da Cunha M F, Meistrich M L, Nader S
Cancer Res. 1987 Feb 15;47(4):1093-7.
Protection of testicular integrity against damage from cyclophosphamide (CY) by simultaneous treatment with a gonadotropin-releasing hormone (GnRH) analogue was reported in BALB/c mice (L.M. Glode et al., Lancet, 1: 1132-1134, 1981). This approach has been used as the basis for clinical trials in various treatment centers (D. H. Johnson et al., Blood, 65:832-836, 1985) in an attempt to prevent iatrogenic sterility in males. This study aims at duplicating the original findings and obtaining quantitative data on spermatogonial killing by CY, and possible protection by GnRH, of differentiating and stem cell spermatogonia. Mice were treated with 23 daily injections of 0.4 micrograms D-leucine-6 GnRH, and with 200 mg/kg CY on Days 8, 15, and 22. Three additional groups of mice received phosphate-buffered saline and bovine serum albumin only, GnRH only, and CY only. Animals were killed at 29 days after the last injection to determine the number of late spermatids in testicular homogenates, and at 56 days for histological measurement of the ratio of elongated spermatids to Sertoli cells in the tubules. The twenty-ninth day assay was a measure of damage to differentiating spermatogonia, whose killing results in temporary sterility. The fifty-sixth day point assay assessed damage to stem spermatogonia, whose killing results in long-term or permanent sterility. Sperm counts at 29 days were identical in saline-treated control mice and GnRH-treated mice; no sperm were present in the CY-treated mice, both with and without GnRH. Thus, killing of differentiating spermatogonia by CY is not prevented by GnRH treatment. Similarly, counts of spermatids at 56 days showed no difference between saline- and GnRH-treated groups; a reduction to approximately 40% of control counts was observed equally with CY and CY plus GnRH treatments. Since GnRH treatment did not alter spermatogonial kinetics in BALB/c mice, it is not surprising that it did not protect against CY-induced damage. Thus, the mouse is not a suitable model for analyzing such effects of GnRH on spermatogenesis, and further studies in other experimental animals are needed if they are to be used as a rationale for clinical administration of GnRH to cancer patients.
在BALB/c小鼠中，有研究报道（L.M. Glode等人，《柳叶刀》，1: 1132 - 1134, 1981），通过同时使用促性腺激素释放激素（GnRH）类似物来保护睾丸完整性免受环磷酰胺（CY）的损害。这种方法已被多个治疗中心用作临床试验的基础（D.H. Johnson等人，《血液》，65:832 - 836, 1985），旨在预防男性医源性不育。本研究旨在重复最初的研究结果，并获取关于CY对精原细胞杀伤以及GnRH对分化型和干细胞型精原细胞可能的保护作用的定量数据。小鼠每日注射23次0.4微克的D - 亮氨酸 - 6 GnRH，并在第8、15和22天注射200毫克/千克的CY。另外三组小鼠分别仅接受磷酸盐缓冲盐水和牛血清白蛋白、仅接受GnRH、仅接受CY。在最后一次注射后29天处死动物，以确定睾丸匀浆中晚期精子细胞的数量；在56天处死以进行组织学测量曲细精管中伸长精子细胞与支持细胞的比例。第29天的检测是对分化型精原细胞损伤的一种衡量，其被杀伤会导致暂时不育。第56天的检测评估对干细胞型精原细胞的损伤，其被杀伤会导致长期或永久性不育。在29天时，生理盐水处理的对照小鼠和GnRH处理的小鼠精子计数相同；接受CY处理的小鼠，无论是否同时接受GnRH，均无精子。因此，GnRH治疗不能预防CY对分化型精原细胞的杀伤。同样，在56天时精子细胞计数显示，生理盐水处理组和GnRH处理组之间没有差异；CY处理组以及CY加GnRH处理组均观察到精子细胞数量减少至对照计数的约40%。由于GnRH治疗并未改变BALB/c小鼠的精原细胞动力学，所以它不能预防CY诱导的损伤也就不足为奇了。因此，小鼠并非分析GnRH对精子发生此类作用的合适模型，如果要将其作为向癌症患者临床应用GnRH的理论依据，还需要在其他实验动物中进行进一步研究。
