Causes of Primary Amenorrhea
Definition
Primary amenorrhea is defined as the absence of menarche by age 15 years, or by age 13 years in the absence of secondary sexual characteristics. 1
Etiologic Categories
The causes of primary amenorrhea can be systematically organized based on the presence or absence of breast development (indicating estrogen exposure) and anatomic findings:
Delayed Puberty (No Breast Development)
This indicates lack of estrogen exposure and represents failure of pubertal initiation. 1
Hypogonadotropic Hypogonadism (Low FSH/LH):
- Constitutional delay of puberty - the most common cause in otherwise healthy adolescents 2, 3
- Functional hypothalamic amenorrhea (FHA) - caused by stress, excessive exercise, low body weight/BMI, eating disorders, or energy deficit 1, 2
- Hypothalamic or pituitary disorders - including tumors, infiltrative diseases, or congenital GnRH deficiency (Kallmann syndrome) 2, 3
- Chronic systemic illness - such as inflammatory bowel disease, celiac disease, or poorly controlled diabetes 2
- Endocrine disorders - including hypothyroidism, hyperthyroidism, Cushing syndrome, or hyperprolactinemia 1, 2
Hypergonadotropic Hypogonadism (Elevated FSH/LH):
- Gonadal dysgenesis - most commonly Turner syndrome (45,X) or other chromosomal abnormalities 2, 3, 4
- Primary ovarian insufficiency (POI) - including autoimmune oophoritis or post-chemotherapy/radiation 1, 3
Normal Breast Development Present
This indicates adequate estrogen production has occurred, narrowing the differential considerably. 5
Anatomic/Outflow Tract Abnormalities:
- Müllerian agenesis (Mayer-Rokitansky-Küster-Hauser syndrome) - congenital absence of uterus and upper two-thirds of vagina with normal ovarian function 5, 6, 4
- Imperforate hymen or transverse vaginal septum - causing outflow obstruction with cryptomenorrhea 2, 4
- Androgen insensitivity syndrome - if pubic/axillary hair is absent despite breast development, this is a critical red flag indicating possible complete androgen insensitivity with absent uterus 1
Functional/Hormonal Causes:
- Polycystic ovary syndrome (PCOS) - characterized by LH:FSH ratio >2, polycystic ovarian morphology, and hyperandrogenism 1, 5
- Functional hypothalamic amenorrhea - from eating disorders, excessive exercise, or psychosocial stress despite having initiated puberty 1, 5
- Hyperprolactinemia - from pituitary adenoma or medications, often with galactorrhea 1, 5
- Thyroid dysfunction - both hypothyroidism and hyperthyroidism 1, 5
Rare Causes:
- Ovarian tumors - such as juvenile granulosa cell tumors that secrete inhibin and suppress FSH, preventing ovulation 7
Critical Diagnostic Distinctions
Absence of Pubic/Axillary Hair with Breast Development
This combination is a critical red flag that distinguishes androgen insensitivity syndrome from simple constitutional delay. The absence of both pubic and axillary hair despite breast development indicates either complete androgen insensitivity or gonadal dysgenesis variants. 1
Structural Abnormalities (PALM-COEIN Classification)
While more commonly associated with abnormal uterine bleeding, structural causes including polyps, adenomyosis, leiomyomas, and endometrial malignancy can occasionally present as amenorrhea. 1
Common Clinical Pitfalls
Do not assume amenorrhea in athletes or stressed adolescents is benign - other pathology including PCOS, thyroid disease, or pituitary tumors must be excluded even when the clinical picture suggests FHA. 1
Do not overlook eating disorders - adolescents frequently minimize or deny disordered eating behaviors, requiring direct questioning about specific restrictive behaviors, purging, and body image concerns. 1, 5
Do not miss structural abnormalities - pelvic ultrasound is mandatory in primary amenorrhea with normal breast development to exclude outflow tract obstruction or Müllerian agenesis, as these require surgical rather than medical management. 1, 5
Consider cancer survivors - approximately 8-10% of female survivors of pediatric cancer develop POI, requiring multidisciplinary management. 1