雄激素信号传导对于前列腺癌和男性健康至关重要。先前的数据表明，增加身体脂肪在局部环境中是不利的，但对于患有转移性疾病的男性来说却有良好的结果。了解肥胖与前列腺癌之间的生物学联系可能会优化 ASI 的治疗指数。我们假设宿主肥胖和雄激素合成与 ASI 对转移性去势抵抗性前列腺癌 (mCRPC) 男性的疗效和毒性有关。对 NCT02703623 进行了事后分析，其中 mCRPC 男性 (n = 186) 接受了治疗使用醋酸阿比特龙、泼尼松和阿帕鲁胺 (AAPA) 治疗 8 周，满意的反应定义为 PSA 下降 > 50%。身体成分通过基线 CT 扫描进行测量。进行种系 DNA WES 的重点是类固醇生成基因的变异。测量治疗前血浆中的脂肪因子水平。参与雄激素合成的 3 个基因（AKR1C3 rs12529、CYP17A1 rs6162、SRD5A2 rs523349）的种系多态性与单独 ADT 基线时（接受 AAPA 之前）的身体成分差异相关。皮下脂肪组织指数升高（SATi，p = 0.02）、内脏脂肪组织指数（VATi，p = 0.03）和BMI（p = 0.04）与AAPA的满意反应相关。瘦素与 VATi (r = 0.47) 和 SATi (r = 0.48) 呈正相关。雄激素合成的遗传多态性与 ADT 暴露后身体成分的差异相关，值得进一步研究作为身体成分毒性的候选标志物。皮下和内脏脂肪增多与 ASI 反应改善有关。© 2024。作者，获得 Springer Nature Limited 的独家许可。

Androgen signaling is central to prostate cancer and men's health. Prior data indicates that increasing body fat is unfavorable in the localized setting yet associated with favorable outcomes in men with metastatic disease. Understanding the biological links between adiposity and prostate cancer may optimize the therapeutic index with ASI. We hypothesized that host adiposity and androgen synthesis are linked to the efficacy and toxicity of ASI for men with metastatic castration-resistant prostate cancer (mCRPC).A post-hoc analysis was done of NCT02703623 where men with mCRPC (n = 186) were treated for 8 weeks with abiraterone acetate, prednisone, and apalutamide (AAPA), and a satisfactory response was defined as a PSA decline >50%. Body composition was measured on baseline CT scans. Germline DNA WES was performed with a focus on variants in steroidogenic genes. Adipokine levels were measured in pre-treatment plasma.Germline polymorphisms in 3 genes involved in androgen synthesis (AKR1C3 rs12529, CYP17A1 rs6162, SRD5A2 rs523349) were associated with differences in body composition at baseline on ADT alone (prior to receipt of AAPA). Elevated subcutaneous adipose tissue index (SATi, p = 0.02), visceral adipose tissue index (VATi, p = 0.03), and BMI (p = 0.04) were associated with satisfactory response to AAPA. Leptin had positive correlation with VATi (r = 0.47) and SATi (r = 0.48).Inherited polymorphisms in androgen synthesis correlated with differences in body composition after exposure to ADT and warrant further investigation as candidate markers for body composition toxicity. Elevated subcutaneous and visceral adiposity were associated with improved response to ASI.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.