The effects of metformin on uterine tissue of hyperandrogenized BALB/c mice

Molecular Human Reproduction

Volumn 15, Issue 7, 2009, Pages 421-432

  Elia, Evelin Mariel ^a   Belgorosky, Denise ^a   Faut, Mónica ^a   Vighi, Susana ^b   Pustovrh, Carolina ^c   Luigi, Devoto ^c   Motta, Alicia Beatriz ^a  

^a Centre de Estudios Farmacologicos y Botanicos   (Argentina)

^b UNIVERSIDAD DE BUENOS AIRES   (Argentina)

^c Inst de Invest Materno Infantil   (Chile)

Author keywords

Metformin; PCOS; Prostaglandins; T lymphocytes; Uterus

Indexed keywords

CATALASE; CYCLOOXYGENASE 2; METFORMIN; NITRIC OXIDE SYNTHASE; PRASTERONE; PROSTAGLANDIN E; PROSTAGLANDIN F2 ALPHA; SUPEROXIDE DISMUTASE;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ANTIINFLAMMATORY ACTIVITY; ANTIOXIDANT ACTIVITY; APOPTOSIS; ARTICLE; BAGG ALBINO MOUSE; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CONTROLLED STUDY; DRUG EFFICACY; ENZYME ACTIVITY; ENZYME BLOOD LEVEL; FEMALE; GENE EXPRESSION; HISTOCHEMISTRY; HYPERANDROGENISM; IMMUNOPHENOTYPING; LYMPHOCYTE FUNCTION; LYMPHOCYTE SUBPOPULATION; LYMPHOCYTIC INFILTRATION; MOUSE; NONHUMAN; OVARY POLYCYSTIC DISEASE; OXIDATIVE STRESS; PRIORITY JOURNAL; PROSTAGLANDIN RELEASE; PROSTAGLANDIN SYNTHESIS INHIBITION; TISSUE TYPES; UTERINE TISSUE;

ANIMALS; BLOTTING, WESTERN; CATALASE; CD4-POSITIVE T-LYMPHOCYTES; CD8-POSITIVE T-LYMPHOCYTES; CYCLOOXYGENASE 2; DEHYDROEPIANDROSTERONE; DINOPROST; ENZYME ACTIVATION; FEMALE; FLOW CYTOMETRY; METFORMIN; MICE; MICE, INBRED BALB C; NITRIC OXIDE SYNTHASE; OXIDATIVE STRESS; POLYCYSTIC OVARY SYNDROME; RADIOIMMUNOASSAY; SUPEROXIDE DISMUTASE; UTERUS;

MUS;

EID: 67649233794     PISSN: 13609947     EISSN: 14602407     Source Type: Journal    
DOI: 10.1093/molehr/gap033     Document Type: Article

References (66)

1. Ajjosa S, Guerriero S, Paoletti AM, Orru M, Melis GB. The anti-androgenic effect of flutamide improves uterine perfusion in women with polycystic ovary syndrome. Fertil Steril 2002;77 1136-1140.
2. Anderson E, Lee MT, Lee G. Cystogenesis of the ovarian antral follicle of the rat: Ultrastructural changes and hormonal profile following the administration of dehydroepiandrosterone. Anat Rec 1992; 234 359-382.
3. Arosh JA, Banu SK, Kimmins S, Chapdelaine P, Maclaren LA, Fortier MA. Effect of interferon-tau on prostaglandin biosynthesis, transport, and signaling at the time of maternal recognition of pregnancy in cattle: evidence of polycrine actions of prostaglandin E2. Endocrinology 2004; 145:5280-5293.
4. Balen A. Polycystic ovary syndrome and cancer. Hum Reprod Update 2001; 7:522-525.
5. Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA. Apparent hydroxyl radical production by peroxynitrite: Implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci USA 1990;87:1620-1624.
6. Boerboom D, Brown KA, Vaillancourt D, Poitras P, Goff AK, Watanabe K. Expression of key prostaglandin synthases in equine endometrium during late diestrus and early pregnancy. Biol Reprod 2004;70 391-399.
7. Brune B. The intimate relation between nitric oxide and superoxide in apoptosis and cell survival. Antioxid Redox Signal 2005;7 497-507.
8. Chance B. Special methods: Catalase. In: Por Glick R (ed). The Assay of Catalase and Peroxidases. New York: Interscience, 1954, 408-424.
9. Diamanti-Kandarakis E, Kouli C, Tsianateli T, Bergiele A. Therapeutic effects of metformin on insulin resistance and hyperandrogenism in polycystic ovary syndrome. Eur J Endocrinol 1998;138:269-274.
10. Doulla-Bell F, Guay JM, Fortier MA. Prostaglandin G/H synthase (PGHS)-2 expression in bovine myometrium: Influence of steroid hormones and PGHS inhibitors. Biol Reprod 1998;59:1433-1437.
11. Ehrmann DA, Cavaghan MK, Imperial J, Sturis J, Rosenfield RL, Polonsky KS. Effects of metformin on insulin secretion, insulin action, and ovarian steroidogenesis in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1997;82:524-530.
12. Elia E, Sander S, Luchetti CG, Solano ME, Di Girolamo G, Gonzalez C, Motta AB. The mechanisms involved in the action of metformin in regulating ovarian function in hyperandrogenized mice. Mol Hum Reprod 2006;12:475-481.
13. Elia E, Vighi S, Lombardi E, Motta AB. Detrimental effects of hiperandrogenism on uterine functions. Int Immunopharmacol 2008; 8:1827-1834.
14. Fedorcsák P, Dale PO, Storeng R, Abyholm T, Tanbo T. The effect of metformin on ovarian stimulation and in vitro fertilization in insulin-resistant women with polycystic ovary syndrome: An open-label randomized cross-over trial. Gynecol Endocrinol 2003;17 207-214.
15. Finn CA. Implantation, menstruation and inflammation. Biol Rev 1986; 61:313-328.
16. Franks S. Polycystic ovary syndrome. N Engl J Med 1995;333 853-861.
17. Fryer LG, Parbu-Patel A, Carling D. The Anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways. J Biol Chem 2002;12 25226-22532.
18. Giudice LC. Endometrium in PCOS: Implantation and predisposition to endocrine CA. Best Pract Res Clin Endocrinol Metab 2006; 20 235-244.
19. Glueck CJ, Fontaine RN, Wang P, Subbiah MT, Weber K, Illig E, Streicher P, Sieve-Smith L, Tracy TM, Lang JE et al. Metformin reduces weight, centripetal obesity, insulin, leptin, and low-density lipoprotein cholesterol in nondiabetic, morbidly obese subjects with body mass index greater than 30. Metabolism 2001;50:856-861.
20. Glueck CJ, Goldenberg N, Wang P, Loftspring M, Sherman A. Metformin during pregnancy reduces insulin, insulin resistance, insulin secretion, weight, testosterone and development of gestational diabetes: prospective longitudinal assessment of women with polycystic ovary syndrome from preconception throughout pregnancy. Hum Reprod 2004;19:510-521.
21. Gunin AG, Mashin IN, Zakharov DA. Proliferation, mitosis orientation and morphogenetic changes in the uterus of mice following chronic treatment with both estrogen and glucocorticoid hormones. J Endocrinol 2001;169:23-31.
22. Harborne L, Fleming R, Lyall H, Norman J, Sattar N. Descriptive review of the evidence for the use of metformin in polycystic ovary syndrome. Lancet 2003;31:894-901.
23. Henmi H, Endo T, Nagasawa K, Hayashi T, Chida M, Akutagawa N, Iwasaki M, Kitajima Y, Kiya T, Nishikawa A et al. Lysyl oxidase and MMP-2 expression in dehydroepiandrosteroneinduced polycystic ovary in rats. Biol Reprod 2001;64:157-162.
24. Hundal RS, Krssak M, Dufour S, Laurent D, Lebon V, Chandramouli V, Inzucchi SE, Schumann WC, Petersen KF, Landau BR et al. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes 2000;49:2063-2069.
25. Jakubowicz DJ, Seppälä M, Jakubowicz S, Rodriguez-Armas O, Rivas-Santiago A, Koistinen H, Koistinen R, Nestler JE. 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. J Clin Endocrinol Metab 2001;86:1126-1133.
26. Kelly RW, King AE, Critchley HO. Inflammatory mediators and endometrial function-focus on the perivascular cell. J Reprod Immunol 2002; 57:81-93.
27. La Marca A, Morgante G, Palumbo M, Cianci A, Petraglia F, De Leo V. Insulin-lowering treatment reduces aromatase activity in response to follicle-stimulating hormone in women with polycystic ovary syndrome. Fertil Steril 2002;78:1234-1239.
28. Lee MT, Anderson E, Lee GY. Changes in ovarian morphology and serum hormones in the rat after treatment with dehydroepiandrosterone. Anat Rec 1991;231:185-192.
29. Lee GY, Croop JM, Anderson E. Multidrug resistance gene expression correlates with progesterone production in dehydroepiandrosteroneinduced polycystic equine chorionic gonadotropin-stimulated ovaries of prepuberal rats. Biol Reprod 1998;58:330-337.
30. Li G, Dong B, Butz DE, Park Y, Pariza MW, Cook ME. NF-kappaB independent inhibition of lipopolysaccharide-induced cyclooxygenase by a conjugated linoleic acid cognate, conjugated nonadecadienoic acid. Biochim Biophys Acta 2006;1761:969-972.
31. Luchetti CG, Solano ME, Sander V, Arcos ML, Gonzalez C, Di Girolamo G, Chiocchio S, Cremaschi G, Motta AB. Effects of dehydroepiandrosterone on ovarian cystogenesis and immune function. J Reprod Immunol 2004; 64:59-74.
32. Luchetti CG, Mikó E, Szekeres-Bartho J, Paz DA, Motta AB. Dehydroepiandrosterone and metformin modulate progesteroneinduced blocking factor (PIBF), cyclooxygenase 2 (COX2) and cytokines in early pregnant mice. J Steroid Biochem Mol Biol 2008;111:200-207.
33. Motta AB, Estevez A, Gimeno MF. The involvement of nitric oxide in corpus luteum regression in the rat: Feedback mechanism between prostaglandin F(2alpha) and nitric oxide. Mol Hum Reprod 1999; 5:1011-1016.
34. Motta AB, Estevez A, Tognetti T, Gimeno MA, Franchi AM. Dual effects of nitric oxide in functional and regressing rat corpus luteum. Mol Hum Reprod 2001;7:43-47.
35. Nestler JE, Jakubowicz 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 1996;29 617-623.
36. Ohno Y, Ohno S, Suzuki N, Kamei T, Inagawa H, Soma G, Inoue M. Role of cyclooxygenase-2 in immunomodulation and prognosis of endometrial carcinoma. Int J Cancer 2005;114:696-701.
37. Ohno S, Ohno Y, Nakada H, Suzuki N, Soma G, Inoue M. Expression of Tn and sialyl-Tn antigens in endometrial cancer: Its relationship with tumor-produced cyclooxygenase-2, tumor-infiltrated lymphocytes and patient prognosis. Anticancer Res 2006;26:4047-4053.
38. Ohno S, Ohno Y, Suzuki N, Soma G, Inoue M. Cyclooxygenase-2 expression correlates with apoptosis and angiogenesis in endometrial cancer tissue. Anticancer Res 2007;27:3765-3770.
39. Okon MA, Laird SM, Tuckerman EM, Li TC. Serum androgen levels in women who have recurrent miscarriages and their correlation with markers of endometrial function. Fertil Steril 1998;69:682-690.
40. Orio F Jr, Palomba S, Cascella T, De Simone B, Manguso F, Savastano S, Russo T, Tolino A, Zullo F, Lombardi G et al. Improvement in endothelial structure and function after metformin treatment in young normal-weight women with polycystic ovary syndrome: Results of a 6-month study. J Clin Endocrinol Metab 2005;90:6072-6076.
41. Ota K, Nakamura J, Li W, Kozakae M, Watarai A, Nakamura N, Yasuda Y, Nakashima E, Naruse K, Watabe K et al. Metformin prevents methylglyoxal-induced apoptosis of mouse Schwann cells. Biochem Biophys Res Commun 2007;357:270-275.
42. Palomba S, Russo T, Orio F Jr, Falbo A, Manguso F, Cascella T, Tolino A, Carmina E, Colao A, Zullo F. Uterine effects of metformin administration in anovulatory women with polycystic ovary syndrome. Hum Reprod 2006;21:457-465.
43. Pillay OC, Te Fong LF, Crow JC, Benjamin E, Mould T, Atiomo W, Menon PA, Leonard AJ, Hardiman P. The association between polycystic ovaries and endometrial cancer. Hum Reprod 2006;21:924-929.
44. Roy S, Mahesh VB, Greenblatt RB. Effect of dehydroepiandrosterone and androstenedione on the reproductive organs of female rats production of cystic changes in the ovary. Nature 1962;196:2-6.
45. Sander V, Solano ME, Elia E, Luchetti CG, Di Girolamo G, Gonzalez C, Motta AB. The influence of dehydroepiandrosterone on early pregnancy in mice. Neuroimmunomodulation 2005;12:285-292.
46. Sander V, Luchetti CG, Solano ME, Elia EM, Di Girolamo G, Gonzalez C, Motta AB. Role of the N,N'dimethylbiguanide metformin in the treatment of female prepuberal BALB/c mice hyperandrogenized with dehydroepiandrosterone. Reproduction 2006;131:591-602.
47. Sharma S, Stolina M, Yang SC, Baratelli F, Lin JF, Atianzar K, Luo J, Zhu L, Lin Y, Huang M et al. Tumor cyclooxygenase 2-dependent suppression of dendritic cell function. Clin Cancer Res 2003;9 961-968.
48. Sir-Petermann T, Maliqueo M, Angel B, Lara HE, Perez-Bravo F, Recabarren SE. Maternal serum androgens in pregnant women with polycystic ovary syndrome: Possible implications in prenatal androgenization. Hum Reprod 2002;17:2573-2579.
49. Solano ME, Sander V, Elia E, Luchetti CG, Di Girolamo G, Gonzalez C, Motta AB. Metformin prevents embryonic resorption induced by hyperandrogenization with dehydroepiandrosterone in mice. Reprod Fertil Dev 2006;18:533-544.
50. Solano ME, Sander VA, Wald MP, Motta AB. Dehydroepinandrosterone and metformin regulate proliferation of murine T lymphocytes. Clin Exp Immunol 2008;153:289-296.
51. Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med 1995;333:550-554.
52. Sugino N, Nakamura Y, Takeda O, Ishimatsu M, Kato H. Changes in activities of superoxide dismutase and lipid peroxide in corpus luteum during pregnancy in rats. J Reprod Fertil 1993;97:347-351.
53. Sugino N, Karube-Harada Y, Kashida S, Takiguchi S, Kato H. Reactive oxygen species stimulate prostaglandin F2α production in human endometrial stromal cells in vitro. Hum Reprod 2001;16 1797-1801.
54. Sugino N, Karube-Harada A, Taketani T, Sakata A, Nakamura Y. Withdrawal of ovarian steroids stimulates prostaglandin F2alpha production through nuclear factor-kappaB activation via oxygen radicals in human endometrial stromal cells: Potential relevance to menstruation. J Reprod Dev 2004;50:215-225.
55. Tosca L, Chabrolle Ch, Uzbekova S, Dupont J. Effects of metformin on bovine granulosa cells steroidogenesis: Possible involvement of adenosine 5 alpha monophosphate-activated protein kinase (AMPK). Biol Reprod 2007;76:368-378.
56. Tuckerman EM, Okon MA, Li T, Laird SM. Do androgens have a direct effect on endometrial function? An in vitro study. Fertil Steril 2000; 74:771-779.
57. Turi A, Di Prospero F, Mazzarini A, Costa M, Cignitti M, Garzetti GG, Romanini C. Lymphocytes subset in hyperandrogenic women with polycystic ovarian disease. Acta Eur Fertil 1988;19:155-157.
58. Velázquez E, Acosta A, Mendoza SG. Menstrual cyclicity after metformin therapy in polycystic ovary syndrome. Obstet Gynecol 1997;90:392-395.
59. Wang Z, Tamura K, Yoshie M, Tamura H, Imakawa K, Kogo H. Prostaglandin F2 alpha-induced functional regression of the corpus luteum and apoptosis in rodents. J Pharmacol Sci 2003;92:19-27.
60. Wu R, Fujii S, Ryan NK, Van der Hoek KH, Jasper MJ, Sini I, Robertson SA, Robker RL, Norman RJ. Ovarian leukocyte distribution and cytokine/ chemokine mRNA expression in follicular fluid cells in women with polycystic ovary syndrome. Hum Reprod 2007;22:527-535.
61. Wink DA, Cook JA, Pacelli R, DeGraff W, Gamson J, Liebmann J, Krishna MC, Mitchell JB. The effect of various nitric oxide-donor agents on hydrogen peroxide-mediated toxicity: A direct correlation between nitric oxide formation and protection. Arch Biochem Biophys 1996;331 241-248.
62. Yasuda Y, Nakashima E, Naruse K. 5′-Amino-4-imidazolecarboxamide riboside induces apoptosis in human neuroblastoma cells via the mitochondrial pathway. Nucleosides Nucleotides 2006;25 1265-1270.
63. Youssef JA, Thibeault DW, Rezaiekhaligh MH, Mabry SM, Norberg MI, Truog WE. Influence of inhaled nitric oxide and hyperoxia on Na,K-ATPase expression and lung edema in newborn piglets. Biol Neonate 1999; 75:199-209.
64. Zhang L, Tang Y, Akbulut H, Zelterman D, Linton PJ, Deisseroth AB. An adenoviral vector cancer vaccine that delivers a tumor-associated antigen/CD40-ligand fusion protein to dendritic cells. Proc Natl Acad Sci USA 2003;100:15101-15106.
65. Zhi YH, Liu RS, Song MM, Tian Y, Long J, Tu W, Guo RX. Cyclooxygenase-2 promotes angiogenesis by increasing vascular endothelial growth factor and predicts prognosis in gallbladder carcinoma. World J Gastroenterol 2005;11:3724-3728.
66. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001;108:1167-1174.