What is the most common cause of secondary amenorrhea in women of reproductive age?

Most Common Cause of Secondary Amenorrhea

The most common causes of secondary amenorrhea in women of reproductive age are four primary conditions occurring with roughly equal frequency: Polycystic Ovary Syndrome (PCOS), Functional Hypothalamic Amenorrhea (FHA), hyperprolactinemia, and Primary Ovarian Insufficiency (POI), with pregnancy being the most common physiological cause that must always be excluded first. 1, 2

Pregnancy: The First Consideration

• A pregnancy test is mandatory as the absolute first step in every case of secondary amenorrhea, as pregnancy and lactation represent the most common physiological causes of amenorrhea in reproductive-age women. 2, 3, 4

The Four Primary Pathological Causes

After excluding pregnancy, secondary amenorrhea is most commonly attributed to four conditions that occur with similar prevalence:

1. Functional Hypothalamic Amenorrhea (FHA)

• FHA accounts for 20-35% of secondary amenorrhea cases, making it one of the most prevalent causes. 1, 5, 2
• FHA results from a functional decrease in pulsatile GnRH secretion, leading to decreased LH pulse frequency. 1, 2
• Triggering factors include stress, excessive exercise, weight loss >5% of body weight over 6 months, eating disorders, and low energy availability (<30 kcal/kg fat-free mass/day). 1, 5
• An LH/FSH ratio <1 is observed in approximately 82% of FHA cases, which helps distinguish it from PCOS. 5

2. Polycystic Ovary Syndrome (PCOS)

• PCOS is recognized as one of the most common causes of secondary amenorrhea, though exact prevalence among amenorrheic women varies. 1, 5, 6
• PCOS is characterized by oligomenorrhea, clinical or biochemical hyperandrogenism, and polycystic ovarian morphology on ultrasound (using Rotterdam criteria). 1
• An LH/FSH ratio >2 strongly suggests PCOS, though this finding has only 35-44% sensitivity. 5
• Patients typically present with higher BMI (often >25 kg/m²), hirsutism, acne, and metabolic abnormalities. 5, 6

3. Hyperprolactinemia

• Hyperprolactinemia accounts for approximately 20% of secondary amenorrhea cases, often accompanied by galactorrhea. 1, 5, 2
• Prolactin suppresses pulsatile GnRH secretion from the hypothalamus, leading to reduced LH pulse frequency and disruption of ovulation. 1
• A single prolactin measurement taken at any time of day is sufficient, though the sample should be drawn at rest (avoiding post-exercise or post-stress collection). 5
• Elevated prolactin warrants exclusion of hypothyroidism by checking TSH; if prolactin remains elevated, pituitary MRI is indicated to evaluate for adenoma. 5

4. Primary Ovarian Insufficiency (POI)

• POI is characterized by elevated FSH and LH levels (>40 IU/L in the menopausal range) in women under age 40. 1, 5
• POI diagnosis requires two elevated FSH values (>40 IU/L) obtained at least four weeks apart. 5
• Patients retain unpredictable ovarian function and should not be considered absolutely infertile. 1, 6

Initial Diagnostic Approach

The initial laboratory panel must include:

• Pregnancy test (urine or serum β-hCG) 2, 4
• Serum FSH, LH, prolactin, and TSH levels 1, 5, 2
• Pelvic ultrasound to evaluate for polycystic ovarian morphology and uterine abnormalities 1, 5, 2

Critical Diagnostic Pitfall: FHA-PCOM vs. PCOS

FHA with polycystic ovarian morphology (FHA-PCOM) affects 40-47% of women with FHA and can be misdiagnosed as PCOS because these patients fulfill Rotterdam criteria for PCOS on imaging. 1, 2

Key distinguishing features:

• FHA-PCOM patients have clear history of FHA triggers (stress, excessive exercise, weight loss, eating disorders) 1, 2
• Negative progestin challenge test (no withdrawal bleed, indicating low estrogen) 1, 2
• **LH/FSH ratio <1** (versus >2 in PCOS) 5
• Lower testosterone, lower AMH, higher SHBG compared to PCOS 5
• Thin endometrium (≤5 mm) indicating estrogen deficiency 5
• Lower BMI (often <18.5 kg/m²) versus higher BMI in PCOS 5

This distinction is critical because FHA-PCOM requires correction of energy deficit and addressing underlying stressors, not PCOS-directed therapy. 2

Additional Important Causes

• Thyroid dysfunction (both hypothyroidism and hyperthyroidism) can cause secondary amenorrhea, identified by abnormal TSH levels. 2, 4
• Chronic diseases including advanced liver disease can disrupt the hypothalamic-pituitary axis. 2
• Women with epilepsy face increased risk of secondary amenorrhea, particularly those with temporal lobe epilepsy (12% versus 1.5% in general population). 1

Common Clinical Pitfalls to Avoid

• Do not prescribe oral contraceptives as first-line therapy for FHA, as this masks the underlying problem without addressing energy deficit and provides false reassurance. 5, 2
• Do not delay bone density assessment—DXA scanning is indicated regardless of age if amenorrhea extends beyond 6 months due to increased fracture risk. 5, 2
• Do not assume amenorrhea in athletes or stressed individuals is benign—other pathology must be excluded even when clinical picture suggests FHA. 5
• Do not use ultrasound to diagnose PCOS in girls whose gynecologic age is <8 years after menarche, as multi-follicular ovaries are common in this developmental stage. 5