Tamada H, Shimizu Y, Inaba T, Kawate N, Sawada T
Laboratory of Theriogenology, Graduate School of Agriculture and Biological Sciences, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan.
J Endocrinol. 2004 Feb;180(2):337-45. doi: 10.1677/joe.0.1800337.
It is well known that progesterone and estrogen are essential hormones for maintaining pregnancy in most mammals. Some specific roles of progesterone for the maintenance of pregnancy have been clarified, but the role of estrogen is not well known. This study examines the effects of the aromatase inhibitor, fadrozole hydrochloride (Fad), on fetuses, uterine physical properties and the mRNA expression of the uterine enzymes that are related to collagen metabolism during late pregnancy in rats. Continuous s.c. infusion with 300 micro g/day Fad from day 14 of pregnancy (day 1=the day of sperm detection) reduced the concentration of plasma estradiol-17beta (E(2)), and did not change that of plasma progesterone, compared with controls. The treatment increased the intrauterine pressure and reduced the size and compliance of the uterine tissue framework. It also caused injuries (hematomata on the extremities) in about one-quarter of fetuses by day 20. The collagen content of the uterine ampullae was not changed by the treatment. Uterine mRNA expressions of matrix metalloproteinase-1 (MMP-1), which degrades collagens, and of lysyl oxidase (LO), which is necessary for the formation of intra- and inter-molecular cross-links of collagen, were examined by quantitative RT-PCR. The treatment with Fad had no effect on the expression of MMP-1 mRNA and increased that of LO mRNA. Daily s.c. injection with 0.2 micro g E(2) restored the changes in uterine physical properties and the mRNA expression of LO caused by the Fad treatment, and prevented fetal injury, indicating that the influences of Fad treatment are due to estrogen deficiency but not to toxicological effects of Fad. These results imply that estrogen deficiency during late pregnancy in rats obstructs development of the uterine tissue framework so as to cause fetal injury. It is possible that an increase in the uterine expression of LO gene may be involved in this obstruction.
众所周知，孕酮和雌激素是大多数哺乳动物维持妊娠所必需的激素。孕酮在维持妊娠方面的一些特定作用已经明确，但雌激素的作用尚不清楚。本研究检测了芳香化酶抑制剂盐酸法倔唑（Fad）对大鼠妊娠晚期胎儿、子宫物理特性以及与胶原代谢相关的子宫酶mRNA表达的影响。从妊娠第14天（第1天=检测到精子的当天）开始，每天皮下连续输注300μg Fad，与对照组相比，可降低血浆雌二醇-17β（E₂）浓度，而血浆孕酮浓度无变化。该处理增加了子宫内压，减小了子宫组织结构的大小和顺应性。到第20天时，约四分之一的胎儿还出现了损伤（肢体血肿）。该处理未改变子宫壶腹部的胶原含量。通过定量RT-PCR检测了降解胶原的基质金属蛋白酶-1（MMP-1）以及胶原分子内和分子间交联形成所必需的赖氨酰氧化酶（LO）的子宫mRNA表达。Fad处理对MMP-1 mRNA表达无影响，但增加了LO mRNA表达。每天皮下注射0.2μg E₂可恢复Fad处理引起的子宫物理特性变化和LO mRNA表达，并预防胎儿损伤，表明Fad处理的影响是由于雌激素缺乏而非Fad的毒理学作用。这些结果表明，大鼠妊娠晚期雌激素缺乏会阻碍子宫组织结构的发育，从而导致胎儿损伤。子宫LO基因表达增加可能参与了这一阻碍过程。
