Abstract
Thyroid hormone replacement for hypothyroidism can be achieved via several approaches utilizing different preparations of thyroid hormones, T3, and/or T4. “Combination therapy” involves administration of both T3 and T4, and was technically the first treatment for hypothyroidism. It was lauded as a cure for the morbidity and mortality associated with myxedema, the most severe presentation of overt hypothyroidism. In the late nineteenth and the early Twentieth centuries, combination therapy per se could consist of thyroid gland transplant, or more commonly, consumption of desiccated animal thyroid, thyroid extract, or thyroglobulin. Combination therapy remained the mainstay of therapy for decades despite development of synthetic formulations of T4 and T3, because it was efficacious and cost effective. However, concerns emerged about the consistency and potency of desiccated thyroid hormone after cases were reported detailing either continued hypothyroidism or iatrogenic thyrotoxicosis. Development of the TSH radioimmunoassay and discovery of conversion of T4-to-T3 in humans led to a major transition in clinical practices away from combination therapy, to adoption of levothyroxine “monotherapy” as the standard of care. Levothyroxine monotherapy has a favorable safety profile and can effectively normalize the serum TSH, the most sensitive marker of hypothyroidism. Whether levothyroxine monotherapy restores thyroid hormone signaling within all tissues remains controversial. Evidence of persistent signs and symptoms of hypothyroidism during levothyroxine monotherapy at doses that normalize serum TSH is mounting. Hence, in the last decade there has been acknowledgment by all thyroid professional societies that there may be a role for the use of combination therapy; this represents a significant shift in the clinical practice guidelines. Further bolstering this trend are the recent findings that the Thr92AlaD2 polymorphism may reduce thyroid hormone signaling, resulting in localized and systemic hypothyroidism. This strengthens the hypothesis that treatment options could be personalized, taking into consideration genotypes and comorbidities. The development of long-acting formulations of liothyronine and continued advancements in development of thyroid regenerative therapy, may propel the field closer to adoption of a physiologic thyroid hormone replacement regimen with combination therapy.
Highlights
Hypothyroidism is a prevalent condition, diagnosed in most cases by an elevation in serum TSH [1]
In the 1970’s, the clinical approach to the hypothyroid patient changed markedly based on (i) the development of immunological assays to measure serum TSH as a more reliable biochemical index of thyroid activity [8], (ii) the accessible pricing of synthetic thyroid hormone formulations, and (iii) the discovery that in humans most circulating T3 is derived via extrathyroidal conversion of T4 [3, 9]
These three factors led to a dramatic change in how hypothyroidism was diagnosed and treated, such that in the last 40 years (i) measurement of serum TSH has become the cornerstone of diagnosis and therapeutic monitoring, (ii) the replacement dosage of thyroid hormone has been substantially decreased, and (iii) “monotherapy” with levothyroxine (LT4) has become a universally accepted first-line approach given its excellent safety index
Summary
Hypothyroidism is a prevalent condition, diagnosed in most cases by an elevation in serum TSH [1]. Combination therapy via natural thyroid preparations remained the dominant therapeutic option for the better part of the twentieth century; dosages were adjusted to resolve symptoms and to normalize BMR/PBI [4,5,6] With this regimen, thyrotoxic side effects were not uncommon [7]. The efficacy of LT4 monotherapy has come into question as with this approach, 10–15% of patients express dissatisfaction due to residual symptoms of hypothyroidism [12, 13], and cognitive impairment [14, 15] This might not have happened in the previous era given the much higher replacement doses of thyroid hormone used prior to the institution of the serum TSH radioimmunoassay (RIA) [3].
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