High-normal thyroid-stimulating hormone in euthyroid subjects is associated with risk of mortality and composite disease endpoint only in women

INTRODUCTION: The aim of the study was to evaluate whether serum thyroid-stimulating hormone (TSH) within the normal range in euthyroid subjects (having normal free triiodothyronine (fT3) and thyroxine (fT4)) is related to the risk of overall mortality or a composite endpoint of death and nonfatal events. MATERIAL AND METHODS: In 614 middle-aged adult hospital screenees, free of uncontrolled diabetes at baseline, the association of sex-specific TSH tertiles with death was prospectively assessed using Cox regression, with the composite endpoint assessed using logistic regression in adjusted analyses, stratified by gender. RESULTS: In total, 64 deaths and additional incident nonfatal events in 141 cases were recorded at a mean 7.55 years’ follow-up. Multivariable linear regression revealed TSH to be significantly associated among men with age (p = 0.006), but in women inversely with fT3 and fT4 (p < 0.001, and p = 0.024 respectively). In logistic regression analysis, adjusted for age, fT3, fT4, systolic blood pressure and serum total cholesterol, sex-specific baseline TSH tertiles were associated in men neither with the risk of death nor with composite endpoint. In contrast, in women, the highest compared with the bottom TSH tertile predicted the risk of composite endpoint (relative risk: 2.02, 95% CI: 1.07–3.82) and, much more strongly, the mortality risk, independently of fT4 increments. CONCLUSIONS: The significant association of higher range of normal serum TSH in euthyroid middle-aged adults with the risk of death and nonfatal adverse outcomes in women alone cannot be accounted for by the action of thyroid hormone and is consistent with involvement of TSH in the pro-inflammatory state.