Insulin resistance and the polycystic ovary syndrome: Mechanism and implications for pathogenesis

Endocrine Reviews

Volumn 18, Issue 6, 1997, Pages 774-800

  Dunaif, Andrea ^a,b  

^a PENN STATE COLLEGE OF MEDICINE   (United States)

^b BRIGHAM AND WOMEN S HOSPITAL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANDROGEN; ANTIANDROGEN; BUSERELIN; FLUTAMIDE; HEXACYCLINE; INSULIN; INSULIN RECEPTOR; LUTEINIZING HORMONE; MEDROXYPROGESTERONE ACETATE; ORAL CONTRACEPTIVE AGENT; SOMATOMEDIN C RECEPTOR; SPIRONOLACTONE; TRIPHASIC CONTRACEPTIVE AGENT; TROGLITAZONE;

ANIMAL CELL; ANIMAL MODEL; CONTROLLED STUDY; DISEASE ASSOCIATION; FEMALE; HUMAN; HUMAN CELL; HYPERANDROGENISM; HYPERINSULINEMIA; INSULIN RELEASE; INSULIN RESISTANCE; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; ORAL DRUG ADMINISTRATION; OVARY POLYCYSTIC DISEASE; PATHOGENESIS; PHENOTYPE; PRIORITY JOURNAL; REVIEW;

DIABETES MELLITUS, TYPE 2; FEMALE; HUMANS; INSULIN; INSULIN RESISTANCE; POLYCYSTIC OVARY SYNDROME;

EID: 0031456016     PISSN: 0163769X     EISSN: None     Source Type: Journal    
DOI: 10.1210/er.18.6.774     Document Type: Review

References (278)

1. Dunaif A, Givens JR, Haseltine F, Merriam GR (eds) 1992 The Polycystic Ovary Syndrome. Blackwell Scientific, Cambridge, MA
2. Franks S 1995 Polycystic ovary syndrome. N Engl J Med 333:853-861
3. Poison DW, Wadsworth J, Adams J, Franks S 1988 Polycystic ovaries - a common finding in normal women. Lancet 1:870-872
4. Pettersson F, Fries H, Nillius SJ 1973 Epidemiology of secondary amenorrhea. Am J Obstet Gynecol 117:80-86
5. Hull MGR 1987 Epidemiology of infertility and polycystic ovarian disease: endocrinological and demographic studies. Gynecol Endocrinol 1:235-245
6. Goldzieher JW, Green JA 1962 The polycystic ovary. I. Clinical and histologic features. J Clin Endocrinol Metab 22:325-338
7. Burghen GA, Givens JR, Kitabchi AE 1980 Correlation of hyperandrogenism with hyperinsulinism in polycystic ovarian disease. J Clin Endocrinol Metab 50:113-116
8. Dunaif A, Hoffman AR 1988 Insulin resistance and hyperandrogenism: clinical syndromes and possible mechanisms. In: Pancheri P, Zichella L (eds) Biorhythms and Stress in the Physiopathology of Reproduction. Hemisphere Publishing Co, Washington, DC, pp 293-317
9. Barbieri RL, Ryan KJ 1983 Hyperandrogenism, insulin resistance, and acanthosis nigricans syndrome: a common endocrinopathy with distinct pathophysiologic features. Am J Obstet Gynecol 147:90
10. Poretsky L, Kalin MF 1987 The gonadotropic function of insulin. Endocr Rev 8:132-141
11. Poretsky L 1991 On the paradox of insulin-induced hyperandrogenism in insulin-resistant states. Endocr Rev 12:3-13
12. Ehrmann DA, Barnes RB, Rosenfield RL 1995 Polycystic ovary syndrome as a form of functional ovarian hyperandrogenism due to dysregulation of androgen secretion. Endocr Rev 16:322-353
13. Crowley WF 1996 New tools for pituitary-gonadal assessment. In: Filicori M, Flagmini C (eds) The Ovary: Regulation, Dysfunction and Treatment. Elsevier, Amsterdam, pp 287-293
14. Achard C, Thiers J 1921 Le virilisme pilaire et son association a l'insuffisance glycolytique (diabete des femmes a barb). Bull Acad Natl Med 86:51-64
15. Kierland RR, Lakatos I, Szijarto L 1947 Acanthosis nigricans: An analysis of data in twenty-two cases and a study of its frequency in necropsy material. J Invest Dermatol 9:299-305
16. Brown J, Winkelmann RK 1968 Acanthosis nigricans: a study of 90 cases. Medicine 47:33-51
17. Barnes ND, Palumbo PJ, Hayles AM, Folgar H 1974 Insulin resistance, skin changes and virilization: a recessively inherited syndrome possibly due to pineal gland dysfunction. Diabetologia 10: 284-289
18. Colle M, Doyard P, Chaussain J, Battin J, Job J 1979 Acanthosis nigricans, hirsutisme et diabete insulin-resistant. Arch Fr Pediatr 36:518-523
19. Taylor SI, Cama A, Accili D, Barbetti F, Quon J, Sierra MDLL, Suzuki Y, Koller E, Levy-Toledano R, Wertheimer E, Moncada VY, Kadowaki H, Kadowaki T 1992 Mutations in the insulin receptor gene. Endocr Rev 13:566-595
20. Dunaif A 1992 Insulin resistance and ovarian hyperandrogenism. The Endocrinologist 2:248-260
21. Kahn CR, Flier JS, Bar RS, Archer JA, Gorden P, Martin MM, Roth J 1976 The syndromes of insulin resistance and acanthosis nigricans. N Engl J Med 294:739-745
22. Flier JS, Kahn R, Roth J, Bar RS 1975 Antibodies that impair insulin receptor binding in an unusual diabetic syndrome with severe insulin resistance. Science 190:63-65
23. O'Rahilly S, Woong HC, Patel P, Turner RC, Flier JS, Moller DE 1991 Detection of mutations in insulin-receptor gene in NIDDM patients by analysis of single-stranded conformation polymorphisms. Diabetes 40:777-782
24. Flier JS, Eastman RC, Minaker KL, Matteson D, Rowe JW 1985 Acanthosis nigricans in obese women with hyperandrogenism. Characterization of an insulin-resistant state distinct from the Type A and B syndromes. Diabetes 34:101-107
25. Dunaif A, Huffman AR, Scully RE, Flier JS, Longcope C, Levy LJ, Crowley Jr WF 1985 The clinical, biochemical and ovarian morphologic features in women with acanthosis nigricans and masculinization. Obstet Gynecol 66:545-552
26. Stuart CA, Peters EJ, Prince MJ, Richards G, Cavallo A, Meyer WJ 1986 Insulin resistance with acanthosis nigricans: the roles of obesity and androgen excess. Metabolism 35:197-205
27. Peters EJ, Stuart CA, Prince MJ 1986 Acanthosis nigricans and obesity: acquired and intrinsic defects in insulin action. Metabolism 35:807-813
28. Pasquali R, Venturoli S, Paradisi R, Capelli M, Parenti N, Melchionda N 1982 Insulin and C-peptide levels in obese patients with polycystic ovaries. Horm Metab Res 14:284-287
29. Shoupe D, Kumar DD, Lobo RA 1983 Insulin resistance in polycystic ovary syndrome. Am J Obstet Gynecol 147:588-592
30. Chang RJ, Nakamura RM, Judd HL, Kaplan SA 1983 Insulin resistance in nonobese patients with polycystic ovarian disease. J Clin Endocrinol Metab 57:356-359
31. Judd HL, Scully RE, Herbst AL, Yen SSC, Ingersol FM, Kliman B 1973 Familial hyperthecosis: comparison of endocrinologic and histologic findings with polycystic ovarian disease. Am J Obstet Gynecol 117:976-982
32. Hughesdon PE 1982 Morphology and morphogenesis of the steinleventhal ovary and of so-called "hyperthecosis." Obstet Gynecol Surv 37:59-77
33. Nagamani M, Dinh TV, Kelver ME 1986 Hyperinsulinemia in hyperthecosis of the ovaries. Am J Obstet Gynecol 154:384-389
34. Keettel WC, Bradbury JT, Stoddard FJ 1957 Observations on the PCO syndrome. Am J Obstet Gynecol 73:954-65
35. Yen SSC, Vela P, Rankin J 1970 Inappropriate secretion of follicle-stimulating hormone and luteinizing hormone in polycystic ovarian disease. J Clin Endocrinol Metab 30:435-442
36. Rebar R, Judd HL, Yen SS, Rakoff J, Vandenberg G, Naftolin F 1976 Characterization of the inappropriate gonadotropin secretion in polycystic ovary syndrome. J Clin Invest 57:1320-9
37. Waldstreicher J, Santoro NF, Hall JE, Filicori M, Crowley Jr WF 1988 Hyperfunction of the hypothalamic-pituitary axis in women with polycystic ovarian disease: indirect evidence for partial gonadotroph desensitization. J Clin Endocrinol Metab 66:165-172
38. Dunaif A, Anderson R, Chapin D, Scully RE, Crowley Jr WF 1984 The effects of continuous androgen secretion upon the hypothalamic-pituitary-axis in women: evidence from a luteinized thecoma of the ovary, J Clin Endocrinol Metab 59:389-393
39. Lobo RA, Goebelsmann U 1980 Adult manifestation of congenital adrenal hyperplasia due to incomplete 21-hydroxylase deficiency mimicking polycystic ovarian disease. Am J Obstet Gynecol 138: 720-726
40. Santen RJ, Bardin CW 1973 Episodic luteinizing hormone secretion in man. Pulse analysis, clinical interpretation, physiologic mechanisms. J Clin Invest 52:2617-28
41. Ehrmann DA, Rosenfield RL, Barnes RB, Brigell DF, Sheikh Z 1992 Detection of functional ovarian hyperandrogenism in women with androgen excess. N Engl J Med 327:157-162
42. Yen SSC 1980 The polycystic ovary syndrome. Clin Endocrinol (Oxf) 12:177-208
43. McKenna TJ, Moore A, Magee F, Cunningham S 1983 Amenorrhea with cryptic hyperandrogenemia. J Clin Endocrinol Metab 56:893-896
44. Mechanick J, Dunaif A 1990 Masculinization: a clinical approach to the diagnosis and treatment of hyperandrogenic women. In: Mazzaferri E (ed) Advances in Endocrinology and Metabolism. Mosley Year Book, Inc, Chicago, IL, pp 129-173
45. Futterweit W, Dunaif A, Yeh H, Kingsley P 1988 The prevalence of hyperandrogenism in 109 consecutive women presenting with diffuse alopecia. J Am Acad Dermatol 19:831-836
46. Lobo RA, Goebelsmann U, Horton R 1983 Evidence for the importance of peripheral tissue events in the development of hirsutism in polycystic ovary syndrome. J Clin Endocrinol Metab 57: 393-397
47. Dunaif A 1992 Polycystic ovary syndrome and obesity. In: Bjorntorp P, Brodoff BN (eds) Obesity. J.B. Lippincott Co., Philadelphia, pp 594-605
48. Quintana B, Chinchilli V, Sieber J, Fultz P, George N, Dunaif A, High risk of glucose intolerance (GI) in women with oligomenorrhea (oligo) or with polycystic ovary syndrome (PCOS). Program of the 77th Annual Meeting of The Endocrine Society, Washington DC, 1995 (Abstract OR3-5:50)
49. Dunaif A, Graf M, Mandeli J, Laumas V, Dobrjansky A 1987 Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance and/or hyperinsulinemia. J Clin Endocrinol Metab 65:499-507
50. Dunaif A, Green G, Phelps RG, Lebwohl M, Futterweit W, Lewy L 1991 Acanthosis nigricans, insulin action, and hyperandrogenism: clinical, histological, and biochemical findings. J Clin Endocrinol Metab 73:590-595
51. Kahn CR 1994 Insulin action, diabetogenes, and the cause of Type II diabetes. Diabetes 43:1066-1084
52. Modan M, Harris MI, Halkin H 1989 Evaluation of WHO and NDDG criteria for impaired glucose tolerance. Diabetes 38:1603-1635
53. Dahlgren E, Johansson S, Lindstedt G, Knutsson F, Oden A, Janson PO, Mattson L, Crona N, Lundberg P 1992 Women with polycystic ovary syndrome wedge resected in 1956 to 1965: a long-term follow-up focusing on natural history and circulating hormones. Fertil Steril 57:505-513
54. Dunaif A, Futterweit W, Segal KR, Dobrjansky A 1989 Profound peripheral insulin resistance, independent of obesity, in the polycystic ovary syndrome. Diabetes 38:1165-1174
55. Dunaif A, Segal KR, Shelley DR, Green G, Dobrjansky A, Licholai T 1992 Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome. Diabetes 41:1257-1266
56. Dunaif A, Sorbara L, Delson R, Green G 1993 Ethnicity and polycystic ovary syndrome are associated with independent and additive decreases in insulin action in Caribbean Hispanic women. Diabetes 42:1462-1468
57. Dunaif A, Finegood DT 1996 β-Cell dysfunction independent of obesity and glucose intolerance in the polycystic ovary syndrome. J Clin Endocrinol Metab 81:942-947
58. Apter D, Butzow T, Laughlin GA, Yen SSC 1995 Metabolic features of polycystic ovary syndrome are found in adolescent girls with hyperandrogenism. J Clin Endocrinol Metab 80:2966-2973
59. Harris MI, Hadden WC, Knowler WC, Bennett PH 1987 Prevalence of diabetes and impaired glucose tolerance and plasma glucose levels in U.S. population aged 20-74 yr. Diabetes 36:523-534
60. DeFronzo RA 1988 The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 37:667-687
61. DeFronzo RA, Tobin JD, Andres R 1979 Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 237:E214-E223
62. Bergman RN, Hope ID, Yang YJ, Watanabe RM, Meador MA, Youn JH, Ader M 1989 Assessment of insulin sensitivity in vivo: a critical review. Diabetes Metab Rev 5:411-429
63. Yki-Jarvinen H, Koivisto VA 1983 Effects of body composition on insulin sensitivity. Diabetes 32:965-969
64. Bogardus C, Lillioja S, Mott DM, Hollenbeck C, Reaven G 1985 Relationship between degree of obesity and in vivo insulin action in man. Am J Physiol 248:E286-E291
65. Caro JF, Dohm LG, Pories WJ, Sinha MK 1989 Cellular alterations in liver, skeletal muscle, and adipose tissue responsible for insulin resistance in obesity and Type II diabetes. Diabetes Metab Rev 5:665-689
66. Kissebah AH, Peiris AN 1989 Biology of regional body fat distribution: relationship to non-insulin-dependent diabetes mellitus. Diabetes Metab Rev 5:83-109
67. Bagatell CJ, Bremner WJ 1996 Androgens in men - uses and abuses. N Engl J Med 334:707-714
68. Morales AJ, Laughlin GA, Bützow T, Maheshwari H, Baumann G, Yen SSC 1996 Insulin, somatotropic, and luteinizing hormones axes in lean and obese women with polycystic ovary syndrome: common and distinct features. J Clin Endocrinol Metab 81:2854-2864
69. Dunaif A, Xia J, Book C, Schenker E, Tang Z 1995 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
70. Dunaif A 1995 Hyperandrogenic anovulation (PCOS): a unique disorder of insulin action associated with an increased risk of NIDDM. Am J Med 98:33-39
71. Holte J, Bergh T, Berne C, Berglund L, Lithell H 1994 Enhanced early insulin response to glucose in relation to insulin resistance in women with polycystic ovary syndrome and normal glucose tolerance. J Clin Endocrinol Metab 78:1052-1058
72. Bergman RN, Phillips LS, Cobelli C 1981 Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity from the response to intravenous glucose. J Clin Invest 68:1456-1467
73. Bergman RN 1989 Toward physiological understanding of glucose tolerance. Minimal model approach. Diabetes 38:1512-1527
74. Kahn SE, Prigeon RL, McCulloch DK, Boyko EJ, Bergman RN, Schwartz MW, Neifing JL, Ward WK, Beard JC, Palmer JP, Porte Jr D 1993 Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Diabetes 42:1663-1672
75. O'Meara NM, Blackman JD, Ehrmann DA, Barnes RB, Jaspan JB, Rosenfield RL, Polonsky KS 1993 Defects in β-cell function in functional ovarian hyperandrogenism. J Clin Endocrinol Metab 76:1241-1247
76. Ehrmann DA, Stuns J, Byrne MM, Karrison T, Rosenfield RL, Polonksy KS 1995 Insulin secretory defects in polycystic ovary syndrome. Relationship to insulin sensitivity and family history of non-insulin-dependent diabetes mellitus. J Clin Invest 96:520-527
77. Weber RFA, Pache TD, Jacobs ML, Docter R, Loriaux DL, Fauser BCJM, Birkenhager JC 1993 The relation between clinical manifestations of polycystic ovary syndrome and beta-cell function. Clin Endocrinol (Oxf) 38:295-300
78. Flier JS, Minaker KL, Landsberg L, Young JB, Pallotta J, Rowe JW 1982 Impaired in vivo insulin clearance in patients with severe target-cell resistance to insulin. Diabetes 31:132-135
79. Marshall S 1985 Kinetics of insulin receptor internalization and recycling in adipocytes. Shunting of receptors to a degradative pathway by inhibitors of recycling. J Biol Chem 260:4136-4144
80. Mahabeer S, Jialal I, Norman RJ, Naidoo C, Reddi K, Joubert SM 1989 Insulin and C-peptide secretion in non-obese patients with polycystic ovarian disease. Horm Metab Res 21:502-506
81. Peiris AN, Mueller RA, Struve MF, Smith GA, Kissebah AH 1987 Relationship of androgenic activity to splanchnic insulin metabolism and peripheral glucose utilization in premenopausal women. J Clin Endocrinol Metab 64:162-169
82. Cheatham B, Kahn CR 1995 Insulin action and the insulin signaling network. Endocr Rev 16:117-142
83. Kahn CR 1985 The molecular mechanism of insulin action. Annu Rev Med 36:429-451
84. Kasuga M, Hedo JA, Yamada KM, Kahn CR 1982 The structure of the insulin receptor and its subunits: evidence for multiple non-reduced forms and a 210 kD possible proreceptor. J Biol Chem 257:10392-10399
85. Ullrich A, Bell JR, Chen EY, Herrera R, Petruzzelli LM, Dull TJ, Gray A, Coussens L, Liao Y-C, Tsubokawa M, Mason A, Seeburg PH, Grunfeld C, Rosen OM, Ramachandran J 1985 Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. Nature 313:756-761
86. Ebina Y, Ellis L, Jarnagin K, Edery M, Graf L, Clauser E, Ou J, Masiarz F, Kan YW, Goldfine ID, Roth RA, Rutter WJ 1985 The human insulin receptor cDNA: the structural basis for hormone-activated transmembrane signalling. Cell 40:747-758
87. Kasuga M, Karlsson FA, Kahn CR 1982 Insulin stimulates the phosphorylation of the 95,000-dalton subunit of its own receptor. Science 215:185-187
88. Ullrich A, Schlessinger J 1990 Signal transduction by receptors with tyrosine kinase activity. Cell 61:203-212
89. Cantley LC, Auger KR, Carpenter C, Duckworth B, Graziani A, Kapeller R, Soltoff S 1991 Oncogenes and signal transduction. Cell 64:281-302 [published erratum appears in Cell 1991 May 31; 65(5): following 914]
90. Cobb MH, Sang BC, Gonzalez R, Goldsmith E, Ellis L 1989 Autophosphorylation activates the soluble cytoplasmic domain of the insulin receptor in an intermolecular reaction. J Biol Chem 264:18701-18706
91. Shoelson SE, Boni-Schnetzler M, Pilch PF, Kahn CR 1991 Autophosphorylation within insulin receptor β-subunits can occur as an intramolecular process. Biochemistry 30:7740-7746
92. Frattali AL, Treadway JL, Pessin JE 1992 Transmembrane signaling by the human insulin receptor kinase. Relationship between intramolecular β subunit trans- and cis-autophosphorylation and substrate kinase activation. J Biol Chem 267:19521-19528
93. Myers Jr MG, Sun XJ, White MF 1994 The IRS-1 signaling system. Trends Biochem Sci 19:289-293
94. Sun XJ, Rothenberg P, Kahn CR, Backer JM, Araki E, Wilden PA, Cahill DA, Goldstein BJ, White MF 1991 Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature 352:73-77
95. Sun XJ, Wang LM, Zhang Y, Yenush L, Myers Jr MG, Glasheen E, Lane WS, Pierce JH, White MF 1995 Role of IRS-2 in insulin and cytokine signalling. Nature 377:173-177
96. Patti ME, Sun XJ, Bruening JC, Araki E, Lipes MA, White MF, Kahn CR 1995 4PS/insulin receptor substrate (IRS)-2 is the alternative substrate of the insulin receptor in IRS-1-deficient mice. J Biol Chem 270:24670-24673
97. Sasaoka T, Rose DW, Jhun BH, Saltiel AR, Draznin B, Olefsky JM 1995 Evidence for a functional role of Shc proteins in mitogenic signaling induced by insulin, insulin-like growth factor-1, and epidermal growth factor. J Biol Chem 269:13689-13694
98. Rose DW, Saltiel AR, Majumdar M, Decker SJ 1994 Insulin receptor substrate 1 is required for insulin-mediated mitogenic signal transduction. Proc Natl Acad Sci USA 91:797-801
99. Waters SB, Yamauchi K, Pessin JE 1993 Functional expression of insulin receptor substrate-1 is required for insulin-stimulated mitogenic signaling. J Biol Chem 268:22231-22234
100. Okada T, Kawano Y, SakakibaraT, Hazeki O, Ui M 1994 Essential role of phosphatidylinositol 3-kinase in insulin-induced glucose transport and antilipolysis in rat adipocytes. J Biol Chem 269:3568-3573
101. Cheatham B, Vlahos CJ, Cheatham L, Wang L, Blenis J, Kahn CR 1994 Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp70 S6 kinase, DNA synthesis and glucose transporter translocation. Mol Cell Biol 14:4902-4911
102. Kruszynska YT, Olefsky JM 1996 Cellular and molecular mechanisms of non-insulin dependent diabetes mellitus. J Invest Med 44:413-428
103. Theroux SJ, Latour DA, Stanley K, Raden DL, Davis RJ 1992 Signal transduction by the epidermal growth factor receptor is attenuated by a COOH-terminal domain serine phosphorylation site. J Biol Chem 267:16620-16626
104. Cochet C, Gill GN, Meisenhelder J, Cooper JA, Hunter T 1984 C-kinase phosphorylates the epidermal growth factor receptor and reduces its epidermal growth factor-stimulated tyrosine protein kinase activity. J Biol Chem 259:2553-2558
105. Bellage GE, Roth RA, Beaudoin J, Mochly-Rosen D, Koshland Jr DE 1986 Protein kinase C directly phosphorylates the insulin receptor in vitro and reduces its protein-tyrosine kinase activity. Proc Natl Acad Sci USA 83:5822-5824
106. Takayama S, White MF, Kahn CR 1988 Phorbol ester-induced serine phosphorylation of the insulin receptor decreases its tyrosine kinase activity. J Biol Chem 263:3440-3447
107. Karasik A, Rothenberg PL, Yamada K, White MF, Kahn CR 1990 Increased protein kinase C activity is linked to reduced insulin receptor autophosphorylation in liver of starved rats. J Biol Chem 265:10226-10230
108. Chin JE, Liu F, Roth RA 1994 Activation of protein kinase Cα inhibits insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1. Mol Endocrinol 8:51-58
109. Muller HK, Kellerer M, Ermel B, Muhlhofer A, Obermaier-Kusser B, Vogt B, Haring HU 1991 Prevention by protein kinase C inhibitors of glucose-induced insulin-receptor tyrosine kinase resistance in rat fat cells. Diabetes 40:1440-1448
110. Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM 1996 IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-α- and obesity-induced insulin resistance. Science 271:665-668
111. Boyle WJ, van der Geer P, Hunter T 1991 Phosphopeptide mapping and phosphoamino acid analysis by two-dimensional separation on thin-layer cellulose plates. Methods Enzymol 201:110-149
112. Fadden P, Haystead TAJ 1995 Quantitative and selective fluorophore labeling of phosphoserine on peptides and proteins: characterization at the attomole level by capillary electrophoresis and laser-induced fluorescence. Anal Biochem 225:81-88
113. Jialal I, Naiker P, Reddi K, Moodley J, Joubert SM 1987 Evidence for insulin resistance in nonobese patients with polycystic ovarian disease. J Clin Endocrinol Metab 64:1066-1069
114. Marsden PJ, Murdoch A, Taylor R 1994 Severe impairment of insulin action in adipocytes from amenorrheic subjects with polycystic ovary syndrome. Metabolism 43:1536-1542
115. Ciaraldi TP, El-Roeiy A, Madar Z, Reichart D, Olefsky JM, Yen SSC 1992 Cellular mechanisms of insulin resistance in polycystic ovarian syndrome. J Clin Endocrinol Metab 75:577-583
116. Ciaraldi TP, Morales AJ, Hickman MG, Odom-Ford R, Olefsky JM, Yen SSC 1997 Cellular insulin resistance in adipocytes from obese polycystic ovary syndrome subjects involves adenosine modulation of insulin sensitivity. J Clin Endocrinol Metab 82:1421-1425
117. Rosenbaum D, Haber RS, Dunaif A 1993 Insulin resistance in polycystic ovary syndrome: decreased expression of GLUT-4 glucose transporters in adipocytes. Am J Physiol 264:E197-E202
118. Caro JF 1991 Clinical Review 26. Insulin resistance in obese and nonobese man. J Clin Endocrinol Metab 73:691-695
119. Freidenberg GR, Reichart D, Olefsky JM, Henry RR 1988 Reversibility of defective adipocyte insulin receptor kinase activity in non-insulin-dependent diabetes mellitus. J Clin Invest 82:1398-1406
120. Sorbara LR, Tang Z, Cama A, Xia J, Schenker E, Kohanski RA, Poretsky L, Koller E, Taylor SI, Dunaif A 1994 Absence of insulin receptor gene mutations in three women with the polycystic ovary syndrome. Metabolism 43:1568-1574
121. Dunaif A, Diamanti E, Defective insulin receptor signaling in vivo in the polycystic ovary syndrome (PCOS). Program of the 57th Annual Scientific Meeting of the American Diabetes Association, Boston, MA, 1997 (Abstract 91)
122. Talbot JA, Bicknell EJ, Rajkhowa M, Krook A, O'Rahilly S, Clayton RN 1996 Molecular scanning of the insulin receptor gene in women with polycystic ovarian syndrome. J Clin Endocrinol Metab 81:1979-1983
123. Lewis RL, Cao L, Perregaux D, Czech MP 1990 Threonine 1336 of the human insulin receptor is a major target for phosphorylation by protein kinase C. Biochemistry 29:1807-1813
124. Pillay TS, Whittaker J, Lammers P, Ullrich A, Siddle K 1991 Multisite serine phosphorylation of the insulin and IGF-1 receptors in transfected cells. FEBS Lett 288:206-211
125. Rapuano M, Rosen OM 1991 Phosphorylation of the insulin receptor by a casein kinase I-like enzyme. J Biol Chem 266:12902-12907
126. Roth RA, Beaudoin J 1987 Phosphorylation of purified insulin receptor by cAMP kinase. Diabetes 36:123-126
127. Stadtmaurer L, Rosen OM 1986 Increasing the cAMP content of IM-9 cells alters the phosphorylation state and protein kinase activity of the insulin receptor. J Biol Chem 261:3402-3407
128. Kemp BE, Graves DJ, Benjamin E, Krebs EG 1977 Role of multiple basic residues in determining the substrate specificity of cyclic AMP-dependent protein kinase. J Biol Chem 252:4888-4893
129. Guo H, Damuni Z 1993 Autophosphorylation-activated protein kinase phosphorylates and inactivates protein phosphatase 2A. Proc Natl Acad Sci USA 90:2500-2504
130. Maddux BA, Sbraccia P, Kumakura S, Sasson S, Youngren J, Fisher A, Spencer S, Grupe A, Henzel W, Stewart TA, Reaven GM, Goldfine ID 1995 Membrane glycoprotein PC-1 and insulin resistance in non-insulin-dependent diabetes mellitus. Nature 373: 448-451
131. Sbraccia P, Goodman PA, Maddux BA, Wong KY, Chen YI, Reaven GM, Goldfine ID 1991 Production of inhibitor of insulin-receptor tyrosine kinase in fibroblasts from patient with insulin resistance and NIDDM. Diabetes 40:295-299
132. Legro RS, Fox J, Dunaif A, Insulin resistance is a potential phenotypic marker for familial polycystic ovary syndrome (PCOS). Proceedings of the 50th Annual Meeting of the American Fertility Society, San Antonio, TX, 1994 (Abstract)
133. Jahanfar S, Eden JA, Warren P, Seppala M, Nguyen TV 1995 A twin study of polycystic ovary syndrome. Fertil Steril 63:478-486
134. Norman RJ, Masters S, Hague W 1996 Hyperinsulinemia is common in family members of women with polycystic ovary syndrome. Fertil Steril 66:942-947
135. Ovesen P, Moller J, Ingerslev HJ, Jorgensen JOL, Mengel A, Schmitz O, George K, Alberti MM, Moller N 1993 Normal basal and insulin-stimulated fuel metabolism in lean women with the polycystic ovary syndrome. J Clin Endocrinol Metab 77:1636-1640
136. Holte J, Bergh T, Berne C, Wide L, Lithell H 1995 Restored insulin sensitivity but persistently increased early insulin secretion after weight loss in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab 80:2586-2593
137. Robinson S, Kiddy D, Gelding SV, Willis D, Niththyananthan R, Bush A, Johnston DG, Franks S 1993 The relationship of insulin insensitivity to menstrual pattern in women with hyperandrogenism and polycystic ovaries. Clin Endocrinol (Oxf) 39:351-355
138. Sampson M, Kong C, Patel A, Unwin R, Jacobs HS 1996 Ambulatory blood pressure profiles and plasminogen activator inhibitor (PAI-1) activity in lean women with and without the polycystic ovary syndrome. Clin Endocrinol (Oxf) 45:623-629
139. Carmina E, Koyama T, Chang L, Stanczyk FZ, Lobo RA 1992 Does ethnicity influence the prevalence of adrenal hyperandrogenism and insulin resistance in polycystic ovary syndrome? Am J Obstet Gynecol 167:1807-1812
140. Norman RJ, Mahabeer S, Masters S 1995 Ethnic differences in insulin and glucose response to glucose between white and Indian women with polycystic ovary syndrome. Fertil Steril 63:58-62
141. Tattersall RB, Fajans SS 1975 A difference between the inheritance of classical juvenile-onset and maturity-onset type diabetes of young people. Diabetes 24:44-53
142. Ghosh S, Schork NJ 1996 Genetic analysis of NIDDM. The study of quantitative traits. Diabetes 45:1-14
143. Lillioja S, Mott DM, Zawadzki JK, Young AA, Abbott WGH, Knowler WC, Bennett PH, Moll P, Bogardus C 1987 In vivo insulin action is familial characteristic in nondiabetic Pima indians. Diabetes 36:1329-1335
144. Hanis CL, Boerwinkle E, Chakraborty R, Ellsworth DL, Concannon P, Stirling B, Morrison VA, Wapelhorst B, Spielman RS, Gogolin-Ewens KJ, Shepard JM, Williams SR, Risch N, Hinds D, Iwasaki N, Ogata M, Omori Y, Petzold C, Rietzch H, Schroder HE, Schulze J, Cox NJ, Menzel S, Boriraj VV, Chen X, Lim LR, Lindner T, Mereu LE, Wang YQ, Xiang K, Yamagata K, Yang Y, Bell GI 1996 A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2. Nat Genet 13:161-166
145. Warram JH, Martin BC, Krolewski AS, Soeldner JS, Kahn CR 1990 Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents. Ann Intern Med 113:909-915
146. Mitrakou A, Kelley D, Mokan M, Veneman T, Pangburn T, Reilly J, Gerich J 1992 Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance. N Engl J Med 326:22-29
147. Pimenta W, Korytkowski M, Mitrakou A, Jenssen T, Yki-Jarvinen H, Evron W, Dailey G, Gerich J 1995 Pancreatic beta-cell dysfunction as the primary genetic lesion in NIDDM. JAMA 273:1855-1861
148. Froguel P, Zouali H, Vionnet N, Velho G, Vaxillaire M, Sun F, Lesage S, Stoffel M, Takeda J, Passa P, Permutt MA, Beckmann JS, Bell GI, Cohen D 1993 Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of diabetes mellitus. N Engl J Med 328:697-702
149. Gerbitz K, Gempel K, Brdiczka D 1996 Mitochondria and diabetes. Genetic, biochemical, and clinical implications of the cellular energy circuit. Diabetes 45:113-126
150. Pillay TS, Langlois WJ, Olefsky JM 1995 The genetics of noninsulin-dependent diabetes mellitus. Adv Genet 32:51-98
151. Beck-Nielsen H 1989 Insulin resistance in skeletal muscles of patients with diabetes mellitus. Diabetes Metab Rev 5:487-493
152. Unger RH 1995 Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genetic and clinical implications. Diabetes 44:863-870
153. Wells AM, Sutcliffe IC, Johnson AB, Taylor R 1993 Abnormal activation of glycogen synthesis in fibroblasts from NIDDM subjects. Diabetes 42:583-89
154. Rothman DL, Magnusson I, Cline G, Gerard D, Kahn CR, Shulman RG, Shulman GI, 1995 Decreased muscle glucose transport/phosphorylation is an early defect in the pathogenesis of non-insulin-dependent diabetes mellitus. Proc Natl Acad Sci USA 92:983-987
155. Price TB, Perseghin G, Duleba A, Chen W, Chase J, Rothman DL, Shulman RG, Shulman GI 1996 NMR studies of muscle glycogen synthesis in insulin-resistant offspring of parents with non-insulin-dependent diabetes mellitus immediately after glycogen-depleting exercise. Proc Natl Acad Sci USA 93:5329-5334
156. Perseghin G, Price TB, Petersen KF, Roden M, Cline GW, Gerow K, Rothman DL, Shulman GI 1996 Increased glucose transport-phosphorylation and muscle glycogen synthesis after exercise training in insulin-resistant subjects. N Engl J Med 335:1357-1362
157. Cox NJ, Xiang K, Fajans SS, Bell GI 1992 Mapping diabetes-susceptibility genes. Lessons learned from search for DNA marker for maturity-onset diabetes of the young. Diabetes 41:401-407
158. Yki-Jarvinen H 1984 Sex and insulin sensitivity. Metabolism 33: 1011-1015
159. Nuutila P, Knuuti MJ, Maki M, Laine H, Ruotsalainen U, Teras M, Haaparanta M, Solin O, Yki-Jarvinen H 1995 Gender and insulin sensitivity in the heart and in skeletal muscles. Studies using positron emission tomography. Diabetes 44:31-36
160. Foley JE, Kashiwagi A, Chang H, Huecksteadt TP, Lillioja S, Verso MA, Reaven G 1984 Sex differences in insulin-stimulated glucose transport in rat and human adipocytes. Am J Physiol 246: E211-E215
161. Moller DE, Flier JS 1991 Insulin resistance-mechanisms, syndromes, and implications. N Engl J Med 325:938-948
162. Godsland IF, Walton C, Felton C, Proudler A, Patel A, Wynn V 1992 Insulin resistance, secretion, and metabolism in users of oral contraceptives. J Clin Endocrinol Metab 74:64-70
163. Speiser PW, Serrat J, New MI, Gertner JM 1992 Insulin insensitivity in adrenal hyperplasia due to nonclassical steroid 21-hydroxylase deficiency. J Clin Endocrinol Metab 75:1421-1424
164. Polderman KH, Gooren JG, Asscherman H, Bakker A, Heine RJ 1994 Induction of insulin resistance by androgens and estrogens. J Clin Endocrinol Metab 79:265-271
165. Holmang A, Larsson BM, Brzezinska Z, Bjomtorp P 1992 Effects of short-term testosterone exposure on insulin sensitivity of muscles in female rats. Am J Physiol 262:E851-E855
166. Rincon J, Holmang A, Wahlstrom EO, Lonnroth P, Bjorntorp P, Zierath JR, Wallberg-Henriksson H 1996 Mechanisms behind insulin resistance in rat skeletal muscle after oophorectomy and additional testosterone treatment. Diabetes 45:615-621
167. Dunaif A, Green G, Futterweit W, Dobrjansky A 1990 Suppression of hyperandrogenism does not improve peripheral or hepatic insulin resistance in the polycystic ovary syndrome. J Clin Endocrinol Metab 70:699-704
168. Diamanti-Kandarakis E, Mitrakou A, Hennes MMI, Platanissiotis D, Kaklas N, Spina J, Georgiadou E, Hoffmann RG, Kissebah AH, Raptis S 1995 Insulin sensitivity and antiandrogenic therapy in women with polycystic ovary syndrome. Metabolism 44:525-531
169. Elkind-Hirsch KE, Valdes CT, Malinak LR 1993 Insulin resistance improves in hyperandrogenic women treated with Lupron. Fertil Steril 60:634-641
170. Moghetti P, Tosi F, Castello R, Magnani CM, Negri C, Brun E, Furlani L, Caputo M, Muggeo M 1996 The insulin resistance in women with hyperandrogenism is partially reversed by antiandrogen treatment: evidence that androgens impair insulin action in women. J Clin Endocrinol Metab 81:952-960
171. Marin P, Krotkiewski M, Bjorntorp P 1992 Androgen treatment of middle-aged, obese men: Effects on metabolism, muscle and adipose tissues. Eur J Med 6:329-336
172. Buffington CK, Givens JR, Kitabchi AE 1991 Opposing actions of dehydroepiandrosterone and testosterone on insulin sensitivity. Diabetes 40:693-700
173. Mortola JF, Yen SSC 1990 The effects of oral dehydroepiandrosterone on endocrine-metabolic parameters in postmenopausal women. J Clin Endocrinol Metab 71:696-704
174. Nestler JE, Barlascini CO, Clore JN, Blackard WG 1988 Dehydroepiandrosterone reduces serum low density lipoprotein levels and body fat but does not alter insulin sensitivity in normal men. J Clin Endocrinol Metab 66:57-61
175. Rittmaster RS, Deshwal N, Lehman L 1993 The role of adrenal hyperandrogenism, insulin resistance, and obesity in the pathogenesis of
176. Nestler JE, Strauss III JF 1991 Insulin as an effector of human ovarian and adrenal steroid metabolism. Endocrinol Metab Clin North Am 20:807-823
177. Diamond MP, Webster BW, Carr RK, Wentz AC, Osteen KG 1985 Human follicular fluid insulin concentrations. J Clin Endocrinol Metab 61:990-992
178. el-Roeiy A, Chen X, Roberts VJ, LeRoith D, Roberts Jr CT, Yen SSC 1993 Expression of insulin-like growth factor-I (IGF-I) and IGF-II and the IGF-I, IGF-II, and insulin receptor genes and localization of the gene products in the human ovary. J Clin Endocrinol Metab 77:1411-1418
179. el-Roeiy A, Chen X, Roberts VJ, Shimasakai S, Ling N, LeRoith D, Roberts Jr CT, Yen SSC 1994 Expression of the genes encoding the insulin-like growth factors (IGF-I and II), the IGF and insulin receptors, and IGF-binding proteins-1-6 and the localization of their gene products in normal and polycystic ovary syndrome ovaries. J Clin Endocrinol Metab 78:1488-1496
180. Czech MP 1982 Structural and functional homologies in the receptors for insulin and the insulin-like growth factors. Cell 31:8-10
181. Froesch ER, Zapf J 1985 Insulin-like growth factors and insulin: comparative aspects. Diabetologia 28:485-493
182. Leroith D, Werner H, Beitner-Johnson D, Roberts Jr CT 1995 Molecular and cellular aspects of the insulin-like growth factor I receptor. Endocr Rev 16:143-163
183. Bach LA, Rechler MM 1995 Insulin-like growth factor binding proteins. Diabetes Rev 3:38-61
184. Hintz RL, Thorsson AV, Enberg G, Hall K 1984 IGF-II binding on human lymphoid cells: demonstration of a common high affinity receptor for insulin like peptides. Biochem Biophys Res Commun 118:774-782
185. Jonas HA, Cox AJ, Harrison LC 1989 Delineation of atypical insulin receptors from classical insulin and type I insulin-like growth factor receptors in human placenta. Biochem J 257:101-107
186. Moxham CP, Duronio V, Jacobs S 1989 Insulin-like growth factor I receptor β-subunit heterogeneity. J Biol Chem 264:13238-13244
187. Moxham CP, Jacobs S 1992 Insulin/IGF-1 receptor hybrids: a mechanism for increasing receptor diversity. J Cell Biochem 48: 136-140
188. Erickson GF 1995 The ovarian connection. In: Adashi EY, Rock JA, Rosenwaks Z (eds) Reproductive Endocrinology, Surgery, and Technology. Raven Press, New York, pp 1141-1160
189. Mason HD, Cwyfan-Hughes SC, Heinrich G, Franks S, Holly JMP 1996 Insulin-like growth factor (IGF) I and II, IGF-binding proteins, and IGF-binding protein proteases are produced by theca and stroma of normal and polycystic human ovaries. J Clin Endocrinol Metab 81:276-284
190. Mason HD, Margara R, Winston RML, Beard RW, Reed MJ, Franks S 1990 Inhibition of oestradiol production by epidermal growth factor in human granulosa cells of normal and polycystic ovaries. Clin Endocrinol (Oxf) 33:404-410
191. Ballotti R, Lammers R, Scimeca J 1989 Intermolecular transphosphorylation between insulin receptors and EGF-insulin receptor chimerae. EMBO J 8:3303-3309
192. Poretsky L, Glover B, Laumas V, Kalin M, Dunaif A 1988 The effects of experimental hyperinsulinemia on steroid secretion, ovarian insulin receptors, and ovarian type I insulin-like-growth-factor receptors in the rat. Endocrinology 122:581-585
193. Willis D, Franks S 1995 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 80:3788-3790
194. Willis D, Mason H, Gilling-Smith C, Franks S 1996 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
195. Dunaif A, Book C-B, Selective intrinsic defects in insulin and IGF-1 action in polycystic ovary syndrome (PCOS) in skin fibroblasts. Program of the 56th Annual Meeting of The American Diabetes Association, San Francisco, CA, 1996 (Abstract 317)
196. Fox JH, Licholai T, Green G, Dunaif A 1993 Differential effects of oral glucose-mediated vs. intravenous hyperinsulinemia on circulating androgen levels in women. Fertil Steril 60:994-1000
197. Dunaif A, Graf M 1989 Insulin administration alters gonadal steroid metabolism independent of changes in gonadotropin secretion in insulin-resistant women with the polycystic ovary syndrome. J Clin Invest 83:23-29
198. Micic D, Popovic V, Nesovic M, Sumarac M, Dragasevic M, Kendereski A, Markovic D, Djordjevic P, Manojlovic D, Micic J 1988 Androgen levels during sequential insulin euglycemic clamp studies in patients with polycystic ovary disease. J Steroid Biochem 31:995-999
199. Nestler JE, Barlascini CO, Matt DW 1989 Suppression of serum insulin by diazoxide reduced serum testosterone levels in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab 68:1027
200. Prelevic GM, Wurzburger MI, Balint-Peric L, Nesic JS 1990 Inhibitory effect of sandostatin on secretion of luteinizing hormone, ovarian steroids in polycystic ovary syndrome. Lancet 336:900-903
201. Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ 1994 Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 43:647-654
202. Dunaif A, Scott D, Finegood D, Quintana B, Whitcomb R 1996 The insulin sensitizing agent troglitazone: a novel therapy for the polycystic ovary syndrome. J Clin Endocrinol Metab 81:3299-3306
203. Plymate SR, Matej LA, Jones RE 1988 Inhibition of sex hormone-binding globulin production in the human hepatoma (Hep G2) cell line by insulin and prolactin. J Clin Endocrinol Metab 67:460-464
204. Nestler JE 1993 Sex hormone-binding globulin: a marker for hyperinsulinemia and/or insulin resistance? J Clin Endocrinol Metab 76:273-274
205. Nestler JE, Jakubowicz DJ 1996 Decreases in ovarian cytochrome P450c17α activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med 335:617-623
206. Gasic S, Bodenburg YH, Nagamani M, Green A, Urban RJ, Troglitazone inhibits progesterone production in porcine granulosa cells. Program of the 79th Annual Meeting of The Endocrine Society, Minneapolis, MN, 1997 (Abstract P2-416)
207. Franks S, Mason H, White D, Willis D 1996 Mechanisms of anovulation in polycystic ovary syndrome. In: Filicori M, Flamigni C (eds) The Ovary: Regulation, Dysfunction and Treatment. Elsevier, Amsterdam, pp 183-186
208. Nestler JE, Singh R, Matt DW, Clore JN, Blackard WG 1990 Suppression of serum insulin level by diazoxide does not alter serum testosterone or sex hormone-binding globulin levels in healthy, nonobese women. Am J Obstet Gynecol 163:1243-1246
209. Adashi EY, Hsueh AJW, Yen SSC 1981 Insulin enhancement of luteinizing hormone and follicle-stimulating hormone release by cultured pituitary cells. Endocrinology 108:1441-1449
210. Beer NA, Jakubowicz DJ, Beer RM, Nestler JE 1994 Disparate effects of insulin reduction with diltiazem on serum dehydroepiandrosterone sulfate levels in obese hypertensive men and women. J Clin Endocrinol Metab 79:1077-1081
211. Moghetti P, Castello R, Negri C, Tosi F, Spiazzi GG, Brun E, Balducci R, Toscano V, Muggeo M 1996 Insulin infusion amplifies 17 α-hydroxycorticosteroid intermediates response to adrenocorticotropin in hyperandrogenic women: apparent relative impairment of 17,20-lyase activity. J Clin Endocrinol Metab 81:881-886
212. Cooper HE, Spellacy WN, Prem KA, Cohen WD 1968 Hereditary factors in Stein-Leventhal syndrome. Am J Obstet Gynecol 100: 371-387
213. Givens JR 1971 Familial ovarian hyperthecosis: a study of two families. Am J Obstet Gynecol 11:959-972
214. Wilroy RS, Givens JR, Weser WL, Coleman SA, Andersen RN, Fish SA 1975 Hyperthecosis - an inheritable form of polycystic ovarian disease. Birth Defects 11:81-85
215. Givens JR 1988 Familial polycystic ovarian disease. Endocrinol Metab Clin North Am 17:1-17
216. Ferriman D, Purdie AW 1979 The inheritance of polycystic ovarian disease and possible relationship to premature balding. Clin Endocrinol (Oxf) 1:291-299
217. Lunde O, Magnus P, Sandvik L, Hoglo S 1989 Familial clustering in the polycystic ovarian syndrome. Gynecol Obstet Invest 28:23-30
218. Mandel FP, Chang RJ, Dupont B, Pollack MS, Levine LS, New MI, Lu JKH, Judd HL 1983 HLA genotyping in family members and patients with familial polycystic ovarian disease. J Clin Endocrinol Metab 56:862-864
219. Ober C, Weil S, Steck T, Billstrand C, Levrant S, Barnes R 1992 Increased risk for polycystic ovary syndrome associated with human leukocyte antigen DQA1*0501. Am J Obstet Gynecol 167: 1803-1806
220. Legro RS 1995 The genetics of polycystic ovary syndrome. Am J Med 98:9S-16S
221. Rojanasakul A, Gustavson KH, Lithell H, Nillius SJ 1985 Tetraploidy in two sisters with the polycystic ovary syndrome. Clin Genet 27:167-174
222. Stenchever MA, Macintyre MN, Jarvis JA, Hempel JM 1968 Cytogenic evaluation of 41 patients with Stein-Leventhal syndrome. Obstet Gynecol 32:794-801
223. Hague WM, Adams J, Reeders ST, Peto TEA, Jacobs HS 1988 Familial polycystic ovaries: a genetic disease? Clin Endocrinol (Oxf) 29:593-605
224. Carey AH, Chan KL, Short F, White DM, Williamson R, Franks S 1993 Evidence for a single gene effect in polycystic ovaries and male pattern baldness. Clin Endocrinol (Oxf) 38:653-658
225. Gharani N, Waterworth DM, Batty S, White D, Gilling-Smith C, Conway GS, McCarthy M, Franks S, Williamson R 1997 Association of the steroid synthesis gene CYP11a with polycystic ovary syndrome and hyperandrogenism. Hum Mol Genet 6:307-403
226. Ibanez L, Potau N, Zampolli M, Prat N, Virdis R, Vicens-Calvet E, Carrascosa A 1996 Hyperinsulinemia in postpubertal girls with a history of premature pubarche and functional ovarian hyperandrogenism. J Clin Endocrinol Metab 81:1237-1243
227. Oppenheimer E, Linder B, DiMartino-Nardi J 1995 Decreased insulin sensitivity in prepubertal girls with premature adrenarche and acanthosis nigricans. J Clin Endocrinol Metab 80:614-618
228. Legro RS, Fox J, Dunaif A, Hyperandrogenic, cycling, insulin sensitive sisters: an additional familial PCOS phenotype. Program of the 10th International Congress of Endocrinology, San Francisco, 1996 (Abstract OR26-6)
229. Conte FA, Grumbach MM, Ito Y, Fisher CR, Simpson ER 1994 A syndrome of female pseudohermaphroditism, hypergonadotropic hypogonadism, and multicystic ovaries associated with missense mutations in the gene encoding aromatase (P450arom). J Clin Endocrinol Metab 78:1287-1292
230. Risma KA, Clay CM, Nett TM, Wagner T, Yun J, Nelson JH 1995 Targeted overexpression of luteinizing hormone in transgenic mice leads to infertility, polycystic ovaries, and ovarian tumors. Proc Natl Acad Sci USA 92:1322-1326
231. Zhang L, Rodriquez H, Ohno S, Miller WL 1995 Serine phosphorylation of human P450c17 increases 17,20 lyase activity: implications for adrenarche and the polycystic ovary syndrome. Proc Natl Acad Sci USA 92:10619-10623
232. Carey AH, Waterworth D, Patel K, White D, Little J, Novelli P, Franks S, Williamson R 1994 Polycystic ovaries and premature male pattern baldness are associated with one allele of the steroid metabolism gene CYP17. Hum Mol Genet 3:1873-1876
233. 232a.Gharani N, Waterworth DM, Williamson R, Franks S 1996 5′ Polymorphism of the CYP17 gene is not associated with serum testosterone levels in women with polycystic ovaries. J Clin Endocrinol Metab 81:4174
234. Waterworth DM, Bennett ST, Gharani N, McCarthy MI, Hague S, Batty S, Conway GS, White D, Todd JA, Franks S, Williamson R 1997 Linkage and association of insulin gene VNTR regulatory polymorphism with polycystic ovary syndrome. Lancet 349:986-990
235. Legro RS, Muhleman DR, Comings DE, Lobo RA, Kovacs BW 1995 A dopamine D3 receptor genotype is associated with hyperandrogenic chronic anovulation and resistant to ovulation induction with clomiphene citrate in female Hispanics. Fertil Steril 63:779-784
236. Legro RS, Shahbahrami B, Lobo RA, Kovacs BW 1995 Size polymorphisms of the androgen receptor among female hispanics and correlation with androgenic characteristics. Obstet Gynecol 83:701-706
237. Lander E, Kruglyak L 1995 Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 11:241-247
238. Barbieri RL, Gao X, Frost RA 1994 Phosphorylation of 17B-hydroxysteroid dehydrogenase in BeWo choriocarcinoma cells. Am J Obstet Gynecol 171:223-230
239. Hollenbeck C, Reaven GM 1987 Variations in insulin-stimulated glucose uptake in healthy individuals with normal glucose tolerance. J Clin Endocrinol Metab 64:1169-1173
240. Laakso M 1993 How good a marker is insulin level for insulin resistance? Am J Epidemiol 137:959-965
241. DeFronzo RA, Ferrannini E 1991 Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 14:173-194
242. Wild RA 1995 Obesity, lipids, cardiovascular risk, and androgen excess. Am J Med 98:27S-32S
243. Talbott E, Guzick D, Clerici A, Berga S, Detre K, Weimer K, Kuller L 1995 Coronary heart disease risk factors in women with polycystic ovary syndrome. Arter Throm Vas Biol 15:821-826
244. Conway GS, Agrawal R, Betteridge DJ, Jacobs HS 1992 Risk factors for coronary artery disease in lean and obese women with the polycystic ovary syndrome. Clin Endocrinol (Oxf) 37:119-125
245. Wild RA, Bartholomew MJ 1988 The influence of body weight on lipoprotein lipids on patients with polycystic ovary syndrome. Am J Obstet Gynecol 159:423-427
246. Wild RA, Alaupovic P, Parker IJ 1992 Lipid and apolipoprotein abnormalities in hirsute women. Am J Obstet Gynecol 166:1191-1197
247. Andersen P, Seljeflot I, Abdelnoor M, Arnesen H, Dale PO, Lovik A, Birkeland K 1995 Increased insulin sensitivity and fibrinolytic capacity after dietary intervention in obese women with polycystic ovary syndrome. Metabolism 44:611-616
248. Sobel BE 1996 Altered fibrinolysis and platelet function in the development of vascular complications of diabetes. Curr Opin Endocrinol Diabetes 3:355-360
249. Ehrmann DE, Schneider DJ, Sobel BE, Cavaghan JI, Rosenfield RL, Polonsky KS 1997 Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovary syndrome. J Clin Endocrinol Metab 82:2108-2116
250. Wild RA, Grubb BG, Hartz A, VanNort JJ, Bachman W, Bartholomew M 1990 Clinical signs of androgen excess as risk factors for coronary artery disease. Fertil Steril 54:255-259
251. Dahlgren E, Janson PO, Johansson S, Lapidus L, Oden A 1992 Polycystic ovary syndrome and risk for myocardial infarction. Acta Obstet Gynecol Scand 71:599-603
252. Birdsall MA, Farquhar CM, White HD 1997 Association between polycystic ovaries and extent of coronary artery disease in women having cardiac catheterization. Ann Intern Med 126:32-35
253. Guzick DS, Talbott EO, Sutton-Tyrrell K, Herzog HC, Kuller LH, Wolfson SK 1996 Carotid atherosclerosis in women with polycystic ovary syndrome: initial results from a case-control study. Am J Obstet Gynecol 174:1224-32
254. Graf M, Brown V, Richards C, Meissner L, Dunaif A 1990 The independent effects of hyperandrogenemia, hyperinsulinemia, and obesity on lipid and lipoprotein profiles in women. Clin Endocrinol (Oxf) 33:119-131
255. Holte J, Bergh T, Berne C, Lithell H 1994 Serum lipoprotein lipid profile in women with the polycystic ovary syndrome: relation to anthropometric, endocrine and metabolic variables. Clin Endocrinol (Oxf) 41:463-471
256. Legro RS, Blanche P, Krauss RM, Lobo RA, Alterations in atherogenic lipoproteins among hyperandrogenic women: influence of insulin and genetic factors. Program of the 40th Annual Meeting of the Society for Gynecologic Investigation, 1993 (Abstract P355:360)
257. Zimmerman S, Phillips RA, Wikenfeld C, Dunaif A, Finegood D, Ardeljan M, Wallenstein S, Gorlin R, Krakoff L 1992 Polycystic ovary syndrome: lack of hypertension despite insulin resistance. J Clin Endocrinol Metab 75:508-513
258. Saad MF, Lillioja S, Nyomba BL 1991 Racial differences in the relation between blood pressure and insulin resistance. N Engl J Med 324:733-739
259. Ryan EA, O'Sullivan MJ, Skyler JS 1985 Insulin action during pregnancy: studies with the euglycemic clamp technique. Diabetes 34:380-389
260. Ryan EA, Imes S, Dating L, McManus R, Finegood DT, Polonsky KS, Stuns J 1995 Defects in insulin secretion and action in women with a history of gestational diabetes. Diabetes 44:506-512
261. Wortsman J, de Angeles S, Futterweit W, Singh KB, Kaufmann RC 1991 Gestational diabetes and neonatal macrosomia in the polycystic ovary syndrome. J Reprod Med 36:659-661
262. Lanzone A, Caruso A, DiSimone N, DeCarolis S, Fulghesu AM, Mancuso S 1995 Polycystic ovary disease. A risk factor for gestational diabetes? J Reprod Med 40:312-316
263. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman J 1994 Positional cloning of the mouse obese gene and its human homologue. Nature 372:425-432
264. Caro JF, Sinha MK, Kolaczynski JW, Zhang PL, Considine RV 1996 Leptin: the tale of an obesity gene. Diabetes 45:1455-1462
265. Brzechffa PR, Jakimiuk AJ, Agarwal SK, Weitsman SR, Buyalos RP, Magoffin DA 1996 Serum immunoreactive leptin concentrations in women with polycystic ovary syndrome. J Glin Endocrinol Metab 81:4166-4169
266. Mantzoros CS, Dunaif A, Flier JS 1997 Leptin concentrations in the polycystic ovary syndrome. J Clin Endocrinol Metab 82:1687-1691
267. Laughlin GA, Morales AJ, Yen SSC 1997 Serum leptin levels in women with polycystic ovary syndrome: the role of insulin resistance/hyperinsulinemia. J Clin Endocrinol Metab 82:1692-1696
268. Korytkowski MT, Mokan M, Horwitz MJ, Berga SL 1995 Metabolic effects of oral contraceptives in women with polvcystic ovary syndrome. J Clin Endocrinol Metab 80:3327-3334
269. Elkind-Hirsch KE, Sherman LD, Malinak R 1993 Hormone replacement therapy alters insulin sensitivity in young women with premature ovarian failure. J Clin Endocrinol Metab 76:472-475
270. Bates G, Whitworth MS 1982 Effect of body weight reduction on plasma androgens in obese, infertile women. Fertil Steril 38:406-409
271. Kiddy DS, Hamilton-Fairley D, Bush A, Short F, Anyaoku V, Reed MJ, Franks S 1992 Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 36:105-111
272. Guzick DS, Wing R, Smith D, Berga SL, Winters SJ 1994 Endocrine consequences of weight loss in obese, hyperandrogenic, anovulatory women. Fertil Steril 61:598-604
273. DeFronzo RA, Barzilai N, Simonson DC 1991 Mechanism of metformin action in obese and lean noninsulin-dependent diabetic subjects. J Clin Endocrinol Metab 73:1294-1301
274. Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE 1995 Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med 333:550-554
275. DeFronzo RA, Goodman AM 1995 Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. N Engl J Med 333:541-549
276. Crave J, Fimbel S, Lejeune H, Cugnardey N, Dechaud H, Pugeat M 1995 Effects of diet and metformin administration on sex hormone-binding globulin, androgens, and insulin in hirsute and obese women. J Clin Endocrinol Metab 80:2057-2062
277. Acbay Ö, Gündoǧdu S 1996 Can metformin reduce insulin resistance in polycystic ovary syndrome? Fertil Steril 65:946-949
278. Ehrmann DA, Cavaghan MK, Imperial J, Sturis J, Rosenfield RL, Polonsky KS 1997 Effects of metformin on insulin secretion, insulin action, and ovarian steroidogenesis in women with polycystic ovary syndrome. J Clin Endocrinol Metab 82:524-530