What initial laboratory tests are recommended for patients with Polycystic Ovary Syndrome (PCOS) seeking to improve fertility?

Laboratory Testing for PCOS and Fertility

For women with PCOS seeking fertility, obtain total testosterone (or free testosterone) via LC-MS/MS, TSH, prolactin, 2-hour oral glucose tolerance test with 75g glucose load, fasting lipid profile, and mid-luteal progesterone to confirm ovulation status. 1

Essential First-Line Hormonal Tests

Androgen Assessment

• Measure total testosterone or free testosterone using liquid chromatography-tandem mass spectrometry (LC-MS/MS) as the primary androgen marker, which shows pooled sensitivity of 74% and specificity of 86% for PCOS diagnosis 1
• Free testosterone demonstrates superior sensitivity of 89% with specificity of 83% compared to total testosterone 1
• LC-MS/MS is mandatory over direct immunoassays, as it provides superior specificity (92% vs 78%) and avoids false positives 1
• If total or free testosterone are normal but clinical suspicion remains high, measure androstenedione (sensitivity 75%, specificity 71%) and DHEAS (sensitivity 75%, specificity 67%) as second-line tests 1

Ovulation Confirmation

• Measure progesterone during mid-luteal phase (approximately day 21 of a 28-day cycle) to confirm anovulation, with levels <6 nmol/L indicating anovulation 2
• This test is critical for fertility assessment as it directly confirms whether ovulation is occurring 2

Exclusion of Other Endocrine Disorders

• Measure thyroid-stimulating hormone (TSH) to rule out thyroid disease as a cause of menstrual irregularity and infertility 2, 1
• Measure prolactin using morning resting serum levels (not post-ictal) to exclude hyperprolactinemia, with levels >20 μg/L considered abnormal 2, 1
• Mildly elevated prolactin may occur in epilepsy patients; rule out hypothyroidism or pituitary tumor 2

Additional Hormonal Tests to Consider

LH and FSH Assessment

• Measure luteinizing hormone (LH) and follicle-stimulating hormone (FSH) between days 3-6 of the menstrual cycle, calculating based on an average of three estimations taken 20 minutes apart 2
• An LH/FSH ratio >2 suggests PCOS, though this is abnormal in only 35-44% of women with PCOS, making it a poor standalone diagnostic marker 2, 1
• FSH >35 IU/L or LH >11 IU/L are considered abnormal 2

Adrenal Androgen Assessment

• Measure DHEAS to rule out non-classical congenital adrenal hyperplasia, with age-specific thresholds: >3800 ng/ml for ages 20-29 and >2700 ng/ml for ages 30-39 2
• Measure androstenedione if testosterone is normal but suspicion remains high, with levels >10.0 nmol/L indicating possible adrenal/ovarian tumor 2
• Measure 17-hydroxyprogesterone if DHEAS is markedly elevated to exclude congenital adrenal hyperplasia 3

Mandatory Metabolic Screening

Glucose Metabolism Assessment

• Perform 2-hour oral glucose tolerance test with 75g glucose load to detect type 2 diabetes and glucose intolerance, as this is superior to hemoglobin A1C or fasting glucose alone for detecting impaired glucose tolerance in PCOS 1, 4
• Obese women with PCOS have 31-35% prevalence of impaired glucose tolerance and 7.5-10% prevalence of type 2 diabetes 4
• Rates of progression from normal glucose tolerance to impaired glucose tolerance, and then to type 2 diabetes, may be as high as 5-15% within 3 years 4
• Measure fasting glucose and insulin levels, with a glucose/insulin ratio >4 suggesting reduced insulin sensitivity 2

Lipid Profile Assessment

• Obtain fasting lipid panel including total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides to assess cardiovascular risk 1, 3
• PCOS patients show trends toward higher triglycerides, lower HDL-cholesterol, and preponderance of small, dense LDL particles 5
• Insulin resistance in PCOS creates a particularly atherogenic lipid profile requiring monitoring 3

Body Composition Assessment

• Calculate body mass index (BMI), with BMI >25 considered obese 2, 1
• Measure waist-hip ratio (WHR) to identify central obesity, with WHR >0.9 indicating truncal obesity 2, 1
• Look for acanthosis nigricans on physical examination, indicating underlying insulin resistance 3

Critical Clinical Pitfalls

Diagnostic Limitations

• Normal testosterone occurs in 30% of women with confirmed PCOS, so the absence of biochemical hyperandrogenism does not exclude PCOS when clinical features and ultrasound findings are present 1
• Direct immunoassays for testosterone have lower specificity (78%) compared to LC-MS/MS (92%) and may lead to false positives 1
• Anti-Müllerian Hormone (AMH) should not be used as a single test for PCOS diagnosis despite showing high sensitivity (92%) and specificity (97%) at thresholds ≥35 pmol/L, as it requires further validation 1, 6

Screening Underutilization

• Many obstetrician-gynecologists underutilize metabolic screening, with only 7% ordering the recommended 2-hour oral glucose tolerance test 7
• The 2-hour oral glucose tolerance test is superior to hemoglobin A1C or fasting glucose for detecting impaired glucose tolerance in PCOS patients 7

Fertility-Specific Considerations

• Assessment for infertility involves evaluating preconceptional issues that may affect response to therapy or lead to adverse pregnancy outcomes 4
• Women with PCOS should be screened and treated for hypertension and diabetes prior to attempting conception 4
• Target 5% weight loss before fertility treatment, as this improves metabolic parameters, ovulation rates, and pregnancy outcomes 3