Treatment, and Neisseria meningitidishas recently emerged as the leading cause of meningitis in children and young adults in the United States (Centers for Disease Control and Prevention [CDC], 2000). The average annualrate of invasive disease such as meningitis, meningococcemia, and Neisseria meningitidis is a leading arthritis is approximately 1.1 cases per 100,000 population, or 2600 cases
Metformin for the treatment of the polycystic ovary syndromeclinical therapeutics Metformin for the Treatment of the Polycystic Ovary Syndrome John E. Nestler, M.D.
This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies, the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines, if they exist, are presented. The article ends with the author's clinical recommendations. A 23-year-old woman with known polycystic ovary syndrome visits her family physi-
cian. She has taken oral contraceptive pills in the past but did not tolerate them and is
not currently receiving any treatment. She has three or four menstrual periods per
year and is not interested in becoming pregnant now, but she will be getting married
in a year. She has heard that the polycystic ovary syndrome is associated with diabetes
and is concerned because both her mother and father have type 2 diabetes. Her body-
mass index (the weight in kilograms divided by the square of the height in meters) is
32, her waist circumference is 38 in. (96.5 cm), her serum total testosterone level is
elevated at 0.9 ng per milliliter (90 ng per deciliter, or 2.9 nmol per liter), her plasma
high-density lipoprotein cholesterol level is 35 mg per deciliter (0.9 mmol per liter),
and her triglyceride level is 190 mg per deciliter (2.1 mmol per liter). Her serum
glucose level 2 hours after the ingestion of 75 g of dextrose is 138 mg per deciliter
(7.7 mmol per liter). The physician wonders whether treatment with metformin
would be beneficial and refers the patient to an endocrinologist.
The Clinical Problem The polycystic ovary syndrome is a clinical diagnosis characterized by the presence From the Departments of Internal Medi- cine, Obstetrics and Gynecology, and Phar- of two or more of the following features: chronic oligo-ovulation or anovulation, macology and Toxicology, Virginia Com- androgen excess, and polycystic ovaries.1 It affects 5 to 10% of women of childbear- monwealth University, Richmond. Address ing age2,3 and is the most common cause of anovulatory infertility in developed reprint requests to Dr. Nestler at the Di- vision of Endocrinology and Metabolism, countries. Common clinical manifestations include menstrual irregularities and Medical College of Virginia, PO Box signs of androgen excess such as hirsutism, acne, and alopecia.
980111, Richmond, VA 23298-0111, or at The polycystic ovary syndrome is associated with important metabolic derange- [email protected].
ments. The prevalence of type 2 diabetes in the United States is 10 times as high N Engl J Med 2008;358:47-54.
among young women with the polycystic ovary syndrome as among normal Copyright 2008 Massachusetts Medical Society. women,4,5 and impaired glucose tolerance or overt type 2 diabetes develops by the age of 30 years in 30 to 50% of obese women with the polycystic ovary syndrome.4‑6 The prevalence of the metabolic syndrome is two to three times as high among women with the polycystic ovary syndrome as among normal women matched for age and body-mass index, and 20% of women with the polycystic ovary syndrome who are younger than 20 years of age have the metabolic syndrome.7 Although outcome data specifically for women with the polycystic ovary syndrome are lack- ing, the risk of fatal myocardial infarction is twice as high among women with severe oligomenorrhea, most of whom would be expected to have the polycystic ovary syndrome, as among women with eumenorrhea.8 n engl j med 358;1 www.nejm.org january 3, 2008 The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF CHICAGO LIBRARIES on May 23, 2013. For personal use only. No other uses without permission. Copyright 2008 Massachusetts Medical Society. All rights reserved. loss,29 metformin,30,31 troglitazone,32 rosiglita- Pathophysiology and Effect zone,23,33 or pioglitazone34), or the reduction of carbohydrate absorption (with the use of acar- The pathophysiological characteristics of the poly- bose35).
cystic ovary syndrome are not fully understood Metformin, a biguanide, is the most widely but are known to involve complex interactions be- used drug for the treatment of type 2 diabetes tween the actions of gonadotropins, the ovaries, worldwide. Its primary action is to inhibit he- androgens, and insulin (Fig. 1). An important ele- patic glucose production, but it also increases ment of this syndrome is insulin resistance. The the sensitivity of peripheral tissues to insulin.36 majority of women with the polycystic ovary syn- The increase in insulin sensitivity, which contrib- drome, regardless of weight, have a form of insu- utes to the efficacy of metformin in the treat- lin resistance that is intrinsic to the syndrome and ment of diabetes, has also been shown in nondia- is poorly understood.9‑11 Obese women with the betic women with the polycystic ovary syndrome.37 polycystic ovary syndrome have an added burden In women with the syndrome, long-term treat- of insulin resistance related to their adiposity.11 ment with metformin may increase ovulation, The insulin resistance that is characteristic of improve menstrual cyclicity, and reduce serum the polycystic ovary syndrome appears to be re- androgen levels30,31; the use of metformin may sponsible for the association of the disorder with also improve hirsutism.38 If published data on type 2 diabetes.12 Insulin resistance may also the effects of metformin in the prevention of dia- underlie the association of the polycystic ovary betes can be extrapolated to women with the syndrome with recognized cardiovascular risk fac- polycystic ovary syndrome, then the drug may tors such as dyslipidemia and hypertension,13 as actually retard progression to glucose intolerance well as with anatomical14‑17 and functional16,18,19 in affected women, as reported in a small, retro- spective study.39 Insulin resistance and compensatory hyperin- sulinemia also play an important role in other Clinical Ev idence aspects of the polycystic ovary syndrome, includ- ing androgen excess and anovulation (Fig. 1). In- In 1996, it was reported that the administration sulin stimulates the ovarian production of an- of metformin to women with the polycystic ovary drogen by activating its homologous receptor,20,21 syndrome reduced circulating insulin levels and and the ovaries of women with the polycystic was associated with decreases in ovarian 17,20- ovary syndrome appear to remain sensitive to in- lyase activity and ovarian secretion of andro- sulin,22 or perhaps hypersensitive to it,23‑25 even gens.40 Most, but not all, subsequent studies con- when classic target tissues such as muscle and firmed the ability of metformin to lower fasting fat manifest resistance to insulin action. In ad- serum insulin30 and androgen31 levels in women dition, hyperinsulinemia inhibits the hepatic pro- with the polycystic ovary syndrome. However, duction of sex hormone–binding globulin,26 fur- studies specifically assessing the effects of met- ther increasing circulating free testosterone levels. formin on clinical signs of androgen excess (e.g., Finally, insulin impedes ovulation, either by di- hirsutism, acne, and androgenetic alopecia) are rectly affecting follicular development or by in- limited.38 directly increasing intraovarian androgen levels With regard to ovulation, in results of a ran- or altering gonadotropin secretion.27 Further evi- domized clinical trial reported in 1998, pretreat- dence of the influence of insulin resistance in ment with metformin, as compared with placebo, the polycystic ovary syndrome is that multiple increased the incidence of ovulation after subse- diverse interventions, which are related to one quent treatment with clomiphene.41 Subsequent- another only in that they lower circulating insu- ly, several studies compared metformin with pla- lin levels, result in increased frequency of ovula- cebo, metformin with no treatment, metformin tion or menses, reduced serum testosterone lev- plus clomiphene with clomiphene alone, or met- els, or both. These interventions include the formin plus clomiphene with placebo. The most inhibition of insulin release (with the use of di- rigorous of these studies were included in a azoxide20 or octreotide28), improvement of insu- meta-analysis by Lord et al. in 2003.30 The meta- lin sensitivity (with the use of diet-induced weight analysis included data from 13 trials and 543 n engl j med 358;1 www.nejm.org january 3, 2008 The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF CHICAGO LIBRARIES on May 23, 2013. For personal use only. No other uses without permission. Copyright 2008 Massachusetts Medical Society. All rights reserved. Clinical Therapeutics resistance
free fatty acids, hormone-binding globulin Figure 1. Pathophysiological Characteristics of the Polycystic Ovary Syndrome (PCOS).
Insulin resistance results in a compensatory hyperinsulinemia, which stimulates ovarian androgen production in an
ovary genetically predisposed to PCOS. Arrest of follicular development (red "X") and anovulation could be caused
by the abnormal secretion of gonadotropins such as follicle-stimulating hormone (FSH) or luteinizing hormone (LH)
(perhaps induced by hyperinsulinemia), intraovarian androgen excess, direct effects of insulin, or a combination of
these factors. Insulin resistance, in concert with genetic factors, may also lead to hyperglycemia and an adverse profile of cardiovascular risk factors. PAI-1 deno D p 4lasminogen12/11/07 -activator inhibitor type 1.
women with the polycystic ovary syndrom Title e; it was ovary syndrome who desire pregnancy, and the concluded that metformin is effective in ME increas- trials yielded conflicting results. The largest of ing the frequency of ovulation (odds r DE atio, 3.88; these trials, the Pregnancy in Polycystic Ovary 95% confidence interval, 2.25 to 6.69).
AUTHOR PLEASE NOTE: e trial,42 included 626 infertile women Since publication of the meta-analysis, three with the poly Figure has been redrawn and type has been reset Please check carefully cystic ovary syndrome. It confirmed additional randomized clinical trialsI sh te been that the addition of metformin to clomiphene published.42‑44 They involved head-to-head com- therapy increased the cumulative ovulation rate parisons of metformin or metformin plus clomi- as compared with administration of clomiphene phene with clomiphene for the short-term induc- alone (60.4% vs. 49.0%, P = 0.003), but the rate of tion of ovulation in women with the polycystic live birth did not differ between the two groups n engl j med 358;1 www.nejm.org january 3, 2008 The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF CHICAGO LIBRARIES on May 23, 2013. For personal use only. No other uses without permission. Copyright 2008 Massachusetts Medical Society. All rights reserved. (26.8% and 22.5%, respectively; P = 0.31). In that sutism, male pattern baldness, and acne) and study, clomiphene was more effective than met- restoring regular menses, thereby preventing endo- formin in inducing ovulation in the short term metrial hyperplasia.
and producing a live birth.
However, given the metabolic derangements With regard to diabetes, two major random- associated with the polycystic ovary syndrome, it ized clinical trials, the Indian Diabetes Preven- seems prudent and appropriate to plan long-term tion Programme (IDPP-1)45 and the U.S. Diabe- therapy that addresses not only management of tes Prevention Program (DPP),46 have shown that the consequences of androgen excess and anovu- the use of metformin decreases the relative risk lation but also the new goals of ameliorating in- for progression to type 2 diabetes (by 26% and sulin resistance and reducing the risks of type 2 31%, respectively) among patients with impaired diabetes and cardiovascular disease. The effect of glucose tolerance at baseline. Whether this effect estrogen–progestin contraceptive agents on glu- of metformin truly represented the prevention of cose tolerance is controversial. Limited evidence progression to diabetes, rather than simply the from controlled, short-term studies suggests that masking of progression by means of lowering the use of oral contraceptives aggravates insulin blood glucose levels, remains controversial. How- resistance and worsens glucose tolerance in wom- ever, after the discontinuation of metformin in en with the polycystic ovary syndrome.48 The use the DPP, diabetes developed in fewer subjects of estrogen–progestin contraceptives is associat- than would have been expected if masking had ed with a twofold increase in the relative risk of been the sole effect.47 To my knowledge, no ran- cardiovascular arterial events in the general fe- domized clinical trial has assessed the effect of male population49; the risk among women with metformin on the progression to type 2 diabetes the polycystic ovary syndrome in particular is specifically in patients with the polycystic ovary unknown.
syndrome. In an uncontrolled, retrospective study Metformin improves insulin sensitivity and, of 50 women with the polycystic ovary syndrome as noted earlier, has been shown to retard or treated with metformin for an average of 43 prevent progression to type 2 diabetes in patients months at an academic medical center, there was with impaired glucose tolerance. Although met- no progression to type 2 diabetes, even though formin has not been specifically shown to reduce 11 women (22.0%) had impaired glucose toler- the risk of cardiovascular events in patients with ance at baseline.39 The annual conversion rate the polycystic ovary syndrome, the available mech- from normal glucose tolerance to impaired glu- anistic and clinical evidence support the use of cose tolerance was only 1.4%, as compared with metformin as a protective measure against the 16 to 19% reported in the literature4,6 for women adverse cardiovascular effects of insulin resis- with the polycystic ovary syndrome who are not tance and insulin excess. In addition, metformin taking metformin.
may decrease circulating androgen levels and may improve ovulation and menstrual cyclicity, thus addressing the traditional goals of long-term treatment. For these reasons, although metfor- The approach to the management of the polycystic min is not approved by the Food and Drug Ad- ovary syndrome depends in part on the patient's ministration for the treatment of the polycystic and physician's principal therapeutic objectives. ovary syndrome, the drug is commonly used for For some women, infertility is the principal issue. this purpose.
Such patients are frequently treated in the short To minimize side effects, metformin therapy term with clomiphene, to induce ovulation. When is initiated at a low dose taken with meals, and fertility is not a concern, an estrogen–progestin the dose is then progressively increased. My prac- contraceptive, with or without an antiandrogen tice is to have patients take 500 mg of metformin such as spironolactone, has been the mainstay of once daily with the largest meal, usually dinner, long-term therapy. This approach is effective in for 1 week; then increase the dose to 500 mg achieving the traditional treatment goals in the twice daily, with breakfast and dinner, for 1 week; polycystic ovary syndrome, which include ame- increase the dose to 500 mg with breakfast and liorating the effects of androgen excess (e.g., hir- 1000 mg with dinner, for 1 week; and finally, n engl j med 358;1 www.nejm.org january 3, 2008 The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF CHICAGO LIBRARIES on May 23, 2013. For personal use only. No other uses without permission. Copyright 2008 Massachusetts Medical Society. All rights reserved. Clinical Therapeutics increase the dose to 1000 mg twice daily, with Women desiring contraception could be given an breakfast and dinner. There is no dose-ranging oral contraceptive agent while continuing to take study of metformin in the polycystic ovary syn- metformin. In cases in which hirsutism remains drome, but a dose-ranging study of patients with troublesome, an oral contraceptive agent, anti- diabetes, using the glycated hemoglobin level as androgen, or both could be added to metformin.
the outcome measure, suggested that a dose of 2000 mg daily is optimal.50 Metformin should not be used in women with renal impairment (a serum creatinine level Lactic acidosis has been reported with the use of >1.4 mg per deciliter [124 μmol per liter]), he- metformin, but this complication is rare (0.3 epi- patic dysfunction, severe congestive heart failure, sode per 10,000 patient-years) in otherwise healthy or a history of alcohol abuse. Given the young patients and is confined primarily to patients who age of women with the polycystic ovary syn- should not have received the drug, because they had drome, these contraindications are rarely an issue. underlying renal or hepatic disease.
Repeat testing during metformin treatment is not The main limiting side effect of metformin, indicated unless an illness or condition (e.g., de- affecting 10 to 25% of patients, is gastrointesti- hydration) that might affect renal or hepatic func- nal distress, namely nausea and diarrhea. If the tion develops.
nausea or diarrhea occurs at a given dose, that When metformin is prescribed, advice about a dose is either maintained or decreased by 500 mg weight-loss diet and a scheduled exercise routine per day for 2 to 4 weeks until the symptoms should also be given. Such interventions are abate. Fortunately, the gastrointestinal side ef- beneficial in preventing diabetes.45,46 In addition, fects of metformin are usually transient; however, weight loss increases the likelihood of resuming in a minority of cases, gastrointestinal distress ovulation, most likely as a result of improved may require the discontinuation of metformin.
Metformin can cause malabsorption of vitamin The patient is asked to maintain a menstrual B12 in some patients receiving long-term therapy. diary, cautioned that fertility may be rapidly es- In one analysis, risk factors for the development tablished, and advised to use a barrier method of this adverse effect included both the daily dose of contraception. Oral contraceptive agents and and duration of metformin therapy as well as antiandrogens are not administered at the initial age.52 Although the likelihood of clinical defi- visit, since they might affect menstruation or ciency of vitamin B12 appears to be low, patients serum androgen levels and confound the assess- should be monitored for signs and symptoms.
ment of the efficacy of metformin. Topical eflor- Metformin is a category B drug, and no tera- nithine can be prescribed for the treatment of togenic effects have been found in animal mod- facial hirsutism.
els. It was administered in South Africa to a Follow-up visits are scheduled at 3 and limited number of women with type 2 diabetes 6 months. Menstrual cyclicity is reviewed and or gestational diabetes, throughout their preg- serum total testosterone is determined at each nancies, and no teratogenic effects or adverse visit. If an improvement in menstrual cyclicity is fetal outcomes were reported.31 noted, it is important to document whether the menses are ovulatory. This can be accomplished Ar e as of Uncertaint y by measuring the serum progesterone level 7 days before the next onset of menses; a serum pro- Although metformin is increasingly used to treat gesterone level of more than 4.0 ng per milliliter patients with the polycystic ovary syndrome, ther- (12.7 nmol per liter) is consistent with the pres- apy is guided in part by the results of random- ence of the luteal phase and ovulation.
ized, controlled trials in populations without the After 6 to 9 months of treatment, the efficacy polycystic ovary syndrome, which showed that of metformin is assessed. If menstrual cyclicity diabetes was prevented. Similar randomized, con- and ovulation are satisfactorily improved, further trolled trials specifically involving patients with treatment is individualized. For some women, the polycystic ovary syndrome are needed. Strate- treatment with metformin alone might suffice. gies for long-term metformin therapy in patients n engl j med 358;1 www.nejm.org january 3, 2008 The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF CHICAGO LIBRARIES on May 23, 2013. For personal use only. No other uses without permission. Copyright 2008 Massachusetts Medical Society. All rights reserved. with the polycystic ovary syndrome are evolving, and the identification of predictors of the re- sponse to metformin, possibly even through phar- The obesity, family history of diabetes, and poly- macogenomic approaches, would improve the cystic ovary syndrome of the patient in the vignette utility of this agent in the management of the put her at high risk for type 2 diabetes. In addi- polycystic ovary syndrome. Although long-term tion to obesity, she has several signs of insulin treatment with metformin seems likely to be ben- resistance, including a low serum high-density eficial in many patients with the polycystic ovary lipoprotein cholesterol level and a high triglycer- syndrome, less clear is when metformin should be ide level, and her data fulfill the Adult Treatment used as monotherapy or in combination with anti- Panel III criteria of the National Cholesterol Edu- androgens or hormonal therapies. The efficacy of cation Program for the metabolic syndrome.55,56 metformin in ameliorating the signs of androgen Although her glucose tolerance is currently nor- excess, such as hirsutism, has not been critically mal, treatment with metformin is reasonable, and a weight-loss diet and exercise are also en- Metformin has been used for many years in couraged.
patients with type 2 diabetes. However, we do Although fertility is not an immediate con- not have data regarding the potential long-term cern, it is likely that metformin will increase the effects of the drug in patients treated for the frequency of ovulation, thereby improving men- polycystic ovary syndrome, in whom therapy, if strual cyclicity. Once menstrual cyclicity has im- effective, may be continued for many years. If a proved, I would determine whether ovulation is woman were to become pregnant, it is unclear occurring by measuring the serum progesterone whether metformin should be continued during level during the presumed luteal phase. Since the pregnancy and, if so, for how long.
patient does not tolerate oral contraceptives, a barrier method of contraception could be recom- mended. When and if the patient desires preg- nancy, fertility may be improved if the frequency The recent position statement of the Androgen of ovulation increases during metformin therapy. Excess Society53 recommends that women with If not, the patient should be evaluated for causes the polycystic ovary syndrome, regardless of of infertility unrelated to anovulation, and the weight, be screened for glucose intolerance with addition of clomiphene to her regimen should be the use of a glucose-tolerance test at the initial discussed.
presentation and every 2 years thereafter. It notes I would see the patient every 3 months during that the use of metformin to treat or prevent the first year, not only to monitor the efficacy of progression to impaired glucose tolerance may metformin but also to reinforce lifestyle changes be considered but should not be mandated until to reduce weight and increase physical activity. there have been well-designed randomized, con- Thereafter, she could be seen every 6 to 12 months, trolled trials demonstrating efficacy. A position depending on the response to treatment. Given statement of the American Association of Clin- that she is at high risk for diabetes, I would repeat ical Endocrinologists54 recommends that met- the oral glucose-tolerance test every 2 to 3 years, formin be considered the initial intervention even if metformin therapy is used.
in most women with the polycystic ovary syn- Supported by grants from the National Institutes of Health drome, particularly those who are overweight or (R01HD035629, K24D040237, and D43TW007692).
No potential conflict of interest relevant to this article was 1. The Rotterdam ESHRE/ASRM-Spon-
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more than 50 distinct clinical collections, which can be used as convenient entry points to clinical content. In each collection, articles are cited in reverse chronologic order, with the most recent first. n engl j med 358;1 www.nejm.org january 3, 2008 The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF CHICAGO LIBRARIES on May 23, 2013. For personal use only. No other uses without permission. Copyright 2008 Massachusetts Medical Society. All rights reserved.
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