What is the workup for a patient with amenorrhea (absent periods)?

Workup for Amenorrhea

Begin with a pregnancy test, followed by measurement of FSH, LH, TSH, and prolactin levels, along with pelvic ultrasonography to identify the underlying cause and guide management. 1

Initial Clinical Assessment

History

• Menstrual history: Document age of menarche, cycle regularity, and duration of amenorrhea (primary amenorrhea if no menarche by age 16; secondary amenorrhea if cessation of regular menses for 3 months or irregular menses for 6 months) 1, 2, 3
• Weight and nutrition: Assess for eating disorders, excessive exercise (Female Athlete Triad), and recent weight changes, as these commonly cause functional hypothalamic amenorrhea 1, 3
• Medication review: Document use of hormonal contraceptives, antipsychotics, antiepileptics, and chemotherapy agents 1, 4
• Symptom assessment: Evaluate for galactorrhea (hyperprolactinemia), hirsutism/acne (hyperandrogenism/PCOS), hot flashes (ovarian insufficiency), and headaches/visual changes (pituitary pathology) 1, 2, 3

Physical Examination

• BMI calculation: Obesity suggests PCOS; low BMI suggests hypothalamic amenorrhea 1
• Tanner staging: Assess breast and pubic hair development to differentiate primary from secondary amenorrhea 1
• Thyroid examination: Palpate for enlargement or nodules 1
• Signs of hyperandrogenism: Look for hirsutism, acne, and male-pattern baldness 3

Laboratory Testing

First-Line Tests (All Patients)

• Pregnancy test (urine β-hCG): Must be performed first to exclude pregnancy, regardless of sexual history 1, 4, 2, 3
• FSH and LH: Elevated FSH (>40 mIU/mL) indicates primary ovarian insufficiency; low/normal FSH with low LH suggests hypothalamic amenorrhea; LH/FSH ratio >2 suggests PCOS 1, 2, 3
• Prolactin: Elevated levels (>25 ng/mL) indicate hyperprolactinemia, often from pituitary adenoma 1, 2, 3
• TSH: Identifies thyroid dysfunction as a reversible cause 1, 2, 3

Second-Line Tests (Based on Initial Results)

• Estradiol level: Low levels (<20 pg/mL) confirm hypoestrogenism in hypothalamic amenorrhea 1
• Testosterone and DHEA-S: Evaluate for hyperandrogenism if PCOS suspected or if signs of virilization present 3
• Karyotype: Indicated in primary amenorrhea with elevated FSH to diagnose Turner syndrome or other chromosomal abnormalities 2, 3, 5
• Progesterone challenge test: Can differentiate PCOS (positive withdrawal bleed) from functional hypothalamic amenorrhea (negative), though endometrial thickness on ultrasound is more reliable 6, 1

Imaging Studies

Pelvic Ultrasonography

• Transvaginal ultrasound (preferred in sexually active patients): More sensitive than transabdominal for detecting structural abnormalities 1, 7
• Assess endometrial thickness: Thin endometrium (<5 mm) suggests estrogen deficiency; thick endometrium (>8 mm) suggests chronic anovulation with unopposed estrogen 6, 1
• Ovarian morphology: Polycystic ovarian morphology (≥12 follicles per ovary or ovarian volume >10 mL) supports PCOS diagnosis 7
• Anatomic abnormalities: Identify Müllerian anomalies, imperforate hymen, or vaginal septum in primary amenorrhea 2, 5

Brain MRI

• Indicated when: Prolactin >100 ng/mL, visual field defects, headaches, or other neurological symptoms to evaluate for pituitary adenoma or hypothalamic lesions 2, 3

Diagnostic Algorithm by FSH Level

Elevated FSH (>40 mIU/mL): Primary Ovarian Insufficiency

• Confirm with repeat FSH 4 weeks later (two elevated values required for diagnosis) 6
• Karyotype if age <40 years to identify Turner syndrome or premature ovarian insufficiency 2, 3, 5
• Note: These patients can maintain unpredictable ovarian function and should not be presumed infertile 2, 3

Low/Normal FSH with Low LH: Hypothalamic Amenorrhea

• Evaluate for: Eating disorders, excessive exercise, stress, low body weight 1, 2, 3
• Screen for low bone density with DEXA scan, as these patients are at high risk for osteoporosis 1, 3
• Check estradiol: Low levels confirm hypoestrogenism 1

Normal FSH and LH (or LH/FSH >2): PCOS

• Assess for metabolic syndrome: Fasting glucose, lipid panel, and consider oral glucose tolerance test 2, 3
• Screen for endometrial hyperplasia if prolonged amenorrhea (>6 months) due to unopposed estrogen 3

Elevated Prolactin: Hyperprolactinemia

• Repeat prolactin to confirm (avoid stress, fasting, recent breast stimulation) 2, 3
• Brain MRI if prolactin >100 ng/mL or if symptoms suggest pituitary adenoma 2, 3
• Exclude medications: Antipsychotics, metoclopramide, and other dopamine antagonists 3

Critical Pitfalls to Avoid

• Never skip the pregnancy test: Even in patients reporting no sexual activity or using contraception, pregnancy must be excluded first 1, 4
• Don't assume amenorrhea equals infertility: Patients with primary ovarian insufficiency can have unpredictable ovarian function and may ovulate sporadically 2, 3
• Recognize tamoxifen interference: Hormone levels and absence of menses are unreliable indicators of menopause during tamoxifen treatment 4
• Don't rely solely on progesterone challenge: Up to 60% of women with functional hypothalamic amenorrhea may have withdrawal bleeding, making this test less reliable than previously thought 6
• Address bone health urgently: Patients with hypothalamic amenorrhea or primary ovarian insufficiency require prompt evaluation and treatment for osteoporosis risk 1, 3