Polycystic Ovary Syndrome

  • Susan B. Zweig
  • Marsha C. Tolentino
  • Leonid Poretsky

Abstract

Polycystic ovary syndrome (PCOS) is a common disorder affecting (depending on the population studied and the definition of the syndrome) between 5 to 20% of reproductive age women.1 If the middle of this range is considered as a realistic prevalence, then PCOS may be the most prevalent endocrine disorder in women. In spite of the widespread presence of PCOS, its precise definition still eludes both investigators and practitioners. Most consensus definitions describe PCOS as a disorder characterized by chronic anovulation and the presence of some degree of hyperandrogenism, with the exclusion of specific disorders that may lead to similar phenotypes, particularly, 21-hydroxylase deficiency and other forms of congenital adrenal hyperplasia. The definition proposed in 1990 by the National Institutes of Health Conference on PCOS requires a minimum of two criteria: menstrual abnormalities due to oligo- or anovulation, and hyperandrogenism of ovarian origin. Other disorders, such as 21-hydroxylase deficiency, androgen secreting tumors, and hyperprolactinemia, must be excluded.2

Keywords

Insulin Resistance Insulin Receptor Polycystic Ovary Polycystic Ovary Syndrome Congenital Adrenal Hyperplasia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Knochenhauer ES, Key TJ, Kahsar-Miller M, Waggoner W, Boots LR, Azziz R. Prevalence of the polycystic ovarian syndrome in unselected black and white women of the Southeastern United States: a prospective study. J Clin Endocrinol Metab 83: 3078–3082, 1998.PubMedCrossRefGoogle Scholar
  2. 2.
    Zawadzki JK, Dunaif A. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In: Dunaif A ed. Polycystic Ovary Syndrome. Boston: Blackwell Scientific, 337–384, 1995.Google Scholar
  3. 3.
    Speroff L, Glass RH, Kase NG, eds. Anovulation and the polycystic ovary. In: Clinical gynecologic endocrinology and infertility, 6`h ed. Baltimore: Lippincott Williams and Wilkins; 487–522, 1999.Google Scholar
  4. 4.
    Kovacs GT, ed. Polycystic ovary syndrome. Cambridge University Press, Cambridge, UK, 2000.Google Scholar
  5. 5.
    Dunaif A. Hyperandrogenic anovulation (PCOS): a unique disorder of insulin action associated with an increased risk of non-insulin-dependent diabetes mellitus. Am J Med [Suppl] 98: 33S - 39S, 1995.CrossRefGoogle Scholar
  6. 6.
    Chereau, A. Mémoires pour servir a l’étude des maladies des ovaries. Paris: Fortin, Masson and Cie, 1844.Google Scholar
  7. 7.
    Stein IF, Leventhal ML. Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 29: 181–186, 1935.Google Scholar
  8. 8.
    Culiner A, Shippel S. Virilism and thecal cell hyperplasia of the ovary syndrome. J Obstet Gynaecol Br Comm 56: 439–445, 1949.CrossRefGoogle Scholar
  9. 9.
    McArthur JW, Ingersoll FW, Worcester J. The urinary excretion of interstitial-cell and follicle-stimulating hormone activity by women with diseases of the reproductive system. J Clin Endocrinol Metab 18: 1202 1215, 1958.Google Scholar
  10. 10.
    De Vane GW, Czekala NM, Judd HL, Yen SS. Circulating gonadotropins, estrogens, and androgens in polycystic ovarian disease. Am J Obstet Gynecol 121: 496–500, 1975.Google Scholar
  11. 11.
    Poretsky L, Cataldo N, Rosenwaks Z, Giudice L. The insulin-related ovarian regulatory system in health and disease. Endocr Rev 20: 535–582, 1999.PubMedCrossRefGoogle Scholar
  12. 12.
    Zumoff B, Freeman R, Coupey S, Saenger P, Markowitz M, Kream J. A chronobiologic abnormality in luteinizing hormone secretion in teenage girls with the polycystic-ovary syndrome. N Engl J Med 309: 1206–1209, 1983.PubMedCrossRefGoogle Scholar
  13. 13.
    McLachlan RI, Healy DL, Burger HG. The ovary. In: Felig P, Baxter JD, Broadus AE, Frohman LA, eds. Endocrinology and Metabolism. 2nd éd. New York: McGraw-Hill Book Company; 951–983, 1987.Google Scholar
  14. 14.
    Pang S, Softness B, Sweeney WJ, New MI. Hirsutism, polycystic ovarian disease, and ovarian 17-ketosteroid reductase deficiency. N Engl J Med 316: 1295–1301, 1987.PubMedCrossRefGoogle Scholar
  15. 15.
    Nelson VL, Qin K-N, Rosenfeld RL, Wood JR, Penning TM, Legro RS, Srauss JF III, McAllister JM. The biochemical basis for increased testosterone production in theca cells propagated from patients with polycystic ovary syndrome. J Clin Endocrinol Metab 86: 5925–5933, 2001.PubMedCrossRefGoogle Scholar
  16. 16.
    Poretsky L and Kalin M. The gonadotropic function of insulin. Endocr Rev 8: 132–141, 1987.PubMedCrossRefGoogle Scholar
  17. 17.
    Archard C, Thiers J. Le virilisme pilaire et son association a l’insuffisance glycolytique (diabete des femmes a barbe). Bull Acad Nat Med 86: 51, 1921.Google Scholar
  18. 18.
    Kahn CR, Flier JS, Bar RS, Archer JA, Gorden R, Martin MM, Roth J. The syndromes of insulin resistance and acanthosis nigricans: insulin-receptor disorders in man. N Engl J Med 294: 739–745, 1976.PubMedCrossRefGoogle Scholar
  19. 19.
    Flier JS, Kahn CR, Roth J, Bar RS. Antibodies that impair insulin receptor binding in an unusual diabetic syndrome with severe insulin resistance. Science 190: 63–65, 1975.PubMedCrossRefGoogle Scholar
  20. 20.
    Taylor SI, Moller DE. Mutations of the insulin receptor gene. In: Moller DE ed. Insulin Resistance. New York: John Wiley and Sons; 83–121, 1993.Google Scholar
  21. 21.
    Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev 18: 774–800, 1997.PubMedCrossRefGoogle Scholar
  22. 22.
    Dunaif A, Book CB, 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 96: 801–810, 1995.PubMedCrossRefGoogle Scholar
  23. 23.
    Poretsky L, Smith D, Seibel M, Pazianos A, Moses AC, Flier JS. Specific insulin binding sites in the human ovary. J Clin Endocrinol Metab 59: 809–811, 1984.PubMedCrossRefGoogle Scholar
  24. 24.
    Poretsky L, Grigorescu F, Seibel M, Moses AC, Flier JS. Distribution and characterization of the insulin and IGF-I receptors in the normal human ovary. J Clin Endocrinol Metab 61: 728–734, 1985.PubMedCrossRefGoogle Scholar
  25. 25.
    El-Roeiy A, Chen X, Roberts VJ, Shimasaki S, Ling N, LeRoith D, Roberts Jr CT, Yen SS. Expression of the genes encoding the insulin-like growth factors (IGF-I and II), the IGF and insulin receptors, and IGFbinding proteins 1–6 and the localization of their gene products in normal and polycystic ovary syndrome ovaries. J Clin Endocrinol Metab 78: 1488–1496, 1994.PubMedCrossRefGoogle Scholar
  26. 26.
    Barbieri RL, Makris A, Ryan KJ. Effects of insulin on steroidogenesis in cultured porcine ovarian theca. Fertil Steril 40: 237–241, 1983.PubMedGoogle Scholar
  27. 27.
    Poretsky L, Clemons J, Bogovich K. Hyperinsulinemia and human chorionic gonadotropin synergistically promote the growth of ovarian follicular cysts in rats. Metabolism 41: 903–910, 1992.PubMedCrossRefGoogle Scholar
  28. 28.
    Poretsky L, Chandrasekher YA, Bai C, Liu HC, Rosenwaks Z, Giudice L. Insulin receptor mediates inhibitory effect of insulin, but not of insulin-like growth factor (IGF)-1, on binding protein 1 (IGFBP-1) production in human granulosa cells. J Clin Endocrinol Metab 81: 493496, 1996.Google Scholar
  29. 29.
    Poretsky L. On the paradox of insulin-induced hyperandrogenism in insulin-resistant states. Endocr Rev 12: 3–13, 1991.PubMedCrossRefGoogle Scholar
  30. 30.
    Joslin EP, Root HF, White P. The growth, development and prognosis of diabetic children. JAMA 85: 420–422, 1925.CrossRefGoogle Scholar
  31. 31.
    Zumoff B, Miller L, Poretsky L, Levitt C, Miller E, Heinz U, Denman H, Jandorek R, Rosenfeld R. Subnormal follicular-phase serum progesterone levels and elevated follicular-phase serum estradiol levels in young women with insulin-dependent diabetes. Steroids 55: 560–564, 1990.PubMedCrossRefGoogle Scholar
  32. 32.
    Poretsky L, Bhargava G, Kalin MF, Wolf SA. Regulation of insulin receptors in the human ovary: in vitro studies. J Clin Endocrinol Metab 67: 774–778, 1988.PubMedCrossRefGoogle Scholar
  33. 33.
    Poretsky L, Bhargava G, Saketos M, Dunaif A. Regulation of human ovarian insulin receptors in vivo. Metabolism 39: 161–166, 1990.PubMedCrossRefGoogle Scholar
  34. 34.
    Saltiel AR. Second messengers of insulin action. Diabetes Care 13: 244256, 1990.Google Scholar
  35. 35.
    Nestler JE, Jakubowicz DJ, De Vargas AF, Brik C, Quintero N, Medina F. Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovarian syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system. J Clin Endocrinol Metab 83: 2001–2005, 1998.PubMedCrossRefGoogle Scholar
  36. 36.
    Poretsky L, Seto-Young D, Shrestha A, Dhillon S, Mirjany M, Liu H-C, Yih MC, Rosenwaks Z. Phosphatidyl-inositol-3 kinase-independent insulin action pathway(s) in the human ovary. J Clin Endocrinol Metab 86: 3115–3119, 2001.PubMedCrossRefGoogle Scholar
  37. 37.
    Poretsky L, Glover B, Laumas V, Kalin M, Dunaif A. The effects of experimental hyperinsulinemia on steroid secretion, ovarian [125I] insulin binding, and ovarian [1251] insulin-like growth factor I binding in the rat. Endocrinology 122: 581–585, 1988.PubMedCrossRefGoogle Scholar
  38. 38.
    Samoto T, Maruo T, Matsuo H, Katayama K, Barnea ER Mochizuki M. Altered expression of insulin and insulin-like growth factor-I receptors in follicular and stromal compartments of polycystic ovarian ovaries. Endocr 40: 413–424, 1993.Google Scholar
  39. 39.
    Willis D, Mason H, Gilling-Smith C, Franks S. Modulation by insulin of follicle-stimulating hormone and luteinizing hormone actions in human granulosa cells of normal and polycystic ovaries. J Clin Endocrinol Metab 81: 302–309, 1996.PubMedCrossRefGoogle Scholar
  40. 40.
    Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med 335: 617–23, 1996.PubMedCrossRefGoogle Scholar
  41. 41.
    Sahin Y, Ayata D, Kelestimur F. Lack of relationship between 17hydroxyprogesterone response to buserelin testing and hyperinsulinemia in polycystic ovary syndrome. Eur J Endocrinol 136: 410–415, 1997.PubMedCrossRefGoogle Scholar
  42. 42.
    Fulghesu AM, Villa P, Pavone V, Guido M, Apa R, Caruso A, Lanzone A, Rossodivita A, Mancuso S. The impact of insulin secretion on the ovarian response to exogenous gonadotropins in polycystic ovarian syndrome. J Clin Endocrinol Metab 82: 644–648, 1997.PubMedCrossRefGoogle Scholar
  43. 43.
    Stuart CA, Nagamani M. Acute augmentation of plasma androstenedione and dehydroepiandrosterone by euglycemic insulin infusion: evidence for a direct effect of insulin on ovarian steroidogenesis. In: Dunaif A, Givens JR, Haseltine FP, Merriam GR eds. Polycystic Ovary Syndrome. Boston: Blackwell Scientific Publications; 279–288, 1992.Google Scholar
  44. 44.
    Stuart CA, Prince MJ, Peters EJ, Meyer WJ. Hyperinsulinemia and hyperandrogenemia: in vivo androgen response to insulin infusion. Obstet Gynecol 69: 921–925, 1987.PubMedGoogle Scholar
  45. 45.
    Poretsky L, Piper B. Insulin resistance, hypersecretion of LH, and a dual-defect hypothesis for the pathogenesis of polycystic ovary syndrome. Obstet Gynecol 84: 613–621, 1994.PubMedGoogle Scholar
  46. 46.
    Adashi EY, Hsueh AJW, Yen SSC. Insulin enhancement of luteinizing hormone and follicle-stimulating hormone release by cultured pituitary cells. Endocrinology 108: 1441–1449, 1981.PubMedCrossRefGoogle Scholar
  47. 47.
    Soldani R, Cagnacci A, Yen SS. Insulin, insulin-like growth factor I (IGF I) and IGF-II enhance basal and gonadotropin-releasing hormone-stimulated luteinizing hormone release from rat anterior pituitary cells in vitro. Eur J Endocrinol 131: 641–645, 1994.PubMedCrossRefGoogle Scholar
  48. 48.
    Nestler JE, Jakubowicz DJ. Lean women with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian P450c17 alpha activity and serum androgens. J Clin Endocrinol Metab 82: 4075–9, 1997.PubMedCrossRefGoogle Scholar
  49. 49.
    Dunaif A, Graf M. Insulin administration alters gonadal steroid metabolism independent of changes in gonadotropin secretion in insulin-resistant women with polycystic ovary syndrome. J Clin Invest 83: 23–29, 1989.PubMedCrossRefGoogle Scholar
  50. 50.
    Plymate SR, Matej LA, Jones RE, Friedl KE. Inhibition of sex hormone-binding globulin production in the human hepatoma (HepG2) cell line by insulin and prolactin. J Clin Endocrinol Metab 67: 460–464, 1988.PubMedCrossRefGoogle Scholar
  51. 51.
    Peiris AN, Stagner JL, Plymate SR, Vogel RL, Heck M, Samols E. Relationship of insulin secretory pulses to sex hormone-binding globulin production in normal men. J Clin Endocrinol Metab 76: 279–282, 1993.PubMedCrossRefGoogle Scholar
  52. 52.
    Fendri S, Arlot S, Marcelli JM, Dubreuil A, Lalau JD. Relationship between insulin sensitivity and circulating sex hormone-binding globulin levels in hyperandrogenic obese women. Int J Obes Relat Metab Disord 18: 755–759, 1994.PubMedGoogle Scholar
  53. 53.
    Nestler JE, Powers LP, Matt DW, Steingold KA, Plymate SR, Rittmaster RS, Clore JN, Blackard WG. A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. J Clin Endocrinol Metab 72: 83–89, 1991.PubMedCrossRefGoogle Scholar
  54. 54.
    Pao CI, Farmer PK, Begovic S, Villafuerte BC, Wu G, Robertson DG, Phillips LS. Regulation of insulin-like growth factor-I (IGF I) and IGFbinding protein I gene transcription by hormones and provision of amino acids in rat hepatocytes. Mol Endocrinol 7: 1561–1568, 1993.PubMedCrossRefGoogle Scholar
  55. 55.
    Lee PD, Giudice LC, Conover CA, Powell DR. Insulin-like growth factor binding protein-1: recent findings and new directions. Proc Soc Exp Biol Med 216: 319–357, 1997.PubMedCrossRefGoogle Scholar
  56. 56.
    Giudice LC. Insulin-like growth factors and ovarian follicular development. Endocr Rev 13: 641–669, 1992.PubMedGoogle Scholar
  57. 57.
    Nagami M, Stuart CA. Specific binding sites for insulin-like growth factor I in the ovarian stroma of women with polycystic ovarian disease and stromal hyperthecosis. Am J Obstet Gynecol 163: 1992–1997, 1990.CrossRefGoogle Scholar
  58. 58.
    Duleba AJ, Spaczynski RZ, Olive DL, Behrman HR. Effects of insulin and insulin-like growth factors on proliferation of rat ovarian theca-interstitial cells. Biol Reprod 56: 891–897, 1997.PubMedCrossRefGoogle Scholar
  59. 59.
    Duleba AJ, Spaczynski RZ, Olive DL. Insulin and insulin-like growth factor I stimulate the proliferation of human ovarian theca-interstitial cells. Fertil Steril 69: 335–340, 1998.PubMedCrossRefGoogle Scholar
  60. 60.
    Watson H, Willis D, Mason H, Modgil G, Wright C, Franks S. The effects of ovarian steroids, epidermal growth factor (EGF), insulin (I), and insulin-like growth factor-1 (IGF-I), on ovarian stromal cell growth. Program of the 79th Annual Meeting of the Endocrine Society, Minneapolis, MN, (Abstract 389 ), 1997.Google Scholar
  61. 61.
    Bogovich K, Clemons J, Poretsky L. Insulin has a biphasic effects on the ability of human chorionic gonadotropin to induce ovarian cysts in the rat. Metabolism 48: 995–1002, 1999.PubMedCrossRefGoogle Scholar
  62. 62.
    Damario M, Bogovich K, Liu HC, Rosenwaks Z, Poretsky L. Synergistic effects of IGF-I and human chorionic gonadotropin in the rat ovary. Metabolism 49: 314–320, 2000.PubMedCrossRefGoogle Scholar
  63. 63.
    De C1ueTJ, Shah SC, Marchese M, Malone JI. Insulin resistance and hyperinsulinemia induce hyperandrogenism in a young type B insulin-resistant female. J Clin Endocrinol Metab 72: 1308–1311, 1991.CrossRefGoogle Scholar
  64. 64.
    Dunaif A, Finegood DT. Beta-cell dysfunction independent of obesity and glucose intolerance in the polycystic ovary syndrome. J Clin Endocrinol Metab 81: 942–947, 1996.PubMedCrossRefGoogle Scholar
  65. 65.
    Legro R, Kunselman A, Dodson W, Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a perspective, controlled study in 254 affected women. J Clin Endocrinol Metab 84: 165–169, 1999.PubMedCrossRefGoogle Scholar
  66. 66.
    Koivunen RM et al. Metabolic and steroidogenic alterations related to increased frequency of polycystic ovaries in women with a history of gestational diabetes. J Clin Endocrinol Metab 86: 2591–2599, 2001.PubMedCrossRefGoogle Scholar
  67. 67.
    The Diabetes Prevention Program Research Group. The Diabetes Prevention Program: baseline characteristics of the randomized cohort. Diabetes Care 23 (11): 1619–1629, 2000.CrossRefGoogle Scholar
  68. 68.
    Fujimoto W. Background and recruitment data for the U.S. Diabetes Prevention Program. Diabetes Care 23: B11 - B13, 2000.Google Scholar
  69. 69.
    Board JA, Rosenberg SM, Smeltzer JS. Spironolactone and estrogenprogestin therapy for hirsuitism. South Med J 80: 483–486, 1987.PubMedCrossRefGoogle Scholar
  70. 70.
    Falsetti L. Gamera A, Tisi G. Efficacy of the combination ethinyl oestradiol and cyproterone acetate on endocrine, clinical and ultrasonographic profile in polycystic ovarian syndrome. Human Reproduction 16: 36–42, 2001.PubMedCrossRefGoogle Scholar
  71. 71.
    Dewis P, Petsos P, Newman M, Anderson DC. The treatment of hirsuitism with a combination of desogestrel and ethinyl oestradiol. Clin Endocrinol 22: 29–36, 1985.CrossRefGoogle Scholar
  72. 72.
    Bates GW, Whitworth NS. Effect of body weight reduction on plasma androgens in obese infertile women. Fertil Steril 38: 406–409, 1982.PubMedGoogle Scholar
  73. 73.
    Pasquali R, Antenucci D, Casimirri F, Venturoli S, Paradisi R, Fabbri R, et al. Clinical and hormonal characteristics of obese and amenorrheic women before and after weight loss. J Clin Endocrinol Metab 68: 173–9, 1989.PubMedCrossRefGoogle Scholar
  74. 74.
    Clark AM, Thornley B, Tomlinson L, Galletley C, Norman RJ. Weight loss in obese infertile women results in improvement in reproductive outcome for all forms of fertility treatment. Hum Reprod 13: 1502–5, 1998.PubMedCrossRefGoogle Scholar
  75. 75.
    Crave JC, Fimbel S, Lejeune H, Cugnardey N, DeChaud H, Pugeat M. Effects of diet and metformin administration on sex hormone-binding globuliln, androgens, and insulin in hirsute and obese women. J Clin Endocrinol Metab 80: 2057–2062, 1995.PubMedCrossRefGoogle Scholar
  76. 76.
    Moghetti P. Castello R. Negri C. Tosi F. Perrone F. Caputo M. Zanolin E. Muggeo M. Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation. J Clin Endocrinol Metab 85: 13946, 2000.Google Scholar
  77. 77.
    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 338: 1876–1880, 1998.PubMedCrossRefGoogle Scholar
  78. 78.
    Bloomgarden ZT, Futterwiet W, Poretsky L. The use of insulin-sensitizing agents in patients with polycystic ovary syndrome. Endocr Pract. 7: 279–286, 2001.PubMedCrossRefGoogle Scholar
  79. 79.
    Velazquez E. Acosta A, Mendoza SG. Menstrual cyclicity after metformin therapy in polycystic ovary syndrome. Obstetrics and Gynecology 90: 392–395, 1997.PubMedCrossRefGoogle Scholar
  80. 80.
    Jakubowicz DJ, Seppala M, Jakubowicz S, Rodriguez-Armas O, Rivas-Santiago A, Koistinen H, Koistinen R, Nestler JE. Insulin reduction with metformin increases luteal phase serum glycodelin and insulin-like growth factor-binding protein 1 concentrations and enhances uterine vascularity and blood flow in the polycystic ovary syndrome. J Clin Endocrinol Metab 86: 1126–1133, 2001.PubMedCrossRefGoogle Scholar
  81. 81.
    Dunaif A, Scott D, Finegood D, Quintana B, Whitcomb R. The insulin-sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. J Clin Endocrinol Metab 81: 3299–3306, 1996.PubMedCrossRefGoogle Scholar
  82. 82.
    Azziz R, Ehrmann D, Legro RS, Whitcomb RW, Hanley R, Fereshetian AG, O’Keefe M, Ghazzi MN. Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: A multicenter, double blind, placebo-controlled trial. J Clin Endocrinol Metab 86: 1626–1632, 2001.Google Scholar
  83. 83.
    Nestler JE, Jakubowicz DJ, Reamer P, Gunn RD, Allan G. Ovulatory and metabolic effects of D-chiro-inositol in the polycystic ovary syndrome. N Engl J Med 340: 1314–1320, 1999.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media New York 2004

Authors and Affiliations

  • Susan B. Zweig
  • Marsha C. Tolentino
  • Leonid Poretsky

There are no affiliations available

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