Polycystic Ovary Syndrome (PCOS): Knowledge Base
PCOS is a syndrome, which means that it is defined by a collection of symptoms.
Major features of polycystic ovarian syndrome (PCOS)
Menstrual irregularities
Anovulation
Signs of hyperandrogenism
Origins
Unclear
PCOS can result from abnormal function of the hypothalamic-pituitary-ovarian (HPO) axis.
Key characteristics
Inappropriate gonadotropin secretion, which is more likely a result of, rather than a cause of, ovarian dysfunction
One of the most consistent biochemical features of PCOS is a raised plasma testosterone level
Stein and Leventhal
The first to recognize an association between the presence of polycystic ovaries and signs of hirsutism and amenorrhea. 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. 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.
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.
Polycystic ovaries
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.
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:
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)
These 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%.
The Androgen Excess and PCOS Society (AE-PCOS) published a position statement in 2006 and its criteria in 2009 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, and Cushing syndrome have been exclude
Oligo-ovulation or anovulation
Clinical/biochemical evidence of hyperandrogenism
Polycystic ovaries on ultrasonograms (>12 small antral follicles in an ovary)
Etiology
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. However, individual variation is considerable, and a particular woman might have normal androgen levels.
PCOS is also associated with peripheral insulin resistance, and hyperinsulinemia; obesity can amplify the degree of both.
Insulin resistance in PCOS can be secondary to a post binding 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.
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.
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.
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.
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.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 may have abnormal hair growth; female siblings may have hirsutism and oligomenorrhea; and mothers may have oligomenorrhea. 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. 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.
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. 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.
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. 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.
Support can be found for an important role for 5-alpha reductase in the pathogenesis of this syndrome.
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. 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.
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 DENND1Agene, which interacts with the ERAP1 gene. Elevation in serum ERAP1 has been previously associated with PCOS and obesity.
Epidemiology
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%.
Up to 10% of women are diagnosed with PCOS during gynecologic visits.
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%. In hirsute women, there was a significant increase in the incidence of acne, menstrual irregularities, polycystic ovaries, and acanthosis nigrans.
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.
Outcomes
Evidence suggests 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.
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. 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. 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.
No known association with breast or ovarian cancer has been found; thus, no additional surveillance is needed.
History
Menstrual disorders
Adrenal enzyme deficiencies
Hirsutism
Infertility
Obesity and metabolic syndrome
Diabetes
Menstrual disorders
Patients with PCOS have abnormal menstruation patterns attributed to chronic anovulation. 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.
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 women 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.
Infertility
A subset of women with PCOS are 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.
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.
Many patients with PCOS have characteristics of metabolic syndrome; one study showed a 43% prevalence of metabolic syndrome in women with PCOS.
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.
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. 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.
Sleep apnea
Many women with PCOS have obstructive sleep apnea syndrome (OSAS), which is an independent risk factor for cardiovascular disease. Ask these patients and/or their partners about excessive daytime somnolence; individuals with obstructive sleep apnea experience apnea/hypopnea episodes during sleep. 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.
Physical examination
Hirsutism and virilization
Excessive body hair in a male pattern of distribtuion
Acne
Male pattern balding or alopecia, increased muscle mass, deepening voice, clitoromegaly should also prompt 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.
Diagnosis
Although no agreed-upon diagnostic criteria currently exist for adolescent polycystic ovarian syndrome (PCOS), hyperandrogenemia is essential for the diagnosis in this age group.
All conditions that mimic PCOS should be ruled out before a diagnosis of PCOS is confirmed. The following should be considered in the differential diagnosis of PCOS:
· Ovarian hyperthecosis
· Congenital adrenal hyperplasia (late-onset)
· Drugs (eg, danazol, androgenic progestins)
· Hypothyroidism
· Idiopathic hirsutism
· Familial hirsutism
· Masculinizing tumors of the adrenal gland or ovary (rapid onset of signs of virilization)
· Cushing syndrome (low K+, striae, central obesity, high cortisol; high androgens in adrenal carcinoma)
· Hyperprolactinemia
· Exogenous anabolic steroid use
· Stromal hyperthecosis (valproic acid)
Although obesity itself is not considered part of the differential diagnosis, obesity is associated with insulin resistance or any condition that is associated with severe insulin resistance (eg, insulin receptoropathies), which may clinically manifest in the same way as PCOS. Obesity may unmask features of PCOS in women who are genetically predisposed to this syndrome.
Differential diagnosis
3-Beta–hydroxysteroid dehydrogenase (3BHSD) deficiency - a rare form of congenital adrenal hyperplasia that results in decreased production of all 3 groups of adrenal steroids: mineralocorticoids, glucocorticoids, and sex steroids.
Acromegaly
Adrenal tumor
Congenital adrenal hyperplasia
Hyperprolactinemia
Hyperthyroidism
Hypothyroidism
Cushing syndrome
Ovarian Tumors
Primary amenorrhea
Approach
The diagnosis of polycystic ovarian syndrome (PCOS) requires the exclusion of all other disorders that can result in menstrual irregularity and hyperandrogenism as above.
Biochemical and/or imaging studies must be done to rule out these other possible disorders and ascertain the diagnosis.
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
Free androgen index (defined as total testosterone divided by sex hormone binding globulin [SHBG] × 100, to give a calculated free testosterone level)
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.
Screening studies
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.
NCAH is a widely underdiagnosed disorder in children and adults; a few NCAH cases are detected by newborn-screening programs but most are missed because of the relatively low baseline levels of 17-hydroxyprogesterone (17OHPG). NCAH may be associated with a variety of hyperandrogenic symptoms presenting either in childhood (precocious puberty), or sometimes later in adulthood (acne, infertility).
Precocious puberty may present in childhood, with advanced bone age, accelerated growth, and premature development of pubic or axillary hair. Nevertheless, growth is eventually arrested because of early epiphyseal fusion which compromises final height (tall children, short adults). Also, a high incidence of molecular defects of CYP21 gene has been shown in a series of Greek children with premature adrenarche.
Androgenic alopecia may be the sole symptom in young women with NCAH.
Moreover, women with 21OHD-NCAH may present with hirsutism which is the most common symptom. The prevalence of hirsutism may increase with age, highlighting the progressive nature of NCAH. NCAH was reported in 14% of young women with hirsutism and oligomenorrhea in a retrospective study, and in 1.2–30% of hirsute, oligomenorrheic women in other published series.
Studies in female patients show that NCAH may present with menstrual irregularities, obesity, short stature, infertility or subfertility and skin disorders, including hirsutism, seborrhea and/or acne in the peripubertal period. These clinical characteristics of NCAH do not differ from those in female patients with polycystic ovary syndrome (PCOS), or hyperinsulinemia. Insulin insensitivity in females with NCAH has been described, but it has not been established whether an association with acne exists in these patients. Nevertheless, insulin resistance results in compensatory hyperinsulinemia which, in turn, may increase the responsiveness of the pilosebaceous unit to androgens.
Some women with NCAH present with PCOS. In these cases, either the cyclicity of gonadotropin release is disrupted, or the ovary is directly affected by adrenal androgen excess. As a result, ovarian cysts are formed, which begin to autonomously produce androgens.4,23, The frequency of NCAH in PCOS has been reported in some studies. A prospective study of 107 Greek women with hirsutism and PCOS, showed that 10% were affected by NCAH.34 A prevalence of 9.52% and 33% have been reported in women suffering from hirsutism and PCOS in Turkey. In a study of Spanish women with hirsutism, irregular menses, acne or androgenic alopecia, NCAH was found in 2.2%, based on biochemical evidence or molecular genotype analysis.
The ACTH stimulation test is the best screening test for evaluating adrenal gland function, and it is valuable in cases of mild forms of congenital adrenal hyperplasia with normal basal adrenal steroids. It has been used for the biochemical diagnosis of NCAH due to other enzyme deficiencies. The test should be performed in the early follicular phase (day 3–7 of the menstrual cycle).
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.
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.
Hormone levels
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.
FSH and LH 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.
TSH and Free T4
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.
Glucose, insulin and lipids
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.
Women diagnosed with prepregnancy PCOS should be screened for gestational diabetes before 20 weeks’ gestation. 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.
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. 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.
Imaging
Ovarian ultrasonography, preferably accomplished by using a transvaginal approach, can be performed to assess ovarian morphology.
CT and MRI
If a tumor is suspected a computed tomography (CT) scan or magnetic resonance image (MRI) to visualize the adrenals and ovaries can be utilized. 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.
Histologic findings
In polycystic ovarian syndrome (PCOS), histologic changes of the ovary include enlarged, sclerotic, multiple cystic follicles
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.
Treatment
Certain lifestyle changes, such as diet and exercise, are considered first-line treatment for adolescent girls and women with polycystic ovarian syndrome (PCOS).
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.
In October 2013, the Endocrine Society released practice guidelines for the diagnosis and treatment of PCOS. The following were among their conclusions:
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.
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 (this has recently changed to aromatase inhibitors).
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.
More investigation is needed to determine the roles of weight loss and statins in PCOS.
Lifestyle modifications
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).
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.
Drug treatment
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.
ACOG notes that eflornithine in conjunction with laser treatment is superior to laser therapy alone in treating hirsutism.
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. 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 has recently changed to aromatase inhibitors. Second-line strategies may be equally effective in infertile women with clomiphene citrate–resistant PCOS. A double-blind trial 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.
Metformin
If a woman 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. One study concluded that the use of metformin throughout pregnancy was associated with a 9-fold decrease in gestational diabetes in women with PCOS. 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.
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 a woman has concomitant adrenal hyperandrogenism, treatment with low-dose prednisone or dexamethasone may be considered.
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.
Metabolic derangements
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. 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
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. 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. This drug also has a small but beneficial effect on metabolic syndrome, as well as potentially causing a modest reduction in androgen levels (11%). Note that women with a body mass index (BMI) greater than 37 kg/m2 may not have a good response to metformin. 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.
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.
Anovulation
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.
An alternative first line therapy to stimulate ovulation is letrozole.
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.
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. In addition, pretreatment with metformin has been shown to enhance the efficacy of clomiphene for inducing ovulation.
A study found that N-acetylcysteine may enhance the effect of clomiphene citrate in inducing ovulation in patients with PCOS.
Patients with PCOS who are infertile but desire pregnancy should be referred for further evaluation and management of infertility. Morbidly obese women with PCOS should also be referred for pregnancy risk and metabolic surgery may be considered in morbidly obese women with PCOS, because many features of this syndrome are reversible with successful weight loss. IVF is reserved for women with PCOS and unsuccessful gonadotropin therapy or those with other indications for this procedure.
HIsutism
A clear primary treatment for hirsutism in women with polycystic ovarian syndrome (PCOS) remains lacking. However, short-term, nonpharmacologic treatments of hirsutism include shaving and the use of chemical depilatories and/or bleaching cream. 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. 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.
Antiandrogens, such as spironolactone, are effective for hirsutism. 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.
Nutrition and acitivity
Women 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 management. 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. 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.
A study by Jamilian et al found that soy isoflavone (50mg per day) administration for 12 weeks in women with PCOS significantly improved markers of insulin resistance, hormonal status, triglycerides, and biomarkers of oxidative stress.
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.
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).
The long term
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.
Participation in a peer support group may alleviate distress and improve self-management.
Guidelines Summary
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:
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.
Medication summary
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.
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.
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).
Anti androgen agents block androgen receptors, thereby inhibiting the effects of male sex hormones. These agents may be used to treat hirsutism in women with PCOS.
Spironolactone is an anti androgen 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.
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.
Topical agents
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.
Oral contraceptives
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.
Selective estrogen receptor modulators
Clomiphene citrate, a selective estrogen receptor modulator, binds to estrogen receptors, inducing ovulation by increasing the output of pituitary gonadotropins.
Clomiphene acts directly by producing a surge of luteinizing hormone and could cause ovulation within days.