At a Glance

Amenorrhea is the absence of menstrual blood flow. Primary amenorrhea should be considered in any patient with secondary sex characteristics who has not experienced periodic menstruation by 15 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 13 years of age should also be worked up for primary amenorrhea.

Loss of pituitary luteinizing hormone (LH) and follicle stimulating hormone (FSH) can cause amenorrhea characterized by hypogonadotropic hypogonadism. There are three general etiologies for loss of pituitary LH and FSH: hypopituitary states, genetic disease with failure to produce gonadotropins, and pituitary tumors. Pituitary dysfunction should be suspected in anyone with a pituitary lesion, traumatic brain injury, granulomatous brain disease, unexplained gonadal dysfunction, brain surgery, congenital craniofacial abnormalities, and previous pregnancy-associated hemorrhage. Signs and symptoms include growth retardation, infertility, and nonspecific findings, such as cold intolerance, fatigue, hypotension, and visual disturbances.

Hypopituitary states can arise from autoimmune or granulomatous pituitary destruction, traumatic brain injury, Sheehan’s postpartum necrosis of the anterior pituitary, or empty sella syndrome. Pituitary development may be compromised by mutations in SF-1, DAX-1, FGFR1, GPR54. More specifically, gonadotrope development may be impaired by mutations in Hesx1 and Prop-1, producing isolated gonadotropin deficiency.

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Prolactin secreting pituitary adenomas can induce hyperprolactinemia, which suppresses LH and FSH, leading to amenorrhea. Some space-filling lesions compress the pituitary stalk and prevent negative feedback from dopamine, leading to hyperprolactinemia. Alternatively, a tumor may constrict the pituitary, preventing normal LH and FSH release. In very rare cases of gonadotropin-secreting pituitary tumors, amenorrhea occurs because of ovarian hyperstimulation syndrome (OHSS).

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

The work-up for primary amenorrhea begins with a careful history and physical exam to look for anatomical defects, development of secondary sexual characteristics, and/or a personal or family history of delayed puberty, mental retardation, short stature, cancer, autoimmune disease, infertility, and/or amenorrhea.

A personal history of galactorrhea, traumatic brain injury, anosomia, chronic disease, significant weight loss, and/or emotional or physical trauma may also contribute to the overall picture.

Physical exam of patients with suspected pituitary dysfunction may reveal a phenotypic woman or normal or short stature and normal/prepubescent internal and external genitalia with minimal development of secondary sex characteristics. The presence of virilization may suggest Polycystic Ovary Syndrome (PCOS) or an androgen secreting adenoma (see chapter on Polycystic Ovary Syndrome (PCOS)).

The laboratory work-up for amenorrhea should always begin with measurement of human chorionic gonadotropin (hCG) to rule out pregnancy. If not pregnant, patients should undergo imaging studies looking for a uterus and gonads. Patients with primary amenorrhea from pituitary dysfunction have a normal uterus. Patients with a detectable uterus should be evaluated for hypothyroidism and prolactinemia. A high thyroid stimulating hormone (TSH) result suggests the 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.

Patients with normal TSH and prolactin should be evaluated for gonadotropic function by measuring LH and FSH.

In patients with primary amenorrhea due to pituitary dysfunction, some or all pituitary hormones may be abnormal. Generally, FSH and LH are low (hypogonadotropic), thereby causing hypogonadism and amenorrhea. Other pituitary hormones may also be low or undetectable, including growth hormone, TSH, and ACTH. Prolactin may be low in cases of pituitary destruction or elevated if a space-filling lesion compresses the pituitary stalk and blocks dopaminergic inhibition of prolactin.

In very rare gonadotropin-secreting tumors, circulating LH and/or FSH concentrations are normal to elevated and estradiol may be significantly elevated, causing ovarian hyperstimulation syndrome (OHSS). Any findings suggestive of pituitary dysfunction should prompt an MRI to look for a pituitary lesion.

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-positive and false-negative results for urine pregnancy tests can occur and may result in a misdiagnosis. False-negative results occur is urine that 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 may be caused by 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 test.

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. LH and FSH should be measured early in the follicular phase of the cycle, if possible.

Concentrations of LH and FSH change dramatically during puberty. Results should be evaluated in the context of age and tanner stage specific reference intervals. Drugs, such as anticonvulsants, clomiphene, and naloxone, may falsely elevate LH, whereas smoking, cimetidine, clomiphene, digitalis, and levodopa elevate 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.

Estrogen can be measured by immunoassay or LC/MS/MS. Because immunoassays are imprecise at low concentrations, it is recommended that estrogen be measured by LC/MS/MS in men and children in early tanner stages. Estrogen concentrations vary throughout the menstrual cycle, even in amenorrheic women, and should be measured in the early follicular phase of the cycle, if possible. Chronic illnesses, such as anemia, hypertension, and liver and kidney diseases, affect estrogen concentrations.

Several Estrogen containing drugs, such as birth control pills and hormone replacements, may interfere with the assays, causing falsely elevated results. Glucocorticoids, antibiotics (ampicillin and tetracycline) and phenothiazines may also cause false elevations in estrogen measurements. Clomiphene and oral contraceptives may reduce estrogen concentrations.

Many pituitary hormones, most notably growth hormone (GH) and adrenocorticotropic hormone (ACTH), vary throughout the day and are best assessed using dynamic testing to either stimulate or suppress hormonal response.

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

What Lab Results Are Absolutely Confirmatory?

Diagnosing a patient with primary amenorrhea due to pituitary dysfunction relies on measuring pituitary hormones and imaging studies. If congenital pituitary malformation is suspected, sequencing of genes involved in pituitary development may be useful. These include SF-1, DAX-1, FGFR1, GPR54, HEXS1, and PROP1.

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

Although diagnosis of hypogonadotropic hypogonadism is fairly simple, elucidation of the cause of disease in patients is challenging. Various causes of disease are identified by assessing other pituitary hormones. Hyperprolactinemia indicates a prolactinoma or other pituitary adenoma. The alpha-subunit of pituitary glycoprotein may be secreted in excess in certain pituitary adenomas. In these tumors, measurement of free alpha subunit may assist in monitoring therapy. Deficiency in all other pituitary hormones suggests global pituitary destruction or malformation. These should all be confirmed by MRI to look for a pituitary lesion.

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?

Free alpha subunit is elevated in up to 30% of pituitary adenomas. Elevations of free alpha-subunit may also occur within 24 hours of ovulation, in end stage renal disease, in hypothyroidism due to elevated TSH, and in women undergoing assisted reproduction or IVF. Baseline measurements are important for detecting nonstimulated secretion.