Click here for Frequently Asked Questions on Optimal Thyroid Replacement.
The majority of patients with hypothyroidism are treated with thyroxine, also known as T4 (Trade names include Synthroid, Eltroxin, Levoxyl etc). Theoretically, pharmacological management of hypothyroidism would mimic what our own thyroid does, which is to produce both T4 and T3. It is important to remember that the majority of thyroid hormone produced and secreted by the thyroid (about 90%) is T4. Very little of the more biologically potent T3 is derived from our thyroid gland. However, our body generates its own T3 from T4 by removing a single iodine molecule, using an enzyme called a deiodinase. This process happens naturally in many of our tissues, hence much of our thyroid-derived T4 is actually converted, in a regulated manner as needed, to T3. Similarly, patients taking thyroxine (T4) supplementation in the form of a tablet or pill will actually convert, in a regulated manner, considerable amounts of administered T4 to T3, as needed constantly throughout the day.
Numerous studies have examined the merits of replacing both T3 and T4 versus T4 alone. Some of these studies have been done in normal subjects, other studies have been carried out in patients with psychiatric illnesses, often depression. A common finding in some, nut not all of these studies is that patients taking some form of T3 supplement feel better, in some subjective or objective measurements of mood or cognitive function, than those taking T4 alone. For example, see the 1999 study in the New England Journal of Medicine, and the accompanying Editorial that reviews the merits of using one hormone or two for the treatment of hypothyroidism. For an overview, see Paradigm shifts in thyroid hormone replacement therapies for hypothyroidism Paradigm shifts in thyroid hormone replacement therapies for hypothyroidism
Hoang and colleagues compared the administration of once daily desiccated thyroid extract (DTE) vs. levothyroxine (T4) in a randomized couble blind cross over design in 70 patients, age 18-65, with stable hypothyroidism. 68/70 patients were taking T4 at the start of the study. Each grain (65 mg) of Armour thyroid provided 38 ug L-T4 and 9 ug liothyronine (T3), with starting doses calculated on the basis that 1 mg DTE = 1.667 microgams L-T4. All patients had a stable TSH level prior to the start of the study and received a battery of psychological, memory, and quality of life testing prior to and at the end of each study period. Overall, the patients showed no significant difference in symptoms scores, general health questionnaires, or neuropsychological testing. However, there was a trend toward improvement in GHQ-12, TSQ, and auditory memory index during treatment with DTE. DTE therapy was also associated with modest weight loss (2.86 lb) but no change in heart rate or blood pressure. At the end of the study, 34 patients (49%) preferred DTE, 13 (19%) preferred L-T4, and 23 (33%) had no preference. These findings were not related to greater TSH suppression, as TSH was actuall slightly higher in the DTE group. Desiccated Thyroid Extract Compared With Levothyroxine in the Treatment of Hypothyroidism: A Randomized, Double-Blind, Crossover Study J Clin Endocrinol Metab. 2013 Mar 28
Celi and colleagues administered L-T4 (thyroxine) vs L-T3 (to fourteen hypothyroid patients, 7 allocated to each group, mean age 49 year old, 13 women/1 man) three times daily for 6 weeks. All study subjects achieved the same level of TSH, however subjects receiving T3 (mean dose of 0.57 ug/kg/day) experienced more weight loss (2 kg) and a greater reduction in plasma cholesterol. No difference in quality of life measurements or cardiovascular parameters was noted, although diastolic blood pressure trended higher in subjects receiving T3. Metabolic effects of liothyronine therapy in hypothyroidism: a randomized, double-blind, crossover trial of liothyronine versus levothyroxine J Clin Endocrinol Metab. 2011 Nov;96(11):3466-74
Nevertheless, many of these studies are small, not well controlled, often non-randomized, and hence may not be valid and generally applicable to the majority of patients with hypothyroidism as is partly the case for the study described in Thyroid hormone replacement therapy in primary hypothyroidism: a randomized trial comparing L-thyroxine plus liothyronine with L-thyroxine alone. Ann Intern Med. 2005 Mar 15;142(6):412-24. Indeed, even in the NEJM article mentioned above, patients taking T3 had higher levels of some thyroid sensitive proteins such as sex hormone binding globulin, suggesting that the T3 group may have been very slightly hyperthyroid, despite normal levels of TSH. Most thyroid specialists and informed patients appreciate the need for more data and better studies of this issue, and several additional studies of T3 supplementation are underway. Furthermore, randomized clinical trials of subclinical hypothyroidism sometimes fail to detect any significant improvement in cognitive function following correction of the mild hypothyroidism A randomized controlled trial of the effect of thyroxine replacement on cognitive function in community-living elderly subjects with subclinical hypothyroidism: the Birmingham Elderly Thyroid study J Clin Endocrinol Metab. 2010 Aug;95(8):3623-32
Two additional randomized trials published in the October 2003 issue of the JCEM examined the potential merit of combining T3 and T4 therapy in patients with hypothyroidism. Although the study designs differed, overall there was little to no evidence that a combination of T3 added to thyroxine provided therapeutic benefit. See 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. 2003 Oct;88(10):4543-50 and Does a combination regimen of thyroxine (T-4)) and 3,5,3'-triiodothyronine improve depressive symptoms better than t(4) alone in patients with hypothyroidism? Results of a double-blind, randomized, controlled trial. J Clin Endocrinol Metab. 2003 Oct;88(10):4551-5.
Similarly, several additional randomized control trials of L-thyroxine alone vs. thyroxine plus T3 did not show any clinical benefit of T3 supplementation. One study assessed the impact of T3, (7.5 ug twice daily) as assessed by a quality of life questionnaire and battery of 13 neuropsychological tests administered before and after the trial, as outlined in Combined levothyroxine plus liothyronine compared with levothyroxine alone in primary hypothyroidism: a randomized controlled trial. JAMA. 2003 Dec 10;290(22):2952-8. The second study assessed the impact of substituting 50 ug of T4 (thyroxine) with 12.5 ug of T3, in a 6 week randomized cross over study design. There was no difference in any clinical endpoint assessed in the different treatment groups with or without T3, as described in Substitution of liothyronine at a 1:5 ratio for a portion of levothyroxine: effect on fatigue, symptoms of depression, and working memory versus treatment with levothyroxine alone. Endocr Pract. 2005 Jul- Aug; 11(4): 223-33
Furthermore, a randomized control trial of T4 alone vs. T4 plus T3 for 12 weeks again failed to show any significant improvements in mood or cognitive function, as outlined in Replacement therapy with levothyroxine plus triiodothyronine (bioavailable molar ratio 14 : 1) is not superior to thyroxine alone to improve well-being and cognitive performance in hypothyroidism. Clin Endocrinol (Oxf). 2004 Jun;60(6):750-7. Similar results, namely a lack of a beneficial effect of combing T3 with T4 were reported in Efficacy of combined levothyroxine and liothyronine as compared with levothyroxine monotherapy in primary hypothyroidism: a randomized controlled trial. Endocr Res. 2009;34(3):80-9.
There is correlative evidence in the psychiatric literature that depressed patients with lower levels of thyroid hormone may take longer to respond to anti-depressant medication. Slower Treatment Response in Bipolar Depression Predicted by Lower Pretreatment Thyroid Function. Am J Psychiatry. 2002 Jan 1;159(1):116-121. Nevertheless, whether intervening in these patients with thyroid hormone replacement would produce a meaningful significant improvement remains unclear. An overview of the changes in thyroid hormone levels that occur in depressed patients, and a summary of known studies of T3 and depression may be found in a review article in the journal Thyroid 1998 Oct;8(10):951-6 The thyroid axis and depression.
Some patients sensitive to and concerned about this issue who feel strongly about the need for exogenous T3 are taking thyroid extract, as available from companies such as Armour Pharmaceuticals, which contains a combination of both T4 and T3.
Some thyroid extract preparations may not always be as standardized, compared to simple thyroxine tablets, with respect to the relative amounts of T4 and T3 in each preparation. Furthermore, taking T3, ideally in physiologically normal amounts but sometimes inadvertently in excess is not always without risk. T3 is ~ 10 times more potent than T4, and can have very significant and rapid effects on heart rate and blood pressure. Whereas T3 is often well tolerated in younger patients taking the correct dose, older patients with known or suspected heart disease should be extremely cautious about taking significant amounts of T3. A single dose of T3 can significantly increase oxygen consumption by the heart, which can be highly problematic and potentially dangerous in patients with coronary artery disease. Accordingly, patients considering T3 as a form of thyroid hormone replacement need to discuss the potential risks and benefits of such therapy in detail with their physician. For an example of cardiac risk in patients with high levels of T3, see Excess triiodothyronine as a risk factor of coronary events Arch Intern Med 2000 Jul 10;160(13):1993-9.
Some patients with low body temperature and a wide constellation of non-specific symptoms that overlap with symptoms seen in hypothyroidism have been labeled with the diagnosis of Wilson's syndrome. Dr. E. D. Wilson named this putative "syndrome" after himself, and the alleged existence of this syndrome has caused much confusion amongst both patients and physicians alike. Although it is claimed that T3 is effective for many of the symptoms of "Wilson's syndrome" this has not been proven in randomized scientific studies. Most authorities who have reviewed the lack of scientific evidence surrounding the actual existence of Wilson's syndrome are dubious about the validity of diagnosis and it is not well accepted among experts in thyroidology. For the American Thyroid Association official position on this issue, see the ATA Statement on "Wilson's Syndrome". Simply treating normal individuals with thyroxine to make them feel better is unlikely to be beneficial. See Effects of supraphysiological doses of L-thyroxine on cognitive function in healthy individuals. Psychiatry Res. 2002 Jun 1;110(2):117-23.
The currently recommended form of treatment for hypothyroidism is T4, which usually results in normal levels of circulating thyroid hormones and TSH in the majority of patients. Treatment of hypothyroidism with excess T3 has potential risks and theoretical benefits, and further study of this issue in well designed controlled randomized clinical trials is required. It is unlikely that taking small amounts of T3 is harmful, if the patient is carefully monitored. Both physicians and patients should keep an open mind about the need for additional scientific data that will address the possibility that combining both T3 and T4 therapy may be helpful in some patients.
I am taking T3 and feel fine, but my doctor says my thyroid function tests are completely abnormal. What is going on?
A Free T4 or total T4 is commonly measured to assess the adequacy of thyroid hormone replacement. In patients taking T3, the T4 is often extremely low, since the thyroid gland will often shut off production of T4 in this situation. Furthermore, depending on what time a blood test is done in relationship to ingestion of the T3 tablet, the T3 level may range from low to normal to high. This variability is due in part to the short half life of T3 in our circulation. In such patients, the TSH is generally the best single determinant of whether thyroid hormone replacement is adequate.
My TSH is 4.8 and apparently normal, but I still feel tired. Can I try a stronger dose of thyroid hormone?
The optimal dose of thyroid hormone and target TSH will vary from patient to patient and should be a matter of discussion between the physician and patient. Although most patients feel well when there TSH is in the normal range, others do not. It is important to remember that levels of thyroid hormone may be only one small contributing element to a given individuals health. In some instances, it may be worth determining whether a patient will feel better on a slightly higher dose of L-thyroxine to achieve a TSH in the low normal range. Conversely, some patients with a low normal TSH of 0.4-0.7 may actually feel mildly hyperthyroid and be more comfortable with a TSH in the high normal range. The treatment goals and clinical outcomes are best discussed, on an individual basis, with your physician or health care provider. Analysis of whether "fine tuning" of thyroid hormone doses to modulate the TSH within the normal range has not shown significant improvements in patient well being or quality of life Small changes in thyroxine dosage do not produce measurable changes in hypothyroid symptoms, well-being or quality of life: results of a double blind, randomized clinical trial. J Clin Endocrinol Metab. 2006 May 2; Nevertheless, there is little harm in trying to find a dose of thyroxine that boosts your level of T3 into the normal/high normal range to see if that results in clinical improvement. Some studies have suggested subtle metabolic derangements in patients treated with conventional replacement doses of L-thyroixine Effects of levothyroxine replacement or suppressive therapy on energy expenditure and body composition. Thyroid. 2015 Dec 23
I hear so much about thyroid extract and the use of T3. Why did my doctor not discuss these options with me?
The currently accepted "gold standard" treatment for hypothyroidism, in the opinion of the majority of thyroid specialists is L-thyroxine. The vast majority of patients do extremely well on thyroxine alone, which is safe, well tolerated, and inexpensive. Furthermore, our bodies generate T3 from the L-thyroxine we ingest, so L-thyroxine can be viewed as a form of a "prodrug", which slowly liberates T3 as needed in various tissues. Many physicians are skeptical that thyroid extract or T3 confers any advantage over L-thyroxine alone. Indeed, analysis of levels of thyroxine (T4) and Triiodothyronine (T3) in normal subjects or in hypothyroid patients without a thyroid gland but taking thyroxine showed no difference in the levels of circulating T3 in the two groups of patients Triiodothyronine levels in athyreotic individuals during levothyroxine therapy. JAMA. 2008 Feb 20;299(7):769-77
More importantly, the medical profession prefers to make decisions regarding treatment on the basis of large well-designed controlled randomized studies. At present, there is little scientific data from large human clinical trials that demonstrates the safety and benefits of using T3 or thyroid extract versus L-thyroxine. If such evidence were to become available, no doubt many more physicians would consider using additional forms of thyroid supplementation compared to just L-thyroxine alone.
I have been on thyroxine for 6 months, my TSH is low normal, and I still don't feel well. Why won't my doctor try me on T3?
Many physicians have been trained to use only thyroxine (T4) for the treatment of hypothyroidism, and are leery of "experimenting" with non-conventional approaches such as T3 supplementation. Furthermore, it is important to realize that not every source of fatigue or "feeling unwell" is attributable to suboptimal thyroid replacement. These types of issues need to be discussed on a case by case basis with your physician, and clearly many physicians will have different philosophies and styles of practice when it comes to considering T3 replacement.
My TSH test is never normal, yet my doctor is a bit vague as to whether I should take thyroid hormone?
In many patients, the TSH may be slightly low (mild hyperthyroidism) or slightly high (mild hypothyroidism), and the patient may or may not have symptoms attributable to the modest change in levels of thyroid hormones. In such cases, it is important to review the general health of each patient, the size of the thyroid gland, the presence or absence of heart disease, osteoporosis, and related medical problems, and the potential risks and benefits of "treating" the abnormal lab value and rendering the TSH normal. It is difficult, even in large scientific studies, to make a firm link between mild abnormalities in thyroid hormone levels, and clinically relevant symptoms as outlined in Summaries for patients. Mild thyroid dysfunction is not associated with anxiety, depression, or cognition in the elderly. Ann Intern Med. 2006 Oct 17;145(8):I52. Analysis of changes in TSH levels in individuals 65 and over with "subclinical hypothyroidism" have shown that TSH levels remain stable or in the same range in the majority of subjects for several years. A substantial proportion of individuals with mild TSH elevations 4.5–6.9, aw their TSH return to normal. Individuals with TSH levels of 10 or more more commonly progressed to development of clinically evident hypothyroidism with further increases in TSH The Natural History of Subclinical Hypothyroidism in the Elderly: The Cardiovascular Health Study J Clin Endocrinol Metab 2012 97: 1962-1969; doi:10.1210/jc.2011-3047
For an overview of the clinical approach to treating "subclinical" disturbances of thyroid hormones, see Subclinical thyroid disease: clinical applications. JAMA. 2004 Jan 14; 291(2): 239-43 and Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA. 2004 Jan 14; 291(2): 228-38. Review.
A similar review of the literature and guidelines to approach the management of patients with "subclinical' hypothyroidism was published by the European Thyroid Association 2013 ETA Guideline: Management of Subclinical Hypothyroidism Eur Thyroid J. 2013 Dec;2(4):215-28
I have subclinical hypothyroidism and I don't feel well. Should I take thyroid hormone?
The answer to this question depends on your general state of health, and will vary depending on the individual patient. Although patients with subclinical hypothyroidism may feel less healthy than control subjects in formal studies Health status in patients with sub-clinical hypothyroidism. Eur J Endocrinol. 2005 May;152(5):713-7, whether treatment with thyroid hormone will result in a clinical improvement cannot be predicted, although many studies associate adverse outcomes with slightly elevated levels of TSH, as outlined in Subclinical Hypothyroidism Is Associated With Increased Risk for All-Cause and Cardiovascular Mortality in Adults J Am Coll Cardiol. 2012 Jun 7. [Epub ahead of print]
Will taking thyroid hormone help me lose weight?
Weight gain can be seen following development of
clinical hypothyroidism. Furthermore, an increased body mass index is
associated with somewhat lower levels of thyroid hormone Small
differences in thyroid function may be important for Body Mass Index and
the occurrence of obesity in the population.
J Clin Endocrinol Metab. 2005 May 3; [Epub ahead of print]. Nevertheless, it is difficult to predict whether treatment with thyroid hormone will be associated with weight loss in individual patients
Is anything known about why some persons require higher doses of thyroid hormone than others?
Factors that influence requirements for thyroid hormone include body weight, hormonal status (menopause, pregnancy), and ingestion of iron, calcium and excess soy. Some individuals exhibit genetic differences in their metabolic conversion of T4 to T3, which can also produce subtle influences on thyroid hormone replacement requirements. See TYPE 2 DEIODINASE POLYMORPHISM (THR92ALA) PREDICTS L-THYROXINE DOSE TO ACHIEVE TARGET TSH LEVELS IN THYROIDECTOMIZED PATIENTS J Clin Endocrinol Metab. 2007 Dec 11; Similarly, patients with autoimmune gastritis appear to require higher doses of thyroxine replacement therapy L-THYROXINE (L-T4) REQUIREMENT IN PATIENTS WITH AUTOIMMUNE HYPOTHYROIDISM AND PARIETAL CELL ANTIBODIES J Clin Endocrinol Metab. 2007 Nov 27;
Observational studies suggest that some patients with lactose intolerance may also require higher doses of thyroxine to achieve target levels of TSH SYSTEMATIC APPRAISAL OF LACTOSE INTOLERANCE AS CAUSE OF INCREASED NEED FOR ORAL THYROXINE J Clin Endocrinol Metab. 2014 May 5:jc20141217.
I had thyroid surgery and I am now taking thyroxine-will this be sufficient produce normal levels of both T4 and T3?
This specific question was examined in a small prospective study of 50 patients with measured levels of thyroid hormones before and after thyroid surgery. No difference in the relative levels of T4 or T3 was found in patients taking thyroxine after surgery compared to levels detected in the same patients prior to surgery and thyroxine therapy. Triiodothyronine levels in athyreotic individuals during levothyroxine therapy JAMA. 2008 Feb 20;299(7):769-77.
My TSH is mildly elevated and I feel fine-will taking thyroid hormone help my brain work better?
There is little information to answer this question from scientific studies. An association study examining cognitive function using a battery of standardized tests did not reveal a significant association between level of TSH and cognitive function-See Mildly elevated TSH and cognition in middle-aged and older adults Thyroid. 2009 Feb;19(2):111-7. Indeed, a randomized controlled clinical trial of thyroxine replacement in older subjects (65 years old and up) to normalize TSH levels over a 12 month period demonstrated no significant improvement in formal tests evaluating cognitive function A Randomized Controlled Trial of the Effect of Thyroxine Replacement on Cognitive Function in Community-Living Elderly Subjects with Subclinical Hypothyroidism: The Birmingham Elderly Thyroid Study J Clin Endocrinol Metab. 2010 May 25. [Epub ahead of print]
How should I take my thyroid hormone?
Thyroxine therapy is usually initiated in a small dose, perhaps 25-50 ug once daily, and a repeat set of blood tests, commonly a TSH, is repeated after ~ 4 weeks to ascertain if the prescribed dose is correct. In young healthy patients without other co-existing illnesses, thyroxine treatment may be initiated at higher doses, with the ultimate expected replacement dose being ~1.6 ug/kg/day (1 kg = 2.2 lbs). It is important to remember that thyroxine (T4) is converted to T3, a more active short-acting form of thyroid hormone, in our bodies by an enzyme known as a deiodinase. Hence prescribing T4 allows the body to convert T4 to T3 as needed in a physiologically regulated manner. Whether prescribing both T4 and T3 confers added benefits over prescribing T4 alone is the subject of ongoing controversy and requires careful study in well designed randomized clinical trials. Thyroxine ingested in the fasted state mayl produce slightly higher levels of circulating thyroid hormone and a lower TSH compared to thyroxine ingested before meals or at bed time as outlined in Timing of Levothyroxine Administration Affects Serum Thyrotropin Concentration. J Clin Endocrinol Metab. 2009 Jul 7. [Epub ahead of print]. In contrast, morning vs. evening ingestion of thyroid hormone was examined in 105 patients with hypothyroidism, who served as their own controls in a cross-over study. In this study, TSH levels were slightly lower, and thyroid hormone levels slightly higher, when thyroxine was ingested at bed time. Effects of evening vs morning levothyroxine intake: a randomized double-blind crossover trial Arch Intern Med. 2010 Dec 13;170(22): 1996-2003. Conflicting results were obtained in a separate study of 152 hypothyroid patients randomized to take thyroxine either in the morning or evening. There was no difference in thyroid hormone profiles or quality of life in the two groups. Can Levothyroxine Be Taken as Evening Dose? Comparative Evaluation of Morning versus Evening Dose of Levothyroxine in Treatment of Hypothyroidism J Thyroid Res. 2011;2011:505239. Hence, the available conflicting data suggest that it is not critical to take thyroxine at a specific time, as long as thyroid hormone levels are monitored and adjusted according to the specific goals established for each patient.