Document Type : Original Research Article

Authors

1 Department of General Surgery, Lorestan University of Medical Sciences, Khorramabad, Iran.

2 Department of Physiology, School of Medicine, Bam University of Medical Sciences, Bam, Iran.

3 MD, Georgian Center for Neuroscience Research, International Center for Intelligent Research, Tbilisi, Georgia.

Abstract

Background and purpose:Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in the women and animals. Some common hormonal therapies are used to treat the PCOS condition. This study was conducted to evaluate the effects of curcumin on rats with PCOS by evaluation of the gene expression of the GLUT4 and Erα and insulin resistance.
Methods: Following induction of PCOS, sixty Sprague–Dawley female rats were divided into four groups including: (1) Control group (2) Control PCOS (3 & 4) those treated with 100 and 200 mg/kg of curcumin respectively. Body weight, fasting blood glucose (FBG), fasting insulin serum (FIS), homeostasis model assessment of insulin resistance (HOMA-IR) and gene expression of GLUT4 and Erα were evaluated.
Results:Induction of PCOS increased body weight, FBG, FIS, HOMA-IR and decreased gene expression of GLUT4 and Erα (p <0.05), but oral administration of curcumin could alleviate adverse effects of PCOS on the mentioned parameters (p <0.05).
Conclusion: It can be concluded that curcumin alleviates adverse effects of PCOS. It can be recommended to use the curcumin for the treatment of patients with PCOS.

Graphical Abstract

Beneficial Effects of Curcuminon on Rats with Polycystic Ovary Syndrome: Evaluation of the Gene Expression of GLUT4, Erα and Insulin Resistance

Keywords

 

1.       Arikawe AP, Iranloye BO, Ogunsola AO, Daramola AO. Chronic fructose consumption as a model of polycystic ovary syndrome in pregnant female sprague-dawley rats. Afr J Biomed Res. 2013; 15(1): 7–13.

 

2.       Zhai HL, Wu H, Xu H, Weng P, Xia FZ, Chen Y, Lu YL. Trace glucose and lipid metabolism in high androgen and high-fat diet induced polycystic ovary syndrome rats. Reprod Biol Endocrinol. 2012; 10: 5. [crossref]

 

3.       Ghasemzadeh A, Farzadi L, Khaki A, Ahmadi SK. Effect of Allium cepa seeds ethanolic extract on experimental polycystic ovary syndrome (PCOS) apoptosis induced by estradiol-valerate. Life Sci. 2013; 10: 170–175.

 

4.       Demirel MA, Ilhan M, Suntar I, Keles  H, Akkol EK. Activity of Corylus avellana seed oil in letrozole-induced polycystic ovary syndrome model in rats. Rev Bras de Farmacogn. 2016; 26(1): 83–88. [crossref]

 

5.       Makker A, Goel MM, Das V,Agarwal A. PI3K‑Akt‑mTOR and MAPK signaling pathways in polycystic ovarian syndrome, uterine leiomyomas and endometriosis: An update. Gynecol Endocrinol. 2012; 28(3): 175‑181. [crossref]

 

6.       Zhao Y, Zhang C, Huang Y, Yu Y, Li R, Li M, Liu N, Liu P,Qiao J. Up‑regulated expression of WNT5a increases inflamma­tion and oxidative stress via PI3K/AKT/NF‑κB signaling in the granulosa cells of PCOS patients. J Clin Endocrinol Metab. 2015; 100(1): 201‑211. [crossref]

 

7.       Skrgatić L, Baldani DP, Gersak K, Cerne JZ, Ferk P, Corić M. Genetic polymorphisms of INS, INSR and IRS‑1 genes are not associated with polycystic ovary syndrome in Croatian women. Coll Antropol. 2013; 37(1): 141‑146. [PMID]

 

8.       Strowitzki T, von Eye HC,Kellerer M, Haring HU. Tyrosine kinase activity of insulin-like growth factor I and insulin receptors in human endometrium during the menstrual cycle: cyclic variation of insulin receptor expression. Fertil. Steril. 1993; 59(2): 315–322. [crossref]

 

9.       Sheets EE, Tsibris JC, Cook NI, Virgin SD, DeMay RM, Spellacy WN. In vitro binding of insulin and epidermal growth factor to human endometrium and endocervix. Am J Obstet Gynecol. 1985; 153(1): 60–65. [crossref]

 

10.    Mioni R, Chiarelli S, Xamin N, Zuliani L, Granzotto M, Mozzanega B, Maffei P, Martini C, Blandamura S, Sicolo N. Evidence for the presence of glucose transporter 4 in the endometriumand its regulation in polycystic ovary syndrome patients. J Clin Endocrinol Metab. 2004; 89(8): 4089–4096. [crossref]

 

11.    Zhai J, Liu C-x, Tian Z-r, Jiang Q-h, Sun Y-p. Effects of metformin on the expression ofGLUT4in endometrium of obese women with polycystic ovary syndrome. Biol Reproduc. 2012; 87(2): 307–314. [crossref]

 

12.    Carvajal R, Rosas C, Kohan K, Gabler F, Vantman D, Romero C, Vega M. Metformin augments the levels of molecules that regulate the expression of the insulin-dependent glucose transporterGLUT4 in the endometria of hyper insulinemic PCOS patients. Hum Reprod. 2013; 28(8): 2235–2244. [crossref]

 

13.    Hulchiy M, Nybacka A, Sahlin L, Hirschberg AL. Endometrial expression of estrogen receptors and the androgen receptorin women with polycystic ovary syndrome: a lifestyle intervention study. J Clin Endocrinol Metab. 2016; 101(2): 561–571. [crossref]

 

14.    Meyer MR, Clegg DJ, Prossnitz ER, Barton M. Obesity, insulin resistance and diabetes: sex differences and role of oestrogen receptors. Acta Physiol (OXF). 2011; 203(1): 259–69. [crossref]

 

15.    Quaynor SD, Stradtman EW, Kim HG, Shen Y, Chorich LP, Schreihofer DA, Layman LC. Delayed puberty and estrogen resistance in a woman with estrogen receptor alpha variant. N.Engl.J.Med. 2013; 369(2): 164–171. [crossref]

 

16.    Badawy Ahmed, Elnashar Abubaker. Treatment options for polycystic ovary syndrome. Int J Womens Health. 2011; 3: 25-35. [crossref]

 

17.    Choi SH, Shapiro H, Robinson GE, Irvine J, Neuman J, Rosen B, et al. Psychological side-effects of clomiphene citrate and human menopausal gonadotrophin.  J Psychosom Obstet Gynaecol. 2005; 26: 93-100. [PMID]

 

18.    Pari L, Murugan P. Effect of tetrahydrocurcumin on blood glucose, plasma insulin and hepatic key enzymes in streptozotocin induced diabetic rats. J Basic Clin Physiol Pharmacol. 2005; 16(4): 257-274. [PMID]

 

19.    Pari L, Murugan P. Antihyperlipidemic effect of curcumin and tetrahydrocurcumin in experimental type 2 diabetic rats. Ren Fail. 2007; 29(7): 881-889. [crossref]

 

20.    Aggarwal BB, Banerjee S, Bharadwaj U, Sung B, Shishodia S, Sethi G. Curcumin induces the degradation of cyclin E expression through ubiquitin-dependent pathway and up-regulates cyclin dependent kinase inhibitors p21 and p27 in multiple human tumorcell lines. Biochem Pharmacol. 2007; 73(7): 1024-1032. [crossref]

 

21.    Watson JL, Greenshields A, Hill R, Hilchie A, Lee PW, Giacomantonio CA, et al. Curcumin-induced apoptosis in ovarian carcinoma cells is p53-independent and involves p38 mitogen activated protein kinase activation and down regulation of Bcl-2and survivin expression and Aktsignalling. Mol Carcinog. 2010; 49(1): 13-24. [crossref]

 

22.    Kadasi A, V.Sirotkin A, Maruniakova N, Kolesarova A, Bulla J, Grossmann R. The effect of Curcumin on secretory activity, proliferation and apoptosis of the porcine ovarian granulose cells. JMBFS. 2012; 2(1): 349-357.

 

23.    Kavitha A, Narendra B, Sathish K, Veena K. Evaluation of effects of Commiphora wightii in dehydroepiandrosterone (DHEA) induced polycystic ovary syndrome (PCOS) in rats. Pharma Tutor. 2016; 4(1): 47–55.

 

24.    Miladpour B, Rasti M, Owji AA, Mostafavipour Z, Khoshdel Z, Noorafshan A, Zal F. Quercetin potentiates trans differentiation of bone marrow mesenchymal stem cells into the beta cellsin vitro. J Endocrinol Invest. 2017; 40(5): 513–521.  [crossref]

 

25.    Neisy A, Zal F, Seghatoleslam A, Alaee S. Amelioration by quercetin of insulin resistance and uterine GLUT4 and ERa gene expression in rats with polycystic ovary syndrome (PCOS). Reprod Fertil Dev. 2019; 31(2): 315-323. [crossref]

 

26.    Mesbahzadeh B, Garmsiri M, Jalalvand F, Shojaie L, Kakar MA. Oral administration of menthol could alleviate adverse effects of polycystic ovarian syndrome in blood biochemical parameters and antioxidant status in experimental Wister rats. GMJ Med. 2017; 1(1):9-14. [crossref]

 

27.    Diamanti-Kandarakis E, Argyrakopoulou G, Economou F, Kandaraki E, Koutsilieris M. Defects in insulin signaling pathways in ovarian steroidogenesis and other tissues in polycystic

 

28.    ovary syndrome (PCOS). J Steroid BiochemMol Biol. 2008; 109(3–5): 242–246. [crossref]

 

29.    Winkler G, Kiss S, Keszthelyi L, Sa´pi Z, Ory I, Salamon F, Kova´cs M, Vargha P, Szekeres O, Speer G. Expression of tumor necrosis factor (TNF)-alpha protein in the subcutaneous and visceral adipose tissue in correlation with adipocyte cell volume, serum TNF alpha, soluble serum TNF-receptor-2 concentrations and C-peptide level. Eur J Endocrinol. 2003; 149(2), 129–135. [crossref]

 

30.    Patel N, Huang C, Klip A. Cellular location of insulin triggered signals and implications for glucose uptake. Pflugers Arch. 2006; 451(4): 499–510. [crossref]

 

31.    Fornes R, Ormazabal P, Rosas C, Gabler F, Vantman D, Romero C, Vega M. Changes in the expression of insulin signaling pathway molecules in endometria from polycystic ovary syndrome women with or without hyper insulinemia. Mol Med. 2010; 16(3–4): 129. [crossref]

 

32.    Riant E, Waget A, Cogo H, Arnal JF, Burcelin R, Gourdy P. Estrogens protect against high-fat diet-induced insulin resistanceand glucose intolerance in mice. Endocrinol. 2009; 150(5): 2109–2117. [crossref]

 

33.    Moradi A, Bahrami M, Eslami G, Mohiti-Ardekani J. The Effect of Curcumin on GLUT4 gene expression as a diabetic resistance marker in C2C12 myoblast cells. Iran J Diabetes Obesity. 6(2): 98-105.

 

1.       Arikawe AP, Iranloye BO, Ogunsola AO, Daramola AO. Chronic fructose consumption as a model of polycystic ovary syndrome in pregnant female sprague-dawley rats. Afr J Biomed Res. 2013; 15(1): 7–13.

2.       Zhai HL, Wu H, Xu H, Weng P, Xia FZ, Chen Y, Lu YL. Trace glucose and lipid metabolism in high androgen and high-fat diet induced polycystic ovary syndrome rats. Reprod Biol Endocrinol. 2012; 10: 5. [crossref]

3.       Ghasemzadeh A, Farzadi L, Khaki A, Ahmadi SK. Effect of Allium cepa seeds ethanolic extract on experimental polycystic ovary syndrome (PCOS) apoptosis induced by estradiol-valerate. Life Sci. 2013; 10: 170–175.

4.       Demirel MA, Ilhan M, Suntar I, Keles  H, Akkol EK. Activity of Corylus avellana seed oil in letrozole-induced polycystic ovary syndrome model in rats. Rev Bras de Farmacogn. 2016; 26(1): 83–88. [crossref]

5.       Makker A, Goel MM, Das V,Agarwal A. PI3K‑Akt‑mTOR and MAPK signaling pathways in polycystic ovarian syndrome, uterine leiomyomas and endometriosis: An update. Gynecol Endocrinol. 2012; 28(3): 175‑181.

[crossref]

6.       Zhao Y, Zhang C, Huang Y, Yu Y, Li R, Li M, Liu N, Liu P,Qiao J. Up‑regulated expression of WNT5a increases inflamma­tion and oxidative stress via PI3K/AKT/NF‑κB signaling in the granulosa cells of PCOS patients. J Clin Endocrinol Metab. 2015; 100(1): 201‑211. [crossref]

7.       Skrgatić L, Baldani DP, Gersak K, Cerne JZ, Ferk P, Corić M. Genetic polymorphisms of INS, INSR and IRS‑1 genes are not associated with polycystic ovary syndrome in Croatian women. Coll Antropol. 2013; 37(1): 141‑146. [PMID]

8.       Strowitzki T, von Eye HC,Kellerer M, Haring HU. Tyrosine kinase activity of insulin-like growth factor I and insulin receptors in human endometrium during the menstrual cycle: cyclic variation of insulin receptor expression. Fertil. Steril. 1993; 59(2): 315–322. [crossref]

9.       Sheets EE, Tsibris JC, Cook NI, Virgin SD, DeMay RM, Spellacy WN. In vitro binding of insulin and epidermal growth factor to human endometrium and endocervix. Am J Obstet Gynecol. 1985; 153(1): 60–65. [crossref]

10.    Mioni R, Chiarelli S, Xamin N, Zuliani L, Granzotto M, Mozzanega B, Maffei P, Martini C, Blandamura S, Sicolo N. Evidence for the presence of glucose transporter 4 in the endometriumand its regulation in polycystic ovary syndrome patients. J Clin Endocrinol Metab. 2004; 89(8): 4089–4096. [crossref]

11.    Zhai J, Liu C-x, Tian Z-r, Jiang Q-h, Sun Y-p. Effects of metformin on the expression ofGLUT4in endometrium of obese women with polycystic ovary syndrome. Biol Reproduc. 2012; 87(2): 307–314. [crossref]

12.    Carvajal R, Rosas C, Kohan K, Gabler F, Vantman D, Romero C, Vega M. Metformin augments the levels of molecules that regulate the expression of the insulin-dependent glucose transporterGLUT4 in the endometria of hyper insulinemic PCOS patients. Hum Reprod. 2013; 28(8): 2235–2244. [crossref]

13.    Hulchiy M, Nybacka A, Sahlin L, Hirschberg AL. Endometrial expression of estrogen receptors and the androgen receptorin women with polycystic ovary syndrome: a lifestyle intervention study. J Clin Endocrinol Metab. 2016; 101(2): 561–571. [crossref]

14.    Meyer MR, Clegg DJ, Prossnitz ER, Barton M. Obesity, insulin resistance and diabetes: sex differences and role of oestrogen receptors. Acta Physiol (OXF). 2011; 203(1): 259–69. [crossref]

15.    Quaynor SD, Stradtman EW, Kim HG, Shen Y, Chorich LP, Schreihofer DA, Layman LC. Delayed puberty and estrogen resistance in a woman with estrogen receptor alpha variant. N.Engl.J.Med. 2013; 369(2): 164–171. [crossref]

16.    Badawy Ahmed, Elnashar Abubaker. Treatment options for polycystic ovary syndrome. Int J Womens Health. 2011; 3: 25-35. [crossref]

17.    Choi SH, Shapiro H, Robinson GE, Irvine J, Neuman J, Rosen B, et al. Psychological side-effects of clomiphene citrate and human menopausal gonadotrophin.  J Psychosom Obstet Gynaecol. 2005; 26: 93-100. [PMID]

18.    Pari L, Murugan P. Effect of tetrahydrocurcumin on blood glucose, plasma insulin and hepatic key enzymes in streptozotocin induced diabetic rats. J Basic Clin Physiol Pharmacol. 2005; 16(4): 257-274. [PMID]

19.    Pari L, Murugan P. Antihyperlipidemic effect of curcumin and tetrahydrocurcumin in experimental type 2 diabetic rats. Ren Fail. 2007; 29(7): 881-889. [crossref]

20.    Aggarwal BB, Banerjee S, Bharadwaj U, Sung B, Shishodia S, Sethi G. Curcumin induces the degradation of cyclin E expression through ubiquitin-dependent pathway and up-regulates cyclin dependent kinase inhibitors p21 and p27 in multiple human tumorcell lines. Biochem Pharmacol. 2007; 73(7): 1024-1032. [crossref]

21.    Watson JL, Greenshields A, Hill R, Hilchie A, Lee PW, Giacomantonio CA, et al. Curcumin-induced apoptosis in ovarian carcinoma cells is p53-independent and involves p38 mitogen activated protein kinase activation and down regulation of Bcl-2and survivin expression and Aktsignalling. Mol Carcinog. 2010; 49(1): 13-24. [crossref]

22.    Kadasi A, V.Sirotkin A, Maruniakova N, Kolesarova A, Bulla J, Grossmann R. The effect of Curcumin on secretory activity, proliferation and apoptosis of the porcine ovarian granulose cells. JMBFS. 2012; 2(1): 349-357.

23.    Kavitha A, Narendra B, Sathish K, Veena K. Evaluation of effects of Commiphora wightii in dehydroepiandrosterone (DHEA) induced polycystic ovary syndrome (PCOS) in rats. Pharma Tutor. 2016; 4(1): 47–55.

24.    Miladpour B, Rasti M, Owji AA, Mostafavipour Z, Khoshdel Z, Noorafshan A, Zal F. Quercetin potentiates trans differentiation of bone marrow mesenchymal stem cells into the beta cellsin vitro. J Endocrinol Invest. 2017; 40(5): 513–521.  [crossref]

25.    Neisy A, Zal F, Seghatoleslam A, Alaee S. Amelioration by quercetin of insulin resistance and uterine GLUT4 and ERa gene expression in rats with polycystic ovary syndrome (PCOS). Reprod Fertil Dev. 2019; 31(2): 315-323. [crossref]

26.    Mesbahzadeh B, Garmsiri M, Jalalvand F, Shojaie L, Kakar MA. Oral administration of menthol could alleviate adverse effects of polycystic ovarian syndrome in blood biochemical parameters and antioxidant status in experimental Wister rats. GMJ Med. 2017; 1(1):9-14. [crossref]

27.    Diamanti-Kandarakis E, Argyrakopoulou G, Economou F, Kandaraki E, Koutsilieris M. Defects in insulin signaling pathways in ovarian steroidogenesis and other tissues in polycystic

28.    ovary syndrome (PCOS). J Steroid BiochemMol Biol. 2008; 109(3–5): 242–246. [crossref]

29.    Winkler G, Kiss S, Keszthelyi L, Sa´pi Z, Ory I, Salamon F, Kova´cs M, Vargha P, Szekeres O, Speer G. Expression of tumor necrosis factor (TNF)-alpha protein in the subcutaneous and visceral adipose tissue in correlation with adipocyte cell volume, serum TNF alpha, soluble serum TNF-receptor-2 concentrations and C-peptide level. Eur J Endocrinol. 2003; 149(2), 129–135. [crossref]

30.    Patel N, Huang C, Klip A. Cellular location of insulin triggered signals and implications for glucose uptake. Pflugers Arch. 2006; 451(4): 499–510. [crossref]

31.    Fornes R, Ormazabal P, Rosas C, Gabler F, Vantman D, Romero C, Vega M. Changes in the expression of insulin signaling pathway molecules in endometria from polycystic ovary syndrome women with or without hyper insulinemia. Mol Med. 2010; 16(3–4): 129. [crossref]

32.    Riant E, Waget A, Cogo H, Arnal JF, Burcelin R, Gourdy P. Estrogens protect against high-fat diet-induced insulin resistanceand glucose intolerance in mice. Endocrinol. 2009; 150(5): 2109–2117. [crossref]

33.    Moradi A, Bahrami M, Eslami G, Mohiti-Ardekani J. The Effect of Curcumin on GLUT4 gene expression as a diabetic resistance marker in C2C12 myoblast cells. Iran J Diabetes Obesity. 6(2): 98-105.