Amenorrhea

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

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

Primary Amenorrhea Testing Algorithm

Secondary Amenorrhea Testing Algorithm

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

Indications for Laboratory Testing

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

Beta-hCG, Serum Qualitative 0020063
Method: Immunoassay

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

Prolactin 0070115
Method: Quantitative Chemiluminescent Immunoassay

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

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

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

Additional Tests Available

Thyroid Stimulating Hormone 0070145
Method: Quantitative Chemiluminescent Immunoassay

Estrogens, Fractionated by Tandem Mass Spectrometry 0093248
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Comments

Diagnose amenorrhea

Components include estradiol, estrone and calculated total estrogens value

Virilization Panel 1 2002028
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Virilization Panel 2 2002281
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Follicle Stimulating Hormone, Serum 0070055
Method: Quantitative Electrochemiluminescent Immunoassay

Luteinizing Hormone, Serum 0070093
Method: Quantitative Electrochemiluminescent Immunoassay

Testosterone, Bioavailable and Sex Hormone Binding Globulin (Includes Total Testosterone), Females or Children 0081057
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry/Electrochemiluminescent Immunoassay
The concentrations of free and bioavailable testosterone are derived from mathematical expressions based on constants for the binding of testosterone to albumin and/or sex hormone binding globulin.

Testosterone Free, Females or Children 0081059
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry/Electrochemiluminescent Immunoassay
Total Testosterone and SHBG are measured and free testosterone is estimated from these measurements.

Comments

Recommended for women and children due to improved accuracy of testosterone by LC-MS/MS

Testosterone, Females or Children 0081058
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Estradiol, Males, Children or Postmenopausal Females by Tandem Mass Spectrometry 0093247
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Fragile X (FMR1) with Reflex to Methylation Analysis 2009033
Method: Polymerase Chain Reaction/Capillary Electrophoresis

Comments

Preferred test for fragile X screening

Preferred test for symptomatic individuals or those with a positive family history

Reflex pattern – repeat lengths of ≥55 will reflex to methylation-specific PCR analysis

Clinical and analytic sensitivity/specificity 99%

Diagnostic errors can occur due to rare sequence variations

Chromosome Analysis, Rule Out Mosaicism 2002287
Method: Giemsa Band

Estrone, by Tandem Mass Spectrometry 0093249
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Beta-hCG, Serum Quantitative 0070025
Method: Chemiluminescent Immunoassay

Androstenedione 2001638
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Dehydroepiandrosterone, Serum or Plasma 2001640
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Free Estradiol by ED/LC-MS/MS 2006160
Method: Quantitative Equilibrium Dialysis/High Performance Liquid Chromatography-Tandem Mass Spectrometry

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

Jenkins R. 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 D, Poth M. Amenorrhea: an approach to diagnosis and management. Am Fam Physician. 2013; 87(11): 781-8. PubMed

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

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

References from the ARUP Institute for Clinical and Experimental Pathology®

Medical Reviewers

Last Update: February 2016