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Metformin Does Not Improve the Reproductive or Metabolic Profile in Women With Polycystic Ovary Syndrome (PCOS)

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Abstract

To determine whether metformin, when given to women with polycystic ovary syndrome (PCOS), promotes folliculogenesis by prompting a drop in free sex steroids resulting in a compensatory follicle stimulating hormone (FSH) rise, we conducted a randomized, double-blind, placebo-controlled crossover clinical trial. Eight mid-reproductive age PCOS participants with mean obese body mass index (BMI) and normal glucose tolerance received 8 weeks of metformin, given in a step-up fashion to a maximum dose of 2000 mg daily or placebo with daily urine sampling, 4–6 weeks washout, and crossover to the remaining arm for 8 weeks. To confirm the effects of metformin on glucose and other metabolic markers, a hyperinsulinemic, euglycemic 3-dose clamp (physiologic: 30 mU/m2 per minute, high: 400 mU/m2 per minute) followed each treatment. Urinary FSH, luteinizing hormone (LH), or pregnanediol glucuronide (Pdg) did not differ by treatment. Glucose disposal, endogenous glucose production, BMI, ovulation rates, serum sex steroids, free fatty acids, and lipids did not significantly differ by treatment, despite good evidence for compliance with the protocol. During the clamp, high-dose insulin administration was associated with an acute drop in serum LH. We conclude that short-term, high-dose metformin exerts minimal effects on both metabolic markers and reproductive hormones in a small sample of overall morbidly obese women.

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References

  1. Knochenhauer ES, Key TJ, Kahsar-Miller M, Waggoner W, Boots LR, Azziz R. Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern united states: a prospective study. J Clin Endocrinol Metab. 1998;83(9):3078–3082.

    CAS  PubMed  Google Scholar 

  2. Yildiz BO, Knochenhauer ES, Azziz R. Impact of obesity on the risk for polycystic ovary syndrome. J Clin Endocrinol Metab. 2008;93(1):162–168.

    Article  CAS  Google Scholar 

  3. Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO. The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab. 2004;89(6):2745–2749.

    Article  CAS  Google Scholar 

  4. Dumesic DA, Abbott DH, Padmanabhan V. Polycystic ovary syndrome and its developmental origins. Rev Endocr Metab Disord. 2007;8(2):127–141.

    Article  Google Scholar 

  5. Waldstreicher J, Santoro NF, Hall JE, Filicori M, Crowley WF Jr. Hyperfunction of the hypothalamicpituitary axis in women with polycystic ovarian disease: indirect evidence for partial gonadotroph desensitization. J Clin Endocrinol Metab. 1988;66(1):165–172.

    Article  CAS  Google Scholar 

  6. Zumoff B, Freeman R, Coupey S, Saenger P, Markowitz M, Kream J. A chronobiologic abnormality in luteinizing hormone secretion in teenage girls with the polycystic-ovary syndrome. N Engl J Med. 1983;309(20):1206–1209.

    Article  CAS  Google Scholar 

  7. Nestler JE, Jakubowicz DJ, de Vargas AF, Brik C, Quintero N, Medina F. Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system. J Clin Endocrinol Metab. 1998;83(6):2001–2005.

    CAS  PubMed  Google Scholar 

  8. Lord JM, Flight IH, Norman RJ. Insulin-sensitising drugs (metformin, troglitazone, rosiglitazone, pioglitazone, D-chiro-inositol) for polycystic ovary syndrome. Cochrane Database Syst Rev. 2003;(3):CD003053.

  9. Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Engl J Med. 1998;338(26):1876–1880.

    Article  CAS  Google Scholar 

  10. 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;335(9):617–623.

    Article  CAS  Google Scholar 

  11. Nestler JE, Powers LP, Matt DW, et al. A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. J Clin Endocrinol Metab. 1991;72(1):83–89.

    Article  CAS  Google Scholar 

  12. Shadid S, Kanaley J, Sheehan M, Jensen M. Basal and insulin-regulated free fatty acid and glucose metabolism in humans. Am J Physiol Endocrinol Metab. 2007;292(6):E1770–1774.

    Article  CAS  Google Scholar 

  13. Al Majali K, Cooper MB, Staels B, Luc G, Taskinen MR, Betteridge DJ. The effect of sensitisation to insulin with pioglitazone on fasting and postprandial lipid metabolism, lipoprotein modification by lipases, and lipid transfer activities in type 2 diabetic patients. Diabetologia. 2006;49(3):527–537.

    Article  CAS  Google Scholar 

  14. Zawadski JK, Dunaif A. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In: Dunaif A, Givens JR, Haseltine FP, Merriam GR, eds. Polycystic Ovary Syndrome. Boston: Blackwell Scientific; 1992:377–384.

    Google Scholar 

  15. Hatch R, Rosenfield RL, Kim MH, Tredway D. Hirsutism: implications, etiology, and management. Am J Obstet Gynecol. 1981;140:815–830.

    Article  CAS  Google Scholar 

  16. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med. 1998;15(7):539–553.

    Article  CAS  Google Scholar 

  17. Diamond MP, Jacob R, Connolly-Diamond M, DeFronzo RA. Glucose metabolism during the menstrual cycle. Assessment with the euglycemic, hyperinsulinemic clamp. J Reprod Med. 1993;38(6):417–421.

    CAS  Google Scholar 

  18. Thornton KL, DeFronzo RA, Sherwin RS, Diamond MP. Micronized estradiol and progesterone: effects on carbohydrate metabolism in reproductive-age women. J Soc Gynecol Investig. 1995;2(4):643–652.

    Article  CAS  Google Scholar 

  19. Saketos M, Sharma N, Adel T, Raghuwanshi M, Santoro N. Time-resolved immunofluorometric assay and specimen storage conditions for measuring urinary gonadotropins. Clin Chem. 1994;40(5):749–753.

    Article  CAS  Google Scholar 

  20. Santoro N, Brown J, Adel T, Skurnick J. Characterization of reproductive hormonal dynamics in the perimenopause. Journal of Clinical Endocrinology & Metabolism. 1996;81(4): 1495–1501.

    CAS  Google Scholar 

  21. Steele R. Influences of glucose loading and of injected insulin on hepatic glucose output. Ann N Y Acad Sci. 1959;82: 420–430.

    Article  CAS  Google Scholar 

  22. Bier DM, Arnold KJ, Sherman WR, Holland WH, Holmes WF, Kipnis DM. In-vivo measurement of glucose and alanine metabolism with stable isotopic tracers. Diabetes. 1977;26(11):1005–1015.

    Article  CAS  Google Scholar 

  23. Brown JB. Pituitary control of ovarian function—concepts derived from gonadotrophin therapy. Aust N Z J Obstet Gynaecol. 1978;18(1):46–54.

    Article  CAS  Google Scholar 

  24. 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(3):269–274.

    Article  CAS  Google Scholar 

  25. Glueck CJ, Wang P, Fontaine R, Tracy T, Sieve-Smith L. Metformin-induced resumption of normal menses in 39 of 43 (91%) previously amenorrheic women with the polycystic ovary syndrome. Metabolism. 1999;48(4):511–519.

    Article  CAS  Google Scholar 

  26. Nestler JE, Jakubowicz DJ. Lean women with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian P450c17 alpha activity and serum androgens. J Clin Endocrinol Metab. 1997;82(12):4075–4079.

    CAS  PubMed  Google Scholar 

  27. Lord J, Thomas R, Fox B, Acharya U, Wilkin T. The effect of metformin on fat distribution and the metabolic syndrome in women with polycystic ovary syndrome- a randomised, double-blind, placebo-controlled trial. BJOG: An International Journal of Obstetrics & Gynaecology. 2006;113(7):817–824.

    Article  CAS  Google Scholar 

  28. Legro RS, Barnhart HX, Schlaff WD, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007;356(6):551–566.

    Article  CAS  Google Scholar 

  29. 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(2):524–530.

    CAS  PubMed  Google Scholar 

  30. Acbay O, Gundogdu S. Can metformin reduce insulin resistance in polycystic ovary syndrome? Fertil Steril. 1996;65(5):946–949.

    Article  CAS  Google Scholar 

  31. Palomba S, Falbo A, Orio Jr F, Tolino A, Zullo F. Efficacy predictors for metformin and clomiphene citrate treatment in anovulatory infertile patients with polycystic ovary syndrome. Fertility and Sterility. In Press.

  32. Maciel GAR, Soares junior JM, Alves da Motta, et al. Nonobese women with polycystic ovary syndrome respond better than obese women to treatment with metformin. Fertil Steril. 2004;81(2):355–360. May 9, 2009. http://journals.ohiolink.edu/ejc/article.cgi?issn=00150282&issue=v81i0002&article=355_nwwposowttwm.

    Article  CAS  Google Scholar 

  33. Moghetti P, Castello R, Negri C, et al. Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation. J Clin Endocrinol Metab. 2000;85(1):139–146.

    CAS  PubMed  Google Scholar 

  34. Srinivasan S, Ambler GR, Baur LA, et al. Randomized, controlled trial of metformin for obesity and insulin resistance in children and adolescents: improvement in body composition and fasting insulin. J Clin Endocrinol Metab. 2006;91(6): 2074–2080.

    Article  CAS  Google Scholar 

  35. Morel Y, Golay A, Perneger T, et al. Metformin treatment leads to an increase in basal, but not insulin-stimulated, glucose disposal in obese patients with impaired glucose tolerance. Diabetic Med. 1999;16(8):650–655.

    Article  CAS  Google Scholar 

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Author information

Author notes

  1. Both of these authors contributed equally to this work.

    No commercial affiliations are associated with this manuscript. Dr Aubuchon is a speaker for Schering Plough. Dr Santoro is a consultant for Quat Rx and has received grant support from Ferring. Dr Stein is a consultant for BMS, Merck, and Daichi Sankyo. All other authors have nothing to disclose.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, University of Cincinnati, Cincinnati, Ohio, United States

    Mira Aubuchon MD

  2. Departments of Obstetrics and Gynecology, Albert Einstein College of Medicine, Bronx, New York, United States

    Harry Lieman MD, Barbara Isaac RN, Goli Adel BS, Alex J. Polotsky MD & Nanette Santoro MD

  3. Departments of Endocrinology, Albert Einstein College of Medicine, Bronx, New York, United States

    Daniel Stein MD

  4. Departments of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, United States

    Hillel W. Cohen DrPH

  5. Department of IVF FLORIDA Reproductive Associates, Margate, Florida, United States

    Vanessa Weitzman MD

  6. Department of Nassau Health Care Corporation, East Meadow, New York, United States

    Maggie Tetrokalashvili MD

Authors
  1. Mira Aubuchon MD
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  2. Harry Lieman MD
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  3. Daniel Stein MD
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  4. Hillel W. Cohen DrPH
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  5. Barbara Isaac RN
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  6. Goli Adel BS
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  7. Vanessa Weitzman MD
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  8. Maggie Tetrokalashvili MD
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  9. Alex J. Polotsky MD
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  10. Nanette Santoro MD
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Corresponding author

Correspondence to Harry Lieman MD.

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Aubuchon, M., Lieman, H., Stein, D. et al. Metformin Does Not Improve the Reproductive or Metabolic Profile in Women With Polycystic Ovary Syndrome (PCOS). Reprod. Sci. 16, 938–946 (2009). https://doi.org/10.1177/1933719109340925

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