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REVIEW

CURRENTOPINION Combination L-T3 and L-T4 therapy for

hypothyroidism

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Leonard Wartofsky

Purpose of review

Because of the longstanding controversy regarding whether hypothyroid patients can be optimally replacedby treatment with levothyroxine (L-T4) alone, numerous studies have addressed potential benefits ofcombined therapy of triiodothyronine (T3) with L-T4. Results of these studies have failed to support apotential benefit of combined therapy. A strong argument for the addition of L-T3 to L-T4 monotherapy hasbeen lacking until recent genetic studies indicated a rationale for such therapy among a small fraction ofthe hypothyroid patient population.

Recent findings

Interest in this issue has focused on the importance of the deiodinases in maintaining the euthyroid stateand the role of genetic polymorphisms in the deiodinase genes that would affect thyroid hormoneconcentrations in both blood and tissues. One such polymorphism in the D2 gene, Thr92Ala, is associatedwith reduced T4 to T3 activation in skeletal muscle and thyroid, linked to obesity and alterations in thyroid-pituitary feedback, and in responses to thyroid hormone treatment.

Summary

Although our professional organizations continue to recommend L-T4 alone for the treatment ofhypothyroidism, the possibility of a D2 gene polymorphism should be considered in patients on L-T4monotherapy who continue to complain of fatigue in spite of dosage achieving low normal serum thyroidstimulating hormone levels. A suggestive clue to the presence of this polymorphism could be a higher thannormal free T4/free T3 ratio. Clinicians could consider adding T3 as a therapeutic trial in selected patients.Future well controlled clinical trials will be required to more fully resolve the controversy.

Keywords

combination T3/T4 therapy, hypothyroidism, thyroxine, triiodothyronine

Department of Medicine, Washington Hospital Center, GeorgetownUniversity, Washington, District of Columbia, USA

Correspondence to Leonard Wartofsky, MD, 110 Irving Street, NW,Washington, DC 20010-2975, USA. Tel: +1 202 877 3109; fax: +1 202877 6292; e-mail: leonard.wartofsky@medstar.net

Curr Opin Endocrinol Diabetes Obes 2013, 20:460–466

DOI:10.1097/01.med.0000432611.03732.49

INTRODUCTION

The overwhelming majority of patients with hypo-thyroidism are treated with a single daily dose ofsynthetic levothyroxine. Other thyroid hormonepreparations are available and include desiccatedthyroid extract United States Pharmacopoiea, atriiodothyronine (T3) preparation, and a mixtureof thyroxine (T4) and T3 (liotrix). Because T4 isconverted to T3, ultimately near normal concen-trations of serum T3 can be restored by administer-ing T4 alone in sufficient dosage. Generally, a T4dose high enough to result in higher free T4 levelsthan in the control state would be required toachieve normal control levels of serum T3. Noexperts have recommended thyroid hormonereplacement with T3 alone, but the debate has beenwhether combination T4 and T3 therapy mightbe somehow better than treatment with T4 alone.

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Whether as sole therapy or in combination with T4,in order to more closely mimic thyroidal T3secretion and normal blood levels, oral supplementsof T3 would need to be given in frequent divideddosage, a regimen that makes good patient com-pliance more problematic. Moreover, until veryrecently, convincing arguments or data demonstrat-ing benefit of concomitant T3 administration havebeen lacking.

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KEY POINTS

� Perhaps 20% of hypothyroid patients continue tocomplain of symptoms suggesting thyroid hormonedeficiency in spite of treatment.

� Levothyroxine monotherapy may not be optimal inall patients.

� The presence of deiodinase polymorphisms mayindicate patients who will benefit from T3/T4combination therapy.

Combination L-T3 and L-T4 therapy for hypothyroidism Wartofsky

BACKGROUND HISTORY

Interest in combined T3 and T4 therapy for hypo-thyroidism has been based upon the longstandingconcern of whether hypothyroid patients can beoptimally replaced by treatment with T4 alone[1,2]. This is because a small fraction of patientson T4 monotherapy continue to complain of per-sistent nonspecific symptoms, such as modestweight gain and fatigue, and those patients whoare on T4 after thyroidectomy often will state thatthe symptoms were not an issue prior to theirsurgery. Based upon patient responses to symptomquestionnaires, studies indicate that patients tendto feel better, at least transiently, when mildlythyrotoxic, whether by T4 therapy [3] or by T3 [4].

Perhaps, the fraction of patients who continueto complain are those who have failed to truly berestored to euthyroidism, as several studies haveshown that 15–27% of patients managed by endo-crinologists are undertreated [5–8]. Moreover, thesefigures are based upon thyroid stimulating hormone(TSH) values within a reference ‘normal’ range, andthe upper limit may be as high as 4.5–5.3 mU/l.Given an upper limit of the reference range forTSH of 2.5 mU/l, it is highly likely that the percent-age of undertreated patients would be considerablyhigher. Perhaps, the number of patients withthese persistent complaints would be dramaticallyminimized if patients were treated with sufficientT4 dosage to bring TSH levels to the range of1.0–1.5 mU/l.

The observation that certain patients continueto be symptomatic and feel suboptimal in spite of a‘normal’ TSH level is clear as well from the study ofSaravanan et al. [9], who reported impaired psycho-logical well-being in T4-treated hypothyroidpatients with normal TSH levels. Potential issuesconfounding these observations have been listedelsewhere [10]. But such issues notwithstanding,concerns regarding therapy with T4 alone haveled to increasing interest in the concept of addingT3 to traditional T4 therapy to potentially mimic

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hormonal secretion patterns from the intact normalthyroid gland more physiologically.

The experimental studies of Escobar-Morrealeet al. [11] in rats examined whether T4 therapy alonemight provide insufficient intracellular levels ofserum TSH or T3. Hypothyroid rats were infusedwith either T4 or T4þT3 and serum and tissue levelsof T4 and T3 measured. A T4 infusion dose alonethat normalized tissue T4 levels was accompanied byhigh serum TSH and low tissue T3 levels. They foundthat no single dose of T4 simultaneously normalizedboth T4 and T3 levels in tissues. Doses of T4 thatwere high enough to normalize both TSH and tissueT3 levels resulted in high tissue T4 levels. Tissuedeiodinase levels were normalized with T4þT3infusion, with the combined treatment restoringeuthyroidism at a lower total T4 dosage. These dataprovided proponents of combined T4þT3 therapywith a rationale for combined therapy.

The important clinical question becomeswhether or not there are convincing data that com-bined T4/T3 therapy provides a sustained improve-ment in clinical status. One of the earliest studiesover 40 years ago by Smith et al. [12] examined theresponses to T4 therapy alone versus combined withT3 (80 mg T4/20 mg T3) in 87 hypothyroid patients.No patient preference was expressed by 48% ofpatients, 38% preferred T4 alone, and 18% preferredT3. Twenty-four patients recorded unpleasant symp-toms such as palpitations, irritability, nervousness,tremors, sweating, or headaches. A possible cardiacrisk to T3 therapy has been of concern to cliniciansfor some time, and Peters et al. [13] described a2.6 relative risk of angina or myocardial infarctionand a 4.8 relative risk of a coronary event duringthe follow-up of 181 of 1049 patients with cardiacadmissions who had elevations in either total orfree T3 levels. Smith et al. further concluded that‘The shortcomings of combined therapy deducedfrom this study suggest that thyroxine has overalladvantages for thyroid hormone replacementtherapy.’

Arguably, the first study ostensibly demonstrat-ing a greater clinical benefit from combined T3/T4therapy than that achieved with T4 alone wasreported by Bunevicius et al. [4]. In that study, 33patients (16 with autoimmune thyroid disease andhypothyroidism and 17 on suppression for thyroidcancer) were being treated with an average dailydose of 0.175 mg T4. Irrespective of the dose thatthey were taking (some as little as 75 mg daily),12.5 mg of T3 was substituted for 50 mg of T4, withthe patients treated in a randomized crossoversequence of 5 weeks’ duration. The authors notedno significant differences in serum TSH, Achillestendon relaxation time, blood pressure, serum

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lipids, or several neuropsychological tests. They didnote that the combined T3/T4 group had higherlevels of sex hormone binding globulin, higher pulserate, and scored better in 10 of 15 mood/physicalstatus analogue tests and in six of 17 cognitiveparameters. Possibledeficiencies in their studydesignand criticism of their methods and conclusions haveincluded issues such as the T4/T3 molar ratio admin-istered was not physiologic and that varied ratiosadministered would have different effects in differentpatients. Analysis of the data indicates that it was thethyroid cancer patients and not the Hashimoto’spatients who seemed to derive benefit from theT3 combination, suggesting that it was the over-dosage that was responsible, as seen in other studies(see above). It was also not clear whether the time oftesting was standardized to time of dosing and thegreater degree of T3 absorption that would occurrespective to T4. Other criticisms [1,2,14] questionedwhether the mood, cognition, and psychometrictests employed were validated in hypothyroidpatients, and why there were no potentially betterend points measured, such as indices of exercisetolerance or myocardial function. The validity of thatskepticism appeared subsequently to be supported bya host of follow-up reports of studies that failed toconfirm their observations, with all studies indicat-ing no benefit to combined L-T4 and L-T3 therapy[15–26], with only one exception [27]. These reportswere subsequently summarized in three meta-analyses [28–30] that came to the same conclusion.Indeed, up until recently, it had been only the studyof Nygaard et al. [27] and studies from the groupof Bunevicius et al. [4,31,32] that have supportedthe possible benefits of coadministration of T3with T4.

Were the study designs in these clinical trialsappropriate and optimal in regard to the doses ofT3 employed? For thyroxine, we know that thyroidalT4 secretion approximates 56 mg/m2 per day, whichamounts to 100 mg of T4 day given an average surfacearea of 1.78 m2. With an approximate 80% effectivegastrointestinal absorption, the optimal T4 replace-ment dose to deliver 100 mg would be 112–125 mg perday. In the case of thyroidal secretion of T3, there is3.3 mg/m2 per day produced, which for a body surfacearea of 1.78 m2, amounts to only 5.9 mg per day, farless than the 10–25 mg given in the above trials. Thus,we cannot invoke inadequate T3 dosage as the expla-nation for the failure of these trials to provide abenefit of T3 combination therapy. We know that80% of circulating T3 is derived from the monodeio-dination of T4 in peripheral tissues, and thus of a totaldaily T3 production rate of 25–30 mg/day, 19–24 mgare derived from T4 and only 6 mg from the thyroidgland.

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The argument can be made that those patientsshowing some ostensible benefit from T3 coadmi-nistration received supraphysiologic dosages of T3.One of the more recently published studies on com-bination T4/T3 therapy did examine the question ofpossible benefit in doses given in a more appropriatemolar ratio, that of 14 : 1 [26]. In a randomized,double-blind study, 23 hypothyroid patientsreceived either T4 alone (100–175 mg/day) or a com-bination of T4/T3 with T3 substituted for 5% of theT4 for treatment periods of 12 weeks’ duration.Again, the usual measurements, including standar-dized psychological testing, were performed toexamine cognitive performance and mood. Exceptfor a suppressed TSH, there were no hormonal,metabolic, or cardiovascular differences, nor anysignificant differences in mood or cognitive per-formance. Rather, mood was significantly impairedin eight of 23 patients taking the combination, all ofwhom had suppressed TSH levels. The authors con-cluded that there was no benefit to T4þT3 andrather, a potential risk from subclinical hyper-thyroidism.

One of the very few studies demonstrating somebenefit of combination therapy came from thegroup of Nygaard et al. from Denmark [27]. Thiswas a randomized, double-blind controlled studyin which 59 patients were treated for consecutive12-week intervals of T4/T3 combination therapyversus T4 monotherapy. The patients’ usual doseof L-T4 was substituted with either 20 or 50 mg ofL-T3 with adjustments in L-T4 dosage as necessary toachieve stable TSH levels between 0.1 and 5.0 mU/l.Symptom questionnaires were performed at base-line and after each treatment period that assessedquality of life (QOL) and other parameters. Signifi-cant differences were seen in seven of 11 scores,suggesting superior outcomes with combinationtherapy. With no differences in serum TSH, 49%of the patients preferred T4þT3 therapy, comparedwith only 15% who preferred T4 monotherapy(P�0.002). The strengths of this study include itscrossover design, the relatively large number ofpatients, and the stability maintained of TSHlevels. However, given the dosage titration methodemployed, patients were treated with relativelymore T3 daily than in most of the prior studies,averaging between 7.5 and 12.5 mg daily, with ratiosof T4/T3 that ranged from 2.5 : 1 to 8 : 1.

THE IDEAL FORMULATION

Perhaps, the ideal combination therapy needs to beas the correct molar ratio, such as a tablet containing112 mg of T4 and 6 mg of T3, and not as a ‘bolus’form, but in a delayed release vehicle. Such a slow or

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Combination L-T3 and L-T4 therapy for hypothyroidism Wartofsky

delayed release combination product of T3 withT4 has been under patented development byHennemann et al. [33] with the kinetic charac-teristics of their product reported. Employing aL-T4/L-T3 mixture, only the T3 appeared to beslowly released. They concluded that their slowrelease L-T4/L-T3 preparation resulted in ‘a con-siderable improvement of serum T4 and T3 values,the T4/T3 ratio, and serum TSH, compared to treat-ment with T4 only’. The serum measurements wereperformed over the course of a 9-h day, with aplateau in serum T3 seen with the slow releasepreparation between 2 and 6 h postingestion, anda decline at 9 h. The latter pattern suggests that theircompound does indeed exhibit some slow releaseproperties, but the decline at 9 h provides littleassurance that an adequate blood level would bemaintained and continue over 24 h in order tomimic T3 release from the intact thyroid gland.One must further speculate that because L-T3 isabsorbed in the proximal small bowel, their slowrelease product would have to be administeredtwice daily.

Without a slow or delayed release preparationfor combination therapy, we must rely on currentlyavailable T3 preparations to supplement a T4 pre-paration. Using current T3 formulations to achieve apremorbid normal profile of thyroid function testsmight require administering the T3 as 5 mg threetimes daily or perhaps 2.5 mg four times daily, whichare certainly not optimal regimens. Should the slowrelease T3 compound of Hennemann et al. [33] onlyrequire twice daily dosage, this could represent animprovement over the latter dosage schedule, buteven a twice daily preparation will create significantproblems in regard to patient compliance or adher-ence to the regimen. As a result of missing theoccasional second daily dose, patients will ingestless than their true daily replacement dosage withresultant inadequately treated hypothyroidism andreturn of all the same symptoms that we are trying toavoid by developing this modified combinedtherapeutic approach.

THE DEIODINASES AND DEIODINASEPOLYMORPHISMS

One may gain insight into a rationale for combi-nation T4/T3 therapy by first understanding thenormal generation of T3 from monodeiodinationof T4, and second the growing evidence of poly-morphisms in the deiodinase that affects thisconversion, which could account for less thanphysiologic T3 generation. There are three deiodi-nase isoforms: deiodinase type I (D1), type 2 (D2),and type 3 (D3) [34,35]. D1 is expressed mainly in

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the thyroid gland, liver, and kidney and may con-vert T4 to T3 as it can catalyze 5’ deiodination. Moreimportant in this regard is the 5’ deiodinativeactivity of D2, which is present in the brain, pitu-itary gland, skeletal muscle, heart, brown adiposetissue, and thyroid [34,35]. By generating and regu-lating intracellular T3, the organism maintainseuthyroidism. Autoregulation allows a greater rateof T3 generation from T4 when T4 concentrationsare low, that is, in hypothyroidism, and a lowerconversion rate in hyperthyroidism [36]. Similarly,the pituitary response to hypothyroidism is gov-erned by intracellular T4 to T3 activation withinthe pituitary. Conceptually, there could be tissuehypothyroidism secondary to relatively low serumT3 in the face of ‘normal’ serum TSH levels that arebeing maintained by intrapituitary conversion of T4to T3 at a rate influenced by relatively high serum T4levels [37–40]. It has been suggested that a hypo-thyroid post-thyroidectomy patient may requirehigher serum T4 levels in order to achieve a ‘normal’serum TSH level when being replaced with L-T4alone. In this situation, the serum T3 levels willbe lower than in the preoperative state or that ofeuthyroid controls [32,39,41]. The iodothyronineprofile in such patients would consist of a higherthan normal FT4 to FT3 ratio or a lower than normalfree T3 to free T4 ratio. These observations couldsuggest that higher serum T4 levels are necessary inthyroidectomized patients in order to generate nor-mal serum T3 concentrations and thereby compen-sate for the absence of the 20% fraction ofcirculating T3 normally derived from the thyroid[42].

The intact thyroid gland produces both T4 andT3 at rates sufficient to establish serum and tissueconcentrations compatible with the euthyroid state.In the absence of the thyroid gland, the organismmust depend solely on T4 to T3 activation in peri-pheral tissues to generate physiologic concentrationsof T3. Given the importance of deiodinases in main-taining the euthyroid state, any genetic polymor-phisms in the deiodinase genes will affect serumand tissue hormone concentrations in general, andin the pituitary gland in particular. One such poly-morphism in the D2 gene, Thr92Ala [43], has beenshown to be associated with reduced T4 to T3 acti-vation in skeletal muscle and thyroid [44]. This latterpolymorphism has been linked to obesity, hyper-tension, and insulin resistance [45,46] and withalterations in thyroid-pituitary feedback [43,47],responses to thyroid hormone treatment [48–51]and cognitive function [52].

Torlontano et al. [51] studied 191 thyroid cancerpatients on T4 replacement after surgery and abla-tion with radiooactive iodine and demonstrated a

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higher T4 dose requirement when the D2 Thr92Alapolymorphism was present. This higher doserequirement was not seen in patients with auto-immune hypothyroidism treated by Heemstraet al. [50]. Other workers observed that patients withthe D2-Thr92Ala polymorphism may prefer combi-nation therapy with T3/T4 in regard to neurocog-nitive function and general sense of well-being[48,49]. Hoftijzer et al. [53] recently reported thatcertain thyroidectomized thyroid cancer patientswho are homozygous for the D2-rs12885300 poly-morphism demonstrate an altered setpoint of thehypothalamus-pituitary-thyroid axis that is associ-ated with weaker negative feedback of FT4 on TSH. Apolymorphism affecting availability of T3 to tissuescould also involve T3 transport, and in this regard,the thyroid hormone transporter, OATP1C1, hasgarnered some attention in view of its associationwith symptoms of fatigue [21].

As more studies on polymorphisms, such asthose in the D2 gene, are being performed, moresupport is gaining for the concept that at least afraction of individuals may have varying needs forthyroid hormone replacement based upon the poly-morphisms present, with a small but real fraction ofthem benefiting from combination T4/T3 treatment[48]. For example, the D2 CC rs225014 polymor-phism was found in 16% of a study population.Patients with this polymorphism taking T4 hadworse baseline general health questionnaire scores,but were noted to demonstrate improved scores oncombination T4/T3 therapy. Interestingly, Nygaardet al. [27] noted that about two-thirds of the patientson T4 monotherapy who were offered participationin a T4/T3 combination therapy trial declined theopportunity, indicating that they felt well on mono-therapy, consistent with the concept that there mayexist a subgroup of patients, that is, those with adeiodinase or other polymorphism affecting tissueavailability of T3.

As multiple studies have demonstrated nobenefit of combination therapy, the results of astudy by Celi et al. [54,55] indicating benefit fromL-T3 therapy compared to L-T4 in hypothyroidpatients were rather surprising. These workers noteda greater degree of weight loss, reduced serumcholesterol, low-density lipoprotein-cholesterol,and apolipoprotein B when patients were takingT3 [55]. Equivalent baseline and thyrotropin releas-ing hormone-stimulated TSH levels were achieved,but there were no changes noted in fasting glucose,insulin sensitivity as measured by the hyperinsuli-nemic-euglycemic clamp, heart rate, blood pressure,or exercise tolerance while on T3 versus T4 treat-ment. T3 was administered in three daily doses andwas associated with TSH levels not significantly

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different from those noted while taking L-T4. Thisstudy has rekindled interest in potential benefits ofadding T3 to the therapy of hypothyroid patients,and in addition, the D2 polymorphism studies pointto the subpopulation most likely to benefit fromsuch combined therapy.

A very recent study by Hoang et al. [56&

] is ofinterest because of the comparison of treatmentwith desiccated thyroid extract (containing T3) totherapy with L-T4 alone in 70 patients on levo-thyroxine. This was a prospective, double-blind,randomized crossover trial of therapy for 6 weekswith dosage adjustment to maintain serum TSHbetween 0.5 and 3.0 mU/l. Outcome measurements,in addition to biochemical parameters, includedfour psychometric test profiles that included theWechsler Memory Scale, a QOL, and a thyroid symp-tom questionnaire, and the Beck Depression Inven-tory. Although there was no improvement noted inQOL, patients on desiccated thyroid extract enjoyedweight loss of approximately 3 lbs in spite of havinga slightly higher serum TSH level, while havinghigher serum T3 and lower serum T4 levels. Thisdegree of weight loss, presumably attributable tohigher T3 levels, is comparable to that seen in thestudy of Celi et al. [55] and could reflect effectson caloric expenditure mediated through thyroidhormone receptor a. After decades of shunningtherapy with desiccated thyroid extract, this studyshould cause endocrinologists to consider relookingat a trial of treatment in those patients who remainsymptomatic on L-T4 monotherapy.

CONCLUSION

In spite of these more recent studies that wouldappear to reopen the debate on combinationT3/T4 therapy, compelling data that would formthe basis for a guideline to such therapy are lack-ing. Hence, the recent guidelines of the AmericanThyroid Association and the American Associationof Clinical Endocrinologists for treatment ofhypothyroidism [57,58] state that ‘although thesatisfaction level of patients on LT4 is not the sameas euthyroid controls, studies of combinationtherapy fail to show an advantage’, and ‘long-termbenefits of T4/T3 are not known’, nor is it known‘whether genotyping will identify patients whowill benefit from T4/T3’, and they conclude that‘treatment is best accomplished using syntheticLT4’.

Certainly, imprecise dosing with current T3preparations is undesirable in view of the risks ofoverdosage or underdosage causing subclinicalhyperthyroidism or subclinical hypothyroidism,respectively, thereby precluding optimal results

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with their use. Availability of a more physiologicslow release T3 product could be of considerableinterest to marketers of products for thyroid hor-mone replacement but proof of true slow releaseover 24 h to enable once a day dosing will first needto be forthcoming. In this regard, a recent abstracthas reported that the oral administration of a singledose of T3 sulfate maintains serum T3 levels in asteady state for at least 24 h [59]. To be comparableto the physiologic state, a T3/T4 compound wouldpresumably mimic the molar ratio of T4/T3 secretedby the thyroid gland, and would achieve both anormal TSH level and a normal T3 level or normalFT3/FT4 ratio. In patients who continue to be symp-tomatic while on T4 monotherapy, perhaps the clueto the presence of a D2 gene polymorphism wouldbe a higher than normal free T4/free T3 molar ratio.Until the ideal compound and a more evidence-based approach becomes available, clinicians treat-ing such a patient with symptoms suggestive ofinsufficient thyroid hormone replacement couldconsider adding T3 as a therapeutic trial, 5 mg twoto three times daily. However, given the presence ofa small segment of the population with D2 poly-morphisms, it would be preferable to perform aclinical trial of T3/T4 in that fraction of the patientpopulation who claim to be symptomatic on T4alone. Such an experimental trial has been recom-mended within the guidelines of the EuropeanThyroid Association (ETA) [60

&&

,61]. On the otherhand, the American Thyroid Association andAmerican Association of Clinical Endocrinologistsguidelines reflect continuing doubt and maintainthat the best management for thyroid hormonereplacement remains levothyroxine alone [57].

Acknowledgements

None.

Conflicts of interest

L.W. serves as a consultant to Asurogen, Genzyme, andIBSA, with no perceived conflict of interest to the contentof this article.

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60.&&

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Volume 20 � Number 5 � October 2013