Women with polycystic ovarian syndrome (PCOS) have abnormalities in the metabolism of androgens and estrogen and in the control of androgen production. PCOS can result from abnormal function of the hypothalamic-pituitary-ovarian (HPO) axis. A woman is diagnosed with polycystic ovaries (as opposed to PCOS) if she has 20 or more follicles in at least 1 ovary[1] (see the image below).
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Low power, H and E of an ovary containing multiple cystic follicles in a patient with PCOS.
Signs and symptoms
The major features of PCOS include menstrual dysfunction, anovulation, and signs of hyperandrogenism.[2] Other signs and symptoms of PCOS may include the following:
Hirsutism
Infertility
Obesity and metabolic syndrome
Diabetes
Obstructive sleep apnea
See Clinical Presentation for more detail.
Diagnosis
On examination, findings in women with PCOS may include the following:
Virilizing signs
Acanthosis nigricans
Hypertension
Enlarged ovaries: May or may not be present; evaluate for an ovarian mass
Testing
Exclude all other disorders that can result in menstrual irregularity and hyperandrogenism, including adrenal or ovarian tumors, thyroid dysfunction, congenital adrenal hyperplasia, hyperprolactinemia, acromegaly, and Cushing syndrome.[3, 4, 5]
Baseline screening laboratory studies for women suspected of having PCOS may include the following:
Thyroid function tests[5] (eg, TSH, free thyroxine)
Serum prolactin level[5]
Total and free testosterone levels
Free androgen index[5]
Serum hCG level
Cosyntropin stimulation test
Serum 17-hydroxyprogesterone (17-OHPG) level
Urinary free cortisol (UFC) and creatinine levels
Low-dose dexamethasone suppression test
Serum insulin-like growth factor (IGF)–1 level
Other tests used in the evaluation of PCOS include the following:
Androstenedione level
FSH and LH levels
GnRH stimulation testing
Glucose level
Insulin level
Lipid panel
Imaging tests
The following imaging studies may be used in the evaluation of PCOS:
Ovarian ultrasonography, preferably using transvaginal approach
Pelvic CT scan or MRI to visualize the adrenals and ovaries
Procedures
An ovarian biopsy may be performed for histologic confirmation of PCOS; however, ultrasonographic diagnosis of PCOS has generally superseded histopathologic diagnosis. An endometrial biopsy may be obtained to evaluate for endometrial disease, such as malignancy.
See Workup for more detail.
Management
Lifestyle modifications are considered first-line treatment for women with PCOS. Such changes include the following[3, 4] :
Diet
Exercise
Weight loss
Pharmacotherapy
Pharmacologic treatments are reserved for so-called metabolic derangements, such as anovulation, hirsutism, and menstrual irregularities. First-line medical therapy usually consists of an oral contraceptive to induce regular menses.
If symptoms such as hirsutism are not sufficiently alleviated, an androgen-blocking agent may be added. First-line treatment for ovulation induction when fertility is desired are letrozole or clomiphene citrate.[3, 4, 6]
Medications used in the management of PCOS include the following:
The major features of polycystic ovarian syndrome (PCOS) include menstrual dysfunction, anovulation, and signs of hyperandrogenism.[2] Although the exact etiopathophysiology of this condition is unclear, PCOS can result from abnormal function of the hypothalamic-pituitary-ovarian (HPO) axis. A key characteristic of PCOS is inappropriate gonadotropin secretion, which is more likely a result of, rather than a cause of, ovarian dysfunction. In addition, one of the most consistent biochemical features of PCOS is a raised plasma testosterone level.[7] (See Etiology and Workup.)
Stein and Leventhal were the first to recognize an association between the presence of polycystic ovaries and signs of hirsutism and amenorrhea (eg, oligomenorrhea, obesity).[8] After women diagnosed with Stein-Leventhal syndrome underwent successful wedge resection of the ovaries, their menstrual cycles became regular, and they were able to conceive.[9] As a consequence, a primary ovarian defect was thought to be the main culprit, and the disorder came to be known as polycystic ovarian disease. (See Etiology and Treatment.)
Further biochemical, clinical, and endocrinologic studies revealed an array of underlying abnormalities. As a result, the condition is now referred to as PCOS, although it may occur in women without ovarian cysts and although ovarian morphology is no longer an essential requirement for diagnosis.
A woman is diagnosed with polycystic ovaries (as opposed to PCOS) if she has 20 or more follicles in at least 1 ovary—measuring 2-9 mm in diameter—or a total ovarian volume greater than 10 cm3.[1] (See the image below.) (See Workup.)
View Image
Longitudinal transabdominal ultrasonogram of an ovary. This image reveals multiple peripheral follicles.
Diagnostic criteria
A 1990 expert conference sponsored by the National Institute of Child Health and Human Disease (NICHD) of the United States National Institutes of Health (NIH) proposed the following criteria for the diagnosis of PCOS:
Oligo-ovulation or anovulation manifested by oligomenorrhea or amenorrhea
Hyperandrogenism (clinical evidence of androgen excess) or hyperandrogenemia (biochemical evidence of androgen excess)
Exclusion of other disorders that can result in menstrual irregularity and hyperandrogenism
In 2003, the European Society for Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM) recommended that at least 2 of the following 3 features are required for PCOS to be diagnosed[10] :
Oligo-ovulation or anovulation manifested as oligomenorrhea or amenorrhea
Hyperandrogenism (clinical evidence of androgen excess) or hyperandrogenemia (biochemical evidence of androgen excess)
Polycystic ovaries (as defined on ultrasonography)
A research analysis by Copp et al pointed out that since the expanded criteria for PCOS diagnosis from the Rotterdam consensus, the estimated number of diagnoses in women of reproduction age increased from 4-6.6% to 21%.[11, 12]
The Androgen Excess and PCOS Society (AE-PCOS) published a position statement in 2006[13] and its criteria in 2009[14] emphasizing that, in the society’s opinion, PCOS should be considered a disorder of androgen excess, as defined by the following:
Clinical/biochemical evidence of hyperandrogenism
Evidence of ovarian dysfunction (oligo-ovulation and/or polycystic ovaries)
Exclusion of related disorders
The Society of Obstetricians and Gynaecologists of Canada (SOGC) indicated that a diagnosis of polycystic ovarian syndrome (PCOS) is made in the presence of at least 2 of the following 3 criteria, when congenital adrenal hyperplasia, androgen-secreting tumors, or Cushing syndrome have been excluded[3] :
Oligo-ovulation or anovulation
Clinical/biochemical evidence of hyperandrogenism
Polycystic ovaries on ultrasonograms (>12 small antral follicles in an ovary)
Women with polycystic ovarian syndrome (PCOS) have abnormalities in the metabolism of androgens and estrogen and in the control of androgen production. High serum concentrations of androgenic hormones, such as testosterone, androstenedione, and dehydroepiandrosterone sulfate (DHEA-S), may be encountered in these patients. However, individual variation is considerable, and a particular patient might have normal androgen levels.
PCOS is also associated with peripheral insulin resistance and hyperinsulinemia, and obesity amplifies the degree of both abnormalities. Insulin resistance in PCOS can be secondary to a postbinding defect in insulin receptor signaling pathways, and elevated insulin levels may have gonadotropin-augmenting effects on ovarian function. Hyperinsulinemia may also result in suppression of hepatic generation of sex hormone–binding globulin (SHBG), which in turn may increase androgenicity.[15]
In addition, insulin resistance in PCOS has been associated with adiponectin, a hormone secreted by adipocytes that regulates lipid metabolism and glucose levels. Lean and obese women with PCOS have lower adiponectin levels than do women without PCOS.[16]
A proposed mechanism for anovulation and elevated androgen levels suggests that, under the increased stimulatory effect of luteinizing hormone (LH) secreted by the anterior pituitary, stimulation of the ovarian theca cells is increased. These cells, in turn, increase the production of androgens (eg, testosterone, androstenedione). Because of a decreased level of follicle-stimulating hormone (FSH) relative to LH, the ovarian granulosa cells cannot aromatize the androgens to estrogens, which leads to decreased estrogen levels and consequent anovulation. Growth hormone (GH) and insulin-like growth factor–1 (IGF-1) may also augment the effect on ovarian function.[17]
Hyperinsulinemia is also responsible for dyslipidemia and for elevated levels of plasminogen activator inhibitor-1 (PAI-1) in patients with PCOS. Elevated PAI-1 levels are a risk factor for intravascular thrombosis.
Polycystic ovaries are enlarged bilaterally and have a smooth, thickened capsule that is avascular. On cut sections, subcapsular follicles in various stages of atresia are seen in the peripheral part of the ovary. The most striking ovarian feature of PCOS is hyperplasia of the theca stromal cells surrounding arrested follicles. On microscopic examination, luteinized theca cells are seen.
Some evidence suggests that patients have a functional abnormality of cytochrome P450c17, the 17-hydroxylase, which is the rate-limiting enzyme in androgen biosynthesis.[16]
PCOS is a genetically heterogeneous syndrome in which the genetic contributions remain incompletely described. PCOS is an inherently difficult condition to study genetically because of its heterogeneity, difficulty with retrospective diagnosis in postmenopausal women, associated subfertility, incompletely understood etiology, and gene effect size.[7] Many published genetics studies in PCOS have been underpowered, and the results of published candidate gene studies have been disappointing.
Studies of family members with PCOS indicate that an autosomal dominant mode of inheritance occurs for many families with this disease. The fathers of women with PCOS can be abnormally hairy; female siblings may have hirsutism and oligomenorrhea; and mothers may have oligomenorrhea.[18] Research has suggested that in a large cohort of women with PCOS, a family history of type 2 diabetes in a first-degree family member is associated with an increased risk of metabolic abnormality, impaired glucose tolerance, and type II diabetes.[18] In addition, a Dutch twin-family study showed a PCOS heritability of 0.71 in monozygotic twin sisters, versus 0.38 in dizygotic twins and other sisters.[19]
An important link between PCOS and obesity was corroborated genetically for the first time by data from a case-control study in the United Kingdom that involved 463 patients with PCOS and more than 1300 female controls.[20] The investigators demonstrated that a variant within the FTO gene (rs9939609, which has been shown to predispose to common obesity) was significantly associated with susceptibility to the development of PCOS.
Wickenheisser et al reported that CYP17 promoter activity was 4-fold greater in cells of patients with PCOS. This research suggests that the pathogenesis of PCOS may be in part related to the gene regulation of CYP17.[21] However, in a study that assessed candidate genes for PCOS using microsatellite markers to look for association in 4 genes— CYP19, CYP17, FST, and INSR —only 1 marker near the INSR gene was found to be significantly associated with PCOS.[22] The authors concluded that a susceptibility locus for PCOS (designated PCOS1) exists in 19p13.3 in the INSR region, but it cannot be concluded that the INSR gene itself is responsible.[22]
Subsequent studies have found additional associations, such as those of 15 regions in 11 genes previously described to influence insulin resistance, obesity, or type 2 diabetes.[23] Individuals with PCOS were found more likely to be homozygous for a variant upstream of the PON1 gene and homozygous for an allele of interest in IGF2. Interestingly, the PON1 gene variant resulted in decreased gene expression, which could increase oxidative stress. The exact result of the IGF2 variant is unclear, but IGF2 stimulates androgen secretion in the ovaries and adrenal glands.[23]
In study by Goodarzi et al, the leucine allele was found to be associated with protection against PCOS, as compared to the valine allele at position 89 in SRD5A2.[24] The leucine allele is associated with a lower enzyme activity.[24] When the results of this study are combined with those of an observational study by Vassiliadi et al, based on urinary steroid profiles in women with PCOS, further support can be found for an important role for 5-alpha reductase in the pathogenesis of this syndrome.[25]
In a genome-wide association study for PCOS in a Han Chinese population, 3 strong regions of association were identified, at 2p16.3, 2p21, and 9q33.3.[26] The polymorphism most strongly associated with PCOS at the 2p16 locus was near several genes involved in proper formation of the testis, as well as a gene that encodes a receptor for luteinizing hormone (LH) and human chorionic gonadotropin (HCG). This polymorphism was also located 211kb upstream from the FSHR gene, which encodes the follicle-stimulating hormone (FSH) receptor.[26]
The polymorphisms most strongly associated with PCOS at the 2q21 locus encode a number of genes, including the THADA gene, which has previously been associated with type 2 diabetes. In addition, 6 significant polymorphisms were identified as being associated with PCOS at the 9q33.3 locus near the DENND1A gene, which interacts with the ERAP1 gene. Elevation in serum ERAP1 has been previously associated with PCOS and obesity.[26]
In the United States, polycystic ovarian syndrome (PCOS) is one of the most common endocrine disorders of reproductive-age women, with a prevalence of 4-12%.[27, 28] Up to 10% of women are diagnosed with PCOS during gynecologic visits.[29] In some European studies, the prevalence of PCOS has been reported to be 6.5-8%.[30, 31]
A great deal of ethnic variability in hirsutism is observed. For example, Asian (East and Southeast Asia) women have less hirsutism than white women given the same serum androgen values. In a study that assessed hirsutism in southern Chinese women, investigators found a prevalence of 10.5%.[32] In hirsute women, there was a significant increase in the incidence of acne, menstrual irregularities, polycystic ovaries, and acanthosis nigricans.[32]
PCOS affects premenopausal women, and the age of onset is most often perimenarchal (before bone age reaches 16 y). However, clinical recognition of the syndrome may be delayed by failure of the patient to become concerned by irregular menses, hirsutism, or other symptoms or by the overlap of PCOS findings with normal physiologic maturation during the 2 years after menarche. In lean women with a genetic predisposition to PCOS, the syndrome may be unmasked when they subsequently gain weight.[15]
Evidence suggest that women with polycystic ovarian syndrome (PCOS) may be at increased risk for cardiovascular and cerebrovascular disease. Women with hyperandrogenism have elevated serum lipoprotein levels similar to those of men.[33, 34, 35, 36]
Approximately 40% of patients with PCOS have insulin resistance that is independent of body weight. These women are at increased risk for type 2 diabetes mellitus and consequent cardiovascular complications.
The American Association of Clinical Endocrinologists and the American College of Endocrinology recommend screening for diabetes by age 30 years in all patients with PCOS, including obese and nonobese women.[37] In patients at particularly elevated risk, testing before 30 years of age may be indicated. Patients who initially test negative for diabetes should be periodically reassessed throughout their lifetime.
Patients with PCOS are also at an increased risk for endometrial hyperplasia and carcinoma.[5, 38] The chronic anovulation in PCOS leads to constant endometrial stimulation with estrogen without progesterone, and this increases the risk of endometrial hyperplasia and carcinoma. The Royal College of Obstetricians and Gynaecologists (RCOG) recommends induction of withdrawal bleeding with progestogens a minimum of every 3-4 months.[5]
No known association with breast or ovarian cancer has been found; thus, no additional surveillance is needed.[5]
Discuss with patients the symptoms of polycystic ovarian syndrome (PCOS) as well as their increased risk for cardiovascular and cerebrovascular disease. Educate women with this condition regarding lifestyle modifications such as weight reduction, increased exercise, and dietary modifications.[3, 4, 5] (See Diet and Activity.)
For more information, see Women's Health Center, as well as Ovarian Cysts, Amenorrhea, and Female Sexual Problems.
The family history of patients with polycystic ovarian syndrome (PCOS) may include the following:
Menstrual disorders
Adrenal enzyme deficiencies
Hirsutism
Infertility
Obesity and metabolic syndrome
Diabetes
Menstrual abnormalities
Patients with PCOS have abnormal menstruation patterns attributed to chronic anovulation. (The patient usually has a history of menstrual disturbance dating back to menarche.) Some women have oligomenorrhea (ie, menstrual bleeding that occurs at intervals of 35 days to 6 months, with < 9 menstrual periods per year) or secondary amenorrhea (an absence of menstruation for 6 months). Dysfunctional uterine bleeding and infertility are the other consequences of anovulatory menstrual cycles. The menstrual irregularities in PCOS usually present around the time of menarche.
A retrospective study by Maslyanskaya et al reported that PCOS was the most common etiology seen in adolescent patients hospitalized for abnormal uterine bleeding (accounting for 33% of 125 hospital admissions).[39]
Hyperandrogenism
Hyperandrogenism clinically manifests as excess terminal body hair in a male distribution pattern. Hair is commonly seen on the upper lip, on the chin, around the nipples, and along the linea alba of the lower abdomen. Some patients have acne and/or male-pattern hair loss (androgenic alopecia).
Other signs of hyperandrogenism (eg, clitoromegaly, increased muscle mass, voice deepening) are more characteristic of an extreme form of PCOS termed hyperthecosis. These signs and symptoms could also be consistent with androgen-producing tumors, exogenous androgen administration, or virilizing congenital adrenal hyperplasia.
Premature adrenarche is a common occurrence and, in some cases, may represent a precursor to PCOS. Hirsutism and obesity may be present in premenarchal adolescent girls with PCOS.
The American College of Obstetricians and Gynecologists (ACOG) recommends screening with 17-hydroxyprogesterone levels in women suspected of having PCOS who are at an increased risk for nonclassical congenital adrenal hyperplasia.[4]
Infertility
A subset of women with PCOS is infertile. Most women with PCOS ovulate intermittently. Conception may take longer than in other women, or women with PCOS may have fewer children than they had planned. In addition, the rate of miscarriage is also higher in affected women.
Obesity and metabolic syndrome
Nearly half of all women with PCOS are clinically obese. A study comparing the body mass index (BMI) in American and Italian women with PCOS showed that American women had a BMI higher than that of their Italian counterparts.[40] Women with PCOS should be assessed for their cardiovascular risk by evaluating their BMI, fasting lipid and lipoprotein levels, and risk factors for metabolic syndrome.[4, 5]
Many patients with PCOS have characteristics of metabolic syndrome; one study showed a 43% prevalence of metabolic syndrome in women with PCOS.[27] In women, metabolic syndrome is characterized by abdominal obesity (waist circumference >35 in), dyslipidemia (triglyceride level >150 mg/dL, high-density lipoprotein cholesterol [HDL-C] level < 50 mg/dL), elevated blood pressure, a proinflammatory state characterized by an elevated C-reactive protein level, and a prothrombotic state characterized by elevated plasminogen activator inhibitor-1 (PAI-1) and fibrinogen levels.[27]
Women with PCOS have an increased prevalence of coronary artery calcification and thickened carotid intima media, which may be responsible for subclinical atherosclerosis. Prospective, long-term cardiovascular-outcome studies in PCOS are needed to assess whether the increased cardiovascular risk in PCOS results in the higher cardiovascular-event rates.
Diabetes mellitus
ACOG recommends screening for type 2 diabetes and impaired glucose tolerance in women with PCOS by obtaining a fasting glucose level and then a 2-hour glucose level after a 75-g glucose load.[4] Approximately 10% of women with PCOS have type 2 diabetes mellitus, and 30-40% of women with PCOS have impaired glucose tolerance by 40 years of age.[41, 42]
Sleep apnea
Many women with PCOS have obstructive sleep apnea syndrome (OSAS), which is an independent risk factor for cardiovascular disease.[5] Ask these patients and/or their partners about excessive daytime somnolence; individuals with obstructive sleep apnea experience apnea/hypopnea episodes during sleep.[43, 44] For women with PCOS with suspected OSAS, there should be a low threshold for referral for sleep assessment. Patients may also be screened for OSAS in the clinic using such tools as the Epworth sleepiness score.
Patients may have excessive body hair in a male distribution pattern, as well as acne. Some patients have virilizing signs, such as male-pattern balding or alopecia, increased muscle mass, deepening voice, or clitoromegaly; these findings should prompt a search for other causes of hyperandrogenism.
The modified Ferriman-Gallwey (mFG) score grades 9 body areas from 0 (no hair) to 4 (frankly virile), including the upper lip, chin, chest, upper abdomen, lower abdomen, thighs, back, arm, and buttocks. A total score of 8 or more is considered abnormal for an adult white woman; a score of 36 is the most severe.
Obesity
Approximately 50% of women with polycystic ovarian syndrome (PCOS) have abdominal obesity, characterized by a waist circumference greater than 35 inches (>88 cm).
Acanthosis nigricans
Acanthosis nigricans is a diffuse, velvety thickening and hyperpigmentation of the skin. It may be present at the nape of the neck, axillae, area beneath the breasts, intertriginous areas, and exposed areas (eg, elbows, knuckles). In patients with PCOS, acanthosis nigricans is thought to be the result of insulin resistance, although syndromic and familial variants are described. Acanthosis nigricans can also be a cutaneous marker of malignancy.
Acanthosis nigricans is staged according to the scoring system below:
Absent (0): Not detectable on close inspection
Present (1): Clearly present on close visual inspection, not visible to the casual observer, extent not measurable
Mild (2): Limited to the base of the skull, usually does not extend to the lateral margins of the neck
Moderate (3): Extends to the lateral margins of the neck but not visible anteriorly
Severe (4): Visible anteriorly
Severe (5): Circumferential
Blood pressure
Patients with signs and symptoms of metabolic syndrome may have elevated blood pressure, with a systolic blood pressure of 130 mm Hg or higher and a diastolic blood pressure of 85 mm Hg or higher.
Enlarged ovaries
Enlarged ovaries may not always be present. Evaluate for an ovarian mass.
The diagnosis of polycystic ovarian syndrome (PCOS) requires the exclusion of all other disorders that can result in menstrual irregularity and hyperandrogenism, including adrenal or ovarian tumors, thyroid dysfunction, congenital adrenal hyperplasia, hyperprolactinemia, acromegaly, and Cushing syndrome.[3, 4, 5] Biochemical and/or imaging studies must be done to rule out these other possible disorders and ascertain the diagnosis. A karyotype usually excludes mosaic Turner syndrome as a cause of the primary amenorrhea.
The Royal College of Obstetricians and Gynaecologists (RCOG) recommends the following baseline screening tests for women with suspected polycystic ovarian syndrome (PCOS): thyroid function tests, serum prolactin levels, and a free androgen index (defined as total testosterone divided by sex hormone binding globulin [SHBG] × 100, to give a calculated free testosterone level).[5]
Patients who are having difficulty conceiving should receive an adequate workup, along with their partners, to rule out factors that might contribute to infertility.
Samples for laboratory studies should be drawn early in the morning, with the patient in a fasting state; in women with regular menses, samples should be taken between days 5 and 9 of the menstrual cycle.[37] A serum human chorionic gonadotropin (hCG) level should be checked to rule out pregnancy in women with oligomenorrhea or amenorrhea.
Late-onset congenital adrenal hyperplasia due to 21-hydroxylase deficiency can be ruled out by measuring serum 17-hydroxyprogesterone levels after a cosyntropin stimulation test. A 17-hydroxyprogesterone level of less than 1000 ng/dL—measured 60 minutes after cosyntropin stimulation—rules out late-onset congenital adrenal hyperplasia.
Women with PCOS should be screened for Cushing syndrome or acromegaly only if there is a clinical suspicion of these conditions. Cushing syndrome can be ruled out by checking a 24-hour urine sample for free cortisol and creatinine. levels of urinary free cortisol that are 4 times the upper limit of normal are diagnostic for Cushing syndrome.[46] An overnight dexamethasone suppression test is also useful for screening for Cushing syndrome.
A serum insulin-like growth factor (IGF) ̶ 1 level should be checked to rule out acromegaly. Serum IGF-1 is a sensitive and specific marker of growth hormone (GH) excess. Normal levels rule out GH excess.
A small percentage of patients with PCOS have elevated prolactin levels (typically >25 mg/dL). Hyperprolactinemia can be excluded by checking a fasting serum prolactin concentration.
Androgen excess can be tested by measuring total and free testosterone levels or a free androgen index. An elevated free testosterone level is a sensitive indicator of androgen excess. Other androgens, such as dehydroepiandrosterone sulfate (DHEA-S), may be normal or slightly above the normal range in patients with polycystic ovarian syndrome (PCOS). levels of sex hormone–binding globulin (SHBG) are usually low in patients with PCOS.
Androstenedione levels are also elevated in women with PCOS. This androgen precursor is 60% ovarian and 40% adrenal in derivation.
Patients with androgen-secreting ovarian or adrenal tumors can present with hirsutism, amenorrhea, and signs of virilization. Although the clinical picture of symptom onset and progression is more predictive than androgen levels, their testosterone level may be greater than 150 ng/dL and their DHEA-S level may be above 800 mcg/dL. DHEA-S is derived from the adrenal gland, and therefore, elevation of DHEA-S would be suggestive of an adrenal origin.
Follicle-stimulating hormone and luteinizing hormone levels
The follicle-stimulating hormone (FSH) level should be checked to rule out primary ovarian failure. In patients with PCOS, FSH levels are within the reference range or low. Luteinizing hormone (LH) levels are elevated for Tanner stage, sex, and age. The LH-to-FSH ratio is usually greater than 3.
Stimulation testing with a long-acting gonadotropin-releasing hormone (GnRH) agonist induces a characteristic rise in ovarian-derived 17-hydroxyprogesterone after 24 hours. This is thought to be a result of excessive 17-hydroxylase activity.
Thyroid-stimulating hormone and free thyroxine levels
Thyroid dysfunction, rather than PCOS, may be the source of amenorrhea and hirsutism. (In patients with PCOS, thyroid function tests are within the reference range.)
Long-standing primary hypothyroidism can be associated with a markedly elevated circulating thyroid-stimulating hormone (TSH) level. Elevated alpha subunit delivery (from one half of the dimeric TSH molecule) can then cross-react with FSH and LH receptors on breast tissue, leading to premature thelarche and, on ovarian tissue, resulting in a PCOS–like picture. These physical findings of the van Wyk-Grumbach syndrome (ie, juvenile hypothyroidism, precocious puberty, and ovarian enlargement) resolve upon thyroxine replacement therapy.
Because the prevalence of impaired glucose tolerance and type 2 diabetes mellitus is high in women with polycystic ovarian syndrome (PCOS)—particularly those who have a body mass index (BMI) greater than 30 kg/m2, have a strong family history of type 2 diabetes, or are older than 40 years—a 75-g oral glucose-tolerance test (OGTT) should be performed. A 2-hour postload glucose value of less than 140 mg/dL indicates normal glucose tolerance; a value of 140-199 mg/dL indicates impaired glucose tolerance; and a value of 200 mg/dL or higher indicates diabetes mellitus.[47]
Women diagnosed with prepregnancy PCOS should be screened for gestational diabetes before 20 weeks’ gestation.[5] These women have a higher rate of gestational diabetes than women in the general population; therefore, refer them for expert obstetric diabetic consultation if abnormal results are found.
Some women with PCOS have insulin resistance and an abnormal lipid profile (cholesterol >200 mg/dL; LDL >160 mg/dL). Approximately one third of women with PCOS who are overweight have impaired glucose tolerance or type 2 diabetes mellitus by 30 years of age.[48]
A study concluded that insulin resistance and inflammatory markers may help identify adolescent girls with PCOS who are at the highest risk of developing the metabolic syndrome.[49] Metabolic heterogeneity also exists in women with PCOS according to phenotypic subgroup, with metabolic dysfunction confined to the subgroup with both oligomenorrhea and hyperandrogenic features.[50]
Ovarian ultrasonography, preferably accomplished by using a transvaginal approach, can be performed to assess ovarian morphology. Perform ultrasonography if the pelvic examination is inadequate, the patient has abdominal pain, testosterone levels are unusually high (eg, >200 ng/dL), it is needed to support the diagnostic criteria, or the patient is amenorrheic (to assess the endometrial thickness and exclude anatomic causes of amenorrhea). (See the image below.)
View Image
Longitudinal transabdominal ultrasonogram of an ovary. This image reveals multiple peripheral follicles.
CT scan and MRI
If a tumor is suspected, obtain a computed tomography (CT) scan or magnetic resonance image (MRI) to visualize the adrenals and ovaries. MRI is an excellent method for imaging the ovaries and is a useful alternative in very obese women in whom the ovaries might not be visualized with transvaginal ultrasonography (TVUS) and in those patients in whom TVUS is inappropriate, such as adolescent girls.
In polycystic ovarian syndrome (PCOS), histologic changes of the ovary include enlarged, sclerotic, multiple cystic follicles (see the image below). As previously stated, a woman is diagnosed with polycystic ovaries (as opposed to PCOS) if she has 20 or more follicles in at least 1 ovary, measuring 2-9 mm in diameter, or a total ovarian volume greater than 10 cm3.[1]
View Image
Low power, H and E of an ovary containing multiple cystic follicles in a patient with PCOS.
Certain lifestyle changes, such as diet and exercise, are considered first-line treatment for adolescent girls and women with polycystic ovarian syndrome (PCOS).[45] Pharmacologic treatments are reserved for so-called metabolic derangements, such as anovulation, hirsutism, and menstrual irregularities. Medications for such conditions include oral contraceptives, metformin, prednisone, leuprolide, clomiphene, and spironolactone.
Mean platelet volume (MPV) is a marker associated with adverse cardiovascular events, and women with newly diagnosed PCOS appear to have significantly elevated MPV levels.[51] Kabil Kucur et al reported that use of ethinyl estradiol/cyproterone acetate or metformin for the treatment of women with PCOS seemed to have similar beneficial effects in reducing MPV.[51]
Consultation with an endocrinologist is necessary for performing an adrenocorticotropic hormone (ACTH) stimulation test or for other causes of menstrual irregularity such as thyroid disease or pituitary adenoma. A reproductive endocrinologist should be consulted if the patient is infertile and desires pregnancy.[52]
In October 2013, the Endocrine Society released practice guidelines for the diagnosis and treatment of PCOS. The following were among their conclusions[53] :
Use the Rotterdam criteria for diagnosing PCOS (presence of 2 of the following: androgen excess, ovulatory dysfunction, or polycystic ovaries).
In adolescents with PCOS, hyperandrogenism is central to the presentation; hormonal contraceptives and metformin are treatment options in this population.[54]
Postmenopausal women do not have a consistent PCOS phenotype.
Exclude alternate androgen-excess disorders and risk factors for cardiovascular disease, diabetes, endometrial cancer, mood disorders, and obstructive sleep apnea.
For menstrual abnormalities and hirsutism/acne, hormonal contraceptives are first-line treatment.
For infertility, clomiphene is first-line treatment.
For metabolic/glycemic abnormalities and for improving menstrual irregularities, metformin is beneficial.
Metformin is of limited or no benefit for managing hirsutism, acne, or infertility.
Overall, thiazolidinediones have an unfavorable risk-benefit ratio.
More investigation is needed to determine the roles of weight loss and statins in PCOS.
The American College of Obstetricians and Gynecologists (ACOG) and the Society of Obstetricians and Gynaecologists of Canada (SOGC) indicate that lifestyle modifications such as weight loss and increased exercise in conjunction with a change in diet consistently reduce the risk of diabetes. This approach has been found to be comparable to or better than treatment with medication and should therefore be considered first-line treatment in managing women with polycystic ovarian syndrome (PCOS).[3, 4] These modifications have been effective in restoring ovulatory cycles and achieving pregnancy in obese women with PCOS. Weight loss in obese women with PCOS also improves hyperandrogenic features.
Medical management of PCOS is aimed at the treatment of metabolic derangements, anovulation, hirsutism, and menstrual irregularity. The use of insulin-sensitizing drugs to improve insulin sensitivity is associated with a reduction in circulating androgen levels, as well as improvement in both the ovulation rate and glucose tolerance.[4] The Endocrine Society has published a clinical practice guideline on hirsutism evaluation and treatment in premenopausal women.[55] ACOG notes that eflornithine in conjunction with laser treatment is superior to laser therapy alone in treating hirsutism.[4]
First-line medical therapy usually consists of an oral contraceptive to induce regular menses. The contraceptive not only inhibits ovarian androgen production but also increases sex hormone-binding globulin (SHBG) production. ACOG recommends use of combination low-dose hormonal contraceptive agents for long-term management of menstrual dysfunction.[4] If symptoms such as hirsutism are not sufficiently alleviated, an androgen-blocking agent may be added. Pregnancy should be excluded before therapy with oral contraceptives or androgen-blocking agents is started.
First-line treatment for ovulation induction when fertility is desired is clomiphene citrate.[3, 4, 6] Second-line strategies may be equally effective in infertile women with clomiphene citrate–resistant PCOS.
A randomized study suggested that combined metformin/letrozole and bilateral ovarian drilling are similarly effective as second-line treatment in infertile women with clomiphene citrate–resistant PCOS.[56] In this study, 146 patients were given metformin and letrozole, and 73 underwent bilateral ovarian drilling. There was significant reduction in testosterone, fasting insulin, and ratio of fasting glucose to fasting insulin in the metformin/letrozole group. There was significant reduction in follicle-stimulating hormone (FSH), luteinizing hormone (LH), and ratio of LH to FSH in the bilateral drilling group. There was no significant difference between the patients in the 2 groups regarding cycle regularity, ovulation, pregnancy rate, and abortion rate.[56]
Another study, a double-blind trial by Legro et al, found that letrozole is more effective than clomiphene in the treatment of infertility in PCOS. Based on treatment periods of up to five cycles, the study, which involved 750 anovulatory women with PCOS, found that the birth rates for letrozole and clomiphene were 27.5% and 19.1%, respectively. The rate of congenital abnormalities and the risk of pregnancy loss in the letrozole and clomiphene groups were found to be comparable, although the likelihood of twin births was lower with letrozole.[57, 58]
Metformin
If the patient develops type 2 diabetes mellitus, consider treatment with oral antihyperglycemic drugs, such as metformin. Metformin can also be considered in other women with PCOS who are insulin resistant and therefore at risk of developing cardiovascular disease, even women without type 2 diabetes.
Clinical trials have shown that metformin can effectively reduce androgen levels, improve insulin sensitivity, and facilitate weight loss in patients with PCOS as early as adolescence.[59, 60, 61, 62] One study concluded that the use of metformin throughout pregnancy was associated with a 9-fold decrease in gestational diabetes in women with PCOS.[63] In addition to having the potential to reduce gestational diabetes in pregnant women with PCOS, metformin may also reduce the risk of preeclampsia in this population.[64]
A long-term study suggested that metformin continued to improve the metabolic profile of women with PCOS over a 36-month treatment course, particularly improving circulating high-density lipoprotein cholesterol (HDL-C), diastolic blood pressure, and body mass index (BMI).[65] However, data are insufficient as yet to recommend metformin to all women with PCOS.
Other agents
If the patient has concomitant adrenal hyperandrogenism, treatment with low-dose prednisone or dexamethasone may be considered.
Depot leuprolide acetate (Lupron) is effective in suppressing ovarian hormone production, which effectively induces menopause; therefore, this drug must be accompanied by hormone replacement therapy. This treatment approach has not gained widespread favor.
Several medications, including benzoyl peroxide, topical retinoids (Retin-A), and topical and oral antibiotics, are effective for acne treatment. Systemic isotretinoin is used for severe or refractory cases.
On March 1, 2012, the US Food and Drug Administration (FDA) updated health care professionals regarding changes to the prescribing information concerning interactions between protease inhibitors (drugs for management of human immunodeficiency virus [HIV] and hepatitis B infection) and certain statin drugs. The combination of these drugs may raise the blood levels of statins and increase the risk for myopathy. Rhabdomyolysis, the most serious form of myopathy, can cause kidney damage and lead to kidney failure, which is life threatening.[66]
On February 28, 2012, the FDA approved important safety label changes for the class of cholesterol-lowering drugs known as statins, including removal of routine monitoring of liver enzymes. Information about the potential for generally nonserious and reversible cognitive side effects and reports of increased blood glucose and glycosylated hemoglobin (HbA1c) levels was added to the statin labels. In addition, extensive contraindication and dose-limitation updates were added to the lovastatin label in situations when this drug is taken with certain medications that can increase the risk for myopathy.[67]
On June 8, 2011, the FDA notified health care professionals of its recommendations for limiting the use of the highest approved dose (80 mg) of the cholesterol-lowering medication simvastatin (Zocor) because of increased risk of muscle damage. The FDA required changes to the simvastatin label to add new contraindications (should not be used with certain medications) and dose limitations for using simvastatin with certain medications.[68]
Sibutramine
On October 8, 2010, Abbott Laboratories and the FDA notified health care professionals and patients about the voluntary withdrawal of the obesity drug sibutramine (Meridia) from the US market because of clinical trial data indicating an increased risk of heart attack and stroke.[69]
In patients with polycystic ovarian syndrome (PCOS) who are obese, endocrine-metabolic parameters markedly improve after 4-12 weeks of dietary restriction. Their sex hormone–binding globulin (SHBG) levels rise, and free testosterone levels fall by 2-fold.[70] Serum insulin and insulin-like growth factor-1 (IGF-1) levels also decrease. In patients with PCOS who are obese, weight loss is associated with a reduction of hirsutism and a return of ovulatory cycles in 30% of women, thereby improving pregnancy rates, as well as improving glucose tolerance and lipid levels.[15, 4]
The Androgen Excess and Polycystic Ovary Syndrome Society recommends lifestyle management as the primary therapy for metabolic complications in overweight and obese women with PCOS.[71] A moderate amount of daily exercise increases levels of IGF-1 binding protein and decreases levels of IGF-1 by 20%. Modest weight loss of 2-5% of total body weight can help restore ovulatory menstrual periods in obese patients with PCOS. A decrease of 500-1000 calories daily, along with 150 minutes of exercise per week, can cause ovulation.
Metformin, an antidiabetic drug, improves insulin resistance and decreases hyperinsulinemia in patients with PCOS.[72] This drug also has a small but beneficial effect on metabolic syndrome, as well as potentially causing a modest reduction in androgen levels (11%).[5] Note that women with a body mass index (BMI) greater than 37 kg/m2 may not have a good response to metformin.[5] An Italian study of 33 patients with PCOS demonstrated that metformin affected thyroid hormone by lowering thyroid-stimulating hormone (TSH) in hypothyroid patients with PCOS, regardless of whether these individuals received levothyroxine or were untreated.[73]
Ascertain that kidney and liver function are normal and that the patient does not have advanced congestive heart failure before starting metformin therapy. The usual starting dose is 500 mg given orally twice a day. Because common adverse effects are nausea, vomiting, and diarrhea, metformin should be taken with meals. Patients who develop these adverse effects can be instructed to decrease the dosage to once a day for a week and then gradually increase the dosage. Also, inform patients that there is a high likelihood that they will have ovulatory cycles while taking metformin. The US Food and Drug Administration (FDA) has not approved metformin for this indication.
A secondary analysis of two randomized, double blind, placebo-controlled trials that included 182 children of mothers with PCOS reported that children exposed to metformin had higher BMI and increased prevalence of overweight/obesity at 4 years of age. The study found that at 4 years of age, the metformin group had higher weight z-score than the placebo group; difference in means 0.38 (0.07 to 0.69), p=0.017, and higher BMI z-score; difference in means 0.45 (0.11 to 0.78), p=0.010. There were also more overweight/obese children in the metformin group; 26 (32%) than in the placebo group; 14 (18%) at 4 years of age; odds ratio (95% CI): 2.17 (1.04 to 4.61), p=0.038. More studies are needed to examine this association.[74]
The American College of Obstetricians and Gynecologists (ACOG) and Society of Obstetricians and Gynaecologists of Canada (SOGC) recommend clomiphene citrate as first-line therapy to stimulate ovulation when fertility is desired.[3, 4, 6]
An alternative first line therapy to stimulate ovulation is letrozole.[58]
Second-line therapy, when clomiphene citrate fails to lead to pregnancy, is either exogenous gonadotropins or laparoscopic ovarian surgery.[3, 4] If gonadotropins are used, a low-dose regimen is recommended,[4] and patients must be monitored with ultrasonography and laboratory studies.[3] Note that gonadotropin therapy is expensive and is associated with an increased risk of multiple pregnancy and ovarian hyperstimulation syndrome.[3]
Evidence suggests that metformin frequently, but not universally, improves ovulation rates and pregnancy rates in women with polycystic ovarian syndrome (PCOS), especially in obese women.[3, 4, 75] In addition, pretreatment with metformin has been shown to enhance the efficacy of clomiphene for inducing ovulation.[76] Consider the combination of metformin and clomiphene in older women with visceral obesity and clomiphene resistance.[3] However, this combination doesn’t significantly improve the live birth rate relative to clomiphene monotherapy.[3] Whether short-course metformin pretreatment (less than 4 weeks) is as effective as conventional long-course metformin remains uncertain.[6, 77]
A study found that N-acetylcysteine may enhance the effect of clomiphene citrate in inducing ovulation in patients with PCOS.[78]
Patients with PCOS who are infertile but desire pregnancy should be referred to a reproductive endocrinologist for further evaluation and management of infertility. Morbidly obese women with PCOS should also be referred for pregnancy risk[3] ; metabolic surgery may be considered in morbidly obese women with PCOS, because many features of this syndrome are reversible with successful weight loss. In vitro fertilization (IVF) is reserved for women with PCOS and unsuccessful gonadotropin therapy or those with other indications for this procedure.[3]
A study by Chen et al found that among infertile women with PCOS, frozen-embryo transfer was associated with a higher rate of live birth, a lower risk of the ovarian hyperstimulation syndrome, and a higher risk of preeclampsia after the first transfer than was fresh-embryo transfer.[79, 80]
A clear primary treatment for hirsutism in women with polycystic ovarian syndrome (PCOS) remains lacking.[4] However, short-term, nonpharmacologic treatments of hirsutism include shaving and the use of chemical depilatories and/or bleaching cream.[81] Plucking or waxing unwanted hair can result in folliculitis and ingrown hairs. Long-term, more permanent measures for unwanted hairs include electrolysis and laser treatment.
Adjunctive eflornithine with laser treatment is superior to laser therapy alone in treating hirsutism.[4] Eflornithine (Vaniqa) is a topical cream that can be used to slow hair growth. This agent works by inhibiting ornithine decarboxylase, which is essential for the rapidly dividing cells of hair follicles.
Weight reduction decreases androgen production in women who are obese; therefore, losing weight can slow hair growth.
Women who do not wish to become pregnant can be effectively treated for hirsutism with oral contraceptives.[82] Oral contraceptives slow hair growth in 60-100% of women with hyperandrogenemia. Therapy can be started with a preparation that has a low dose of estrogen and a nonandrogenic progestin. Preparations that have norgestrel and levonorgestrel should be avoided because of their androgenic activity. There is also a risk of thrombotic events in obese women who use oral contraceptives; therefore, the proper precautions should be exercised to prevent such events. Oral contraceptives containing cyproterone acetate are also very effective in the treatment of more severe hirsutism[83] ; however, this combination of agents has not been approved by the FDA for use in the United States.
Antiandrogens, such as spironolactone, are effective for hirsutism.[84] Spironolactone (50-100 mg twice daily) is an effective primary therapy for hirsutism. Because of the potential teratogenic effects of spironolactone, patients require an effective form of contraception (eg, an oral contraceptive). Adverse effects of spironolactone include gastrointestinal discomfort and irregular menstrual bleeding, which can be managed by adding an oral contraceptive.
Ovulation induction with clomiphene citrate, metformin, or both does not alter hirsutism in infertile hirsute women with PCOS.[85]
Patients with polycystic ovarian syndrome (PCOS) who have impaired glucose tolerance should start a comprehensive program of diet and exercise to reduce their risk of developing diabetes mellitus. Encourage moderate physical activity, provided the patient has no contraindications. Discourage smoking because of the increased risk of cardiovascular disease. In addition, obese women with PCOS can benefit from a low-calorie diet for weight reduction.
A diet patterned after the type 2 diabetes diet has been recommended for PCOS patients.[86] This diet emphasizes increased fiber; decreased refined carbohydrates, trans fats, and saturated fats; and increased omega-3 and omega-9 fatty acids. However, in some obese patients with PCOS, weight loss has improved menstrual regularity.[87] Omega-3 fatty acid supplementation has been shown to reduce liver fat content and other cardiovascular risk factors in women with PCOS, including those with hepatic steatosis, although these effects have not yet been proven to translate into a reduction in cardiometabolic events.[88]
A study by Jamilian et al found that soy isoflavone administration for 12 weeks in women with PCOS significantly improved markers of insulin resistance, hormonal status, triglycerides, and biomarkers of oxidative stress.[89, 90]
Women with an abnormal lipid profile should be counseled on ways to manage the dyslipidemia. Such measures include eating a diet low in cholesterol and saturated fats and increasing physical activity. Guidelines from the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, or ATP III) (2001) serve as a guide for the treatment of women with PCOS and dyslipidemia. The NCEP is currently updating the ATP III guidelines; Readers are encouraged to check the National Health Lung and Blood Institute Web site for the most recent guidelines: http://www.nhlbi.nih.gov/guidelines/cholesterol/atp4/index.htm
Accumulating evidence suggests an association of vitamin D deficiency with metabolic syndrome. One study found insufficient levels of 25-hydroxyvitamin D (< 30 ng/mL) in almost 75% of PCOS patients, with lower levels in those with metabolic syndrome (17.3 ng/mL) than in those without metabolic syndrome (25.8 ng/mL).[91]
Surgical management of polycystic ovarian syndrome (PCOS) is aimed mainly at restoring ovulation. Ovarian wedge resection has fallen out of favor because of postoperative adhesion formation and the successful introduction of ovulation-inducing medications.
Various laparoscopic methods, including electrocautery, laser drilling, and multiple biopsy, have been used with the goal of creating focal areas of damage in the ovarian cortex and stroma. According to the Society of Obstetricians and Gynaecologists of Canada (SOGC), laparoscopic ovarian drilling may be considered in women with clomiphene-resistant PCOS, especially in the presence of other laparoscopic indications.[3] A small French study also suggested that surgical management via ovarian drilling with hydrolaparoscopy may be beneficial in cases of PCOS that are resistant to clomiphene citrate.[92]
Potential complications must be considered as well. These include formation of adhesions and ovarian atrophy. Multiple pregnancy rates are lower with ovarian drilling than with gonadotropin treatment (1% vs 16%, respectively), but there are ongoing concerns about the long-term effects of ovarian drilling on ovarian function.[93]
Polycystic ovarian syndrome (PCOS) is a disease with many long-term complications. Patients need regular follow-up with their physicians for early detection and management of any untoward sequelae associated with the syndrome (see Prognosis).
Women with PCOS who conceive are at increased risk for gestational diabetes, preeclampsia, cesarean delivery, and preterm and postterm delivery. In addition, their newborns are at increased risk of being large for gestational age, but they are not at increased risk of stillbirth or neonatal death.[94]
Participation in a peer support group may alleviate distress and improve self-management.[95]
In November 2015, the American Association of Clinical Endocrinologists (AACE), American College of Endocrinology (ACE), and Androgen Excess and PCOS Society (AES) released new guidelines in the evaluation and treatment of PCOS. Among their opinions and recommendations are the following[96] :
See the list below:
The diagnostic criteria for PCOS should include two of the following three criteria: chronic anovulation, hyperandrogenism (clinical/biologic), and polycystic ovaries
In addition to clinical findings, obtain levels of serum 17-hydroxyprogesterone and anti-Müllerian hormone to aid the diagnosis of PCOS.
Free testosterone levels are more sensitive for determining androgen excess than total T levels and should be obtained with equilibrium dialysis techniques
Women with PCOS should also be evaluated and/or treated for reproductive function, hirsutism, alopecia, and acne.
Adolescent girls with PCOS remain a diagnostic and therapeutic challenge. Girls whose oligomenorrhea persists 2-3 years past menarche typically have ongoing menstrual anomalies and are at higher risk for having an underlying ovarian or adrenal dysfunction. First-line monotherapy in this age group includes metformin monotherapy and/or combination therapy with oral contraceptive agents and antiandrogen agents.
Drugs used in the treatment of polycystic ovarian syndrome (PCOS) include metformin (off-label use), spironolactone, eflornithine (topical cream to treat hirsutism), and oral contraceptives. Oral contraceptives containing a combination of estrogen and progestin increase sex hormone–binding globulin (SHBG) levels and thereby reduce the free testosterone level. Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels are also suppressed. This restores cyclic exposure of the endometrium to estrogen-progestin, with the resumption of menstrual periods and decreased hirsutism. However, the use of oral contraceptives may be associated with an increased risk of thrombosis and metabolic abnormalities.
An oral contraceptive containing ethinyl estradiol and a progestin with minimal androgenic activity, such as norgestimate, norethindrone, or desogestrel, should be selected. Ethinyl estradiol combined with drospirenone (Yasmin) has a progestin that acts as an antiandrogen and thus may add antiandrogenic effects.
Withdrawal bleeding can be induced with medroxyprogesterone (Provera) given for 5-10 days before the start of oral contraceptive therapy. Pregnancy must be ruled out before oral contraceptive therapy is started.
The indications, contraindications, and adverse effects of metformin therapy should be carefully reviewed with the patient before such therapy is begun. In addition, women starting metformin therapy should be informed that such treatment may result in ovulatory menstrual cycles and increase the probability of pregnancy. It is worth noting that metformin has the potential to reduce preeclampsia and gestational diabetes in pregnant women with PCOS.[64]
Women taking spironolactone require reliable contraception. An oral contraceptive is preferable, but if that form of contraception is contraindicated, another type of contraception should be used.
FDA safety alerts
Statins
On March 1, 2012, the US Food and Drug Administration (FDA) notified health care professionals of updates to the prescribing information concerning interactions between protease inhibitors (drugs for management of human immunodeficiency virus [HIV] and hepatitis B infection) and certain statin drugs. Protease inhibitors and statins taken together may raise the blood levels of statins and increase the risk for muscle injury (myopathy). The most serious form of myopathy, called rhabdomyolysis, can damage the kidneys and lead to kidney failure, which can be fatal.
On February 28, 2012, the FDA approved important safety label changes for the class of cholesterol-lowering drugs known as statins. The changes include removal of routine monitoring of liver enzymes from drug labels. Information about the potential for generally non-serious and reversible cognitive side effects and reports of increased blood glucose and glycosylated hemoglobin (HbA1c) levels has been added to the statin labels. The lovastatin label has been extensively updated with new contraindications and dose limitations when it is taken with certain medicines that can increase the risk for muscle injury.
On June 8, 2011, the FDA notified health care professionals that it recommended limiting the use of the highest approved dose of the cholesterol-lowering medication simvastatin (80 mg) because of increased risk of muscle damage. The FDA required changes to the simvastatin label to add new contraindications (should not be used with certain medications) and dose limitations for using simvastatin with certain medicines.
Sibutramine
On October 8, 2010, Abbott Laboratories and the FDA notified health care professionals and patients about the voluntary withdrawal of sibutramine (Meridia), an obesity drug, from the US market because of clinical trial data indicating an increased risk of heart attack and stroke.
Clinical Context:
Metformin reduces insulin resistance; it is an insulin sensitizer. Hepatic glucose output is decreased and peripheral, insulin-stimulated uptake is increased. Metformin may also decrease TSH levels in hypothyroidism patients with polycystic ovarian syndrome (PCOS), regardless of whether they are treated with thyroxine or not (off-label use).
Clinical Context:
Insulin is effective when metformin cannot control hyperglycemia. Several short-acting and long-acting dosage forms are available. Insulin must be initiated in conjunction with dietary assessment and nutritional management by a registered clinical dietitian as part of an overall weight-management system. Insulin is seldom indicated as a first-line agent for PCOS, unless a patient also has a diagnosis of diabetes.
Clinical Context:
Spironolactone is an antiandrogen agent that is a nonspecific androgen-receptor blocker. It may be used in conjunction with oral contraceptive pills to treat hirsutism by reducing hair diameter. Initiate oral contraceptive pills first to avoid worsening of menstrual irregularities and to prevent pregnancy, because spironolactone may have feminizing effects on the male fetus. Periodically assess adverse effects (eg, fluid and electrolyte abnormalities). Spironolactone is also used as a potassium-sparing diuretic.
Clinical Context:
Leuprolide is not a first-line agent in PCOS and therefore is not used often for this syndrome. This agent suppresses ovarian and testicular steroidogenesis by decreasing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels. Gonadotropin-releasing hormone (GnRH) analogs with oral contraceptive pills are an option to consider for hirsutism in women who fail to respond to combined therapy with spironolactone and oral contraceptive pills. Anatomic effects of androgens (eg, clitoromegaly and deepening of the voice) are not responsive to GnRH analogs.
Clinical Context:
Finasteride is a 5-alpha-reductase inhibitor that is approved for use in benign prostatic hypertrophy and in male-pattern alopecia. This agent blocks conversion of testosterone to its more active metabolite, dihydrotestosterone. Finasteride tends to be a second-line agent for hirsutism in PCOS, when hirsutism persists despite the use of first-line agents (ie, oral contraceptives). This agent is more effective when used in combination with oral contraceptive pills. Due to the potential for teratogenic effects (eg, risk of genital ambiguity in male fetuses), finasteride therapy must be used in conjunction with a reliable form of contraception in sexually active women.
Antiandrogen agents block androgen receptors, thereby inhibiting the effects of male sex hormones. These agents may be used to treat hirsutism in women with PCOS.
Clinical Context:
Eflornithine is indicated for the reduction of unwanted facial hair in women. It interferes with ornithine decarboxylase (needed for hair growth) in skin hair follicles. Eflornithine does not have a depilatory action; instead, it appears to retard hair growth and improve appearance where applied. Improvement may be seen in as short a period as 4-8 weeks, although 6 months of treatment may be required. Keep in mind that in clinical studies, hair returned to its previous condition 8 weeks after discontinuation of eflornithine (ie, hirsutism may return following discontinuation of eflornithine).
Note: The use of eflornithine has been studied only on the face and adjacent involved areas under the chin of individuals with hypertrichosis; therefore, limit use of this drug to these areas. Patients will likely need other hair-removal methods in conjunction with eflornithine therapy.
Clinical Context:
Ethinyl estradiol reduces the secretion of LH and FSH from the pituitary by decreasing the amount of GnRH. Use ethinyl estradiol 30-35 mg combined with any form of progesterone. Restoration of the regular menstrual cycles prevents endometrial hyperplasia associated with anovulation. Improvement of hyperandrogenic effects are seen in 60-100% of women, but usually, at least 6-12 months of use are required. Perform a pregnancy test before therapy. If the patient has had no menstrual period for 3 months, induce withdrawal bleeding with medroxyprogesterone acetate (Provera) 5-10 mg/day for 10 days; then, begin therapy with oral contraceptives.
Clinical Context:
Medroxyprogesterone has no effect on androgen production. Progestins stop the proliferation of endometrial cells, allowing organized sloughing of cells after withdrawal.
Oral contraceptive agents reduce the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland by decreasing the amount of gonadotropin-releasing hormone (GnRH). All oral contraceptives decrease ovarian androgen production. By inhibiting gonadotropin secretion and, therefore, tertiary follicle development, ovarian secretion of testosterone and androstenedione is decreased. All oral contraceptives increase sex hormone-binding globulin (SHBG) and, therefore, reduce free testosterone. Evidence indicates that high doses of contraceptive progestins may inhibit 5-alpha reductase. Oral contraceptives also decrease the production of adrenal androgens, particularly dehydroepiandrosterone sulfate (DHEA-S).
Different contraceptive preparations have different effects on ovarian androgen production and SHBG. However, they all reduce levels of free testosterone equally (by approximately 50%). Free testosterone levels achieved with oral contraceptive preparations are unrelated to the increased levels of SHBG. Preparations that result in higher SHBG levels also result in higher total testosterone levels. That is, a decrease in free testosterone level is the same for all oral contraceptives and, although some of these preparations increase SHBG levels more than others, this is off-set by a concomitant increase in total testosterone level.
Restoration of regular menstrual cycles prevents endometrial hyperplasia associated with anovulation. Oral contraceptives also improve acne and hirsutism.
Clomiphene citrate, a selective estrogen receptor modulator, binds to estrogen receptors, inducing ovulation by increasing the output of pituitary gonadotropins.
Clinical Context:
Benzoyl peroxide elicits action by releasing active oxygen; this agent is effective in vitro against Propionibacterium acnes, an anaerobe found in sebaceous follicles and comedones. Benzoyl peroxide also elicits a keratolytic and desquamative effect, which may also contribute to its efficacy.
Clinical Context:
The exact mechanism of tretinoin is unknown. It appears to decrease cohesiveness of follicular epithelial cells with a decrease microcomedo formation. This agent also increases turnover of follicular cells to cause extrusion of comedones.
Clinical Context:
Adapalene binds to specific retinoic acid nuclear receptors and modulates cellular differentiation, keratinization, and inflammatory processes. Its exact mechanism of action for treatment of acne is unknown.
Clinical Context:
Although its exact mechanism of action is unknown, erythromycin inhibits protein synthesis in susceptible organisms by reversibly binding to 50S ribosomal subunits, thereby inhibiting translocation of aminoacyl transfer-RNA and inhibiting polypeptide synthesis.
Clinical Context:
Clindamycin is an antibacterial agent that binds to the 50S ribosomal subunits of susceptible bacteria and prevents elongation of peptide chains by interfering with peptidyl transfer, thereby suppressing protein synthesis. This agent reduces surface fatty acids on the skin; however, its exact mechanism of action in treating acne is unknown.
Clinical Context:
Sodium sulfacetamide is a para-aminobenzoic acid (PABA) inhibitor. This agent restricts folic acid synthesis that is required for bacterial growth.
What is polycystic ovarian syndrome (PCOS)?What are the signs and symptoms of polycystic ovarian syndrome (PCOS)?Which physical findings suggest polycystic ovarian syndrome (PCOS)?Which lab tests are performed in the workup of polycystic ovarian syndrome (PCOS)?Which imaging studies are performed in the workup of polycystic ovarian syndrome (PCOS)?Which procedures are performed in the workup of polycystic ovarian syndrome (PCOS)?What is the first-line treatment for polycystic ovarian syndrome (PCOS)?What are the pharmacologic treatments for polycystic ovarian syndrome (PCOS)?What are the surgical options for treating polycystic ovarian syndrome (PCOS)?What are the signs and symptoms of polycystic ovarian syndrome (PCOS)?What are the diagnostic criteria for polycystic ovarian syndrome (PCOS)?What is the role of androgens and estrogen metabolism in the etiology of polycystic ovarian syndrome (PCOS)?What is the role of insulin resistance in the etiology of polycystic ovarian syndrome (PCOS)?What is the role of anovulation in the etiology of polycystic ovarian syndrome (PCOS)?What is the role of hyperinsulinemia in the etiology of polycystic ovarian syndrome (PCOS)?How are ovaries characterized in polycystic ovarian syndrome (PCOS)?What functional abnormality may be found in women with polycystic ovarian syndrome (PCOS)?What is the role of genetics in the etiology of polycystic ovarian syndrome (PCOS)?Which gene linked to obesity may be an etiologic factor in polycystic ovarian syndrome (PCOS)?Which genes have been associated with polycystic ovarian syndrome (PCOS)?What is the prevalence of polycystic ovarian syndrome (PCOS) in the US?What is the ethnic variability for hirsutism among women with polycystic ovarian syndrome (PCOS)?In what age group is polycystic ovarian syndrome (PCOS) commonly diagnosed?Polycystic ovarian syndrome (PCOS) increases the risk of developing which conditions?What is the prevalence of insulin resistance in women with polycystic ovarian syndrome (PCOS)?What are the AACE and the ACE recommendations for diabetes screening in women with polycystic ovarian syndrome (PCOS)?What is the risk for endometrial hyperplasia and carcinoma in patients with polycystic ovarian syndrome (PCOS)?What is the risk for breast or ovarian cancer in patients with polycystic ovarian syndrome (PCOS)?What education should be given to patients with polycystic ovarian syndrome (PCOS)?Which family history suggests polycystic ovarian syndrome (PCOS)?Which menstrual irregularities suggest polycystic ovarian syndrome (PCOS)?Which manifestations of hyperandrogenism suggest polycystic ovarian syndrome (PCOS)?What are the ACOG recommendations for screening with 17-hydroxyprogesterone levels in women with polycystic ovarian syndrome (PCOS)?What effect does polycystic ovarian syndrome (PCOS) have on fertility?What is the prevalence of obesity among women with polycystic ovarian syndrome (PCOS)?What is the prevalence of metabolic syndrome among women with polycystic ovarian syndrome (PCOS)?Which cardiovascular disorders are at increased risk in women with polycystic ovarian syndrome (PCOS)?What are the ACOG recommendations for diabetes screening in women with polycystic ovarian syndrome (PCOS)?How prevalent is sleep apnea among women with polycystic ovarian syndrome (PCOS)?Which findings of hyperandrogenism suggest polycystic ovarian syndrome (PCOS)?What is the modified Ferriman-Gallwey (mFG) scoring system and how is it used in the evaluation of suspected polycystic ovarian syndrome (PCOS)?How prevalent is abdominal obesity in women with polycystic ovarian syndrome (PCOS)?What causes acanthosis nigricans in women with polycystic ovarian syndrome (PCOS)?How is acanthosis nigricans staged in women with polycystic ovarian syndrome (PCOS)?What does a finding of high blood pressure suggest in women with polycystic ovarian syndrome (PCOS)?What are the physical findings of ovaries in polycystic ovarian syndrome (PCOS)?Which disorders should be included in the differential diagnosis of polycystic ovarian syndrome (PCOS)?What are the differential diagnoses for Polycystic Ovarian Syndrome?How is polycystic ovarian syndrome (PCOS) diagnosed?What baseline screening tests are recommended by the RCOG for women with suspected polycystic ovarian syndrome (PCOS)?When is an infertility evaluation indicated in women with suspected polycystic ovarian syndrome (PCOS)?When should lab samples be obtained for the workup of polycystic ovarian syndrome (PCOS)?How is late-onset congenital hyperplasia due to 21-hydroxilase deficiency differentiated from polycystic ovarian syndrome (PCOS)?When is screening for Cushing syndrome or acromegaly indicated in the workup of polycystic ovarian syndrome (PCOS)?How is hyperprolactinemia differentiated from polycystic ovarian syndrome (PCOS)?What is the role of androgen level testing in the workup of polycystic ovarian syndrome (PCOS)?How are androgen-secreting ovarian or adrenal tumors differentiated from polycystic ovarian syndrome (PCOS)?What is the role of follicle-stimulating hormone (FSH) level testing in the workup of polycystic ovarian syndrome (PCOS)?How is hypothyroidism differentiated from polycystic ovarian syndrome (PCOS)?What is the role of oral glucose-tolerance testing in the workup of polycystic ovarian syndrome (PCOS)?When should pregnant women with polycystic ovarian syndrome (PCOS) be screened for gestational diabetes?What does insulin resistance and inflammatory markers suggest in adolescents with polycystic ovarian syndrome (PCOS)?What is the role of ultrasonography in the workup of polycystic ovarian syndrome (PCOS)?When are CT scanning and MRI indicated in the workup of polycystic ovarian syndrome (PCOS)?Which histologic changes in ovaries suggest polycystic ovarian syndrome (PCOS)?What is the first-line treatment for polycystic ovarian syndrome (PCOS)?What do elevated mean platelet volume (MPV) levels suggest in women with polycystic ovarian syndrome (PCOS)?Which specialists should be consulted in the management of polycystic ovarian syndrome (PCOS)?What are the Endocrine Society practice guidelines for the diagnosis and treatment of polycystic ovarian syndrome (PCOS)?How effective are lifestyle changes in the treatment of polycystic ovarian syndrome (PCOS)?What are the goals of medical management of polycystic ovarian syndrome (PCOS)?What is the first line medical therapy for polycystic ovarian syndrome (PCOS)?How is infertility treated in women with polycystic ovarian syndrome (PCOS)?What is the role of metformin in the treatment of polycystic ovarian syndrome (PCOS)?What is the role of corticosteroids in the treatment of polycystic ovarian syndrome (PCOS)?What is the role of leuprolide acetate (Lupron) in the treatment of polycystic ovarian syndrome (PCOS)?Which medications can be used to treat acne in women with polycystic ovarian syndrome (PCOS)?What are the FDA warnings for the use of statins?What are the AE-PCOS recommendations for the treatment of metabolic complications of polycystic ovarian syndrome (PCOS)?What is the role of metformin in the treatment of polycystic ovarian syndrome (PCOS)?What do the ACOG and SOGC recommend as first-line therapy for ovulation stimulation in women with polycystic ovarian syndrome (PCOS)?What is the second-line therapy for ovulation stimulation in women with polycystic ovarian syndrome (PCOS)?Which drugs are effective in treating anovulation in women with polycystic ovarian syndrome (PCOS)?What are the treatment options for infertility in women with polycystic ovarian syndrome (PCOS)?What is the role of frozen-embryo transfer for the treatment of infertility in polycystic ovarian syndrome (PCOS)?What are the treatment options for hirsutism secondary to polycystic ovarian syndrome (PCOS)?What is the role of contraceptives in the treatment of hirsutism secondary to polycystic ovarian syndrome (PCOS)?What is the role of antiandrogens for the treatment of hirsutism secondary to polycystic ovarian syndrome (PCOS)?Is clomiphene citrate or metformin effective in reducing hirsutism secondary to polycystic ovarian syndrome (PCOS)?How can women with polycystic ovarian syndrome (PCOS) lower their risk for developing diabetes mellitus?What is the role of soy isoflavone in the treatment of women with polycystic ovarian syndrome (PCOS)?How is dyslipidemia treated in women with polycystic ovarian syndrome (PCOS)?Does vitamin D deficiency increase the risk for metabolic syndrome in women with polycystic ovarian syndrome (PCOS)?What is the role of surgical intervention for the treatment of polycystic ovarian syndrome (PCOS)?What monitoring is needed for women with polycystic ovarian syndrome (PCOS)?What conditions are women with polycystic ovarian syndrome (PCOS) at increased risk for during pregnancy?What are the benefits of peer support groups in the treatment of polycystic ovarian syndrome (PCOS)?What are the AACE, ACE, and AE-PCOS guidelines for treatment and management of polycystic ovarian syndrome (PCOS)?Which medications are used to treat polycystic ovarian syndrome (PCOS)?What FDA warnings exist for medications used in the treatment of polycystic ovarian syndrome (PCOS)?Which medications in the drug class Acne Agents, Topical are used in the treatment of Polycystic Ovarian Syndrome?Which medications in the drug class Selective Estrogen Receptor Modulators are used in the treatment of Polycystic Ovarian Syndrome?Which medications in the drug class Oral Contraceptives are used in the treatment of Polycystic Ovarian Syndrome?Which medications in the drug class Topical Hair-Removal Agents are used in the treatment of Polycystic Ovarian Syndrome?Which medications in the drug class Antiandrogens are used in the treatment of Polycystic Ovarian Syndrome?Which medications in the drug class Hypoglycemic Agents are used in the treatment of Polycystic Ovarian Syndrome?
Richard Scott Lucidi, MD, FACOG, Associate Professor of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Virginia Commonwealth University School of Medicine
Disclosure: Nothing to disclose.
Specialty Editors
Frances E Casey, MD, MPH, Director of Family Planning Services, Department of Obstetrics and Gynecology, VCU Medical Center
Disclosure: Nothing to disclose.
Chief Editor
Richard Scott Lucidi, MD, FACOG, Associate Professor of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Virginia Commonwealth University School of Medicine
Disclosure: Nothing to disclose.
Acknowledgements
Elizabeth Alderman, MD Director of Fellowship Training Program, Director of Adolescent Ambulatory Service, Professor of Clinical Pediatrics, Department of Pediatrics, Division of Adolescent Medicine, Albert Einstein College of Medicine and Children's Hospital at Montefiore
Elizabeth Alderman, MD is a member of the following medical societies: American Academy of Pediatrics, American Pediatric Society, North American Society for Pediatric and Adolescent Gynecology, and Society for Adolescent Medicine
Disclosure: Merck Honoraria Speaking and teaching
A David Barnes, MD, PhD, MPH, FACOG Consulting Staff, Department of Obstetrics and Gynecology, Mammoth Hospital (Mammoth Lakes, California), Pioneer Valley Hospital (Salt Lake City, Utah), Warren General Hospital (Warren, Pennsylvania), and Mountain West Hospital (Tooele, Utah)
A David Barnes, MD, PhD, MPH, FACOG is a member of the following medical societies: American College of Forensic Examiners, American College of Obstetricians and Gynecologists, American Medical Association, Association of Military Surgeons of the US, and Utah Medical Association
Disclosure: Nothing to disclose.
Robert J Ferry Jr, MD Le Bonheur Chair of Excellence in Endocrinology, Professor and Chief, Division of Pediatric Endocrinology and Metabolism, Department of Pediatrics, University of Tennessee Health Science Center
Robert J Ferry Jr, MD is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, American Medical Association, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research, and Texas Pediatric Society
Disclosure: Eli Lilly & Co Grant/research funds Investigator; MacroGenics, Inc Grant/research funds Investigator; Ipsen, SA (formerly Tercica, Inc) Grant/research funds Investigator; NovoNordisk SA Grant/research funds Investigator; Diamyd Grant/research funds Investigator; Bristol-Myers-Squibb Grant/research funds Other; Amylin Other; Pfizer Grant/research funds Other; Takeda Grant/research funds Other
Stephen Kemp, MD, PhD Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas for Medical Sciences College of Medicine, Arkansas Children's Hospital
Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, and Southern Society for Pediatric Research
Disclosure: Nothing to disclose.
Lynne Lipton Levitsky, MD Chief, Pediatric Endocrine Unit, Massachusetts General Hospital; Associate Professor of Pediatrics, Harvard Medical School
Lynne Lipton Levitsky, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Diabetes Association, American Pediatric Society, Endocrine Society, Pediatric Endocrine Society, and Society for Pediatric Research
Jordan G Pritzker, MD, MBA, FACOG Assistant Professor of Obstetrics/Gynecology and Women's Health, Women's Comprehensive Health Center, Hofstra University School of Medicine; Attending Physician, Department of Obstetrics and Gynecology, Long Island Jewish Medical Center
Disclosure: Nothing to disclose.
Kathy Silverman, DO Albert Einstein College of Medicine and Montefiore Medical Center
Disclosure: Nothing to disclose.
Phyllis W Speiser, MD Chief, Division of Pediatric Endocrinology, Steven and Alexandra Cohen Children's Medical Center of New York; Professor of Pediatrics, Hofstra-North Shore LIJ School of Medicine at Hofstra University
Phyllis W Speiser, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, Endocrine Society, Pediatric Endocrine Society, and Society for Pediatric Research
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
Andrea Leigh Zaenglein, MD Associate Professor of Dermatology and Pediatrics, Department of Dermatology, Milton S Hershey Medical Center, Pennsylvania State University College of Medicine
Andrea Leigh Zaenglein, MD is a member of the following medical societies: American Academy of Dermatology, American Acne and Rosacea Society, and Society for Pediatric Dermatology
American College of Obstetricians and Gynecologists. Polycystic ovary syndrome. Washington, DC: American College of Obstetricians and Gynecologists; 2009. ACOG practice bulletin; no. 108.
Royal College of Obstetricians and Gynaecologists. Long-term consequences of polycystic ovary syndrome. London, UK: Royal College of Obstetricians and Gynaecologists; 2007. Green-top guideline; no. 33.
Hackethal V. PCOS Diagnosis: One Size Does Not Fit All. Medscape News & Perspective. Available at http://www.medscape.com/viewarticle/884712#vp_1. August 25, 2017; Accessed: August 28, 2017.
American Association of Clinical Endocrinologists. American Association of Clinical Endocrinologists position statement on metabolic and cardiovascular consequences of polycystic ovary syndrome. National Guideline Clearinghouse. Available at http://guideline.gov/summary/summary.aspx?doc_id=7108. Accessed: August 28, 2009.
Emery G. Letrozole produces more babies in women with polycystic ovary syndrome: study. Medscape from WebMD. 2014 Jul 10. Available at http://www.medscape.com/viewarticle/828062. Accessed: July 14, 2014.
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US Food and Drug Administration. Safety: statin drugs - drug safety communication: class labeling change. Posted: February 28, 2012. Available at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm293670.htm. Accessed: May 22, 2012.
US Food and Drug Administration. Safety: Zocor (simvastatin): label change - new restrictions, contraindications, and dose limitations. Posted: June 8, 2011. Available at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm258384.htm. Accessed: May 22, 2012.
US Food and Drug Administration. Safety: Meridia (sibutramine): market withdrawal due to risk of serious cardiovascular events. Posted: October 8, 2010. Available at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm228830.htm. Accessed: May 22, 2012.
Hackethal V. Frozen Embryos Tied to Higher Live Birth Rates in PCOS. Medscape Medical News. Available at http://www.medscape.com/viewarticle/867343. August 11, 2016; Accessed: August 11, 2016.
Busko M. Soy Isoflavones Tied to Improved Metabolic Markers in PCOS. http://www.medscape.com/viewarticle/867076#vp_2. Available at http://www.medscape.com/viewarticle/867076#vp_2. August 04, 2016; Accessed: August 11, 2016.
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