood to brain. J. Neurophysiol., 72(1):380-391, 1994.

    11. Rudas, P. and Bartha, T.: Thyroxine and triiodothyronine uptake by the brain of chickens. Acta Vet. Hung, 41(3-4):395-408, 1993.

    12. Palha, J.A., Fernandes, R., Morreale de Escobar, et al.: Transthyretin regulates thyoid hormone levels in the choroid plexus, but not in the brain parenchyma: study in a transthyretin-null mouse model. Endocrinology, 141:3267-3272, 2000.

    13. Palha, J.A., Nissanov, J., Fernandes, R., et al.: Thyroid hormone distribution in the mouse brain: the role of transthyretin. Neuroscience, 113:837-847, 2002.

    14. Walsh, J.P., Shiels, L., Mun Lim, E.E., et al.: Combined thyroxine/liothyronine treatment does not improve well-being, quality of life, or cognitive function compared to thyroxine alone: a randomized controlled trial in patients with primary hypothyroidism. J. Clin. Endocrinol. Metab., 88(10):4543-4550, 2003.

    15. Sawka, A.M., Gerstein, H.C., Marriott, M.J., et al.: Does a combination regimen of thyroxine (T4) and 3,5,3'-triiodothyronine improve depressive symptoms better than T4 alone in patients with hypothyroidism? Results of a double-blind, randomized, controlled trial. J. Clin. Endocrinol. Metab., 88(10):4551-4555, 2003.

    16. Clyde, P.W., Harari, A.E., Getka, E.J., and Shakir, K.M.M.: Combined levothyroxine plus liothyronine compared with levothyroxine alone in primary hypothyroidism: a randomized controlled trial. J.A.M.A., 290:2952-2958, 2003.

    17. Cassio, A., Cacciari, E., Cicgnani, A., et al.: Treatment of congenital hypothyroidism: thyroxine alone or thyroxine plus triiodothyronine? Pediatrics, 111(5):1055-1060, 2003.

    18. Saravanan, P., Chau, W.F., Roberts, N., et al.: Psychological well-being in patients on ‘adequate’ doses of L-thyroxine: results of a large, controlled community-based questionnaire study. Clin. Endocrinol. (Oxf.), 57(5):577-585, 2002.

  2. I'll add this:

    Research Shows Combo Therapy Associated with Weight Loss
    It's common knowledge among patients, and some medical professionals, that a substantial number of patients with hypothyroidism will continue to have various complaints and symptoms, despite treatment with levothyroxine that maintains so-called "normal" TSH levels. One study in 2002 found that, (Saravanan et. al. Psychological well-being in patients on ‘adequate’ doses of l-thyroxine: Clin Endocrinol (Oxf) 57:577–585), compared with controls, more than 13% was not satisfied with their health condition, reflecting dissatisfaction with their treatment. The primary complaints were fatigue, weight gain, body aches/pains, and clumsiness.

    According to the Bente C. Appelhof, MD, from the University of Amsterdam in the Netherlands, and colleagues: "Controversy remains about the value of combined treatment with LT4 and LT3, compared with LT4 alone, in primary hypothyroidism.

    It is a well-known clinical notion that a fair proportion of patients with hypothyroidism remains with health complaints, despite substitution therapy with levothyroxine and normalization of serum TSH [thyroid-stimulating hormone] values."

    Other animal studies have shown that replacement therapy with levothyroxine (LT4) alone does not ensure euthyroidism -- normal thyroid levels -- in all tissues. Instead, euthyroidism could only be achieved by a combinated treatment of LT4 and liothyronine (LT3). Various studies have focused on this issue, looking at whether LT4 therapy might not be enough to restore euthyroidism in human tissues as well. While patients consistently report a preference for the combined studies, researchers have not been able to isolate specific improvement factor that are clinically measurable.

    Now, researchers have identified at least one factor that appears to be related to combination therapy -- weight loss.

    Research published in the May 2005 issue of the Journal of Clinical Endocrinology and Metabolism reported on a recent study that found that patients preferred thyroid treatment that included a combination of levothyroxine (T4) and T3, rather than the usual levothyroxine (T4 only) treatment, and that combination treatment was associated with weight loss. This clinical trial is the largest to date, and the first since the Bunevicius study published in the New England Journal of Medicine in 1999 that confirms a beneficial effect of combination T4/T3 therapy for hypothyroidism.

    The double-blind, randomized, controlled clinical trial looked at 141 patients with primary autoimmune hypothyroidism, who were broken into groups who were treated with T4/T3 in a ratio of 5:1, 10:1, as well as a group that continued with their previous T4-only treatment. After 15 weeks, the study showed a clear preference on the part of the patients for the combination treatments, and in particular, the 5:1 treatment featuring a higher level of T3, versus the T4-only treatment.

    Some particular findings of interest:

    * A decrease in body weight -- but not a decrease in serum TSH -- was correlated with increased satisfaction with study medication.
    * In both combination groups, there was a decrease in weight, most pronounced in the 5:1 ratio group, who had a mean decrease of 1.7 kg, or 3.75 pounds. Theh 10:1 group had a mean weight loss of 1 pound. The T4-only group had no change in weight.
    * Of the patients who preferred combined therapy, 44% had serum TSH less than 0.11.
    * Measurable changes in mood, fatigue, well-being, and neurocognitive functions could not be identified to explain the patient preference for the combination treatment.

    One key flaw in the study was that some patients receiving combination treatment were receiving suppressive doses, which is considered overtreatment. They had TSH levels below the normal range, and would therefore be considered hyperthyroid.

    "Patients preferred combined LT4/LT3 therapy to usual LT4 therapy, but changes in mood, fatigue, well-being, and neurocognitive functions could not satisfactorily explain why the primary outcome was in favor of LT4/LT3 combination therapy," the authors write. "Decrease in body weight was associated with satisfaction with study medication."

    While the study authors could not find any measurable reason to recommend the combination therapy, they did conclude: "Nevertheless, the outcome of this study does not preclude the possibility that a certain subgroup of patients may benefit from combined LT4/LT3 therapy."

    Source: Appelhof BC, et. al. "Combined therapy with levothyroxine and liothyronine in two ratios, compared with levothyroxine monotherapy in primary hypothyroidism: a double-blind, randomized, controlled clinical trial." J Clin Endocrinol Metab. 2005 May;90(5):2666-74.
    Updated: May 20, 2005

    I need Dr D to help us weed through some of this!!! Is it T4, T3, or T4/T3???

  3. For Dr D:

    I've had good results with the T4 alone. My wife has not has as good of results. I be interested in trying the combo with her.

    The article says a ration of 5:1 of T4:T3 is best. If she's on 100mcg of T4, does that mean 20mcg of T3 or should the doses of both be knocked down due to the combining of two thyroid meds?? Maybe start her off at 50mcg T4 and 10 mcg T3 and go from there??

    Thanks Dr!!

  4. Quote Originally Posted by CRUNCH
    For Dr D:

    I've had good results with the T4 alone. My wife has not has as good of results. I be interested in trying the combo with her.

    The article says a ration of 5:1 of T4:T3 is best. If she's on 100mcg of T4, does that mean 20mcg of T3 or should the doses of both be knocked down due to the combining of two thyroid meds?? Maybe start her off at 50mcg T4 and 10 mcg T3 and go from there??

    Thanks Dr!!
    I basically agree with the conclusion in the article, but if I was only going to take one, it would be T4 solo. A 4:1 or 5:1 ratio combo is probably best though and I would not correct your wife's dose for potency if she is already not responding. I'd just give her the additional 20-25mcg of T3 on top of her T4. If the T4 dose is high enough, the T3 is not required, unless one is an idiopathic non-responder to T4, as some appear to be. Keep me posted CRUNCH and let me know how she's doing!

  5. Another question:

    Does she take the T3 at the same time as the T4, in the morning, one hour before eating??

    Thanks Dr D!!

  6. Quote Originally Posted by CRUNCH
    Another question:

    Does she take the T3 at the same time as the T4, in the morning, one hour before eating??

    Thanks Dr D!!
    Yes, take them together at the same time everyday. You get the best bioavailability and synergy that way after fasting all night. There can be no proteins in your stomach at all when you take it, or they will inhibit assimilation to some degree. Take with at least 4oz of water. Then you can eat 45min later with the liquid preps of 60min later if you're using pills.

  7. You're the man Dr D! I'll keep you updated.
  8. Tbg

    Has your wife been tested for thyroxine binding globulin? A lot of people (especially women for some reason) can show a high level of t3 count and have an unchanged, lower value of free t3 which is believed to be the only t3 that is biologically active.

    Some men who don't see benefits from testosterone therapy will have tests that yield normal or high blood levels of testosterone, but the testosterone is rendered inactive by sex-hormone-binding-globulin.

    There's a lot of false interpretations of thyroid conditions if not enough tests are taken. My mother is being treated for Wilson's RT3 syndrome, but before I recommended that she go back to the endocrinologist and have further tests taken, they just assumed she had chronic fatigue syndrome.


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