Polycystic Ovarian Syndrome

Polycystic Ovarian Syndrome

697-704_TJNP716_Ruby_CP 10/2/08 11:02 AM Page 697 Polycystic Ovarian Syndrome An Evidence-Based Approach to Reducing Metabolic Consequences Laura ...

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Polycystic Ovarian Syndrome An Evidence-Based Approach to Reducing Metabolic Consequences Laura A. Ruby ABSTRACT Polycystic ovarian syndrome (PCOS) is an endocrine metabolic disorder seen in women that continues to perplex health care providers.This confusion exists, in part, because the disorder has a wide spectrum of phenotypic expression, which lends itself to variable clinical presentation.The presence of suboptimal diagnostic criteria leads to further confusion in the respect that insulin resistance, which is thought to be the underlying pathophysiologic condition associated with PCOS, is not addressed in the current diagnostic guidelines.This is evidenced by the fact that women with PCOS have a significantly higher rate of impaired glucose tolerance, type 2 diabetes, and other associated disorders such as dyslipidemias, hypertension, and potentially, cardiovascular disease. Health care clinicians need a comprehensive approach to recognize the variable clinical features associated with PCOS to ensure that high-risk women are being identified and screened early in the disease progression. Primary interventions must focus on the implementation of an evidence-based approach aimed at reducing the cardiometabolic consequences of PCOS, thus preventing progression to type 2 diabetes and potentially, cardiovascular disease. Keywords: Amenorrhea, cardio-metabolic risk, hirsutism, insulin resistance

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OVERVIEW Polycystic ovarian syndrome (PCOS) is an endocrinemetabolic disorder seen in women that continues to perplex health care providers.This confusion exists, in part, because the disorder has a wide spectrum of phenotypic expression, which lends itself to variable clinical presentation.1 Additionally, the presence of suboptimal diagnostic criteria leads to further confusion. Polycystic Ovarian Syndrome (PCOS), first described by Stein and Leventhal in 1935, is one of the most common endocrine disorders affecting women in their reproductive years.2 Prevalence rates from 5% to 10 % of all women in their child-bearing years are affected with this condition.3 DIAGNOSTIC CRITERIA After much debate, the 1990 National Institute of Health Conference proposed the following minimal criteria for the diagnosis of polycystic ovarian syndrome: menstrual irregularity due to oligomenorrhea and/or annovulation, and evidence of hyperandrogenism, either clinical (hirsutism, acne, and male pattern balding) and/or biochemical (elevated serum androgen concentrations). Other causes of hyperandrogenism and menstrual irregularity such as congenital adrenal hyperplasia, androgen-secreting tumors, and hyperprolactinemia, must be excluded.4 The guidelines were re-examined by the Rotterdam Consensus Workshop in 2003 and revised to include polycystic ovaries by ultrasound (as defined by enlarged ovaries with at least 12 follicles).5 At least 2 of the 3 listed clinical manifestations must be present to confirm the medical diagnosis of POCS. Despite this revision, much controversy remains around the current diagnostic criteria for PCOS (Table 1). Menstrual Irregularities The menstrual irregularity associated with PCOS typically begins in the peripubertal phase.The onset of menses may be delayed or an irregular pattern may emerge. Oligomennorhea (fewer than 9 menstrual periods per year) or amenorrhea (no menses for 3 or more consecutive months) can occur.Typically, the menstrual cycles are annovulatory, resulting in infertility.6 Conversely, Carmina7 reported that 15% to 20% of hyperandrogenic women with normal menses are considered to be affected by PCOS, making the diagnosis of PCOS even more challenging. Chronic annovulation in 698

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Table 1. Diagnostic Criteria for PCOS • Menstrual irregularity due to oligomenorrhea or anovulation • Hyperandrogenism, clinical (hirsutism, acne, or male pattern balding) or biochemical (elevated serum androgens) • Polycystic ovaries by ultrasound (12 or more follicles in each ovary ranging from 2 to 9 mm in diameter and/or increased ovarian volume ⬎ 10 ml) Two of three criteria are required for the diagnosis of PCOS. Other causes of hyperandrogenism, such as congenital adrenal hyperplasia, androgen-secreting tumors, and elevated prolactin, should be excluded. Adapted from the Rotterdam consensus workshop (2003).5

women with normal menses can be diagnosed by measuring serum progesterone on day 21 through 23 of the menstrual cycle. Progesterone is secreted by the corpus luteum during the luteal phase of ovulation.Although the reference range for progesterone may vary, the level should be with in the reported “luteal phase” range if ovulation occurred. Several low progesterone readings over time suggest the presence of annovulatory cycles. Infertility Infertility and annovulation may be caused by hyperinsulinism, which drives the leutinizing hormone (LH) effect on the ovarian theca cells to produce excessive androgens. Elevated serum androgens interfere with the process of follicular maturation, thus inhibiting ovulation and resulting in more arrested follicles.3 Thus, PCOS is one of the most common forms of infertility seen in females. Furthermore, PCOS is associated with a higher rate of early miscarriages and gestational diabetes.3 Excessive Androgen Production Although most women with PCOS have both clinical and biochemical evidence of androgen excess, it is important to note that not all women present with the associated skin manifestations. Clinical manifestions of hyperandrogenism occurring in up to 80% of PCOS affected women are typically suggested by the presence of hirsutism, and to a lesser extent acne and male pattern hair loss.2,3 Hirsutism is the development of androgen-dependent terminal body hair in women. Signs of severe androgen excess, however, should trigger an investigation for the presence of androgen-producing tumors.2,6 October 2008

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Other common hormonal abnormalities that may be present in women with PCOS include an elevation in metabolically active or free testosterone due to a decrease in sex hormone-binding globulin, an increased LH to FSH ratio, increased adrenal production of DHEAS, and alterations in insulin-glucose regulation.2

duction.11 In turn, excessive androgen production is responsible for the various clinical and hormonal abnormalities associated with PCOS. Obesity is typically a secondary pathogenic condition that is capable of amplifying the factors leading to exaggerated ovarian androgen secretion.11

Insulin Resistance Other Metabolic Consequences The term polycystic ovarian syndrome can be misleadIn addition to risk of diabetes mellitus, many other metaing because it implies that the ovaries are responsible bolic consequences are reported in PCOS-affected for the underlying pathologic condition, when in fact, females.Approximately 50% of women with PCOS presimpaired insulin action is the culprit. Unfortunately, ent with an android pattern of obesity.10 Insulin resistthe criteria established for the diagnosis of PCOS does ance, increased visceral adiposity, and increased waist to not address the frequently observed characteristics of hip ratio have been strongly linked with cardiovascular insulin resistance, hyperinsulinism, and obesity comdisease.13 Cardiovascular disease and atherosclerosis is now monly seen in women with PCOS.8 In fact, women considered to be an inflammatory disorder, while insulin with PCOS have a signifiresistance has been connected cantly higher rate of to increased serum inflammaimpaired glucose tolerance, tory markers. Serum concentraWhile it is clear that women ranging from 18% to 40%, tions of C-reactive protein with PCOS are subject to a with an increased prevalence (CRP) were elevated in a retroof type 2 diabetes reported spective study of 116 women variety of potential as high as 15% compared to PCOS compared a control cardiometabolic risk factors, 2.3% in the general populagroup of BMI-matched 9 tion. subject.14 Thus far, no well further investigation regarding The connection between designed random-controlled cardiovascular outcomes PCOS and impaired insulin trials are available to clarify the sensitivity has been demonpotential connection between is needed. strated in several studies. PCOS and coronary heart disThe etiology of the insulin ease. Observational data is condefect is hypothesized to be related to (1) excessive flicting.A 30-year study of women undergoing ovarian serine phosphorylation of insulin receptor;2 (2) beta wedge resection (presumed to have PCOS) failed to cell dysfunction, which increases the woman’s risk of show an increase in cardiovascular mortality despite an developing Type 2 Diabetes;2 and/or (3) decreased elevated rate of cardio-metabolic risk factors.15,16 Coninsulin signaling due to an enzyme deficiency.3 versely, the Nurses Health Study demonstrated an The presence of insulin resistance in PCOSincreased risk of nonfatal and fatal coronary disease in affected women is independent of total body fat, in women with menstrual irregularity.17 No biochemical or that both lean and obese women with PCOS may clinical data related to the participants’ androgen status demonstrate clinical or biochemical evidence of were measured, making retrospective PCOS classification insulin resistance and hyperinsulinism.6 Several impossible. descriptive studies have reinforced the connection Lipid abnormalities are frequently seen in PCOSbetween insulin resistance and PCOS, which is affected females.Abdominal obesity and insulin resistance reported as being seven-fold higher in women with alter the release of free fatty acids from adipose tissue, PCOS when compared to the rates in age- and increasing hepatic triglyceride production and suppressweight-matched women.10,12 ing high density lipoprotein production, both of which Insulin resistance and associated hyperinsulinism are proven cardiovascular risks.2 In addition, women are now considered important causative factors that with PCOS have been reported to be 4 times more may determine the excessive ovarian androgen prolikely to be treated for hypertension.13 www.npjournal.org

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Table 2. Clinical Features Clinical features of hyperinsulinism • Android pattern of obesity • Acanthosis nigricans • Excessive skin tags History of IGT, gestational diabetes, or Type 2 diabetes Absent, irregular, and/or heavy menses, suggesting annovulation Clinical evidence of excessive androgen production • Hirsutism (unwanted dark hair growth usually present on the face, upper lip, chin, neck, chest, lower abdomen, upper thighs, or back) • Acne • Male pattern balding Associated co-morbid conditions • Dyslipidemias • Hypertension • Cardiovascular disorders Infertility or history infertility assistance Women with abrupt onset of clinical symptoms, severe symptoms consistent with virilization (severe frontal balding, severe pustular acne, or clitoromegaly), or late onset of symptoms (third decade of life or later) are not typical for PCOS. Further testing to rule out other causes of hyperandrogenism should be instituted.6

While it is clear that women with PCOS are subject to a variety of potential cardio-metabolic risk factors, further investigation regarding cardiovascular outcomes is needed. IDENTIFYING HIGH-RISK WOMEN The key to successful management is identifying highrisk women early in the progression of PCOS. Many providers assume most women will present with the classic clinical features of oligomenorrhea, hirsutism, and infertility, when in fact, the clinical presentation may vary considerably among women. Not all women present with the skin manifestations of hyperandrogenism and, as previously mentioned, a subset of women with PCOS may present with regular menstrual cycles, making diagnosis even more challenging. A summary of clinical features that may be associated with PCOS is provided in Table 2. DIAGNOSTIC RECOMMENDATIONS Consideration should be given to endocrine referral for detailed hormonal testing.The endocrinologic work up for PCOS may include extensive hormonal and metabolic testing.Table 3 lists common hormonal 700

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tests used for the diagnosis of PCOS. Additionally, women with clinical or biochemical hyperandrogenism should have further testing to rule out the presence of congenital adrenal hyperplasia and/or excessive cortisol production. No consensus has been reached in determining the best measurement for insulin resistance. Many specialist use surrogate markers such as fasted insulin, C-peptide levels, or insulin levels in response to a glucose load in attempt to measure insulin resistance and hyperinsulinism.The gold standard used in many research trials to measure insulin sensitivity is the euglycemic clamp.This technique requires a continuous insulin infusion with frequent blood glucose sampling, making it impractical for clinical use.10 In reality, most women present with clinical features related to hyperinsulinism, which makes the cost-benefit value of complicated insulin testing questionable. Practice recommendations from the Rotterdam consensus meeting suggests that biochemical testing of insulin or insulin resistance is not essential to confirm the diagnosis of PCOS or to initiate treatment.18 Early screening for impaired glucose tolerance and type 2 diabetes is critical. Many women with undiagnosed PCOS present for endocrine consultation the first time at the onset of type 2 diabetes. Simply testing serum-fasted glucose levels is not adequate in screening women with PCOS and may overlook many women with existing impaired glucose tolerance.The current ADA clinical guidelines recommend the use of a 75-gram oral 2-hour glucose tolerance testing in screening high-risk individuals, such as women with PCOS.19 Additional testing should focus on other comorbid conditions such as dyslipidemias, hypertension, and cardiovascular disorders. Lifestyle Intervention Weight loss is one of the key goals for improving metabolic parameters in obese PCOS women. Obesity worsens the clinical features of PCOS and is a clinical predictor of menstrual dysfunction and hirsutism.20 Several studies have shown a relationship between weight loss and decreased abdominal adiposity, hyperandrogenism, and insulin resistance, resulting in improved menstrual regularity, fertililty, lipids, and diabetes risk factors.21-23 The Diabetes Prevention Trial (DPP) supported the benefits of aggressive lifestyle modification in individuals at high metabolic risk, showing a 58% reduction in progression to type 2 diabetes.24 October 2008

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Anecdotally, lifestyle changes are difficult for individuals to maintain, for a variety of reasons.Weight loss in PCOS-affected women is typically a difficult and slow process, making lifestyle modification extremely frustrating and difficult to adhere to. Recent evidence suggests that this difficulty with weight loss may, in part, also be related to dysregulation of appetite control25 and severe insulin resistance and hyperinsulinism.21-23 Combining insulin sensitizers with lifestyle intervention appears to be more effective than lifestyle change alone.26 Metformin Currently, insulin sensitizers such as metformin are being used for the primary treatment of PCOS. Metformin is the only insulin sensitizer approved by the FDA for PCOS. Multiple trials have demonstrated the beneficial effects of metformin in the treatment of PCOS. Metformin is an oral biguanide whose primary action is reduction of hepatic gluconeogenesis. Increased hepatogluconeogenesis is observed in the insulin-resistant state, which translates into hyperinsulinism. Metformin reduces serum insulin levels in insulin-resistant subjects without provoking hypoglycemia.27 Most commonly reported adverse effects include nausea and diarrhea, which can be minimized with an incremental dosing protocol starting at 500 mg once daily, while working up to a total daily dose of 1500 to 2000 mg.The use of an extended-release preparation and instructing women to take metformin at meal time may also decrease the incidence of side effects. Rare reports of lactic acidosis are exclusive to subjects with co-existing renal, hepatic, or heart failure.27 Iodinated contrast studies may lead to changes in renal function, which has been associated with lactic acidosis.The current recommendation is to discontinue metformin prior to the procedure or radiologic test and resume 48 hours post procedure if renal function remains normal. In 2002, the Cochrane Database published a metaanalysis on the use of insulin-sensitizing drugs for the treatment of PCOS.28 A total of 15 randomized controlled trials were included in the meta-analysis, which reflected improved ovulation and pregnancy rates, reduced fasted insulin levels, LDL cholesterol, and blood pressure in women with PCOS treated with insulin sensitizers. Metformin was found to be an effective treatment for annovulation, with some benefit on metabolic parameters. Metformin was recommended as an adjunct to, rather than a replacement for, lifestyle modification.28 www.npjournal.org

Table 3. Common Hormonal Tests Used to Diagnose PCOS Hormones Tested Pituitary Hormones

Possible Abnormalities

FSH - follicle stimulating hormone B LH:FSH ratio LH – leutinizing hormone Mild B prolactin Prolactin

Ovarian Hormones Estradiol Progesterone Free and total testosterone Sex hormone-binding globulin

B ? B ?

free estradiol progesterone free testosterone SHBG

Adrenal Hormones DHEAS 17-hydroxyprogesterone Androstenidione Cortisol

Mild B DHEAS *B17 OHP suggests adrenal source – 21 hydroxylase ? related to congenital adrenal hyperplasia

Adapted from Dunitz.2

Metformin vs Placebo: Several trials have been conducted to compare the effects of metformin versus placebo in women on body fat, fat distribution, insulin activity,and biochemical and clinical markers of hyperandrogenism. All of the metformin-treated groups demonstrated a significant reduction in body weight and BMI, with improved menstrual regularity.The reported benefit in clinical hirsutism, however, varied among the studies.26-34 Metformin Only: Twenty-four women with PCOS were studied for the “before and after” effects after an 8week course treatment with metformin. Spontaneous menstruation returned in 81% percent of the subjects.A significant decrease in waist circumference and increased insulin sensitivity were reported. No difference in the hirsutism score was noted after treatment with metformin.30 Metformin vs Oral Contraceptives: Few studies have compared the effects of oral contraceptives (OCs) with insulin sensitizers. Papenu et al35 compared the effect of OCs versus metformin on various clinical outcomes in 32 women with PCOS. Treatment outcomes after 6 months demonstrated a statistically significant decrease in waist/hip ratios, hyperandrogenism, and insulin resistance, with improved menstrual cyclicity with the metformintreated group compared to superior effects on clinical The Journal for Nurse Practitioners - JNP

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features of hyperandrogenism (acne and hirsutism) in the OC-treated group. Conversely, a different trial suggested that metformin is as efficacious as oral contraceptive in the improvement of subjective and objective reports of hirsutism.36 Similarly, both studies report increased insulin resistance and worsening glycemic control in the oral contraceptive treatment groups.35,36 In general, metformin has consistently shown to decrease body weight and BMI and has shown improvement in menstrual cyclicity, insulin sensitivity, and glycemic patterns in women with PCOS, independent of body weight.26-34 Improved menstrual regularity with restoration of ovulatory cycles occurs in approximately 50% of women treated with insulin sensitizers alone.31 Women who are not interested in conception must be advised to use some form of birth control to avoid unplanned pregnancy due to metformin’s potential impact on ovulation. Despite the fact the metformin is classified as a pregnancy category B drug, its use in pregnancy remains controversial. Several small observational studies have suggested that the use of metformin throughout pregnancy may decrease the occurrence of gestational diabetes37 and decrease the rate of spontaneous abortion in women with PCOS38,39 with no adverse major neonatal outcomes.40 Unfortunately, the evidence is limited and needs further investigation with controlled clinical trials. Thiazolidenediones Alternatively, the use of thiazolidenediones (TZDs) can be used in women who do not tolerate metformin or as adjuctive therapy in the treatment of PCOS-related variables. Thiazolidenediones target insulin resistance through enhanced glucose uptake in adipose and muscle tissue, causing a reduction in serum insulin levels.41 Three TZDs have been available for use, including: troglitazone, rosiglitazone, and pioglitazone.The FDA withdrew troglitazone from the market in 1999 due to reports of fatal liver toxicity.Thus far, pioglitazone and rosiglitazone have not demonstrated similar effects.41 TZD vs Placebo: The effects of varying doses of troglitazone versus placebo on the hormonal levels and glycemic patterns were measured in women with PCOS. Significant decreases in serum androgens, clinical hirsutism, and nearly all glycemic parameters were noted.42 Unfortunately, trogliti702

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zone was eventually pulled from the market due to excessive liver toxicity. TZD Only A “before and after” study investigated the effects of pioglitazone on metabolic and hormonal outcomes in a small group of women with PCOS. Outcomes showed improved insulin response, decreased serum androgens, and decreased LH response after 60 days of treatment.41 Thiazoledinediones vs Metformin A comparison of metformin and pioglitazone in 52 women with PCOS revealed improved insulin resistance and glycemic patterns in both treatment groups. Similar effects in serum androgens and hirsutism were noted in both groups. Despite improved insulin resistance, a statistically significant increase in body weight, BMI, and waist-hip ratios were noted in the pioglitazone-treated group.43 Yilmaz et al44 also compared the effects of metformin to rosiglitizone in 96 women with PCOS. Both drugs decreased serum androgens however, clinical hirsutism was significantly reduced by 40% in the rosiglitazone group compared to only 19% in the metformin group. Again, BMI increased in the rosiglitazone group, with no detrimental impact on insulin and glycemic parameters. In summary,TZDs have similar effects on insulin and glycemic patterns compared to metformin, with several studies reporting superior effects on hyperandrogenism. One major disadvantage of TZDs, which may limit its use in PCOS, is increased body weight, which can be considerable in some women. In addition to increased weight gain and BMI, the potential for liver toxicity requires long-term monitoring of liver function.Thiazolidenediones are pregnancy category C drugs and therefore should not be used in women attempting or at risk for pregnancy. SECONARY INTERVENTIONS Secondary interventions for PCOS focus on the management of menstrual irregularities, infertility, and hyperandrogenism. Menstrual Irregularities Oral contraceptives, containing low doses of synthetic estrogens and progestins, which inhibit the ovulatory October 2008

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process, have been traditionally used to manage menstrual irregularities associated with PCOS in women not interested in conception.45 Despite the potential risks related to coronary and venous thrombosis, and the possible affects on insulin-glucose regulation, the relative risk of low-dose oral contraceptives is thought to be low in non-smoking young females.46 Considerable concern, however, should be given to the potential impact oral contraceptives may exert in women already at high metabolic risk.

that terminal hair follicles have a 6-month lifespan, hence, improvement of clinical hyperandrogenism may take 6 to 9 months to be actualized. The treatment of hirsutism can be a frustrating challenge to women as well as to their providers. Most women will need a combination of some form of mechanical hair removal in addition to pharmacologic treatment. Expensive laser treatments should be avoided until the underlying pathologic conditions, insulin resistance and hyperandrogenism, have been addressed. Unfortunately, most women will not achieve permanent Significant improvement in hair removal, but will more serum androgens, as well as likely experience a decrease in hirsutism scores, are observed the severity their hirsutism in subjects treated with over time.

Fertility Clomiphene citrate has been typically used as first-line therapy for restoration of fertility in women affected with PCOS. Previous studies suggesting the use combined anti-androgen drugs such as metformin and clomiphene IMPLICATIONS FOR PRACTICE oral contraceptives and have been challenged by more While insulin resistance is not spironolactone. recent studies showing part of the current diagnostic improved fertility with a criteria for PCOS, its clinical three-fold increase in birth impact cannot be ignored.Tra47 rate with clomiphene alone. Again, more clinical trials ditional treatment of PCOS centers on short-term sympare needed to clarify the conflicting evidence. tom management and does not address the underlying pathophysiology that places PCOS-affected women at Hyperandrogenism high cardiometabolic risk. In fact, the mainstay of tradiExisting treatment of clinical hyperandrogenism, such as tional therapy, oral contraceptives, has been shown to hirsutism, acne, and male pattern hair loss has heavily worsen insulin resistance and impaired glucose tolerance relied on suppressing ovarian and adrenal androgen proin some women with PCOS. duction.While metformin use is associated with a PCOS is a significant health care problem seen by decrease in serum-free testosterone, only minimal providers in many health care settings. Health care cliniimprovement in clinical hirsutism is seen.28 Spironolaccians need a comprehensive approach to recognize the tone blocks androgens receptors, while oral contracepvariable clinical features associated with PCOS to assure tives suppress ovarian androgen production. Drosperithat high-risk women are being identified and screened none, found in the oral contraceptives YAZ and Yasmin, early in the disease progression. Primary interventions is the only progestin with antiandrogenic affects must focus on the implementation of an evidence-based approved by the FDA for use in the United States.46 approach aimed at reducing the cardio-metabolic conseAndrogen antagonists such as Finasteride, are infrequences of PCOS, thus preventing progression to type 2 quently used due to the potential occurrence of severe diabetes and potentially, cardiovascular disease. Secondary adverse effects. Finasteride is a pregnancy category X interventions focus on restoration of normal menses, fertildrug due to its association with severe fetal defects and ity, and treatment of hyperandrogenism, while paying close should be avoided in all women of child-bearing age.45 attention to the emotional needs of the PCOS patient. Significant improvement in serum androgens, as well Much of the research available to guide the evidenceas hirsutism scores, are observed in subjects treated with based approach of PCOS is based on small experimental anti-androgen drugs such as oral contraceptives and studies or observational trials, making the generalizability spironolactone.46 Providers need to reinforce the fact of much of the evidence limited. Clearly, more investigawww.npjournal.org

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tion is needed to better understand and manage the underlying cardio-metabolic consequences associated with this potentially life-altering disorder.

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31. References 1. Chang R. The reproductive phenotype in polycytic ovary syndrome. Nat Clin Pract Endocrinol Metab. 2007;3(10):688-695. 2. Dunitz M. Polycystic ovarian syndrome. Boston: Blackwell Science, Inc. 2001. 3. Dhindsa G, Bhatia R, Bhatia V. Insulin resistance, insulin sensitization and inflammation in polycystic ovarian syndrome. J Postgrad Med. 2004;50(2):140144. 4. Zawadski JK, Dunaif A. Diagnostic criteria for polycystic ovarian syndrome: towards a rational approach. In: Dunaif A, Givens JR, Haseltine FP, Merriam GE, editors. Polycystic ovary syndrome. Boston: Blackwell Scientific Publications; 2001, 1192:337. 5. Rotterdam ESHRE/ASRM - Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria & long term health risks related to polycystic ovarian syndrome. Hum Reprod. 2004;19:41-47. 6. Barbieri R, Ehrmann D. Clinical manifestations of polycystic ovarian syndrome. UpToDate [serial online]. 2007;Version 16.1:5/8/08. Available from: http://www.uptodate.com/. Accessed May 18, 2008. 7. Carmina E. Diagnosing PCOS in women who menstruate regularly. Contemporary Obstet Gynecol. 2003;48:53-64. 8. Ehrman DA. Polycystic ovary syndrome. New Engl J Med. 2005;352:1223. 9. Ehrman DA, Barnes R, Rosenfiled R, Cavaghan M. The prevalence of impaired glucose tolerance and diabetes in women with polycystic ovarian syndrome. Diabetes Care. 1999;22:141 10. Bhatia V. Insulin resistance in polycystic ovarian disease. South Med J. 2005;98(9):902-909. 11. Pasquali R, Gambineri A. Insulin-sensitizing agents in polycytic ovary syndrome. Eur J Endocrinol. 2006;154:1360-1365. 12. American Association of Clinical Endocrinologists Polycystic Ovary Syndrome Writing Committee. American association of clinical endocrinologists position statement on metabolic and cardiovascular consequences of polycystic ovary syndrome. Endocr Pract. 2005;11:126-134. 13. Hopkinson Z, Sattar N, Fleming R, Greer I. Polycystic ovarian syndrome: the metabolic syndrome comes to gynecology. BMJ. 1998:1-13. 14. Boulman N, Levy Y, Leiba R. Increased C-reactive protein levels in the polycystiv ovarian syndrome: marker of cardiovascular disease. J Clin Endocrinol Metabol. 2004;89:2160. 15. Pierpoint T, McKeigue, PM, Isaacs AJ, et al. Mortality of women with polycystic ovarian syndrome at long-term follow up. J Clin Epidemiol. 1998;51:581. 16. Wild S, Pierpoint T, McKeigue P, Jacobs H. Cardiovascular disease in women with polycystic ovary syndrome at long-term follow up: a retrospective cohort study. Clin Endocrinol. 2000;52:595. 17. Solomon CG, Hu FB, Dunaif A, et al. Menstrual cycle irregularity and risk for future cardiovascular disease. J Clin Endocrinol Metab. 2002;87:2013. 18. Rotterdam ESHRE/ASRM - Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risk related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004;19:41. 19. American Diabetes Association. Clinical practice recommendations 2005. Diabetes Care. 2005;28(Suppl 1):S1-79. 20. Laitinen J, Toponen S, Martikainen H, et al. Body size from birth to adulthood as a predictor of self reported polycystic ovarian syndrome symptoms. Int J Obes Rel Metabol Disord. 2003;27:710-715. 21. Douglass C, Gower B, Darnell B, Ovalle F, Oster R, et al. Role of diet in the treatment of polycystic ovary syndrome. Fertil Steril. 2006;85(3):679-688. 22. Moren L, Brinkworth G, Noakes, M, Norman R. Symposium: diet, nutrition and exercise in reproduction. Effects of lifestyle modification in polycystic ovarian syndrome. Reprod BioMed. 2006;12(5):569-578. 23. Pasquali R, Antenucci D, Casimirri F, et al. Clinical and hormonal characteristics of obese and amenorrheic women before and after weight loss. J Clin Endocrinol Metab. 1989;68:173. 24. Golderg R, Haffner S, Ratner R, Marcovina S, Fowler S. The effect of metformin & intensive lifestyle on the metabolic syndrome: the diabetes prevention program randomized trial. Annal Intern Med. 2005;142:611. 25. Hirschberg A, Naessen S, Stridberg M, et al. Impaired cholecystokinin secretion and disturbed appetite regulation in women with PCOS. Gynecol Endocrinol. 2004;19:79-87. 26. Pasquali R, Gambineri A, Biscotti D, Vicennati V, Gagliardi L, et al. Effect of long-term treament with metformin added to hypocaloric diet on body compostion, fat distribution, and androgen and insulin levels in abdominally obese women with and without the polycystic ovary syndrome. J Clin Endocrinol Metab. 2006;85(8):2767-2774. 27. Lam P, Cheung L, Haines C. Revisit of metformin treatment in polycystic ovarian syndrome. Gynecol Endocrinol. 2004;19:121-128. 28. Lord J, Flight I, Norman R. Insulin sensitizing drugs for polycystic ovarian syndrome. Cochrane Database Syst Rev. 2004;3:1-117. 29. Moghetti P, Castello R, Negir C, et al. Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary

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Laura A. Ruby, MS, CRNP,ACNP, is an endocrinology nurse practitioner at Wellspan Endocrinology in Gettysburg, PA. She has a special interest in managing women with PCOS and other pre-diabetic conditions. She can be reached at [email protected] In compliance with national with national ethical guidelines, the author reports no relationships with business or industry that would pose a conflict of interest. 1555-4155/08/$ see front matter © American College of Nurse Practitioners doi:10.1016/j.nurpra.2008.08.007

October 2008