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
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 Lab Tests
Exclude pregnancy for negative urine test or when urine test not available
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
Recommended initial test in the evaluation of suspected hyperandrogenemia in women and children
Acceptable test for evaluating androgen deficiency in men
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
Suitable for measurement of estradiol in adult premenopausal women
In all other groups, the preferred test is estrogens, fractionated by tandem mass spectrometry
Preferred test for screening and monitoring of thyroid function
Recommended test for evaluating endogenous estrogen status in postmenopausal women, men, or children
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
Aid in the detection of nonclassical congenital adrenal hyperplasia in individuals presenting with hyperandrogenism
Acceptable test in the evaluation of suspected hyperandrogenemia in women and children
Acceptable test for evaluating androgen deficiency in men
Most sensitive test for detection of hyperandrogenemia in women and children
Acceptable test for androgen deficiency in men
Use in conjunction with free testosterone in the evaluation of suspected hyperandrogenemia in women and children
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
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
If serum estrone measurement is needed, preferred test is estrogens, fractionated by 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
Adjunct test for the investigation of hyperandrogenic and adrenal disorders
Not recommended for initial evaluation of polycystic ovarian syndrome
Direct measure of free estradiol in serum
Most accurate measure of bioactive estradiol
Medical Experts Genzen, Jonathan R., MD, PhD, Chief Operations Officer, Medical Director of Automated Core Laboratory and Farmington Health Center Clinical 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 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® Testing Algorithms Related Topics Last Update: October 2019
