What are the causes of secondary amenorrhea in a female patient of reproductive age?

Causes of Secondary Amenorrhea

Most Common Etiologies

Secondary amenorrhea in reproductive-age women is most commonly caused by four primary conditions: Polycystic Ovary Syndrome (PCOS), Functional Hypothalamic Amenorrhea (FHA), hyperprolactinemia, and Primary Ovarian Insufficiency (POI). 1

Functional Hypothalamic Amenorrhea (FHA)

• FHA accounts for 20-35% of secondary amenorrhea cases and represents a functional decrease in pulsatile GnRH secretion leading to decreased LH pulses. 1, 2

• Key triggering factors include:

  • Stress and increased stress sensitivity 2
  • Vigorous exercise patterns (particularly >10 hours/week of intense training) 3
  • Weight loss and low BMI 2
  • Caloric restriction or energy deficit (<30 kcal/kg fat-free mass/day) 3
  • Psychological disorders 2

• Laboratory findings show low or normal FSH and LH levels, with a negative progestin challenge test. 2

• Critical complication: Patients face 2-fold increased fracture risk and decreased bone density, requiring DXA scan if amenorrhea extends beyond 6 months. 3

Polycystic Ovary Syndrome (PCOS)

• PCOS is one of the most common causes of secondary amenorrhea, characterized by polycystic ovarian morphology on ultrasound. 1, 2

• Laboratory findings include LH:FSH ratio >2, which strongly suggests PCOS. 2

• Patients require screening for glucose intolerance, dyslipidemia, and metabolic syndrome. 4

• Important diagnostic pitfall: FHA-PCOM affects 40-47% of women with FHA and can be misdiagnosed as PCOS because these patients fulfill Rotterdam criteria despite having functional hypothalamic amenorrhea with polycystic ovarian morphology. 1, 2

Hyperprolactinemia

• Hyperprolactinemia accounts for approximately 20% of secondary amenorrhea cases. 1, 2

• Clinical presentation may include galactorrhea, though this is not always present. 2

• Laboratory findings show elevated serum prolactin levels, and patients may require pituitary imaging to exclude adenoma. 2

• In women with epilepsy, functional hyperprolactinemia occurs at increased rates due to postictal prolactin elevations and interictal epileptic activity propagated to the hypothalamus. 5

Primary Ovarian Insufficiency (POI)

• POI is characterized by elevated FSH and LH levels in the menopausal range in women under age 40. 1, 2

• Critical point: Patients with POI can maintain unpredictable ovarian function and should not be presumed infertile. 1, 4

• Hormone replacement therapy is indicated to reduce risk of osteoporosis, cardiovascular disease, and urogenital atrophy. 3

Additional Important Causes

Thyroid Dysfunction

• Both hypothyroidism and hyperthyroidism can cause secondary amenorrhea, identified by abnormal TSH levels. 2

Advanced Liver Disease

• In women with advanced liver disease, altered estrogen metabolism and disruption of the hypothalamic-pituitary axis with low FSH and LH can lead to anovulation and amenorrhea. 5

• Amenorrhea or oligomenorrhea occurs in more than 25% of women with advanced liver disease and nearly 75% of premenopausal women awaiting liver transplant. 5

• Excess alcohol intake directly affects the hypothalamic-pituitary axis and ovarian function. 5

Epilepsy-Related Causes

• Women with temporal lobe epilepsy have a 12% rate of hypothalamic amenorrhea (hypogonadotropic hypogonadism) compared to 1.5% in the general population. 5, 1

• Antiepileptic drugs (carbamazepine, phenobarbital, phenytoin) induce hepatic cytochrome P450-dependent steroid hormone breakdown and SHBG production, reducing biologically active sex hormone concentrations. 5

• Women with epilepsy face increased risk of premature menopause, with 4% experiencing primary gonadal failure in their third decade versus 1% expected in the general population. 5

Diagnostic Approach Algorithm

First-Line Evaluation

• Pregnancy test is mandatory as the first step in all cases of secondary amenorrhea. 2, 3

• Initial laboratory panel must include serum FSH, LH, prolactin, and TSH levels. 1, 2, 3

• Pelvic ultrasound should be performed to evaluate for polycystic ovarian morphology and uterine abnormalities. 2, 3

Interpretation of Initial Results

• Low/normal FSH and LH with negative progestin challenge → FHA 2

• LH:FSH ratio >2 with polycystic ovaries → PCOS 2

• Elevated FSH and LH → POI 2

• Elevated prolactin → Hyperprolactinemia (obtain pituitary imaging) 2

• Abnormal TSH → Thyroid dysfunction 2

Additional Testing When Indicated

• Androgen profile for suspected PCOS or signs of hyperandrogenism 2

• Progestin challenge test to determine estrogen status 2, 3

• Energy availability calculation (>30 kcal/kg fat-free mass/day) for suspected FHA 3

• DXA scan for bone mineral density if amenorrhea extends beyond 6 months 3

Critical Diagnostic Pitfalls

FHA-PCOM Misdiagnosis

• FHA-PCOM patients have polycystic ovarian morphology but require completely different treatment than PCOS. 1, 2

• Distinguish FHA-PCOM from PCOS by:

  • Clear history of FHA triggers (energy deficit, excessive exercise, stress) 1
  • Negative progestin challenge test indicating low estrogen 1
  • Lower LH levels (not elevated LH:FSH ratio) 1
  • Higher SHBG levels compared to PCOS 1
  • Lean body type with low or normal BMI 2

• Treatment for FHA-PCOM requires correction of energy deficit, not PCOS-directed therapy. 2

Common Clinical Errors 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 does not protect bone mineral density as effectively as physiologic estrogen replacement. 3

• Do not assume amenorrhea in athletes or stressed patients is benign – other pathology must be excluded even when clinical picture suggests FHA. 3

• Do not overlook eating disorders, as patients frequently minimize or deny disordered eating behaviors requiring direct questioning about specific behaviors. 3

• Do not delay bone density assessment – DXA scanning is indicated regardless of age if amenorrhea extends beyond 6 months. 3