Amenorrhea

Amenorrhea (the absence of menstruation) can be primary or secondary. Primary amenorrhea is failure of menses to occur by one of the following:

Age 16 or 2 yr after the onset of puberty About age 14 in girls who have not gone through puberty (eg, growth spurt, development of secondary sexual characteristics)

If patients have had no menstrual periods by age 13 and have no signs of puberty (eg, any type of breast development), they should be evaluated for primary amenorrhea. Secondary amenorrhea is cessation of menses after they have begun. Usually, patients should be evaluated for secondary amenorrhea if menses have been absent for 3 mo or 3 typical cycles because from menarche until perimenopause, a menstrual cycle lasting > 90 days is unusual. Pathophysiology Normally, the hypothalamus generates pulses of gonadotropin-releasing hormone (GnRH). GnRH stimulates the pituitary to produce gonadotropins (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]), which are released into the bloodstream. Gonadotropins stimulate the ovaries to produce estrogen (mainly estradiol), androgens (mainly testosterone), and progesterone. These hormones do the following:

FSH stimulates tissues around the developing oocytes to convert testosterone to estradiol. Estrogen stimulates the endometrium, causing it to proliferate. LH, when it surges during the menstrual cycle, promotes maturation of the dominant oocyte, release of the oocyte, and formation of the corpus luteum, which produces progesterone. Progesterone changes the endometrium into a secretory structure and prepares it for egg implantation (endometrial decidualization).

If pregnancy does not occur, estrogen and progesterone production decreases, and the endometrium breaks down and is sloughed during menses. Menstruation occurs 14 days after ovulation in typical cycles. 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 syndrome]) prevent normal menstrual flow despite normal hormonal stimulation.

Etiology Amenorrhea is usually classified as anovulatory or ovulatory. Each type has many causes, but overall, the most common causes of amenorrhea include

Pregnancy (the most common cause in women of reproductive age) Constitutional delay of puberty Functional hypothalamic anovulation (eg, due to excessive exercise, eating disorders, or stress) Use or abuse of drugs (eg, oral contraceptives, depoprogesterone, antidepressants, antipsychotics) Breastfeeding Polycystic ovary syndrome

Contraceptives can cause the endometrium to thin, sometimes resulting in amenorrhea; menses usually begin again about 3 mo after stopping oral contraceptives. Antidepressants and antipsychotics can elevate prolactin, which stimulates the breasts to produce milk and can cause amenorrhea. Some disorders can cause ovulatory or anovulatory amenorrhea. Congenital anatomic abnormalities cause only primary amenorrhea. All disorders that cause secondary amenorrhea can cause primary amenorrhea. Anovulatory amenorrhea The most common causes include

involve a disruption of the hypothalamic-pituitary-ovarian axis. Thus, causes

Hypothalamic dysfunction (particularly functional hypothalamic anovulation) Pituitary dysfunction Premature ovarian failure Endocrine disorders that cause androgen excess (particularly polycystic ovary syndrome)

Anovulatory amenorrhea is usually secondary but may be primary if ovulation never beginseg, because of a genetic disorder. If ovulation never begins, puberty and development of secondary sexual characteristics are abnormal. Genetic disorders that confer a Y chromosome increase the risk of ovarian germ cell cancer. Table 1 Some Causes of Anovulatory Amenorrhea Cause Hypothalamic dysfunction, structural Examples Genetic disorders (eg, congenital gonadotropin-releasing hormone deficiency, GnRH receptor gene mutations that result in low FSH and estradiol levels and a high LH level, 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

Hypothalamic dysfunction, functional

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, if excessive HIV infection Immunodeficiency Psychiatric disorders (eg, stress, depression, obsessive-compulsive disorder, schizophrenia) Psychoactive drugs Undernutrition

Pituitary dysfunction

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)

Ovarian dysfunction

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 syndrome [45,X], idiopathic accelerated ovarian follicular atresia) Gonadal dysgenesis (incomplete ovarian development, sometimes secondary to genetic disorders) Irradiation to the pelvis

Metabolic disorders (eg, Addison disease, diabetes mellitus, galactosemia) Viral infections (eg, mumps) Other endocrine Androgen insensitivity syndrome (testicular feminization) Congenital adrenal virilism (congenital adrenal hyperplasiaeg, due to 17hydroxylase deficiency or 17,20-lyase deficiency) or adult-onset adrenal virilism Cushing syndrome, Drug-induced virilization (eg, by androgens, antidepressants,danazol, or highdose 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

dysfunction

gonadotropin (gestational trophoblastic disease) *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 syndrome secondary to an adrenal tumor.

Ovulatory amenorrhea The most common causes include

Chromosomal abnormalities Congenital anatomic genital abnormalities that obstruct menstrual flow Table 2 Some Causes of Ovulatory Amenorrhea Cause Congenital genital abnormalities Examples Cervical stenosis (rare) Imperforate hymen Pseudohermaphroditism Transverse vaginal septum Vaginal or uterine aplasia (eg, Mllerian agenesis) Acquired uterine abnormalities Asherman syndrome Endometrial TB Obstructive fibroids and polyps

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, a mass, or bulging of the cervix. 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 for postpartum hemorrhage or infection (Asherman syndrome), cause secondary ovulatory amenorrhea.

Evaluation Girls are evaluated if

They have no signs of puberty (eg, breast development, growth spurt) by age 13. Pubic hair is absent at age 14. Menarche has not occurred by age 16 or by 2 yr after the onset of puberty (development of secondary sexual characteristics).

Women of reproductive age should have a pregnancy test after missing one menses. They are evaluated for amenorrhea if

They are not pregnant and have missed menstrual cycles for 3 mo or 3 typical cycles. They have < 9 menses a year. They have a sudden change in menstrual pattern.

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; new drugs; a recent change in weight, diet, or exercise intensity; and, in patients with secondary amenorrhea, risk factors for Asherman syndrome (eg, D & C, endometrial ablation, endometritis, obstetric injury, uterine surgery). Drug history should include specific questions about use of drugs that affect dopamine (eg, antihypertensives, antipsychotics, opioids, tricyclic antidepressants), cancer chemotherapy drugs (eg, busulfan, chlorambucil, cyclophosphamide), and sex hormones that can cause virilization (eg, androgens, estrogens, high-dose progestins) and questions about recent use of contraceptives. 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 has been deficient. 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 due to jaundice or carotenemia, black patches due to acanthosis nigricans) should be noted. Red flags The following findings are of particular concern:

Delayed puberty Virilization Visual field defects

Interpretation of findings Pregnancy should not be excluded based on history; a pregnancy test is required. Sidebar 1 Pearls & Pitfalls

If amenorrhea occurs in girls with secondary sexual characteristics or in women of reproductive age, do a pregnancy test regardless of sexual and menstrual history.

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 :

Galactorrhea suggests hyperprolactinemia (eg, pituitary dysfunction, use of certain drugs); if visual field defects and headaches are also present, pituitary tumors should be considered. Symptoms and signs of estrogen deficiency (eg, hot flushes, night sweats, vaginal dryness or atrophy) suggest premature ovarian failure. Virilization suggests androgen excess (eg, polycystic ovary syndrome, androgen-secreting tumor, Cushing syndrome, use of certain drugs). If patients have a high BMI, acanthosis nigricans, or both, polycystic ovary syndrome is likely. Findings Suggesting Possible Causes of Amenorrhea Finding Use of certain drugs Drugs that affect dopamine (which helps regulate Galactorrhea prolactin secretion):

Table 3 Other Findings Possible Possible Cause

Hyperprolactinemia

Antihypertensives (eg,methyldopa, reserpine, verapamil) Antipsychotics, 2nd generation (eg, molindone, olanzapine,risperidone) Antipsychotics, conventional (eg,haloperidol, phenothiazines,pimozide) Cocaine Estrogens GI drugs (eg, cimetidine,metoclopramide) Hallucinogens Opioids (eg, codeine, morphine) Tricyclic antidepressants (eg,clomipramine, desipramine) Drug-induced virilization

Hormones and certain other drugs that affect the Virilization balance of estrogenic and androgenic effects (eg, androgens, antidepressants,danazol, high-dose progestins) Body habitus High body mass index (eg, > 30 kg/m2) Virilization Low body mass index (eg, < 18.5 kg/m2)

Estrogen excess Polycystic ovary syndrome hypothalamic

Risk factors such as Functional a chronic disorder, dieting, or an eating disorder anovulation

Hypothermia, bradycardia, hypotension

Functional

hypothalamic

anovulation due to anorexia nervosa or starvation hypothalamic

Reduced gag reflex, Functional palatal lesions, subconjunctival hemorrhages Short stature Primary amenorrhea, Turner syndrome webbed widely nipples Skin abnormalities Warm, moist skin Coarse, thick skin; loss of eyebrow hair Tachycardia, tremor Hyperthyroidism neck, spaced

anovulation due to bulimia with frequent vomiting

Bradycardia, delayed Hypothyroidism deep reflexes, tendon weight

gain, constipation Acne Virilization Androgen excess due to

Polycystic ovary syndrome An tumor androgen-secreting

Cushing syndrome Adrenal virilism Drugs (eg, androgens, antidepressants,danazol, high-dose progestins)

Striae

Moon facies, buffalo Cushing syndrome hump, obesity, extremities, virilization, hypertension truncal thin

Acanthosis nigricans Vitiligo or hyperpigmentation of the palm

Obesity, virilization Orthostatic

Polycystic ovary syndrome Addison's disease

hypotension General findings suggesting estrogenic or androgenic abnormalities Symptoms of estrogen deficiency (eg, hot flushes, Risk factors such as Premature ovarian failure night sweats, particularly with vaginal dryness or atrophy) oophorectomy, chemotherapy, pelvic irradiation Hirsutism with virilization Androgen excess due to

or

Polycystic ovary syndrome An tumor androgen-secreting

Cushing syndrome Adrenal virilism Drugs (eg, androgens, antidepressants,danazol, high-dose progestins)

Primary amenorrhea

Androgen excess due to

True hermaphroditism Pseudohermaphroditism An tumor androgen-secreting

Adrenal virilism Gonadal dysgenesis A genetic disorder

Enlarged ovaries

Androgen excess due to

17-Hydroxylase deficiency Polycystic ovary syndrome An androgen-secreting ovarian tumor

Breast and genital abnormalities Galactorrhea Hyperprolactinemia

Nocturnal headache, Pituitary tumor visual field defects Absence or incomplete development of breasts Normal adrenarche (and of secondary sexual characteristics) Primary ovarian failure anovulatory

amenorrhea due to isolated

Absence adrenarche

of Primary amenorrhea dysfunction

anovulatory due to

hypothalamic-pituitary

Absence adrenarche smell Delay of breast development and secondary sexual Family characteristics history

of Kallmann syndrome with

impaired sense of

of Constitutional delay of growth and puberty

delayed menarche

Normal breast development and secondary sexual Cyclic characteristics with primary amenorrhea

abdominal Genital outflow obstruction

pain, bulging vagina, uterine distention

Ambiguous genitals

True hermaphroditism Pseudohermaphroditism Virilization

Fused labia, clitoral enlargement at birth

Androgen exposure during the 1st

trimester,

possibly

indicating Congenital adrenal virilism True hermaphroditism Drug-induced virilization tumor

Clitoral enlargement after birth

Virilization

Androgen-secreting (usually ovarian) Adrenal virilism Use of anabolic steroids

Normal

external

genitals

with

incompletely Apparent absence of Androgen characteristics cervix and uterus syndrome

insensitivity

developed pubic hair)

secondary

sexual

(sometimes with breast development but minimal

Ovarian enlargement (bilateral)

Symptoms

of Premature ovarian failure due to autoimmune oophoritis

estrogen deficiency

Virilization

17-Hydroxylase deficiency Polycystic ovary syndrome

Lesions Pelvic mass (unilateral) 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. Pelvic pain Pelvic tumors

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 syndrome (see Adrenal Disorders: Cushing 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 givingmedroxyprogesterone

5 to 10 mg po once/day or another progestin for 7 to 10 days.

If bleeding occurs, amenorrhea is probably not caused by an endometrial lesion (eg, Asherman syndrome) or outflow tract obstruction, and the cause is probably hypothalamic-pituitary dysfunction, ovarian failure, or estrogen excess.

If bleeding does not occur, an estrogen (eg, conjugated equine estrogen 1.25 mg,estradiol

2 mg) once/day is given for 21 days, followed by medroxyprogesterone 10 mg po once/day or another progestin for 7 to 10 days. If bleeding does not occur after estrogen is given, patients may have an endometrial lesion or outflow tract obstruction. However, bleeding may not occur in patients who do not have these abnormalities (eg, because the uterus is insensitive to estrogen); thus, the trial using estrogen and progestin may be repeated for confirmation. 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

Inducing ovulation if pregnancy is desired Treating symptoms and long-term effects of estrogen deficiency (eg, osteoporosis) Treating symptoms and managing long-term effects of estrogen excess (eg, prolonged bleeding, persistent or marked breast tenderness, risk of endometrial hyperplasia and cancer) Minimizing hirsutism and long-term effects of androgen excess (eg, cardiovascular disorders, hypertension) Primary amenorrhea in patients without normal secondary sexual characteristics is usually anovulatory (eg, due to a genetic disorder). Always exclude pregnancy by testing rather than by history. Primary amenorrhea is evaluated differently from secondary amenorrhea. If patients have primary amenorrhea and normal secondary sexual characteristics, do pelvic ultrasonography to check for congenital anatomic genital tract obstruction. If patients have signs of virilization, check for conditions that cause androgen excess (eg, polycystic ovary syndrome, an androgen-secreting tumor, Cushing syndrome, use of certain drugs). If patients have symptoms and signs of estrogen deficiency (eg, hot flushes, night sweats, vaginal dryness or atrophy), check for premature ovarian failure. If patients have galactorrhea, check for conditions that cause hyperprolactinemia (eg, pituitary dysfunction, use of certain drugs). .

Key Points