What is the workup for secondary amenorrhea (absence of menstruation)?

Diagnostic Workup for Secondary Amenorrhea

The workup for secondary amenorrhea should begin with pregnancy testing, followed by systematic hormonal evaluation including FSH, LH, prolactin, and TSH levels to identify the underlying cause, which is most commonly functional hypothalamic amenorrhea (FHA) or polycystic ovary syndrome (PCOS).

Initial Assessment

• Perform a pregnancy test as the first step in evaluation, as pregnancy is the most common cause of missed menses 1, 2
• Document detailed menstrual history including previous regularity, duration of amenorrhea (defined as absence of menses for >3 months in women with previously regular cycles or >6 months in women with irregular cycles) 3, 4
• Assess for potential triggers of functional hypothalamic amenorrhea (FHA) including:
  • Recent weight loss or low BMI 1, 2
  • Excessive exercise patterns 1, 2
  • Psychological stress 1, 2
  • Caloric restriction or energy deficit 1, 2
• Evaluate for clinical signs of hyperandrogenism (acne, hirsutism) which may suggest PCOS 4

Laboratory Evaluation

• Measure serum FSH and LH levels to differentiate between hypothalamic-pituitary causes and ovarian causes 2, 3
  • Low/normal FSH and LH suggest hypothalamic amenorrhea
  • Elevated FSH suggests primary ovarian insufficiency
  • LH:FSH ratio >2 suggests PCOS
• Check serum prolactin to rule out hyperprolactinemia, which accounts for approximately 20% of secondary amenorrhea cases 2, 3
• Evaluate thyroid function with TSH measurement 2, 3
• Consider testosterone and DHEAS levels if signs of hyperandrogenism are present 4

Imaging and Additional Testing

• Perform pelvic ultrasound to evaluate for:
  • Polycystic ovarian morphology (PCOM), defined as ≥20 follicles of 2-9mm per ovary or ovarian volume >10ml 1
  • Uterine abnormalities 5
• Consider progestin challenge test to assess estrogen status and outflow tract patency:
  • Administer oral progesterone 400mg daily for 10 days 6
  • Withdrawal bleeding suggests adequate estrogen levels and patent outflow tract
  • Absence of withdrawal bleeding suggests hypoestrogenism or outflow obstruction 4

Differential Diagnosis

• Functional hypothalamic amenorrhea (FHA) - characterized by low/normal gonadotropins, negative progestin challenge, and identifiable stressors 1, 2
• Polycystic ovary syndrome (PCOS) - characterized by hyperandrogenism, oligo/anovulation, and often polycystic ovaries on ultrasound 3, 4
• FHA-PCOM - a special entity where patients have features of both FHA and polycystic ovarian morphology, affecting approximately 40-47% of women with FHA 1, 2
• Hyperprolactinemia - elevated prolactin levels with or without pituitary adenoma 3, 4
• Primary ovarian insufficiency - elevated FSH, low estradiol 3, 4
• Thyroid dysfunction - abnormal TSH levels 2, 3

Management Considerations

• For FHA:
  • Address underlying causes including weight restoration, stress reduction, and decreased exercise intensity 1, 2
  • Consider hormone replacement therapy to prevent bone loss and other consequences of hypoestrogenism 2, 6
• For PCOS:
  • Consider cyclic progesterone (400mg daily for 10 days each month) to induce regular withdrawal bleeding 6
  • Address metabolic risks with lifestyle modifications 2, 4
• For FHA-PCOM:
  • Requires careful evaluation as these patients have features of both conditions 1, 2
  • May have higher BMI, higher AMH and testosterone levels compared to FHA without PCOM 1

Follow-Up and Monitoring

• Monitor bone mineral density in patients with prolonged hypoestrogenic states 2
• Regular assessment of menstrual patterns to evaluate treatment response 2
• Screen for complications related to specific diagnoses (e.g., metabolic syndrome in PCOS) 3, 4

Special Considerations

• Patients with FHA-PCOM may be misdiagnosed with PCOS as they fulfill Rotterdam criteria (amenorrhea and polycystic ovaries) 1
• Differentiate between FHA-PCOM and PCOS based on:
  • Presence of typical FHA triggers (stress, energy deficit, exercise) 1
  • Negative progestin challenge test in FHA vs. positive in PCOS 2, 4
  • Lower LH levels in FHA vs. higher LH:FSH ratio in PCOS 1, 2