Amenorrhea

Amenorrhea is defined as the absence of menstrual flow and is classified as either primary or secondary. After pregnancy is excluded by hCG testing, initial evaluation includes thyroid stimulating hormone (TSH), prolactin, follicle stimulating hormone (FSH), and luteinizing hormone (LH) tests.

Diagnosis

Indications for Testing

Presence of amenorrhea

Initial Evaluation and Testing for Primary Amenorrhea

  • Urinary or serum beta human chorionic gonadotropin (hCG) 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, or 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
        • LH and FSH elevated – primary ovarian failure confirmed
        • LH and FSH normal – functional hypothalamic amenorrhea confirmed
          • Consider eating disorder, stress/chronic illness, delayed puberty, gonadotropin-releasing hormone (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)

Initial Evaluation and Testing for Secondary Amenorrhea

  • Urinary or serum beta hCG 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 ultrasound 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 turcica
          • Positive – discontinue medication
        • High TSH – primary hypothyroidism confirmed

Imaging Studies

See above workup for when to order imaging study.

Differential Diagnosis

See Classifications in Background.

Background

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 5 years after breast development if that occurs before age 10​
    • Etiology (most common)
      • Gonadal dysgenesis/agenesis
      • 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 1 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 requires developed endometrium, normal outflow tract, and functioning hypothalamic-pituitary-ovarian axis
  • Hypothalamus secretes gonadotropin-releasing hormone (GnRH), 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 occurs
  • 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

ARUP Laboratory Tests

Primary Tests

Rule out thyroid disease as etiology of amenorrhea

Assess thyroid function

Identify risk in patients with palpable thyroid nodules

Screening for anterior pituitary tumor

Aid in determining etiology of ovarian dysfunction

Provides a calculated value for free testosterone concentration using total testosterone measured by mass spectrometry

May be used to evaluate hyperandrogenism in children and cisgender females, monitor testosterone-suppressing hormone therapies (eg, antiandrogens or estrogens), evaluate testosterone status in individuals with protein-binding abnormalities, or evaluate hypogonadism in cisgender males

Indicator of adrenal androgen production

Aid in the investigation of virilizing endocrinopathies in conjunction with other sex steroids

Not recommended for initial evaluation of polycystic ovarian syndrome

Use this immunoassay to measure estradiol in adult premenopausal cisgender females and individuals on estrogen hormone therapies

Not recommended when low estradiol concentrations, such as those found in children, cisgender males, and postmenopausal females, are expected, or for monitoring antiestrogen (eg, aromatase inhibitor) therapy; the preferred estradiol test in these cases is Estradiol (Adult Males, Children, Postmenopausal Females, or Individuals on Estrogen-Suppressing Hormone Therapy) 

Not recommended in the evaluation of estradiol status for individuals with protein-binding abnormalities or individuals on hormonal contraception; the preferred estradiol test for these individuals is Estradiol, Free, by Dialysis and Mass Spectrometry 

Related Tests

Preferred test for screening and monitoring of thyroid function

Use to evaluate estrogen status in children, cisgender males, and postmenopausal cisgender females

Most useful when low estrogen concentrations are expected, regardless of the patient’s sex assigned at birth 

Aid in the detection and subclassification of hyperandrogenism

Most useful in cisgender females and children with moderate/severe hirsutism or hirsutism of any degree when it is sudden in onset or rapidly progressive

Hirsutism evaluation panel is generally preferred

Panel includes androstenedione; dehydroepiandrosterone, serum or plasma; and testosterone, females or children

Aid in the detection of nonclassical congenital adrenal hyperplasia in individuals presenting with hyperandrogenism

Panel includes androstenedione; 17-hydroxyprogesterone quantitative by HPLC-MS/MS, serum or plasma; testosterone, females or children; and dehydroepiandrosterone, serum or plasma

Provides a calculated value for bioavailable testosterone concentration using total testosterone measured by mass spectrometry

May be used to evaluate hyperandrogenism in children and cisgender females, monitor testosterone-suppressing hormone therapies (eg, antiandrogens or estrogens), evaluate testosterone status in individuals with protein-binding abnormalities, or evaluate hypogonadism in cisgender males 

Provides a calculated value for free testosterone concentration using total testosterone measured by mass spectrometry

May be used to evaluate hyperandrogenism in children and cisgender females, monitor testosterone-suppressing hormone therapies (eg, antiandrogens or estrogens), evaluate testosterone status in individuals with protein-binding abnormalities, or evaluate hypogonadism in cisgender males

Use this mass spectrometry test to measure a wide range of testosterone concentrations

Most useful when low concentrations are expected, regardless of the patient’s sex assigned at birth

Use to monitor testosterone-suppressing hormone therapies (eg, antiandrogens or estrogens)

Free or bioavailable testosterone measurements may provide supportive information

Use this mass spectrometry test to measure a wide range of estradiol concentrations

Most useful when low estradiol concentrations are expected, regardless of the patient’s sex assigned at birth

Use to monitor estradiol in individuals on estrogen-suppressing hormone therapies (eg, aromatase inhibitors or testosterone)

Preferred test to diagnose fragile X syndrome and carrier screening in individuals with a positive family history

Diagnostic errors can occur due to rare sequence variations

Increased number of cells counted/analyzed to rule out low-level mosaicism

Rarely indicated in clinical practice; the preferred test for the measurement of estrone is Estrogens, Fractionated, by Mass Spectrometry 

Aid in the investigation of virilizing endocrinopathies and in managing congenital adrenal hyperplasia in conjunction with other sex steroids

Not recommended for initial evaluation of polycystic ovarian syndrome

Adjunct test for the investigation of hyperandrogenic and adrenal disorders

Not recommended for initial evaluation of polycystic ovarian syndrome

Use to directly measure free estradiol

May be used to evaluate estradiol status for individuals with protein-binding abnormalities or individuals on hormonal contraception

References

Additional Resources

Medical Experts

Contributor
Contributor

Lehman

Christopher M. Lehman, MD
Associate Professor of Pathology (Clinical), University of Utah
Medical Director, University of Utah Health Hospital Clinical Laboratory, ARUP Laboratories
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