Hori Jun-Ichi, Koga Daisuke, Kakizaki Hidehiro, Watanabe Tsuyoshi
Department of Microscopic Anatomy and Cell Biology, Asahikawa Medical University.
Department of Renal and Urologic Surgery, Asahikawa Medical University.
Biomed Res. 2018;39(4):197-214. doi: 10.2220/biomedres.39.197.
Despite their pharmacologically opposite actions, long-acting depot formulations of both GnRH agonists and antagonists have been clinically applied for treatment of androgen-sensitive prostate cancer. Sustained treatment with GnRH analogues commonly suppresses both the synthesis and release of gonadotropins, leading to depletion of testicular testosterone. To clarify the underlying differences in the effects of GnRH agonists and antagonists on spermatogenesis, we compared histological changes in the seminiferous epithelium after administration of depot formulations of GnRH agonist leuprorelin and antagonist degarelix to male rats. Testicular weight had markedly declined by 28 days after administration of both GnRH analogues, although the testicular weight was decreased more promptly by leuprorelin compared with degarelix. Shortly after administration, massive exfoliation of premature spermatids and anomalous multinucleated giant cells was observed in seminiferous tubules of leuprorelin-treated rats, probably via the initial hyperstimulatory effects on the hypothalamic-pituitary-testicular axis, whereas no discernible changes were found in those of degarelix-treated rats. Long term treatment with both types of GnRH analogues similarly induced a marked reduction in the height of the epithelium and deformation of apical cytoplasm in Sertoli cells, resulting in premature detachment of spermatids from the epithelium. Lipid droplets had accumulated progressively in Sertoli cells, especially in those of degarelix-treated rats. These findings clearly demonstrate the differences in the effects of GnRH agonists and antagonists on the spermatogenic process. This study suggests that an appropriate choice of GnRH analogues is necessary to minimize their adverse effects on spermatogenesis when reproductive functions should be preserved in patients.
尽管促性腺激素释放激素（GnRH）激动剂和拮抗剂在药理作用上相反，但两者的长效缓释制剂已在临床上用于治疗雄激素敏感性前列腺癌。GnRH类似物的持续治疗通常会抑制促性腺激素的合成和释放，导致睾丸睾酮耗竭。为了阐明GnRH激动剂和拮抗剂对精子发生作用的潜在差异，我们比较了给雄性大鼠注射GnRH激动剂亮丙瑞林和拮抗剂地加瑞克的长效缓释制剂后，生精上皮的组织学变化。两种GnRH类似物给药后28天，睾丸重量均显著下降，不过与地加瑞克相比，亮丙瑞林使睾丸重量下降得更快。给药后不久，在亮丙瑞林治疗的大鼠的生精小管中观察到大量早熟精子细胞脱落和异常多核巨细胞，这可能是由于对下丘脑-垂体-睾丸轴的初始超刺激作用，而在地加瑞克治疗的大鼠中未发现明显变化。两种类型的GnRH类似物长期治疗同样导致支持细胞上皮高度显著降低和顶端细胞质变形，导致精子细胞过早从上皮脱落。脂滴在支持细胞中逐渐积累，尤其是在地加瑞克治疗的大鼠中。这些发现清楚地证明了GnRH激动剂和拮抗剂对精子发生过程作用的差异。这项研究表明，当需要保留患者的生殖功能时，选择合适的GnRH类似物以尽量减少其对精子发生的不良影响是必要的。
