T4+T3 Combination Therapy: An Unsolved Problem of Increasing Magnitude and Complexity

Abstract

Thyroxine (T4)+triiodothyronine (T3) combination therapy can be considered in case of persistent symptoms despite normal serum thyroid stimulating hormone in levothyroxine (LT4)-treated hypothyroid patients. Combination therapy has gained popularity in the last two decades, especially in countries with a relatively high gross domestic product. The prevalence of persistent symptoms has also increased; most frequent are complaints about energy levels and fatigue (80% to 90%), weight management (70% to 75%), memory (60% to 80%), and mood (40% to 50%). Pathophysiological explanations for persistent problems are unrealistic patient expectations, comorbidities, somatic symptoms, related disorders (Diagnostic and Statistical Manual of Mental Disorders [DSM-5]), autoimmune neuroinflammation, and low tissue T3. There is fair circumstantial evidence for the latter cause (tissue and specifically brain T3 content is normalized by T4+T3, not by T4 alone), but the other causes are viewed as more relevant in current practice. This might be related to the 'hype' that has emerged surrounding T4+T3 therapy. Although more and better-designed trials are needed to validate the efficacy of T4+T3 combination, the management of persistent symptoms should also be directed towards alternative causes. Improving the doctor-patient relationship and including more and better information is crucial. For example, dissatisfaction with the outcomes of T4 treatment for subclinical hypothyroidism can be anticipated as recent trials have demonstrated that LT4 is hardly effective in improving symptoms associated with subclinical hypothyroidism.

Use of thyroid hormones in hypothyroid and euthyroid patients: A survey of members of the Endocrine Society of Australia

“…While 49% of respondents would consider prescribing LT3 in patients with ongoing symptoms of hypothyroidism with normal TSH on LT4, most respondents believe ongoing symptoms despite adequate biochemistry are due to psychosocial factors, comorbidities, patients' unrealistic expectations, and burden of chronic disease, rather than the inability of LT4 to restore normal physiology. These beliefs appear to be consistent with surveys of endocrinologists in other countries across the world suggesting that many endocrinologists do not believe that different preparations are likely to benefit symptomatic patients 12,13,15,16,18,22,25 . A recent international patient questionnaire has highlighted the discord between the views of patients and physicians regarding reasons for dissatisfaction with treatment, 26 but also that dissatisfaction is significantly associated with patients' personality traits 27 .…”

“…These beliefs appear to be consistent with surveys of endocrinologists in other countries across the world suggesting that many endocrinologists do not believe that different preparations are likely to benefit symptomatic patients. 12,13,15,16,18,22,25 A recent international patient questionnaire has highlighted the discord between the views of patients and physicians regarding reasons for dissatisfaction with treatment, 26 but also that dissatisfaction is significantly associated with patients' personality traits. 27 However, many continue to prescribe LT3 + LT4 combination therapy for this group.…”

Cardiovascular mechanisms of thyroid hormones and heart failure: Current knowledge and perspectives

“…However, the therapeutic approach to NTIS, with or without HF, is still a matter of debate. In the case of persistent symptoms despite previous substitutional levothyroxine therapy and serum TSH values within the reference range, the T 4 plus T 3 combination has been suggested as a treatment option by the European Thyroid Association[ 30 ] regardless of reported contradictory findings[ 31 , 32 ]. Perhaps natural measures to raise T 3 , such as lowering stress levels, having a healthy diet, along with emphasis on regular exercise[ 33 ] and selenium intake[ 34 ], may achieve clinically relevant improvement through changes in TH levels in HF patients.…”

Levothyroxine: Conventional and Novel Drug Delivery Formulations

“…Although the predominant treatment of thyroxine supplementation is LT4 monotherapy, 10% to 15% of patients have persistent or recurrent hypothyroid symptoms (weight gain, fatigue, memory loss, etc.) despite normal TH levels and medical adhesion ( 142 , 143 ). This phenomenon is assumed to be attributed to a low level of circulating T3, which plays a superior role to T4 in the feedback of the hypothalamus–pituitary–thyroid axis ( 144 ).…”

“…Based on the theory above, clinicians have returned to combined therapy of T4 plus T3 to eliminate hypothyroid symptoms, with strict indications. Clinicians supported that only hypothyroid patients treated with a stable dose of LT4 for at least 6 months, who had experienced persistent symptoms and had a normal serum TSH level, should receive T4 plus T3 combination therapy ( 143 , 147 ). However, those with associated comorbidities (eg, autoimmune diseases and psychological dysfunctions) or unrealistic expectations should not receive combination therapy ( 148 , 149 ).…”