Effect of Vitamin E on Serum Levels of Vascular Endothelial Growth Factor and Angiopoietin-1 in Women with Polycystic Ovary Syndrome: A Pilot Randomized, Placebo-Controlled Trial

Document Type : Original Article

Authors

1 Department of Biochemistry and Diet Therapy, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran

2 Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran

3 Nutrition Research Center, Department of Biochemistry and Diet Therapy, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran

4 Women’s Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

Abstract

Background: Angiogenesis disturbances are common in women with polycystic ovary syndrome (PCOS). Vitamin
E has antiangiogenic properties. Data on the effects of vitamin E on angiogenesis in PCOS is limited, so the current
study was conducted to evaluate its effects on angiogenic indices in PCOS patients.

Materials and Methods: This randomized, double-blind, placebo-controlled trial was performed on 43 women
aged 20-40 years, diagnosed with PCOS (Rotterdam criteria). It was performed at the referral clinic affiliated to
Tabriz University of Medical Sciences, Tabriz, Iran, from April 2017 to September 2017. Patients were randomly
assigned into two groups to receive either 400 IU/day vitamin E -as alpha tocopheryl acetate- (n=22) or placebo
(n=21), for 8 weeks. Anthropometric, and angiogenic parameters including body weight, fat mass and fat free
mass, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiopoietin-1 (Ang-
1), and angiopoietin-2 (Ang-2) were measured by standard methods at the beginning and at the end of study.
Statistical Package for Social Science version 25 was used for statistical analysis and p significant.

Results: After adjusting for potential confounders, we observed that vitamin E supplementation significantly reduced
body weight, fat mass, Ang-1, Ang-1/Ang-2 ratio and VEGF (p <0.01). We did not observe any considerable effect for
vitamin E on Ang-2 level or bFGF.

Conclusion: Vitamin E supplementation for 8 weeks in the PCOS women had beneficial effects on body weight, Ang-
1, Ang-1/Ang-2 ratio, and VEGF level (Registration number: IRCT201610193140N18).

Keywords


1.Goodman NF, Cobin RH, Futterweit W, Glueck JS, Legro RS,Carmina E. American Association of Clinical Endocrinologists,American College of Endocrinology, and Androgen Excess andPCOS Society disease state clinical review: guide to the bestpractices in the evaluation and treatment of polycystic ovarysyndrome-part 1. Endocr Pract. 2015; 21(11): 1291-1300.
2.Setji TL, Brown AJ. Polycystic ovary syndrome: update on diagnosis and treatment. Am J Med. 2014; 127(10): 912-919.
3.Jalilian A, Kiani F, Sayehmiri F, Sayehmiri K, Khodaee Z, AkbariM.Prevalence of polycystic ovary syndrome and its associatedcomplications in Iranian women: a meta-analysis. Iran J ReprodMed. 2015; 13(10): 591-604.
4.Tal R, Seifer DB, Arici A. The emerging role of angiogenic factordysregulation in the pathogenesis of polycystic ovarian syndrome.Semin Reprod Med. 2015; 33(3): 195-207.
5.Abramovich D, Irusta G, Bas D, Cataldi NI, Parborell F, TesoneM.Angiopoietins/TIE2 system and VEGF are involved in ovarianfunction in a DHEA rat model of polycystic ovary syndrome.Endocrinology. 2012; 153(7): 3446-3456.
6.Berisha B, Schams D, Rodler D, Pfaffl MW. Angiogenesis in theovary-the most important regulatory event for follicle and corpusluteum development and function in cow-an overview. Anat HistolEmbryol. 2016; 45(2): 124-130.
7.Scotti L, Parborell F, Irusta G, De Zuñiga I, Bisioli C, Pettorossi H, et al. Platelet-derived growth factor BB and DD and angiopoietin1 arealtered in follicular fluid from polycystic ovary syndrome patients.Mol Reprod Dev. 2014; 81(8): 748-756.
8.Di Pietro M, Pascuali N, Parborell F, Abramovich D. Ovarianangiogenesis in polycystic ovary syndrome. Reproduction(Cambridge, England). 2018; 155(5): R199-R209.
9.Wells SR, Jennings MH, Rome C, Hadjivassiliou V, Papas KA,Alexander JS. alpha-, gamma-and delta-tocopherols reduceinflammatory angiogenesis in human microvascular endothelialcells. J Nutr Biochem. 2010; 21(7): 589-597.
10.Kurdoglu Z, Ozkol H, Tuluce Y, Koyuncu I. Oxidative status and itsrelation with insulin resistance in young non-obese women withpolycystic ovary syndrome. J Endocrinol Invest. 2012; 35(3): 317-321.
11.Rahmani E, Samimi M, Afshar Ebrahimi F, Foroozanfard F, AhmadiS, Rahimi M, et al. The effects of omega-3 fatty acids and vitaminE co-supplementation on gene expression of lipoprotein (a) andoxidized low-density lipoprotein, lipid profiles and biomarkers ofoxidative stress in patients with polycystic ovary syndrome. Mol Cell Endocrinol. 2017; 439: 247-255.
12.Fatemi F, Mohammadzadeh A, Sadeghi MR, Akhondi MM,Mohammadmoradi S, Kamali K, et al. Role of vitamin E and D3supplementation in intra-cytoplasmic sperm injection outcomesof women with polycystic ovarian syndrome: a double blindedrandomized placebo-controlled trial. Clin Nutr ESPEN. 2017; 18:23-30.
13.Mondul AM, Rager HC, Kopp W, Virtamo J, Albanes D.Supplementation with alpha-tocopherol or beta-carotene reducesserum concentrations of vascular endothelial growth factor-D, butnot –A or-C, in male smokers. J Nutr. 2011; 141(11): 2030-2034.
14.García OP, Long KZ, Rosado JL. Impact of micronutrientdeficiencies on obesity. Nutr Rev. 2009; 67(10): 559-572.
15.Lauritsen MP, Bentzen JG, Pinborg A, Loft A, Forman JL, ThuesenLL, et al. The prevalence of polycystic ovary syndrome in a normalpopulation according to the Rotterdam criteria versus revisedcriteria including anti-Müllerian hormone. Hum Reprod. 2014;29(4): 791-801.
16.Izadi A, Ebrahimi S, Shirazi S, Taghizadeh S, Parizad M, FarzadiL, et al. Hormonal and metabolic effects of coenzyme Q10 and/or vitamin E in patients with polycystic ovary syndrome. J ClinEndocrinol Metab. 2018; 104(2): 319-327.
17.Samimi M, Zarezade Mehrizi M, Foroozanfard F, Akbari H, Jamilian M, Ahmadi S, et al. The effects of coenzyme Q10 supplementationon glucose metabolism and lipid profiles in women with polycysticovary syndrome: a randomized, double-blind, placebo-controlledtrial. Clin Endocrinol. 2017; 86(4): 560-566.
18.Aghanejad Nozari R, Farshbaf-Khalili A, Sattarzadeh N, AsghariJafarabad M. The effect of counseling on menstrual hygiene,physical activity, and nutritional status of female adolescentstudents: A randomized controlled field trial. Crescent J MedicalBiol Sci. 2019; 6(3): 393-402.
19.Estebsari F, Shojaeizadeh D, Mostafaei D, Farahbakhsh M.Planning and evaluation of an educational program based onPRECEDE model to improve physical activity in female students.Hayat. 2010; 16(1): 48-54.
20.Li H, Lei N, Zhang M, Li Y, Xiao H, Hao X. Pharmacokinetics of along-lasting anti-VEGF fusion protein in rabbit. Exp Eye Res. 2011;97(1): 154-159.
21.Gunanti IR, Marks GC, Al-Mamun A, Long KZ. Low serumconcentrations of carotenoids and vitamin E are associated withhigh adiposity in Mexican-American children. J Nutr. 2014; 144(4):489-495.
22.Joosen AM, Bakker AH, Zorenc AH, Kersten S, Schrauwen P,Westerterp KR. PPARgamma activity in subcutaneous abdominalfat tissue and fat mass gain during short-term overfeeding. Int JObes (Lond). 2006; 30(2): 302-307.
23.Liu GS, Chan EC, Higuchi M, Dusting GJ, Jiang F. Redoxmechanisms in regulation of adipocyte differentiation: beyond ageneral stress response. Cells. 2012; 1(4): 976-993.
24.Zhang Y, Li Y, Liang X, Gao J. Effects of dietary vitamin Esupplementation on growth performance, fatty acid composition,lipid peroxidation and peroxisome proliferator-activated receptors(PPAR) expressions in juvenile blunt snout bream Megalobramaamblycephala. Fish Physiol Biochem. 2017; 43(4): 913-922.
25.Harfouche R, Malak NA, Brandes RP, Karsan A, Irani K, HussainSN. Roles of reactive oxygen species in angiopoietin-1/tie-2 receptor signaling. FASEB J. 2005; 19(12): 1728-1730.
26.Prauchner CA. Angiogenesis inhibition by antioxidants.International Journal of Biomedical Science and Engineering.2014; 2(6-1): 7-19.
27.Di Pietro M, Parborell F, Irusta G, Pascuali N, Bas D, Bianchi MS,et al. Metformin regulates ovarian angiogenesis and folliculardevelopment in a female polycystic ovary syndrome rat model.Endocrinology. 2015; 156(4): 1453-1463.
28.Kim YW, Byzova TV. Oxidative stress in angiogenesis and vascular disease. Blood. 2014; 123(5): 625-631.
29.Saghiri MA, Asatourian A, Ershadifar S, Moghadam MM, SheibaniN.Vitamins and regulation of angiogenesis:[A, B1, B2, B3, B6, B9,B12, C, D, E, K]. J Funct Foods. 2017; 38: 180-196.
30.Peitsidis P, Agrawal R. Role of vascular endothelial growth factor in women with PCO and PCOS: a systematic review. Reprod BiomedOnline. 2010; 20(4): 444-452.
31.El Behery MM, Diab AE, Mowafy H, Ebrahiem MA, Shehata AE.Effect of laparoscopic ovarian drilling on vascular endothelialgrowth factor and ovarian stromal blood flow using 3-dimensionalpower Doppler. Int J Gynaecol Obstet. 2011; 112(2): 119-121.
32.Irani M, Seifer DB, Grazi RV, Irani S, Rosenwaks Z, Tal R. VitaminD decreases serum VEGF correlating with clinical improvementin vitamin D-deficient women with PCOS: a randomized placebo-controlled trial. Nutrients. 2017; 9(4): 334.
33.Chuang CH, Huang CS, Hu ML. Vitamin E and rutin synergisticallyinhibit expression of vascular endothelial growth factor throughdown-regulation of binding activity of activator protein-1 in humanpromyelocytic leukemia (HL-60) cells. Chem Biol Interact. 2010;183(3): 434-441.
34.Shibata A, Nakagawa K, Sookwong P, Tsuduki T, Oikawa S,Miyazawa T. delta-Tocotrienol suppresses VEGF inducedangiogenesis whereas alpha-tocopherol does not. J Agric FoodChem. 2009; 57(18): 8696-8704.
35.Zingg JM, Meydani M, Azzi A. α-Tocopheryl phosphate—Anactivated form of vitamin E important for angiogenesis andvasculogenesis? Biofactors. 2012; 38(1): 24-33.
36.Zingg JM, Libinaki R, Lai CQ, Meydani M, Gianello R, Ogru E, et al. Modulation of gene expression by α-tocopherol and α-tocopherylphosphate in THP-1 monocytes. Free Radic Biol Med. 2010;49(12): 1989-2000.
37.Zingg JM, Azzi A, Meydani M. Induction of VEGF expression byalpha-tocopherol and alpha-tocopheryl phosphate via PI3Kγ/PKBand hTAP1/SEC14L2-mediated lipid exchange. J Cell Biochem.2015; 116(3): 398-407.
38.Qiao J, Feng HL. Extra-and intra-ovarian factors in polycystic ovary syndrome: impact on oocyte maturation and embryo developmental competence. Hum Reprod Update. 2010; 17(1): 17-33.
39.Tal R, Segars JH. The role of angiogenic factors in fibroidpathogenesis: potential implications for future therapy. HumReprod Update. 2014; 20(2): 194-216.
40.Artini PG, Monti M, Matteucci C, Valentino V, Cristello F,Genazzani AR. Vascular endothelial growth factor and basicfibroblast growth factor in polycystic ovary syndrome duringcontrolled ovarian hyperstimulation. Gynecol Endocrinol. 2006;22(8): 465-470.