Endometriosis-Associated Infertility: The Role of Biomarkers of Apoptosis and Proliferation in Early Noninvasive Diagnosis

INTRODUCTION: Endometriosis is a common disease that affects up to 15% of women in the reproductive period and leads to infertility in 25%–50% of cases. The diagnosis of endometriosis is delayed for years due to blurred and diverse clinical presentation, therefore, search for a noninvasive biomarker of endometriosis is an important problem of modern medicine. AIM: To study the significance of changes in the profile of biomarkers: regulator of Wnt/β-catenin signaling pathway (axis inhibition protein 1; AXIN-1), soluble cytokeratin 19 fragment (cytokeratin fragment antigen 21-1; CYFRA-21-1), cancer antigen 125 (carbohydrate antigen 125; CA-125) in blood plasma of patients with endometriosis-associated infertility (before surgery and in the postoperative period).

The study included two groups of female patients. The first group consisted of 20 patients of reproductive age with cystic ovarian endometriosis and infertility. All the patients underwent surgical intervention using a laparoscope and a video system, in all the patients the diagnosis of endometriosis was confirmed histologically. Three times in specified periods (before surgery, on the 10th day of the postoperative period, at 6 months), patients with cystic ovarian endometriosis and infertility were taken biomaterial (blood) with further determination of AXIN-1, CYFRA-21-1, CA-125 in blood plasma. The second group consisted of patients of reproductive age with no gynecological pathology. In the second group, biological material (blood) was taken once with further determination of AXIN-1, CYFRA-21-1, CA-125 in blood plasma.

Based on the analysis of the measurement data and comparison of their levels, it was found that the content of the studied AXIN-1, СA-125 biomarkers in patients with cystic ovarian endometriosis and infertility was higher than in patients without gynecological pathology (p < 0.05). As for CYFRA-21-1 biomarker, initially lower values were noted compared to the control group (p < 0.05), however, in the postoperative period, the content of CYFRA-21-1 increased and reached values close to those of healthy patients.

Determining the levels of AXIN-1, CYFRA-21-1 apoptosis biomarkers and CA-125 proliferation biomarker in blood of patients with endometriosis-associated infertility gives an insight into the pathophysiological processes in the endometrioid ovarian cysts and may be helpful in development of new noninvasive diagnostic methods and target treatment methods.

Full Text About the authors Mikhail A. Kiselev Ryazan State Medical University Author for correspondence. Email: [email protected] ORCID iD: 0000-0002-8294-9038 SPIN-code: 7098-2877 Russian Federation, Ryazan Natalya B. Repina Ryazan State Medical University Email: [email protected] ORCID iD: 0000-0001-5916-3574 SPIN-code: 4119-5550 MD, Cand. Sci. (Med.), Associate Professor Russian Federation, RyazanAlexander A. Nikiforov Ryazan State Medical University Email: [email protected] ORCID iD: 0000-0003-0866-9705 SPIN-code: 8366-5282 MD, Cand. Sci. (Med.), Associate Professor Russian Federation, RyazanLarisa V. Nikiforova Ryazan State Medical University Email: [email protected] ORCID iD: 0000-0003-4369-0729 SPIN-code: 8735-8565 Russian Federation, Ryazan Maria N. Dmitrieva Ryazan State Medical University Email: [email protected] ORCID iD: 0000-0003-0915-026X SPIN-code: 1083-9650 Cand. Sci. (Pedagogy), Associate Professor Russian Federation, RyazanIlya A. Usachev Ryazan Regional Clinical Perinatal Center Email: [email protected] ORCID iD: 0000-0003-2257-5297 SPIN-code: 6548-7363 Russian Federation, Ryazan Anton M. Kiselev Derzhavin Tambov State University Email: [email protected] ORCID iD: 0000-0002-8288-1395 SPIN-code: 6719-5527 MD, Cand. Sci. (Med.), Associate Professor Russian Federation, TambovReferences - Ikhtiyarova GA, Aslonova MZh, Kurbanova ZSh, et al. Promising diagnostic tools for endometriosis given the pathogenic role of genetic factors. Russian Journal of Woman and Child Health. 2021;4(1):12–6. (In Russ). doi: 10.32364/2618-8430-2021-4-1-12-16 - Zhang A, Wang G, Jia L, et al. Exosome-mediated microRNA-138 and vascular endothelial growth factor in endometriosis through inflammation and apoptosis via the nuclear factor-κB signaling pathway. Int J Mol Med. 2019;43(1):358–70. doi: 10.3892/ijmm.2018.3980 - Anastasiu CV, Moga MA, Elena Neculau A, et al. Biomarkers for the Noninvasive Diagnosis of Endometriosis: State of the Art and Future Perspectives. Int J Mol Sci. 2020;21(5):1750. doi: 10.3390/ijms21051750 - Moga MA, Bălan A, Dimienescu OG, et al. Circulating miRNAs as Biomarkers for Endometriosis and Endometriosis-Related Ovarian Cancer — An Overview. J Clin Med. 2019;8(5):735. doi: 10.3390/jcm8050735 - Orazov MR, Dukhin AO, Shkreli I, et al. Forecasting of fertility in women with recurrent ovarian endometriosis. Research'n Practical Medicine Journal. 2016;(S):120–1. (In Russ). - Falcone T, Flyckt R. Clinical Management of Endometriosis. Obstet Gynecol. 2018;131(3):557–71. doi: 10.1097/aog.0000000000002469 - Hamilton KM, Van Hise K, Truong MD, et al. Surgical management of endometriosis to optimize fertility. Curr Opin Obstet Gynecol. 2023;35(4):389–94. doi: 10.1097/gco.0000000000000876 - Hudson QJ, Perricos A, Wenzl R, et al. Challenges in uncovering non-invasive biomarkers of endometriosis. Exp Biol Med (Maywood). 2020;245(5):437–47. doi: 10.1177/1535370220903270 - Kiesel L, Sourouni M. Diagnosis of endometriosis in the 21st century. Climacteric. 2019;22(3):296–302. doi: 10.1080/13697137.2019.1578743 - Ukrainets RV, Korneva YuS. Endometrial cell apoptosis impairment associated with hormonal imbalance as a key factor in the development of endometriosis. Problems of Endocrinology. 2019;65(2):140–4. (In Russ). doi: 10.14341/probl9983 - Dihm K, Ek M, Roth B, et al. Plasma AXIN1 expression exhibit negative correlations with inflammatory biomarkers and is associated with gastrointestinal symptoms in endometriosis. Biomed Rep. 2020;12(5):211–21. doi: 10.3892/br.2020.1282 - Tang T, Lai H, Huang X, et al. Application of serum markers in diagnosis and staging of ovarian endometriosis. J Obstet Gynaecol Res. 2021;47(4):1441–50. doi: 10.1111/jog.14654 - Luisi S, Pinzauti S, Regini C, et al. Serum markers for the noninvasive diagnosis of endometriosis. Womens Health (Lond). 2015;11(5):603–10. doi: 10.2217/whe.15.46 - Ek M, Roth B, Engström G, et al. AXIN1 in Plasma or Serum Is a Potential New Biomarker for Endometriosis. Int J Mol Sci. 2019; 20(1):189. doi: 10.3390/ijms20010189 - Cho H–Y, Kyung MS. CYFRA 21-1 and Placental Growth Factor as Screening Markers for Endometriosis. Med Sci Monit. 2019;25:1087–92. doi: 10.12659/msm.912787 - Shu S, Fan QB, Lang JH. Investigation on endometrium from menstrual blood as a source of non-invasive tissue. Zhonghua Fu Chan Ke Za Zhi. 2019;54(8):527–33. (In Chin.). doi: 10.3760/cma.j.issn.0529-567x.2019.08.005 - d'Argent M, Stratopoulou CA, Cussac S, et al. Are lower levels of apoptosis and autophagy behind adenomyotic lesion survival? Reprod Biomed Online. 2023;47(3):103248. doi: 10.1016/j.rbmo.2023.06.003 - Burghaus S, Drazic P, Wölfler M, et al. Multicenter evaluation of blood-based biomarkers for the detection of endometriosis and adenomyosis: A prospective non-interventional study. Int J Gynaecol Obstet. 2024;164(1):305–14. doi: 10.1002/ijgo.15062