Amenorrhea

  • Diagnosis
  • Algorithms
  • Background
  • Lab Tests
  • References
  • Related Topics

Indications for Testing

  • Presence of amenorrhea

Initial Evaluation and Testing for Primary Amenorrhea

  • Urinary or serum beta human chorionic gonadotropin 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, 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
        • LSH and FSH elevated – primary ovarian failure confirmed
        • LSH and FSH normal – functional hypothalamic amenorrhea confirmed
          • 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 – order serum dehydroepiandrosterone sulfate (DHEA-S)
              • Elevated – consider androgen-secreting tumor
              • Not elevated – consider polycystic ovary syndrome (PCOS)

Initial Evaluation and Testing for Secondary Amenorrhea

  • Urinary or serum beta human chorionic gonadotropin 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 US 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 turnica
          • Positive – discontinue medication
        • High TSH – primary hypothyroidism confirmed

Imaging Studies

  • See above workup for when to order imaging study

Differential Diagnosis

  • See classifications in Clinical Background

Amenorrhea is defined as the absence of menstrual flow and is classified as primary and secondary.

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 five years after breast development if that occurs before age 10​
    • Etiology (most common)
      • Gonadal dysgenesis/agenesis
        • Turner syndrome (see Growth Hormone Deficiency topic, Pediatrics section, Genetic diseases with primary effects on growth table)
      • Receptor abnormalities and enzyme deficiencies
      • 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 one 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 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 – absence of secondary sexual characteristics common; congenital anomalies of the urogenital system
  • Secondary – variable body habitus (PCOS or anorexic body habitus), galactorrhea, hirsutism
Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Beta-hCG, Urine Qualitative 0020229
Method: Immunoassay

Recommended Use 

Exclude pregnancy

Beta-hCG, Serum Qualitative 0020063
Method: Immunoassay

Recommended Use 

Exclude pregnancy for negative urine test or when urine test not available

Thyroid Stimulating Hormone with reflex to Free Thyroxine 2006108
Method: Quantitative Electrochemiluminescent Immunoassay

Recommended Use 

Rule out thyroid disease as etiology of amenorrhea

Prolactin 0070115
Method: Quantitative Chemiluminescent Immunoassay

Recommended Use 

Rule out prolactinemia

Luteinizing Hormone and Follicle Stimulating Hormone 0070193
Method: Quantitative Electrochemiluminescent Immunoassay

Recommended Use 

Aid in determining etiology of ovarian dysfunction

Testosterone, Free and Total (Includes Sex Hormone Binding Globulin), Females or Children 0081056
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry/Electrochemiluminescent Immunoassay
The concentration of free testosterone is derived from a mathematical expression based on the constant for the binding of testosterone to sex hormone binding globulin.

Follow-up 

Aid in evaluation of secondary amenorrhea

Dehydroepiandrosterone Sulfate, Serum 0070040
Method: Quantitative Electrochemiluminescent Immunoassay

Recommended Use 

Aid in evaluation of secondary amenorrhea

Estradiol, Adult Premenopausal Female, Serum or Plasma 0070045
Method: Quantitative Chemiluminescent Immunoassay

Recommended Use 

Aid in evaluation of secondary amenorrhea

Guidelines

Practice Committee of American Society for Reproductive Medicine. Current evaluation of amenorrhea. Fertil Steril. 2008; 90(5 Suppl): S219-25. PubMed

General References

Bloomfield D. Secondary amenorrhea. Pediatr Rev. 2006; 27(3): 113-4. PubMed

Heiman DL. Amenorrhea. Prim Care. 2009; 36(1): 1-17, vii. PubMed

Jenkins RR. Chapter 115 Menstrual Problems. Kliegman RM, Behrman RE, Jensen HB, Stanton BF eds. Nelson Textbook of Pediatrics, 18th ed. Philadelphia, PA: Saunders, an imprint of Elsevier Inc, 2007.

Klein DA, Poth MA. Amenorrhea: an approach to diagnosis and management. Am Fam Physician. 2013; 87(11): 781-8. PubMed

Master-Hunter T, Heiman DL. Amenorrhea: evaluation and treatment. Am Fam Physician. 2006; 73(8): 1374-82. PubMed

Rebar RW. Premature ovarian failure. Obstet Gynecol. 2009; 113(6): 1355-63. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Ray JA, Kushnir MM, Bunker A, Rockwood AL, Meikle W. Direct measurement of free estradiol in human serum by equilibrium dialysis-liquid chromatography-tandem mass spectrometry and reference intervals of free estradiol in women. Clin Chim Acta. 2012; 413(11-12): 1008-14. PubMed

Medical Reviewers

Meikle, A. Wayne, MD, Medical Director, Endocrinology and Automated Endocrinology at ARUP Laboratories; Professor of Medicine, Endocrinology, and Pathology, University of Utah

Miller, Christine E., MS, LCGC, Genetic Counselor, Molecular Genetics at ARUP Laboratories; Faculty, Graduate Program in Genetic Counseling, University of Utah

Straseski, Joely A., PhD, MS, MT(ASCP), DABCC, Medical Director, Endocrinology at ARUP Laboratories; Assistant Professor of Clinical Pathology, University of Utah

Last Update: August 2016

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