Major Causes of Secondary Amenorrhea

Definition and Epidemiology

Secondary amenorrhea is defined as cessation of previously irregular menstruation for longer than 6 months. 1, 2
Secondary amenorrhea affects approximately 3-4% of women in the general population. 1

Functional hypothalamic amenorrhea is responsible for approximately 20-35% of secondary amenorrhea cases. 1
FHA is characterized by chronic anovulation without identifiable organic causes, caused by functional reduction in GnRH pulsatile secretion leading to decreased LH pulses. 1
Main contributing factors to FHA include stress and increased stress sensitivity, vigorous exercise patterns, weight loss and low BMI, psychological disorders, and caloric restriction or energy deficit. 1, 2, 3
Laboratory findings in FHA include low/normal FSH and LH levels and negative progestin challenge test. 2, 3

Hyperprolactinemia accounts for approximately 20% of secondary amenorrhea cases. 2
Clinical features of hyperprolactinemia may include galactorrhea. 3
Laboratory findings include elevated serum prolactin levels. 2, 3
Patients with hyperprolactinemia may require pituitary imaging. 3

FHA-PCOM affects approximately 40-47% of women with FHA, featuring characteristics of both FHA and PCOM. 2
FHA-PCOM patients have higher BMI than FHA-non-PCOM patients, higher AMH and testosterone levels, higher LH response to GnRH test, and lower SHBG levels. 4, 5
FHA-PCOM can be misdiagnosed as PCOS as they fulfill Rotterdam criteria; differentiation based on typical FHA triggers, negative progestin challenge, and lower LH levels is essential. 2

Pregnancy test should be the first step in evaluating secondary amenorrhea. 2
Initial laboratory evaluation should include measurement of serum FSH, LH, prolactin, and TSH levels. 2, 3
Pelvic ultrasound should be performed to evaluate for PCOM and uterine abnormalities. 2, 3
Additional testing may include androgen profile for suspected PCOS. 3
Progestin challenge test can be used to determine estrogen status. 3

Polycystic ovarian morphology occurs in 41.9-48% of women with Functional Hypothalamic Amenorrhea (FHA), which is substantially higher than the 14-33% prevalence in the general population 6, 7
The mechanism involves altered intra-ovarian regulation of folliculogenesis that is independent from gonadotropin levels (which are characteristically low in FHA) 7, 8
These are arrested follicles that accumulate due to the hypothalamic suppression preventing normal follicular development and ovulation, not simply "cystic eggs" 6

Approximately 38% with incidental PCOM (normal variant that happens to coexist) 9, 7
Approximately 10% with some underlying PCOS features that are currently masked by hypothalamic suppression 9, 7
The remaining cases where PCOM develops as a consequence of the hypothalamic state itself 7

Key differentiating features in FHA-PCOM include history of energy deficit (calorie restriction/dieting) 6, low or normal BMI (lean body type) 6, 10, absence of hyperandrogenic symptoms (no hirsutism, no hair loss) 6, 9
Laboratory features expected in FHA-PCOM include low estradiol levels with negative progestin challenge test 6, 8, low or low-normal LH and FSH (not the elevated LH:FSH ratio seen in PCOS) 6, normal or only mildly elevated androgens (not the frank hyperandrogenism of PCOS) 9, 8, and higher SHBG compared to PCOS patients 8, 11

FHA-PCOM requires correction of energy deficit as primary treatment, not PCOS-directed therapy 6, 10
Risk of bone density loss from hypoestrogenism needs addressing 6, 10
If fertility treatment needed, pulsatile GnRH therapy is more appropriate than typical PCOS ovulation induction 6