The Effects of Nateglinide and Octreotide on the Uterus in Rats with Experimentally Developed Polycystic Ovary Syndrome: A Histopathological Study

Year 2026, Issue: Advanced Online Publication, 139 - 148

Ömür Gülsüm Deniz , Pınar Kırıcı Ebru Annaç , Selçuk Kaplan

https://doi.org/10.18621/eurj.1752916

Abstract

Objectives: It was aimed to investigate the histopathological effects of Nateglinide (NG) and Octreotide (OC) on uterine morphology in rats with experimentally induced polycystic ovary syndrome (PCOS).

Methods: Forty-two female Sprague-Dawley rats (10-12 weeks old, 340-360 g) were divided into six groups (n=7 per group) as Control, PCOS, PCOS+NG, NG only, PCOS+OC, OC only. PCOS was induced via daily oral administration of Letrozole (1 mg/kg) for 21 days. Treatment groups received NG (oral, 30 days) or OC (intraperitoneal, 0.1 mg/kg/day for 30 days). After the experiment, the uterus tissues of all rats were dissected and subjected to histopathological examinations after histological procedures.

Results: Histopathological analysis revealed significant uterine damage in the PCOS group compared to other groups (P<0.01). In contrast, the Control, NG-only, and OC-only groups showed normal uterine architecture with intact epithelium, organized glands, and normal stromal structure and there were no significant differences between related groups (P>0.05). Treatment with NG or OC in PCOS rats led to improved epithelial and glandular morphology and reduced Mast cell density, no evidence of edema, and inflammation was found in the connective tissue of these treated groups, suggesting partial improvement of PCOS-induced uterine pathology (P<0.01).

Conclusions: NG and OC treatments ameliorated PCOS-induced uterine histopathological changes, suggesting their potential to improve endometrial morphology. These findings may have implications for therapeutic strategies aimed at enhancing endometrial receptivity and highlighting the importance of addressing endometrial health in therapeutic strategies beyond ovarian treatment in PCOS patients.

Keywords

Polycystic Ovary Syndrome , Nateglinide , Octreotide , Uterus , Histopathology , Rat

Ethical Statement

The present study was approved by the Adıyaman University Animal Experiments Local Ethics Committee (Decision no.: 2022/030-5-2 and date: 26.05.2022). All experimental procedures were carried out accordance with the U.K. Animals (Scientific Procedures) Act, 1986 and associated guidelines, EU Directive 2010/63/EU for animal experiments, or the National Institutes of Health guide for the care and use of Laboratory animals (NIH Publications No. 8023, revised 1978).

References

• 1. Deswal R, Narwal V, Dang A, Pundir CS. The Prevalence of Polycystic Ovary Syndrome: A Brief Systematic Review. J Hum Reprod Sci. 2020;13(4):261-271. doi: 10.4103/jhrs.JHRS_95_18.
• 2. Teede H, Deeks A, Moran L. Polycystic ovary syndrome: A complex condition with psychological, reproductive and metabolic manifestations that impacts on health across the lifespan. BMC Med. 2010;8:41. doi: 10.1186/1741-7015-8-41.
• 3. Meier RK. Polycystic Ovary Syndrome. Nurs Clin North Am. 2018;53(3):407-420. doi: 10.1016/j.cnur.2018.04.008.
• 4. Garad RM, Teede HJ. Polycystic ovary syndrome: improving policies, awareness, and clinical care. Curr Opin Endocr Metab Res. 2020;12:112-118. doi: 10.1016/j.coemr.2020.04.007.
• 5. Rédei GP. Polycystic ovarian disease (Stein-Leventhal syndrome). Encyclopedia Genetics Genomics Proteomics Inf. 2008:1528.
• 6. Alshdaifat E, Sindiani A, Amarin Z, et al. M. Awareness of polycystic ovary syndrome: A university students' perspective. Ann Med Surg (Lond). 2021;72:103123. doi: 10.1016/j.amsu.2021.103123.
• 7. Piltonen TT. Polycystic ovary syndrome: Endometrial markers. Best Pract Res Clin Obstet Gynaecol. 2016;37:66-79. doi: 10.1016/j.bpobgyn.2016.03.008.
• 8. Teede HJ, Norman RJ, Garad RM. A new evidence-based guideline for assessment and management of polycystic ovary syndrome. Med J Aust. 2018;209(7):299-300. doi: 10.5694/mja18.00635.
• 9. Zhang C, Ma J, Wang W, Sun Y, Sun K. Lysyl oxidase blockade ameliorates anovulation in polycystic ovary syndrome. Hum Reprod. 2018;33(11):2096-2106. doi: 10.1093/humrep/dey292.
• 10. Xue Z, Li J, Feng J, et al. Research Progress on the Mechanism Between Polycystic Ovary Syndrome and Abnormal Endometrium. Front Physiol. 2021;12:788772. doi: 10.3389/fphys.2021.788772.
• 11. Shukla A, Rasquin LI, Anastasopoulou C. Polycystic Ovarian Syndrome. 2025 Jul 7. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan–.
• 12. Helvaci N, Yildiz BO. Polycystic ovary syndrome as a metabolic disease. Nat Rev Endocrinol. 2025;21(4):230-244. doi: 10.1038/s41574-024-01057-w.
• 13. Mansour A, Noori M, Hakemi MS, et al. Hyperandrogenism and anthropometric parameters in women with polycystic ovary syndrome. BMC Endocr Disord. 2024;24(1):201. doi: 10.1186/s12902-024-01733-y.
• 14. Hayes E, Winston N, Stocco C. Molecular crosstalk between insulin-like growth factors and follicle-stimulating hormone in the regulation of granulosa cell function. Reprod Med Biol. 2024;23(1):e12575. doi: 10.1002/rmb2.12575.
• 15. Aboeldalyl S, James C, Seyam E, Ibrahim EM, Shawki HE, Amer S. The role of chronic inflammation in polycystic ovarian syndrome—a systematic review and meta-analysis. Int J Mol Sci. 2021 ;22(5):2734. doi: 10.3390/ijms22052734.
• 16. Wang F, Wang S, Zhang Z, et al. Defective insulin signaling and the protective effects of dimethyldiguanide during follicular development in the ovaries of polycystic ovary syndrome. Mol Med Rep. 2017;16(6):8164-8170. doi: 10.3892/mmr.2017.7678.
• 17. Che Y, Yu J, Li YS, Zhu YC, Tao T. Polycystic ovary syndrome: Challenges and possible solutions. J Clin Med. 2023;12(4):1500. doi: 10.3390/jcm12041500.
• 18. Toko H, Ogino M, Nishiwaki A, Kojina M, Aiba T. An underlying mechanism for the altered hypoglycemic effects of nateglinide in rats with acute peripheral inflammation. Biol Pharm Bull. 2025;48(1):51-59. doi: 10.1248/bpb.b24-00582.
• 19. Henninot A, Collins JC, Nuss JM. The current state of peptide drug discovery: back to the future? J Med Chem. 2018;61(4):1382-1414. doi: 10.1021/acs.jmedchem.7b00318.
• 20. Lamberts SWJ, Hofland LJ. Octreotide, 40 years later. Eur J Endocrinol. 2019;181(5):R173-R183. doi: 10.1530/EJE-19-0074.
• 21. Saad MA, Eltarzy MA, Abdel Salam RM, Ahmed MAE. Liraglutide mends cognitive impairment by averting Notch signaling pathway overexpression in a rat model of polycystic ovary syndrome. Life Sci. 2021;265(15):118731. doi: 10.1016/j.lfs.2020.118731.
• 22. Kirici P, Kaplan S, Annac E, et al. The effect of nateglinide and octreotide on follicular morphology and free radical scavenging system in letrazole-induced rat model of PCOS. Eur Rev Med Pharmacol Sci. 26(23):8893-8902. doi: 10.26355/eurrev_202212_30563.
• 23. Goodarzi MO, Dumesic DA, Chazenbalk G, Azziz R. Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Nat Rev Endocrinol. 2011;7(4):219-231. doi: 10.1038/nrendo.2010.217.
• 24. Su P, Chen C, Sun Y. Physiopathology of polycystic ovary syndrome in endocrinology, metabolism and inflammation. J Ovarian Res. 2025;18(1):34. doi: 10.1186/s13048-025-01621-6.
• 25. Sørensen AE, Udesen PB, Wissing ML, Englund ALM, Dalgaard LT. MicroRNAs related to androgen metabolism and polycystic ovary syndrome. Chem Biol Interact. 2016;259(Pt A):8-16. doi: 10.1016/j.cbi.2016.06.008.
• 26. Hoeger KM, Dokras A, Piltonen T. Update on PCOS: Consequences, challenges, and guiding treatment. J Clin Endocrinol Metab. 2021;106(3):e1071-e1083. doi: 10.1210/clinem/dgaa839.
• 27. Moghetti P, Tosi F, Bonin C, et al. Divergences in insulin resistance between the different phenotypes of the polycystic ovary syndrome. J Clin Endocrinol Metab. 2013;98(4):E628-37. doi: 10.1210/jc.2012-3908.
• 28. Zhao H, Zhang J, Cheng X, Nie X, He B. Insulin resistance in polycystic ovary syndrome across various tissues: an updated review of pathogenesis, evaluation, and treatment. J Ovarian Res. 2023;16(1):9. doi: 10.1186/s13048-022-01091-0.
• 29. Hu M, Zhang Y, Guo X, et al. Hyperandrogenism and insulin resistance induce gravid uterine defects in association with mitochondrial dysfunction and aberrant reactive oxygen species production. Am J Physiol Endocrinol Metab. 2019;316(5):E794-E809. doi: 10.1152/ajpendo.00359.2018.
• 30. Bracho GS, Acosta MV, Altamirano GA, et al. Uterine histopathology and steroid metabolism in a polycystic ovary syndrome rat model. Mol Cell Endocrinol. 2024;585:112198. doi: 10.1016/j.mce.2024.112198.
• 31. Atiomo W, Alqutami F, Albasha S, Hachim M. Deciphering the role of insulin-like growth factor 1 in endometrial cancer in patients with polycystic ovary syndrome: protocol for a methodological approach using cell culture experiments. JMIR Res Protoc. 2023;12(1):e48127. doi: 10.2196/48127.
• 32. Park JC, Lim SY, Jang TK, et al. Endometrial histology and predictable clinical factors for endometrial disease in women with polycystic ovary syndrome. Clin Exp Reprod Med. 2011;38(1):42-46. doi: 10.5653/cerm.2011.38.1.42.
• 33. Al-Jefout M, Al-Qtaitat A, Al-Rahal D, et al. Endometrial thickness as a predictor of endometrial hyperplasia in infertile patients with polycystic ovary syndrome. Open J Obstet Gynecol. 2018;08(02):92-104. doi: 10.4236/ojog.2018.82012.
• 34. Ball AJ, Flatt PR, McClenaghan NH. Acute and long-term effects of nateglinide on insulin secretory pathways. Br J Pharmacol. 2004;142(2):367-373. doi: 10.1038/sj.bjp.0705766.
• 35. Lanzone A, Fulghesu AM, Guido M, Cucinelli F, Caruso A, Mancuso S. Somatostatin treatment reduces the exaggerated response of adrenocorticotropin hormone and cortisol to corticotropin-releasing hormone in polycystic ovary syndrome. Fertil Steril. 1997;67(1):34-39. doi: 10.1016/s0015-0282(97)81852-3.
• 36. Van der Meer M, De Boer JAM, Hompes PGA, Schoemaker J. Octreotide, a somatostatin analogue, alters ovarian sensitivity to gonadotrophin stimulation as measured by the follicle stimulating hormone threshold in polycystic ovary syndrome. Hum Reprod. 1998;13(6):1465-1469. doi: 10.1093/humrep/13.6.1465.
• 37. Morris RS, Carmina E, Vijod MA, Stanczyk FZ, Lobo RA. Alterations in the sensitivity of serum insulin-like growth factor 1 and insulin-like growth factor binding protein-3 to octreotide in polycystic ovary syndrome. Fertil Steril. 1995;63(4):742-746. doi: 10.1016/s0015-0282(16)57475-5.