臨床婦人科産科60巻9号

2006年09月発行

今月の臨床 PCOS─新たな視点

PCOSに関連した新しい分子，遺伝子

3．遺伝子異常

著者： 池田禎智¹ 中村和人¹ 峯岸敬¹

所属機関： ¹群馬大学大学院医学系研究科生殖再生分化学（産科婦人科学教室）

ページ範囲：P.1210 - P.1213

文献概要

はじめに

　多嚢胞性卵巣症候群（polycystic ovary syndrome : PCOS）は性成熟期の女性において比較的高頻度に認められる内分泌疾患であり，種々の代謝異常との関連性も知られている．その発症は複数の遺伝的要因と環境的要因によるとされているが，いまだ明らかになっていない．遺伝的要因としてアンドロゲンをはじめとするステロイドの合成や糖代謝，卵胞発育などにかかわる遺伝子について種々の報告がなされているが，現在のところ一致した見解は得られていない．その理由として，（1）PCOSはその臨床症状として排卵障害に伴う不妊症を呈するため疾患を持つ家系の存続が難しく，遺伝的解析に限界があること，（2）PCOSの臨床像が一様ではなく解析の対象となる集団の設定が困難であり，それぞれの施設が独自の基準で症例を収集し解析していること，（3）表現型が女性にしか現れず，男性におけるそれは不明であること，（4）調査対象に人種や民族間の差があることなどが挙げられる．このような現状を鑑みたうえで，本稿ではいままでに報告されたPCOSのさまざまな遺伝的要因について主に概説したい．

参考文献

1）Cooper HE, Spellacy WN, Prem KA, et al:Hereditary factors in the Stein-Leventhal syndrome. Am J Obstet Gynecol 100:371-387, 1968

2）Givens JR, Wiser WL, Coleman SA:Familial ovarian hyperthecosis:a study of two families. Am J Obstet Gynecol 110:959-972, 1971

3）Legro RS, Strauss JF:Molecular progress in infertility:polycystic ovary syndrome. Fertil Steril 78:569-576, 2002

4）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

5）Jahanfar S, Eden JA, Warren P, et al:A twin study of polycystic ovary syndrome. Fertil Steril 63:478-486, 1995

6）The 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

7）Gilling-Smith C, Willis DS, Beard RW, et al:Hypersecretion of androstenedione by isolated thecal cells from polycystic ovaries. J Clin Endocrinol Metab 79:1158-1165, 1994

8）Gharani N, Waterworth DM, Batty S, et al:Association of the steroid synthesis gene CYP11a with polycystic ovary syndrome and hyperandrogenism. Hum Mol Genet 6:397-402, 1997

9）Diamanti-Kandarakis E, Bartzis MI, Bergiele AT, et al:Microsatellite polymorphism（tttta）（n）at -528 base pairs of gene CYP11alpha influences hyperandrogenemia in patients with polycystic ovary syndrome. Fertil Steril 73:735-741, 2000

10）Escobar-Morreale HF, San Millan JL, Smith RR, et al:The presence of the 21-hydroxylase deficiency carrier status in hirsute women:phenotype-genotype correlations. Fertil Steril 72:629-638, 1999

11）Witchel SF, Aston CE:The role of heterozygosity for CYP21 in the polycystic ovary syndrome. J Pediatr Endocrinol Metab 13（Suppl 5）: 1315-1317, 2000

12）Mifsud A, Ramirez S, Yong EL:Androgen receptor gene CAG trinucleotide repeats in anovulatory infertility and polycystic ovaries. J Clin Endocrinol Metab 85:3484-3488, 2000

13）Xita N, Tsatsoulis A, Chatzikyriakidou A, et al:Association of the（TAAAA）n repeat polymorphism in the sex hormone-binding globulin（SHBG）gene with polycystic ovary syndrome and relation to SHBG serum levels. J Clin Endocrinol Metab 88:5976-5980, 2003

14）Barbieri RL, Makris A, Randall RW, et al:Insulin stimulates androgen accumulation in incubations of ovarian stroma obtained from women with hyperandrogenism. J Clin Endocrinol Metab 62:904-910, 1986

15）Amato P, Simpson JL:The genetics of polycystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol 18:707-718, 2004

16）Waterworth DM, Bennett ST, Gharani N, et al: Linkage and association of insulin gene VNTR regulatory polymorphism with polycystic ovary syndrome. Lancet 349:986-990, 1997

17）Urbanek M, Legro RS, Driscoll DA, et al:Thirty-seven candidate genes for polycystic ovary syndrome:strongest evidence for linkage is with follistatin. Proc Natl Acad Sci USA 96:8573-8578, 1999

18）Siegel S, Futterweit W, Davies TF, et al:A C／T single nucleotide polymorphism at the tyrosine kinase domain of the insulin receptor gene is associated with polycystic ovary syndrome. Fertil Steril 78:1240-1243, 2002

19）Tucci S, Futterweit W, Concepcion ES, et al:Evidence for association of polycystic ovary syndrome in caucasian women with a marker at the insulin receptor gene locus. J Clin Endocrinol Metab 86:446-449, 2001

20）Ehrmann DA, Schwarz PE, Hara M, et al:Relationship of calpain-10 genotype to phenotypic features of polycystic ovary syndrome. J Clin Endocrinol Metab 87:1669-1673, 2002

21）Deeb SS, Fajas L, Nemoto M, et al:A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet 20:284-287, 1998

22）Korhonen S, Heinonen S, Hiltunen M, et al:Polymorphism in the peroxisome proliferator-activated receptor-gamma gene in women with polycystic ovary syndrome. Hum Reprod 18:540-543, 2003

23）Yilmaz M, Ergun MA, Karakoc A, et al:Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma gene in first-degree relatives of subjects with polycystic ovary syndrome. Gynecol Endocrinol 21:206-210, 2005

24）Wood JR, Nelson VL, Ho C, et al:The molecular phenotype of polycystic ovary syndrome（PCOS）theca cells and new candidate PCOS genes defined by microarray analysis. J Biol Chem 278:26380-26390, 2003

25）Hughesdon PE:Morphology and morphogenesis of the Stein-Leventhal ovary and of so-called ﾒhyperthecosisﾓ. Obstet Gynecol Surv 37:59-77, 1982

26）Webber LJ, Stubbs S, Stark J, et al:Formation and early development of follicles in the polycystic ovary. Lancet 362:1017-1021, 2003

27）Franks S, McCarthy M:Genetics of ovarian disorders:polycystic ovary syndrome. Rev Endocr Metab Disord 5:69-76, 2004