Amenorrhea is absence or abnormal cessation of menstruation in women of reproductive age
Majority of cases are associated with polycystic ovary syndrome, hyperprolactinemia, hypothalamic amenorrhea, or primary ovarian insufficiency (ovarian failure)
Primary amenorrhea is defined as failure to reach menarche by age 15 years in adolescent girls with otherwise normal secondary sexual development or within 5 years after breast development that occurred before age 10 years r1
Secondary amenorrhea is defined as cessation of previously regular menses for 3 months or longer, cessation of previously irregular menses for 6 months or longer,r2 or fewer than 9 menstrual cycles per year in females with oligomenorrhea r1
Diagnose based on history, physical examination, and measurement of serum hCG, follicle-stimulating hormone, prolactin, and TSH levels
In patients with primary amenorrhea, also perform pelvic ultrasonography to evaluate for absence of uterus or other structural abnormalities
Further testing is directed by initial test findings and clinical context; may include karyotype tests, pituitary MRI scanning, serum androgen levels, or progesterone challenge test
Management is based on the underlying cause and generally consists of treating cause (if possible) and providing hormone therapy to achieve physiologic hormone levels, relieve symptoms, and prevent complications (eg, osteoporosis, infertility)
Pitfalls
Always perform pregnancy test; sexual history may corroborate results but does not replace pregnancy test
Counsel patients who have primary ovarian failure about possible fertility; spontaneous pregnancy can occur and contraception should be used unless pregnancy is desired
Terminology
Clinical Clarification
Amenorrhea is absence or abnormal cessation of menstruation in women of reproductive age r1
Amenorrhea not related to menopause, pregnancy, or lactation occurs in 3% to 4% of women r1
Majority of cases are accounted for by polycystic ovary syndrome, hyperprolactinemia, hypothalamic amenorrhea, or primary ovarian insufficiency (ovarian failure) r1
Defined as failure to reach menarche by age 15 years in adolescent girls with otherwise normal secondary sexual development or within 5 years after breast development that occurred before age 10 years
Failure of breast development to start by age 13 years also requires evaluation
Defined as cessation of previously regular menses for 3 months or longer, cessation of previously irregular menses for 6 months or longer,r2 or fewer than 9 menstrual cycles per year in women with oligomenorrhea r1
Diagnosis
Clinical Presentation
History
Suspect primary amenorrhea if any of the following are true: r1
Absence of menarche by age 15 years in adolescent girls with otherwise normal secondary sexual development c1
Absence of menarche within 5 years after breast development that occurred before age 10 years c2
Absence of menarche and breast development by age 13 years c3
Suspect secondary amenorrhea if any of the following are true: r1
Absence of menses for 3 months or longer if previously regular, or 6 months or longer if previously irregular c4c5
Fewer than 9 menstrual cycles per year in women with oligomenorrhea c6
Evaluate for potential underlying cause of amenorrhea: r1
Family history of delayed menarche suggests constitutional delay of puberty r1c8
Vasomotor symptoms (eg, night sweats, hot flashes) may indicate primary ovarian insufficiency or natural menopause r3c9c10c11c12c13c14
Previous chemotherapy or radiation therapy may suggest impairment of specific organ (eg, brain, pituitary gland, ovaries) r1c15c16c17c18c19c20
Severe and/or persistent headaches, intractable vomiting, or changes in thirst, urination, or vision may indicate a central nervous system tumor or empty sella syndrome r1c21c22c23c24c25c26c27c28c29c30c31c32
Cyclic abdominal pain may indicate imperforate hymen or transverse vaginal septum r1c34c35
Prior or current use of illegal or prescription drugs (eg, opiates, antipsychotics, antidepressants, antihypertensives, antihistamines) may alter prolactin levels r1c36c37c38c39c40c41c42c43
Acne, increased facial hair, and male pattern hair loss may indicate hyperandrogenism, polycystic ovary syndrome, ovarian or adrenal tumor, congenital adrenal hyperplasia, or Cushing syndrome r2c44c45c46c47c48c49c50c51c52c53c54c55c56c57c58c59c60c61
Temperature intolerance, palpitations, diarrhea, constipation, or tremor may suggest thyroid disease r2c62c63c64c65c66
History of dieting, weight loss, malnutrition, eating disorders, excessive exercise, or psychosocial stress may suggest functional hypothalamic amenorrhea r4c67c68c69c70c71c72
Results lower than reference range may indicate constitutional delay of puberty or Turner syndrome r1c73c74d1
Elevated BMI may be associated with polycystic ovary syndrome r1c75
Low BMI may be associated with functional hypothalamic amenorrhea r4c76
Evaluate for clinical signs associated with specific underlying causes
Goiter or thyroid nodule indicate thyroid disorder c77c78
Dysmorphic features such as webbed neck, low hairline, and short stature indicate Turner syndrome r1c79c80c81
Central obesity, buffalo hump, striae, and hypertension indicate Cushing syndrome c82c83c84c85d2
Hirsutism (particularly facial hair), acne, or male pattern baldness may indicate hyperandrogenism, caused by polycystic ovary syndrome (most commonly), ovarian or adrenal tumor, congenital adrenal hyperplasia, or Cushing syndrome r1
Evaluate secondary sexual characteristics (ie, breast development and pubic hair growth) and determine Tanner stage r1
Tanner stage inconsistent with age may indicate constitutional delay of puberty, Turner syndrome, or other rare gonadal anomalies r2c86c87c88
Inspect external genitalia and perform pelvic and speculum examination (if no vaginal obstruction) r1
Clitoromegaly suggests an androgen-secreting tumor or congenital adrenal hyperplasia r2c89c90
Bulging, bluish mass at entrance to vagina suggests imperforate hymen r5c91c92
Short, blind vaginal pouch suggests a transverse vaginal septum, müllerian agenesis, or androgen insensitivity syndrome r5c93c94c95c96c97c98
Thin or red vaginal mucosa may indicate low estrogen levels r1c99c100
Absent or abnormal cervix or uterus suggests müllerian agenesis or androgen insensitivity syndrome r1c101c102c103c104c105c106
Cervical scarring may suggest intrauterine synechiae caused by an operation on the uterus (Asherman syndrome) r1c107
Causes and Risk Factors
Causes
Amenorrhea indicates failure of the hypothalamic-pituitary-gonadal axis to induce cyclic changes in the endometrium that result in menses; also may indicate absence of end organs or obstruction of the outflow tract r6c108c109c110
May result from abnormality at any level of the reproductive tract; however, majority of cases of nonphysiologic amenorrhea are associated with polycystic ovary syndrome, hyperprolactinemia, hypothalamic amenorrhea, or primary ovarian insufficiency (ovarian failure) r1c111c112c113c114
Women who compete in sports activities are 3 times more likely to have primary or secondary amenorrhea r1c221
Highest prevalence is in long-distance runners r1c222
Diagnostic Procedures
Primary diagnostic tools
Diagnose based on history, physical examination, and laboratory tests r1c223
Initial testing consists of serum hCG, follicle-stimulating hormone, prolactin, and TSH levels; some sources also suggest measuring estradiolr1
In patients with primary amenorrhea, also perform pelvic ultrasonography to evaluate for absence of uterus or other structural abnormalities
Further testing is directed by initial test findings and clinical context
If uterus is absent, perform karyotype testing and obtain serum testosterone levels r1
46,XX and female-range serum testosterone level indicates müllerian agenesis as the cause of amenorrhea r1
46,XY and male-range serum testosterone level indicates androgen insensitivity as the cause of amenorrhea r1
If serum prolactin levels are persistently elevated and other causes have been excluded, perform pituitary MRI r1
If TSH level is outside reference range, perform thyroid function tests to exclude thyroid disease r1
If follicle-stimulating hormone level is low or within reference range, evaluate for anatomic outflow tract abnormalities, polycystic ovary syndrome, endocrine disorders, and causes of hypothalamic pituitary disorders
May require pelvic ultrasonography; measurement of serum luteinizing hormone, testosterone, dehydroepiandrosterone sulfate, and 17-hydroxyprogesterone levels; or pituitary MRI r1r29
Consider progesterone challenge to induce withdrawal bleeding or hysteroscopy to evaluate for Asherman syndrome if patient has history of obstetric or gynecologic procedures r30
Consider possible eating disorder, excessive exercise, weight loss, or chronic disease as cause r1
If follicle-stimulating hormone level is elevated, evaluate for causes of ovarian insufficiency r1r31
Confirm by repeating follicle-stimulating hormone measurement in 1 month and evaluating serum estradiol r3
May require testing for 17α-hydroxylase deficiency, karyotype and genetic analysis, or screening for autoimmune causes of ovarian insufficiency (eg, levels of TSH, thyroid autoantibodies, fasting glucose, electrolytes) r1
High levels (basal follicle-stimulating hormone greater than 30-40 milliunits/mL) are associated with primary ovarian insufficiency and Turner syndrome r31
Low levels are associated with functional hypothalamic amenorrhea and hypothalamic-pituitary disorders r1
Levels within reference range may be observed in polycystic ovary syndrome, Asherman syndrome, and several other potential causes of amenorrhea
Consider in patients with laboratory test results within reference range and a history of obstetric or gynecologic instrumentation
Administer oral medroxyprogesterone at 10 mg daily for 7 to 10 days; withdrawal bleeding on cessation excludes an outflow tract abnormality and suggests adequate endogenous estrogen level r2
If patient fails to bleed on withdrawal of medroxyprogesterone, administer estrogen and progestin together (eg, oral conjugated estrogen at 2.5 mg/day for 25 days with oral medroxyprogesterone at 5-10 mg/day added for the final 10 days of therapy); failure to bleed indicates endometrium is abnormal owing to scarring r6
Confirm presence of intrauterine synechiae by visualizing the endometrial cavity with ultrasonography
Defined as absence of menstruation for 1 year or longer
Average age 49 to 52 years; preceded by period of perimenopause, which may be characterized by irregular menses and symptoms associated with hypoestrogenism
Differentiated from other causes of amenorrhea based on patient age, symptoms, and elevated follicle-stimulating hormone level r31
Differential diagnosis based on underlying cause c247
Characterized by ovarian follicle depletion or dysfunction with cessation of menses before age 40 years; may be caused by a variety of genetic or acquired (eg, chemotherapy, radiation therapy) factors
Accounts for approximately 12% of secondary amenorrhea cases r1
Differentiated from other common causes of amenorrhea based on history, physical examination, and laboratory tests r1
Follicle-stimulating hormone levels are persistently within menopausal range with associated estrogen deficiency
Treat with estrogen and progestin to support bone, cardiovascular, and sexual health r1
May be daily transdermal, oral, or vaginal estradiol with cyclic progesterone for 10 to 12 days each month; oral contraceptive pills may be used if contraception is also desired r31
Oral contraceptive pills provide higher doses of estrogen and progesterone than necessary for hormone replacement alone r31
Adolescents and young women may need higher doses of estrogen than menopausal women to ensure adequate replacement and prevent bone loss r31
In adolescents with absent or incomplete breast development, initiate low-dose estrogens and increase slowly before administering graduated progesterones until breast development is complete r1
Treatment aims to restore reproductive function, if desired; reduce associated hirsutism and acne; and prevent long-term complications resulting from insulin resistance. May consist of: r29
Low-dose oral contraceptive pills. Generally, those containing progestins with less androgenic effects (eg, desogestrel, norethindrone, norgestimate, drospirenone) are preferred
If menstrual cycle does not return after lifestyle changes, treat with estrogen and progestin to support bone, cardiovascular, and sexual health; oral contraceptive pills may be used if contraception is desired
Endocrine Society clinical practice guidelines suggest against patients with functional hypothalamic amenorrhea taking oral contraceptive pills for the sole purpose of regaining menses or improving bone mineral density r9
Metformin Hydrochloride Oral tablet; Adult females: 500 mg PO 3 times per daily. Normal menstruation returns in 33% after 1 month. When added to clomiphene for infertility, approx. 86% ovulate compared to 8% on clomiphene alone. Weight loss and diet control recommended to prevent metformin-failure in severely obese patients.
Ethinyl Estradiol, Desogestrel Oral tablet, Inert Oral tablet; Adult and Adolescent females: 1 tablet (containing 0.15 mg desogestrel and 30 mcg of ethinyl estradiol) PO daily for 21 days, followed by 7 days without drug.
Norethindrone Acetate, Ethinyl Estradiol Oral tablet; Adult and Adolescent females: 1 tablet (containing either 1 mg norethindrone acetate in combination with 20 mcg of ethinyl estradiol or alternatively, 1.5 mg norethindrone acetate in combination with 30 mcg of ethinyl estradiol) PO once daily for 21 days, followed by a period of 7 days without drug.
Drospirenone, Ethinyl Estradiol Oral tablet, Inert Oral tablet; Adult and Adolescent females: Follow dose as for routine contraception for specific product as specified in product label: 1 tablet PO daily of selected product. Treatment for 6 to 12 months may be required; OCs have limited utility when the underlying cause of the condition is not related to a hypoestrogenic or hyperandrogenic state.
Inert Oral tablet, Norgestimate, Ethinyl Estradiol Oral tablet; Adult and Adolescent females: Follow dose as for routine contraception.
Medroxyprogesterone Acetate Oral tablet; Adult and Adolescent females: 5 to 10 mg PO once daily for 5 to 10 days, starting anytime during the cycle; usually given later in cycle (days 16 to 21). If the endometrium has been primed with estrogens, administer 10 mg PO once daily for 10 days starting on the 16th day of the cycle. Withdrawal bleeding usually occurs 3 to 7 days after discontinuation of therapy.
Cabergoline Oral tablet; Adults: Initially, 0.25 mg PO twice per week. Then, may titrate by 0.25 mg/dose no more than every 4 weeks up to 1 mg PO twice per week if needed. Use lowest effective dose. Once weekly administration has also been found effective at dosages of 0.5 to 3 mg/week PO.
Nondrug and supportive care
Supplement with adequate vitamin D and calcium to support bone health r5
Follow-up is based on underlying cause, clinical response to treatment, and patient's desire for fertility versus contraception
Follow-up may include bone-density monitoring every 1 to 2 years in adolescents with estrogen deficiency; however, this is not universally recommended r31
Cardiovascular disease (increased risk in patients with early loss of ovarian function; added risk in patients with Turner syndrome) c268c269
Endocrine disorders (increased risk of hypothyroidism, adrenal insufficiency, and diabetes in patients with primary ovarian insufficiency) c270c271c272
Metabolic syndrome (in patients with polycystic ovary syndrome) r29c273
Gonadal tumors (occur in up to 25% of women with a Y chromosome) r1c274
Endometrial hyperplasia and endometrial cancer (in patients with unopposed estrogen, such as those with polycystic ovary syndrome) c275c276
Pregnancy can occur, and may be unexpected/unwanted
Prognosis
Depends on underlying cause of amenorrhea
Most women resume menses upon treatment of underlying cause r1
Women with hypothalamic functional amenorrhea who seek pregnancy may expect ovulation rates of approximately 90% and conception rates of approximately 30% per ovulatory cycle after gonadotropin therapy r6
Women with premature ovarian failure may achieve pregnancy via in vitro fertilization with oocyte donation, but induction of ovulation with gonadotropin therapy rarely results in pregnancy r6
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