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Research Articles and Papers on:

T3 / T4 Combination Therapy



Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine

J Clin Invest. doi:10.1172/JCI77588.
Published January 2, 2015
Copyright © 2015, The American Society for Clinical Investigation.

Joao Pedro Werneck de Castro1,2, Tatiana L. Fonseca1,2, Cintia B. Ueta1, Elizabeth A. McAninch1,2, Sherine Abdalla1, Gabor Wittmann3, Ronald M. Lechan3, Balazs Gereben4 and Antonio C. Bianco1,2

The current treatment for patients with hypothyroidism is levothyroxine (L-T4) along with normalization of serum thyroid-stimulating hormone (TSH). However, normalization of serum TSH with L-T4 monotherapy results in relatively low serum 3,5,3′-triiodothyronine (T3) and high serum thyroxine/T3 (T4/T3) ratio. In the hypothalamus-pituitary dyad as well as the rest of the brain, the majority of T3 present is generated locally by T4 deiodination via the type 2 deiodinase (D2); this pathway is self-limited by ubiquitination of D2 by the ubiquitin ligase WSB-1. Here, we determined that tissue-specific differences in D2 ubiquitination account for the high T4/T3 serum ratio in adult thyroidectomized (Tx) rats chronically implanted with subcutaneous L-T4 pellets. While L-T4 administration decreased whole-body D2-dependent T4 conversion to T3, D2 activity in the hypothalamus was only minimally affected by L-T4. In vivo studies in mice harboring an astrocyte-specific Wsb1 deletion as well as in vitro analysis of D2 ubiquitination driven by different tissue extracts indicated that D2 ubiquitination in the hypothalamus is relatively less. As a result, in contrast to other D2-expressing tissues, the hypothalamus is wired to have increased sensitivity to T4. These studies reveal that tissue-specific differences in D2 ubiquitination are an inherent property of the TRH/TSH feedback mechanism and indicate that only constant delivery of L-T4 and L-T3 fully normalizes T3-dependent metabolic markers and gene expression profiles in Tx rats.

The full paper is available here:


Conversion to Armour Thyroid from Levothyroxine Improved Patient Satisfaction in the Treatment of Hypothyroidism

Journal of Endocrinology, Diabetes & Obesity Volume 2, Issue 3
July-September 2014

Gary M. Pepper* and Paul Y. Casanova-Romero

Abstract: The use of Armour Thyroid (desiccated thyroid) in the treatment of hypothyroidism has generated debate among endocrinologists although there is evidence that a significant percentage of patients prefer this medication to T4-only replacement strategies. In this retrospective analysis we investigate the preference for replacement therapy of patients with persistent subjective symptoms of hypothyroidism on T4-only treatment who subsequently switched to Armour Thyroid (AT).

Methods: 450 consecutive patients being treated for hypothyroidism were screened. Of these, 154 had been switched from either generic or brand T4 replacement to AT for treatment of persistent symptoms of hypothyroidism. Patients undergoing treatment for thyroid cancer or on suppression therapy for nodular thyroid disease were excluded. Patients were instructed to have their blood sampled for thyroid function testing in the morning after taking their medication. After a minimum of 4 weeks on medication patients were asked to compare AT treatment versus T4-only treatment using a 5 point satisfaction rating scale. Results are reported as mean ± SD.

Results: On a 5 point Satisfaction Rating Scale with "5" indicative of the highest level of satisfaction, 117 (78.0%) patients gave a score of greater than "3" in preference for AT. Three patients treated with AT and one treated with LT4 reported adverse events, all minor. TSH was 1.30 ± 1.9 mIU/L and T3 1.81 ± 0.78 pmol/L on L-T4 monotherapy while TSH was 1.27 ± 2.2 mIU/L and T3 2.31 ± 1.33 pmol/L on AT (NS for TSH and p<0.003 for T3 ). T4 to T3 ratio on L-T4 monotherapy was 8.45 ± 3.7 while it was 4.70 ± 2.0 (p<0.001) on AT. There was no significant change in weight after switching to AT.

Conclusion: AT treatment was preferred over LT4 replacement therapy by 78% of patients with hypothyroidism in the sub-group with persistent subjective complaints while on T4-only therapy. No serious adverse events were noted while on AT treatment including 30 subjects aged 65 yrs or older. AT could be a reasonable alternative choice for treating this sub-group of patients with hypothyroidism.

The full article is available here:


The pharmacodynamic equivalence of levothyroxine and liothyronine. A randomized, double blind, cross-over study in thyroidectomized patients

Clin Endocrinol (Oxf). 2010 May ;

Francesco S. Celi1, Marina Zemskova2, Joyce D. Linderman1, Nabeel I. Babar1, Monica C.
Skarulis1, Gyorgy Csako3, Robert Wesley4, Rene Costello3, Scott R. Penzak5, and Frank


Context—The substitution of liothyronine (L-T3) for levothyroxine (L-T4) is commonly employed during thyroid hormone (TH) withdrawal in preparation for diagnostic and therapeutic interventions on thyroid cancer patients. Presently, only limited data are available on the L-T3 for L-T4 therapeutic substitution.

Objective—To characterize the pharmcodynamic equivalence of L-T3 and L-T4
Design—Randomized, double-blind, cross-over intervention study.
Setting—NIH Clinical Center.
Patients—10 thyroidectomized patients.

Interventions—Study participants were treated with L-T3 or L-T4 with a target TSH ≥0.5≤1.5 mU/l for at least 30 days before undergoing inpatient testing. Following testing, subjects crossed- over according to the same scheme.

Main outcome measures—Area under the serum concentration-time curve of TSH from 0 to 60 minutes (AUC 0-60) and peak TSH serum concentration (Cmax) following thyrotropin-releasing hormone (TRH) stimulation test, total L-T4 and L-T3 dose (mcg/kg), and L-T4/L-T3 ratio.

Results—No difference was observed for time 0 TSH values between L-T3 and L-T4 replacement phases (1.48± 0.77 vs. 1.21± 0.62 mU/l, p=0.293) at average daily doses of 40.3±11.3 mcg LT-3 and 115.2±38.5 mcg LT-4, L-T3: L-T4 ratio 0.36±0.06. TRH stimulation test resulted in similar L-T3 vs.L-T4 TSH responses with AUC 0-60 of 326.1 (95% CI 232.6-457.1) and 247.1 (95% CI 153.8-397.1) mU*min /l (p=0.285); and Cmax of 6.83 (95% CI 4.88-9.55) and 5.23 (95% CI 3.31-8.3) mU/l (p=0.383).

The full paper is available here:



Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomized rat.

Endocrinology. 1996 Jun;137(6):2490-502.

Escobar-Morreale HF1, del Rey FE, Obregón MJ, de Escobar GM.
Author information

We have recently shown that it is not possible to restore euthyroidism completely in all tissues of thyroidectomized rats infused with T4 alone. The present study was undertaken to determine whether this is achieved when T3 is added to the continuous sc infusion of T4. Thyroidectomized rats were infused with placebo or T4 (0.80 and 0.90 microgram/100 g BW.day), alone or in combination with T3 (0.10, 0.15, or 0.20 microgram/100 g BW.day). Placebo-infused intact rats served as euthyroid controls. Plasma and 12 tissues were obtained after 12 days of infusion. Plasma TSH and plasma and tissue T4 and T3 were determined by RIA. Iodothyronine deiodinase activities were assayed using cerebral cortex, pituitary, brown adipose tissue, liver, and lung. Circulating and tissue T4 levels were normal in all the groups infused with thyroid hormones. On the contrary, T3 in plasma and most tissues and plasma TSH only reached normal levels when T3 was added to the T4 infusion. The combination of 0.9 microgram T4 and 0.15 microgram T3/100 g BW.day resulted in normal T4 and T3 concentrations in plasma and all tissues as well as normal circulating TSH and normal or near-normal 5'-deiodinase activities. Combined replacement therapy with T4 and T3 (in proportions similar to those secreted by the normal rat thyroid) completely restored euthyroidism in thyroidectomized rats at much lower doses of T4 than those needed to normalize T3 in most tissues when T4 alone was used. If pertinent to man, these results might well justify a change in the current therapy for hypothyroidism.



Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats.

H F Escobar-Morreale, M J Obregón, F Escobar del Rey, and G Morreale de Escobar

J Clin Invest. Dec 1995; 96(6): 2828–2838.


We have studied whether, or not, tissue-specific regulatory mechanisms provide normal 3,5,3'-triiodothyronine (T3) concentrations simultaneously in all tissues of a hypothyroid animal receiving thyroxine (T4), an assumption implicit in the replacement therapy of hypothyroid patients with T4 alone. Thyroidectomized rats were infused with placebo or 1 of 10 T4 doses (0.2-8.0 micrograms per 100 grams of body weight per day). Placebo-infused intact rats served as controls. Plasma and 10 tissues were obtained after 12-13 d of infusion. Plasma thyrotropin and plasma and tissue T4 and T3 were determined by RIA. Iodothyronine-deiodinase activities were assayed using cerebral cortex, liver, and lung. No single dose of T4 was able to restore normal plasma thyrotropin, T4 and T3, as well as T4 and T3 in all tissues, or at least to restore T3 simultaneously in plasma and all tissues. Moreover, in most tissues, the dose of T4 needed to ensure normal T3 levels resulted in supraphysiological T4 concentrations. Notable exceptions were the cortex, brown adipose tissue, and cerebellum, which maintained T3 homeostasis over a wide range of plasma T4 and T3 levels. Deiodinase activities explained some, but not all, of the tissue-specific and dose related changes in tissue T3 concentrations. In conclusion, euthyroidism is not restored in plasma and all tissues of thyroidectomized rats on T4 alone. These results may well be pertinent to patients on T4 replacement therapy.

The full text (as a scanned copy of the original print version) is avaialbel to download from here:



Combination Treatment with T4 and T3:
Toward Personalized Replacement Therapy in Hypothyroidism?

Bernadette Biondi, and Leonard Wartofsky
DOI: http://dx.doi.org/10.1210/jc.2011-3399
Received: December 18, 2011
Accepted: April 12, 2012
Published Online: May 16, 2012


Levothyroxine therapy is the traditional lifelong replacement therapy for hypothyroid patients. Over the last several years, new evidence has led clinicians to evaluate the option of combined T3 and T4 treatment to improve the quality of life, cognition, and peripheral parameters of thyroid hormone action in hypothyroidism. The aim of this review is to assess the physiological basis and the results of current studies on this topic.

Evidence Acquisition:
We searched Medline for reports published with the following search terms: hypothyroidism, levothyroxine, triiodothyronine, thyroid, guidelines, treatment, deiodinases, clinical symptoms, quality of life, cognition, mood, depression, body weight, heart rate, cholesterol, bone markers, SHBG, and patient preference for combined therapy. The search was restricted to reports published in English since 1970, but some reports published before 1970 were also incorporated. We supplemented the search with records from personal files and references of relevant articles and textbooks. Parameters analyzed included the rationale for combination treatment, the type of patients to be selected, the optimal T4/T3 ratio, and the potential benefits of this therapy on symptoms of hypothyroidism, quality of life, mood, cognition, and peripheral parameters of thyroid hormone action.

Evidence Synthesis:
The outcome of our analysis suggests that it may be time to consider a personalized regimen of thyroid hormone replacement therapy in hypothyroid patients.

Further prospective randomized controlled studies are needed to clarify this important issue. Innovative formulations of the thyroid hormones will be required to mimic a more perfect thyroid hormone replacement therapy than is currently available.

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T3/T4 Combination Therapy

Abstract taken from: http://www.endocrine-abstracts.org

Endocrine Abstracts 3 S40
British Endocrine Societies Joint Meeting 2002
Harrogate, UK
08 April 2002 - 11 April 2002

AD Toft
Endocrine Clinic, Royal Infirmary, Edinburgh, UK.

The first treatment for hypothyroidism introduced at the end of the 19th century was animal thyroid extract which contained both T3and T4. Because of variable potency it was widely replaced by synthetic T4 from the 1960s in high doses of 200-400 ug daily to compensate for the lack of T3. The development of TSH assays showed that a dose of T4 of 100-150 ug daily was usually adequate to restore serum TSH to normal. Because a suppressed serum TSH has been shown to be a risk factor for osteoporosis, atrial fibrillation, and most recently for excess cardiovascular mortality, there is a consensus that the correct treatment of hypothyroidism is a dose of thyroxine which restores euthyroidism and maintains both T4 and TSH in their respective reference ranges. However, a significant minority of patients only achieve the desired sense of well-being if serum TSH is suppressed. Furthermore, patients rendered hypothyroid following treatment of thyrotoxicosis and taking a dose of T4 which maintains a normal TSH, gain more weight than those who do not become hypothyroid. Studies in hypothyroid rats suggest that it is only possible to restore universal tissue euthyroidism using a combination of T3and T4. In patients in whom long-term T4 therapy was substituted by the equivalent combination of T3 and T4 scored better in a variety of neuropsychological tests. It would appear that the treatment of hypothyroidism is about to come full circle.


Improvements in quality of Life in Hypothyroid Patients taking Armour thyroid

Abstract taken from : http://www.endocrine-abstracts.org
Endocrine Abstracts (2008) 15 P359
DH Lewis, J Kumar, P Goulden & DJ Barnes
Maidstone and Tunbridge Wells NHS Trust, Tunbrige Wells, Kent, UK.

Armour thyroid (Armour) is unlicensed in the UK for the treatment of hypothyroidism. It is natural porcine-derived thyroid replacement with 1 grain containing 38 mcg levothyroxine (T4) and 9 mcg L-triiodothyronine (T3), and unspecified amounts of T1, T2 and calcitonin. We have used Armour as a third line agent in selected patients who have not responded adequately to T4 monotherapy, and combination T4/T3 therapy since 2003.

Aim: To assess changes in symptoms of hypothyroidism in patients treated with Armour.

Methods: Forty patients (38 female) who had been prescribed Armour between 2005 and 2006 were identified using hospital Pharmacy records. A simple questionnaire was sent to these patients to assess changes to quality of life whilst they were taking Armour.

Results: Thirty-five patients (88%) returned the questionnaire. All patients had been prescribed either T4 and/or combination T4/T3 therapy before commencing Armour. Twenty-nine were still taking Armour at the time of the questionnaire. Three of these twenty-nine patients did not answer the quality of life questions, one of whom was unable to tolerate T4 and T3 due to nausea.

Of the patients still taking Armour, 72% found improvement in energy levels, 52% dry skin, 52% hair loss and 55% cold intolerance. There was no difference in constipation, arthragia, myalgia or ability to lose weight. Most patients (62%) had improvements in 3 or more symptoms of hypothyroidism.

In the 6 patients who were no longer taking Armour, there were no significant improvements in any parameter.

Conclusion: In appropriately selected hypothyroid patients, Armour appears to improve the quality of life in patients who have either had an inadequate clinical response to conventional T4/T3 therapy or are unable to tolerate such therapy.