Treatment of polycystic ovary syndrome in adults

INTRODUCTION — The polycystic ovary syndrome (PCOS) is an important cause of androgen excess, menstrual irregularity, and cardiometabolic dysfunction in women. When fully expressed, the manifestations include irregular menstrual cycles, hirsutism, obesity, insulin resistance, and anovulatory infertility.

The treatment of PCOS will be reviewed here. The epidemiology and pathogenesis, diagnostic criteria, and clinical manifestations of PCOS are described in detail separately. (See "Epidemiology, phenotype, and genetics of the polycystic ovary syndrome in adults" and "Diagnosis of polycystic ovary syndrome in adults" and "Clinical manifestations of polycystic ovary syndrome in adults".)

OVERVIEW OF APPROACH — Women with PCOS have multiple abnormalities that require attention, including oligomenorrhea, hyperandrogenism, anovulatory infertility, and metabolic risk factors such as obesity, insulin resistance, dyslipidemia, and impaired glucose tolerance. Weight loss, which can restore ovulatory cycles and improve metabolic risk, is the first-line intervention for most women. Our overall approach is similar to that described by the Endocrine Society Clinical Guidelines [1] and the international guidelines for the assessment and management of PCOS [2].

Goals — The overall goals of therapy of women with PCOS include:

●Amelioration of hyperandrogenic features (hirsutism, acne, scalp hair loss)

●Management of underlying metabolic abnormalities and reduction of risk factors for type 2 diabetes and cardiovascular disease

●Prevention of endometrial hyperplasia and carcinoma, which may occur as a result of chronic anovulation

●Contraception for those not pursuing pregnancy, as women with oligomenorrhea ovulate intermittently and unwanted pregnancy may occur

●Ovulation induction for those pursuing pregnancy

Lifestyle changes — We suggest diet and exercise for weight reduction as the first step for overweight and obese women with PCOS. Available evidence suggests that lifestyle interventions (diet, exercise, and behavioral interventions) are more effective than minimal treatment for weight loss and for improving insulin resistance and hyperandrogenism [3]. In addition, there appear to be reproductive benefits as well. (See 'Weight reduction' below and 'Weight loss' below.)

Oral contraceptives and risk assessment — Combined estrogen-progestin oral contraceptives (COCs) are the mainstay of pharmacologic therapy for women with PCOS for managing hyperandrogenism and menstrual dysfunction and for providing contraception. COCs are associated with an increased risk of venous thromboembolism (VTE) in all users but particularly in obese women. There have been concerns that the presence of PCOS per se may represent an additional independent risk factor for VTE, but available data do not support this concept. (See "Clinical manifestations of polycystic ovary syndrome in adults", section on 'Venous thromboembolism'.)

Our approach to the use of COCs in women with PCOS is the same as in women without PCOS. Risk factors for VTE including obesity, patient age, and family history of VTE should be assessed. We currently suggest using caution if COCs are prescribed to obese women (body mass index [BMI] ≥30 kg/m²) over age 40 years because these women are at particularly high risk for VTE. Other relative and absolute contraindications to COC use are outlined in the Centers for Disease Control and Prevention (CDC) United States Medical Eligibility Criteria for Contraceptive Use. Alternatives to COCs include cyclic progestin therapy, continuous progestin therapy (progestin-only pills [the "mini-pill"]), or a progestin-releasing intrauterine device (IUD). Cyclic progestin therapy can induce regular withdrawal uterine bleeding and reduce the risk of endometrial hyperplasia. Both continuous progestin therapy (eg, a progestin-only pill such as norethindrone 0.35 mg/day) and the progestin-releasing IUD provide contraception and reduce the risk of endometrial hyperplasia. (See 'Endometrial protection' below and "Combined estrogen-progestin contraception: Side effects and health concerns", section on 'Cardiovascular effects'.)

Patient satisfaction with care — Women with PCOS commonly report long delays in diagnosis and dissatisfaction with their care. In a cross-sectional study of 134 women with PCOS and 198 controls without PCOS who completed an online evaluation of their health care providers, those with PCOS had less trust in their primary care providers, perceived them as less qualified to treat PCOS-related health concerns, and argued with them more often [4]. These observations highlight opportunities for improving care for women with PCOS. (See "Diagnosis of polycystic ovary syndrome in adults", section on 'Delays in diagnosis'.)

WOMEN NOT PURSUING PREGNANCY

Menstrual dysfunction

Endometrial protection — The chronic anovulation seen in PCOS is associated with an increased risk of endometrial hyperplasia and possibly endometrial cancer. (See "Clinical manifestations of polycystic ovary syndrome in adults", section on 'Endometrial cancer risk' and "Endometrial carcinoma: Epidemiology, risk factors, and prevention", section on 'Chronic anovulation'.)

We suggest combined estrogen-progestin oral contraceptives (COCs) as first-line therapy for menstrual dysfunction and endometrial protection [1,2].

COCs provide a number of benefits in women with PCOS, including:

●Daily exposure to progestin, which antagonizes the endometrial proliferative effect of estrogen

●Contraception in those not pursuing pregnancy, as women with oligomenorrhea ovulate intermittently and unwanted pregnancy may occur

●Cutaneous benefits for hyperandrogenic manifestations (see 'Androgen excess' below)

COCs affect insulin sensitivity, carbohydrate metabolism, and lipid metabolism; the effects depend upon the estrogen dose and androgenicity of the progestin. However, there is no evidence that women with PCOS are at greater risk for either metabolic adverse effects or cardiovascular complications of COCs. (See 'Metabolic effects of COCs in PCOS' below and "Combined estrogen-progestin contraception: Side effects and health concerns" and "Clinical manifestations of polycystic ovary syndrome in adults", section on 'Venous thromboembolism'.)

Absence of pregnancy should be documented before COCs are begun.

An approach to starting COCs in women with PCOS is described below (see 'Choice of oral contraceptive' below). Risks and side effects of COCs (including unscheduled bleeding) are similar to those for women without PCOS. Unscheduled bleeding and an overview of estrogen-progestin COCs are reviewed in detail separately. (See "Combined estrogen-progestin contraception: Side effects and health concerns" and "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use".)

For women with PCOS who choose not to or cannot take COCs, alternative treatments for endometrial protection are intermittent or continuous progestin therapy, or a progestin-releasing intrauterine device (IUD) [5]. In this setting, we recommend medroxyprogesterone acetate (5 to 10 mg) for 10 to 14 days every one to two months. An alternative, but one that has been less well studied, is natural micronized progesterone 200 mg (given for the same duration every one to two months). Patients should be made aware that progestin therapy alone will not reduce the symptoms of acne or hirsutism, nor will it provide contraception. However, continuous progestin therapy with norethindrone 0.35 mg daily provides both contraception and endometrial protection. This is a progestin-only contraceptive that is also referred to as the "mini-pill." An alternative progestin option that provides both endometrial protection and contraception are the levonorgestrel-releasing IUDs. (See "Intrauterine contraception: Background and device types", section on 'Levonorgestrel IUD' and "Intrauterine contraception: Candidates and device selection", section on 'Endometrial protection'.)

Metformin is a potential alternative to restore menstrual cyclicity as it restores ovulatory menses in approximately 30 to 50 percent of women with PCOS [6,7]. Its ability to provide endometrial protection is less well established, and we therefore consider it to be second-line therapy [8,9]. (See "Metformin for treatment of the polycystic ovary syndrome".)

When metformin is used, we suggest monitoring to confirm that ovulatory cycles have been established. This can be done with luteal phase serum progesterone measurements or transvaginal ultrasound. (See "Evaluation of the menstrual cycle and timing of ovulation", section on 'Assessment of ovulation' and "Metformin for treatment of the polycystic ovary syndrome", section on 'Oligomenorrhea'.)

Androgen excess

Hirsutism — Our approach to the management of hirsutism is consistent with the 2018 Endocrine Society Clinical Practice Guidelines on Hirsutism, which suggest a COC as first-line pharmacologic therapy for most women [10]. In addition, both the Endocrine Society Clinical Practice Guidelines on the Diagnosis and Treatment of Polycystic Ovary Syndrome and international guidelines for the assessment and management of PCOS [2] suggest COCs as first-line therapy for hirsutism [1]. An antiandrogen is then added after six months if the cosmetic response is suboptimal (see "Management of hirsutism in premenopausal women"). COCs and an antiandrogen may sometimes be started simultaneously at the outset, particularly when the cutaneous manifestations are bothersome to the patient. However, we typically postpone starting the antiandrogen until completion of at least one month of COC. A serum or urine pregnancy test should be obtained in women with oligomenorrhea or amenorrhea prior to starting either the COC or spironolactone. (See "Management of hirsutism in premenopausal women", section on 'Antiandrogens'.)

For women with hirsutism and contraindications to COCs, we sometimes use spironolactone alone, but an alternative form of contraception is essential because, if pregnancy occurs, an antiandrogen such as spironolactone could prevent development of normal external genitalia in a male fetus. Spironolactone alone does not regularize menstrual cycles, and in fact, it is sometimes associated with menstrual irregularities.

Choice of oral contraceptive — We typically start with a COC containing 20 mcg of ethinyl estradiol combined with a progestin such as norethindrone or norethindrone acetate, progestins that have lower androgenicity, but similar VTE risk compared with levonorgestrel-containing COCs (table 1). (See "Combined estrogen-progestin contraception: Side effects and health concerns", section on 'Venous thromboembolism'.)

Progestins with lower androgenicity include desogestrel, cyproterone acetate, and drospirenone, but all have been associated with a possible higher risk of venous thromboembolism (VTE). Norgestimate is a progestin with low androgenicity and similar VTE risk to norethindrone and levonorgestrel. However, there are currently no COCs containing 20 mcg of ethinyl estradiol with norgestimate.

Higher doses of ethinyl estradiol (30 to 35 mcg) are needed in some women for optimal suppression of ovarian androgens and management of hyperandrogenic features. Although transdermal or vaginal ring preparations are potential options, they have not been well studied for the management of hirsutism. The risk of VTE with the transdermal and vaginal ring preparations appear to be similar to COCs containing levonorgestrel. (See "Contraception: Hormonal contraceptive vaginal rings", section on 'Cardiovascular and thromboembolic events' and "Contraception: Transdermal contraceptive patches", section on 'Risk of venous thrombotic events'.)

Antiandrogens — After six months, if the patient is not satisfied with the clinical response to COC monotherapy (for hyperandrogenic symptoms), we typically add spironolactone 50 to 100 mg twice daily. (See "Management of hirsutism in premenopausal women", section on 'Antiandrogens'.)

Other available antiandrogens include finasteride, which inhibits 5-alpha-reductase type 2, the enzyme that converts testosterone to dihydrotestosterone (DHT), and dutasteride, an inhibitor of both 5-alpha-reductase types 1 and 2. No clinical trial data are available for dutasteride use in hirsute women. These drugs should never be used in women who are not using reliable contraception, as there is a substantial risk of preventing the development of normal male external genitalia during early pregnancy. (See "Management of hirsutism in premenopausal women", section on 'Antiandrogens'.)

Cyproterone acetate is an antiandrogen that is available in most countries, but not the United States. Flutamide is also effective, but we recommend not using it because of its potential hepatotoxicity. (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use" and "Management of hirsutism in premenopausal women", section on 'Antiandrogens'.)

Other — Gonadotropin-releasing hormone (GnRH) agonists are also sometimes used to suppress ovarian androgen production; "add-back" estrogen-progestin therapy is necessary to avoid bone loss and estrogen deficiency symptoms. Although this approach is effective, it is limited by its complexity and cost. (See "Management of hirsutism in premenopausal women", section on 'Treatments not routinely recommended'.)

Although some clinicians use metformin to treat hirsutism, the Endocrine Society Clinical Practice Guidelines suggest against its routine use as it is associated with minimal or no benefit and is less effective than treatment with COCs and/or antiandrogens [10]. (See "Metformin for treatment of the polycystic ovary syndrome", section on 'Hirsutism'.)

Hirsutism can also be treated by removal of hair by mechanical means such as shaving, waxing, depilatories, electrolysis, or laser treatment. In addition, eflornithine hydrochloride cream (13.9%) is a topical drug that inhibits hair growth. It is not a depilatory and must be used indefinitely to prevent regrowth. (See "Removal of unwanted hair" and "Management of hirsutism in premenopausal women", section on 'Role of direct hair removal methods'.)

Acne and androgenetic alopecia — The management of acne and scalp hair loss (androgenetic alopecia) in women with PCOS are reviewed in detail separately. (See "Male pattern hair loss (androgenetic alopecia in males): Management" and "Acne vulgaris: Overview of management" and "Acne vulgaris: Management of moderate to severe acne in adolescents and adults".)

Metabolic abnormalities

Obesity — Weight loss, which can restore ovulatory cycles and improve metabolic risk, is the first-line intervention for most women. The approach to obesity management is the same as that for patients without PCOS, starting with lifestyle changes (diet and exercise) [11], followed by pharmacotherapy, and, when necessary, bariatric surgery [12]. (See 'Weight reduction' below and "Obesity in adults: Overview of management" and "Outcomes of bariatric surgery", section on 'Polycystic ovary syndrome'.)

Weight reduction — We suggest weight-loss strategies using calorie-restricted diets combined with exercise for women with PCOS and obesity. Although there are no large randomized trials of exercise-specific interventions, a systematic review of exercise therapy in PCOS concluded that there may be modest weight loss and improvements in ovulation and insulin sensitivity [13]. (See "Obesity in adults: Role of physical activity and exercise", section on 'Adding exercise to diet is only minimally beneficial for weight loss' and "Obesity in adults: Dietary therapy".)

Even modest weight loss (5 to 10 percent reduction in body weight) in women with PCOS may result in restoration of normal ovulatory cycles [14-16] and improved pregnancy rates [17] in short-term studies. However, the response to weight loss is variable; not all individuals have restoration of ovulation or menses despite similar weight reduction [11,12,18]. In addition, there are no randomized trials and no long-term data on reproductive or metabolic outcomes with weight loss.

Weight loss results in a decrease in serum androgen concentrations and, in some instances, improvements in hirsutism. However, data demonstrating an improvement in hirsutism are limited [3,11].

There is no good evidence that one type of diet is superior to another for women with PCOS. Low-carbohydrate diets have become very popular for women with PCOS, based upon the notion that less carbohydrate leads to less hyperinsulinemia and therefore less insulin resistance. However, a 12-week study of a high protein/low carbohydrate diet (30 percent protein, 40 percent carbohydrate, 30 percent fat) and a low protein/high carbohydrate diet (15 percent protein, 55 percent carbohydrate, 30 percent fat) were equally effective for weight loss, improvements in menstrual cyclicity, insulin resistance, dyslipidemia, and abdominal fat in one study of 28 overweight women with PCOS [19]. It is not known if an extremely low carbohydrate diet would be any more effective for these endpoints. (See "Obesity in adults: Dietary therapy", section on 'Low-carbohydrate diets'.)

Bariatric surgery — Bariatric surgery is another strategy for weight loss in women with PCOS. In one study of 17 obese women with PCOS with a mean body mass index (BMI) of 50.7 kg/m², bariatric surgery was associated with a mean weight loss after 12 months of 41±9 kg, restoration of ovulatory cycles, and improvements in insulin resistance, hyperandrogenemia, and hirsutism scores [12]. A retrospective chart review and meta-analysis of 29 studies reported similar benefits for women with PCOS [20,21]. (See "Bariatric surgery for management of obesity: Indications and preoperative preparation" and "Outcomes of bariatric surgery", section on 'Polycystic ovary syndrome'.)

Insulin resistance/type 2 diabetes — Several drugs, including biguanides (metformin) and thiazolidinediones (pioglitazone, rosiglitazone), can reduce insulin levels in women with PCOS. These drugs may also reduce ovarian androgen production (and serum free testosterone concentrations) and restore normal menstrual cyclicity [22-25]. (See "Metformin for treatment of the polycystic ovary syndrome" and "Thiazolidinediones in the treatment of type 2 diabetes mellitus".)

Although there had been widespread enthusiasm and use of metformin for a number of indications in PCOS, clinical data no longer support this approach. A detailed discussion of metformin use in PCOS is found elsewhere. (See "Metformin for treatment of the polycystic ovary syndrome".)

Strategies recommended by the American Diabetes Association (ADA) for prevention of type 2 diabetes are discussed separately. The approach in women with PCOS is the same as for women without PCOS. (See "Prevention of type 2 diabetes mellitus".)

Thiazolidinediones have been less well studied than metformin, but they appear to improve insulin sensitivity and hyperandrogenemia [22-28]. However, because of limited clinical data, potential weight gain, and a possible association with cardiovascular adverse events, we do not recommend the use of thiazolidinediones in women with PCOS who do not have diabetes. (See "Thiazolidinediones in the treatment of type 2 diabetes mellitus".)

Though not specifically approved for PCOS, liraglutide is approved for individuals with a BMI of 30 kg/m² or greater. Limited data in women with PCOS suggest that liraglutide results in greater weight loss than placebo [29,30]. (See "Obesity in adults: Drug therapy", section on 'Liraglutide'.)

Metabolic effects of COCs in PCOS — In healthy women, combined estrogen-progestin oral contraceptive (COC) use decreases insulin sensitivity, but in general, this decrease is not clinically significant [31]. It has been assumed that COC use would also worsen insulin sensitivity in women with PCOS, although data are conflicting, with studies showing an improvement [32], worsening [33], or no change [34] in insulin sensitivity. When compared with metformin, COCs may be less beneficial for insulin sensitivity, but better for androgen suppression and menstrual cycle control [35]. There are also theoretical concerns that women with PCOS may be at particular risk for cardiovascular complications with COCs, given their other underlying cardiovascular risk factors. However, there are no COC risk data specific to women with PCOS. (See "Combined estrogen-progestin contraception: Side effects and health concerns", section on 'Cardiovascular effects'.)

The effects of combination COC-metformin therapy are reviewed elsewhere. (See "Metformin for treatment of the polycystic ovary syndrome", section on 'Adding metformin to oral contraceptives'.)

Dyslipidemia — The approach to treatment of dyslipidemia in women with PCOS is the same as for other patients with dyslipidemia. Exercise and weight loss are the first-line approach, followed by pharmacotherapy, if needed. (See "Statins: Actions, side effects, and administration".)

Statins — Statins are effective for dyslipidemia in women with PCOS but do not appear to have other clinically important metabolic or endocrine effects. In a meta-analysis of four trials in 244 women randomly assigned to a statin (simvastatin or atorvastatin) or placebo for 6 to 12 months, statin therapy decreased serum low-density lipoprotein (LDL) and triglycerides, but had no effect on high-density lipoprotein (HDL), fasting insulin, or C-reactive protein. A small decrease in serum testosterone was observed, but there were no improvements in menstrual cycle regularity, ovulation, acne, hirsutism, or BMI [36].

Obstructive sleep apnea — Sleep apnea, a common disorder in women with PCOS, is an important determinant of insulin resistance, glucose intolerance, and type 2 diabetes (see "Clinical manifestations of polycystic ovary syndrome in adults"). In one report of women with PCOS and obstructive sleep apnea, treatment with continuous positive airway pressure (CPAP) improved insulin sensitivity and reduced diastolic blood pressure [37]. Similar benefit was reported in a meta-analysis of eight studies [38].

Nonalcoholic steatohepatitis — The prevalence of nonalcoholic steatohepatitis (NASH) appears to be increased in women with PCOS. Both weight loss and metformin use appear to improve metabolic and hepatic function in these women [39,40]. (See "Clinical manifestations of polycystic ovary syndrome in adults", section on 'Nonalcoholic fatty liver disease'.)

Depression/anxiety — There is evidence that women with PCOS have impaired quality of life and higher rates of depression and anxiety when compared with women of similar BMI without PCOS [41]. However, the efficacy and safety of antidepressant therapy has not yet been established in women with PCOS and anxiety or depression [42]. (See "Clinical manifestations of polycystic ovary syndrome in adults", section on 'Psychosocial issues' and "Diagnosis of polycystic ovary syndrome in adults", section on 'Depression and anxiety disorders'.)

WOMEN PURSUING PREGNANCY

Weight loss — For anovulatory women with PCOS who are overweight or obese, we suggest weight loss prior to initiating ovulation induction therapy. The approach to obesity management is the same as that for patients without PCOS, starting with lifestyle changes (diet and exercise) [11], followed by pharmacotherapy (if not pursuing pregnancy), and, when necessary, bariatric surgery [12]. (See 'Weight reduction' above and "Obesity in adults: Overview of management" and "Outcomes of bariatric surgery", section on 'Polycystic ovary syndrome'.)

Even modest weight loss of 5 to 10 percent has been associated with an improvement in metabolic status [43], a reduction in serum androgen concentrations, and resumption of ovulation in some studies [11,12,14-19,44,45]. Not all women develop ovulatory cycles despite similar degrees of weight loss [11,12,16,18]. In addition, data on pregnancy rates and outcomes have been limited [3].

However, a post hoc comparison of two multicenter, concurrent trials in overweight/obese women with PCOS and anovulatory infertility reported higher ovulatory and live birth rates with pretreatment lifestyle modification and weight loss when compared with immediate treatment with clomiphene citrate [46]. The two concurrent trials included:

●The Treatment of Hyperandrogenism versus Insulin Resistance in Infertile Polycystic Ovary Syndrome (OWL-PCOS) Women, an open-label study of overweight or obese women with PCOS and anovulatory infertility assigned to 16 weeks of pretreatment with continuous oral contraceptives (COCs; n = 47), lifestyle modification (including caloric restriction, antiobesity medication, behavioral medication, and exercise; n = 48), or the combination of both (COCs and lifestyle; n = 47) followed by up to four cycles of clomiphene citrate for ovulation induction.

●Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) trial (n = 187), a double-blinded trial of up to five cycles of clomiphene or letrozole. Data was extracted only from patients in the clomiphene treatment group who met the body mass index (BMI) criteria for the OWL-PCOS study. Only the first four clomiphene cycles were analyzed.

In PPCOS II, after four cycles of clomiphene (with no pretreatment), the cumulative per-cycle ovulatory and live birth rates were 45 and 10.2 percent; (227 of 619 cycles, 19 of 187 patients). In OWL-PCOS, a 16-week pretreatment lifestyle intervention resulted in an approximate 6.5 percent weight loss from baseline and improvements in ovulatory and live birth rates (62 and 25 percent, respectively; 80 of 129 cycles and 12 of 48 patients). Pretreatment with oral contraceptives (alone or combined with lifestyle intervention) did not affect outcomes.

Although we encourage weight loss in obese woman with PCOS and anovulatory infertility, our approach is somewhat different in older women (≥37 years) or in those whose testing shows diminished ovarian reserve. In these settings, we typically offer either immediate ovulation induction or a short (three-month) attempt at weight loss followed by ovulation induction. We do not suggest a longer attempt to lose weight.

Ovulation induction medications

●For oligo-ovulatory women with PCOS undergoing ovulation induction, we now suggest letrozole as first-line therapy over clomiphene citrate, regardless of the patient's BMI. Before starting letrozole, the clinician must discuss that this use of the drug is not approved by the US Food and Drug Administration (FDA) for this purpose and that there is an available alternative (clomiphene citrate). (See "Ovulation induction with letrozole", section on 'Outcomes'.)

●Clomiphene citrate had been the first-line drug for this population for many years, with metformin used as an alternative. However, both clomiphene and metformin appear to be less effective for live birth rates than letrozole [47]. In women with PCOS, an ovulatory rate of 80 percent and a cumulative pregnancy rate of 30 to 40 percent can be expected. Cumulative pregnancy rate is dependent on patient BMI, with higher BMI levels associated with lower cumulative pregnancy rate. (See "Ovulation induction with clomiphene citrate".)

●A multistep approach to the management of anovulatory infertility in women with PCOS is shown in the table (table 2). (See "Ovulation induction with letrozole".)

●Metformin – Metformin is a drug whose major effect is to reduce hepatic glucose output and thereby lower serum insulin concentrations. Metformin has been used to promote ovulation either alone or in combination with clomiphene, but clomiphene or letrozole monotherapy appears to be superior to metformin monotherapy on live birth rates. Its role in treating infertility is limited [1]. Clinical trial data supporting this are reviewed elsewhere. (See "Metformin for treatment of the polycystic ovary syndrome", section on 'Anovulatory infertility'.)

Current guidelines recommend against the routine use of metformin in obese women with PCOS (including ovulation induction), except in women with glucose intolerance who have failed lifestyle interventions [1,48]. Metformin therapy for PCOS and strategies for prevention of type 2 diabetes are discussed in more detail separately. (See "Metformin for treatment of the polycystic ovary syndrome" and "Prevention of type 2 diabetes mellitus".)

●Gonadotropin therapy – Another method to induce ovulation is administration of exogenous gonadotropins [49]. A study of 225 women with PCOS treated over a 10-year period at one center found rates of ovulation and pregnancy of 72 percent and 45 percent, respectively, after the administration of low-dose gonadotropins [50]. Exogenous gonadotropin therapy is reviewed in detail elsewhere. Women with PCOS and anovulatory infertility treated with gonadotropins are at high risk for ovarian hyperstimulation syndrome (OHSS).

Exogenous gonadotropin regimens are complex and expensive and are best carried out by experienced clinicians; most clinicians recommend an assessment of fallopian tube patency before initiating these relatively aggressive therapies. (See "Pathogenesis, clinical manifestations, and diagnosis of ovarian hyperstimulation syndrome" and "Prevention of ovarian hyperstimulation syndrome" and "Overview of ovulation induction".)

●Other medications

•Thiazolidinedione therapy has been investigated for induction of ovulation [8,51-53], but we do not suggest its use because of concern about its cardiovascular safety. (See 'Insulin resistance/type 2 diabetes' above and "Thiazolidinediones in the treatment of type 2 diabetes mellitus".)

•Although women with PCOS are not likely gonadotropin-releasing hormone (GnRH) deficient, pulsatile GnRH is moderately effective for ovulation induction. It is currently available in Europe, but not in the United States. In one study of 41 patients undergoing 114 ovulation induction cycles, 56 percent of women ovulated, and 40 percent of ovulatory patients achieved pregnancy [54]. Ovulatory cycles were associated with lower BMI and fasting insulin, and higher baseline serum follicle-stimulating hormone (FSH) concentrations. Thus, pulsatile GnRH may be a reasonable option, particularly for lean women with PCOS.

Acupuncture — Infertility centers often offer acupuncture as an adjunctive therapy to women with PCOS undergoing ovulation induction or in vitro fertilization (IVF). However, available evidence suggests that it does not improve live birth rates when used alone or combined with clomiphene citrate (compared with sham acupuncture alone or with clomiphene) [55,56]. The addition of acupuncture during IVF cycles does not improve outcomes. (See "In vitro fertilization: Overview of clinical issues and questions".)

Laparoscopic surgery — In the past, wedge resection of the ovaries was a standard treatment for infertility in women with PCOS. However, this approach has been abandoned, both because of the efficacy of clomiphene and because of the high incidence of pelvic adhesions seen with wedge resection. A substitute for wedge resection, laparoscopic ovarian laser electrocautery, may be effective in some women with PCOS. However, given the other pharmacologic options for ovulation induction, surgery is not often indicated.

For women who do not respond to ovulation induction with either letrozole or clomiphene citrate, laparoscopic ovarian drilling (also referred to as laparoscopic ovarian diathermy or electrocoagulation) is a surgical option for second-line treatment. When compared with gonadotropin therapy, another second-line treatment, ovarian drilling has similar efficacy but results in lower risk of high order multiple gestations or OHSS (table 3) [57,58]. Disadvantages of ovarian drilling include surgical risk and potential adhesion formation. Although laparoscopic ovarian drilling has been utilized for decades, the technique has never been standardized regarding the energy source, number of punctures, dose and duration per puncture, or whether one or both ovaries should be treated. Based on limited dose-ranging studies, three to six punctures per ovary at 40 W of coagulating (modulated) current for four seconds per puncture seems reasonable [59,60].

Ovarian drilling likely reduces ovarian secretion of androgens and proteins, resulting in an increase in LH and FSH secretion. In turn, following ovarian drilling, the ovary is more responsive to stimulation by endogenous gonadotropins favoring the growth of a dominant ovarian follicle and ovulation. Following ovarian drilling ovulatory cycles occur in approximately 80 percent of patients with a range of 30 to 90 percent, in published studies [61]. The normalization of ovulatory function continued for many years in the majority of patients following ovarian drilling [62-65].

In vitro fertilization — If weight loss, ovulation induction with medications, and/or laparoscopic ovarian laser electrocautery are unsuccessful, the next step is IVF. Without co-interventions, women with PCOS are at increased risk for both multiple gestation and OHSS. Women with PCOS who undergo IVF have lower rates of OHSS with the transfer of frozen rather than fresh embryos. (See "In vitro fertilization: Overview of clinical issues and questions".)

The risk of OHSS is high in women with PCOS undergoing controlled ovarian hyperstimulation for IVF, and metformin administration before or during IVF cycles may reduce this risk [66-68]. The best evidence comes from a meta-analysis of 12 randomized clinical trials including 1123 women with PCOS undergoing IVF or intracytoplasmic sperm injection and embryo transfer (IVF/ICSI-ET) [69]. The rate of OHSS in women randomized to metformin was 48 in 478 (10 percent), which was lower than in women not receiving metformin: 84 in 469, 18 percent (odds ratio [OR] 0.43; 95% CI, 0.24-0.78). The difference was only significant for women with a BMI >26 kg/m². In addition, like other previous reports [67,68], metformin did not improve clinical pregnancy rates or live birth rates. Rates of OHSS are now as low as 1 percent in many programs who use multiple modifications of earlier regimens. (See "Pathogenesis, clinical manifestations, and diagnosis of ovarian hyperstimulation syndrome".)

For women at high risk for OHSS (overweight or obese with PCOS), adding metformin to the stimulation regimen remains a reasonable option to lower OHSS risk further. (See "Metformin for treatment of the polycystic ovary syndrome", section on 'IVF pretreatment'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Polycystic ovary syndrome" and "Society guideline links: Hirsutism".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Polycystic ovary syndrome (The Basics)")

●Beyond the Basics topics (see "Patient education: Polycystic ovary syndrome (PCOS) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Overview – The management of polycystic ovary syndrome (PCOS) requires treatment of individual components of the syndrome, including menstrual dysfunction and the risk of endometrial hyperplasia, hyperandrogenism (hirsutism and acne), metabolic risk factors (obesity, glucose intolerance, and dyslipidemia), and, in some women, anovulatory infertility. The choice of therapy depends upon whether the patient is pursuing pregnancy or not. The treatment of hirsutism and approach to ovulation induction in women with PCOS are reviewed separately. (See 'Overview of approach' above and "Management of hirsutism in premenopausal women" and "Ovulation induction with letrozole", section on 'Ovulation induction in PCOS'.)

●Women not pursuing pregnancy

•Menstrual dysfunction – For women with PCOS, oligomenorrhea, and chronic anovulation we suggest combined estrogen-progestin oral contraceptive (COC) therapy (Grade 2C) (see 'Menstrual dysfunction' above). The goal of COCs for these women is to prevent endometrial hyperplasia and provide contraception (as women with oligomenorrhea ovulate intermittently and unwanted pregnancy may occur). COCs are the mainstay of pharmacologic therapy for managing hyperandrogenic symptoms. For women with PCOS who choose not to or cannot take COCs, we typically use intermittent progestin therapy. (See 'Menstrual dysfunction' above.)

•Women with hyperandrogenic symptoms – For most women with hirsutism or other androgenic manifestations such as acne or female pattern hair loss, we also suggest starting with a COC (Grade 2C) (in addition to lifestyle measures). (See 'Androgen excess' above and "Management of hirsutism in premenopausal women".)

We typically start with a COC containing 20 mcg of ethinyl estradiol combined with a progestin such as norethindrone or norethindrone acetate, progestins that have lower androgenicity, but similar VTE risk compared with levonorgestrel-containing COCs. Higher doses of ethinyl estradiol are needed in some women for optimal management of hyperandrogenic symptoms. Concerns about VTE risk with newer progestins and with drospirenone are reviewed separately. (See 'Choice of oral contraceptive' above and "Combined estrogen-progestin contraception: Side effects and health concerns", section on 'Venous thromboembolism'.)

If the patient is not satisfied with the clinical response to six months of COC monotherapy (for hyperandrogenic manifestations), we add spironolactone, an antiandrogen. (See 'Androgen excess' above and "Management of hirsutism in premenopausal women".)

•Metabolic disorders – Weight loss (which can restore ovulatory cycles, improve metabolic risk, and possibly improve live birth rates) is the intervention for most women. Women who have already developed type 2 diabetes and/or dyslipidemia require specific interventions for these disorders. These disorders also require management during pregnancy. (See 'Weight loss' above and 'Insulin resistance/type 2 diabetes' above and 'Dyslipidemia' above.)

●Women pursuing pregnancy

•Anovulatory infertility and ovulation induction – For women with PCOS and anovulatory infertility, attempts at weight loss should be tried first in those with obesity. If this does not restore ovulatory cycles, ovulation induction is required. Letrozole, an aromatase inhibitor, is now the first-line ovulation induction agent over clomiphene citrate for women with PCOS. Before starting letrozole, the clinician must discuss that use of the drug is not approved for this indication, and that clomiphene is an alternative. (table 2) (See 'Women pursuing pregnancy' above and "Ovulation induction with letrozole", section on 'Suggested approach'.)