How should I evaluate a woman with three months of secondary amenorrhea?

Workup for Secondary Amenorrhea (3 Months)

Initial Mandatory Step

Begin with a urine pregnancy test immediately—this is non-negotiable regardless of patient history or reported sexual activity. 1, 2, 3, 4

First-Line Laboratory Panel

Order the following hormonal tests simultaneously after excluding pregnancy:

• Serum FSH and LH – measured between cycle days 3-6 if any bleeding occurs, or at any time in complete amenorrhea 1, 2
• Serum prolactin – single morning resting sample (not post-exercise or post-stress) 5, 1, 2
• TSH – to identify reversible thyroid dysfunction 1, 2, 4
• Estradiol – helps differentiate functional hypothalamic amenorrhea (low) from PCOS (normal/elevated) 1, 2

Critical History Elements

Document these specific details to guide interpretation:

• Weight trajectory – any loss >5% body weight in past 6 months, current BMI, and calculate waist-to-hip ratio (>0.9 suggests PCOS) 5, 1, 2
• Exercise patterns – hours per week and intensity; >10 hours/week of intense training warrants energy availability assessment 1
• Eating behaviors – use direct questioning about restrictive eating, calorie counting, purging, or laxative use (patients frequently minimize these) 1
• Medication review – specifically antipsychotics, antiepileptics, and hormonal contraceptives 2
• Associated symptoms – galactorrhea (suggests hyperprolactinemia), hirsutism/acne (suggests PCOS or hyperandrogenism), headaches or visual changes (suggests pituitary pathology) 5, 1, 2

Physical Examination Priorities

• Calculate BMI – obesity (>25 kg/m²) associated with PCOS; low BMI (<18.5 kg/m²) suggests functional hypothalamic amenorrhea 5, 1
• Assess for hyperandrogenism – male-pattern hair distribution, acne, androgenetic alopecia 5, 2
• Check for galactorrhea – express nipples to detect occult discharge 5
• Thyroid palpation – identify enlargement or nodules 2

Interpretation Algorithm Based on FSH Results

Elevated FSH (>35-40 IU/L)

• Diagnosis: Primary Ovarian Insufficiency – confirm with repeat FSH 4 weeks later (requires two elevated values) 1, 2, 3
• Next steps: Karyotype if age <40 years to identify Turner syndrome; refer to endocrinology for hormone replacement therapy 1
• Critical caveat: These patients maintain unpredictable ovarian function and should NOT be presumed infertile 1, 3, 4

Low or Normal FSH with Elevated Prolactin (>20 μg/L)

• Diagnosis: Hyperprolactinemia – rule out hypothyroidism first (check TSH), then obtain pituitary MRI if prolactin remains elevated 5, 1, 2
• Common pitfall: Mild prolactin elevation occurs in epilepsy patients; ensure sample was not post-ictal 5

Low or Normal FSH with Normal Prolactin

• Calculate LH/FSH ratio:

  • Ratio >2: Strongly suggests PCOS—proceed to pelvic ultrasound and consider androgen profile (testosterone, DHEA-S) if hirsutism present 5, 1, 2
  • Ratio <1: Seen in 82% of functional hypothalamic amenorrhea cases 1, 2

• Check estradiol level:

  • **Low estradiol (<30 pg/mL):** Confirms functional hypothalamic amenorrhea—assess energy availability (>30 kcal/kg fat-free mass/day required) 1
  • Normal/elevated estradiol: More consistent with PCOS despite low LH/FSH ratio 1, 2

Imaging Studies

Pelvic ultrasound (transvaginal preferred) is indicated when: 5, 1, 2

• LH/FSH ratio >2 (evaluate for polycystic ovarian morphology)
• Any palpable adnexal mass
• Concern for structural abnormality

Assess endometrial thickness on ultrasound: 1, 2

• <5 mm suggests estrogen deficiency (functional hypothalamic amenorrhea)

• 8 mm suggests chronic anovulation with unopposed estrogen (PCOS)

Pituitary MRI is indicated for: 5, 1

• Persistent hyperprolactinemia after excluding hypothyroidism
• Galactorrhea with normal prolactin
• Headaches or visual field defects

Red Flags Requiring Urgent Evaluation

• Significant weight loss or eating disorder signs – requires multidisciplinary eating disorder team 1
• Headaches with visual changes – obtain pituitary MRI urgently 1
• Severe hirsutism or virilization – measure testosterone; levels >2.5 nmol/L warrant evaluation for androgen-secreting tumor 5, 2

Bone Health Assessment

Obtain DXA scan for bone mineral density if amenorrhea persists >6 months, regardless of age—prolonged hypoestrogenic states significantly increase osteoporosis risk, and 90% of peak bone mass is attained by age 18. 1

Common Diagnostic Pitfalls to Avoid

• Do not assume amenorrhea in athletes is benign – other pathology must be excluded even when clinical picture suggests functional hypothalamic amenorrhea 1
• Do not prescribe oral contraceptives as first-line therapy – this masks the underlying problem without addressing energy deficit and provides false reassurance about bone health 1
• Do not overlook ovarian tumors – inhibin-producing granulosa cell tumors can mimic hypothalamic amenorrhea with low FSH/LH but will have adnexal mass on imaging 6
• Do not misdiagnose functional hypothalamic amenorrhea with polycystic ovarian morphology as PCOS – functional hypothalamic amenorrhea patients have low LH, low estradiol, thin endometrium, and LH/FSH ratio <1 despite ovarian appearance 1, 2