What is the recommended workup for primary or secondary amenorrhea in a reproductive‑age woman?

Workup for Amenorrhea

All patients with amenorrhea require immediate pregnancy testing followed by a systematic hormonal panel including serum TSH, free T4, prolactin, FSH, LH, and estradiol to identify the underlying etiology and guide management. 1

Initial Evaluation

History - Key Elements to Assess

Focus your history on these specific domains that directly impact diagnosis:

• Menstrual patterns: Age of menarche (if occurred), prior cycle regularity, duration of amenorrhea
• Energy balance: Eating patterns, restrictive behaviors, exercise intensity and frequency, recent weight changes
• Stress factors: Psychosocial stressors, psychiatric conditions
• Medication exposure: Hormonal contraceptives, psychotropics, chemotherapy
• Symptom clusters:
  • Hyperandrogenic: Acne, hirsutism, male-pattern hair loss
  • Hypoestrogenic: Hot flashes, vaginal dryness, decreased libido
  • Hyperprolactinemic: Galactorrhea, visual changes, headaches
  • Thyroid: Heat/cold intolerance, weight changes, fatigue
• Chronic illness: Inflammatory conditions, autoimmune disease, malabsorption
• Family history: Age of menarche in relatives, premature menopause, endocrine disorders 1

Physical Examination - Critical Findings

Perform a complete physical examination including external gynecologic evaluation (and bimanual examination in selected cases, particularly primary amenorrhea) to exclude anatomic causes. 1

Specific examination components:

• Anthropometrics: Height, weight, BMI trends
• Vital signs: Bradycardia (suggests functional hypothalamic amenorrhea)
• Pubertal development: Tanner staging, breast development timeline
• Skin: Acanthosis nigricans (hyperinsulinism), hypercarotenemia, cool/mottled extremities (energy deficit)
• Hyperandrogenism signs: Hirsutism, acne, clitoromegaly
• Thyroid: Goiter, thyromegaly
• Breast: Galactorrhea
• Neurologic: Visual fields, fundoscopy (papilledema), lateralizing signs
• Gynecologic external exam: Vaginal mucosa (thin/reddened in hypoestrogenism), imperforate hymen (bluish bulge), Müllerian anomalies 1

Laboratory Workup

First-Line Testing (All Patients)

Obtain this initial panel on all patients: 1

1. β-hCG (pregnancy test) - mandatory first step
2. TSH and free T4 - detect thyroid dysfunction
3. Prolactin - identify hyperprolactinemia
4. FSH and LH - distinguish hypogonadotropic vs hypergonadotropic causes
5. Estradiol (E2) - assess estrogen status
6. AMH (anti-Müllerian hormone) - evaluate ovarian reserve 1

Additional Baseline Testing

For comprehensive evaluation, particularly when chronic illness suspected:

• Complete blood count
• Comprehensive metabolic panel (electrolytes, glucose, BUN, creatinine, liver function)
• Hemoglobin A1C (if glucose elevated)
• ESR and/or CRP (if chronic inflammatory condition suspected) 1

Conditional Testing Based on Clinical Presentation

Obtain total testosterone and DHEA-S if clinical hyperandrogenism present (hirsutism, acne, clitoromegaly). 1

Obtain 8 AM 17-hydroxyprogesterone if late-onset congenital adrenal hyperplasia suspected. 1

Interpretation Algorithm

Pattern Recognition

The pattern of hormone levels is more critical than absolute values: 1

• Low/low-normal LH + low FSH + low E2 → Functional hypothalamic amenorrhea or hypothalamic/pituitary disorder
• Elevated FSH (>25-40 mIU/mL on two occasions) → Primary ovarian insufficiency; consider karyotyping 2, 3
• Elevated prolactin → Hyperprolactinemia; obtain brain MRI to evaluate for prolactinoma
• Elevated TSH → Primary hypothyroidism
• Elevated androgens → PCOS or other hyperandrogenic disorder; evaluate for metabolic syndrome 1

Imaging Considerations

Individualize imaging based on hormonal results:

• Pelvic ultrasound: Consider as alternative to bimanual exam, evaluate for PCOS morphology, anatomic abnormalities, or adnexal masses 1
• Brain MRI: Indicated for elevated prolactin, visual field defects, or suspected hypothalamic/pituitary pathology
• Karyotyping: Required for primary ovarian insufficiency, especially in younger patients or primary amenorrhea 2, 4

Critical Pitfalls to Avoid

1. Never assume infertility in primary ovarian insufficiency - ovarian function remains unpredictable; patients require both contraception counseling and fertility preservation discussion 3, 5

2. Don't miss functional hypothalamic amenorrhea complications - screen for eating disorders, assess bone density (DEXA scan), as these patients face significant osteoporosis risk 1, 6

3. In FHA, expect "low-normal" values - TSH and free T4 in lower normal range, testosterone in lower normal range, prolactin in low-normal range; these typically normalize with weight restoration 1

4. PCOS requires metabolic screening - glucose tolerance testing, lipid panel, blood pressure monitoring for metabolic syndrome and endometrial cancer risk 2, 3

5. Primary amenorrhea by age 15 or 3 years post-thelarche demands evaluation - don't delay workup 2, 4

6. Secondary amenorrhea threshold: 3 months for regular cycles, 6 months for irregular cycles 2, 3