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 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.

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 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.

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, 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 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

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 thyroxine-binding 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 Walsh, et al 200331 Siegmund, et al 200430 Rodriguez, et al 200533 Escobar-Morreale 200534 Saravanan 200535
Number of study participants (n)/cohort 33
Patients with chronic autoimmune thyroiditis or thyroid cancer treated by near-total thyroidectomy
10
Women with sub-total thyroidectomy for Graves’ disease
46
Ages 24–65 with primary hypothyroidism
40
Patients with depressive symptoms and primary hypothyroidism
110
85% autoimmune or idiopathic hypothyroidism. Remaining had post-surgical hypothyroidism,Graves’ disease, and Hashimoto’s disease.
23
Hypothyroidism due to surgery/radioiodine (21) or autoimmune thyroiditis (2)
27
Primary hypothyroidism
28
Women with overt primary hypothyroidism
697
Family practice patients 18–75 with T4 dose > 100 mcg/day and no T4 adjustments in the past 3 months. Thyroid CA and Secondary Hypothyroidism excluded.
Study design Randomized control, crossover-design Double blind, cross-over study Randomized control trial Randomized control trial Double blind, randomized control trial with cross-over design Double blind, randomized control trial with cross-over design Double blind, randomized control trial with cross-over design Double blind, randomized cross-over trial Double blind, randomized cross-over trial
Treatment Original T4 dosage at baseline vs original dosage minus 50 mcg T4 replaced by 12.5 mcg of T3 per day. Original T4 dosage at baseline vs original dosage minus 50 mcg T4 replaced by 10 mcg T3 per day. Original T4 dosage at baseline vs original dosage minus 50 mcg T4 replaced with 7.5 mcg T3 given twice a day. Original T4 dose at baseline vs half of original T4 dosage plus 12.5 mcg of T3 twice a day. Original T4 dosage vs original dose minus 50 mcg T4 plus 10 mcg T3 once a day. Original T4 dosage vs original does minus 5% T4 replaced by T3 in that amount once a day. Original T4 dosage vs original dose minus 50 mcg T4 replaced by 10 mcg T3 once a day. 100 mcg T4e vs 75 mcg T4 plus 5 mcg T3.All pts received 87.5 mcg thyroxine plus 7.5 mcg T3 per day during the last 8 weeks. Original T4 dosage vs original dose minus 50 mcg T4 plus 10 mcg T3 per day.
Length of study periods (in weeks) 5 5 16 15 10 12 6 8 12
Improved condition from combination therapy Significant improvement in 2/8 cognitive tests; 4/9 mood scores; 4/8 mood reports; 3/7 physical symptoms. Symptoms tended to decrease after combined treatment. Mental state tended to improve with combined treatment, cognitive tests did not improve. No changes measured by HRQL questionnaire and standard measures of cognitive performance. No changes detected by all subscalres of the Symptom Check List-90, the Comprehensive Epidemiological Screen for Depression, and the Multiple Outcome Study. No changes in cognitive function, quality of life scores, Thyroid Symptom Questionaire scores, subjective satisfaction with treatment, or 8 of 10 visual analog scales. No improvement in mood scores, cognitive performance vs T4 monotherapy. No changes in measures of fatigue, symptoms of depression, or working memory. No objective advantage was identified with the combination treatment; however, subjective tests found a significant preference of patients for the combination treatment. Possibly a subgroup of patients showing transient improvement with combined Rx/No conclusive evidence of specific benefits. Large, sustained placebo effect also seen.
Bunevicius, et al 19997 Bunevicius 200232 Clyde, et al 200328 Sawka, et al 200329 Walsh, et al 200331 Siegmund, et al 200430 Rodriguez, et al 200533 Escobar-Morreale 200534 Saravanan 200535
Number of study participants (n)/cohort 33
Patients with chronic autoimmune thyroiditis or thyroid cancer treated by near-total thyroidectomy
10
Women with sub-total thyroidectomy for Graves’ disease
46
Ages 24–65 with primary hypothyroidism
40
Patients with depressive symptoms and primary hypothyroidism
110
85% autoimmune or idiopathic hypothyroidism. Remaining had post-surgical hypothyroidism,Graves’ disease, and Hashimoto’s disease.
23
Hypothyroidism due to surgery/radioiodine (21) or autoimmune thyroiditis (2)
27
Primary hypothyroidism
28
Women with overt primary hypothyroidism
697
Family practice patients 18–75 with T4 dose > 100 mcg/day and no T4 adjustments in the past 3 months. Thyroid CA and Secondary Hypothyroidism excluded.
Study design Randomized control, crossover-design Double blind, cross-over study Randomized control trial Randomized control trial Double blind, randomized control trial with cross-over design Double blind, randomized control trial with cross-over design Double blind, randomized control trial with cross-over design Double blind, randomized cross-over trial Double blind, randomized cross-over trial
Treatment Original T4 dosage at baseline vs original dosage minus 50 mcg T4 replaced by 12.5 mcg of T3 per day. Original T4 dosage at baseline vs original dosage minus 50 mcg T4 replaced by 10 mcg T3 per day. Original T4 dosage at baseline vs original dosage minus 50 mcg T4 replaced with 7.5 mcg T3 given twice a day. Original T4 dose at baseline vs half of original T4 dosage plus 12.5 mcg of T3 twice a day. Original T4 dosage vs original dose minus 50 mcg T4 plus 10 mcg T3 once a day. Original T4 dosage vs original does minus 5% T4 replaced by T3 in that amount once a day. Original T4 dosage vs original dose minus 50 mcg T4 replaced by 10 mcg T3 once a day. 100 mcg T4e vs 75 mcg T4 plus 5 mcg T3.All pts received 87.5 mcg thyroxine plus 7.5 mcg T3 per day during the last 8 weeks. Original T4 dosage vs original dose minus 50 mcg T4 plus 10 mcg T3 per day.
Length of study periods (in weeks) 5 5 16 15 10 12 6 8 12
Improved condition from combination therapy Significant improvement in 2/8 cognitive tests; 4/9 mood scores; 4/8 mood reports; 3/7 physical symptoms. Symptoms tended to decrease after combined treatment. Mental state tended to improve with combined treatment, cognitive tests did not improve. No changes measured by HRQL questionnaire and standard measures of cognitive performance. No changes detected by all subscalres of the Symptom Check List-90, the Comprehensive Epidemiological Screen for Depression, and the Multiple Outcome Study. No changes in cognitive function, quality of life scores, Thyroid Symptom Questionaire scores, subjective satisfaction with treatment, or 8 of 10 visual analog scales. No improvement in mood scores, cognitive performance vs T4 monotherapy. No changes in measures of fatigue, symptoms of depression, or working memory. No objective advantage was identified with the combination treatment; however, subjective tests found a significant preference of patients for the combination treatment. Possibly a subgroup of patients showing transient improvement with combined Rx/No conclusive evidence of specific benefits. Large, sustained placebo effect also seen.
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 Walsh, et al 200331 Siegmund, et al 200430 Rodriguez, et al 200533 Escobar-Morreale 200534 Saravanan 200535
Number of study participants (n)/cohort 33
Patients with chronic autoimmune thyroiditis or thyroid cancer treated by near-total thyroidectomy
10
Women with sub-total thyroidectomy for Graves’ disease
46
Ages 24–65 with primary hypothyroidism
40
Patients with depressive symptoms and primary hypothyroidism
110
85% autoimmune or idiopathic hypothyroidism. Remaining had post-surgical hypothyroidism,Graves’ disease, and Hashimoto’s disease.
23
Hypothyroidism due to surgery/radioiodine (21) or autoimmune thyroiditis (2)
27
Primary hypothyroidism
28
Women with overt primary hypothyroidism
697
Family practice patients 18–75 with T4 dose > 100 mcg/day and no T4 adjustments in the past 3 months. Thyroid CA and Secondary Hypothyroidism excluded.
Study design Randomized control, crossover-design Double blind, cross-over study Randomized control trial Randomized control trial Double blind, randomized control trial with cross-over design Double blind, randomized control trial with cross-over design Double blind, randomized control trial with cross-over design Double blind, randomized cross-over trial Double blind, randomized cross-over trial
Treatment Original T4 dosage at baseline vs original dosage minus 50 mcg T4 replaced by 12.5 mcg of T3 per day. Original T4 dosage at baseline vs original dosage minus 50 mcg T4 replaced by 10 mcg T3 per day. Original T4 dosage at baseline vs original dosage minus 50 mcg T4 replaced with 7.5 mcg T3 given twice a day. Original T4 dose at baseline vs half of original T4 dosage plus 12.5 mcg of T3 twice a day. Original T4 dosage vs original dose minus 50 mcg T4 plus 10 mcg T3 once a day. Original T4 dosage vs original does minus 5% T4 replaced by T3 in that amount once a day. Original T4 dosage vs original dose minus 50 mcg T4 replaced by 10 mcg T3 once a day. 100 mcg T4e vs 75 mcg T4 plus 5 mcg T3.All pts received 87.5 mcg thyroxine plus 7.5 mcg T3 per day during the last 8 weeks. Original T4 dosage vs original dose minus 50 mcg T4 plus 10 mcg T3 per day.
Length of study periods (in weeks) 5 5 16 15 10 12 6 8 12
Improved condition from combination therapy Significant improvement in 2/8 cognitive tests; 4/9 mood scores; 4/8 mood reports; 3/7 physical symptoms. Symptoms tended to decrease after combined treatment. Mental state tended to improve with combined treatment, cognitive tests did not improve. No changes measured by HRQL questionnaire and standard measures of cognitive performance. No changes detected by all subscalres of the Symptom Check List-90, the Comprehensive Epidemiological Screen for Depression, and the Multiple Outcome Study. No changes in cognitive function, quality of life scores, Thyroid Symptom Questionaire scores, subjective satisfaction with treatment, or 8 of 10 visual analog scales. No improvement in mood scores, cognitive performance vs T4 monotherapy. No changes in measures of fatigue, symptoms of depression, or working memory. No objective advantage was identified with the combination treatment; however, subjective tests found a significant preference of patients for the combination treatment. Possibly a subgroup of patients showing transient improvement with combined Rx/No conclusive evidence of specific benefits. Large, sustained placebo effect also seen.
Bunevicius, et al 19997 Bunevicius 200232 Clyde, et al 200328 Sawka, et al 200329 Walsh, et al 200331 Siegmund, et al 200430 Rodriguez, et al 200533 Escobar-Morreale 200534 Saravanan 200535
Number of study participants (n)/cohort 33
Patients with chronic autoimmune thyroiditis or thyroid cancer treated by near-total thyroidectomy
10
Women with sub-total thyroidectomy for Graves’ disease
46
Ages 24–65 with primary hypothyroidism
40
Patients with depressive symptoms and primary hypothyroidism
110
85% autoimmune or idiopathic hypothyroidism. Remaining had post-surgical hypothyroidism,Graves’ disease, and Hashimoto’s disease.
23
Hypothyroidism due to surgery/radioiodine (21) or autoimmune thyroiditis (2)
27
Primary hypothyroidism
28
Women with overt primary hypothyroidism
697
Family practice patients 18–75 with T4 dose > 100 mcg/day and no T4 adjustments in the past 3 months. Thyroid CA and Secondary Hypothyroidism excluded.
Study design Randomized control, crossover-design Double blind, cross-over study Randomized control trial Randomized control trial Double blind, randomized control trial with cross-over design Double blind, randomized control trial with cross-over design Double blind, randomized control trial with cross-over design Double blind, randomized cross-over trial Double blind, randomized cross-over trial
Treatment Original T4 dosage at baseline vs original dosage minus 50 mcg T4 replaced by 12.5 mcg of T3 per day. Original T4 dosage at baseline vs original dosage minus 50 mcg T4 replaced by 10 mcg T3 per day. Original T4 dosage at baseline vs original dosage minus 50 mcg T4 replaced with 7.5 mcg T3 given twice a day. Original T4 dose at baseline vs half of original T4 dosage plus 12.5 mcg of T3 twice a day. Original T4 dosage vs original dose minus 50 mcg T4 plus 10 mcg T3 once a day. Original T4 dosage vs original does minus 5% T4 replaced by T3 in that amount once a day. Original T4 dosage vs original dose minus 50 mcg T4 replaced by 10 mcg T3 once a day. 100 mcg T4e vs 75 mcg T4 plus 5 mcg T3.All pts received 87.5 mcg thyroxine plus 7.5 mcg T3 per day during the last 8 weeks. Original T4 dosage vs original dose minus 50 mcg T4 plus 10 mcg T3 per day.
Length of study periods (in weeks) 5 5 16 15 10 12 6 8 12
Improved condition from combination therapy Significant improvement in 2/8 cognitive tests; 4/9 mood scores; 4/8 mood reports; 3/7 physical symptoms. Symptoms tended to decrease after combined treatment. Mental state tended to improve with combined treatment, cognitive tests did not improve. No changes measured by HRQL questionnaire and standard measures of cognitive performance. No changes detected by all subscalres of the Symptom Check List-90, the Comprehensive Epidemiological Screen for Depression, and the Multiple Outcome Study. No changes in cognitive function, quality of life scores, Thyroid Symptom Questionaire scores, subjective satisfaction with treatment, or 8 of 10 visual analog scales. No improvement in mood scores, cognitive performance vs T4 monotherapy. No changes in measures of fatigue, symptoms of depression, or working memory. No objective advantage was identified with the combination treatment; however, subjective tests found a significant preference of patients for the combination treatment. Possibly a subgroup of patients showing transient improvement with combined Rx/No conclusive evidence of specific benefits. Large, sustained placebo effect also seen.

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. 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. 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 mono-therapy).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. Hypothyroid-specific 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.

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.

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 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 deiodinase double knock-out mice had normal serum T3 levels and only mild neurological impairments.53 Type III deiodinase is also strongly expressed in neurons,54 where it catalyzes deiodination 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 production of active T3 and suggest that other yet unknown deiodinases may play a role in the conversion of T4 to T3. Due to the need for peripheral conversion, deiodinase activity is particularly important in T4 monotherapy.

Figure 2

Challenges in thyroid hormone replacement therapy.

Figure 3

The metabolism of T3 and T4 into active and inactive intermediates involves the action of 3 types of deiodinases. The thyroid gland secretes approximately 100 μg of T4 and 6 μg of T3 daily.87 An additional 24 μg of T3 is produced as a result of the deiodination of T4 in extrathyroidal tissues.87 Thyroid hormone is activated when the prohormone T4 is converted to the active hormone (T3) through the removal of an iodine atom from its outer ring and deactivated when an iodine atom is removed from its inner ring (which converts thyroxine to the inactive rT3). Deiodination occurs mainly within the cells; thus, cell-specific deiodinases play an important role in determining the activity of thyroid hormone. Three deiodinases are found in humans: (1) Type 1 (found mainly in the liver and kidney), which can remove iodine both rings; (2) Type 2 (found mainly in skeletal muscle and in the heart, fat, thyroid, and central nervous system [including the brain]), which can induce deiodination in the outer ring, 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 20% of T3 is actually made in the thyroid gland. It has been observed that tissues in need of thyroid hormone convert T4 to T3 at different rates; therefore, the administration of T3 as well as T4 may be a better solution for hypothyroidism than T4 alone.88

The importance of the deiodinases is further illustrated by the dynamic way in which they are regulated. Deiodinase activity follows circadian rhythms, varying with the season and body tissue (due to tissue-specific variations in expression). In this context, serum thyroid hormone levels may remain steady while intracellular its concentrations vary with deiodinase activity.55 Based on the importance of deiodinases, it is plausible that patients with impaired neuronal deiodinase activity would 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 mediated by other transporters. Prospective candidates include members of the L-type amino acid transporter family and the MCT10 transporter (Figure 4).60,61 Thyroxine transport into the astrocytes may also be important in T4 monotherapy. Any impairment in T4 uptake by the astrocyte could reduce the amount of T3 delivered to the neurons. This would be a local effect in the form of small changes in T3 levels that would not be detected in peripheral circulation. It is possible that T4/T3 combination therapy may improve clinical outcomes when T4 uptake is impaired; this hypothesis has not been tested in humans.

Thyroid Hormone Receptors and Molecular Signaling in the Brain

Thyroid hormones signal through nuclear thyroid hormone receptors THR-α and THR-β as both homodimers and heterodimers. Hormone-receptor complexes bind to thyroid hormone response elements (THREs) in the promoter region of target genes, which are then transcribed (Figure 4).62,63 In the brain, THR-α1 is the most highly expressed nuclear thyroid receptor; 70%–80% of T3 binds to THR-α1.64 Despite its widespread distribution in neural tissue, deletion of all of the thyroid hormone receptors in the brain does not produce a typical hypothyroid phenotype. This suggests that the lack 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 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.

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

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 serotonin-specific 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.

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,4047 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 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.7884 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.

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Abbreviations

     
  • MALT

    mucosal-associated lymphoid tissue

  •  
  • NF-κB

    nuclear factor kappaB

  •  
  • FISH

    fluorescent in situ hybridization

  •  
  • TRH

    thyroid-releasin hormone

  •  
  • TBG

    thyroxine-binding globulin