What are the causes of amenorrhea?

Causes of Amenorrhea

Primary Amenorrhea

Primary amenorrhea results from either chromosomal abnormalities leading to ovarian failure or anatomic defects preventing menstrual outflow. 1, 2

Chromosomal and Ovarian Causes

• Turner syndrome is the most common chromosomal cause, characterized by elevated FSH levels indicating primary ovarian insufficiency 1, 3
• Delayed puberty accounts for a significant proportion of primary amenorrhea cases 1
• Primary ovarian insufficiency presents with elevated FSH and LH levels in the menopausal range 1

Anatomic Abnormalities

• Müllerian agenesis (Rokitansky syndrome) presents with absent uterus despite normal breast development 2, 3
• Outflow tract obstruction (imperforate hymen, transverse vaginal septum) causes primary amenorrhea with normal hormones and breast development 1
• Androgen insensitivity syndrome presents with absent uterus and absent pubic/axillary hair despite breast development 1, 3

Hypogonadotropic Causes

• Constitutional delay of puberty, defined as no breast development by age 13 years, requires earlier intervention 1
• Congenital hypogonadotropic hypogonadism presents with low FSH, LH, and estradiol levels 3

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Secondary Amenorrhea

The four most common causes of secondary amenorrhea are Polycystic Ovary Syndrome (PCOS), Functional Hypothalamic Amenorrhea (FHA), hyperprolactinemia, and Primary Ovarian Insufficiency (POI). 4

Functional Hypothalamic Amenorrhea (FHA)

• FHA accounts for 20-35% of secondary amenorrhea cases and results from decreased pulsatile GnRH secretion 1, 4
• Triggered by low energy availability (<30 kcal/kg fat-free mass/day), excessive exercise (>10 hours/week intense training), or psychological stress 1, 5
• Laboratory findings show low LH, low FSH, low estradiol (<30 pg/mL), and LH/FSH ratio <1 in 82% of cases 1, 5
• Critical pitfall: 40-47% of FHA patients have polycystic ovarian morphology (FHA-PCOM), which can be misdiagnosed as PCOS but requires completely different treatment 4, 5

Polycystic Ovary Syndrome (PCOS)

• PCOS is the most common cause of irregular menstrual cycles, affecting 4-6% of women 1, 5
• Characterized by accelerated GnRH pulse secretion, insulin resistance, and hyperandrogenism 5
• Laboratory findings typically show LH:FSH ratio >2, distinguishing it from FHA 5, 6
• Associated with increased risk for glucose intolerance, dyslipidemia, and metabolic syndrome 2, 7

Hyperprolactinemia

• Accounts for approximately 20% of secondary amenorrhea cases 1, 4
• Often associated with pituitary adenoma, requiring MRI evaluation 6, 8
• Presents with galactorrhea in many cases, though galactorrhea may be absent 1, 3
• Generalized or temporal lobe seizures can cause postictal prolactin elevations 5

Primary Ovarian Insufficiency (POI)

• Defined by elevated FSH levels in the menopausal range in women younger than 40 years 1, 6
• Approximately 8-10% of female pediatric cancer survivors develop POI 1
• Patients can maintain unpredictable ovarian function and should not be presumed infertile 2, 7

Thyroid Dysfunction

• Both hypothyroidism and hyperthyroidism cause amenorrhea by disrupting the hypothalamic-pituitary-ovarian axis 1, 4
• Identified by abnormal TSH levels in initial screening 4, 8

Other Endocrine Causes

• Cushing syndrome causes amenorrhea through cortisol excess suppressing the GnRH pulse generator 5
• Late-onset congenital adrenal hyperplasia presents with hirsutism and elevated androgens 1, 3
• Advanced liver disease causes menstrual irregularities in >25% of women through altered estrogen metabolism 4, 5

Medication and Iatrogenic Causes

• Older antiepileptic medications (carbamazepine, phenobarbital, phenytoin) induce degradation of steroid hormones and increase SHBG production 5
• Women with epilepsy face 4% risk of primary gonadal failure in their third decade 4
• Chemotherapy and radiation therapy can cause POI 1

Structural Causes (PALM-COEIN Classification)

• Polyps, adenomyosis, leiomyomas, and endometrial malignancy/hyperplasia can cause amenorrhea 9
• Asherman syndrome (intrauterine adhesions) results from uterine instrumentation 6

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Critical Diagnostic Distinctions

FHA-PCOM vs True PCOS

This is the most important diagnostic trap in amenorrhea evaluation. 4, 5

• FHA-PCOM patients have polycystic ovarian morphology but require energy deficit correction, not PCOS therapy 4
• Distinguished by clear history of FHA triggers (weight loss, excessive exercise, stress), negative progestin challenge test, lower LH levels, and higher SHBG levels 4
• Do not prescribe oral contraceptives as first-line for FHA, as this masks the underlying energy deficit without addressing the cause 1, 4

Physiologic vs Pathologic Causes

• Pregnancy and lactation are the most common physiological causes and must be excluded first 6, 8
• In adolescents, normal menstrual cycles range 21-45 days, wider than the adult range of 21-35 days 1

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Long-Term Health Consequences

Bone Health

• Prolonged hypoestrogenic states significantly increase osteoporosis risk, with FHA associated with 2-fold increased fracture risk 1, 5
• 90% of peak bone mass is attained by age 18, making adolescent amenorrhea particularly concerning 1
• DXA scan is indicated if amenorrhea extends beyond 6 months, regardless of age 1, 4

Cardiovascular Risk

• One-third of FHA patients show endothelial dysfunction, indicating increased cardiovascular disease risk 1
• Prolonged hypoestrogenism increases cardiovascular disease risk in POI patients 1, 6

Endometrial Cancer Risk

• Patients with PCOS require screening and intervention to attenuate endometrial cancer risk from unopposed estrogen 7