Amenorrhea - Algorithm & Differentials

Amenorrhea SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendation A female patient with primary amenorrhea and sexual development, including pubic hair, should be evaluated for the presence of a uterus and vagina. Women with secondary amenorrhea should receive pregnancy tests. Women with polycystic ovary syndrome should be tested for glucose intolerance.

Evidence rating

References

C

1, 18

C C

1-3, 6 21

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, diseaseoriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, see page 1313 or http://www.aafp.org/afpsort.xml.

TABLE 1

Normal Female Pubertal Development Tanner stage Developmental stage (age in years)

Anatomic drawing

Breast development

Pubic hair development

Initial growth acceleration (8 to 10)

Elevation of papilla only; no pubic hair

1

1

Thelarche (9 to 11)

See adrenarche for stage 2 development

2

1

Adrenarche (9 to 11)

2

2

Peak growth (11 to 13)

3

3

Menarche (12 to 14)

4

4

Adult characteristics (13 to 16)

5

5

Illustrations by Renee Cannon. Information from references 4 and 5.

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Amenorrhea

7.5 percent of participants had abnormal prolactin levels and 4.2 percent had abnormal TSH levels. If TSH and prolactin levels are normal, a progestogen challenge test (Table 33,14) can help evaluate for a patent outflow tract and detect endogenous estrogen that is affecting the endometrium. A withdrawal bleed usually occurs two to seven days after the challenge test.3 A nega-

tive progestogen challenge test signifies an outflow tract abnormality or inadequate estrogenization. An estrogen/ progestogen challenge test (Table 33,14) can differentiate the two diagnoses. A negative estrogen/progestogen challenge test typically indicates an outflow tract obstruction. A positive test indicates an abnormality within the hypothalamic-pituitary axis or the ovaries.

TABLE 2

History and Physical Examination Findings Associated with Amenorrhea Findings

Associations

Patient history Exercise, weight loss, current or previous chronic illness, illicit drug use Menarche and menstrual history Prescription drug use Previous central nervous system chemotherapy or radiation Previous pelvic radiation Psychosocial stressors; nutritional and exercise history Sexual activity Family history Genetic defects Pubic hair pattern Infertility Menarche and menstrual history (mother and sisters) Pubertal history (e.g., growth delay) Physical examination Anthropomorphic measurements; growth chart Body mass index Dysmorphic features (e.g., webbed neck, short stature, widely spaced nipples) Rudimentary or absent uterus; pubic hair Striae, buffalo hump, significant central obesity, easy bruising, hypertension, or proximal muscle weakness Tanner staging (Table 1) Thyroid examination Transverse vaginal septum; imperforate hymen Undescended testes; external genital appearance; pubic hair Virilization; clitoral hypertrophy Review of systems Anosmia Cyclic abdominal pain; breast changes Galactorrhea; headache and visual disturbances Hirsutism or acne Signs and symptoms of hypothyroidism or hyperthyroidism Vasomotor symptoms

Hypothalamic amenorrhea Primary versus secondary amenorrhea Multiple, depending on medication Hypothalamic amenorrhea Premature ovarian failure Anorexia or bulimia nervosa Pregnancy Multiple causes of primary amenorrhea Androgen insensitivity syndrome Multiple Constitutional delay of growth and puberty Constitutional delay of growth and puberty Constitutional delay of growth and puberty Polycystic ovary syndrome Turner’s syndrome Müllerian agenesis Cushing’s disease Primary versus secondary amenorrhea Thyroid disease Outflow tract obstruction Androgen insensitivity syndrome Androgen-secreting tumor Kallmann syndrome Outflow tract obstruction or müllerian agenesis Pituitary tumor Polycystic ovary syndrome Thyroid disease Premature ovarian failure

Information from references 2 and 6 through 8.

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Amenorrhea

Evaluation of Primary Amenorrhea History and physical examination completed for a patient with primary amenorrhea

Secondary sexual characteristics present

No

Yes

Measure FSH and LH levels.

FSH and LH < 5 IU per L

Hypogonadotropic hypogonadism (Table 4)

Perform ultrasonography of uterus.

FSH > 20 IU per L and LH > 40 IU per L

Hypergonadotropic hypogonadism

Uterus absent or abnormal

Uterus present or normal

Karyotype analysis

Outflow obstruction

No Karyotype analysis

46,XX

Premature ovarian failure

45,XO

46,XY

46,XX

Androgen insensitivity syndrome

Müllerian agenesis

Evaluate for secondary amenorrhea (Figure 2).

Yes Imperforate hymen or transverse vaginal septum

Turner’s syndrome

Figure 1. Algorithm for the evaluation of primary amenorrhea. (FSH = follicle-stimulating hormone; LH = luteinizing hormone.) Information from references 1, 7, 9, and 10.

Gonadotropin levels can further help determine the source of the abnormality. Elevated follicle-stimulating hormone (FSH) or luteinizing hormone (LH) levels suggest an ovarian abnormality (hypergonadotropic hypogonadism). Normal or low FSH or LH levels suggest a pituitary or hypothalamic abnormality (hypogonadotropic hypogonadism). Magnetic resonance imaging (MRI) of the sella turcica can rule out a pituitary tumor. Normal MRI indicates a hypothalamic cause of amenorrhea.3 Differential Diagnosis of Primary Amenorrhea Causes of primary amenorrhea should be evaluated in the context of the presence or absence of secondary sexual characteristics. Table 43,6,15 includes the differential diagnosis of primary amenorrhea. PRESENCE OF SECONDARY SEXUAL CHARACTERISTICS

If a patient with amenorrhea has breast development and minimal or no pubic hair, the usual diagnosis is androgen insensitivity syndrome (i.e., patient is phenotypically female but genetically male with undescended testes). A karyotype analysis is needed to determine proper treatment. If testes April 15, 2006

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are present, they should be removed because of the high risk of malignant transformation after puberty.1 If a patient has normal secondary sexual characteristics, including pubic hair, the physician should perform MRI or ultrasonography to determine if a uterus is present. Müllerian agenesis (the congenital absence of a vagina and abnormal uterine development [usually rudimentary]) causes approximately 15 percent of primary amenorrhea.16 The etiology is thought to involve embryonic activation of the antimüllerian hormone, causing malformation of the female genital tract.7,17 Patients may have cyclic abdominal pain if there is endometrial tissue in the rudimentary uterus, mittelschmerz, or breast tenderness. An absent or truncated vagina and an abnormal adult uterus confirm müllerian agenesis. Karyotype analysis should be performed to determine if the patient is genetically female.8 If the patient has a normal uterus, outflow tract obstruction should be considered. An imperforate hymen or a transverse vaginal septum can cause congenital outflow tract obstruction, which typically is associated with cyclic abdominal pain from blood accumulation in the uterus and vagina.1 If the outflow tract is patent, the

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Amenorrhea Evaluation of Secondary Amenorrhea Patient presenting with secondary amenorrhea; negative pregnancy test

Check TSH and prolactin levels.

Both normal

Normal TSH level, abnormal prolactin level

Normal prolactin level, abnormal TSH level

Progestogen challenge test (Table 3)

Thyroid disease Prolactin b 100 ng per mL (100 mcg per L)

Withdrawal bleed

No withdrawal bleed

Normogonadotropic hypogonadism (Table 4)

Estrogen/progestogen challenge test (Table 3)

Consider other causes (Table 4).

Prolactin > 100 ng per mL

Perform MRI to evaluate for prolactinoma.

Negative MRI

Consider other causes (Table 4). Withdrawal bleed

No withdrawal bleed

Check FSH and LH levels.

Outflow obstruction

FSH and LH < 5 IU per L

FSH > 20 IU per L and LH > 40 IU per L

Hypergonadotropic hypogonadism (Table 4)

Perform MRI to evaluate for pituitary tumor.

Normal MRI: hypogonadotropic hypogonadism (Table 4)

Figure 2. Algorithm for the evaluation of secondary amenorrhea. (TSH = thyroid-stimulating hormone; MRI = magnetic resonance imaging; FSH = follicle-stimulating hormone; LH = luteinizing hormone.) Information from references 1 through 3 and 6.

physician should continue an evaluation similar to that for secondary amenorrhea (Figure 21-3,6).1 ABSENCE OF SECONDARY SEXUAL CHARACTERISTICS

Diagnosis of patients with amenorrhea and no secondary sexual characteristics is based on laboratory test results and karyotype analysis. The most common cause of hypogonadotropic hypogonadism (low FSH and LH levels) in primary amenorrhea is constitutional delay of growth and puberty.16,17 A detailed family history also may help detect this etiology, because it often is familial. Hypogonadotropic hypogonadism associated with con1378 American Family Physician

stitutional delay of growth and puberty is indistinguishable from that associated with hypothalamic or pituitary failure.10 Watchful waiting is appropriate for constitutional delay of growth and puberty. Kallmann syndrome, which is associated with anosmia, also can cause hypogonadotropic hypogonadism.18 Hypergonadotropic hypogonadism (elevated FSH and LH levels) in patients with primary amenorrhea is caused by gonadal dysgenesis or premature ovarian failure. Turner’s syndrome (45,XO karyotype) is the most common form of female gonadal dysgenesis. Characteristic physical findings include webbing of the neck, widely

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Amenorrhea TABLE 4

Causes of Amenorrhea Hyperprolactinemia Prolactin b100 ng per mL (100 mcg per L) Altered metabolism Liver failure Renal failure Ectopic production Bronchogenic (e.g., carcinoma) Gonadoblastoma Hypopharynx Ovarian dermoid cyst Renal cell carcinoma Teratoma Breastfeeding Breast stimulation Hypothyroidism Medications Oral contraceptive pills Antipsychotics Antidepressants Antihypertensives Histamine H2 receptor blockers Opiates, cocaine Prolactin > 100 ng per mL Empty sella syndrome Pituitary adenoma

Hypergonadotropic hypogonadism Gonadal dysgenesis Turner’s syndrome* Other* Postmenopausal ovarian failure Premature ovarian failure Autoimmune Chemotherapy Galactosemia Genetic 17-hydroxylase deficiency syndrome Idiopathic Mumps Pelvic radiation Hypogonadotropic hypogonadism Anorexia or bulimia nervosa Central nervous system tumor Constitutional delay of growth and puberty* Chronic illness Chronic liver disease Chronic renal insufficiency Diabetes Immunodeficiency Inflammatory bowel disease Thyroid disease Severe depression or psychosocial stressors Cranial radiation

Hypogonadotropic hypogonadism (continued) Excessive exercise Excessive weight loss or malnutrition Hypothalamic or pituitary destruction Kallmann syndrome* Sheehan’s syndrome Normogonadotropic Congenital Androgen insensitivity syndrome* Müllerian agenesis* Hyperandrogenic anovulation Acromegaly Androgen-secreting tumor (ovarian or adrenal) Cushing’s disease Exogenous androgens Nonclassic congenital adrenal hyperplasia Polycystic ovary syndrome Thyroid disease Outflow tract obstruction Asherman’s syndrome Cervical stenosis Imperforate hymen* Transverse vaginal septum* Other Pregnancy Thyroid disease

*—Causes of primary amenorrhea only. Information from references 3, 6, and 15.

with no other identified secondary cause. The primary etiology of PCOS is unknown, but resistance to insulin is thought to be a fundamental component.21 The diagnosis of PCOS is primarily clinical, although laboratory studies may be needed to rule out other causes of hyperandrogenism (Table 56,21). Significantly elevated testosterone or dehydroepiandrosterone sulfate levels indicate a possible androgen-secreting tumor (ovarian or adrenal). Levels of 17-hydroxyprogesterone can help diagnose adult-onset congenital adrenal hyperplasia. Cushing’s disease is rare; therefore, patients should only be screened when characteristic signs and symptoms (e.g., striae, buffalo hump, significant central obesity, easy bruising, hypertension, proximal muscle weakness) are present.21,22 Patients with PCOS have excess unopposed circulating estrogen, increasing their risk of endometrial cancer threefold.21 The insulin resistance associated with PCOS increases a patient’s risk of diabetes mellitus two- to 1380 American Family Physician

fivefold; therefore, testing for glucose intolerance should be considered.21-24 The primary treatment for PCOS is weight loss through diet and exercise. Modest weight loss can lower androgen levels, improve hirsutism, normalize menses, and decrease insulin resistance. It may take months to see these results, however.21 Use of oral contraceptive pills or cyclic progestational agents can help maintain a normal endometrium. The optimal cyclic progestin regimen to prevent endometrial cancer is unknown, but a monthly 10- to 14-day regimen is recommended.21 Insulin sensitizing agents such as metformin (Glucophage) can reduce insulin resistance and improve ovulatory function.21,25,26 HYPERGONADOTROPIC HYPOGONADISM

Ovarian failure can cause menopause or can occur prematurely. On average, menopause occurs at 50 years of age and is caused by ovarian follicle depletion. Premature

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Amenorrhea Table 1. Major Causes of Amenorrhea Outflow tract

Pituitary

Hypothalamic

Other endocrine gland disorders

Congenital

Autoimmune disease

Eating disorder

Adrenal disease

Complete androgen resistance

Cocaine

Adult-onset adrenal hyperplasia

Imperforate hymen

Cushing syndrome

Functional (overall energy deficit)

Müllerian agenesis

Empty sella syndrome

Chronic disease

Transverse vaginal septum

Hyperprolactinemia

Gonadotropin deficiency (e.g., Kallmann syndrome)

Acquired Asherman syndrome (intrauterine synechiae) Cervical stenosis Primary ovarian insufficiency Congenital Gonadal dysgenesis (other than Turner syndrome) Turner syndrome or variant Acquired Autoimmune destruction Chemotherapy or radiation

Infiltrative disease (e.g., sarcoidosis)

Infection (e.g., meningitis, tuberculosis, syphilis)

Medications

Malabsorption

Antidepressants

Rapid weight loss (any cause)

Antihistamines Antihypertensives

Stress

Antipsychotics Opiates Other pituitary or central nervous system tumor

Androgen-secreting tumor Constitutional delay of puberty Cushing syndrome Ovarian tumors (androgen producing) Polycystic ovary syndrome (multifactorial) Thyroid disease

Traumatic brain injury

Physiologic

Tumor

Breastfeeding Contraception Exogenous androgens

Prolactinoma

Menopause

Sheehan syndrome

Pregnancy

Information from references 1, 2, and 4 through 11.

HISTORY

Patients should be asked about eating and exercise patterns, changes in weight, previous menses (if any), medication use, chronic illness, presence of galactorrhea, and symptoms of androgen excess, abnormal thyroid function, or vasomotor instability. Taking a sexual history can help corroborate the results of, but not replace, the pregnancy test. Family history should include age at menarche and presence of chronic disease. Although it is normal for menses to be irregular in the first few years after menarche, the menstrual interval is not usually longer than 45 days.7,12 PHYSICAL EXAMINATION

The physician should measure the patient’s height, weight, and body mass index, and perform thyroid palpation and Tanner staging. Breast development is an excellent marker for ovarian estrogen production.1 Acne, virilization, or hirsutism may suggest hyperandrogenemia. Genital examination may reveal virilization, evidence of an outflow tract obstruction, or a missing or malformed organ. Thin vaginal mucosa is suggestive of low estrogen.7 Dysmorphic features such as a webbed neck or low hairline may suggest Turner syndrome.13 LABORATORY EVALUATION

The initial workup includes a pregnancy test and serum luteinizing hormone, follicle-stimulating hormone, prolactin, and thyroid-stimulating hormone levels. If history or examination suggests a hyperandrogenic state, serum free and total testosterone and dehydroepiandrosterone sulfate concentrations are useful.14 If the patient 782  American Family Physician

is short in stature, a karyotype analysis should be performed to exclude Turner syndrome.1,15 If the presence of endogenous estradiol secretion is not evident from the physical examination (e.g., breast development), serum estradiol may be measured.7 A complete blood count and comprehensive metabolic panel may be useful if history or examination is suggestive of chronic disease.7 FURTHER TESTING

Pelvic ultrasonography can help confirm the presence or absence of a uterus, and can identify structural abnormalities of reproductive tract organs. If a pituitary tumor is suspected, magnetic resonance imaging (MRI) may be indicated.8 Hormonal challenge (e.g., medroxyprogesterone acetate [Provera], 10 mg orally per day for seven to 10 days) with anticipation of a withdrawal bleed to confirm functional anatomy and adequate estrogenization, has traditionally been central to the evaluation.2 Some experts defer this testing because its correlation with estrogen status is relatively unreliable.1,6,13,16,17 Differential Diagnosis and Treatment ANATOMIC ABNORMALITIES

Müllerian agenesis, a condition characterized by a congenital malformation of the genital tract, may present with normal breast development without menarche, and may be associated with urinary tract defects and fused vertebrae.18 Other congenital abnormalities that may cause amenorrhea include imperforate hymen and transverse vaginal septum. In these conditions, products of menstruation accumulate behind the defect and can lead to cyclic or acute pelvic pain. Physical examination,

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Amenorrhea Table 2. Findings in the Evaluation of Amenorrhea Findings

Associations

History Chemotherapy or radiation

Impairment of specific organ (e.g., brain, pituitary, ovary)

Family history of early or delayed menarche

Constitutional delay of puberty

Galactorrhea

Pituitary tumor

Hirsutism, acne

Hyperandrogenism, PCOS, ovarian or adrenal tumor, CAH, Cushing syndrome

Illicit or prescription drug use

Multiple; consider effect on prolactin

Menarche and menstrual history

Primary versus secondary amenorrhea; new disease

Sexual activity

Pregnancy

Significant headaches or vision changes

Central nervous system tumor, empty sella syndrome

Temperature intolerance, palpitations, diarrhea, constipation, tremor, depression, skin changes

Thyroid disease

Vasomotor symptoms

Primary ovarian insufficiency, natural menopause

Weight loss, excessive exercise, poor nutrition, psychosocial stress, diets

Functional hypothalamic amenorrhea

Physical examination Abnormal thyroid examination

Thyroid disorder

Anthropomorphic measurements; growth charts

Multiple; Turner syndrome, constitutional delay of puberty

Body mass index

High: PCOS Low: Functional hypothalamic amenorrhea

Dysmorphic features (webbed neck, short stature, low hairline)

Turner syndrome

Male pattern baldness, increased facial hair, acne

Hyperandrogenism, PCOS, ovarian or adrenal tumor, CAH, Cushing syndrome

Pelvic examination Absence or abnormalities of cervix or uterus

Rare congenital causes

Clitoromegaly

Androgen-secreting tumor, CAH

Presence of transverse vaginal septum or imperforate hymen

Outflow tract obstruction

Reddened or thin vaginal mucosa

Decreased endogenous estrogen

Striae, buffalo hump, central obesity, hypertension

Cushing syndrome

Tanner staging abnormal

Turner syndrome, constitutional delay of puberty, rare causes

Laboratory testing (refer to local reference values) Complete blood count and metabolic panel abnormalities

Chronic disease

Estradiol

Low: Poor endogenous estrogen production (suggestive of poor ovarian function)

Follicle-stimulating hormone and luteinizing hormone

High: Primary ovarian insufficiency, Turner syndrome Low: Functional hypothalamic amenorrhea Normal: PCOS, Asherman syndrome, multiple others

Free and total testosterone; dehydroepiandrosterone sulfate

High: Hyperandrogenism, PCOS, ovarian or adrenal tumor, CAH, Cushing syndrome

Karyotype

Abnormal: Turner syndrome, rare chromosomal disorders

Pregnancy test

Positive: Pregnancy, ectopic pregnancy

Prolactin

High: Pituitary adenoma, medications, hypothyroidism, other neoplasm

Thyroid-stimulating hormone

High: Hypothyroidism Low: Hyperthyroidism

Diagnostic imaging Magnetic resonance imaging of head or sella

Tumor (e.g., microadenoma)

Pelvic ultrasonography

Morphology of pelvic organs

CAH = congenital adrenal hyperplasia; PCOS = polycystic ovary syndrome. Adapted with permission from Master-Hunter T, Heiman DL. Amenorrhea: evaluation and treatment. Am Fam Physician. 2006;73(8):1376, with additional information from references 1, 2, 6, and 7.

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Amenorrhea Diagnosis of Primary Amenorrhea Perform history and physical examination (Table 2)

Pregnancy test; serum LH, FSH, TSH, and prolactin levels; pelvic ultrasonography or other laboratory testing if clinically indicated

Pregancy test positive – pregnant (exclude ectopic pregnancy if indicated) Abnormal TSH level – order thyroid function tests and treat thyroid disease Abnormal prolactin level – magnetic resonance imaging of the pituitary to exclude adenoma; consider medications

Uterus present?

No Yes

Karyotype; free and total testosterone levels

Low FSH and LH levels

Normal FSH and LH levels

Elevated FSH and LH levels

Functional amenorrhea (if energy deficit), constitutional delay of puberty; rarely, primary gonadotropin-releasing hormone deficiency

Consider outflow tract obstruction; also consider all other causes of amenorrhea with normal gonadotropin levels (Figure 2)

Primary ovarian insufficiency

Order karyotype to evaluate for Turner syndrome or presence of Y chromatin

46,XX

46,XY

Müllerian agenesis, expect female-range serum testosterone level

Androgen insensitivity syndrome, expect malerange serum testosterone level

Figure 1. A diagnostic approach to primary amenorrhea. (FSH = follicle-stimulating hormone; LH = luteinizing hormone; TSH = thyroid-stimulating hormone.) Information from references 1, 2, 5 through 8, 10, and 11.

as well as ultrasonography or MRI, is key to diagnosis, and surgical correction is usually warranted.18 Rare causes of amenorrhea include complete androgen insensitivity syndrome, which is characterized by normal breast development, sparse or absent pubic and axillary hair, and a blind vaginal pouch; and 5-alpha reductase deficiency, which is characterized by partially virilized genitalia.1 In these conditions, serum testosterone levels will be in the same range as those found in males of the same age.19 The karyotype will be 46,XY, and testicular tissue should be removed to avoid malignant transformation.20 A structural cause of secondary amenorrhea is Asherman syndrome: intrauterine synechiae caused by uterine instrumentation during gynecologic or obstetric procedures, which can be evaluated and treated with hysteroscopy.2,21 PRIMARY OVARIAN INSUFFICIENCY

Primary ovarian insufficiency, a condition characterized by follicle depletion or dysfunction leading to a continuum of impaired ovarian function, is suggested by a concentration of follicle-stimulating hormone in the menopausal range (per reference laboratory), confirmed on two occasions separated by one month, and 784  American Family Physician

diagnosed in patients younger than 40 years with amenorrhea or oligomenorrhea.6 Other terms, including premature ovarian failure, are used synonymously with primary ovarian insufficiency.6,9 Up to 1% of women may experience primary ovarian insufficiency. This condition differs from menopause, in which the average age is 50 years, because of age and less long-term predictability in ovarian function.6,22,23 More than 90% of cases unrelated to a syndrome are idiopathic, but they can be attributed to radiation, chemotherapeutic agents, infection, tumor, empty sella syndrome, or an autoimmune or infiltrative process.6 Patients with primary ovarian insufficiency should be counseled about possible infertility, because up to 10% of such patients may achieve temporary and unpredictable remission.24 Hormone therapy (e.g., 100 mcg of daily transdermal estradiol or 0.625 mg of daily conjugated equine estrogen [Premarin] on days 1 through 26 of the menstrual cycle, and 10 mg of cyclic medroxyprogesterone acetate for 12 days [e.g., days 14 through 26] of the menstrual cycle) 6 until the average age of natural menopause is usually recommended to decrease the likelihood of osteoporosis, ischemic heart disease, and vasomotor symptoms.9 Combined oral contraceptives (OCs) deliver higher concentrations of estrogen and

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Amenorrhea

Diagnosis of Secondary Amenorrhea Perform history and physical examination (Table 2) Review medications including contraceptives and illicit drugs

Pregnancy test positive – pregnant (exclude ectopic pregnancy if indicated) Abnormal TSH level – order thyroid function tests and treat thyroid disease

Pregnancy test; serum LH, FSH, TSH, and prolactin levels; pelvic ultrasonography or other laboratory testing if clinically indicated

Elevated FSH and LH levels

Repeat in one month; consider serum estradiol

Primary ovarian insufficiency, natural menopause; order karyotype, especially if patient is of short stature, to rule out Turner syndrome or variant

Abnormal prolactin level – MRI of the pituitary to exclude adenoma; consider medications

Normal or low FSH and LH levels

Evidence of disordered eating, excessive exercise, or poor nutritional status

Most likely functional amenorrhea, but consider chronic illness

Evidence of high intracranial pressure (e.g., headache, vomiting, vision changes)

Consider MRI of head to evaluate for neoplasm

Evidence of hyperandrogenism

Order serum testosterone, DHEA-S, 17-hydroxyprogesterone testing

Elevated 17hydroxyprogesterone level

Consider late-onset congenital adrenal hyperplasia

Meets criteria for polycystic ovary syndrome

Screen for metabolic syndrome; treat accordingly

History of obstetric or gynecologic procedures; consider induction of withdrawal bleed or hysteroscopy to evaluate for Asherman syndrome

Rapid onset of symptoms or very high serum androgen levels; consider adrenal and ovarian imaging to evaluate for tumor

Figure 2. A diagnostic approach to secondary amenorrhea. (DHEA-S = dehydroepiandrosterone sulfate; FSH = follicle-stimulating hormone; LH = luteinizing hormone; MRI = magnetic resonance imaging; TSH = thyroid-stimulating hormone.) Information from references 1, 2, 4, 6 through 8, 10, and 11.

progesterone than necessary for hormone therapy, may confer thromboembolic risk, and may theoretically be ineffective at suppressingfollicle-stimulating hormone for contraceptive purposes in this population; thus, a barrier method or intrauterine device is appropriate in sexually active patients.6,13,25,26 For optimal bone health, patients with primary ovarian insufficiency should be advised to perform weightbearing exercises and supplement calcium (e.g., 1,200 mg daily) and vitamin D3 (e.g., 800 IU daily) intake.6,27 There is evidence of genetic predisposition to primary ovarian insufficiency, and patients without evidence of a syndrome should be tested for FMR1 gene premutation (confers risk of fragile X syndrome in their offspring) and thyroid and adrenal autoantibodies.6,28-30 Turner syndrome, a condition characterized by a chromosomal pattern of 45,X or a variant, can present June 1, 2013

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with a classic phenotype including a webbed neck, a low hairline, cardiac defects, and lymphedema.13,15 Some patients who have Turner syndrome have only short stature and variable defects in ovarian function (even with possible fertility).6,13,15 Thus, all patients with short stature and amenorrhea should have a karyotype analysis.15 Because patients require screening for a number of systemic problems, including coarctation of the aorta, other cardiac lesions, renal abnormalities, hearing problems, and hypothyroidism, and because they may require human growth hormone treatment and hormone replacement therapy, physicians inexperienced with Turner syndrome should consult an endocrinologist.13,15 HYPOTHALAMIC AND PITUITARY CAUSES

The ovaries require physiologic stimulation by pituitary gonadotropins for appropriate follicular development

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