REVIEW

URRENT
C
OPINION

Combination L-T3 and L-T4 therapy for

hypothyroidism
Leonard Wartofsky

Purpose of review
Because of the longstanding controversy regarding whether hypothyroid patients can be optimally replaced
by treatment with levothyroxine (L-T4) alone, numerous studies have addressed potential benefits of
combined therapy of triiodothyronine (T3) with L-T4. Results of these studies have failed to support a
potential benefit of combined therapy. A strong argument for the addition of L-T3 to L-T4 monotherapy has
been lacking until recent genetic studies indicated a rationale for such therapy among a small fraction of
the hypothyroid patient population.
Recent findings
Interest in this issue has focused on the importance of the deiodinases in maintaining the euthyroid state
and the role of genetic polymorphisms in the deiodinase genes that would affect thyroid hormone
concentrations in both blood and tissues. One such polymorphism in the D2 gene, Thr92Ala, is associated
with reduced T4 to T3 activation in skeletal muscle and thyroid, linked to obesity and alterations in thyroidpituitary feedback, and in responses to thyroid hormone treatment.
Summary
Although our professional organizations continue to recommend L-T4 alone for the treatment of
hypothyroidism, the possibility of a D2 gene polymorphism should be considered in patients on L-T4
monotherapy who continue to complain of fatigue in spite of dosage achieving low normal serum thyroid
stimulating hormone levels. A suggestive clue to the presence of this polymorphism could be a higher than
normal 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

INTRODUCTION
The overwhelming majority of patients with hypothyroidism are treated with a single daily dose of
synthetic levothyroxine. Other thyroid hormone
preparations are available and include desiccated
thyroid extract United States Pharmacopoiea, a
triiodothyronine (T3) preparation, and a mixture
of thyroxine (T4) and T3 (liotrix). Because T4 is
converted to T3, ultimately near normal concentrations of serum T3 can be restored by administering T4 alone in sufficient dosage. Generally, a T4
dose high enough to result in higher free T4 levels
than in the control state would be required to
achieve normal control levels of serum T3. No
experts have recommended thyroid hormone
replacement with T3 alone, but the debate has been
whether combination T4 and T3 therapy might
be somehow better than treatment with T4 alone.
www.co-endocrinology.com

Whether as sole therapy or in combination with T4,

in order to more closely mimic thyroidal T3
secretion and normal blood levels, oral supplements
of T3 would need to be given in frequent divided
dosage, a regimen that makes good patient compliance more problematic. Moreover, until very
recently, convincing arguments or data demonstrating benefit of concomitant T3 administration have
been lacking.

Department of Medicine, Washington Hospital Center, Georgetown

University, 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: +1 202
877 6292; e-mail: leonard.wartofsky@medstar.net
Curr Opin Endocrinol Diabetes Obes 2013, 20:460466
DOI:10.1097/01.med.0000432611.03732.49
Volume 20
Number 5
October 2013

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

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

KEY POINTS

Perhaps 20% of hypothyroid patients continue to
complain of symptoms suggesting thyroid hormone
deficiency in spite of treatment.

Levothyroxine monotherapy may not be optimal in
all patients.

The presence of deiodinase polymorphisms may
indicate patients who will benefit from T3/T4
combination therapy.

BACKGROUND HISTORY
Interest in combined T3 and T4 therapy for hypothyroidism has been based upon the longstanding
concern of whether hypothyroid patients can be
optimally replaced by treatment with T4 alone
[1,2]. This is because a small fraction of patients
on T4 monotherapy continue to complain of persistent nonspecific symptoms, such as modest
weight gain and fatigue, and those patients who
are on T4 after thyroidectomy often will state that
the symptoms were not an issue prior to their
surgery. Based upon patient responses to symptom
questionnaires, studies indicate that patients tend
to feel better, at least transiently, when mildly
thyrotoxic, whether by T4 therapy [3] or by T3 [4].
Perhaps, the fraction of patients who continue
to complain are those who have failed to truly be
restored to euthyroidism, as several studies have
shown that 1527% of patients managed by endocrinologists are undertreated [58]. Moreover, these
figures are based upon thyroid stimulating hormone
(TSH) values within a reference normal range, and
the upper limit may be as high as 4.55.3 mU/l.
Given an upper limit of the reference range for
TSH of 2.5 mU/l, it is highly likely that the percentage of undertreated patients would be considerably
higher. Perhaps, the number of patients with
these persistent complaints would be dramatically
minimized if patients were treated with sufficient
T4 dosage to bring TSH levels to the range of
1.01.5 mU/l.
The observation that certain patients continue
to be symptomatic and feel suboptimal in spite of a
normal TSH level is clear as well from the study of
Saravanan et al. [9], who reported impaired psychological well-being in T4-treated hypothyroid
patients with normal TSH levels. Potential issues
confounding these observations have been listed
elsewhere [10]. But such issues notwithstanding,
concerns regarding therapy with T4 alone have
led to increasing interest in the concept of adding
T3 to traditional T4 therapy to potentially mimic

hormonal secretion patterns from the intact normal

thyroid gland more physiologically.
The experimental studies of Escobar-Morreale
et al. [11] in rats examined whether T4 therapy alone
might provide insufficient intracellular levels of
serum TSH or T3. Hypothyroid rats were infused
with either T4 or T4 T3 and serum and tissue levels
of T4 and T3 measured. A T4 infusion dose alone
that normalized tissue T4 levels was accompanied by
high serum TSH and low tissue T3 levels. They found
that no single dose of T4 simultaneously normalized
both T4 and T3 levels in tissues. Doses of T4 that
were high enough to normalize both TSH and tissue
T3 levels resulted in high tissue T4 levels. Tissue
deiodinase levels were normalized with T4 T3
infusion, with the combined treatment restoring
euthyroidism at a lower total T4 dosage. These data
provided proponents of combined T4 T3 therapy
with a rationale for combined therapy.
The important clinical question becomes
whether or not there are convincing data that combined T4/T3 therapy provides a sustained improvement in clinical status. One of the earliest studies
over 40 years ago by Smith et al. [12] examined the
responses to T4 therapy alone versus combined with
T3 (80 mg T4/20 mg T3) in 87 hypothyroid patients.
No patient preference was expressed by 48% of
patients, 38% preferred T4 alone, and 18% preferred
T3. Twenty-four patients recorded unpleasant symptoms such as palpitations, irritability, nervousness,
tremors, sweating, or headaches. A possible cardiac
risk to T3 therapy has been of concern to clinicians
for some time, and Peters et al. [13] described a
2.6 relative risk of angina or myocardial infarction
and a 4.8 relative risk of a coronary event during
the follow-up of 181 of 1049 patients with cardiac
admissions who had elevations in either total or
free T3 levels. Smith et al. further concluded that
The shortcomings of combined therapy deduced
from this study suggest that thyroxine has overall
advantages for thyroid hormone replacement
therapy.
Arguably, the first study ostensibly demonstrating a greater clinical benefit from combined T3/T4
therapy than that achieved with T4 alone was
reported by Bunevicius et al. [4]. In that study, 33
patients (16 with autoimmune thyroid disease and
hypothyroidism and 17 on suppression for thyroid
cancer) were being treated with an average daily
dose of 0.175 mg T4. Irrespective of the dose that
they were taking (some as little as 75 mg daily),
12.5 mg of T3 was substituted for 50 mg of T4, with
the patients treated in a randomized crossover
sequence of 5 weeks duration. The authors noted
no significant differences in serum TSH, Achilles
tendon relaxation time, blood pressure, serum

1752-296X 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins

www.co-endocrinology.com

461

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Thyroid

lipids, or several neuropsychological tests. They did

note that the combined T3/T4 group had higher
levels of sex hormone binding globulin, higher pulse
rate, and scored better in 10 of 15 mood/physical
status analogue tests and in six of 17 cognitive
parameters. Possible deficiencies in their study design
and criticism of their methods and conclusions have
included issues such as the T4/T3 molar ratio administered was not physiologic and that varied ratios
administered would have different effects in different
patients. Analysis of the data indicates that it was the
thyroid cancer patients and not the Hashimotos
patients who seemed to derive benefit from the
T3 combination, suggesting that it was the overdosage that was responsible, as seen in other studies
(see above). It was also not clear whether the time of
testing was standardized to time of dosing and the
greater degree of T3 absorption that would occur
respective to T4. Other criticisms [1,2,14] questioned
whether the mood, cognition, and psychometric
tests employed were validated in hypothyroid
patients, and why there were no potentially better
end points measured, such as indices of exercise
tolerance or myocardial function. The validity of that
skepticism appeared subsequently to be supported by
a host of follow-up reports of studies that failed to
confirm their observations, with all studies indicating no benefit to combined L-T4 and L-T3 therapy
[1526], with only one exception [27]. These reports
were subsequently summarized in three metaanalyses [2830] that came to the same conclusion.
Indeed, up until recently, it had been only the study
of Nygaard et al. [27] and studies from the group
of Bunevicius et al. [4,31,32] that have supported
the possible benefits of coadministration of T3
with T4.
Were the study designs in these clinical trials
appropriate and optimal in regard to the doses of
T3 employed? For thyroxine, we know that thyroidal
T4 secretion approximates 56 mg/m2 per day, which
amounts to 100 mg of T4 day given an average surface
area of 1.78 m2. With an approximate 80% effective
gastrointestinal absorption, the optimal T4 replacement dose to deliver 100 mg would be 112125 mg per
day. In the case of thyroidal secretion of T3, there is
3.3 mg/m2 per day produced, which for a body surface
area of 1.78 m2, amounts to only 5.9 mg per day, far
less than the 1025 mg given in the above trials. Thus,
we cannot invoke inadequate T3 dosage as the explanation for the failure of these trials to provide a
benefit of T3 combination therapy. We know that
80% of circulating T3 is derived from the monodeiodination of T4 in peripheral tissues, and thus of a total
daily T3 production rate of 2530 mg/day, 1924 mg
are derived from T4 and only 6 mg from the thyroid
gland.
462

www.co-endocrinology.com

The argument can be made that those patients

showing some ostensible benefit from T3 coadministration received supraphysiologic dosages of T3.
One of the more recently published studies on combination T4/T3 therapy did examine the question of
possible benefit in doses given in a more appropriate
molar ratio, that of 14 : 1 [26]. In a randomized,
double-blind study, 23 hypothyroid patients
received either T4 alone (100175 mg/day) or a combination of T4/T3 with T3 substituted for 5% of the
T4 for treatment periods of 12 weeks duration.
Again, the usual measurements, including standardized psychological testing, were performed to
examine cognitive performance and mood. Except
for a suppressed TSH, there were no hormonal,
metabolic, or cardiovascular differences, nor any
significant differences in mood or cognitive performance. Rather, mood was significantly impaired
in eight of 23 patients taking the combination, all of
whom had suppressed TSH levels. The authors concluded that there was no benefit to T4 T3 and
rather, a potential risk from subclinical hyperthyroidism.
One of the very few studies demonstrating some
benefit of combination therapy came from the
group of Nygaard et al. from Denmark [27]. This
was a randomized, double-blind controlled study
in which 59 patients were treated for consecutive
12-week intervals of T4/T3 combination therapy
versus T4 monotherapy. The patients usual dose
of L-T4 was substituted with either 20 or 50 mg of
L-T3 with adjustments in L-T4 dosage as necessary to
achieve stable TSH levels between 0.1 and 5.0 mU/l.
Symptom questionnaires were performed at baseline and after each treatment period that assessed
quality of life (QOL) and other parameters. Significant differences were seen in seven of 11 scores,
suggesting superior outcomes with combination
therapy. With no differences in serum TSH, 49%
of the patients preferred T4 T3 therapy, compared
with only 15% who preferred T4 monotherapy
(P 0.002). The strengths of this study include its
crossover design, the relatively large number of
patients, and the stability maintained of TSH
levels. However, given the dosage titration method
employed, patients were treated with relatively
more T3 daily than in most of the prior studies,
averaging between 7.5 and 12.5 mg daily, with ratios
of T4/T3 that ranged from 2.5 : 1 to 8 : 1.

THE IDEAL FORMULATION

Perhaps, the ideal combination therapy needs to be
as the correct molar ratio, such as a tablet containing
112 mg of T4 and 6 mg of T3, and not as a bolus
form, but in a delayed release vehicle. Such a slow or
Volume 20
Number 5
October 2013

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

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

delayed release combination product of T3 with

T4 has been under patented development by
Hennemann et al. [33] with the kinetic characteristics of their product reported. Employing a
L-T4/L-T3 mixture, only the T3 appeared to be
slowly released. They concluded that their slow
release L-T4/L-T3 preparation resulted in a considerable improvement of serum T4 and T3 values,
the T4/T3 ratio, and serum TSH, compared to treatment with T4 only. The serum measurements were
performed over the course of a 9-h day, with a
plateau in serum T3 seen with the slow release
preparation between 2 and 6 h postingestion, and
a decline at 9 h. The latter pattern suggests that their
compound does indeed exhibit some slow release
properties, but the decline at 9 h provides little
assurance that an adequate blood level would be
maintained and continue over 24 h in order to
mimic T3 release from the intact thyroid gland.
One must further speculate that because L-T3 is
absorbed in the proximal small bowel, their slow
release product would have to be administered
twice daily.
Without a slow or delayed release preparation
for combination therapy, we must rely on currently
available T3 preparations to supplement a T4 preparation. Using current T3 formulations to achieve a
premorbid normal profile of thyroid function tests
might require administering the T3 as 5 mg three
times daily or perhaps 2.5 mg four times daily, which
are certainly not optimal regimens. Should the slow
release T3 compound of Hennemann et al. [33] only
require twice daily dosage, this could represent an
improvement over the latter dosage schedule, but
even a twice daily preparation will create significant
problems in regard to patient compliance or adherence to the regimen. As a result of missing the
occasional second daily dose, patients will ingest
less than their true daily replacement dosage with
resultant inadequately treated hypothyroidism and
return of all the same symptoms that we are trying to
avoid by developing this modified combined
therapeutic approach.

THE DEIODINASES AND DEIODINASE

POLYMORPHISMS
One may gain insight into a rationale for combination T4/T3 therapy by first understanding the
normal generation of T3 from monodeiodination
of T4, and second the growing evidence of polymorphisms in the deiodinase that affects this
conversion, which could account for less than
physiologic T3 generation. There are three deiodinase isoforms: deiodinase type I (D1), type 2 (D2),
and type 3 (D3) [34,35]. D1 is expressed mainly in

the thyroid gland, liver, and kidney and may convert T4 to T3 as it can catalyze 5 deiodination. More
important in this regard is the 5 deiodinative
activity of D2, which is present in the brain, pituitary gland, skeletal muscle, heart, brown adipose
tissue, and thyroid [34,35]. By generating and regulating intracellular T3, the organism maintains
euthyroidism. Autoregulation allows a greater rate
of T3 generation from T4 when T4 concentrations
are low, that is, in hypothyroidism, and a lower
conversion rate in hyperthyroidism [36]. Similarly,
the pituitary response to hypothyroidism is governed by intracellular T4 to T3 activation within
the pituitary. Conceptually, there could be tissue
hypothyroidism secondary to relatively low serum
T3 in the face of normal serum TSH levels that are
being maintained by intrapituitary conversion of T4
to T3 at a rate influenced by relatively high serum T4
levels [3740]. It has been suggested that a hypothyroid post-thyroidectomy patient may require
higher serum T4 levels in order to achieve a normal
serum TSH level when being replaced with L-T4
alone. In this situation, the serum T3 levels will
be lower than in the preoperative state or that of
euthyroid controls [32,39,41]. The iodothyronine
profile in such patients would consist of a higher
than normal FT4 to FT3 ratio or a lower than normal
free T3 to free T4 ratio. These observations could
suggest that higher serum T4 levels are necessary in
thyroidectomized patients in order to generate normal serum T3 concentrations and thereby compensate for the absence of the 20% fraction of
circulating T3 normally derived from the thyroid
[42].
The intact thyroid gland produces both T4 and
T3 at rates sufficient to establish serum and tissue
concentrations compatible with the euthyroid state.
In the absence of the thyroid gland, the organism
must depend solely on T4 to T3 activation in peripheral tissues to generate physiologic concentrations
of T3. Given the importance of deiodinases in maintaining the euthyroid state, any genetic polymorphisms in the deiodinase genes will affect serum
and tissue hormone concentrations in general, and
in the pituitary gland in particular. One such polymorphism in the D2 gene, Thr92Ala [43], has been
shown to be associated with reduced T4 to T3 activation in skeletal muscle and thyroid [44]. This latter
polymorphism has been linked to obesity, hypertension, and insulin resistance [45,46] and with
alterations in thyroid-pituitary feedback [43,47],
responses to thyroid hormone treatment [4851]
and cognitive function [52].
Torlontano et al. [51] studied 191 thyroid cancer
patients on T4 replacement after surgery and ablation with radiooactive iodine and demonstrated a

1752-296X 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins

www.co-endocrinology.com

463

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Thyroid

higher T4 dose requirement when the D2 Thr92Ala

polymorphism was present. This higher dose
requirement was not seen in patients with autoimmune hypothyroidism treated by Heemstra
et al. [50]. Other workers observed that patients with
the D2-Thr92Ala polymorphism may prefer combination therapy with T3/T4 in regard to neurocognitive function and general sense of well-being
[48,49]. Hoftijzer et al. [53] recently reported that
certain thyroidectomized thyroid cancer patients
who are homozygous for the D2-rs12885300 polymorphism demonstrate an altered setpoint of the
hypothalamus-pituitary-thyroid axis that is associated with weaker negative feedback of FT4 on TSH. A
polymorphism affecting availability of T3 to tissues
could also involve T3 transport, and in this regard,
the thyroid hormone transporter, OATP1C1, has
garnered some attention in view of its association
with symptoms of fatigue [21].
As more studies on polymorphisms, such as
those in the D2 gene, are being performed, more
support is gaining for the concept that at least a
fraction of individuals may have varying needs for
thyroid hormone replacement based upon the polymorphisms present, with a small but real fraction of
them benefiting from combination T4/T3 treatment
[48]. For example, the D2 CC rs225014 polymorphism was found in 16% of a study population.
Patients with this polymorphism taking T4 had
worse baseline general health questionnaire scores,
but were noted to demonstrate improved scores on
combination T4/T3 therapy. Interestingly, Nygaard
et al. [27] noted that about two-thirds of the patients
on T4 monotherapy who were offered participation
in a T4/T3 combination therapy trial declined the
opportunity, indicating that they felt well on monotherapy, consistent with the concept that there may
exist a subgroup of patients, that is, those with a
deiodinase or other polymorphism affecting tissue
availability of T3.
As multiple studies have demonstrated no
benefit of combination therapy, the results of a
study by Celi et al. [54,55] indicating benefit from
L-T3 therapy compared to L-T4 in hypothyroid
patients were rather surprising. These workers noted
a greater degree of weight loss, reduced serum
cholesterol, low-density lipoprotein-cholesterol,
and apolipoprotein B when patients were taking
T3 [55]. Equivalent baseline and thyrotropin releasing hormone-stimulated TSH levels were achieved,
but there were no changes noted in fasting glucose,
insulin sensitivity as measured by the hyperinsulinemic-euglycemic clamp, heart rate, blood pressure,
or exercise tolerance while on T3 versus T4 treatment. T3 was administered in three daily doses and
was associated with TSH levels not significantly
464

www.co-endocrinology.com

different from those noted while taking L-T4. This

study has rekindled interest in potential benefits of
adding T3 to the therapy of hypothyroid patients,
and in addition, the D2 polymorphism studies point
to the subpopulation most likely to benefit from
such combined therapy.
A very recent study by Hoang et al. [56 ] is of
interest because of the comparison of treatment
with desiccated thyroid extract (containing T3) to
therapy with L-T4 alone in 70 patients on levothyroxine. This was a prospective, double-blind,
randomized crossover trial of therapy for 6 weeks
with dosage adjustment to maintain serum TSH
between 0.5 and 3.0 mU/l. Outcome measurements,
in addition to biochemical parameters, included
four psychometric test profiles that included the
Wechsler Memory Scale, a QOL, and a thyroid symptom questionnaire, and the Beck Depression Inventory. Although there was no improvement noted in
QOL, patients on desiccated thyroid extract enjoyed
weight loss of approximately 3 lbs in spite of having
a slightly higher serum TSH level, while having
higher serum T3 and lower serum T4 levels. This
degree of weight loss, presumably attributable to
higher T3 levels, is comparable to that seen in the
study of Celi et al. [55] and could reflect effects
on caloric expenditure mediated through thyroid
hormone receptor a. After decades of shunning
therapy with desiccated thyroid extract, this study
should cause endocrinologists to consider relooking
at a trial of treatment in those patients who remain
symptomatic on L-T4 monotherapy.
&

CONCLUSION
In spite of these more recent studies that would
appear to reopen the debate on combination
T3/T4 therapy, compelling data that would form
the basis for a guideline to such therapy are lacking. Hence, the recent guidelines of the American
Thyroid Association and the American Association
of Clinical Endocrinologists for treatment of
hypothyroidism [57,58] state that although the
satisfaction level of patients on LT4 is not the same
as euthyroid controls, studies of combination
therapy fail to show an advantage, and long-term
benefits of T4/T3 are not known, nor is it known
whether genotyping will identify patients who
will benefit from T4/T3, and they conclude that
treatment is best accomplished using synthetic
LT4.
Certainly, imprecise dosing with current T3
preparations is undesirable in view of the risks of
overdosage or underdosage causing subclinical
hyperthyroidism or subclinical hypothyroidism,
respectively, thereby precluding optimal results
Volume 20
Number 5
October 2013

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

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

with their use. Availability of a more physiologic

slow release T3 product could be of considerable
interest to marketers of products for thyroid hormone replacement but proof of true slow release
over 24 h to enable once a day dosing will first need
to be forthcoming. In this regard, a recent abstract
has reported that the oral administration of a single
dose of T3 sulfate maintains serum T3 levels in a
steady state for at least 24 h [59]. To be comparable
to the physiologic state, a T3/T4 compound would
presumably mimic the molar ratio of T4/T3 secreted
by the thyroid gland, and would achieve both a
normal TSH level and a normal T3 level or normal
FT3/FT4 ratio. In patients who continue to be symptomatic while on T4 monotherapy, perhaps the clue
to the presence of a D2 gene polymorphism would
be a higher than normal free T4/free T3 molar ratio.
Until the ideal compound and a more evidencebased approach becomes available, clinicians treating such a patient with symptoms suggestive of
insufficient thyroid hormone replacement could
consider adding T3 as a therapeutic trial, 5 mg two
to three times daily. However, given the presence of
a small segment of the population with D2 polymorphisms, it would be preferable to perform a
clinical trial of T3/T4 in that fraction of the patient
population who claim to be symptomatic on T4
alone. Such an experimental trial has been recommended within the guidelines of the European
Thyroid Association (ETA) [60 ,61]. On the other
hand, the American Thyroid Association and
American Association of Clinical Endocrinologists
guidelines reflect continuing doubt and maintain
that the best management for thyroid hormone
replacement remains levothyroxine alone [57].
&&

Acknowledgements
None.
Conflicts of interest
L.W. serves as a consultant to Asurogen, Genzyme, and
IBSA, with no perceived conflict of interest to the content
of this article.

REFERENCES AND RECOMMENDED

READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
&
of special interest
&& of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (p. 499).
1. Cooper DS. Combined T4 and T3 therapy: back to the drawing board. JAMA
2003; 290:30023004.
2. Kaplan MM, Sarne DH, Schneider AB. Editorial: in search of the
impossible dream? Thyroid hormone replacement therapy that treats all
symptoms in all hypothyroid patients. J Clin Endocrinol Metab 2003;
88:45404542.

3. Carr D, McLeod DT, Parry G, et al. Fine adjustment of thyroxine replacement

dosage: comparison of the thyrotrophin releasing hormone test using a
sensitive thyrotrophin assay with measurement of free thyroid hormones
and clinical assessment. Clin Endocrinol 1988; 28:325333.
4. Bunevicius R, Kazanavicius G, Zalinkevicius R, Prange AJ Jr. Effects of
thyroxine as compared with thyroxine plus triiodothyronine in patients with
hypothyroidism. N Engl J Med 1999; 340:424429.
5. Canaris GJ, Manowitz NR, Mayor GM, Ridgway EC. The Colorado thyroid
disease prevalence study. Arch Int Med 2000; 160:526534.
6. Ross DS, Daniels GH, Gouveia D. The use and limitations of a chemiluminescent thyrotropin assay as a single thyroid function test in an outpatient
endocrine clinic. J Clin Endocrinol Metab 1990; 71:764769.
7. Parle JV, Franklyn JA, Cross KW, et al. Thyroxine prescription in the
community: serum thyroid stimulating hormone level assays as an indicator of undertreatment or overtreatment. Br J Gen Pract 1993; 43:107109.
8. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T4, and thyroid
antibodies in the United States population (19881994): National Health
and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab
2002; 87:489499.
9. Saravanan P, Chau 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) 2002; 57:
577585.
10. Wartofsky L. Combined levotriiodothyronine and levothyroxine therapy for
hypothyroidism: are we a step closer to the magic formula? Thyroid 2004;
14:247248.
11. Escobar-Morreale HF, Escobar del Rey FE, Obregon MJ, Morreale de
Escobar G. Only the combined treatment with thyroxine and triiodothyronine
ensures euthyroidism in all tissues of the thyroidectomized rat. Endocrinology
1996; 137:24902502.
12. Smith RN, Taylor SA, Massey JC. Controlled clinical trial of combined
triiodothyronine and thyroxine in the treatment of hypothyroidism. Br Med J
1970; 4:145148.
13. Peters A, Ehlers M, Blank B, et al. Excess triiodothyronine as a risk factor of
coronary events. Arch Intern Med 2000; 160:19931999.
14. Toft AD. Thyroid hormone replacement: one hormone or two? N Engl J Med
1999; 340:469470.
15. Clyde PW, Harari AE, Getka EJ, Shakir KMM. Combined levothyroxine plus
liothyronine compared with levothyroxine alone in primary hypothyroidism.
JAMA 2003; 290:29522958.
16. Levitt A, Silverberg J. T4 plus T3 treatment for hypothyroidism: a double-blind
comparison with usual T4. Program 74th Annual Meeting, American Thyroid
Association, Los Angeles, CA, 2002. Vol. 4 p. 112.
17. Sawka AM, Gerstein HC, Marriott MJ, 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 doubleblind, randomized, controlled trial. J Clin Endocrinol Metab 2003; 88:4551
4555.
18. Walsh JP, Shiels L, Lim EM, 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 2003; 88:45434550.
19. Cassio A, Cacciari E, Cicognani A, et al. Treatment for congenital hypothyroidism: thyroxine alone or thyroxine plus triiodothyronine? Pediatrics
2003; 111:10551060.
20. Saravanan P, Simmons DJ, Greenwood R, et al. Partial substitution of
thyroxine (T4) with tri-iodothyronine in patients on T4 replacement therapy:
results of a large community-based randomized controlled trial. J Clin
Endocrinol Metab 2005; 90:805812.
21. Appelhof BC, Fliers E, Wekking EM, 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; 90:2666
2674.
22. Escobar-Morreale HF, Botella-Carretero JI, Gomez-Bueno M, et al. Thyroid
hormone replacement therapy in primary hypothyroidism: a randomized trial
comparing L-thyroxine plus liothyronine with L-thyroxine alone. Ann Intern Med
2005; 142:412424.
23. Fadeyev VV, Morgunova TB, Sytch JP, Melnichenko GA. TSH and thyroid
hormones concentrations in patients with hypothyroidism receiving replacement therapy with l-thyroxine alone or in combination with l-triiodothyronine.
Hormones 2005; 4:101107.
24. Regalbuto C, Maiorana R, Alagona C, et al. Effects of either LT4 monotherapy
or LT4/LT3 combined therapy in patients totally thyroidectomized for thyroid
cancer. Thyroid 2007; 17:323331.
25. Rodriguez T, Lavis VR, Meininger JC, et al. 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; 11:223233.
26. Siegmund W, Spieker K, Weike AI, et al. 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 2004; 60:750757.

1752-296X 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins

www.co-endocrinology.com

465

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Thyroid
27. Nygaard B, Jensen EW, Kvetny J, et al. Effect of combination therapy with
thyroxine (T4) and 3,5,3-triiodothyronine versus T4 monotherapy in patients
with hypothyroidism, a double-blind, randomised cross-over study. Eur J
Endocrinol 2009; 161:895902.
28. Grozinsky-Glasberg S, Fraser A, Nahshoni E, et al. Thyroxine-triiodothyronine
combination therapy versus thyroxine monotherapy for clinical hypothyroidism: meta-analysis of randomized controlled trials. J Clin Endocrinol Metab
2006; 91:25922599.
29. Ma C, Xie J, Huang X, et al. Thyroxine alone or thyroxine plus triiodothyronine
replacement therapy for hypothyroidism. Nucl Med Commun 2009; 30:586
593.
30. Joffe RT, Brimacombe M, Levitt AJ, Stagnaro-Green A. Treatment of clinical
hypothyroidism with thyroxine and triiodothyronine: a literature review and
metaanalysis. Psychosomatics 2007; 48:379384.
31. Bunevicius R, Prange AJ Jr. Mental improvement after replacement therapy
with thyroxine plus triiodothyronine: relationship to cause of hypothyroidism.
Int J Neuropsychopharmacol 2000; 3:167174.
32. Bunevicius R, Jakuboniern N, Jurkevicius R, et al. Thyroxine vs. thyroxine plus
triiodothyronine in treatment of hypothyroidism after thyroidectomy for
Graves disease. Endocr J 2002; 18:129133.
33. Hennemann G, Docter R, Visser TJ, et al. Thyroxine plus low-dose, slowrelease triiodothyronine replacement in hypothyroidism: proof of principle.
Thyroid 2004; 14:271275.
34. Pilo A, Iervasi G, Vitek F, et al. Thyroidal and peripheral production of 3,5,3triiodothyronine in humans by multicompartmental analysis. Am J Physiol
1990; 258:E715E726.
35. Bianco AC, Salvatore D, Gereben B, et al. Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases.
Endocr Rev 2002; 23:3889.
36. Biondi B, Cooper DS. The clinical significance of subclinical thyroid dysfunction. Endocr Rev 2008; 29:76131.
37. Surks MI, Boucai L. Age- and race-based serum thyrotropin reference limits.
J Clin Endocrinol Metab 2010; 95:496502.
38. Liewendahl K, Helenius T, Lamberg BA, et al. Free thyroxine, free triiodothyronine, and thyrotropin concentrations in hypothyroid and thyroid carcinoma patients receiving thyroxine therapy. Acta Endocrinol (Copenh) 1987;
116:418424.
39. Woeber KA. 2002 Levothyroxine therapy and serum free thyroxine and
free triiodothyronine concentrations. J Endocrinol Invest 2002; 25:106
109.
40. Jonklaas J, Davidson B, Bhagat S, Soldin SJ. Triiodothyronine levels in
athyreotic individuals during levothyroxine therapy. JAMA 2008; 299:769
777.
41. Fish LH, Schwartz HL, Cavanaugh J, et al. Replacement dose, metabolism,
and bioavailability of levothyroxine in the treatment of hypothyroidism. Role of
triiodothyronine in pituitary feedback in humans. N Engl J Med 1987; 316:
764770.
42. Biondi B, Cooper DS. Benefits of thyrotropin suppression versus the risks of
adverse effects in differentiated thyroid cancer. Thyroid 2010; 20:135
146.
43. Gullo D, Latina A, Frasca F, et al. Levothyroxine monotherapy cannot
guarantee euthyroidism in all athyreotic patients. PLoS One 2011; 6:
e22552.
44. Peeters RP, van den Beld AW, van Toor H, et al. A polymorphism in type I
deiodinase is associated with circulating free insulin-like growth factor I levels
and body composition in humans. J Clin Endocrinol Metab 2005; 90:256
263.
45. Mentuccia D, Proietti-Pannunzi L, Tanner K, et al. Association between a novel
variant of the human type 2 deiodinase gene Thr92Ala and insulin resistance:
evidence of interaction with the Trp64Argvariant of the beta-3-adrenergic
receptor. Diabetes 2002; 51:880883.

466

www.co-endocrinology.com

46. Gumieniak O, Perlstein TS, Williams JS, et al. Ala92 type 2 deiodinase allele
increases risk for the development of hypertension. Hypertension 2007;
49:461466.
47. Butler PW, Smith SM, Linderman JD, et al. The Thr92Ala 5 type 2 deiodinase
gene polymorphism is associated with a delayed triiodothyronine secretion in
response to the thyrotropin-releasing hormone-stimulation test: a pharmacogenomic study. Thyroid 2010; 20:14071412.
48. Panicker V, Saravanan P, Vaidya B, et al. Common variation in the DIO2 gene
predicts baseline psychological well being and response to combination
thyroxine plus triiodothyronine therapy in hypothyroid patients. J Clin Endocrinol Metab 2009; 94:16231629.
49. Appelhof BC, Peeters RP, Wiersinga WM, et al. Polymorphisms in type
2deiodinase are not associated with well being, neurocognitive functioning,
and preference for combined thyroxine/3,5,3-triiodothyronine therapy. J Clin
Endocrinol Metab 2005; 90:62966299.
50. Heemstra KA, Hoftijzer HC, van der Deure WM, et al. Thr92Ala polymorphism
in the type 2 deiodinase is not associated with T4 dose in athyroid patients or
patients with Hashimoto thyroiditis. Clin Endocrinol (Oxf) 2009; 71:279283.
51. Torlontano M, Durante C, Torrente I, et al. Type 2 deiodinase polymorphism
(threonine 92 alanine) predicts L-thyroxine dose to achieve target thyrotropin
levels in thyroidectomized patients. J Clin Endocrinol Metab 2008; 93:910
913.
52. Bunevicius R, Prange AJ. Mental improvement after replacement therapy with
thyroxine plus triiodothyronine: relationship to cause of hypothyroidism. Int J
Neuropsychopharmacol 2000; 3:167174.
53. Hoftijzer HC, Heemstra KA, Visser TJ, et al. The type 2 deiodinase ORFaGly3Asp polymorphism (rs12885300) influences the set point of the hypothalamus-pituitary-thyroid axis in patients treated for differentiated thyroid
carcinoma. J Clin Endocrinol Metab 2011; 96:E1527E1533.
54. Celi FS, Zemskova M, Linderman JD, et al. The pharmacodynamic equivalence
of levothyroxine and liothyronine: a randomized, double blind, cross-over study
in thyroidectomized patients. Clin Endocrinol 2010; 72:709715.
55. Celi FS, Zemskova M, Linderman JD, et al. Metabolic effects of liothyronine
therapy in hypothyroidism: a randomized, double-blind, crossover trial
of liothyronine versus levothyroxine. J Clin Endocrinol Metab 2011; 96:
34663474.
56. Hoang TD, Olsen CH, Mai VQ, et al. Desiccated thyroid extract compared to
&
levothyroxine in the treatment of hypothyroidism: a randomized, double-blind,
crossover study. J Clin Endocrinol Metab 2013; 98:19821990.
Note that this study was not strictly speaking a comparison of T4 monotherapy to
therapy with T4 and T3.
57. Garber JR, Cobin RH, Gharib H, et al., American Association of Clinical
Endocrinologists and American Thyroid Association Taskforce on Hypothyroidism in Adults. Clinical practice guidelines for hypothyroidism in adults:
cosponsored by the American Association of Clinical Endocrinologists and
the American Thyroid Association. Thyroid 2012; 22:12001235.
58. Garber JR, Cobin RH, Gharib H, et al., American Association of Clinical
Endocrinologists and American Thyroid Association Taskforce on Hypothyroidism in Adults. Clinical practice guidelines for hypothyroidism in adults:
cosponsored by the American Association of Clinical Endocrinologists and
the American Thyroid Association. Endocr Pract 2012; 18:9881028;
Erratum in: Endocr Pract. 2013 Jan-Feb;19:175.
59. Santini F, Giannetti M, Ricco I, et al. Steady state serum T3 concentrations for
48 h following the oral administration of a single dose of T3 sulfate [abstract].
Endocrine Society 2013 Annual Meeting.
60. Wiersinga WM, Duntas L, Fadeyev V, et al. Guidelines: the use of L-T4 L-T3
&&
in the treatment of hypothyroidism. Eur Thyroid J 2012; 1:5557.
An insightful editorial comment on the controversy.
61. Perros P. European Thyroid Association Guidelines on L-T4 L-T3 combination for hypothyroidism: a weary step in the right direction. Eur Thyroid J 2012;
1:5154.

Volume 20
Number 5
October 2013

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.