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

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.