Diagnosis and management of polycystic ovarian syndrome.

Patients with PCOS often request treatment for cycle irregularity, heavy bleeding, acne or hirsutism, and weight management ( Table 2 ). Management options for polycystic ovarian syndrome according to symptoms 1 , 20 Be aware of weight stigma and increased risk for disordered eating May cause breakthrough bleeding Patients may continue to have irregular, although lighter, bleeding Patients may continue to have irregular, although lighter, bleeding Start at 500 mg and increase by 500 mg every 1–2 wk Cannot be used for endometrial protection in the event of amenorrhea but may help induce regular ovulation Cannot be used for endometrial protection in the event of amenorrhea but may help induce regular ovulation Can be used during or before external hair removal methods Must be used with effective contraception given teratogenicity (i.e., CHCs or progestin-based contraception if CHCs are contraindicated) Do not use in combination with CHC containing dropirenone Requires monitoring with electrolytes 3 mo after starting and then annually and with dose adjustments Must be used with effective contraceptiongiven teratogenicity (i.e., CHCs or progestin-based contraception if CHCs contraindicated) Be aware of weight stigma and increased risk for disordered eating Start at 500 mg and increase by 500 mg every 1–2 wk According to general guidelines Be aware of weight stigma and increased risk for disordered eating Start at 500 mg and increase by 500 mg every 1–2 wk Although considered first-line by many guidelines, still considered as off-label use in Canada If cycling regularly, start on day 2–5 If irregular cycles, can start randomly after negative home pregnancy test or medroxyprogesterone-induced withdrawal bleed Consider measuring serum progesterone level 3 wk after starting letrozole to confirm ovulation Note: CHC = combined hormonal contraceptive. Among patients who are overweight or obese, weight loss of 5%–10% can help to reduce the severity of symptoms, including menstrual cycle irregularity, acne, hirsutism and alopecia. 16 , 22 No specific diet or exercise recommendations for PCOS are available, and clinicians should be particularly sensitive to weight stigma as patients with PCOS are at risk of dysmorphic body image and disordered eating. 1 Combined hormonal contraceptives are first-line medical treatment options for cycle regulation and hirsutism or acne. No evidence demonstrates the superiority of 1 form of CHC over another in minimizing symptoms and, thus, guidelines cannot recommend which to choose. 1 , 7 Several mechanisms are involved when treating hyperandrogenism with CHCs; the estrogenic component increases SHBG, which decreases the amount of free testosterone, and both the estrogen and progestin provide negative feedback mechanisms to pituitary LH production and thus decrease production of LH-induced ovarian androgen. 23 Many patients specifically desire cycle regularity, although this is not medically necessary provided cycles are fewer than 90 days apart. Cycle irregularity may be associated with heavy bleeding. Combined hormonal contraceptives are first-line agents that provide predictable bleeding patterns. When estrogen is contraindicated or not tolerated, progestin-only methods include oral and injectable progestins, the levonorgestrel intrauterine device and the etonogestrel subdermal implant. Oral progestins can be used cyclically (i.e., 3 wk on and 1 wk off) or in rescue fashion (i.e., short course taken after > 90 d amenorrhea) to induce regular withdrawal bleeding. Continuous use of progestins will likely result in amenorrhea. Patients should be reassured that this is a normal outcome with this medication and should not be confused with oligomenorrhea in untreated PCOS. The levonorgestrel intrauterine device and the etonogestrel subdermal implant may provide patients with endometrial protection, as well as less menstrual pain and bleeding, but may not allow for predictability in menstrual bleeding. Many progestins have high androgenic activity and may worsen clinical hyperandrogenism. 7 When amenorrhea exceeds 90 days, endometrial protection is critical. The risk of endometrial cancer is 2–6 times higher among people with PCOS than the general population and often presents before menopause. 1 Patients with prolonged amenorrhea should be offered CHCs or progestins to maintain a nonproliferative endometrial lining ( Table 2 ). An endometrial biopsy should be considered for all patients with amenorrhea exceeding 90 days, especially if this occurs frequently. 24 Some patients are not candidates for CHCs or prefer not to be on a hormonal medication. Metformin, an insulin sensitizer, can be used as a nonhormonal alternative for PCOS by promoting modest weight loss and reducing insulin levels, which may subsequently have an impact on cycle regularity and hyperandrogenism. 1 A meta-analysis of 22 randomized control trials (RCTs) of metformin for treatment of PCOS found a reduction in BMI (−0.53), testosterone (−13.36 ng/dL) and fasting glucose (−2.39 mg/dL). 1 Subgroup analyses demonstrated that metformin lowered BMI, fasting glucose and total and low-density lipoprotein cholesterol among patients with BMI greater than 25, while the free androgen index and fasting insulin were lowered among patients with a BMI less than or equal to 25. 1 The efficacy of metformin in reducing clinical features of PCOS remains uncertain. However, given the improvements in metabolic markers, metformin should be considered in patients with PCOS and a BMI greater than 25. 1 Metformin has been compared with CHCs in 22 RCTs. 1 Between the 2 treatments, no statistically significant differences were shown for weight, BMI or hirsutism, with very low certainty of evidence. Compared with metformin, CHCs did significantly improve menstrual irregularities, with moderate certainty of evidence. Compared with CHCs, insulin and cholesterol levels were improved with metformin with low to very low certainty of evidence. 1 The addition of metformin to CHCs can be considered in patients with PCOS in high metabolic risk groups, which includes those with a BMI greater than 30, those with impaired glucose tolerance, ethnic groups with high metabolic risk factors and those with other diabetes risk factors. 1 Inositol is an over-the-counter supplement that can be considered in management of PCOS. It belongs to the vitamin B complex group and is involved in many signalling cascades, including downstream of FSH and insulin. It may have a role in improving insulin sensitivity. 1 , 20 A recent meta-analysis showed that inositol, in particular myo-inositol, reduced BMI (mean difference 0.45 kg/m 2 ) compared with placebo. 20 Cycle normalization was higher in the inositol group (relative risk [RR] 1.79). Myo-inositol has minimal adverse effects, although more studies are needed to further support this. Furthermore, as inositol is a supplement, there is no regulation of what is commercially available to consumers and thus it must be used with caution. 1 , 20 Anti-androgen agents can be considered for patients with clinical hyperandrogenism after 6 months of CHCs with no improvement or in those with contraindications for CHCs. Medical treatment of hirsutism can reduce new hair growth but cannot reverse hair growth that was previously established. 7 Only external hair removal techniques such as mechanical laser and light therapy (i.e., laser removal) can be used for previous hair growth. Addition of topical eflornithine may improve outcomes of mechanical laser and light therapy. 7 Metformin and inositol may also indirectly reduce androgen levels, although their specific effect on the clinical reduction of hirsutism and acne has not been shown. 1 Anti-androgen agents such as spironolactone, cyproterone acetate and finasteride must be used with effective contraception given their teratogenicity; evidence also supports the reduction of hirsutism with the addition of an anti-androgen to CHCs. 1

Long-term complications such as hypertension, impaired glucose tolerance, type 2 diabetes, metabolic syndrome, non-alcoholic fatty liver disease, depression, anxiety, obstructive sleep apnea and cardiovascular disease (i.e., ischemic heart disease, myocardial infarction and cardiovascular mortality) have all been associated with PCOS. 16 These conditions tend to present earlier among people with PCOS than age-matched controls. 27 People with PCOS and a BMI greater than 25 are at higher risk of long-term health complications than patients with PCOS and a BMI of 25 or less. Ongoing care for patients can often be fragmented as the emphasis in PCOS can be overly focused on reproduction rather than long-term sequelae. 28 Baseline and follow-up assessments, as outlined in Box 4 , should be performed for all patients with PCOS. Measurement of height, weight and body mass index Measurement of blood pressure Cardiovascular risk assessment including cigarette smoking, physical activity and family history of premature cardiovascular disease. Assessment of lipid profile (cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides) Assessment of glycemic status, ideally with oral glucose tolerance test Assessment for obstructive sleep apnea symptoms (i.e., snoring with waking unrefreshed, daytime sleepiness or fatigue) Screening for depression and anxiety Screening for amenorrhea exceeding 90 d Polycystic ovarian syndrome may be associated with hypertension. A recent meta-analysis showed that the risk of hypertension was increased only among patients of reproductive age (pooled RR 1.72, 95% confidence interval [CI] 1.43–2.07) but not among menopausal patients who had PCOS during their reproductive years (pooled RR 1.26, 95% CI 0.95–1.67). 29 As such, patients with PCOS should have blood pressure measurements annually and at any time when fertility is desired since patients are at increased risk of hypertensive disorders in pregnancy. 1 Data on cardiovascular risk outcomes show inconsistent findings, although this is likely owing to the low event rate of major adverse cardiovascular events among premenopausal women. 28 Recently, several meta-analyses have suggested with very low to low certainty that females with PCOS have higher ORs or incidence rate ratios for composite cardiovascular disease, composite ischemic heart disease, myocardial infarction, stroke and cardiovascular mortality. 1 Thus, monitoring of cardiovascular risk profiles, including lipid profiles, should be undertaken both at baseline and on an ongoing basis for all patients with PCOS. 1 Polycystic ovarian syndrome is also related to hyperinsulinemia, impaired glucose intolerance and type 2 diabetes. 9 , 16 , 22 A meta-analysis of 41 studies indicated an increased risk of type 2 diabetes among patients with PCOS compared with those without PCOS (OR 2.87, 95% CI 1.37–6.01). 1 Hyperinsulinemia is present in 75% of patients with PCOS and a BMI of 25 or less and 95% of patients with a BMI greater than 25. 1 Polycystic ovarian syndrome is associated with a higher risk of obstructive sleep apnea, independent of BMI. In a recent meta-analysis of 8 studies, those with PCOS had a 10 times higher chance of obstructive sleep apnea than those without PCOS, with an odds ratio (OR) of 9.52 (95% CI 3.90–23.26). 3 Patients with PCOS should be assessed for symptoms of obstructive sleep apnea, screened using appropriate tools (e.g., Berlin Questionnaire) and directed for a sleep study and treatment if obstructive sleep apnea is identified. 3 Patients with PCOS also have a high prevalence of depression and anxiety. In a meta-analysis of 47 studies, depression was more likely among patients with PCOS than those without PCOS (OR 2.59, 95% CI 2.11–3.16). 1 In a meta-analysis of 27 studies reporting on anxiety, patients with PCOS had a higher risk of anxiety than those without, with an OR of 2.68 (95% CI 2.08–3.44). 1 Polycystic ovarian syndrome can have a negative impact on body image and self-esteem, and is also associated with a higher rate of disordered eating. 1

If a patient intends to conceive, clinicians should communicate that irregular or prolonged (> 35 d) cycles may still be sporadically ovulatory. 25 Conversely, contraception is needed if pregnancy is not desired. Time to pregnancy is longer on average; a large population-based study in Sweden observed that spontaneous conception took an average of 2 years longer among patients with PCOS. 26 Ovulatory function and, thus, cycle regularity tend to improve as patients age, although all patients are subject to age-related fertility decline regardless of PCOS. 27 In the population-based study from Sweden, the cumulative probability of childbirth after spontaneous conception was 55% among patients with PCOS, compared with 73.8% among women without PCOS. 26 With assisted reproduction, the cumulative probability of childbirth was the same among both patients with PCOS (80%) and those without (78%). 26 First-line options for management of return of ovulatory cycles that can be initiated by primary care physicians include weight loss of 5%–10% for patients with overweight or obesity, metformin, inositol or letrozole. 1 It is reasonable to trial these methods for 6–12 months in patients younger than 35 years. Metformin and inositol are safe in pregnancy; however, unless the patient has concurrent type 2 diabetes, no convincing evidence supports continuing these medications in pregnancy. Referral to a fertility specialist for ovulation induction with letrozole, gonadotropins or laparoscopic ovarian drilling (i.e., use of a monopolar needle to puncture the ovarian cortex) can be considered at any time. 1 Pregnant patients with PCOS are at increased risk of miscarriage, gestational weight gain, gestational diabetes, hypertension, preeclampsia, intrauterine growth restriction, preterm delivery and cesarean delivery; some of the risks may be mitigated by maintenance of a normal BMI. 1 Given the known contribution of PCOS to impaired glycemic status, screening for impaired fasting glucose or impaired glucose tolerance with a 75-g oral glucose tolerance test should be considered before conception. 3 When not completed before conception, it should be performed at the first prenatal visit before 20 weeks’ gestation and again at 24–28 weeks’ gestation. 1 Although the quality of evidence is low, an oral glucose tolerance test is the preferred method for identification of insulin resistance among patients with PCOS. 1

Polycystic ovarian syndrome, a common endocrinological disorder among reproductive-aged females, presents with menstrual irregularities, hyperandrogenism and polycystic ovarian morphology. It is associated with important long-term health consequences such as hypertension, neoplastic risks, metabolic consequences, adverse cardiovascular outcomes, psychological impacts and adverse reproductive outcomes. Early diagnosis can allow for improvement in symptoms and mitigation of long-term health complications.