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.
Quick Answers for Clinicians
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)
- Elevated – order serum dehydroepiandrosterone sulfate (DHEA-S)
- LH and FSH elevated – primary ovarian failure confirmed
- Anatomic abnormality
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
- Order serum estradiol
- 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
- Order free testosterone, DHEA-S
- 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
- Normal – evaluate medication history
- Order TSH
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
- Nelson Textbook of Pediatrics (2007)
- Other possible definitions
- 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
- Gonadal dysgenesis/agenesis
- Most common definition – lack of menstrual flow by 15 years
- 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)
- One of the following (American Society for Reproductive Medicine, 2008)
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
Exclude pregnancy
Immunoassay
Exclude pregnancy for negative urine test or when urine test not available
Immunoassay
Rule out thyroid disease as etiology of amenorrhea
Assess thyroid function
Identify risk in patients with palpable thyroid nodules
Quantitative Electrochemiluminescent Immunoassay
Screening for anterior pituitary tumor
Quantitative Chemiluminescent Immunoassay
Aid in determining etiology of ovarian dysfunction
Quantitative Electrochemiluminescent Immunoassay
Recommended initial test in the evaluation of suspected hyperandrogenemia in women and children
Acceptable test for evaluating androgen deficiency in men
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.
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
Quantitative Electrochemiluminescent Immunoassay
Suitable for measurement of estradiol in adult premenopausal women
In all other groups, the preferred test is estrogens, fractionated by tandem mass spectrometry
Quantitative Chemiluminescent Immunoassay
Preferred test for screening and monitoring of thyroid function
Quantitative Chemiluminescent Immunoassay
Recommended test for evaluating endogenous estrogen status in postmenopausal women, men, or children
Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry
Aid in the detection and subclassification of hyperandrogenism
Most useful in women 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
Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry
Aid in the detection of nonclassical congenital adrenal hyperplasia in individuals presenting with hyperandrogenism
Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry
Panel includes androstenedione; 17-hydroxyprogesterone quantitative by HPLC-MS/MS, serum or plasma; testosterone, females or children; and dehydroepiandrosterone, serum or plasma
Quantitative Electrochemiluminescent Immunoassay
Quantitative Electrochemiluminescent Immunoassay
Acceptable test in the evaluation of suspected hyperandrogenemia in women and children
Acceptable test for evaluating androgen deficiency in men
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.
Most sensitive test for detection of hyperandrogenemia in women and children
Acceptable test for androgen deficiency in men
Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry/Electrochemiluminescent Immunoassay
Total Testosterone and SHBG are measured and free testosterone is estimated from these measurements.
Use in conjunction with free testosterone in the evaluation of suspected hyperandrogenemia in women and children
Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry
Suitable for measurement of estradiol in men, children, or postmenopausal women
Preferred test for adult premenopausal women is estradiol, adult premenopausal female, serum or plasma
Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry
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
Polymerase Chain Reaction/Capillary Electrophoresis
Increased number of cells counted/analyzed to rule out low-level mosaicism
Giemsa Band
Rarely indicated
If serum estrone measurement is needed, preferred test is estrogens, fractionated by tandem mass spectrometry
Quantitative High Performance Liquid Chromatography-Tandem 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
Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry
Adjunct test for the investigation of hyperandrogenic and adrenal disorders
Not recommended for initial evaluation of polycystic ovarian syndrome
Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry
Direct measure of free estradiol in serum
Most accurate measure of bioactive estradiol
Quantitative Equilibrium Dialysis/High Performance Liquid Chromatography-Tandem Mass Spectrometry
Chemiluminescent Immunoassay
Medical Experts
Genzen

Lehman

Straseski

References
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Nelson Textbook of Pediatrics - Menstrual Problems - Amenorrhea
Jenkins RR. Menstrual Problems. Chapter 115. Kliegman RM, Behrman RE, Jensen HB, et al, eds. Nelson Textbook of Pediatrics, 18th ed. Philadelphia, PA: Saunders, an imprint of Elsevier Inc, 2007.
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Smy L, Straseski JA. Measuring estrogens in women, men, and children: Recent advances 2012-2017. Clin Biochem. 2018;62:11-23.
Panel includes androstenedione; dehydroepiandrosterone, serum or plasma; and testosterone, females or children