CLINICAL OBSTETRICS AND GYNECOLOGY Volume 54, Number 4, 675684 r 2011, Lippincott Williams & Wilkins

Polycystic Ovary Syndrome: Current Infertility Management

MIRA AUBUCHON, MD* and RICHARD S. LEGRO, MDw *Department of Obstetrics, Gynecology, and Womens Health, University of Missouri School of Medicine, Missouri Center for Reproductive Medicine and Fertility, Columbia, Missouri and w Department of Obstetrics and Gynecology, Penn State University College of Medicine, MS Hershey Medical Center, Hershey, Pennsylvania
Abstract: This review summarizes the diagnosis of polycystic ovary syndrome and management of associated infertility. The goal is to guide clinicians through basic evaluation, initial treatment, and briefly describe more complex therapies. Key words: polycystic ovary syndrome, PCOS, infertility, ovulation

Case Report
Ms B is a 30-year-old nulligravid white woman who has been attempting conception for 6 months without success, prompting referral to a reproductive endocrinology/infertility specialist. Before attempting conception, she was taking oral contraceptives since age 16. She experienced normal pubertal milestones and had menarche at age 14, but subsequent menses came only 3 to 4 times per year, for which oral contraceptives were prescribed. She cycled normally on oral
Correspondence: Richard S. Legro, MD, Penn State University College of Medicine, MS Hershey Medical Center, Department of Obstetrics and Gynecology, H103, RM C3604, 500 University Drive, Hershey, PA 17033. E-mail: rsl1@psu.edu Conflict of interest disclosures can be found on page 682.
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contraceptives, but since discontinuing them 6 months ago she has had only 2 menses. Over the past 3 years she has gained 40 pounds, which she attributes to a more sedentary lifestyle and eating a lot of junk since she got married. Ever since she was a teenager she has noticed some chin and abdominal hair but this has worsened since she stopped her oral contraceptive such that she shaves her chin weekly. Otherwise her past medical and surgical histories are negative, and she takes only a prenatal vitamin with folic acid. She is a nonsmoking grade school teacher who avoids alcohol and recreational drugs and has had only 1 lifetime sexual partner, has had normal cervical cytology screening within the last year, and denies any sexually transmitted infections. An only child, her family history is notable for type 2 diabetes in multiple members. Ms Bs husband Mr B is a 31-year-old nonsmoking white investment banker who has not previously fathered children. Aside from being overweight, past medical and surgical histories are negative, and he does
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Aubuchon and Legro well as metabolic syndrome. Tubal patency evaluation was offered but the couple opted to avoid invasive testing in favor of medical therapy. The patient was encouraged to lose weight before conception through improved nutrition and exercise. Metformin starting at 500 mg daily was begun and increased by 500 mg/d/wk until a goal dose of 2000 mg daily was reached,3 along with oral medroxyprogesterone acetate 10 mg for 10 days to initiate a withdrawal bleed. From cycle days 3 to 7, she took clomiphene citrate 50 mg. She failed to ovulate by urine predictor kits and cervical mucus changes, confirmed with a day 21 serum progesterone level <3 ng/mL. Subsequently the dose of clomiphene was increased to 100 mg, which did result in ovulation. She conceived with her third cycle of clomiphene 100 mg and metformin cotreatment and timed intercourse. Metformin was discontinued once pregnancy was diagnosed and she is now at 18 weeks gestation with a singleton viable fetus.

not take any medications. He reached pubertal milestones with his peers and denies any history of libido problems, or erectile or ejaculatory dysfunction. He also counts his wife as his only lifetime sexual partner, and denies any sexually transmitted infections. Mr B drinks a glass of wine once to twice weekly, avoids recreational drugs, and his family history is unremarkable. Physical examination of Ms B indicated a body mass index (BMI) of 36 kg/ m2 and blood pressure of 110/80. She had normal scalp hair distribution and texture but coarse upper lip, chin, lower back, lower abdomen, and inner thigh hair, with a total modified Ferriman-Gallwey score of 13. Examination of the thyroid and breasts was normal and she had no abdominal striae. Her external genitalia appeared normal without clitoromegaly. Uterine and ovarian sizes were difficult to assess on bimanual examination. Laboratory testing performed on Ms B indicated a negative serum human chorionic gonadotropin, dehydroepiandrosterone sulfate 280 mcg/dL (normalr275 mcg/dL), and total testosterone 90 ng/dL (normalr88 ng/dL).1 Normal parameters were found for 17 a-hydroxyprogesterone, thyroid stimulating hormone, prolactin, renal panel, and hepatic function panel. Her 2-hour glucose tolerance test (75 g load) was normal, but lipids indicated elevated triglycerides 200 mg/dL (normalr150 mg/dL) and low high-density lipoprotein cholesterol 31 mg/dL (normalZ50 mg/dL).2 Transabdominal ultrasound indicated a normal-sized anteverted uterus with endometrial thickness of 0.8 cm and ovaries each having more than 15 follicles <10 mm and volumes of 12 to 15 cm3. There were no developing or dominant follicles and no functional cysts. Semen analysis that included assessment of strict morphology of Mr B showed all parameters to be normal. Ms B was given the diagnoses of primary infertility owing to anovulation and polycystic ovary syndrome (PCOS), as www.clinicalobgyn.com

Introduction
PCOS is a heterogeneous disorder affecting at least 7% of the adult female population1 and is the leading cause of anovulatory infertility.4 The cardinal features of polycystic ovary syndrome are oligo-ovulation, hyperandrogenism, and polycystic ovary morphology. As infertility is the focus of this article, the phenotype that will most occupy us is the anovulatory one. There are little data to suggest that hyperandrogenism or polycystic ovaries per se are either a cause of or associated with infertility. In addition, as infertility involves a couple and ovulation is just 1 component, a comprehensive infertility evaluation should precede ovulation induction. For example, in the Pregnancy in Polycystic Ovary Syndrome (PPCOS) study, 5% of women with PCOS had bilateral tubal occlusion and 10% of male

PCOS and Infertility partners had severe oligospermia, prompting study exclusion and referral for treatment.3

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Diagnosis and Workup of PCOS

Diagnosis of PCOS by both the Rotterdam and Androgen Excess and PCOS Society criteria requires at least 2 of the following 3: anovulation typified by r9 menses per year, hyperandrogenic symptoms or hyperandrogenemia, and polycystic ovary morphology on transvaginal ultrasound.46 Other potential etiologies must be excluded such as thyroid disease, hyperprolactinemia, ovarian failure, androgen secreting tumors, and congenital adrenal hyperplasia.46 Common hyperandrogenic symptoms include acne and/or hirsutism with a modified Ferriman-Gallwey score Z6, usually owing to increased midline androgen-dependent hair growth, and less commonly androgenic alopecia, whereas laboratory testing may indicate elevated levels of total or bioavailable testosterone and dehydroepiandrosterone sulfate.46 Follicular phase ultrasound suggests polycystic ovary morphology when either ovary has Z12 follicles each <10 mm diameter or when the volume of either ovary is Z10 cm3, in the absence of dominant follicles or large ovarian cysts.46 An elevated luteinizing hormone to follicle stimulating hormone ratio is not required as false negative findings can occur owing to the pulsatile nature of these hormones and the attenuated ratios frequently seen with obesity.4 BMI is not used for diagnosis as PCOS is present in both lean and obese women.4 However, obesity exacerbates the condition.4 The pathophysiology remains unknown, but likely involves multiple organ system dysfunction at the hypothalamus, pituitary, ovary, adrenal gland, liver, adipose, and skeletal muscle, exacerbated by defective

postreceptor insulin action.4,7 Other workup should address metabolic sequelae of PCOS such as hyperlipidemia, hypertension, nonalcoholic fatty liver, and glucose intolerance.2 Patients should additionally be screened for sleep disorders and depression.2 Although many patients with PCOS are insulin resistant, insulin resistance testing is not routinely recommended owing to a lack of standardized screening, variation of normal results by population, and unknown predictive value regarding who will respond to treatment.7

Ovulation Induction
NO TREATMENT

Spontaneous ovulation in PCOS does occur, but infrequently. Over the course of 12 weeks, ovulation occurred in 32% of PCOS menstrual cycles with a median time of 67 days to first ovulation in placebo-treated participants in the Troglitazone in PCOS trial.8 Although ovulation frequency increases as PCOS women age, they are less likely to conceive and deliver a baby.9
WEIGHT LOSS

Preconceptual weight loss of 5% to 10% is often recommended as first-line therapy to promote ovulation and conception and improve obstetric outcomes for overweight and obese women with PCOS, with the caveats that the weight loss must occur before infertility therapy and that supporting studies are limited by sample size, most are uncontrolled, and few address live birth rates.2,10,11 No specific dietary composition seems superior, so a moderate 500 to 1000 kcal daily reduction in intake is reasonable.10,11 Concurrent moderate exercise of at least 30 minutes daily may improve ovulation rates independently of weight loss but has not definitively improved reproductive outcomes.10,11 Bariatric surgery www.clinicalobgyn.com

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Aubuchon and Legro However in a recent randomized trial the multiples rate has been r5%.3 It is considered first-line medical therapy for anovulatory infertility in PCOS.3,10,12 After spontaneous or progesterone-induced menses, dosing typically starts at 50 mg daily beginning cycle day 2 to 5 and continues for 5 days, and ovulation can be confirmed with luteal phase progesterone levels.3,10 Dosing increases by 50 mg increments to a maximum daily dose of 150 mg per cycle until ovulation is achieved, after which it is continued for a maximum of 6 ovulatory cycles.10,3 Higher doses up to 250 mg have also been used to achieve ovulation although this is done off-label.13 For patients of advanced reproductive age or those who have not achieved conception within 6 cycles, further clomiphene cycles can be used but consideration should be given for more aggressive therapies10 and referral to a reproductive specialist is suggested (Fig. 1). The role of progestin withdrawal after an anovulatory cycle remains uncertain, and protocols have been used that do

induces dramatic weight loss that improves PCOS symptoms but is not considered a first-line therapy as its effects particularly on early pregnancy are unknown.10 Although not approved for weight loss, the insulin sensitizer metformin may induce a modest 2 kg loss over 6 months of use, but this may not be sustainable over the long term,4,12 nor has the weight loss secondary to metformin been associated with improved pregnancy rates.12
CLOMIPHENE CITRATE

Clomiphene citrate is an oral agent approved for ovulation induction that acts to inhibit estrogen at the hypothalamus, prompting increased pituitary gonadotropin secretion to promote follicular growth.4 Side effects include hot flashes, mood changes, headaches, rare visual disturbances prompting discontinuation, and rare ovarian hyperstimulation syndrome (OHSS).4,10 Treatment is generally associated with B8% multiple pregnancy rate, of which B1% is triplets or more.4

FIGURE 1. syndrome.

Algorithm for initial PCOS infertility therapy. PCOS indicates polycystic ovary

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PCOS and Infertility not routinely use progestin withdrawals but continue to achieve acceptable pregnancy rates.3,14 During the randomized placebo-controlled PPCOS trial, 43% of clomiphene users experienced ovulation in the first month of therapy and 49% over the course of 6 months, with B2 ovulations per participant.3 Clomiphene led to a live birth rate of 23% over 6 months of use.3 This trial is quoted throughout this review because it remains the only trial of clomiphene and metformin specifically designed and powered to address live birth outcomes.
METFORMIN

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COMBINATION CLOMIPHENE AND METFORMIN

Metformin is an oral insulin sensitizer approved for the treatment of type 2 diabetes mellitus and glucose intolerance, but is widely used off-label for ovulation induction in PCOS patients. The mechanisms of this action include decreased circulating androgens and insulin, increasing sex hormone binding globulin, and potentially direct effects on the hypothalamus or ovary.4 Side effects include gastrointestinal disturbance, which may be ameliorated with extended release formulations and caution should be used in patients with renal or hepatic dysfunction to avoid rare instances of lactic acidosis.10 Dosing typically begins at 500 mg daily which is then gradually increased in 500 mg increments by week up to a maximum dose of 1500 to 2000 mg.3,13,15 In the PPCOS trial, ovulation rates for metformin users were 22% in the first month and 29% over 6 months, with 1 ovulation per participant.3 This improvement in ovulation is similar to that seen with lifestyle modification regimens.10 An advantage of therapy is that multiple pregnancy rates are not increased, but the live birth rate over 6 months was only 7%.3 Metformin monotherapy may allow higher ovulation and pregnancy rates in women with nonobese BMI, but still does not seem superior to clomiphene.12

When PPCOS trial participants took both clomiphene and metformin, ovulation rates were dramatically higher than clomiphene at 52% in the first month and 60% over 6 months, with B3 ovulations per participant.3 However, the live birth rate over 6 months was B27%, which was not statistically different from clomiphene alone and illustrates that ovulation is not an appropriate surrogate marker for live birth.3,12 Certain subgroups may benefit from combined therapy (Fig. 2). Combined therapy was associated with higher live birth rates in participants with BMI Z 35 and less-severe hirsutism (modified FerrimanGallwey score <6).9 Clomiphene alone and the combined groups whose participants were rage 34, had mild hirsutism (score <8), and had been attempting conception for <1.5 years had the highest cumulative rates of live birth at >60%.9 However, the benefit of combined therapy on live birth rates has been debated in the literature, with some meta-analyses finding no benefit.12
THIAZOLIDINEDIONES

Alternative insulin sensitizers such as pioglitazone and rosiglitazone have also been used in PCOS for ovulation induction to avoid metformin-associated side effects, but the associated weight gain, less favorable pregnancy profile, and possible cardiovascular risk limit their use for this purpose.12 They remain off-label, experimental, unproven therapies for infertility.
AROMATASE INHIBITORS

Aromatase inhibitors such as letrozole or anastrazole decrease estradiol production at the ovary, decreasing the negative feedback on the pituitary and stimulating gonadotropin release to promote ovulation.15 These are used off-label for PCOS www.clinicalobgyn.com

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FIGURE 2. Estimated live birth rates for combined clomiphene and metformin (COM) versus clomiphene alone (CC). Black >40%, White 20% to 40%, Hatched <20%. Hirsute low (modified Ferriman-Gallwey <8), high (>16). A, Infertility <1.5 years. B, Infertility Z1.5 years. Adapted from Rausch et al.9

ovulation induction with excellent tolerability and may be advantageous over clomiphene in terms of reduced multiple gestation.16 A recent phase II, prospective, randomized, double-blind, multicenter, dose-finding, noninferiority study found lower ovulation rates with 5 days of anastrazole up to 10 mg daily compared with clomiphene 50 mg, but comparable pregnancy rates when ovulation did occur.16 Therefore, efficacy concerns, controversial safety, and cost indicate that further large randomized trials of other aromatase inhibitors and pregnancy outcomes are needed before routine www.clinicalobgyn.com

use can be recommended. However, they can still be considered provided that the patient is informed of the risks and benefits,10 particularly in the setting of clomiphene resistance (discussion follows).

TREATMENT WITH CLOMIPHENE RESISTANCE OR CLOMIPHENE FAILURE

Previous anovulation to clomiphene monotherapy at maximal doses of clomiphene is termed clomiphene resistance, which affects 20% of PCOS patients.17 Only 10% will ovulate after readministration of

PCOS and Infertility clomiphene,18 so additional therapies have been suggested. At this point, referral to a reproductive specialist is suggested. The alternative to the therapies that follow is limited to assisted reproductive technologies such as in-vitro fertilization (IVF) (Fig. 1). Lifestyle modification alone does not appreciably improve ovulation rates in clomiphene resistance.18 However, the addition of clomiphene after 2 weeks of lifestyle modification, which was continued for a total of 6 weeks, led to ovulation rates of 38%.18 Metformin plus clomiphene in clomiphene-resistant patients also seems to improve per-cycle ovulation and pregnancy,12 with rates of 70% and 14%, respectively13,15 (Fig. 1). Letrozole 2.5 mg daily for 5 days starting on cycle day 3 had similar ovulation and pregnancy rates to the metformin-clomiphene combination for 3 months15 (Fig. 1). High dose dexamethasone 2 mg/day from day 3-12 in combination with clomiphene 100 mg/day 3-7 has also been reported to improve ovulation and pregnancy rates compared to clomiphene alone19, but we suggest using with caution in patients at high risk for hyperglycemia. Gonadotropin injections are typically offered to patients who have not ovulated with oral therapies (Fig. 1). Live birth rates over 6 cycles of therapy are reported to be 60%.17 However, multiple pregnancy rates are estimated at 16% and therapy is associated with a 16% to 40% cancellation rate owing to excessive follicle development and concern for OHSS.17 To reduce these risks, low doses of follicle stimulating hormone starting at 37.5 to 75 units and slow increases are recommended to achieve monofollicular growth.10 The injections are expensive, and unlike oral therapies ultrasound and estradiol monitoring are necessary to adjust stimulation dose and determine if cancellation is needed.10 Therefore, the treatment carries substantial out of pocket cost for the patient.17

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Laparoscopic ovarian drilling involves small holes drilled by cautery or laser into the ovarian stroma and is thought to improve ovulation through decreasing ovarian androgens and subsequent favorable pituitary gonadotropin response, thus improving the hormonal milieu surrounding the follicles.17 Cumulative live birth rates were similar after 6 months of diathermy compared with combined clomiphene-metformin in a small study13 so it may be worthwhile trying the combined therapy before proceeding to surgery (Fig. 1). In fact, surgery is typically offered when the only remaining alternative is gonadotropin therapy.17 A meta-analysis indicated that ovulation and live birth rates were similar in the 6 to 12 months after drilling as compared with 3 to 6 cycles of gonadotropin therapy, regardless of whether adjunctive clomiphene or gonadotropin therapy was used.17 Multiple pregnancy rates are lower than for gonadotropins, estimated at 1% to 10% depending on what adjunctive therapies if any were used.17 Risks include postsurgical ovarian adhesions and concern for premature ovarian failure in addition to the risks from laparoscopic surgery itself.10

Obstetric Risk and PCOS

Independent of obesity, PCOS patients are at higher risk of gestational diabetes, pregnancy-induced hypertension, preeclampsia, and preterm birth.4 They may also be at increased risk for pregnancy loss,4,20 though increased pregnancy loss rates have not been noted in randomized trials.12 Obesity may further exacerbate pregnancy risks in addition to PCOS. Women with PCOS should be counseled about these risks before pregnancy. However the best method to prevent these complications is unknown. www.clinicalobgyn.com

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Aubuchon and Legro during IVF.10 Multiple pregnancy is by and large associated with the number of embryos transferred, Therefore, IVF allows for more control to transfer fewer or even a single embryo to minimize this risk.10 Reassuringly, PCOS patients do not have an increased risk of IVF failure and in fact pregnancy rates per cycle are similar to non-PCOS patients at B35%.10

METFORMIN TREATMENT DURING PREGNANCY

Metformin is considered safe in pregnancy with a Food and Drug Administration Category B designation.4 Given the known efficacy of metformin to improve type 2 diabetes, impaired glucose tolerance, and gestational diabetes, as well as nonrandomized reports indicating reduced miscarriage risk in PCOS,20,21 it would seem that metformin given before conception or early in pregnancy would prevent these outcomes. However, current evidence does not support this conclusion. A meta-analysis of 17 randomized controlled trials evaluating preconceptional metformin on miscarriage risk showed no benefit.20 Furthermore, metformin initiated B10 weeks gestation and continued through delivery did not improve rates of preeclampsia, preterm delivery, or gestational diabetes in a recent large, multicenter, randomized, doubleblind, placebo-controlled trial.21 Therefore, routine use of metformin for prophylaxis is not recommended.

Summary
Infertility associated with PCOS is in most cases treatable, although patients may still experience obstetric complications that are not preventable. Whenever possible, patients should be counseled to achieve a healthy weight before conception, and underlying medical conditions such as impaired glucose tolerance should also be addressed preconceptionally. In treatment-naive patients, clomiphene citrate alone is considered first-line therapy, though combination therapy with metformin may be helpful in morbidly obese and less hirsute patients. Patients should be reassessed frequently and alternative therapies or reproductive specialist referral offered if they remain anovulatory or nonpregnant after 6 cycles despite ovulation, particularly if they are of advanced reproductive age. For clomiphene-resistant patients, consideration can be given to addition of metformin, aromatase inhibitors, laparoscopic ovarian drilling, gonadotropin injections, or IVF.

Assisted Reproductive Technologies

IVF is the most common of these technologies, and involves removal of oocytes from the patient and fertilizing them in the laboratory, followed by transferring some of the resultant embryos into the patients uterus. Stimulation of the ovaries requires gonadotropin injections and additional medications in the form of gonadotropin releasing hormone analogs that are given to prevent premature ovulation and human chorionic gonadotropin given 36 hours before oocyte retrieval to allow oocyte maturation. As with gonadotropins used for ovulation induction, IVF is associated with risks of OHSS and multiple gestations and as such, cycle cancellation may be necessary.10 Metformin appears to be of benefit in reducing the incidence of OHSS www.clinicalobgyn.com

Disclosures
Conflict of Interest Disclosure for Richard S. Legro, MD: In 2010, Dr Legro received travel reimbursement from Scientific Advisory Committee and Ferring Pharmaceuticals, (Seville Spain); Korea National of Health and National Institute of Health (Bethesda, MD); American Society of Reproductive Medicine (Birmingham, AL); Obstetrics and Maternal Fetal Biology Subcommittee

PCOS and Infertility (Bethesda, MD); Agency for Healthcare Research and Quality (Bethesda, MD); American Board of Obstetrics and Gynecology (Dallas, TX); Greater Toronto Area Reproductive Medicine Society (Toronto, ON, Canada); American Congress of Obstetrics and Gynecologists (Washington, DC); American Society for Reproductive Immunology (Nemacolin Woodlands, PA); Reproductive Medical Center of Peking University Third Hospital and Asian Journal of Andrology (Beijing, China); National Institute of Child Health and Human Development Pediatric and Adolescent Gynecology Research Think Panel (Bethesda, MD); American Association for Clinical Chemistry Incorporated (Anaheim, CA); Scientific Committee International Federation of Fertility Societies (Munich, Germany); Canadian Fertility and Andrology Society (Vancouver, BC, Canada); Magee Womens Hospital (Pittsburgh, PA); The University of Illinois (Chicago, IL); European Society of Human Reproduction and Embryology (Brussels, Belgium); Asia Oceana Congress (Kuala Lumpur, Malaysia) Georgetown University Hospital (Washington, DC); Heilongjiang University (Harbin, China); and Royal College of Obstetrician and Gynecologists (London, UK). In 2010, Dr Legro received honoraria for lectures from Korea National Institute of Health and National Institute of Health (Bethesda, MD); Greater Toronto Area Reproductive Medicine Society (Toronto, ON, Canada); American College of Obstetrics and Gynecologists (Washington, DC); National Institute of Child Health and Human Development Pediatric and Adolescent Gynecology Research Think Panel (Bethesda, MD); Magee Womens Hospital (Pittsburgh, PA); University of Illinois (Chicago, IL); and Georgetown University Hospital (Washington, DC). In 2010, Dr Legro received honoraria for consulting from American Society of Reproductive Medicine (Birmingham, AL); National Institute of Child Health and Human Development (Bethesda,

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MD); and American Board of Obstetrics and Gynecology (Dallas, TX). In 2011, Dr Legro received travel reimbursement from British Fertility Society, The Association for Clinical Embryologists & Society for Reproductive & Fertility (Dublin, Ireland); First Affiliated Hospital, Heilongjiang University of Chinese Medicine (Harbin, China); The Israel Fertility Society (Herzliya, Israel); American Society of Reproductive Medicine (Birmingham, AL); University of Michigan (Ann Arbor, MI); Weill Cornell Medical College (New York, NY); Reproductive Medicine Network (Bethesda, MD); American Board of Obstetrics & Gynecology (Dallas, TX); Taiwan Society of Reproductive Medicine (Taiwan); Northwestern University (Chicago, IL); Specialized Cooperative Centers Program in Reproductive & Infertility Research (Chicago, IL); The Endocrine Society (New York, NY); V Conference Gynaecological Endocrinology (Santiago, Chile); and European Society of Human Reproduction & Embryology (Stockholm, Sweden). In 2011, Dr Lego received honoraria for lectures from Taiwan Society of Reproductive Medicine (Taiwan) and Northwestern University (Chicago, IL). In 2011, Dr Legro received honoraria for consulting from American Society of Reproductive Medicine (Birmingham, AL); National Institute of Child Health and Human Development (Bethesda, MD); and American Board of Obstetrics and Gynecology (Dallas, TX).

References
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