Hypothalamic-Pituitary-Thyroid Axis Set Point Alterations Are Associated With Body Composition in Androgen-Deprived Men
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Rudolf Hoermann1, Ada S Cheung1,2, Michele Milne1
1Department of Medicine, The University of Melbourne, Heidelberg 3084, Victoria, Australia.
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.
Insights
Androgen deprivation therapy (ADT) for prostate cancer increases thyroid-stimulating hormone (TSH) and alters thyroid hormone conversion. These changes are linked to body composition shifts and leptin, not directly to low testosterone.
Area of Science:
- Endocrinology
- Oncology
- Metabolic Health
Background:
- Androgen deprivation therapy (ADT) for prostate cancer is linked to adverse metabolic changes, including insulin resistance.
- The precise mechanisms driving these metabolic alterations, particularly concerning thyroid function, remain unclear.
Purpose of the Study:
- To prospectively investigate whether ADT or its metabolic consequences affect thyroid function in men with prostate cancer.
- To examine changes in thyrotropin (TSH) and thyroid hormones during ADT.
Main Methods:
- A prospective case-control study followed men with nonmetastatic prostate cancer starting ADT (n=34) and age-matched controls (n=29) for 12 months.
- Thyroid function (TSH, FT4, FT3) and body composition were assessed. Statistical analysis used linear mixed models to compare groups.
Main Results:
- Men on ADT showed a significant increase in TSH and FT4, alongside reduced FT3-FT4 conversion after 12 months.
- TSH changes correlated with weight, BMI, and fat mass, and were strongly associated with leptin levels.
- No significant correlations were found between TSH changes and insulin resistance, testosterone, or other sex hormones.
Conclusions:
- ADT induces significant alterations in the hypothalamic-pituitary-thyroid axis, characterized by increased TSH without peripheral hypothyroidism.
- These thyroid function changes appear primarily mediated by ADT-induced body composition modifications and leptin, rather than androgen deficiency itself.
- Further research is needed to establish causality and the clinical implications of these thyroid axis adaptations.
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