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.

IHH results from GnRH deficiency. Female patients present with primary amenorrhea and lack of secondary sex characteristics. When associated with anosmia, the disorder is termed Kallmann syndrome. GnRH deficiency occurs in 1 in 8000 males and 1 in 40,000 females and may be X-linked, autosomal dominant, autosomal recessive, or sporadic. The X-linked form is associated with a mutation in the KAL1 gene that encodes anosmin, a neural cell adhesion protein thought to be important in providing the scaffolding for GnRH neurons in their migration from the olfactory placode to the hypothalamus during embryonic development. Similarly, mutations in fibroblast growth factor-8 (FGF8) or its receptor (FGFR1) also disrupt neuronal and olfactory nerve migration. Thus GnRH neurons fail to reach their target in the hypothalamus. All other hypothalamic-pituitary function is normal. Investigators have found that mutations in the kisspeptin/Kiss receptor system that mediates GnRH secretion at puberty can also cause IHH. In these young women, estrogen administration is used to initiate the development of secondary sexual characteristics, and fertility can be attained using pulsatile GnRH or gonadotropin therapy.

 Hyperprolactinemia

 Hypothalamic amenorrhea

Elevated prolactin levels may result from prolactinomas, hypothyroidism, medications (usually psychotropic drugs), or pregnancy. Hyperprolactinemia impairs the normal function of the HPG axis at multiple levels, but the major site of inhibition is the hypothalamic GnRH pulse generator. As prolactin levels rise, luteal phase defects develop, ovulation ceases, and menstrual cycles become shorter and irregular. Higher levels of prolactin are associated with amenorrhea. Treatment of the underlying cause of the elevated prolactin level usually normalizes menstrual cycles.

Hypothalamic amenorrhea refers to amenorrhea resulting from acquired disorders of the GnRH pulse generator. Excessive stress, exercise, and weight loss have been shown to act centrally to disrupt the GnRH-induced pulsatile gonadotropin secretory pattern. In men, GnRH-induced LH pulses normally occur every 2 hours. In contrast, the LH pulse pattern in women must change across the menstrual cycle, accelerating from every 90 to 60 minutes across the follicular phase to every 30 minutes at ovulation and then slowing from every hour to every 4 to 8 hours across the luteal phase. Disruption of this precisely timed pattern results in anovulation, irregular menses, and, eventually, amenorrhea.

Hypothalamic amenorrhea may result from several types of gonadotropin secretory disorders. Some women with anorexia nervosa have absent GnRH-induced LH pulsations (prepubertal pattern), some have pulsations only at night (early pubertal pattern), and still others have LH pulses throughout the 24-hour period, but they are significantly reduced in amplitude or frequency.

The diagnosis depends on excluding other causes of amenorrhea and then relies heavily on a history of weight loss, high levels of exercise or stress, or a combination of these. Supportive findings on physical examination include evidence of decreased estrogen effects and absence of other major illnesses. Laboratory testing usually reveals low serum estradiol and low or low-normal serum LH and FSH levels; the test for βhCG is negative, and the prolactin level is normal. Elevated FSH levels with low estradiol levels, in contrast, indicate probable POI.

Short-term consequences of estrogen deficiency may include painful intercourse, hot flashes, and sleep disturbances. Among the more important long-term consequences are osteoporosis and premature coronary artery disease.

Interventions to reduce stress and balance nutritional intake with degree of exercise should be attempted initially. If these interventions are unsuccessful, estrogen replacement therapy (usually with oral contraceptives) can be instituted. However, data are mixed on the protective effect of estrogen on bone health in women with anorexia nervosa. Fertility, if desired, may be achieved by ovulation induction with clomiphene in mild cases or with human menopausal gonadotropins or pulsatile GnRH administration if the disorder is more severe.

 Premature ovarian failure (high FSH, later high LH, and low estradiol)

 PCOS (low FSH, high LH, and normal estradiol)

 Gonadotropin-secreting pituitary tumors (high FSH and/or LH, often in postmenopausal women, low estradiol)

POI, which is defined as menopause before age 40 years, may result from surgical removal or autoimmune destruction of the ovaries. Autoimmune destruction of the ovaries is characterized by a history of normal puberty and regular menses followed by the early onset of hot flashes, irregular menses, and eventual amenorrhea. Elevated serum FSH levels are the laboratory hallmark of gonadal failure secondary to loss of inhibin. To avoid misdiagnosis, blood for FSH and estradiol should be drawn in the early follicular phase (day 1-5 after onset of spontaneous or induced menses), because FSH levels rise along with LH at midcycle in normally ovulating women. Turner syndrome mosaics (XO/XX) may have several menses before they undergo menopause; therefore, a karyotype may be helpful if ovarian failure occurs in adolescence or the early 20s. Measurement of antimüllerian hormone (AMH) may predict the age of menopause and assess for POI. AMH is produced by granulosa cells in the ovary and decreases over time with eventual absence at the time of menopause.

Both patients and family members are at risk for other autoimmune disorders, including primary adrenal insufficiency (Addison disease), autoimmune thyroid disorders (Graves’ disease, Hashimoto thyroiditis), type 1 diabetes mellitus, pernicious anemia (vitamin B₁₂ deficiency), celiac sprue (often with vitamin D and iron deficiency), and/or rheumatologic disorders.

Estrogen therapy, usually in combination with progesterone, is used to decrease postmenopausal bone loss and premature coronary artery disease. Options for fertility in women with POI include incubation of donor eggs with the partner’s sperm with in vitro fertilization protocols, along with sex hormonal preparation of the patient to enable her to carry the fetus in her uterus.

Hyperandrogenic anovulation refers to the cluster of disorders that manifest with irregular menses or amenorrhea and signs of androgen excess, such as hirsutism and acne. The disorders in this group include PCOS, androgen-secreting tumors of the ovaries or adrenal glands, Cushing syndrome, CAH (classic or attenuated form), and obesity-induced irregular menses. PCOS is the most common disorder of this type, described in 6% to 10% of reproductive age women.

Most patients with PCOS present in adolescence with a history of early menarche (< 12 years) and persistently irregular menses. Hirsutism and acne beginning in the teenage years are other common features of the disorder. Approximately 60% of patients become overweight. Patients also frequently have signs of insulin resistance, including acanthosis nigricans, a velvety, hyperpigmented cutaneous lesion on the neck and in the axillae. Irregular, anovulatory menses lead to infertility, and the resultant unopposed estrogen exposure increases the risk of endometrial hyperplasia and carcinoma.

Experts disagree on whether PCOS is a primary disorder of the central nervous system, the adrenal glands, or the ovaries or whether it is caused by insulin resistance. Existing data support the presence of an abnormal hypothalamic GnRH pulse generator at the time of puberty that is set too fast in PCOS, in contrast to hypothalamic amenorrhea, in which it is too slow. The pituitary gonadotropin response to GnRH is rate dependent; rapid GnRH pulses stimulate LH secretion but inhibit FSH production. The increased LH/FSH secretory ratio results in multiple ovarian follicle recruitment, but no dominant follicle development and an inability to trigger a GnRH-induced LH surge, thus causing anovulation and the appearance of multiple subcapsular cysts. The GnRH pattern triggers constant estrogen and enhanced androgen production by the ovaries. Other experts have suggested that a primary ovarian defect triggers the abnormal GnRH-induced LH pulse pattern. The ovarian prohormones (DHEA and androstenedione) and testosterone may be elevated; for unclear reasons, the adrenal androgens, DHEA and DHEAS, may be increased as well. High levels of circulating androgens decrease hepatic production of sex hormone–binding globulin (SHBG), thereby allowing more free androgen to target the skin and hair follicles and inducing the development of acne and hirsutism. Insulin resistance also plays a role in the ultimate picture; hyperinsulinemia augments ovarian androgen production to reduce SHBG levels further and increase the levels of free, biologically active androgens.

The 1990 National Institutes of Health criteria were modified by the Rotterdam criteria in 2003. The Rotterdam criteria include two of the following three features: oligoovulation or anovulation, clinical or biochemical signs of hyperandrogenism, and polycystic ovaries by ultrasound examination. Other causes such as Cushing syndrome, CAH, and androgen-secreting tumors should be excluded.

The initial goals are to suppress androgen production and action and to ensure regular shedding of the endometrium, to decrease the risk of developing endometrial hyperplasia. Birth control pills are the treatment of choice; an antiandrogen, such as spironolactone, may be added if hirsutism is a major problem. Intermittent cycling with progesterone (Provera or Prometrium) is an alternative for endometrial protection, but it does not suppress the elevated androgens and their ultimate impact on ovarian morphology and function.

Fertility may be achieved with clomiphene citrate or human menopausal gonadotropins. Data show that clomiphene citrate is more efficacious than metformin for induction of ovulation and increased live births. There was a higher incidence of multiple births in the clomiphene group (5% versus 0%) than the metformin group. This trial was in contrast to other previous, smaller trials, which found similar rates in ovulation between the two medications but did not report live birth rates. The patients in this trial were also heavier, with an average body mass index (BMI) of 36.0 and 35.6 kg/m² in the clomiphene and metformin groups, respectively, although the results were not different in the subgroup of patients with a BMI lower than 30 kg/m².

Studies have shown that reducing insulin resistance and serum insulin levels with metformin results in modest decreases in serum androgen levels, decreased blood pressure, improved lipid levels, improvement in menstrual regularity, and improved ovulation in response to clomiphene citrate. The thiazolidinedione class of insulin sensitizers had shown promise, but weight gain and cardiovascular concerns limited their use. Small trials are investigating the potential of glucagon-like peptide-1 (GLP-1) therapy in PCOS. Predictors of responders to metformin may include patients with a family history of type 2 diabetes, history of rapid weight gain, and lack of severe obesity. Oral glucose tolerance testing and/or hemoglobin A_1C testing should be considered in all patients with PCOS.

Long-term consequences of PCOS include infertility, endometrial cancer, obesity, metabolic syndrome (hypertension, central adiposity, dyslipidemia, hyperglycemia), and type 2 diabetes. Epidemiologic studies have not yet defined a clear-cut increase in cardiovascular events, but long-term studies are under way.

Androgen-producing ovarian and adrenal tumors are suggested by rapid progression of hirsutism and virilization (temporal hair recession, clitoris enlargement, breast atrophy, as well as high serum androgen levels [testosterone or DHEAS]). These tumors are usually associated with a serum testosterone level greater than 200 ng/dL or a DHEAS level greater than 1000 ng/mL. However, no level of testosterone or DHEAS absolutely confirms or excludes the diagnosis. The diagnosis of these tumors depends on accurate imaging studies.

CAH (most commonly resulting from 21-hydroxylase deficiency) manifests in infancy with ambiguous genitalia in girls and occasionally with salt-wasting syndromes. Milder forms manifest in adolescence with early pubarche and irregular menses. Family history and ethnicity (Ashkenazi Jews, Italians, Hispanics, Eskimos) increase the suspicion for CAH. CAH is diagnosed by high basal (> 2-3 ng/mL) or adrenocorticotropic hormone (ACTH)–stimulated (> 10 ng/mL) levels of 17-hydroxyprogesterone with the test performed in the follicular phase.

Obesity-induced hyperandrogenic anovulation is suggested by a history of normal puberty and menses until progressive weight gain triggers the development of hirsutism, acne, oligomenorrhea, and, later, amenorrhea. Affected women have low serum levels of FSH and LH in the follicular phase, in contrast to women with PCOS (see subsequent discussion).

Fat tissue contains aromatase and 5-alpha-reductase enzymes. Aromatase converts androgens to estrogens; when aromatase is present in increased amounts, as in obesity, constant (rather than fluctuating) serum estrogen levels are produced, inhibiting LH and FSH secretion and thereby impairing normal ovulation. Increased activity of 5-alpha-reductase, which converts testosterone to dihydrotestosterone (DHT), results in excessive DHT production that promotes the development of hirsutism and acne. Primary treatment with weight loss often results in restoration of normal reproductive function.