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Investigation of the Effects of Crataegus Monogyna on Methotrexate-Induced Ovarian Damage

Year 2025, Volume: 9 Issue: 2, 135 - 141, 08.08.2025

Abstract

Purpose: Methotrexate (MTX), a folic acid antagonist, is widely used in the treatment of various diseases. Despite its therapeutic benefits, MTX has been associated with toxicity in several organs, especially those of the genital system. Crataegus monogyna (CM) is a flavonoid-rich plant commonly found in many regions and known for its antioxidant and protective properties. Although MTX-induced ovarian damage has been previously studied, no research has investigated the potential protective effect of CM on this damage. This study aimed to evaluate the effect of CM on MTX-induced ovarian injury in rats.

Materials and Methods: Thirty female rats were randomly divided into five groups (n=6): Control: Received only water and food ad libitum for 14 days. Sham: Given a single dose of physiological saline on day 1 and distilled water by gavage for 14 days. MTX: Received a single intraperitoneal dose of 20 mg/kg MTX on day 1. MTX+CM: Treated with 200 mg/kg CM via gavage one hour before MTX administration and continued CM for 14 days. CM: Received 200 mg/kg CM via gavage for 14 days. At the end of the experiment, all animals were sacrificed under anesthesia. Ovarian tissues were collected, fixed in 10% formalin, processed, and examined histologically.

Results: In the MTX group, vascular congestion and hemorrhage, atrophic ovarian follicles, collagen accumulation, and mononuclear cell infiltration were observed. These pathological findings were significantly reduced in the MTX+CM treatment group.

Conclusion: It was observed that CM showed a protective effect against MTX-induced ovarian damage.

References

  • 1. Bedoui Y, Guillot X, Sélambarom J, ve ark. Methotrexate an old drug with new tricks. Int J Mol Sci. 2019;20(20):5023.
  • 2. WHO model lists of essential medicines. https://www.who.int/publications/i/item/WHOMVPEMPIAU2019.06. Erişim tarihi 9 Eylül, 2024.
  • 3. Chan E, Cronstein B. Methotrexate-how does it really work? Nat Rev Rheumatol. 2010;6(3):175-178.
  • 4. Salih SM, Elsarrag SZ, Prange E, ve ark. Evidence to incorporate inclusive reproductive health measures in guidelines for childhood and adolescent cancer survivors. J Pediatr Adolesc Gynecol. 2015;28(2):95-101.
  • 5. Loren AW, Mangu PB, Beck LN, ve ark. Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013;31(19):2500-2510.
  • 6. Kierszenbaum AL. Follicle Development and Menstrual Cycle. In: Canale ST, ed. Histology and Cell Biology - Introduction to Pathology. Palme Publishing; 2006:565-575.
  • 7. Edson M, Nagaraja A, Matzuk M. The mammalian ovary from genesis to revelation. Endocr Rev. 2009;30(6):624-712.
  • 8. Senthilkumaran B, Yoshikuni M, Nagahama Y. A shift in steroidogenesis occurring in ovarian follicles prior to oocyte maturation. Mol Cell Endocrinol. 2004;215 (1-2):11-18.
  • 9. Yang H, Xie Y, Yang D, Ren D. Oxidative stress-induced apoptosis in granulosa cells involves JNK, p53 and Puma. Oncotarget. 2017;8(15):25310-25322.
  • 10. Gulgun M, Erdem O, Oztas E, ve ark. Proanthocyanidin prevents methotrexate-induced intestinal damage and oxidative stress. Exp Toxicol Pathol. 2010;62(2):109-115.
  • 11. Rigelsky J, Sweet B. Hawthorn: pharmacology and therapeutic uses. Am J Heal Syst Pharm. 2002;59(5): 417-422.
  • 12. Keser S, Celik S, Turkoglu S, Yilmaz Ö, Turkoglu I. The investigation of some bioactive compounds and antioxidant properties of hawthorn (Crataegus monogyna subsp. monogyna Jacq). J Intercult Ethnopharmacol. 2014;3(2):51-55.
  • 13. Hwang H, Bleske B, Ghannam M, et al. Effects of hawthorn on cardiac remodeling and left ventricular dysfunction after 1 month of pressure overload-induced cardiac hypertrophy in rats. Cardiovasc Drugs Ther. 2008;22(1):19-28.
  • 14. Hortu I, Ozceltik G, Ergenoglu A, Yigitturk G, Atasoy O, Erbas O. Protective effect of oxytocin on a methotrexate-induced ovarian toxicity model. Arch Gynecol Obs. 2020;301(5):1317-1324.
  • 15. Rababa’h A, Al Yacoub O, El-Elimat T, ve ark. The effect of hawthorn flower and leaf extract (Crataegus Spp.) on cardiac hemostasis and oxidative parameters in Sprague Dawley rats. Heliyon. 2020;6(8):04617.
  • 16. Soyman Z, Uzun H, Bayindir N. Can ebselen prevent cisplatin-induced ovarian damage? Arch Gynecol Obs. 2018;297:1549-1555.
  • 17. Osman AMM, Bayoumi HM, Al-Harthi SE, Damanhouri ZA, ElShal MF. Modulation of doxorubicin cytotoxicity by resveratrol in a human breast cancer cell line. Cancer Cell Int. 2012;12(1):47.
  • 18. Bath R, Brar N, Forouhar F, Wu G. A review of methotrexate-associated hepatotoxicity. J Dig Dis. 2014;15(10):517-524.
  • 19. Inoue K, Yuasa H. Molecular basis for pharmacokinetics and pharmacodynamics of methotrexate in rheumatoid arthritis therapy. Drug Metab Pharmacokinet. 2014;29(1):12-19.
  • 20. Kiremitli T, Kiremitli S, Akselim B, ve ark. Protective effect of Coenzyme Q10 on oxidative ovarian and uterine damage induced by methotrexate in rats. Hum Exp Toxicol. 2021;40(9):1537-1544.
  • 21. Shamberger R, Sherins R, Ziegler J. Effects of postoperative adjuvant chemotherapy and radiotherapy on ovarian function in women undergoing treatment for soft tissue sarcoma. J Natl Cancer Inst. 1981;67(6): 1213-1218.
  • 22. Uz E, Öktem F, Yılmaz H. The activities of purine-catabolizing enzymes and the level of nitric oxide in rat kidneys subjected to methotrexate: protective effect of caffeic acid phenethyl ester. Mol Cell Biochem. 2005;277(1-2):165-170.
  • 23. Özcan P, Fıçıcıoğlu C, Kizilkale O. Can Coenzyme Q10 supplementation protect the ovarian reserve against oxidative damage? J Assist Reprod Genet. 2016;33(9):1223-1230.
  • 24. Ata N, Kulhan N, Kulhan M, ve ark. The effect of resveratrol on oxidative ovary-damage induced by methotrexate in rats (Resveratrol oxidative ovary-damage). Gen Physiol Biophys. 2019;38(6):519-524.
  • 25. Turkler C, Onat T, Yildirim E, ve ark. An experimental study on the use of lycopene to prevent infertility due to acute oxidative ovarian damage caused by a single high dose of methotrexate. Adv Clin Exp Med. 2020;29(1):5-11.
  • 26. Famurewa A, Folawiyo A, Enohnyaket E. Beneficial role of virgin coconut oil supplementation against acute methotrexate chemotherapy-induced oxidative toxicity and inflammation in rats. Integr Med Res. 2018;7(3):257-263.
  • 27. Kang L, Yu J, Hyun Y, ve ark. Therapeutic potential of coenzyme Q10 in mitochondrial dysfunction during tacrolimus-induced beta cell injury. Sci Rep. 2019;34(1):103-797.
  • 28. Ez-Zahra Amrati, F Mssillou I, Boukhira S, ve ark. Phenolic composition of Crataegus monogyna Jacq. extract and its anti-inflammatory, hepatoprotective, and antileukemia effects. Pharm. 2024;17(6):786.

Metotreksat Kaynaklı Ovaryum Hasarında Crataegus Monogyna Etkisinin Araştırılması

Year 2025, Volume: 9 Issue: 2, 135 - 141, 08.08.2025

Abstract

Amaç: Folik asit antagonisti olan Metotreksat (MTX), çeşitli hastalıkların tedavisinde yaygın olarak kullanılmaktadır. Terapötik faydalarına rağmen, MTX’in özellikle genital sistemle ilişkili organlar başta olmak üzere birçok organda toksisiteye yol açtığı bilinmektedir. Crataegus monogyna (CM) birçok bölgede yaygın olarak bulunan ve flavonoid içeriği yüksek olan bir bitkidir; antioksidan ve koruyucu özellikleriyle tanınır. MTX’in ovaryum üzerinde oluşturduğu hasar daha önce çalışılmış olsa da CM’nin bu hasara karşı olası koruyucu etkisiyle ilgili herhangi bir araştırmaya rastlanmamıştır. Bu çalışmanın amacı, CM’nin MTX kaynaklı ovaryum hasarı üzerindeki etkisini değerlendirmektir.

Araçlar ve Yöntem: 30 adet dişi rat her grupta 6 hayvan olacak şekilde rastgele 5 gruba ayrılmıştır: Kontrol: 14 gün boyunca ad libitum su ve yemle beslenen ratlardan oluşan grup. Sham: 1.gün tek doz serum fizyolojik (SF) ve 14 gün gavajla distile su verilen ratlardan oluşan grup. MTX: 1.gün tek doz 20 mg/kg MTX uygulanan grup. MTX+CM Grubu: Tek doz MTX uygulamadan 1 saat önce ve 14 gün boyunca gavajla 200 mg/kg CM verilen ratlardan oluşan grup. CM: 14 gün boyunca gavajla 200 mg/kg CM verilen ratlardan oluşan grup. Deney sonunda tüm hayvanlar anestezi altında sakrifiye edilmiştir. Ovaryum dokuları alınarak %10’luk formalin içinde tespit edilmiş, histolojik inceleme için rutin doku takip işlemlerinden geçirilmiştir.

Bulgular: MTX grubunda vasküler konjesyon ve hemoraji, atrofik ovaryan foliküller, kolajenöz madde birikimi, mononükleer hücre infiltrasyonu görülmüştür. Tedavi grubu olan MTX+CM grubunda ise bu bulgular önemli derecede azalmıştır.

Sonuç: MTX kaynaklı ovaryum hasarına karşı CM’nin koruyucu bir etki gösterdiği görülmüştür.

References

  • 1. Bedoui Y, Guillot X, Sélambarom J, ve ark. Methotrexate an old drug with new tricks. Int J Mol Sci. 2019;20(20):5023.
  • 2. WHO model lists of essential medicines. https://www.who.int/publications/i/item/WHOMVPEMPIAU2019.06. Erişim tarihi 9 Eylül, 2024.
  • 3. Chan E, Cronstein B. Methotrexate-how does it really work? Nat Rev Rheumatol. 2010;6(3):175-178.
  • 4. Salih SM, Elsarrag SZ, Prange E, ve ark. Evidence to incorporate inclusive reproductive health measures in guidelines for childhood and adolescent cancer survivors. J Pediatr Adolesc Gynecol. 2015;28(2):95-101.
  • 5. Loren AW, Mangu PB, Beck LN, ve ark. Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013;31(19):2500-2510.
  • 6. Kierszenbaum AL. Follicle Development and Menstrual Cycle. In: Canale ST, ed. Histology and Cell Biology - Introduction to Pathology. Palme Publishing; 2006:565-575.
  • 7. Edson M, Nagaraja A, Matzuk M. The mammalian ovary from genesis to revelation. Endocr Rev. 2009;30(6):624-712.
  • 8. Senthilkumaran B, Yoshikuni M, Nagahama Y. A shift in steroidogenesis occurring in ovarian follicles prior to oocyte maturation. Mol Cell Endocrinol. 2004;215 (1-2):11-18.
  • 9. Yang H, Xie Y, Yang D, Ren D. Oxidative stress-induced apoptosis in granulosa cells involves JNK, p53 and Puma. Oncotarget. 2017;8(15):25310-25322.
  • 10. Gulgun M, Erdem O, Oztas E, ve ark. Proanthocyanidin prevents methotrexate-induced intestinal damage and oxidative stress. Exp Toxicol Pathol. 2010;62(2):109-115.
  • 11. Rigelsky J, Sweet B. Hawthorn: pharmacology and therapeutic uses. Am J Heal Syst Pharm. 2002;59(5): 417-422.
  • 12. Keser S, Celik S, Turkoglu S, Yilmaz Ö, Turkoglu I. The investigation of some bioactive compounds and antioxidant properties of hawthorn (Crataegus monogyna subsp. monogyna Jacq). J Intercult Ethnopharmacol. 2014;3(2):51-55.
  • 13. Hwang H, Bleske B, Ghannam M, et al. Effects of hawthorn on cardiac remodeling and left ventricular dysfunction after 1 month of pressure overload-induced cardiac hypertrophy in rats. Cardiovasc Drugs Ther. 2008;22(1):19-28.
  • 14. Hortu I, Ozceltik G, Ergenoglu A, Yigitturk G, Atasoy O, Erbas O. Protective effect of oxytocin on a methotrexate-induced ovarian toxicity model. Arch Gynecol Obs. 2020;301(5):1317-1324.
  • 15. Rababa’h A, Al Yacoub O, El-Elimat T, ve ark. The effect of hawthorn flower and leaf extract (Crataegus Spp.) on cardiac hemostasis and oxidative parameters in Sprague Dawley rats. Heliyon. 2020;6(8):04617.
  • 16. Soyman Z, Uzun H, Bayindir N. Can ebselen prevent cisplatin-induced ovarian damage? Arch Gynecol Obs. 2018;297:1549-1555.
  • 17. Osman AMM, Bayoumi HM, Al-Harthi SE, Damanhouri ZA, ElShal MF. Modulation of doxorubicin cytotoxicity by resveratrol in a human breast cancer cell line. Cancer Cell Int. 2012;12(1):47.
  • 18. Bath R, Brar N, Forouhar F, Wu G. A review of methotrexate-associated hepatotoxicity. J Dig Dis. 2014;15(10):517-524.
  • 19. Inoue K, Yuasa H. Molecular basis for pharmacokinetics and pharmacodynamics of methotrexate in rheumatoid arthritis therapy. Drug Metab Pharmacokinet. 2014;29(1):12-19.
  • 20. Kiremitli T, Kiremitli S, Akselim B, ve ark. Protective effect of Coenzyme Q10 on oxidative ovarian and uterine damage induced by methotrexate in rats. Hum Exp Toxicol. 2021;40(9):1537-1544.
  • 21. Shamberger R, Sherins R, Ziegler J. Effects of postoperative adjuvant chemotherapy and radiotherapy on ovarian function in women undergoing treatment for soft tissue sarcoma. J Natl Cancer Inst. 1981;67(6): 1213-1218.
  • 22. Uz E, Öktem F, Yılmaz H. The activities of purine-catabolizing enzymes and the level of nitric oxide in rat kidneys subjected to methotrexate: protective effect of caffeic acid phenethyl ester. Mol Cell Biochem. 2005;277(1-2):165-170.
  • 23. Özcan P, Fıçıcıoğlu C, Kizilkale O. Can Coenzyme Q10 supplementation protect the ovarian reserve against oxidative damage? J Assist Reprod Genet. 2016;33(9):1223-1230.
  • 24. Ata N, Kulhan N, Kulhan M, ve ark. The effect of resveratrol on oxidative ovary-damage induced by methotrexate in rats (Resveratrol oxidative ovary-damage). Gen Physiol Biophys. 2019;38(6):519-524.
  • 25. Turkler C, Onat T, Yildirim E, ve ark. An experimental study on the use of lycopene to prevent infertility due to acute oxidative ovarian damage caused by a single high dose of methotrexate. Adv Clin Exp Med. 2020;29(1):5-11.
  • 26. Famurewa A, Folawiyo A, Enohnyaket E. Beneficial role of virgin coconut oil supplementation against acute methotrexate chemotherapy-induced oxidative toxicity and inflammation in rats. Integr Med Res. 2018;7(3):257-263.
  • 27. Kang L, Yu J, Hyun Y, ve ark. Therapeutic potential of coenzyme Q10 in mitochondrial dysfunction during tacrolimus-induced beta cell injury. Sci Rep. 2019;34(1):103-797.
  • 28. Ez-Zahra Amrati, F Mssillou I, Boukhira S, ve ark. Phenolic composition of Crataegus monogyna Jacq. extract and its anti-inflammatory, hepatoprotective, and antileukemia effects. Pharm. 2024;17(6):786.
There are 28 citations in total.

Details

Primary Language Turkish
Subjects Pathology
Journal Section Original Articles
Authors

Emine Sarman 0000-0002-4671-9315

Early Pub Date August 1, 2025
Publication Date August 8, 2025
Submission Date September 13, 2024
Acceptance Date January 12, 2025
Published in Issue Year 2025 Volume: 9 Issue: 2

Cite

APA Sarman, E. (2025). Metotreksat Kaynaklı Ovaryum Hasarında Crataegus Monogyna Etkisinin Araştırılması. Ahi Evran Medical Journal, 9(2), 135-141.
AMA Sarman E. Metotreksat Kaynaklı Ovaryum Hasarında Crataegus Monogyna Etkisinin Araştırılması. Ahi Evran Med J. August 2025;9(2):135-141.
Chicago Sarman, Emine. “Metotreksat Kaynaklı Ovaryum Hasarında Crataegus Monogyna Etkisinin Araştırılması”. Ahi Evran Medical Journal 9, no. 2 (August 2025): 135-41.
EndNote Sarman E (August 1, 2025) Metotreksat Kaynaklı Ovaryum Hasarında Crataegus Monogyna Etkisinin Araştırılması. Ahi Evran Medical Journal 9 2 135–141.
IEEE E. Sarman, “Metotreksat Kaynaklı Ovaryum Hasarında Crataegus Monogyna Etkisinin Araştırılması”, Ahi Evran Med J, vol. 9, no. 2, pp. 135–141, 2025.
ISNAD Sarman, Emine. “Metotreksat Kaynaklı Ovaryum Hasarında Crataegus Monogyna Etkisinin Araştırılması”. Ahi Evran Medical Journal 9/2 (August 2025), 135-141.
JAMA Sarman E. Metotreksat Kaynaklı Ovaryum Hasarında Crataegus Monogyna Etkisinin Araştırılması. Ahi Evran Med J. 2025;9:135–141.
MLA Sarman, Emine. “Metotreksat Kaynaklı Ovaryum Hasarında Crataegus Monogyna Etkisinin Araştırılması”. Ahi Evran Medical Journal, vol. 9, no. 2, 2025, pp. 135-41.
Vancouver Sarman E. Metotreksat Kaynaklı Ovaryum Hasarında Crataegus Monogyna Etkisinin Araştırılması. Ahi Evran Med J. 2025;9(2):135-41.

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