Rivas Ana, Fisher Jane S, McKinnell Chris, Atanassova Nina, Sharpe Richard M
Medical Research Council Human Reproductive Sciences Unit, Center for Reproductive Biology, University of Edinburgh Academic Center, Edinburgh, United Kingdom EH16 4SB.
Endocrinology. 2002 Dec;143(12):4797-808. doi: 10.1210/en.2002-220531.
This study tested the hypothesis that testis/reproductive tract abnormalities induced in the rat by neonatal treatment with diethylstilbestrol (DES) result from disturbance of the androgen-estrogen balance. Male rats were treated neonatally with a dose of DES (0.1 micro g) that induced either no or small effects on its own or with a dose (10 micro g) that induced major reproductive tract abnormalities. To allow quantification, the abnormalities chosen for study were distension of the rete testis and efferent ducts and reduction in epithelial cell height in the efferent ducts and vas deferens. To alter the androgen-estrogen balance, other rats were treated with DES (0.1 micro g) in combination with a treatment to suppress either androgen production [GnRH antagonist (GnRHa)] or androgen action (flutamide); other rats were treated with GnRHa or flutamide alone. Testosterone levels were measured to verify the effects of treatment. Combined administration of DES (0.1 micro g) plus GnRHa or flutamide induced significantly greater distension/overgrowth of the rete testis and efferent ducts (ED) and a reduction in epithelial cell height of the ED than did DES (0.1 micro g) administered alone. Neither GnRHa nor flutamide affected rete or ED distension when administered alone, but both significantly reduced ED epithelial cell height. Neonatal treatment with bisphenol-A (100 micro g) with or without GnRHa had no significant effect on any of these parameters. In contrast to the ED, a reduction in cell height of the vas deferens was induced to an equal extent by DES (10 micro g), DES (0.1 micro g) with GnRHa, and GnRHa alone, suggesting greater sensitivity of this tissue to both androgen and estrogen action. The induction of major abnormalities in rats treated with DES (10 micro g) was coincident with loss of androgen receptor immunoexpression in affected tissues. Reduced androgen receptor immunoexpression was also induced by combined treatment with DES (0.1 micro g) plus GnRHa or flutamide, whereas treatment with any of these compounds alone had no or only minor effects. These findings suggest that reduced androgen action sensitizes the reproductive tract to estrogens, demonstrating that the balance in action between androgens and estrogens, rather than their absolute levels, may be of fundamental importance in determining normal or abnormal development of some regions of the male reproductive tract.
新生大鼠经己烯雌酚（DES）处理后诱导的睾丸/生殖道异常是由雄激素 - 雌激素平衡紊乱所致。雄性大鼠在新生期接受一剂DES（0.1μg）处理，该剂量单独使用时对其影响不明显或影响较小，或者接受一剂（10μg）处理，该剂量会诱导严重的生殖道异常。为了进行量化，选择用于研究的异常情况为睾丸网和输出小管扩张以及输出小管和输精管上皮细胞高度降低。为了改变雄激素 - 雌激素平衡，其他大鼠接受DES（0.1μg）与抑制雄激素产生的处理[促性腺激素释放激素拮抗剂（GnRHa）]或雄激素作用的处理（氟他胺）联合治疗；其他大鼠单独接受GnRHa或氟他胺治疗。测量睾酮水平以验证治疗效果。与单独给予DES（0.1μg）相比，DES（0.1μg）加GnRHa或氟他胺联合给药诱导的睾丸网和输出小管扩张/过度生长明显更严重，且输出小管上皮细胞高度降低。单独给予GnRHa或氟他胺时，对睾丸网或输出小管扩张均无影响，但两者均显著降低输出小管上皮细胞高度。新生期用双酚A（100μg）处理，无论是否加GnRHa，对这些参数均无显著影响。与输出小管不同，DES（10μg）、DES（0.1μg）加GnRHa以及单独的GnRHa均能同等程度地诱导输精管细胞高度降低，这表明该组织对雄激素和雌激素作用更敏感。用DES（10μg）处理的大鼠中主要异常的诱导与受影响组织中雄激素受体免疫表达的丧失同时发生。DES（0.1μg）加GnRHa或氟他胺联合治疗也会诱导雄激素受体免疫表达降低，而单独使用这些化合物中的任何一种均无影响或仅有轻微影响。这些发现表明，雄激素作用降低会使生殖道对雌激素敏感，这表明雄激素和雌激素作用之间的平衡，而非其绝对水平，可能在决定雄性生殖道某些区域的正常或异常发育中至关重要。
