Exp Clin Endocrinol Diabetes 2014; 122(05): 261-267
DOI: 10.1055/s-0034-1372578
Mini-Review
© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York

Phosphatidylinositide-3 Kinase: A Newer Molecular Target in Metabolic and Hormonal Pathway of Polycystic Ovary Syndrome

K. N. Shah
1   Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India
,
S. S. Patel
1   Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India
› Author Affiliations
Further Information

Publication History

received 04 December 2013
first decision 05 February 2014

accepted 18 March 2014

Publication Date:
07 April 2014 (online)

Abstract

Polycystic ovary syndrome is characterized by hyperandrogenemia, hyperinsulinemia and/or abnormal ovulation, which are the 3 main consequences of polycystic ovary syndrome. The occurrence of polycystic ovary syndrome is higher and 1 out of 45 women gets affected by this disorder. The pathophysiology of polycystic ovary syndrome is very unique, and many hormonal and metabolic changes occur at molecular level. Polycystic ovary syndrome is a hormonal disorder that affects multiple organ systems within the body, which is caused by insensitivity to the hormone insulin. The target organs of insulin action are skeletal muscles, adipose tissue, fibroblasts where metabolic actions of insulin take place. In polycystic ovary syndrome condition, due to insulin resistance, the actions like glucose uptake and glycogen synthesis gets declined along with exhibiting steroidogenic effect in ovaries. The action of phophatidylinositide-3 kinase varies in different tissues. It plays major role in several kinases. The inhibition and activation of phophatidylinositide-3 kinase in different tissues results in differential outcomes. The inhibition of phophatidylinositide-3 kinase in ovary leads to decreased androgen synthesis and the activation affects the positive actions of insulin like glucose uptake. Targeting the hyperandrogenemia of polycystic ovary syndrome, we can get more ameliorating action in polycystic ovary syndrome because glucose uptake, which is mediated by phophatidylinositide-3 kinase activation, is not much altered during polycystic ovary syndrome as much as the androgen levels in polycystic ovary syndrome. Therefore, it is beneficial to control the androgen level. Thus, phophatidylinositide-3 kinase inhibition can be a promising target in the treatment of polycystic ovary syndrome.

 
  • References

  • 1 Baillargeon JP, Iuorno MJ, Nestler JE. Insulin sensitizers for polycystic ovary syndrome. Clin Obstet Gynecol 2003; 46: 325-340
  • 2 Teede H, Deeks A, Moran L. Polycystic ovary syndrome: a complex condition with psychological, reproductive and metabolic manifestations that impacts on health across the lifespan. BMC Med 2010; 8: 41-51
  • 3 Gordon JD, Rydfors J, Druzin M et al. Reproductive endocrinology. In: Gordon JD. (ed.) Obstetrics, Gynecology and Infertility, Handbook for clinicians. Virginia: ScrubHill Press; 2007: 492-506
  • 4 The Rotterdam ESHRE ASRM-sponsored PCOS Consensus Workshop Group . Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004; 81: 19-25
  • 5 Diamanti-Kandarakis E, Kandarakis H, Legro RS. The role of genes and environment in the etiology of PCOS. Endocrine 2006; 30: 19-26
  • 6 Strauss 3rd JF. Some new thoughts on the pathophysiology and genetics of polycystic ovary syndrome. Ann N Y Acad Sci 2003; 997: 42-48
  • 7 Amato P, Simpson JL. The genetics of polycystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol 2004; 18: 707-718
  • 8 O’Meara NM, Blackman JD, Ehrmann DA et al. Defects in beta-cell function in functional ovarian hyperandrogenism. J Clin Endocrinol Metab 1993; 76: 1241-1247
  • 9 Dunaif A, Xia J, Book CB et al. Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. A potential mechanism for insulin resistance in the polycystic ovary syndrome. J Clin Invest 1995; 96: 801-810
  • 10 Poretsky L, Smith D, Seibel M et al. Specific insulin binding sites in human ovary. J Clin Endocrinol Metab 1984; 59: 809-811
  • 11 Virkamäki A, Ueki K, Kahn CR. Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin resistance. J Clin Invest 1999; 103: 931-943
  • 12 Cheatham B, Kahn CR. Insulin action and the insulin signaling network. Endocr Rev 1995; 16: 117-142
  • 13 Cantrell DA. Phosphoinositide 3-kinase signalling pathways. J Cell Sci 2001; 114: 1439-1445
  • 14 Lawrence JCJ, Roach PJ. New insight into the role and mechanism of glycogen synthase activation by insulin. Diabetes 1997; 46: 541-547
  • 15 Saltiel AR. Diverse signaling pathways in the cellular actions of insulin. Am J Physiol 1996; 270: E375-E385
  • 16 White MF, Yenush L. The IRS-signaling system: a network of docking proteins that mediate insulin and cytokine action. Curr Top Microbiol Immunol 1998; 228: 179-208
  • 17 Vanhaesebroeck B, Leevers SJ, Ahmadi K et al. Synthesis and function of 3-phosphorylated inositol lipids. Annu Rev Biochem 2001; 70: 535-602
  • 18 Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002; 296: 1655-1657
  • 19 Stephens LR, Eguinoa A, Erdjument-Bromage H et al. The Gbc sensitivity of a PI3K is dependent upon a tightly associated adaptor, p101. Cell 1997; 89: 105-114
  • 20 Dowler S, Currie RA, Campbell DG et al. Identification of pleckstrin-homology-domain-containing proteins with novel phosphoinositide-binding specificities. Biochem J 2000; 351: 19-27
  • 21 Rohrschneider LR, Fuller JF, Wolf I et al. Structure, function and biology of SHIP proteins. Genes Dev 2000; 14: 505-520
  • 22 Wishart MJ, Dixon JE. PTEN and myotubularin phosphatases: from 3-phosphoinositide dephosphorylation to disease. Trends Cell Biol 2002; 12: 579-585
  • 23 Dunaif A, Segal KR, Shelley DR et al. Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome. Diabetes 1992; 41: 1257-1266
  • 24 Ciaraldi TP, El-Roeiy A, Madar Z et al. Cellular mechanisms of insulin resistance in polycystic ovarian syndrome. J Clin Endocrinol Metab 1992; 75: 577-583
  • 25 Ciaraldi TP, Morales AJ, Hickman MG et al. Cellular insulin resistance in adipocytes from obese polycystic ovary syndrome subjects involves adenosine modulation of insulin sensitivity. J Clin Endocrinol Metab 1997; 82: 1421-1425
  • 26 Lystedt E, Westergren H, Brynhildsen J et al. Subcutaneous adipocytes from obese hyperinsulinemic women with polycystic ovary syndrome exhibit normal insulin sensitivity but reduced maximal insulin responsiveness. Eur J Endocrinol 2005; 153: 831-835
  • 27 Rosenbaum D, Haber R, Dunaif A. Insulin resistance in polycystic ovary syndrome: decreased expression of GLUT4 glucose transporters in adipocytes. Am J Physiol 2003; 264: E197-E202
  • 28 Diamanti-Kandarakis E, Papavasiliou A. Molecular mechanisms of insulin resistance in polycystic ovary syndrome. Trends Mol Med 2006; 12: 324-332
  • 29 Goodarzi MO, Antoine HJ, Pall M et al. Preliminary evidence of glycogen synthase kinase 3 beta as a genetic determinant of the polycystic ovary syndrome. Fertil Steril 2007; 87: 1473-1476
  • 30 Cortón M, Botella-Carretero JI, Bengurıa A et al. Differential gene expression profile in omental adipose tissue in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2007; 92: 328-337
  • 31 Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev 1997; 18: 774-800
  • 32 Taylor SI, Cama A, Accili D et al. Mutations in the Insulin Receptor Gene. Endocr Rev 1992; 13: 566-595
  • 33 Hotamisligil GS, Peraldi P, Budavari A et al. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science 1996; 271: 665-668
  • 34 Maddux BA, Sbraccia P, Kumakura S et al. Membrane glycoprotein PC-1 and insulin resistance in non-insulin-dependent diabetes mellitus. Nature 1995; 373: 448-451
  • 35 Griffin ME, Marcucci MJ, Cline GW et al. Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes 1999; 48: 1270-1274
  • 36 Book CB, Dunaif A. Selective insulin resistance in the polycystic ovary syndrome. J Clin Endocrinol Metab 1999; 84: 3110-3116
  • 37 DeFronzo RA, Jacot E, Jequier E et al. The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes 1981; 30: 1000-1007
  • 38 Corbould A, Kim YB, Youngren JF. Insulin resistance in the skeletal muscle of women with PCOS involves intrinsic and acquired defects in insulin signaling. Am J Physiol Endocrinol Metab 2005; 288: E1047-E1054
  • 39 Holman A, Svedberg J, Jennische E et al. Effects of testosterone on muscle insulin sensitivity and morphology in female rats. Am J Physiol 1990; 259: E555-E560
  • 40 Manneras L, Cajander S, Holman A et al. A new rat model exhibiting both ovarian and metabolic characteristics of polycystic ovary syndrome. Endocrinology 2007; 148: 3781-3791
  • 41 Dunaif A, Wu X, Lee A et al. Defects in insulin receptor signaling in vivo in the polycystic ovary syndrome (PCOS). Am J Physiol Endocrinol Metab 2001; 281: E392-E399
  • 42 Nestler JE, Jakubowicz DJ, de Vargas AF et al. Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system. J Clin Endocrinol Metab 1998; 83: 2001-2005
  • 43 Willis D, Franks S. Insulin action in human granulosa cells from normal and polycystic ovaries is mediated by the insulin receptor and not the type-I insulin-like growth factor receptor. J Clin Endocrinol Metab 1995; 80: 3788-3790
  • 44 Cara JR, Rosenfield RL. Insulin-like growth factor I and insulin potentiate luteinizing hormone induced androgen synthesis by rat ovarian thecal interstitial cells. Endocrinology 1988; 123: 733-739
  • 45 Buyalos RP. Insulin-like growth factor binding proteins in disorders of androgen excess. Sem Reprod Endocrinol 1994; 12: 21-25
  • 46 Romero G, Garmey JC, Veldhuis JD. The involvement of inositol phosphoglycan mediators in the modulation of steroidogenesis by insulin and insulin-like growth factor-I. Endocrinology 1993; 132: 1561-1568
  • 47 Nestler JE. Role of obesity and insulin in the development of anovulation. In: Filicori M, Flamigni C. (ed.) Ovulation Induction: Basic Science and Clinical Advances. Amsterdam: Elsevier; 1994: 103-114
  • 48 Unger JW, Livingston JN, Moss AM. Insulin receptors in the central nervous system: localization, signalling mechanisms and functional aspects. Prog Neurobiol 1991; 36: 343-362
  • 49 Burger CW, Korsen T, Van Kessel H. Pulsatile luteinizing hormone patterns in the follicular phase of the menstrual cycle, polycystic ovarian disease (PCOD) and non-PCOD secondary amenorrhea. J Clin Endocrinol Metab 1985; 61: 1126-1132
  • 50 Diamanti-Kandarakis E, Papavassiliou AG. Molecular mechanisms of insulin resistance in polycystic ovary syndrome. Trends Mol Med 2006; 12: 324-332
  • 51 Munir I, Yen H, Geller DH et al. Insulin augmentation of 17a-hydroxylase activity is mediated by phosphatidyl inositol 3-kinase but not extracellular signal-regulated kinase-1/2 in human ovarian theca cells. Endocrinology 2004; 145: 175-183
  • 52 Nelson-Degrave VL, Wickenheisser JK, Hendricks KL et al. Alterations in mitogen-activated protein kinase kinase and extracellular regulated kinase signaling in theca cells contribute to excessive androgen production in polycystic ovary syndrome. Mol Endocrinol 2005; 19: 379-390
  • 53 Poretsky L, Seto-Young D, Shrestha A et al. Phosphatidyl-inositol-3 kinase-independent insulin action pathway(s) in the human ovary. J Clin Endocrinol Metab 2001; 86: 3115-3119
  • 54 Seto-Young D, Zajac J, Liu HC et al. The role of mitogen-activated protein kinase in insulin and insulin-like growth factor I (IGF-I) signaling cascades for progesterone and IGF-binding protein-1 production in human granulosa cells. J Clin Endocrinol Metab 2003; 88: 3385-3391
  • 55 Flores JA, Garmey JC, Nestler JE et al. Sites of inhibition of steroidogenesis by activation of protein kinase-C in swine ovarian (granulosa) cells. Endocrinology 1993; 132: 1983-1990
  • 56 Greisen S, Ledet T, Ovesen P. Effects of androstenedione, insulin and luteinizing hormone on steroidogenesis in human granulosa luteal cells. Hum Reprod 2001; 16: 2061-2065
  • 57 Sekar N, Lavoie HA, Veldhuis JD. Concerted regulation of steroidogenic acute regulatory gene expression by luteinizing hormone and insulin (or insulin-like growth factor I in primary cultures of porcine granulosa luteal cells. Endocrinology 2000; 141: 3983-3992
  • 58 Erickson GF, Magoffin DA, Cragun JR et al. The effects of insulin and insulin-like growth factors-I and -II on estradiol production by granulosa cells of polycystic ovaries. J Clin Endocrinol Metab 1990; 70: 894-902
  • 59 Bals-Pratsch M, Grober B, Seifert B et al. Early Onset and High Prevalence of Gestational Diabetes in PCOS and Insulin Resistant Women Before and After Assisted Reproduction. Exp Clin Endocrinol Diabetes 2011; 119: 338-342
  • 60 Moeini A, Mansoori M, Eslami B et al. Evaluating Endometrial Hyperplasia in Infertile Women with Polycystic Ovarian Syndrome in Roointan-Arash Hospital. J Reprod Infertil 2008; 8: 330-336
  • 61 Temple KA, Watson S, Whitmore H et al. Obstructive Sleep Apnea in Women with Polycystic Ovary Syndrome Increases the Risk of Abnormal Glucose Tolerance. Endocr Rev 2012; 33: 47-54
  • 62 Hachmi BSL, Hachmi BSS, Bouzid C et al. Hypertension in polycystic ovary syndrome. Arch Mal Coeur Vaiss 2006; 99: 687-690
  • 63 Carmina E, Lobo RA. Polycystic Ovary Syndrome (PCOS): Arguably the Most Common Endocrinopathy Is Associated with Significant Morbidity in Women. J Clin Endocrinol Metab 1999; 84: 1897-1899
  • 64 Wang JX, Davies MJ, Norman RJ. Polycystic ovarian syndrome and the risk of spontaneous abortion following assisted reproductive technology treatment. Hum Reprod 2001; 16: 2606-2609