Amenorrhea, or the absence of menstrual flow, may be classified as primary or secondary. Primary amenorrhea is defined as a lack of menstrual flow by 15 years of age in the presence of normal growth and secondary sexual characteristics. Secondary amenorrhea is defined as the absence of menstrual flow for more than 3 months in individuals who previously had regular menstrual cycles, or 6 months in individuals with a history of irregular menstruation. The evaluations of primary and secondary amenorrhea are similar.
Amenorrhea has many causes, which presents a challenge in investigating its etiology. These causes may be acquired, congenital, structural, hormonal, physiologic, or induced. For example, the most common cause of amenorrhea is pregnancy. Breastfeeding, use of contraceptives, hysterectomy, and menopause are also common causes. Amenorrhea may arise from dysfunction of the hypothalamic, pituitary, adrenal, thyroid, or multiple other glands, such as in congenital adrenal hyperplasia, polycystic ovary syndrome, or functional hypothalamic amenorrhea. Anatomic causes (eg, cervical stenosis, transverse vaginal septum) bear consideration, as do chronic illnesses, including celiac and inflammatory bowel diseases. Primary ovarian insufficiency, which can be iatrogenic, due to autoimmune disease, or related to conditions such as Turner syndrome, should also be considered.
Because there are many potential etiologies of amenorrhea, its evaluation is multifaceted and includes many nonlaboratory considerations (eg, age). Laboratory evaluation for amenorrhea (primary or secondary) should be informed by the clinical situation and may include measurement of hormones, including thyroid-stimulating hormone (TSH), free thyroxine (T4), prolactin, follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), anti-Mullerian hormone (AMH), testosterone, and dehydroepiandrosterone sulfate (DHEAS). Karyotyping and genetic analysis may also be indicated, depending on clinical presentation and laboratory results.
Quick Answers for Clinicians
Primary amenorrhea occurs in individuals who have not yet begun to menstruate by 15 years of age. Evaluation for primary amenorrhea is appropriate in individuals who are ≥15 years of age and exhibit normal growth and secondary sexual characteristics, or in individuals who are three years postthelarche. Secondary amenorrhea occurs in individuals who have previously menstruated. Evaluation for secondary amenorrhea is appropriate in individuals who previously had regular menses but have not menstruated in >3 months, or in individuals who previously had irregular menses but have not menstruated in ≥6 months.
Functional hypothalamic amenorrhea (FHA) is a disorder that is caused by suppression of the hypothalamic-pituitary axis. FHA can result from body weight loss, excessive exercise, disordered eating, medication (eg, oral contraceptives or chemotherapy), and stress. FHA is generally considered a diagnosis of exclusion. Detailed recommendations for the diagnosis of FHA can be found in Functional Hypothalamic Amenorrhea: An Endocrine Society Clinical Practice Guideline.
Indications for Testing
Laboratory testing for primary amenorrhea is appropriate in cases of lack of menstrual flow by 15 years of age in the presence of normal growth and secondary sexual characteristics. In the absence of secondary sexual characteristics, testing is appropriate at 14 years of age in the absence of menstrual flow.
Laboratory testing for secondary amenorrhea is appropriate in the absence of menstrual flow for more than 3 months in individuals who previously had regular menstrual cycles, or 6 months in individuals with a history of irregular menstruation.
The laboratory testing strategy should be informed by clinical evaluation and patient history. For example, in cases of primary amenorrhea, physical and pelvic examination should be performed to identify potential anatomic abnormalities. Factors such as excessive exercise, disordered eating, certain medications (eg, chemotherapy or oral contraceptives), and hirsutism should also inform test selection. Laboratory test results may vary based on clinical situation and individual variance.
For a visual overview of amenorrhea testing, refer to the Amenorrhea Testing Algorithm.
ARUP Laboratory Tests
Quantitative Electrochemiluminescent Immunoassay
Quantitative Electrochemiluminescent Immunoassay
Quantitative Chemiluminescent Immunoassay
For additional estrogen tests and information on test selection, refer to the ARUP Estrogen Tests Comparison
Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry/Electrochemiluminescent Immunoassay/Calculation
For additional testosterone tests and information on test selection, refer to the ARUP Testosterone Tests Comparison
Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry
Practice Committee of American Society for Reproductive Medicine. Current evaluation of amenorrhea. Fertil Steril. 2008;90(5 Suppl):S219-S225.
Klein DA, Paradise SL, Reeder RM. Amenorrhea: a systematic approach to diagnosis and management. Am Fam Physician. 2019;100(1):39-48.
Gordon CM, Ackerman KE, Berga SL, et al. Functional hypothalamic amenorrhea: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2017;102(5):1413-1439.