Macrophage migration inhibitory factor in human fertility: A systematic review of clinical and reproductive implications, 2015-2025

- Search | Clin Exp Reprod Med > Epub ahead of print | Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine involved in inflammatory and immune regulation. This systematic review evaluated current evidence on the association between MIF and human reproductive function in male and female populations. PubMed, Scopus, Embase, and Google Scholar were systematically searched for studies published from 2015 to 2025. After duplicate removal and eligibility screening, 12 studies were included. Data on study design, population characteristics, reproductive conditions, and MIF expression were extracted and synthesized qualitatively. The included studies reported associations between altered or elevated MIF levels and several reproductive and pregnancy-related conditions, including endometriosis, polycystic ovary syndrome, recurrent pregnancy loss, endometrioma, and hypertensive disorders of pregnancy. MIF was frequently implicated in inflammatory pathways and hormonal regulation within reproductive tissues. The available evidence suggests that MIF may be involved in disease pathophysiology and may have potential as a biomarker in selected reproductive disorders. Overall, current evidence indicates that MIF is associated with multiple reproductive pathologies and may contribute to inflammatory and endocrine regulation in fertility-related conditions. However, further well-designed studies are needed to clarify its diagnostic and clinical utility in reproductive medicine. Male-factor infertility is implicated in approximately 50% of infertility cases [1,2]. Male infertility is commonly associated with genetic factors and lifestyle-related exposures [3,4]. Although diagnostic approaches have advanced substantially, particularly through genomic and molecular testing, further research is needed to expand current knowledge and address cases that remain difficult to treat [5,6]. Infertility is typically defined as the inability of a couple to achieve pregnancy after 1 year of regular, unprotected intercourse [7,8]. Globally, infertility affects approximately 180 million couples [9,10]. Several factors, including age, medication use, surgical history, environmental toxin exposure, genetic abnormalities, and systemic disease, may contribute to infertility in either partner [11-13]. The primary goals of evaluating male infertility are to identify contributing factors, provide appropriate treatment, and offer counseling when curative treatment is not available [14,15]. Macrophage migration inhibitory factor (MIF), a ubiquitous cytokine secreted by Leydig cells and highly expressed in the epididymis, plays an important role in sperm maturation and motility [16,17]. Beyond its role in male reproductive physiology, MIF has also been described as an inflammatory mediator in female reproductive health. Elevated MIF expression has been reported in several gynecological and reproductive disorders, including endometriosis, polycystic ovary syndrome (PCOS), recurrent pregnancy loss, implantation failure, and hypertensive disorders of pregnancy (HDP). Through its involvement in immune regulation, inflammation, angiogenesis, and tissue remodeling, MIF may contribute to infertility pathogenesis and adverse reproductive outcomes in women. Therefore, clarifying the role of MIF in both male and female reproductive systems may provide insight into fertility-related disorders and potential diagnostic applications [18-20]. This review explores the association between MIF and fertility and identifies potential diagnostic pathways for infertility management. This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive literature search was performed in PubMed, Scopus, Embase, and Google Scholar to identify relevant studies published between January 2015 and January 2025. The search strategy combined controlled vocabulary and free-text terms related to ‘macrophage migration inhibitory factor’ and reproductive outcomes, including ‘infertility,’ ‘fertility,’ ‘reproduction,’ ‘endometriosis,’ ‘polycystic ovary syndrome,’ and ‘pregnancy complications.’ All retrieved records were imported into EndNote 21 (Clarivate), and duplicates were removed before screening. Studies were included if they were original research articles that investigated the role of MIF in human reproductive or fertility-related conditions, involved male and/or female human populations, and were published in English with the full text or abstract available. Review articles, meta-analyses, case reports, conference abstracts, editorials, preprints, animal studies, in vitro studies, studies without relevant reproductive or fertility-related outcomes, and articles with insufficient methodological or outcome data were excluded. Two independent reviewers screened titles and abstracts for eligibility. Full-text articles were then assessed for inclusion according to predefined criteria. Disagreements were resolved through discussion with a third reviewer. The selection process is shown in the PRISMA flow diagram (Fig. 1). Data were independently extracted from the included studies using a standardized data extraction form. Extracted variables included the first author, publication year, country, study design, sample size, reproductive condition, tissue or organ involved, and reported role or effect of MIF. Risk of bias was assessed qualitatively for all included studies. Two independent reviewers evaluated each study across key domains, including selection bias, measurement bias, potential confounding, and reporting bias. Because study designs and outcome measures were heterogeneous, a standardized risk-of-bias tool was not applied. Disagreements between reviewers were resolved through discussion and consensus. In this review, PubMed, Scopus, Embase, and Google Scholar were searched, and 2,002 records remained after duplicate removal. These records were stored in EndNote 21. During title and abstract screening, 1,095 articles were excluded because they were not relevant to the research topic. The full texts or detailed contents of 907 studies were then assessed for eligibility. Of these, 895 studies were excluded because they were irrelevant to the research question, lacked sufficient information, were meta-analyses, reviews, review articles or protocols, were not published in English, were preprints, theses, books, or animal studies, or did not have full text available. After keyword review and eligibility assessment, 12 articles were selected, and their methods and results were reviewed, as shown in Fig. 1. Twelve articles were analyzed in this systematic review. As shown in Table 1, the review examined the role of MIF in infertility and reproductive disorders [18-29]. The included studies addressed several conditions, including endometriosis, recurrent pregnancy loss, endometrioma, PCOS, and HDP. The tissues and organs evaluated included the uterus, ovaries, placenta, and testes. Studies published from 2020 to 2024 further examined the role of MIF in selected reproductive conditions. In 2020, Chekini et al. [26] reported an association between MIF and endometrioma in Iran. In 2023, Yu et al. [27] in China described the relationship between MIF and metabolic abnormalities in overweight patients with PCOS. Guan et al. [28] examined the role of MIF in HDP in 2023. In 2024, Rahmawati et al. [29] in Indonesia reported that high systemic levels of soluble cluster of differentiation 163 (sCD163) and MIF were associated with endometriosis severity. Although most included studies focused on female reproductive disorders, one study evaluated MIF in male infertility. Zhang et al. [22] reported that scrotal heat stress (SHS) was associated with increased seminal levels of MIF, nitric oxide, nitric oxide synthase, and caspase-3, accompanied by impaired semen quality. These findings suggest that MIF may participate in inflammatory and oxidative stress pathways that affect male reproductive function and sperm quality. As shown in Fig. 2, risk of bias and reporting quality varied among the reviewed studies. However, all included publications reported information on MIF in infertility or fertility-related disorders. This review investigated the role of MIF in several reproductive disorders, including endometriosis, recurrent pregnancy loss, endometrioma, PCOS, and HDP. We examined the potential biological and clinical implications of MIF in reproductive medicine. Although several studies suggest that MIF may have value as a diagnostic biomarker or therapeutic target, current evidence remains insufficient to support direct therapeutic application in clinical practice. In 2015, Mannelli et al. [21] investigated the effects of bisphenol A (BPA) on the receptivity and secretory function of human decidual cells. Among the cytokines present in the endometrial environment, MIF is a key component of the proinflammatory milieu that characterizes early pregnancy and is highly expressed at the implantation site by trophoblasts and decidual tissue. MIF secretion increased across all treatments and concentrations. Excessive increases in MIF at the implantation site may occur after maternal BPA exposure and may adversely affect pregnancy and fetal health. This study indicated that MIF production is required for pregnancy-related cellular function, but that BPA-related dysregulation of MIF may reduce cell viability and negatively affect pregnancy [21]. In 2015, Mahdian et al. [20] reported that relative mRNA expression of MIF, cluster of differentiation 74 (CD74), and cyclooxygenase-2 (COX-2) was significantly higher in ectopic endometrium than in eutopic and control endometrium. Women with endometriosis also had higher circulating MIF levels than controls. Dynamic expression of MIF, CD74, and COX-2 during the menstrual cycle may contribute to reproduction, inflammation, and endometrial remodeling. High serum MIF levels may also be useful in diagnosing endometriosis. Overall, that study supported a role for MIF in endometriosis and suggested that MIF may serve as an adjunct diagnostic marker and as a molecular target for further investigation in endometrial remodeling and drug development [20]. In the same year, Comba et al. [19] showed that blood and tissue MIF levels were lower in patients with recurrent pregnancy loss, possibly reflecting disruption of the maternal–fetal interface. The authors suggested that modulation of interleukin-18 (IL-18), leukemia inhibitory factor, MIF, IL-12, interferon-γ, and intercellular adhesion molecule 1 (ICAM-1) in blood and tissue may improve future implantation rates and pregnancy outcomes [19]. Zhang et al. [22] evaluated changes in semen quality, sperm parameters, seminal nitric oxide, nitric oxide synthase, and MIF levels in men after SHS. Their findings suggested that SHS may reversibly affect semen quality and that increased seminal nitric oxide, nitric oxide synthase, MIF, and caspase-3 levels may be associated with infertility-related changes in seminal plasma. Accordingly, SHS may alter MIF levels and contribute to impaired male fertility [22]. Graham et al. [23] reported that increased microRNA-451 (miR-451) expression may limit endometriotic cell survival by regulating MIF expression. Conversely, low miR-451 expression and high MIF expression may promote cell survival. The shift from low to high miR-451 expression was proposed to modulate MIF expression, thereby limiting or prolonging the survival of endometriotic lesions [23]. Zhang and Mu [24] found that MIF overexpression may contribute to endometriosis progression. Their study showed that MIF expression was increased in endometrial tissue, correlated with 17β-estradiol (E2) levels, and was more prominent in endometrial cells from women with endometriosis than in those from women without endometriosis. These findings suggest that MIF contributes to endometriosis pathogenesis and is regulated by steroid hormones. This evidence supports further evaluation of MIF as a diagnostic marker and potential therapeutic target in endometriosis [24]. Mejia-Montilla et al. [25] showed that obese and non-obese women with PCOS had higher MIF levels than control women. High MIF levels may also be associated with cardiovascular disease risk in this population. Calan et al. [18] showed in 2016 that plasma MIF levels were significantly lower in eumenorrheic women than in women with PCOS. In the PCOS group, MIF was positively correlated with luteinizing hormone (LH) and free testosterone. These findings suggest that PCOS is associated with increased MIF and that MIF may be involved in PCOS pathogenesis and ovulatory regulation [18]. In 2020, Chekini et al. [26] demonstrated a strong association between a novel MIF haplotype and endometrioma. MIF expression in individuals with endometrioma was consistent at both transcript and protein levels, implicating the −173C/G promoter variant as a potentially important factor. Yu et al. [27] reported in 2023 that overweight patients with PCOS had lower levels of gonadal hormones, including LH, and higher levels of inflammatory markers. MIF was among the inflammatory cytokines that were significantly increased in overweight patients with PCOS. The authors suggested that inflammatory cytokines, including MIF, may have diagnostic and therapeutic relevance in PCOS [27]. In 2023, Guan et al. [28] used Mendelian randomization analysis to show that IL-9, MIF, macrophage inflammatory protein 1β (MIP-1β), IL-13, and IL-16 may be associated with the etiology of HDP. These findings suggest a possible relationship between inflammatory cytokines and HDP and may inform future investigation of therapeutic targets [28]. Rahmawati et al. [29] reported in 2024 that women with endometriosis had significantly higher serum sCD163 and MIF levels than controls. Serum MIF levels were positively correlated with endometriosis-related measures, and serum sCD163 and MIF significantly differentiated endometriosis from non-endometriosis in infertility cases [29]. Across studies of male and female infertility and pregnancy-related disorders, including altered endometrium, endometriosis, recurrent pregnancy loss, PCOS, endometrioma, and HDP, MIF emerged as a promising biomarker and potential therapeutic target. However, further mechanistic and prospective clinical studies are required before routine clinical implementation can be recommended [30-36]. Despite growing evidence linking MIF to reproductive pathophysiology, current data remain largely observational and heterogeneous. The lack of standardized methodologies across studies and the limited availability of longitudinal data restrict the ability to establish causal relationships. Future research should prioritize mechanistic studies and well-designed prospective cohorts to better define the clinical utility of MIF in reproductive medicine. This systematic review synthesizes current evidence on the role of MIF across a range of reproductive disorders in male and female populations. Including multiple reproductive conditions provides an integrated perspective on the potential contribution of inflammatory pathways to fertility-related diseases. However, the small number of eligible studies and their predominantly observational designs limit the ability to draw definitive causal conclusions. In addition, heterogeneity in study design, population characteristics, and outcome measures prevented quantitative synthesis. Therefore, these findings should be interpreted as exploratory and hypothesis-generating rather than confirmatory. This systematic review suggests that MIF is associated with several reproductive and pregnancy-related disorders, likely through inflammatory and immunological pathways. Although MIF shows promise as a potential biomarker in reproductive medicine, current evidence remains insufficient to support its routine clinical application. Further large-scale prospective studies are needed to clarify its diagnostic and therapeutic relevance in fertility- and pregnancy-related conditions. Author contributions Conceptualization: SH, GA, OR. Methodology: FM, FSA, GA, OR. Formal analysis: FM, FSA. Data curation: SH, FM, FSA, GA, OR. Visualization: SH, OR. Software: FM, FSA. Validation: SH, GA, OR. Investigation: SH, GA, OR. Supervision: OR. Writing-original draft: SH, GA, OR. Writing-review & editing: GA, OR. Approval of final manuscript: SH, FM, FSA, GA, OR. | Tissue/organ | Condition | Study population (sample size and sex) | Reported role of MIF | Year | Country | Reference | | |---|---|---|---|---|---|---|---| | 1 | Uterus | Altered endometrium | 6 Women | Bisphenol A exposure stimulated MIF secretion, with the lowest concentration showing the strongest effect. | 2015 | Poland | [21] | | 2 | Uterus | Endometriosis | 36 Women | MIF, CD74, and COX-2 expression increased during the menstrual cycle; elevated serum MIF may have diagnostic value in endometriosis. | 2015 | Iran | [20] | | 3 | Uterus/placenta | Recurrent pregnancy loss | 41 Women | Altered levels of MIF and other cytokines, including IL-18 and LIF, were associated with implantation failure and pregnancy loss. | 2015 | Turkey | [19] | | 4 | Testis | Male infertility (scrotal heat stress) | 25 Men | Heat stress increased nitric oxide, nitric oxide synthase, MIF, and caspase-3 levels, potentially impairing sperm quality. | 2015 | China | [22] | | 5 | Uterus | Endometriosis | 30 Women | miR-451 regulates MIF expression and may influence the survival of endometriotic cells. | 2015 | USA | [23] | | 6 | Uterus | Endometriosis | 102 Women | Elevated MIF expression correlated with estradiol levels and increased sensitivity to hormonal stimulation. | 2015 | China | [24] | | 7 | Ovary | PCOS | 140 Women | Plasma MIF levels were higher in patients with PCOS, particularly in obese individuals. | 2015 | Venezuela | [25] | | 8 | Ovary | PCOS | 170 Women | MIF may be involved in ovulation regulation and PCOS pathogenesis. | 2016 | Turkey | [18] | | 9 | Ovary | Endometrioma | 235 Women | The MIF−173G/C polymorphism was associated with an increased risk of endometrioma. | 2020 | Iran | [26] | | 10 | Ovary | PCOS | 947 Women | MIF was associated with insulin resistance and chronic inflammation in overweight patients with PCOS. | 2023 | China | [27] | | 11 | Organs involved in pregnancy | HDP | 8,293 individuals | Mendelian randomization analysis showed a causal association between MIF and reduced HDP risk. | 2023 | China | [28] | | 12 | Uterus | Endometriosis | 87 Women | Elevated serum MIF and sCD163 levels correlated with endometriosis severity and infertility. | 2024 | Indonesia | [29] | MIF, macrophage migration inhibitory factor; CD74, cluster of differentiation 74; COX-2, cyclooxygenase-2; IL-18, interleukin-18; LIF, leukemia inhibitory factor; miR-451, microRNA-451; PCOS, polycystic ovary syndrome; HDP, hypertensive disorders of pregnancy; sCD163, soluble cluster of differentiation 163. 1. Sharma A. Male infertility; evidences, risk factors, causes, diagnosis and management in human. Ann Clin Lab Res 2017;5:188. 2. Eisenberg ML, Esteves SC, Lamb DJ, Hotaling JM, Giwercman A, Hwang K, et al. Male infertility. Nat Rev Dis Primers 2023;9:49. 4. Tesarik J. Lifestyle and environmental factors affecting male fertility, individual predisposition, prevention, and intervention. Int J Mol Sci 2025;26:2797. 5. Schilit SLP. Recent advances and future opportunities to diagnose male infertility. Curr Sex Health Rep 2019;11:331-41. 6. Ferlin A, Dipresa S, Delbarba A, Maffezzoni F, Porcelli T, Cappelli C, et al. Contemporary genetics-based diagnostics of male infertility. Expert Rev Mol Diagn 2019;19:623-33. 7. Awonuga AO, Camp OG, Biernat MM, Abu-Soud HM. Overview of infertility. Syst Biol Reprod Med 2025;71:116-42. 8. Upadhyay Y, Chhabra A, Nagar JC. A women infertility: an overview. Asian J Pharm Res Dev 2020;8:99-106. 9. Thoma M, Fledderjohann J, Cox C, Adageba RK. Biological and social aspects of human infertility: a global perspective. In: McQueen DV, editor. Oxford research encyclopedia of global public health. Oxford Academic; 2021 [cited 2026 Jul 8]. Available from: https://academic.oup.com/edited-volume/61794/chapter-abstract/545995288?redirectedFrom=fulltext 10. Stellar C, Garcia-Moreno C, Temmerman M, van der Poel S. A systematic review and narrative report of the relationship between infertility, subfertility, and intimate partner violence. Int J Gynaecol Obstet 2016;133:3-8. 11. Bala R, Singh V, Rajender S, Singh K. Environment, lifestyle, and female infertility. Reprod Sci 2021;28:617-38. 12. Ma Y, He X, Qi K, Wang T, Qi Y, Cui L, et al. Effects of environmental contaminants on fertility and reproductive health. J Environ Sci (China) 2019;77:210-7. 13. Khizroeva J, Nalli C, Bitsadze V, Lojacono A, Zatti S, Andreoli L, et al. Infertility in women with systemic autoimmune diseases. Best Pract Res Clin Endocrinol Metab 2019;33:101369. 14. Schlegel PN, Sigman M, Collura B, De Jonge CJ, Eisenberg ML, Lamb DJ, et al. Diagnosis and treatment of infertility in men: AUA/ASRM Guideline Part I. J Urol 2021;205:36-43. 15. Medenica S, Abazovic D, Ljubic A, Vukovic J, Begovic A, Cucinella G, et al. The role of cell and gene therapies in the treatment of infertility in patients with thyroid autoimmunity. Int J Endocrinol 2022;2022:4842316. 16. Vashisht A, Gahlay GK. Understanding seminal plasma in male infertility: emerging markers and their implications. Andrology 2024;12:1058-77. 17. Syriou V, Papanikolaou D, Kozyraki A, Goulis DG. Cytokines and male infertility. Eur Cytokine Netw 2018;29:73-82. 18. Calan M, Kume T, Yilmaz O, Arkan T, Kocabas GU, Dokuzlar O, et al. A possible link between luteinizing hormone and macrophage migration inhibitory factor levels in polycystic ovary syndrome. Endocr Res 2016;41:261-9. 19. Comba C, Bastu E, Dural O, Yasa C, Keskin G, Ozsurmeli M, et al. Role of inflammatory mediators in patients with recurrent pregnancy loss. Fertil Steril 2015;104:1467-74.e1. 20. Mahdian S, Aflatoonian R, Yazdi RS, Yaghmaei P, Ramazanali F, Afsharian P, et al. Macrophage migration inhibitory factor as a potential biomarker of endometriosis. Fertil Steril 2015;103:153-9.e3. 21. Mannelli C, Szostek AZ, Lukasik K, Carotenuto C, Ietta F, Romagnoli R, et al. Bisphenol A modulates receptivity and secretory function of human decidual cells: an in vitro study. Reproduction 2015;150:115-25. 22. Zhang MH, Zhang AD, Shi ZD, Wang LG, Qiu Y. Changes in levels of seminal nitric oxide synthase, macrophage migration inhibitory factor, sperm DNA integrity and caspase-3 in fertile men after scrotal heat stress. PLoS One 2015;10:e0141320. 23. Graham A, Falcone T, Nothnick WB. The expression of microRNA-451 in human endometriotic lesions is inversely related to that of macrophage migration inhibitory factor (MIF) and regulates MIF expression and modulation of epithelial cell survival. Hum Reprod 2015;30:642-52. 24. Zhang X, Mu L. Association between macrophage migration inhibitory factor in the endometrium and estrogen in endometriosis. Exp Ther Med 2015;10:787-91. 25. Mejia-Montilla J, Alvarez-Mon M, Reyna-Villasmil E, Torres-Cepeda D, Santos-Bolivar J, Reyna-Villasmil N, et al. Macrophage migration inhibitory factor in obese and non obese women with polycystic ovary syndrome. Endocrinol Nutr 2015;62:31-7. 26. Chekini Z, Poursadoughian Yaran A, Ansari-Pour N, Shahhoseini M, Ramazanali F, Aflatoonian R, et al. A novel gene-wide haplotype at the macrophage migration inhibitory factor (MIF) locus is associated with endometrioma. Eur J Obstet Gynecol Reprod Biol 2020;247:6-9. 27. Yu J, Zhou Y, Ding J, Zhang D, Yu C, Huang H. Characteristics and possible mechanisms of metabolic disorder in overweight women with polycystic ovary syndrome. Front Endocrinol (Lausanne) 2023;13:970733. 28. Guan S, Bai X, Ding J, Zhuang R. Circulating inflammatory cytokines and hypertensive disorders of pregnancy: a two-sample Mendelian randomization study. Front Immunol 2023;14:1297929. 29. Rahmawati NY, Ahsan F, Santoso B, Mufid AF, Sa’adi A, Dwiningsih SR, et al. Soluble factors CD14, CD163, and migration inhibitory factor are associated with endometriosis-related infertility. Gynecol Obstet Invest 2024;89:335-45. 30. Monseur BC, Morris JR, Hipp HS, Berghella V. Hypertensive disorders of pregnancy and infertility treatment: a population-based survey among United States women. J Assist Reprod Genet 2019;36:1449-56. 31. Palomba S, Piltonen TT, Giudice LC. Endometrial function in women with polycystic ovary syndrome: a comprehensive review. Hum Reprod Update 2021;27:584-618. 32. Cui Z, Zhou L, An X, Liu W, Li J, Zhang Y, et al. The combination of circEPSTI1 and MIF offers diagnostic value for endometrial cancer. Int J Gen Med 2024;17:1395-403. 33. AlAshqar A, Reschke L, Kirschen GW, Borahay MA. Role of inflammation in benign gynecologic disorders: from pathogenesis to novel therapies. Biol Reprod 2021;105:7-31. 34. Kang I, Bucala R. The immunobiology of MIF: function, genetics and prospects for precision medicine. Nat Rev Rheumatol 2019;15:427-37.