Amenorrhea is defined as the absence of menstrual flow.

Epidemiology

• Prevalence – 3-4% when not due to pregnancy, lactation or menopause
  • Secondary amenorrhea more common than primary amenorrhea

Classifications

• Primary
  • One of the following
    • 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
  • Etiology (most common)
    • Gonadal dysgenesis/agenesis
      • Turner syndrome
    • Enzymatic deficiencies
      • Congenital adrenal hyperplasia
    • Congenital anomalies (includes vaginal, cervical and uterine etiologies)
    • 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
    • Presence of secondary sexual characteristics and previous menstrual flow but no menstrual flow for 3 months in women with previously normal menstruation
    • No menstrual flow for 9 months in women with previous oligomenorrhea
  • Etiology (most common)
    • PCOS
    • Hypothyroidism
    • Pituitary disease – hyperprolactinemia
    • Eating disorder
    • Excessive exercise
    • Depression
    • Ovarian failure
    • Medication-induced
      • Antidepressants
      • Antipsychotics
      • Chemotherapy
      • Oral contraceptives
    • Tumor
    • Craniopharyngioma
    • Fragile X syndrome

Pathophysiology

• Normal menses require developed endometrium, normal outflow tract and functioning hypothalamic-pituitary-ovarian axis
• Hypothalamus secretes gonadotropin releasing hormone, 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 occur
• Interruption in pathway at any point can result in amenorrhea

Clinical Presentation

• Primary – may have absence of secondary sexual characteristics or congenital anomalies of the urogenital system
• Secondary – variable body habitus consistent with PCOS, anorexic body habitus, galactorrhea, hirsutism

Indications for Testing

• Presence of amenorrhea without identifiable cause

Laboratory Testing

• Initial evaluation of primary amenorrhea – urinary or serum beta human chorionic gonadotropin to exclude pregnancy; if negative, proceed with pelvic examination (may also consider pelvic ultrasound if unable to confirm presence of uterus)
  • Anatomic abnormality
    • Uterus present – consider transverse vaginal septum, imperforate hymen, abnormal cervical os, other vaginal abnormality
    • Uterus absent – proceed with free testosterone testing
      • Normal – consider chromosome analysis
      • High – androgen insensitivity
  • Normal pelvic examination – proceed with thyroid stimulating hormone, prolactin
    • Elevated prolactin – perform MRI of head
    • Elevated TSH – hypothyroidism
    • Normal prolactin, TSH – order LH and FSH
      • Elevated – primary ovarian failure
        • Consider X-chromosome abnormality, Turner syndrome, FSH receptor deficiency, autoimmune gonadal destruction
      • Normal – functional hypothalamic amenorrhea
        • Consider eating disorder, stress/chronic illness, delayed puberty, GNRH deficiency, pituitary disorders, medication-induced
        • If hypertensive, consider 17-hydroxylase deficiency
        • If virilization present, order free testosterone
          • Elevated – DHEA-S, serum; if DHEA-S is elevated, consider androgen-secreting tumor or PCOS
• Initial evaluation of secondary amenorrhea – negative pregnancy test demonstrated; measure prolactin, LH/FSH
  • Normal prolactin, low/normal LH/FSH, no hirsutism
    • Serum estradiol
      • Normal – hypothalamic dysfunction; consider testing for fragile X syndrome
      • Low – pituitary or hypothalamic abnormality
  • Normal prolactin, high LH, normal/low FSH, hirsutism, virilization, acne
    • Free testosterone, dehydroepiandrosterone sulfate
      • Elevated free testosterone (high) – rule out tumor with pelvic US or abdominal CT
      • Elevated free testosterone (moderate) – ovarian hyperandrogenism (PCOS)
      • 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; consider chromosome analysis for X chromosome abnormalities
  • High prolactin, normal LH/FSH
    • TSH
      • Normal – consider medication history
        • Negative – CT/MRI
        • Positive – discontinue medication
      • High TSH – primary hyperthyroidism

 Imaging Studies

• See above workup for when to order imaging study

Differential Diagnosis

• Pregnancy
• Thyroid disease
• Most of the other diseases in the differential are found in the Background tab under the Classifications heading

Tests generally appear in the order most useful for common clinical situations

General

• Ankarberg-Lindgren C, Norjavaara E. Estradiol in pediatric endocrinology. Am J Clin Pathol. 2009; 132 (6) :978-980.PubMed
• Bloomfield D. Secondary amenorrhea. Pediatr Rev. 2006; 27 (3) :113-114.PubMed
• Goswami D, Conway GS. Premature ovarian failure. Hum Reprod Update. 2005; 11 (4) :391-410.PubMed
• Heiman DL. Amenorrhea. Prim Care. 2009; 36 (1) :1-17, vii.PubMed
• Master-Hunter T, Heiman DL. Amenorrhea: evaluation and treatment. Am Fam Physician. 2006; 73 (8) :1374-1382.PubMed
• Practice Committee of the American Society for Reproductive Medicine Current evaluation of amenorrhea. Fertil Steril. 2008; 90 (5 Suppl) :S219-S225.PubMed
• Rebar RW. Premature ovarian failure. Obstet Gynecol. 2009; 113 (6) :1355-1363.PubMed
• Rudolph LM. Cytogenetics of Infertility. In Gersen SL, Keagle MB, eds. The Principles of Clinical Cytogenetics. Totowa, New Jersey: Humana Press Inc, 2005. pp. 247-265.
• Warren MP, Hagey AR. The genetics, diagnosis and treatment of amenorrhea. Minerva Ginecol. 2004; 56 (5) :437-455.PubMed
• Wilson GR, Haddad JE, Haddad CJ. Amenorrhea: common causes and evaluation. Compr Ther. 2005; 31 (4) :270-278.PubMed

Adrenal Hyperfunction
Growth Hormone Deficiency
Hypopituitarism
Infertility
Osteoporosis
Polycystic Ovarian Syndrome