Pathogenesis of polycystic ovary syndrome: What is the role of obesity?

Metabolism: Clinical and Experimental

Volumn 53, Issue 3, 2004, Pages 358-376

  Salehi, Marzieh ^a   Bravo Vera, Rafael ^a   Sheikh, Arsalan ^a   Gouller, Alina ^a   Poretsky, Leonid ^a,b  

^a ALBERT EINSTEIN COLLEGE OF MEDICINE   (United States)

^b BETH ISRAEL MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; ANTIANDROGEN; BUSERELIN; DIANE; FLUTAMIDE; GOSERELIN; INOSITOL DERIVATIVE; METFORMIN; ORAL CONTRACEPTIVE AGENT; PIOGLITAZONE; ROSIGLITAZONE; SPIRONOLACTONE; TROGLITAZONE; HORMONE;

CLINICAL FEATURE; CLINICAL TRIAL; HUMAN; HYPERINSULINEMIA; INSULIN RESISTANCE; OBESITY; OVARY POLYCYSTIC DISEASE; PATHOGENESIS; PRIORITY JOURNAL; REVIEW; BLOOD; ENDOCRINE DISEASE; FEMALE; GENETICS; HYPERINSULINISM; PATHOLOGY;

ENDOCRINE SYSTEM DISEASES; FEMALE; HORMONES; HUMANS; HYPERINSULINISM; INSULIN RESISTANCE; OBESITY; POLYCYSTIC OVARY SYNDROME;

EID: 2542490223     PISSN: 00260495     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.metabol.2003.10.005     Document Type: Review

References (212)

1. Stein IF, Leventhal ML: Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 29:181-191, 1935
2. Zawadski JK, Dunaif A: Diagnostic criteria for polycystic ovary syndrome: Towards a rational approach, in Dunaif A, Givens JR, Hasetline FP (eds): Polycystic Ovary Syndrome. Current Issues in Endocrinology and Metabolism. Boston, MA, Blackwell Scientific, 1992, pp 377-384
3. Polson DW, Adams J, Wadsworth J, et al: Polycystic ovaries - a common finding in normal women. Lancet 1:870-872, 1988
4. Adams J, Polson DW, Franks S: Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism. BMJ 293:355-359, 1986
5. Wentz AC, White RI, Migeon CJ, et al: Differential ovarian and adrenal vein catheterization. Am J Obstet Gynecol 125:1000-1007, 1976
6. Givens JR, Wiser WL, Coleman SA, et al: Familial ovarian hyperthecosis: A study of two families. Am J Obstet Gynecol 11:959, 1971
7. Simpson JL: Elucidating the genetics of polycystic ovary syndrome, in Dunaif A, Givens JR, Hasetline FP, et al (eds): Polycystic Ovary Syndrome. Current Issues in Endocrinology and Metabolism. Boston, MA, Blackwell Scientific, 1992, pp 59-69
8. 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 84:38-43, 1999
9. Solomon CG: The epidemiology of polycystic ovary syndrome. Prevalence and associated disease risks. Endocrinol Metab Clin North Am 28:247-263, 1999
10. Knochenhauer ES, Key TJ, Kahsar-Miller M, et al: Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: A prospective study. J Clin Endocrinol Metab 83:3078-3082, 1998
11. Diamanti-Kandarakis E, Kouli CR, Bergiele AT, et al: A survey of polycystic ovary syndrome in the Greek island of Lesbos: Hormonal and metabolic profile. J Clin Endocrinol Metab 84:4006-4011, 1999
12. Roumain J, Charles MA, de Courten MP, et al: The relationship of menstrual irregularity to type 2 diabetes in Pima Indian women. Diabetes Care 21:346-349, 1998
13. Chang RJ, Nakamura RM, Judd HL, et al: Insulin resistance in nonobese patients with polycystic ovarian disease. J Clin Endocrinol Metab 57:356-359, 1983
14. Klein S, Romijin JA: Obesity, in Larsen PR, Kronenberg HM, Melmed S (eds): Williams Textbook of Endocrinology (ed 10). Philadelphia, PA, Saunders, 2002, pp 1619-1641
15. Rabinowitz D, Zierler KL: Forearm metabolism in obesity and its response to intraarterial insulin. Characterization of insulin resistance and evidence for adaptative hyperinsulinism. J Clin Invest 12:2173-2181, 1962
16. Janssen I, Katzmarzyk PT, Ross R: Body mass index, waist circumference, and health risk: Evidence in support of current National Institutes of Health guidelines. Arch Intern Med 162:2074-2079, 2002
17. Kissebah AH, Vydelingum N, Murray R, et al: Relation of body fat distribution to metabolic complications of obesity. J Clin Endocrinol Metab 54:254-260, 1982
18. Larsson B, Svärdsudd K, Welin L, et al: Abdominal adipose tissue distribution, obesity and risk of cardiovascular disease and death: 13 year follow-up of participants in the study of men born in 1913. BMJ 288:1401-1404, 1984
19. Lapidus L, Bengtsson C, Larsson B, et al: Distribution of adipose tissue and risk of cardiovascular disease and death: A 12 year follow-up of participants in the population study of women in Gothenburg, Sweden. BMJ 289:1257-1261, 1984
20. Stokes J III, Garrison RJ, Kannel WB: The independent contributions of various indices of obesity to the 22-year incidence of coronary heart disease: The Framingham, Heart Study, in Vague J, Björntorp P, Guy-Grand B (eds): Metabolic Complications of Human Obesities. Amsterdam, The Netherlands, Elsevier, 1985, pp 49-57
21. Ross R, Freeman J, Hudson R, et al: Abdominal obesity, muscle composition, and insulin resistance in premenopausal women. J Clin Endocrinol Metab 87:5044-5051, 2002
22. Buffington CK, Kitabchi AE: Evidence for a defect in insulin metabolism in hyperandrogenic women with polycystic ovary syndrome. Metabolism 43:1367-1372, 1994
23. Peiris AN, Struve MF, Kissebah AH: Relationship of body fat distribution to the metabolic clearance of insulin in premenopausal women. Int J Obes 11:581-589, 1987
24. Holte J, Bergh T, Beme C, et al: Serum lipoprotein lipid profile in women with the polycystic ovary syndrome: Relation to anthropometric, endocrine and metabolic variables. Clin Endocrinol (Oxf) 41:463-471, 1994
25. Ek I, Arner P, Ryden M, et al: A unique defect in the regulation of visceral fat cell lipolysis in the polycystic ovary syndrome as an early link to insulin resistance. Diabetes 51:484-492, 2002
26. Havel RJ, Kane JP, Balasse EO, et al: Splanchnic metabolism of free fatty acids and production of triglyserides of very low-density lipoproteins in normotriglyceridemic and hypertriglyceridemic humans. J Clin Invest 49:2017-2035, 1970
27. Basu A, Basu R, Shah P, et al: Systemic and regional free fatty acid metabolism in type 2 diabetes. Am J Physiol 280:E1000-E1006, 2001
28. Svedberg J, Bjorntorp P, Smith U, et al: Free-fatty acid inhibition of insulin binding, degradation, and action in isolated rat hepatocytes. Diabetes 39:570-574, 1990
29. Boden G: Role of fatty acids in the pathogenesis of insulin resistance and NIIDM. Diabetes 46:3-10, 1997
30. Kelley DE: Skeletal muscle triglycerides: An aspect of regional adiposity and insulin resistance. Ann N Y Acad Sci 967:135-145, 2002
31. Hotamisligil GS, Peraldi P, Budavari A: IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science 271:665-668, 1996
32. Hrebicek A, Rypka M, Chmela Z, et al: Tumor necrosis factor alpha in various tissues of insulin-resistant obese Koletsky rats: Relations to insulin receptor characteristics. Physiol Res 48:83-86, 1999
33. Escobar-Morreale HF, Calvo RM, Sancho J, et al: TNF-alpha and hyperandrogenism: A clinical, biochemical, and molecular genetic study. J Clin Endocrinol Metab 86:3761-3767 2001
34. Gonzalez F, Thusu K, Abdel-Rahman E, et al: Elevated serum levels of tumor necrosis factor alpha in normal-weight women with polycystic ovary syndrome. Metabolism 48:437-441, 1999
35. Spaczynski RZ, Arici A, Duleba AJ: Tumor necrosis factor-α stimulates proliferation of rat ovarian theca-interstitial cells. Biol Reprod 61:993-998, 1999
36. Yen SSC, Vela P, Rankin J: Inappropriate secretion of follicle-stimulating hormone and luteinizing hormone in polycystic ovarian disease. J Clin Endocrinol Metab 30:435-442, 1970
37. Taylor AE, McCourt B, Martin KA, et al: Determinants of abnormal gonadotropin secretion in clinically defined women with polycystic ovary syndrome. J Clin Endocrinol Metab 82:2248-2256, 1997
38. Marshall JC, Eagleson CA: Neuroendocrine aspects of polycystic ovary syndrome. Endocrinol Metab Clin North Am 28:295-324, 1999
39. Yen SSC, Chaney C, Judd HL: Functional aberrations of the hypohalamic-pituitary system in PCOS - a consideration of pathogenesis, in Endocrine Function of the Human Ovary. New York, NY, Academic, 1976, pp 273
40. Poretsky L, Cataldo N, Rosenwaks Z, et al: The insulin-related ovarian regulatory system in health and disease. Endocr Rev 20:535-582, 1999
41. Hashizume T, Kumahara A, Fujino M, et al: Insulin-like growth factor I enhances gonadotropin-releasing hormone-stimulated luteinizing hormone release from bovine anterior pituitary cells. Anim Reprod Sci 70:13-21, 2002
42. Kovacs P, Parlow AF, Karkanias GB: Effect of centrally administered insulin on gonadotropin-releasing hormone neuron activity and luteinizing hormone surge in the diabetic female rat. Neuroendocrinology 76:357-365, 2002
43. Barnes RB: Central opioid activity in polycystic ovary syndrome with and without dopaminergic inhibition. J Clin Endocrinol Metab 61:779-782, 1985
44. Loverro G, Lorusso F, Mei L, et al: The plasma homocysteine levels are increased in polycystic ovary syndrome. Gynecol Obstet Invest 53:157-162, 2002
45. Arroyo A, Laughlin GA, Morales AJ: Inappropriate gonadotropin secretion in polycystic ovary syndrome: Influence of adiposity. J Clin Endocrinol Metab 82:3728-3733, 1997
46. Morales AJ, Laughlin GA, Butzow T: Insulin, somatotropic, and luteinizing hormone axes in lean and obese women with polycystic ovary syndrome: Common and distinct features. J Clin Endocrinol Metab 81:2854-2864, 1996
47. Levin JH, Carmina E, Lobo RA: Is the inappropriate gonadotropin secretion of patients with polycystic ovarian syndrome similar to that of patients with adult onset congenital adrenal hyperplasia? Fertil Steril 56:635-640, 1991
48. Wajchenberg BL, Achando SS, Okada H, et al: Determination of the sources of androgen overproduction in hirsutism associated with polycystic ovarian syndrome by simultaneous adrenal and ovarian venous cathetherization: Comparison with the dexamethasone suppression test. J Clin Endocrinol Metab 63:1204-1210, 1986
49. Kirschner MA, Jacobs JB: Combined ovarian and adrenal vein cathetherization to determine the sites of androgen overproduction in hirsute women. J Clin Endocrinol Metab 33:199-209, 1971
50. Chang RJ, Laufer LR, Meldrum DR, et al: Steroid secretion in polycystic ovarian disease after ovarian suppression by a long-acting gonadotropin-releasing hormone agonist. J Clin Endocrinol Metab 56:997-903, 1983
51. Gadir AA, Khatim MS, Mowafi RS, et al: Hormonal changes in patients with polycystic ovarian disease after ovarian electrocautery or pituitary desensitation. Clin Endocrinol (Oxf) 32:749-754, 1990
52. Rosenfield RL: Ovarian and adrenal function in polycystic ovary syndrome. Endocrinol Metab Clin North Am 28:265-293, 1999
53. Rosenfield RL: Studies of the nature of 17-hydroxyprogesterone hyperresponsiveness to gonadotropin-releasing hormone agonist challenge in functional ovarian hyperandrogenism. J Clin Endocrinol Metab 79:1686-1692, 1994
54. Rosenfeld RI, Barnes RB, Cara JF, et al: Dysregulation of cytochrome P450c 17 alpha as the cause of polycystic ovarian syndrome. Fertil Steril 53:785-791, 1990
55. Ehrmann DA, Rosenfeld RL, Barnes RB, et al: Detection of functional ovarian hyperandrogenism in women with androgen axis. N Engl J Med 327:157-162, 1992
56. Zhang LH, Rodriguez H, Ohno S, et al: Serine phosphorilation of human p450c17 alpha increases 17,20-lyase activity; implications for adrenarche and PCOS. Proc Natl Acad Sci USA 92:10619-10623, 1995
57. DeVane GW, Czekala NM, Judd HL, et al: Circulating gonadotropins, estrogens, and androgens in polycystic ovarian disease. Am J Obstet Gynecol 121:496-500, 1975
58. Hatch R, Rosenfield RL, Kim MH, et al: Hirsutism: Implications, etiology, and management. Am J Obstet Gynecol 140:815-830, 1981
59. Yen SSC: The polycystic ovary syndrome. Clin Endocrinol (Oxf) 12:177-207, 1980
60. Kiddy DS, Sharp PS, White DM, et al: Differences in clinical and endocrine features between obese and non-obese subjects with polycystic ovary syndrome: An analysis of 263 consecutive cases. Clin Endocrinol 32:213-220, 1990
61. Lobo RA, Paul WL, Goebelsmann U: Dehydroepiandrosterone sulfate as an indicator of adrenal androgen function. Obstet Gynecol 57:69-73, 1981
62. Gross MD, Wortsman J, Shapiro B, et al: Scintigraphic evidence of adrenal cortical dysfunction in the polycystic ovary syndrome. J Clin Endocrinol Metab 62:197-201, 1986
63. Ehrmann DA, Rosenfield RL, Barnes RB: Detection of functional ovarian hyperandrogenism in women with androgen excess. N Engl J of Med 327:157-162, 1992
64. Bardin CW, Hembree WC, Lipsett MB: Suppression of testosterone and androstenedione production rates with dexamethasone in women with idiopathic hirsutism and polycystic ovaries. J Clin Endocrinol Metab 28:1300-1306, 1968
65. Pasquali R, Vicennati V: Activity of the hypothalamic-pituitary-adrenal axis in different obesity phenotypes. Int J Obes Relat Metab Disord 24:S47-49, 2000 (suppl 2)
66. Invitti C, De Martin M, Delitala G: Altered morning and night-time pulsatile corticotropin and cortisol release in polycystic ovary syndrome. Metabolism 47:143-148, 1998
67. Rodin A, Thakkar H, Taylor N, et al: Hyperandrogenism in polycystic ovary syndrome-evidence of dysregulation of 11β-hydroxysteroid dehydrogenase. N Engl J Med 330:460-465, 1994
68. Jessop DS, Dallman MF, Fleming D, et al: Resistance to glucocorticoid feedback in obesity. J Clin Endocrinol Metab 86:4109-4114, 2001
69. Strain GW, Zumoff B, Kream J, et al: Sex difference in the influence of obesity on the 24 hr mean plasma concentration of cortisol. Metabolism 31:209-212, 1982
70. Chin D, Shackleton C, Prasad VK: Increased 5 alpha-reductase and normal 11beta-hydroxysteroid dehydrogenase metabolism of C19 and C21 steroids in a young population with polycystic ovarian syndrome. J Pediatr Endocrinol Metab 13:253-259, 2000
71. Gennarelli G, Holte J, Stridsberg M, et al: Response of the pituitary-adrenal axis to hypoglycemic stress in women with the polycystic ovary syndrome. J Clin Endocrinol Metab 84:76-81, 1999
72. Guven M, Acbay O, Sultuybek G: Glucocorticoid receptors on mononuclear leukocytes in polycystic ovary syndrome. Int J Gynaecol Obstet 63:33-37, 1998
73. Dunaif A: Preface, polycystic ovary syndrome. Endocrinol Metab Clin North Am 28:11A-12A, 1999
74. Christman GM, Randolph JF, Kelch RP, et al: Reduction of gonadotropin-releasing hormone pulse frequency is associated with subsequent selective follicle-stimulating hormone secretion in women with polycystic ovarian disease. J Clin Endocrinol Metab 72:1278-1285, 1991
75. Pastor CL, Griffin-Korf ML, Aloi JA, et al: Polycystic ovarian syndome-evidence for reduced sensitivity of the GnRH pulse generator to inhibition by estradiol and progesterone. J Clin Endocrinol Metab 88:582-590, 1987
76. Daniels TL, Berga SL: Resistance of GnRH drive to sex steroid induced suppression in hyperandrogenemic anovulation. J Clin Endocrinol Metab 82:4179-4183, 1997
77. Jakimiuk AJ, Weitsman SR, Brzechffa PR, et al: Aromatase mRNA expression in individual follicles from polycystic ovaries. Mol Hum Reprod 4:1-8, 1998
78. Erickson GF, Hsueh AJ, Quigley ME, et al: Functional studies of aromatase activity in human granulosa cells from normal and polycystic ovaries. J Clin Endocrinol Metab 49:514-519, 1979
79. Poretsky L, Glover B, Laumas V, et al: The effects of experimental hypefinsulinemia on steroid secretion, ovarian 125I insulin binding, and ovarian 125I insulin-like growth-factor I binding in the rat. Endocrinology 122:581-585, 1988
80. Gabrielove JL: The pathogenesis of the polycystic ovary syndrome: A hypothesis. Endocr Practice 8:127-132, 2002
81. Jones ME, Thoburn AW, Britt KL: Aromatase-deficient (ArKO) mice accumulate excess adipose tissue. J Steroid Biochem Mol Biol 79:3-9, 2001
82. Jones ME, Thorburn AW, Britt KL, et al: Aromatase-deficient (ArKO) mice have a phenotype of increased adiposity. Proc Natl Acad Sci USA 97:12735-12740, 2000
83. Morishima A, Grumbach MM, Simpson ER, et al: Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab 80:3689-3698, 1995
84. Carani C, Qin K, Simoni M, et al: Effect of testosterone and estradiol in a man with aromatase deficiency. N Engl J Med 337:91-95, 1997
85. MacGillivray MH, Morishima A, Conte F, et al: Pediatric endocrinology update: An overview. The essential roles of estrogens in pubertal growth, epiphyseal fusion and bone turnover: Lessons from mutations in the genes for aromatase and estrogen receptor. Horm Res 49:2-8, 1998
86. Mu YM, Yanase T, Nishi Y, et al: Insulin sensitizer, troglitazone, directly inhibits aromatase activity in human ovarian granulosa cells. Biochem Biophys Res Commun 271:710-713, 2000
87. 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 144:619-628, 2001
88. Mitwally MF, Casper RF: Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate. Fertil Steril 75:305-309, 2001
89. Cleland WH, Mendelson CR, Simpson ER: Effects of aging and obesity on aromatase activity of human adipose cells. J Clin Endocrinol Metab 60:174-177, 1985
90. Longcope C, Baker R, Johnston CC Jr: Androgen and estrogen metabolism: Relationship to obesity. Metabolism 35:235-237, 1986
91. Bulun SE, Simpson ER: Competitive reverse transcription-polymerase chain reaction analysis indicates that levels of aromatase cytochrome P450 transcripts in adipose tissue of buttocks, thighs, and abdomen of women increase with advancing age. J Clin Endocrinol Metab 78:428-432, 1994
92. Kirschner MA, Samojlik E, Drejka M, et al: Androgen-estrogen metabolism in women with upper body versus lower body obesity. J Clin Endocrinol Metab 70:473-479, 1990
93. Pasquali R, Casimirri F: The impact of obesity on hyperandrogenism and polycystic ovary syndrome in premenopausal women. Clin Endocrinol 39:1-16, 1993
94. Gambineri A, Pelusi C, Vicennati V, et al: Obesity and the polycystic ovary syndrome. Int J Obes Relat Metab Disord 26:883-896, 2002
95. Ahima RS, Flier JS: Leptin, in DeGroot LJ, Jameson JL, Burger HG, et al (eds): Endocrinology (ed 4). Philadelphia, PA, Saunders, 2001, pp 605-615
96. Coleman DL: Obese and diabetes: Two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia 14:141-148, 1978
97. Zhang Y, Proenca R, Maffei M, et al: Positional cloning of the mouse obese gene and its human homologue. Nature 372:425-432, 1994
98. Boden G, Chen X, Mozzoli M, et al: Effect of fasting on serum leptin in normal human subjects. J Clin Endocrinol Metab 81:3419-3423, 1996
99. Bray GA, York DA: The MONA LISA hypothesis in the time of leptin. Recent Prog Horm Res 53:95-117, 1998
100. Dube MG, Xu B, Kalra PS, et al: Disruption in neuropeptide Y and leptin signaling in obese ventromedial hypothalamic-lesioned rats. Brain Res 816:38-46, 1999
101. Frederich RC, Lollmann B, Hamann A, et al: Expression of ob mRNA and its encoded protein in rodents: Impact of nutrition and obesity. J Clin Invest 96:1658-1663, 1995
102. Maffei M, Halaas J Ravussin E: Leptin levels in human and rodent: Measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1:1155-1161, 1995
103. Frederich RC, Hamann A, Anderson S, et al: Leptin levels reflect body lipid content in mice: Evidence for diet-induced resistance to leptin action. Nat Med 1:1311-1314, 1995
104. Caro JF, Kolaczynski JW, Nyce MR, et al: Decreased cerebrospinal-fluid/serum leptin ratio in obesity: A possible mechanism for leptin resistance. Lancet 348:159-161, 1996
105. Lin L, Martin R, Schaffhauser AO: Acute changes in the response to peripheral leptin with alteration in the diet composition. Am J Physiol 280:R504-R509, 2001
106. Friedman JM, Halaas JL: Leptin and regulation of body weight in mammals. Nature 395:763-770, 1998
107. Kolaczynski JW, Ohannesian JP, Considine RV, et al: Response of leptin to short-term and prolonged overfeeding in humans. J Clin Endocrinol Metab 81:4162-4165, 1996
108. Caro JF, Sinha MK, Kolaczynski JW, et al: Leptin: The tale of an obesity gene. Diabetes 45:1455-1462, 1996
109. Poretsky L, Lesser M, Brillon D: Lack of postprandial leptin peaks in patients with type 2 diabetes mellitus. Diabetes Obes Metab 3:105-111, 2001
110. Marshall FHA, Peel WR: "Fatness" as a cause of sterility. J Agric Sci (Cambridge) 3:383-389, 1908
111. Evans HM, Bishop KS: On the relations between fertility and nutrition. II. The ovulation rhythm in the rat on inadequate nutritional regimes. J Metab Res 1:335-356, 1922
112. Frisch RE: Body fat, menarche, fitness and fertility, in Frisch RE (ed): Adipose Tissue and Reproduction. Progress in Reproductive Biology and Medicine, vol 14. Cambridge, MA, Karger Basel, 1990, pp 1-26
113. Chehab FF, Lim ME, Lu R: Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nat Genet 12:318-320, 1996
114. Ahima RS, Prabakaran D, Mantzoros C, et al: Role of leptin in the neuroendocrine response to fasting. Nature 382:250-252, 1996
115. Ahima RS, Dushay J, Flier SN: Leptin accelerates the onset of puberty in normal female mice. J Clin Invest 99:391-395, 1997
116. Mantzoros CS, Flier JS, Rogol AD: A longitudinal assessment of hormonal and physical alterations during normal puberty in boys. J Clin Endocrinol Metab 82:1066-1070, 1997
117. Clayton PE, Gill MS, Hall CM, et al: Serum leptin through childhood and adolescence. Clin Endocrinol (Oxf) 46:727-733, 1997
118. Blum WF, Englaro P, Hanitsch S, et al: Plasma leptin levels in healthy children and adolescents: Dependence on body mass index, body fat mass, gender, pubertal stage, and testosterone. J Clin Endocrinol Metab 82:2904-2910, 1997
119. Laughlin GA, Morales AJ, Yen SSC: Serum leptin levels in women with polycystic ovary syndrome: The role of insulin resistance/hyperinsulinemia. J Clin Endocrinol Metab 82:1692-1696, 1997
120. Mantzoros CS, Dunaif A, Flier JS: Leptin concentrations in the polycystic ovary syndrome. J Clin Endocrinol Metab 82:1687-1697, 1997
121. Carmina E, Ferin M, Gonzalez F, et al: Evidence that insulin and androgens may participate in the regulation of serum leptin levels in women. Fertil Steril 72:926-931, 1999
122. Pirwany IR, Fleming R, Sattar N, et al: Circulating leptin concentrations and ovarian function in polycystic ovary syndrome. Eur J Endocrinol 145:289-294, 2001
123. Spritzer PM, Poy M, Wiltgen D, et al: Leptin concentrations in hirsute women with polycystic ovary syndrome or idiopathic hirsutism: Influence on LH and relationship with hormonal, metabolic, and anthropometrics measurements. Hum Reprod 16:1340-1346, 2001
124. Pasquali R, Gambineri A, Biscotti D, et al: Effect of long-term treatment with metformin added to hypocaloric diet on body composition, fat distribution, and androgen ad insulin levels in abdominally obese women with and without the polycystic ovary syndrome. J Clin Endocrinol Metab 85:2767-2774, 2000
125. Kowalska I, Kinalski M, Straczkowski M: Insulin, leptin, IGF-1 and insulin-dependent protein concentrations after insulin-sensitizing therapy in obese women with polycystic ovary syndrome. Eur J Endocrinol 144:509-515, 2001
126. Nestler JE, Jakubowicz DJ, De Vargas AF, et al: Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system. J Clin Endocrinol Metab 83:2001-2005, 1998
127. Dunaif A: Insulin resistance and the polycystic ovary syndrome: Mechanism and implications for pathogenesis. Endocr Rev 18:774-800, 1997
128. Ciaraldi, TP, El-Roeiy A, Madar Z, et al: Cellular mechanisms of insulin resistance in polycystic ovarian syndrome. J Clin Endocrinol Metab 75:577-583, 1992
129. Rosenbaum D, Haber RS, Dunaif A: Insulin resistance in polycystic ovary syndrome: Decreased expression of GLUT-4 glucose transporters in adipocytes. Am J Physiol 264:E197-E202, 1993
130. Dunaif A, Xia J, Book CB, et al: Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle: A potential mechanism of insulin resistance in the polycystic ovary syndrome. J Clin Invest 96:81-10, 1995
131. Archard C, Thiers J: Le virilisme pilaire et son association a l'insuffisance glycolytique (diabetes des femmes a barbe). Bull Acad Natl Med 86:51, 1921
132. Burghen GA, Givens JR, Kitabchi AE: Correlation of hyperandrogenism with hyperinsulinism in polycystic ovarian disease. J Clin Endocrinol Metab 50:113-116, 1980
133. Kitabchi AE, Imseis RE, Bush AJ, et al: Racial differences in the correlation between gonadal androgens and serum insulin levels. Diabetes Care 22:1524-1529, 1999
134. Cohen JC, Hickman R: Insulin resistance and diminished glucose tolerance in powerlifters ingesting anabolic steroids. J Clin Endocrinol Metab 64:960-963, 1987
135. Polderman KH, Gooren JG, Asscherman H: Induction of insulin resistance by androgens and estrogens. J Clin Endocrinol Metab 79:265-271, 1994
136. Woodard TL, Burghen GA, Kitabchi AE: Glucose intolerance and insulin resistance in aplastic anemia treated with oxymetholone. J Clin Endocrinol Metab 53:905-908, 1981
137. Lemieux S, Lewis GF, Ben-Chetrit A: Correction of hyperandrogenemia by laparoscopic ovarian cautery in women with polycystic ovarian syndrome is not accompanied by improved insulin sensitivity or lipid-lipoprotein levels. J Clin Endocrinol Metab 84:4278-4282, 1999
138. Nagamani M, Van Dinh T, Kelver ME: Hyperinsulinemia in hyperthecosis of the ovaries. Am J Obstet Gynecol 154:384-389, 1986
139. Dunaif A, Green G, Futterweit W: Suppression of hyperandrogenism does not improve peripheral or hepatic insulin resistance in the polycystic ovary syndrome. J Clin Endocrinot Metab 70:699-704, 1990
140. Geffner ME, Kaplan SA, Bersch N: Persistence of insulin resistance in polycystic ovarian disease after inhibition of ovarian steroid secretion. Fertil Steril 45:327-333, 1986
141. Ibanez L, Potau N, Marcos MV: Treatment of hirsutism, hyperandrogenism, oligomenorrhea, dyslipidemia, and hyperinsulinism in nonobese, adolescent girls: Effect of flutamide. J Clin Endocrinol Metab 85:3251-3255, 2000
142. Taylor SI, Dons RF, Hernandez E: Insulin resistance associated with androgen excess in women with autoantibodies to the insulin receptor. Ann Intern Med 97:851-855, 1982
143. Kahn CR, Flier RS, Archer JA, et al: The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man. N Engl J Med 294:739-745, 1976
144. Ovesen P, Moller J, Ingerslev HJ: Normal basal and insulin-stimulated fuel metabolism in lean women with the polycystic ovary syndrome. J Clin Endocrinol Metab 77:1636-1640, 1993
145. Shriock ED, Buffington CK, Hubert GD: Divergent correlations of circulating dehydroepiandrosterone sulfate and testosterone with insulin levels and insulin receptor binding. J Clin Endocrinol Metabol 66:1329-1331, 1988
146. Flier JS, Kahn CR, Roth J, et al: Antibodies that impair insulin receptor binding in an unusual diabetic syndrome with severe insulin resistance. Science 190:63-65, 1975
147. El-Roeiy A, Chen X, Roberts VJ, et al: 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 77:1411-1414, 1993
148. Hernandez ER, Hurwitz A, Vera A, et al: Expression of the genes encoding the insulin-like growth factors and their receptors in the human ovary. J Clin Endocrinol Metab 74:419-425, 1992
149. Channing, CP, Tsai V, Sachs D: Role of insulin, thyroxin and cortisol in luteinization of porcine granulosa cells grown in chemically defined media. Biol Reprod 15:235-247, 1976
150. Veldhuis JD, Furlanetto RW: Trophic actions of human somatomedin C/insulin-like growth factor I on ovarian cells: In vitro studies with swine granulosa cells. Endocrinology 116:1235-1242, 1985
151. Adashi EY, Resnick CE, Svoboda ME, et al: Somatomedin-C synergizes with follicle-stimulating hormone in the acquisition of progestin biosynthetic capacity by cultured rat granulosa cells. Endocrinology 116:2135-2142, 1985
152. Nestler JE, Jacubowicz 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 335:617-623, 1996
153. Antilla L, Ding YQ, Ruutainen K, et al: Clinical features and circulating gonadotropin, insulin and androgen interactions in women with polycystic ovarian disease. Fertil Steril 55:1057-1061, 1991
154. Poretsky L, Seto-Young D, Shrestha A, et al: Phosphatidylinositol-3 kinase-independent insulin action pathway(s) in the human ovary. J Clin Endocrinol Metab 86:3115-3119, 2001
155. White MF, Kahn CR: Mechanisms of insulin action, in Moller DE (ed): Insulin Resistance. New York, NY, Wiley, 1991, pp 9-47
156. Seto-Young D, Zajac J, Hung-Ching L, et al: The role of mitogen-activated protein kinase in insulin and insulin-like growth factor I (IGF-I) signaling cascades for progesterone and IGF-binding protein-1 production in human granulosa cells. J Clin Endocrinol Metab 88:3385-3391, 2003
157. Poretsky L, Grigorescu F, Seibel M, et al: Distribution and characterization of insulin and insulin-like growth factor I receptors in normal human ovary. J Clin Endocrinol Metab 61:728-734, 1985
158. Poretsky L, Bhargava G, Kalin MF, et al: Regulation of insulin receptors in the human ovary: In vitro studies. J Clin Endocrinol Metab 67:774-778, 1988
159. Suikkari AM, Koivisto VA, Rutanen EM, et al: Insulin regulates the serum levels of low molecular weight insulin-like growth factor-binding protein. J Clin Endocrinol Metab 66:266-272, 1988
160. Poretsky L, Chandrasekher YA, Bai C, et al: Insulin receptor mediates inhibitory effect of insulin, but not of insulin-like growth factor (IGF)-I, on IGF binding protein 1 (IGFBP-1) production in human granulosa cells. J Clin Endocrinol Metab 81:493-496, 1996
161. Buyalos RP, Pekonen F, Halme JK, et al: The relationship between circulating androgens, obesity, and hyperinsulinemia on serum insulin-like growth factor binding protein-I in the polycystic ovarian syndrome. Am J Obstet Gynecol 172:932-939, 1995
162. Garcia-Rudaz MC: Amplified and orderly growth hormone secretion characterizes lean adolescents with polycystic ovary syndrome. Eur J Endocrinol 147:207-216, 2002
163. Slowinska-Srzednicka J, Zgliczynski W, Makowska A, et al: An abnormality of the growth hormone/insulin-like growth factor-1 axis in women with polycystic ovarian syndrome with coexisting obesity. J Clin Endocrinol Metab 74:1432-1435, 1992
164. Veldhuis JD, Iranmanesh A, Ho KKY, et al: Dual defects in pulsatile growth hormone secretion and clearance subserve the hyposomatropinism of obesity in man. J Clin Endocrinol Metab 72:51-59, 1991
165. Ferriman D, Galleway JD: Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 21:1440-1447, 1961
166. Balen AH, Tan SL, MacDougall J, et al: Miscarriage rates following in-vitro fertilization are increased in women with polycystic ovaries and reduced by pituitary desensitization with buserelin. Hum Reprod 8:959-964, 1993
167. Wiegerinck M: Early pregnancy loss in chronic hyperandrogenic anovulation, in Coelingh-Bennink HJT (eds): Chronic Hyperandrogenic Anovulation. London, UK, Parthenon, 1991, pp 169
168. White DM: Induction of ovulation with low-dose gonadotropins in polycystic ovary syndrome: An analysis of 109 pregnancies in 225 women. J Clin Endocrinol Metab 81:3821-3824, 1996
169. Dunaif A, Graf M, Mandeli J, et al: Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance, and/or hyperinsulinemia. J Clin Endocrinol Metab 65:499-507, 1987
170. Talbott E, Guzick D, Clerici A, et al: Coronary heart disease risk factors in women with polycystic ovary syndrome. Arterioscler Thromb Vasc Biol 15:821-826, 1995
171. Franks S: Medical progress: Polycystic ovary syndrome. N Engl J Med 333:853-861, 1995
172. Asuncion M, Calvo RM, San Millan JL, et al: A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain. J Clin Endocrinol Metab 85:2434-2438, 2000
173. Carmina E, Koyama T, Chang L, et al: Does ethnicity influence the prevalence of adrenal hyperandrogenism and insulin resistance in polycystic ovary syndrome? Am J Obstet Gynecol 167:1807-1812, 1992
174. Kauffman RP, Baker VM, Dimarino P, et al: Polycystic ovarian syndrome and insulin resistance in white and Mexican American women: A comparison of two distinct populations. Am J Obstet Gynecol 187:1362-1369, 2002
175. Balen AH, Conway GS, Kaltsas G, et al: Polycystic ovary syndrome: The spectrum of the disorder in 1741 patients. Hum Reprod 10:2107-2111, 1995
176. Gill S, Taylor AE, Martin KA, et al: Specific factors predict the response to pulsatile gonadotropin-releasing hormone therapy in polycystic ovarian syndrome. J Clin Endocrinol Metab 86:2428-2436, 2001
177. Stuart CA, Peters EJ Prince MJ, et al: Insulin resistance with acanthosis nigricans: The roles of obesity and androgen excess. Metabolism 35:197-205, 1986
178. Conway GS, Jacobs HS: Acanthosis nigricans in obese women with the polycystic ovary syndrome: Disease spectrum not distinct entity. Postgrad Med J 66:536-538, 1990
179. Legro RS, Kunselman AR, Dodson WC, et al: Prevalence and predictors of risk of type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: A prospective controlled study in 254 affected women. J Clin Endocrinol Metab 84:165-169, 1999
180. Conway GS, Agrawal R, Betteridge DJ, et al: Risk factors for coronary artery disease in lean and obese women with the polycystic ovary syndrome. Clin Endocrinol 37:119-125, 1992
181. Sampson M, Kong C, Patel A, et al: Ambulatory blood pressure profiles and plasminogen activator inhibitor (PAI-1) activity in lean women with and without the polycystic ovary syndrome. Clin Endocrinol 45:623-629, 1996
182. Wild RA, Grubb B, Hartz A, et al: Clinical signs of androgen excess as risk factors for coronary artery disease. Fertil Steril 54:255-259, 1990
183. Kelly CJ, Lyall H, Petrie JR, et al: A specific elevation in tissue plasminogen activator antigen in women with polycystic ovarian syndrome. J Clin Endocrinol Metab 87:3287-3290, 2001
184. Vgontzas AN, Legro RS, Bixler EO, et al: Polycystic ovary syndrome is associated with obstructive sleep apnea and daytime sleepiness: Role of insulin resistance. J Clin Endocrinol Metab 86:517-520, 2001
185. Gjonnaess H: The course and outcome of pregnancy after ovarian electrocautery in women with polycystic ovarian syndrome: The influence of body-weight. Br J Obstet Gynaecol 96:714-719, 1989
186. Urman B, Sarac E, Dogan L, et al: Pregnancy in infertile PCOD patients. Complications and outcome. J Reprod Med 42:501-505, 1997
187. Thadhani R, Stampfer MJ, Hunter DJ, et al: High body mass index and hypercholesterolemia: Risk of hypertensive disorders of pregnancy. Obstet Gynecol 94:543-550, 1999
188. De Vries MJ, Dekker GA, Schoemaker J: Higher risk of preeclampsia in the polycystic ovary syndrome. A case control study. Eur J Obstet Gynecol Reprod Biol 76:91-95, 1998
189. Huber-Buchholz MM, Carey DGP, Norman RJ: Restoration of reproductive potential by lifestyle modification in obese polycystic ovary syndrome: Role of insulin sensitivity and luteinizing hormone. J Clin Endocrinol Metab 84:1470-1474, 1999
190. Kiddy DS, Hamilton-Fairley D, Bush A, et al: Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin Endocrinol 38:105-111, 1992
191. Guzick DS, Berga SL, Wing R, et al: Endocrine consequences of weight loss in obese, hyperandrogenic, anovulatory women. Fertil Steril 61:598-604, 1994
192. Velazquez EM, Mendoza S, Hamer T, et al: 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, 1994
193. Arslanian SA, Lewy V, Danadian K: 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 87:1555-1559, 2002
194. Moghetti P, Castello R, Negri C, et al: 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 85:139-146, 2000
195. Acbay O, Gundogdu S: Can metformin reduce insulin resistance in polycystic ovary syndrome? Fertil Steril 65:946-949, 1996
196. Dunaif A, Scott D, Finegood D, et al: The insulin-sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. J Clin Endocrinol Metab 81:3299-3306, 1996
197. Ehrmann DA, Schneider DJ, Sobel BE, et al: 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, 1997
198. Baillargeon JP, Jakubowicz DJ, Iuorno MJ, et al: Effects of metformin and rosiglitazone, alone and in combination, in lean women with polycystic ovary syndrome and normal indices of insulin sensitivity. Proceedings of the 84th Annual Meeting of the Endocrine Society, San Francisco, CA, June 19-22, 2000 (abstr OR10-1)
199. Mercado-Asis LB, Faller TM, Mercado AB: Long term follow-up of Filipino patients with polycystic ovary syndrome (PCOS) with insulin sensitizer: From troglitazone to rosiglitazone. Proceedings of the 84th Annual Meeting of the Endocrine Society, San Francisco, CA, June 19-22, 2000 (abstr P1-57)
200. Brettenthaler N, De Geyter C, Huber P, et al: Effect of the insulin sensitizer pioglitazone on insulin resistance and hyperandrogenaemia in women with polycystic ovary syndrome: A placebo controlled double blind randomised trial. Diabetes 52:A140, 2003 (suppl 1)
201. Bloomgarden ZT, Futterweit W, Poretsky L: Use of insulin-sensitizing agents in patients with polycystic ovary syndrome. Endocr Practice 7:279-286, 2001
202. Nestler JE, Jakubowicz DJ, Reamer P, et al: Ovulatory and metabolic effects of D-chiro-inositol in the polycystic ovary syndrome, N Engl J Med 340:1314-1320, 1999
203. De Leo V, Lanzetta D, D'Antona D, et al: Hormonal effects of flutamide in young women with polycystic ovary syndrome. J Clin Endocrinol Metab 83:99-102, 1998
204. Diamanti-Kandarakis E, Mitrakou A, Hennes MM, et al: Insulin sensitivity and antiandrogenic therapy in women with polycystic ovary syndrome, Metabolism 44:525-531, 1995
205. Moghetti P, Tosi F, Castello R, et al: 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, 2000
206. Pasquali R, Gambineri A, Anconetani B, et al: The natural history of the metabolic syndrome in young women with the polycystic ovary syndrome and the effect of long-term oestrogen-progestagen treatment. Clin Endocrinol (Oxf) 50:517-527, 1999
207. Cibula D, Hill M, Fanta M, et al: Does obesity diminish the positive effect of oral contraceptive treatment on hyperandrogenism in women with polycystic ovarian syndrome? Hum Reprod 16:940-944, 2001
208. Dahlgren E, Landin K, Krotkiewski M, et al: Effects of two antiandrogen treatments on hirsutism and insulin sensitivity in women with polycystic ovary syndrome, Hum Reprod 13:2706-2711, 1998
209. Morin-Papunen LC, Vauhkonen I, Koivunen RM, et al: Endocrine and metabolic effects of metformin versus ethinyl estradiol-cyproterone acetate in obese women with polycystic ovary syndrome: A randomized study. J Clin Endocrinol Metab 85:3161-3168, 2000
210. Poretsky L, Clemons J, Bogovich K: Hyperinsulinemia and human chorionic onadotropin synergistically promote the growth of ovarian follicular cysts in rats. Metabolism 41:903-910, 1992
211. Welt CK, Taylor AE, Martin KA, et al: Serum inhibin B in polycystic ovary syndrome: Regulation by insulin and luteinizing hormone. J Clin Endocrinol Metab 87:5559-5565, 2002
212. Singh A, Hamilton-Fairley D, Koistinen R, et al: Effect of insulin-like growth factor-type I (IGF-I) and insulin on the secretion of sex hormone binding globulin and IGF-I binding protein (IBP-I) by human hepatoma cells. J Endocrinol 124:R1-3, 1990