The role of metformin in the management of polycystic ovary syndrome

Current Opinion in Obstetrics and Gynecology

Volumn 15, Issue 6, 2003, Pages 483-488

  Tsilchorozidou, Tasoula ^b   Prelevic, Gordana M ^a  

^a MIDDLESEX HOSPITAL   (United Kingdom)

^b NONE

Author keywords

Insulin resistance; Metabolic outcome; Metformin; Polycystic ovary syndrome; Reproductive outcome

Indexed keywords

ANDROGEN; ANTIANDROGEN; CLOMIFENE CITRATE; CYPROTERONE ACETATE; ESTRADIOL; ETHINYLESTRADIOL; FLUTAMIDE; FOLLITROPIN; GONADOTROPIN; INSULIN; INSULIN SENSITIZING AGENT; LUTEINIZING HORMONE; METFORMIN; PLACEBO;

ADIPOSE TISSUE; BODY MASS; CLINICAL TRIAL; DISEASE CONTROL; DRUG EFFECT; DRUG MEGADOSE; DRUG POTENTIATION; DRUG USE; ENDOCRINE DISEASE; HIP; HIRSUTISM; HUMAN; HYPERANDROGENISM; HYPERINSULINEMIA; INSULIN RESISTANCE; INSULIN SENSITIVITY; LOW DRUG DOSE; MENSTRUAL IRREGULARITY; METABOLIC DISORDER; OBESITY; OVARY POLYCYSTIC DISEASE; OVULATION; PREGNANCY DIABETES MELLITUS; PREGNANCY RATE; PRIORITY JOURNAL; REPRODUCTION; REVIEW; STEROIDOGENESIS; WEIGHT REDUCTION;

FEMALE; HUMANS; HYPOGLYCEMIC AGENTS; INSULIN RESISTANCE; METFORMIN; POLYCYSTIC OVARY SYNDROME; REPRODUCTION;

EID: 1542512186     PISSN: 1040872X     EISSN: None     Source Type: Journal    
DOI: 10.1097/00001703-200312000-00005     Document Type: Review

References (57)

1. Adams J, Franks S, Polson DW, et al. Multifollicular ovaries: clinical and endocrine features and response to pulsatile gonadotropin releasing hormone. Lancet 1985; 2:1375-1379.
2. Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2002; 108:1167-1174.
3. Velazquez EM, Mendoza S, Hamer T, et al. 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.
4. Velazquez EM, Mendoza SG, Wang P, Glueck CJ. Metformin therapy is associated with a decrease in plasma plasminogen activator inhibitor-1, lipoprotein(a), and immunoreactive insulin levels in patients with the polycystic ovary syndrome. Metabolism 1997; 46:454-457.
5. 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; 335:617-623.
6. 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.
7. Diamanti-Kandarakis E, Baillargeon JP, Iuorno MJ, et al. A modern medical quandary: polycystic ovary syndrome, insulin resistance, and oral contraceptive pills. J Clin Endocrinol Metab 2003; 88:1927-1932.
8. 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; 85:139-146.
9. Morin-Papunen LC, Vauhkonen I, Koivunen RM, et al. Endocrine and metabolic effects of metformin versus ethinyl estradiol-cyproterone acetate in obese women with polycystic ovary syndrome: a randomized study. J Clin Endocrinol Metab 2000; 85:3161-3168.
10. 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; 82:4075-4079.
11. 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.
12. Morin-Papunen L, Vauhkonen I, Koivunen R, et al. Metformin versus ethinyl estradiol-cyproterone acetate in the treatment of nonobese women with polycystic ovary syndrome: a randomized study. J Clin Endocrinol Metab 2003; 88:148-156. An interesting study that assesses the effects of COC (combined oral contraceptive pill) versus metformin on the metabolic, biochemical and endocrine parameters in lean PCOS women. It also provides a possible explanation for the favourable effects of metformin in this subgroup of PCOS women.
13. Pasquali R, Gambineri A, Biscotti D, 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.
14. Kocak M, Caliskan E, Simsir C, Haberal A. Metformin therapy improves ovulatory rates, cervical scores, and pregnancy rates in clomiphene citrate-resistant women with polycystic ovary syndrome. Fertil Steril 2002; 77:101-106. An important RCT (randomized controlled trials) study evaluating the effect of metformin on endometrial thickness and cervical scores in clomiphene citrate-resistant women. It provides additional evidence on how metformin alone or in combination with clomiphene citrate could increase pregnancy rates in PCOS women.
15. 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; 338:1876-1880.
16. Chou KH, von Eye Corleta H, Capp E, Spritzer PM. Clinical, metabolic and endocrine parameters in response to metformin in obese women with polycystic ovary syndrome: a randomized, double-blind and placebo-controlled trial. Horm Metab Res 2003; 35:86-91.
17. Ng EH, Wat NM, Ho PC. 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.
18. Acbay O, Gundogdu S. Can metformin reduce insulin resistance in polycystic ovary syndrome? Fertil Steril 1996; 65:946-949.
19. Crave JC, Fimbel S, Lejeune H, et al. 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.
20. Vandermolen DT, Ratts VS, Evans WS, et al. Metformin increases the ovulatoty rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone. Fertil Steril 2001; 75:310-315.
21. Fleming R, Hopkinson ZE, Wallace AM, et al. Ovarian function and metabolic factors in women with oligomenorrhea treated with metformin in a randomized double blind placebo-controlled trial. J Clin Endocrinol Metab 2002; 87:569-574. An important study that provides a detailed endocrinological assessment of ovarian function in vivo in the context of a large randomized placebo-controlled trial of metformin in PCOS.
22. Harborne L, Fleming R, Lyall H, et al. Descriptive review of the evidence for the use of metformin in polycystic ovary syndrome. Lancet 2003; 361:1894-1901. An excellent review of the evidence for the use of metformin based mainly on randomized control trials.
23. Dunaif A, Graf M, Mandeli J, et al. Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance, and/or hyperinsulinemia. J Clin Endocrinol Metab 1987; 65:499-507.
24. Robinson S, Kiddy D, Gelding SV, et al. The relationship of insulin insensitivity to menstrual pattern in women with hyperandrogenism and polycystic ovaries. Clin Endocrinol (Oxf) 1993; 39:351-355.
25. Sampson M, Kong C, Patel A, et al. Ambulatory blood pressure profiles and plasminogen activator inhibitor (PAI-1) activity in lean women with and without the polycystic ovary syndrome. Clin Endocrinol (Oxf) 1996; 45:623-629.
26. Ehrmann DA, Cavaghan MK, Imperial J, et al. 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.
27. Pirwany IR, Yates RW, Cameron IT, Fleming R. Effects of the insulin sensitizing drug metformin on ovarian function, follicular growth and ovulation rate in obese women with oligomenorrhoea. Hum Reprod 1999; 14:2963-2968.
28. Morin-Papunen LC, Koivunen RM, Ruokonen A, Martikainen HK. Metformin therapy improves the menstrual pattern with minimal endocrine and metabolic effects in women with polycystic ovary syndrome. Fertil Steril 1998; 69:691-696.
29. Kolodziejczyk B, Duleba AJ, Spaczynski RZ, Pawelczyk L. Metformin therapy decreases hyperandrogenism and hyperinsulinemia in women with polycystic ovary syndrome. Fertil Steril 2000; 73:1149-1154.
30. Ibanez L, Valls C, Potau N, et al. Sensitization to insulin in adolescent girls to normalize hirsutism, hyperandrogenism, oligomenorrhea, dyslipidemia, and hyperinsulinism after precocious pubarche. J Clin Endocrinol Metab 2000; 85:3526-3530.
31. Kazerooni T, Dehghan-Kooshkghazi M. Effects of metformin therapy on hyperandrogenism in women with polycystic ovarian syndrome. Gynecol Endocrinol 2003; 17:51-56.
32. Kelly CJ, Gordon D. The effect of metformin on hirsutism in polycystic ovary syndrome. Eur J Endocrinol 2002; 147:217-221.
33. Ibanez L, de Zegher F. Low-dose combination of flutamide, metformin and an oral contraceptive for non-obese, young women with polycystic ovary syndrome. Hum Reprod 2003; 18:57-60.
34. Morales AJ, Laughlin GA, Butzow T, et al. Insulin, somatotropic, and luteinizing hormone axes in lean and obese women with polycystic ovary syndrome: common and distinct features. J Clin Endocrinol Metab 1996; 81:2854-2864.
35. Ovesen P, Moller J, Ingerslev HJ, et al. Normal basal and insulin-stimulated fuel metabolism in lean women with the polycystic ovary syndrome. J Clin Endocrinol Metab 1993; 77:1636-1640.
36. Holte J, Bergh T, Berne C, et al. Enhanced early insulin response to glucose in relation to insulin resistance in women with polycystic ovary syndrome and normal glucose tolerance. J Clin Endocrinol Metab 1994; 78:1052-1058.
37. Glueck CJ, Wang P, Fontaine R, et al. Metformin-induced resumption of normal menses in 39 of 43 (91%) previously amenorrheic women with the polycystic ovary syndrome. Metabolism 1999; 48:511-519.
38. Glueck CJ, Wang P, Fontaine R, et al. Metformin to restore normal menses in oligo-amenorrheic teenage girls with polycystic ovary syndrome (PCOS). J Adolesc Health 2001; 29:160-169.
39. Unluhizarci K, Kelestimur F, Bayram F, et al. The effects of metformin on insulin resistance and ovarian steroidogenesis in women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 1999; 51:231-236.
40. Baysal B, Batukan M, Batukan C. Biochemical and body weight changes with metformin in polycystic ovary syndrome. Clin Exp Obstet Gynecol 2001; 28:212-214.
41. Vrbikova J, Hill M, Starka L, Vondra K. Prediction of the effect of metformin treatment in patients with polycystic ovary syndrome. Gynecol Obstet Invest 2002; 53:100-104.
42. Ibanez L, Valls C, Ferrer A, et al. Sensitization to insulin induces ovulation in nonobese adolescents with anovulatory hyperandrogenism. J Clin Endocrinol Metab 2001; 86:3595-3598.
43. Costello MF, Eden JA. A systematic review of the reproductive system effects of metformin in patients with polycystic ovary syndrome. Fertil Steril 2003; 79:1-13. An excellent and comprehensive eview of the reproductive outcomes of metformin treatment in PCOS since its firs use in 1994.
44. la Marca A, Morgante G, Paglia T, et al. Effects of metformin on adrenal steroidogenesis in women with polycystic ovary syndrome. Fertil Steril 1999; 72:985-989.
45. Attia GR, Rainey WE, Carr BR. Metformin directly inhibits androgen production in human thecal cells. Fertil Steril 2001; 76:517-524.
46. Mansfield R, Galea R, Brincat M, et al. Metformin has direct effects on human ovarian steroidogenesis. Fertil Steril 2003; 79:956-962.
47. Batukan C, Baysal B. Metformin improves ovulation and pregnancy rates in patients with polycystic ovary syndrome. Arch Gynecol Obstet 2001; 265:124-127.
48. Rull K, Vali M. Metformin reverses anovulation in hyperinsulinemic patients with polycystic ovary syndrome. Diabetol Croatica 2001; 30:19-22.
49. Heard MJ, Pierce A, Carson SA, Buster JE. Pregnancies following use of metformin for ovulation induction in patients with polycystic ovary syndrome. Fertil Steril 2002; 77:669-673.
50. El-Biely MM, Habba M. The use of metformin to augment the induction of ovulation in obese infertile patients with polycystic ovary syndrome. Middle East Fertil Soc J 2001; 6:43-49.
51. De Leo V, la Marca A, Ditto A, et al. Effects of metformin on gonadotropin-induced ovulation in women with polycystic ovary syndrome. Fertil Steril 1999; 72:282-285.
52. Yarali H, Yildiz BO, Demirol A, et al. Co-administration of metformin during rFSH treatment in patients with clomiphene citrate-resistant polycystic ovarian syndrome: a prospective randomized trial. Hum Reprod 2002; 17:289-294.
53. George SS, George K, Irwin C, et al. Sequential treatment of metformin and clomiphene citrate in clomiphene-resistant women with polycystic ovary syndrome: a randomized, controlled trial. Hum Reprod 2003; 18:299-304.
54. Garber AJ, Duncan TG, Goodman AM, et al. Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose-response trial. Am J Med 1997; 103:491-497.
55. Nestler JE. Should patients with polycystic ovarian syndrome be treated with metformin? An enthusiastic endorsement. Hum Reprod 2002; 17:1950-1953. An excellent review summarizing the evidence of metformin to treat infertility in women with PCOS. An algorithmic approach is also provided for the use of insulin-sensitizing drugs for the treatment of anovulatory infertility of women with PCOS.
56. Glueck CJ, Wang P, Goldenberg N, Sieve-Smith L. Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin. Hum Reprod 2002; 17:2858-2864.
57. Jakubowicz DJ, Iuorno MJ, Jakubowicz S, et al. Effects of metformin on early pregnancy loss in the polycystic ovary syndrome. J Clin Endocrinol Metab 2002; 87:524-529.