Amenorrhea

Diagnosis

Indications for Testing

Presence of amenorrhea

Initial Evaluation and Testing for Primary Amenorrhea

• Urinary or serum beta human chorionic gonadotropin (hCG) to exclude pregnancy – if negative, proceed with physical and pelvic examination to rule out uterine absence (may require ultrasonography to confirm)
  • Anatomic abnormality
    • Uterus present – consider transverse vaginal septum, imperforate hymen, abnormal cervical os, or other vaginal abnormality
    • Uterus absent – order free testosterone testing
      • Normal – consider chromosome analysis
      • High – androgen insensitivity confirmed
  • Normal pelvic examination – order thyroid stimulating hormone (TSH), prolactin, follicle stimulating hormone (FSH), and luteinizing hormone (LH)
    • Elevated prolactin – MRI of head
    • Abnormal TSH – thyroid disease
    • Normal prolactin, TSH
      • LH and FSH elevated – primary ovarian failure confirmed
        • Consider X-chromosome abnormality, Turner syndrome, FSH receptor deficiency, autoimmune gonadal destruction, fragile X syndrome
      • LH and FSH normal – functional hypothalamic amenorrhea confirmed
        • Consider eating disorder, stress/chronic illness, delayed puberty, gonadotropin-releasing hormone (GnRH) deficiency, pituitary disorders, medication-induced
        • If hypertensive, consider 17-hydroxylase deficiency
        • If virilization present, order free testosterone
          • Elevated – order serum dehydroepiandrosterone sulfate (DHEA-S)
            • Elevated – consider androgen-secreting tumor
            • Not elevated – consider polycystic ovarian syndrome (PCOS)

Initial Evaluation and Testing for Secondary Amenorrhea

• Urinary or serum beta hCG to exclude pregnancy
  • If negative pregnancy test, measure prolactin, LH/FSH, TSH
  • Abnormal TSH – thyroid disease
  • Normal prolactin, low/normal LH/FSH, normal TSH, no hirsutism
    • Order serum estradiol
      • Normal – hypothalamic dysfunction; consider testing for fragile X syndrome
      • Low – pituitary or hypothalamic abnormality
    • Consider eating disorder, excessive exercise
  • Normal prolactin, high LH, normal/low FSH, hirsutism, virilization, acne
    • Order free testosterone, DHEA-S
      • Elevated free testosterone (high) – rule out tumor with pelvic ultrasound or abdominal CT
      • Elevated free testosterone (moderate) – ovarian hyperandrogenism (PCOS) confirmed
      • Elevated DHEA-S (high) – rule out adrenal tumor with adrenal CT
      • Elevated DHEA-S (moderate) – adrenal hyperandrogenism or PCOS
  • Normal prolactin, high LH/FSH – ovarian failure (may represent menopause); consider chromosome analysis for X chromosome abnormalities
  • High prolactin, normal LH/FSH
    • Order TSH
      • Normal – evaluate medication history
        • Negative – CT/MRI, sella turcica
        • Positive – discontinue medication
      • High TSH – primary hypothyroidism confirmed

Imaging Studies

See above workup for when to order imaging study.

Differential Diagnosis

See Classifications in Background.

Background

Epidemiology

• Prevalence – 3-4% (excluding pregnancy, lactation, or menopause)
  • Secondary amenorrhea is more common than primary amenorrhea

Classifications

• Primary
  • Most common definition – lack of menstrual flow by 15 years
    • Other possible definitions
      • Nelson Textbook of Pediatrics (2007)
        • Lack of menstrual flow by age 14 and absence of secondary sexual characteristics
        • Lack of menstrual flow by age 16 and presence of secondary sexual characteristics
      • American Society for Reproductive Medicine (2008)
        • Lack of menstrual flow by 15 years in the presence of secondary sexual characteristics
        • Lack of menstrual flow within 5 years after breast development if that occurs before age 10​
  • Etiology (most common)
    • Gonadal dysgenesis/agenesis
      • Turner syndrome (see the Genetic diseases with primary effects on growth table in the Pediatrics section of Growth Hormone Deficiency)
    • Receptor abnormalities and enzyme deficiencies
      • Congenital adrenal hyperplasia
      • Androgen insensitivity syndrome
      • 5-alpha-reductase deficiency
      • Estrogen resistance
    • Congenital anomalies (includes vaginal, cervical, and uterine etiologies)
      • Includes Müllerian agenesis (Mayer-Rokitansky-Küster-Hauser syndrome)
    • Constitutional-delayed puberty
    • Eating disorder
    • Excessive exercise
    • Hyperprolactinemia
    • Primary ovarian failure
    • Androgen insensitivity
    • Polycystic ovarian syndrome (PCOS)
    • Pituitary/hypothalamic dysfunction
• Secondary
  • One of the following (American Society for Reproductive Medicine, 2008)
    • Absence of menstrual flow for 3 months in women with previously normal menstruation PLUS presence of secondary sexual characteristics
    • Absence of menstrual flow for 9 months in women with previous oligomenorrhea
    • ​In women with regular menses, a delay of as little of 1 week in menses may prompt evaluation for pregnancy
  • Etiology (most common)
    • Pregnancy and other hyperadrenergic disorders
    • PCOS
    • Hypothalamic disease (eg, functional hypothalamic amenorrhea, craniopharyngioma)
      • Eating disorder/excessive exercise
      • Depression
    • Thyroid disease (eg, hypothyroidism)
    • Pituitary disease (eg, hyperprolactinemia)
    • ​Ovarian disease
      • Primary ovarian insufficiency
      • Ovarian tumors
    • Medication-induced
      • Antidepressants
      • Antipsychotics
      • Chemotherapy
      • Oral contraceptives
    • Fragile X syndrome
    • Systemic Illnesses (eg, diabetes mellitus, celiac disease)
    • Uterine disease (eg, Asherman syndrome)

Pathophysiology

• Normal menses requires developed endometrium, normal outflow tract, and functioning hypothalamic-pituitary-ovarian axis
• Hypothalamus secretes gonadotropin-releasing hormone (GnRH), causing anterior pituitary release of follicle stimulating hormone (FSH) and luteinizing hormone (LH)
• LH and FSH surge stimulates the ovary to secrete estrogen, progestin, and androgen
• FSH causes a follicle to be dominant and release an ovum (thought to be from LH spike)
• Progestin from corpus luteum suppresses FSH and LH
• Without fertilization, the corpus luteum involutes, estrogen and progestin levels fall, and menses occurs
• Interruption in pathway at any point can result in amenorrhea

Clinical Presentation

• Primary – absence of secondary sexual characteristics common; congenital anomalies of the urogenital system
• Secondary – variable body habitus (PCOS or anorexic body habitus), galactorrhea, hirsutism