Abstract
Endometriosis (EMT) -related infertility has been a challenge for clinical research. Many studies have confirmed that abnormal alterations in the immune microenvironment and glycolysis are instrumental in causing EMT-related infertility. Recently, our research team identified several key glycolysis-immune-related genes in the endometrial cells of EMT patients. This study aimed to further investigate the expression patterns of pyruvate dehydrogenase kinase 3 (PDK3), glypican-3 (GPC3), and alcohol dehydrogenase 6 (ADH6), which are related to glycolysis and immunity, in the follicular microenvironment of infertile patients with EMT using enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR) assays. According to the results, compared to the patients with tubal factor infertility, the concentrations of PDK3 and GPC3 were considerably increased in the follicular environment of EMT patients, while ADH6 expression was significantly reduced. The number of oocytes retrieved, the transferable embryo rate, and the cumulative clinical pregnancy rate of EMT patients were significantly reduced, and there was a correlation with the level of PDK3, GPC3, and ADH6 in Follicular Fluid (FF). The area under the receiver operating characteristic (ROC) curve for predicting clinical pregnancy in infertile patients with EMT for PDK3, GPC3, ADH6, and their combination was 0.732, 0.705, 0.855, and 0.879, respectively (P < 0.05). In conclusion, our research indicates that glycolysis-immune-related genes may contribute to infertility in EMT patients through immune infiltration, and disruption of mitochondrial and oocyte functions. The combined detection of PDK3, GPC3, and ADH6 in FF helps to predict clinical pregnancy outcomes in infertile patients with EMT.
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References
Saunders PTK, Horne AW. Endometriosis: Etiology, pathobiology, and therapeutic prospects. Cell. 2021;184(11):2807–24.
Kalaitzopoulos DR, Samartzis N, Kolovos GN, et al. Treatment of endometriosis: A review with comparison of 8 guidelines. BMC Womens Health. 2021;21(1):397.
Taylor HS, Kotlyar AM, Flores VA. Endometriosis is a chronic systemic disease: Clinical challenges and novel innovations. Lancet. 2021;397(10276):839–52.
Rolla E. Endometriosis: Advances and controversies in classification, pathogenesis, diagnosis, and treatment. F1000Res. 2019;8:F1000 Faculty Rev-529.
Yao Q, **g G, Zhang X, et al. Cinnamic acid inhibits cell viability, invasion, and glycolysis in primary endometrial stromal cells by suppressing NF-kappaB-induced transcription of PKM2. Biosci Rep. 2021;9:BSR20211828.
Kobayashi H, Imanaka S. Understanding the molecular mechanisms of macrophage polarization and metabolic reprogramming in endometriosis: A narrative review. Reprod Med Biol. 2022;21(1):e12488.
Lu C, Qiao P, Fu R, et al. Phosphorylation of pfkfb4 by pim2 promotes anaerobic glycolysis and cell proliferation in endometriosis. Cell Death Dis. 2022;13(9):790.
Kalezic A, Udicki M, Srdic Galic B, et al. Tissue-specific Warburg effect in breast cancer and cancer-associated adipose tissue-relationship between AMPK and glycolysis. Cancers (Basel). 2021;13(11):2731.
Chen Q, Jiao Y, Yin Z, et al. Establishment of a novel glycolysis-immune-related diagnosis gene signature for endometriosis by machine learning. J Assist Reprod Genet. 2023;40(5):1147–61.
Prins JR, Marissen LM, Scherjon SA, et al. Is there an immune modulating role for follicular fluid in endometriosis? A narrative review. Reproduction. 2020;159(1):R45–54.
Sreerangaraja Urs DB, Wu WH, Komrskova K, et al. Mitochondrial function in modulating human granulosa cell steroidogenesis and female fertility. Int J Mol Sci. 2020;21(10):3592.
Bonavina G, Taylor HS. Endometriosis-associated infertility: From pathophysiology to tailored treatment. Front Endocrinol (Lausanne). 2022;13:1020827.
Castiglione Morelli MA, Iuliano A, Schettini SCA, et al. Nmr metabolic profiling of follicular fluid for investigating the different causes of female infertility: A pilot study. Metabolomics. 2019;15(2):19.
Karaer A, Tuncay G, Mumcu A, et al. Metabolomics analysis of follicular fluid in women with ovarian endometriosis undergoing in vitro fertilization. Syst Biol Reprod Med. 2019;65(1):39–47.
Trapero C, Vidal A, Fernandez-Montolí ME, et al. Impaired expression of ectonucleotidases in ectopic and eutopic endometrial tissue is in favor of ATP accumulation in the tissue microenvironment in endometriosis. Int J Mol Sci. 2019;20(22):5532.
Broi MGD, Ferriani RA, Navarro PA. Ethiopathogenic mechanisms of endometriosis-related infertility. JBRA Assist Reprod. 2019;23(3):273–80.
Mabrouk M, Del Forno S, Spezzano A, et al. Painful love: Superficial dyspareunia and three dimensional transperineal ultrasound evaluation of pelvic floor muscle in women with endometriosis. J Sex Marital Ther. 2020;46(2):187–96.
Pirtea P, Cicinelli E, De Nola R, et al. Endometrial causes of recurrent pregnancy losses: Endometriosis, adenomyosis, and chronic endometritis. Fertil Steril. 2021;115(3):546–60.
Giorgi VSI, Ferriani RA, Navarro PA. Follicular fluid from infertile women with mild endometriosis impairs in vitro bovine embryo development: Potential role of oxidative stress. Rev Bras Ginecol Obstet. 2021;43(2):119–25.
Kong Y, Shao Y, Ren C, et al. Endometrial stem/progenitor cells and their roles in immunity, clinical application, and endometriosis. Stem Cell Res Ther. 2021;12(1):474.
Lu J, Ling X, Liu L, et al. Emerging hallmarks of endometriosis metabolism: A promising target for the treatment of endometriosis. Biochim Biophys Acta Mol Cell Res. 2023;1870(1):119381.
Pocate-Cheriet K, Santulli P, Kateb F, et al. The follicular fluid metabolome differs according to the endometriosis phenotype. Reprod Biomed Online. 2020;41(6):1023–37.
Ortiz CN, Torres-Reveron A, Appleyard CB. Metabolomics in endometriosis: Challenges and perspectives for future studies. Reprod Fertil. 2021;2(2):R35–50.
Kolanska K, Alijotas-Reig J, Cohen J, et al. Endometriosis with infertility: A comprehensive review on the role of immune deregulation and immunomodulation therapy. Am J Reprod Immunol. 2021;85(3):e13384.
Jiang Z, Liu Z, Li M, et al. Increased glycolysis correlates with elevated immune activity in tumor immune microenvironment. EBioMedicine. 2019;42:431–42.
Feng L, Cheng K, Zang R, et al. miR-497–5p inhibits gastric cancer cell proliferation and growth through targeting PDK3. Biosci Rep. 2019;39(9):BSR20190654.
Cui L, Cheng Z, Liu Y, et al. Overexpression of pdk2 and pdk3 reflects poor prognosis in acute myeloid leukemia. Cancer Gene Ther. 2020;27(1–2):15–21.
Xu J, Shi Q, Xu W, et al. Metabolic enzyme pdk3 forms a positive feedback loop with transcription factor hsf1 to drive chemoresistance. Theranostics. 2019;9(10):2999–3013.
Lu CW, Lin SC, Chen KF, et al. Induction of pyruvate dehydrogenase kinase-3 by hypoxia-inducible factor-1 promotes metabolic switch and drug resistance. J Biol Chem. 2008;283(42):28106–14.
Varga J, Reviczka A, Hakova H, et al. Predictive factors of endometriosis progression into ovarian cancer. J Ovarian Res. 2022;15(1):5.
Atkins HM, Bharadwaj MS, O’Brien Cox A, et al. Endometrium and endometriosis tissue mitochondrial energy metabolism in a nonhuman primate model. Reprod Biol Endocrinol. 2019;17(1):70.
Hou X, Zhang L, Han L, et al. Differing roles of pyruvate dehydrogenase kinases during mouse oocyte maturation. J Cell Sci. 2015;128(13):2319–29.
Fu Y, Urban DJ, Nani RR, et al. Glypican-3-specific antibody drug conjugates targeting hepatocellular carcinoma. Hepatology. 2019;70(2):563–76.
Ning J, Jiang S, Li X, et al. Gpc3 affects the prognosis of lung adenocarcinoma and lung squamous cell carcinoma. BMC Pulm Med. 2021;21(1):199.
Shi L, Xue X, Tian H, et al. Wee1 promotes endometriosis via the wnt/beta-catenin signaling pathway. Reprod Biol Endocrinol. 2021;19(1):161.
Valsechi MC, Oliveira AB, Conceição AL, et al. GPC3 reduces cell proliferation in renal carcinoma cell lines. BMC Cancer. 2014;14:631.
Anand P, Hausladen A, Wang YJ, et al. Identification of s-nitroso-coa reductases that regulate protein s-nitrosylation. Proc Natl Acad Sci U S A. 2014;111(52):18572–7.
Liu X, Li T, Kong D, et al. Prognostic implications of alcohol dehydrogenases in hepatocellular carcinoma. BMC Cancer. 2020;20(1):1204.
Yang H, Cui Y, Zhu Y. Comprehensive analysis reveals signal and molecular mechanism of mitochondrial energy metabolism pathway in pancreatic cancer. Front Genet. 2023;14:1117145.
Palanikumar L, Karpauskaite L, Al-Sayegh M, et al. Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function. Nat Commun. 2021;12(1):3962.
Acknowledgements
The authors thank all research assistants of the Reproductive Medicine Centre of Tongji Hospital affiliated with Tongji University for their assistance in the collection and analysis of data.
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This study was supported by grants from the Shanghai Science and Technology Commission Project (NO.20Z21900400 and NO.22410761100) and the Clinical Research Project of Tongji Hospital (ITJ(ZD)2208).
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This study was approved by the ethics committee of Tongji Hospital affiliated with Tongji University (Ethics approval number: 2020-KYSB-118).
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Guo, S., Chen, Q., Liang, J. et al. Correlation of Glycolysis-immune-related Genes in the Follicular Microenvironment of Endometriosis Patients with ART Outcomes. Reprod. Sci. (2024). https://doi.org/10.1007/s43032-024-01518-7
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DOI: https://doi.org/10.1007/s43032-024-01518-7