Clomiphene citrate causes aberrant tubal apoptosis and estrogen receptor activation in rat fallopian tube: implications for tubal ectopic pregnancy.

• 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.

Nyckelord

Animals

Apoptosis

drug effects

Body Weight

drug effects

Cell Movement

drug effects

Clomiphene

administration & dosage

adverse effects

Epithelial Cells

drug effects

Estradiol

pharmacology

Fallopian Tubes

cytology

drug effects

metabolism

pathology

Female

Gonadal Steroid Hormones

blood

Oocytes

drug effects

Organ Size

drug effects

Pregnancy

Pregnancy

Tubal

chemically induced

Rats

Rats

Sprague-Dawley

Receptors

Estrogen

metabolism

Selective Estrogen Receptor Modulators

administration & dosage

adverse effects

Superovulation

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)