Amenorrhea

Diagnosis

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 – order free testosterone testing
      • Normal – consider chromosome analysis
      • High – androgen insensitivity confirmed
  • Normal pelvic examination – order thyroid stimulating hormone (TSH), prolactin
    • Elevated prolactin – order MRI of head
    • Elevated TSH – hypothyroidism
    • Normal prolactin, TSH – order LH and FSH
      • Elevated – primary ovarian failure confirmed
        • Consider X-chromosome abnormality, Turner syndrome, FSH receptor deficiency, autoimmune gonadal destruction
      • 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 DHEA-S, serum
            • Elevated – consider androgen-secreting tumor
            • Not elevated – consider polycystic ovary syndrome (PCOS)
• Initial evaluation of secondary amenorrhea – urinary or serum beta human chorionic gonadotropin to exclude pregnancy; measure prolactin, LH/FSH
  • Normal prolactin, low/normal LH/FSH, no hirsutism
    • Order 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
    • Order free testosterone, dehydroepiandrosterone sulfate
      • 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; consider chromosome analysis for X chromosome abnormalities
  • High prolactin, normal LH/FSH
    • Order TSH
      • Normal – consider medication history
        • Negative – CT/MRI
        • Positive – discontinue medication
      • High TSH – primary hypothyroidism confirmed

 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

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 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
    • 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)
    • 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 – 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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
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
Testosterone, Urine 2004772 Method: Quantitative Gas Chromatography-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) Screen with Reflex to Fragile X (FMR1) Diagnostic 2001946 Method: Polymerase Chain Reaction/Fragment Analysis	If screen suggests a pre- or full mutation, Fragile X Diagnostic will be added for analysis of sizing and methylation
Fragile X (FMR1) Diagnostic 0040011 Method: Southern Blot/Polymerase Chain Reaction/Fragment Analysis
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

Diagnostic Algorithm

  Primary Amenorrhea Testing Algorithm

  Secondary Amenorrhea Testing Algorithm