Amenorrhea
Amenorrhea (the absence of menstruation) can be primary or secondary.
Primary amenorrhea is failure of menses to occur by age 15 years in patients with normal growth and secondary sexual characteristics. However 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 the absence of menses for ≥ 6 months or the length of 3 cycles after the establishment of regular menstrual cycles (1). However, patients with previously regular cycles are evaluated for secondary amenorrhea if menses have been absent for ≥ 3 months, and patients with previously irregular cycles are evaluated for secondary amenorrhea if menses have been absent for ≥ 6 months.
General reference
-
1. American College of Obstetricians and Gynecologists (ACOG): Revitalize: Gynecology Data Definitions, 2018. Accessed 7/8/19.
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]—see figure The idealized cyclic changes in pituitary gonadotropins, estradiol, progesterone, and uterine endometrium during the normal menstrual cycle), 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:
-
Follicle-stimulating hormone activates aromatase in granulosa cells around the developing oocytes to convert androgens to estradiol.
-
Estrogen stimulates the endometrium, causing it to proliferate.
-
Luteinizing hormone, 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, resulting in anovulatory amenorrhea, and menstrual flow may not occur. 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 can be classified based on a number of different criteria, such as
Anatomic causes can generally be identified by physical examination.
For general clinical evaluation, it is useful to classify amenorrhea as follows:
Each type of amenorrhea 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
Contraceptives can cause the endometrium to thin, sometimes resulting in amenorrhea; menses usually begin again about 3 months 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 of anovulatory amenorrhea involve a disruption of the hypothalamic-pituitary-ovarian axis. Thus, causes include
-
Hypothalamic dysfunction (particularly functional hypothalamic anovulation)
-
Pituitary dysfunction
-
Primary ovarian insufficiency (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 begins—eg, 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.
Some Causes of Anovulatory Amenorrhea
Cause |
Examples |
|
Hypothalamic dysfunction, structural |
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 histiocytosis, lymphoma, sarcoidosis, tuberculosis) Irradiation to the hypothalamus Tumors of the hypothalamus |
|
Hypothalamic dysfunction, functional |
Cachexia Chronic disorders, particularly respiratory, gastrointestinal, hematologic, renal, or hepatic (eg, Crohn disease, cystic fibrosis, sickle cell disease, thalassemia major) Dieting Eating disorders (eg, anorexia nervosa, bulimia) Exercise, if excessive Psychiatric disorders (eg, stress, depression, obsessive-compulsive disorder, schizophrenia) Psychoactive drugs |
|
Pituitary dysfunction |
Aneurysms of the pituitary Hyperprolactinemia* Idiopathic hypogonadotropic hypogonadism Infiltrative disorders of the pituitary (eg, hemochromatosis, Langerhans cell granulomatosis, sarcoidosis, tuberculosis) Isolated gonadotropin deficiency Kallmann syndrome (hypogonadotropic hypogonadism with anosmia) Postpartum pituitary necrosis (Sheehan 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 dysfunction |
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† Drug-induced virilization (eg, by androgens, antidepressants, danazol, or high-dose progestins)† Obesity (which causes excess extraglandular production of estrogen) True hermaphroditism† Tumors producing androgens (usually ovarian or adrenal)† Tumors producing estrogens or tumors producing human chorionic 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. |
|
|
FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; LH = luteinizing hormone. |
|
Ovulatory amenorrhea
The most common causes of ovulatory amenorrhea include
Some Causes of Ovulatory Amenorrhea
Obstructive abnormalities are usually accompanied by normal hormonal function. Such obstruction may result in
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 for primary amenorrhea if
Girls and women of reproductive age should be evaluated for secondary amenorrhea if they have previously been menstruating and have
-
Missed menstrual cycles for ≥ 3 months if they previously had regular menstrual cycles or ≥ 6 months if they previously had irregular menstrual cycles (1)
-
< 9 menses a year
-
A sudden change in menstrual pattern
Evaluation of secondary amenorrhea should always include a pregnancy test.
Evaluation reference
-
1. Rebar R: Evaluation of amenorrhea, anovulation, and abnormal bleeding. In Endotext [Internet]. edited by KR Feingold, B Anawalt, A Boyce, et al. South Dartmouth (MA), MDText.com Inc, 2000.
History
History of present illness includes the following:
-
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
-
When the last normal menstrual period occurred
-
How long and heavy menses is
-
Whether menses are accompanied by significant discomfort (which may indicate structural abnormalities)
-
Whether patients have cyclic breast tenderness and mood changes
-
When they reached certain growth and development milestones, including age at thelarche (development of breasts at puberty)
Review of systems should cover symptoms suggesting possible causes, including the following:
-
Galactorrhea, headaches, and visual field defects: Pituitary disorders
-
Fatigue, weight gain, and cold intolerance: Hypothyroidism
-
Palpitations, nervousness, tremor, and heat intolerance: Hyperthyroidism
-
Palpitations: Anorexia nervosa with electrolyte abnormalities (eg, hypokalemia, hypomagnesemia)
-
Acne, hirsutism, and deepening of the voice: Androgen excess
-
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 the following:
-
Functional hypothalamic anovulation, such as stress; chronic illness; new drugs; and a recent change in weight, diet, or exercise intensity
-
In patients with secondary amenorrhea, Asherman syndrome (eg, dilation and curettage [D & C], endometrial ablation, endometritis, obstetric injury, uterine surgery)
Drug history should include specific questions about use of drugs, such as the following:
-
Drugs that affect dopamine (eg, antihypertensives, antipsychotics, opioids, tricyclic antidepressants)
-
Cancer chemotherapy drugs (eg, busulfan, chlorambucil, cyclophosphamide)
-
Sex hormones that can cause virilization (eg, androgens, estrogens, high-dose progestins, over-the-counter [OTC] anabolic steroids)
-
Contraceptives, particularly recent use
-
Systemic corticosteroids
-
OTC products and supplements, some of which contain bovine hormones or interact with other drugs
Family history should include height of family members and any cases of delayed puberty or genetic disorders in family members, including Fragile X syndrome.
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 the Tanner 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
Interpretation of findings
Pregnancy should not be excluded based on history; a pregnancy test is required, typically a high-sensitivity urine test or, occasionally, a blood test. Results are usually accurate several days before a missed menstrual period and often as early as several days after conception. Some OTC tests are not highly accurate.
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 Findings Suggesting Possible Causes of Amenorrhea):
-
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 primary ovarian insufficiency (premature ovarian failure) or functional hypothalamic anovulation (eg, due to excessive exercise, a low body weight, or low body fat)
-
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 |
Other Possible Findings |
Possible Cause |
Use of certain drugs |
||
|
Drugs that affect dopamine (which helps regulate prolactin secretion):
|
Galactorrhea |
Hyperprolactinemia |
|
Hormones and certain other drugs that affect the balance of estrogenic and androgenic effects (eg, androgens, antidepressants, danazol, high-dose progestins) |
Virilization |
Drug-induced virilization |
Body habitus |
||
|
High body mass index (eg, > 30 kg/m2) |
— |
Estrogen excess |
|
Virilization |
||
|
Low body mass index (eg, < 18.5 kg/m2) |
Risk factors such as a chronic disorder, dieting, or an eating disorder |
Functional hypothalamic anovulation |
|
Hypothermia, bradycardia, other arrhythmias and/or palpitations, hypotension |
Functional hypothalamic anovulation due to anorexia nervosa or starvation, possibly with electrolyte abnormalities (eg, hypokalemia, hypomagnesemia) |
|
|
Reduced gag reflex, palatal lesions, subconjunctival hemorrhages |
Functional hypothalamic anovulation due to bulimia with frequent vomiting |
|
|
Short stature |
Primary amenorrhea, webbed neck, widely spaced nipples |
|
Skin abnormalities |
||
|
Warm, moist skin |
Tachycardia, tremor |
|
|
Coarse, thick skin; loss of eyebrow hair |
Bradycardia, delayed deep tendon reflexes, weight gain, constipation |
|
|
Acne |
Virilization |
Androgen excess due to |
|
Striae |
Moon facies, buffalo hump, truncal obesity, thin extremities, virilization, hypertension |
|
|
Acanthosis nigricans |
Obesity, virilization |
|
|
Vitiligo or hyperpigmentation of the palm |
Orthostatic hypotension |
|
General findings suggesting estrogenic or androgenic abnormalities |
||
|
Symptoms of estrogen deficiency (eg, hot flushes, night sweats, particularly with vaginal dryness or atrophy) |
Risk factors such as oophorectomy, chemotherapy, or pelvic irradiation |
Functional hypothalamic anovulation |
|
Hirsutism with virilization |
― |
Androgen excess due to |
|
Primary amenorrhea |
Androgen excess due to |
|
|
Enlarged ovaries |
Androgen excess due to |
|
Breast and genital abnormalities |
||
|
Galactorrhea |
— |
Hyperprolactinemia |
|
Nocturnal headache, visual field defects |
Pituitary tumor |
|
|
Absence or incomplete development of breasts (and of secondary sexual characteristics) |
Normal adrenarche |
Primary anovulatory amenorrhea due to isolated ovarian failure |
|
Absence of adrenarche |
Primary anovulatory amenorrhea due to hypothalamic-pituitary dysfunction |
|
|
Absence of adrenarche with impaired sense of smell |
||
|
Delay of breast development and secondary sexual characteristics |
Family history of delayed menarche |
Constitutional delay of growth and puberty |
|
Normal breast development and secondary sexual characteristics with primary amenorrhea |
Cyclic abdominal pain, bulging vagina, uterine distention |
Genital outflow obstruction |
|
Ambiguous genitals |
― |
True hermaphroditism Pseudohermaphroditism Virilization |
|
Fused labia, clitoral enlargement at birth |
― |
Androgen exposure during the 1st trimester, possibly indicating
|
|
Clitoral enlargement after birth |
Virilization |
Androgen-secreting tumor (usually ovarian) Use of anabolic steroids |
|
Normal external genitals with incompletely developed secondary sexual characteristics (sometimes with breast development but minimal pubic hair) |
Apparent absence of cervix and uterus |
Androgen insensitivity syndrome |
|
Ovarian enlargement (bilateral) |
Symptoms of estrogen deficiency |
Primary ovarian insufficiency due to autoimmune oophoritis |
|
Virilization |
17-Hydroxylase deficiency |
|
Lesions |
||
|
Pelvic mass (unilateral) |
Pelvic pain |
Intraperitoneal tumors or abscesses Bowel obstruction Endometriomas Enlarged kidney Pelvic kidney Pelvic tumors Structural pelvic abnormalities Volvulus |
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 algorithm Evaluation of primary amenorrhea) differs from that to secondary amenorrhea (see algorithm Evaluation of secondary amenorrhea), although no specific general approaches or algorithms are universally accepted.
If patients have primary amenorrhea and normal secondary sexual characteristics, testing should begin with pelvic ultrasonography to check for congenital anatomic genital tract obstruction.
Evaluation of primary amenorrhea [a]
![Evaluation of primary amenorrhea [a]](/-/media/manual/professional/images/gyn_primary_amenorrhea_algorithm_no_fnts_change.gif?thn=0&sc_lang=en)
Evaluation of secondary amenorrhea*
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. 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 erythrocyte sedimentation rate (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 follicle-stimulating hormone (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 progestogen to try to stimulate withdrawal bleeding can be done (progesterone challenge test).
The progesterone challenge test begins by giving medroxyprogesterone 5 to 10 mg po once a day or another progestogen 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 insufficiency, or estrogen excess.
-
If bleeding does not occur, an estrogen (eg, conjugated equine estrogen 1.25 mg, estradiol 2 mg) orally once a day is given for 21 days, followed by medroxyprogesterone 10 mg orally once a day or another progestogen 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 luteinizing hormone (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, cardiovascular disorders, vaginal atrophy)
-
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)
Key Points
-
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, begin testing with 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 primary ovarian insufficiency and conditions that cause functional hypothalamic anovulation.
-
If patients have galactorrhea, check for conditions that cause hyperprolactinemia (eg, pituitary dysfunction, use of certain drugs).
Drugs Mentioned In This Article
| Drug Name | Select Trade |
|---|---|
medroxyprogesterone |
PROVERA |
cyclophosphamide |
CYTOXAN (LYOPHILIZED) |
metoclopramide |
REGLAN |
clomipramine |
ANAFRANIL |
progesterone |
CRINONE |
chlorambucil |
LEUKERAN |
Testosterone |
DELATESTRYL |
desipramine |
NORPRAMIN |
risperidone |
RISPERDAL |
haloperidol |
HALDOL |
olanzapine |
ZYPREXA |
cimetidine |
TAGAMET |
methyldopa |
No brand name |
verapamil |
CALAN |
estradiol |
ESTRADERM, ESTROGEL, VIVELLE |
estrogens |
Estrogens |
reserpine |
No US brand name |
morphine |
DURAMORPH PF, MS CONTIN |
busulfan |
MYLERAN |
pimozide |
ORAP |
