What is the initial step in the workup of a patient presenting with amenorrhea (absence of menstruation)?

Amenorrhea Workup

The initial step in evaluating amenorrhea is to obtain a pregnancy test (urine or serum β-hCG), followed immediately by measurement of FSH, LH, prolactin, and TSH levels to guide further diagnostic evaluation. 1, 2, 3

Initial Diagnostic Algorithm

Step 1: Rule Out Pregnancy

• Pregnancy must be excluded first in all reproductive-age women, as it is the most common cause of amenorrhea 2, 3
• Obtain urine or serum β-hCG before proceeding with any further workup 2

Step 2: Essential Laboratory Panel

Once pregnancy is excluded, obtain the following hormone levels simultaneously 1, 2:

• FSH and LH: Differentiates hypothalamic/pituitary causes from ovarian failure 1
• Prolactin: Rules out hyperprolactinemia 1, 3
• TSH: Assesses thyroid function 1, 3
• Estradiol: Evaluates ovarian function 1

Step 3: Interpret Results and Direct Further Workup

Elevated FSH (>40 mIU/mL):

• Indicates primary ovarian insufficiency (POI) 2
• Confirm with second FSH measurement 2
• These patients can maintain unpredictable ovarian function and should not be presumed infertile 3

Elevated Prolactin:

• Repeat measurement to confirm (spurious elevation is common) 2
• If persistently elevated, obtain pituitary MRI to evaluate for prolactinoma 2
• Refer to endocrinology for management 2

Low/Normal FSH and LH:

• Suggests hypothalamic or pituitary dysfunction 1, 3
• Evaluate for functional hypothalamic amenorrhea (FHA): assess for eating disorders, excessive exercise, stress, low BMI 1, 3
• Calculate energy availability (energy intake minus exercise energy expenditure) in athletes 1

Normal FSH/LH with normal prolactin and TSH:

• Consider polycystic ovary syndrome (PCOS) 1, 3
• Measure total and free testosterone levels 1
• Obtain pelvic ultrasound to assess for polycystic ovarian morphology 2

Additional Imaging Studies

Pelvic ultrasound should be performed to: 2

• Assess uterine and ovarian anatomy
• Identify structural abnormalities
• Evaluate for polycystic ovarian morphology

Special Considerations

Bone Health Assessment:

• Obtain DXA scan if amenorrhea ≥6 months, BMI <18.5 kg/m², history of disordered eating/excessive exercise, or menarche ≥16 years 1
• Patients with hypothalamic amenorrhea are at significant risk for decreased bone density 3

Athletes:

• Evaluate for Female Athlete Triad or Relative Energy Deficiency in Sport (RED-S) 1
• Interdisciplinary approach with sports medicine, nutrition, and mental health professionals may be required 1

Cancer Survivors:

• Young women treated with alkylating agents or pelvic radiation are at high risk for POI 2
• Amenorrhea during tamoxifen treatment does not reliably indicate menopause; hormone levels are unreliable 2
• Women on aromatase inhibitors who develop amenorrhea require baseline and serial monitoring of estradiol and gonadotropins 2

Critical Pitfalls to Avoid

• Failing to rule out pregnancy first is the most common error 1, 2
• Misdiagnosing functional hypothalamic amenorrhea with polycystic ovarian morphology (FHA-PCOM) as PCOS: Look for low LH:FSH ratio (<1 in ~82% of FHA), low endometrial thickness, and clear causes of FHA (excessive exercise, underweight, stress) 4
• Neglecting bone health assessment in patients with prolonged amenorrhea leads to missed osteoporosis risk 1
• Assuming infertility in patients with primary ovarian insufficiency, as ovarian function can be unpredictable 3, 5