Direct effects of metformin in the endometrium: A hypothetical mechanism for the treatment of women with PCOS and endometrial carcinoma

Journal of Experimental and Clinical Cancer Research

Volumn 33, Issue 1, 2014, Pages

  Shao, Ruijin ^a   Li, Xin ^a,b   Feng, Yi ^a,b   Lin, Jin Fang ^b   Billig, Håkan ^a  

^a UNIVERSITY OF GOTHENBURG   (Sweden)

^b FUDAN UNIVERSITY   (China)

Author keywords

Endometrial carcinoma; Insulin resistance; MATEs; Metformin; OCTs; PCOS

Indexed keywords

ANDROGEN; ESTROGEN RECEPTOR; GLUCOSE TRANSPORTER 4; INSULIN; INSULIN RECEPTOR SUBSTRATE 1; MESSENGER RNA; METFORMIN; MULTIDRUG AND TOXIN EXTRUSION PROTEIN 1; MULTIDRUG AND TOXIN EXTRUSION PROTEIN 2; ORGANIC CATION TRANSPORTER 1; ORGANIC CATION TRANSPORTER 2; ORGANIC CATION TRANSPORTER 3; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PROGESTERONE RECEPTOR; PROTEIN KINASE B; PROTEIN KINASE LKB1; SOMATOMEDIN BINDING PROTEIN 1; SOMATOMEDIN C;

ANTINEOPLASTIC ACTIVITY; APOPTOSIS; CANCER SURVIVAL; CELL DIFFERENTIATION; CELL GROWTH; CELL METABOLISM; CELL PROLIFERATION; CELL SURVIVAL; ENDOMETRIUM; ENDOMETRIUM CARCINOMA; ENDOMETRIUM CELL; ENDOMETRIUM HYPERPLASIA; GLUCONEOGENESIS; GLUCOSE METABOLISM; HUMAN; INSULIN RESISTANCE; INSULIN SENSITIVITY; NON INSULIN DEPENDENT DIABETES MELLITUS; OVARY POLYCYSTIC DISEASE; OVERALL SURVIVAL; PARACRINE SIGNALING; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN LOCALIZATION; PROTEIN PHOSPHORYLATION; RECURRENCE FREE SURVIVAL; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM; TUMOR GROWTH;

ANIMALS; ANTINEOPLASTIC AGENTS; CARCINOMA; ENDOMETRIAL NEOPLASMS; ENDOMETRIUM; FEMALE; HUMANS; METFORMIN; ORGANIC CATION TRANSPORT PROTEINS; PARACRINE COMMUNICATION; POLYCYSTIC OVARY SYNDROME; STROMAL CELLS;

EID: 84901696394     PISSN: None     EISSN: 17569966     Source Type: Journal    
DOI: 10.1186/1756-9966-33-41     Document Type: Review

References (110)

1. Cancer Facts & Figures. AmericanCancerSociety, American Cancer Society, Surveil Res 2013 1 1 60
2. Endometrial cancer. Amant F, Moerman P, Neven P, Timmerman D, Van Limbergen E, Vergote I, Lancet 2005 366 491 505 (Pubitemid 41111699)
3. Progesterone: the ultimate endometrial tumor suppressor. Yang S, Thiel KW, Leslie KK, Trends Endocrinol Metab 2011 22 145 152
4. MDM2 SNP309 polymorphism contributes to endometrial cancer susceptibility: evidence from a meta-analysis. Peng Q, Mo C, Qin A, Lao X, Chen Z, Sui J, Wu J, Zhai L, Yang S, Qin X, Li S, J Exp Clin Cancer Res 2013 32 85
5. Type I and II endometrial cancers: have they different risk factors? Setiawan VW, Yang HP, Pike MC, McCann SE, Yu H, Xiang YB, Wolk A, Wentzensen N, Weiss NS, Webb PM, van den Brandt PA, van de Vijver K, Thompson PJ, Strom BL, Spurdle AB, Soslow RA, Shu XO, Schairer C, Sacerdote C, Rohan TE, Robien K, Risch HA, Ricceri F, Rebbeck TR, Rastogi R, Prescott J, Polidoro S, Park Y, Olson SH, Moysich KB, et al. J Clin Oncol 2013 31 2607 2618
6. Endometrial carcinoma. Di Cristofano A, Ellenson LH, Ann Rev Pathol 2007 2 57 85 (Pubitemid 46448060)
7. Endometrial carcinoma in women aged 40 years and younger. Garg K, Soslow RA, Arch Pathol Lab Med 2014 138 335 342
8. Hormone therapy for younger patients with endometrial cancer. Lee WL, Lee FK, Su WH, Tsui KH, Kuo CD, Hsieh SL, Wang PH, Taiwan J Obstet Gynecol 2012 51 495 505
9. Polycystic ovary syndrome and the risk of gynaecological cancer: a systematic review. Chittenden BG, Fullerton G, Maheshwari A, Bhattacharya S, Reprod Biomed Online 2009 19 398 405
10. Polycystic ovary syndrome increases the risk of endometrial cancer in women aged less than 50 years: an Australian case-control study. Fearnley EJ, Marquart L, Spurdle AB, Weinstein P, Webb PM, Cancer Causes Control 2010 21 2303 2308
11. Evaluating the association between endometrial cancer and polycystic ovary syndrome. Haoula Z, Salman M, Atiomo W, Hum Reprod 2012 27 1327 1331
12. Polycystic ovary syndrome and endometrial carcinoma. Hardiman P, Pillay OC, Atiomo W, Lancet 2003 361 1810 1812 (Pubitemid 36638434)
13. Polycystic ovary syndrome. Ehrmann DA, N Engl J Med 2005 352 12 1223 1236
14. Lifestyle changes in women with polycystic ovary syndrome. Moran LJ, Hutchison SK, Norman RJ, Teede HJ, Cochrane Database Syst Rev 2011 7 D007506
15. Polycystic ovary syndrome. Norman RJ, Dewailly D, Legro RS, Hickey TE, Lancet 2007 370 685 697 (Pubitemid 47285318)
16. Epidemiology, diagnosis, and management of polycystic ovary syndrome. Sirmans SM, Pate KA, Clin Epidemiol 2013 6 1 13
17. Progesterone receptor isoforms A and B: new insights into the mechanism of progesterone resistance for the treatment of endometrial carcinoma. Shao R, Ecancermedicalscience 2013 7 381
18. Endometrial cancer: reviving progesterone therapy in the molecular age. Yang S, Thiel KW, De Geest K, Leslie KK, Discov Med 2011 12 205 212
19. Conservative treatment may be beneficial for young women with atypical endometrial hyperplasia or endometrial adenocarcinoma. Jadoul P, Donnez J, Fertil Steril 2003 80 1315 1324 (Pubitemid 37532439)
20. Continuous intrauterine compared with cyclic oral progestin administration in perimenopausal HRT. Boon J, Scholten PC, Oldenhave A, Heintz AP, Maturitas 2003 46 69 77 (Pubitemid 37098293)
21. Altered gene expression profiling in endometrium: evidence for progesterone resistance. Aghajanova L, Velarde MC, Giudice LC, Semin Reprod Med 2010 28 51 58
22. Endometrial progesterone resistance and PCOS. Li X, Feng Y, Lin JF, Billig H, Shao R, J Biomed Sci 2014 21 2
23. Prospective evaluation of insulin resistance among endometrial cancer patients. Burzawa JK, Schmeler KM, Soliman PT, Meyer LA, Bevers MW, Pustilnik TL, Anderson ML, Ramondetta LM, Tortolero-Luna G, Urbauer DL, Chang S, Gershenson DM, Brown J, Lu KH, Am J Obstet Gynecol 2011 204 355 e351-357
24. Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review. Kaaks R, Lukanova A, Kurzer MS, Cancer Epidemiol Biomarkers Prev 2002 11 1531 1543 (Pubitemid 36020003)
25. PCOS and obesity: insulin resistance might be a common etiology for the development of type I endometrial carcinoma. Li X, Shao R, Am J Ccancer Res 2014 4 73 79
26. Metformin for the treatment of the polycystic ovary syndrome. Nestler JE, N Engl J Med 2008 358 47 54
27. Metformin-mode of action and clinical implications for diabetes and cancer. Pernicova I, Korbonits M, Nat Rev Endocrinol 2014 10 143 156
28. Metformin in cancer therapy: a new perspective for an old antidiabetic drug? Ben Sahra I, Le Marchand-Brustel Y, Tanti JF, Bost F, Mol Cancer Ther 2010 9 1092 1099
29. Metformin: multi-faceted protection against cancer. Del Barco S, Vazquez-Martin A, Cufi S, Oliveras-Ferraros C, Bosch-Barrera J, Joven J, Martin-Castillo B, Menendez JA, Oncotarget 2011 2 896 917
30. Evidence-based and potential benefits of metformin in the polycystic ovary syndrome: a comprehensive review. Palomba S, Falbo A, Zullo F, Orio F Jr, Endocr Rev 2009 30 1 50
31. Metformin in cancer: translational challenges. Dowling RJ, Niraula S, Stambolic V, Goodwin PJ, J Mol Endocrinol 2012 48 31 R43
32. Metformin therapy and risk of cancer in patients with type 2 diabetes: systematic review. Franciosi M, Lucisano G, Lapice E, Strippoli GF, Pellegrini F, Nicolucci A, PLoS One 2013 8 71583
33. Metformin use and endometrial cancer survival. Nevadunsky NS, Van Arsdale A, Strickler HD, Moadel A, Kaur G, Frimer M, Conroy E, Goldberg GL, Einstein MH, Gynecol Oncol 2014 132 236 240
34. Metformin is associated with improved survival in endometrial cancer. Ko EM, Walter P, Jackson A, Clark L, Franasiak J, Bolac C, Havrilesky LJ, Secord AA, Moore DT, Gehrig PA, Bae-Jump V, Gynecol Oncol 2014 132 438 442
35. Metformin is a potent inhibitor of endometrial cancer cell proliferation-implications for a novel treatment strategy. Cantrell LA, Zhou C, Mendivil A, Malloy KM, Gehrig PA, Bae-Jump VL, Gynecol Oncol 2010 116 92 98
36. Metformin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and modulation of the mTOR pathway. Hanna RK, Zhou C, Malloy KM, Sun L, Zhong Y, Gehrig PA, Bae-Jump VL, Gynecol Oncol 2012 125 458 469
37. Metformin downregulates the insulin/IGF-I signaling pathway and inhibits different uterine serous carcinoma (USC) cells proliferation and migration in p53-dependent or -independent manners. Sarfstein R, Friedman Y, Attias-Geva Z, Fishman A, Bruchim I, Werner H, PLoS One 2013 8 61537
38. Metformin treatment exerts antiinvasive and antimetastatic effects in human endometrial carcinoma cells. Tan BK, Adya R, Chen J, Lehnert H, Sant Cassia LJ, Randeva HS, J Clin Endocrinol Metab 2011 96 808 816
39. Metformin promotes progesterone receptor expression via inhibition of mammalian target of rapamycin (mTOR) in endometrial cancer cells. Xie Y, Wang YL, Yu L, Hu Q, Ji L, Zhang Y, Liao QP, J Steroid Biochem Mol Biol 2011 126 113 120
40. Preventing endometrial cancer risk in polycystic ovarian syndrome (PCOS) women: Could metformin help? Shafiee MN, Khan G, Ariffin R, Abu J, Chapman C, Deen S, Nunns D, Barrett DA, Seedhouse C, Atiomo W, Gynecol Oncol 2014 132 248 253
41. Hormone receptor dynamics in a receptive human endometrium. Critchley HO, Saunders PT, Reprod Sci 2009 16 191 199
42. Progesterone action in endometrial cancer, endometriosis, uterine fibroids, and breast cancer. Kim JJ, Kurita T, Bulun SE, Endocr Rev 2013 34 130 162
43. Histopathology of endometrial hyperplasia and endometrial carcinoma: an update. Horn LC, Meinel A, Handzel R, Einenkel J, Ann Diagn Pathol 2007 11 297 311 (Pubitemid 47043499)
44. Profiling of endogenous estrogens, their precursors, and metabolites in endometrial cancer patients: association with risk and relationship to clinical characteristics. Audet-Walsh E, Lepine J, Gregoire J, Plante M, Caron P, Tetu B, Ayotte P, Brisson J, Villeneuve L, Belanger A, Guillemette C, J Clin Endocrinol Metab 2011 96 330 E339
45. The effects of metformin and letrozole on endometrium and ovary in a rat model. Oner G, Ozcelik B, Ozgun MT, Ozturk F, Gynecol Endocrinol 2011 27 1084 1086
46. Comparison of antiproliferative effects of metformine and progesterone on estrogen-induced endometrial hyperplasia in rats. Tas M, Kutuk MS, Serin IS, Ozgun MT, Oner G, Ozturk F, Gynecol Endocrinol 2013 29 311 314
47. Effects of metformin on mammalian target of rapamycin in a mouse model of endometrial hyperplasia. Erdemoglu E, Guney M, Giray SG, Take G, Mungan T, Eur J Obstet Gynecol Reprod Biol 2009 145 195 199
48. Chemopreventive effects of metformin on obesity-associated endometrial proliferation. Zhang Q, Celestino J, Schmandt R, McCampbell AS, Urbauer DL, Meyer LA, Burzawa JK, Huang M, Yates MS, Iglesias D, Broaddus RR, Lu KH, Am J Obstet Gynecol 2013 209 24 e21-24 e12
49. Combination of Diane-35 and metformin to treat early endometrial carcinoma in PCOS women with insulin resistance. Li X, Guo JR, Lin JF, Feng Y, Billig H, Shao R, J Cancer 2014 5 173 181
50. Does Metformin affect ER, PR, IGF-1R, beta-catenin and PAX-2 expression in women with diabetes mellitus and endometrial cancer? Markowska A, Pawalowska M, Filas V, Korski K, Grybos M, Sajdak S, Olejek A, Bednarek W, Spiewankiewicz B, Lubin J, Markowska J, Diabetol Metab Syndr 2013 5 76
51. N-acetyl cysteine plus clomiphene citrate versus metformin and clomiphene citrate in treatment of clomiphene-resistant polycystic ovary syndrome: a randomized controlled trial. Abu Hashim H, Anwar K, El-Fatah RA, J Womens Health (Larchmt) 2010 19 2043 2048
52. Combined metformin and clomiphene citrate versus laparoscopic ovarian diathermy for ovulation induction in clomiphene-resistant women with polycystic ovary syndrome: a randomized controlled trial. Abu Hashim H, El Lakany N, Sherief L, J Obstet Gynaecol Res 2011 37 169 177
53. Is metformin a primary ovulatory agent in patients with polycystic ovary syndrome? Cheang KI, Sharma ST, Nestler JE, Gynecol Endocrinol 2006 22 595 604 (Pubitemid 44915725)
54. Short-term metformin treatment for clomiphene citrate-resistant women with polycystic ovary syndrome. Kazerooni T, Ghaffarpasand F, Kazerooni Y, Kazerooni M, Setoodeh S, Int J Gynaecol Obstet 2009 107 50 53
55. Metformin therapy improves ovulatory rates, cervical scores, and pregnancy rates in clomiphene citrate-resistant women with polycystic ovary syndrome. Kocak M, Caliskan E, Simsir C, Haberal A, Fertil Steril 2002 77 101 106 (Pubitemid 34093900)
56. The effects of metformin and rosiglitazone, alone and in combination, on the ovary and endometrium in polycystic ovary syndrome. Legro RS, Zaino RJ, Demers LM, Kunselman AR, Gnatuk CL, Williams NI, Dodson WC, Am J Obstet Gynecol 2007 196 402 e401-410; discussion 402 e410-401
57. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. Lord JM, Flight IH, Norman RJ, BMJ 2003 327 951 953
58. Efficacy of combined metformin-letrozole in comparison with metformin-clomiphene citrate in clomiphene-resistant infertile women with polycystic ovarian disease. Sohrabvand F, Ansari S, Bagheri M, Hum Reprod 2006 21 1432 1435 (Pubitemid 44445018)
59. Acetaldehyde-stimulated PKC activity in airway epithelial cells treated with smoke extract from normal and smokeless cigarettes. Wyatt TA, Schmidt SC, Rennard SI, Tuma DJ, Sisson JH, Proc Soc Exp Biol Med 2000 225 91 97
60. The effects of metformin on insulin resistance, clomiphene-induced ovulation and pregnancy rates in women with polycystic ovary syndrome. Sahin Y, Yirmibes U, Kelestimur F, Aygen E, Eur J Obstet Gynecol Reprod Biol 2004 113 214 220 (Pubitemid 38456778)
61. Insulin reduction with metformin increases luteal phase serum glycodelin and insulin-like growth factor-binding protein 1 concentrations and enhances uterine vascularity and blood flow in the polycystic ovary syndrome. Jakubowicz DJ, Seppala M, Jakubowicz S, Rodriguez-Armas O, Rivas-Santiago A, Koistinen H, Koistinen R, Nestler JE, J Clin Endocrinol Metab 2001 86 1126 1133 (Pubitemid 32322992)
62. Uterine effects of metformin administration in anovulatory women with polycystic ovary syndrome. Palomba S, Russo T, Orio F Jr, Falbo A, Manguso F, Cascella T, Tolino A, Carmina E, Colao A, Zullo F, Hum Reprod 2006 21 457 465 (Pubitemid 43159923)
63. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Diamanti-Kandarakis E, Dunaif A, Endocr Rev 2012 33 981 1030
64. Treatment of obesity in polycystic ovary syndrome: a position statement of the Androgen Excess and Polycystic Ovary Syndrome Society. Moran LJ, Pasquali R, Teede HJ, Hoeger KM, Norman RJ, Fertil Steril 2009 92 1966 1982
65. Treatment of atypical endometrial hyperplasia with an insulin-sensitizing agent. Session DR, Kalli KR, Tummon IS, Damario MA, Dumesic DA, Gynecol Endocrinol 2003 17 405 407 (Pubitemid 37338871)
66. Reverse of progestin-resistant atypical endometrial hyperplasia by metformin and oral contraceptives. Shen ZQ, Zhu HT, Lin JF, Obstet Gynecol 2008 112 465 467
67. Molecular determinants of outcome with mammalian target of rapamycin inhibition in endometrial cancer. Mackay HJ, Eisenhauer EA, Kamel-Reid S, Tsao M, Clarke B, Karakasis K, Werner HM, Trovik J, Akslen LA, Salvesen HB, Tu D, Oza AM, Cancer 2014 120 603 610
68. Clinical pharmacokinetics of metformin. Graham GG, Punt J, Arora M, Day RO, Doogue MP, Duong JK, Furlong TJ, Greenfield JR, Greenup LC, Kirkpatrick CM, Ray JE, Timmins P, Williams KM, Clin Pharmacok 2011 50 81 98
69. Organic cation transporters (OCTs, MATEs), in vitro and in vivo evidence for the importance in drug therapy. Nies AT, Koepsell H, Damme K, Schwab M, Handb Exp Pharmacol 2011 201 105 167
70. Multidrug and toxin extrusion proteins (MATE/SLC47); role in pharmacokinetics. Staud F, Cerveny L, Ahmadimoghaddam D, Ceckova M, Int J Biochem Cell Biol 2013 45 2007 2011
71. Coordinate regulation of heterogeneous nuclear ribonucleoprotein dynamics by steroid hormones in the human Fallopian tube and endometrium in vivo and in vitro. Shao R, Wang X, Weijdegard B, Norstrom A, Fernandez-Rodriguez J, Brannstrom M, Billig H, Am J Physiol Endocrinol Metab 2012 302 1269 E1282
72. Regulation of human organic cation transporter hOCT2 by PKA, PI3K, and calmodulin-dependent kinases. Cetinkaya I, Ciarimboli G, Yalcinkaya G, Mehrens T, Velic A, Hirsch JR, Gorboulev V, Koepsell H, Schlatter E, Am J Physiol Renal Physiol 2003 284 293 F302
73. Regulation of the human organic cation transporter hOCT1. Ciarimboli G, Struwe K, Arndt P, Gorboulev V, Koepsell H, Schlatter E, Hirsch JR, J Cell Physiol 2004 201 420 428 (Pubitemid 39456441)
74. Reduced expression of organic cation transporters rOCT1 and rOCT2 in experimental diabetes. Grover B, Buckley D, Buckley AR, Cacini W, J Pharmacol Exp Ther 2004 308 949 956 (Pubitemid 38263970)
75. Metformin inhibits human androgen production by regulating steroidogenic enzymes HSD3B2 and CYP17A1 and complex I activity of the respiratory chain. Hirsch A, Hahn D, Kempna P, Hofer G, Nuoffer JM, Mullis PE, Fluck CE, Endocrinology 2012 153 4354 4366
76. Organic cation transporter 1 polymorphisms predict the metabolic response to metformin in women with the polycystic ovary syndrome. Gambineri A, Tomassoni F, Gasparini DI, Di Rocco A, Mantovani V, Pagotto U, Altieri P, Sanna S, Fulghesu AM, Pasquali R, J Clin Endocrinol Metab 2010 95 204 E208
77. Cellular and molecular mechanisms of metformin: an overview. Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F, Clin Sci (Lond) 2012 122 253 270
78. Role of AMP-activated protein kinase in mechanism of metformin action. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE, J Clin Invest 2001 108 1167 1174 (Pubitemid 32995375)
79. Metformin directly inhibits androgen production in human thecal cells. Attia GR, Rainey WE, Carr BR, Fertil Steril 2001 76 517 524
80. Metformin has direct effects on human ovarian steroidogenesis. Mansfield R, Galea R, Brincat M, Hole D, Mason H, Fertil Steril 2003 79 956 962 (Pubitemid 36385020)
81. Metformin augments the levels of molecules that regulate the expression of the insulin-dependent glucose transporter GLUT4 in the endometria of hyperinsulinemic PCOS patients. Carvajal R, Rosas C, Kohan K, Gabler F, Vantman D, Romero C, Vega M, Hum Reprod 2013 28 2235 2244
82. Effects of metformin on bovine granulosa cells steroidogenesis: possible involvement of adenosine 5' monophosphate-activated protein kinase (AMPK). Tosca L, Chabrolle C, Uzbekova S, Dupont J, Biol Reprod 2007 76 368 378
83. Insulin-lowering effects of metformin in women with early breast cancer. Goodwin PJ, Pritchard KI, Ennis M, Clemons M, Graham M, Fantus IG, Clin Breast Cancer 2008 8 501 505
84. Insulin resistance: a significant risk factor of endometrial cancer. Mu N, Zhu Y, Wang Y, Zhang H, Xue F, Gynecol Oncol 2012 125 751 757
85. Understanding obesity and endometrial cancer risk: opportunities for prevention. Schmandt RE, Iglesias DA, Co NN, Lu KH, Am J Obstet Gynecol 2011 205 518 525
86. A prospective evaluation of insulin and insulin-like growth factor-I as risk factors for endometrial cancer. Gunter MJ, Hoover DR, Yu H, Wassertheil-Smoller S, Manson JE, Li J, Harris TG, Rohan TE, Xue X, Ho GY, Einstein MH, Kaplan RC, Burk RD, Wylie-Rosett J, Pollak MN, Anderson G, Howard BV, Strickler HD, Cancer Epidemiol Biomarkers Prev 2008 17 921 929 (Pubitemid 351536424)
87. Insulin resistance and cancer: epidemiological evidence. Tsugane S, Inoue M, Cancer Sci 2010 101 1073 1079
88. Endometrial carcinoma: molecular alterations involved in tumor development and progression. Yeramian A, Moreno-Bueno G, Dolcet X, Catasus L, Abal M, Colas E, Reventos J, Palacios J, Prat J, Matias-Guiu X, Oncogene 2013 32 403 413
89. Uterine insulin-like growth factor-1: regulation of expression and its role in estrogen-induced uterine proliferation. Murphy LJ, Ghahary A, Endocr Rev 1990 11 443 453 (Pubitemid 20261695)
90. Insulin signaling, resistance, and the metabolic syndrome: insights from mouse models into disease mechanisms. Guo S, J Endocrinol 2014 220 1 T23
91. Insulin/IGF-I receptor hybrids: a mechanism for increasing receptor diversity. Moxham CP, Jacobs S, J Cell Biochem 1992 48 136 140
92. Overexpression of the insulin-like growth factor I receptor and activation of the AKT pathway in hyperplastic endometrium. McCampbell AS, Broaddus RR, Loose DS, Davies PJ, Clin Cancer Res 2006 12 6373 6378 (Pubitemid 44799707)
93. Overexpression of the insulin receptor isoform a promotes endometrial carcinoma cell growth. Wang CF, Zhang G, Zhao LJ, Qi WJ, Li XP, Wang JL, Wei LH, PLoS One 2013 8 69001
94. PTEN level in tumor suppression: how much is too little? Carracedo A, Alimonti A, Pandolfi PP, Cancer Res 2011 71 629 633
95. Personalized therapy in endometrial cancer: challenges and opportunities. Westin SN, Broaddus RR, Cancer Biol Ther 2012 13 1 13
96. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA, Montminy M, Cantley LC, Science 2005 310 1642 1646 (Pubitemid 41780780)
97. Ovulatory response to treatment of polycystic ovary syndrome is associated with a polymorphism in the STK11 gene. Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, Steinkampf MP, Coutifaris C, McGovern PG, Cataldo NA, Gosman GG, Nestler JE, Giudice LC, Ewens KG, Spielman RS, Leppert PC, Myers ER, J Clin Endocrinol Metab 2008 93 792 800 (Pubitemid 351398555)
98. Loss of tuberous sclerosis complex-2 function and activation of mammalian target of rapamycin signaling in endometrial carcinoma. Lu KH, Wu W, Dave B, Slomovitz BM, Burke TW, Munsell MF, Broaddus RR, Walker CL, Clin Cancer Res 2008 14 2543 2550
99. Regulated transport of the glucose transporter GLUT4. Bryant NJ, Govers R, James DE, Nat Rev Mol Cell Biol 2002 3 267 277 (Pubitemid 34619262)
100. Changes in the expression of insulin signaling pathway molecules in endometria from polycystic ovary syndrome women with or without hyperinsulinemia. Fornes R, Ormazabal P, Rosas C, Gabler F, Vantman D, Romero C, Vega M, Mol Med 2010 16 129 136
101. Evidence for the presence of glucose transporter 4 in the endometrium and its regulation in polycystic ovary syndrome patients. Mioni R, Chiarelli S, Xamin N, Zuliani L, Granzotto M, Mozzanega B, Maffei P, Martini C, Blandamura S, Sicolo N, Vettor R, J Clin Endocrinol Metab 2004 89 4089 4096 (Pubitemid 39071517)
102. Obesity reduces the expression of GLUT4 in the endometrium of normoinsulinemic women affected by the polycystic ovary syndrome. Mozzanega B, Mioni R, Granzotto M, Chiarelli S, Xamin N, Zuliani L, Sicolo N, Marchesoni D, Vettor R, Ann N Y Acad Sci 2004 1034 364 374 (Pubitemid 40362374)
103. Effects of metformin on the expression of GLUT4 in endometrium of obese women with polycystic ovary syndrome. Zhai J, Liu CX, Tian ZR, Jiang QH, Sun YP, Biol Reprod 2012 87 29
104. Effects of testosterone and metformin on glucose metabolism in endometrium. Zhang L, Liao Q, Fertil Steril 2010 93 2295 2298
105. Tumor stroma and regulation of cancer development. Tlsty TD, Coussens LM, Ann Rev Pathol 2006 1 119 150
106. Role of stromal-epithelial interactions in hormonal responses. Cunha GR, Cooke PS, Kurita T, Arch Histol Cytol 2004 67 417 434 (Pubitemid 40424552)
107. Progesterone receptor signaling in the microenvironment of endometrial cancer influences its response to hormonal therapy. Janzen DM, Rosales MA, Paik DY, Lee DS, Smith DA, Witte ON, Iruela-Arispe ML, Memarzadeh S, Cancer Res 2013 73 4697 4710
108. The influence of insulin on secretion of IGF-I and IGFBP-I in cultures of human endometrial stromal cells. Lin J, Li R, Zhou J, Chinese Med J 2003 116 301 304 (Pubitemid 36504069)
109. IGFs and IGF-binding proteins in the regulation of human ovarian and endometrial function. Wang HS, Chard T, J Endocrinol 1999 161 1 13 (Pubitemid 29170186)
110. Insulin-like growth factor binding protein-1 (IGFBP-1): a multifunctional role in the human female reproductive tract. Fowler DJ, Nicolaides KH, Miell JP, Hum Reprod Update 2000 6 495 504