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Serine Phosphorylation, Insulin Resistance, and the Regulation of Androgen Synthesis

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Insulin Resistance and Polycystic Ovarian Syndrome

Part of the book series: Contemporary Endocrinology ((COE))

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Abstract

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenemia and disordered gonadotropin secretion, often associated with insulin resistance. It is likely that PCOS is a group of distinct diseases with similar clinical phenotypes but different pathophysiological mechanisms, rather than being one disease caused by a single molecular defect. The serine phosphorylation hypothesis can potentially explain two major features of the syndrome: insulin resistance and hyperandrogenemia. Understanding the cell biology of androgen biosynthesis and insulin action will permit delineating the pathophysiologies of PCOS and may lead to more specific pharmacological therapy.

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References

  1. Knochenhauer ES, Key TJ, Kahsar-Miller M, Waggoner W, Boots LR, Azziz R. Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. J Clin Endocrinol Metab 1998;83:3078–3082.

    Article  CAS  PubMed  Google Scholar 

  2. Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO. The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab 2004;89:2745–2749.

    Article  CAS  PubMed  Google Scholar 

  3. Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev 1997;18:774–800.

    Article  CAS  PubMed  Google Scholar 

  4. Sam S, Dunaif A. Polycystic ovary syndrome: syndrome XX. Trends Endocrinol Metab 2003;14:365–370.

    Article  CAS  PubMed  Google Scholar 

  5. Venkatesan AM, Dunaif A, Corbould A. Insulin resistance in polycystic ovary syndrome: progress and paradoxes. Recent Prog Horm Res 2001;56:295–308.

    Article  CAS  PubMed  Google Scholar 

  6. Orio F Jr., Palomba S, Spinelli L, et al. The cardiovascular risk of young women with polycystic ovary syndrome: an observational, analytical, prospective case-control study. J Clin Endocrinol Metab 2004;89:3696–3701.

    Article  CAS  PubMed  Google Scholar 

  7. Legro RS. Polycystic ovary syndrome and cardiovascular disease: a premature association? Endocr Rev 2003;24:302–312.

    Article  PubMed  Google Scholar 

  8. Tsilchorozidou T, Overton C, Conway GS. The pathophysiology of polycystic ovary syndrome. Clin Endocrinol 2004;60:1–17.

    Article  CAS  Google Scholar 

  9. Zhang L-H, Rodriguez H, Ohno S, Miller WL. Serine phosphorylation of human P450c17 increases 17,20-lyase activity: implications for adrenarche and the polycystic ovary syndrome. Proc Natl Acad Sci USA 1995;92:10,619–10,623.

    Article  CAS  PubMed  Google Scholar 

  10. Miller WL. Molecular biology of steroid hormone synthesis. Endocr Rev 1988;9:295–318.

    Article  CAS  PubMed  Google Scholar 

  11. Izquierdo D, Foyouzi N, Kwintkiewicz J, Duleba AJ. Mevastatin inhibits ovarian theca-interstitial cell proliferation and steroidogenesis. Fertil Steril 2004;82 Suppl 3:1193–1197.

    Article  CAS  PubMed  Google Scholar 

  12. Miller WL, Strauss JF 3rd. Molecular pathology and mechanism of action of the steroidogenic acute regulatory protein, StAR. J Steroid Biochem Mol Biol 1999;69:131–141.

    Article  CAS  PubMed  Google Scholar 

  13. Bose HS, Sugawara T, Strauss JF 3rd, Miller WL. The pathophysiology and genetic of congenital lipoid adrenal hyperplasia. International congenital lipoid adrenal hyperplasia consortium. N Engl J Med 1996;335:1870–1878.

    Article  CAS  PubMed  Google Scholar 

  14. Bose HS, Pescovitz OH, Miller WL. Spontaneous feminization in a 46, XX female patient with congenital lipoid adrenal hyperplasia due to a homozygous frameshift mutation in the steroidogenic acute regulatory protein. J Clin Endocrinol Metab 1997;82:1511–1515.

    Article  CAS  PubMed  Google Scholar 

  15. Kahsar-Miller MD Conway-Myers BA, Boots LR, Azziz R. Steroidogenic acute regulatory protein (StAR) in the ovaries of healthy women and those with polycystic ovary syndrome. Am J Obstet Gynecol 2001;185:1381–1387.

    Article  CAS  PubMed  Google Scholar 

  16. Nakajin S, Shively JE, Yuan PM, Hall PF. Microsomal cytochrome P-450 from neonatal pig testis: two enzymatic activities (17α-hydroxylase and c17,20-lyase) associated with one protein. Biochemistry 1981;20:4037–4042.

    Article  CAS  PubMed  Google Scholar 

  17. Zuber MX, Simpson ER, Waterman MR. Expression of bovine 17α-hydroxylase cytochrome P-450 cDNA in nonsteroidogenic (COS 1) cells. Science 1986;234:1258–1261.

    Article  CAS  PubMed  Google Scholar 

  18. Wickenheisser JK, Quinn PG, Nelson VL, Legro RS, Stauss JF 3rd, McAllister JM. Differential activity of the cytochrome P450 17α-hydroxylase and steroidogenic acute regulatory protein gene promoters in normal and polycystic ovary syndrome theca cells. J Clin Endocrinol Metab 2000;85:2304–2311.

    Article  CAS  PubMed  Google Scholar 

  19. Jakimiuk AJ, Weitsman SR, Navab A, Magoffin DA. Luteinizing hormone receptor, steroidogenesis acute regulatory protein, and steroidogenic enzyme messenger ribonucleic acids are overexpressed in thecal and granulosa cells from polycystic ovaries. J Clin Endocrinol Metab 2001;86:1318–1323.

    Article  CAS  PubMed  Google Scholar 

  20. Miller WL, Auchus RJ, Geller DH. The regulation of 17,20 lyase activity. Steroids 1997;62:133–142.

    Article  CAS  PubMed  Google Scholar 

  21. Auchus RJ, Lee TC, Miller WL. Cytochrome b5 augments the 17,20-lyase activity of human P450c17 without direct electron transfer. J Biol Chem 1998;273:3158–3165.

    Article  CAS  PubMed  Google Scholar 

  22. Lachance Y, Luu-The V, Labrie C, et al. Characterization of human 3β-hydroxysteroid dehydrogenase/Δ5-Δ4-isomerase gene and its expression in mammalian cells. J Biol Chem 1990;265:20,469–20,475.

    CAS  PubMed  Google Scholar 

  23. Labrie F, Simard J Luu-The V, et al. Structure and tissue-specific expression of 3β-hydroxysteroid dehydrogenase/5-ene-4-ene isomerase genes in human and rat classical and peripheral steroidogenic tissues. J Steroid Biochem Mol Biol 1992;41:421–435.

    Article  CAS  PubMed  Google Scholar 

  24. Pang S. Congenital adrenal hyperplasia owing to 3β-hydroxysteroid dehydrogenase deficiency. Endocrinol Metab Clin North Am 2001;30:81–99.

    Article  CAS  PubMed  Google Scholar 

  25. Carbunaru G, Prasad P, Scoccia B, et al. The hormonal phenotype of nonclassic 3β-hydroxysteroid dehydrogenase (HSD3B) deficiency in hyperandrogenic females is associated with insulin-resistant polycystic ovary syndrome and is not a variant of inherited HSD3B2 deficiency. J Clin Endocrinol Metab 2004;89:783–794.

    Article  CAS  PubMed  Google Scholar 

  26. Simpson ER, Mahendroo MS, Means GD, et al. Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocr Rev 1994;15:342–355.

    CAS  PubMed  Google Scholar 

  27. Penning TM. Molecular endocrinology of hydroxysteroid dehydrogenases. Endocr Rev 1997;18:281–305.

    Article  CAS  PubMed  Google Scholar 

  28. Mahendroo MS, Russell DW. Male and female isoenzymes of steroid 5α-reductase. Rev Reprod 1999;4:179–183.

    Article  CAS  PubMed  Google Scholar 

  29. Tremblay Y, Ringler GE, Morel Y, et al. Regulation of the gene for estrogenic 17-ketosteroid reductase lying on chromosome 17cen→q25. J Biol Chem 1989;264:20,458–20,462.

    CAS  PubMed  Google Scholar 

  30. Miller WL. Androgen biosynthesis from cholesterol to DHEA. Mol Cell Endocrinol 2002;198:7–14.

    Article  CAS  PubMed  Google Scholar 

  31. Orentreich N, Brind JL, Rizer RL Vogelman JH. Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. J Clin Endocrinol Metab 1984;59:551–555.

    Article  CAS  PubMed  Google Scholar 

  32. Simpson ER, Mahendroo MS, Means GD, et al. Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocr Rev 1994;15:342–355.

    CAS  PubMed  Google Scholar 

  33. Geissler WM, Davis DL, Wu L, et al. Male pseudohermaphroditism caused by mutations of testicular 17β-hydroxysteroid dehydrogenase 3. Nat Genet 1994;7:34–39.

    Article  CAS  PubMed  Google Scholar 

  34. Dufort I, Rheault P, Huang XF, Soucy P, Luu-The V. Characteristics of a highly labile human type 5 17β-hydroxysteroid dehydrogenase. Endocrinology 1999;140:568–574.

    Article  CAS  PubMed  Google Scholar 

  35. Lachelin GC, Judd HL, Swanson SC, Hauck ME, Parker DC, Yen SS. Long term effects of nightly dexamethasone administration in patients with polycystic ovarian disease. J Clin Endocrinol Metab 1982;55:768–773.

    Article  CAS  PubMed  Google Scholar 

  36. Rittmaster RS, Thompson DL. Effect of leuprolide and dexamethasone on hair growth and hormone levels in hirsute women: the relative importance of the ovary and the adrenal in the pathogenesis of hirsutism. J Clin Endocrinol Metab 1990;70:1096–1102.

    Article  CAS  PubMed  Google Scholar 

  37. Hoffman DI, Klove K, Lobo RA. The prevalence, and significance of elevated dehydroepiandrosterone sulfate levels in anovulatory women. Fertil Steril 1984;42:76–81.

    CAS  PubMed  Google Scholar 

  38. Barnes RB, Rosenfield RL, Burstein S, Ehrmann DA. Pituitary-ovarian responses to nafarelin testing in the polycystic ovary syndrome. N Engl J Med 1989;320:559–565.

    Article  CAS  PubMed  Google Scholar 

  39. Ehrmann DA, Rosenfield RL, Barnes RB, Brigell DF, Sheikh Z. Detection of functional ovarian hyperandrogenism in women with androgen excess. N Engl J Med 1992;327:157–162.

    CAS  PubMed  Google Scholar 

  40. Heineman MJ, Thomas CM, Doesburg WH, Rolland R. Hormonal characteristics of women with clinical features of the polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol 1984;17:263–271.

    Article  CAS  PubMed  Google Scholar 

  41. De Vane GW, Czekala NM, Judd HL, Yen SS. Circulating gonadotropins, estrogens, and androgens in polycystic ovarian disease. Am J Obstet Gynecol 1975;121:496–500.

    Google Scholar 

  42. Legro RS, Kunselman AR, Demers L, Wang SC, Bentley-Lewis R, Dunaif A. Elevated dehydroepiandrosterone sulfate levels as the reproductive phenotype in the brothers of women with polycystic ovary syndrome. J Clin Endocrinol Metab 2002;87:2134–2138.

    Article  CAS  PubMed  Google Scholar 

  43. Legro RS, Driscoll D, Strauss JF 3rd, Fox J, Dunaif A. Evidence for a genetic basis for hyperandrogenism in polycystic ovary syndrome. Proc Natl Acad Sci USA 1998;95:14,956–14,960.

    Article  CAS  PubMed  Google Scholar 

  44. Burghen GA, Givens JR, Kitabchi AE. Correlation of hyperandrogenism with hyperinsulinism in polycystic ovarian disease. J Clin Endocrinol Metab 1980;50:113–116.

    Article  CAS  PubMed  Google Scholar 

  45. Conway GS, Jacobs HS, Holly JM, Wass JA. Effects of luteinizing hormone, insulin, insulin-like growth factor-I and insulin-like growth factor small binding protein 1 in the polycystic ovary syndrome. Clin Endocrinol 1990;33:593–603.

    CAS  Google Scholar 

  46. Robinson S, Kiddy D, Gelding SV, et al. The relationship of insulin insensitivity to menstrual pattern in women with hyperandrogenism and polycystic ovaries. Clin Endocrinol 1993;39:351–355.

    Article  CAS  Google Scholar 

  47. Nagamani M, Van Dinh T, Kelver ME. Hyperinsulinemia in hyperthecosis of the ovaries. Am J Obstet Gynecol 1986;154:384–389.

    CAS  PubMed  Google Scholar 

  48. Geffner ME, Kaplan SA, Bersch N, Golde DW, Landaw EM, Chang RJ. Persistence of insulin resistance in polycystic ovarian disease after inhibition of ovarian steroid secretion. Fertil Steril 1986;45:327–333.

    CAS  PubMed  Google Scholar 

  49. Dunaif A, Green G, Futterweit W, Dobrjansky A. Suppression of hyperandrogenism does not improve peripheral or hepatic insulin resistance in the polycystic ovary syndrome. J Clin Endocrinol Metab 1990;70:699–704.

    Article  CAS  PubMed  Google Scholar 

  50. Diamanti-Kandarakis E, Mitrakou A, Hennes MM, et al. Insulin sensitivity and antiandrogenic therapy in women with polycystic ovary syndrome. Metabolism 1995;44:525–531.

    Article  CAS  PubMed  Google Scholar 

  51. Diamond MP, Grainger D, Diamond MC, Sherwin RS, Defronzo RA. Effects of methyltestosterone and insulin secretion and sensitivity in women. J Clin Endocrinol Metab 1998;83:4420–4425.

    Article  CAS  PubMed  Google Scholar 

  52. Speiser PW, Serrat J, New MI, Gertner JM. Insulin insensitivity in adrenal hyperplasia due to non-classical steroid 21-hydroxylase deficiency. J Clin Endocrinol Metab 1992;75:1421–1424.

    Article  CAS  PubMed  Google Scholar 

  53. Barbieri RL, Makris A, Ryan KJ. Insulin stimulates androgen accumulation in incubations of human ovarian stroma and theca. Obstet Gynecol 1984;64:73S–80S.

    CAS  PubMed  Google Scholar 

  54. Cara JF, 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.

    Article  CAS  PubMed  Google Scholar 

  55. Hernandez ER, Resnick CE, Holtzclaw WD, Payne DW, Adashi EY. Insulin as a regulator of androgen biosynthesis by cultured rat ovarian cells: cellular mechanism(s) underlying physiological and pharmacological hormonal actions. Endocrinology 1988;122:2034–2043.

    Article  CAS  PubMed  Google Scholar 

  56. Nestler JE. Insulin regulation of human ovarian androgens. Hum Reprod 1997;12:53–62.

    CAS  PubMed  Google Scholar 

  57. Nestler JE, Powers LP, Matt DW, et al. A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. J Clin Endocrinol Metab 1991;72:83–89.

    Article  CAS  PubMed  Google Scholar 

  58. LeRoith D, McGuinness M, Shemer J, et al. Insulin-like growth factors. Biol Signals 1992;1:173–181.

    Article  CAS  PubMed  Google Scholar 

  59. Ibáñez L, Potau N, Zampolli M, Rique S, Saenger P, Carrascosa A. Hyperinsulinemia and decreased insulin-like growth factor-binding protein-1 are common features in prepubertal and pubertal girls with a history of premature pubarche. J Clin Endocrinol Metab 1997;82:2283–2288.

    Article  PubMed  Google Scholar 

  60. Franks S, Gilling-Smith C, Watson H, Willis D. Insulin action in the normal and polycystic ovary. Endocrinol Metab Clin North Am 1999;28:361–378.

    Article  CAS  PubMed  Google Scholar 

  61. Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17α activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med 1996; 335:617–623.

    Article  CAS  PubMed  Google Scholar 

  62. Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Engl J Med 1998;338:1876–1880.

    Article  CAS  PubMed  Google Scholar 

  63. Hasegawa I, Murakawa H, Suzuki M, Yamamoto Y, Kurabayashi T, Tanaka K. Effect of troglitazone on endocrine and ovulatory performance in women with insulin resistance-related polycystic ovary syndrome. Fertil Steril 1999;71:323–327.

    Article  CAS  PubMed  Google Scholar 

  64. Azziz R, Ehrmann D, Legro RS, et al. Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: a multicenter, double blind, placebo-controlled trial. J Clin Endocrinol Metab 2001;86:1626–1632.

    Article  CAS  PubMed  Google Scholar 

  65. Azziz R, Ehrmann DA, Legro RS, Fereshetian AG, O’Keefe M, Ghazzi MN, PCOS/Troglitazone Study Group. Troglitazone decreases adrenal androgen levels in women with polycystic ovary syndrome. Fertil Steril 2003;79:932–937.

    Article  PubMed  Google Scholar 

  66. DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The multicenter metformin study group. N Engl J Med 1995;333:541–549.

    Article  CAS  PubMed  Google Scholar 

  67. Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 2000;384 Pt 3:607–614.

    Article  Google Scholar 

  68. Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001;108:1167–1174.

    CAS  PubMed  Google Scholar 

  69. Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med 1995;333:550–554.

    Article  CAS  PubMed  Google Scholar 

  70. Vrbikova J, Hill M, Starka L, et al. The effects of long-term metformin treatment on adrenal and ovarian steroidogenesis in women with polycystic ovary syndrome. Eur J Endocrinol 2001;144:619–628.

    Article  CAS  PubMed  Google Scholar 

  71. Arslanian SA, Lewy V, Danadian K, Saad R. Metformin therapy in obese adolescents with polycystic ovary syndrome and impaired glucose tolerance: amelioration of exaggerated adrenal response to adrenocorticotropin with reduction of insulinemia/insulin resistance. J Clin Endocrinol Metab 2002;87:1555–1559.

    Article  CAS  PubMed  Google Scholar 

  72. la Marca A, Egbe TO, Morgante G, Paglia T, Cianci A, De Leo V. Metformin treatment reduces ovarian cytochrome P-450c17α response to human chorionic gonadotrophin in women with insulin resistance-related polycystic ovary syndrome. Hum Reprod 2000;15:21–23.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  74. Mansfield R, Galea R, Brincat M, Hole D, Mason H. Metformin has direct effects on human ovarian steroidogenesis. Fertil Steril 2003;79:956–962.

    Article  PubMed  Google Scholar 

  75. Arlt W, Auchus RJ, Miller WL. Thiazolidinediones but not metformin directly inhibit the steroidogenic enzymes P450c17 and 3β-hydroxysteroid dehydrogenase. J Biol Chem 2001;276:16,767–16,771.

    Article  CAS  PubMed  Google Scholar 

  76. Spiegelman BM. PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes 1998;47:507–514.

    Article  CAS  PubMed  Google Scholar 

  77. Kersten S, Desvergne B, Wahli W. Roles of PPARs in health and disease. Nature 2000;405;421–424.

    Article  CAS  PubMed  Google Scholar 

  78. Mitwally MFM, Witchel SF, Casper RF. Troglitazone: a possible modulator of ovarian steroidogenesis. J Soc Gynecol Investig 2002;9:163–167.

    Article  CAS  PubMed  Google Scholar 

  79. Guido M, Romualdi D, Giuliani M, Costantini B, Apa R, Lanzone A. Effect of pioglitazone treatment on the adrenal androgen response to corticotropin in obese patients with polycystic ovary syndrome. Hum Reprod 2004;19:534–539.

    Article  CAS  PubMed  Google Scholar 

  80. Arlt W, Neogi P, Gross C, Miller WL. Cinnamic acid based thiazolidinediones inhibit human P450c17 and 3β-hydroxysteroid dehydrogenase and improve insulin sensitivity independent of PPARγ agonist activity. J Mol Endocrinol 2004;32:425–436.

    Article  CAS  PubMed  Google Scholar 

  81. Cheatham B, Kahn CR. Insulin action and the insulin signaling network. Endocr Rev 1995;16: 117–142.

    CAS  PubMed  Google Scholar 

  82. Ullrich A, Bell JR, Chen EY, et al. Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. Nature 1985;313:756–761.

    Article  CAS  PubMed  Google Scholar 

  83. Goldfine ID. The insulin receptor: molecular biology and transmembrane signaling. Endocr Rev 1987;8:235–255.

    Article  CAS  PubMed  Google Scholar 

  84. Saltiel AR. Diverse signaling pathways in the cellular actions of insulin. Am J Physiol 1996; 270(3 Pt 1):E375–E385.

    CAS  PubMed  Google Scholar 

  85. Watson RT, Kanzaki M, Pessin JE. Regulated membrane trafficking of the insulin-responsive glucose transporter 4 in adipocytes. Endocr Rev 2004;25:177–204.

    Article  CAS  PubMed  Google Scholar 

  86. Kahn CR. The molecular mechanism of insulin action. Annu Rev Med 1985;36:429–451.

    Article  CAS  PubMed  Google Scholar 

  87. Dunaif A, Segal KR, Shelley DR, Green G, Dobrjansky A, Licholai T. Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome. Diabetes 1992;41:1257–1266.

    Article  CAS  PubMed  Google Scholar 

  88. Conway GS, Avey C, Rumsby G. The tyrosine kinase domain of the insulin receptor gene is normal in women with hyperinsulinaemia and polycystic ovary syndrome. Hum Reprod 1994;9:1681–1683.

    CAS  PubMed  Google Scholar 

  89. Talbot JA, Bicknell EJ, Rajkhowa M, Krook A, O’Rahilly S, Clayton RN. Molecular scanning of the insulin receptor gene in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1996;81: 1979–1983.

    Article  CAS  PubMed  Google Scholar 

  90. Ciaraldi TP, el-Roeiy A, Madar Z, Reichart D, Olefsky JM, Yen SS. Cellular mechanisms of insulin resistance in polycystic ovary syndrome. J Clin Endocrinol Metab 1992;75:577–583.

    Article  CAS  PubMed  Google Scholar 

  91. Dunaif A, Xia J, Book C-B, Schenker E, Tang Z. 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.

    Article  CAS  PubMed  Google Scholar 

  92. Bollage GE, Roth RA, Beaudoin J, Mochly-Rosen D, Doshland DE Jr. Protein kinase C directly phosphorylates the insulin receptor in vitro and reduces its protein-tyrosine kinase activity. Proc Natl Acad Sci USA 1986;83:5822–5824.

    Article  Google Scholar 

  93. Stadtmauer L, Rosen OM. Increasing the cAMP content of IM-9 cells alters the phosphorylation state and protein kinase activity of the insulin receptor. J Biol Chem 1986;261:3402–3407.

    CAS  PubMed  Google Scholar 

  94. Takayama S, White MF, Kahn CR. Phorbol ester-induced serine phosphorylation of the insulin receptor decreases its tyrosine kinase activity. J Biol Chem 1988;263:3440–3447.

    CAS  PubMed  Google Scholar 

  95. Chin JE, Dickens M, Tavare JM, Roth RA. Overexpression of protein kinse C isoenzymes α, βI, γ, and ε in cells overexpressing the insulin receptor. Effects on receptor phosphorylation and signaling. J Biol Chem 1993;268:6338–6347.

    CAS  PubMed  Google Scholar 

  96. Li M, Youngren JF, Dunaif A, et al. Decreased insulin receptor (IR) autophosphorylation in fibroblasts from patients with PCOS: effects of serine kinase inhibitors and IR activators. J Clin Endocrinol Metab 2002;87:4088–4093.

    Article  CAS  PubMed  Google Scholar 

  97. Guo H, Damuni Z. Autophosphorylation-activated protein kinase phosphorylates and inactivates protein phosphatase 2A. Proc Natl Acad Sci USA 1993;90:2500–2504.

    Article  CAS  PubMed  Google Scholar 

  98. Paz K, Hemi R, LeRoith D, et al. A molecular basis for insulin resistance. J Biol Chem 1997;272: 29,911–29,918.

    Article  CAS  PubMed  Google Scholar 

  99. Pirola L, Johnston AM, Obberghen EV. Modulation of insulin action. Diabetologia 2004;47: 170–184.

    Article  CAS  PubMed  Google Scholar 

  100. Liberman Z, Eldar-Finkelman H. Serine 332 phosphorylation of insulin receptor substrate-1 by glycogen synthase kinase-3 attenuates insulin signaling. J Biol Chem 2005;280:4422–4428.

    Article  CAS  PubMed  Google Scholar 

  101. Dresner A, Laurent D, Marcucci M, et al. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Invest 1999;103:253–259.

    Article  CAS  PubMed  Google Scholar 

  102. Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Speigelman BM. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-α-and obesity-induced insulin resistance. Science 1996;271:665–668.

    Article  CAS  PubMed  Google Scholar 

  103. Holte J, Bergh T, Berne C, Lithell H. Serum lipoprotein lipid profile in women with the polycystic ovary syndrome: relation to anthropometric, endocrine and metabolic variables. Clin Endocrinol 1994;41:463–471.

    Article  CAS  Google Scholar 

  104. Robinson S, Henderson AD, Gelding SV, et al. Dyslipidaemia is associated with insulin resistance in women with polycystic ovaries. Clin Endocrinol 1996;44:277–284.

    Article  CAS  Google Scholar 

  105. Naz RK, Thurston D, Santoro N. Circulating tumor necrosis factor (TNF)-α in normally cycling women and patients with premature ovarian failure and polycystic ovaries. Am J Reprod Immunol 1995;34:170–175.

    CAS  PubMed  Google Scholar 

  106. Spranger J, Kroke A, Mohlig M, et al. Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes 2003;52:812–817.

    Article  CAS  PubMed  Google Scholar 

  107. Ciaraldi TP, Carter L, Nikoulina S, Mudaliar S, McClain DA, Henry RR. Glucosamine regulation of glucose metabolism in cultured human skeletal muscle cells: divergent effects on glucose transport/phosphorylation and glycogen synthase in non-diabetic and type 2 diabetic subjects. Endocrinology 1999;140:3971–3980.

    Article  CAS  PubMed  Google Scholar 

  108. Previs SF, Withers DJ, Ren JM, White MF, Shulman GI. Contrasting effects of IRS-1 versus IRS-2 gene disruption on carbohydrate and lipid metabolism. J Biol Chem 2000;275:38,990–38,994.

    Article  CAS  PubMed  Google Scholar 

  109. Cho H, Mu J, Kim JK, et al. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKBβ). Science 2001;292:1728–1731.

    Article  CAS  PubMed  Google Scholar 

  110. 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.

    Article  CAS  PubMed  Google Scholar 

  111. Meyre D, Bouatia-Naji N, Tounian A, et al. Variants of ENPP1 are associated with childhood and adult obesity and increase the risk of glucose intolerance and type 2 diabetes. Nat Genet 2005; 37:863–867.

    Article  CAS  PubMed  Google Scholar 

  112. Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 1989;38:1165–1174.

    Article  CAS  PubMed  Google Scholar 

  113. Poretsky L. On the paradox of insulin-induced hyperandrogenism in insulin-resistant states. Endocr Rev 1991;12:3–13.

    Article  CAS  PubMed  Google Scholar 

  114. Taylor SI. Lilly Lecture: molecular mechanisms of insulin resistance. Lessons learned from patients with mutations in the insulin-receptor gene. Diabetes 1992;41:1473–1490.

    Article  CAS  PubMed  Google Scholar 

  115. 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.

    Article  CAS  PubMed  Google Scholar 

  116. Book C-B, Dunaif A. Selective insulin resistance in the polycystic ovary syndrome. J Clin Endocrinol Metab 1999;84:3110–3116.

    Article  CAS  PubMed  Google Scholar 

  117. Govind A, Obhrai MS, Clayton RN. Polycystic ovaries are inherited as an autosomal dominant trait: analysis of 29 polycystic ovary syndrome and 10 control families. J Clin Endocrinol Metab 1999;84:38–43.

    Article  CAS  PubMed  Google Scholar 

  118. Legro RS, Strauss JF 3rd. Molecular progress in infertility: polycystic ovary syndrome. Fertil Steril 2002;78:569–576.

    Article  PubMed  Google Scholar 

  119. Diamanti-Kandarakis E, Piperi C. Genetics of polycystic ovary syndrome: searching for the way out of the labyrinth. Hum Reprod Update 2005;11:631–643.

    Article  CAS  PubMed  Google Scholar 

  120. Ibáñez L, Potau N, Virdis R, et al. Postpubertal outcome in girls diagnosed of premature pubarche during childhood: increased frequency of functional ovarian hyperandrogenism. J Clin Endocrinol Metab 1993;76:1599–1603.

    Article  PubMed  Google Scholar 

  121. Oppenheimer E, Linder B, DiMartino-Nardi J. Decreased insulin sensitivity in prepubertal girls with premature pubarche and acanthosis nigricans. J Clin Endocrinol Metab 1995;80:614–618.

    Article  CAS  PubMed  Google Scholar 

  122. Ibáñez L, Potau N, Virdis R, et al. Hyperinsulinemia in postpubertal girls with a history of premature pubarche and functional ovarian hyperandrogenism. J Clin Endocrinol Metab 1996;81: 1237–1243.

    Article  PubMed  Google Scholar 

  123. Martens JWM, Geller DH, Arlt W, et al. Enzymatic activities of P450c17 stably expressed in fibroblasts from patients with the polycystic ovary syndrome. J Clin Endocrinol Metab 2000; 85:4338–4346.

    Article  CAS  PubMed  Google Scholar 

  124. Virshup DM. Protein phosphatase 2A: a panoply of enzymes. Curr Opin Cell Biol 2000;12:180–185.

    Article  CAS  PubMed  Google Scholar 

  125. Pandey AV, Mellon SH, Miller WL. Protein phosphatase 2A and phosphoprotein SET regulate androgen production by P450c17. J Biol Chem 2003;278:2837–2844.

    Article  CAS  PubMed  Google Scholar 

  126. Pandey AV, Miller WL. Regulation of 17,20 lyase activity by cytochrome b 5 and by serine phosphorylation of P450c17. J Biol Chem 2005;280:13,265–13,271.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pediatrics, University of California, San Francisco, CA

    Andrew A. Bremer MD, PhD & Walter L. Miller MD

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  1. Andrew A. Bremer MD, PhD
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  2. Walter L. Miller MD
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Editors and Affiliations

  1. Endocrine Section of First Department of Internal Medicine, Athens University School of Medicine, Athens, Greece

    Evanthia Diamanti-Kandarakis MD, PhD

  2. Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA

    John E. Nestler MD

  3. Division of Endocrinology and Human Reproduction, Second Department of Obstetrics and Gynaecology, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Dimitrios Panidis MD, PhD

  4. Endocrinology Unit, Department of Internal Medicine and Gastroenterology and C.R.B.A., S. Orsola-Malpighi Hospital, Alma Mater Studiorum University of Bologna, Bologna, Italy

    Renato Pasquali MD

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Bremer, A.A., Miller, W.L. (2007). Serine Phosphorylation, Insulin Resistance, and the Regulation of Androgen Synthesis. In: Diamanti-Kandarakis, E., Nestler, J.E., Panidis, D., Pasquali, R. (eds) Insulin Resistance and Polycystic Ovarian Syndrome. Contemporary Endocrinology. Humana Press. https://doi.org/10.1007/978-1-59745-310-3_8

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  • DOI: https://doi.org/10.1007/978-1-59745-310-3_8

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