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Feb.02.2023

Polycystic Ovary Syndrome

Synopsis

Key Points

  • Polycystic ovary syndrome is a heterogeneous endocrine disorder that occurs in about 5% to 10%r1 of reproductive-aged women
  • Common clinical manifestations include oligomenorrhea, acne, and hirsutism
  • Diagnosis is made when at least 2 of the following occur: hyperandrogenism (clinical and/or biochemical), ovulatory dysfunction, or polycystic ovarian morphologic features
  • Important comorbidities include obesity, type 2 diabetes, obstructive sleep apnea, depression, and nonalcoholic fatty liver disease
  • Treatment addresses several issues, including overweight/obesity, metabolic abnormalities, anovulation, acne, hirsutism, endometrial protection, infertility, and cardiovascular risk factors
  • For most components of disease, primary treatment is weight loss through lifestyle modification r2
  • First line pharmacologic therapy is oral contraceptives, which are effective for reducing signs of hyperandrogenism and regulating menstrual cycle r3
  • Additional pharmacologic options include metformin to treat metabolic dysfunction and clomiphene or letrozole to induce ovulation r4r5
  • Complications include those related to pregnancy (eg, increased risk of adverse maternal, fetal, and neonatal outcomes) and increased risks of endometrial cancer, nonfatal stroke, and possibly cardiovascular events r6
  • Polycystic ovary syndrome is a lifelong disorder, and pharmacologic therapy and lifestyle measures to improve metabolic and endocrine status are intended to reduce risk of future cardiovascular disease r7

Pitfalls

  • Diagnosis of polycystic ovary syndrome should not be ruled out on the basis of androgen levels that fall within reference range; polycystic ovary syndrome remains a possibility if all other diagnostic criteria are met and there is clinical evidence of hyperandrogenemia
    • Biochemical hyperandrogenemia is not always demonstrable with laboratory assays, often because of inadequate methods r8
  • Some hyperandrogenic women with eumenorrhea still have chronic anovulation and may be considered to be affected by polycystic ovary syndrome r9
    • 15% to 40% of women with hyperandrogenism and regular menses have ovulatory dysfunction r3
  • Rapid onset and progression of virilizing signs (eg, male pattern hair growth, deepening of voice, clitoromegaly) are not typical of polycystic ovary syndrome and are worrisome for underlying ovarian or adrenal neoplasm r9

Terminology

Clinical Clarification

  • Polycystic ovary syndrome is a heterogeneous endocrine disorder presenting in reproductive-aged women
  • Diagnostic criteria require at least 2 of the following abnormalities: hyperandrogenism (clinical and/or biochemical), ovulatory dysfunction, or polycystic ovarian morphologic features r10
  • People with polycystic ovary syndrome suffer reproductive and metabolic abnormalities, and they are at risk for infertility, impaired glucose tolerance, type 2 diabetes mellitus, dyslipidemia, endometrial cancer, and cardiovascular disease
  • Condition is estimated to occur in about 5% to 10% of reproductive-aged women r1

Diagnosis

Clinical Presentation

History

  • Reproductive history
    • Menstrual dysfunction occurs in 75% to 85% of patients r9
      • Oligomenorrhea or amenorrhea (infrequent or absent menstrual bleeding) is the most common pattern, with most intervals longer than 35 days r3c1c2
      • Polymenorrhea (less than 21-day intervals) is relatively rare r3c3
      • Onset is usually in adolescence; may start at menarche or shortly thereafter r9
      • In some adolescents, condition is noted by absence of established regular menses r3
      • Ovulatory dysfunction can be present subclinically with no obvious disruption in regularity of vaginal bleeding r9
        • 15% to 40% of women with hyperandrogenism and regular menses have ovulatory dysfunction r3
    • History of infertility
      • Common presenting issue; nearly 70% of patients report infertility r11c4
  • Hair and skin concerns
    • Excessive terminal body hair growth is a common concern c5
    • Hirsutism develops gradually and worsens with weight gain c6c7
    • Acne can occur with hirsutism; overall, acne is less common as a presenting complaint (15%-30% of patients) r12c8
      • During adolescence, acne is not considered a firm sign of hyperandrogenism; however, if it persists into the mid-20s or 30s, it is often a sign of hyperandrogenism r5
    • Hair loss, when it occurs, is most pronounced over vertex or crown and spares frontal hairline r1c9

Physical examination

  • Signs of hyperandrogenism
    • Hirsutism (about 75% of patients; more severe in abdominally obese patientsr13) c10
      • Excessive terminal hair that appears in a male pattern (eg, chest, midline lower abdomen, above lip)
        • Terminal hairs grow more than 5 mm in length, are pigmented, and have a central core of compacted cells, which gives a denser color and coarser feel and shape r14
        • Substantial numbers of terminal hairs over chin, neck, lower face, and sideburns indicate androgen excess r5
      • Ferriman-Gallwey score of 8 or higher is generally considered representative of hirsutism r15
    • Acne (60% of patients, at some point) r16c11
    • Acanthosis nigricans (37% of patients) r16r17c12
    • Androgenic alopecia (about 5% of patientsr8) c13
      • Typically affects vertex or crown in diffuse pattern r5
    • Acrochordons c14
  • Ovulatory dysfunction
    • Some ovarian cysts may be palpated as adnexal swelling or masses, but most cysts in polycystic ovary syndrome are nonpalpable (and many cases of the syndrome involve no cysts) c15c16
  • Overweight or obesity (about 75% of patientsr18) c17
    • Central distribution of adiposity also may be present in those with BMI in reference range r19
      • Overweight: BMI of 25 kg/m² or higher
      • Obese: BMI of 28 kg/m² or higher
      • Waist circumference greater than 88 cm is considered abdominal obesity in women
      • Waist to hip ratio greater than 0.8 is considered unhealthy

Causes and Risk Factors

Causes

  • Polycystic ovary syndrome is a multifactorial disorder arising from the interaction of abnormal genetic, metabolic, endocrine, and environmental factors all contributing to disease r20c18
  • Inherent abnormalities of ovarian steroidogenesis and follicular development are involved in pathogenesis r3c19c20
  • Additional endocrine abnormalities include rapid pulses of gonadotropin-releasing hormone, an excess of luteinizing hormone, and insufficient follicle-stimulating hormone secretion, all of which contribute to excessive ovarian androgen production and ovulatory dysfunction r3c21c22

Risk factors and/or associations

Age
  • Usually begins to present during adolescence, but disorder manifests well into adulthood c23c24
  • Prevalence of menstrual dysfunction declines with age, particularly as menopause nears r21c25c26c27
Genetics
  • Clusters in families and both female and male relatives can show stigmata of the syndrome r22c28
  • Complex, polygenic disorder with multiple alleles associated with a small degree of risk r22c29
    • Genome-wide association studies implicate many genes, including: r23
      • LHCGR (luteinizing hormone/choriogonadotropin receptor)
      • FSHR (follicle-stimulating hormone receptor)
      • INSR (insulin receptor)
      • DENND1A (DENN domain–containing 1A)
      • THADA (THADA armadillo repeat–containing)
Ethnicity/race
  • Ethnic variations affect phenotypic expression r22
    • Patients of European ancestry tend to display more midline hirsutism than those of East Asian ancestry c30c31
    • Patients of African ancestry have higher rates of hypertension and cardiovascular risk factors c32c33
    • Hispanic patients are at greater risk for metabolic syndrome and type 2 diabetes r24c34c35
    • Patients of Mediterranean ancestry tend to have more body hair than most patients of Asian ancestry, who have relatively little r25c36c37
Other risk factors/associations
  • Associated with several cardiometabolic diseases or conditions that should be assessed and monitored
    • Obesity (about 75% of patients) r18c38
    • Type 2 diabetes mellitus (about 10% of patients) r26c39
    • Dyslipidemia (about 70% of patients) r27c40
    • Obstructive sleep apnea r28c41
    • Nonalcoholic steatohepatitis c42
    • Subclinical vascular disease r29c43

Diagnostic Procedures

Primary diagnostic tools

  • Consider this diagnosis in any reproductive-aged woman with clinical signs of hyperandrogenemia (most commonly, hirsutism) or irregular menstrual cycles c44
  • Diagnostic criteria (Rotterdam criteriar30) in adults require that at least 2 of the following 3 conditions be met: r10
    • Clinical or biochemical hyperandrogenism
      • Clinical hyperandrogenism may include hirsutism, acne, or androgenic alopecia
        • Assess degree of hirsutism using Ferriman-Gallwey score (8 or higher is generally considered abnormal) r15
      • Biochemical hyperandrogenemia is determined by elevated serum androgen level. An absolute diagnostic level does not exist for polycystic ovary syndrome, owing to variability in testosterone assays and lack of laboratory test standardization
      • About 25% of patients do not exhibit clinical features of hyperandrogenism but have biochemical evidence of hyperandrogenemia r31
    • Oligo-ovulation or anovulation
      • Anovulation may manifest as frequent bleeding at intervals of fewer than 21 days or infrequent bleeding at intervals of more than 35 days
        • Cycle length longer than 35 days suggests chronic anovulation, but if cycle length is slightly longer than reference range (32-35 days) or slightly irregular, further testing for ovulatory dysfunction with progesterone levels is recommended r5
        • Ovulatory dysfunction can be reliably assessed only after 1 or more years have elapsed since menarche. Before 1 year, irregular cycles are part of the normal pubertal transition r32
      • Chronic anovulation can also be determined by eliciting history that patient has fewer than 9 menstrual cycles annually r31
    • Ovarian size or morphology on pelvic ultrasonography
      • Polycystic ovary morphology is designated by a follicle number per ovary of 20 or more or an ovarian volume of 10 mL or more on either ovary, ensuring that no corpora lutea, cysts, or dominant follicles are present r33
  • Polycystic ovary syndrome is a diagnosis of exclusion r10
    • Common disorders that should be excluded include:
      • Thyroid disease (hypothyroidism or hyperthyroidism)
      • Hyperprolactinemia
      • Nonclassic congenital adrenal hyperplasia
    • When considering diagnosis, obtain laboratory tests to exclude other common conditions (this exclusion is required to assign diagnosis), such as:
      • Serum TSH level to screen for thyroid dysfunction
      • Serum prolactin level to test for hyperprolactinemia
      • 17-hydroxyprogesterone level (obtained before 8 AM) to test for congenital adrenal hyperplasia
    • Carefully consider (and exclude, if suspected) other diagnoses in select patients, depending on presentation, including:
      • Pregnancy
      • Functional hypothalamic amenorrhea
      • Primary ovarian insufficiency
      • Androgen-secreting tumor
      • Cushing syndrome
      • Acromegaly
  • Diagnosis in an adolescent requires special considerations r34
    • Diagnosis in adolescents is controversial because it is complicated by several factors r35
      • Many features of polycystic ovary syndrome (including acne, menstrual irregularities, and hyperinsulinemia) are common in normal puberty
      • Menstrual irregularities with anovulatory cycles and varied cycle length are common in adolescents for approximately 2 years after menarche owing to immaturity of hypothalamic-pituitary-ovarian axis
      • Multicystic ovaries are a common normal finding in adolescents owing to natural ovarian development at menarche
    • Proposed criteria for diagnosis in adolescents include the otherwise unexplained combination of: r36
      • Abnormal uterine bleeding pattern that meets both of the following requirements:
        • Abnormal for gynecologic age (eg, ovulatory dysfunction that persists more than 2 years after menarche) r37
          • Cycles shorter than 19 days or longer than 90 days are abnormal at any stage r36
          • 75% of menstrual cycles range from 21 to 45 days during first postmenarchal (gynecologic) year r36
          • 95% of adolescents achieve 21- to 40-day adult menstrual cyclicity by fifth gynecologic year r36
        • Persistent symptoms for 1 to 2 years r37
      • Unequivocal evidence of hyperandrogenism, including at least 1 of the following:
        • Persistent testosterone elevation above adult reference range, obtained from a reliable reference laboratory
        • Moderate to severe hirsutism
        • Moderate to severe inflammatory acne vulgaris, which is also an indication to test for hyperandrogenemia
    • Appropriate imaging criteria are not established for polycystic ovaries in adolescents r8
      • In adolescent females, large, multicystic ovaries are a common finding; therefore, ultrasonography is not a recommended investigation in patients younger than 17 years r5
  • Additional ancillary laboratory testing (eg, levels of gonadotropins, progesterone, antimüllerian hormone, and others to assist with differential diagnosis) may be helpful in select patients when diagnosis remains inconclusive or uncertain

Laboratory

  • Serum androgen levels
    • As an initial assessment, measure both total testosterone and sex hormone–binding globulin r22c45c46
      • Obtain these tests in the follicular phase (days 1-13 of the menstrual cycle) so that values may be compared with a matched reference range r9
      • Serum testosterone level above reference range indicates hyperandrogenemia
        • Total testosterone level greater than 150 nanograms/dL, particularly if found in a patient with abrupt or rapidly progressive symptoms, is concerning for an androgen-secreting tumor r3
      • Important factors to consider regarding assay methodology for total testosterone levels:
        • Most accurate total testosterone measurements are made using mass spectrometry after liquid or gas chromatography r38
        • Reference ranges vary according to the specific laboratory used
        • Many total testosterone radioimmunoassays are inconsistent and lack adequate sensitivity in women and children, especially at lower levels of testosterone (ie, less than 50 nanograms/dL) r39
        • Equilibrium dialysis methods are the gold standard but are almost never used owing to technical complexity and extreme costs r9
      • If sex hormone–binding globulin level is low (and total testosterone level is within reference range), estimate free testosterone level using calculations r38
        • Calculate free testosterone level using total testosterone and sex hormone–binding globulin levels
          • Calculated free testosterone levels have a fairly good concordance and correlation with free testosterone levels as measured by equilibrium dialysis methods
        • Online calculator using total testosterone and sex hormone–binding globulin levels (plus empiric serum albumin level) is available r40
    • Tests of other measurable androgens that are usually not recommended include free testosterone level by direct assay, dehydroepiandrosterone sulfate level, and androstenedione level
      • Do not measure free testosterone level by direct assay; commercial direct free testosterone assays that use analog radioimmunoassays are unreliable and inaccurate in women c47
      • Bioactive testosterone (albumin-bound)r14 and free androgen index (100 × [total testosterone / sex hormone–binding globulin])r1 are alternatives
      • Value of measuring levels of androgens other than testosterone is relatively low r4
        • Dehydroepiandrosterone sulfate is a precursor of a weak androgen and is a general marker of adrenal hyperandrogenism r41c48
          • Approximately 20% to 30% of patients have elevated levels r42
        • Androstenedione is another androgen precursor c49
          • Approximately 18% of patients have elevated levels
    • Reliable assessment of androgen levels is not possible in women using hormonal contraception owing to effects on production of sex hormone–binding globulin and androgens r33
  • Additional ancillary testing may be helpful for some patients
    • Serum gonadotropin level c50
      • Excludes other conditions such as primary ovarian insufficiency
      • Hypersecretion of luteinizing hormone occurs in a large proportion of patients r43
      • Random serum luteinizing hormone levels are not always a reliable diagnostic tool owing to the pulsatile nature of luteinizing hormone secretion and because obesity suppresses luteinizing hormone levels r9r44
      • Elevated luteinizing hormone to follicle-stimulating hormone ratio supports diagnosis of polycystic ovary syndrome; however, absence of an elevated luteinizing hormone level is of no diagnostic value
    • Serum antimüllerian hormone level r45c51
      • May be elevated in polycystic ovary syndrome, thus it serves as a discriminating test versus other diseases in differential diagnosis
      • Optimal threshold for distinguishing polycystic ovary syndrome varies both by age of patient and assay used r46
    • Serum progesterone level c52
      • Serum progesterone level on day 20 to 24 of menstrual cycle is a useful test for determining anovulation r9
      • Generally, if progesterone level is below 3 to 4 nanograms/mL on day 20 to 24, the cycle is deemed to be oligo-/anovulatory r9
  • Required laboratory tests to exclude other common or similar conditions r10
    • Serum TSH level c53
      • TSH level above the upper limit of reference range could reflect hypothyroidism, whereas a level less than 0.1 milliunits/L could suggest hyperthyroidism
      • Further evaluate abnormal levels by measuring peripheral hormone levels (eg, free thyroxine, total triiodothyronine)
    • Serum prolactin level c54
      • Serum prolactin level above the upper limit of reference range indicates hyperprolactinemia; further evaluation by an endocrinologist is recommended
    • Serum 17-hydroxyprogesterone level c55
      • Obtain early morning sample, before 8 AM
      • Basal follicular phase 17-hydroxyprogesterone level less than 200 nanograms/dL effectively rules out nonclassic congenital adrenal hyperplasia r3
      • If the basal level falls near cutoff, a cosyntropin stimulation test is required (adrenocorticotropic hormone–stimulated 17-hydroxyprogesterone level greater than 1000 nanograms/dL is found in nonclassic congenital adrenal hyperplasia) r47

Imaging

  • Pelvic ultrasonography (transvaginal approach is preferred)
    • Obtain for women with hyperandrogenemia and normal menstrual cycles or women with oligomenorrhea or amenorrhea but without hyperandrogenemia c56c57c58
    • If a woman has both oligomenorrhea or amenorrhea and clinical or biochemical evidence of hyperandrogenism, the diagnostic criteria have been met. Ultrasonography to determine presence of polycystic ovaries is unnecessary r32
    • In adolescent females, large, multicystic ovaries are a common finding; therefore, ultrasonography is not a recommended investigation in patients younger than 17 years r5c59
    • Polycystic ovary morphology is designated by a follicle number per ovary of 20 or more and/or an ovarian volume of 10 mL or more on either ovary, ensuring that no corpora lutea, cysts, or dominant follicles are present r33
      • These features are demonstrated using endovaginal ultrasonic transducers with a frequency bandwidth that includes 8 MHz r33
      • If using older technology or transabdominal ultrasonography, assignment of polycystic morphology can be based on ovarian volume alone, using a threshold of 10 mL or more on either ovary r33
    • Finding anatomic polycystic ovaries, without an ovulation disorder or hyperandrogenism, does not equate with a diagnosis of polycystic ovary syndrome
      • About 25% of asymptomatic women with regular menses have polycystic ovary morphology on ultrasonogram r48
      • Sole presence of polycystic ovaries on ultrasonogram is not associated with a reduction in fertility r9

Other diagnostic tools

  • Ferriman-Gallwey visual scoring system for hirsutism r49c60
    • Scoring system that uses visual grading of hair growth over 9 androgen-sensitive body areas (upper lip, chin, chest, arm, upper abdomen, lower abdomen, upper back, lower back, and thighs)
    • Each body area is assigned a numerical value from 0 to 4, with 0 indicating no terminal hair growth in the body area being examined and 4 indicating marked terminal hair growth
    • All individual body area scores are totaled to obtain a final score
      • A score of 8 or more is typically considered abnormal r50
      • Threshold for an abnormal score varies by ethnicity
        • Certain ethnicities are naturally less or more hirsute, so that scores of 2 to 3 or higher in women of Chinese or Thai ancestry are considered elevated, whereas scores of 9 to 10 or higher in women of Mediterranean, Hispanic, and Middle Eastern ancestry are elevated
    • Approximately 70% of patients who complain of being hirsute have a Ferriman-Gallwey score of 3 or higher r51
    • If excessive hair growth has been treated with cosmetic measures (eg, chemical depilatories, electrolysis), the Ferriman-Gallwey scoring system is not valid r25

Differential Diagnosis

Most common

  • Conditions displaying signs of hyperandrogenism
    • Nonclassic congenital adrenal hyperplasia r47c61d1
      • Most common form is due to partial deficiency of 21-hydroxylase
      • Like polycystic ovary syndrome, nonclassic congenital adrenal hyperplasia presents with hirsutism or irregular menses during adolescence or early adulthood r52
      • Differentiate by laboratory testing with an early morning serum 17-hydroxyprogesterone level obtained in the early follicular phase of the menstrual cycle
        • Basal serum 17-hydroxyprogesterone level of 200 to 400 nanograms/dL is suggestive of congenital adrenal hyperplasia, whereas 17-hydroxyprogesterone level is typically within reference range (less than 200 nanograms/dL) in polycystic ovary syndrome r47
        • Cosyntropin stimulation test (250 mcg) is needed if the 17-hydroxyprogesterone level is near the upper limit of reference range r47
      • Diagnosis of nonclassic congenital adrenal hyperplasia (due to 21-hydroxylase deficiency) is confirmed if a follicular-phase serum 17-hydroxyprogesterone is greater than 1000 nanograms/dL after cosyntropin stimulation r47
        • Testing and interpretation of these tests is usually complex; referral to endocrinologist is recommended
    • Androgen-secreting tumors c62
      • Androgen-secreting tumors of adrenal or ovarian origin typically present with progressive and rapid onset of virilization, including deepening tone of voice, male pattern hair growth, and clitoromegaly
        • In polycystic ovary syndrome, hirsutism develops gradually and intensifies with weight gain
        • In virilizing states caused by androgen-secreting tumors, hirsutism is of rapid onset and is often associated with clitoromegaly and oligomenorrhea r5
      • Androgen levels are markedly elevated r3
        • Total testosterone level is most often greater than 150 nanograms/dL in malignant ovarian tumors r25
        • Dehydroepiandrosterone sulfate level is several-fold increased in malignant adrenal tumors r25
      • Polycystic ovary syndrome and androgen-secreting tumors are distinguished by imaging, with ultrasonographic imaging of ovaries or with CT or MRI of adrenal glands that shows a suspicious solid mass
        • Suggestive imaging findings (solid mass) will favor androgen-secreting neoplasm, although a definitive diagnosis requires histologic confirmation of surgically resected specimen r53
    • Cushing syndrome r54c63
      • Condition of pathologic excess of glucocorticoids due to pituitary, adrenal, or other unusual tumors
      • As with polycystic ovary syndrome, signs and symptoms can include central obesity and glucose intolerance
      • Cushing syndrome is more likely when a large number of signs and symptoms, especially those with high discriminatory index (eg, proximal myopathy, facial plethora, violaceous striae, bruising) are present
      • 24-hour urinary free cortisol level, late-night salivary cortisol level, or a 1-mg overnight dexamethasone suppression test are reasonable screening tests
        • Results suggestive of Cushing syndrome that require further investigation are increased 24-hour urinary free cortisol level, inappropriately elevated midnight salivary cortisol level, and unsuppressed morning serum cortisol level after dexamethasone
        • At least 1 repeated abnormal test result is required for a positive screen
        • Testing and interpretation of these tests is usually complex; referral to endocrinologist is recommended
    • Ovarian hyperthecosis r55c64
      • Rare, nonneoplastic cause of ovarian stromal proliferation and hyperandrogenemia that occurs almost exclusively in postmenopausal women
      • As with polycystic ovary syndrome, signs include acne and abdominal obesity; however, other clinical signs are more severe, with greater degree of virilization, clitoromegaly, and temporal balding
      • Biochemical hyperandrogenemia is present in both polycystic ovary syndrome and ovarian hyperthecosis; however, testosterone levels are usually much higher in ovarian hyperthecosis, approaching levels seen in androgen-secreting adrenal or ovarian tumors
      • Imaging studies (ultrasonographyr56 or pelvic MRIr57) may show enlarged ovaries, but normal appearing ovaries also may be seen
      • Ovarian hyperthecosis is definitively identified by pathologic analysis of tissue after oophorectomy
  • Conditions causing oligomenorrhea or amenorrhea
    • Thyroid dysfunction d2
      • Both excessr58 and insufficientr59 circulating thyroid hormones can cause menstrual dysfunction c65c66d3
      • As with polycystic ovary syndrome, patients with hypothyroidism often report weight gain or difficulty losing weight r59
      • Neither hyperthyroidism nor hypothyroidism causes significant signs of hyperandrogenism r3
      • Serum TSH level above upper limit of reference range with low free thyroxine level suggests hypothyroidism;r59TSH level below lower limit, usually less than 0.1 milliunits/L, with high free thyroxine level suggests hyperthyroidismr58
      • Low or reference range TSH level with a low free thyroxine level may indicate central hypothyroidism r59
    • Hyperprolactinemia r60c67c68
      • As with polycystic ovary syndrome, amenorrhea or oligomenorrhea is a common presenting symptom
      • Hirsutism can occur in a small percentage of women with hyperprolactinemia from various causes r61
      • Hyperprolactinemia is determined by serum prolactin level that is above upper limit of reference range for assay r62
    • Pregnancy c69
      • Presents with history of amenorrhea, along with other common symptoms of pregnancy including breast fullness and uterine cramping
      • Pregnancy is not accompanied by significant signs of hyperandrogenism
      • Differentiated by serum or urine hCG level
    • Functional hypothalamic amenorrhea r63c70d4
      • Form of chronic anovulation not due to identifiable organic causes but instead triggered by weight loss, vigorous exercise, or stress
        • Menstrual cycle interval persistently exceeds 45 days or patient has amenorrhea for 3 months or more
      • Prominent features include amenorrhea, clinical history of low body weight or BMI, excessive exercise, and a physical examination in which signs of androgen excess are absent
      • Patients with functional hypothalamic amenorrhea have characteristically low or low-normal luteinizing hormone level, follicle-stimulating hormone level within reference range (which is usually higher than luteinizing hormone level), estradiol level below 50 pg/mL, and progesterone level less than 1 nanogram/mL r63
        • Estradiol measurements are limited in that they reflect and assess a single time point; no single estradiol value establishes a diagnosis of functional hypothalamic amenorrhea
    • Primary ovarian insufficiency r64c71c72d5
      • Heterogeneous condition of declining ovarian function and reduced fertility caused by a premature reduction of initial ovarian follicle number, an increase in follicle destruction, or poor follicular response to gonadotropins
      • May occur as part of a syndrome (ie, Turner syndrome, autoimmune polyendocrinopathy) or as an isolated condition r65
      • Typically presents with secondary amenorrhea, before age 40 years, often combined with symptoms of estrogen deficiency including hot flashes and urogenital symptoms r66
      • Condition requires that patient has at least 4 months of abnormal menstrual patterns (amenorrhea, oligomenorrhea, polymenorrhea, or metrorrhagia) and a follicle-stimulating hormone level that falls within menopause range r65
      • Differentiated on basis of elevated follicle-stimulating hormone level (which must be found on 2 separate occasions in primary ovarian insufficiency)

Treatment

Goals

  • Eliminate or lessen severity of physical stigmata of hyperandrogenism (ie, acne, hirsutism)
  • Restore normal menses (to avoid infertility and to protect against endometrial hyperplasia or carcinoma)
  • Improve metabolic derangements and achieve normal glucose tolerance
  • Achieve and maintain BMI within reference range
  • Induce ovulation, if pregnancy is desired

Disposition

Recommendations for specialist referral

  • Refer to endocrinologist for assistance making diagnosis and for treatment and monitoring of metabolic abnormalities and hirsutism
  • Refer to reproductive endocrinologist for infertility treatments
  • Refer to gynecologist for treatment of prolonged amenorrhea or persistently abnormal vaginal bleeding to evaluate for endometrial hyperplasia r4
  • Refer to dietitian for meal planning to aid in weight loss

Treatment Options

Treatment involves addressing various disease components, including overweight and obesity, metabolic abnormalities, anovulation, acne, hirsutism, endometrial protection, infertility, and cardiovascular risk factors r67

  • For most components of disease, primary treatment is weight loss through lifestyle modification

Treatment options for anovulation

  • Lifestyle modifications to achieve weight loss (at least 5% of body weight) can increase ovulation and pregnancy rates in some women r68r69r70
  • Hormonal contraceptives are first line pharmacologic therapy to treat menstrual irregularity for patients who are not trying to become pregnant. Hormonal contraceptives also ameliorate features of hyperandrogenism (hirsutism and acne) and provide endometrial protection through withdrawal bleeding r71
  • Consider metformin as second line therapy in patients who cannot take or do not tolerate hormonal contraceptives

Treatment options to address obesity or overweight and to improve metabolic health

  • First line therapy is lifestyle modification, which includes dietary changes and exercise, to achieve weight loss
  • Metformin may be added to target metabolic abnormalities (eg, impaired glucose tolerance, diabetesr72)

Treatment options for acne and hirsutism

  • Base treatment on patient's degree of distress caused by hirsutism, rather than clinician's quantitative or qualitative assessments
  • Hormonal contraceptives are first line pharmacologic therapy r71
    • If results of hormonal contraceptives are suboptimal, can add antiandrogen drugs (eg, spironolactone) after 6 months, preferably in combination with an oral contraceptive (or substituted) r73
  • Additional useful pharmacologic therapies for symptoms related to hyperandrogenism include: r14
    • Antibiotics, topical retinoids, or isotretinoin for acne d6
    • Minoxidil for androgenic alopecia
    • Eflornithine for hirsutism
  • Nonpharmacologic cosmetic therapies for hirsutism include shaving, depilating, hair bleaching, electrolysis, and laser hair removal r73

Treatment options for infertility r74

  • Lifestyle modifications for weight loss are recommended in patients who are overweight or obese r69r75
    • Weight reduction of 5% to 10% in total body weight can increase pregnancy rate and decrease requirements for ovulation-induction agentsr77r76
    • Preconception weight loss through lifestyle modification (caloric restriction plus physical activity) before ovulation induction improves ovulation and live birth rates r68
    • Both antiobesity medications and bariatric surgery promote weight loss, but their use is discouraged before infertility treatment owing to safety concerns and mixed pregnancy outcomes r74
  • Pharmacotherapy options include clomiphene, aromatase inhibitors, gonadotropins, and metformin
    • First line pharmacologic therapy for infertility is ovulation induction using either letrozole or clomiphene r10
      • Letrozole is superior to clomiphene for achieving pregnancy and live births
        • Patients with polycystic ovary syndrome are about 50% more likely to have a live birth with letrozole compared with clomiphene r74r78
        • Letrozole may be preferred in overweight or obese patients
      • Clomiphene is an alternative first line agent for ovulation induction owing to more safety data r78
    • Second line pharmacologic option for infertility is usually ovarian stimulation using low-dose urinary or recombinant gonadotropins r79
      • Cumulative 1- and 2-year singleton live birth rates are approximately 50% and 70%, respectively r80
      • Administration and management is complex and ideally is done under guidance of a reproductive endocrinologist
    • Third line pharmacologic option for infertility is metformin r81
      • For the purpose of treating infertility, metformin alone increases ovulation rate but is inferior to other agents such as clomiphene or letrozole;r81 use of metformin with clomiphene may offer better responsesr82
      • A combination strategy using metformin with clomiphene may increase pregnancy rates, but the net effect on live births is not knownr84r83
  • Can use assisted reproductive technology (eg, in vitro fertilization) if lifestyle and pharmacologic approaches are unsuccessful r3
  • With both reproductive and metabolic treatments, combination therapies (eg, metformin-clomiphene) generally offer greater benefit

Drug therapy

  • Hormonal contraceptives r71
    • Primarily used to treat menstrual irregularity, but also have modest efficacy in treatment of hirsutism and acne
      • Available data show that long-term use of oral contraceptives does not improve or worsen cardiometabolic risk parameters (eg, lipid metabolism, insulin resistance) in polycystic ovary syndrome r29
    • Selection of oral contraceptive
      • Daily dose of 20 to 30 mcg of ethinyl estradiol decreases ovarian androgen production
      • Theoretically, the ideal progestins for an oral contraceptive in polycystic ovary syndrome are third-generation or those with the lowest androgenic profile (though these have highest risk for thromboembolism)
        • Drospirenone and dienogest are considered progestins with minimal androgenicity r14r85
      • No definitive evidence for differences in efficacy among various oral contraceptives for ameliorating hyperandrogenism or regulating menstrual cycle
        • Observable improvement in acne and hirsutism requires a minimum of 6 months r71
      • Most clinically important risk of oral contraceptive use is venous thromboembolism, especially in obese women r86
        • Among all women, newest third-generation oral contraceptives have approximately 2-fold increased risk of venous thromboembolism compared with second-generation options
        • Available data suggest a 1.5- to 2-fold increased risk of venous thromboembolism in polycystic ovary syndrome owing to its inherent prothrombotic state; however, absolute risk of venous thrombosis is very small
    • For hirsutism, a 6-month trial of oral contraceptive is reasonable, and an antiandrogen drug can be added in combination if there is suboptimal response (usually most effective when used in combination with antiandrogens) r5
      • For any treatment for hirsutism, a trial of at least 6 months is necessary before changes occur; therefore, it is recommended to allow 6 months of drug therapy before making changes in dose, switching to a new medication, or adding a medication r73
    • Oral contraceptive choices c73c74c75c76c77c78c79c80c81c82c83c84c85c86c87c88c89c90c91
      • Inert Oral tablet, Norgestimate, Ethinyl Estradiol Oral tablet; Adults: 0.18 to 0.25 mg norgestimate/0.025 to 0.035 mg ethinyl estradiol PO once daily for 21 days, followed by 7 days of inert, inactive tablets as for routine contraception.
      • Ethinyl Estradiol, Desogestrel Oral tablet, Inert Oral tablet; Adult and Adolescent females: Follow dose as for routine contraception.
      • Drospirenone, Ethinyl Estradiol Oral tablet, Inert Oral tablet; Adult and Adolescent females: Follow dose as for routine contraception for specific product as specified in product label: 1 tablet PO daily of selected product. Treatment for 6 to 12 months may be required; OCs have limited utility when the underlying cause of the condition is not related to a hypoestrogenic or hyperandrogenic state.
  • Antiandrogens
    • Primarily used to treat hirsutism (clinical hyperandrogenism), often in combination with an oral contraceptive r87
    • Spironolactone (first line antiandrogen for hirsutism and acner88) c92c93
      • Effective in decreasing degree of hirsutism and, to a lesser extent, acne r87r89
      • Spironolactone Oral tablet; Adult females: 50 to 200 mg/day PO in 1 or 2 divided doses.
    • Finasteride (second line antiandrogen for hirsutism;r88 off-label use) c94c95
      • Finasteride Oral tablet [Alopecia]; Adult, non-pregnant women: 5 mg PO once daily either alone or in combination with oral contraceptives shown to reduce hirsutism in women with mild hirsutism; minimal adverse reactions compared to other antiandrogens.
  • Aromatase inhibitors
    • Used for ovulation induction
      • Letrozole c96
        • Off-label letrozole is a first line therapy used to achieve pregnancy with live birth for subfertile women with polycystic ovary syndrome r90
        • Letrozole Oral tablet; Adult premenopausal patients: Limited studies indicate 2.5 mg, 5 mg, or 7.5 mg PO once daily on days 3 through 7 of the menstrual cycle may be effective; alternatively, a 20-mg single dose on day 3 of the menstrual cycle has also been studied. Ovulation and pregnancy rates are similar to those achieved with clomiphene. Ensure patient is NOT pregnant prior to starting letrozole, as letrozole may cause birth defects.
      • Note: Anastrozole, which is a potent and highly selective aromatase inhibitor, is ineffective for ovulation induction r91
  • Selective estrogen receptor modulators
    • Used for ovulation induction
    • Clomiphene c97
      • Clomiphene Citrate Oral tablet; Adult premenopausal patients: Initially, 50 mg PO once daily for 5 days. Patients with PCOS may need lower initial doses (i.e., 25 mg PO once daily for 5 days). In patients with recent menstrual bleeding or progestin-induced bleeding, initiate on or about the fifth day of the cycle following the first day of withdrawal or menstrual bleeding. Therapy may be started at any time in patients who have not had recent uterine bleeding. If ovulation does not occur with this dosing regimen, increase to 100 mg PO once daily for 5 days with the next cycle. If ovulation has not occurred after 3 courses of treatment, re-evaluate the patient. If pregnancy does not occur within a total of 6 cycles, discontinue. Prolonged administration of the drug is not recommended. NOTE: Do not give HCG following clomiphene if the ovaries are abnormally enlarged, greater than 3 follicles of 15 mm size are present, an ovarian cyst is present, or the serum estradiol concentration exceeds 2000 pg/mL. Consult specialized references for the monitoring of specific fertility protocols.
  • Gonadotropin therapy
    • Typically used for ovulation induction after clomiphene or letrozole
    • Options include urinary gonadotropins or recombinant follicle-stimulating hormone (live birth rates are similar) r79c98c99
  • Biguanides
    • Metformin c100
      • Used primarily to improve metabolic status in patients whose condition does not respond adequately to lifestyle measures
        • Metformin is best used as an adjuvant to lifestyle modification but not as a substitute for it r32
      • Has some efficacy in normalizing ovulatory cyclicity but minimal impact on hirsutism r87
      • Increases overall pregnancy rates but live birth rates are only marginally increased r83
        • Metformin alone is less effective than clomiphene alone for ovulation induction, clinical pregnancy, and live birth r81
        • Metformin-clomiphene improves ovulation and clinical pregnancy rates but does not improve live-birth rates when compared with clomiphene alone r81
      • Does not provide endometrial protection unless normal ovulatory function is restored r3
      • Metformin Hydrochloride Oral tablet; Adult females: 500 mg PO 3 times per daily. Normal menstruation returns in 33% after 1 month. When added to clomiphene for infertility, approx. 86% ovulate compared to 8% on clomiphene alone. Weight loss and diet control recommended to prevent metformin-failure in severely obese patients.
  • Topical eflornithine c101
    • Slows growth of unwanted facial hair r92
      • Eflornithine Hydrochloride Topical cream [Cosmetic Use]; Adult, Geriatric, and Adolescent females: Apply a thin layer twice daily, at least 8 hours apart, to affected facial area(s).
  • Minoxidil c102
    • Modestly effective for treatment of alopecia r93
      • Minoxidil Topical solution; Adult men and women: Apply 1 ml topically bid to area of desired hair growth. MAX: 2 ml/day.

Nondrug and supportive care

Education

  • Counsel patient on lifelong nature of syndrome and need for ongoing follow-up to ascertain metabolic status and cardiovascular complications c103

Lifestyle and weight management counseling r67

  • Permanent lifestyle modifications are emphasized in all patients c104c105c106
    • Weight loss improves metabolic parameters, clinical manifestations of androgen excess, and ovulatory dysfunction
    • Reducing insulin resistance through weight loss is important for reducing long-term cardiovascular risks
  • Advise calorie-restricted diet if patient is overweight or obese c107c108
    • No evidence that one type of diet is superior to another to induce and sustain weight loss r10
  • Advise a program with a minimum of 30 minutes of activity daily,r10 or for modest weight loss and greater health benefits, advise a program with a minimum of 250 minutes weekly of moderate intensity activity or 150 minutes weekly of vigorous intensityr32c109
    • No large randomized trials examining efficacy of exercise therapy exist specifically for polycystic ovary syndrome, but there is suggestion that engaging in physical activity can induce weight loss, reduce triglyceride levels, raise HDL-C level, reduce insulin resistance, and improve ovulation r94r95
  • Behavioral strategies for weight management include specific goal setting and frequent self-monitoring of body weight r2c110c111

Cosmetic methods for hair removal

  • Short-term mechanical methods include shaving, chemical depilation, plucking, waxing, and bleaching r14c112c113c114c115c116
  • Long-term methods include electrolysis, laser therapy, and intense pulsed light therapy r14c117c118c119
    • Photoepilation offers better outcomes for those whose unwanted hair is auburn, brown, or black; electrolysis is recommended for those with white or blond hair r73
    • Women of Mediterranean and Middle Eastern ancestry with facial hirsutism are at increased risk of developing paradoxical hypertrichosis with photoepilation therapy r73
Procedures
In vitro fertilization c120
General explanation
  • Procedure involves several components, including ovarian stimulation, oocyte retrieval, fertilization of oocytes in vitro (either spontaneously or by intracytoplasmic sperm injection), and subsequent transfer of embryos into uterine cavity
  • Frozen embryo transfer may be ideal for infertile women with polycystic ovary syndrome given that a higher rate of live birth occurs in these women, compared with procedures that involve fresh embryo transfer r96r97
Indication
  • Treatment of infertility, if lifestyle measures and ovulation induction agents are unsuccessful
Contraindications
  • Primary ovarian failure (donor oocytes must be used)
Complications
  • Ovarian hyperstimulation syndrome
  • Multiple gestation

Comorbidities

  • Longitudinal screening for cardiometabolic risk factors is recommended in all patients r3
  • Obesity (about 75% of patients) r18c121
    • Adiposity influences development, maintenance, and severity of cardiometabolic and endocrine features of disease r29
    • Assess with annual BMI calculation and waist circumference measurement r10
  • Metabolic dysfunction
    • Insulin resistance, glucose intolerance, and type 2 diabetes are common comorbidities
      • More than 50% of patients are insulin resistant, even those whose weight falls within reference range r98c122c123c124
      • Impaired glucose tolerance occurs in 35% of adult patients r26
      • Approximately 25% of adolescent patients have metabolic syndrome r99
      • Type 2 diabetes occurs in 10% of patients (also influenced by age, adiposity, and family history) r26
    • Screen for impaired glucose tolerance and type 2 diabetes with a 2-hour oral glucose tolerance test, repeated every 3 to 5 years depending on various factors such as degree of overweight or obesity, presence of central adiposity, and interval weight gain r10
      • Oral glucose tolerance test is preferred to other methods because it is more sensitive in this population and capable of detecting glucose abnormalities earlier than hemoglobin A1C test r10
  • Dyslipidemia c125
    • Approximately 70% of patients with newly diagnosed disease have abnormal lipid levels, including increased total cholesterol level, high triglyceride levels, high LDL-C level, and decreased HDL-C level r27
    • Screen with semiannual measurement of blood lipid levels, or more frequently if there has been interval weight gain r10
    • Treatment or primary prevention of atherosclerotic cardiovascular disease depends on several factors, including LDL-C level, age, presence of diabetes, and estimated risk of cardiac event within 10 years following guidance established for the general population r100d7
  • Obstructive sleep apnea c126
    • Prevalence of sleep apnea is 5- to 30-fold higher for patients with polycystic ovary syndrome, even after adjustment for age and BMI r29
    • Screen with symptom assessment, and if apparent apnea/hypopnea is identified, obtain polysomnography r10
    • Successful treatment of obstructive sleep apnea with CPAP improves insulin sensitivity and reduces diastolic blood pressure r101
  • Hypertension c127c128
    • At menopause, women with polycystic ovary syndrome have risk of developing hypertension that is 2.5-fold higher than that of age-matched controls; hypertension may accelerate atherosclerotic cardiovascular disease r29
    • Screen with blood pressure measurement at each visit r10
  • Nonalcoholic fatty liver disease and steatohepatitis r102c129c130
    • Nonalcoholic fatty liver disease is frequently seen in patients with polycystic ovary syndrome, likely as a result of insulin resistance as well as obesity
    • Maintain awareness of condition, but routine screening is not recommended r10
  • Depression and anxiety r103c131c132
    • Increased incidence and prevalence over lifetime r104r105
    • Screen for depression and anxiety at diagnosis, then periodically r10

Special populations

  • Adolescents r39
    • Diagnosis can be difficult owing to overlap between normal pubertal development and characteristic features of polycystic ovary syndrome
    • Suggested criteria include demonstration of chemical and/or biochemical hyperandrogenism and presence of persistent oligomenorrhea for at least 2 years after menarche r39
    • Hormonal contraceptives
      • In early adolescence, using hormonal contraceptives is controversial
      • Ideal hormonal contraceptive regimen and appropriate duration of therapy for adolescents are uncertain
      • Consider hormonal contraceptives for patients with proven hyperandrogenism with sexual maturity of Tanner stage 4 to 5 when menarche should have occurred
      • Some experts suggest continuing with hormonal contraceptives until the patient is gynecologically mature (5 years postmenarcheal) or has lost a substantial amount of weight
    • Metformin therapy
      • Small, short-term studies have found that metformin restores menstrual regularity and improves hyperandrogenemia, insulin resistance, and glucose intolerance in obese and nonobese adolescents with polycystic ovary syndrome
      • 2 sequential, randomized, placebo-controlled trials of metformin in adolescents with polycystic ovary syndrome demonstrated improvements in hyperandrogenemia, ovulation, and dyslipidemia r106
  • Postmenopausal women
    • Presumptive diagnosis of polycystic ovary syndrome can be based on long-term history of oligomenorrhea and hyperandrogenism during reproductive years
    • After menopause, 2 of the key diagnostic criteria of polycystic ovary syndrome (irregular menses and polycystic ovaries on transvaginal ultrasonography) are no longer applicable, because by definition, menopausal women have amenorrhea, and the small follicles seen in the premenopausal ovary become difficult to detect in the menopausal ovary
    • With aging, there is gradual decrease in severity of cardinal features of polycystic ovary syndrome (eg, anovulation, hirsutism) as menopause approaches,r107 but androgen levels are still higher than in postmenopausal women without history of polycystic ovary syndromer108r109
    • Most women who had polycystic ovary syndrome during their reproductive years continue to manifest both metabolic phenotype and unfavorable cardiovascular risk factors r110
    • Owing to long duration of exposure to cardiovascular risk factors, maintain vigilance for monitoring lipid levels, blood pressure, and glycemia in accordance with standards of care in this population of women d5

Monitoring

  • Long-term monitoring of cardiometabolic risk factors
    • Once diagnosis of polycystic ovary syndrome is made, evaluate and screen longitudinally for cardiometabolic risk factors r10
      • Type 2 diabetes
        • Perform oral glucose tolerance test, repeated every 3 to 5 years depending on various factors such as degree of overweight or obesity, presence of central adiposity, and interval weight gain r10c133
      • Obesity
        • Annually calculate BMI and measure waist circumference r10c134c135
      • Depression and anxiety
        • Periodically assess with a validated screening tool such as those of the Patient Health Questionnairer111 series r10c136c137
      • Obstructive sleep apnea
        • Screen with symptom assessment, and if apparent apnea/hypopnea is identified, obtain polysomnography r10c138
      • Dyslipidemia
        • Obtain fasting lipid levels semiannually, or more frequently if there has been interval weight gain c139c140
      • Hypertension
        • Screen with blood pressure measurement at each office visit r10c141
  • Monitoring of oral contraceptive effects r71
    • Measure blood pressure 3 months after start of oral contraceptives, then annually thereafter c142c143
    • Measure glucose and lipid profile annually while oral contraceptives are used c144c145
  • Monitoring of metformin
    • Obtain serum creatinine level and estimated GFR at least annually in all patients c146c147
    • Consider monitoring vitamin B₁₂ levels c148
  • Monitoring of antiandrogen therapy
    • Monitoring response to treatment can be done objectively using Ferriman-Gallwey system, scoring at baseline and, if possible, at each visit r25c149
    • Treatment can be continued as long as patient desires and should be discontinued if pregnancy is contemplated r25
    • Monitoring testosterone levels after instituting pharmacologic therapy is generally unnecessary because hirsutism scores correlate poorly with serum androgen levels r14

Complications and Prognosis

Complications

  • Polycystic ovary syndrome in pregnancy is associated with significantly increased risk of adverse maternal, fetal, and neonatal outcomes r112
    • Higher risk of gestational complications (eg, miscarriage, gestational diabetes mellitus, preeclampsia) r1c150c151c152d8
    • Higher risk of premature delivery and cesarean section r1c153c154
    • Newborns of women with polycystic ovary syndrome have higher risk of perinatal death r112c155
  • Increased risk of nonfatal stroke r113c156
  • Possible increased risk of cardiovascular disease r22
    • Limited data show increased cardiovascular morbidity and mortality c157c158
  • Increased risk of endometrial cancer (2.7-fold increased riskr114) c159

Prognosis

  • Polycystic ovary syndrome is a lifelong disorder associated with long-term cardiovascular, metabolic, and reproductive consequences beyond those that present at initial clinical presentation
    • Menstrual and fertility problems evolve into metabolic complications as age advances r7
  • Available data on cardiovascular morbidity and mortality in women with polycystic ovary syndrome are limited in quality, and thus conclusions regarding associations are controversial r6r115

Screening and Prevention

Screening c160

Prevention

  • Loss of body weight has been shown to ameliorate some aspects of polycystic ovary syndrome, including hirsutism and anovulation; although not formally proven in well-designed trials, it is reasonable to advise measures to attain and maintain a BMI within reference range in adolescent and reproductive-aged women c161c162c163c164
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