Al-Bader Maie, Kilarkaje Narayana
Departments of Physiology, Faculty of Medicine, Kuwait University, Kuwait.
Departments of Anatomy, Faculty of Medicine, HSC, Kuwait University, PO Box 24923, Safat 13110, Kuwait.
Eur J Pharmacol. 2015 Jan 15;747:150-9. doi: 10.1016/j.ejphar.2014.12.006. Epub 2014 Dec 15.
Cytotoxic anticancer chemotherapy affects pituitary-testicular hormonal axis in humans and in animals. This study investigated the effects on Leydig cells of three cycles of bleomycin, etoposide and cisplatin (0.75, 7.5, and 1.5mg/kg, respectively; BEP) chemotherapy in rat testis. The chemotherapy has induced hyperplasia of and degenerative changes in Leydig cells at the end of BEP exposure, which remained so even after a recovery time of 63 days. The increased testicular oxidative stress at the end of the chemotherapy returned to normal level after the recovery time. The chemotherapy has stimulated the transcription of scavenger receptor class type-B1 (SCARB1), steroidogenic acute-regulatory protein (StAR), cytochrome P450 cholesterol side-chain cleavage (CYP11A1), CYP17A1, and inhibited that of 17β-hydroxysteroid dehydrogenase (HSD17B6) and CYP19A1 in association with increased cholesterol and decreased testosterone levels. Even after the recovery time, the chemotherapy still had inhibitory effects on the transcription of all of the above genes in addition to luteinizing hormone receptor and HSD3B1, but not on the StAR gene. The cholesterol and testosterone levels also did not show any significant differences with the control group. The decreased testosterone level at the end of chemotherapy was probably due to inhibition of HSD3B1 and HSD17B6 genes. In conclusion, clinically relevant dose-levels and treatment protocols of BEP chemotherapy adversely affect Leydig cell function. The BEP chemotherapy inhibits the transcription of steroidogenic enzymes and that these effects sustain over an extended period of time without returning to normal levels.
细胞毒性抗癌化疗会影响人类和动物的垂体-睾丸激素轴。本研究调查了博来霉素、依托泊苷和顺铂（分别为0.75、7.5和1.5mg/kg；BEP）三个周期化疗对大鼠睾丸中Leydig细胞的影响。化疗在BEP暴露结束时诱导了Leydig细胞的增生和退行性变化，即使在63天的恢复时间后仍保持如此。化疗结束时睾丸氧化应激增加，恢复后恢复到正常水平。化疗刺激了B1类清道夫受体（SCARB1）、类固醇生成急性调节蛋白（StAR）、细胞色素P450胆固醇侧链裂解酶（CYP11A1）、CYP17A1的转录，并抑制了17β-羟基类固醇脱氢酶（HSD17B6）和CYP19A1的转录，同时胆固醇水平升高，睾酮水平降低。即使在恢复时间后，化疗除了对黄体生成素受体和HSD3B1外，对上述所有基因的转录仍有抑制作用，但对StAR基因没有影响。胆固醇和睾酮水平与对照组也没有显著差异。化疗结束时睾酮水平降低可能是由于HSD3B1和HSD17B6基因受到抑制。总之，BEP化疗的临床相关剂量水平和治疗方案对Leydig细胞功能有不利影响。BEP化疗抑制了类固醇生成酶的转录，并且这些影响会持续很长时间而不会恢复到正常水平。
