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, absence of any breast development by age 13 should prompt evaluation for primary amenorrhea.
Secondary amenorrhea is the absence of menses for ≥ 6 months or for the length of 3 cycles after the establishment of regular menstrual cycles ( 1 General references 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... read more , 2 General references 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... read more ). 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.
1. American College of Obstetricians and Gynecologists (ACOG): Revitalize: Gynecology Data Definitions. Accessed 11/30/20.
2. The Practice Committee of the American Society for Reproductive Medicine: Current evaluation of amenorrhea. Fertil Steril 90 (5 Suppl):S219–S225, 2008. doi:10.1016/j.fertnstert.2008.08.038
Pathophysiology of Amenorrhea
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 The idealized cyclic changes in pituitary gonadotropins, estradiol (E2), progesterone (P), 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 Menstrual Cycle Hormonal interaction between the hypothalamus, anterior pituitary gland, and ovaries regulates the female reproductive system. The hypothalamus secretes a small peptide, gonadotropin-releasing... read more occurs 14 days after ovulation in typical cycles.
The idealized cyclic changes in pituitary gonadotropins, estradiol (E2), progesterone (P), and uterine endometrium during the normal menstrual cycle
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 of Amenorrhea
Amenorrhea can be classified based on a number of different criteria, such as
Primary or secondary
Anatomic causes (including pregnancy), chronic anovulation, or ovarian failure
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)
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.
Hypothalamic dysfunction (particularly functional hypothalamic anovulation)
Primary ovarian insufficiency (premature ovarian failure)
Endocrine disorders that cause androgen excess (particularly polycystic ovary syndrome Polycystic Ovary Syndrome (PCOS) Polycystic ovary syndrome is a clinical syndrome characterized by mild obesity, irregular menses or amenorrhea, and signs of androgen excess (eg, hirsutism, acne). Most patients have multiple... read more )
Women with amenorrhea due to hypothalamic dysfunction have lower levels of serum leptin (an anorectic hormone produced by fat cells); lower levels may contribute to decreased gonadotropin production.
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.
The central nervous system-hypothalamic-pituitary-gonadal target organ axis
Ovarian hormones have direct and indirect effects on other tissues (eg, bone, skin, muscle).
FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; LH = luteinizing hormone.
Congenital anatomic genital abnormalities that obstruct menstrual flow
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
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 of Amenorrhea
Girls are evaluated for primary amenorrhea if
They have no signs of puberty (eg, breast development, growth spurt) by age 13.
Menarche has not occurred by age 15 in patients with normal growth and development of secondary sexual characteristics.
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 Evaluation reference 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... read more )
< 9 menses a year
A sudden change in menstrual pattern
Evaluation of secondary amenorrhea should always include a pregnancy test.
1. Rebar R: Evaluation of amenorrhea, anovulation, and abnormal bleeding [updated, 2018]. In Endotext [Internet], edited by KR Feingold, B Anawalt, A Boyce, et al. South Dartmouth (MA), MDText.com Inc, 2000.
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, hearing loss, and visual field defects: Pituitary disorders Introduction to Pituitary Disorders The pituitary gland controls the functions of peripheral endocrine glands (see figure The pituitary and its target organs). Pituitary structure and function and relationships between the hypothalamus... read more
Palpitations: Anorexia nervosa Anorexia Nervosa Anorexia nervosa is characterized by a relentless pursuit of thinness, a morbid fear of obesity, a distorted body image, and restriction of intake relative to requirements, leading to a significantly... read more with electrolyte abnormalities (eg, hypokalemia, hypomagnesemia)
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; a recent change in weight, diet, or exercise intensity; and a prior history of eating disorders (because many women are more likely to admit to a past than a current history)
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, antiseizure drugs)
Cancer chemotherapy drugs (eg, alkylating drugs such as bendamustine, cyclophosphamide, and ifosfamide; busulfan; chlorambucil)
Sex hormones that can cause virilization (eg, androgens, estrogens, high-dose progestins, over-the-counter [OTC] anabolic steroids)
Contraceptives, particularly recent use
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 Fragile X Syndrome Fragile X syndrome is a genetic abnormality on the X chromosome that leads to intellectual disability and behavioral disorders. Diagnosis is with molecular DNA analysis. Treatment is supportive... read more .
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 Galactorrhea Galactorrhea is lactation in any men or in women who are not breastfeeding. It is generally due to a prolactin-secreting pituitary adenoma. Diagnosis is by measurement of prolactin levels and... read more (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 (eg, imperforate hymen, vaginal septum, vaginal, cervical, or uterine aplasia). 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. Clinicians should check for enlargement of the uterus, ovaries, and clitoris.
General examination focuses on evidence of virilization, including hirsutism Hirsutism and Hypertrichosis Hirsutism is the excessive growth of thick or dark hair in women in locations that are more typical of male hair growth patterns (eg, mustache, beard, central chest, shoulders, lower abdomen... read more , 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). Virilization results from increased androgen production by the adrenal glands and ovaries. 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.
Clinicians should check for hypothermia, bradycardia, hypotension, and reduced subcutaneous fat, which suggest anorexia nervosa, and for dental erosion, palatal lesions, reduced gag reflex, subconjunctival hemorrhage, and subtle hand changes with calluses on the dorsum of the hand (due to frequent vomiting), which suggest bulimia.
The following findings are of particular concern:
Visual field defects
Impaired sense of smell
A spontaneous milky discharge
A significant increase or decrease in weight
Interpretation of findings
Pearls & Pitfalls
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).
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 and clitoral enlargement suggest 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.
History and physical examination help direct testing.
Pregnancy should not be excluded based on history; a pregnancy test is required. High-sensitivity urine tests should be done, and occasionally, a blood test may be required. Results are usually accurate several days before a missed menstrual period and often as early as several days after conception. Some over-the-counter (OTC) tests are less sensitive and accurate.
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 Evaluation of primary amenorrhea [a] ) differs from that to secondary amenorrhea (see algorithm Evaluation of secondary amenorrhea 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. MRI may be needed if abnormalities are identified.
Evaluation of primary amenorrhea [a]
[a] Normal values are
Although these values are representative, normal ranges may vary between laboratories.
Prolactin 50–100 ng/mL is considered mildly elevated and is usually due to use of a drug. Prolactin > 100 ng/mL is considered elevated and is more likely to be due to a tumor.
[b] Some clinicians measure LH levels when they measure FSH levels or when FSH levels are equivocal.
[c] If patients have primary amenorrhea and normal secondary sexual characteristics, testing should begin with pelvic ultrasonography to check for congenital anatomic genital tract obstruction.
[d] Constitutional delay of growth and puberty is possible.
[e] Possible diagnoses include functional hypothalamic chronic anovulation and genetic disorders (eg, congenital gonadotropin-releasing hormone deficiency, Prader-Willi syndrome).
[f] Possible diagnoses include Cushing syndrome, exogenous androgens, congenital adrenal virilism, and polycystic ovary syndrome.
[g] Possible diagnoses include Turner syndrome and disorders characterized by Y chromosome material.
[h] Pubic hair may be sparse.
DHEAS = dehydroepiandrosterone sulfate; FSH = follicle-stimulating hormone; LH = luteinizing hormone.
Evaluation of secondary amenorrhea*
* Normal values are
Although these values are representative, normal ranges may vary between laboratories.
Prolactin 50–100 ng/mL is considered mildly elevated and is usually due to a drug adverse effect. Prolactin > 100 ng/mL is considered elevated and is more likely to be due to a tumor.
† Some clinicians simultaneously measure FSH and LH levels.
‡ Clinicians should check for the presence of Y chromosome and Fragile X syndrome.
DHEAS = dehydroepiandrosterone sulfate; FSH = follicle-stimulating hormone; LH = luteinizing hormone; PCOS = polycystic ovary syndrome; 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 syndrome Cushing Syndrome Cushing syndrome is a constellation of clinical abnormalities caused by chronic high blood levels of cortisol or related corticosteroids. Cushing disease is Cushing syndrome that results from... read more . 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 orally 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 of Amenorrhea
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 Osteoporosis Osteoporosis is a progressive metabolic bone disease that decreases bone mineral density (bone mass per unit volume), with deterioration of bone structure. Skeletal weakness leads to fractures... read more , 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 Hirsutism and Hypertrichosis Hirsutism is the excessive growth of thick or dark hair in women in locations that are more typical of male hair growth patterns (eg, mustache, beard, central chest, shoulders, lower abdomen... read more 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, 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
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|ESTRADERM, ESTROGEL, VIVELLE|
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