Investigating the Effects of Ziziphus Jujuba Extract, Metformin, and Myoinositol on Pregnancy Outcomes and Metabolic Parameters in PCOS Women Undergoing Ovulation Induction: A Randomized Controlled Trial Protocol

Document Type : Protocol Study

Authors

1 Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

2 Women's Health Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

3 Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran.

4 Department of Community Medicine and Public Health, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

5 Research Committee Student, School of Dentistry, Mashhad University of Medical Science, Mashhad, Iran.

6 Metabolic Syndrome Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Abstract

Introduction: Ziziphus jujuba, a flavonoids rich plant and is renowned for its potent antioxidant properties with diverse health benefits across various conditions. This study aims to evaluate the efficacy of Ziziphus jujuba as an adjunct therapy for improving pregnancy outcomes in infertile women diagnosed with normogonadotropic normoestrogenic Polycystic Ovary Syndrome (PCOS) undergoing ovulation induction with letrozole. Methods: A total of 196 participants diagnosed with PCOS and infertility will be recruited from the Milad Infertility Center in Mashhad, Iran. Participants will be randomly assigned to one of four groups: Ziziphus jujuba, Myoinositol, Metformin, or Placebo, with each group consisting of 49 individuals. Over 12 weeks, participants will receive their allocated intervention in conjunction with letrozole for ovulation induction. Clinical and biochemical parameters associated with pregnancy outcomes, including biochemical and clinical pregnancy rates, will be assessed. Results: A total of 196 participants will be included in this study, with 49 participants assigned to each group. It is hypothesized that the Ziziphus jujuba group will exhibit improved glucose metabolism and reduced insulin resistance, as measured by fasting blood glucose (FBG) and triglyceride-glucose (TyG) indices, along with enhanced lipid profiles and reduced inflammatory markers, compared to the other groups. These anticipated metabolic improvements are expected to lead to a higher pregnancy rate in the Ziziphus jujuba group than in the different study groups. Conclusion: This study aims to investigate the potential of Ziziphus jujuba as an adjunctive therapy to improve pregnancy outcomes in infertile women diagnosed with PCOS undergoing letrozole-induced ovulation induction. The findings are expected to provide valuable insights into the role of herbal medicine in addressing fertility challenges associated with PCOS, potentially presenting a cost-effective and accessible alternative to conventional pharmaceutical treatments.

Keywords

Main Subjects

References

  1. Carson SA, Kallen AN. Diagnosis and management of Infertility: A Review. JAMA. 2021;326(1):65-76.
  2. Daar AS, Merali Z. Infertility and social suffering: the case of ART in developing countries. Current Practices and Controversies in Assisted Reproduction. 2002;15:21.
  3. Mehri N, Messkoub M, Kunkel S. Trends, Determinants and the Implications of Population Aging in Iran. Ageing International. 2020;45(4):327-43.
  4. Mascarenhas MN, Flaxman SR, Boerma T, Vanderpoel S, Stevens GA. National, regional, and global trends in infertility prevalence since 1990: a systematic analysis of 277 health surveys. PLoS medicine. 2012;9(12):e1001356.
  5. Mustafa M, Sharifa A, Hadi J, IIIzam E, Aliya S. Male and female infertility: causes, and management. IOSR Journal of Dental and Medical Sciences. 2019;18(9):27-32.
  6. Melo AS, Ferriani RA, Navarro PA. Treatment of infertility in women with polycystic ovary syndrome: approach to clinical practice. Clinics. 2015;70:765-9.
  7. Zehravi M, Maqbool M, Ara I. Polycystic ovary syndrome and infertility: an update. International journal of adolescent medicine and health. 2021;34(2):1-9.
  8. Collée J, Mawet M, Tebache L, Nisolle M, Brichant G. Polycystic ovarian syndrome and infertility: overview and insights of the putative treatments. Gynecological Endocrinology. 2021;37(10):869-74.
  9. Morley LC, Tang T, Yasmin E, Norman RJ, Balen AH. Insulin‐sensitising drugs (metformin, rosiglitazone, pioglitazone, D‐chiro‐inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database of Systematic Reviews. 2017(11).
  10. Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. New England Journal of Medicine. 2007;356(6):551-66.
  11. Johnson N, Stewart A, Falkiner J, Farquhar C, Milsom S, Singh V-P, et al. PCOSMIC: a multi-centre randomized trial in women with PolyCystic Ovary Syndrome evaluating Metformin for Infertility with Clomiphene. Human reproduction. 2010;25(7):1675-83.
  12. Bailey CJ, Day C. Metformin: its botanical background. Practical diabetes international. 2004;21(3):115-7.
  13. Tarry-Adkins JL, Grant ID, Ozanne SE, Reynolds RM, Aiken CE. Efficacy and side effect profile of different formulations of metformin: a systematic review and meta-analysis. Diabetes Therapy. 2021;12(7):1901-14.
  14. 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 systematic review and meta-analysis of randomized controlled trials. Reproductive Biology and Endocrinology. 2023;21(1):10.
  15. Fauser BC, Tarlatzis BC, Rebar RW, Legro RS, Balen AH, Lobo R, et al. Consensus on women’s health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Fertility and sterility. 2012;97(1):28-38. e25.
  16. Pundir J, Psaroudakis D, Savnur P, Bhide P, Sabatini L, Teede H, et al. Inositol treatment of anovulation in women with polycystic ovary syndrome: a meta‐analysis of randomised trials. BJOG: An International Journal of Obstetrics & Gynaecology. 2018;125(3):299-308.
  17. Facchinetti F, Unfer V, Dewailly D, Kamenov ZA, Diamanti-Kandarakis E, Laganà AS, et al. Inositols in polycystic ovary syndrome: An overview on the advances. Trends in Endocrinology & Metabolism. 2020;31(6):435-47.
  18. Morgante G, Orvieto R, Di Sabatino A, Musacchio MC, De Leo V. The role of inositol supplementation in patients with polycystic ovary syndrome, with insulin resistance, undergoing the low-dose gonadotropin ovulation induction regimen. Fertility and sterility. 2011;95(8):2642-4.
  19. Akbaribazm M, Goodarzi N, Rahimi M. Female infertility and herbal medicine: An overview of the new findings. Food science & nutrition. 2021;9(10):5869-82.
  20. Lu Y, Bao T, Mo J, Ni J, Chen W. Research advances in bioactive components and health benefits of jujube (Ziziphus jujuba Mill.) fruit. Journal of Zhejiang University-Science B. 2021;22(6):431-49.
  21. Farhadnejad H, Asghari G, Hedayati M, Sahranavard S, Teymoori F, Mirmiran P, et al. Effect of Ziziphus jujube on cardiometabolic factors and systemic inflammation in type 2 diabetic patients: A randomized controlled trial. Clinical Nutrition ESPEN. 2022;49:53-60.
  22. Yazdanpanah Z, Ghadiri‐Anari A, Mehrjardi AV, Dehghani A, Zardini HZ, Nadjarzadeh A. Effect of Ziziphus jujube fruit infusion on lipid profiles, glycaemic index and antioxidant status in type 2 diabetic patients: a randomized controlled clinical trial. Phytotherapy Research. 2017;31(5):755-62.
  23. Irannejad niri Z, Shidfar F, Jabbari M, Zarrati M, Hosseini A, Malek M, et al. The effect of dried Ziziphus vulgaris on glycemic control, lipid profile, Apo‐proteins and hs‐CRP in patients with type 2 diabetes mellitus: A randomized controlled clinical trial. Journal of Food Biochemistry. 2021;45(3):e13193.
  24. Tripathi S. Ziziphus jujuba: A phytopharmacological review. 2014.
  25. Tahergorabi Z, Abedini MR, Mitra M, Fard MH, Beydokhti H. "Ziziphus jujuba": A red fruit with promising anticancer activities. Pharmacogn Rev. 2015;9(18):99-106.
  26. Liu C, Dai M. The effects of Chinese herbal medicine on the pregnancy outcomes of infertile women with polycystic ovary syndrome undergoing in vitro fertilization-embryo transfer: a systematic review and meta-analysis. 2021.
  27. Azami Movahed M, Mahboubi Rabbani M, Bayanati M. Research advances in bioactive components and therapeutic benefits of jujube fruit, a mini review. Research Journal of Pharmacognosy. 2024;11(4):93-104.
  28. Agrawal A, Mahey R, Kachhawa G, Khadgawat R, Vanamail P, Kriplani A. Comparison of metformin plus myoinositol vs metformin alone in PCOS women undergoing ovulation induction cycles: randomized controlled trial. Gynecological Endocrinology. 2019;35(6):511-4.
  29. Mostafa UE-S, Labban L. Effect of Zizyphus jujuba on serum lipid profile and some anthropometric measurements. Advancement in Medicinal Plant Research. 2013;1(3):49-55.
  30. Prabhakar P, Mahey R, Gupta M, Khadgawat R, Kachhawa G, Sharma JB, et al. Impact of myoinositol with metformin and myoinositol alone in infertile PCOS women undergoing ovulation induction cycles-randomized controlled trial. Gynecological Endocrinology. 2021;37(4):332-6.
  31. Xu Y, Qiao J. Association of insulin resistance and elevated androgen levels with polycystic ovarian syndrome (PCOS): a review of literature. Journal of healthcare engineering. 2022;2022.
  32. Hazlehurst JM, Singh P, Bhogal G, Broughton S, Tahrani AA. How to manage weight loss in women with obesity and PCOS seeking fertility? Clinical endocrinology. 2022;97(2):208-16.
  33. Hu L, Ma L, Xia X, Ying T, Zhou M, Zou S, et al. Efficacy of bariatric surgery in the treatment of women with obesity and polycystic ovary syndrome. The Journal of Clinical Endocrinology & Metabolism. 2022;107(8):e3217-e29.
  34. Guo F, Gong Z, Fernando T, Zhang L, Zhu X, Shi Y. The lipid profiles in different characteristics of women with PCOS and the interaction between dyslipidemia and metabolic disorder states: a retrospective study in Chinese population. Frontiers in Endocrinology. 2022;13:892125.
  35. International evidence-based guideline for the assessment and management of polycystic ovary syndrome 2018. 2018.
  36. Li YM, Hao Kx, Xie H, Jiang JG. The Hypoglycemic Activities and Underlying Mechanisms of Two Saponins‐Rich Components from Fried Ziziphus jujuba Mill. Kernel. Molecular Nutrition & Food Research. 2023:2200364.
  37. Ji X, Peng Q, Yuan Y, Shen J, Xie X, Wang M. Isolation, structures and bioactivities of the polysaccharides from jujube fruit (Ziziphus jujuba Mill.): A review. Food chemistry. 2017;227:349-57.
  38. Qiao L, Zou C, van der Westhuyzen DR, Shao J. Adiponectin reduces plasma triglyceride by increasing VLDL triglyceride catabolism. Diabetes. 2008;57(7):1824-33.
  39. Hemmati M, Asghari S, Zohoori E, Karamian M. Hypoglycemic effects of three Iranian edible plants; jujube, barberry and saffron: Correlation with serum adiponectin level. Pak J Pharm Sci. 2015;28(6):2095-9.
  40. Shirdel Z, Maadani H, Mirbadalzadeh R. Investigation into the hypoglycemic effect of hydroalcoholic extract of Ziziphus Jujuba Leaves on blood glucose and lipids in Alloxan-Induced diabetes in rats. Journal of Diabetes and Metabolic Disorders. 2009;8:2.
  41. Hemmati M, Zohoori E, Mehrpour O, Karamian M, Asghari S, Zarban A, et al. Anti-atherogenic potential of jujube, saffron and barberry: anti-diabetic and antioxidant actions. EXCLI journal. 2015;14:908.
  42. Asadi Nejad K, Arzaei M. Comparison of the effect of Shilan (Jujube) medicinal capsule with metformin on ovarian cysts in patients with polycystic ovary syndrome. Journal of Traditional Medicine of Islam and Iran. 2016;7(1):53-8. [in Persian]
  43. Mirazi, Naser, Poursher, Izadi. Study of the effect of hydroalcoholic extract of jujube fruit (Zizyphus jujube L.) in rats with polycystic ovary syndrome. Armaghane Danesh. 2019;24(5):746-62.[in Persian]
Journal of Nutrition,Fasting and Health
Volume 13, Issue 3
September 2025
Pages 146-156

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History

  • Receive Date: 25 December 2024
  • Revise Date: 15 January 2025
  • Accept Date: 19 January 2025

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