# Polycystic Ovary Syndrome: Diagnosis and Long-Term Management

## Overview

Polycystic ovary syndrome is the most common endocrine disorder in reproductive-age women, affecting 6 to 12% of this population. It is a syndrome of chronic anovulation and hyperandrogenism with significant metabolic, reproductive, and psychological implications that require long-term primary care management.

## Diagnostic Criteria

### Rotterdam Criteria (Most Widely Used)

The Rotterdam criteria, which are the most widely used, require 2 of the following 3 features: oligo-anovulation (cycles longer than 35 days, fewer than 8 cycles per year, or amenorrhea), clinical or biochemical hyperandrogenism (hirsutism with a Ferriman-Gallwey score of 8 or above, acne, androgenic alopecia, or elevated total or free testosterone or DHEA-S), and polycystic ovarian morphology on ultrasound (12 or more follicles of 2 to 9 mm per ovary or ovarian volume exceeding 10 mL, with an updated threshold of 20 or more follicles using modern ultrasound technology).

### Other Criteria Systems

The NIH 1990 criteria are stricter, requiring both hyperandrogenism and oligo-anovulation. The AE-PCOS Society criteria require hyperandrogenism plus either ovulatory dysfunction or polycystic ovaries.

### Important Diagnostic Considerations

PCOS is a diagnosis of exclusion, meaning other causes must be ruled out before the diagnosis is confirmed. Ultrasound is not required if both hyperandrogenism and oligo-anovulation are present. Ultrasound criteria should not be used for diagnosis in adolescents, as multi-follicular ovaries are a normal finding in teens. Anti-Mullerian hormone, which is elevated in PCOS, may serve as a surrogate marker for polycystic morphology but is not yet incorporated into standard diagnostic criteria.

## Differential Diagnosis (Must Exclude)

Before confirming a PCOS diagnosis, thyroid disease should be excluded with TSH, and hyperprolactinemia should be excluded with prolactin. Non-classic congenital adrenal hyperplasia is screened for with an early morning 17-hydroxyprogesterone, where a level below 200 ng/dL essentially rules out the condition. Cushing syndrome should be evaluated with 24-hour urinary cortisol, late-night salivary cortisol, or a 1 mg overnight dexamethasone suppression test when clinical suspicion exists. Androgen-secreting tumors should be suspected when there is rapid virilization or a total testosterone level exceeding 200 ng/dL. Hypothalamic amenorrhea, characterized by low FSH and low estradiol, is associated with low BMI, excessive exercise, and stress.

## Initial Workup

The initial laboratory workup includes total and free testosterone (or calculated free testosterone using SHBG), DHEA-S if an adrenal source of androgens is suspected, TSH, prolactin, and early-morning follicular-phase 17-hydroxyprogesterone. Metabolic evaluation includes fasting glucose and insulin (with a 2-hour 75g oral glucose tolerance test preferred for glucose tolerance assessment), lipid panel, and hemoglobin A1c. Liver enzymes should be obtained as a baseline before medication initiation. FSH and LH may be considered, as an LH-to-FSH ratio exceeding 2 is suggestive but not diagnostic of PCOS.

## Phenotypes

| Phenotype | Features Present | Metabolic Risk |
|-----------|-----------------|----------------|
| A (Classic) | Hyperandrogenism + oligo-anovulation + polycystic ovaries | Highest |
| B | Hyperandrogenism + oligo-anovulation | High |
| C (Ovulatory) | Hyperandrogenism + polycystic ovaries | Moderate |
| D (Non-hyperandrogenic) | Oligo-anovulation + polycystic ovaries | Lowest |

PCOS is classified into four phenotypes with different metabolic risk profiles. Phenotype A, the classic form, includes hyperandrogenism, oligo-anovulation, and polycystic ovaries, and carries the highest metabolic risk. Phenotype B includes hyperandrogenism and oligo-anovulation without polycystic morphology. Phenotype C, or ovulatory PCOS, includes hyperandrogenism and polycystic ovaries with regular ovulation. Phenotype D, the non-hyperandrogenic form, includes oligo-anovulation and polycystic ovaries and carries the lowest metabolic risk.

## Metabolic Complications

Insulin resistance is present in 50 to 70% of women with PCOS regardless of BMI and drives many features of the syndrome. The risk of type 2 diabetes is increased 5 to 10 fold, necessitating screening with an oral glucose tolerance test at diagnosis and then every 1 to 3 years. Metabolic syndrome is found in up to 40% of affected women and should be screened for regularly. Dyslipidemia with elevated triglycerides, low HDL, and elevated LDL is common. Non-alcoholic fatty liver disease has increased prevalence and warrants monitoring of ALT. Obstructive sleep apnea, with higher prevalence even in lean PCOS, should be screened for with questionnaires such as the Berlin or STOP-BANG. Cardiovascular disease risk is increased over the long term, and modifiable risk factors should be managed aggressively.

## Management

### Lifestyle Modification (First-Line for All Patients)

Lifestyle modification is first-line for all patients with PCOS. Weight loss of 5 to 10% improves ovulation, insulin sensitivity, and androgen levels. Structured exercise should include 150 minutes per week of moderate-intensity aerobic activity plus resistance training. Dietary counseling should be individualized, as no single diet has been proven superior, though Mediterranean, DASH, and reduced glycemic index diets may be beneficial. Behavioral support helps sustain lifestyle changes.

### Menstrual Regulation and Endometrial Protection

Chronic anovulation with unopposed estrogen increases the risk of endometrial hyperplasia and cancer. Combined oral contraceptives are first-line for menstrual regulation and also treat hirsutism and acne. Any COC is effective, though those with anti-androgenic progestins such as drospirenone, cyproterone acetate, or dienogest may have added benefit. Cyclic progestin with medroxyprogesterone 10 mg for 10 to 14 days every 1 to 3 months is appropriate when COCs are contraindicated. The LNG-IUD provides endometrial protection but does not address hyperandrogenism. At minimum, a withdrawal bleed should occur every 3 months to prevent endometrial buildup.

### Hyperandrogenism Management

#### Hirsutism

COCs are first-line, as they suppress ovarian androgen production and increase SHBG. Spironolactone at 50 to 200 mg daily acts as an anti-androgen, but it takes 6 or more months to produce visible improvement and is teratogenic, requiring reliable contraception. Topical eflornithine (Vaniqa) slows facial hair growth and serves as an adjunct. Physical hair removal options include electrolysis (permanent), laser hair removal (long-term reduction), waxing, and shaving. Finasteride, a 5-alpha reductase inhibitor, is used off-label and is also teratogenic. Patients should be counseled that 6 to 12 months are needed to assess response to anti-androgen therapy.

#### Acne

COCs, especially those with drospirenone or norgestimate, are effective. Spironolactone is useful as an adjunct. Standard acne management with topical retinoids, benzoyl peroxide, and topical or oral antibiotics applies. Isotretinoin is reserved for severe cystic acne with dermatology referral.

#### Androgenic Alopecia

Topical minoxidil at 2% (off-label for women, with 5% potentially more effective), spironolactone, and COCs are the main treatment options.

### Insulin Resistance and Metabolic Management

Metformin at 500 to 2000 mg daily improves insulin sensitivity and may restore ovulation in some patients. While not FDA-approved for PCOS, it is widely used and is first-line for impaired glucose tolerance or type 2 diabetes in PCOS. It serves as a second-line option for menstrual irregularity when COCs are contraindicated or not desired. The extended-release formulation is better tolerated with fewer gastrointestinal side effects. Inositol, specifically myo-inositol and D-chiro-inositol in a 40-to-1 ratio, is a supplement with emerging evidence for insulin sensitization and ovulation. Statin therapy follows standard guidelines when dyslipidemia is present. GLP-1 receptor agonists have emerging evidence for metabolic benefits in PCOS with obesity but are not yet standard of care.

### Fertility Management

Letrozole is the first-line ovulation induction agent, having demonstrated superiority to clomiphene in the NICHD trial with higher live birth rates. Clomiphene citrate, a selective estrogen receptor modulator, is now second-line. Metformin serves as an adjunct to ovulation induction and may improve ovulation rates, especially in obese patients. Gonadotropins are a second-line injectable therapy requiring monitoring to avoid ovarian hyperstimulation syndrome. IVF is reserved for refractory cases and achieves high success rates but carries increased OHSS risk. Ovarian drilling, a laparoscopic procedure, is rarely performed now given the availability of pharmacologic alternatives. Weight loss improves fertility outcomes and should be encouraged prior to fertility treatment.

## Mental Health Considerations

Depression and anxiety are 3 to 4 times more prevalent in women with PCOS and should be screened for with PHQ-9 and GAD-7 at diagnosis and periodically thereafter. Body image concerns, hirsutism, and infertility contribute to psychological distress. Eating disorders may be more common and should be screened for before recommending weight loss. Referral for psychological support should be provided as needed.

## Adolescent PCOS

Diagnosis in adolescents is challenging because of overlap with normal pubertal physiology. Menstrual irregularity is normal for 2 to 3 years post-menarche, and persistent irregularity beyond this warrants evaluation. Ultrasound criteria should not be used for diagnosis in this age group. An "at risk for PCOS" designation may be appropriate when diagnostic criteria are not fully met, with longitudinal follow-up planned. COCs are first-line for menstrual regulation and acne or hirsutism management. Lifestyle modification is especially important for prevention of metabolic complications.

## Long-Term Monitoring

Annual monitoring should include fasting glucose, OGTT, or A1c, along with lipid panel and blood pressure. Endometrial assessment is warranted if prolonged amenorrhea exceeding 3 months occurs without a withdrawal bleed. Weight, BMI, and waist circumference should be tracked at each visit. Depression and anxiety screening should be performed periodically. As patients age, transition to comprehensive cardiovascular risk management becomes increasingly important.

<image>A diagnostic algorithm for PCOS showing the Rotterdam criteria with three main branches (hyperandrogenism, oligo-anovulation, polycystic ovarian morphology), the differential diagnosis exclusions required (thyroid disease, NCCAH, Cushing syndrome, hyperprolactinemia), and the four PCOS phenotypes with their relative metabolic risk profiles.</image>

<image>A management framework for PCOS organized by treatment goals: menstrual regulation (COCs, cyclic progestin, LNG-IUD), hyperandrogenism (spironolactone, COCs, eflornithine, laser), metabolic health (lifestyle, metformin, statins), fertility (letrozole, clomiphene, gonadotropins), and mental health screening, with first-line and second-line options for each category.</image>

<image>A comparison of the four PCOS phenotypes (A through D) displayed as a table showing which Rotterdam criteria are present in each, the relative prevalence, metabolic risk level, and recommended screening intensity for diabetes, cardiovascular disease, and endometrial hyperplasia for each phenotype.</image>

## Clinical Pearls

PCOS is a diagnosis of exclusion, and TSH, prolactin, and 17-hydroxyprogesterone should always be checked to rule out common mimics before confirming the diagnosis. A 2-hour 75g oral glucose tolerance test is more sensitive than fasting glucose or A1c for detecting glucose intolerance in PCOS, with up to 40% of glucose abnormalities missed by fasting glucose alone. Letrozole has replaced clomiphene as the first-line ovulation induction agent based on the NICHD trial showing higher live birth rates. Spironolactone takes 6 to 12 months to show visible improvement in hirsutism, and expectations should be set early while ensuring reliable contraception due to teratogenicity. Endometrial protection is essential: women with PCOS who are not on hormonal contraception should have a withdrawal bleed at least every 3 months to prevent hyperplasia. Lean PCOS, in women with a BMI below 25, exists and still carries metabolic risk, and the diagnosis should not be dismissed based on normal weight. Mental health screening should be routine in PCOS management, as depression, anxiety, and eating disorders are significantly more prevalent. Adolescent PCOS diagnosis should be made cautiously, and ultrasound criteria should not be used in this age group.

## References

- Teede HJ et al. International Evidence-Based Guideline for PCOS. Monash University. 2023
- Legro RS et al. Letrozole vs. Clomiphene for Infertility in PCOS (NICHD). N Engl J Med. 2014
- Azziz R et al. PCOS: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016
- ACOG Practice Bulletin No. 194: Polycystic Ovary Syndrome. Obstet Gynecol. 2018
- Escobar-Morreale HF. Polycystic Ovary Syndrome: Definition, Aetiology, Diagnosis and Treatment. Nat Rev Endocrinol. 2018