Dynamic Thiol/Disulfide Homeostasis as an Oxidative Stress Biomarker in Male and Female Infertility and Assisted Reproduction: A Systematic Review and Meta-Analysis
Abstract
Oxidative stress is often blamed for infertility, yet most redox markers used in reproductive research are hard to compare between laboratories. Dynamic thiol/disulfide homeostasis (TDH), measured with the automated assay of Erel and Neşelioğlu, gives native thiol (NT), total thiol (TT), disulfide (SS) and three ratio indices from a single sample. We systematically reviewed human studies that used this assay in male or female infertility and in assisted reproduction. Web-engine, Crossref and DOAJ searches with citation chasing yielded 204 records, and 28 studies met the criteria (23 in women, 5 in men). All but one came from Turkey. Thirteen studies had usable group data and were pooled with random-effects models (REML, Hartung-Knapp). In the serum or plasma of infertile women, absolute NT, TT and SS did not differ significantly from those of controls, and heterogeneity was high. The ratio indices were more consistent. SS/NT (Hedges' g 0.34, 95% CI 0.06 to 0.62), SS/TT (g 0.53, 0.11 to 0.94) and NT/TT (g −0.54, −1.03 to −0.05) all moved toward oxidation, and 14 of 15 studies showed a higher SS/NT. Follicular fluid estimates were imprecise. The five male studies, on varicocele and idiopathic infertility, reported only oxidative shifts but could not be pooled. The signal was weak. It faded when three studies with atypical absolute values were removed, and the certainty of evidence was very low. TDH ratios are promising research markers, but assay standardization and larger, better designed studies are needed before clinical use.
Keywords:
Thiol/disulfide homeostasis, native thiol, disulfide, oxidative stress, female infertility, male infertility, polycystic ovary syndrome, varicocele, assisted reproductive technologyDOI
https://doi.org/10.37022/wjcmpr.v8i3.442References
1. Cox CM, Thoma ME, Tchangalova N, Mburu G, Bornstein MJ, Johnson CL, et al. Infertility prevalence and the methods of estimation from 1990 to 2021: a systematic review and meta-analysis. Hum Reprod Open. 2022;2022(4):hoac051. doi:10.1093/hropen/hoac051
2. Carson SA, Kallen AN. Diagnosis and management of infertility. JAMA. 2021;326(1):65-76. doi:10.1001/jama.2021.4788
3. Agarwal A, Baskaran S, Parekh N, Cho CL, Henkel R, Vij S, et al. Male infertility. Lancet. 2021;397(10271):319-333. doi:10.1016/S0140-6736(20)32667-2
4. Agarwal A, Aponte-Mellado A, Premkumar BJ, Shaman A, Gupta S. The effects of oxidative stress on female reproduction: a review. Reprod Biol Endocrinol. 2012;10:49. doi:10.1186/1477-7827-10-49
5. Aitken RJ, Drevet JR. The importance of oxidative stress in determining the functionality of mammalian spermatozoa: a two-edged sword. Antioxidants (Basel). 2020;9(2):111. doi:10.3390/antiox9020111
6. Jones DP. Redefining oxidative stress. Antioxid Redox Signal. 2006;8(9-10):1865-1879. doi:10.1089/ars.2006.8.1865
7. Sies H, Berndt C, Jones DP. Oxidative stress. Annu Rev Biochem. 2017;86:715-748. doi:10.1146/annurev-biochem-061516-045037
8. Sies H, Jones DP. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat Rev Mol Cell Biol. 2020;21(7):363-383. doi:10.1038/s41580-020-0230-3
9. Jones DP, Liang Y. Measuring the poise of thiol/disulfide couples in vivo. Free Radic Biol Med. 2009;47(10):1329-1338. doi:10.1016/j.freeradbiomed.2009.08.021
10. Erel O, Neselioglu S. A novel and automated assay for thiol/disulphide homeostasis. Clin Biochem. 2014;47(18):326-332. doi:10.1016/j.clinbiochem.2014.09.026
11. Erel Ö, Erdoğan S. Thiol-disulfide homeostasis: an integrated approach with biochemical and clinical aspects. Turk J Med Sci. 2020;50(7):1728-1738. doi:10.3906/sag-2003-64
12. Turell L, Radi R, Alvarez B. The thiol pool in human plasma: the central contribution of albumin to redox processes. Free Radic Biol Med. 2013;65:244-253. doi:10.1016/j.freeradbiomed.2013.05.050
13. Oettl K, Marsche G. Redox state of human serum albumin in terms of cysteine-34 in health and disease. Methods Enzymol. 2010;474:181-195. doi:10.1016/S0076-6879(10)74011-8
14. Da Broi MG, Giorgi VSI, Wang F, Keefe DL, Albertini D, Navarro PA. Influence of follicular fluid and cumulus cells on oocyte quality: clinical implications. J Assist Reprod Genet. 2018;35(5):735-751. doi:10.1007/s10815-018-1143-3
15. Balhorn R. The protamine family of sperm nuclear proteins. Genome Biol. 2007;8(9):227. doi:10.1186/gb-2007-8-9-227
16. Seligman J, Kosower NS, Weissenberg R, Shalgi R. Thiol-disulfide status of human sperm proteins. J Reprod Fertil. 1994;101(2):435-443. doi:10.1530/jrf.0.1010435
17. Kosower NS, Katayose H, Yanagimachi R. Thiol-disulfide status and acridine orange fluorescence of mammalian sperm nuclei. J Androl. 1992;13(4):342-348. doi:10.1002/j.1939-4640.1992.tb00335.x
18. Ellman GL. Tissue sulfhydryl groups. Arch Biochem Biophys. 1959;82(1):70-77. doi:10.1016/0003-9861(59)90090-6
19. Balık AR, Özbek İptec B, Yılmaz G, Kozacı LD, Erel Ö, Biçer C. Effects of storage conditions on thiol disulfide homeostasis. Medicine Science. 2021;10(2):450-454. doi:10.5455/medscience.2020.11.236
20. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. doi:10.1136/bmj.n71
21. Biyik I, Erten O, Isiklar OO, Ince O, Soysal C, Berikten D, et al. Comparison of serum human Klotho levels and thiol/disulfide homeostasis in women with polycystic ovary syndrome and in healthy women. Taiwan J Obstet Gynecol. 2021;60(3):487-491. doi:10.1016/j.tjog.2021.03.017
22. Atalay Mert S, Dilbaz B, Kinay T, Dilbaz S, Kayikcioglu F, Neselioglu S, et al. Evaluation of oxidative stress with "dynamic thiol/disulfide homeostasis" in cases with endometrioma. Med Sci Discov. 2022;9(8):458-464. doi:10.36472/msd.v9i8.784
23. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25(9):603-605. doi:10.1007/s10654-010-9491-z
24. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924-926. doi:10.1136/bmj.39489.470347.AD
25. Hedges LV. Distribution theory for Glass's estimator of effect size and related estimators. J Educ Stat. 1981;6(2):107-128. doi:10.3102/10769986006002107
26. Luo D, Wan X, Liu J, Tong T. Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Stat Methods Med Res. 2018;27(6):1785-1805. doi:10.1177/0962280216669183
27. Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol. 2014;14:135. doi:10.1186/1471-2288-14-135
28. IntHout J, Ioannidis JPA, Borm GF. The Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard DerSimonian-Laird method. BMC Med Res Methodol. 2014;14:25. doi:10.1186/1471-2288-14-25
29. Röver C, Knapp G, Friede T. Hartung-Knapp-Sidik-Jonkman approach and its modification for random-effects meta-analysis with few studies. BMC Med Res Methodol. 2015;15:99. doi:10.1186/s12874-015-0091-1
30. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557-560. doi:10.1136/bmj.327.7414.557
31. IntHout J, Ioannidis JPA, Rovers MM, Goeman JJ. Plea for routinely presenting prediction intervals in meta-analysis. BMJ Open. 2016;6(7):e010247. doi:10.1136/bmjopen-2015-010247
32. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177-188. doi:10.1016/0197-2456(86)90046-2
33. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629-634. doi:10.1136/bmj.315.7109.629
34. Campbell M, McKenzie JE, Sowden A, Katikireddi SV, Brennan SE, Ellis S, et al. Synthesis without meta-analysis (SWiM) in systematic reviews: reporting guideline. BMJ. 2020;368:l6890. doi:10.1136/bmj.l6890
35. Thomson HJ, Thomas S. The effect direction plot: visual display of non-standardised effects across multiple outcome domains. Res Synth Methods. 2013;4(1):95-101. doi:10.1002/jrsm.1060
36. Ozler S, Oztas E, Tokmak A, Ergin M, Isci E, Eren F, et al. The association of thiol/disulphide homeostasis and lipid accumulation index with cardiovascular risk factors in overweight adolescents with polycystic ovary syndrome. Clin Endocrinol (Oxf). 2016;84(4):516-523. doi:10.1111/cen.12965
37. Yildirim M, Turkyilmaz E, Neselioglu S, Alisik M, Avsar AFY. Dynamic thiol-disulphide status in polycystic ovary syndrome and its association with the pathogenesis of the disease. Gynecol Obstet Invest. 2017;82(1):54-59. doi:10.1159/000445744
38. Sevimli H, Koca C, Senyurt M, Erel O, Laloglu E, Carlioglu A. May thiol/disulfide homeostasis predict adult PCOS? Endocr Abstr. 2017;49:EP1108. doi:10.1530/endoabs.49.ep1108
39. Tola EN, Köroğlu N, Ergin M, Oral HB, Turgut A, Erel Ö. The role of follicular fluid thiol/disulphide homeostasis in polycystic ovary syndrome. Balkan Med J. 2018;35(4):306-310. doi:10.4274/balkanmedj.2017.1140
40. Aydın GA, Turan Özsoy HG, Ankaralı H, Özgen G, Neşelioğlu S. The association of dynamic thiol-disulfide homeostasis and inflammatory markers in patients with polycystic ovary syndrome. Taiwan J Obstet Gynecol. 2020;59(1):79-84. doi:10.1016/j.tjog.2019.11.012
41. Ege S, Bademkıran MH, Peker N, Özgün Z, Bağlı İ, Erdem S, et al. Increased oxidative stress is associated with thiol/disulphide homeostasis in clomiphene citrate resistant polycystic ovary syndrome. J Obstet Gynaecol. 2021;41(3):467-470. doi:10.1080/01443615.2020.1786033
42. Laleli B, Timur B. Examination of oxidative stress level in adolescents with polycystic ovary syndrome by biochemical parameters. Gümüşhane Univ J Health Sci. 2021;10(4):935-942. doi:10.37989/gumussagbil.1003117
43. Songur Dağlı S, İlanbey B. Effect of obesity on thiol/disulfide balance in patients with polycystic ovary syndrome. Ann Clin Anal Med. 2022;13(10):1088-1091. doi:10.4328/ACAM.21217
44. Sen B, Gonultas S, Albayrak C, Temur S, Acar I, Ozkan BN, et al. Evaluation of oxidative stress and inflammation in patients with polycystic ovary syndrome. Obstet Gynecol Sci. 2024;67(4):414-420. doi:10.5468/ogs.24031
45. Aygün Arı D, Pehlivantürk Kızılkan M, Güven AG, Kanbur N, Derman O, Erel Ö, et al. Polikistik over sendromu olan ergenlerde oksidatif stres parametrelerinin değerlendirilmesi [Evaluation of oxidative stress parameters in adolescents with polycystic ovary syndrome]. J Curr Pediatr. 2025;23(1):30-38. doi:10.4274/jcp.2025.65768
46. Horasanlı JE, Avcıoğlu G, Erel Ö, Neşelioğlu S, Bağcı FÖ, Erkuş MK. Oxidative stress and thiol-disulfide levels in infertile women with polycystic ovary syndrome. Ann Clin Anal Med. 2026;17(1):23-27. doi:10.4328/ACAM.22653
47. Turkyilmaz E, Yildirim M, Cendek BD, Baran P, Alisik M, Dalgaci F, et al. Evaluation of oxidative stress markers and intra-extracellular antioxidant activities in patients with endometriosis. Eur J Obstet Gynecol Reprod Biol. 2016;199:164-168. doi:10.1016/j.ejogrb.2016.02.027
48. Topbas Selcuki NF, Yalcin Bahat P, Kaya C, Neselioglu S, Bagci K, Goksu M, et al. The role of dynamic thiol/disulfide homeostasis for the evaluation of oxidative stress in endometriosis patients. Marmara Med J. 2022;35(2):143-147. doi:10.5472/marumj.1120611
49. Isik H, Sahbaz A, Timur H, Aynioglu O, Atalay Mert S, Balık AR, et al. The use of thiol/disulfide as a novel marker in premature ovarian failure. Gynecol Obstet Invest. 2017;82(2):113-118. doi:10.1159/000445745
50. Bozkaya VÖ, Yumusak OH, Ozaksit G, Tenekecioğlu E, Gül İbrişim E, Alkan M, et al. The role of oxidative stress on subclinical atherosclerosis in premature ovarian insufficiency and relationship with carotid intima-media thickness. Gynecol Endocrinol. 2020;36(8):687-692. doi:10.1080/09513590.2020.1766439
51. Aksin Ş, Yilmaz M. The role of thiol/disulfide homeostasis in unexplained primary infertile patients: a prospective cohort study. Medicine (Baltimore). 2025;104(9):e41641. doi:10.1097/MD.0000000000041641
52. Savaş HB, Cimşir MT, Güney T. Clinical significance of thiol-disulfide homeostasis in unexplained infertility. Turk J Clin Biochem. 2025;23(2):66-78. doi:10.56615/tkbd.2025.08
53. Ozdemir AZ, Karlı P, Neşelioğlu S. Does thiol/disulfide homeostasis affect the number of metaphase 2 oocyte in the treatment of in vitro fertilization? Future Sci OA. 2020;6(2):FSO452. doi:10.2144/fsoa-2019-0132
54. Erdoğan K, Şanlıer N, Utlu E, Güvey H, Kahyaoğlu İ, Neşelioğlu S, et al. Serum and follicular fluid thiol/disulfide homeostasis in diminished ovarian reserve patients undergoing in vitro fertilization/intracytoplasmic sperm injection treatment. Cureus. 2023;15(2):e35476. doi:10.7759/cureus.35476
55. Türkyılmaz E, Erbaba B, Neşelioğlu S, Yılmaz NK, Tekin ÖM. Evaluation of the follicular fluid thiol/disulfide balance among patients with poor ovarian response. Clin Exp Reprod Med. 2025;52(2):134-140. doi:10.5653/cerm.2024.06863
56. Bakir NA, Al-Ghazali BS, Shakir N, Abbood MS. Association of serum and follicular fluid thiol/disulfide homeostasis in patients undergoing intracytoplasmic sperm injection. Int J Clin Obstet Gynaecol. 2025;9(1):156-163. doi:10.33545/gynae.2025.v9.i1c.1578
57. Gul M, Bugday MS, Erel O. Thiol-disulphide homoeostasis as an oxidative stress marker in men with varicocele. Andrologia. 2018;50(4):e12982. doi:10.1111/and.12982
58. Sonmez MG, Kozanhan B, Deniz CD, Iyisoy MS, Kilinc MT, Ecer G, et al. The effect of oxidative stress which can be demonstrated with thiol/disulfide homeostasis in varicocele patients on sperm parameters. Clin Lab. 2018;64(11):1823-1828. doi:10.7754/Clin.Lab.2018.180306
59. Coban S, Ustundag Y, Turkoglu AR, Guzelsoy M, Aydos MM, Keles I, et al. Thiol-disulphide balance in infertility secondary to varicocele. Andrologia. 2019;51(8):e13300. doi:10.1111/and.13300
60. Gok B, Gok G, Koc E, Hamidi N, Alijla A, Asil E, et al. The change in thiol-disulphide homeostasis levels as an oxidative stress marker after varicocelectomy: is there a relationship with sperm parameters? Andrologia. 2020;52(3):e13515. doi:10.1111/and.13515
61. Micoogullari U, Cakici MC, Kilic FU, Kisa E, Ozcift B, Caglayan A, et al. Evaluation of the role of thiol/disulfide homeostasis in the etiology of idiopathic male infertility with a novel and automated assay. Syst Biol Reprod Med. 2022;68(2):162-168. doi:10.1080/19396368.2021.2003481
62. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004;19(1):41-47. doi:10.1093/humrep/deh098
63. Korkmaz O, Karabulut S, Macit P, Cakici C. Follicular fluid oxidative stress and antioxidant defense in relation to maternal age, ovarian reserve, and in vitro fertilization outcomes. Free Radic Res. 2026;60(2):147-156. doi:10.1080/10715762.2026.2629303
64. Wang D, Yang G, You X, Zhang Z. Meta-analysis of changes in thiol-disulfide homeostasis during preeclampsia. Biomol Biomed. 2024;24(1):30-39. doi:10.17305/bb.2023.9430
65. Murri M, Luque-Ramírez M, Insenser M, Ojeda-Ojeda M, Escobar-Morreale HF. Circulating markers of oxidative stress and polycystic ovary syndrome (PCOS): a systematic review and meta-analysis. Hum Reprod Update. 2013;19(3):268-288. doi:10.1093/humupd/dms059
66. Teede HJ, Tay CT, Laven J, Dokras A, Moran LJ, Piltonen TT, et al. Recommendations from the 2023 international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Hum Reprod. 2023;38(9):1655-1679. doi:10.1093/humrep/dead156
67. Scutiero G, Iannone P, Bernardi G, Bonaccorsi G, Spadaro S, Volta CA, et al. Oxidative stress and endometriosis: a systematic review of the literature. Oxid Med Cell Longev. 2017;2017:7265238. doi:10.1155/2017/7265238
68. Erkenekli K, Sanhal CY, Yucel A, Bicer CK, Erel O, Uygur D. Thiol/disulfide homeostasis in patients with idiopathic recurrent pregnancy loss assessed by a novel assay: report of a preliminary study. J Obstet Gynaecol Res. 2016;42(2):136-141. doi:10.1111/jog.12860
69. Agarwal A, Hamada A, Esteves SC. Insight into oxidative stress in varicocele-associated male infertility: part 1. Nat Rev Urol. 2012;9(12):678-690. doi:10.1038/nrurol.2012.197
70. Bergsma AT, Li HT, Eliveld J, Bulthuis MLC, Hoek A, van Goor H, et al. Local and systemic oxidative stress biomarkers for male infertility: the ORION study. Antioxidants (Basel). 2022;11(6):1045. doi:10.3390/antiox11061045
71. Alsalman ARS, Almashhedy LA, Hadwan MH. Effect of oral zinc supplementation on the thiol oxido-reductive index and thiol-related enzymes in seminal plasma and spermatozoa of Iraqi asthenospermic patients. Biol Trace Elem Res. 2018;184(2):340-349. doi:10.1007/s12011-017-1215-8
72. Agarwal A, Parekh N, Panner Selvam MK, Henkel R, Shah R, Homa ST, et al. Male oxidative stress infertility (MOSI): proposed terminology and clinical practice guidelines for management of idiopathic male infertility. World J Mens Health. 2019;37(3):296-312. doi:10.5534/wjmh.190055
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