Skip to main content Accessibility help
×
Home
  • Cited by 1
  • Print publication year: 2007
  • Online publication date: September 2009

6 - Insulin sensitizers in the treatment of polycystic ovary syndrome

Summary

Introduction

Polycystic ovary syndrome (PCOS) is a common endocrinopathy affecting 6–10% of reproductive-age women (Azziz et al. 2004). The definition has evolved over time. The National Institute of Health diagnostic criteria, released in 1990 (Table 6.1) (Zawadzki and Dunaif 1992), highlighted the clinical features of PCOS including ovarian dysfunction (anovulation, irregular cycles, infertility) and hyperandrogenism (hirsutism and acne). The recent and more controversial Rotterdam criteria broaden the condition to include ovarian ultrasound features (Table 6.1) (Zawadski and Dunaif 1992, Group TREAC 2004).

Despite recognition of the important role that insulin resistance plays in PCOS, diagnostic criteria for PCOS do not currently encompass insulin resistance. The difficulties surrounding the diagnosis of PCOS are likely to reflect multiple factors. These include the lack of clarity on the etiology of PCOS, the lack of simple, accurate methods to measure insulin resistance, and the heterogeneity of clinical syndrome that is PCOS today. With greater understanding of PCOS, sub-categories are likely to emerge in what is essentially a heterogeneous syndrome (Norman et al. 1995). This is important to consider when evaluating results of clinical trials, as effects of therapy may vary across the heterogeneous spectrum that is labeled as PCOS today.

The pathogenesis of PCOS is not well understood. A combination of genetic and environmental factors contributes, with potential etiological factors including insulin resistance, ovarian dysfunction, hyperandrogenism, and hypothalamic pituitary abnormalities. Increasingly it is recognized that in the majority of women with PCOS, insulin resistance leading to hyperinsulinemia plays a central role (Dunaif 1997).

REFERENCES
Arslanian, S. A., Lewy, V., Danadian, K., and Saad, R. (2002) Metformin therapy in obese adolescents with polycystic ovary syndrome and impaired glucose tolerance: amelioration of exaggerated adrenal response to adrenocorticotropin with reduction of insulinemia/insulin resistance. J. Clin. Endocrinol. Metab. 87:1555–1559.
Azziz, R., Ehrmann, D., Legro, R. S., et al. (2001) Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: a multicenter, double blind, placebo-controlled trial. J. Clin. Endocrinol. Metab. 86:1626–1631.
Azziz, R., Woods, K., Reyna, R., et al. (2004) The prevalence and features of the polycystic ovary syndrome in an unselected population. J. Clin. Endocrinol. Metab. 89:2745–2749.
Baillargeon, J. P., Jakubowicz, D. J., Iuorno, M. J., Jakubowicz, S., and Nestler, J. E. (2004) Effects of metformin and rosiglitazone, alone and in combination, in nonobese women with polycystic ovary syndrome and normal indices of insulin sensitivity. Fertil. Steril. 82:893–902.
Bedaiwwy, M. A. M. K., Goldberg, J. M., Nelson, D., and Falcone, T. (2001) Effect of metformin on mouse embryo development. Fertil. Steril. 76:1078–1079.
Bray, G. (2004) Medical consequences of obesity. J. Clin. Endocrinol. Metab. 89:2583–2589.
Brettenthaler, N., Geyter, C., Huber, P. R., and Keller, U. (2004) Effect of the insulin sensitizer pioglitazone on insulin resistance, hyperandrogenism, and ovulatory dysfunction in women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 89:3835–3840.
Carmina, E. (2002) Anti-androgens for the treatment of hirsutism. Exp. Opin. Invest. Drugs 11:357–363.
Chan, J., Rimm, E., Colditz, G., Stampfer, M., and Willett, W. (1994) Obesity, fat distribution and weight gain as risk factors for clinical diabetes in men. Diabetes Care 17:961–969.
Chou, K. H., Eye Corleta, H., Capp, E., and Spritzer, P. M. (2003) 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. 35:86–91.
Creatas, G., Koliopoulos, C., and Mastorakos, G. (2000) Combined oral contraceptive treatment of adolescent girls with polycystic ovary syndrome. Ann. N. Y. Acad. Sci. 900:245–252.
Leo, V., Marca, A., and Petraglia, F. (2003) Insulin-lowering agents in the management of polycystic ovary syndrome. Endocr. Rev. 24:633–637.
Diamanti-Kandarakis, E., Kouli, C., Tsianateli, T., and Bergiele, A. (1998) Therapeutic effects of metformin on insulin resistance and hyperandrogenism in polycystic ovary syndrome. Eur. J. Endocrinol. 138:269–274.
Dunaif, A. (1997) Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr. Rev. 18:774–800.
Ehrmann, D. A., Cavaghan, M. K., Imperial, J., et al. (1997) Effects of metformin on insulin secretion, insulin action, and ovarian steroidogenesis in women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 82:524–530.
Elter, K., Imir, G., and Durmusoglu, F. (2002) 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. 17:1729–1737.
Escobar-Morreale, H. F., Miguel, L., and Jose, S. (2000) Treatment of hirsutism with ethinyl estradiol-desogestrel contraceptive pills has beneficial effects on the lipid profile and improves insulin sensitivity. Fertil. Steril. 74:816–819.
Fleming, R., Hopkinson, Z. E., Wallace, A. M., Greer, I. A., and Sattar, N. (2002) Ovarian function and metabolic factors in women with oligomenorrhea treated with metformin in a randomized double blind placebo-controlled trial. J. Clin. Endocrinol. Metab. 87:569–574.
Ganie, M. A., Khurana, M. L., Eunice, M., et al. (2004) Comparison of efficacy of spironolactone with metformin in the management of polycystic ovary syndrome: an open-labeled study. J. Clin. Endocrinol. Metab. 89:2756–2762.
Glueck, C. J., Wang, P., Kobayashi, S., Phillips, H., and Sieve-Smith, L. (2002) Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome. Fertil. Steril. 77:520–525.
Glueck, C. J., Goldenberg, N., Streicher, P., and Wang, P. (2003a) Metformin and gestational diabetes. Curr. Diab. Rep. 3:303–312.
Glueck, C. J., Moreira, A., Goldenberg, N., Sieve, L., and Wang, P. (2003b) Pioglitazone and metformin in obese women with polycystic ovary syndrome not optimally responsive to metformin. Hum. Reprod. 18:1618–1625.
Glueck, C. J., Goldenberg, N., Pranikoff, J., et al. (2004) Height, weight, and motor–social development during the first 18 months of life in 126 infants born to 109 mothers with polycystic ovary syndrome who conceived on and continued metformin through pregnancy. Hum. Reprod. 19:1323–1330.
Godsland, I. F., Crook, D., Simpson, R., et al. (1990) The effects of different formulations of oral contraceptive agents on lipid and carbohydrate metabolism. N. Engl. J. Med. 323:1375–1380.
Group TREAC (2004) Revised 2003 consensus on diagnostic criteria and long term health risks related to polycystic ovary syndrome. Fertil. Steril. 81:19–25.
Hacihanefioglu, B., Somunkiran, A., Mahmutoglu, I., et al. (2002) Effect of hypertension therapy with the angiotensin-converting enzyme inhibitor lisinopril on hyperandrogenism in women with polycystic ovary syndrome. Fertil. Steril. 77:526–528.
Harborne, L., Fleming, R., Lyall, H., Sattar, N., and Norman, J. (2003) Metformin or antiandrogen in the treatment of hirsutism in polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 88:4166–4171.
Holte, J., Bergh, T., Berne, C., Wilde, L., and Lithell, H. (1995) Restored insulin sensitivity but persistently increased early insulin secretion after weight loss in obese women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 80:2586–2593.
Holte, J., Gennarelli, G., Berne, C., Bergh, T., and Lithell, H. (1996) Elevated daytime blood pressure in women with polycystic ovary syndrome: a sign of a pre-hypertensive state?Hum. Reprod. 11:23–28.
Katz, A., Nambi, S. S., Mather, K., et al. (2000) Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J. Clin. Endocrinol. Metab. 85:2402–2410.
Knowler, W., Barrett-Connor, E., Fowler, S., et al. (2002) Diabetes Prevention Program Research Group: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N. Engl. J. Med. 346:393–403.
Legro, R. S., Kunselman, A. R., Dodson, W. C., and Dunaif, A. (1999) Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J. Clin. Endocrinol. Metab. 84:165–168.
Lord, J. M., Flight, I. H., and Norman, R. J. (2003) Insulin-sensitising drugs (metformin, troglitazone, rosiglitazone, pioglitazone, d-chiro-inositol) for polycystic ovary syndrome. Cochrane Database Syst Rev. 3:CD003053.
Meyer, C., McGrath, B., Cameron, J., and Teede, H. J. (2005) Vascular dysfunction and metabolic parameters in polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 90:4630–4635.
Meyer, C. M. B. and Teede, H. J. (2005) Overweight women with polycystic ovary syndrome have evidence of subclinical cardiovascular disease. J. Clin. Endocrinol. Metab. 90:5711–5716.
Moghetti, P., Castello, R., Negri, C., et al. (2000) 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. 85:139–146.
Moran, L. J., Noakes, M., Clifton, P. M., Tomlinson, L., and Norman, R. J. (2003) Dietary composition in restoring reproductive and metabolic physiology in overweight women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 88:812–819.
Morin-Papunen, L. C., Vauhkonen, I., Koivunen, R. M., et al. (2000) 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. 85:3161–3168.
National Health and Medical Research Council (2003) Clinical Practice Guidelines for the Management of Overweight and Obesity in Adults.
Nestler, J. E. and Jakubowicz, D. J. (1996) Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N. Engl. J. Med. 335:617–623.
Nestler, J. E. and Jakubowicz, D. J. (1997) Lean women with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian P450c17 alpha activity and serum androgens. J. Clin. Endocrinol. Metab. 82:4075–4079.
Norman, R. J., Masters, S. C., Hague, W., et al. (1995) Metabolic approaches to the subclassification of polycystic ovary syndrome. Fertil. Steril. 63:329–335.
Norman, R. J., Masters, L., Milner, C. R., Wang, J. X., and Davies, M. J. (2001) Relative risk of conversion from normoglycaemia to impaired glucose tolerance or non-insulin dependent diabetes mellitus in polycystic ovarian syndrome. Hum. Reprod. 16:1995–1998.
Palomba, S., Orio, F. Jr., Falbo, A., et al. (2005) Prospective parallel randomized, double-blind, double-dummy controlled clinical trial comparing clomiphene citrate and metformin as the first-line treatment for ovulation induction in nonobese anovulatory women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 90:4068–4074.
Paradisi, G., Steinberg, H., Shepard, M., Hook, G., and Baron, A. D. (2003) Troglitazone therapy improves endothelial function to near normal levels in women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 88:576–580.
Pasquali, R., Gambineri, A., Biscotti, D., et al. (2000) 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. 85:2767–2775.
Pierpoint, T., McKeigue, P., Isaacs, A., Wild, S., and Jacobs, H. (1998) Mortality of women with polycystic ovary syndrome at long term follow-up. J. Clin. Epidemiol. 51:581–586.
Pirwany, I. and Tulandi, T. (2003) Laparoscopic treatment of polycystic ovaries: is it time to relinquish the procedure?Fertil. Steril. 80:241–251.
Radziuk, J. (2000) Insulin sensitivity and its measurement: structural commonalities among the methods. J. Clin. Endocrinol. Metab. 85:4426–4433.
Romualdi, D., Guido, M., Ciampelli, M., et al. (2003) Selective effects of pioglitazone on insulin and androgen abnormalities in normo- and hyperinsulinaemic obese patients with polycystic ovary syndrome. Hum. Reprod. 18:1210–1218.
Salpeter, S., Greyber, E., Pasternak, G., and Salpeter, E. (2003) Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Arch. Intern. Med. 163:2594–2602.
Sampson, M., Kong, C., Patel, A., Unwin, R., and Jacobs, H. S. (1996) Ambulatory blood pressure profiles and plasminogen activator inhibitor (PAI-1) activity in lean women with and without the polycystic ovary syndrome. Clin. Endocrinol. (Oxf.) 45:623–629.
Sepilian, V. and Nagamani, M. (2005) Effects of rosiglitazone in obese women with polycystic ovary syndrome and severe insulin resistance. J. Clin. Endocrinol. Metab. 90:60–65.
Talbot, E., Clerici, A., and Berga, S. (1998) Adverse lipid and coronary heart disease profiles in young women with polycystic ovary syndrome: results of a case control study. J. Clin. Epidemiol. 51:415–422.
Vandermolen, D. T. R. V., Evans, W. S., Stovall, D. W., Kauma, S. W., and Nestler, J. E. (2001) Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in pateints with polycystic ovarian syndrome who are resistant to clomiphene citrate alone. Fertil. Steril. 75:310–315.
Velazquez, E., Mendosa, S., Hamer, T., Sosa, F., and Glueck, C. (1994) Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 43:647–654.
Wild, R. A. (1995) Obesity, lipids, cardiovascular risk, and androgen excess. Am. J. Med. 98:27S–32S.
Wild, R. A., Painter, P., Coulson, P., Carruth, K., and Ranney, G. (1985) Lipoprotein lipid concentrations and cardiovascular risk in women with polycystic ovarian syndrome. J. Clin. Endocrinol. Metab. 61:946–951.
Wild, S., Pierpoint, T., McKeigue, P., and Jacobs, H. (2000) Cardiovascular disease in women with polycystic ovary syndrome at longterm follow-up: a retrospective cohort study. Clin. Endocrinol. (Oxf.) 52:595–600.
Yarali, H., Yildiz, B. O., Demirol, A., et al. (2002) Co-administration of metformin during rFSH treatment in patients with clomiphene citrate-resistant polycystic ovarian syndrome: a prospective randomized trial. Hum. Reprod. 17:289–294.
Yildiz, B. (2004) Recent advances in the treatment of polycystic ovarian syndrome. Exp. Opin. Invest. Drugs 13:1295–1305.
Yki-Jarvinen, H. (2004) Drug therapy: thiazolidinediones. N. Engl. J. Med. 351:1106–1118.
Zawadzki J. and Dunaif A. (1992) Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In Dunaif, A. and Givens, J. F. H. (eds.) Polycystic Ovary Syndrome, pp. 377–384. Cambridge, MA: Blackwell Scientific.