Amenorrhea (absence of menses) can be a transient, intermittent, or permanent condition resulting from dysfunction of the hypothalamus, pituitary, ovaries, uterus, or vagina.
Amenorrhea is classified as either primary (absence of menarche by age 16 years) or secondary (absence of menses for more than three cycles or six months in women who previously had menses). Pregnancy is the most common cause of secondary amenorrhea.
Diagnosis of secondary amenorhea
Step 1: Rule out pregnancy.
A pregnancy test is the first step in evaluating secondary amenorrhea. Measurement of serum beta subunit of hCG is the most sensitive test.
Step 2: Assess the history
Recent stress; change in weight, diet or exercise habits; or illnesses that might result in hypothalamic amenorrhea should be sought.
Drugs associated with amenorrhea, systemic illnesses that can cause hypothalamic amenorrhea, recent initiation or discontinuation of an oral contraceptive, androgenic drugs (danazol) or high-dose progestin, and antipsychotic drugs should be evaluated.
Headaches, visual field defects, fatigue, or polyuria and polydipsia may suggest
Symptoms of estrogen deficiency include hot flashes, vaginal dryness, poor sleep, or decreased libido.
Gal actorrhea is suggestive of hyperprolactinemia. Hirsutism, acne, and a history of irregular menses are suggestive of hyperandrogenism.
A history of obstetrical catastrophe, severe bleeding, dilatation and curettage, or endometritis or other infection that might have caused scarring of the endometrial lining suggests Asherman's syndrome.
Causes of Primary and Secondary Amenorrhea
Causes of Amenorrhea due to Abnormalities in the Hypothalamic-Pituitary-Ovarian Axis
|Congenital abnormality in Mullerian development
||Isolated defect Testicular feminization syndrome 5-Alpha-reductase deficiency Vanishing testes syndrome Defect in testis determining factor
|Congenital defect of urogenital sinus development
||Agenesis of lower vagina
|Acquired ablation or scarring of the endometrium
||Asherman’s syndrome Tuberculosis
|Disorders of hypothalamic-pituitary ovarian axis
|| Functional hypothalamic amenorrhea |
Weight loss, eating disorders
Severe or prolonged illness
Congenital gonadotropin-releasing hormone deficiency
Inflammatory or infiltrative diseases Brain tumors - eg, craniopharyngioma
Pituitary stalk dissection or compression
Brain injury - trauma, hemorrhage, hydrocephalus
Other syndromes - Prader-Willi, Laurence-Moon-Biedl
Other pituitary tumorsacromegaly, corticotroph adenomas (Cushing's disease)
Other tumors - meningioma, germinoma, glioma
Empty sella syndrome Pituitary infarct or apoplexy
||Ovarian failure (menopause)
Premature (before age 40 years)
Exogenous androgen use
Step 3: Physical examination.
Measurements of height and weight, signs of other illnesses, and evidence of cachexia should be assessed. The skin, breasts, and genital tissues should be evaluated for estrogen deficiency. The breasts should be palpated, including an attempt to express galactorrhea. The skin should be examined for hirsutism, acne, striae, acanthosis nigricans, vitiligo, thickness or thinness, and easy bruisability.
Step 4: Basic laboratory testing.
In addition to measurement of serum hCG to rule out pregnancy, minimal laboratory testing should include measurements of serum prolactin, thyrotropin, and FSH to rule out hyperprolactinemia, thyroid disease, and ovarian failure (high serum FSH). If there is hirsutism, acne or irregular menses, serum dehydroepiandrosterone sulfate (DHEA-S) and testosterone should be measured.
Step 5: Follow-up laboratory evaluation
High serum prolactin concentration.
Prolactin secretion can be transiently increased by stress or eating. Therefore, serum prolactin should be measured at least twice before cranial imaging is obtained, particularly in those women with small elevations (<50 ng/mL). These women should be screened for thyroid disease with a TSH and free T4 because hypothyroidism can cause hyperprolactinemia.
Women with verified high serum prolactin values should have a cranial MRI unless a very clear explanation is found for the elevation (eg, antipsychotics). Imaging should rule out a hypothalamic or pituitary tumor.
High serum FSH concentration.
A high serum FSH concentration indicates the presence of ovarian failure. This test should be repeated monthly on three occasions to confirm. A karyotype should be considered in most women with secondary amenorrhea age 30 years or younger.
High serum androgen concentrations.
A high serum androgen value may suggest the diagnosis of polycystic ovary syndrome or may suggest an androgen-secreting tumor of the ovary or adrenal gland. Further testing for a tumor might include a 24-hour urine collection for cortisol and 17-ketosteroids, determination of serum 17- hydroxyprogesterone after intravenous injection of corticotropin (ACTH), and a dexamethasone suppression test. Elevation of 17-ketosteroids, DHEA-S, or 17-hydroxyprogesterone is more consistent with an adrenal, rather than ovarian, source of excess androgen.
Normal or low serum gonadotropin concentrations and all other tests normal:
This result is one of the most common outcomes of laboratory testing in women with amenorrhea. Women with hypothalamic amenorrhea (caused by marked exercise or weight loss to more than 10 percent below the expected weight) have normal to low serum FSH values. Cranial MRI is indicated in all women without an a clear explanation for hypogonadotropic hypogonadism and in most women who have visual field defects or headaches. No further testing is required if the onset of amenorrhea is recent or is easily explained (eg, weight loss, excessive exercise) and there are no symptoms suggestive of other disease.
High serum transferrin saturation may indicate hemochromatosis, high serum angiotensin-converting enzyme values suggest sarcoidosis, and high fasting blood glucose or hemoglobin A1c values indicate diabetes mellitus.
Normal serum prolactin and FSH concentrations with history of uterine instrumentation preceding amenorrhea Evaluation for Asherman's syndrome should be completed. A progestin challenge should be performed (medroxyprogesterone acetate 10 mg for 10 days). If withdrawal bleeding occurs, an outflow tract disorder has been ruled out. If bleeding does not occur, estrogen and progestin should be administered.
Athletic women should be counseled on the need for increased caloric intake or reduced exercise. Resumption of menses usually occurs.
Nonathletic women who are underweight should receive nutritional counseling and treatment of eating disorders.
Hyperprolactinemia is treated with a dopamine agonist. Cabergoline (Dostinex) or bromocriptine (Parlodel) are used for most adenomas. Ovulation, regular menstrual cycles, and pregnancy may usually result.
Ovarian failure should be treated with hormone replacement therapy.
Hyperandrogenism is treated with measures to reduce hirsutism, resume menses, and fertility and preventing endometrial hyperplasia, obesity, and metabolic defects.
Asherman's syndrome is treated with hysteroscopic lysis of adhesions followed by longterm estrogen administration to stimulate regrowth of endometrial tissue.