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Journal of Ovarian Research
Published in: Journal of Ovarian Research 1/2011

Open Access 01-12-2011 | Research

Metformin therapy in a hyperandrogenic anovulatory mutant murine model with polycystic ovarian syndrome characteristics improves oocyte maturity during superovulation

Authors: Mary E Sabatini, Lankai Guo, Maureen P Lynch, Joseph O Doyle, HoJoon Lee, Bo R Rueda, Aaron K Styer

Published in: Journal of Ovarian Research | Issue 1/2011

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Abstract

Background

Metformin, an oral biguanide traditionally used for the treatment of type 2 diabetes, is widely used for the management of polycystic ovary syndrome (PCOS)-related anovulation. Because of the significant prevalence of insulin resistance and glucose intolerance in PCOS patients, and their putative role in ovulatory dysfunction, the use of metformin was touted as a means to improve ovulatory function and reproductive outcomes in PCOS patients. To date, there has been inconsistent evidence to demonstrate a favorable effect of metformin on oocyte quality and competence in women with PCOS. Given the heterogeneous nature of this disorder, we hypothesized that metformin may be beneficial in mice with aberrant metabolic characteristics similar to a significant number of PCOS patients. The aim of this study was to gain insight into the in vitro and in vivo effects of metformin on oocyte development and ovulatory function.

Methods

We utilized metformin treatment in the transgenic ob/ob and db/db mutant murine models which demonstrate metabolic and reproductive characteristics similar to women with PCOS. Results: Metformin did not improve in vitro oocyte maturation nor did it have an appreciable effect on in vitro granulosa cell luteinization ( progesterone production) in any genotype studied. Although both mutant strains have evidence of hyperandrogenemia, anovulation, and hyperinsulinemia, only db/db mice treated with metformin had a greater number of mature oocytes and total overall oocytes compared to control. There was no observed impact on body mass, or serum glucose and androgens in any genotype.

Conclusions

Our data provide evidence to suggest that metformin may optimize ovulatory performance in mice with a specific reproductive and metabolic phenotype shared by women with PCOS. The only obvious difference between the mutant murine models is that the db/db mice have elevated leptin levels raising the questions of whether their response to metformin is related to elevated leptin levels and/or if a subset of PCOS women with hyperleptinemia may be responsive to metformin therapy. Further study is needed to better define a subset of women with PCOS that may be responsive to metformin.
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Literature
1.
Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS) Hum Reprod 2004, 19: 41–47.
2.
Goodarzi MO, Azziz R: Diagnosis, epidemiology, and genetics of the polycystic ovary syndrome. Best Pract Res Clin Endocrinol Metab 2006, 20: 193–205. 10.1016/j.beem.2006.02.005PubMedCrossRef
3.
Park KH, Kim JY, Ahn CW, Song YD, Lim SK, Lee HC: Polycystic ovarian syndrome (PCOS) and insulin resistance. Int J Gynaecol Obstet 2001, 74: 261–267. 10.1016/S0020-7292(01)00442-8PubMedCrossRef
4.
Apridonidze T, Essah PA, Iuorno MJ, Nestler JE: Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005, 90: 1929–1935. 10.1210/jc.2004-1045PubMedCrossRef
5.
Talbott EO, Zborowski JV, Rager JR, Boudreaux MY, Edmundowicz DA, Guzick DS: Evidence for an association between metabolic cardiovascular syndrome and coronary and aortic calcification among women with polycystic ovary syndrome. J Clin Endocrinol Metab 2004, 89: 5454–5461. 10.1210/jc.2003-032237PubMedCrossRef
6.
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.PubMedCrossRef
7.
Voutilainen R, Franks S, Mason HD, Martikainen H: Expression of insulin-like growth factor (IGF), IGF-binding protein, and IGF receptor messenger ribonucleic acids in normal and polycystic ovaries. J Clin Endocrinol Metab 1996, 81: 1003–1008. 10.1210/jc.81.3.1003PubMed
8.
Burger CW, Korsen T, van Kessel H, van Dop PA, Caron FJ, Schoemaker J: Pulsatile luteinizing hormone patterns in the follicular phase of the menstrual cycle, polycystic ovarian disease (PCOD) and non-PCOD secondary amenorrhea. J Clin Endocrinol Metab 1985, 61: 1126–1132. 10.1210/jcem-61-6-1126PubMedCrossRef
9.
Berga SL, Yen SS: Opioidergic regulation of LH pulsatility in women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 1989, 30: 177–184. 10.1111/j.1365-2265.1989.tb03739.xCrossRef
10.
11.
Chang RJ: A practical approach to the diagnosis of polycystic ovary syndrome. Am J Obstet Gynecol 2004, 191: 713–717. 10.1016/j.ajog.2004.04.045PubMedCrossRef
12.
Dunaif A, Graf M, Mandeli J, Laumas V, Dobrjansky A: Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance, and/or hyperinsulinemia. J Clin Endocrinol Metab 1987, 65: 499–507. 10.1210/jcem-65-3-499PubMedCrossRef
13.
Nestler JE: Role of hyperinsulinemia in the pathogenesis of the polycystic ovary syndrome, and its clinical implications. Semin Reprod Endocrinol 1997, 15: 111–122. 10.1055/s-2007-1016294PubMedCrossRef
14.
Barbieri RL, Gargiulo AR: Metformin for the treatment of the polycystic ovary syndrome. Minerva Ginecol 2004, 56: 63–79.PubMed
15.
Palomba S, Oppedisano R, Tolino A, Orio F, Zullo F: Outlook: metformin use in infertile patients with polycystic ovary syndrome: an evidence-based overview. Reprod Biomed Online 2008, 16: 327–335. 10.1016/S1472-6483(10)60592-5PubMedCrossRef
16.
Lord JM, Flight IH, Norman RJ: Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ 2003, 327: 951–953. 10.1136/bmj.327.7421.951PubMedCentralPubMedCrossRef
17.
Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ: Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 1994, 43: 647–654. 10.1016/0026-0495(94)90209-7PubMedCrossRef
18.
Palomba S, Orio F Jr, Falbo A, Russo T, Tolino A, Zullo F: Clomiphene citrate versus metformin as first-line approach for the treatment of anovulation in infertile patients with polycystic ovary syndrome. J Clin Endocrinol Metab 2007, 92: 3498–3503. 10.1210/jc.2007-1009PubMedCrossRef
19.
Brewer C, Acharya S, Thake F, Tang T, Balen A: Effect of metformin taken in the 'fresh' in vitro fertilization/intracytoplasmic sperm injection cycle upon subsequent frozen embryo replacement in women with polycystic ovary syndrome. Hum Fertil (Camb) 2010, 13: 134–142. 10.3109/14647273.2010.504805CrossRef
20.
Creanga AA, Bradley HM, McCormick C, Witkop CT: Use of metformin in polycystic ovary syndrome: a meta-analysis. Obstet Gynecol 2008, 111: 959–968. 10.1097/AOG.0b013e31816a4ed4PubMedCrossRef
21.
Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, Steinkampf MP, Coutifaris C, McGovern PG, Cataldo NA, et al.: Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007, 356: 551–566. 10.1056/NEJMoa063971PubMedCrossRef
22.
Tso LO, Costello MF, Albuquerque LE, Andriolo RB, Freitas V: Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome. Cochrane Database Syst Rev 2009, CD006105.
23.
Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, et al.: Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001, 108: 1167–1174.PubMedCentralPubMedCrossRef
24.
Salt IP, Johnson G, Ashcroft SJ, Hardie DG: AMP-activated protein kinase is activated by low glucose in cell lines derived from pancreatic beta cells, and may regulate insulin release. Biochem J 1998,335(Pt 3):533–539.PubMedCentralPubMed
25.
da Silva Xavier G, Leclerc I, Salt IP, Doiron B, Hardie DG, Kahn A, Rutter GA: Role of AMP-activated protein kinase in the regulation by glucose of islet beta cell gene expression. Proc Natl Acad Sci USA 2000, 97: 4023–4028. 10.1073/pnas.97.8.4023PubMedCentralPubMedCrossRef
26.
Minokoshi Y, Alquier T, Furukawa N, Kim YB, Lee A, Xue B, Mu J, Foufelle F, Ferre P, Birnbaum MJ, et al.: AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 2004, 428: 569–574. 10.1038/nature02440PubMedCrossRef
27.
Andersson U, Filipsson K, Abbott CR, Woods A, Smith K, Bloom SR, Carling D, Small CJ: AMP-activated protein kinase plays a role in the control of food intake. J Biol Chem 2004, 279: 12005–12008.PubMedCrossRef
28.
Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D, Kahn BB: Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 2002, 415: 339–343. 10.1038/415339aPubMedCrossRef
29.
Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamashita S, Noda M, Kita S, Ueki K, et al.: Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 2002, 8: 1288–1295. 10.1038/nm788PubMedCrossRef
30.
Bilodeau-Goeseels S, Sasseville M, Guillemette C, Richard FJ: Effects of adenosine monophosphate-activated kinase activators on bovine oocyte nuclear maturation in vitro. Mol Reprod Dev 2007, 74: 1021–1034. 10.1002/mrd.20574PubMedCrossRef
31.
Mayes MA, Laforest MF, Guillemette C, Gilchrist RB, Richard FJ: Adenosine 5'-monophosphate kinase-activated protein kinase (PRKA) activators delay meiotic resumption in porcine oocytes. Biol Reprod 2007, 76: 589–597. 10.1095/biolreprod.106.057828PubMedCrossRef
32.
Chen J, Hudson E, Chi MM, Chang AS, Moley KH, Hardie DG, Downs SM: AMPK regulation of mouse oocyte meiotic resumption in vitro. Dev Biol 2006, 291: 227–238. 10.1016/j.ydbio.2005.11.039PubMedCrossRef
33.
Tosca L, Solnais P, Ferre P, Foufelle F, Dupont J: Metformin-induced stimulation of adenosine 5' monophosphate-activated protein kinase (PRKA) impairs progesterone secretion in rat granulosa cells. Biol Reprod 2006, 75: 342–351. 10.1095/biolreprod.106.050831PubMedCrossRef
34.
Tosca L, Chabrolle C, Uzbekova S, Dupont J: Effects of metformin on bovine granulosa cells steroidogenesis: possible involvement of adenosine 5' monophosphate-activated protein kinase (AMPK). Biol Reprod 2007, 76: 368–378. 10.1095/biolreprod.106.055749PubMedCrossRef
35.
Tosca L, Rame C, Chabrolle C, Tesseraud S, Dupont J: Metformin decreases IGF1-induced cell proliferation and protein synthesis through AMP-activated protein kinase in cultured bovine granulosa cells. Reproduction 2010, 139: 409–418. 10.1530/REP-09-0351PubMedCrossRef
36.
Lee SH, Kwon KI: Pharmacokinetic-pharmacodynamic modeling for the relationship between glucose-lowering effect and plasma concentration of metformin in volunteers. Arch Pharm Res 2004, 27: 806–810. 10.1007/BF02980152PubMedCrossRef
37.
Coleman DL, Hummel KP: The influence of genetic background on the expression of the obese (Ob) gene in the mouse. Diabetologia 1973, 9: 287–293. 10.1007/BF01221856PubMedCrossRef
38.
Coleman DL: Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia 1978, 14: 141–148. 10.1007/BF00429772PubMedCrossRef
39.
Bachmanov AA, Reed DR, Beauchamp GK, Tordoff MG: Food intake, water intake, and drinking spout side preference of 28 mouse strains. Behav Genet 2002, 32: 435–443. 10.1023/A:1020884312053PubMedCentralPubMedCrossRef
40.
41.
Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, Steinkampf MP, Coutifaris C, McGovern PG, Cataldo NA, et al.: Ovulatory response to treatment of polycystic ovary syndrome is associated with a polymorphism in the STK11 gene. J Clin Endocrinol Metab 2008, 93: 792–800.PubMedCentralPubMedCrossRef
42.
Dunaif A: Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev 1997, 18: 774–800. 10.1210/er.18.6.774PubMed
43.
Yu Ng EH, Ho PC: Polycystic ovary syndrome in asian women. Semin Reprod Med 2008, 26: 14–21. 10.1055/s-2007-992920PubMedCrossRef
44.
Moll E, Bossuyt PM, Korevaar JC, Lambalk CB, van der Veen F: Effect of clomifene citrate plus metformin and clomifene citrate plus placebo on induction of ovulation in women with newly diagnosed polycystic ovary syndrome: randomised double blind clinical trial. BMJ 2006, 332: 1485. 10.1136/bmj.38867.631551.55PubMedCentralPubMedCrossRef
45.
Allahbadia GN, Merchant R: Polycystic ovary syndrome in the Indian Subcontinent. Semin Reprod Med 2008, 26: 22–34. 10.1055/s-2007-992921PubMedCrossRef
46.
Rice S, Pellatt L, Ramanathan K, Whitehead SA, Mason HD: Metformin inhibits aromatase via an extracellular signal-regulated kinase-mediated pathway. Endocrinology 2009, 150: 4794–4801. 10.1210/en.2009-0540PubMedCentralPubMedCrossRef
47.
Onalan G, Selam B, Baran Y, Cincik M, Onalan R, Gunduz U, Ural AU, Pabuccu R: Serum and follicular fluid levels of soluble Fas, soluble Fas ligand and apoptosis of luteinized granulosa cells in PCOS patients undergoing IVF. Hum Reprod 2005, 20: 2391–2395. 10.1093/humrep/dei068PubMedCrossRef
48.
Marciniak A, Nawrocka-Rutkowska J, Brodowska A, Sienkiewicz R, Szydlowska I, Starczewski A: Leptin concentrations in patients with polycystic ovary syndrome before and after met-formin treatment depending on insulin resistance, body mass index and androgen con-centrations--introductory report. Folia Histochem Cytobiol 2009, 47: 323–328. 10.2478/v10042-009-0032-0PubMedCrossRef
49.
Franks S, Gilling-Smith C, Watson H, Willis D: Insulin action in the normal and polycystic ovary. Endocrinol Metab Clin North Am 1999, 28: 361–378. 10.1016/S0889-8529(05)70074-8PubMedCrossRef
50.
Richardson MC, Ingamells S, Simonis CD, Cameron IT, Sreekumar R, Vijendren A, Sellahewa L, Coakley S, Byrne CD: Stimulation of lactate production in human granulosa cells by metformin and potential involvement of adenosine 5' monophosphate-activated protein kinase. J Clin Endocrinol Metab 2009, 94: 670–677. 10.1210/jc.2008-2025PubMedCrossRef
51.
Palomba S, Falbo A, Russo T, Orio F, Tolino A, Zullo F: Systemic and local effects of metformin administration in patients with polycystic ovary syndrome (PCOS): relationship to the ovulatory response. Hum Reprod 2010, 25: 1005–1013. 10.1093/humrep/dep466PubMedCrossRef
52.
Shi D, Dyck MK, Uwiera RR, Russell JC, Proctor SD, Vine DF: A unique rodent model of cardiometabolic risk associated with the metabolic syndrome and polycystic ovary syndrome. Endocrinology 2009, 150: 4425–4436. 10.1210/en.2008-1612PubMedCrossRef
53.
Manneras L, Cajander S, Holmang A, Seleskovic Z, Lystig T, Lonn M, Stener-Victorin E: A new rat model exhibiting both ovarian and metabolic characteristics of polycystic ovary syndrome. Endocrinology 2007, 148: 3781–3791. 10.1210/en.2007-0168PubMedCrossRef
54.
Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA, Montminy M, Cantley LC: The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 2005, 310: 1642–1646. 10.1126/science.1120781PubMedCentralPubMedCrossRef
55.
Pellatt LJ, Rice S, Mason HD: Phosphorylation and activation of AMP-activated protein kinase (AMPK) by metformin in the human ovary requires insulin. Endocrinology 2011, 152: 1112–1118. 10.1210/en.2009-1429PubMedCrossRef
Metadata
Title
Metformin therapy in a hyperandrogenic anovulatory mutant murine model with polycystic ovarian syndrome characteristics improves oocyte maturity during superovulation
Authors
Mary E Sabatini
Lankai Guo
Maureen P Lynch
Joseph O Doyle
HoJoon Lee
Bo R Rueda
Aaron K Styer
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Journal of Ovarian Research / Issue 1/2011
Electronic ISSN: 1757-2215
DOI
https://doi.org/10.1186/1757-2215-4-8

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