At a Glance

Amenorrhea is the absence of menstrual blood flow. Primary amenorrhea should be considered in a patient with secondary sex characteristics who has not experienced periodic menstruation by 16 years of age or 5 years after breast development. Patients who have not developed secondary sex characteristics, especially the absence of breast development, and have not established periodic menstruation by age 13 should also be worked up for primary amenorrhea.

Turner Syndrome (TS) due to the complete deletion of all or part of the X chromosome results in primary amenorrhea. TS patients are phenotypic females with short stature, gonadal dysgenesis, and little or no development of secondary sex characteristics. Further, TS patients may also present with a webbed neck, edema of the hands and feet, congenital heart disease, hypothyroidism, and/or a shield shaped chest. Amenorrhea occurs in patients with TS because of absent or limited ovarian function due to inappropriate development (gonadal dysgenesis) or premature ovarian failure.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

The diagnostic work-up for primary amenorrhea should begin with measurement of human chorionic gonadotropin (hCG) to rule out pregnancy in patients with secondary sex characteristics. Although many with TS do not develop secondary sex characteristics, pregnancies do occur in 1% of patients.

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Patients without secondary sex characteristics and/or a negative pregnancy test should have a pelvic exam or ultrasonography to determine if a uterus is present. Because of the varying degrees of developmental defects in TS due to mosaicism of the second X chromosome, patients may or may not develop a uterus.

In patients with a detectable uterus, hypothyroidism and prolactinemia should be ruled out. A high thyroid stimulating hormone (TSH) result suggests the primary amenorrhea is due to primary hypothyroidism and should be followed with fT4 analysis. A reduced fT4 confirms hypothyroidism. An elevated prolactin result should prompt a physician to perform an MRI in search of a pituitary adenoma. Prolactin inhibits gonadotropin function, thus, causing amenorrhea in nursing mothers and patients with prolactinomas.

Patients with normal TSH and prolactin should be evaluated for TS by measuring luteinizing hormone (LH) and follicle stimulating hormone (FSH) to assess gonadotropic function. High concentrations of FSH and/or LH in multiple specimens are suggestive of primary ovarian failure and consistent with TS. However, karyotyping confirms the diagnosis of TS in patients with primary amenorrhea, ovarian failure, and/or an absent uterus.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

False-negative results can occur with urine pregnancy tests and may result in a misdiagnosis. False-negative results can occur if urine is too dilute. To ensure an appropriate urine specimen, perform urine pregnancy testing on first morning voids and check the protein concentration by measuring the urine specific gravity and/or urine creatinine. False-negative results can also occur due to the variant effect. This phenomenon occurs when high concentrations of hCG isoforms in urine (hCG beta core fragment) are not recognized by both antibodies in the assay. Instead, they interfere with one antibody and cause a false-negative result. One can test for the variant effect by diluting the urine sample and repeating the testing.

Prolactin is mildly elevated by stress, herpes simplex virus (HSV) infections in the chest wall, and numerous drugs, including dopamine agonists, proton pump inhibitors, antipsychotics (risperidone, phenothiazines, haloperidol), antihypertensives (methyldopa, reserpine, verapamil), estrogens, and illicit drugs (amphetamines, cannabinoids, opiates, etc). Any of these may lead to dysregulation of gonadotropins, amenorrhea, and infertility.

LH and FSH are episodically released from the pituitary, and concentrations may vary, depending on when they are measured during the day. First morning specimens are recommended. LH and FSH concentrations change throughout the menstrual cycle, even in amenorrheic patients. It is recommended to measure LH and FSH early in the follicular phase of the cycle if possible.

Concentrations of LH and FSH change dramatically during puberty. Evaluate results in the context of age and Tanner stage specific reference intervals. Drugs, such as anticonvulsants, clomiphene, and naloxone, may falsely elevated LH, whereas smoking, cimetidine, clomiphene, digitalis, and levodopa cause elevated FSH. Artificially low LH and FSH results may occur in patients taking oral contraceptives and hormone treatments. Phenothiazines reduce FSH concentrations, whereas digoxin decreases LH.

As is the case with many immunoassays, heterophilic antibodies can cause false-positive results. Therefore, caution should be taken when elevated hCG, TSH, prolactin, LH, and/or FSH results do not match the clinical picture.

What Lab Results Are Absolutely Confirmatory?

A standard 30-cell karyotyping analysis should be ordered in any female with primary amenorrhea, unexplained growth failure or delay in the onset of puberty, absent uterus, or any of the following clinical symptoms:

edema of the hands or feet

cardiac abnormalities

low hairline

webbed neck

low set ears

chronic otitis media

broad chest

flat feet

Identification of a 45,X or 45,X mosaic karyotype in an amenorrheic patient with an elevated FSH confirms the cause of primary amenorrhea.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

In rare cases, a hidden mosaicism may lead to a normal karyotype in TS patients. If the peripheral blood karyotype is normal in patients with clinical signs and symptoms of TS, karyotyping analysis should be performed by culturing skin fibroblasts.

TS patients may have portions of the Y chromosome. The presence of Y chromosome material increases a TS patient’s risk for gonadoblastoma, thus, gonadectomy is recommended for all patients with Y mosaicism. The presence of Y chromosome mosaicism should be confirmed in any TS patient with virilization and/or Y chromosome material by identifying the SRY region via fluorescence in situ hybridization (FISH) or DNA analysis.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Chemotherapy and/or radiation may affect the yield of metaphase chromosomes, reducing the ability to perform karyotyping analyses