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.

Tabs Content

Clinical Overview

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
      - Consider X-chromosome abnormality, Turner syndrome, FSH receptor deficiency, autoimmune gonadal destruction, fragile X syndrome
    - 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)
        Elevated – consider androgen-secreting tumor
        
        Not elevated – consider polycystic ovarian syndrome (PCOS)

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
    - Turner syndrome (see the Genetic diseases with primary effects on growth table in the Pediatrics section of Growth Hormone Deficiency)
  - Receptor abnormalities and enzyme deficiencies
    - Congenital adrenal hyperplasia
    - Androgen insensitivity syndrome
    - 5-alpha-reductase deficiency
    - Estrogen resistance
  - 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 Lab Tests

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

Assess thyroid function

Identify risk in patients with palpable thyroid nodules

Reflex pattern – if the thyroid stimulating hormone is outside the reference interval, then thyroxine, free (free T4) testing will be added

Prolactin 0070115
Method: Quantitative Chemiluminescent Immunoassay

Recommended Use

Screening for anterior pituitary tumor

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.

Recommended Use

Recommended initial test in the evaluation of suspected hyperandrogenemia in women and children

Acceptable test for evaluating androgen deficiency in men

Dehydroepiandrosterone Sulfate, Serum 0070040
Method: Quantitative Electrochemiluminescent Immunoassay

Recommended Use

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

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

Recommended Use

Suitable for measurement of estradiol in adult premenopausal women

In all other groups, the preferred test is estrogens, fractionated by tandem mass spectrometry

Medical Experts

Genzen, Jonathan R., MD, PhD, Laboratory Section Chief, Clinical Chemistry, and Medical Director, Automated Core Laboratory, at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

Lehman, Christopher M., MD, Co-Medical Director, University Hospitals and Clinics Clinical Laboratory; Professor of Clinical Pathology, University of Utah

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

References

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

Resources 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

Testing Algorithms

Primary Amenorrhea Testing Algorithm

Read more about Primary Amenorrhea Testing Algorithm

Secondary Amenorrhea Testing Algorithm

Read more about Secondary Amenorrhea Testing Algorithm

Last Update: June 2018

Amenorrhea

Diagnosis

Indications for Testing

Initial Evaluation and Testing for Primary Amenorrhea

Initial Evaluation and Testing for Secondary Amenorrhea

Imaging Studies

Differential Diagnosis

Background

Epidemiology

Classifications

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

Resources from the ARUP Institute for Clinical and Experimental Pathology®

Primary Amenorrhea Testing Algorithm

Secondary Amenorrhea Testing Algorithm

ARUP Laboratories

ARUP Websites

ARUP Consult


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	Amenorrhea. ARUP Consult^©. Retrieved April 17, 2019, from: https://arupconsult.com/content/amenorrhea

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Amenorrhea

Diagnosis

Indications for Testing

Initial Evaluation and Testing for Primary Amenorrhea

Initial Evaluation and Testing for Secondary Amenorrhea

Imaging Studies

Differential Diagnosis

Background

Epidemiology

Classifications

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

Resources from the ARUP Institute for Clinical and Experimental Pathology®

Primary Amenorrhea Testing Algorithm

Secondary Amenorrhea Testing Algorithm

ARUP Laboratories

ARUP Websites

ARUP Consult