Hypothalamic-Pituitary-Thyroid Axis Set Point Alterations Are Associated With Body Composition in Androgen-Deprived Men

Objective: Androgen deprivation therapy (ADT) given to men with prostate cancer is associated with metabolically adverse changes in body composition leading to insulin resistance, but the underlying mechanisms are not fully understood. We investigated prospectively whether androgen deprivation or its consequences may be associated with alterations in thyroid function in men. Design: We performed a prespecified secondary analysis of a prospective case control study. Methods: We prospectively followed men with nonmetastatic prostate cancer newly commencing ADT (n = 34) and age-matched controls (n = 29) for 12 months. We assessed secondary outcomes on thyrotropin (TSH) and thyroid hormones using a linear mixed model to determine mean adjusted differences (MADs) between groups. Results: After a 12-month follow-up period, TSH increased in cases compared with control subjects [MAD, 0.69 mIU/L; 95% confidence interval (CI), 0.58-0.82; P < 0.001]. This was accompanied by a rise in FT4 (MAD, 2.2 pmol/L; 95% CI, 1.1-3.2; P < 0.001), reduced FT3-FT4 conversion (MAD, -0.07; 95% CI, -0.10 to -0.4; P < 0.001), and stable FT3. TSH change correlated significantly with changes in weight, body mass index, and fat mass in cases but not with waist circumference, lean mass, visceral fat, insulin resistance, testosterone, sex hormone binding globulin, and estradiol. The rise in TSH after 12 months was strongly associated with changes in leptin. Conclusions: A profound rise in TSH in the absence of peripheral hypothyroidism under ADT suggests set point adaptations of the hypothalamic-pituitary-thyroid axis. This appears to be mediated by body composition changes and by the fat-associated hormone leptin rather than by androgen deficiency. Further studies are required to determine the causality and biological implications of these findings