Factors Associated with Adverse Effects of Postoperative TSH-Directed Levothyroxine Therapy in Adults with Differentiated Thyroid Cancer: A Scoping Review

Abstract

Background: Postoperative thyrotropin (TSH)-directed levothyroxine is used to reduce recurrence risk in selected patients with differentiated thyroid cancer (DTC), but treatment-related adverse effects may vary based on patient susceptibility and treatment exposure. Contemporary guidelines increasingly require balancing anticipated oncologic benefit against potential harm. This scoping review synthesizes patient-, treatment-, and disease-related factors associated with adverse effects of postoperative TSH-directed levothyroxine therapy in adults with DTC. Methods: This scoping review was reported following PRISMA-ScR guidelines and prospectively registered on the Open Science Framework. MEDLINE, Embase, and Cochrane CENTRAL were searched from January 1, 2011, to February 24, 2026. Eligible studies reported associations between patient-, treatment-, or disease-related factors and adverse effects among adults with DTC receiving postoperative TSH-directed levothyroxine therapy. Data were summarized descriptively and synthesized narratively, with stratification according to TSH exposure definition. Results: Of 7361 records screened, 35 studies including 11,819 patients were included. Skeletal outcomes were most frequently reported (51.4%), followed by cardiometabolic (40.0%), neuropsychological (11.4%), reproductive (2.9%), and muscular outcomes (2.9%). TSH exposure definitions varied substantially: 18 studies evaluated subnormal TSH, 2 low-normal TSH, 8 mixed categories spanning subnormal and low-normal TSH, 4 continuous biochemical/treatment measures, and 3 unclear exposures. Greater suppression intensity was the most consistently reported treatment-related factor associated with adverse skeletal outcomes, particularly in studies evaluating subnormal TSH. Longer treatment duration was associated with skeletal harm in selected studies. Postmenopausal status emerged as a relatively consistent patient-level factor, whereas associations with age and body mass index were variable. Evidence for cardiometabolic, neuropsychological, reproductive, and muscular outcomes was less extensive and less consistent, and disease-related factors were infrequently examined. Only two studies conducted prediction/discrimination analyses, both involving skeletal outcomes. Conclusions: Evidence on adverse effects associated with TSH-directed levothyroxine therapy in DTC is most consistent for skeletal outcomes and predominantly derives from studies evaluating subnormal TSH exposure. The available literature provides limited evidence for clinically applicable prediction of toxicity or cumulative treatment burden. Future longitudinal studies should better characterize the intensity and persistence of biochemical exposure and develop outcome-specific prediction models integrating baseline susceptibility, organ vulnerability, and longitudinal treatment exposure to support individualized TSH management.