Investigation of the effects of astaxanthin in experimental polycystic ovary syndrome (PCOS) in rats

Document Type : Original Article

Authors

1 Department of Histology and Embryology, Faculty of Medicine, Kafkas University, Kars, Turkey

2 Department of Histology and Embryology, Faculty of Medicine, Alanya Alaaddin Keykubat University, Antalya, Turkey

3 Department of Histology and Embryology, Faculty of Medicine, Ataturk University, Erzurum, Turkey

4 Philosophy Doctor Degree, Department of Histology and Embryology, Erzurum City Hospital, Erurum, Turkey

Abstract

Objective(s): The aim of this study was to investigate the effect of Astaxanthin (ASX) on ovaries in letrozole-induced polycystic ovary syndrome (PCOS) model in female rats by histopathological, immunohistochemical and biochemical techniques.
Materials and Methods: Seventy two Sprague-Dawley female rats with an average weight of 200-250 gr and 10-12 weeks old were randomly divided into 9 groups. PCOS model was applied to all groups except healthy group. In the study, low (10 mg / kg) moderate (20 mg / kg) and high (40 mg / kg) doses of ASX were given to the experimental animals in the PCOS-induced groups for 7 days. At the end of the experiment, ovarian tissues were evaluated histopathologically, immunohistochemically, and biochemically.
Results: When the histopathological findings were examined, many cystic follicles, apoptotic and necrotic cells were found in the follicles in the PCOS group. In addition, significant decrease in apoptotic and necrotic cells were observed in PCOS+MET+ASX and PCOS+ASX groups. In immunohistochemical staining findings, while TNF-α, NF-κB and IL-6 expression levels showed significant increase in PCOS group, these expression levels were decreased in PCOS+MET+ASX and PCOS+ASX groups. In the biochemical evaluations, while MDA were increased, SOD were decreased in the PCOS group. MDA level were decreased while SOD levels were increased in the PCOS+MET+ASX and PCOS+ASX groups. 
Conclusion: In addition to the formation of insulin resistance in the tissue, severe oxidative stress damage occurs in ovarian tissue during PCOS. Metformin improved PCOS by correcting insulin resistance. In this period, the administration of ASX with Metformin protected the ovary from oxidative stress damage.

Keywords

Main Subjects


1. Witchel SF, Oberfield SE, Pena AS. Polycystic ovary syndrome: pathophysiology, presentation, and treatment with emphasis on adolescent girls. J Endocr Soc 2019; 3:1545-1573.
2. Sheehan MT. Polycystic ovarian syndrome: diagnosis and management. Clin Med Res 2004; 2:13-27.
3. Unal E, Yildirim R, Tas FF, Demir V, Onay H, Haspolat YK. Aromatase deficiency due to a novel mutation in CYP19A1 gene. J Clin Res Pediatr Endocrinol 2018; 10:377-381.
4. Kafali H, Iriadam M, Ozardali I, Demir N. Letrozole-induced polycystic ovaries in the rat: A new model for cystic ovarian disease. Arch Med Res 2004; 35:103-108.
5. Rosenfield RL, Ehrmann DA. The pathogenesis of polycystic ovary syndrome (PCOS): the hypothesis of PCOS as functional ovarian hyperandrogenism revisited. Endocr Rev 2016; 37:467-520.
6. Johansson J, Stener-Victorin E. Polycystic ovary syndrome: effect and mechanisms of acupuncture for ovulation induction. Evid Based Complement Alternat Med 2013; 2013:1-16.
7. 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; 10:49-80.
8. Kumariya S, Ubba V, Jha RK, Gayen JR. Autophagy in ovary and polycystic ovary syndrome: role, dispute and future perspective. Autophagy 2021; 17:2706-2733.
9. Dumesic DA, Padmanabhan V, Abbott DH. Polycystic ovary syndrome and oocyte developmental competence. Obstet Gynecol Surv 2008; 63:39-48.
10. Lai Q, Xiang W, Li Q, Zhang H, Li Y, Zhu G, et al. Oxidative stress in granulosa cells contributes to poor oocyte quality and IVF-ET outcomes in women with polycystic ovary syndrome. Front Med 2018; 12:518-524.
11. Rocha AL, Oliveira FR, Azevedo RC, Silva VA, Peres TM, Candido AL, et al. Recent advances in the understanding and management of polycystic ovary syndrome. F1000Res 2019; 8:565-576.
12. Abdalla MA, Deshmukh H, Atkin S, Sathyapalan T. A review of therapeutic options for managing the metabolic aspects of polycystic ovary syndrome. Ther Adv Endocrinol Metab 2020; 11:1-19.
13. Sanchez-Garrido MA, Tena-Sempere M. Metabolic dysfunction in polycystic ovary syndrome: pathogenic role of androgen excess and potential therapeutic strategies. Mol Metab 2020; 35:100937-100953.
14. Higuera-Ciapara I, Felix-Valenzuela L, Goycoolea FM. Astaxanthin: a review of its chemistry and applications. Crit Rev Food Sci Nutr 2006; 46:185-196.
15. Ambati RR, Phang SM, Ravi S, Aswathanarayana RG. Astaxanthin: sources, extraction, stability, biological activities and its commercial applications--a review. Mar Drugs 2014; 12:128-152.
16. Villaro S, Ciardi M, Morillas-Espana A, Sanchez-Zurano A, Acien-Fernandez G, Lafarga T. Microalgae derived astaxanthin: research and consumer trends and industrial use as food. Foods 2021; 10:1-17.
17. Snell TW, Carberry J. Astaxanthin bioactivity is determined by stereoisomer composition and extraction method. Nutrients 2022; 14:1522-1532.
18. Igielska-Kalwat J, Goscianska J, Nowak I. [Carotenoids as natural antioxidants]. Postepy Hig Med Dosw 2015; 69:418-428.
19. Brotosudarmo THP, Limantara L, Setiyono E, Heriyanto. Structures of astaxanthin and their consequences for therapeutic application. Int J Food Sci 2020; 2020:1-16.
20. Kim SH, Kim H. Inhibitory effect of astaxanthin on oxidative stress-induced mitochondrial dysfunction-a mini-review. Nutrients 2018; 10:1137-1151.
21. Feng W, Wang Y, Guo N, Huang P, Mi Y. Effects of astaxanthin on inflammation and insulin resistance in a mouse model of gestational diabetes mellitus. Dose Response 2020;18:1-11.
22. Choudhury KR, Yagle KJ, Swanson PE, Krohn KA, Rajendran JG. A robust automated measure of average antibody staining in immunohistochemistry images. J Histochem Cytochem 2010; 58:95-107.
23. Toktay E, Tastan TB, Gurbuz MA, Erbas E, Demir O, Ugan RA, et al. Potential protective effect of astaxanthin on ovary ischemia-reperfusion injury. Iran J Basic Med Sci 2022; 25:173-178.
24. Ndefo UA, Eaton A, Green MR. Polycystic ovary syndrome: a review of treatment options with a focus on pharmacological approaches. P T 2013; 38:336-355.
25. Mortensen M, Rosenfield RL, Littlejohn E. Functional significance of polycystic-size ovaries in healthy adolescents. J Clin Endocrinol Metab 2006; 91:3786-3790.
26. Blank SK, Helm KD, McCartney CR, Marshall JC. Polycystic ovary syndrome in adolescence. Ann N Y Acad Sci 2008; 1135:76-84.
27. Papalou O, Victor VM, Diamanti-Kandarakis E. Oxidative stress in polycystic ovary syndrome. Curr Pharm Des 2016;22: 2709-2722.
28. Zuo T, Zhu M, Xu W. Roles of oxidative stress in polycystic ovary syndrome and cancers. Oxid Med Cell Longev 2016; 2016:1-14.
29. Liu J, Zhang D. [The role of oxidative stress in the pathogenesis of polycystic ovary syndrome]. Sichuan Da Xue Xue Bao Yi Xue Ban 2012; 43:187-190.
30. Vural Keles D, Uslu H, Keles ON, Unal B, Alp HH. [Investigation of the protective effects of beta-D-glucan against invasive encapsulated Streptococcus pneumoniae sepsis in splenectomized rats]. Mikrobiyol Bul 2015; 49:314-326.
31. Li C, Chen L, Zhao Y, Chen S, Fu L, Jiang Y, et al. Altered expression of miRNAs in the uterus from a letrozole-induced rat PCOS model. Gene 2017; 598:20-26.
32. Lang Q, Yidong X, Xueguang Z, Sixian W, Wenming X, Tao Z. ETA-mediated anti-TNF-alpha therapy ameliorates the phenotype of PCOS model induced by letrozole. PLoS One 2019; 14:1-17.
33. Gozukara I, Dokuyucu R, Ozgur T, Ozcan O, Pinar N, Kurt RK, et al. Histopathologic and metabolic effect of ursodeoxycholic acid treatment on PCOS rat model. Gynecol Endocrinol 2016; 32:492-497.
34. Wang F, Yu B, Yang W, Liu J, Lu J, Xia X. Polycystic ovary syndrome resembling histopathological alterations in ovaries from prenatal androgenized female rats. J Ovarian Res 2012; 5:15-22.
35. Lashen H. Role of metformin in the management of polycystic ovary syndrome. Ther Adv Endocrinol Metab 2010; 1:117-128.
36. Tsilchorozidou T, Prelevic GM. The role of metformin in the management of polycystic ovary syndrome. Curr Opin Obstet Gynecol 2003; 15:483-488.
37. Murri M, Luque-Ramirez 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; 19:268-288.
38. Hong Y, Yin Y, Tan Y, Hong K, Zhou H. The flavanone, naringenin, modifies antioxidant and steroidogenic enzyme activity in a rat model of letrozole-induced polycystic ovary syndrome. Med Sci Monit 2019; 25:395-401.
39. Balendra V, Singh SK. Therapeutic potential of astaxanthin and superoxide dismutase in alzheimer’s disease. Open Biol 2021; 11:1-11.
40. Islam MA, Al Mamun MA, Faruk M, Ul Islam MT, Rahman MM, Alam MN, et al. Astaxanthin ameliorates hepatic damage and oxidative stress in carbon tetrachloride-administered rats. Pharmacognosy Res 2017; 9:84-91.
41. Idriss HT, Naismith JH. TNF alpha and the TNF receptor superfamily: structure-function relationship(s). Microsc Res Tech 2000; 50:184-195.
42. Wu G, Hu X, Ding J, Yang J. Abnormal expression of HSP70 may contribute to PCOS pathology. J Ovarian Res 2019; 12:74-81.
43. Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol 2014; 6:1-16.
44. Gabay C. Interleukin-6 and chronic inflammation. Arthritis Res Ther 2006; 2:3-9.
45. Atreya R, Mudter J, Finotto S, Mullberg J, Jostock T, Wirtz S, et al. Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in crohn disease and experimental colitis in vivo. Nat Med 2000; 6:583-588.
46. Linardopoulos S, Corrigall V, Panayi GS. Activation of HLA-DR and interleukin-6 gene transcription in resting T cells via the CD2 molecule: relevance to chronic immune-mediated inflammation. Scand J Immunol 1992; 36:469-477.
47. Gonzalez F, Rote NS, Minium J, Kirwan JP. Increased activation of nuclear factor kappaB triggers inflammation and insulin resistance in polycystic ovary syndrome. J Clin Endocrinol Metab 2006; 91:1508-1512.
48. Jabarpour M, Aleyasin A, Nashtaei MS, Lotfi S, Amidi F. Astaxanthin treatment ameliorates ER stress in polycystic ovary syndrome patients: A randomized clinical trial. Sci Rep 2023; 13:3376-3386.