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Primary amenorrhea is defined either as absence of menses by age 14 years with the absence of growth or development of secondary sexual characteristics (eg, breast development) or as absence of menses by age 16 years with normal development of secondary sexual characteristics.

Secondary amenorrhea is defined as the cessation of menstruation for at least 6 months or for at least 3 of the previous 3 cycle intervals. Since only 3 diagnoses are unique to primary amenorrhea and never cause secondary amenorrhea, differentiating primary from secondary amenorrhea does little to enhance the clinician's understanding of the etiology.

Diagnoses unique to primary amenorrhea include vaginal agenesis, androgen insensitivity syndrome, and Turner syndrome (45,XO). The remaining diagnoses should be considered in patients with both primary and secondary amenorrhea.

The causes of amenorrhea are listed below. Organize clinical evaluation on the basis of sexual development and basic developmental physiology. With such a vast differential diagnosis, one way to organize and memorize the causes of amenorrhea can be in its relationships with generalized pubertal delay, normal pubertal development, or genital tract abnormalities.

Causes of amenorrhea

• Generalized pubertal delay
  • Constitutional delay
  • Hypergonadotropic hypogonadism
    • Turner syndrome
    • Gonadal dysgenesis with mosaic karyotype
    • Pure gonadal dysgenesis (Perrault syndrome, Swyer syndrome)
    • Gonadotropin-resistant ovary syndrome
    • Acquired causes, eg, high-dose alkylating chemotherapy, pelvic radiation, and autoimmune oophoritis
  • Hypogonadotropic hypogonadism
    • Chronic conditions, eg, starvation, excessive exercise, depression, psychological stress, marijuana use, Crohn disease, cystic fibrosis, sickle cell disease, thalassemia major, HIV infection, renal disease, thyroid disease, diabetes mellitus, and anorexia nervosa
    • Slow-growing central nervous system (CNS) tumors, eg, adenomas, craniopharyngiomas, meningiomas, and pituitary microadenomas
    • Abnormal hypothalamic development, eg, Kallman syndrome, Prader-Willi syndrome, and Laurence-Moon-Biedl syndrome
    • Acquired miscellaneous disorders, eg, infiltration disorders (sarcoidosis, Langerhans cell histiocytosis, syphilis, tuberculomas), ischemia disorders (caused by trauma, aneurysm, obstruction of the aqueduct of Sylvius), and destruction (concentrated high-dose radiation exposure)
• Normal puberty
  • Associated with hyperandrogenicity, eg, polycystic ovary syndrome, late-onset 21-hydroxylase deficiency (nonclassic congenital adrenal hyperplasia), immaturity of the hypothalamic-pituitary-ovarian axis, Cushing disease, androgen-producing ovarian or adrenal tumors, and ovarian stromal hypertrophy
  • Associated with absence of hirsutism or virilization, eg, immaturity of the hypothalamic-pituitary-ovarian axis and pregnancy
  • Hypergonadotropic hypogonadism, eg, ovarian failure, high-dose alkylating chemotherapy, pelvic radiation, and autoimmune oophoritis
• Anomalies of the genital tract
  • Mullerian agenesis, eg, Mayer-Rokitansky-Kuster-Hauser syndrome
  • Congenital or acquired anatomic obstruction, eg, imperforate hymen, transverse vaginal septum, Asherman syndrome, and endometrial destruction due to severe infection

Hypergonadotropic hypogonadism

Puberty is considered delayed when no breast development is evident at 13.5 years, pubic hair is absent at 14 years, and menarche is absent at 16 years. The most common cause of delayed puberty is constitutional delay. Another common reason for delayed puberty is ovarian failure, which also is termed hypergonadotropic hypogonadism. Elevated levels of FSH and LH characterize hypergonadotropic hypogonadism with low estrogen production.

The most common example of hypergonadotropic hypogonadism is found in Turner syndrome, which is caused by a 45,X karyotype. Clinical manifestations of Turner syndrome include a webbed neck, short stature, broad shieldlike chest, anomalous auricles, and hypoestrogenemia resulting in sexual immaturity. Gonadal dysgenesis fits the same pattern of high FSH and LH and low estradiol levels. Gonadal dysgenesis is caused by a mosaic karyotype with an abnormal X chromosome or with a normal karyotype (46,XX) and streak ovaries. Individuals with Perrault syndrome have gonadal dysgenesis, a normal karyotype, and neurosensory deafness. Sawyer syndrome is illustrated by a phenotypically immature female with a 46,XY karyotype without testis-determining factor on the Y chromosome. Another rare cause of hypergonadotropic hypogonadism is gonadotropin-resistant ovary syndrome, which is characterized by FSH-resistant ovaries.

Acquired causes of hypergonadotropic hypogonadism can result from high-dose alkylating chemotherapy and radiation treatments to the pelvis. Elevated ESR and anti-ovarian antibody levels may suggest autoimmune oophoritis, but such tests rarely are needed. Autoimmune oophoritis is an exclusionary diagnosis. Like all forms of hyperandrogenic hypogonadotropic amenorrhea, these conditions are not reversible.

Hypogonadotropic hypogonadism

Hypogonadotropic hypogonadism occurs when FSH and LH levels are low. The most common causes of hypogonadotropic hypogonadism include chronic illness, starvation, excessive exercise, anorexia nervosa, depression, stress, and marijuana use. Hypogonadotropic hypogonadism involves slowed GnRH release caused by multifactorial components of decreased body fat and increased b endorphins.

Chronic illness can affect pubertal development adversely by interfering with metabolism through malabsorption and poor nutrition (eg, Crohn disease, diabetes mellitus, hypothyroidism and hyperthyroidism, cystic fibrosis, anorexia nervosa, excessive exercise).

Tumors in the CNS can compress the portal vessels and impede the flow of GnRH from the hypothalamus to the pituitary gland. Pituitary adenomas, craniopharyngiomas, and meningiomas are examples of slow-growing nonmetastatic tumors that are uncommon causes of hypogonadotropic hypogonadism. Anterior pituitary prolactinomas releasing prolactin hormone are the most common pituitary tumors to cause hypogonadotropic hypogonadism.

Other acquired disorders can disrupt pituitary function by destructive means, such as ischemia, infiltration, and obstruction. Head trauma, cranial aneurysms, and infiltrative processes (eg, sarcoidosis, syphilis, tuberculomas) are examples of conditions that can disrupt pituitary function.

Abnormal development of the hypothalamus can result in hypogonadotropic hypogonadism. Kallman syndrome presents with anosmia, pubertal delay, and a normal response to exogenous gonadotropins from an embryonic lack of protein coded for by the gene KAL1, which prevents GnRH-producing cells from migrating from the olfactory area to the hypothalamus. Other syndromes associated with hypothalamic dysfunction include Prader-Willi syndrome and Laurence-Moon-Biedl syndrome.

Frequently, amenorrhea with normal puberty is associated with hirsutism. The most common cause in this setting is polycystic ovary (PCO) syndrome. PCO syndrome is characterized by anovulation, hirsutism, and obesity. Other than anovulation, the other characteristics may not always be present. Ovarian hyperthecosis results in hyperandrogenicity, which is evident by signs of hirsutism, acne, and obesity and can be associated with type 2 diabetes mellitus and acanthosis nigricans. Hyperthecosis also can cause virilization as seen in clitoromegaly, temporal balding, and deepened voice change. See Polycystic Ovarian Syndrome for a more in-depth discussion of this entity.

Another cause of hirsutism is the rare late-onset 21-hydroxylase deficiency, which is caused by mutations in the 21-hydroxylase gene resulting in excessive 17-hydroxyprogesterone levels. This deficiency also is termed nonclassic congenital adrenal hyperplasia and can occur in 1-10% of women with hirsutism. Other causes of hyperandrogenism include Cushing disease, ovarian stromal hypertrophy, and androgen-producing tumors of the ovary and adrenal glands. Exogenous anabolic steroid use should be considered in the differential for hyperandrogenic amenorrhea.

Anovulation remains the most common cause of amenorrhea in the setting of nonvirilization. Anovulation is caused by immaturity of the hypothalamic-pituitary-ovarian axis, which can be apparent after discontinuation of various hormonal contraception medications and can result in loss of menses for several months. Idiopathic premature menopause occurs in 1% of women younger than 40 years. Premature ovarian failure can be idiopathic, secondary to chemotherapy or radiation therapy, or autoimmune in origin.

Hyperprolactinemia is a pituitary cause of amenorrhea in the presence of normal puberty. Hyperprolactinemia can occur as a consequence of breastfeeding, microadenomas of the pituitary, and use of psychoactive medications (eg, haloperidol, phenothiazines, amitriptyline, benzodiazepines, cocaine, marijuana).

Amenorrhea may be caused by thyroid disorders, including hyperthyroidism and hypothyroidism. Hypogonadotropic hypogonadism can occur from the same causes as delayed puberty (see Amenorrhea with Delayed Puberty). In addition, Sheehan syndrome, which results from panhypopituitarism after pituitary infarction from postpartum hemorrhage or shock, can present as pubertal amenorrhea.

Amenorrhea resulting from genital tract anomalies can arise from the absence of reproductive organs. Mayer-Rokitansky-Hauser syndrome is an anomaly of the genital tract characterized by vaginal agenesis. The uterus usually is absent, and the vagina is foreshortened. Since the ovaries function normally and produce estradiol, breasts are normal in shape and contour. Pubarche also is normal in this patient population, so pubic hair remains normal. Mayer-Rokitansky-Hauser syndrome accounts for 15% of primary amenorrhea cases and is second to Turner syndrome as the most common cause of primary amenorrhea.

Androgen insensitivity syndrome (previously termed testicular feminization) accounts for 10% of patients with amenorrhea. Androgen insensitivity syndrome is caused by an abnormality of the androgen receptor. The gonads are testicles producing testosterone; however, testosterone has no effect because the androgen receptor is nonfunctional. The phenotypic appearance in patients with this condition is female, but the circulating hormonal pattern is male. Androgen insensitivity syndrome is a maternal X-linked recessive disease in which the testes remain intra-abdominal or partially descended, and pubic hair is sparse.

Spontaneous testicular regression is a rare disorder of genetic males that results in a female phenotype with an absent uterus. In addition, certain enzyme deficiencies affecting androgen production can result in male pseudohermaphrodites. All disorders that are phenotypically female but chromosomally male (XY) require that the gonads be removed to avert cancerous changes.

Primary amenorrhea can result from an imperforate hymen, which presents as a boggy uterus and cyclic abdominal pain. Asherman syndrome occurs after an overzealous curettage of the endometrial lining, which results in adhesions or synechiae that prevent the endometrium from responding to estradiol. Significant infections that destroy the endometrial lining also can result in primary or secondary amenorrhea.

Algorithm for evaluation of amenorrhea with delayed puberty

Obtain results for the following laboratory studies: Thyroid function tests, bone age, and LH, FSH, prolactin levels.

• If TSH levels are elevated and thyroxine (T4) levels are low, the cause is hypothyroidism.
• If the bone age is delayed, the cause is constitutional delay.
• If the bone age is normal, obtain LH, FSH, and prolactin levels.
• If LH and FSH levels are elevated, obtain a karyotype.
  • If the karyotype is 45,XO, the cause is gonadal dysgenesis (ie, Turner syndrome). Amenorrhea can also occur when one of the two X chromosomes is abnormal such as a ring chromosome, or if a partial loss of the p or q arm of the X chromosome is occurs.
  • If the karyotype is 46,XX, the primary cause is ovarian failure. Obtain an autoimmune workup. Consider an etiology of autoimmune oophoritis, effects of radiation therapy or chemotherapy, 17-a-hydroxylase deficiency, or resistant ovary syndrome.
• If LH and FSH levels are low or within reference range, obtain a head MRI.
  • If head MRI findings are abnormal, the cause is pituitary tumor, pituitary destruction, or hypothalamic disease.
  • If Prolactin levels are elevated obtain a head MRI.
    • If head MRI findings are abnormal, the cause is pituitary tumor or a brain lesion disrupting the pituitary stalk. If the MRI is normal, the cause may be marijuana use, or psychiatric medicine specifically dopamine antagonist medications which lead to a decrease in prolactin inhibiting factor and a subsequent increase in serum prolactin levels.
    • If head MRI findings are normal with normal history and physical examination findings, the etiology may be drug use, an eating disorder, athleticism, or psychosocial stress.
    • If head MRI findings are normal but clinical evaluation and screening study findings are abnormal, chronic disease can be excluded.

Algorithm for evaluation of amenorrhea with normal puberty

Obtain a pregnancy test.

• If the pregnancy test result is positive, refer the patient to the appropriate specialist.
• If the pregnancy test result is negative, obtain TSH and prolactin levels.
• If TSH and prolactin levels are within reference range, perform a progestin challenge.
  • If withdrawal bleeding occurs, consider anovulatory cycles to exclude PCO syndrome.
  • If no withdrawal bleeding occurs and E₂/progestin challenge results are negative, consider Asherman syndrome or outlet obstruction.
  • If withdrawal bleeding occurs after E₂/progestin challenge and findings in the uterus and vagina are normal, obtain FSH and LH levels.
    • If FSH and LH levels are low or within reference range, obtain a head MRI.
      • If MRI findings are abnormal, consider hypothalamic disease, pituitary destruction, or pituitary tumor.
      • If MRI findings are normal, proceed with clinical evaluation to exclude chronic disease, anorexia nervosa, marijuana or cocaine use, athleticism, or psychosocial stress.
    • If FSH and LH levels are high, obtain a karyotype.
      • If the karyotype is abnormal, consider Turner mosaic or mixed gonadal dysgenesis.
      • If the karyotype is normal (46,XX), the cause is ovarian failure. Obtain an autoimmune workup. Consider autoimmune oophoritis, premature ovarian failure, exposure to radiation therapy or chemotherapy, or resistant ovary syndrome.
• If TSH and prolactin levels are elevated, the cause is hypothyroidism and hyperprolactinemia.

Check testosterone and DHEAS levels in patients with hirsutism.

• If the testosterone level is greater than 90 mcg/mL and the DHEAS level is greater than 700 ng/mL, consider PCOS, congenital adrenal hyperplasia, hyperthecosis, or an androgen-secreting tumor.
• If testosterone and DHEAS levels are within reference range or moderately elevated, perform a progestin challenge. If withdraw bleeding occurs, the diagnosis is PCOS.

Algorithm for evaluation of genital tract abnormalities

Obtain a pelvic ultrasound. If the uterus is absent, obtain a karyotype.

• If the karyotype is 46,XY, obtain testosterone levels.
  • If testosterone levels are within reference range or are high (male range), the cause is androgen insensitivity.
  • If testosterone levels are within reference range or are low (female range), the cause is testicular regression or gonadal enzyme deficiency.
• If the karyotype is 46,XX, the cause is müllerian agenesis (ie, Rokitansky-Kuster-Hauser syndrome).

Other than pregnancy, constitutional delay, anovulation, and chronic illness, most of the other disorders causing amenorrhea may require referral to a subspecialist for treatment of patients. Many of the treatment methods require surgery or specific therapies. For the adolescent with constitutional delay and anovulation, the goal should be to restore ovulatory cycles, and if ovulatory cycles are not restored spontaneously, estrogen-progestin therapy is indicated. Reassure patients because tremendous anxiety is associated with the diagnosis of amenorrhea.

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