Approach Considerations
In most cases, clinical variables alone are not adequate to define the pathophysiologic mechanism disrupting the menstrual cycle. The clinician must be concerned with an array of potential diseases and disorders involving many organ systems. However, the history and physical findings help in selecting tests.
Thyroid-stimulating hormone (TSH), b-HCG, prolactin, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) measurements are always the first line of testing. If hirsutism is predominant upon examination, include androgen testing: measure testosterone, dehydroepiandrosterone sulfate (DHEAS), androstenedione, and 17-OH progesterone to determine the organ of cause (eg, ovary vs adrenal gland).
If the history or physical findings suggest a chronic disease process, indicated tests may include of the erythrocyte sedimentation rate (ESR), liver function tests, blood urea nitrogen (BUN) determination, creatinine determination, and urinalysis.
If the history and physical findings suggest a delay in puberty, assessing FSH and LH levels and determining bone age are important in differentiating pubertal delays as a cause.
Testing in secondary amenorrhea
Pregnancy is the most common cause of secondary amenorrhea. A pregnancy test (measurement of serum or urinary human chorionic gonadotropin) is recommended as a first step in evaluation of a secondary amenorrhea.
After pregnancy testing, all women who present with 3 months of secondary amenorrhea should have a diagnostic evaluation initiated at that visit. As stated by Speroff et al, "Few problems in gynecologic endocrinology are as challenging or taxing to the clinician as amenorrhea. The clinician must be concerned with an array of potential diseases and disorders involving, in many instances, unfamiliar organ systems, some carrying morbid and even lethal consequences for the patient." [52]
A complete blood cell count, urinalysis, and serum chemistries should be evaluated to help rule out systemic disease. Serum prolactin, FSH, estradiol, and thyrotropin levels should also be measured routinely in the initial evaluation of amenorrhea once pregnancy has been excluded. In the future, determination of anti-müllerian hormone levels may become the preferred initial test for diagnosing PCOS. [53]
Pelvic ultrasonography may identify congenital abnormalities of the uterus, cervix, and vagina, or absence of these organs. Magnetic resonance imaging can detect hypothalamic/pituitary lesions. Hysterosalpingography and hysteroscopy are indicated in cases of possible Asherman syndrome.
Hormonal Studies
Hormonal studies may include assays of prolactin, FSH, LH, estradiol, thyroid hormones, or androgens.
Prolactin
Prolactin levels in excess of 200 ng/mL are not observed except in the case of prolactin-secreting pituitary adenoma (prolactinoma) or anti depressants such as Risperidone. [54] In general, the serum prolactin level correlates with the size of the tumor. For more details, see Hyperprolactinemia.
Psychotropic drugs, hypothyroidism, stress, and meals can also raise prolactin levels. Repeat prolactin levels in a fasting state without recent nipple stimulation or sexual intercourse to verify a persistent elevation. Persistent elevations require further evaluation if the cause is not readily apparent.
FSH, LH, and estradiol
An FSH level of approximately 40 mIU/mL is indicative of ovarian insufficiency. However, this is assay-dependent and some patients have a lower menopausal level of FSH; check the reference range for the laboratory where the test is performed. If a repeat value in 1 month confirms this finding and amenorrhea still persists, then the diagnosis of premature ovarian failure/primary ovarian insufficiency is confirmed.
LH levels are elevated in cases of 17,20 lyase deficiency, 17-hydroxylase deficiency, and premature ovarian failure.
Serum estradiol levels undergo wide fluctuations during the normal menstrual cycle. During the early follicular phase of the menstrual cycle, levels may be lower than 50 pg/mL. During the preovulatory estradiol surge, levels in the range of 400 pg/mL are not uncommon. In healthy menopausal women, estradiol levels are routinely lower than 20 pg/mL.
Thyroid hormones
Disorders of the thyroid gland may result in menstrual irregularities; however, for it to present as primary amenorrhea is uncommon. Measure thyrotropin and free thyroxine (T4) if symptoms of hypothyroidism or hyperthyroidism are present.
Androgens
Checking levels of testosterone and dehydroepiandrosterone sulfate helps identify hyperandrogenic conditions resulting in amenorrhea. For more details, see Polycystic Ovarian Syndrome.
Imaging Studies to Consider
Ultrasonography
Pelvic ultrasonography may identify congenital abnormalities of the uterus, cervix, and vagina, or absence of these organs. However, a report of absence of the uterus on ultrasonography does not always mean that the patient does not have a uterus. In primary amenorrhea in association with estrogen deficient states, the uterine fund us may be underdeveloped and may not be readily visible at the time of ultrasonography to less experienced examiners. With proper estrogen replacement, it may reach the normal size.
Pelvic ultrasonography may be helpful in determining ovarian morphology as well. However, in most cases of amenorrhea without androgen access, the information obtained with ovarian ultrasonography does not change clinical management.
Magnetic resonance imaging
MRI of the pituitary and hypothalamus is often indicated in the evaluation of amenorrhea. Request imaging of the hypothalamic/pituitary area specifically, rather than a study of the entire brain. This achieves higher resolution. MRI is indicated in the following circumstances:
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Associated headaches or visual-field cuts
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Profound estrogen deficiency with otherwise unexplained amenorrhea
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Hyperprolactinemia
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Elevated gonadotropins in the setting of markedly elevated serum estradiol level
Questionnaires
Several validated tools are available to measure dietary intake, mood disorder, and eating disorders. These tools include the following:
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Minnesota Nutrition Data Systems evaluation - to assess dietary intake
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Beck Depression Inventory - to assess mood
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Modifiable Activity Questionnaire - to assess the patient's level of physical activity
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Paffenbarger Physical Activity Questionnaire
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Multidimensional Eating Disorder Inventory - for anorexia and bulimia [55]
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Bulimia Test-Revised (BULIT-R) [56]
Progesterone Withdrawal Test
Prior to the development of readily available assays to measure serum levels of estradiol, the progesterone challenge test was used as a bioassay with which to demonstrate estrogen effect at the level of the endometrium. Progesterone has been shown to predictably induce a withdrawal bleed if the circulating serum estradiol level is at least 50 pg/mL. However, the progesterone withdrawal test can provide inappropriately reassuring information that may delay the etiology of ovarian insufficiency.
The progesterone withdrawal test is no substitute for evaluating ovarian health. Demonstrating the presence of normally functioning ovaries requires the concurrent measurement of serum estradiol and FSH.
Algorithms for Evaluation of Amenorrhea
Amenorrhea with delayed puberty
Obtain studies of thyroid function (thyroid-stimulating hormone [TSH] and thyroxine [T4]) and bone age. If TSH levels are elevated and T4 levels are low, the cause is hypothyroidism. If the bone age is delayed, the cause is constitutional delay.
If the bone age is normal, obtain LH, FSH, and prolactin levels. If LH and FSH levels are elevated, obtain a karyotype.
If the karyotype is 45,X, the cause is gonadal dysgenesis (ie, Turner syndrome). Amenorrhea can also occur when 1 of the 2 X chromosomes is abnormal, such as a ring chromosome, or if a partial loss of the p or q arm of the X chromosome occurs. If the karyotype is 46,XX, the primary cause is ovarian failure from pure gonadal dysgenesis.
Perform an autoimmune workup. Consider an etiology of autoimmune oophoritis, effects of radiation therapy or chemotherapy, 17-alpha-hydroxylase deficiency, or resistant ovary syndrome. Check for neurosensory loss.
If the karyotype is 46,XY, the cause is Swyer syndrome. The patient has streak gonads and neither testosterone nor anti-müllerian hormone is produced; thus, the patient has an external female phenotype but no internal female reproductive organs and does not enter puberty. The gonads have an increased incidence of malignant transformation and should be removed.
If LH and FSH levels are low or within the reference range and bone age is normal, obtain a head MRI. If head MRI findings are abnormal, the cause is pituitary tumor, pituitary destruction, or hypothalamic disease
If prolactin levels are elevated, obtain a head MRI. If head MRI findings are abnormal, the cause is pituitary tumor or a brain lesion disrupting the pituitary stalk. If the MRI finding is normal, the cause may be marijuana use or psychiatric medicine, specifically dopamine antagonist medications, which lead to a decrease in prolactin inhibiting factor and a subsequent increase in serum prolactin levels.
If head MRI findings are normal with normal history and physical examination findings, the etiology may be drug use, an eating disorder, athleticism, or psychosocial stress.
If head MRI findings are normal but clinical evaluation and screening study findings are abnormal, chronic disease can be excluded.
Amenorrhea with normal puberty with uterus present
Obtain a pregnancy test. If the pregnancy test result is positive, refer the patient to the appropriate specialist. If the pregnancy test result is negative, obtain TSH, prolactin, FSH, and LH levels.
If the TSH level is elevated, the diagnosis is hypothyroidism. If the prolactin level is elevated, the diagnosis is hyperprolactinemia. Causes of hyperprolactinemia include prolactinoma, CNS tumors, and medications. MRI is indicated.
If the FSH level is low, obtain a MRI of the brain. If MRI findings are abnormal, consider hypothalamic disease, pituitary disease, or pituitary tumor. If MRI findings are normal, proceed with clinical evaluation to exclude chronic disease, anorexia nervosa, marijuana or cocaine use, and social or psychological stresses.
If FSH is elevated, premature ovarian failure is the diagnosis. Obtain a karyotype. If the karyotype is abnormal, mosaic Turner syndrome may be present. If the karyotype is normal (46,XX), the cause is premature ovarian failure. An association with fragile X syndrome may be observed. [57] If fragile X syndrome is present, family members should be offered genetic testing.
Consider premature ovarian failure due to the following:
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Autoimmune oophoritis
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Exposure to radiation or chemotherapy
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Resistant ovary syndrome
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Karyotype abnormality (Turner syndrome)
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Multiple endocrine neoplasm (MEN) syndrome
If TSH, prolactin, and FSH levels are within reference range, perform a progestin challenge test. If withdrawal bleeding occurs, consider anovulation secondary to PCO syndrome. If no withdrawal bleed occurs, proceed with estradiol (E2) priming, followed by a progestin challenge.
If the challenge does not induce menses, consider Asherman syndrome, outlet obstruction, or endometrial thinning secondary to elevated androgens (PCO syndrome) or hypothalamic amenorrhea with decreased estrogen production.
If the challenge induces menses, a hypothalamic dysfunction with low circulating E2 is present. An acquired hypothalamic cause of amenorrhea after puberty has been achieved is a diagnosis of exclusion. The FSH and LH levels may be low or may be below the reference range. The causes include eating disorders, caloric restriction, exercise, stress, and medications.
If hirsutism and/or acne are present, check testosterone, dehydroepiandrosterone sulfate (DHEAS), and 17-hydroxy (17-OH) progesterone level. If the testosterone and DHEAS levels are within the reference range or are moderately elevated, perform a progesterone challenge. If withdrawal bleeding occurs, the diagnosis is PCOS. If the 17-OH progesterone level is elevated, the diagnosis is adult-onset adrenal hyperplasia.
If the testosterone level or DHEAS is 2 or more times higher than the reference range, consider PCOS, hyperthecosis, or an androgen-secreting tumor of the ovary or adrenal gland
Amenorrhea with genital tract abnormalities
Obtain a pelvic sonography. If the uterus is absent and the vagina foreshortened, obtain a karyotype. If the karyotype is 46,XY, obtain testosterone levels.
If testosterone levels are within reference range or are high (male range), the cause is androgen insensitivity or 5-alpha-reductase deficiency. Surgical gonad removal is recommended in patients with androgen insensitivity. If testosterone levels are within reference range or are low (female range), the cause is testicular regression or gonadal enzyme deficiency. Surgical gonad removal is recommended.
If the karyotype is 46,XX, the cause is Müllerian agenesis (ie, Rokitansky-Kuster-Hauser syndrome).
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Hypothalamus, pituitary and ovaries form a functional endocrine axis, known as HPO axis with hormonal regulations and feedback loops.
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Primary amenorrhea flowchart.
