The Troublesome Cushing’s Syndrome
March 31, 2023 / General Health / By Hemopet https://hemopet.org/the-troublesome-cushings-syndrome/?utm_source=Klaviyo&utm_medium=campaign&_kx=qjTvDeFUAmu9T1-bVDHL1OrzQOTI-Sa8jw_Kf-MGhbY%3D.Ypvfhc
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.
“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.
Does My Dog Have Cushings Disease?
Veterinarian Jeff Kahler explains the symptoms of Cushing’s disease and how it is diagnosed and treated. The example of a 10-year-old Scottie with hair loss on his flanks, increased drinking and eating, and apparent weight gain illustrates a possible case of Cushing’s disease, which involves hormonal abnormality. Owners concerned about the disease or anything unusual should see a veterinarian for an examination. The Modesto Bee (Calif.)
Mac is a 10-year-old Scottish terrier who has lived with Joe and Paula for almost all of his life. He has always been a healthy dog. Joe and Paula give Mac a monthly tablet for prevention of heartworm disease and intestinal parasites as well as a monthly topical flea preventative. He is fed a good diet and is not allowed to eat from their table. Recently, Mac has displayed some changes in his body and his habits and Joe and Paula are concerned.
Mac has begun to lose hair mostly on his sides and he seems to be getting a bit portly. He has been stout as described by Joe and Paula, all his life but lately he looks like he’s getting fat. He has become a much more aggressive eater and his thirst has become increased as well. Through their research, Joe and Paula have concluded that Mac might have Cushing’s disease and wanted some advice on how to proceed. Their need for veterinary intervention is obvious and acknowledged by Joe and Paula, but they would like to be educated on the diagnosis of Cushing’s disease as well as its treatment. They would also like to know if there might be another possible cause for the changes in Mac’s stature and behavior.
I must commend Joe and Paula on their active role in trying to determine what might be Mac’s problem. When caretakers are familiar with their companions and the changes that are apparent, it can make our jobs as veterinarians and investigators much easier. Joe and Paula are of course correct in surmising Mac’s need to see his veterinarian, and they are also correct in their conclusion that he may have Cushing’s disease.
Cushing’s disease is something we have discussed here before but some of the information bears repeating. This disease is one of the more common in the group called endocrine disorders. These diseases involve hormone systems in the body. In the case of Cushing’s disease, the specific area of concern involves the adrenal gland or glands and sometimes the pituitary gland. The “technical” name of the disease is hyperadrenocortisism. This is because it involves increase in the size and production of the area in one or both adrenal glands responsible for producing cortisone. With this increase in produced cortisone, the symptoms of Cushing’s disease occur. These include increased appetite and thirst, increased panting, thinning and loss of hair over time, usually equally on both sides of the body, development of a pot-bellied appearance, and thinning of the skin. Any or all of these symptoms can occur with this disease. Mac’s symptoms as described by Joe and Paula certainly do fit.
There are two types of Cushing’s disease. One type involves the development of a tumor in the pituitary gland in the brain that produces an excess of a hormone called adrenocorticotropic hormone (ACTH), which stimulates part of each of the adrenal glands to produce too much cortisone. The other form of the disease involves the development of a tumor in one of the adrenal glands that directly produces excess cortisone and causes the disease. The pituitary form of the disease is far more common.
To diagnose Cushing’s disease, we use blood samples testing for the presence of cortisone in the blood before and after stimulation of the adrenal glands. If the testing is positive, treatment for the disease can be initiated and is usually effective in eliminating the symptoms. Not all dogs that are positive for Cushing’s disease need to be treated right away. It depends on the severity of the symptoms and which type is involved. Of the two forms of the disease, the pituitary form is more amenable to treatment with medication. An important point to understand about this form of the disease is that it is not considered curable. It can be effectively treated. The adrenal tumor form of the disease is curable in some cases by removal of the tumor, although some of these tumors are not amenable to surgery.
As far as the possibility of another disease causing Mac’s symptoms, diabetes and low thyroid condition are two that come to mind. I strongly suspect, as do Joe and Paula, that Mac has Cushing’s disease.