Fertility and Sterility
Volume 91, Issue 2 , Pages 500-508 , February 2009

Possible metformin effect on adrenal androgens during pretreatment and IVF cycle in women with polycystic ovary syndrome

  • Sigrun B. Kjøtrød, M.D.

      Affiliations

    • IVF Unit, Department of Obstetrics and Gynaecology, St. Olavs Hospital, University Hospital of Trondheim, Trondheim, Norway
    • Corresponding Author InformationReprint requests: Sigrun Kjøtrød, M.D., IVF-Unit, Department of Obstetrics and Gynaecology, St. Olavs Hospital, Trondheim University Hospital, Olav Kyrres gt 17, N-7006 Trondheim, Norway (FAX: +47 72573901).
  • ,
  • Arne Sunde, Ph.D.

      Affiliations

    • IVF Unit, Department of Obstetrics and Gynaecology, St. Olavs Hospital, University Hospital of Trondheim, Trondheim, Norway
    • Department of Laboratory Medicine, Women's and Children's Health, Norwegian University of Science and Technology, Trondheim, Norway
  • ,
  • Vidar von Düring, M.D.

      Affiliations

    • IVF Unit, Department of Obstetrics and Gynaecology, St. Olavs Hospital, University Hospital of Trondheim, Trondheim, Norway
  • ,
  • Sven M. Carlsen, M.D., Ph.D.

      Affiliations

    • Department of Endocrinology, St. Olavs Hospital, University Hospital of Trondheim, Trondheim, Norway
    • Department of Laboratory Medicine, Women's and Children's Health, Norwegian University of Science and Technology, Trondheim, Norway

Received 17 September 2007 ,Revised 19 November 2007 ,Accepted 19 November 2007.

References 

  1. 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 (PCOS). Hum Reprod. 2004;19:411–417
  2. Velazquez EM, Mendoza S, Hamer T, Sosa F, Gluck 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
  3. Baillargeon JP, Jakubowicz DJ, Iuorno MJ, Jakubowicz S, Nestler JE. Effects of metformin and rosiglitazone, alone and in combination, in nonobese women with polycystic ovary syndrome and normal indices of insulin sensitivity. Fertil Steril. 2004;82:893–902
  4. Elter K, Imir G, Durmusoglu F. Clinical, endocrine and metabolic effects of metformin added to ethinyl estradiol-cyproterone acetate in non-obese women with polycystic ovarian syndrome: a randomized controlled study. Hum Reprod. 2002;17:1729–1737
  5. Moghetti P, Castello R, Negri C, Tosi F, Perrone F, Muggeo M, 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;851:139–146
  6. Hung Yu Ng E, Ming Sun Wat N, Chung Ho P. Effects of metformin on ovulation rate, hormonal and metabolic profiles in women with clomiphene-resistant polycystic ovaries: a randomized, double-blinded placebo-controlled trial. Hum Reprod. 2001;16:1625–1631
  7. Pasquali R, Gambineri A, Biscotti D, Vicennati V, Gagliardi L, Morselli-Labate AM, et al. Effect of long-term treatment with Metformin added to hypocaloric diet on body composition, fat distribution, and androgen and insulin levels in abdominally obese women with and without the polycystic ovary syndrome. J Clin Endocrinol Metab. 2000;85:2767–2774
  8. Kocak I, Ustun Cazip. Effects of metformin on insulin resistance, androgen concentration, ovulation and pregnancy rates in women with polycystic ovary syndrome following laparoscopic ovarian drilling. J Obstet Gynaecol. 2006;32:292–298
  9. Tang T, Glanville J, Orsi N, Barth J, Balen AH. The use of metformin for women with PCOS undergoing IVF treatment. Hum Reprod. 2006;21:1416–1425
  10. Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Myers ER, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007;356:551–566
  11. Ehrmann DA, Cavagham MK, Imperial J, Sturis J, Rosenfeld 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. Acbay O, Gundogdu S. Can metformin reduce insulin resistance in polycystic ovary syndrome?. Fertil Steril. 1996;65:946–949
  13. Crave JC, Fimbel S, Lejune H, Cugnardey N, Dechaud H, Pugeat . Effects of diet and metformin administration on sex-hormone binding globulin, androgens, and insulin in hirsute and obese women. J Clin Endocrinol Metab. 1995;80:2057–2062
  14. Fleming R, Hopkinson ZE, Wallace AM, Greer IA, Sattar N. Ovarian function and metabolic factors in women with oligoamenorrhea treated with metformin in a randomized double blind placebo-controlled trial. J Clin Endocrinol Metab. 2002;87:569–574
  15. Aruna J, Mittal S, Kumar S, Misra R, Dadhwal V, Vimala N. Metformin therapy in women with polycystic ovary syndrome. Int J Gynecol Obstet. 2004;87:237–241
  16. Hoeger KM, Kochman L, Wixom N, Craig K, Miller RK, GuzickA randomized DS. 48-week, placebo-controlled trial of intensive lifestyle modification and/or metformin therapy in overweight women with polycystic ovary syndrome: a pilot study. Fertil Steril. 2004;82:421–429
  17. Sturrock NDC, Lannon B, Fay TN. Metformin does not enhance ovulation induction in clomiphene resistant polycystic ovary syndrome in clinical practice. Br J Clin Pharmacol. 2001;53:469–473
  18. Vandermolen DT, Ratts VS, Evans WS, Stovall DW, Kauma , Nestler JE. Metformin increases the ovulatory rate and pregnancy rate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone. Fertil Steril. 2001;75(2):310–315
  19. Vanky E, Salvesen KA, Heimstad R, Fougner KJ, Romundstad P, Carlsen SM. Metformin reduces pregnancy complications without affecting androgen levels in pregnant polycystic ovary syndrome women: results of a randomized study. Hum Reprod. 2004;19:1734–1740
  20. Labrie F, Luu-The V, Labrie C, Belanger A, Simard J, Pelletier G, et al. Endocrine and intracrine sources of androgens in women: inhibition of breast cancer and other roles of androgens and their precursor dehydroepiandrosterone. Endocr Rev. 2003;24:152–182
  21. Labrie F, Luu-The V, Lin SX, Simard J, Labrie C, Belanger A, et al. Intracrinology: the role of the family of 17β-hydroxysteroid dehydrogenases in human physiology and disease. J Mol Endocrinol. 2000;25:1–16
  22. Lobo RA, Paul WL, Goebelsman U. Dehydroepiandrosterone sulphate as an indicator of adrenal androgen function. Obstet Gynecol. 1981;57:69
  23. Abraham GE. Ovarian and adrenal contribution to peripheral androgens during the menstrual cycle. J Clin Endocrinol Metab. 1974;39:340–346
  24. Mikulecky M, Kreze A, Putz Z, Moravcik M. Daily variation of serum cortisol 17-hydroxyprogesterone and five androgens in healthy women. Braz J Med Biol Res. 1995;28:485–490
  25. Longcope C. Dehydroepiandrosterone metabolism. J Endocrinol. 1996;150:125–127
  26. Hoffmann DI, Klove K, Lobo RA. The prevalence and significance of elevated dehydroepiandrosterone sulfate levels in anovulatory women. Fertil Steril. 1984;42:76–81
  27. Kumar A, Woods KS, Bartolucci AA, Azziz R. Prevalence of adrenal androgen excess in patients with the polycystic ovary syndrome (PCOS). J Clin Endocrinol (Oxf). 2005;62:644–649
  28. Haning RV, Flood CA, Hackett RJ, Loughlin JS, McClure N, Longscope C. Metabolic clearance rate of dehydroepiandrosterone sulphate, its metabolism to testosterone, and its intrafolllicular metabolism to dehydrotestosterone, androsterone, testosterone, and dihydrotestosterone in vivo. J Clin Endocrinol Metab. 1991;72:1088–1095
  29. Bonser J, Walker J, Purohit A, Reed MJ, Potter BVL, Mason HD, et al. Human granulosa cells are a site of sulphatase activity and are able to utilize dehydroepiandrosterone sulphate as a precursor for oestradiol production. J Endocrinol. 2000;167:465–471
  30. Fassnacht M, Schlenz N, Schneider SB, Wudy SA, Allolio B, Arlt W. Beyond adrenal and ovarian androgen generation: increased peripheral 5α-reductase activity in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2003;88:2760–2766
  31. Jakimiuk AJ, Weitsman SR, Magoffin DA. 5α-reductase activity in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 1999;847:2414–2418
  32. Agarwal SK, Judd HL, Magoffin DA. A mechanism for the suppression of estrogen production in polycystic ovary syndrome. J Clin Endocrinol Metab. 1996;81:3686–3691
  33. Lobo RA, Paul WL, Gentzschein E, Serafini PC, Catalino JA, Horton R, et al. Production of 3 alpha-androstanediol glucuronide in human genital skin. J Clin Endocrinol Metab. 1987;65:711–714
  34. Kjøtrød SB, von During V, Carlsen SM. Metformin treatment before IVF/ICSI in women with polycystic ovary syndrome; a prospective, randomized, double blind study. Hum Reprod. 2004;19:1–8
  35. Adams J, Polson DW, Franks S. Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism. Br Med J. 1986;293:355–359
  36. Dehenin L, Jondet M, Scholler R. Androgen and 19-nonstereoid profiles in human preovulatory follicles from stimulated cycles: an isotope dilution mass spectrometric study. J Stereoid Biochem. 1987;26:399–405
  37. Moran C, Knochenhauer E, Boots LR, Azziz R. Adrenal androgen excess in hyperandrogenism: relation to age and body mass. Fertil Steril. 1999;71:671–674
  38. Shimokata H, Muller DC, Fleg JL, Sorkin J, Ziemba AW, Andres R. Age as an independent determinant of glucose tolerance. Diabetes. 1991;40:44–51
  39. Kreisberg RA. Aging, glucose metabolism, and diabetes: current concepts. Geriatrics. 1987;42:67–72
  40. Wild RA, Umstot ES, Andersen RN, Ranney GB, Givens JR. Androgen parameters and their correlation with body weight in one hundred thirty-eight women thought to have hyperandrogenism. Am J Obstet Gynecol. 1983;146:602–606
  41. Carmina E, Lobo RA. Prevalence and metabolic characteristics of adrenal androgen excess in hyperandrogenic women with different phenotypes. J Endocrinol Invest. 2007;30:111–116
  42. Carmina E. Ovarian and adrenal hyperandrogenism. Ann N Y Acad Sci. 2006;1092:130–137
  43. Schriock ED, Buffington CK, Hubert GD. Divergent correlations of circulating dehydroepiandrosterone sulphate and testosterone with insulin levels and insulin receptor binding. J Clin Endocrinol Metab. 1990;66:1329–1331
  44. Diamond MP, Grainger DA, Laudano AJ, Starick-Zych K, DeFronzo RA. Effect of acute physiological elevations of insulin on circulating androgen levels in nonobese women. J Clin Endocrinol Metab. 1991;72:883–887
  45. Buyalos RP, Geffner ME, Azziz R, Judd HL. Impact of overnight dexamethasone suppression on the adrenal androgen response to an oral glucose tolerance test in women with and without polycystic ovary syndrome. Hum Reprod. 1997;12:1138–1141
  46. Nestler JE, Beer NA, Jakubowicz DJ, Beer RM. Effects of a reduction in circulating insulin by metformin on serum dehydroepiandrosterone sulfate in nondiabetic men. J Clin Endocrinol Metab. 1994;78:549–554
  47. Nestler JE, Beer NA, Jackubowicz DJ, Colombo C, Beer RM. Effects of insulin reduction with benfluorex on serum dehydroepiandrosterone (DHEA), DHEA sulphate, and blood pressure in hypertensive middle-aged and elderly men. J Clin Endocrinol Metab. 1995;80:700–706
  48. Glueck CJ, Moreira A, Goldenberg N, Sieve L, Wang Ping. Pioglitazone and metformin in obese women with polycystic ovary syndrome not optimally responsive to metformin. Hum Reprod. 2003;18:1618–1625
  49. Greisen S, Ledet T, Ovesen P. Effects of androstenedione, insulin and luteinizing hormone on stereoidogenesis in human granulosa luteal cells. Hum Reprod. 2001;16:2061–2065

PII: S0015-0282(07)04127-1

doi: 10.1016/j.fertnstert.2007.11.069

Fertility and Sterility
Volume 91, Issue 2 , Pages 500-508 , February 2009