l-Thyroxine monotherapy for athyreotic rats results in a high T4:T3 ratio at doses sufficient to normalize serum TSH levels (8). Yet, the brain, liver, and skeletal muscle tissues of these l-thyroxine–treated animals continue to exhibit markers of hypothyroidism (9), probably because of the inability of l-thyroxine monotherapy to restore tissue levels of T3 (8). This is probably a direct consequence of lower serum T3 levels and the relatively high T4 concentration in these tissues, which inactivates the type 2 iodothyronine deiodinase (D2). In the hypothalamus, loss of D2 is minimal in the presence of T4, which increases sensitivity to T4 levels and explains TSH normalization, despite relatively lower levels of serum T3. Only combination therapy with l-thyroxine plus l-triiodothyronine normalized all thyroid hormone–dependent measures (9), including serum and tissue T3 levels (8). Whether tissue-specific markers of hypothyroidism are restored with l-thyroxine monotherapy in humans remains to be determined, as does the ability of l-thyroxine plus l-triiodothyronine combination therapy to normalize the serum T4:T3 ratio without adverse events. The development of a novel drug delivery system for l-triiodothyronine would facilitate these studies (5).
To document that this was a result of trends toward lower doses, an unblinded study tracked well-being according to various doses and found that the highest well-being was achieved at supraoptimal doses, resulting in a suppressed TSH (65). However, a blinded trial did not reproduce this finding (66). In a call to the public, a 1997 British Thyroid Foundation newsletter asked readers to recount personal history of residual hypothyroid symptoms. More than 200 patients responded, 54 of whom specifically mentioned that they did not feel well despite normal serum markers of thyroid function (67, 68). Because of this surge in symptomatic patients, some clinicians advocated titrating dose by symptoms rather than serum TSH, reminiscent of the period before the 1970s (69).
For starters, consider the effect that hypothyroidism can have on weight. Hypothyroidism (also called low thyroid or underactive thyroid) is marked by insufficient hormone production in the thyroid — the butterfly-shaped gland located at the bottom-front of your neck. This gland affects the body’s metabolic processes, and often, sudden weight gain is an early sign of low thyroid.

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