Abstract
Polycystic ovary syndrome (PCOS) is associated with about 75 % of all cases of anovulatory infertility. Insulin resistance is frequently associated with PCOS, occurring in 80 % of women with PCOS and central obesity, but also in 30–40 % of lean women with PCOS. As a result of the reduction in insulin sensitivity, hyperinsulinaemia is invoked as a compensatory mechanism and this is of prime importance in the pathophysiology of PCOS as hyperinsulinaemia, which is significantly exacerbated by obesity, is a key factor in the pathogenesis of hyperandrogenism. Weight loss often seems to be an unsurmountable object for the obese patient with PCOS and the alternative possibility of using insulin lowering drugs, particularly metformin, is theoretically attractive. Although metformin as a mono-agent is capable of improving menstrual frequency and restoring ovulation in patients who have oligo-anovulation and PCOS, when used as first line therapy and compared to clomifene (CC), it fairs very poorly. In a large North American randomised controlled trial, CC was found to be superior to metformin as there was a significant difference in the number of clinical pregnancies and live full-term singleton births (22.6 % vs 7.2 %) using CC and metformin respectively. Insulin sensitizers should not be used as first-choice agents for induction of ovulation in women with PCOS and their administration does not appear to decrease the incidence of early pregnancy losses. The combination of metformin and CC is no better than CC alone except perhaps in CC resistant patients. Evidence for a possible role for long-term metformin treatment for the prevention of the long-term sequelae of PCOS is awaited.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Legro RS, Finegood D, Dunaif A. A fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 1998;83:2694–8.
Carmina E, Lobo RA. Polycystic ovary syndrome: arguably the most common endocrinopathy is associated with significant morbidity in women. J Clin Endocrinol Metab. 1999;84:1897–9.
Poretsky L, Cataldo NA, Rosenwaks Z, Giudice LA. The insulin-related ovarian regulatory system in health and disease. Endoc Rev. 1999;20:535–82.
Homburg R. Adverse effect of luteinizing hormone on fertility: fact or fantasy. Baillieres Clin Obstet Gynaecol. 1996;12:555.
Dale O, Tanbo T, Haug E, Abyholm T. The impact of insulin resistance on the outcome of ovulation induction with low-dose FSH in women with polycystic ovary syndrome. Hum Reprod. 1998;13:567–70.
Hamilton-Fairley D, Kiddy D, Watson H, et al. Association of moderate obesity with a poor pregnancy outcome in women with polycystic ovary treated with low dose gonadotrophin. Br J Obstet Gynaecol. 1992;99:128–31.
White DM, Polson DW, Kiddy D, et al. Induction of ovulation with low-dose gonadotrophins in polycystic ovary syndrome: an analysis of 109 pregnancies in 225 women. J Clin Endocrinol Metab. 1996;81:3821–4.
Kiddy DS, Hamilton-Fairley D, Bush A, et al. Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin Endocrinol (Oxf). 1992;36:105–11.
Pasquali R, Antenucci D, Casmirri F, et al. Clinical and hormonal characteristics of obese amenorrheic hyperandrogenic women before and after weight loss. J Clin Endocrinol Metab. 1989;68:173–9.
Clark AM, Ledger W, Galletly C, et al. Weight loss results in significant improvement in pregnancy and ovulation rates in anovulatory obese women. Hum Reprod. 1995;10:2705–12.
Velazquez EM, Acosta A, Mendoza SG. Menstrual cyclicity after metformin therapy in polycystic ovary syndrome. Obstet Gynecol. 1997;90:392–5.
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;87:569–74.
Mansfield R, Galea R, Brincat M, et al. Metformin has direct effects on human ovarian steroidogenesis. Fertil Steril. 2003;79:956–62.
Harbourne L, Fleming R, Lyall H, et al. Descriptive review of the evidence for the use of metformin in polycystic ovary syndrome. Lancet. 2003;361:1894–901.
Nestler JE, Stovall D, Akhter N, et al. Strategies for the use of insulin-sensitizing drugs to treat infertility in women with polycystic ovary syndrome. Fertil Steril. 2002;77:209–15.
Legro RS, Barnhart HX, Schlaff WD, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007;356:551–66.
Zain MM, Jamaluddin R, Ibrahim A, Norman R. Comparison of clomiphene citrate, metformin, or the combination of both for first-line ovulation induction, achievement of pregnancy, and live birth in Asian women with polycystic ovary syndrome: a randomized controlled trial. Fertil Steril. 2009;91:514–21.
Tang T, Glanville J, Hayden CJ, White D, Barth JH, Balen AH. Combined lifestyle modification and metformin in obese patients with polycystic ovary syndrome. A randomized, placebo-controlled, double-blind multicentre study. Hum Reprod. 2006;21:80–9.
Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev. 2010;20(1):CD003053.
Thessaloniki ESHRE/ASRM- sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Hum Reprod. 2008;23:462–77.
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. Br Med J. 2006;332:1485–8.
Vandermolen DT, Ratts VS, Evans WS, et al. Metformin increases the ovulatory rate and pregnancy rate with clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone. Fertil Steril. 2001;75:310–5.
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.
De Leo V, la Marca A, Ditto A, et al. Effects of metformin on gonadotropin-induced ovulation women with polycystic ovary syndrome. Fertil Steril. 1999;72:282–5.
Kjotrod 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;19:1315–22.
Vanky E, Stridsklev S, Heimstad R, et al. Metformin versus placebo from first trimester to delivery in polycystic ovary syndrome: a randomized, controlled multicenter study. J Clin Endocrinol Metab. 2010;95:E448–55.
Homburg R. Polycystic ovary syndrome in adolescence – a therapeutic conundrum. Hum Reprod. 2004;19:1039–42.
Author information
Authors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Homburg, R. (2014). Insulin Lowering Agents. In: Ovulation Induction and Controlled Ovarian Stimulation. Springer, Cham. https://doi.org/10.1007/978-3-319-05612-8_10
Download citation
DOI: https://doi.org/10.1007/978-3-319-05612-8_10
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-05611-1
Online ISBN: 978-3-319-05612-8
eBook Packages: MedicineMedicine (R0)