Female infertility is one of the major reproductive health issue affecting majority of women worldwide. Several factors including environmental, hormonal and physical may affect the physiology of ovary to release quality grade oocyte required for fertilization and early embryonic development. The quality of oocyte is dependent on several factors within the follicular microenvironment and even after ovulation. One of the major factors that affect oocyte quality is the induction of apoptosis. Apoptosis plays a major role to eliminate majority of germ cells from the cohort of ovary during various stages of folliculogenesis. Few numbers of oocytes are selectively recruited to get ovulated during entire reproductive life span in female. Prior to ovulation, these oocytes achieve meiotic competency that may last for several months in rodents to several years in human. Inability to achieve meiotic competency within the follicular microenvironment and spontaneous egg activation (SEA) immediately after ovulation may deteriorate oocyte quality. Thus, induction of apoptosis or meiotic arrest at Metaphase-I stage (M-I) or SEA could reduce female fertility and may cause infertility.

The clomiphene citrate (CC) is a first line of medicine used for ovulation induction in women worldwide. CC has good ovulation induction ability in anovulatory women but the pregnancy rate is very poor. This discrepancy might be due to the anti-estrogenic effect of CC at various level including ovary and oocytes. The hypoestrogenic conditions due to CC treatment inhibit follicular growth and development, induce susceptibility of oocytes towards apoptosis and deteriorate oocyte quality after ovulation. CC induces reactive oxygen species (ROS) mediated granulosa cells as well as oocyte apoptosis within the follicle of the ovary. Apoptosis deteriorates oocyte quality and thereby reproductive outcome. Supplementation of estradiol 17β or natural antioxidant such as melatonin prevents anti-estrogenic effects of CC and improves oocyte quality by scavenging CC induced generation of ROS. Thus, we propose that the supplementation of estradiol 17β and/or melatonin along with CC may be beneficial to overcome the anti-estrogenic effect of CC during infertility management in human.