Residency · Residency · Obstetrics Gynecology

Polycystic Ovary Syndrome

Overview

Polycystic ovary syndrome is the most common endocrine disorder in reproductive-age women, affecting 6 to 13% of this population depending on the diagnostic criteria used. It is the leading cause of anovulatory infertility and carries significant metabolic implications that extend well beyond the reproductive system. PCOS is a lifelong condition that requires longitudinal, multidisciplinary management.

Diagnostic Criteria

Rotterdam Criteria (2003, Most Widely Used)

The Rotterdam criteria require two of three features for diagnosis: oligo-ovulation or anovulation manifesting as irregular menstrual cycles, clinical and/or biochemical hyperandrogenism, and polycystic ovarian morphology on ultrasound. The ultrasound threshold was originally defined as 12 or more follicles measuring 2 to 9 mm per ovary or an ovarian volume greater than 10 mL. With modern high-resolution ultrasound, the threshold has been updated to 20 or more follicles per ovary. Other causes of hyperandrogenism and anovulation must be excluded before the diagnosis is made.

NIH 1990 Criteria

The NIH criteria are more restrictive, requiring both chronic anovulation and clinical or biochemical hyperandrogenism. This definition identifies the phenotype with the highest metabolic risk.

Androgen Excess Society (2006)

The Androgen Excess Society criteria require hyperandrogenism (clinical or biochemical) plus ovarian dysfunction (oligo-anovulation or polycystic ovaries). Under this framework, hyperandrogenism is considered essential for diagnosis.

PCOS Phenotypes (Rotterdam)

The Rotterdam criteria define four phenotypes. Phenotype A, the classic form, includes hyperandrogenism, ovulatory dysfunction, and polycystic ovaries and carries the highest metabolic risk. Phenotype B includes hyperandrogenism and ovulatory dysfunction without polycystic ovarian morphology. Phenotype C, sometimes called ovulatory PCOS, includes hyperandrogenism and polycystic ovaries with regular ovulation. Phenotype D includes ovulatory dysfunction and polycystic ovaries without hyperandrogenism and carries the mildest metabolic risk.

Clinical Features

Reproductive

The most common presentation is oligomenorrhea or amenorrhea. Anovulatory infertility is a major concern. Women with PCOS have a 2- to 3-fold increased risk of recurrent early pregnancy loss. Chronic unopposed estrogen from anovulation significantly increases the risk of endometrial hyperplasia and endometrial cancer.

Hyperandrogenism

Clinical signs of hyperandrogenism include hirsutism, scored using the modified Ferriman-Gallwey system with a threshold of 4 to 8, reflecting terminal hair growth in androgen-dependent areas. Acne is often inflammatory and distributed along the jawline and chin. Androgenic alopecia presents as female pattern hair loss with central thinning and a preserved frontal hairline. Biochemical hyperandrogenism is characterized by elevated total and/or free testosterone, mildly elevated DHEA-S (though marked elevation suggests an adrenal tumor), and low sex hormone-binding globulin, which results in higher levels of free testosterone.

Metabolic

Insulin resistance is present in 50 to 70% of PCOS patients, independent of BMI. Obesity affects 50 to 80% of patients, typically with a central or abdominal distribution. Metabolic syndrome is 2 to 3 times more prevalent than in the general population. The risk of type 2 diabetes is increased 7-fold. Dyslipidemia, characterized by elevated triglycerides and low HDL, is common. Non-alcoholic fatty liver disease and obstructive sleep apnea are additional metabolic complications. Cardiovascular disease risk is increased, although clear mortality data are still evolving.

Psychological

Depression and anxiety are 2 to 3 times more prevalent in women with PCOS. Reduced quality of life, body image concerns, and disordered eating are common and should be actively screened for.

<image>Infographic showing the multisystem manifestations of PCOS organized by organ system: reproductive (irregular periods, infertility, endometrial cancer risk), dermatologic (hirsutism, acne, alopecia), metabolic (insulin resistance, diabetes, dyslipidemia, fatty liver), and psychological (depression, anxiety, reduced quality of life)</image>

Evaluation and Workup

Hormonal Assessment

Total and free testosterone are measured to document biochemical hyperandrogenism. DHEA-S is mildly elevated in PCOS, but marked elevation above 700 mcg/dL should raise concern for an adrenal tumor. 17-hydroxyprogesterone is drawn in the early morning to rule out non-classic congenital adrenal hyperplasia; if the level exceeds 200 ng/dL, an ACTH stimulation test should follow. TSH is checked to rule out thyroid dysfunction. Prolactin is measured to exclude hyperprolactinemia. FSH and estradiol help rule out premature ovarian insufficiency in patients with amenorrhea. LH is often elevated, and an LH-to-FSH ratio greater than 2 to 3:1 is suggestive of PCOS but not diagnostic. If Cushing syndrome is suspected based on clinical features such as moon facies, striae, or proximal weakness, 24-hour urine cortisol or an overnight dexamethasone suppression test should be performed.

Metabolic Assessment

Fasting glucose and insulin can be used to estimate insulin resistance via the HOMA-IR calculation. A 2-hour oral glucose tolerance test using a 75-gram glucose load is recommended at diagnosis and every 1 to 3 years thereafter. A fasting lipid panel should be obtained. Hemoglobin A1C can be used but may underestimate diabetes risk in PCOS.

Pelvic Ultrasound

Pelvic ultrasound is not required for diagnosis when both hyperandrogenism and oligo-anovulation are present. It should not be used as the sole diagnostic criterion in adolescents, since polycystic ovarian morphology is a normal finding in up to 30% of adolescent ovaries. The updated threshold for polycystic morphology is 20 or more follicles per ovary with high-resolution probes, or an ovarian volume greater than 10 mL.

Anti-Mullerian Hormone (AMH)

AMH is often elevated in PCOS, reflecting the high antral follicle count. It has been proposed as a potential diagnostic criterion but is not yet included in formal diagnostic frameworks. It may replace ultrasound in the diagnostic algorithm in the future, though this remains controversial.

Differential Diagnosis

Before diagnosing PCOS, several conditions must be excluded. Non-classic congenital adrenal hyperplasia from 21-hydroxylase deficiency can present identically. Thyroid disorders, hyperprolactinemia, and Cushing syndrome must be ruled out. Androgen-secreting tumors of the ovary or adrenal gland, functional hypothalamic amenorrhea, premature ovarian insufficiency, and exogenous androgen use (including supplements) are all part of the differential.

Management

Lifestyle Modification (First-Line for All Patients)

Weight loss of just 5 to 10% improves ovulatory function, insulin sensitivity, and androgen levels. Structured diet and exercise programs are recommended, though no specific diet has been proven superior; caloric restriction is the fundamental principle. Regular aerobic exercise of at least 150 minutes per week at moderate intensity, combined with resistance training, is advised. Behavioral and psychological support should be incorporated into the management plan.

Menstrual Regulation and Endometrial Protection

Combined oral contraceptives are the first-line treatment for menstrual regulation, hyperandrogenism, and endometrial protection. Formulations with anti-androgenic progestins such as drospirenone, cyproterone acetate, or desogestrel are preferred when possible. Ethinyl estradiol-containing pills should be avoided in patients with contraindications such as venous thromboembolism risk, migraines with aura, or hypertension. Cyclic progestins, typically medroxyprogesterone 10 mg for 10 to 14 days every 1 to 3 months, can be used to induce withdrawal bleeding and prevent endometrial hyperplasia. The levonorgestrel-releasing intrauterine device provides excellent endometrial protection but does not address hyperandrogenism.

Hirsutism Treatment

Spironolactone at 50 to 200 mg daily is an effective anti-androgen for hirsutism and acne but requires reliable contraception because it is teratogenic. Combined oral contraceptives reduce free testosterone by increasing SHBG. Topical eflornithine inhibits ornithine decarboxylase in hair follicles and slows facial hair growth. Hair removal methods including laser hair removal, electrolysis, waxing, and threading provide cosmetic benefit. Finasteride, a 5-alpha reductase inhibitor, is less commonly used and is also teratogenic. Anti-androgen therapy takes 6 to 12 months to show full effect.

Acne Treatment

Combined oral contraceptives, especially those with anti-androgenic progestins, are effective. Spironolactone is helpful for hormonal acne. Topical retinoids, benzoyl peroxide, and topical antibiotics are standard dermatologic therapies. Isotretinoin may be used for severe cystic acne but requires strict contraception.

Insulin Resistance and Metabolic Management

Metformin at 1,500 to 2,000 mg daily improves insulin sensitivity and may restore ovulation in some patients, though it is not considered first-line for fertility (letrozole is superior). It is useful as an adjunct for metabolic risk reduction. Gastrointestinal side effects are common, so starting at a low dose and titrating up is recommended; the extended-release formulation is better tolerated. GLP-1 receptor agonists such as liraglutide and semaglutide show emerging evidence for weight loss and metabolic improvement in PCOS but are not yet FDA-approved for this indication. Statin therapy should follow standard guidelines for dyslipidemia. Screening for obstructive sleep apnea is recommended, especially in obese patients.

Infertility Treatment

Letrozole is the first-line agent for ovulation induction in PCOS. The NICHD randomized controlled trial demonstrated that letrozole produced superior live birth rates compared to clomiphene. The dose is 2.5 to 7.5 mg daily on cycle days 3 to 7. Clomiphene citrate at 50 to 150 mg daily on cycle days 5 to 9 is an alternative first-line option. Gonadotropins (injectable FSH) are second-line, requiring close monitoring due to the high risk of ovarian hyperstimulation syndrome and multiple pregnancy in PCOS patients. Laparoscopic ovarian drilling is rarely used and is reserved for patients resistant to clomiphene or letrozole who cannot undergo gonadotropin therapy. In vitro fertilization is appropriate for refractory cases, with PCOS patients at high risk for OHSS; a GnRH antagonist protocol with an agonist trigger is preferred. Metformin may be used as an adjunct to improve the response to ovulation induction agents.

<image>Treatment algorithm for PCOS organized by primary concern: irregular periods (OCPs, cyclic progestins, LNG-IUD), hirsutism/acne (spironolactone, OCPs, topical therapy), metabolic syndrome (lifestyle modification, metformin), and infertility (letrozole first-line, clomiphene, gonadotropins, IVF), with lifestyle modification as the foundation for all</image>

Long-Term Screening

Endometrial assessment should be performed if a patient goes more than 3 months without menses and is not on hormonal therapy; this includes ultrasound or biopsy if the endometrium is thickened. Diabetes screening with an oral glucose tolerance test should be repeated every 1 to 3 years, or at minimum an A1C should be checked. A fasting lipid panel should be obtained annually. Blood pressure should be monitored regularly. Mental health screening for depression and anxiety should occur at each visit. Cardiovascular risk should be assessed on an ongoing basis.

Adolescent PCOS

Diagnosing PCOS in adolescents is challenging because normal physiologic features overlap with diagnostic criteria. Irregular menstrual cycles are expected during the first 2 years after menarche, and polycystic ovarian morphology is common in adolescent ovaries. Diagnosis requires clear evidence of both hyperandrogenism and persistent oligo-anovulation that extends beyond 2 years after menarche. Ultrasound criteria should not be used for diagnosis in adolescents. Treatment focuses on lifestyle modification, combined oral contraceptives for menstrual regulation, and addressing psychosocial concerns. Metabolic complications should be screened for early.

Clinical Pearls

PCOS is a diagnosis of exclusion. Always rule out thyroid disease, hyperprolactinemia, non-classic congenital adrenal hyperplasia, and Cushing syndrome before making the diagnosis.

17-hydroxyprogesterone should be checked in all patients with hyperandrogenism to exclude non-classic CAH, which has a prevalence of 1 to 5% among hyperandrogenic women.

Letrozole is now the first-line agent for ovulation induction in PCOS, having surpassed clomiphene based on the NICHD randomized controlled trial demonstrating higher live birth rates.

Endometrial cancer risk is significantly increased in PCOS due to chronic unopposed estrogen. Endometrial protection should be ensured in all oligomenorrheic patients.

Insulin resistance occurs in lean PCOS patients as well; 30 to 40% of normal-weight women with PCOS are insulin resistant.

AMH is emerging as a potential diagnostic biomarker but is not yet validated for clinical diagnosis.

A 5 to 10% weight loss can restore ovulatory cycles in many PCOS patients. Lifestyle modification remains the foundation of treatment.

References

• ACOG Practice Bulletin No. 194: Polycystic Ovary Syndrome (2018)
• International Evidence-based Guideline for PCOS Assessment and Management (2023 Update, Monash University)
• Legro RS et al. Letrozole versus clomiphene for infertility in PCOS. N Engl J Med. 2014;371:119-129
• Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus. Fertil Steril. 2004;81:19-25
• Teede HJ et al. Recommendations from the international evidence-based guideline for PCOS. Hum Reprod. 2018;33:1602-1618
• Azziz R et al. Polycystic ovary syndrome. Nat Rev Dis Primers. 2016;2:16057

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