At a Glance

Approximately 1% of women of reproductive age experience secondary amenorrhea, a cessation of menses. In women who have previously experienced regular menstrual cycles, secondary amenorrhea is the absence of menstruation for 6 months. In women who have previously experienced irregular menstrual cycles, secondary amenorrhea is the absence of menstruation for 12 months. Secondary amenorrhea is a symptom caused by many pathological states, including pregnancy, polycystic ovary syndrome (PCOS), Cushing’s syndrome, hypopituitarism, hypothyroidism, and hyperprolactinemia. Some patients do not demonstrate an obvious etiology for their amenorrhea; however, the diagnostic evaluation should lead to the correct diagnosis if the problem is approached in a logical, stepwise manner.

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

In diagnosing the underlying cause of amenorrhea, the first step should always be to rule out pregnancy with a negative urine or serum hCG result. Next, levels of thyroid stimulating hormone (TSH), prolactin, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) should be ordered. If all of these basal hormone levels are within acceptable limits, Cushing’s syndrome may be considered. An elevated basal measurement of blood cortisol may indicate Cushing’s syndrome.

The two most common tests for diagnosis of Cushing’s syndrome are the dexamethasone suppression test and a 24-hour urinary free cortisol. Both tests are equally sensitive.

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In the dexamethasone suppression test, the patient is given a low dose of dexamethasone, a glucocorticoid that simulates cortisol action and provides negative feedback to the pituitary gland. Therefore, after dosing with dexamethasone, blood levels of cortisol should suppress. If there is no suppression, then the results are suggestive of Cushing’s syndrome.

The 24-hour urinary free cortisol involves collecting the patient’s urine several times over a 24-hour period. Coritsol levels greater than the normal limits in the 24-hour urine sample may indicate Cushing’s syndrome.

More recently, late-night saliva measurements have been suggested. Cortisol production is usually suppressed at night but not in Cushing’s patients. An elevated cortisol level in a late-night sample of either saliva or plasma/serum is suggestive of Cushing’s syndrome. Although saliva is easy to collect, it is not a routine matrix in most clinical laboratories. It requires specialized handling, and assays are typically not as sensitive as in plasma/serum-based methods.

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?

Cortisol levels can be increased by oral contraceptives, hydrocortisone, and spironolactone. Levels can be decreased by some steroid hormones.

For the 24-hour urinary cortisol and/or late-night measurements, the patient may require a hospital stay of 48 hours to avoid falsely elevated cortisol levels that are due to stress.

What Tests Should I Request to Determine the Cause?

High-dose Dexamethasone Suppression Test

This test is performed the same as the diagnostic dexamethasone suppression test, but it uses higher doses of dexamethasone. The higher dosage usually suppresses cortisol levels in patients with pituitary adenomas, but not in those with ectopic ACTH-producing tumors.

Corticotropin-Releasing Hormone (CRH) Stimulation Test

Because CRH acts directly on the pituitary, administration of CRH by injection usually results in a rise in blood levels of adrenocorticotropic hormone (ACTH) and cortisol in patients with pituitary adenomas. Patients with ectopic ACTH-producing tumors will not demonstrate this response.

Distinguishing Mild Cushing's Syndrome from Pseudo-Cushings Syndrome.

Pseudo-Cushing’s syndrome is often found in people who have depression, anxiety disorders, alcoholism, or poorly controlled diabetes. These patients have high cortisol levels, but do not develop the long-term effects of Cushing’s syndrome, so they do not require treatment targeted at the endocrine glands.

A combination of Dexamethasone/CRH test is required to distinguish mild Cushing’s from pseudo-Cushing’s. In this test, a low dose of dexamethasone is preadministered before the CRH injection. In patients with pseudo-Cushing’s syndrome, the dexamethasone prevents the CRH from causing an increase in cortisol. When blood cortisol is elevated after CRH administration, Cushing’s syndrome is likely.