臨床婦人科産科64巻2号

2010年02月発行

今月の臨床 ここが知りたい―PCOSの最新情報

PCOSの病因─最近の考え方

著者： 高橋俊文¹ 五十嵐秀樹¹ 倉智博久¹

所属機関： ¹山形大学医学部産科婦人科学講座

ページ範囲：P.130 - P.141

文献概要

はじめに

　多嚢胞性卵巣症候群（polycystic ovary syndrome : PCOS）は，性成熟期女性の5～10％に認められる頻度の高い疾患である^1）．月経異常や不妊症の主要な原因の1つであるのみならず，肥満，脂質異常を伴い心疾患系疾患やメタボリック症候群のリスク因子としても重要である．また，PCOSによる排卵障害や肥満は，子宮内膜に対して持続的なエストロゲン刺激をもたらし，若年性の子宮体癌を引き起こすことが知られている．しかし，このように女性のライフスタイル全般にわたって重大な影響を及ぼす疾患であるPCOSの病因はいまだに学説の域をでないのが現状である．その本体には，PCOS自体がheterogeneousな病像の集合体である点が根底にある．本稿では，近年病因として最も重要視されているインスリン抵抗性や高アンドロゲン血症を中心に述べる．さらに，インスリン抵抗性に関与するアディポネクチン，摂食調節に関与するグレリンやレプチン，卵胞発育に関与する抗ミューラー管ホルモンならびに遺伝子異常に関する最近の知見を紹介する．

参考文献

1） Ehrmann DA : Polycystic ovary syndrome. N Engl J Med 352 : 1223─1236, 2005

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

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

4） 水沼英樹，苛原　稔，久具宏司，他 : 生殖・内分泌委員会 : 本邦におる多嚢胞性卵巣症候群の新しい診断基準の設定に関する小委委員会（平成17年度～平成18年度）検討結果報告．日産婦会誌59 : 868─886，2007

5） Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group : Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 81 : 19─25, 2004

6） 糖尿病治療ガイド2006～2007（日本糖尿病学会編）．pp7─9．文光堂，2006

7） DeUgarte CM, Bartolucci AA, Azziz R : Prevalence of insulin resistance in the polycystic ovary syndrome using the homeostasis model assessment. Fertil Steril 83 : 1454─1460, 2005

8） 松崎利也，苛原　稔 : PCOS─新たな展開─PCOSの治療法の進歩（1）PCOSの不妊に対するメトホルミンを用いた薬物療法．HORMONE FRONTIER IN GYNECOLOGY 15 : 51─61，2008

9） Palomba S, Falbo A, Zullo F, et al : Evidence-based and potential benefits of metformin in the polycystic ovary syndrome : a comprehensive review. Endocr Rev 30 : 1─50, 2009

10） Elkind-Hirsch KE, Valdes CT,Malinak LR : Insulin resistance improves in hyperandrogenic women treated with Lupron. Fertil Steril 60 : 634─641, 1993

11） 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, 1996

12） Polderman KH, Gooren LJ, Asscheman H, et al : Induction of insulin resistance by androgens and estrogens. J Clin Endocrinol Metab 79 : 265─271, 1994

13） Tamori Y, Kasuga M : Obesity and insulin resistance. Nippon Rinsho 67 : 236─244, 2009

14） Hotamisligil GS, Shargill NS, Spiegelman BM : Adipose expression of tumor necrosis factor-alpha : direct role in obesity-linked insulin resistance. Science 259 : 87─91, 1993

15） 山内敏正，門脇　孝 : アディポカインネットワークと炎症．医学のあゆみ229 : 512─518，2009

16） Azziz R, Sanchez LA, Knochenhauer ES, et al : Androgen excess in women : experience with over 1000 consecutive patients. J Clin Endocrinol Metab 89 : 453─462, 2004

17） Strowitzki T, Halser B, Demant T : Body fat distribution, insulin sensitivity, ovarian dysfunction and serum lipoproteins in patients with polycystic ovary syndrome. Gynecol Endocrinol 16 : 45─51, 2002

18） Douchi T, Ijuin H, Nakamura S, et al : Body fat distribution in women with polycystic ovary syndrome. Obstet Gynecol 86 : 516─519, 1995

19） Kirchengast S, Huber J : Body composition characteristics and body fat distribution in lean women with polycystic ovary syndrome. Hum Reprod 16 : 1255─1260, 2001

20） Lord J, Thomas R, Fox B, et al : The central issue? Visceral fat mass is a good marker of insulin resistance and metabolic disturbance in women with polycystic ovary syndrome. Bjog 113 : 1203─1209, 2006

21） Yamauchi T, Kamon J, Waki H, et al : The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7 : 941─946, 2001

22） 山内敏正，門脇　孝 : 大きく変わる肥満症のとらえ方─摂食とエネルギー消費のバランス機構　末梢からのアプローチアディポネクチンとアディポネクチン受容体．最新医学63 : 60─71，2008

23） Toulis KA, Goulis DG, Farmakiotis D, et al : Adiponectin levels in women with polycystic ovary syndrome : a systematic review and a meta-analysis. Hum Reprod Update 15 : 297─307, 2009

24） Pierre P, Froment P, Negre D, et al : Role of adiponectin receptors, AdipoR1 and AdipoR2, in the steroidogenesis of the human granulosa tumor cell line, KGN. Hum Reprod 24 : 2890─2901, 2009

25） Lagaly DV, Aad PY, Grado-Ahuir JA, et al : Role of adiponectin in regulating ovarian theca and granulosa cell function. Mol Cell Endocrinol 284 : 38─45, 2008

26） Zhang Y, Proenca R, Maffei M, et al : Positional cloning of the mouse obese gene and its human homologue. Nature 372 : 425─432, 1994

27） Baskin DG, Blevins JE, Schwartz MW : How the brain regulates food intake and body weight : the role of leptin. J Pediatr Endocrinol Metab 14 Suppl 6 : 1417─1429, 2001

28） Mizuno TM, Kleopoulos SP, Bergen HT, et al : Hypothalamic pro-opiomelanocortin mRNA is reduced by fasting and［corrected］in ob／ob and db／db mice, but is stimulated by leptin. Diabetes 47 : 294─297, 1998

29） Brzechffa PR, Jakimiuk AJ, Agarwal SK, et al : Serum immunoreactive leptin concentrations in women with polycystic ovary syndrome. J Clin Endocrinol Metab 81 : 4166─4169, 1996

30） Zachow RJ, Magoffin DA : Direct intraovarian effects of leptin : impairment of the synergistic action of insulin-like growth factor-I on follicle-stimulating hormone-dependent estradiol-17 beta production by rat ovarian granulosa cells. Endocrinology 138 : 847─850, 1997

31） Jacobs HS, Conway GS : Leptin, polycystic ovaries and polycystic ovary syndrome. Hum Reprod Update 5 : 166─171, 1999

32） Hosoda K, Masuzaki H, Ogawa Y, et al : Development of radioimmunoassay for human leptin. Biochem Biophys Res Commun 221 : 234─239, 1996

33） 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

34） Martin SS, Qasim A, Reilly MP : Leptin resistance : a possible interface of inflammation and metabolism in obesity-related cardiovascular disease. J Am Coll Cardiol 52 : 1201─1210, 2008

35） Wren AM, Seal LJ, Cohen MA, et al : Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab 86 : 5992, 2001

36） Tschop M, Smiley DL, Heiman ML : Ghrelin induces adiposity in rodents. Nature 407 : 908─913, 2000

37） Schofl C, Horn R, Schill T, et al : Circulating ghrelin levels in patients with polycystic ovary syndrome. J Clin Endocrinol Metab 87 : 4607─4610, 2002

38） Pagotto U, Gambineri A, Vicennati V, et al : Plasma ghrelin, obesity, and the polycystic ovary syndrome : correlation with insulin resistance and androgen levels. J Clin Endocrinol Metab 87 : 5625─5629, 2002

39） Orio F Jr., Lucidi P, Palomba S, et al : Circulating ghrelin concentrations in the polycystic ovary syndrome. J Clin Endocrinol Metab 88 : 942─945, 2003

40） Micic D, Sumarac-Dumanovic M, Kendereski A, et al : Total ghrelin levels during acute insulin infusion in patients with polycystic ovary syndrome. J Endocrinol Invest 30 : 820─827, 2007

41） Kuzuya M, Ando F, Iguchi A, et al : Preproghrelin Leu72Met variant contributes to overweight in middle-aged men of a Japanese large cohort. Int J Obes（Lond）30 : 1609─1614, 2006

42） Wang K, Wang L, Zhao Y, et al : No association of the Arg51Gln and Leu72Met polymorphisms of the ghrelin gene and polycystic ovary syndrome. Hum Reprod 24 : 485─490, 2009

43） 竹内　亨 : PCOS─新たな展開─最近のトピックス．HORMONE FRONTIER IN GYNECOLOGY 15 : 75─84, 2008

44） Vendola KA, Zhou J, Adesanya OO, et al : Androgens stimulate early stages of follicular growth in the primate ovary. J Clin Invest 101 : 2622─2629, 1998

45） 田嶋公久，小辻文和 : PCOS─新たな展開─PCOSとアンドロゲン．HORMONE FRONTIER IN GYNECOLOGY 15 : 19─24, 2008

46） Agarwal SK, Judd HL, Magoffin DA : A mechanism for the suppression of estrogen production in polycystic ovary syndrome. J Clin Endocrinol Metab 81 : 3686─3691, 1996

47） San Roman GA, Magoffin DA : Insulin-like growth factor binding proteins in ovarian follicles from women with polycystic ovarian disease : cellular source and levels in follicular fluid. J Clin Endocrinol Metab 75 : 1010─1016, 1992

48） Blank SK, McCartney CR, Helm KD, et al : Neuroendocrine effects of androgens in adult polycystic ovary syndrome and female puberty. Semin Reprod Med 25 : 352─359, 2007

49） Munsterberg A, Lovell-Badge R : Expression of the mouse anti-mullerian hormone gene suggests a role in both male and female sexual differentiation. Development 113 : 613─624, 1991

50） Weenen C, Laven JS, Von Bergh AR, et al : Anti-Mullerian hormone expression pattern in the human ovary : potential implications for initial and cyclic follicle recruitment. Mol Hum Reprod 10 : 77─83, 2004

51） Hirobe S, He WW, Gustafson ML, et al : Mullerian inhibiting substance gene expression in the cycling rat ovary correlates with recruited or graafian follicle selection. Biol Reprod 50 : 1238─1243, 1994

52） Ueno S, Kuroda T, Maclaughlin DT, et al : Mullerian inhibiting substance in the adult rat ovary during various stages of the estrous cycle. Endocrinology 125 : 1060─1066, 1989

53） van Rooij IA, Tonkelaar I, Broekmans FJ, et al : Anti-mullerian hormone is a promising predictor for the occurrence of the menopausal transition. Menopause 11 : 601─606, 2004

54） Broekmans FJ, Soules MR, Fauser BC : Ovarian aging : mechanisms and clinical consequences. Endocr Rev 30 : 465─493, 2009

55） Lambalk CB, van Disseldorp J, de Koning CH, et al : Testing ovarian reserve to predict age at menopause. Maturitas 63 : 280─291, 2009

56） Broekmans FJ, Visser JA, Laven JS, et al : Anti-Mullerian hormone and ovarian dysfunction. Trends Endocrinol Metab 19 : 340─347, 2008

57） Themmen AP : Anti-Mullerian hormone ; its role in follicular growth initiation and survival and as an ovarian reserve marker. J Natl Cancer Inst Monogro : 18─21, 2005

58） Visser JA,Themmen AP : Anti-Mullerian hormone and folliculogenesis. Mol Cell Endocrinol 234 : 81─86, 2005

59） Durlinger AL, Gruijters MJ, Kramer P, et al : Anti-Mullerian hormone attenuates the effects of FSH on follicle development in the mouse ovary. Endocrinology 142 : 4891─4899, 2001

60） Grossman MP, Nakajima ST, Fallat ME, et al : Mullerian-inhibiting substance inhibits cytochrome P450 aromatase activity in human granulosa lutein cell culture. Fertil Steril 89 : 1364─1370, 2008

61） Streuli I, Fraisse T, Pillet C, et al : Serum antimullerian hormone levels remain stable throughout the menstrual cycle and after oral or vaginal administration of synthetic sex steroids. Fertil Steril 90 : 395─400, 2008

62） La Marca A, Giulini S, Orvieto R, et al : Anti-Mullerian hormone concentrations in maternal serum during pregnancy. Hum Reprod 20 : 1569─1572, 2005

63） Mohamed KA, Davies WA, Lashen H : Antimullerian hormone and pituitary gland activity after prolonged down-regulation with goserelin acetate. Fertil Steril 86 : 1515─1517, 2006

64） La Marca A, Pati M, Orvieto R, et al : Serum anti-mullerian hormone levels in women with secondary amenorrhea. Fertil Steril 85 : 1547─1549, 2006

65） van Elburg AA, Eijkemans MJ, Kas MJ, et al : Predictors of recovery of ovarian function during weight gain in anorexia nervosa. Fertil Steril 87 : 902─908, 2007

66） Laven JS, Mulders AG, Visser JA, et al : Anti-Mullerian hormone serum concentrations in normoovulatory and anovulatory women of reproductive age. J Clin Endocrinol Metab 89 : 318─323, 2004

67） Carlsen SM, Vanky E, Fleming R : Anti-Mullerian hormone concentrations in androgen-suppressed women with polycystic ovary syndrome. Hum Reprod 24 : 1732─1738, 2009

68） Fleming R, Deshpande N, Traynor I, et al : Dynamics of FSH-induced follicular growth in subfertile women : relationship with age, insulin resistance, oocyte yield and anti-Mullerian hormone. Hum Reprod 21 : 1436─1441, 2006

69） Das M, Gillott DJ, Saridogan E, et al : Anti-Mullerian hormone is increased in follicular fluid from unstimulated ovaries in women with polycystic ovary syndrome. Hum Reprod 23 : 2122─2126, 2008

70） Jahanfar S, Eden JA : Genetic and non-genetic theories on the etiology of polycystic ovary syndrome. Gynecol Endocrinol 10 : 357─364, 1996

71） Escobar-Morreale HF, Luque-Ramirez M, San Millan JL : The molecular-genetic basis of functional hyperandrogenism and the polycystic ovary syndrome. Endocr Rev 26 : 251─282, 2005

72） Simoni M, Tempfer CB, Destenaves B, et al : Functional genetic polymorphisms and female reproductive disorders ; Part I : Polycystic ovary syndrome and ovarian response. Hum Reprod Update 14 : 459─484, 2008