The ameliorating effects of apigenin and chrysin alone and in combination on polycystic ovary syndrome induced by dehydroepiandrosterone in rats

Year 2024, Volume: 37 Issue: 2, 198 - 207, 31.05.2024

Buket Berk , Nevin İlhan , Solmaz Susam , Fatma Tedik , Nalan Kaya Tektemur

https://doi.org/10.5472/marumj.1479311

Abstract

Objective: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age and is
one of the main causes of ovulation infertility, affecting 5-10% of women. Inflammation, hormonal imbalances, and disruption of the
oxidant-antioxidant balance are the main factors in the pathophysiology of PCOS. This study was designed to answer the question of
whether apigenin and chrysin have therapeutic effects on the dehydroepiandrosterone (DHEA)-induced rat model of PCOS.
Materials and Methods: The experimental PCOS model was created by administering 6 mg/100g DHEA subcutaneously to 21-day-old
female Wistar rats for 28 days, followed by treatment with natural agents 50 mg/kg apigenin and 50 mg/kg chrysin by oral gavage twice
a week for one month. The predominant cell type was determined by microscopic analysis in vaginal smears daily from day 10 to day
28 of the experiment. In tissue supernatants, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities, and
malondialdehyde (MDA) levels were obtained by spectrophotometric method with appropriate manual methods; follicle-stimulating
hormone (FSH), luteinizing hormone (LH), progesterone, interleukin (IL)-18, IL-1β, and IL-13 levels were determined by enzymelinked
immunosorbent assay (ELISA) method. In addition, histological sections obtained from ovarian tissue samples were stained
with hematoxylin-eosin and examined under a light microscope.
Results: The results showed that treatment with apigenin and chrysin alone and in combination reduced MDA, LH, FSH, progesterone,
IL-1β, IL-13, and IL-18 levels compared with PCOS rats. Furthermore, enzymatic activities of antioxidants including CAT, SOD, and
GPx in the ovaries increased in therapeutic groups compared to the PCOS group.
Conclusion: In conclusion, this study demonstrates the potential therapeutic efficacy of apigenin and chrysin, either alone or in
combination, in alleviating the hormonal imbalances, inflammation, and oxidative stress in DHEA-induced PCOS rats. Apigenin,
in particular, emerges as a promising agent for PCOS treatment, showing superiority over chrysin and combination treatments in
ameliorating cystic follicles and improving various parameters associated with PCOS pathophysiology. These findings suggest that
apigenin holds promise as a novel therapeutic agent for PCOS and warrants further investigation in clinical settings.

Keywords

Polycystic ovary syndrome, Dehydroepiandrosterone, Apigenin, Chrysin

References

• Yu J, Ding C, Hua Z, Jiang X, Wang C. Protective effects of berberine in a rat model of polycystic ovary syndrome mediated via the PI3K/AKT pathway. Journal of Obstetrics and Gynaecology Research 2021;47:1789-803. doi:10.1111/ jog.14730.
• Kim JJ. Update on polycystic ovary syndrome. Clin Exp Reprod Med 2021;48:194-7. doi:10.5653/cerm.2020.04329.
• Azziz R. Polycystic ovary syndrome. Obstet Gynecol 2018;132:321-36. doi: 10.1097/AOG.000.000.0000002698.
• Fan Q, He J-F, Wang Q-R, et al. Functional polymorphism in the 5’-UTR of CR2 is associated with susceptibility to nasopharyngeal carcinoma. Oncol Rep 2013;30:11-6. doi: 10.3892/or.2013.2421.
• Xu Y, Qiao J. Association of insulin resistance and elevated androgen levels with polycystic ovarian syndrome (PCOS): A review of literature. J Healthc Eng 2022;2022 :2022:9240569. doi: 10.1155/2022/9240569.
• Roy S, Mahesh VB, Greenblatt RB. Effect of dehydroepiandrosterone and Δ4-androstenedione on the reproductive organs of female rats: production of cystic changes in the ovary. Nature 1962;196(4849):42-3. doi: 10.1038/196042a0.
• Ryu Y, Kim SW, Kim YY, Ku S-Y. Animal models for human polycystic ovary syndrome (PCOS) focused on the use of indirect hormonal perturbations: a review of the literature. Int J Cell Sci Mol Biol 2019;20:2720. doi: 10.3390/ijms20112720.
• Susam S, Çıkım G. A review on the potential pharmacological effects of apigenin. Archives Medical Review Journal 2023;32:113-9. doi:10.17827/aktd.1267942.
• Oguz SH, Yildiz BO. An update on contraception in polycystic ovary syndrome. Endocrinol Metab (Seoul) 2021;36:296-311. doi: 10.3803/EnM.2021.958.
• Iervolino M, Lepore E, Forte G, Laganà AS, Buzzaccarini G, Unfer V. Natural molecules in the management of polycystic ovary syndrome (PCOS): an analytical review. Nutrients 2021;13:1677. doi: 10.3390/nu13051677.
• Balamurugan S, Vijayakumar S, Prabhu S, Yabesh JM. Traditional plants used for the treatment of gynaecological disorders in Vedaranyam taluk, South India-An ethnomedicinal survey. Int J Tradit Complement Med Res 2018;8:308-23. doi: 10.1016/j.jtcme.2017.06.009.
• Naz S, Imran M, Rauf A, Orhan IE, Shariati MA, Shahbaz M, et al. Chrysin: Pharmacological and therapeutic properties. Life Sci 2019;235:116797. doi: 10.1016/j.lfs.2019.116797.
• Stompor-Gorący M, Bajek-Bil A, Machaczka M. Chrysin: Perspectives on contemporary status and future possibilities as pro-health agent. Nutrients 2021;13:2038. doi: 10.3390/ nu13062038.
• Motta A B. Dehydroepiandrosterone to induce murine models for the study of polycystic ovary syndrome. J Steroid Biochem Mol Biol 2010;119:105-11. doi: 10.1016/j.jsbmb.2010.02.015.
• Adel A, Mansour A, Mohammad A, et al. Potential antioxidant activity of apigenin in the obviating stress-mediated depressive symptoms of experimental mice. Molecules 2022;27:9055. doi:10.3390/molecules27249055.
• Pai S A, Martis E A, Munshi R P, Gursahani M S, Mestry S N, Juvekar A R. Chrysin mitigated obesity by regulating energy intake and expenditure in rats. Int J Tradit Complement Med Res 2019:10: 577-85. doi: 10.1016/j.jtcme.2019.09.002.
• Classics Lowry O, Rosebrough N, Farr A, Randall R. Protein measurement with the Folin phenol reagent. J Biol Chem 1951;193:265-75. doi: 10.1016/S0021-9258(19)52451-6.
• Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979;95:351-8. doi: 10.1016/0003-2697(79)90738-3.
• Sun Y, Oberley LW, Li Y. A simple method for clinical assay of superoxide dismutase. Clin Chem 1988;34:497-500. doi:10.1093/clinchem/34.3.497.
• Aebi H. Catalase methods of enzymatic analysis. In: Hu B, editor.New York: Academic Press Inc, 1974:673-77. doi: 10.1016/S0076-6879(84)05016-3.
• Paglia DE, Valentine WN. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. JLM 1967;70:158-69. doi: 002.221.4367900765.
• Zhuang Z, Pan X, Zhao K, et al. The effect of Interleukin-6 (IL-6), Interleukin-11 (IL-11), signal transducer and activator of transcription 3 (STAT3), and AKT signaling on adipocyte proliferation in a rat model of polycystic ovary syndrome. Med Sci Monit 2019;25:7218. doi: 10.12659/MSM.916385.
• Souza AZd, Fonseca A, Izzo V, Clauzet R, Salvatore C. Ovarian histology and function after total abdominal hysterectomy. Obstet Gynecol 1986;68:847-9.
• Ndefo UA, Eaton A, Green MR. Polycystic ovary syndrome: a review of treatment options with a focus on pharmacological approaches. Pharmacy and Therapeutics 2013;38:336.
• Yuan R, Lin Y. Traditional Chinese medicine.Pharmacology and Therapeutics 2000;86:191-8. doi: 10.1016/s0163- 7258(00)00039-5.
• Podolsky S H, Greene J A. 2011. Combination drugs—hype, harm, and hope. NEJM AI 2011;365:488-91. doi: 10.1056/ NEJMp1106161.
• Nallathambi A, Bhargavan R. Regulation of estrous cycle by Cynodon dactylon in letrozole induced polycystic ovarian syndrome in Wistars albino rats. Anat Cell Biol 2019;52:511- 7. doi: 10.5115/acb.19.114.
• Baptiste CG, Battista M-C, Trottier A, Baillargeon J-P. Insulin and hyperandrogenism in women with polycystic ovary syndrome. J Steroid Biochem Molec Biol 2010;122:42-52. doi: 10.1016/j.jsbmb.2009.12.010.
• Furat Rencber S, Kurnaz Ozbek S, Eraldemır C, et al. Effect of resveratrol and metformin on ovarian reserve and ultrastructure in PCOS: an experimental study. J Ovarian Res 2018;11:1-16. doi: 10.1186/s13048.018.0427-7.
• Orlowski M, Sarao MS. Physiology, follicle stimulating hormone. Follicle StatPearls Publishing, NCBI Bookshelf: 2018.
• Reed BG, Carr BR, Feingold KR. The normal menstrual cycle and the control of ovulation. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000
• Holesh JE, Bass AN, Lord M. Physiology, ovulation. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan 2023 May 1. 2017.
• Lee YH, Yang H, Lee SR, Kwon SW, Hong E-J, Lee HW. Welsh onion root (Allium fistulosum) restores ovarian functions from letrozole induced-polycystic ovary syndrome. Nutrients 2018;10:1430. doi: 10.3390/nu10101430.
• Zheng S, Chen Y, Ma M, Li M. Mechanism of quercetin on the improvement of ovulation disorder and regulation of ovarian CNP/NPR2 in PCOS model rats. J.Formosan Med.Assoc 2022;121:1081-92. doi: 10.1016/j.jfma.2021.08.015.
• Shrivastava VK. Turmeric extract alleviates endocrinemetabolic disturbances in letrozole-induced PCOS by increasing adiponectin circulation: A comparison with Metformin. Metabolism Open 2022;13:100160. doi: 10.1016/j. metop.2021.100160.
• Mihanfar A, Nouri M, Roshangar L, Khadem-Ansari MH. Therapeutic potential of quercetin in an animal model of PCOS: Possible involvement of AMPK/SIRT-1 axis. Eur J Med Chem Rep 2021;900:174062. doi: 10.1016/j.ejphar.2021.174062.
• Cable J, Grider M. Physiology, progesterone. In: StatPearls. StatPearls Publishing Copyright© 2022, StatPearls Publishing LLC Treasure Island: 2022.
• Szeliga A, Rudnicka E, Maciejewska-Jeske M, et al. Neuroendocrine determinants of polycystic ovary syndrome. Int J Environ Health Res 2022;19:3089. doi: 10.3390/ ijerph19053089.
• Adelakun SA, Ukwenya VO, Peter AB, Siyanbade AJ, Akinwumiju CO. Therapeutic effects of aqueous extract of bioactive active component of Ageratum conyzoides on the ovarian-uterine and hypophysis-gonadal axis in rat with polycystic ovary syndrome: Histomorphometric evaluation and biochemical assessment. Metabolism Open 2022;15:100201. doi: 10.1016/j.metop.2022.100201.
• Khazaei F, Ghanbari E, Khazaei M. Improved hormonal and oxidative changes by Royal Jelly in the rat model of PCOS: An experimental study. Int J Reprod Biomed 2021;19:515. doi: 10.18502/ijrm.v19i6.9373.
• Li Y, Zheng Q, Sun D, et al. Dehydroepiandrosterone stimulates inflammation and impairs ovarian functions of polycystic ovary syndrome. J Cell Physiol 2019;234:7435-47. doi: 10.1002/jcp.27501.
• Amato G, Conte M, Mazziotti G, et al. Serum and follicular fluid cytokines in polycystic ovary syndrome during stimulated cycles. Obstet Gynecol 2003;101:1177-82. doi: 10.1016/s0029-7844(03)00233-3.
• Ebejer K, Calleja-Agius J. The role of cytokines in polycystic ovarian syndrome. Gynecology Endocrinolology 2013;29:536- 40. doi: 10.3109/09513.590.2012.760195.
• Dinarello CA, Novick D, Kim S, Kaplanski G. Interleukin-18 and IL-18 binding protein. Front Immunol 2013;4:289. doi: 10.3389/fimmu.2013.00289.
• Yang Y, Qiao J, Li R, Li M-Z. Is interleukin-18 associated with polycystic ovary syndrome. Reprod Biol Endocrinol 2011;9:1- 5. doi: 10.1186/1477-7827-9-7.
• Wu G, Hu X, Ding J, Yang J. The effect of glutamine on Dehydroepiandrosterone-induced polycystic ovary syndrome rats. J Ovarian Res 2020;13:1-7. doi: 10.1186/ s13048.020.00650-7.
• Wang W, Zheng J, Cui N, et al. Baicalin ameliorates polycystic ovary syndrome through AMP-activated protein kinase. J Ovarian Res 2019;12:1-12. doi: 10.1186/s13048.019.0585-2.
• Brenjian S, Moini A, Yamini N, et al. Resveratrol treatment in patients with polycystic ovary syndrome decreased proinflammatory and endoplasmic reticulum stress markers. Am J Reprod Immunol 2020;83:e13186. doi: 10.1111/aji.13186.
• Gallinelli A, Ciaccio I, Giannella L, Salvatori M, Marsella T, Volpe A. Correlations between concentrations of interleukin-12 and interleukin-13 and lymphocyte subsets in the follicular fluid of women with and without polycystic ovary syndrome. Fertil Steril 2003;79:1365-72. doi: 10.1016/ s0015-0282(03)00344-3.
• Stokkeland LMT, Giskeødegård GF, Ryssdal M, et al. Changes in serum cytokines throughout pregnancy in women with polycystic ovary syndrome. The J Clin Endocrinol Metab 2022;107:39-52. doi: 10.1210/clinem/dgab684.
• Huang Y, Zhang X. Luteolin alleviates polycystic ovary syndrome in rats by resolving insulin resistance and oxidative stress. Am J Physiol Endocrinol Metab 2021;320:E1085-E92. doi: 10.1152/ajpendo.00034.2021.
• Haslan MA, Samsulrizal N, Hashim N, Zin NSNM, Shirazi FH, Goh YM. Ficus deltoidea ameliorates biochemical, hormonal, and histomorphometric changes in letrozoleinduced polycystic ovarian syndrome rats. BMC Complement Med Ther 2021;21:1-13. doi: 10.1186/s12906.021.03452-6.
• Koohestani Y, Abdi A, Salehiyeh S, Pourmirzaei F, Çiftci M, Emir Çoban O. Protective effect of apigenin on ovarian follicles in polycystic ovary syndrome-induced rats. Med Lab J 2022; 16:2. doi: 10.29252/mlj.16.2.7.
• Darabi P, Khazali H, Mehrabani Natanzi M. Therapeutic potentials of the natural plant flavonoid apigenin in polycystic ovary syndrome in rat model: via modulation of pro-inflammatory cytokines and antioxidant activity, Gynecology Endocrinology 2020; 36: 582-7. doi: 10.1080/09513.590.2019.1706084.