Thyroid Hormones and Metabolic Syndrome: A Narrative Review of Findings from 18 Years of Follow-up in Tehran Thyroid Study (TTS)

Abstract

Context: Thyroid dysfunction and metabolic syndrome (MetS) share similar pathophysiological features, suggesting a bidirectional relationship between these two prevalent endocrinological disorders. This review summarizes findings from 18 years of follow-up in the Tehran Thyroid Study (TTS), a large community-based prospective cohort, focusing on the association between thyroid function and MetS. Evidence Acquisition: We systematically reviewed TTS publications (until 2025) on thyroid function and MetS. Exposures included thyroid-stimulating hormone (TSH), free thyroxine (FT4), thyroid peroxidase antibody (TPOAb), and thyroid feedback indices [Thyroid Feedback Quantile-Based Index (TFQI), Thyrotroph T4 Resistance Index (TT4RI), and TSH Index (TSHI)]. Outcomes were MetS and its components. Study designs ranged from cross-sectional and prospective cohort to joint longitudinal/time-to-event models. Results: Cross-sectional TTS analyses showed an inverse association between FT4 (but not TSH) and the prevalence of MetS. Among 3,755 euthyroid adults, a 1-unit increase in FT4 was associated with lower odds of MetS (OR 0.96, 95% CI: 0.92 - 0.99). Across thyroid functional states, overt hypothyroidism had the highest MetS prevalence (41.6%); in men, overt hypothyroidism was associated with higher odds of MetS versus euthyroidism (OR 2.9, 95% CI: 1.04 - 8.40). Prospective TTS analyses supported a modest thyroid-to-MetS direction. In a 10-year cohort of 2,393 participants without MetS at baseline, declining FT4 over follow-up predicted incident MetS in non-obese adults (OR 0.57, 95% CI: 0.34 - 0.96) and was associated with lower odds of incident abdominal obesity and hypertriglyceridemia. In joint longitudinal-time-to-event models (n = 1,436; median 9-year follow-up), higher time-varying TSH was associated with higher MetS risk (HR 1.17, 95% CI: 1.01 - 1.28), while higher FT4 predicted lower MetS risk (HR 0.54, 95% CI: 0.29 - 0.97). In the reverse direction, baseline MetS did not independently predict incident thyroid dysfunction over 9 years (n = 4,905; adjusted HR, 0.95; 95% CI: 0.77 - 1.18). Thyroid hormone sensitivity indices were not associated with MetS overall, although higher TFQI was associated with hypertension (OR 1.14, 95% CI: 1.05 - 1.23). Conclusions: Eighteen years of follow-up in TTS suggest a modest, mostly one-way thyroid-MetS association. Higher (or high-normal) TSH and lower FT4 modestly increase MetS risk, whereas baseline MetS did not significantly increase the risk of later thyroid dysfunction.