Reproduction and Metabolism: Insights from Polycystic Ovary Syndrome

다국어 초록 (Multilingual Abstract)

Until the 1980s, polycystic ovary syndrome (PCOS) was considered to be a poorly defined reproductive disorder. During that decade,it was recognized that PCOS was associated with profound insulin resistance and a substantially increased risk for type 2 diabetes mellitus in young women. Accordingly, the mechanisms linking the reproductive and metabolic features of the syndrome became the subject of intense investigation. Insulin is now recognized as a reproductive as well as a metabolic hormone and insulin signaling in the central nervous system participates in normal reproductive function. These insights have been directly translated into a novel therapy for PCOS with insulin sensitizing drugs. Androgens also have reversible metabolic actions to decrease insulin sensitivity and increase visceral fat. Prenatal androgen administration to non-human primates, sheep and rodents produces reproductive and metabolic features of PCOS suggesting that the disorder also has developmental origins. PCOS is highly heritable and male as well as female relatives have reproductive and metabolic phenotypes. A number of confirmed genetic susceptibility loci have now been mapped for PCOS and genes in well-known as well as novel biologic pathways have been implicated in disease pathogenesis.

참고문헌 (Reference)

1 Welt CK, "Variants in DENND1A are associated with polycystic ovary syndrome in women of European ancestry" 97 : E1342-E1347, 2012

2 Puurunen J, "Unfavorable hormonal, metabolic, and inflammatory alterations persist after menopause in women with PCOS" 96 : 1827-1834, 2011

3 Barry JA, "Umbilical vein testosterone in female infants born to mothers with polycystic ovary syndrome is elevated to male levels" 30 : 444-446, 2010

4 Gambineri A, "Treatment with flutamide, metformin, and their combination added to a hypocaloric diet in overweightobese women with polycystic ovary syndrome: a randomized, 12-month, placebo-controlled study" 91 : 3970-3980, 2006

5 Spielman RS, "Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM)" 52 : 506-516, 1993

6 Urbanek M, "Thirty-seven candidate genes for polycystic ovary syndrome: strongest evidence for linkage is with follistatin" 96 : 8573-8578, 1999

7 Kahn CR, "The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man" 294 : 739-745, 1976

8 Bremer AA, "The serine phosphorylation hypothesis of polycystic ovary syndrome: a unifying mechanism for hyperandrogenemia and insulin resistance" 89 : 1039-1048, 2008

9 Hickey M, "The relationship between maternal and umbilical cord androgen levels and polycystic ovary syndrome in adolescence: a prospective cohort study" 94 : 3714-3720, 2009

10 Azziz R, "The prevalence and features of the polycystic ovary syndrome in an unselected population" 89 : 2745-2749, 2004

11 Dunaif A, "The insulinsensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome" 81 : 3299-3306, 1996

12 Moghetti P, "The insulin resistance in women with hyperandrogenism is partially reversed by antiandrogen treatment: evidence that androgens impair insulin action in women" 81 : 952-960, 1996

13 Urbanek M, "The genetics of the polycystic ovary syndrome" 3 : 103-111, 2007

14 Diamanti-Kandarakis E, "The effect of a pure antiandrogen receptor blocker, flutamide, on the lipid profile in the polycystic ovary syndrome" 83 : 2699-2705, 1998

15 Nestler JE, "Suppression of serum insulin level by diazoxide does not alter serum testosterone or sex hormone-binding globulin levels in healthy, nonobese women" 163 (163): 1243-1246, 1990

16 Nestler JE, "Suppression of serum insulin by diazoxide reduces serum testosterone levels in obese women with polycystic ovary syndrome" 68 : 1027-1032, 1989

17 Dunaif A, "Suppression of hyperandrogenism does not improve peripheral or hepatic insulin resistance in the polycystic ovary syndrome" 70 : 699-704, 1990

18 Zhang LH, "Serine phosphorylation of human P450c17 increases 17,20-lyase activity: implications for adrenarche and the polycystic ovary syndrome" 92 : 10619-10623, 1995

19 Book CB, "Selective insulin resistance in the polycystic ovary syndrome" 84 : 3110-3116, 1999

20 Palmert MR, "Screening for abnormal glucose tolerance in adolescents with polycystic ovary syndrome" 87 : 1017-1023, 2002

21 Veldhuis JD, "Role of endogenous opiates in the expression of negative feedback actions of androgen and estrogen on pulsatile properties of luteinizing hormone secretion in man" 74 : 47-55, 1984

22 Holte J, "Restored insulin sensitivity but persistently increased early insulin secretion after weight loss in obese women with polycystic ovary syndrome" 80 : 2586-2593, 1995

23 Brothers KJ, "Rescue of obesity-induced infertility in female mice due to a pituitary-specific knockout of the insulin receptor" 12 : 295-305, 2010

24 Wu S, "Reproductive tissues maintain insulin sensitivity in diet-induced obesity" 61 : 114-123, 2012

25 Goodarzi MO, "Replication of association of DENND1A and THADA variants with polycystic ovary syndrome in European cohorts" 49 : 90-95, 2012

26 Evans DJ, "Relationship of androgenic activity to body fat topography, fat cell morphology, and metabolic aberrations in premenopausal women" 57 : 304-310, 1983

27 Dunaif A, "Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome" 38 : 1165-1174, 1989

28 Knochenhauer ES, "Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study" 83 : 3078-3082, 1998

29 Ehrmann DA, "Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome" 22 : 141-146, 1999

30 Legro RS, "Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women" 84 : 165-169, 1999

31 Apridonidze T, "Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome" 90 : 1929-1935, 2005

32 Shaw LJ, "Postmenopausal women with a history of irregular menses and elevated androgen mea surements at high risk for worsening cardiovascular event-free survival: results from the National Institutes of Health: National Heart, Lung, and Blood Institute sponsored Women’s Ischemia Syndrome Evaluation" 93 : 1276-1284, 2008

33 Teede H, "Polycystic ovary syndrome: a complex condition with psychological, reproductive and metabolic manifestations that impacts on health across the lifespan" 8 : 41-, 2010

34 Ciaraldi TP, "Polycystic ovary syndrome is associated with tissue-specific differences in insulin resistance" 94 : 157-163, 2009

35 Gambineri A, "Polycystic ovary syndrome is a risk factor for type 2 diabetes: results from a long-term prospective study" 61 : 2369-2374, 2012

36 Ehrmann DA, "Polycystic ovary syndrome as a form of functional ovarian hyperandrogenism due to dysregulation of androgen secretion" 16 : 322-353, 1995

37 Dumesic DA, "Polycystic ovary syndrome and its developmental origins" 8 : 127-141, 2007

38 Eagleson CA, "Polycystic ovarian syndrome: evidence that flutamide restores sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by estradiol and progesterone" 85 : 4047-4052, 2000

39 Herzog AG, "Polycystic ovarian syndrome in women with epilepsy: epileptic or iatrogenic?" 39 : 559-560, 1996

40 Tee MK, "Pathways leading to phosphorylation of p450c17 and to the posttranslational regulation of androgen biosynthesis" 149 : 2667-2677, 2008

41 Ehrmann DA, "PCOS/Troglitazone Study Group: Effects of race and family history of type 2 diabetes on metabolic status of women with polycystic ovary syndrome" 90 : 66-71, 2005

42 Ovesen P, "Normal basal and insulin-stimulated fuel metabolism in lean women with the polycystic ovary syndrome" 77 : 1636-1640, 1993

43 Marshall JC, "Neuroendocrine aspects of polycystic ovary syndrome" 28 : 295-324, 1999

44 Taylor SI, "Mutations in the insulin receptor gene" 13 : 566-595, 1992

45 Pierpoint T, "Mortality of women with polycystic ovary syndrome at long-term follow-up" 51 : 581-586, 1998

46 Mendoza S, "Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy" 43 : 647-654, 1994

47 Maliqueo M, "Metabolic parameters in cord blood of newborns of women with polycystic ovary syndrome" 92 : 277-282, 2009

48 Sir-Petermann T, "Metabolic and reproductive features before and during puberty in daughters of women with polycystic ovary syndrome" 94 : 1923-1930, 2009

49 Solomon CG, "Menstrual cycle irregularity and risk for future cardiovascular disease" 87 : 2013-2017, 2002

50 Elbers JM, "Long-term testosterone administration increases visceral fat in female to male transsexuals" 82 : 2044-2047, 1997

51 Garg A, "Lipodystrophies: genetic and acquired body fat disorders" 96 : 3313-3325, 2011

52 DeFronzo RA, "Lilly lecture, The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM" 37 : 667-687, 1987

53 Achard C, "Le Virilisme pilaire et son association a l’insuffisance glycolytique (diabete des femme a barbe)" 86 : 51-83, 1921

54 Vague J, "La différentiation sexuelle. Facteur determinant des formes de l’obesité" 55 : 339-340, 1947

55 Ehrmann DA, "Insulin secretory defects in polycystic ovary syndrome. Relationship to insulin sensitivity and family history of non-insulin-dependent diabetes mellitus" 96 : 520-527, 1995

56 Eriksen M, "Insulin resistance is not conserved in myotubes established from women with PCOS" 5 : e14469-, 2010

57 Corbould A, "Insulin resistance in the skeletal muscle of women with PCOS involves intrinsic and acquired defects in insulin signaling" 288 : E1047-E1054, 2005

58 Legro RS, "Insulin resistance in the sisters of women with polycystic ovary syndrome: association with hyperandrogenemia rather than menstrual irregularity" 87 : 2128-2133, 2002

59 Rosenbaum D, "Insulin resistance in polycystic ovary syndrome: decreased expression of GLUT-4 glucose transporters in adipocytes" 264 (264): E197-E202, 1993

60 Rajkhowa M, "Insulin resistance in polycystic ovary syndrome is associated with defective regulation of ERK1/2 by insulin in skeletal muscle in vivo" 418 : 665-671, 2009

61 Diamanti-Kandarakis E, "Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications" 2012

62 Moghetti P, "Insulin infusion amplifies 17 alpha-hydroxycorticosteroid intermediates response to adrenocorticotropin in hyperandrogenic women: apparent relative impairment of 17,20-lyase activity" 81 : 881-886, 1996

63 Franks S, "Insulin action in the normal and polycystic ovary" 28 : 361-378, 1999

64 Willis D, "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" 80 : 3788-3790, 1995

65 Anderson H, "Infants of women with polycystic ovary syndrome have lower cord blood androstenedione and estradiol levels" 95 : 2180-2186, 2010

66 Polderman KH, "Induction of insulin resistance by androgens and estrogens" 79 : 265-271, 1994

67 Rice S, "Impaired insulin-dependent glucose metabolism in granulosa-lutein cells from anovulatory women with polycystic ovaries" 20 : 373-381, 2005

68 Ek I, "Impaired adipocyte lipolysis in nonobese women with the polycystic ovary syndrome: a possible link to insulin resistance?" 82 : 1147-1153, 1997

69 Urbanek M, "Identification of a polycystic ovary syndrome susceptibility variant in fibrillin-3 and association with a metabolic phenotype" 92 : 4191-4198, 2007

70 Burks DJ, "IRS-2 pathways integrate female reproduction and energy homeostasis" 407 : 377-382, 2000

71 Cole B, "Human fetal ovary development involves the spatiotemporal expression of p450c17 protein" 91 : 3654-3661, 2006

72 Patel SM, "Higher serum testosterone concentration in older women is associated with insulin resistance, metabolic syndrome, and cardiovascular disease" 94 : 4776-4784, 2009

73 Vink JM, "Heritability of polycystic ovary syndrome in a Dutch twin-family study" 9 : 2100-2104, 2006

74 Kashar-Miller M, "Heritability and the risk of developing androgen excess" 69 : 261-268, 1999

75 Yildiz BO, "Glucose intolerance, insulin resistance, and hyperandrogenemia in first degree relatives of women with polycystic ovary syndrome" 88 : 2031-2036, 2003

76 Chen ZJ, "Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3" 43 : 55-59, 2011

77 Shi Y, "Genome-wide association study identifies eight new risk loci for polycystic ovary syndrome" 44 : 1020-1025, 2012

78 Hirschhorn JN, "Genome-wide association studies for common diseases and complex traits" 6 : 95-108, 2005

79 Semple RK, "Genetic syndromes of severe insulin resistance" 32 : 498-514, 2011

80 Franks S, "Follicle dynamics and anovulation in polycystic ovary syndrome" 14 : 367-378, 2008

81 Jordan CD, "Fibrillins in adult human ovary and polycystic ovary syndrome: is fibrillin-3 affected in PCOS?" 58 : 903-915, 2010

82 Lovejoy JC, "Exogenous androgens influence body composition and regional body fat distribution in obese postmenopausal women: a clinical research center study" 81 : 2198-2203, 1996

83 Dunaif A, "Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. A potential mechanism for insulin resistance in the polycystic ovary syndrome" 96 : 801-810, 1995

84 Sam S, "Evidence for metabolic and reproductive phenotypes in mothers of women with polycystic ovary syndrome" 103 : 7030-7035, 2006

85 Dunaif A, "Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome" 41 : 1257-1266, 1992

86 Legro RS, "Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome" 95 : 14956-14960, 1998

87 Martens JW, "Enzymatic activities of P450c17 stably expressed in fibroblasts from patients with the polycystic ovary syndrome" 85 : 4338-4346, 2000

88 Corbould A, "Enhanced mitogenic signaling in skeletal muscle of women with polycystic ovary syndrome" 55 : 751-759, 2006

89 Legro RS, "Elevated dehydroepiandrosterone sulfate levels as the reproductive phenotype in the brothers of women with polycystic ovary syndrome" 87 : 2134-2138, 2002

90 Sam S, "Dyslipidemia and metabolic syndrome in the sisters of women with polycystic ovary syndrome" 90 : 4797-4802, 2005

91 Dunaif A, "Drug insight: insulin-sensitizing drugs in the treatment of polycystic ovary syndrome: a reappraisal" 4 : 272-283, 2008

92 Hill JW, "Direct insulin and leptin action on pro-opiomelanocortin neurons is required for normal glucose homeostasis and fertility" 11 : 286-297, 2010

93 Dunaif A, "Defects in insulin receptor signaling in vivo in the polycystic ovary syndrome (PCOS)" 281 : E392-E399, 2001

94 O’Meara NM, "Defects in beta-cell function in functional ovarian hyperandrogenism" 76 : 1241-1247, 1993

95 Li M, "Decreased insulin receptor (IR) autophosphorylation in fibroblasts from patients with PCOS: effects of serine kinase inhibitors and IR activators" 87 : 4088-4093, 2002

96 Morgani GB, "De Sedibus et Causis Morborum per Anatomen Indagata [The seats and causes of diseases investigated by anatomy]" Re-mondini 1765

97 Burghen GA, "Correlation of hyperandrogenism with hyperinsulinism in polycystic ovarian disease" 50 : 113-116, 1980

98 Dunaif A, "Clinical, biochemical, and ovarian morphologic features in women with acanthosis nigricans and masculinization" 66 : 545-552, 1985

99 Ciaraldi TP, "Cellular mechanisms of insulin resistance in polycystic ovarian syndrome" 75 : 577-583, 1992

100 Schmidt J, "Cardiovascular disease and risk factors in PCOS women of postmenopausal age: a 21-year controlled follow-up study" 96 : 3794-3803, 2011

101 Randeva HS, "Cardiometabolic aspects of the polycystic ovary syndrome" 2012

102 Kissebah AH, "Biology of regional body fat distribution: relationship to non-insulin-dependent diabetes mellitus" 5 : 83-109, 1989

103 Nelson VL, "Augmented androgen production is a stable steroidogenic phenotype of propagated theca cells from polycystic ovaries" 13 : 946-957, 1999

104 Wild RA, "Assessment of cardiovascular risk and prevention of cardiovascular disease in women with the polycystic ovary syndrome: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society" 95 : 2038-2049, 2010

105 Kirschner MA, "Androgen-estrogen metabolism in women with upper body versus lower body obesity" 70 : 473-479, 1990

106 Grundy SM, "American Heart Association; National Heart, Lung, and Blood Institute: Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement" 112 : 2735-2752, 2005

107 Coviello AD, "Adolescent girls with polycystic ovary syndrome have an increased risk of the metabolic syndrome associated with increasing androgen levels independent of obesity and insulin resistance" 91 : 492-497, 2006

108 Flier JS, "Acanthosis nigricans in obese women with hyperandrogenism. Characterization of an insulin-resistant state distinct from the type A and B syndromes" 34 : 101-107, 1985

109 Ek I, "A unique defect in the regulation of visceral fat cell lipolysis in the polycystic ovary syndrome as an early link to insulin resistance" 51 : 484-492, 2002

110 Diamanti-Kandarakis E, "A survey of the polycystic ovary syndrome in the Greek island of Lesbos: hormonal and metabolic profile" 84 : 4006-4011, 1999

111 International HapMap Consortium, "A haplotype map of the human genome" 437 : 1299-1320, 2005