New Mexico VA Health Care System, Albuquerque, NM, USA.
University of New Mexico School of Medicine, Albuquerque, NM, USA.
Endocrine. 2019 Sep;65(3):692-706. doi: 10.1007/s12020-019-02008-6. Epub 2019 Jul 19.
To evaluate the influence of single nucleotide polymorphisms (SNPs) of CYP19A1 on the response and susceptibility to side effects from testosterone therapy. This is a prospective, single-arm study of men with low-morning serum testosterone (<10.68 nmol/l) administered testosterone cypionate 200 mg intramuscularly every 2 weeks for 18 months.
We measured areal bone mineral density (aBMD) and body composition by dual energy X-ray absorptiometry, tibial volumetric BMD and geometry by peripheral quantitative computer tomography, bone turnover markers by enzyme-linked immunosorbent assay, testosterone, and estradiol by liquid-chromatography/mass-spectroscopy, genotyping by microarray, CYP19A1 expression by quantitative polymerase chain reaction, hematocrit and prostate-specific antigen (PSA).
We enrolled 105 men (40-74-years-old). SNPs rs1062033 and rs700518 were associated with significant differences in outcomes at 18 months. The GG genotype in rs1062033 had significant increase in whole body aBMD, but had significant decrease in tibial bone size compared to the CG and CC genotypes. Body composition analysis showed that the CC genotype of rs1062033, and the AA genotype of rs700518, had significant increase in total lean and appendicular lean mass compared to CG and GG, and AG and GG, respectively. The GG genotype of rs700518 had significant increase in PSA (GG = 105.8 ± 23.3% vs. AG + AA = 53.4 ± 11.3%, p = 0.046) while hematocrit changes were comparable among genotypes. CYP19A1 expression was highest in GG genotype in both SNPs.
For the first time, we demonstrated that CYP19A1 SNPs influence response to testosterone therapy in hypogonadal men, highlighting the importance of genetic profiling in therapeutics even for common clinical conditions.
评估 CYP19A1 单核苷酸多态性（SNP）对睾酮治疗反应和不良反应易感性的影响。这是一项前瞻性、单臂研究，纳入了血清睾酮水平低（<10.68 nmol/L）的男性，给予每 2 周肌内注射 200mg 醋酸环丙孕酮，共 18 个月。
我们通过双能 X 射线吸收法测量骨矿物质密度（BMD）和身体成分，通过外周定量计算机断层扫描测量胫骨体积 BMD 和几何形状，通过酶联免疫吸附试验测量骨转换标志物，通过液相色谱/质谱法测量睾酮和雌二醇，通过微阵列进行基因分型，通过定量聚合酶链反应测量 CYP19A1 表达，通过血细胞比容和前列腺特异性抗原（PSA）进行测量。
我们纳入了 105 名年龄在 40-74 岁的男性。SNP rs1062033 和 rs700518 与 18 个月时的结果显著相关。与 CG 和 CC 基因型相比，rs1062033 的 GG 基因型全身体 BMD 显著增加，但胫骨骨大小显著减小。身体成分分析表明，与 CG 和 GG 相比，rs1062033 的 CC 基因型和 rs700518 的 AA 基因型总瘦体重和四肢瘦体重显著增加，与 AG 和 GG 相比也是如此。与 AG 和 AA 基因型相比，rs700518 的 GG 基因型 PSA 显著增加（GG = 105.8 ± 23.3% vs. AG + AA = 53.4 ± 11.3%，p = 0.046），而血细胞比容变化在基因型之间无差异。在这两个 SNP 中，CYP19A1 表达在 GG 基因型中最高。
我们首次证明 CYP19A1 SNP 影响低睾酮血症男性对睾酮治疗的反应，强调了即使对于常见的临床情况，遗传谱分析在治疗中的重要性。
