What are the causes of secondary amenorrhea?

Causes of Secondary Amenorrhea

Secondary amenorrhea is most commonly caused by functional hypothalamic amenorrhea, polycystic ovary syndrome, hyperprolactinemia, and primary ovarian insufficiency, with pregnancy being the most common physiological cause that must be excluded first. 1, 2

Definition

Secondary amenorrhea is defined as:

• Cessation of previously regular menstruation for more than three months
• Cessation of previously irregular menstruation for longer than 6 months 3, 1
• Affects approximately 3-4% of women in the general population 3

Major Etiological Categories

1. Pregnancy and Lactation

• Most common physiological causes that must be excluded first 1, 2

2. Functional Hypothalamic Amenorrhea (FHA)

• Responsible for approximately 20-35% of secondary amenorrhea cases 3
• Characterized by chronic anovulation without identifiable organic causes 3
• Caused by functional reduction in GnRH pulsatile secretion leading to decreased LH pulses 3
• Main contributing factors:
  • Stress and increased stress sensitivity 3, 1, 4
  • Vigorous exercise/excessive exercise patterns 3, 1, 4
  • Weight loss and low BMI 3, 1
  • Psychological disorders 3, 4
  • Caloric restriction or energy deficit 1, 4
• Laboratory findings: low/normal FSH and LH levels 1, 4
• Negative progestin challenge test 1, 4

3. Polycystic Ovary Syndrome (PCOS)

• One of the most common causes of secondary amenorrhea 3, 1
• Characterized by:
  • Hyperandrogenism (clinical or biochemical) 1, 2
  • Oligo/anovulation 1, 2
  • Polycystic ovarian morphology (PCOM) on ultrasound 1
• Laboratory findings: LH:FSH ratio >2 suggests PCOS 1
• Associated with increased risk for metabolic syndrome 2

4. Hyperprolactinemia

• Accounts for approximately 20% of secondary amenorrhea cases 1, 5
• Often associated with pituitary adenomas 5
• Clinical features may include galactorrhea 4
• Laboratory findings: elevated serum prolactin levels 1, 4
• May require pituitary imaging 4
• Treated with prolactin-lowering drugs like bromocriptine 6, 5

5. Primary Ovarian Insufficiency (POI)

• Previously known as premature ovarian failure 2, 7
• Characterized by hypergonadotropic hypogonadism 5
• Laboratory findings: elevated FSH and LH levels 1, 5
• Patients can maintain unpredictable ovarian function 2, 7

6. Thyroid Dysfunction

• Hypothyroidism or hyperthyroidism can cause secondary amenorrhea 1, 4
• Laboratory finding: abnormal TSH levels 1, 4

7. Chromosomal Abnormalities

• Approximately 5.3% of secondary amenorrhea cases may be due to chromosomal abnormalities 8
• Examples include:
  • 45,X (Turner syndrome)
  • 47,XXX
  • Structural abnormalities of X chromosome 8

8. Anatomical Causes

• Outflow tract abnormalities 7
• Uterine abnormalities (acquired or congenital) 5
• Asherman syndrome (intrauterine adhesions) 7

9. FHA-PCOM (Special Entity)

• Affects approximately 40-47% of women with FHA 1
• Features of both FHA and PCOM 1
• Characterized by:
  • Higher BMI than FHA-non-PCOM patients 3
  • Higher AMH and testosterone levels 3
  • Higher LH response to GnRH test 3
  • Lower SHBG levels 3
• Can be misdiagnosed as PCOS as they fulfill Rotterdam criteria 1

Diagnostic Approach

1. Pregnancy test as the first step 1
2. Measure serum FSH, LH, prolactin, and TSH levels 1, 4
3. Pelvic ultrasound to evaluate for PCOM and uterine abnormalities 1, 4
4. Additional testing based on initial results:
   • Androgen profile for suspected PCOS 4
   • Karyotype analysis for suspected chromosomal abnormalities 7
   • Pituitary imaging for hyperprolactinemia 4
   • Progestin challenge test to determine estrogen status 4

Clinical Considerations

• Patients with FHA are at risk for decreased bone density 1, 7
• PCOS patients require screening for glucose intolerance and dyslipidemia 2
• Patients with hyperprolactinemia may require careful monitoring if treated with bromocriptine, especially those with cardiovascular disease 6
• Patients with primary ovarian insufficiency should not be presumed infertile 2, 7
• FHA-PCOM patients may be misdiagnosed with PCOS; differentiation based on typical FHA triggers, negative progestin challenge, and lower LH levels is essential 1