THE CONCEPT OF HORMONE REPLACEMENT THERAPY IS commonly credited to Brown-Sequard, who in 1889 at age 72 years injected himself with an extract of dog testicles and noted enhanced vitality and mental acuity. The concept of “internal secretion” arose from these experiments, and soon thereafter Murray successfully treated myxedema with “juice” extracted from sheep thyroid glands. Replacement therapy with virtually all clinically relevant hormones has been possible since the middle of the 20th century. The challenge, however, is to administer these hormones in deficiency states in a way that precisely replicates the complex manner in which they are endogenously secreted. Insulin replacement in patients with type 1 diabetes is an obvious example of this difficulty. Even the most sophisticated patient using an external insulin pump and continuous glucose monitoring has difficulty mimicking normal insulin secretion without being subjected to potentially dangerous hypoglycemia. In contrast with the difficulties in replacing protein hormones like insulin that have complex secretory patterns, substitution therapy with small molecules like steroid hormones and thyroxine (T4) is thought to be relatively simple. However, this is clearly not the case, given the commonly observed adverse effects of hormone excess or insufficiency when clinicians attempt to treat hypogonadism with sex steroids, adrenal insufficiencywithglucocorticoids,andhypothyroidismwith T4. One might think reduplicating normal thyroid physiology with T4 therapy would be simple, because T4 and triiodothyronine(T3) serumlevelsdonotdisplaypulsatilityorhave a circadian rhythm. Why then does the treatment of hypothyroidismcontinue tobe thesubjectof somuchclinical investigation and continue to engender so much contention? The controversy surrounding thyroid hormone therapy stems, in part, from important aspects of normal thyroid physiology. It is T3 rather than T4 that mediates thyroid hormone action by binding to nuclear thyroid hormone receptors present in virtually all tissues. Serum T3 has 2 sources: approximately 20% of daily T3 secretion comes directly from the thyroid and the other 80% is derived from the monodeiodination of T4 to activate T3 in peripheral tissues. Thus, T4 serves as a prohormone for T3, having essentially no intrinsic biological activity of its own. Specific selenoprotein deiodinases catalyze the deiodination process; variations in their activity may determine in part the serum levels of T4, T3, and thyroid-stimulating hormone (TSH) in each individual. The major source of T3 within peripheral tissues is from the circulating T3 pool, although a variable portion arises from locally deiodinated T4 within each tissue. In adults, serum T3 levels are also regulated by changes in deiodinase activity brought about by starvation, overfeeding, acute and chronic illness, and certain drugs. Given the complex regulation of T4 conversion to T3, it is theoretically possible that replacement therapy with pure T4 may not precisely reduplicate a thyroid hormonal milieu that involves 2 hormones, not 1. Although studies performed several decades ago showed clearly that normal serum T3 levels can be achieved with pure T4, there has been lingering doubt about whether the serum T3 levels that are attained with T4 therapy are truly normal for the individual patient. This uncertainty led to studies exploring combination T4 plus T3 therapy. Experiments in thyroidectomized rats showing that T4 therapy alone could not completely restore tissue T3 levels to normal further fueled misgivings about T4 therapy’s ability to match normal physiology. However, except for 2 studies conducted by the same group of investigators, none of the numerous other randomized controlled studies comparing T4 vs T4/T3 combinations has shown any benefit of combined treatment to improve hypothyroid symptoms or sense of well-being (summarized in a meta-analysis). Some patients, especially those made mildly hyperthyroid by T3 therapy, preferred combined T4/T3 therapy over pure T4, but patients in general had no preference for one treatment over another. It has also been suggested that patients with thyroidectomy might benefit more from combined T4/T3 treatment than patients with spontaneous hypothyroidism who usually have some remaining endogenous thyroid function, but this also could not be confirmed. The reasons for the failure of virtually all studies to show the benefit of T4/T3 therapy have been variously ascribed to the insensitivity of the instruments used to assess well-being, incorrect T3 dosing, or the relatively short half-life of T3 leading to fluctuating unphysiological serum T3 levels. To ad-
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Open Access
Oct 29, 2021
A Weinstein 
