What are the possible causes of sudden onset of amenorrhea in a woman with a prior history of regular menses and a negative pregnancy test?

Sudden Onset Amenorrhea: Differential Diagnosis

The most common causes of sudden secondary amenorrhea with negative pregnancy test are Polycystic Ovary Syndrome (PCOS), Functional Hypothalamic Amenorrhea (FHA), hyperprolactinemia, and Primary Ovarian Insufficiency (POI), which together account for the vast majority of cases. 1, 2

Primary Diagnostic Categories

Most Common Endocrine Causes

Polycystic Ovary Syndrome (PCOS)

• PCOS is the single most common cause of secondary amenorrhea, affecting 4-6% of women in the general population 3
• Characterized by elevated androgens, irregular or absent periods, and polycystic ovarian morphology on ultrasound 3
• Laboratory findings typically show LH:FSH ratio >2 3
• Patients are at risk for glucose intolerance, dyslipidemia, and metabolic syndrome 4

Functional Hypothalamic Amenorrhea (FHA)

• Accounts for 20-35% of secondary amenorrhea cases 1, 2
• Results from functional reduction in pulsatile GnRH secretion due to stress, excessive exercise, or inadequate nutrition 1, 3
• Stress hormones (cortisol and catecholamines) directly suppress the GnRH pulse generator 3
• Patients are at 2-fold increased risk of fractures and decreased bone mineral density 1
• Energy availability <30 kcal/kg fat-free mass/day is a key diagnostic finding 1

Hyperprolactinemia

• Accounts for approximately 20% of secondary amenorrhea cases 1, 2
• Often associated with pituitary adenoma 5
• May present with galactorrhea, though this is not always present 1
• Prolactin levels >20 μg/L are considered abnormal 3

Primary Ovarian Insufficiency (POI)

• Characterized by elevated FSH (>35 IU/L) and LH (>11 IU/L) levels 3
• Patients can maintain unpredictable ovarian function and should not be presumed infertile 3, 4
• Requires hormonal replacement therapy to reduce risk of osteoporosis, cardiovascular disease, and urogenital atrophy 1

Additional Important Causes

Thyroid Dysfunction

• Both hypothyroidism and hyperthyroidism can cause amenorrhea by affecting the hypothalamic-pituitary-ovarian axis 3, 2
• Identified by abnormal TSH levels 2

Medication-Induced

• Oral contraceptives frequently induce irregular bleeding patterns, especially during first three months of use 3
• Contraceptive patch detachment ≥48 hours can cause delayed periods 3

Chronic Medical Conditions

• Advanced liver disease causes menstrual irregularities in >25% of women through altered estrogen metabolism 3, 2
• Women with epilepsy face increased risk of premature menopause, with 4% experiencing primary gonadal failure in their third decade 2

Initial Diagnostic Workup

Mandatory First-Line Laboratory Tests

• Serum FSH, LH, prolactin, and TSH levels 1, 2
• LH and FSH should be measured based on average of three estimations taken 20 minutes apart between day 3 and 6 of the cycle 3
• Prolactin measurement can be taken at any time of day using age-specific and sex-specific reference ranges 1

Imaging Studies

• Pelvic ultrasound to evaluate for polycystic ovarian morphology and uterine abnormalities 1, 2
• Assess endometrial thickness: thin endometrium (<5 mm) indicates estrogen deficiency 1
• Pituitary MRI indicated if prolactin >20 μg/L or clinical features suggest hypothalamic-pituitary axis abnormality 3

Additional Testing Based on Clinical Suspicion

• Progestin challenge test to determine estrogen status 1
• Mid-luteal progesterone testing to confirm ovulation if cycles resume 1
• Androgen profile for suspected PCOS 1
• Energy availability calculation: assess if consuming >30 kcal/kg fat-free mass/day 1

Critical Diagnostic Pitfall: FHA-PCOM vs. True PCOS

Approximately 40-47% of women with FHA have polycystic ovarian morphology (FHA-PCOM), which can be misdiagnosed as PCOS 3, 2

Key Distinguishing Features:

• FHA-PCOM shows clear history of FHA triggers (stress, excessive exercise, weight loss) 2
• Negative progestin challenge test in FHA-PCOM vs. positive in PCOS 2
• Lower LH levels and higher SHBG levels in FHA-PCOM 2
• LH/FSH ratio <1 in approximately 82% of FHA cases 1

This distinction is critical because FHA-PCOM requires correction of energy deficit as primary treatment, not PCOS-directed therapy 2

Red Flags Requiring Urgent Evaluation

• Galactorrhea suggesting hyperprolactinemia 1
• Headaches or visual changes suggesting pituitary pathology 1
• Signs of eating disorder or significant weight loss 1
• Hirsutism or acne suggesting hyperandrogenism 1

Long-Term Health Consequences

Bone Health

• Prolonged hypoestrogenic states significantly increase osteoporosis risk 1, 3
• DXA scan for bone mineral density assessment is mandatory if amenorrhea extends beyond 6 months, regardless of age 1, 2
• 90% of peak bone mass is attained by age 18, making early intervention critical in adolescents 1

Cardiovascular Risk

• About one-third of FHA patients reveal decreased reactive hyperemia index, consistent with endothelial dysfunction 1
• Women with menstrual disorders have higher risk of developing hypertension and other cardiometabolic risk factors 3

Endometrial Health

• Patients with PCOS are at increased risk for endometrial hyperplasia and endometrial cancer 6

Common Pitfalls to Avoid

• Do not prescribe oral contraceptives as first-line therapy for FHA, as this masks the problem without addressing the underlying energy deficit and provides false reassurance 1, 2
• Do not assume amenorrhea in athletes or stressed individuals is benign – other pathology must be excluded even when clinical picture suggests FHA 1
• Do not overlook eating disorders – adolescents frequently minimize symptoms, and direct questioning about specific behaviors is necessary 1
• Do not delay bone density assessment – DXA scanning is indicated regardless of age if amenorrhea extends beyond 6 months 1, 2