IL-18 and IL-18 binding protein concentration in ovarian follicular fluid of women with unexplained infertility to PCOS during in vitro fertilization

https://doi.org/10.1016/j.jri.2020.103083Get rights and content

Highlights

  • The IL-18 levels of follicular fluid were increased in PCOS women.

  • The elevated FF IL-18 levels have no correlation with the serum IL-18 levels.

  • The expression of IL-18 in the follicular fluid of the overweight PCOS patients was increased compared to the normal weight PCOS patients.

  • The FF IL-18 and IL-18BP may have a local involvement in the pathogenesis of PCOS.

Abstract

The correlation between the concentration of interleukin (IL) 18 in follicular fluid and the pathogenesis of Polycystic Ovary Syndrome (PCOS) is unclear. Therefore, we tested the IL-18 and IL-18 binding protein (IL-18BP) levels in follicular fluid (FF) and serum in PCOS women undergoing reproductive measures and to explore their possibly correlation with PCOS. Serum and pooled follicular fluid levels of IL-18, IL-18BP and IL-18/IL-18BP ratios were evaluated in sixty patients with PCOS and sixty women with unexplained infertility undergoing in vitro fertilization. The FF IL-18 levels were increased in PCOS group than the CON group (p < 0.01), and the IL-18 levels were significantly higher in the FF than in serum in PCOS group. Furthermore, the elevated FF IL-18 levels have no correlation with the serum IL-18 levels. Additionally, the expression of IL-18 in the follicular fluid of the overweight PCOS patients was increased compared to the normal weight PCOS patients, while in the overweight patients, FF IL-18 was significantly higher in the PCOS group than in the control group. The FF IL-18 and IL-18BP may have a local involvement in the pathogenesis of PCOS. The PCOS itself and overweight will aggravate the local inflammatory response in the ovary. Further studies are needed to elucidate this issue.

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.

References (28)

  • M. Kanazawa et al.

    Criteria and classification of obesity in Japan and Asia-Oceania

    World Rev. Nutr. Diet.

    (2005)
  • R.L. Kennedy et al.

    Cytokines in endocrinology: their roles in health and in disease

    J. Endocrinol.

    (1991)
  • S. Li et al.

    A missense variant rs4645843 in TNF-α gene is a risk factor of polycystic ovary syndrome in the uygur population

    Tohoku J. Exp. Med.

    (2017)
  • V. Machelon et al.

    Production of ovarian cytokines and their role in ovulation in the mammalian ovary

    Eur. Cytokine Netw.

    (1997)
  • Cited by (21)

    • Genetic basis of metabolism and inflammation in PCOS

      2023, Human Reproductive and Prenatal Genetics
    • Systemic and ovarian inflammation in women with polycystic ovary syndrome

      2022, Journal of Reproductive Immunology
      Citation Excerpt :

      Immunohistochemical staining showed that PCOS ovaries were infiltrated throughout with a large number of macrophages and lymphocytes, which is consistent with what we called persistent low-grade chronic inflammation in PCOS ovaries (Xiong et al., 2011). IL-18 and IL-18 binding protein (IL-18BP) levels are increased in the follicular fluid (FF) of PCOS patients (Zhang et al., 2020). Significantly, although the IL-18 concentration is increased in both serum and FF, its level in FF is much higher than that in the serum, and these increases are not related, which suggests localized production of IL-18 in the PCOS ovarian microenvironment(Azziz et al., 2011).

    • The follicular fluid adipocytokine milieu could serve as a prediction tool for fertility treatment outcomes

      2021, Reproductive BioMedicine Online
      Citation Excerpt :

      The strength of this study design included the matching that was done: to minimize the biological variability between the groups, to increase the statistical power, and to tease out differences in the follicular fluid milieu that could be attributed to increasing BMI. Cases of patients with polycystic ovary syndrome (PCOS) and/or endometriosis were excluded to avoid the effects these conditions may have on the composition of the follicular fluid (Karaer et al., 2019; Zhang et al., 2020). The correlation analyses between predictive adipocytokines and BMI helped us determine whether differences in predictive abilities between different BMI strata and the complete cohorts stemmed from loss of power (i.e. smaller sample sizes) or from disruption of the follicular fluid composition in the overweight population.

    View all citing articles on Scopus
    1

    Co-first author.

    View full text