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

Abstract

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.

Advances in applied homeostatic modelling of the relationship between thyrotropin and free thyroxine

“…Set point adaptation may occur in response to minor disturbance, not only dramatic events such as severe non-thyroidal illness [ 49 ]. As an example, a change in body composition in androgen deprived patients with prostatic cancer was associated with a concomitant rise in both hormones TSH and FT4, indicating a shift in regulation from the controlling to a tracking mode [ 49 , 50 ].…”

Recent Advances in Thyroid Hormone Regulation: Toward a New Paradigm for Optimal Diagnosis and Treatment

“…Pathophysiological challenges other than thyroid disease may disturb the equilibria between TSH and thyroid hormones, requiring setpoint adjustment of the hypothalamic–pituitary–thyroid axis (Figures 1 A–C). Weight gain or loss, alterations in body composition, and aging may cause profound changes (Figure 1 C), frequently switching the control mode from negative feedback to tracking FT4 rather than opposing it ( 36 , 39 , 40 ). This inversion of the TSH–FT4 correlation is clinically important to recognize, but it may be missed or misinterpreted as subclinical hypothyroidism when relying on TSH measurement as sole diagnostic test.…”

“…They also respond to alterations in the energetic and metabolic needs of the body and interact with TRH neurons ( 41 , 42 , 44 – 48 ). Fat cells release adipokines such as leptin into the circulation which directly or indirectly stimulate pituitary TSH secretion ( 36 , 39 , 40 , 42 , 45 ). In a vicious cycle, TSH may promote leptin release through TSH receptor activation on adipocytes ( 49 ).…”

“…While rising with weight gain TSH decreases again after weight loss ( 36 , 39 , 50 , 51 ). Central and peripheral deiodinases are also sensitive to nutritional factors and body composition, adjusting T4 to T3 conversion to maintain T3 stability under varying conditions ( 39 , 40 ). As transporters, deiodinases and thyroid hormone receptors subtypes differ in both their expressions and T3 affinities, central responses may readily diverge from peripheral equilibria ( 52 – 54 ).…”

Persisting adverse body composition changes 2 years after cessation of androgen deprivation therapy for localised prostate cancer

“…The mechanism behind the persisting body composition changes in the setting of low testosterone is unknown. The increase in fat mass may be related to factors other than direct effects of low testosterone including changes in energy regulation or set point changes in the hypothalamic-pituitary-thyroid axis (27), decreased physical activity or mood effects that can occur with treatment of prostate cancer. However, it is clear from obesity literature that adiposity, once gained, as occurs in an accelerated fashion with ADT, is difficult to shed due to a shift in the body's homeostatic set point and counter-regulatory hormones, which promote fat regain (28).…”