The Troublesome Cushing’s Syndrome

Cushing’s syndrome in dogs is complex, difficult to diagnose, and tricky to treat. Before we get into all of that, we need to review the mechanisms that may cause it. 

The Physiological Mechanisms

The pituitary gland is located in the brain. The adrenal glands lie near the kidneys. The pituitary gland tells the adrenal glands what to do. 

How does the pituitary gland do this? Well, it releases a chemical called adrenocorticotropic hormone (ACTH). ACTH then stimulates the adrenal glands to release another hormone called cortisol, which is commonly known as the “flight or fight” stress hormone. 

When the Pituitary-Adrenal Connection Goes Awry 

Pituitary-Dependent (PDH) – If the pituitary gland develops a tumor that is most often benign, it will overproduce and release more ACTH. This overproduction of ACTH causes the adrenal glands to overproduce and release more cortisol. Once the pituitary gland realizes that there is an excess of cortisol circulating in the body, it will then underproduce ACTH. This form of Cushing’s disease accounts for 80-85% of the cases in dogs. 

Adrenal-Dependent (ADH) – More rarely, an adrenal gland can develop a tumor that may be cancerous. This, too, can cause the release of excessive amounts of cortisol and suppresses the release of ACTH.

Drug-Related – Oral or injectable prescription glucocorticoid steroids (a class of corticosteroids) can cause another form of Cushing’s syndrome, termed “iatrogenic Cushing’s syndrome” . They suppress the adrenal glands by adding extra cortisol to help fight skin or inflammatory conditions. When given in excessive amounts or over a long period of time, they can cause the iatrogenic Cushing’s syndrome. 

Atypical Cushing’s – In dogs with atypical Cushing’s syndrome due to a problem with the pituitary gland or ADH , we can observe 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. 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. This form of Cushing’s syndrome can be more difficult to diagnose and measurement of 17-Hyroxy (17-OHP) progesterone before and after giving ACTH is often required (see more below). 

Wait! I thought it was called Cushing’s disease?

Cushing’s disease is a form of Cushing’s syndrome and specifically refers to those with PDH tumors. Cushing’s syndrome is the general state of excessive levels of cortisol in the blood. In any event, the medical term for high levels of cortisol circulating in the blood is hyperadrenocorticism

Signs of Cushing’s Syndrome

The most telltale sign of Cushing’s syndrome is a pot-bellied appearance. Additional signs are panting, dark spots, bladder infections, thin hair and/or skin, fat pads, excessive drinking and eating, and excessive amounts of calcium deposits in the skin (calcinosis cutis/skin mineralization). 

This constellation of Cushing’s signs are called Cushingoid. 

Diagnosing Cushing’s Syndrome

We can analogize the current diagnostics for Cushing’s syndrome with shopping for a couch. Have you ever gone couch shopping and you like certain features from different couches, but nothing’s perfect? For instance, you like the cushions on one model, but detest the armrests? Or, you like the armrests on another, but it has an upholstered skirt that you don’t like? Let’s not even get into the length, height, depth, fabric, patterns or colors! 

Anyway, Cushing’s diagnostics are similar to the variety of couches: there are a lot of options, nothing’s perfect and all of it costs a bundle. But, unlike a couch, you cannot customize the diagnostics. 

This is not to negate Cushing’s testing. Indeed, you need to have positive confirmation of Cushing’s syndrome and the location of the problem (pituitary or adrenal) before medicating. 

Urinary Cortisol to Creatinine Ratio (UCCR) – This test is used as a pre-screening tool to rule out Cushing’s syndrome by measuring the first morning urine at home. However, stress can cause this number to fluctuate greatly, which is why you need to collect your pet’s urine at home (one teaspoon is enough in a clean plastic dish) when he first gets up and has not exercised, and then take it into your veterinarian to run this test. Even if it is negative, and the veterinarian still highly suspects Cushing’s syndrome, further testing is necessary. 

Ultrasound – An abdominal ultrasound helps by pointing us in the right direction. With PDH, both adrenal glands are abnormally enlarged. Whereas ADH, only one adrenal gland is enlarged and the other is small or atrophied. 

ACTH Stimulation Test – If any dog has been given steroids in the past, this is the test experts want to use to diagnose iatrogenic Cushing’s syndrome. However, ACTH stimulation has a sensitivity of only 60%-85% (percentage of true positives), and a specificity 60%-93% (percentage of true false negatives). Additionally, it does not indicate the location causing the Cushing’s syndrome. 

If this is the chosen test, it is wise to concurrently analyze 17-Hydroxyprogesterone (17-OHP) concentrations in response to ACTH administration. Dogs with atypical Cushing’s disease have an exaggerated 17-OHP response to ACTH. Other dogs with Cushing’s syndrome 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. 

By the way, diagnosis of atypical Cushing’s disease may also include measurement of: androstenedione, estradiol, progesterone and aldosterone.

Low Dose Dexamethasone Suppression Test (LDDS) – This is considered the gold standard for testing for Cushing’s syndrome at this time unless iatrogenic Cushing’s disease is suspected. It can distinguish between PDH and ADH. The sensitivity is good at 95%, but the specificity is poor and only 50%-75%.

Endogenous ACTH (eACTH) – Endogenous ACTH should not be used to diagnose Cushing’s disease, but will help with location and secondary confirmation. The sample has to be prepared properly at the veterinarian’s office to ensure stability, then frozen, and sent frozen to a veterinary reference laboratory. Due to all of these handling factors, it is really not an ideal test unless the blood collection is at a research institution. 

Zomedica has developed an in-house, point-of-care diagnostic machine that measures eACTH using bulk acoustic wave technology. (This is not an endorsement; we simply want you to know your options.) An LDDS test or ACTH will still need to be conducted. 

Options to Treat Cushing’s Syndrome

If Cushing’s syndrome is confirmed, veterinarians have only a handful of treatment options. In fact, many veterinarians choose not to medicate for the disease based on bloodwork, other currently prescribed medications, additional conditions, and potential side effects of the Cushing’s disease medications.

Surgery – If it is ADH, surgical removal of the tumor is possible but can be very difficult, especially if it has spread. However, due to the complexity of removal, most cases are treated with medication. 

Trilostane (Vetoryl) – At this time, this is the only prescription medication approved by the Food and Drug Administration (FDA) to treat both PDH and ADH. Trilostane works by stopping the production of cortisol in the adrenal glands. However, it should not be given to a dog that takes certain medications for heart disease, is pregnant, and/or has kidney or liver disease. Additionally, the ACTH stimulation test is preferred to monitor trilostane therapy. Return of clinical signs of Cushing’s disease can occur in some dogs while still on trilostane.

Common side effects are poor or reduced appetite, vomiting, lack of energy, diarrhea, and weakness. More serious (but considered rare) side effects include bloody diarrhea, collapse, severe sodium/potassium imbalance, and destruction of the adrenal gland that may result in death.

Selegiline (Anipryl) – Selegiline is an monoamine oxidase inhibitor (MAOI), and is also FDA approved, but only for uncomplicated PDH. It should not be given to dogs that take other MAOIs, meperidine, tramadol, tricyclic antidepressants, selective serotonin reuptake inhibitors, or alpha-2 agonists.

Side effects include vomiting, diarrhea, restlessness, disorientation/confusion, aggression, repetitive movements, tiredness, drooling, itchiness, licking, trembling, and lack of appetite. Rare, but serious side effects, include deafness and panting more than usual. 

Mitotane (Lysodren) – Mitotane is a human chemotherapy drug that veterinarians can prescribe “off-label” to treat Cushing’s disease. It works by destroying the layers of the adrenal gland that produce cortisol. It should be used cautiously in pets with diabetes mellitus or kidney or liver disease. The following medications should be used with caution when given with mitotane: central nervous system (CNS) depressant drugs, fentanyl, insulin, midazolam, phenobarbital, selegiline, spironolactone, or warfarin.

Common side effects are decreased appetite, vomiting and diarrhea. Other side effects include lethargy, incoordination, weakness, or yellowing of the skin, gums, or whites of the eyes.

Regular monitoring of cortisol levels is required.

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 given in combination with phytoestrogens (isoflavones, lignans, and genistein) is 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.

References

“Adrenal Function Testing.” The College of Veterinary Medicine at Michigan State University, Michigan State University, https://cvm.msu.edu/vdl/laboratory-sections/endocrinology/adrenal-function-testing

Behrend, E N et al. “Diagnosis of spontaneous canine hyperadrenocorticism: 2012 ACVIM consensus statement (small animal).” Journal of veterinary internal medicine vol. 27,6 (2013): 1292-304. doi:10.1111/jvim.12192, https://onlinelibrary.wiley.com/doi/full/10.1111/jvim.12192

Dodds, W. Jean. “Diagnosing Atypical Cushing’s Disease/Syndrome in Dogs.” Dr. Jean Dodds’ Pet Health Resource, Tumblr, 17 Apr. 2016, https://drjeandoddspethealthresource.tumblr.com/post/142960916541/atypical-cushings-dog#.Y6CxAXbMLIW

“Treating Cushing’s Disease in Dogs.” U.S. Food and Drug Administration, FDA, 8 July 2021, https://www.fda.gov/consumers/consumer-updates/treating-cushings-disease-dogs

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