Step 2 Assess the history

1. Recent stress; change in weight, diet or exercise habits; or illnesses that might result in hypothalamic amenorrhea should be sought.

2. 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.

3. Headaches, visual field defects, fatigue, or polyuria and polydipsia may suggest hypothalamic-pituitary disease.

4. Symptoms of estrogen deficiency include hot flashes, vaginal dryness, poor sleep, or decreased libido.

5. Galactorrhea is suggestive of hyperprolactinemia. Hirsutism, acne, and a history of irregular menses are suggestive of hyperandrogenism.

6. 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

Abnormality

Causes

Pregnancy

Anatomic abnormalities

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 Imperforate hymen

Acquired ablation or scarring of the endometrium

Asherman's syndrome Tuberculosis

Disorders of hypothalamic-pituitary ovarian axis

Hypothalamic dysfunction

Pituitary dysfunction Ovarian dysfunction

Causes of Amenorrhea due to Abnormalities in the Hypothalamic-Pituitary-Ovarian Axis

Abnormality

Causes

Hypothalamic dysfunction

Functional hypothalamic amenorrhea

Weight loss, eating disorders

Exercise

Stress

Severe or prolonged illness Congenital gonadotropin-releasing hormone deficiency Inflammatory or infiltrative diseases

Brain tumors - eg, craniopharyngioma Pituitary stalk dissection or compression

Cranial irradiation

Brain injury - trauma, hemorrhage, hydrocephalus

Other syndromes - Prader-Willi, Laurence-Moon-Biedl

Pituitary dysfunction

Hyperprolactinemia Other pituitary tumors-acromegaly, corticotroph adenomas (Cushing's disease) Other tumors - meningioma, germinoma, glioma Empty sella syndrome Pituitary infarct or apoplexy

Ovarian dysfunction

Ovarian failure (menopause) Spontaneous Premature (before age 40 years) Surgical

Other

Hyperthyroidism Hypothyroidism Diabetes mellitus Exogenous androgen use

Drugs Associated with Amenorrhea

Drugs that Increase Prolactin

Antipsychotics Tricyclic antidepressants Calcium channel blockers

Drugs with Estrogenic Activity

Digoxin, marijuana, oral contraceptives

Drugs with Ovarian Toxicity

Chemotherapeutic agents

C. 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.

D. 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.

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