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Menarche ordinarily occurs between ages 11 and 15 years (average in the United States: 12.7 years) (see also Chapter 18-04). The failure of any menses to appear is termed “primary amenorrhea,” and evaluation is commenced (1) at age 14 years if neither menarche nor any breast development has occurred or if height is in the lowest 3%, or (2) at age 16 years if menarche has not occurred.

ETIOLOGY OF PRIMARY AMENORRHEA

The differential diagnoses for primary amenorrhea include hypothalamic-pituitary causes, hyperandrogenism, ovarian causes (gonadal dysgenesis, Müllerian dysgenesis), disorders of sexual development (pseudohermaphroditism), uterine causes, and pregnancy.

A. Hypothalamic-Pituitary Causes (With Low or Normal FSH)

The most common cause of primary amenorrhea is a variant of normal known as constitutional delay of growth and puberty, which accounts for about 30% of delayed puberty cases. There is a strong genetic basis for this condition; over 50% of girls with it have a family history of delayed puberty. However, constitutional delay of growth and puberty is a diagnosis of exclusion.

A genetic deficiency of GnRH and gonadotropins may be isolated or associated with other pituitary deficiencies or diminished olfaction (Kallmann syndrome). Hypothalamic lesions, particularly craniopharyngioma, may be present. Pituitary tumors may be nonsecreting or may secrete PRL or GH. Cushing syndrome may be caused by corticosteroid treatment, a cortisol-secreting adrenal tumor, or an ACTH-secreting pituitary tumor. Hypothyroidism can delay adolescence. Head trauma or encephalitis can cause gonadotropin deficiency. Primary amenorrhea may also be caused by severe illness, vigorous exercise (eg, ballet dancing, running), stressful life events, dieting, or anorexia nervosa; however, these conditions should not be assumed to account for amenorrhea without a full endocrinologic evaluation. (See Hypopituitarism.)

B. Uterine Causes (With Normal FSH)

Müllerian agenesis (Mayer-Rokitansky-Küster-Hauser syndrome) results in a missing uterus and variable degrees of upper vaginal hypoplasia. It is the most common cause of permanent primary amenorrhea. Affected women have intact ovaries and undergo an otherwise normal puberty. Such women ovulate and fertility is possible with in vitro fertilization and surrogacy.

An imperforate hymen is occasionally the reason for the absence of visible menses.

C. Hyperandrogenism (With Low or Normal FSH)

Polycystic ovaries and ovarian tumors can secrete excessive testosterone. Excess testosterone can also be secreted by adrenal tumors or by adrenal hyperplasia caused by steroidogenic enzyme defects such as P450c21 deficiency (salt-wasting) or P450c11 deficiency (hypertension). Androgenic steroid abuse may also cause this syndrome.

D. Ovarian Causes (With High FSH)

Gonadal dysgenesis (Turner syndrome and variants) is a frequent cause of primary amenorrhea. Autoimmune ovarian failure is another cause. Rare deficiencies in certain ovarian steroidogenic enzymes are causes of primary hypogonadism without virilization: 3-beta-hydroxysteroid dehydrogenase deficiency (adrenal insufficiency with low serum 17-hydroxyprogesterone) and P450c17 deficiency (hypertension and hypokalemia with high serum 17-hydroxyprogesterone). Deficiency ...

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