Bookstaff R C, Moore R W, Peterson R E
School of Pharmacy, University of Wisconsin, Madison 53706.
Toxicol Appl Pharmacol. 1990 Jun 15;104(2):212-24. doi: 10.1016/0041-008x(90)90296-7.
Tetrachlorodibenzo-p-dioxin (TCDD) decreases plasma androgen concentrations in male rats, without increasing plasma luteinizing hormone (LH) concentrations. If plasma LH concentrations had increased appropriately, plasma androgen concentrations in these animals would have returned to normal. The mechanism by which TCDD prevents the compensatory increase in plasma LH concentrations was therefore investigated. TCDD was found to have no effect on the plasma disappearance of iv administered LH. Therefore, the failure of plasma LH concentrations to rise was not due to increased clearance of LH from the circulation, but rather to an effect of TCDD on LH synthesis and/or secretion by the pituitary. In the absence of gonadal steroids (i.e., in castrated rats) TCDD did not prevent the compensatory increase in plasma LH concentrations from occurring. This was shown by 20-fold increases in plasma LH concentrations in both control and TCDD-treated rats 1 week after castration. Thus, (1) the presence of gonadal steroids is required for TCDD to prevent the compensatory increase in plasma LH concentrations, and (2) TCDD does not impair LH secretion by acting, itself, as an androgen or estrogen. TCDD treatment also did not affect pituitary LH content in castrated, testosterone-implanted rats. The above findings demonstrate that TCDD does not decrease the maximum rate at which the pituitary can synthesize and secrete LH. Rather, TCDD alters the feedback regulation of LH secretion when gonadal steroids are present. To determine if TCDD affects the potency of testosterone and its metabolites 5 alpha-dihydrotestosterone and 17 beta-estradiol as feedback inhibitors of LH secretion, rats were dosed with TCDD, castrated, and implanted with sustained-release capsules containing graded amounts of each steroid. Seven days later, the potencies of all three hormones as feedback inhibitors of LH secretion were increased by TCDD, with little effect on their plasma concentrations. The TCDD dose dependence for the increased effectiveness of testosterone as a feedback inhibitor of LH secretion (ED50 10 micrograms/kg) was similar to that reported for the imbalance between plasma LH and androgen concentrations (ED50 15 micrograms/kg). Also, time courses for both responses were similar; each was detected within 1 day of TCDD dosing and each was fully developed after 7 days. We conclude that the mechanism by which TCDD prevents the compensatory increase in plasma LH concentrations in male rats is by increasing the potencies of androgens (and estrogens) as feedback inhibitors of LH secretion.
四氯二苯并 - 对 - 二噁英（TCDD）可降低雄性大鼠的血浆雄激素浓度，而不会增加血浆促黄体生成素（LH）浓度。如果血浆LH浓度适当升高，这些动物的血浆雄激素浓度将会恢复正常。因此，对TCDD阻止血浆LH浓度代偿性升高的机制进行了研究。发现TCDD对静脉注射的LH在血浆中的消失没有影响。所以，血浆LH浓度未能升高并非由于LH从循环中清除增加，而是由于TCDD对垂体LH合成和/或分泌的影响。在没有性腺类固醇的情况下（即去势大鼠），TCDD并不能阻止血浆LH浓度的代偿性升高。这在去势后1周，对照大鼠和TCDD处理大鼠的血浆LH浓度均升高20倍中得到证实。因此，（1）性腺类固醇的存在是TCDD阻止血浆LH浓度代偿性升高所必需的，（2）TCDD本身并不作为雄激素或雌激素来损害LH分泌。TCDD处理也不影响去势并植入睾酮的大鼠垂体中的LH含量。上述发现表明，TCDD不会降低垂体合成和分泌LH的最大速率。相反，当性腺类固醇存在时，TCDD会改变LH分泌的反馈调节。为了确定TCDD是否影响睾酮及其代谢产物5α - 二氢睾酮和17β - 雌二醇作为LH分泌反馈抑制剂的效力，给大鼠注射TCDD，进行去势，并植入含有不同剂量每种类固醇的缓释胶囊。7天后，TCDD增加了所有三种激素作为LH分泌反馈抑制剂的效力，而对它们的血浆浓度影响很小。TCDD使睾酮作为LH分泌反馈抑制剂效力增加的剂量依赖性（半数有效剂量为10微克/千克）与血浆LH和雄激素浓度失衡的报道相似（半数有效剂量为15微克/千克）。而且，两种反应的时间进程相似；在TCDD给药后1天内均可检测到，且在7天后均完全显现。我们得出结论，TCDD阻止雄性大鼠血浆LH浓度代偿性升高的机制是增加雄激素（和雌激素）作为LH分泌反馈抑制剂的效力。
