IL-18 and IL-18 binding protein concentration in ovarian follicular fluid of women with unexplained infertility to PCOS during in vitro fertilization
Introduction
Polycystic ovary syndrome (PCOS) is one of the most common endocrine and metabolic disorders in women (Ehrmann, 2005). The prevalence in women of childbearing age is reported to be 5%–20% (Crespo et al., 2018). It is a complex and heterogeneous disorder, and its physiopathology is not yet clear. There is growing evidence of chronic inflammatory state in patients with PCOS, which may be associated with the pathogenesis of PCOS (Patel, 2018).
Previous studies have shown that the expression of some inflammatory and acute phase proteins in peripheral blood of PCOS patients is increased, such as interleukin (IL) 1, IL-6, tumor necrosis factor alpha (TNF- alpha) and serum C- reactive protein (CRP) (Rashid et al., 2017; Mohammadi et al., 2017; Li et al., 2017), and have been shown to influence ovarian function ovulation, fertilization and implantation in women with PCOS (Vural et al., 2010), but the role of precise cytokine regulation is still far from a definite solution.
Remarkably, PCOS appears to be an evolutionarily conserved disorder (Azziz et al., 2011). Ovulation is a complex inflammatory-like process that involves follicular production of inflammatory cytokines, induction of prostaglandins, and the recruitment of immune cells, including leukocytes, neutrophils, and macrophages (Shirasuna et al., 2013; Smolikova et al., 2012). Follicular fluid contains factors responsible for oocyte maturation and ovulation; therefore some disturbances of its composition may affect folliculogenesis (Lédée et al., 2011). The previous studies on chronic low inflammation in PCOS were mainly concentrated in the serum or endometrium, rather than the follicle fluid (FF), while the study on the expression of IL-18 in the follicular fluid of the PCOS patients was very few.
IL-18 is a proinflammatory cytokine starting the cascade of additional inflammatory cytokines including TNFα, IL-1β, IL-6, and IL-2 receptor. It was discovered quite recently and was believed to be an exclusively pro-inflammatory cytokine able to induce strong Th1 responses in immunocompetent cells (Tsutsui et al., 2004). Although initially thought to be produced mainly by macrophages and adipocytes, now it has been found that IL-18 is synthesizes by a variety of cells including Kupffer cells, T and B cells, osteoblasts and dendritic cells, and a wide range of nonimmune cell types, including normal ovarian cells (Machelon and Emilie, 1997). IL-18 binding protein (IL-18BP) is a secreted 40 kDa glycoprotein which possesses a high affinity to IL-18. It binds the mature form of IL-18 and blocks its interaction with IL-18R, thus inhibits the biological activity of IL-18 (Esmailbeig and Ghaderi, 2017).
Previous studies showed that the serum IL-18 level in PCOS patients was significantly higher than that in healthy women (Zhang et al., 2006). Significantly higher IL-18 levels were also detected in serum and peritoneal fluid of patients with severe ovarian hyperstimulation syndrome (Barak et al., 2004). Furthermore, the expression of both IL-18 and IL-18R was found in the ovaries of pregnant mice (Tsuji et al., 2001). IL-18 has been suggested to favor ovarian folliculogenesis (Ozörnek et al., 1999). Inactivation of IL-18R with murine monoclonal antibody during ovarian stimulation reduced the number of ovulated oocytes and inhibited the expansion of cumulus cells surrounding the ovum (Tsuji et al., 2001).
The primary aim of the current study was to determine IL-18 and IL-18BP levels in follicular fluid and serum in PCOS women undergoing reproductive measures and to explore their possibly correlation with the pathogenesis of PCOS. The effect of follicular fluid and serum IL-18 levels on obesity was also analyzed.
Section snippets
Materials and methods
Sixty patients with PCOS admitted to the Department of Gynecology Endocrine, Tianjin Central Obstetrics and Gynecology Hospital, from August 2017 to August 2018 were selected as the PCOS group. Another sixty women with unexplained infertility undergoing IVF during the same period were selected as the control group (Fig. 1). This study was approved by the ethical committee of the Tianjin Central Gynecology and Obstetrics Hospital (TCGOH A17-04). Patients who choose to enter the study signed an
Characteristics of the study population
This study included sixty PCOS patients (27 overweight patients, 33 normal weight patients) and sixty control group (29 overweight control participants and 31 normal weight control participants).
The demographic features, biochemical, and hormonal data of PCOS group and normal group are showed in Table 1. No statistically significant differences were found between the groups in relation to age, basal FSH, estradiol levels, and simulation days. Although there was a trend towards increased BMI in
Discussion
As far as we know, the pathogenesis of PCOS is very complicated. Recent studies have shown that the inflammatory response in the ovary of PCOS patients seems to be very important and may be closely related to the pathogenesis of PCOS (Zafari et al., 2017).
IL-18 is a multifunctional cytokine that has a critical role in ovarian physiologic function. Within the normal ovary it is involved in follicular development and atresia, ovulation, and steroidogenesis (Vidal-Vanaclocha et al., 2006). The
Funding
This research was supported by the Tianjin Key Laboratory of Human Development and Reproductive Regulation.
Declaration of Competing Interest
None.
Acknowledgments
The authors are grateful to the staff of the Division of Reproductive Maternity Assisting Department at the Tianjin Central Gynecology and Obstetrics Hospital for their kind assistance and collaboration in data collection.
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Co-first author.