BACKGROUND
The thyroid gland mainly produces the thyroid hormone thyroxine (T4), which is converted in other tissues to the active hormone triiodothyronine (T3). The thyroid is regulated by the hormone TSH. Hypothyroidism occurs when the thyroid gland is underactive and doesn’t produce enough thyroid hormone. This is diagnosed with an increase in TSH levels and a decrease in the T4. The symptoms of hypothyroidism include being tired, cold, constipated, having decreased energy and gaining weight. Hypothyroidism is usually treated by levothyroxine (L-T4) which usually resolves the thyroid-related symptoms. However, the symptoms of hypothyroidism are not specific and may be caused by any other disorders. This may complicate the treatment of hypothyroidism, as some patients continue to have symptoms despite the return of the thyroid hormone and TSH levels to the normal range.

For patients with continued symptoms on treatment with L-T4 alone, alternative treatment options with desiccated thyroid extract (DTE) or combination therapy (L-T4 with liothyronine, L-T3) have been used with some success. Indeed, a few small studies suggest that some patients seem to prefer regimens that include L-T3. The current study aimed to evaluate the clinical effects of DTE, L-T4, and combination therapy (L-T4 and L-T3) in patients with hypothyroidism.

THE FULL ARTICLE TITLE
Shakir MKM et al 2021 Comparative effectiveness of levothyroxine, desiccated thyroid extract, and levothyroxine + liothyronine in hyporthyroidism. J Clin Endocrinol Metab. Epub 2021 Jun 29. PMID: 34185829.

SUMMARY OF THE STUDY
This was a randomized, double-blind crossover study. A total of 75 patients participated in the study. These patients were beneficiaries of the U.S. military health care system, between the age of 18 and 65 years, diagnosed with hypothyroidism, and on a stable dose of L-T4 (or an equivalent dose for combination therapy or DTE) for at least 6 months. A majority of the study population was Caucasian (77.3%) and female (77.3%), with an average age of 50 years. At the time of enrollment, greater than 90% were on L-T4 therapy alone.

Participants were randomly assigned to one of three treatment groups: L-T4, L-T4+L-T3, or DTE for a 22-week period. After the first 6 weeks on the treatment, a serum TSH level was checked and the dose was adjusted accordingly. Once the TSH level was at goal, patients continued the medication for an additional 16 weeks. Thereafter, the participant was crossed over to the next treatment group. Measurements were obtained at baseline and at the end of each study period. Memory testing was performed using the Wechsler Memory Scale Fourth Edition (WMS-IV). Hypothyroidism symptoms were assessed with the 12-Item General Health Questionnaire (GHQ-12), a thyroid symptom questionnaire (TSQ-36), and the Beck Depression Inventory (BDI). The primary outcomes included performance on memory testing, mood, quality of life, and symptoms.

Analyses at the end of the study period showed no differences in the TSQ-36 and GHQ-12 questionnaires or in the BDI and WMS-IV test assessments between treatment groups. No significant difference was noted in serum TSH levels between the treatment groups. In those who took a T3-containing preparation, the serum total T3 was 30 to 50% higher and the serum T4 30% lower than in those on L-T4 alone group. In the overall study population, there was no significant difference in treatment preference.

Subgroup analysis of the top 20 of the most symptomatic patients showed a strong preference for treatments containing L-T3 and improved performance on TSQ-36, GHQ-12, BDI, and visual memory index. The treatments were all tolerated well, with no reported adverse effects.

WHAT ARE THE IMPLICATIONS OF THIS STUDY?
In patients with hypothyroidism, no major differences were found between L-T4 therapy, DTE or combination therapy with regard to symptomatic control, quality of life, treatment preference, or serum TSH levels. A subgroup analysis of the most symptomatic patients did reveal improved performance on memory testing and improvement in quality of life, with a preference for T3-containing treatments. Importantly, there were no adverse effects in any of the treatment groups. Further larger studies are indicated.

— Alan P. Farwell, MD

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