Clomiphene Citrate Induces ROS-Mediated Apoptosis in Mammalian Oocytes

Abstract

The clomiphene citrate (CC), a nonsteroidal triphenylethylene compound, is a first line of medicine used for the induction of ovulation in anovulatory women worldwide. In spite of high ovulation induction with the use of CC, the pregnancy rate is much lower. Such a discrepancy could be due to the peripheral anti-estrogenic effect of CC, particularly at the level of ovary, endometrium and cervical mucus. CC induces ovulation by binding to the estrogen receptors and generates hypoestrogrnic state in hypothalamus leading to release of pituitary gonadotropins. CC may have a direct effect at the level of ovary but the molecular mechanism remains unclear. Animal studies suggest that the CC induces apoptosis in granulosa cells and results hypoestrogenic state in the ovary. Reduced estradiol 17β level in the ovary affects development and maturation of oocyte leading to oocyte apoptosis. Further, CC increases hydrogen peroxide (H2O2) level and thereby bax protein expression and DNA fragmentation in cumulus-granulosa cells as well as in oocytes. The exogenous supplementation of either estradiol 17β or melatonin reduces H2O2 level in ovary, delays meiotic cell cycle progression in oocyte and protects oocyte apoptosis. Hence, supplementation of estradiol 17β or melatonin along with CC could be beneficial to protect granulosa cell as well as oocyte apoptosis and inhibit deterioration of oocyte quality. Thus, maintenance of oocyte quality may overcome the adverse effect caused due to CC treatment during infertility management.

Implications from early life stress on the development of mouse ovarian follicles: Focus on oxidative stress

“…This concept is further enhanced by investigations that have shown OS induced apoptosis in granulosa cells resulting in the reduction of estradiol levels and atresia of follicles . Chaube et al ., showed that OS disrupts granulosa cells‐oocyte communication resulting in decreased quality of oocytes . This notion is further supported by the observations that the OS caused chromosomal segregation disorders, shortening of telomere, oocyte fragmentation and fertilization failures .…”

Calcium Signaling During Meiotic Cell Cycle Regulation and Apoptosis in Mammalian Oocytes

“…The increased cytochrome c activates upstream and downstream caspases in mouse oocytes (Liu et al, ; Zhang and Fissore, ). The caspase‐3 disrupt the histoarchitecture of oocyte by disrupting the structural and regulatory proteins, which results several biochemical and morphological changes during oocyte apoptosis (Chaube et al, , ,; Tripathi et al, , , ; Tiwari et al, , ; Zhu et al, ) (Fig. ).…”

Moderate increase of reactive oxygen species triggers meiotic resumption in rat follicular oocytes

“…It is generally accepted that ROS act as signal molecules in a wide variety of cells, including germ cells in mammals . A moderate increase of ROS is beneficial for meiotic cell cycle progression in vitro , while high levels of ROS induce cell cycle arrest and apoptosis . Generation of ROS is associated with a reduced level of 3′,5′‐cyclic adenosine monophosphate (cAMP) as well as 3′,5′‐cyclic guanosine monophosphate (cGMP) levels during spontaneous meiotic resumption from diplotene arrest in rat oocytes cultured in vitro .…”