What are the causes of amenorrhea (absence of menstruation)?

Causes of Amenorrhea

Amenorrhea is primarily caused by disruptions in the hypothalamic-pituitary-ovarian axis, with the most common etiologies being polycystic ovary syndrome, hypothalamic amenorrhea, hyperprolactinemia, and primary ovarian insufficiency. 1

Primary vs. Secondary Amenorrhea

Primary Amenorrhea

Primary amenorrhea is defined as:

• No menarche by age 15 years, or by age 13 years in the absence of secondary sexual characteristics 2
• Common causes include:
  • Chromosomal irregularities leading to primary ovarian insufficiency (e.g., Turner syndrome) 3
  • Anatomical abnormalities (e.g., Müllerian agenesis, transverse vaginal septum, imperforate hymen) 4

Secondary Amenorrhea

Secondary amenorrhea is defined as:

• Cessation of regular menses for 3 months or irregular menses for 6 months 5, 3
• Affects approximately 3-4% of women in the general population 5

Major Causes of Amenorrhea

1. Functional Hypothalamic Amenorrhea (FHA)

• Accounts for 20-35% of secondary amenorrhea cases 5
• Characterized by chronic anovulation without identifiable organic causes 5
• Caused by functional reduction in GnRH pulsatile secretion leading to decreased LH pulses 5
• Main contributing factors:
  • Stress and increased stress sensitivity 5
  • Vigorous exercise patterns 5
  • Weight loss and low BMI 5
  • Psychological disorders 5
  • Caloric restriction or energy deficit 5
• Laboratory findings: low/normal FSH and LH levels 5
• Patients with hypothalamic amenorrhea should be evaluated for eating disorders and are at risk for decreased bone density 3

2. Polycystic Ovary Syndrome (PCOS)

• One of the most common causes of secondary amenorrhea 5
• Characterized by:
  • Polycystic ovarian morphology (≥20 follicles of 2-9mm per ovary or ovarian volume >10ml) 2
  • LH:FSH ratio >2 5
  • Hyperandrogenism 6
• Patients with PCOS are at risk for glucose intolerance, dyslipidemia, and other aspects of metabolic syndrome 3

3. Hyperprolactinemia

• Accounts for approximately 20% of secondary amenorrhea cases 5
• Clinical features may include galactorrhea 5
• Laboratory findings include elevated serum prolactin levels 5
• May be associated with pituitary adenoma 7
• Causes include:
  • Medications
  • Pituitary tumors
  • Hypothyroidism
  • Functional hyperprolactinemia in epilepsy patients 6

4. Primary Ovarian Insufficiency (POI)

• Laboratory findings include elevated FSH and LH levels 5
• Patients can maintain unpredictable ovarian function and should not be presumed infertile 3, 1
• May occur earlier in women with epilepsy than in the general population 6

5. Thyroid Dysfunction

• Both hypothyroidism and hyperthyroidism can cause amenorrhea 5
• Laboratory findings include abnormal TSH levels 5

6. Advanced Liver Disease

• Altered estrogen metabolism and disruption of hypothalamic-pituitary axis 6
• Low follicle-stimulating hormone and luteinizing hormone leading to anovulation, amenorrhea, and infertility 6
• Amenorrhea or oligomenorrhea seen in >25% of women with advanced liver disease and nearly 75% of premenopausal women awaiting liver transplant 6

7. Anatomical Causes (Primary Amenorrhea)

• Müllerian agenesis 4
• Transverse vaginal septum 4
• Imperforate hymen 4

8. Other Causes

• Pregnancy (most common physiological cause) 7
• Lactation 7
• Medications (including certain antiepileptic drugs) 6
• Chronic diseases 1
• Chromosomal abnormalities 3

Special Considerations

Epilepsy and Amenorrhea

• Epilepsy can directly affect the hypothalamic-pituitary axis 6
• Antiepileptic drugs may decrease or increase biologically active sex hormone levels 6
• Functional hyperprolactinemia is more common in women with epilepsy 6
• Left unilateral temporolimbic epilepsy has been associated with PCOS, while right temporolimbic epilepsy with hypothalamic amenorrhea 6

Athletes with Amenorrhea

• Require evaluation for Relative Energy Deficiency in Sport (RED-S) 2
• At risk for decreased bone density 5
• DXA scan recommended for bone mineral density assessment if amenorrhea lasts >6 months 2

FHA-PCOM (Special Entity)

• Affects 40-47% of women with FHA, featuring characteristics of both FHA and PCOM 5
• Can be misdiagnosed as PCOS as they fulfill Rotterdam criteria 5
• Differentiation based on typical FHA triggers, negative progestin challenge, and lower LH levels 5

Diagnostic Approach

• First step: pregnancy test 5
• Initial laboratory evaluation: serum FSH, LH, prolactin, and TSH levels 5
• Pelvic ultrasound to evaluate for PCOM and uterine abnormalities 5
• Additional testing may include androgen profile for suspected PCOS 5
• Progestin challenge test can be used to determine estrogen status 5

Amenorrhea should be viewed as a symptom rather than a diagnosis, requiring thorough evaluation to identify the underlying cause and prevent long-term complications such as osteoporosis, endometrial hyperplasia, and heart disease 4, 1, 8.