Viewpoints on Polycystic Ovary Syndrome – Clinical Research
Volume 29, Number 4 – August 2004
John E. Nestler, M.D., Professor Division Head, Internal Medicine/Endocrinology & Metabolism, Medical College of Virginia,Virginia Commonwealth University
The polycystic ovary syndrome (PCOS) affects five to 10 percent of reproductive age women, and is the most common cause of female infertility due to anovulation in the United States. Arguably, the most significant advance in our understanding of the syndrome during the past decade has been the appreciation that women with PCOS suffer from insulin resistance that is independent of obesity. Hence, lean women with PCOS possess a form of insulin resistance that is intrinsic to the syndrome and poorly understood. At the same time obese women with PCOS are markedly insulin resistant because they suffer from the combination of the insulin resistance intrinsic to PCOS and the insulin resistance of excess adiposity.
Treatment of PCOS can be divided into acute therapy to enhance fertility, and chronic therapy to address traditional therapeutic targets such as signs of androgen excess, oligomenorrhea and risk for endometrial hyperplasia/cancer. Because women with PCOS are at markedly increased risk for developing type 2 diabetes and, although more controversial, cardiovascular disease, novel targets for chronic therapy should likely also include prevention of diabetes and cardiovascular disease.
Space limitations and the nature of the two questions posed dictate that this review focus primarily on acute therapy for fertility. However, it should be noted that a cogent argument can be advanced for the use of Metformin as chronic therapy in most women with PCOS. The basis for such a proposal includes, but is not limited to, the fact that 1) insulin resistance is highly prevalent among women with PCOS, 2) women with PCOS compose one of the groups at highest risk for the development of type 2 diabetes, and 3) the use of insulin sensitizing drugs in non-diabetic women at high risk for diabetes has been shown to decrease conversion to type 2 diabetes1, 2. Insulin resistance may also play a role in the putative increased risk for cardiovascular disease in PCOS3-6, and emerging evidence suggests that insulin-sensitizing drugs may ameliorate this risk7-9. Insulin-sensitizing drug therapy should be coupled with lifestyle modification, a nonpharmacologic intervention for improving insulin sensitivity. The use of insulin-sensitizing drugs as chronic therapy for PCOS is a controversial and critical issue, and the reader is referred to an editorial that addresses the issue in greater detail10.
Insulin resistance and its compensatory hyperinsulinemia may hinder ovulation in PCOS through a variety of mechanisms, including but not limited to increased intraovarian androgens, altered gonadotropin secretory dynamics, or direct actions of insulin on the ovary. Consonant with the adverse effect of insulin resistance on ovulation, improving insulin sensitivity in PCOS, either through diet and exercise or administration of an insulin-sensitizing drug, has been reported to increase the frequency of ovulation, improve menstrual cyclicity, enhance the success rate of induction of ovulation with clomiphene citrate, and decrease ovarian androgen production11. These salutary effects have been observed in both lean and obese women with PCOS, and suggested guidelines for the use of Metformin to enhance pregnancy have been published12.
The insulin-sensitizing drug studied most widely in PCOS is Metformin. The efficacy of Metformin in enhancing fertility in PCOS was recently confirmed by a meta-analysis published by the Cochrane Library13. This critical analysis of the world literature assessed 13 randomized trials involving 543 women with PCOS, and reported that Metformin significantly increased the frequency of ovulation compared to placebo (odds ratio of 3.9; CI 2.3-6.7). When Metformin was used in conjunction with clomiphene citrate it was superior to clomiphene alone in inducing an ovulation (odds ratio of 4.4; CI 2.4-8.2) and yielding a clinical pregnancy (odd ratio of 4.4; CI 2.0-9.9). In fact, the number needed to treat (NNT) for Metformin monotherapy was only 4.4, and for Metformin plus clomiphene 3.0. In comparison to drugs administered for the treatment of hypertension, hyperlipidemia, hyperlipidemia, or osteoporosis where the NNT is commonly between 15-25, the efficacy of Metformin appears dramatic. Moreover, these studies likely underestimated the true benefit of Metformin, since most were short-term (3-6 months), and Metformin treatment may require several months to achieve a full effect.
It is noteworthy that the majority of studies of Metformin in PCOS did not screen women for the presence of insulin resistance or use insulin resistance as an inclusion criterion. Moreover, studies involving lean women with PCOS have reported equally positive findings. No clear predictors of a positive response to Metformin have been identified, and even lean women with seemingly normal indices of insulin action respond to treatment with Metformin.
Given the demonstrated efficacy of Metformin in PCOS, the lack of confirmed predictors of positive response, and the limited risk of toxicity, a strong case can be made for an empiric trial of Metformin in all women with PCOS pursuing pregnancy.
Nonetheless, several questions remain. Is Metformin monotherapy superior to clomiphene citrate in the induction of ovulation? Should Metformin be added to clomiphene immediately, or only after demonstrated failure of clomiphene alone? Although Metformin is a class B drug that appears to be safe during pregnancy, are there untoward effects of Metformin for ovulation induction that have not been identified?
An National Institutes of Health (NIH) trial, currently being conducted by the Reproductive Medicine Network (RMN) will soon answer many of these queries. The goal of the trial is to determine the optimal pharmacologic therapy for initial induction of ovulation in women with PCOS who are seeking pregnancy. Eligible women are randomized to one of three treatment arms (Metformin alone, clomiphene alone, or Metformin plus clomiphene), and the primary outcome measure is a live birth. Approximately 450 women have entered the trial thus far, and a total of 678 women will be studied. More information on the trial and participating sites can be found at http://rmn.dcri.duke.edu
Whether women with PCOS should remain on Metformin during pregnancy is a more difficult and controversial question. PCOS is associated with a 30 to 40 percent rate of early pregnancy loss (EPL), defined as miscarriage of a clinically recognized pregnancy during the first trimester. In most cases no apparent cause can be identified but, in addition to defects in the developing embryo, adverse alterations in endometrial function may play a role.
In this regard, hyperinsulinemia has been identified as an independent risk factor for EPL. Studies in PCOS suggest that hyperinsulinemia suppresses endometrial expression of glycodelin14, a protein whose circulating concentration may reflect endometrial function. Conversely, administration of Metformin to women with PCOS has been shown to increase circulating glycodelin15. Glycodelin is secreted by the endometrium, may inhibit the endometrial immune response to the embryo, and likely plays a critical role during implantation and in the maintenance of pregnancy. Moreover, both EPL and retarded endometrial development are associated with decreased secretion of glycodelin from secretory endometrium.
Two retrospective studies have reported that continued administration of Metformin during pregnancy markedly decreased EPL in PCOS16, 17. However, neither study identified the requisite duration of administration of Metformin, nor did they exclude the possibility that simply conceiving on Metformin might have conferred full benefit. No randomized controlled trial has been conducted to test the hypothesis that administration of Metformin during pregnancy decreases EPL in PCOS. With these caveats in mind, it may be reasonable to maintain a pregnant woman with PCOS on Metformin through the first trimester if there is a history of prior miscarriage, and then discontinuing the Metformin since the period of greatest risk will have passed. What should we do with a woman with PCOS who is pregnant for the first time? My personal approach is to discuss with the woman our understanding of the literature to date, and to let her wishes help guide the decision process.
In summary, Metformin is an important and effective treatment of infertility in PCOS. Since predictors of response have not been identified, the response rate is high (as reflected by a low NNT), and risks are low, an empiric trial of Metformin in all women with PCOS seeking pregnancy seems reasonable. Guidelines for the use of Metformin for this purpose have been suggested. However, many questions regarding the treatment of infertility with Metformin remain outstanding, and we all await the findings of large-scale trials such as the RMN trial currently underway.
NOTE: SCROLL PAST ALL OF THE FOLLOWING REFERENCES TO SEE PART TWO OF THIS ARTICLE, “SHOULD ALL PCOS WOMEN BE TREATED WITH METFORMIN.”
1 Buchanan TA, Xiang AH, Peters RK, Kjos SL, Marroquin A, Goico J,Ochoa C, Tan S, Berkowitz K, Hodis HN, Azen SP. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. Diabetes 2002; 51(9):2796-2803.
2 Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM. Reduction in the incidence of type 2 diabetes with lifestyle intervention or Metformin. N Engl J Med 2002; 346:393-403.
3 Christian RC, Dumesic DA,Behrenbeck T, Oberg AL, Sheedy PF, Fitzpatrick LA. Prevalence and predictors of coronary artery calcification in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2003; 88(6):2562-2568.
4 Paradisi G, Steinberg HO, Hempfling A, Cronin J, Hook G, Shepard MK, Baron AD. Polycystic ovary syndrome is associated with endothelial dysfunction. Circulation 2001; 103(10):1410-1415.
5 Talbott EO, Guzick DS, Sutton-Tyrrell K, McHugh-Pemu KP, Zborowski JV, Remsberg KE, Kuller LH. Evidence for association between polycystic ovary syndrome and premature carotid atherosclerosis in middle-aged women. Arterioscler Thromb Vasc Biol 2000; 20(11):2414-2421.
6 Dereli D, Ozgen G, Buyukkececi F, Guney E, Yilmaz C. Platelet dysfunction in lean women with polycystic ovary syndrome and association with insulin sensitivity. J Clin Endocrinol Metab 2003; 88(5):2263-2268.
7 Morin-Papunen L, Rautio K, Ruokonen A, Hedberg P, Puukka M, Tapanainen JS. Metformin reduces serum C-reactive protein levels in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2003; 88(10):4649-4654.
8 Paradisi G, Steinberg HO, Shepard MK, Hook G, Baron AD. Troglitazone therapy improves endothelial function to near normal levels in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2003; 88(2):576-580.
9 Diamanti-Kandarakis E, Spina G, Kouli C, Migdalis I. Increased endothelin-1 levels in women with polycystic ovary syndrome and the beneficial effect of Metformin therapy. J Clin Endocrinol Metab 2001;86(10):4666-4673.
10 Diamanti-Kandarakis E, Baillargeon JP, Iuorno MJ, Jakubowicz DJ, Nestler JE. A modern medical quandary: polycystic ovary syndrome, insulin resistance, and oral contraceptive pills. J Clin Endocrinol Metab 2003; 88(5):1927-1932.
11 Baillargeon JP, Iuorno MJ, Nestler JE. Insulin sensitizers for polycystic ovary syndrome. Clin Obstet Gynecol 2003; 46(2):325-340.
12 Nestler JE, Stovall DW, Akhter N, Iuorno MJ, Jakubowicz DJ. Strategies for the use of insulin-sensitizing drugs to treat infertility in women with polycystic ovary syndrome. Fertil Steril
13 Lord JM, Flight IH, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and metaanalysis. BMJ 2003; 327(7421):951- 953.
14 Jakubowicz DJ, Essah PA, Seppala M, Jakubowicz S, Baillargeon JP, Koistinen R, Nestler JE. Reduced Serum Glycodelin and Insulin-Like Growth Factor-Binding Protein-1 in Women with Polycystic Ovary Syndrome during First Trimester of Pregnancy. J Clin Endocrinol Metab 2004;
15 Jakubowicz DJ, Seppala M, Jakubowicz S, Rodriguez-Armas O, Rivas-Santiago A, Koistinen H, Koistinen R, Nestler JE. Insulin reduction with Metformin increases luteal phase serum glycodelin and insulin-like growth factorbinding protein 1 concentrations and enhances uterine vascularity and blood flow in the polycystic ovary syndrome. J Clin Endocrinol Metab 2001;86:1126-1133.
16 Glueck CJ, Phillips H, Cameron D, Sieve-Smith L, Wang P. Continuing Metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study. Fertil Steril 2001; 75:46-52.
17 Jakubowicz DJ, Iuorno MJ, Jakubowicz S, Roberts KA, Nestler JE. Effects of Metformin on early pregnancy loss in the polycystic ovary syndrome. J Clin Endocrinol Metab 2002; 87:524-529.