Review

Correspondence Division of Endocrinology, Metabolism and Molecular Medicine, Feinberg School of Medicine, Northwestern University, 303 E Chicago Avenue, Tarry 15-709, Chicago, IL 60611, USA

Email a-dunaif@northwestern.edu

Introduction

Polycystic ovary syndrome (PCOS) is among the most common endocrine disorders in women of reproductive age, and affects 7% of this population.^{1, 2, 3} PCOS was originally identified as a reproductive disorder characterized by enlarged, sclerocystic ovaries, menstrual disturbances, obesity, infertility and hirsutism.^{4, 5} This syndrome is the leading cause of anovulatory infertility.¹ Over the past 25 years or so,⁶ research has shown that PCOS is an important metabolic disorder that is associated with a substantially increased risk for type 2 diabetes mellitus (T2DM) as well as for the metabolic syndrome^{7, 8}—a constellation of cardiovascular risk factors associated with insulin resistance.⁹ Reproductive morbidities associated with insulin resistance, such as gestational diabetes mellitus (GDM) and pre-eclampsia, are also more common in affected women.^{10, 11}

As would be expected from the presence of these cardiovascular disease risk factors, affected women have an increased prevalence of atherosclerosis.¹² Nevertheless, no increase in cardiovascular events has yet been demonstrated, because there have been no prospective, long-term studies that have followed affected women until ages where such events become common.^{7, 12} Women with PCOS have defects in both insulin action and secretion.¹³ These defects are independent of obesity, although it substantially worsens these parameters.¹³ The molecular mechanisms of insulin resistance in PCOS differ from those in other common insulin-resistant states, such as obesity and T2DM.^{13, 14}

Numerous studies have documented that hyperinsulinemia and insulin resistance not only amplify the reproductive abnormalities of PCOS, but also have key roles in the pathogenesis of the metabolic defects.^{7, 13} This insight has led to development of a major new therapeutic strategy based on insulin-sensitizing drugs (ISDs), particularly metformin. This article reviews the effects of ISDs on the reproductive and metabolic components of PCOS with particular attention to randomized, controlled trials (RCTs).

Diagnosis of polycystic ovary syndrome

The 1990 NIH–NICHD (National Institute of Child Health and Human Development) conference on PCOS proposed what have become known as the NIH diagnostic criteria: hyperandrogenism (clinical and/or biochemical) and chronic anovulation with the exclusion of specific disorders of the ovary, adrenal, thyroid and pituitary glands (Box 1).¹³ The presence of polycystic ovaries (PCO), with morphology assessed by ultrasound, was not included as a diagnostic criterion because of the lack of specificity of this finding.¹⁵ PCO can be present in women with normal ovulation and sex-hormone levels, whereas women with all the endocrine features of PCOS can occasionally have normal ovarian morphology as assessed by ultrasound examination.^{15, 16}

In 2003, an international conference in Rotterdam¹⁷ proposed revised criteria for PCOS that included PCO. The Rotterdam criteria require the presence of two of the three following findings: hyperandrogenism; chronic anovulation; and PCO (Box 1). All women considered to have PCOS according to the NIH criteria would also be identified by use of the Rotterdam criteria; however, the Rotterdam criteria also include women with PCO who would be excluded by the NIH criteria: those with PCO, hyperandrogenism and ovulatory cycles, and those with PCO, chronic anovulation and normal androgen levels.

Ovulatory women with PCO seem to be less insulin-resistant than anovulatory women with PCO;^{18, 19, 20} further, a study published in 2007²¹ suggests that women with PCO, chronic anovulation and normal androgen levels are not insulin-resistant. These observations limit the usefulness of the Rotterdam criteria, and accordingly an expert panel of the Androgen Excess Society (AES) recommended that PCOS should be considered a disorder of androgen excess and that the NIH diagnostic criteria should be used (Box 1).²² The AES also recommended that women with hyperandrogenism, PCO and ovulatory cycles should be considered to have a PCOS phenotype; thus, hyperandrogenism and infrequent or irregular ovulation, as well as hyperandrogenism, regular ovulation and PCO, also fulfill AES criteria for PCOS (Box 1). This Review is, however, limited to PCOS as defined by the NIH, since the majority of published studies used these diagnostic criteria; moreover, only women who fulfill the NIH criteria have been demonstrated to be at high risk for metabolic sequelae of PCOS, such as glucose intolerance⁷ and the metabolic syndrome.⁸

Insulin-sensitizing drugs

The biguanide, metformin, and the thiazolidinediones troglitazone (which is no longer available), pioglitazone, and rosiglitazone, are all antidiabetic drugs that act by improving the sensitivity of peripheral tissues to insulin,²³ which results in decreased circulating insulin levels. Metformin inhibits hepatic glucose production through multiple effects on glucose metabolism, and it also increases glucose uptake in peripheral tissues and reduces fatty acid oxidation.²⁴ One mechanism for these pleiotropic actions seems to be the activation of 5'-AMP-activated protein kinase,²⁵ mediated by action on a proximal kinase—serine–threonine protein kinase 11 (previously termed LKB1).²⁶ Thiazolidinediones increase peripheral glucose uptake more potently than metformin does.²⁷ They also decrease hepatic glucose production but to a lesser degree than metformin.^{27, 28}

Thiazolidinediones are ligands for peroxisome proliferator-activated receptor (PPAR),²³ which is part of the superfamily of nuclear receptors. PPAR receptors are essential for adipocyte differentiation and growth, and thiazolidinediones actually increase the number of subcutaneous adipocytes.²³ This increase in adipose mass might contribute to their beneficial effects on glucose homeostasis since it is hypothesized that triglycerides can be partitioned into these newly differentiated subcutaneous adipocytes from muscle and liver, which decreases the adverse effects of lipids on insulin action, so-called lipotoxicity.²⁹ Thiazolidinediones also improve insulin signaling and glucose uptake.²³ In addition, thiazolidinediones have a number of other effects on lipid metabolism, inflammatory pathways and vascular biology.²³ A direct result of thiazolidinediones' mechanism of action is an increase in subcutaneous adipose mass, often accompanied by weight gain.²³

D-Chiro-inositol is a naturally occurring substance that is postulated to improve insulin sensitivity by enhancing signal transduction via an alternative pathway for insulin action, mediated by inositolphosphoglycans.^{30, 31} It has never been approved for clinical use in diabetes and is mentioned only since there are several studies showing efficacy of this agent as a treatment for PCOS.

Insulin-sensitizing drugs in polycystic ovary syndrome

ISDs were first used in women with PCOS in 1994, to investigate the role of insulin resistance in the pathogenesis of the syndrome. In the original report by Velazquez and colleagues,³² menses became more regular with metformin use and there was a significant reduction in circulating androgen levels. There were, however, also significant decreases in body weight so that it was not possible to conclude that these benefits were accounted for solely by improvements in insulin sensitivity. In 1996, studies in which women with PCOS received troglitazone demonstrated that this treatment decreased androgen levels in parallel with decreases in insulin levels and improvements in insulin sensitivity without changes in body weight.³³

There have been numerous subsequent studies of the reproductive and metabolic effects of ISDs in PCOS (Table 1) that are summarized in a meta-analysis of RCTs³⁴ published in 2003; however, only metformin had multiple placebo-controlled trials suitable for analysis. There were 14 such RCTs and all were fairly small: in the treatment arm, the median number of patients was 16 (range 10–45); in the placebo arm there was a median of 15 women (range 8–62). There was one large RCT of troglitazone with approximately 150 individuals per arm among the additional studies included in the meta-analysis.

Table 1 Insulin-sensitizing agents used in polycystic ovary syndrome.

Full tableFigures & Tables indexDownload Power Point slide (204K)

Metformin and thiazolidinediones had similar metabolic effects in PCOS to their effects in T2DM. Compared with placebo, metformin therapy resulted in significant decreases in fasting glucose and insulin levels as well as in area under the curve (AUC; i.e. the curve of concentration versus time) for insulin levels after oral glucose administration in the meta-analysis.³⁴ Mechanistic studies have shown that metformin improves insulin-mediated glucose disposal in women with PCOS.³⁵ Thiazolidinediones also decrease fasting glucose and insulin levels, AUCs for glucose and insulin levels, and glycosylated hemoglobin levels compared with placebo in women with PCOS.^{36, 37} Mechanistic studies have shown that troglitazone improves insulin-mediated glucose disposal³⁸ as well as insulin-secretory defects³⁹ in women with PCOS.

In general, the beneficial effects of ISDs on reproductive parameters are seen only in association with a reduction in circulating insulin levels, consistent with the hypothesis that this reduction is the mechanism for their beneficial effects in PCOS.⁴⁰ Thiazolidinediones do, however, seem to have direct effects on steroidogenesis that could contribute to these changes.^{41, 42} Controversy exists as to whether metformin has direct effects on steroidogenesis.^{41, 43} Part of the efficacy of thiazolidinediones and metformin in PCOS might, therefore, be related to direct actions on steroidogenesis as well as to their insulin-sensitizing effects.

Reproductive actions of insulin-sensitizing drugs

Anovulation and infertility

Metformin has gained wide acceptance for the treatment of infertility in PCOS on the basis of its efficacy in inducing ovulation. Treatment, either with metformin alone compared with placebo, or with metformin plus clomiphene citrate compared with clomiphene alone, was significantly superior for ovulation induction in the meta-analysis of RCTs.³⁴ This action of metformin probably results from its insulin-sensitizing effects, since thiazolidinediones also significantly increase the number of ovulatory menstrual cycles. The troglitazone RCT showed that this drug was significantly more effective than placebo in promoting ovulation in a dose-dependent manner in women with PCOS.³⁶ Smaller studies with the currently available thiazolidinediones—pioglitazone and rosiglitazone—suggest that they have similar efficacy for ovulation induction to that of troglitazone.^{37, 49, 50} It has also been suggested that metformin used in conjunction with gonadotropin therapy for ovulation induction improves unifollicular development^{51, 52} and conception rates, and reduces ovarian hyperstimulation syndrome.⁵³

When clinical pregnancy rates were assessed rather than ovulation rates in the meta-analysis of ISDs,³⁴ only metformin in combination with clomiphene was significantly more effective than clomiphene alone. By contrast, metformin alone was no more effective than placebo with regard to clinical pregnancy rates. Since the publication of the aforementioned meta-analysis, there have been three RCTs of metformin compared with clomiphene alone or in combination that have examined conception and/or live-birth rates as end points (Table 2).^{54, 55, 56}

Table 2 Summary of recent randomized, placebo-controlled trials of clomiphene citrate compared with metformin.

Full tableFigures & Tables indexDownload Power Point slide (246K)

A single-center, Italian, placebo-controlled RCT⁵⁴ in nonobese (BMI <30 kg/m²) women with PCOS compared metformin alone with clomiphene alone (50 patients per arm) as first-line therapy. This RCT found similar ovulation rates in both treatment arms, but a significantly increased conception rate in the metformin arm. An extension study suggested that the live-birth rate was also higher with metformin than with clomiphene, but this outcome was not an end point of the RCT itself. A nonrandomized trial from this same group of investigators,⁵⁷ done in women with PCOS and a range of body weights (40 individuals per arm), found similar ovulation, conception and spontaneous abortion rates with metformin alone compared with clomiphene alone as first-line therapy for infertility.

A large (100 patients per arm), multicenter Dutch RCT⁵⁵ examined ovulation as a primary end point and pregnancy as a secondary end point. This trial found no benefit from a combination of metformin plus clomiphene compared with clomiphene alone, for either end point, in previously untreated women with newly diagnosed PCOS; 55–60% of women in each arm had BMI >25 kg/m².

The only RCT⁵⁶ to examine live-birth rates as the primary end point was a very large (200 women per arm) US multicenter study of metformin alone compared with clomiphene alone compared with combination therapy. This trial found that metformin alone was inferior to clomiphene alone for ovulation, conception (among those who ovulated) and live-birth rates. Combination therapy resulted in significantly higher ovulation rates than either treatment alone, despite no significant differences in pregnancy or live-birth rates compared with clomiphene alone. There were no significant differences in the rates of multiple pregnancies between the groups, although all such pregnancies occurred in women who were treated with clomiphene, alone or in combination.

When the live-birth rate (rather than ovulation or conception rates) is examined as an end point, there is no difference in efficacy between metformin in combination with clomiphene or clomiphene alone;^{55, 56} further, use of metformin on its own results in significantly lower rates of ovulation, conception and live births than are observed with combination therapy.⁵⁶ The US RCT⁵⁶ did find that ovulation and conception rates were significantly higher with combination therapy than with clomiphene alone, analogous to the results of the meta-analysis,³⁴ whereas the Dutch RCT⁵⁵ found these therapies to be equivalent. Of note, the meta-analysis was based on a series of small, primarily single-center trials whereas the recent studies were large, multicenter studies with robust statistical power.⁵⁸

Differences in the patient populations with respect to body weight, duration of infertility (e.g. newly diagnosed or not), previous treatment (e.g. failure to respond to clomiphene treatment alone), or ethnicity could also have contributed to the differing results. The US RCT⁵⁶ used extended-release metformin (1 g twice daily) whereas all other studies used an immediate-release preparation. The extended-release preparation has similar efficacy for glycemic control⁵⁹ to the immediate-release form. There were significant decreases in BMI and total testosterone levels and significant increases in levels of sex-hormone-binding globulin with extended-release metformin in the US trial. There were, however, no significant changes in fasting markers of insulin resistance.

There is evidence for a dose–response effect of immediate-release metformin in obese women with PCOS;⁴⁷ fasting markers of insulin resistance did not change when 500 mg of this formulation was given three times daily, but improved when 850 mg of immediate-release metformin was given three times daily. Different metformin preparations might, therefore, have differences in efficacy in PCOS. It is important to note, however, that most RCTs of ovulation induction in PCOS have used 1.5–1.7 g daily rather than maximal doses of immediate-release metformin.^{34, 57}

Metabolic abnormalities

Comparative studies

Adverse effects

In most RCTs, metformin caused a significantly increased incidence of nausea, vomiting and gastrointestinal distress in women with PCOS.^{34, 56} There are no published reports of lactic acidosis with metformin therapy in women with PCOS and a meta-analysis of metformin RCTs in patients with T2DM indicated that this adverse event did not occur if the prescribing precautions were followed, and the drug was not administered to individuals with compromised renal or hepatic function.⁹³

The manufacturer withdrew the first thiazolidinedione approved for clinical use—troglitazone—from the market in 2000 because of hepatoxicity.²³ In the RCT of troglitazone therapy in women with PCOS, there were no significant differences compared with placebo in the development of elevated hepatic enzymes.³⁶ Hepatoxicity does not seem to be a thiazolidinedione class effect and has not been noted with pioglitazone or rosiglitazone.^{23, 37} Thiazolidinediones are, however, associated with weight gain, in part related to their mechanism of action as PPAR ligands, and fluid retention that could result in edema and dilutional anemia.²³ Dose-dependent weight gain has been reported in some studies of thiazolidinediones in women with PCOS,^{36, 37, 48, 49} but not in others.^{33, 50, 82} In the one RCT that reported additional adverse events of treatment with a currently available thiazolidinedione,³⁷ an increase in peripheral edema, sleep disorders, headache and stomach pain (sic) was seen with pioglitazone therapy compared with placebo in women with PCOS.

Two large, placebo-controlled RCTs of the currently available thiazolidinediones found significantly increased rates of heart failure—in patients with T2DM and macrovascular disease who were receiving pioglitazone in addition to other antidiabetic therapy,⁹⁴ and in generally healthy individuals with impaired glucose tolerance or impaired fasting glucose who were receiving rosiglitazone for diabetes prevention,⁹⁵ respectively. A meta-analysis published in 2007⁹⁶ suggested that there was a significant increase in the risk for cardiovascular events in patients with T2DM receiving rosiglitazone. An interim analysis of data from an open-label, randomized trial,⁹⁷ however, found no significant increase in myocardial infarction in patients with T2DM who were receiving rosiglitazone in addition to metformin and sulfonylurea, compared with patients receiving metformin and sulfonylurea alone. Rosiglitazone was associated with an increased risk for heart failure; however, both the study by Nissen and Wolski⁹⁶ and the interim analysis⁹⁷ have limitations.⁹⁸

Accordingly, there are substantial new cardiovascular safety concerns about thiazolidinediones, in addition to the well-substantiated reports of an increased risk for heart failure. As a consequence of these issues, as well as concerns about the safety of thiazolidinediones during pregnancy, these drugs should be used only with extreme caution in otherwise healthy women with PCOS until further safety data are available.

Conclusions

Most data suggest that the NIH diagnostic criteria for PCOS identify those women who are at risk for the metabolic sequelae of the disorder. Recent RCTs suggest that clomiphene is equivalent or superior to metformin alone for the treatment of anovulatory infertility in women with PCOS. There are no data to support metformin use during pregnancy to reduce either spontaneous abortion rates or the risk for GDM.

Lifestyle modification is the first-line therapy in overweight and obese women with PCOS who have features of metabolic syndrome and/or impaired glucose tolerance (Table 3).^{99, 100} Metformin remains a useful additional therapy in such patients. In women with PCOS and T2DM, metformin is an appropriate first-line medical therapy.

Table 3 Author's recommended therapies for polycystic ovary syndrome.

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It is important to caution women who are receiving metformin monotherapy and are not interested in conception about the need for added contraception. Menstrual bleeding could, furthermore, become more regular in women who receive insulin-sensitizer monotherapy in the absence of ovulation^{33, 101} and it is unknown whether such anovulatory bleeding is sufficient for endometrial protection.^{89, 102} In clinical practice it is, therefore, prudent to ensure that menses are ovulatory in patients on insulin-sensitizer monotherapy.

Unless there is a metabolic benefit (e.g. weight loss, reversal of glucose intolerance or of the metabolic syndrome) to support continued insulin-sensitizer therapy, there are minimal data to guide therapy since there are no RCTs that support the use of these drugs in any population of individuals with insulin resistance per se. The potential cardiovascular risk of thiazolidinediones precludes their use in healthy women with PCOS, although these agents could still have a role in women with PCOS and T2DM.

Acknowledgments

Charles P Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

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