At a Glance

Ectopic ACTH syndrome (EAS) is caused by nonpituitary tumors that secrete either adrenocorticotropic hormone (ACTH) and/or corticotropin-releasing hormone (CRH) and cause bilateral adrenal hyperplasia. Clinical presentation resembles Cushing’s syndrome (CS): amenorrhea, hirsutism, hypertension, impotence, muscular wasting, skin atrophy, neuropsychiatric dysfunction, osteoporosis, truncal–central obesity, weight gain–water retention, moon face, weakness, fatigue, backache, headache, increased thirst, increased urination, diabetes mellitus (DM), and osteoporosis.

The male to female ratio is 1:1; men are more likely to have EAS as cause of CS. It is the cause of CS in most cancer patients.

Most of the cases are associated with:

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Small cell lung carcinoma

Bronchial carcinoid tumors

Thymic carcinoid/thymoma

Pancreatic islet cell tumors


Medullary carcinoma

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

Plasma ACTH levels are generally useful in distinguishing EAS and associated CS, particularly to separate ACTH dependent from ACTH independent causes. ACTH is a polypeptide hormone that exists principally as a chain, 39 amino acids long, with a molecular mass of approximately 4,500 daltons. It is produced by the anterior pituitary gland, and its biological function is to stimulate cortisol secretion by the adrenal cortex. ACTH secretion is, in turn, controlled by the hypothalamic hormone corticotropin releasing factor (CRF) and by negative feedback from cortisol.

In EAS, plasma ACTH levels are normal to very high (>500 pg/mL), but most patients have levels greater than 200 pg/mL. In ACTH independent tumors (Adrenal), plasma ACTH levels are very low to undetectable. Conversely, in ACTH dependent tumors (ACTH secreting pituitary macroadenomas and neuroendocrine), plasma ACTH levels are normal to high. Cortisol levels are frequently measured at the same time as ACTH.

Laboratory tests for the detection of Cushing’s syndrome are detailed within the chapter on Adrenal Adenomas.

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?

Plasma levels of ACTH exhibit a significant diurnal variation. ACTH is normally highest in the early morning (6-8am) and lowest in the evening (6-11pm). Because ACTH is released in bursts, its levels in the blood can vary from minute to minute. As ACTH is very unstable in blood, proper handling of specimen is important. At least 2-3 samples at the same hour on consecutive days or 3 samples 30-60 minutes apart on the same day are useful.

Most commercial radioimmunoassays (RIAs) are insensitive and nonspecific, measuring intact ACTH, precursors and fragments. Highly sensitive immunoradiometric assay (IRMA) assays measure intact ACTH only. RIAs are recommended for investigating ectopic ACTH-producing tumors, because some of the tumors secrete ACTH precursors and fragments. IRMA assays are more sensitive than RIAs and are useful for investigating disorders of hypothalamic-pituitary adrenal system.

Patients taking glucocorticoids may have suppressed levels of ACTH with an apparent high level of cortisol.

Pregnancy, menstrual cycle, and stress increase secretion.

What Lab Results Are Absolutely Confirmatory?

Inferior petrosal sinus sampling (IPSS) is the preferred test to differentiate Cushing’s disease from EAS. IPSS is based on the premise that a gradient of ACTH levels will exist as one samples venous blood further from the ACTH source. Hence, if the source of ACTH is a pituitary neoplasm, its early venous drainage, namely the inferior petrosal sinus, will have greater ACTH levels than the periphery.

Considering the periodic nature of ACTH secretion, CRH-induced stimulation of a neoplastic pituitary ACTH source can be employed to augment the sensitivity of this test. The sensitivity and specificity of this procedure is 96-100% in various series. The positive predictive value of this test is high, since there are virtually no false positives and false negative are uncommon. To some extent, it can even lateralize the site of the pituitary tumor to guide microsurgery.

IPSS/peripheral blood ACTH ratio greater than 3 is consistent with pituitary source of ACTH.

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

The metyrapone stimulation test has been recommended in the past. The test is rarely used now, however, because it does not discriminate well between Cushing’s disease and EAS, the compound is difficult to obtain, access to the necessary assays is limited, and the possible need for inpatient admission is inconvenient.

The optimal strategy for detecting these tumors has not been defined. The available modalities (computerized tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and octreotide scintigraphy) are complementary.

CT and MRI scans can identify and localize anatomically some tumors. In 1 prospective study the sensitivity of CT was higher (53%) than that of MRI (37%), although confidence intervals overlapped. It is cost-effective to obtain images of the chest first, since most ACTH-secreting tumors are located there.

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?

Measurements of plasma ACTH and serum cortisol should be made in the morning, if possible, when concentrations are usually at their highest value.