Infertility is defined as the failure to conceive after 12 months or more of regular unprotected sexual intercourse (Gurunath et al., 2011, Zegers-Hochschild et al., 2009). In recent years, the number of patients seeking treatment for infertility has increased year by year, and the age of infertility has tended to be younger. In the United States, 11% of married women have impaired fertility (Chandra et al., 2013). According to the World Health Organization (WHO), female and male infertility will be the third most prevalent disease in the world after cancer and cardiovascular diseases in the 21st century (Qiao and Feng, 2014). Approximately 15%–20% of women of childbearing age experience infertility. Furthermore, infertility affects approximately 600,000–800,000 people worldwide and is a growing health problem (Winter et al., 2023). The American Medical Association recognizes infertility as a distinct and complex disease process, emphasizing the long-term health impact of the disease (Dupree, 2018).

The occurrence and development of infertility is the result of multiple genes and multiple factors. Deepening research on the pathological mechanism(s) of infertility in modern medicine has resulted in immune factors receiving increasing attention. Infertility is often accompanied by abnormal immune function and changes in cytokine content and activity, and observational studies have suggested a role for cytokines in infertility. The pro-inflammatory cytokine interleukin (IL)-1β was significantly elevated in male infertility patients (Sadia et al., 2023). The circulating cytokines monocyte chemotactic protein (MCP)-1, tumor necrosis factor (TNF)-α, and IL-6 were elevated in obese women, contributing to infertility and adverse pregnancy outcomes (Ahmad and Haque, 2022, Gosman et al., 2006). In a prospective study, the serum concentration of IL-6 in infertile patients was significantly higher than that in fertile patients (Gica et al., 2020). Another prospective study reported that the serum levels of IL-10 and transforming growth factor (TGF)-β1 were increased in an infertile group with endometriosis (Yan et al., 2020). Serum levels of TNF-α, IL-8, IL-6, and TGF-β1 were significantly increased in patients with secondary tubal factor infertility (Yan et al., 2020).

Mendelian randomization (MR) studies can provide an effective way to make causal inferences in observational studies (Sekula et al., 2016). MR analysis can minimize confounding and reduce reverse causation bias. Because genetic variation is randomly assigned before birth, genetic variation is used as instrumental variables (IVs) as exposure and the disease as the outcome to explore causal evidence for disease occurrence and development. Existing research evidence is limited to the effect of a single cytokine on infertility outcomes, whether from observational studies or randomized controlled trials. To date, this is the first MR analysis to explore the causal relationship between cytokines and the risk of female and male infertility. Determining the cytokines and molecular mechanisms required for an optimal immune microenvironment can help infertile patients achieve better pregnancy outcomes to determine its predictive value as a minimally invasive marker for fertility assessment.