Skip to main content

Advertisement

SpringerLink
Log in

Role of the PI3K-Akt Signaling Pathway in the Pathogenesis of Polycystic Ovary Syndrome

  • Review
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

This review aimed to focus on the recent progress of the understanding of the role of phosphatidylinositol 3-kinase (PI3K) in polycystic ovary syndrome (PCOS). In recent years, it has been increasingly recognized that PI3K plays an important role in PCOS whose pathogenesis is unclear. However, research continues into revealing the details of how PI3Ks are involved in developing PCOS. Previous studies have shown that activation of the PI3K-protein kinase B (Akt) signaling pathway has important effects on insulin resistance and endometrial cancer. Knowledge of the action of PI3K in PCOS might provide valuable information to further validate the pathogenesis of PCOS and suggest new methods of treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Fauser BC, Tarlatzis BC, Rebar RW, et al. Consensus on women’s health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Fertil Steril. 2012;97(1):28–38.e25.

    Article  PubMed  Google Scholar 

  2. Li R, Zhang Q, Yang D, et al. Prevalence of polycystic ovary syndrome in women in China: a large community-based study. Hum Reprod. 2013;28(9):2562–2569.

    Article  PubMed  Google Scholar 

  3. Mao C, Zhou J, Yang Z, et al. KRAS, BRAF and PIK3CA mutations and the loss of PTEN expression in Chinese patients with colorectal cancer. PLoS One. 2012;7(5): e36653.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Sansal I, Sellers WR. The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol. 2004;22(14):2954–2963.

    Article  CAS  PubMed  Google Scholar 

  5. Wei X, Lu QJ, Sun HX, Qi YF, Wang JO, Cao CC. Expression and significance of p-AKT, p-GSK3beta and beta-catenin in epithelial carcinoma of ovary. Zhonghua Bing Li Xue Za Zhi. 2012;41(2):86–90.

    CAS  PubMed  Google Scholar 

  6. Zhang H, Xu W, Li B, et al. Curcumin promotes cell cycle arrest and inhibits survival of human renal cancer cells by negative modulation of the PI3K/AKT signaling pathway. Cell Biochem Biophys. 2015;73(3):681–686.

    Article  CAS  PubMed  Google Scholar 

  7. Wang T, Gong X, Jiang R, Li H, Du W, Kuang G. Ferulic acid inhibits proliferation and promotes apoptosis via blockage of PI3K/Akt pathway in osteosarcoma cell. Am J Transl Res. 2016;8(2):968–980.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Villavicencio A, Goyeneche A, Telleria C, et al. Involvement of Akt, Ras and cell cycle regulators in the potential development of endometrial hyperplasia in women with polycystic ovarian syndrome. Gynecol Oncol. 2009;115(1):102–107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Rea S, James DE. Moving GLUT4: the biogenesis and trafficking of GLUT4 storage vesicles. Diabetes. 1997;46(11):1667–1677.

    Article  CAS  PubMed  Google Scholar 

  10. Moore AM, Prescott M, Marshall CJ, Yip SH, Campbell RE. Enhancement of a robust arcuate GABAergic input to gonadotropin-releasing hormone neurons in a model of polycystic ovarian syndrome. Proc Natl Acad Sci USA. 2015;112(2):596–601.

    Article  CAS  PubMed  Google Scholar 

  11. Pielecka J, Quaynor SD, Moenter SM. Androgens increase gonadotropin-releasing hormone neuron firing activity in females and interfere with progesterone negative feedback. Endocrinology. 2006;147(3):1474–1479.

    Article  CAS  PubMed  Google Scholar 

  12. Sullivan SD, Moenter SM. GABAergic integration of progesterone and androgen feedback to gonadotropin-releasing hormone neurons. Biol Reprod. 2005;72(1):33–41.

    Article  CAS  PubMed  Google Scholar 

  13. Apter D, Butzow T, Laughlin GA, Yen SS. Accelerated 24-hour luteinizing hormone pulsatile activity in adolescent girls with ovarian hyperandrogenism: relevance to the developmental phase of polycystic ovarian syndrome. J Clin Endocrinol Metab. 1994;79(1):119–125.

    CAS  PubMed  Google Scholar 

  14. Priyadarshani A, Chuttani K, Mittal G, Bhatnagar A. Radiolabeling, biodistribution and gamma scintigraphy of noscapine hydrochloride in normal and polycystic ovary induced rats. J Ovarian Res. 2010;3:10.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Lasagna L, Owens AH Jr, Shnider BI, Gold GL. Toxicity after large doses of noscapine. Cancer Chemother Rep. 1961;15:33–34.

    CAS  PubMed  Google Scholar 

  16. Mourey RJ, Dawson TM, Barrow RK, Enna AE, Snyder SH. [3H]noscapine binding sites in brain: relationship to indoleamines and the phosphoinositide and adenylyl cyclase messenger systems. Mol Pharmacol. 1992;42(4):619–626.

    CAS  PubMed  Google Scholar 

  17. Mooraki A, Jenabi A, Jabbari M, et al. Noscapine suppresses angiotensin converting enzyme inhibitors-induced cough. Nephrology (Carlton). 2005;10(4):348–350.

    Article  CAS  Google Scholar 

  18. Karlsson MO, Dahlstrom B, Eckernas SA, Johansson M, Alm AT. Pharmacokinetics of oral noscapine. Eur J Clin Pharmacol. 1990;39(3):275–279.

    Article  CAS  PubMed  Google Scholar 

  19. Doi SA, Towers PA, Scott CJ, Al-Shoumer KA. PCOS: an ovarian disorder that leads to dysregulation in the hypothalamic-pituitary-adrenal axis? Eur J Obstet Gynecol Reprod Biol. 2005;118(1):4–16.

    Article  CAS  PubMed  Google Scholar 

  20. Dafopoulos K, Venetis C, Pournaras S, Kallitsaris A, Messinis IE. Ovarian control of pituitary sensitivity of luteinizing hormone secretion to gonadotropin-releasing hormone in women with the polycystic ovary syndrome. Fertil Steril. 2009;92(4):1378–1380.

    Article  CAS  PubMed  Google Scholar 

  21. Rojas J, Chavez M, Olivar L, et al. Polycystic ovary syndrome, insulin resistance, and obesity: navigating the pathophysiologic labyrinth. Int J Reprod Med. 2014;2014:719050.

    PubMed  PubMed Central  Google Scholar 

  22. Sekar N, Garmey JC, Veldhuis JD. Mechanisms underlying the steroidogenic synergy of insulin and luteinizing hormone in porcine granulosa cells: joint amplification of pivotal sterol-regulatory genes encoding the low-density lipoprotein (LDL) receptor, steroidogenic acute regulatory (stAR) protein and cytochrome P450 side-chain cleavage (P450scc) enzyme. Mol Cell Endocrinol. 2000;159(1-2):25–35.

    Article  CAS  PubMed  Google Scholar 

  23. Morley P, Calaresu FR, Barbe GJ, Armstrong DT. Insulin enhances luteinizing hormone-stimulated steroidogenesis by porcine theca cells. Biol Reprod. 1989;40(4):735–743.

    Article  CAS  PubMed  Google Scholar 

  24. Rice S, Christoforidis N, Gadd C, et al. Impaired insulin-dependent glucose metabolism in granulosa-lutein cells from anovulatory women with polycystic ovaries. Hum Reprod. 2005;20(2):373–381.

    Article  CAS  PubMed  Google Scholar 

  25. Hendrix AO, Selgrade JF. Bifurcation analysis of a menstrual cycle model reveals multiple mechanisms linking testosterone and classical PCOS. J Theor Biol. 2014;361:31–40.

    Article  CAS  PubMed  Google Scholar 

  26. Baculescu N. The role of androgen receptor activity mediated by the CAG repeat polymorphism in the pathogenesis of PCOS. J Med Life. 2013;6(1):18–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Dicker A, Kaaman M, van Harmelen V, Astrom G, Blanc KL, Ryden M. Differential function of the alpha2A-adrenoceptor and Phosphodiesterase-3B in human adipocytes of different origin. Int J Obes (Lond). 2005;29(12):1413–1421.

    Article  CAS  Google Scholar 

  28. Blank SK, McCartney CR, Marshall JC. The origins and sequelae of abnormal neuroendocrine function in polycystic ovary syndrome. Hum Reprod Update. 2006;12(4):351–361.

    Article  CAS  PubMed  Google Scholar 

  29. Eagleson CA, Gingrich MB, Pastor CL, et al. Polycystic ovarian syndrome: evidence that flutamide restores sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by estradiol and progesterone. J Clin Endocrinol Metab. 2000;85(11):4047–4052.

    CAS  PubMed  Google Scholar 

  30. Comninos AN, Jayasena CN, Dhillo WS. The relationship between gut and adipose hormones, and reproduction. Hum Reprod Update. 2014;20(2):153–174.

    Article  CAS  PubMed  Google Scholar 

  31. Ackerman KE, Slusarz K, Guereca G, et al. Higher ghrelin and lower leptin secretion are associated with lower LH secretion in young amenorrheic athletes compared with eumenorrheic athletes and controls. Am J Physiol Endocrinol Metab. 2012;302(7): E800–806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Tersigni C, Di Nicuolo F, D’Ippolito S, Veglia M, Castellucci M, Di Simone N. Adipokines: new emerging roles in fertility and reproduction. Obstet Gynecol Surv. 2011;66(1):47–63.

    Article  PubMed  Google Scholar 

  33. Moreno M, Ordonez P, Alonso A, Diaz F, Tolivia J, Gonzalez C. Chronic 17beta-estradiol treatment improves skeletal muscle insulin signaling pathway components in insulin resistance associated with aging. Age (Dordr). 2010;32(1):1–13.

    Article  CAS  Google Scholar 

  34. Zhang J, Yang Y, Zhang Z, et al. Gankyrin plays an essential role in estrogen-driven and GPR30-mediated endometrial carcinoma cell proliferation via the PTEN/PI3K/AKT signaling pathway. Cancer Lett. 2013;339(2):279–287.

    Article  CAS  PubMed  Google Scholar 

  35. Song L, Li D, Gu Y, et al. MicroRNA-126 targeting PIK3R2 inhibits NSCLC A549 cell proliferation, migration, and invasion by regulation of PTEN/PI3K/AKT pathway. Clin Lung Cancer. 2016;17(5):e65–e75.

    Article  CAS  PubMed  Google Scholar 

  36. Alayev A, Salamon RS, Schwartz NS, Berman AY, Weiner SL, Holz MK. Combination of rapamycin and resveratrol for treatment of bladder cancer. J Cell Physiol. 2017;232(2):436–446

    Article  CAS  PubMed  Google Scholar 

  37. Zhang J, Yu XH, Yan YG, Wang C, Wang WJ. PI3K/Akt signaling in osteosarcoma. Clin Chim Acta. 2015;444:182–192.

    Article  CAS  PubMed  Google Scholar 

  38. Gao YF, Zhang MN, Wang TX, Wu TC, Ai RD, Zhang ZS. Hypoglycemic effect of D-chiro-inositol in type 2 diabetes mellitus rats through the PI3K/Akt signaling pathway. Mol Cell Endocrinol. 2016;433:26–34.

    Article  CAS  PubMed  Google Scholar 

  39. Di Sarra D, Tosi F, Bonin C, et al. Metabolic inflexibility is a feature of women with polycystic ovary syndrome and is associated with both insulin resistance and hyperandrogenism. J Clin Endocrinol Metab. 2013;98(6):2581–2588.

    Article  PubMed  CAS  Google Scholar 

  40. Zhang HY, Zhangm YF, Han YK, Xue FY, Zhao XH, Zhang XL. Activation and significance of the PI3K/Akt pathway in endometrium with polycystic ovary syndrome patients. Chinese J Obstetr Gynecol. 2012;47(1):19–23.

    CAS  Google Scholar 

  41. Long M, Zhou J, Li D, Zheng L, Xu Z, Zhou S. Long-term over-expression of neuropeptide Y in hypothalamic paraventricular nucleus contributes to adipose tissue insulin resistance partly via the Y5 receptor. PLoS One. 2015;10(5): e0126714.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Guan X. The CNS glucagon-like peptide-2 receptor in the control of energy balance and glucose homeostasis. Am J Physiol Regul Integr Comp Physiol. 2014;307(6): R585–R596.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Joao AL, Reis F, Fernandes R. The incretin system ABCs in obesity and diabetes-novel therapeutic strategies for weight loss and beyond. Obes Rev. 2016;17(7):553–572.

    Article  CAS  PubMed  Google Scholar 

  44. Owolabi BO, Ojo OO, Srinivasan DK, Conlon JM, Flatt PR, Abdel-Wahab YH. Glucoregulatory, endocrine and morphological effects of [P5K]hymenochirin-1B in mice with diet-induced glucose intolerance and insulin resistance. Naunyn Schmiedebergs Arch Pharmacol. 2016;389(7):769–781.

    Article  CAS  PubMed  Google Scholar 

  45. Shi X, Zhou F, Li X, et al. Central GLP-2 enhances hepatic insulin sensitivity via activating PI3K signaling in POMC neurons. Cell Metab. 2013;18(1):86–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Højlund K. Metabolism and insulin signaling in common metabolic disorders and inherited insulin resistance. Dan Med J. 2014;61(7): B4890.

    PubMed  Google Scholar 

  47. Thauvin-Robinet C, Auclair M, Duplomb L, et al. PIK3R1 mutations cause syndromic insulin resistance with lipoatrophy. Am J Hum Genet. 2013;93(1):141–149.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Fruman DA, Mauvais-Jarvis F, Pollard DA, et al. Hypoglycaemia, liver necrosis and perinatal death in mice lacking all isoforms of phosphoinositide 3-kinase p85 alpha. Nat Genet. 2000;26(3):379–382.

    Article  CAS  PubMed  Google Scholar 

  49. Zhang K, Li L, Qi Y, et al. Hepatic suppression of Foxo1 and Foxo3 causes hypoglycemia and hyperlipidemia in mice. Endocrinology. 2012;153(2):631–646.

    Article  CAS  PubMed  Google Scholar 

  50. Braccini L, Ciraolo E, Campa CC, et al. PI3K-C2gamma is a Rab5 effector selectively controlling endosomal Akt2 activation downstream of insulin signalling. Nat Commun. 2015;6:7400.

    Article  CAS  PubMed  Google Scholar 

  51. Yang M, Ren Y, Lin Z, et al. Kruppel-like factor 14 increases insulin sensitivity through activation of PI3K/Akt signal pathway. Cell Signal. 2015;27(11):2201–2208.

    Article  CAS  PubMed  Google Scholar 

  52. Wang L, Zhang N, Pan HP, Wang Z, Cao ZY. MiR-499-5p Contributes to Hepatic Insulin Resistance by Suppressing PTEN. Cell Physiol Biochem. 2015;36(6):2357–2365.

    Article  CAS  PubMed  Google Scholar 

  53. Sharma BR, Kim HJ, Rhyu DY. Caulerpa lentillifera extract ameliorates insulin resistance and regulates glucose metabolism in C57BL/KsJ-db/db mice via PI3K/AKT signaling pathway in myocytes. J Transl Med. 2015;13:62.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Gandhi GR, Jothi G, Antony PJ, et al. Gallic acid attenuates high-fat diet fed-streptozotocin-induced insulin resistance via partial agonism of PPARgamma in experimental type 2 diabetic rats and enhances glucose uptake through translocation and activation of GLUT4 in PI3K/p-Akt signaling pathway. Eur J Pharmacol. 2014;745:201–216.

    Article  CAS  PubMed  Google Scholar 

  55. Li S, Chen H, Wang J, Wang X, Hu B, Lv F. Involvement of the PI3K/Akt signal pathway in the hypoglycemic effects of tea polysaccharides on diabetic mice. Int J Biol Macromol. 2015;81:967–974.

    Article  CAS  PubMed  Google Scholar 

  56. Jiang L, Huang J, Chen Y, et al. Identification of several circulating microRNAs from a genome-wide circulating microRNA expression profile as potential biomarkers for impaired glucose metabolism in polycystic ovarian syndrome. Endocrine. 2016;53(1):280–290.

    Article  CAS  PubMed  Google Scholar 

  57. Rivero R, Garin CA, Ormazabal P, et al. Protein expression of PKCZ (Protein Kinase C Zeta), Munc18c, and Syntaxin-4 in the insulin pathway in endometria of patients with polycystic ovary syndrome (PCOS). Reprod Biol Endocrinol. 2012;10:17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ormazabal P, Romero C, Gabler F, Quest AF, Vega M. Decreased phosphorylation of Y(1)(4)caveolin-1 in endometrial tissue of polycystic ovary syndrome patients may be related with an insulin resistant state in this tissue. Horm Metab Res. 2013;45(4):291–296.

    CAS  PubMed  Google Scholar 

  59. Carvajal R, Rosas C, Kohan K, et al. Metformin augments the levels of molecules that regulate the expression of the insulin-dependent glucose transporter GLUT4 in the endometria of hyperinsulinemic PCOS patients. Hum Reprod. 2013;28(8):2235–2244.

    Article  CAS  PubMed  Google Scholar 

  60. Fornes R, Ormazabal P, Rosas C, et al. Changes in the expression of insulin signaling pathway molecules in endometria from polycystic ovary syndrome women with or without hyperinsulinemia. Mol Med. 2010;16(3-4):129–136.

    Article  CAS  PubMed  Google Scholar 

  61. Crosbie EJ, Roberts C, Qian W, Swart AM, Kitchener HC, Renehan AG. Body mass index does not influence post-treatment survival in early stage endometrial cancer: results from the MRC ASTEC trial. Eur J Cancer. 2012;48(6):853–864.

    Article  PubMed  Google Scholar 

  62. Jamilian M, Razavi M, Fakhrie Kashan Z, Ghandi Y, Bagherian T, Asemi Z. Metabolic response to selenium supplementation in women with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial. Clin Endocrinol (Oxf). 2015;82(6):885–891.

    Article  CAS  Google Scholar 

  63. Asemi Z, Karamali M, Esmaillzadeh A. Metabolic response to folate supplementation in overweight women with polycystic ovary syndrome: a randomized double-blind placebo-controlled clinical trial. Mol Nutr Food Res. 2014;58(7):1465–1473.

    Article  CAS  PubMed  Google Scholar 

  64. Echiburu B, Crisosto N, Maliqueo M, et al. Metabolic profile in women with polycystic ovary syndrome across adult life. Metabolism. 2016;65(5):776–782.

    Article  CAS  PubMed  Google Scholar 

  65. Choi SM, Tucker DF, Gross DN, et al. Insulin regulates adipocyte lipolysis via an Akt-independent signaling pathway. Mol Cell Biol. 2010;30(21):5009–5020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Maiuri T, Ho J, Stambolic V. Regulation of adipocyte differentiation by distinct subcellular pools of protein kinase B (PKB/Akt). J Biol Chem. 2010;285(20):15038–15047.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Chijiwa T, Mishima A, Hagiwara M, et al. Inhibition of forskolin-induced neurite outgrowth and protein phosphorylation by a newly synthesized selective inhibitor of cyclic AMP-dependent protein kinase, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89), of PC12D pheochromocytoma cells. J Biol Chem. 1990;265(9):5267–5272.

    CAS  PubMed  Google Scholar 

  68. Kato Y, Ozaki N, Yamada T, Miura Y, Oiso Y. H-89 potentiates adipogenesis in 3T3-L1 cells by activating insulin signaling independently of protein kinase A. Life Sci. 2007;80(5):476–483.

    Article  CAS  PubMed  Google Scholar 

  69. Wang S, Xu Q, Shu G, et al. N-Oleoyl glycine, a lipoamino acid, stimulates adipogenesis associated with activation of CB1 receptor and Akt signaling pathway in 3T3-L1 adipocyte. Biochem Biophys Res Commun. 2015;466(3):438–443.

    Article  CAS  PubMed  Google Scholar 

  70. Aubin D, Gagnon A, Sorisky A. Phosphoinositide 3-kinase is required for human adipocyte differentiation in culture. Int J Obes (Lond). 2005;29(8):1006–1009.

    Article  CAS  Google Scholar 

  71. Qin JH, Ma JZ, Yang XW, et al. A triterpenoid inhibited hormone-induced adipocyte differentiation and alleviated dexamethasone-induced insulin resistance in 3T3-L1 adipocytes. Nat Prod Bioprospect. 2015;5(3):159–166.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Li L, Mo H, Zhang J, Zhou Y, Peng X, Luo X. The role of heat shock protein 90B1 in patients with polycystic ovary syndrome. PLoS One. 2016;11(4): e0152837.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Wu XK, Zhou SY, Liu JX, et al. Selective ovary resistance to insulin signaling in women with polycystic ovary syndrome. Fertil Steril. 2003;80(4):954–965.

    Article  PubMed  Google Scholar 

  74. Abramovich D, Irusta G, Parborell F, Tesone M. Intrabursal injection of vascular endothelial growth factor trap in eCG-treated prepubertal rats inhibits proliferation and increases apoptosis of follicular cells involving the PI3K/AKT signaling pathway. Fertil Steril. 2010;93(5):1369–1377.

    Article  CAS  PubMed  Google Scholar 

  75. Mani AM, Fenwick MA, Cheng Z, Sharma MK, Singh D, Wathes DC. IGF1 induces up-regulation of steroidogenic and apoptotic regulatory genes via activation of phosphatidylinositol-dependent kinase/AKT in bovine granulosa cells. Reproduction. 2010;139(1):139–151.

    Article  CAS  PubMed  Google Scholar 

  76. Restuccia DF, Hynx D, Hemmings BA. Loss of PKBbeta/Akt2 predisposes mice to ovarian cyst formation and increases the severity of polycystic ovary formation in vivo. Dis Model Mech. 2012;5(3):403–411.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Li Q, He H, Zhang YL, et al. Phosphoinositide 3-kinase p110delta mediates estrogen- and FSH-stimulated ovarian follicle growth. Mol Endocrinol. 2013;27(9):1468–1482.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Adhikari D, Zheng W, Shen Y, et al. Tsc/mTORC1 signaling in oocytes governs the quiescence and activation of primordial follicles. Hum Mol Genet. 2010;19(3):397–410.

    Article  CAS  PubMed  Google Scholar 

  79. Sun X, Su Y, He Y, et al. New strategy for in vitro activation of primordial follicles with mTOR and PI3K stimulators. Cell Cycle. 2015;14(5):721–731.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Goto M, Iwase A, Ando H, Kurotsuchi S, Harata T, Kikkawa F. PTEN and Akt expression during growth of human ovarian follicles. J Assist Reprod Genet. 2007;24(11):541–546.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Williams SA, Blache D, Martin GB, Foot R, Blackberry MA, Scaramuzzi RJ. Effect of nutritional supplementation on quantities of glucose transporters 1 and 4 in sheep granulosa and theca cells. Reproduction. 2001;122(6):947–956.

    Article  CAS  PubMed  Google Scholar 

  82. Nishimoto H, Matsutani R, Yamamoto S, et al. Gene expression of glucose transporter (GLUT) 1, 3 and 4 in bovine follicle and corpus luteum. J Endocrinol. 2006;188(1):111–119.

    Article  CAS  PubMed  Google Scholar 

  83. Kim E, Seok HH, Lee SY, et al. Correlation between expression of glucose transporters in granulosa cells and oocyte quality in women with polycystic ovary syndrome. Endocrinol Metab (Seoul). 2014;29(1):40–47.

    Article  Google Scholar 

  84. McLaughlin M, Kinnell HL, Anderson RA, Telfer EE. Inhibition of phosphatase and tensin homologue (PTEN) in human ovary in vitro results in increased activation of primordial follicles but compromises development of growing follicles. Mol Hum Reprod. 2014;20(8):736–744.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Lim W, Jeong W, Song G. Delphinidin suppresses proliferation and migration of human ovarian clear cell carcinoma cells through blocking AKT and ERK1/2 MAPK signaling pathways. Mol Cell Endocrinol. 2016;422:172–181.

    Article  CAS  PubMed  Google Scholar 

  86. Hein GJ, Panzani CG, Rodriguez FM, et al. Impaired insulin signaling pathway in ovarian follicles of cows with cystic ovarian disease. Anim Reprod Sci. 2015;156:64–74.

    Article  CAS  PubMed  Google Scholar 

  87. Kim SY, Ebbert K, Cordeiro MH, et al. Cell autonomous phosphoinositide 3-kinase activation in oocytes disrupts normal ovarian function through promoting survival and overgrowth of ovarian follicles. Endocrinology. 2015;156(4):1464–1476.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Chen XY, Xia HX, Guan HY, Li B, Zhang W. Follicle loss and apoptosis in cyclophosphamide-treated mice: what’s the matter? Int J Mol Sci. 2016;17(6):1–8.

    CAS  Google Scholar 

  89. Qu F, Wang FF, Lu XE, et al. Altered aquaporin expression in women with polycystic ovary syndrome: hyperandrogenism in follicular fluid inhibits aquaporin-9 in granulosa cells through the phosphatidylinositol 3-kinase pathway. Hum Reprod. 2010;25(6):1441–1450.

    Article  CAS  PubMed  Google Scholar 

  90. Fukuda S, Orisaka M, Tajima K, Hattori K, Kotsuji F. Luteinizing hormone-induced Akt phosphorylation and androgen production are modulated by MAP Kinase in bovine theca cells. J Ovarian Res. 2009;2(1):17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Anjali G, Kaur S, Lakra R, et al. FSH stimulates IRS-2 expression in human granulosa cells through cAMP/SP1, an inoperative FSH action in PCOS patients. Cell Signal. 2015;27(12):2452–2466.

    Article  CAS  PubMed  Google Scholar 

  92. Hunzicker-Dunn ME, Lopez-Biladeau B, Law NC, Fiedler SE, Carr DW, Maizels ET. PKA and GAB2 play central roles in the FSH signaling pathway to PI3K and AKT in ovarian granulosa cells. Proc Natl Acad Sci USA. 2012;109(44):E2979–E2988.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Kaur S, Archer KJ, Devi MG, Kriplani A, Strauss JF, 3rd, Singh R. Differential gene expression in granulosa cells from polycystic ovary syndrome patients with and without insulin resistance: identification of susceptibility gene sets through network analysis. J Clin Endocrinol Metab. 2012;97(10):E2016–E2021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Ulloa-Aguirre A, Reiter E, Bousfield G, Dias JA, Huhtaniemi I. Constitutive activity in gonadotropin receptors. Adv Pharmacol. 2014;70:37–80.

    Article  CAS  PubMed  Google Scholar 

  95. Zhao Y, Zhang C, Huang Y, et al. Up-regulated expression of WNT5a increases inflammation and oxidative stress via PI3K/AKT/NF-kappaB signaling in the granulosa cells of PCOS patients. J Clin Endocrinol Metab. 2015;100(1):201–211.

    Article  CAS  PubMed  Google Scholar 

  96. Shah KN, Patel SS. Phosphatidylinositide 3-kinase inhibition: a new potential target for the treatment of polycystic ovarian syndrome. Pharm Biol. 2016;54(6):975–983.

    Article  CAS  PubMed  Google Scholar 

  97. Attia GR, Rainey WE, Carr BR. Metformin directly inhibits androgen production in human thecal cells. Fertil Steril. 2001;76(3):517–524.

    Article  CAS  PubMed  Google Scholar 

  98. Zhou HY, Huang SL. Current development of the second generation of mTOR inhibitors as anticancer agents. Chin J Cancer. 2012;31(1):8–18.

    PubMed  PubMed Central  Google Scholar 

  99. Zhang HY, Zhang YF, Han YK, Xue FX, Zhao XH, Zhang XL. Activation and significance of the PI3K/Akt pathway in endometrium with polycystic ovary syndrome patients. Zhonghua Fu Chan Ke Za Zhi. 2012;47(1):19–23.

    CAS  PubMed  Google Scholar 

  100. Matulonis U, Vergote I, Backes F, et al. Phase II study of the PI3K inhibitor pilaralisib (SAR245408; XL147) in patients with advanced or recurrent endometrial carcinoma. Gynecol Oncol. 2015;136(2):246–253.

    Article  CAS  PubMed  Google Scholar 

  101. Ferreira GD, Germeyer A, de Barros Machado A, et al. Metformin modulates PI3K and GLUT4 expression and Akt/PKB phosphorylation in human endometrial stromal cells after stimulation with androgen and insulin. Eur J Obstet Gynecol Reprod Biol. 2014;175:157–162.

    Article  CAS  PubMed  Google Scholar 

  102. Soares HP, Ni Y, Kisfalvi K, Sinnett-Smith J, Rozengurt E. Different patterns of Akt and ERK feedback activation in response to rapamycin, active-site mTOR inhibitors and metformin in pancreatic cancer cells. PLoS One. 2013;8(2): e57289.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Ning J, Clemmons DR. AMP-activated protein kinase inhibits IGF-I signaling and protein synthesis in vascular smooth muscle cells via stimulation of insulin receptor substrate 1 S794 and tuberous sclerosis 2 S1345 phosphorylation. Mol Endocrinol. 2010;24(6):1218–1229.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Xu H, Zhou Y, Liu Y, et al. Metformin improves hepatic IRS2/PI3K/Akt signaling in insulin-resistant rats of NASH and cirrhosis. J Endocrinol. 2016;229(2):133–144.

    Article  CAS  PubMed  Google Scholar 

  105. Uegaki K, Kanamori Y, Kigawa J, et al. PTEN-positive and phosphorylated-Akt-negative expression is a predictor of survival for patients with advanced endometrial carcinoma. Oncol Rep. 2005;14(2):389–392.

    CAS  PubMed  Google Scholar 

  106. Nerstedt A, Johansson A, Andersson CX, Cansby E, Smith U, Mahlapuu M. AMP-activated protein kinase inhibits IL-6-stimulated inflammatory response in human liver cells by suppressing phosphorylation of signal transducer and activator of transcription 3 (STAT3). Diabetologia. 2010;53(11):2406–2416.

    Article  CAS  PubMed  Google Scholar 

  107. Uchida S, Uchida H, Maruyama T, et al. Molecular analysis of a mutated FSH receptor detected in a patient with spontaneous ovarian hyperstimulation syndrome. PLoS One. 2013;8(9): e75478.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Guangdong Women and Children Hospital, Guangzhou Medical University, Guangzhou, 510010, China

    Tiantian Li MS, Wenfeng Chen MS, Li Li MD, Xiaofang Li MS & Ying Lu MS

  2. Laboratory of Chinese Medicine Quality Research, Macau University of Science and Technology, Macau, China

    Hui Mo MD, Li Li MD & Yao Xiao MS

  3. Guangzhou Family Planning Specialty Hospital, Guangzhou, China

    Jing Zhang MS

Authors
  1. Tiantian Li MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hui Mo MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wenfeng Chen MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Li Li MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yao Xiao MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jing Zhang MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiaofang Li MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ying Lu MS
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Li Li MD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, T., Mo, H., Chen, W. et al. Role of the PI3K-Akt Signaling Pathway in the Pathogenesis of Polycystic Ovary Syndrome. Reprod. Sci. 24, 646–655 (2017). https://doi.org/10.1177/1933719116667606

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719116667606

Keywords

Search

Navigation