Amenorrhea is the absence of menstrual periods. Primary amenorrhea is the failure ever to begin menses; secondary amenorrhea refers to cessation of menstrual periods after cyclic menses have been established. Oligomenorrhea refers to lighter, irregular menses.

Puberty usually begins after age 8 years in girls and is heralded by the initiation of breast development. The average age for girls in the United States to begin menses is 12 years. This event generally signals the end of the pubertal process, occurring after the growth spurt and most somatic changes are completed. National Health and Nutrition Examination Survey (NHANES) data have noted the average age of menarche to be decreasing slightly, and African American girls have a mean earlier age of breast development onset when compared with white girls (8.9 years versus 10.0 years).

The process is triggered by kisspeptin activation of gonadotropin-releasing hormone (GnRH)–induced episodic secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland. The pulsatile release of gonadotropins activates the ovaries and causes maturation of follicles and production of estrogen and, later, progesterone. These gonadal steroids give feedback at the level of the hypothalamus and pituitary to regulate GnRH and gonadotropin secretion. A final maturation event is the development of positive feedback by estradiol to induce the midcycle LH surge that stimulates ovulation. In many adolescents, menstrual cycles are anovulatory, and thus irregular, for the first 12 to 18 months. As the hypothalamic-pituitary-gonadal (HPG) axis matures, ovulatory cycles become more frequent. In normal adult women, all but one or two cycles per year are ovulatory.

Primary amenorrhea is defined as lack of menses by age 16 years or lack of secondary sexual characteristics by age 14 years. It usually results from abnormal anatomic development of the female reproductive organs or from a hormonal disorder involving the hypothalamus, pituitary gland, or ovaries (Box 47-1). The presence of normal secondary sexual characteristics in such patients suggests an anatomic problem, such as obstruction or failure of development of the uterus or vagina. In contrast, a lack of secondary sexual characteristics indicates a probable hormonal cause.

Idiopathic hypogonadotropic hypogonadism (IHH) can result from maturational arrest of GnRH-producing neurons during embryonic development (also called Kallmann syndrome when associated with anosmia) or failure of GnRH secretion at the time of puberty. The kisspeptin/Kiss receptor system has been shown to regulate GnRH secretion at puberty. Mutations in this pathway, as well as the GnRH receptor in the pituitary, may also cause failure of or impaired sexual maturation. Pituitary tumors, craniopharyngiomas, and Rathke pouch cysts can cause impaired LH and FSH secretion in adolescence that disrupts sexual maturation.

Ovarian function may be impaired because of gonadal dysgenesis secondary to Turner syndrome (45,XO karyotype) or destruction by chemotherapy or radiation before the completion of sexual maturation. The presence of ambiguous genitalia or palpable gonads in the labia or inguinal area may indicate a disorder of sexual differentiation, such as congenital adrenal hyperplasia (CAH) (21-hydroxylase deficiency) or an androgen resistance syndrome (testicular feminization) caused by mutations in the androgen receptor.

Secondary amenorrhea, which is much more common than primary amenorrhea, occurs postpubertally. The causes are outlined in Box 47-2. Pregnancy should be excluded in all amenorrheic women. Onset of irregular menses after prior regular menses with associated hot flashes should suggest premature ovarian insufficiency (POI; i.e., premature menopause). Hypothalamic amenorrhea occurs in 3% to 5% of women and is caused by abnormal GnRH-induced gonadotropin secretion, often as a result of stress or eating disorders, but it is a diagnosis of exclusion. Hyperprolactinemia caused by medications or tumors occurs in 10% of amenorrheic women. Pituitary tumors can also result in secondary amenorrhea. Hyperandrogenic anovulatory disorders such as polycystic ovary syndrome (PCOS), CAH, and, rarely, gonadal or adrenal tumors are usually associated with oligomenorrhea rather than amenorrhea and signs and symptoms of excess androgens, such as hirsutism and acne.

One must determine whether the disorder is anatomic or hormonal, congenital or acquired, and where the defect is located. A complete history and physical examination provide the first essential clues. Pregnancy testing should always be ordered. Timed measurement of serum gonadotropin levels (LH and FSH) should be done within the first 5 days after the onset of spontaneous or induced menses. However, patients who have been taking birth control pills or other forms of hormonal contraceptives may need to wait a cycle to ensure accurate results. Patients with low or normal levels of LH and FSH (hypogonadotropic hypogonadism) have a disorder at the level of the hypothalamus or pituitary gland. In contrast, patients with high LH and/or FSH levels (hypergonadotropic hypogonadism) may have a defect at the level of either the ovary or the hypothalamic-pituitary unit (e.g., PCOS, in which the hypothalamic GnRH pulse generator is abnormally accelerated or a gonadotrope pituitary tumor that secretes the gonadotropins FSH and/or LH).

Other laboratory tests to consider include a prolactin level to exclude hyperprolactinemia and thyroid function tests to exclude thyroid disorders. In a patient with signs of excess androgens, dehydroepiandrosterone (DHEA) sulfate (DHEAS) and testosterone levels should be obtained. In the appropriate patient, Cushing syndrome should be excluded with a 24-hour urine free cortisol test, 1-mg dexamethasone suppression test, or late night salivary cortisol testing. Exclusion may require more than one test.