Diagnosis of canine hyperadrenocorticism: What is the role of the sex hormone profile? (Proceedings)

August 1, 2011

J. Catharine Scott-Moncrieff, MA, Vet MB, MS, MRCVS, DACVIM, DECVIM, DSAM

Article

Approximately 80 to 85% of cases of hyperadrenocorticism in dogs are due to pituitary dependent hyperadrenocorticism (PDH), with the remainder due to an adrenocortical tumor (AT). Cortisol is the most common secretory product of the adrenal gland in hyperadrenocorticism.

Signalment

The median age for hyperadrencocorticism in dogs is 11 years. There is a slight increased predisposition for females (55-65%). Larger breeds may be affected more frequently with AT than smaller breeds.

Clinical signs of hyperadrenocorticism

Clinical signs include polydipsia, polyuria, polyphagia, abdominal enlargement, hepatomegaly, cutaneous changes (alopecia, cutaneous atrophy, calcinosis cutis, hyperpigmentation), muscle weakness, decreased exercise tolerance, excessive panting, hypertension, truncal obesity, lethargy, weight gain, and immunosuppression, Hypertension has been documented in up to 80% of dogs with HAC. Neurologic abnormalities attributed to the presence of a space occupying pituitary mass include change in behavior, inappetance, obtundation, aggressiveness, anisocoria, apparent blindness and seizures.

Laboratory changes in hyperadrenocorticism

Common laboratory abnormalities include leukocytosis, monocytosis, eosinopenia, lymphopenia and mild polycythemia. Increased alkaline phosphatase (ALP) is found in 95% of dogs with hyperadrenocorticism. Serum alanine aminotransferase (ALT) concentrations are more mildly increased. Other biochemical changes include hypercholesterolemia, hyperglycemia, hypophosphatemia, hypernatremia, and hypokalemia. Urinalysis may reveal low urine specific gravity, glucosuria, proteinuria or evidence of urinary tract infection. Urinary tract infection is identified in up to 50% of dogs with hyperadrenocorticism, although as few as 5% have clinical signs. Dogs with HAC also have increased risk for calcium containing urolithiasis.

Diagnosis of hyperadrenocorticism

Diagnosis of Cushing's syndrome is made by consideration of historical findings, physical examination, review of a laboratory minimum data base (CBC, serum biochemical profile, urinalysis) and performance of specific endocrine function tests. The standard tests for Cushing's syndrome include the ACTH stimulation test, low dose dexamethasone suppression (LDDS) test, and urine cortisol:creatinine ratio. Measurement of a baseline cortisol is of little value for diagnosis.

Which test should be performed first?

If clinical signs of hyperadrenocorticism are present and there is no history of exogenous corticosteroid administration, the LDDS is the most appropriate initial test. If this test is abnormal or borderline the ACTH stimulation test may be used to confirm or support the diagnosis and obtain a baseline for monitoring response to treatment. If hyperadrenocorticism is not confirmed by the LDDS test, an ACTH stimulation test should be performed if clinical suspicion for the disease is high. Testing should be repeated in 1-3 months if testing is negative but no other cause of the clinical signs is identified. In dogs with obvious clinical signs of hyperadrenocorticism and persistent normal cortisol testing, measurement of a sex hormone profile should be considered (see below). In animals with concurrent disease or any history of exogenous steroids, the ACTH stimulation test is the test of choice for initial testing. In dogs in which the clinical suspicion for hyperadrenocorticism is low, but hyperadrencorticism needs to be ruled out (e.g. dogs with persistent increase in alkaline phosphatase), the cortisol:creatinine ratio is an excellent screening test.

Sex hormone profiles in dogs with hyperadrenocorticism

More recently it has been recognized that increased circulating concentrations of steroid adrenal hormones other than cortisol (e.g. progesterone, 17- hydroxyprogesterone) may be associated with clinical signs that are indistinguishable from those due to glucocorticoids. This is hypothesized to be due to the marked intrinsic glucocorticoid activity of progestagens. Dogs with both PDH and AT have increases of other steroid adrenal hormones both before and after stimulation with ACTH. Hormones that are commonly increased include dehydroepiandrosterone, androstenedione, progesterone, and 17-hydroxyprogesterone. The specific profile varies from dog to dog but in most dogs with hyperadrenocorticism, at least one steroid hormone other than cortisol is increased, and often 2-3 are increased. Concentration of 17-hydroxyprogesterone in dogs with hyperadrenocorticism has been evaluated more extensively than other sex hormones and studies suggest that 55-85% of dogs with hyperadrenocorticism have an increase in 17-hydroxyprogesterone after stimulation with ACTH. Dogs with non-adrenal illness also have increases in 17-hydroxyprogesterone. Of 35 dogs with neoplasia that had no clinical signs of hyperadrenocorticism, 11 had high post ACTH 17-hydroxyprogesterone concentrations, whereas only 3 dogs had high cortisol concentrations. This suggests that the specificity of 17-hydroxyprogesterone for diagnosis of hyperadrenocorticism is less than that of serum cortisol.

Atypical hyperadrenocorticism

This term is used to describe cases of hyperadrenocorticism (both PDH and ADH) in which clinical signs and response to treatment are consistent with a diagnosis of hyperadrenocorticism, but the standard screening tests (ACTH stimulation test, low dose dexamethasone suppression test) are normal. In dogs with PDH, cortisol secretion is usually normal while in sex hormone secreting adrenal tumors, cortisol secretion is typically suppressed below the reference range. A sex hormone profile panel before and after ACTH stimulation should be considered in dogs that have clinical signs and clinical laboratory evidence of hyperadrenocorticism, no evidence of other cause for their clinical signs, but normal or borderline cortisol testing. Sex hormone measurement should also be considered in dogs with clinical signs of hyperadrenocorticism and suppressed cortisol concentrations after ACTH stimulation if treatment with exogenous steroids or mitotane can be ruled out. The protocol is identical to that for a standard ACTH stimulation test, but the profile requires a larger volume of serum. Marked increases in 2 or 3 adrenal steroid hormone concentrations (1.5 to 2.0 greater than the high end of the reference range) are supportive of a diagnosis of hyperadrenocorticism in patients with appropriate clinical signs of hyperadrenocorticism but normal or borderline cortisol testing. This clinical opinion needs to be confirmed in by further retrospective and prospective studies. Sex hormone profiles are not recommended for routine diagnosis of hyperadrenocorticism. Concentrations of sex hormones vary depending on sexual status; therefore reference ranges must be established based on sex and neuter status.

Differentiation of pdh from adrenal tumors

Endocrine function tests such as the high and low dose dexamethasone suppression tests, endogenous ACTH concentration and diagnostic imaging are used to differentiate PDH from AT. Suppression of the basal cortisol by more than 50% 4 or 8 hours after administration of either a low or high dose of dexamethasone is diagnostic for PDH. Lack of suppression however, is not diagnostic for ADH and additional testing is required. If greater than 50% suppression is seen at 4 or 8 hours on a LDDS, a HDDS test is unnecessary. Reference ranges for endogenous ACTH vary. In our laboratory, ACTH concentrations >15 pg/ml are consistent with a diagnosis of PDH while ACTH concentrations <10 pg/ml are suggestive of ADH; however some dogs with PDH have low values probably due to episodic ACTH secretion. The endogenous ACTH concentration should never be relied on alone to confirm a diagnosis of adrenal tumor.

Diagnostic imaging

Approximately 57% of adrenal tumors are identified on abdominal radiographs as a soft tissue mass or a mineralized opacity, compared to 72% with ultrasonography. Other radiographic findings may include hepatomegaly, osteopenia, dystrophic mineralization and distension of the urinary bladder. Thoracic radiographs may reveal evidence of metastasis, pulmonary thromboembolism or mineralization. In dogs with PDH, ultrasound of the adrenal glands typically reveals bilaterally symmetrical enlargement of the adrenal glands with preservation of normal adrenal architecture. The glands may not be identical in size but the difference in thickness is usually less than 5mm. The size of the adrenal glands may be within the normal range in some dogs with PDH. In dogs with a functional adrenal tumor there is unilateral adrenal gland enlargement with abnormal adrenal gland architecture. Evidence of tumor thrombus within the vena cava is detected on ultrasound in 11% of dogs with adrenocortical tumors and evidence of distant metastasis to the liver, kidneys, and other abdominal organs may be present. Bilateral adrenal tumors and macronodular hyperplasia of the adrenal gland in dogs with PDH may complicate the interpretation of ultrasound findings. Computed tomography is also a useful tool for evaluating the adrenal glands, especially in dogs with adrenal tumors. MRI or CT of the brain is helpful in determining pituitary tumor size in dogs with PDH. Approximately 70% of dogs with PDH have a detectable pituitary tumor on CT or MRI.