Download The Challenges and Complexities of Thyroid Hormone Replacement

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Submitted 12.7.09 | Accepted 12.21.09
The Challenges and Complexities of Thyroid
Hormone Replacement
Shayri M. Kansagra, BS,1 Christopher R. McCudden, PhD,2 Monte S. Willis, MD, PhD2,3
(1Department of Molecular Biology, University of North Carolina at Chapel Hill, 2Department of Pathology & Laboratory Medicine,
University of North Carolina at Chapel Hill, 3McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC)
DOI: 10.1309/LMB39TH2FZGNDGIM
Abstract
Hypothyroidism is an endocrine disorder
affecting 1%-10% of the population. Symptoms
of hypothyroidism include fatigue, lethargy,
and decreased cognitive performance. The
mainstay therapy for hypothyroidism is
synthetic thyroxine (T4) because of its long
half-life and conversion to the bioactive
form 3-5-3’ triiodothyronine (T3). Recently,
treatment research has re-emerged from
clinicians who found that patients still
experienced significant psychological morbidity,
such as decreases in cognitive performance,
mood, and physical status, despite appropriate
standard T4 therapy. It was subsequently
reported that patients treated with both
T3 and T4 experienced better cognitive
functioning compared to patients treated with
T4 alone. This review discusses the current
literature comparing cognitive improvement
in combination T3/T4 therapies to T4
monotherapy in the context of the most recent
Hypothyroidism is an endocrine disorder affecting
1%-10% of the global population.1-3 Although hypothyroidism can affect any demographic, it is much more common
in women older than 60.1-3 Hypothyroidism is defined as an
inadequate production of thyroid hormones by the thyroid
gland and can cause numerous symptoms including fatigue,
weakness, weight gain, and depression. The thyroid hormones
affect every organ and cell type in the body, leading to widespread symptoms when it is lacking. Hypothyroidism can have
profound effects on the cardiovascular system,4 the endocrine
system,5-8 nervous system, and brain.8-10 Several pituitary hormones are affected by hypothyroidism including prolactin,11
LH, and FSH,12 which may underlie abnormalities in libido,
erectile dysfunction, and fertility.13 Symptoms of hypothyroidism relate to the severity of the underlying disease. The disease
ranges from sub-clinical hypothyroidism with only subtle biochemical abnormities to overt clinical hypothyroidism where
there are several severe symptoms associated with significantly
decreased thyroid hormone levels. The most severe forms of
hypothyroidism are congenital, leaving newborn children with
growth failures and permanent intellectual disability if not
treated within the first few weeks of life.14,15 However, most
clinical studies of hormone replacement therapy focus on adult
populations with later onset of hypothyroidism.
There are 2 main thyroid hormones produced by the thyroid gland, thyroxine (T4) and triiodothyronine (T3). Both
T4 and T3 are synthesized in response to thyroid stimulating
hormone (TSH) from the pituitary by follicular cells in the
biological research on thyroid metabolism and
signaling in neurons that might help explain
the conflicting cognitive results in these studies
and help develop new paradigms to test in the
future.
Keywords: hypothyroidism, thyroxine (T4),
triiodothyronine (T3), combination therapy,
thyroid hormone, thyroid gland
thyroid gland. Thyroid follicles contain a precursor protein
called thyroglobulin, which provides a backbone of tyrosine
residues that are sequentially iodinated and coupled enzymatically to yield T3 and T4. In healthy individuals, the thyroid
gland predominately produces T4, which is released into the
circulation and transported by several binding proteins to
target tissues for biological effect or further conversion. Both
endogenous and synthetic T4 (used in therapy) are converted
by peripheral tissues into T3, the most bioactive form of thyroid hormone, by a series of deiodinases. There are 3 types of
deiodinases distributed in the body, which convert T4 to T3,
and metabolize T3 into other forms such as diiodothyronine
(T2) and reverse T3 (rT3). Although these isoforms have
been traditionally considered biologically inactive, there is
evidence that rT3 is involved in regulating actin polymerization in the brain. In addition, both type I and II deiodinases
are expressed in astrocytes and neurons, supporting a specific
need for differential thyroid hormone signaling in the brain.
Thyroid hormone receptor expression is also highly regulated
in both the developing and adult brain. Two types of thyroid hormone receptors (TRα1 and TRβ1) are found in the
brain, with differing spatiotemporally expression in neurons.
Thyroid hormone receptors act both independently and cooperatively to control brain development, sensory function, and
behavior.16 Collectively, the distribution of the deiodinases,
the bioactivity of thyroid hormone metabolites, and the spatiotemporal regulation of receptors in the brain have implications in the treatment of patients with hypothyroidism.
Corresponding Author
Abbreviations
Monte S. Willis, MD, PhD
[email protected]
MALT, mucosal-associated lymphoid tissue; NF-κB, nuclear factor
kappaB; FISH, fluorescent in situ hybridization; TRH, thyroidreleasin hormone; TBG, thyroxine-binding globulin
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The necessity for biochemical regulation of thyroid hormone action in the brain is exemplified by the neurological
manifestations of hypothyroidism. Patients with hypothyroidism commonly display cognitive impairment, depression, and
other neurological dysfunctions. Accordingly, many studies
of hypothyroidism rely on the measurement of neurological
functions such as mood and cognition when comparing treatment efficacy. While there is strong evidence that cognitive
impairment and depression are associated with overt clinical
hypothyroidism, there is some controversy as to how frequently
neurological impairment occurs in sub-clinical hypothyroidism.17 In a series of studies recently reviewed,17 only 2 out of
6 reports demonstrated a clear connection between cognitive
impairment and hypothyroidism. Collectively, the literature
supports that mood and cognitive deficits occur over a range
of disease severity. Regardless of the equivocal nature of such
measures in sub-clinical disease, neurocognitive tests, such as
mood, depression, and quality of life (QOL) remain a mainstay
in studies of hypothyroidism pharmacotherapy.
Historically, patients with hypothyroidism were treated
with crude thyroid extracts, containing T4, T3, and other
compounds. With the discovery of T4, therapy shifted to use
of this purified compound. Subsequent synthesis of T3 lead to
the introduction of a combination T4 and T3 therapy, which
for several decades was considered the acceptable standard.
However, it was observed that combination therapy often
led to hyperthyroidism due to an excess T3, and as a result,
current guidelines from the American Association of Clinical
Endocrinologists recommend that clinical hypothyroidism be
treated with synthetic T4 (levothyroxine) alone.18 In addition
to the actual therapeutic agent itself, there are many other
challenges for thyroid hormone replacement therapy. These
range from compliance and dosing to drug interactions and
comorbidities. The many different facets of pharmacology
should be considered when assessing the efficacy of hypothyroidism treatment.
Recently, there has been a re-emergence of research into
the treatment of hypothyroidism as clinicians reported that
some patients continued to have symptoms of hypothyroidism despite biochemically appropriate T4 therapy.19 A series
of papers followed providing conflicting evidence regarding
the benefits of combination T3/T4 vs T4 monotherapy. This
review is focused on comparing combination T3/T4 to T4
monotherapy in the context of new and emerging complexities in thyroid hormone biology.
Diagnosis and Pathophysiology of
Hypothyroidism
Hypothyroidism is defined as the deficient production of
thyroid hormones from the thyroid gland. Hypothyroidism is
broadly classified as a primary, secondary, or tertiary disease
depending on the underlying cause. In primary disease there is
impaired hormone release from the thyroid gland; in secondary
disease, there is defective TSH signaling from the pituitary; in
tertiary or central disease, the hypothalamus fails to stimulate
thyroid hormone release.20 Hypothyroidism ranges in severity
from subclinical disease, where patients may be asymptomatic,
to full blown clinical disease, where patients are severely affected in the presence of multiple laboratory abnormalities.21
Because of the range of symptom severity and the relatively common and non-specific nature of clinical findings,
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diagnosis of hypothyroidism is highly dependent on laboratory testing. The frontline laboratory test for hypothyroidism
is thyroid-stimulating hormone (TSH). TSH is elevated in
primary hypothyroidism as the pituitary responds to the relative lack of circulating T3 and T4; TSH is abnormal in all
clinical and subclinical cases of primary hypothyroidism.21 As
the disease progresses toward clinical or overt hypothyroidism,
T4 and T3 become measurably decreased.21 In secondary and
tertiary hypothyroidism, TSH, T4, and T3 levels are variably
abnormal depending on the duration, cause, and severity of
disease. As a result of the complexity of hypothyroid etiology,
laboratory testing for hypothyroidism is complex and beyond
the scope of this review.22
In the Western world, the most common cause of hypothyroidism is Hashimoto’s thyroiditis,23 where autoantibodies
promote destruction of thyroid tissue. Several other common
causes of primary hypothyroidism are the result of treatment
for thyroid hormone excess (hyperthyroidism) including radioablation or surgical thyroidectomy.24-26 Irrespective of the
individual pathophysiology, treatment of hypothyroidism
involves thyroid hormone replacement.
History of Treatment for Hypothyroidism
Historically, before thyroid hormones were identified,
patients with hypothyroidism were treated with ovine thyroid
gland extracts. Thyroxine was isolated in 1914 and became
clinically available several decades later. Since the 1930s, T4
became the therapy of choice for hypothyroidism. Synthesis of
T3 during the 1950s led to the development of combination
therapy, which was first used clinically during the 1960s.27 It
was later found that T4 is converted to T3 through peripheral
deiodination and that an excess of T3 leads to hyperthyroidism introducing an entirely different set of symptoms (Figure
1).28 In addition to avoiding the risk for hyperthyroidism,
T4 monotherapy is widely used because of its long half-life
of (6–7 days) compared to only 2.5 days for T3. The short
half-life of T3 results in peak serum levels within 2–4 hours
following oral administration29 and accordingly the need for
relatively frequent dosing. With effective peripheral conversion, a low risk of hyperthyroidism, and less frequent dosing,
T4 is widely considered a much more convenient and effective therapy for patients.
Pharmacology of Thyroid Hormone Therapy
In standard replacement therapy, T4 is given orally at
doses of 1.6 µg/kg/day; this translates to a dose of 120 µg/
day in a 75 kg adult. However, doses range from 50–200 µg/
day in efforts to balance the risk for hyperthyroidism with
clinical symptoms of hypothyroidism.30 Dosage also depends
on the cause of hypothyroidism, where individuals with total
thyroidectomy will need higher doses of T4 than those with
mild Hashimotos' thyroiditis. Once ingested, roughly 80%
of a given dose of T4 is absorbed into the body;31 this too
is variable depending on the timing of food intake.32 Drug
formulation is also a consideration, where generic T4 may
have slightly different additives than brand name preparations
affecting absorption.33 Although studies have shown equivalence,34 it is recommended that patients stay with the same
brand over the course of therapy.35 As discussed above, there
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Figure 1_Overview of thyroid hormone regulation.
Thyroid-releasing hormone (TRH) is synthesized and
stored in the paraventricular nuclei in the hypothalamus.
TRH stimulates cells in the anterior pituitary gland to
release thyrotropin (also known as TSH) into the circulation, where it binds with receptors on cells in the thyroid
gland, thereby stimulating the release of thyroid hormone. Both inactive T4, with 4 iodine moieties attached,
and T3, with 3 iodine moieties attached, are released
as a result of this interaction. As the hypothalamus and
pituitary sense that thyroid hormones in the circulation
are inadequate, increased amounts of TRH and TSH are
secreted. Excessive thyroid hormone has an inhibitory
effect (denoted as [-]) on the secretion of TRH and TSH.
Circulating T3 and T4 bind primarily with thyroxinebinding globulin (TBG), transthyretin (pre-albumin), and
albumin. Inactive T4 is converted to active T3 in the
peripheral tissues by iodothyronine deiodinases, which
exerts its action on nuclear thyroid hormone receptors.
Table 1_Summary of Major Studies to Date Which Compared Combined T3/T4 Therapies to Single T4 Monotherapies
for Hypothyroidism
Bunevicius, et al 19997
Bunevicius 200232
Clyde, et al 200328
Sawka, et al 200329
Number of study
33 10
46
40
participants (n)/cohort Patients with chronic autoimmune
Women with sub-total thyroid-
Ages 24-65 with primary Patients with depressive
thyroiditis or thyroid cancer treated ectomy for Graves’ disease hypothyroidism symptoms and primary by near-total thyroidectomy hypothyroidism Study design
Randomized control, crossover-design Double blind, cross-over study
Randomized control trial
Randomized control trial
Treatment
Original T4 dosage at baseline vs Original T4 dosage at baseline vs Original T4 dosage at baseline vs Original T4 dose at baseline vs
original dosage minus 50 mcg T4 original dosage minus 50 mcg original dosage minus 50 mcg half of original T4 dosage replaced by 12.5 mcg of T3 per day. T4 replaced by 10 mcg T3 T4 replaced with 7.5 mcg plus 12.5 mcg of T3 twice per day. T3 given twice a day. a day. Length of study periods
5
5
(in weeks)
16
15
Improved condition from Significant improvement
Symptoms tended to decrease
No changes measured by
No changes detected by all
combination therapy in 2/8 cognitive tests; 4/9 mood after combined treatment. HRQL questionnaire and subscalres of the Symptom scores; 4/8 mood reports; 3/7 Mental state tended to improve standard measures of Check List-90, the Compre- physical symptoms. with combined treatment, cognitive performance. hensive Epidemiological cognitive tests did not improve. Screen for Depression, and the Multiple Outcome Study. 340
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are also pure T3 formulations (Liothyronine), combination
T4/T3 preparations (Liotrix; mixture of T4/T3 at a 4:1 ratio),
and animal extracts containing T4 and T3 (Thyroid United
States Pharmacopeia). These preparations are also subject to
brand and even lot to lot variability, particularly in the case
of porcine thyroid extracts.36
T4/T3 Combination Compared With T4
Monotherapy
The recent resurgence into hypothyroidism treatment
research derives from the experience of clinicians who found
that some patients remain symptomatic while on prescribed
T4 replacement therapy. For example, 1 survey conducted
in the United Kingdom revealed that patients treated with
T4 had significantly more psychological morbidity compared
with euthyroid controls.37 This was supported by findings in
animal models, where hypothyroid rats realized normal thyroid hormone levels on a combination of T3 and T4 (in the
ratio normally secreted by the rat thyroid gland) but not with
T4 monotherapy.38 This led to a landmark study by Bunevicius and colleagues who assessed whether T4/T3 combination therapy had any advantages over T4 monotherapy for
hypothyroidism (Table 1).19 To compare therapies, they used
a crossover study design with 33 patients on different regimens of monotherapy and combination therapy over 2 different 5-week periods.19 Combination therapy was achieved by
replacing 50 µg of the patient’s usual T4 dose (ranging from
100–300 µg/day) with 12.5 µg of T3.19 Patients who received
combination therapy had lower total and free T4 levels and
higher T3 levels than patients who received T4 monotherapy.
Walsh, et al 200331
Siegmund, et al 200430
It was reported that cognitive performance and mood were
significantly improved or normalized after treatment.19 These
findings prompted a series of papers aimed at assessing the potential advantages of combination therapy over monotherapy
for hypothyroidism.19,39-43
Following the landmark paper, Bunevicius and colleagues
performed a second crossover trial in women who had undergone a subtotal thyroidectomy as a treatment for Graves’
disease (Table 1).44 In this study, T4 therapy consisted of either
the patient’s regular dose of T4 or combination therapy, which
was achieved by replacing 50 µg of the usual T4 dose with 10
µg of T3. After a period of 5 weeks, the patients were crossed
over blindly to the opposite treatment. In patients who received combination therapy, the severity of symptoms of hypothyroidism and hyperthyroidism had a tendency to decrease,
as indicated by patient scores on a standard symptom scale.
Mental status also tended to improve with combination therapy
compared with monotherapy, based on apparent improvement
in mood (indicated by Visual Analogue Scale [VAS] scores).
However, there was no difference in cognitive performance improvement (indicated by improved scores on the Digit Symbol
and Digit Span tests of the Wechsler Adult Intelligence Scale).
Although this study was small (n=13), the authors concluded
its findings were consistent with those of their earlier study in
terms of demonstrating a relationship between T4/T3 combination therapy and improved mental function.44
Challenges to Combination Therapy
These initial reports suggested that a change in the treatment for primary hypothyroidism should be considered.
Rodriguez, et al 200533
Escobar-Morreale 200534
Saravanan 200535
110
23
27
28
697
85% autoimmune or idiopathic Hypothyroidism due to surgery/ Primary hypothyroidism
Women with overt primary
Family practice patients 18-75
hypothyroidism. Remaining radioiodine (21) or auto- hypothyroidism with T4 dose > 100 mcg/day
had post-surgical hypo- immune thyroiditis (2) and no T4 adjustments
thyroidism,Graves’ disease, in the past 3 months.
and Hashimoto’s disease. Thyroid CA and Secondary
Hypothyroidism excluded.
Double blind, randomized Double blind, randomized
Double blind, randomized
Double blind, randomized Double blind, randomized cross control trial with cross-over control trial with cross-over control trial with cross-over cross-over trial over trial
design design design
Original T4 dosage vs original Original T4 dosage vs original
Original T4 dosage vs original 100 mcg T4e vs 75 mcg T4
Original T4 dosage vs original
dose minus 50 mcg T4 plus does minus 5% T4 replaced by dose minus 50 mcg T4 plus 5 mcg T3. All pts received dose minus 50 mcg T4 plus
10 mcg T3 once a day.
T3 in that amount once a day. replaced by 10 mcg T3 87.5 mcg thyroxine plus 7.5 mcg 10 mcg T3 per day.
once a day. T3 per day during the last
8 weeks.
10
12
6
8
12
No changes in cognitive
No improvement in mood
No changes in measures of
No objective advantage was
Possibly a subgroup of patients
function, quality of life scores, scores, cognitive performance fatigue, symptoms of identified with the combination showing transient improvement
Thyroid Symptom Questionaire vs T4 monotherapy. depression, or working treatment; however, subjective with combined Rx/No conclusive
scores, subjective satisfaction memory. tests found a significant evidence of specific benefits.
with treatment, or 8 of 10 preference of patients for the Large, sustained placebo effect
visual analog scales. combination treatment. also seen.
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Consequently, a number of other investigators sought to
confirm these findings (Table 1). Throughout these papers are
key differences in study design. In particular it is important
to note the type of hypothyroidism in the study population
and the time period for different treatments. We therefore
provide a high level of detail necessary to allow the reader
to adequately compare the various reports.
One of the first follow-up studies was a randomized,
double-blind, placebo-controlled trial performed by Clyde
and colleagues. The study included 46 active-duty military personnel and members of their families (age range:
24–65 years) with primary hypothyroidism who had been
treated for at least 6 months with levothyroxine (T4 monotherapy).40 In this study, patients received either their usual
dose of levothyroxine or T3/T4 combination therapy, which
was achieved by reducing the levothyroxine dose by 50 µg
daily and replacing it with liothyronine (the l-isomer of
T3) at a dosage of 7.5 µg twice daily for 4 months.40 These
investigators intentionally avoided the crossover design used
by the Bunevicius team in their 1999 study to preclude the
possibility of a “testing effect” influencing patient performance. The testing effect refers to the relative improvement
patients can display simply as a result of repeating the same
cognitive test. Thus, in the study by Clyde and colleagues,
half of the patients were assigned to levothyroxine alone and
the other half to T4/T3 combination therapy. Hypothyroidspecific health-related QOL, as well as body weight, serum
lipids, and neuropsychological factors, were evaluated before
and after treatment.40 No significant difference between
levothyroxine monotherapy and combination levothyroxine/
liothyronine therapy were identified for any of these factors. Notably, the lack of improvement in psychological test
results40 was in sharp contrast to the findings of the Bunevicius team.19,44 It was discussed that these differences may
be explained by significant testing effects in the Bunevicius
study. Specifically, 76% of the thyroid cancer patients were
randomized to the control group for the first phase of the
Bunevicius crossover study. This group was therefore subject
to repeat testing after crossing to the combined therapy increasing the likelihood of improvement on T4/T3 simply
by experimental design.
In another study, Sawka and colleagues studied 40
individuals with symptoms of depression who were taking
levothyroxine for primary hypothyroidism (Table 1).41 The
investigators randomized these patients into either T4 plus a
placebo or T4/T3 combination therapy for 15 weeks. Combination therapy was achieved by reducing their pre-study T4
dose by 50% and adding 12.5 µg of T3 twice daily. The T4
and T3 doses were adjusted to maintain target TSH levels.
Extensive assessments of self-rated mood and well-being again
did not identify any differences in symptoms between the 2
treatment groups.41 The study design of the Sawka group was
considered an improvement over that of the original Bunevicius paper in several respects: (1) stable doses of T4 prior
to the study; (2) patients with symptoms of depression who
would be the most likely to exhibit improvement; and (3)
avoidance of overtreatment (many of the Bunevicius study
patients had suppressed TSH indicating excess thyroid hormone). With this study, evidence was beginning to mount
against T3/T4 combination therapy. Other studies that also
failed to detect improvement in mood and neurocognitive
measures after combination therapy are summarized in Table
1 and discussed below.
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At the same time as the report by Sawka and colleagues
described above, there was a double-blind, randomized, controlled trial with a crossover design published by Walsh and
colleagues (Table 1).43 In this study, patients with poor QOL
scores and relatively severe symptoms were selected. Of the
110 patients enrolled in this study, 85% (n=94) had autoimmune or idiopathic hypothyroidism, and the remaining 15%
(n=12) had postsurgical hypothyroidism, a history of Graves’
disease, or Hashimoto’s disease. The daily T4 dose taken by
each patient was reduced by 50 µg and replaced with either
50 µg of T4 (monotherapy) or 10 µg liothyronine (combination therapy).43 Each treatment was given for a 10-week
period, and these 2 periods were separated by a 4-week washout period, during which patients resumed their usual T4
dosage. No significant difference in cognitive function, QOL,
Thyroid Symptom Questionnaire, subjective satisfaction
with treatment, or 8 of 10 VAS scores was identified between
treatment groups.43 In the discussion, Walsh and colleagues
highlighted the importance of the treatment and washout
period lengths. They stated that the study by Bunevicius did
not allow a long enough time period (only 5 weeks) to achieve
equilibrium or to allow the effects of the previous therapy to
clear (no washout).
In another trial, Siegmund and colleagues conducted
a double-blind, randomized, controlled crossover trial42 in
23 patients with hypothyroidism due to surgery/radioablation (n=21) or autoimmune thyroiditis (n=2) (Table 1). The
patients received either 100% of their previous T4 dose or
95% of the previous dose with the remaining 5% replaced
by T3 (combination therapy). They found that TSH levels
were suppressed to a greater degree with combination therapy
than with T4 therapy alone, but measurements of mood and
cognitive function did not differ between the 2 treatment
groups.42 Interestingly, mood was significantly impaired (n=8)
and subclinical hyperthyroidism (characterized by an increase
in steady-state free T3 levels) was identified in the patients
taking combination therapy.42 These authors again cited the
short treatment period and thyroid cancer population used
in the Bunevicius study to explain the differences between
their results and the landmark report. Finally, Rodriguez and
colleagues focused on a reduction in fatigue as a clinical end
point of T4/T3 combination therapy,45 with secondary end
points consisting of improvement in depressive symptoms and
working memory, as well as the serum thyroid hormone profile and other physical parameters (Table 1).45 They selected
30 patients with a diagnosis of primary hypothyroidism stabilized with T4 monotherapy from diabetes and endocrinology
clinics. The patients were screened for evidence of significant
fatigue and symptoms of depression or anxiety. The investigators assigned patients into the following 2 categories: (1) 14
patients to a normal dose of T4 plus a placebo and (2) 16
patients to a normal T4 dose minus 50 µg combined with 10
µg of T3.45 Importantly, they used a 6-week treatment period
(versus 5 weeks in the Bunevicius trial) allowing T4 hormone
levels to reach a steady state, and added a washout period for
patients receiving combination therapy before crossing over
to the opposite treatment. While only 27 patients completed
the trial, there were no significant differences in fatigue or
symptoms of depression identified between treatment groups
suggesting that combination therapy was not significantly better than T4 monotherapy.45 Collectively, this group of studies
largely refuted the initial landmark report that combination
T4/T3 therapy improves neurocognitive measures.
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Perceived Improvements in Combination
Therapy?
In contrast to the investigations summarized above, there
are 2 recent studies supporting T3/T4 combination therapy
over T4 monotherapy for hypothyroidism. In a randomized,
double-blind, crossover trial in 28 women with overt primary
hypothyroidism, Escobar-Marraeale and colleagues46 compared the standard 100 µg daily T4 treatment with the combination of 75 µg T4 plus 5 µg liothyronine (T3) daily for 8
weeks; after this period they administered 87.5 µg T4 plus 7.5
µg T3 (add-on combination therapy) to every patient over the
subsequent 8 weeks (Table 1). No improvement in primary
or secondary end points was seen after combination therapy.
However, 12 patients preferred the combination therapy, 6
preferred the add-on combination treatment, and 2 preferred
the standard treatment (6 had no preference).46 Thus, despite
the absence of any measurable physiologic advantages, there
was a distinct preference for combination therapy.
Concerned that many of the previous studies were underpowered, Saravanan and colleagues performed the largest study to date comparing combination therapy with T4
monotherapy (Table 1). They conducted a double-blind,
randomized, and controlled trial in 697 patients with hypothyroidism. Patients received T4 monotherapy or 50 µg less of
the original T4 dose plus 10 µg of T3.47 After 3 months, the
control group demonstrated an improvement in psychiatric
scores (based on a General Health Questionnaire [GHQ])
compared to baseline (ie, placebo effect), which was sustained
for 1 year.47 Changes that could be attributed to the T3 intervention were more modest; they included improvements
in the GHQ score and the Hospital Anxiety and Depression
Analog Scale scores for mood, but the initial improvements
were lost at 12 months.47 Although these findings may be
consistent with improvement, they do not provide conclusive
evidence that combination therapy is beneficial compared to
T4 alone. They also demonstrate a large and sustained placebo
Figure 2_Challenges in thyroid hormone replacement therapy.
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effect that may make the findings of thyroid hormone administration studies difficult to evaluate.47
Overall the clinical studies comparing T4/T3 combination therapy to T4 monotherapy therapy reviewed here are
conflicting and do not justify changing currently accepted
treatment practices. While differences in study design are a
common theme in the discussions of these papers, the conflicting data may reflect our limited understanding of the
effects of thyroid activity on the brain and the complexity
of systemic and cellular regulation of T3 and T4. There are
in fact numerous additional considerations that may affect
the overall efficacy of thyroid hormone replacement therapy,
which are summarized in Figure 2. Exemplifying 1 of these
many aspects are recent studies of thyroid signaling at the
molecular level in neurons.48 This particular aspect is important, because the benefits seen with T4/T3 combination
therapy have been largely psychological in nature and, thus,
related to neurocognitive brain function.
Deiodinases and Thyroid Hormone Metabolism
The main hormone produced by the thyroid, the prohormone T4, is converted to T3 in peripheral target tissue
cells by deiodinases (Figure 3). Conversion of T4 to T3 is in
fact responsible for most of the T3 in the body. Deiodinase
activity varies from tissue to tissue. Type I deiodinase is found
mainly in the liver and kidney, Type II deiodinase in brain
astrocytes, and Type III deiodinase in brain neurons. Animal
studies have shown that approximately 80% of the active
T3 in the brain is produced locally49 by Type II deiodinase,
which catalyzes deiodination in the outer ring (Figure 3). In
the brain, Type II deiodinases are found in astrocytes, where
they convert T4 into T3.50 T3 then interacts with the α and
β thyroid receptors in oligodendrocytes and neurons. The role
of deiodinases in the production of T3 has been studied in
animal models.
A mouse model deficient
in Type II deiodinases was recently created to determine the
role of this enzyme in neuronal
function.51 Type II deiodinase
knock-out mice exhibit normal circulating T3 levels but
increased T4 and TSH levels,
supporting that Type II deiodinase regulates the hypothalamic-pituitary-thyroid axis. In the
brain, however, T4 levels were
elevated, whereas T3 levels
were substantially decreased (by
50%), indicating a reduction
in T3 production. Despite low
T3 levels in the brain, neural
function—indicated by learning, memory, and locomotor skills—was unaffected in
contrast to findings in animals
with severe hypothyroidism.52
Other studies have used mice
devoid of any 5'-deiodinase activity to assess the role of these
enzymes in brain function.
Unexpectedly, Type I/Type II
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psychologically benefit from
T3/T4 combination therapy.
Thyroid Hormone
Transporters
Prior to conversion of T4
to T3 by deiodinases in astrocytes, T4 must move across the
blood-brain barrier and into
cells. Although the transporter
responsible for this is unknown,
a possible candidate is Oatp1c1.
Oatp1c1 is a member of the
organic anion transporting
polypeptide family for which
T4, and inactive rT3, are
substrates.56,57 In parallel, T3
produced in astrocytes is transported to neurons and oligodendrocytes, where it is taken up by
the monocarboxylate transporter
8 (MCT8).58 Monocarboxylate
transporter 8 is a membrane
protein specific for T3 transport
that is highly expressed in the
liver and brain. However, T3
transport is only mildly affected
in MCT8-/- mice,59 suggesting
that uptake into neural tissue is
Figure 3_The metabolism of T3 and T4 into active and inactive intermediates involves the action of 3
mediated by other transporters.
types of deiodinases. The thyroid gland secretes approximately 100 µg of T4 and 6 µg of T3 daily.87
Prospective candidates include
An additional 24 µg of T3 is produced as a result of the deiodination of T4 in extrathyroidal tissues.87
members of the L-type amino
Thyroid hormone is activated when the prohormone T4 is converted to the active hormone (T3) through
acid transporter family and the
the removal of an iodine atom from its outer ring and deactivated when an iodine atom is removed
MCT10 transporter (Figure
from its inner ring (which converts thyroxine to the inactive rT3). Deiodination occurs mainly within the
4).60,61 Thyroxine transport
cells; thus, cell-specific deiodinases play an important role in determining the activity of thyroid horinto the astrocytes may also be
mone. Three deiodinases are found in humans: (1) Type 1 (found mainly in the liver and kidney), which
important in T4 monotherapy.
can remove iodine both rings; (2) Type 2 (found mainly in skeletal muscle and in the heart, fat, thyroid,
Any impairment in T4 uptake
and central nervous system [including the brain]), which can induce deiodination in the outer ring,
by the astrocyte could reduce
making it the main activating enzyme; and (3) Type 3 (found in fetal tissue and in the placenta), which
induces deiodination in the inner ring only and, thus is the main inactivating enzyme. Approximately
the amount of T3 delivered to
20% of T3 is actually made in the thyroid gland. It has been observed that tissues in need of thyroid
the neurons. This would be a
hormone convert T4 to T3 at different rates; therefore, the administration of T3 as well as T4 may be
local effect in the form of small
a better solution for hypothyroidism than T4 alone.88
changes in T3 levels that would
not be detected in peripheral
deiodinase double knock-out mice had normal serum T3 levels
circulation. It is possible that T4/T3 combination therapy may
and only mild neurological impairments.53 Type III deiodinase
improve clinical outcomes when T4 uptake is impaired; this
is also strongly expressed in neurons,54 where it catalyzes deiohypothesis has not been tested in humans.
dination in the inner ring, thereby inactivating local hormones
and, thus, opposing Type III deiodinase activity. These studies
identify the key roles for Type I and Type II deiodinases in the
Thyroid Hormone Receptors and Molecular
production of active T3 and suggest that other yet unknown
Signaling in the Brain
deiodinases may play a role in the conversion of T4 to T3. Due
to the need for peripheral conversion, deiodinase activity is parThyroid hormones signal through nuclear thyroid horticularly important in T4 monotherapy.
mone receptors THR-α and THR-β as both homodimers and
The importance of the deiodinases is further illustrated
heterodimers. Hormone-receptor complexes bind to thyroid
by the dynamic way in which they are regulated. Deiodinase
hormone response elements (THREs) in the promoter region
activity follows circadian rhythms, varying with the season and
of target genes, which are then transcribed (Figure 4).62,63 In
body tissue (due to tissue-specific variations in expression). In
the brain, THR-α1 is the most highly expressed nuclear thythis context, serum thyroid hormone levels may remain steady
roid receptor; 70%–80% of T3 binds to THR-α1.64 Despite
while intracellular its concentrations vary with deiodinase acits widespread distribution in neural tissue, deletion of all of
tivity.55 Based on the importance of deiodinases, it is plausible
the thyroid hormone receptors in the brain does not produce
that patients with impaired neuronal deiodinase activity would
a typical hypothyroid phenotype. This suggests that the lack
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Overview
of T3 has worse consequences than the lack of THRs (reviewed by Forrest and Vennstrom, 2000,65 Bernal, 2007,66
O’Shea and Williams, 2002,67 and Flamant and Samarut,
2003.63) It also supports thyroid hormone bioactivity that is
not dependent on canonical thyroid hormone receptors.
Thyroid Hormone Receptor-Independent
Signaling in the Brain
Thyroid hormones have been shown to exert numerous biological effects in the brain independent of THRs. For
example, thyroid hormones can influence brain function by
interacting with the p85 regulatory subunit of phosphoinositide 3-kinase (PI3K) in the cytosol (Figure 4).68 Interaction
between T3 with PI3Ks in endothelial cells is central to responses to middle cerebral artery occlusion (ie, activation of
the Akt-pathway and rapid induction of nitric oxide synthesis,
which results in a reduction in infarct size).69
Thyroxine is also capable of thyroid receptor-independent
bioactivity, where T4 binds to membrane receptors formed by
αVβ3 integrin. This complex stimulates the mitogen-activated
protein kinase (MAPK) pathway, resulting in phosphorylation
of downstream transcription factors and associated changes in
gene expression (Figure 4).70 Thyroxine and reverse T3 (rT3,
but not T3) also stimulate actin polymerization in cultured
astrocytes and cerebellar granule cells to promote neuronal
growth.71,72 In animal models, actin polymerization has been
linked to regulation of growth hormone, where hypothyroid
rats had fewer somatotrophs.
It is also known that thyroid hormones regulate mitochondria directly and indirectly. Mitochondria contain
thyroid binding elements, which allow the thyroid hormones
to regulate oxidative phosphorylation directly. Through additional complex and poorly understood signaling pathways,
thyroid hormones also regulate ATP levels by promoting
mitochondriogenesis, uncoupling protein synthesis, and
inducing proton leak.73 While these processes can occur systemically, both body temperature and energy regulation have
direct implications for brain function.
Besides the well-known thyroid hormones T4 and T3,
there are also biologically significant hormone derivatives
that were recently discovered. Thyronamine and 3-iodothyronamine (decarboxylated thyroid hormone derivatives) may
also play a role in brain function or development.74 The
complexity of T3 and T4 signaling pathways at the molecular
Figure 4_Thyroid hormone action and metabolism in the cells. The transport of T3 into target cells occurs by thyroid hormone transporters
and subsequent binding of thyroid receptor/retinoic acid (RXR) dimmers, which stimulate transcription of target genes. Thyroxine preferentially
binds αVβ3 integrins to stimulate MAPK signaling pathways; T4 and rT3 stimulate actin polymerization. Triiodothyronine has also been shown
to affect several mitochondrial functions and NO production via PI3K activation. All of these functions rely on deiodinase (D) activities (denoted
as D1-D3). Adapted from Horn and Heuer, 2009.48
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June 2010 ■ Volume 41 Number 6 ■ LABMEDICINE
345
Overview
level is just beginning to be delineated. Emerging evidence
about thyroid signaling strongly suggests the existence of independent signaling pathways for T3 and T4. It may take some
time to completely delineate the molecular signaling pathways
for T3 and T4, but this information may allow us to understand the mechanisms underlying the controversy between
T3/T4 combination and monotherapy and provide a basis
for the development of future therapeutic approaches.
T3 Treatment Augments Psychiatric Therapy
Consistent with the animal models supporting specific
needs for thyroid hormone in the brain are human studies
demonstrating that T3 influences the potency of serotonin
and catecholamine.75-77 In a recent investigation of the role
of T3 in treatment-resistant depression in patients with bipolar II disorder and bipolar disorder not otherwise specified
(BP-NOS), 84% of the patients reported improved function,
and 33% reported full remission.78 Triiodothyronine has also
been used to augment anti-depressants such as serotoninspecific reuptake inhibitors (SSRI)79,80,81 and tricyclic antidepressants (TCAs). 82 83 Triiodothyronine augmentation
for treating nonpsychotic major depressive disorder (MDD)
with lithium has also been studied. While T3 augmentation
did not improve symptoms, it was associated with fewer side
effects and less attrition.84 These studies have shown that
T3 augmentation is promising for a number of psychiatric
therapeutic regimens,85 but its application in other diseases
remains to be explored. It is possible that the improvements
seen in T3/T4 combination therapy may reflect the effects
of T3 on serotonin and catecholamine function in the brain.
the complex and poorly understood T3 and T4 signaling
in neurons. Such mechanisms may include differential signaling in response to T3 and T4 in neurons, including T4
signaling through αVβIII integrins induced by MAPK70
and T3 signaling through PI3K.68 Regardless of the mechanisms, T3 is increasingly being used as adjunct therapy in
an increasing number of psychiatric diseases because of its
positive effects on serotonin and the catecholamines.78-84
Finally, it is possible that combination therapy has no benefits, as was suggested in recent meta-analyses.86 However,
because of our incomplete knowledge of thyroid signaling
biology and the complexities of assessing the efficacy of
thyroid hormone replacement (Figure 2), it remains to be
definitively proven whether combination therapy should
replace standard treatment for hypothyroidism. LM
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a community: The Whickham survey. Clin Endocrinol (Oxf). 1977;7:481–493.
2. Vanderpump MP, Tunbridge WM, French JM, et al. The incidence of thyroid
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3. Canaris GJ, Manowitz NR, Mayor G, et al. The Colorado thyroid disease
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Summary
Over the last 4 decades, treatment for hypothyroidism
has evolved from the use of crude whole thyroid preparations
(which provided both T4 and T3) to T4 monotherapy. This
evolution is the result of technological advances, fear of iatrogenic hyperthyroidism due to excessive amounts of active
T3, and pharmacological considerations (eg, half life), which
enable convenient daily dosing for T4. During this evolution
there remained evidence that patients treated adequately with
T4 still experienced a number of symptoms, including deficits
in cognition and mood, their ability to focus, and their general mental well-being.
An early landmark study by Bunevicius and colleagues demonstrated that T4/T3 combination therapy
for hypothyroidism improved mood and cognition compared with T4 monotherapy in patients with chronic
autoimmune thyroiditis and post-thyroid cancer total
thyroidectomy.19,44 However, the use of combination
therapy remains controversial as several investigators
were unable to reproduce these findings in 6 subsequent
studies,40-47 while 2 recent studies support a benefit for
T4/T3 combination therapy in specific subsets of patients
(Table 1).46,47 In the recent large studies of thyroid function, investigators identified a substantial placebo effect,47
which has made it difficult to delineate how combination
therapy is associated with clinical benefits. It is also possible that combination therapy only works in a subset of
patients because of yet unidentified mechanisms related to
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