Lamberts S W, Uitterlinden P, de Jong F H
Department of Medicine, Erasmus University, Rotterdam, The Netherlands.
Cancer Res. 1988 Nov 1;48(21):6063-8.
The effects of the s.c. administration of a depot formulation of the luteinizing hormone-releasing hormone (LHRH) analogue Zoladex were studied in normal male rats, alone and in combination with three drugs with "antiandrogenic" action (ketoconazole, cyproterone acetate, and RU 23908) on prostatic weight and on circulating hormone levels in order to investigate whether these antiandrogens might prevent the LHRH-A-induced initial increase in these parameters. These effects were compared with those caused by surgical castration. In addition the effects of the antiandrogens on the activity of the hypothalamic-pituitary-adrenal axis were investigated. The depot LHRH analogue caused an initial increase in ventral prostatic weight after 4 days but suppressed the prostatic and testicular weights, the pituitary luteinizing hormone (LH) content, and plasma LH and testosterone levels after 10 and 17 days. All three antiandrogenic drugs used prevented the initial LHRH analogue-induced rise in prostatic weight, while RU 23908 suppressed its weight after only 4 days. After 10 and 17 days cyproterone acetate and RU 23908 had a similar significantly greater suppressive effect on prostatic and testicular weights than the LHRH analogue alone, while the additive inhibitory effect of ketoconazole was smaller. Surgical castration suppressed prostatic weight significantly more after 4 days, while its effects after 10 and 17 days were similar to that exerted by the combination of LHRH-A and RU 23908. The antigonadotropic effect of cyproterone acetate and the indirect gonadotropin-stimulating effects of ketoconazole and RU 23908 were not recognized in rats simultaneously treated with the LHRH analogue and did not interfere with the LHRH analogue-induced rapid depletion of the pituitary LH content and the decrease in circulating LH and testosterone levels. The LHRH analogue stimulated circulating progesterone and suppressed 17-hydroxyprogesterone levels. Ketoconazole and cyproterone acetate caused disorders in the pituitary-adrenal axis via different mechanisms: ketoconazole caused adrenal hypertrophy with normal circulating corticosterone levels caused by a compensatory increase in ACTH secretion; while cyproterone acetate exerted glucocorticoid-like effects causing a depletion of the pituitary adrenocorticotropic hormone content, adrenal atrophy, and lowered corticosterone levels. The addition of RU 23908 did not change the LHRH agonist-induced changes in adrenocortical activity.(ABSTRACT TRUNCATED AT 400 WORDS)
在正常雄性大鼠中，研究了皮下注射促黄体生成激素释放激素（LHRH）类似物诺雷德的长效制剂的作用，该制剂单独使用以及与三种具有“抗雄激素”作用的药物（酮康唑、醋酸环丙孕酮和RU 23908）联合使用对前列腺重量和循环激素水平的影响，以研究这些抗雄激素是否能预防LHRH类似物诱导的这些参数的初始增加。将这些作用与手术去势所引起的作用进行比较。此外，还研究了抗雄激素对下丘脑-垂体-肾上腺轴活性的影响。长效LHRH类似物在4天后导致前列腺腹侧重量最初增加，但在10天和17天后抑制了前列腺和睾丸重量、垂体促黄体生成素（LH）含量以及血浆LH和睾酮水平。所使用的三种抗雄激素药物均能预防LHRH类似物诱导的前列腺重量的初始增加，而RU 23908仅在4天后就抑制了其重量。在10天和17天后，醋酸环丙孕酮和RU 23908对前列腺和睾丸重量的抑制作用明显大于单独使用LHRH类似物，而酮康唑的相加抑制作用较小。手术去势在4天后对前列腺重量的抑制作用明显更强，而其在10天和17天后的作用与LHRH类似物和RU 23908联合使用所产生的作用相似。在与LHRH类似物同时治疗的大鼠中，未发现醋酸环丙孕酮的抗促性腺激素作用以及酮康唑和RU 23908的间接促性腺激素刺激作用，且这些作用未干扰LHRH类似物诱导的垂体LH含量的快速减少以及循环LH和睾酮水平的降低。LHRH类似物刺激循环孕酮水平并抑制17-羟孕酮水平。酮康唑和醋酸环丙孕酮通过不同机制导致垂体-肾上腺轴紊乱：酮康唑导致肾上腺肥大，促肾上腺皮质激素（ACTH）分泌代偿性增加，使循环皮质酮水平正常；而醋酸环丙孕酮发挥类糖皮质激素作用，导致垂体促肾上腺皮质激素含量减少、肾上腺萎缩以及皮质酮水平降低。添加RU 23908并未改变LHRH激动剂诱导的肾上腺皮质活性变化。（摘要截选至400字）
