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Amenorrhea (the absence of menstruation) can be primary or secondary.
Primary amenorrhea is failure of menses to occur by any of the following:
Secondary amenorrhea is cessation of menses after they have begun; evaluation for amenorrhea is usually done if menses are absent for > 6 mo.
Pathophysiology
Normally, the hypothalamus generates pulses of gonadotropin-releasing hormone (GnRH), which stimulates the pituitary to produce gonadotropins (follicle-stimulating hormone [FSH] and luteinizing hormone [LH])—see Female Reproductive Endocrinology: Menstrual Cycle). Gonadotropins stimulate the ovaries to produce estrogen (mainly estradiol), androgens (mainly testosterone), and progesterone. Estrogen stimulates the endometrium, causing it to proliferate. After ovulation, the corpus luteum produces progesterone, which causes the endometrium to become secretory and prepares it for egg implantation. If pregnancy does not occur, estrogen and progesterone production decreases, and the endometrium breaks down and is sloughed during menses.
When part of this system malfunctions, ovulatory dysfunction occurs; the cycle of gonadotropin-stimulated estrogen production and cyclic endometrial changes is disrupted, and menstrual flow does not occur, resulting in anovulatory amenorrhea. Most amenorrhea, particularly secondary amenorrhea, is anovulatory.
However, amenorrhea can occur when ovulation is normal, as occurs when genital anatomic abnormalities (eg, congenital anomalies causing outflow obstruction, intrauterine adhesions [Asherman's syndrome]) prevent normal menstrual flow despite normal hormonal stimulation.
Etiology
Amenorrhea is usually classified as anovulatory (see Table 1: Menstrual Abnormalities: Some Causes of Anovulatory Amenorrhea ) or ovulatory (see Table 2: Menstrual Abnormalities: Some Causes of Ovulatory Amenorrhea). Each type has many causes, but overall, the most common causes of amenorrhea include
Contraceptives can cause the endometrium to thin, sometimes resulting in amenorrhea. Antidepressants and antipsychotics can elevate prolactin.
Some disorders can cause ovulatory or anovulatory amenorrhea. Congenital anatomic abnormalities cause only primary amenorrhea.
Anovulatory amenorrhea:
The most common causes (see Table 1: Menstrual Abnormalities: Some Causes of Anovulatory Amenorrhea) involve a disruption of the hypothalamic-pituitary-ovarian axis. Thus, causes include
Anovulatory amenorrhea is usually secondary but may be primary if ovulation never begins—eg, because of a genetic disorder. If ovulation never begins, puberty and development of secondary sexual characteristics are abnormal.
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Table 1
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| Some Causes of Anovulatory Amenorrhea |
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Cause
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Examples
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Hypothalamic dysfunction, structural
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Genetic disorders (eg, congenital gonadotropin-releasing hormone deficiency, Prader-Willi syndrome)
Infiltrative disorders of the hypothalamus (eg, Langerhans' cell granulomatosis, lymphoma, sarcoidosis, TB)
Irradiation to the hypothalamus
Traumatic brain injury
Tumors of the hypothalamus
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Hypothalamic dysfunction, functional
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Cachexia
Chronic disorders, particularly respiratory, GI, hematologic, renal, or hepatic (eg, Crohn's disease, cystic fibrosis, sickle cell disease, thalassemia major)
Dieting
Drug abuse (eg, of alcohol, cocaine, marijuana, or opioids)
Eating disorders (eg, anorexia nervosa, bulimia)
Exercise (excessive)
HIV infection
Immunodeficiency
Psychiatric disorders (eg, stress, depression, obsessive-compulsive disorder, schizophrenia)
Psychoactive drugs
Undernutrition
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Pituitary dysfunction
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Aneurysms of the pituitary
Hyperprolactinemia*
Idiopathic hypogonadotropic hypogonadism
Infiltrative disorders of the pituitary (eg, hemochromatosis, Langerhans' cell granulomatosis, sarcoidosis, TB)
Isolated gonadotropin deficiency
Kallmann syndrome (hypogonadotropic hypogonadism with anosmia)
Postpartum pituitary necrosis (Sheehan's syndrome)
Traumatic brain injury
Tumors of the brain (eg, meningioma, craniopharyngioma, gliomas)
Tumors of the pituitary (eg, microadenoma)
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Ovarian dysfunction
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Autoimmune disorders (eg, autoimmune oophoritis as may occur in myasthenia gravis, thyroiditis, or vitiligo)
Chemotherapy (eg, high-dose alkylating drugs)
Genetic abnormalities, including chromosomal abnormalities (eg, congenital thymic aplasia, fragile X syndrome, Turner's syndrome)
Gonadal dysgenesis (incomplete ovarian development, sometimes secondary to genetic disorders)
Irradiation to the pelvis
Metabolic disorders (eg, Addison's disease, diabetes mellitus, galactosemia)
Viral infections (eg, mumps)
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Other endocrine dysfunction
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Androgen insensitivity syndrome (testicular feminization)
Congenital adrenal virilism (congenital adrenal hyperplasia—eg, due to 17-hydroxylase deficiency or 17,20-lyase deficiency) or adult-onset adrenal virilism†
Cushing's syndrome†,‡
Drug-induced virilization (eg, by androgens, antidepressants, danazol, or high-dose progestins)†
Hyperthyroidism
Hypothyroidism
Obesity (which causes excess extraglandular production of estrogen)
Polycystic ovary syndrome†
True hermaphroditism†
Tumors producing androgens (usually ovarian or adrenal)†
Tumors producing estrogens or tumors producing human chorionic gonadotropin (gestational trophoblastic disease)
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*Hyperprolactinemia due to other conditions (eg, hypothyroidism, use of certain drugs) may also cause amenorrhea.
†Females with these disorders may have virilization or ambiguous genitals.
‡Virilization may occur in Cushing's syndrome secondary to an adrenal tumor.
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Ovulatory amenorrhea:
The most common causes (see Table 2: Menstrual Abnormalities: Some Causes of Ovulatory Amenorrhea) include
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Table 2
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| Some Causes of Ovulatory Amenorrhea |
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Cause
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Examples
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Congenital genital abnormalities
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Cervical stenosis (rare)
Imperforate hymen
Pseudohermaphroditism
Transverse vaginal septum
Vaginal or uterine aplasia (eg, Müllerian agenesis)
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Acquired uterine abnormalities
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Asherman's syndrome
Endometrial TB
Obstructive fibroids and polyps
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Obstructive abnormalities are usually accompanied by normal hormonal function. Such obstruction may result in hematocolpos (accumulation of menstrual blood in the vagina), which can cause the vagina to bulge, or in hematometra (accumulation of blood in the uterus), which can cause uterine distention or a mass. Because ovarian function is normal, external genital organs and other secondary sexual characteristics develop normally. Some congenital disorders (eg, those accompanied by vaginal aplasia or a vaginal septum) also cause urinary tract and skeletal abnormalities.
Some acquired anatomic abnormalities, such as endometrial scarring after instrumentation or postpartum hemorrhage (Asherman's syndrome), cause secondary ovulatory amenorrhea.
Evaluation
Girls are evaluated if
Women of reproductive age should have a pregnancy test after missing one menses. They are evaluated for amenorrhea if
History:
History of present illness includes whether menses have ever occurred (to distinguish primary from secondary amenorrhea) and, if so, how old patients were at menarche, whether periods have ever been regular, and when the last normal menstrual period occurred. History should also include duration and flow of menses; presence or absence of cyclic breast tenderness and mood changes; and growth, development, and age at thelarche (development of breasts at puberty).
Review of systems should cover symptoms suggesting possible causes, including galactorrhea, headaches, and visual field defects (pituitary disorders); fatigue, weight gain, and cold intolerance (hypothyroidism); palpitations, nervousness, tremor, and heat intolerance (hyperthyroidism); acne, hirsutism, and deepening of the voice (androgen excess); and, for patients with secondary amenorrhea, hot flushes, vaginal dryness, sleep disturbance, fragility fractures, and decreased libido (estrogen deficiency). Patients with primary amenorrhea are asked about symptoms of puberty (eg, breast development, growth spurt, presence of axillary and pubic hair) to help determine whether ovulation has occurred.
Past medical history should note risk factors for functional hypothalamic anovulation, such as stress; chronic illness; a recent change in weight, diet, or exercise intensity; and, in patients with secondary amenorrhea, risk factors for Asherman's syndrome (eg, D & C, endometritis, obstetric injury, uterine surgery).
Drug history should include specific questions about use of drugs that affect dopamine (eg, antihypertensives, antipsychotics, opioids, tricyclic antidepressants) and sex hormones that can cause virilization (eg, androgens, estrogens, high-dose progestins).
Family history should include height of family members and any cases of delayed puberty or genetic disorders in family members.
Physical examination:
Clinicians should note vital signs and body composition and build, including height and weight, and should calculate body mass index (BMI). Secondary sexual characteristics are evaluated; breast and pubic hair development are staged using Tanner's method. If axillary and pubic hair is present, adrenarche has occurred.
With the patient seated, clinicians should check for breast secretion by applying pressure to all sections of the breast, beginning at the base and moving toward the nipple. Galactorrhea (breast milk secretion not temporally associated with childbirth) may be observed; it can be distinguished from other types of nipple discharge by finding fat globules in the fluid using a low-power microscope.
Pelvic examination is done to detect anatomic genital abnormalities; a bulging hymen may be caused by hematocolpos, which suggests genital outflow obstruction. Pelvic examination findings also help determine whether estrogen is adequate. In postpubertal females, thin, pale vaginal mucosa without rugae and pH > 6.0 indicate estrogen deficiency. The presence of cervical mucus with spinnbarkeit (a stringy, stretchy quality) usually indicates adequate estrogen.
General examination focuses on evidence of virilization, including hirsutism, temporal balding, acne, voice deepening, increased muscle mass, clitoromegaly (clitoral enlargement), and defeminization (a decrease in previously normal secondary sexual characteristics, such as decreased breast size and vaginal atrophy). Hypertrichosis (excessive growth of hair on the extremities, head, and back), which is common in some families, is differentiated from true hirsutism, which is characterized by excess hair on the upper lip and chin and between the breasts. Skin discoloration (eg, yellow of jaundice or carotenemia, black patches of acanthosis nigricans) should be noted.
Red flags:
The following findings are of particular concern:
Interpretation of findings:
Pregnancy should not be excluded by history; a pregnancy test is required.
In primary amenorrhea, the presence of normal secondary sexual characteristics usually reflects normal hormonal function; amenorrhea is usually ovulatory and typically due to a congenital anatomic genital tract obstruction. Primary amenorrhea accompanied by abnormal secondary sexual characteristics is usually anovulatory (eg, due to a genetic disorder).
In secondary amenorrhea, clinical findings sometimes suggest a mechanism (see Table 3: Menstrual Abnormalities: Findings Suggesting Possible Causes of Amenorrhea):
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Table 3
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| Findings Suggesting Possible Causes of Amenorrhea |
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Finding
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Other Possible Findings
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Possible Cause
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Use of certain drugs
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Drugs that affect dopamine (which helps regulate prolactin secretion):
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Galactorrhea
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Hyperprolactinemia
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Hormones and certain other drugs that affect the balance of estrogenic and androgenic effects (eg, androgens, antidepressants, danazol, high-dose progestins)
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Virilization
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Drug-induced virilization
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Body habitus
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High body mass index (eg, > 30 kg/m2)
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Virilization
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Estrogen excess
Polycystic ovary syndrome
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Low body mass index (eg, < 18.5 kg/m2)
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Risk factors such as a chronic disorder, dieting, or an eating disorder
Hypothermia, bradycardia, hypotension
Reduced gag reflex, palatal lesions, subconjunctival hemorrhages
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Functional hypothalamic anovulation
Functional hypothalamic anovulation due to anorexia nervosa or starvation
Functional hypothalamic anovulation due to bulimia with frequent vomiting
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Short stature
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Primary amenorrhea, webbed neck, widely spaced nipples
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Turner's syndrome
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Skin abnormalities
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Warm, moist skin
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Tachycardia, tremor
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Hyperthyroidism
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Coarse, thick skin; loss of eyebrow hair
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Bradycardia, delayed deep tendon reflexes, weight gain, constipation
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Hypothyroidism
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Acne
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Virilization
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Androgen excess due to polycystic ovary syndrome, an androgen-secreting tumor, Cushing's syndrome, adrenal virilism, or drugs (eg, androgens, antidepressants, danazol, high-dose progestins)
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Striae
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Moon facies, buffalo hump, truncal obesity, thin extremities, virilization, hypertension
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Cushing's syndrome
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Acanthosis nigricans
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Obesity, virilization
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Polycystic ovary syndrome
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Vitiligo or hyperpigmentation of the palm
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Orthostatic hypotension
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Addison's disease
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General findings suggesting estrogenic or androgenic abnormalities
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Symptoms of estrogen deficiency (eg, hot flushes, night sweats, particularly with vaginal dryness or atrophy)
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Risk factors such as oophorectomy, chemotherapy, or pelvic irradiation
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Premature ovarian failure
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Hirsutism with virilization
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Primary amenorrhea
Enlarged ovaries
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Androgen excess due to polycystic ovary syndrome, an androgen-secreting tumor, Cushing's syndrome, adrenal virilism, or drugs (eg, androgens, antidepressants, danazol, high-dose progestins)
Androgen excess due to true hermaphroditism, pseudohermaphroditism, an androgen-secreting tumor, adrenal virilism, gonadal dysgenesis, or a genetic disorder
Androgen excess due to 17-hydroxylase deficiency, polycystic ovary syndrome, or an androgen-secreting ovarian tumor
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Breast and genital abnormalities
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Galactorrhea
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Nocturnal headache, visual field defects
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Hyperprolactinemia
Pituitary tumor
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Absence or incomplete development of breasts (and of secondary sexual characteristics)
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Normal adrenarche
Absence of adrenarche
Absence of adrenarche with impaired sense of smell
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Primary anovulatory amenorrhea due to isolated ovarian failure
Primary anovulatory amenorrhea due to hypothalamic-pituitary dysfunction
Kallmann syndrome
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Delay of breast development and secondary sexual characteristics
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Family history of delayed menarche
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Constitutional delay of growth and puberty
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Normal breast development and secondary sexual characteristics with primary amenorrhea
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Cyclic abdominal pain, bulging vagina, uterine distention
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Genital outflow obstruction
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Ambiguous genitals
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True hermaphroditism
Pseudohermaphroditism
Virilization
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Fused labia, clitoral enlargement at birth
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Androgen exposure during the 1st trimester, possibly indicating congenital adrenal virilism, true hermaphroditism, or drug-induced virilization
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Clitoral enlargement after birth
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Virilization
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Androgen-secreting tumor (usually ovarian)
Adrenal virilism
Use of anabolic steroids
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Normal external genitals with incompletely developed secondary sexual characteristics (sometimes with breast development but minimal pubic hair)
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Apparent absence of cervix and uterus
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Androgen insensitivity syndrome
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Ovarian enlargement (bilateral)
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Symptoms of estrogen deficiency
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Premature ovarian failure due to autoimmune oophoritis
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Virilization
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17-Hydroxylase deficiency
Polycystic ovary syndrome
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Lesions
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Pelvic mass (unilateral)
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Pelvic pain
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Pelvic tumors
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Testing:
History and physical examination help direct testing.
If girls have secondary sexual characteristics, a pregnancy test should be done to exclude pregnancy and gestational trophoblastic disease as a cause of amenorrhea. Women of reproductive age should have a pregnancy test after missing one menses.
The approach to primary amenorrhea (see Fig. 1: Menstrual Abnormalities: Evaluation of primary amenorrhea. ) differs from that to secondary amenorrhea (see Fig. 2: Menstrual Abnormalities: Evaluation of secondary amenorrhea.), although no specific general approaches or algorithms are universally accepted.
DHEAS = dehydroepiandrosterone sulfate; FSH = follicle-stimulating hormone; LH = luteinizing hormone; TSH = thyroid-stimulating hormone.
If symptoms or signs suggest a specific disorder, specific tests may be indicated regardless of what an algorithm recommends. For example, patients with abdominal striae, moon facies, a buffalo hump, truncal obesity, and thin extremities should be tested for Cushing's syndrome (see Adrenal Disorders: Cushing's Syndrome). Patients with headaches and visual field defects or evidence of pituitary dysfunction require brain MRI.
If clinical evaluation suggests a chronic disease, liver and kidney function tests are done, and ESR is determined.
Often, testing includes measurement of hormone levels; total serum testosterone or dehydroepiandrosterone sulfate (DHEAS) levels are measured only if signs of virilization are present. Certain hormone levels should be remeasured to confirm the results. For example, if serum prolactin is high, it should be remeasured; if serum FSH is high, it should be remeasured monthly at least twice. Amenorrhea with high FSH levels (hypergonadotropic hypogonadism) suggests ovarian dysfunction; amenorrhea with low FSH levels (hypogonadotropic hypogonadism) suggests hypothalamic or pituitary dysfunction.
If patients have secondary amenorrhea without virilization and have normal prolactin and FSH levels and normal thyroid function, a trial of estrogen and a progestin to try to stimulate withdrawal bleeding can be done (progesterone challenge test). The trial begins by giving medroxyprogesterone 5 to 10 mg po once/day or another progestin for 7 to 10 days.
However, because this trial takes weeks and results can be inaccurate, diagnosis of some serious disorders may be delayed significantly; thus, brain MRI should be considered before or during the trial.
Mildly elevated levels of testosterone or DHEAS suggest polycystic ovary syndrome, but levels can be elevated in women with hypothalamic or pituitary dysfunction and are sometimes normal in hirsute women with polycystic ovary syndrome. The cause of elevated levels can sometimes be determined by measuring serum LH. In polycystic ovary syndrome, circulating LH levels are often increased, increasing the ratio of LH to FSH.
Treatment
Treatment is directed at the underlying disorder; with such treatment, menses sometimes resume. For example, most abnormalities obstructing the genital outflow tract are surgically repaired.
If a Y chromosome is present, bilateral oophorectomy is recommended because risk of ovarian germ cell cancer is increased.
Problems associated with amenorrhea may also require treatment, including
Key Points
Last full review/revision January 2010 by JoAnn V. Pinkerton, MD
Content last modified January 2010
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