Amenorrhea

Diagnosis

Indications for Testing

  • Presence of amenorrhea without identifiable cause

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 – order 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 – 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
    • 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

Clinical Background

Amenorrhea is defined as the absence of menstrual flow.

Epidemiology

  • Prevalence – 3-4% (excluding 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 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
      • 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
    • Etiology (most common)

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
Test Name and Number Recommended Use Limitations Follow Up
Beta-hCG, Urine Qualitative 0020229
Method: Immunoassay

Exclude pregnancy

   
Beta-hCG, Serum Qualitative 0020063
Method: Immunoassay

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

Rule out thyroid disease as etiology of amenorrhea

   
Prolactin 0070115
Method: Quantitative Chemiluminescent Immunoassay

Rule out prolactinemia

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

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.

Aid in evaluation of secondary amenorrhea

   
Dehydroepiandrosterone Sulfate, Serum 0070040
Method: Quantitative Electrochemiluminescent Immunoassay

Aid in evaluation of secondary amenorrhea

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

Aid in evaluation of secondary amenorrhea

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Thyroid Stimulating Hormone 0070145
Method: Quantitative Chemiluminescent Immunoassay
Estrogens, Fractionated by Tandem Mass Spectrometry 0093248
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

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.

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

Preferred test for Fragile X screening

If an intermediate to expanded allele (≥45 CGG repeats) is detected by PCR and capillary electrophoresis, methylation analysis will be added to
determine the size of the expanded CGG repeat

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