The effect of synbiotics pomegranate juice on cardiovascular risk factors in PCOS patients: a randomized, triple-blinded, controlled trial

  • Z. Esmaeilinezhad
  • R. Barati-Boldaji
  • N. R. Brett
  • J. O. T. de Zepetnek
  • N. Bellissimo
  • S. BabajafariEmail author
  • Z. Sohrabi
Original Article



Polycystic ovarian syndrome (PCOS) is one of the most common metabolic and endocrine disorders. Functional foods like pomegranate and probiotics are those that are considered to have beneficial effects on metabolic diseases beyond their basic nutritional value. So, we aimed to evaluate the effect of synbiotic pomegranate juice (SPJ) on cardiovascular risk factors on PCOS patients.


This was a randomized, triple-blinded, 8-week trial. Participants were randomly assigned to receive 300 mL/day of pomegranate juice (PJ), synbiotic beverage (SB), synbiotic pomegranate juice (SPJ), or placebo beverage (PB). Biochemical indices (lipid profile, Total Antioxidant Capacity (TAC), Malondialdehyde (MDA), high sensitive C-Reactive Protein (hs-CRP)) and blood pressure were assessed before and after the intervention.


Participants in the PJ, SB, and SPJ groups experienced improvement in their lipid profile, oxidative stress, inflammation, and blood pressure during the time. Compared to placebo, Total Cholesterol (TC) was lower in the SB group (P < 0.01), LDL-c was lower in the SPJ and SB groups (P < 0.01), and HDL-c was higher in the SPJ and PJ groups (P < 0.01). With regards to oxidative stress and inflammation, when compared with placebo, MDA was lower in the SPJ, SB, and PJ groups (P < 0.001), TAC was increased in the SPJ and PJ groups (P\(<\) 0.001), and hs-CRP was decreased in the PJ group (P = 0.02). Blood pressure (BP) was lower in the SPJ and PJ groups compared to placebo (P < 0.001; P < 0.01, respectively).


Consuming daily SPJ for 8 weeks improved metabolic, oxidative, inflammatory, and BP outcomes in females with PCOS. This trial was registered in the Iranian Registry of Clinical Trials (IRCT20170207032439N2).


Synbiotic Oxidative stress Dyslipidemia Polycystic ovarian syndrome Punicaceae 



This study was supported by Shiraz University of Medical Sciences. The authors would like to thank the patients who participated in this trial.


The present article was extracted from the thesis written by Zahra Esmaeilinezhad. This article was financially supported by Shiraz University of Medical Sciences grants No12983. The author declared that they have no other relevant financial interest.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict ofinterest.

Ethical approval

This study was reviewed and approved by the ethics committee of Shiraz University of Medical Sciences in Iran and was registered in the Iranian registry of clinical trials (IRCT No.: IRCT20170207032439N2).

Informed consent

All participants provided written informed consent prior to enrolling in the study.


  1. 1.
    Silva Dantas W et al (2013) Metabolic disturbance in PCOS: clinical and molecular effects on skeletal muscle tissue. Sci World J 2013:178364CrossRefGoogle Scholar
  2. 2.
    Romanowski MD et al (2015) Prevalence of non-alcoholic fatty liver disease in women with polycystic ovary syndrome and its correlation with metabolic syndrome. Arq Gastroenterol 52(2):117–123PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Tan S et al (2010) Large effects on body mass index and insulin resistance of fat mass and obesity associated gene (FTO) variants in patients with polycystic ovary syndrome (PCOS). BMC Med Genet 11(1):12PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Tehrani FR et al (2011) The prevalence of polycystic ovary syndrome in a community sample of Iranian population: Iranian PCOS prevalence study. Reprod Biol Endocrinol 9(1):39PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Diamanti-Kandarakis E, Dunaif A (2012) Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr Rev 33(6):981–1030PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Dahan M, Abbasi F, Reaven G (2019) Relationship between surrogate estimates and direct measurement of insulin resistance in women with polycystic ovary syndrome. J Endocrinol Invest 42(8):987–993PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Ebrahimi-Mamaghani M et al (2015) Association of insulin resistance with lipid profile, metabolic syndrome, and hormonal aberrations in overweight or obese women with polycystic ovary syndrome. J Health Popul Nutr 33(1):157PubMedPubMedCentralGoogle Scholar
  8. 8.
    Duleba AJ, Dokras A (2012) Is PCOS an inflammatory process? Fertil Steril 97(1):7–12PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Radosh L (2009) Drug treatments for polycystic ovary syndrome. Am Fam Physician 79(8):671–676PubMedPubMedCentralGoogle Scholar
  10. 10.
    Guo Y et al (2016) Association between polycystic ovary syndrome and gut microbiota. PLoS One 11(4):e0153196PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Tremellen K, Pearce K (2012) Dysbiosis of gut microbiota (DOGMA)–a novel theory for the development of polycystic ovarian syndrome. Med Hypotheses 79(1):104–112PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Rivera-Espinoza Y, Gallardo-Navarro Y (2010) Non-dairy probiotic products. Food Microbiol 27(1):1–11PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Ooi L-G, Liong M-T (2010) Cholesterol-lowering effects of probiotics and prebiotics: a review of in vivo and in vitro findings. Int J Mol Sci 11(6):2499–2522PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Ghanei N et al (2018) The probiotic supplementation reduced inflammation in polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial. J Funct Foods 42:306–311CrossRefGoogle Scholar
  15. 15.
    Shamasbi SG et al (2018) The effect of resistant dextrin as a prebiotic on metabolic parameters and androgen level in women with polycystic ovarian syndrome: a randomized, triple-blind, controlled, clinical trial. Eur J Nutr 58(2):629–640CrossRefGoogle Scholar
  16. 16.
    Karimi E et al (2018) Effects of synbiotic supplementation on metabolic parameters and apelin in women with polycystic ovary syndrome: a randomised double-blind placebo-controlled trial. Br J Nutr 119(4):398–406PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Sohrab G et al (2014) Effects of pomegranate juice consumption on inflammatory markers in patients with type 2 diabetes: a randomized, placebo-controlled trial. J Res Med Sci 19(3):215PubMedPubMedCentralGoogle Scholar
  18. 18.
    Bishayee A et al (2016) Pomegranate exerts chemoprevention of experimentally induced mammary tumorigenesis by suppression of cell proliferation and induction of apoptosis. Nutr Cancer 68(1):120–130PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Kojadinovic MI et al (2017) Consumption of pomegranate juice decreases blood lipid peroxidation and levels of arachidonic acid in women with metabolic syndrome. J Sci Food Agric 97(6):1798–1804PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Moazzen H, Alizadeh M (2017) Effects of pomegranate juice on cardiovascular risk factors in patients with metabolic syndrome: a double-blinded, randomized crossover controlled trial. Plant Foods Hum Nutr 72(2):126–133PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Rom O et al (2017) Acrolein increases macrophage atherogenicity in association with gut microbiota remodeling in atherosclerotic mice: protective role for the polyphenol-rich pomegranate juice. Arch Toxicol 91(4):1709–1725PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Seeram NP et al (2006) Pomegranate juice ellagitannin metabolites are present in human plasma and some persist in urine for up to 48 hours. J Nutr 136(10):2481–2485PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Seeram NP, Lee R, Heber D (2004) Bioavailability of ellagic acid in human plasma after consumption of ellagitannins from pomegranate (Punica granatum L.) juice. Clinica Chimica Acta 348(1–2):63–68CrossRefGoogle Scholar
  24. 24.
    Shukla M et al (2008) Bioavailable constituents/metabolites of pomegranate (Punica granatum L) preferentially inhibit COX2 activity ex vivo and IL-1beta-induced PGE 2 production in human chondrocytes in vitro. J Inflamm 5(1):9CrossRefGoogle Scholar
  25. 25.
    Esmaeilinezhad Z et al (2019) Effect of synbiotic pomegranate juice on glycemic, sex hormone profile and anthropometric indices in PCOS: a randomized, triple blind, controlled trial. Nutr Metab Cardiovasc Dis 29(2):201–208PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Bazarganipour F et al (2013) Health-related quality of life and its relationship with clinical symptoms among Iranian patients with polycystic ovarian syndrome. Iran J Reprod Med 11(5):371–378PubMedPubMedCentralGoogle Scholar
  27. 27.
    Shoaei T, Heidari-Beni M, Tehrani HG (2015) Effects of probiotic supplementation on pancreatic β-cell function and c-reactive protein in women with polycystic ovary syndrome: a randomized double-blind placebo-controlled clinical trial. Int J Prev Med 6:27PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Saghaei M (2004) Random allocation software for parallel group randomized trials. BMC Med Res Methodol 4(1):26PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Tolić M-T et al (2015) Phenolic content, antioxidant capacity and quality of chokeberry (Aronia melanocarpa) products. Food Technol Biotechnol 53(2):171–179PubMedPubMedCentralGoogle Scholar
  30. 30.
    Brand-Williams W, Cuvelier M-E, Berset C (1995) Use of a free radical method to evaluate antioxidant activity. LWT Food Sci Technol 28(1):25–30CrossRefGoogle Scholar
  31. 31.
    Vujovic A et al (2010) Evaluation of different formulas for LDL-C calculation. Lipids Health Dis 9:27PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Reitznerová A et al (2017) Lipid peroxidation process in meat and meat products: a comparison study of malondialdehyde determination between modified 2-Thiobarbituric acid spectrophotometric method and reverse-phase high-performance liquid chromatography. Molecules 22(11):1988PubMedCentralCrossRefGoogle Scholar
  33. 33.
    Kandiel MMM, El Khawagah ARM (2018) Evaluation of semen characteristics, oxidative stress, and biochemical indices in Arabian horses of different ages during the hot summer season. Iran J Vet Res 19(4):270–275PubMedPubMedCentralGoogle Scholar
  34. 34.
    Wu Y et al (2017) Effect of probiotic Lactobacillus on lipid profile: a systematic review and meta-analysis of randomized, controlled trials. PLoS One 12(6):e0178868PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Tajabadi-Ebrahimi M et al (2017) A randomized controlled clinical trial investigating the effect of synbiotic administration on markers of insulin metabolism and lipid profiles in overweight type 2 Diabetic patients with coronary heart disease. Exp Clin Endocrinol Diabetes 125(1):21–27PubMedPubMedCentralGoogle Scholar
  36. 36.
    Eslamparast T et al (2014) Effects of synbiotic supplementation on insulin resistance in subjects with the metabolic syndrome: a randomised, double-blind, placebo-controlled pilot study. Br J Nutr 112(3):438–445PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Rouhi SZT et al (2017) The effect of pomegranate fresh juice versus pomegranate seed powder on metabolic indices, lipid profile, inflammatory biomarkers, and the histopathology of pancreatic islets of Langerhans in streptozotocin-nicotinamide induced type 2 diabetic Sprague-Dawley rats. BMC Complement Altern Med 17:156PubMedCentralCrossRefGoogle Scholar
  38. 38.
    Salwe KJ et al (2015) Evaluation of antidiabetic, hypolipedimic and antioxidant activity of hydroalcoholic extract of leaves and fruit peel of Punica granatum in male Wistar albino rats. J Nat Sci Biol Med 6(1):56–62PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Sadeghipour A et al (2014) Lipid lowering effect of Punica granatum L peel in high lipid diet fed male rats. Evid Based Complement Alternat Med 2014:432650PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Esmaillzadeh A et al (2004) Concentrated pomegranate juice improves lipid profiles in diabetic patients with hyperlipidemia. J Med Food 7(3):305–308PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Pasquali R, Gambineri A (2018) New perspectives on the definition and management of polycystic ovary syndrome. J Endocrinol Invest 41(10):1123–1135PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Lye HS, Rusul G, Liong MT (2010) Removal of cholesterol by lactobacilli via incorporation and conversion to coprostanol. J Dairy Sci 93(4):1383–1392PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Zou X et al (2014) Mitochondrial dysfunction in obesity-associated nonalcoholic fatty liver disease: the protective effects of pomegranate with its active component punicalagin. Antioxid Redox Signal 21(11):1557–1570PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Murri M et al (2013) Circulating markers of oxidative stress and polycystic ovary syndrome (PCOS): a systematic review and meta-analysis. Human Reprod Update 19(3):268–288CrossRefGoogle Scholar
  45. 45.
    Hosseini B et al (2016) Effects of pomegranate extract supplementation on inflammation in overweight and obese individuals: a randomized controlled clinical trial. Complement Ther Clin Pract 22:44–50PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Fuster-Munoz E et al (2016) Effects of pomegranate juice in circulating parameters, cytokines, and oxidative stress markers in endurance-based athletes: a randomized controlled trial. Nutrition 32(5):539–545PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Sohrab G et al (2015) Pomegranate (Punicagranatum) juice decreases lipid peroxidation, but has no effect on plasma advanced glycated end-products in adults with type 2 diabetes: a randomized double-blind clinical trial. Food Nutr Res 59:28551PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Shishehbor F et al (2016) Effects of concentrated pomegranate juice on subclinical inflammation and cardiometabolic risk factors for type 2 diabetes: a quasi-experimental study. Int J Endocrinol Metab 14(1):e33835PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Bahmani F et al (2016) The Consumption of synbiotic bread containing Lactobacillus sporogenes and inulin affects nitric oxide and malondialdehyde in patients with type 2 diabetes mellitus: randomized, double-blind, placebo-controlled trial. J Am Coll Nutr 35(6):506–513PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Farrokhian A, Raygan F, Soltani A, Tajabadi-Ebrahimi M, Esfahani MS, Karami AA, Asemi Z (2019) The effects of synbiotic supplementation on carotid intima-media thickness, biomarkers of inflammation, and oxidative stress in people with overweight, diabetes, and coronary heart disease: a randomized, double-blind, placebo-controlled trial. Probiotics Antimicrob Proteins 11(1):133–142PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Karamali M, Nasiri N, Shavazi NT, Jamilian M, Bahmani F, Tajabadi-Ebrahimi M, Asemi Z (2018) The effects of synbiotic supplementation onpregnancy outcomes in gestational diabetes. Probiotics Antimicrob Proteins 10(3):496–503PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Sun W et al (2016) Pomegranate extract decreases oxidative stress and alleviates mitochondrial impairment by activating AMPK-Nrf2 in hypothalamic paraventricular nucleus of spontaneously hypertensive rats. Sci Rep 6:34246PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Asemi Z et al (2014) Effects of synbiotic food consumption on metabolic status of diabetic patients: a double-blind randomized cross-over controlled clinical trial. Clin Nutr 33(2):198–203PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Zamani B et al (2017) Synbiotic supplementation and the effects on clinical and metabolic responses in patients with rheumatoid arthritis: a randomised, double-blind, placebo-controlled trial. Br J Nutr 117(8):1095–1102PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    D’Souza A et al (2010) Effects of probiotics, prebiotics, and synbiotics on messenger RNA expression of caveolin-1, NOS, and genes regulating oxidative stress in the terminal ileum of formula-fed neonatal rats. Pediatr Res 67(5):526PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Moazzen H, Alizadeh M (2017) Effects of pomegranate juice on cardiovascular risk factors in patients with metabolic syndrome: a double-blinded, randomized crossover controlled trial. Plant Foods Hum Nutr 72(2):126–133PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Tajadadi-Ebrahimi M et al (2014) Effects of daily consumption of synbiotic bread on insulin metabolism and serum high-sensitivity C-reactive protein among diabetic patients: a double-blind, randomized, controlled clinical trial. Ann Nutr Metab 65(1):34–41PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Mandal A, Bhatia D, Bishayee A (2017) Anti-inflammatory mechanism involved in pomegranate-mediated prevention of breast cancer: the role of NF-κB and Nrf2 signaling pathways. Nutrients 9(5):436PubMedCentralCrossRefGoogle Scholar
  59. 59.
    Scarinci E et al (2019) Increased fibulin-1 plasma levels in polycystic ovary syndrome (PCOS) patients: possible contribution to the link between PCOS and cardiovascular risk. J Endocrinol Invest 42(1):91–96PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Shema-Didi L et al (2014) Does Pomegranate intake attenuate cardiovascular risk factors in hemodialysis patients? Nutr J 13:18PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Stockton A et al (2017) Effect of pomegranate extract on blood pressure and anthropometry in adults: a double-blind placebo-controlled randomised clinical trial. J Nutr Sci 6:e39PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Agerholm-Larsen L et al (2000) Effect of 8 week intake of probiotic milk products on risk factors for cardiovascular diseases. Eur J Clin Nutr 54(4):288–297PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Naruszewicz M et al (2002) Effect of Lactobacillus plantarum 299v on cardiovascular disease risk factors in smokers. Am J Clin Nutr 76(6):1249–1255PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Costabile A et al (2017) An in vivo assessment of the cholesterol-lowering efficacy of Lactobacillus plantarum ECGC 13110402 in normal to mildly hypercholesterolaemic adults. PLoS One 12(12):e0187964PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Yap WB et al (2016) Lactobacillus casei strain C1 attenuates vascular changes in spontaneously hypertensive rats. Korean J Physiol Pharmacol 20(6):621–628PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2019

Authors and Affiliations

  • Z. Esmaeilinezhad
    • 1
  • R. Barati-Boldaji
    • 1
  • N. R. Brett
    • 2
  • J. O. T. de Zepetnek
    • 3
  • N. Bellissimo
    • 2
  • S. Babajafari
    • 1
    Email author
  • Z. Sohrabi
    • 1
  1. 1.Nutrition Research Center, School of Nutrition and Food SciencesShiraz University of Medical SciencesShirazIran
  2. 2.School of NutritionRyerson UniversityTorontoCanada
  3. 3.Faculty of Kinesiology and Health StudiesUniversity of ReginaReginaCanada

Personalised recommendations