Basics
Description
Amenorrhea is the absence of menstruation. It is divided into 2 categories:
- Primary amenorrhea is the failure to begin menstruation by 16 years of age in girls with otherwise appropriate pubertal development or by age 14 years in the absence of secondary sexual characteristics. This diagnosis should also be considered if a girl has not menstruated within 2 years of obtaining Tanner IV breast development regardless of her age.
- Secondary amenorrhea is the cessation of menstruation for 3 cycles or 6 months in girls and women with previously established regular cycles:
- Should not be used when referring to girls who are within 2 years of menarche because regular ovulatory cycles have not yet been established; their periods are unpredictable.
A regular menstrual cycle is a sign of good health. The absence of menses or disruption of regular cycles once they have been established can result from systemic disease, genetic or anatomic abnormalities, physical or emotional stress, or unrecognized pregnancy. The goal of the evaluation is to identify the underlying cause.
Epidemiology
There is insufficient information about the incidence of amenorrhea in contemporary pediatric populations.
- Primary amenorrhea
- Approximately 5% of girls in North America fail to reach menarche by 14.5 years of age.
- The most common chromosomal abnormality associated with primary amenorrhea is Turner syndrome, occurring in 1 to 2,500 female live births.
- Secondary amenorrhea
- Excluding pregnancy, anovulation is the most common cause of secondary amenorrhea.
- Amenorrhea associated with obesity or polycystic ovary syndrome (PCOS) is becoming a common cause of both primary and secondary amenorrhea among adolescents in developing countries.
General Prevention
- Healthy lifestyle avoiding excess weight gain or weight reduction
- Avoidance of excessive athletic activity or training
- Management of emotional stress
- Adherence with chronic disease management (adequate glycemic control for persons with diabetes) and avoidance of additional physiologic stressors
Etiology
Menstruation requires the presence of functional female internal genitalia with an intact and patent outflow tract and appropriate stimulation and regulation of the endometrial lining by the hypothalamic-pituitary-ovarian axis. Genetic disorders, anatomic abnormalities, or disruption at any level of the hormonal axis can each lead to amenorrhea.
Diagnosis
Approach to the Patient
A stepwise approach to the evaluation, guided by the history and physical exam, is recommended.
- Phase 1: Exclude pregnancy by urine or serum β-hCG testing.
- Phase 2: Obtain a complete menstrual history to differentiate between primary and secondary amenorrhea to help identify the underlying cause.
- Phase 3: Perform a directed physical exam.
- Phase 4: Initiate stepwise diagnostic testing to assess for causes of amenorrhea.
History
- Age of patient
- Genetic abnormalities should be a consideration in younger patients with primary amenorrhea.
- Premature ovarian failure is a stronger consideration with increasing patient age.
- Past and current medical history
- Prior/current/chronic illness including autoimmune, renal, thyroid, or liver disease; diabetes; or cancer (radiation or chemotherapy), which may be the underlying cause of amenorrhea
- Stressful life events
- Stress can lead to amenorrhea but should be considered a diagnosis of exclusion.
- Growth and weight changes
- Consider endocrinopathy, genetic disease, PCOS, rapid weight gain, eating disorder, or other chronic disease.
- Behavioral
- Eating disorder and/or excessive exercise
- Headaches
- Assess for visual field defects, dizziness (suggesting pituitary tumor or other intracranial process)
- Reproductive and menstrual history
- Age at menarche
- Menstrual cycle history: regularity, flow, duration; characteristics of last menstrual period (normal or abnormal)
- Sexual history: sexual activity, prior pregnancy, current or prior contraceptive use (Depo-Provera can cause amenorrhea for up to 18 months)
- A history of symptoms of pre/perimenstrual molimina (breast tenderness, fluid retention, cramping) suggests prior ovulatory cycles.
- Risk factors for uterine scarring, such as prior gynecologic surgery
- Galactorrhea
- Spontaneous milky discharge from the breast suggests elevated prolactin or thyroid abnormality or may be due to manual stimulation, medications, pituitary tumor, or illicit drug use (cannabis, opiates, amphetamines).
- Abdominal or pelvic pain
- Cyclic or intermittent severe abdominal/pelvic pain suggests a uterine anomaly or obstruction.
- Skin and hair
- Excess hair growth (inquire about shaving, plucking, or waxing), acne, balding, and acanthosis nigricans are symptoms of androgen excess and suggest PCOS, congenital adrenal hyperplasia (rare), or a tumor (rare).
- Easy bruising or violaceous striae suggest Cushing syndrome.
- Medications
- Hormonal medications (e.g., Depo-Provera or hormonal contraceptives), cytotoxic medications, illicit drugs, antidepressant drugs, antipsychotic drugs (e.g., risperidone), and other medications including opiates
Physical Exam
- General appearance, height, and weight with calculation of body mass index (BMI, in kg/m2):
- Obesity raises suspicion of PCOS or possible Cushing syndrome.
- Athleticism or underweight suggests female athlete triad or eating disorder, respectively.
- Stigmata of Turner syndrome (short stature, webbed neck, etc.) or other genetic syndromes
- Abnormal growth pattern suggests endocrinopathy, dietary restriction, chronic disease, or genetic disorder.
- Skin exam
- Acne, hirsutism (increased facial hair, midline hair over sternum and lower abdomen), acanthosis nigricans, and balding are suggestive of virilization or PCOS.
- Bruises or pigmented striae suggest Cushing syndrome.
- Tanner staging and breast exam
- Abnormal Tanner stage for chronologic age suggests an endocrine, metabolic, or genetic abnormality.
- Galactorrhea suggests abnormalities in prolactin or thyroid.
- Thyroid nodule or enlargement
- Evaluate for hyperthyroidism or hypothyroidism.
- Abdominal mass
- Evaluate for uterine obstruction, tumor
- Genitourinary exam
- Abnormal external genitalia suggest outflow tract abnormalities.
- Clitoral enlargement is a sign of virilization and raises suspicion for an androgen-secreting tumor or congenital adrenal hyperplasia.
- The decision to do a digital or speculum pelvic exam should be based on the patient's age/maturity/gynecologic history/and ability to tolerate the exam. When presented with primary amenorrhea, an ultrasound should be used to evaluate anatomy (see the following discussion). An ultrasound may be needed as an adjunct to laboratory testing when evaluating secondary amenorrhea.
Diagnostic Tests & Interpretation
Lab
- Standard initial testing: pregnancy test, FSH/LH, estradiol, TSH, free T4, prolactin (8 a.m.)
- For primary amenorrhea, include genetic testing by checking a karyotype for sex chromosome abnormalities.
- If PCOS is suspected or virilization is identified, also include total and free testosterone, dehydroepiandrosterone-sulfate (DHEA-S), and 17-hydroxyprogesterone.
- If Cushing syndrome is suspected, consider an overnight dexamethasone suppression test or 24-hour urinary free cortisol excretion.
Imaging
- Imaging should be used selectively.
- Transvaginal or pelvic ultrasound
- Confirm presence of normal m ¼llerian structures (uterus and ovaries) for patients with primary amenorrhea.
- Exclude ovarian mass and renal abnormalities based on abnormal physical exam or laboratory results.
- MRI of the pituitary gland if indicated based on neurologic symptoms, galactorrhea, and/or laboratory results (elevated prolactin)
Differential Diagnosis
- Pregnancy
- Outflow tract abnormalities
- Imperforate hymen, transverse vaginal septum, m ¼llerian agenesis, androgen insensitivity syndrome
- Ovarian failure
- Chromosomal abnormalities and other inherited defects such as Turner syndrome and androgen insensitivity syndrome
- Radiation- or chemotherapy-induced ovarian failure, autoimmune premature ovarian failure, idiopathic premature ovarian failure
- Chronic anovulation
- Androgen excess: PCOS (common), congenital adrenal hyperplasia, ovarian or adrenal tumor
- Elevated prolactin: prolactinoma, medications, hypothyroidism, others. Remember that stress can cause mild elevations in serum prolactin that are not pathologic.
- Low or normal LH/FSH: chronic or systemic illness, eating disorders, extreme obesity, excessive exercise, psychological stress, hypopituitarism
- Thyroid disease
- Cortisol excess: Cushing syndrome
- Medications:
- Cytotoxic, hormonal contraception, opiates, psychiatric medications, and others
Treatment
- Identification and management depends on the underlying disorder.
- Estrogen/progestin hormonal therapy may have a role but should not be initiated prior to completing a full evaluation.
- Premature use of hormonal therapy may alter subsequent testing.
- Contraindications to hormone therapy must be ruled out (refer to World Health Organization [WHO] Medical Eligibility Criteria at http://www.who.int/reproductivehealth/publications/family_planning/en/).
Additional Therapies
- Behavioral interventions: An interdisciplinary team may be required to effectively manage eating disorders, complex behavior problems, or emotional symptoms.
Additional Reading
- Domine F, Dadoumont C, Bourguignon JP. Eating disorders throughout female adolescence. Endocr Dev. 2012;22:271-286. [View Abstract]
- Gray SH. Menstrual disorders. Pediatr Rev. 2013;34(1):6-17. [View Abstract]
- Roupas ND, Georgopoulos NA. Menstrual function in sports. Hormones. 2011;10(2):104-116. [View Abstract]
- Santoro N. Update in hyper- and hypogonadotropic amenorrhea. J Clin Endocrinol Metab. 2011;96(11):3281-3288. [View Abstract]
- Slap GB. Menstrual disorders in adolescence. Best Pract Res Clin Obstet Gynaecol. 2003;17(1):75-92. [View Abstract]
- Viswanathan V, Eugster EA. Etiology and treatment of hypogonadism in adolescents. Pediatr Clin North Am. 2011;58(5):1181-1200. [View Abstract]
Codes
ICD09
- 626 Absence of menstruation
- 256.8 Other ovarian dysfunction
ICD10
- N91.2 Amenorrhea, unspecified
- N91.0 Primary amenorrhea
- N91.1 Secondary amenorrhea
- E28.8 Other ovarian dysfunction
SNOMED
- 14302001 Amenorrhea (finding)
- 8913004 Primary physiologic amenorrhea (finding)
- 86030004 Secondary physiologic amenorrhea (finding)
- 444769001 anovulatory amenorrhea (finding)
- 57260004 Dietary amenorrhea (finding)
- 413487000 Amenorrhea associated with obesity (finding)
FAQ
- Q: What are the normal benchmarks for evaluating pubertal development in girls?
- A: Normal benchmarks for evaluating pubertal development in girls: breast development by age 12-13 years, menarche ~2 years after breast development (by age 14 years), or menarche within 2 years of achieving Tanner IV breast stage
- Q: Does a patient who says she has never had sex still need a pregnancy test?
- A: Yes.