Translator Disclaimer
1 June 2009 Clomiphene Citrate Causes Aberrant Tubal Apoptosis and Estrogen Receptor Activation in Rat Fallopian Tube: Implications for Tubal Ectopic Pregnancy
Ruijin Shao, Magdalena Nutu, Birgitta Weijdegård, Emil Egecioglu, Julia Fernandez-Rodriguez, Linda Karlsson-Lindahl, Kristina Gemzell-Danielsson, Christina Bergh, Håkan Billig
Author Affiliations +
Abstract

Clomiphene citrate (CC) therapy for disorders of anovulatory infertility has been linked to an increased frequency of tubal ectopic pregnancy. Although CC enhances apoptotic processes in the ovaries, villi, and decidual tissues, its effect on apoptosis in the fallopian tube is unknown. Here, we show that chronic treatment with CC induces tubal apoptosis, but not necrosis, through an intrinsic mitochondria-dependent signaling pathway in vivo. The apoptosis was specific to epithelial cells in the isthmus, and the damage was reversed with 17beta-estradiol (E2); however, pretreatment or concomitant treatment with E2 did not protect against tubal apoptosis induced by chronic treatment with CC. Chronic treatment activated estrogen receptors (ESRs), particularly cilia-localized ESR2A (formerly ERbeta2). In contrast to E2, acute treatment of superovulating rats with a high dose of CC or the ESR2-selective agonist 2,3-bis (4-hydroxyphenyl)-propionitrile (DPN) significantly delayed the transport of oocyte-cumulus complexes through the fallopian tube. Our findings suggest that in response to chronic CC therapy, isthmus-specific apoptosis of epithelial cells and activation of cilia-ESR2A act in parallel to block gamete and embryo passage through the fallopian tube, eventually resulting in tubal ectopic pregnancy.

Ruijin Shao, Magdalena Nutu, Birgitta Weijdegård, Emil Egecioglu, Julia Fernandez-Rodriguez, Linda Karlsson-Lindahl, Kristina Gemzell-Danielsson, Christina Bergh, and Håkan Billig "Clomiphene Citrate Causes Aberrant Tubal Apoptosis and Estrogen Receptor Activation in Rat Fallopian Tube: Implications for Tubal Ectopic Pregnancy," Biology of Reproduction 80(6), 1262-1271, (1 June 2009). https://doi.org/10.1095/biolreprod.108.074237
Received: 15 October 2008; Accepted: 1 February 2009; Published: 1 June 2009
JOURNAL ARTICLE
10 PAGES


Share
SHARE
KEYWORDS
clomiphene citrate
ectopic pregnancy
estradiol receptor
estrogen receptor
fallopian tubes
intrinsic and extrinsic apoptotic pathways
RIGHTS & PERMISSIONS
Get copyright permission
Back to Top