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For clinical recommendations, the supporting evidence was appraised, and the strength of each clinical recommendation was assessed, using the American College of Physicians system. When responses were not suitable for a formal clinical recommendation, a summary response statement without a formal clinical recommendation was developed. The responses to questions were formatted, when possible, in the form of a formal clinical recommendation statement. Ethics reviews were provided, when relevant, by a bioethicist. Clinical reviews were supplemented, when relevant, with related mechanistic and bench research literature reviews, performed by our team of translational scientists. The clinical literature relating to each question was then reviewed. Methods: Task force members identified 24 questions relevant to the treatment of hypothyroidism. This document is intended to inform clinical decision-making on thyroid hormone replacement therapy it is not a replacement for individualized clinical judgment. We wished to determine whether there are sufficient new data generated by well-designed studies to provide reason to pursue such therapies and change the current standard of care. The purpose of this task force was to review the goals of levothyroxine therapy, the optimal prescription of conventional levothyroxine therapy, the sources of dissatisfaction with levothyroxine therapy, the evidence on treatment alternatives, and the relevant knowledge gaps. Background: A number of recent advances in our understanding of thyroid physiology may shed light on why some patients feel unwell while taking levothyroxine monotherapy.