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
  • Sexual history may indicate possible pregnancy ^c7
  • 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}
  • Galactorrhea may indicate a pituitary tumor ^r4c33
  • 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}

Physical examination

• Measure height, weight, and BMI ^r1
  • 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

• 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}
• Anatomic causes ^r1
  • Congenital
    • Müllerian agenesis (Mayer-Rokitansky-Küster-Hauser syndrome) ^c115
    • Complete androgen insensitivity syndrome (testicular feminization) ^c116
    • Imperforate hymen ^c117
    • Transverse vaginal septum ^c118
    • Isolated vaginal agenesis ^c119
    • Isolated cervical agenesis ^c120
    • Congenital endometrial hypoplasia or aplasia ^c121c122
  • Acquired
    • Intrauterine synechiae (Asherman syndrome) ^c123
    • Cervical stenosis ^c124
    • Head trauma/concussion ^r7
• Primary ovarian insufficiency (eg, ovarian failure, primary hypogonadism, hypergonadotropic hypogonadism) ^r6r8c125
  • Congenital
    • Gonadal dysgenesis ^c126
      • Turner syndrome (45,X) ^c127
      • Mosaicism ^c128
      • Pure gonadal dysgenesis (46,XX or 46,XY) ^c129
      • Fragile X premutation ^c130
    • Gonadal agenesis ^c131
    • Enzymatic deficiencies ^r1c132
      • 17α-hydroxylase deficiency ^c133
      • 17,20-lyase deficiency ^c134
      • Aromatase deficiency ^c135
  • Acquired
    • Chemotherapy or radiation therapy ^c136c137
    • Mumps oophoritis ^c138
    • Autoimmune oophoritis ^c139
    • Idiopathic ^c140
• Hypothalamic causes ^r1
  • Dysfunction due to: ^r1
    • Psychogenic stress ^r9c141
    • Excessive exercise ^r9c142
    • Malnourishment, rapid weight loss, or dieting ^{r9c143c144c145}
    • Eating disorders (eg, anorexia nervosa, bulimia) ^c146c147c148
    • Pseudocyesis ^c149
  • Isolated gonadotropin deficiency (ie, Kallmann syndrome, idiopathic hypogonadotropic hypogonadism) ^{r1c150c151c152}
  • Infection (eg, tuberculosis, meningitis, syphilis) ^{r1c153c154c155}
  • Chronic systemic disease ^r1c156
  • Hypothalamic tumor ^r1c157
  • Traumatic brain injury ^c158
• Pituitary causes ^r1c159
  • Pituitary tumors (prolactinomas or other hormone-secreting pituitary tumors) ^r1c160c161
  • Autoimmune disease (eg, lymphocytic hypophysitis) ^c162c163
  • Empty sella syndrome ^c164
  • Galactosemia ^c165
  • Hyperprolactinemia ^c166
  • Medications (eg, antidepressants, antihistamines, antipsychotics, antihypertensives, opioids) ^{r2c167c168c169c170c171}
  • Cocaine use ^r2c172
  • Sheehan syndrome ^c173
  • Sarcoidosis ^c174
  • Panhypopituitarism ^c175
  • Hemochromatosis ^c176
• Other endocrine gland disorders ^r1
  • Congenital or adult-onset adrenal hyperplasia ^c177c178
  • Cushing syndrome ^c179
  • Thyroid disease ^r1c180
  • Ovarian tumors (androgen producing) ^r1c181
  • Arterial aneurysm ^c182
  • Constitutional delay of puberty ^c183
  • Gonadotropin mutations ^c184
• Polycystic ovary syndrome
• Physiologic ^r2
  • Pregnancy ^c185
  • Menopause ^c186
  • Breastfeeding ^c187
• Iatrogenic
  • Hormonal contraception ^c188
  • Exogenous androgen use ^c189

Risk factors and/or associations

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 estradiol^r1
  • 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

Laboratory

• Serum hCG ^r1c224
  • Positive test result indicates pregnancy as the cause of amenorrhea
• TSH ^r1c225c226
  • Low levels (less than 0.01 milliunits/L) indicate hyperthyroidism ^r32
  • High levels (greater than 4.5 milliunits/L) indicate hypothyroidism ^r33
• Prolactin ^{r1c227c228c229c230c231}
  • High levels can be associated with pituitary adenoma, other neoplasms, hypothyroidism, and illicit or prescription drug use
• Follicle-stimulating hormone ^r1c232
  • 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
• Luteinizing hormone ^c233
  • Low levels are associated with functional hypothalamic amenorrhea and hypothalamic-pituitary disorders ^r1
• Estradiol ^r1c234
  • Low levels (less than 50 pg/mL) suggest abnormal ovarian function ^r31
• Free and total testosterone and dehydroepiandrosterone sulfate ^r1c235c236
  • High levels can indicate hyperandrogenism, polycystic ovary syndrome, ovarian or adrenal tumor, congenital aqueductal stenosis, or Cushing syndrome
• 17-hydroxyprogesterone ^r4c237
  • Elevated levels may indicate late-onset adrenal hyperplasia
• Karyotype analysis ^r1c238
  • Abnormal karyotype may indicate Turner syndrome (45,X), müllerian agenesis (46,XX), complete androgen insensitivity syndrome (46,XY) or 5-alpha reductase deficiency (46,XY), and other rare chromosomal disorders
• Genetic testing ^c239
  • FMR1 gene mutation in fragile X syndrome carriers is associated with primary ovarian insufficiency ^r2

Imaging

• Pelvic ultrasonography ^r1c240
  • Evaluate presence and morphology of uterus and morphology of ovaries for insight into underlying cause of amenorrhea
    • Absent or abnormal uterus suggests a rare congenital cause, such as müllerian agenesis or androgen insensitivity syndrome ^r1
    • Intrauterine adhesions or synechiae may be evident (also known as Asherman syndrome) ^r1
    • Presence of ovarian cysts indicates polycystic ovary syndrome ^r1
• MRI of the head or sella to determine potential causes of amenorrhea ^r1c241c242
  • Lesions within the sellar/suprasellar region suggest pituitary tumor or nonfunctioning adenoma ^r34
  • Abnormalities, obstruction, or narrowing of the cerebral aqueduct indicate congenital aqueductal stenosis ^r1

Functional testing

• Progesterone challenge test ^c243
  • 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

Procedures

Most common

• Differential diagnosis of amenorrhea
  • Pregnancy ^r1c245
    • Causes cessation of menses
    • Differentiated from other causes of amenorrhea based on sexual history and positive pregnancy test result or ultrasonogram showing presence of fetus
  • Menopause ^c246d3
    • 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
  • Functional hypothalamic amenorrhea ^r4c248
    • Absence or cessation of menses due to suppression of the hypothalamic-pituitary-ovarian axis in absence of organic or anatomic diseases ^r4
    • Characterized by suppression of gonadotropin-releasing hormone pulsatility ^r4
    • Differentiated from other common causes of amenorrhea based on history, physical examination, and laboratory tests ^r4
      • Possible patient history of excessive exercise, weight loss, dieting, or psychological stress
      • No signs of anatomic abnormality or hyperandrogenism (eg, acne, hirsutism) ^r4
      • Typically, serum estradiol level is low and luteinizing hormone and follicle-stimulating hormone levels are low to within reference range ^r4
  • Primary ovarian insufficiency ^r1c249
    • 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
      • Karyotyping may reveal genetic cause ^r1
  • Polycystic ovary syndrome ^r1c250d4
    • Endocrine disorder associated with peripheral insulin resistance, hyperandrogenism, polycystic ovaries, and ovulatory dysfunction
    • 24% of patients present with amenorrhea; 76% present with oligomenorrhea ^r1
    • Characterized by follicle-stimulating hormone levels that are low or within reference range, chronic anovulation, hyperandrogenism, and infertility ^r1
    • Differentiated from other common causes of amenorrhea based on history, physical examination, and laboratory test results
      • Patients are commonly overweight or obese and often present with oligomenorrhea rather than amenorrhea
      • Clinical or biochemical signs of hyperandrogenism may be present
      • Follicle-stimulating hormone levels are typically low to within reference range
      • Ultrasonogram demonstrates polycystic ovaries
  • Hyperprolactinemia ^c251
    • Elevated serum prolactin level; may result from pituitary or hypothalamic tumor, medications, or hypothyroidism
    • Accounts for approximately 13% of secondary amenorrhea cases ^r1
    • Differentiated from other common causes of amenorrhea based on history, physical examination, and laboratory tests
      • Women may present with galactorrhea
      • Characterized by serum prolactin levels higher than 25 mcg/L ^r36
      • MRI of pituitary may reveal adenoma

Recommendations for specialist referral

• Refer to or consult with obstetrician-gynecologist
• Refer to reproductive endocrinologist or infertility specialist if pregnancy is desired

Drug therapy

• Biguanides (oral hypoglycemic agents) ^c252
  • Metformin ^r29c253
    • 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.
• Oral contraceptives ^r1c254
  • Estrogen-progestin ^{c255c256c257c258}
    • Follow dose as for routine contraception
      • 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.
  • Progestogens ^c259
    • 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.
• Dopamine agonists ^{r1c260c261c262c263}
  • 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
• Psychosocial support

Comorbidities ^c264