Substitution of Liothyronine for a Portion of Levothyroxine
Substitution of Liothyronine for a Portion of Levothyroxine
Objective: To attempt to confirm a previous report of superior effectiveness of using two thyroid hormones rather than one hormone to treat hypothyroidism.
Methods: This trial attempted to replicate prior findings, which suggested that substituting 12.5 µg of liothyronine (LT3) for 50 µg of levothyroxine (LT4) might improve mood, cognition, and physical symptoms in patients with primary hypothyroidism. Additionally, this trial aimed to extend the previous findings to fatigue and to assess for differential effects in subjects with low fatigue and high fatigue at baseline. A randomized, double-blind, two-period, crossover design was used. At an endocrinology and diabetes clinic, 30 adult subjects with primary hypothyroidism stabilized on LT4 were recruited. Patients randomly assigned to treatment sequence 1 received their standard LT4 dose in one capsule and placebo in another. Patients assigned to sequence 2 received their usual LT4 dose minus 50 µg in one capsule and 10 µg of LT3 in the other. At the end of the first 6 weeks, subjects were crossed over to receive the other treatment. Carryover and treatment effects were assessed by t tests.
Results: Of the 30 enrolled study subjects, 27 completed the trial. The mean LT4 dose was 121 ± 26 µg/day at baseline. No significant differences in fatigue and symptoms of depression were found between treatments. Measures of working memory were unchanged. During substitution treatment, the free thyroxine index was reduced by 0.7 (P<0.001), total serum thyroxine was reduced by 3.0 µg/dL (P<0.001), and total serum triiodothyronine was increased by 20.5 ng/dL (P = 0.004).
Conclusion: With regard to the outcomes measured, substitution of LT3 at a 1:5 ratio for a portion of baseline LT4 yielded no better results than did treatment with the original dose of LT4 alone.
In the United States, hypothyroidism affects as many as 9.5% of the population. Modern medical practice directs that these patients be treated with levothyroxine (LT4) alonea synthetic hormone that replaces the inactive thyroid hormone thyroxine (T4). Nevertheless, questions have been posed about the adequacy of treating hypothyroidism with only one hormone since at least the early 1970s. Reasons for this demurral are that the thyroid gland secretes triiodothyronine (T3) in addition to T4 and that some patients treated with LT4 alone report that they continue to experience symptoms of hypothyroidism. A large, controlled, community-based study recently supported the notion that psychologic well-being may be suboptimal and symptoms of hypothyroidism may be increased in hypothyroid patients treated with LT4 alone in comparison with control subjects of similar age and sex (that is, despite normal thyrotropin [thyroid-stimulating hormone or TSH] levels).
Most trials to date that have compared the use of one hormone versus two in the treatment of hypothyroidism have been hindered by limitations that necessitate further study. The earliest trial was published in 1970. At that time, sensitive measures of TSH were not yet widely available, a situation that resulted in considerable hormone overreplacement. In addition to using high doses of LT4, the 1970 trial replaced liothyronine (LT3) for LT4 on a microgram-per-microgram basis without regard for the fact that LT3 is 3 to 8 times as potent. The inevitable result was that study subjects experienced substantial side effects on the combined treatment. In 1999, a trial substituting 12.5 µg of LT3 for 50 µg of daily LT4 was reported by Bunevicius et al. This substitution ratio was more physiologic compared with that used in the earlier trial and resulted in improved mood, cognition, and physical symptoms. A commentary published concurrently, however, called for replication of findings before any change in practice could be entertained.
It was in this context that the present study was planned in 2000. Since then, additional trials have been reported, including one in infants born with congenital hypothyroidism (CH). None of these trials was able to replicate the original findings, however. In the study of infants with CH, subjects were given a substitution ratio of LT3 for LT4 of 1:5. Although not statistically significant, at 3 months the infants receiving substitution treatment had TSH values twice as high as those receiving LT4 alone. Psychometric quotients (psychomotor evaluations) in the infants with CH were significantly lower than those in healthy matched control subjects, but no significant differences were noted between infants with CH treated with LT4 alone versus substitution treatment.
In a second trial by Bunevicius et al, no significant differences were found on measures of mood, cognition, or physiologic variables between treatments. In yet another studythe largest to dateoutcomes were tissue hypothyroidism, symptoms of hypothyroidism, quality of life, depression and anxiety, cognitive functioning, and treatment satisfaction. In this study, subjects who received substitution treatment had significantly higher depression and anxiety scores in comparison with those given LT4 alone. This study also reported a mean TSH level that was twice as high (P<0.001) in patients with substitution treatment versus LT4 alone (substitution ratio, 1:5). Additionally, tissue hypothyroidism (that is, Zulewski scores) was significantly higher in those receiving the substitution intervention. Another study focused on measures of depression and found no appreciable improvement in self-reported mood when subjects received substitution treatment. In this study, however, the actual ratio of substitution varied because the protocol required that the prestudy dose of LT4 be halved and replaced by 25 µg of LT3. Then the LT3 and LT4 doses were titrated upward to maintain TSH levels within normal limits. Additionally, the report of this small trial did not include a statistical power analysis. In another trial, neurocognitive functioning and hypothyroid health-related quality of life were the primary outcomes. This trial reported no significant differences in neurocognition or quality of life between the two treatment regimens. In this report, however, the validity and reliability of the hypothyroid health-related quality-of-life instrument were not reported, and the instrument had many depression items. Finally, the most recently reported trial also failed to demonstrate any advantage with substitution treatment (ratio, 1:5). This last trial also tested a ratio of 1:1.7. Limitations to the second regimen included no randomization to treatment and a supraphysiologic dose that resulted in overreplacement of thyroid hormone.
Objective: To attempt to confirm a previous report of superior effectiveness of using two thyroid hormones rather than one hormone to treat hypothyroidism.
Methods: This trial attempted to replicate prior findings, which suggested that substituting 12.5 µg of liothyronine (LT3) for 50 µg of levothyroxine (LT4) might improve mood, cognition, and physical symptoms in patients with primary hypothyroidism. Additionally, this trial aimed to extend the previous findings to fatigue and to assess for differential effects in subjects with low fatigue and high fatigue at baseline. A randomized, double-blind, two-period, crossover design was used. At an endocrinology and diabetes clinic, 30 adult subjects with primary hypothyroidism stabilized on LT4 were recruited. Patients randomly assigned to treatment sequence 1 received their standard LT4 dose in one capsule and placebo in another. Patients assigned to sequence 2 received their usual LT4 dose minus 50 µg in one capsule and 10 µg of LT3 in the other. At the end of the first 6 weeks, subjects were crossed over to receive the other treatment. Carryover and treatment effects were assessed by t tests.
Results: Of the 30 enrolled study subjects, 27 completed the trial. The mean LT4 dose was 121 ± 26 µg/day at baseline. No significant differences in fatigue and symptoms of depression were found between treatments. Measures of working memory were unchanged. During substitution treatment, the free thyroxine index was reduced by 0.7 (P<0.001), total serum thyroxine was reduced by 3.0 µg/dL (P<0.001), and total serum triiodothyronine was increased by 20.5 ng/dL (P = 0.004).
Conclusion: With regard to the outcomes measured, substitution of LT3 at a 1:5 ratio for a portion of baseline LT4 yielded no better results than did treatment with the original dose of LT4 alone.
In the United States, hypothyroidism affects as many as 9.5% of the population. Modern medical practice directs that these patients be treated with levothyroxine (LT4) alonea synthetic hormone that replaces the inactive thyroid hormone thyroxine (T4). Nevertheless, questions have been posed about the adequacy of treating hypothyroidism with only one hormone since at least the early 1970s. Reasons for this demurral are that the thyroid gland secretes triiodothyronine (T3) in addition to T4 and that some patients treated with LT4 alone report that they continue to experience symptoms of hypothyroidism. A large, controlled, community-based study recently supported the notion that psychologic well-being may be suboptimal and symptoms of hypothyroidism may be increased in hypothyroid patients treated with LT4 alone in comparison with control subjects of similar age and sex (that is, despite normal thyrotropin [thyroid-stimulating hormone or TSH] levels).
Most trials to date that have compared the use of one hormone versus two in the treatment of hypothyroidism have been hindered by limitations that necessitate further study. The earliest trial was published in 1970. At that time, sensitive measures of TSH were not yet widely available, a situation that resulted in considerable hormone overreplacement. In addition to using high doses of LT4, the 1970 trial replaced liothyronine (LT3) for LT4 on a microgram-per-microgram basis without regard for the fact that LT3 is 3 to 8 times as potent. The inevitable result was that study subjects experienced substantial side effects on the combined treatment. In 1999, a trial substituting 12.5 µg of LT3 for 50 µg of daily LT4 was reported by Bunevicius et al. This substitution ratio was more physiologic compared with that used in the earlier trial and resulted in improved mood, cognition, and physical symptoms. A commentary published concurrently, however, called for replication of findings before any change in practice could be entertained.
It was in this context that the present study was planned in 2000. Since then, additional trials have been reported, including one in infants born with congenital hypothyroidism (CH). None of these trials was able to replicate the original findings, however. In the study of infants with CH, subjects were given a substitution ratio of LT3 for LT4 of 1:5. Although not statistically significant, at 3 months the infants receiving substitution treatment had TSH values twice as high as those receiving LT4 alone. Psychometric quotients (psychomotor evaluations) in the infants with CH were significantly lower than those in healthy matched control subjects, but no significant differences were noted between infants with CH treated with LT4 alone versus substitution treatment.
In a second trial by Bunevicius et al, no significant differences were found on measures of mood, cognition, or physiologic variables between treatments. In yet another studythe largest to dateoutcomes were tissue hypothyroidism, symptoms of hypothyroidism, quality of life, depression and anxiety, cognitive functioning, and treatment satisfaction. In this study, subjects who received substitution treatment had significantly higher depression and anxiety scores in comparison with those given LT4 alone. This study also reported a mean TSH level that was twice as high (P<0.001) in patients with substitution treatment versus LT4 alone (substitution ratio, 1:5). Additionally, tissue hypothyroidism (that is, Zulewski scores) was significantly higher in those receiving the substitution intervention. Another study focused on measures of depression and found no appreciable improvement in self-reported mood when subjects received substitution treatment. In this study, however, the actual ratio of substitution varied because the protocol required that the prestudy dose of LT4 be halved and replaced by 25 µg of LT3. Then the LT3 and LT4 doses were titrated upward to maintain TSH levels within normal limits. Additionally, the report of this small trial did not include a statistical power analysis. In another trial, neurocognitive functioning and hypothyroid health-related quality of life were the primary outcomes. This trial reported no significant differences in neurocognition or quality of life between the two treatment regimens. In this report, however, the validity and reliability of the hypothyroid health-related quality-of-life instrument were not reported, and the instrument had many depression items. Finally, the most recently reported trial also failed to demonstrate any advantage with substitution treatment (ratio, 1:5). This last trial also tested a ratio of 1:1.7. Limitations to the second regimen included no randomization to treatment and a supraphysiologic dose that resulted in overreplacement of thyroid hormone.
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