Polycystic Ovary Syndrome

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 subclinical with no obvious disruption in regularity of vaginal bleeding ^r9
      • 15% to 40% of females 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 concern (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 patients with abdominal obesity^r13) ^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 results in 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 patients^r8) ^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 patients^r18) ^c17
  • Central distribution of adiposity may also 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 females
    • Waist to hip ratio greater than 0.8 is considered unhealthy

Causes

• Polycystic ovary syndrome is a multifactorial disorder arising from the interaction of abnormal genetic, metabolic, endocrine, and environmental factors 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

Primary diagnostic tools

• Consider this diagnosis in any reproductive-aged female with clinical signs of hyperandrogenemia (most commonly, hirsutism) or irregular menstrual cycles ^c44
• Diagnostic criteria (Rotterdam criteria^r30) for 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 for select patients, depending on presentation, including:
    • Pregnancy
    • Functional hypothalamic amenorrhea
    • Primary ovarian insufficiency
    • Androgen-secreting tumor
    • Cushing syndrome
    • Acromegaly
• Diagnosis for an adolescent requires special considerations ^r34
  • Diagnosis for 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 for 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 for 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 for 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 for 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 females ^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 for females 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 is associated with lower 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 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 milliunit/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 (ACTH–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 females with hyperandrogenemia and normal menstrual cycles or females with oligomenorrhea or amenorrhea but without hyperandrogenemia ^c56c57c58
  • If a female 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 for 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
    • Transvaginal approach is the most accurate for diagnosis ^r33
    • Transabdominal ultrasonography should report ovarian volume with a threshold of 10 mL or more in either ovary or follicle number per section of 10 or more in either ovary in adults ^r33
  • Finding anatomical polycystic ovaries, without an ovulation disorder or hyperandrogenism, does not equate to a diagnosis of polycystic ovary syndrome
    • About 25% of asymptomatic females with regular menses have polycystic ovary morphology on ultrasonography ^r48
    • Sole presence of polycystic ovaries on ultrasonography 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 females of Chinese or Thai ancestry are considered elevated, whereas scores of 9 to 10 or higher in females of Mediterranean, Hispanic, and Middle Eastern ancestry are considered elevated
  • Approximately 70% of patients who report hirsutism 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

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
      • Interpretation of these test results 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 presence of malignant ovarian tumors ^r25
      • Dehydroepiandrosterone sulfate level is several-fold increased in presence of 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, and 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
      • Interpretation of these test results 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 females
    • 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 (ultrasonography^r56 or pelvic MRI^r57) may show enlarged ovaries, but normal appearing ovaries may also be seen
    • Ovarian hyperthecosis is definitively identified by pathologic analysis of tissue after oophorectomy
• Conditions causing oligomenorrhea or amenorrhea
  • Thyroid dysfunction ^d2
    • Both excess^r58 and insufficient^r59 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 milliunit/L, with high free thyroxine level suggests hyperthyroidism^r58
    • 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 females 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)

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

Drug therapy

• Hormonal contraceptives ^r72
  • 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 ^r14r90
    • 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 ^r72
    • Most clinically important risk of oral contraceptive use is venous thromboembolism, especially in obese females ^r91
      • Among all females, 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 ^r79
  • 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 ^r92
  • Spironolactone (first line antiandrogen for hirsutism and acne^r93) ^c92c93
    • Effective in decreasing degree of hirsutism and, to a lesser extent, acne ^r92r94
    • Spironolactone Oral tablet; Adult females: 50 to 200 mg/day PO in 1 or 2 divided doses.
  • Finasteride (second line antiandrogen for hirsutism;^r93 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 females with polycystic ovary syndrome ^r95
      • 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 ^r96
• Selective estrogen receptor modulators
  • Used for ovulation induction
  • Clomiphene ^c97
    • Clomiphene Citrate Oral tablet; Premenopausal Adults: 50 mg PO once daily for 5 days for the first cycle. Patients with PCOS may need lower initial doses (i.e., 25 mg PO once daily for 5 days). Initiate on or about the fifth day of the cycle following the first day of withdrawal/menstrual bleeding. Start at any time in those who have not had recent uterine bleeding. If ovulation does not occur, increase to 100 mg PO once daily for 5 days with the next cycle. Reevaluate if ovulation has not occurred after 3 cycles. If pregnancy does not occur within a total of 6 cycles, discontinue.
• 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) ^r85c98c99
• Biguanides
  • Metformin ^c100
    • Usual first line agent for patients with concomitant type 2 diabetes
    • Used to improve metabolic status for 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 ^r92
    • Increases overall pregnancy rates but live birth rates are only marginally increased ^r89
      • Metformin alone is less effective than clomiphene alone for ovulation induction, clinical pregnancy, and live birth ^r87
      • Metformin-clomiphene improves ovulation and clinical pregnancy rates but does not improve live-birth rates when compared with clomiphene alone ^r87
    • 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 ^r97
    • 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 ^r98
    • Minoxidil Topical solution; Adults: 1 mL topically twice daily onto the scalp in the hair loss area.

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 for 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 intensity^r32c109
  • 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 ^r99r100
• Behavioral strategies for weight management include specific goal setting and frequent self-monitoring of body weight ^r2c110c111
• Weight loss medication and bariatric surgery are other strategies for weight loss ^r74

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 ^r79
  • Females of Mediterranean and Middle Eastern ancestry with facial hirsutism are at increased risk for developing paradoxical hypertrichosis with photoepilation therapy ^r79

Comorbidities

• Longitudinal screening for cardiometabolic risk factors is recommended for all patients ^r3
  • Polycystic ovary syndrome is associated with cardiovascular risk factors such as impaired glucose tolerance, dyslipidemia, hypertension, metabolic syndrome, type 2 diabetes, and elevated inflammatory markers ^r103
• 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 ^{r104c122c123c124}
    • Impaired glucose tolerance occurs in 35% of adult patients ^r26
    • Approximately 25% of adolescent patients have metabolic syndrome ^r105
    • Type 2 diabetes is more common (occurring in 10%) and develops at an earlier age in patients with polycystic ovary syndrome ^r26r106
  • 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 ^r107d7
• 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 ^r108
• Hypertension ^c127c128
  • At menopause, females 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 ^r109c129c130
  • 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 ^r110c131c132
  • Increased incidence and prevalence over lifetime ^r111r112
  • 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 ^r113
  • 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 after menarche) or has lost a substantial amount of weight
  • Metformin therapy
    • Small, short-term studies have found that metformin restores menstrual regularity and decreases hyperandrogenemia, insulin resistance, and glucose intolerance in adolescents who have polycystic ovary syndrome with or without obesity
    • 2 sequential, randomized, placebo-controlled trials of metformin among adolescents with polycystic ovary syndrome demonstrated improvement in ovulation and decreases in hyperandrogenemia and dyslipidemia ^r114
• Postmenopausal females
  • 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 for polycystic ovary syndrome (irregular menses and polycystic ovaries on transvaginal ultrasonography) are no longer applicable because, by definition, menopausal females 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,^r115but androgen levels are still higher than in postmenopausal females without history of polycystic ovary syndrome^r116r117
  • Most females who had polycystic ovary syndrome during their reproductive years continue to manifest both metabolic phenotype and unfavorable cardiovascular risk factors ^r118
  • Owing to long duration of exposure to cardiovascular risk factors, maintain vigilance in monitoring lipid levels, blood pressure, and glycemia in accordance with standards of care for this population of females ^d5