Diagnosing Atypical Cushing’s Disease/Syndrome in Dogs

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Diagnosing Atypical Cushing's Disease or Syndrome in Dogs



Canine hyperadrenocorticism (HAC; Cushing’s disease or syndrome) is a relatively common endocrinopathy in middle aged dogs, especially females. However, to confirm a suspected clinical diagnosis, adrenal function testing should be performed only in dogs with clinical and/or biochemical evidence of HAC, and not in dogs with non-adrenal related disease, as results are often misleading. There are 2 forms of HAC; the more common pituitary-dependent hyperadrenocorticism (PDH) and the adrenal-dependent hyperadrenocorticism (ADH) usually caused by an adrenal tumor.

Clinical signs

Classical clinical signs of HAC in dogs include, excessive drinking and urinating, increased appetite, pot belly and/or unexplained weight gain, rear muscle wasting and weakness, fat pads, thin skin and poor or sparse hair coat, and frequent urinary tract, ear, feet and skin infections.


The standard, so-called dynamic tests for confirming HAC are the adrenocorticotrophic hormone (ACTH) and Low-Dose Dexamethasone Suppression (LDDS) tests. For an initial screening assessment, the Urine Cortisol:Creatinine Ratio (UCCR) test is also used. It requires a collection of urine at home before the pet has exercised at all.

But, some suspected cases of canine HAC have normal ACTH stimulation and LDDS test results. These cases may have the atypical form of Cushing’s disease, which can be diagnosed by measuring serum 17-Hydroxyprogesterone (17-OHP) concentrations in response to ACTH administration. Affected dogs have an exaggerated 17-OHP response to ACTH. Other dogs with HAC could have deranged steroid production pathways, such that certain steroid precursors may be abnormally increased and responsible for the presenting clinical signs, whereas cortisol concentrations are normal.

For dogs with atypical Cushing’s disease of PDH etiology, enlargement of the liver, liver pathology, and bilaterally enlarged adrenal glands are usually present. An increased endogenous ACTH level is seen, along with the usual clinical signs, blood work results and hair coat problems. For dogs with atypical Cushing’s disease of ADH etiology, enlargement of the liver, liver pathology, and a unilaterally enlarged adrenal gland are usually present. The other adrenal gland can be atrophied (shrunken). There is a decreased endogenous ACTH level and the usual clinical signs, blood work results and hair coat problems.

Diagnosis of atypical Cushing’s disease may also include measurement of: androstenedione, estradiol, progesterone and aldosterone.  

Test Submission Requirements

The test requires 50 μl of serum collected 1 hour post-synthetic ACTH or 2 hours post-ACTH gel administration. The test can be added on to a previously submitted post-ACTH serum sample, as it is not necessary to measure the resting (pre-ACTH ) 17- OHP


Classical and Atypical HAC Mitotane (Lysodren). Most intermediate adrenal hormones and cortisol are decreased by mitotane. A common side effect is decreased appetite. Regular monitoring of cortisol levels is required.  

Trilostane (Vetoryl). Enzyme inhibition by trilostane offers effective control of Cushing’s syndrome, but the long-term effects of it causing elevated intermediate steroids remain poorly defined. Therapy is given once or twice daily; the most common side effects are lethargy and reduced appetite. Return of clinical signs of Cushing’s disease can occur in some dogs while still on trilostane.

Melatonin.  The enzymes that are typically elevated in HAC are inhibited by melatonin. Also, in dogs with adrenal disease treated with melatonin, repeat adrenal steroid panels show that cortisol levels are consistently reduced. Melatonin treatment for cases of mild to moderate canine adrenal disease can be effective, and particularly in cases where adrenal sex steroids are increased.

Melatonin plus phytoestrogens. Melatonin has in combination with phytoestrogens (isoflavones, lignans, and genistein) are known to inhibit adrenal steroid production. Combinations of melatonin and phytoestrogens, especially the SDG flax hull or HMR Norwegian spruce lignans have proven increased efficacy in treating these conditions.

Primary adrenal tumors (ADH-HAC).  Control of the secretory activity of adrenal tumors with propranolol, leuprolide and deslorelin can be used. Surgical removal of adrenal tumors is rarely successful, and age and health considerations also impact this decision.


Elevated post-ACTH 17-OHP (and possibly other adrenal sex hormones) may be useful in confirming a diagnosis in dogs with atypical HAC. Dogs suspected of having HAC, but with normal or low cortisol concentrations after receiving ACTH or LDD, and with no history of steroid administration within at least 2 weeks, should be evaluated for a sex hormone-producing adrenal tumor with 17-OHP testing and ultrasonography of their adrenal glands.

W. Jean Dodds, DVM
Hemopet / NutriScan
11561 Salinaz Avenue
Garden Grove, CA 92843

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