26-33: Primary Amenorrhea

Menarche ordinarily occurs between ages 11 and 15 years (average in the United States: 12.7 years) (see also Chapter 18). 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.

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 in P450 aromatase (P450arom) activity produces female hypogonadism associated with polycystic ovaries, tall stature, osteoporosis, and virilization.

E. 46, XY Disorders of Sexual Development (Pseudohermaphroditism)

Complete androgen insensitivity syndrome is caused by homozygous inactivating mutations in the androgen receptor. 46, XY individuals with complete androgen insensitivity syndrome are born with normal external female genitalia, although some may have labial or inguinal swellings due to cryptorchid testes. Affected individuals are phenotypic girls and experience normal breast development at puberty, but fail to develop sexual hair and have primary amenorrhea. Investigation of the amenorrhea reveals an absent uterus, short vagina, and intra-abdominal gonads (testes). Serum testosterone levels are high and karyotype is 46 XY. Such individuals function as normal but infertile women but may require vaginal dilatation or surgery. Intra-abdominal testes have a low risk of developing germ cell tumors through adolescence, but the risk increases to about 5% during adulthood, when it is advisable that they be surgically removed. Following gonadectomy, such women require replacement estrogen.

Partial androgen insensitivity syndrome in 46, XY individuals results in variable degrees of ambiguous genitalia. Newborns have micropenis, hypospadias, and bifid scrotum.

Other disorders include Swyer syndrome, Frasier syndrome, and Denys-Drash syndrome. Patients with XY gonadal dysgenesis (Swyer syndrome and others) have streak gonads, normal external female genitalia, vagina, and uterus but no ovaries; they may have sparse pubic hair but do not experience puberty. 46 XY patients with Frasier syndrome and Denys-Drash syndrome have female or ambiguous external genitalia and kidney disease. In these conditions, streak gonads are prone to gonadoblastomas and must therefore be removed surgically. Many other disorders of sexual development cause ambiguous genitalia, including impaired testicular development or function, certain forms of congenital adrenal hyperplasia, and 5-alpha-reductase deficiency (5-ARD).

F. Pregnancy (With High hCG)

Pregnancy may be the cause of primary amenorrhea even when the patient refutes having had sexual intercourse.

A. Symptoms and Signs

Patients with primary amenorrhea require a thorough history and physical examination to look for signs of the conditions noted above. Headaches or visual field abnormalities implicate a hypothalamic or pituitary tumor. Signs of pregnancy may be present. Blood pressure elevation, acne, and hirsutism should be noted. Short stature may be seen with an associated GH or thyroid hormone deficiency. Short stature with manifestations of gonadal dysgenesis indicates Turner syndrome. Olfactory deficits are seen in Kallmann syndrome. Obesity and short stature may be signs of Cushing syndrome. Tall stature may be due to eunuchoidism or acromegaly. Hirsutism or virilization suggests excessive testosterone.

An external pelvic examination plus a rectal examination should be performed to assess hymen patency and the presence of a uterus.

B. Laboratory and Radiologic Findings

The initial endocrine evaluation should include serum FSH, LH, PRL, total and free testosterone, TSH, FT₄, and beta-hCG (pregnancy test). Patients who are virilized or hypertensive require serum electrolyte determinations and further hormonal evaluation (see Hirsutism & Virilization, above). MRI of the hypothalamus and pituitary is used to evaluate teens with primary amenorrhea and low or normal FSH and LH—especially those with high PRL levels. Pelvic duplex/color sonography is very useful. Girls who have a normal uterus and high FSH without the classic features of Turner syndrome may require a karyotype to diagnose X chromosome mosaicism.

Treatment of primary amenorrhea is directed at the underlying cause. Girls with permanent hypogonadism are treated with HRT.