Journal of Reproduction & Infertility

Journal of Reproduction & Infertility

Exploring the Therapeutic Potential of Sodium Hydrosulfide in Alleviating Oxidative Stress and Ovarian Dysfunction in a Rat Model of Polycystic Ovary Syndrome

Authors
Maryam Vaziripour
Mahdieh Faghihi
Mina Ranjbaran
Bahareh Asadi
Arash Abdi
Farzaneh Kianian
Mahdi Hajiaqaei
Behjat Seifi
Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
10.18502/jri.v25i2.16007
Abstract
Background: Oxidative stress is known to play a key role in the occurrence of polycystic ovary syndrome (PCOS), the most common cause of anovulatory infertility. The purpose of the current study was to investigate whether diminished activity of ovarian enzymes responsible for hydrogen sulfide (H2S) production, cystathionine β-synthase (CBS), and cystathionine γ-lyase (CSE) contributes to oxidative stress in PCOS. The study also explored whether administration of sodium hydrosulfide (NaSH), an H2S donor, could ameliorate PCOS symptoms by reducing oxidative stress. Methods: The rats were randomly assigned into three groups (n=6): control, PCOS, and PCOS+NaSH. PCOS was induced by intramuscular injection of estradiol valerate in the PCOS and PCOS+NaSH groups. The PCOS+NaSH group received 30 μmol/L/day of NaSH in drinking water for 27 days after PCOS induction. Ovarian tissue samples were analyzed for oxidative stress indices including malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity. Additional analyses measured H2S levels, CBS, and CSE activity. Results: PCOS induction led to a significant decrease in SOD activity, H2S levels, and CBS and CSE activity, accompanied by a significant increase in MDA levels (p<0.0001). Furthermore, PCOS caused severe histological alterations in the ovaries. However, administration of NaSH effectively restored all measured parameters to pre-PCOS induction levels (p<0.0001). Conclusion: This study showed that the decrease in the activity of H2S-producing enzymes and H2S levels may contribute to oxidative stress in PCOS. Therefore, administration of H2S donor NaSH can be considered as a potential therapeutic strategy for PCOS patients.
Keywords
Cystathionine β
synthase
Cystathionine γ
lyase
Hydrogen Sulfide
Infertility
Ovary
oxidative stress
PCOS
  1. Singh S, Pal N, Shubham S, Sarma DK, Verma V, Marotta F, et al. Polycystic ovary syndrome: etiology, current management, and future therapeutics. J Clin Med. 2023;12(4):1454.
  2. Joham AE, Norman RJ, Stener-Victorin E, Legro RS, Franks S, Moran LJ, et al. Polycystic ovary syndrome. Lancet Diabetes Endocrinol. 2022;10(9):668-80.
  3. Kim CH, Lee SH. Effectiveness of lifestyle modification in polycystic ovary syndrome patients with obesity: a systematic review and meta-analysis. Life (Basel). 2022;12(2):308.
  4. Bednarska S, Siejka A. The pathogenesis and treatment of polycystic ovary syndrome: what's new? Adv Clin Exp Med. 2017;26(2):359-67.
  5. Bargiota A, Diamanti-Kandarakis E. The effects of old, new and emerging medicines on metabolic aberrations in PCOS. Ther Adv Endocrinol Metab. 2012;3(1):27-47.
  6. Dubey P, Reddy S, Boyd S, Bracamontes C, Sanchez S, Chattopadhyay M, et al. Effect of nutritional supplementation on oxidative stress and hormonal and lipid profiles in PCOS-affected females. Nutrients. 2021;13(9):2938.
  7. Mancini A, Bruno C, Vergani E, d’Abate C, Giacchi E, Silvestrini A. Oxidative stress and low-grade inflammation in polycystic ovary syndrome: controversies and new insights. Int J Mol Sci. 2021;22(4):1667.
  8. Shan H, Luo R, Guo X, Li R, Ye Z, Peng T, et al. Abnormal endometrial receptivity and oxidative stress in polycystic ovary syndrome. Front Pharmacol. 2022;13:904942.
  9. Liu X, Hussain R, Mehmood K, Tang Z, Zhang H, Li Y. Mitochondrial-Endoplasmic Reticulum Communication-Mediated Oxidative Stress and Autophagy. Biomed Res Int. 2022;2022:6459585.
  10. Hao Y, Wang H, Fang L, Bian J, Gao Y, Li C. H2S donor and bone metabolism. Front Pharmacol. 2021;12:661601.
  11. Cirino G, Szabo C, Papapetropoulos A. Physiological roles of hydrogen sulfide in mammalian cells, tissues, and organs. Physiol Rev. 2023;103(1):31-276.
  12. Gao L, Wu TW, Ni X. Gas transmitters in female reproductive system. Sheng Li Xue Bao. 2016;68(5):611-20.
  13. Mitidieri E, Vanacore D, Turnaturi C, Sorrentino R, d’Emmanuele di Villa Bianca R. Uterine dysfunction in diabetic mice: the role of hydrogen sulfide. Antioxidants (Basel). 2020;9(10):917.
  14. Murphy B, Bhattacharya R, Mukherjee P. Hydrogen sulfide signaling in mitochondria and disease. FASEB J. 2019;33(12):13098-125.
  15. Daneasa A, Cucolas C, Lenghel LM, Olteanu D, Orasan R, Filip GA. Letrozole vs estradiol valerate induced PCOS in rats: glycemic, oxidative and inflammatory status assessment. Reproduction. 2016;151(4):401-9.
  16. Lorian K, Kadkhodaee M, Kianian F, Abdi A, Ranjbaran M, Ashabi G, et al. Long‐term NaHS administration reduces oxidative stress and apoptosis in a rat model of left‐side varicocele. Andrologia. 2020;52(2):e13496.
  17. Ramadoss M, Vijayaraman M, Jessica A. Estradiol valerate dose determination for PCOS induction. Int J Pharm Biol Sci. 2019;9(2):1131-6.
  18. Kianian F, Seifi B, Kadkhodaee M, Sadeghipour HR, Ranjbaran M. Nephroprotection through modifying the apoptotic tnf-α/erk1/2/bax signaling pathway and oxidative stress by long-term sodium hydrosulfide administration in ovalbumin-induced chronic asthma. Immunol Invest. 2022;51(3):602-18.
  19. Pourmirzaei F, Ranjbaran M, Kadkhodaee M, Kianian F, Lorian K, Abdi A, et al. Sperm and testicular dysfunction during cecal ligation and puncture-induced sepsis in male rats and effects of tannic acid through reducing testicular oxidative stress and inflammation. Iran J Basic Med Sci. 2021;24(11):1554-60.
  20. Shafie A, Kianian F, Ashabi G, Kadkhodaee M, Ranjbaran M, Hajiaqaei M, et al. Beneficial effects of combination therapy with testosterone and hydrogen sulfide by reducing oxidative stress and apoptosis: Rat experimental varicocele model. Int J Reprod Biomed. 2022;20(11):941-54.
  21. Chinwe GS, Azuka OI, Adaeze NC. Resveratrol supplementation rescues pool of growing follicles and ovarian stroma from Cisplatin-induced toxicity on the ovary in sprague-dawley rats: an experimental study. Int J Reprod Biomed. 2018;16(1):19-30.
  22. Ighodaro O, Akinloye O. First line defence antioxidants-superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX): their fundamental role in the entire antioxidant defence grid. Alexandria J Med. 2018;54(4):287-93.
  23. Bandariyan E, Mogheiseh A, Ahmadi A. The effect of lutein and Urtica dioica extract on in vitro production of embryo and oxidative status in polycystic ovary syndrome in a model of mice. BMC Complement Med Ther. 2021;21(1):55.
  24. Nawrocka-Rutkowska J, Szydłowska I, Jakubowska K, Olszewska M, Chlubek D, Rył A, et al. Assessment of the parameters of oxidative stress depending on the metabolic and anthropometric status indicators in women with PCOS. Life (Basel). 2022;12(2):225.
  25. Zeber-Lubecka N, Ciebiera M, Hennig EE. Polycystic ovary syndrome and oxidative stress-from bench to bedside. Int J Mol Sci. 2023;24(18):14126.
  26. Scammahorn JJ, Nguyen IT, Bos EM, Van Goor H, Joles JA. Fighting oxidative stress with sulfur: Hydrogen sulfide in the renal and cardiovascular systems. Antioxidants (Basel). 2021;10(3):373.
  27. Bries AE, Webb JL, Vogel B, Carrillo C, Keating AF, Pritchard SK, et al. Letrozole-induced polycystic ovary syndrome attenuates cystathionine-β synthase mRNA and protein abundance in the ovaries of female sprague dawley rats. J Nutr. 2021;151(6):1407-15.
  28. Li D, Liu HX, Fang YY, Huo JN, Wu QJ, Wang TR, et al. Hyperhomocysteinemia in polycystic ovary syndrome: decreased betaine-homocysteine methyltransferase and cystathionine β-synthase-mediated homocysteine metabolism. Reprod Biomed Online. 2018;37(2):234-41.
  29. Novera W, Lee ZW, Nin DS, Dai MZY, Binte Idres S, Wu H, et al. Cysteine deprivation targets ovarian clear cell carcinoma via oxidative stress and iron-sulfur cluster biogenesis deficit. Antioxid Redox Signal. 2020;33(17):1191-208.
  30. Areloegbe SE, Peter MU, Oyeleke MB, Olaniyi KS. Low-dose spironolactone ameliorates adipose tissue inflammation and apoptosis in letrozole-induced PCOS rat model. BMC Endocr Disord. 2022;22(1):224.
  31. Pruett JE, Everman SJ, Hoang NH, Salau F, Taylor LC, Edwards KS, et al. Mitochondrial function and oxidative stress in white adipose tissue in a rat model of PCOS: effect of SGLT2 inhibition. Biol Sex Differ. 2022;13(1):45.
  32. Witchel SF, Oberfield SE, Peña AS. Polycystic ovary syndrome: pathophysiology, presentation, and treatment with emphasis on adolescent girls. J Endocr Soc. 2019;3(8):1545-73.
  33. Greff D, Juhász AE, Váncsa S, Váradi A, Sipos Z, Szinte J, et al. Inositol is an effective and safe treatment in polycystic ovary syndrome: a sys-tematic review and meta-analysis of randomized controlled trials. Reprod Biol Endocrinol. 2023;21 (1):10.
  34. deOliveira TA, Marchesan LB, Spritzer PM. Potas-sium levels in women with polycystic ovary syn-drome using spironolactone for long‐term. Clin Endocrinol (Oxf). 2024;100(3):278-83.
Journal of Reproduction & Infertility
Volume 25, Issue 2
Spring 2024
Pages 133-139