据报道，治疗前列腺癌的激素疗法 (HT) 会导致身体成分发生不良变化。临床上，患者之间的身体成分变化是异质的，但身体成分毒性的生物学和临床决定因素尚不清楚。在此，我们检验了以下假设：类固醇生成基因的遗传多态性与 HT 后身体成分的差异变化相关。接受 8 个月 LHRH 类似物 (LHRHa)/-醋酸阿比特龙 (AAP) 治疗的生化复发性前列腺癌 (BCR) 男性如果满足以下条件，则符合资格：1) 治疗前后 L3 的 CT 成像，以及 2) 收集的有核细胞。回顾性提取心脏代谢合并症。使用基于人工智能的分割工具测量身体成分。进行种系 DNA 全外显子组或基因组测序。在接受 8 个月 HT 治疗的 162 名男性中，中位骨骼肌质量 (SMMi) 减少了 6.6%，皮下脂肪增加了 12.3%。患有 2 型糖尿病的男性治疗后 SMMi 损失较高（-11.1% vs. -6.3%，p = 0.003）。对于 150 名进行种系 NGS 的男性，SRD5A2 rs523349 基因型与 HT 后骨骼肌密度的差异性损失相关（-1.3% 与 -7.1%，p=0.04）。此外，HSD3B1 rs104703 基因型与基线内脏脂肪组织减少相关（63.0 cm2/m2 对比 77.9，p=0.05）。在患有 BCR 的男性中，HT 导致骨骼肌显着损失和皮下脂肪组织增加。 SRD5A2 和 T2DM 的遗传多态性与不同的骨骼肌毒性相关。这些发现表明，遗传多态性可能导致 HT 观察到的身体成分毒性。

Hormone therapy (HT) to treat prostate cancer is reported to cause adverse changes in body composition. Clinically, interpatient body composition changes are heterogeneous, but the biologic and clinical determinants of body composition toxicity are unknown. Herein, we test the hypothesis that inherited polymorphisms in steroidogenic genes are associated with differential change in body composition after HT. Men with biochemically recurrent prostate cancer (BCR) who received 8 months of LHRH analog (LHRHa) +/- abiraterone acetate (AAP) were eligible if they had: 1) CT imaging of L3 prior to and after treatment, and 2) nucleated cells collected. Cardiometabolic co-morbidities were retrospectively extracted. Body composition was measured using an AI-based segmentation tool. Germline DNA whole exome or genome sequencing was performed. In 162 men treated with 8 months of HT, median skeletal muscle mass (SMMi) loss was 6.6% and subcutaneous adipose gain was 12.3%. Men with type 2 diabetes had higher loss of SMMi after treatment (-11.1% vs. -6.3%, p = 0.003). For the 150 men with germline NGS, SRD5A2 rs523349 genotype was associated with differential loss in skeletal muscle density after HT, (-1.3% vs. -7.1%, p=0.04). In addition, HSD3B1 rs104703 genotype was associated with decreased baseline visceral adipose tissue (63.0 cm2/m2 vs. 77.9, p=0.05). In men with BCR, HT induced notable loss of skeletal muscle and increased subcutaneous adipose tissue. An inherited polymorphism in SRD5A2 and T2DM were associated with differential skeletal muscle toxicity. These findings suggest that inherited polymorphisms may contribute to the body composition toxicity observed with HT.