The Challenges and Complexities of Thyroid Hormone Replacement

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]

Table 1. Summary of Major Studies to Date Which Compared Combined T3/T4 Therapies to Single T4 Monotherapies for Hypothyroidism
	Bunevicius, et al 1999^[7]	Bunevicius 2002^[32]	Clyde, et al 2003^[28]	Sawka, et al 2003^[29]	Walsh, et al 2003^[31]	Siegmund, et al 2004^[30]	Rodriguez, et al 2005^[33]	Escobar-Morreale 2005^[34]	Saravanan 2005^[35]
Number of study participants (n)/cohort	33	10	46	40	110	23	27	28	697
	Patients with chronic autoimmune thyroiditis or thyroid cancer treated by near-total thyroidectomy	Women with sub-total thyroid-ectomy for Graves' disease	Ages 24–65 with primary hypothyroidism	Patients with depressive symptoms and primary hypothyroidism	85% autoimmune or idiopathic hypothyroidism. Remaining had post-surgical hypo-thyroidism,Graves' disease, and Hashimoto's disease.	Hypothyroidism due to surgery/radioiodine (21) or auto-immune thyroiditis (2)	Primary hypothyroidism	Women with overt primary hypothyroidism	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 1999^[7]

Bunevicius 2002^[32]

Clyde, et al 2003^[28]

Sawka, et al 2003^[29]

Walsh, et al 2003^[31]

Siegmund, et al 2004^[30]

Rodriguez, et al 2005^[33]

Escobar-Morreale 2005^[34]

Saravanan 2005^[35]

Number of study participants (n)/cohort

110

697

Patients with chronic autoimmune thyroiditis or thyroid cancer treated by near-total thyroidectomy

Women with sub-total thyroid-ectomy for Graves' disease

Ages 24–65 with primary hypothyroidism

Patients with depressive symptoms and primary hypothyroidism

85% autoimmune or idiopathic hypothyroidism. Remaining had post-surgical hypo-thyroidism,Graves' disease, and Hashimoto's disease.

Hypothyroidism due to surgery/radioiodine (21) or auto-immune thyroiditis (2)

Primary hypothyroidism

Women with overt primary hypothyroidism

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

Double blind, randomized control trial with cross-over Design

Double blind, randomized control trial with cross-over design

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)

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.

The Challenges and Complexities of Thyroid Hormone Replacement

T4/T3 Combination Compared with T4 Monotherapy

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