Shail K Chaube1*, Meenakshi Tiwari1, Anumegha Gupta1, Alka Sharma1, Shilpa Prasad1, Ashutosh N Pandey1, Pramod K Yadav1, Sabana Khatun1 and Tulsidas G Shrivastav2
1Department of Zoology, Institute of science Banaras Hindu University, Varanasi-221005, India
2Department of Reproductive Biomedicine, National Institute of Health and Family Welfare, New Delhi-110067,India
Submission: May 15, 2017; Published: July 05, 2017
*Corresponding author: Shail K Chaube, Cell Physiology Laboratory, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi-221005, India, Tel: 091-542-6702516; Fax: 091-542-2368174; Email: firstname.lastname@example.org; email@example.com
How to cite this article: Chaube SK, Tiwari M, Gupta A, Sharma A, Prasad S, et al. Clomiphene Citrate and Oocyte Quality. Glob J Reprod Med. 2017; 1(4): 555570. DOI: 10.19080/GJORM.2017.01.555570
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.
Ovary is a dynamic organ and generates excess amount of reactive oxygen species (ROS) during follicular growth, development, maturation and ovulation . The increased level of ROS is scavenged by antioxidant systems . A moderate increase of ROS could be beneficial for oocyte meiotic maturation and reproductive outcome [3-5]. Overproduction of ROS or depletion of enzymatic antioxidant systems causes oxidative stress .
Anovulation is one of the major causes of reproductive failure in sub-fertile and infertile women [6,7]. In the absence of other reproductive problems, successful ovulation induction and good quality oocyte often restores normal fertility in human . In a common clinical practice, gonadotropins are used to stimulate ovary in infertile or subfertile women [9,10]. However, anti-estrogens are widely used to induce ovulation in these patients. Clomiphene citrate (CC) is a non-steroidal ovulation-inducing drug that has been used in humans for more than 40 years [11,12]. Ovarian stimulation by gonadotropins is an expensive treatment. CC is an inexpensive, safe and effective alternative to gonadotropins .
For ovulation induction, CC has been used as a first line of medicine . It is similar to estrogen and thus binds to estrogen receptors (ER) . It triggers hypothalamic gonadotropin-releasing hormone (GnRH) secretion that stimulates release of pituitary gonadotropins . Pituitary gonadotropins surge trigger growth and development of ovarian follicles [13,15]. CC treatment generates dominant follicle and results in the ovulation of metaphase-II (M-II) arrested oocytes required for successful fertilization in various assisted reproductive technology (ART) programs (Figure 1). Although CC has been used for ovulation induction widely, the possible mechanism of its action at the level of ovary still remains ill understood.
In spite of having good ovulation induction ability of CC (60% - 85%), the pregnancy rate is much lower (10% -20%) [10,16]. The higher incidence of miscarriage has been reported in the conception cycle after CC treatment . Such a discrepancy could be due to anti-estrogenic effect of CC, particularly at the level of ovary, cervical mucus and endometrium [17,18]. The anti-estrogenic effects of CC may result apoptosis in granulosa cells and oocyte in ovary . Studies suggest that CC induces apoptosis in human granulosa cells cultured in vitro . CC induces granulosa cell apoptosis that reduces estradiol 17β level in the ovary of rat [20, 21] as well as in monkey .
The CC induced hypoestrogenic conditions may induce generation of ROS . Animal studies suggest that CC treatment increases hydrogen peroxide (H2O2) level and reduces catalase activity in rat . The increased level of ROS induces overexpression of bax protein and thereby DNA fragmentation both in granulosa cells and oocytes [20,21,24-32]. Granulosa cell apoptosis results in reduced estradiol 17β level in ovary [21,2426]. The reduced level of estradiol 17β may deteriorate oocyte quality by inducing susceptibility of oocytes towards apoptosis. These oocytes are not of good quality and their use reduces ART outcome.
The anti-estrogenic condition due to CC treatment is one ofthe major side effects that affects the development and maturation of oocytes in the ovary and reduces oocyte quality after ovulation. To overcome the anti-estrogenic effect of CC, supplementation of exogenous estradiol 17β has been recommended [20,23, 33]. This is further supported by the observations that the exogenous estradiol 17β prevents apoptosis and thereby deterioration of oocyte quality [20,23].
The antiestrogenic effect of CC can also be prevented by the supplementation of a naturally occurring antioxidant such as melatonin . Melatonin scavenges free radicals , induces superoxide dismutase  and glutathione peroxidase activities to prevent oxidative damage in human . Animal studies suggest that melatonin induces catalase activity, reduces H2O2 level and prevents CC-induced oocyte apoptosis .
Based on existing clinical as well as animal studies, we conclude that use of either estradiol 17β or melatonin along with CC would be beneficial to overcome the anti-estrogenic effects of CC at the level of ovary during infertility management in human.