间质细胞特异性凋亡和抗雌激素机制可能解释了枸橼酸氯米酚治疗后人类子宫缺陷的原因。

Stromal cell-specific apoptotic and antiestrogenic mechanisms may explain uterine defects in humans after clomiphene citrate therapy.

机构信息

Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.

出版信息

Am J Obstet Gynecol. 2010 Jul;203(1):65.e1-65.e10. doi: 10.1016/j.ajog.2010.03.039. Epub 2010 May 21.

DOI:10.1016/j.ajog.2010.03.039

PMID:20494331

Abstract

OBJECTIVE

The purpose of this study was to investigate clomiphene citrate (CC)-induced modulation of uterine cell function in vivo.

STUDY DESIGN

Prepubertal female Sprague-Dawley rats were treated intraperitoneally with CC for 6 or 24 hours or with a combination of CC and/or 17-beta-estradiol (E2) for 4 days.

RESULTS

Chronic CC treatment induced apoptosis in a fraction of uterine stromal cells by activating the caspase-3-mediated apoptotic pathway. The damage was prevented by successive E2 treatment; however, pretreatment or concomitant treatment with E2 did not protect against CC-induced uterine apoptosis. CC decreased the protein expression of estrogen receptor alpha and increased its phosphorylation but did not affect estrogen receptor beta expression or phosphorylation. Furthermore, changes in Hoxa11, p27, and progesterone receptor protein levels and localization were associated with CC treatment.

CONCLUSION

We provide novel mechanistic insights into cellular and molecular events by which CC regulates uterine stromal cell function and hence the implantation process and pregnancy outcome.

摘要

目的

本研究旨在探讨枸橼酸氯米酚（CC）在体内对子宫细胞功能的调节作用。

研究设计

将未成年雌性 Sprague-Dawley 大鼠经腹腔给予 CC 处理 6 或 24 小时，或给予 CC 与 17-β-雌二醇（E2）联合处理 4 天。

结果

慢性 CC 处理通过激活半胱氨酸天冬氨酸蛋白酶-3 介导的凋亡途径诱导部分子宫基质细胞凋亡。这种损伤可通过连续的 E2 处理来预防；然而，E2 的预处理或同时处理并不能防止 CC 诱导的子宫细胞凋亡。CC 降低了雌激素受体 α 的蛋白表达，并增加了其磷酸化，但不影响雌激素受体 β 的表达或磷酸化。此外，Hoxa11、p27 和孕激素受体蛋白水平和定位的变化与 CC 处理有关。