Cushing’s Disease in Dogs
Cushing's disease is common in older dogs, but both diagnosis and treatment can be complicated.
Article by CJ Puotinen and Mary Straus, published in the Whole Dog Journal, November 2011
Also see these related articles:
- Addison's Disease: The Great Pretender
- New Treatment for Pituitary-Dependent Cushing's Disease
- Healthy Low-Fat Diets
- Calcium Oxalate Kidney and Bladder Stones
- Canine Diabetes
Cody (pictured above), a Springer Spaniel, had tumors on both adrenal glands. He survived a bilateral adrenalectomy, requiring treatment for Addison's for the rest of his life.
Sometimes life-threatening illnesses develop so slowly that no one pays much attention. An older dog who’s always thirsty drinks huge quantities of water. He’s hungrier than usual and has developed a pot belly. He pants all the time, and now his hind legs are losing muscle tone and getting weak. Many owners dismiss these as normal signs of aging, but they are classic symptoms of Cushing’s disease, which affects an estimated 100,000 dogs in the United States every year.
Also known as hyperadrenocorticism, Cushing’s is the opposite of Addison's disease (see Addison's Disease: The Great Pretender in last months WDJ). Both illnesses involve the adrenal glands, which produce cortisol – a stress hormone that helps prepare a dog for fight or flight by breaking down muscle and fat to convert into glucose. While Addison’s disease results from insufficient cortisol, Cushing’s disease results from too much – and prolonged exposure to cortisol can have negative effects on the entire body. Cushing’s disease puts dogs at increased risk for diabetes, pancreatitis, calcium oxalate bladder stones, pulmonary thromboembolism, hypertension (high blood pressure), urinary tract infections, protein-losing kidney disease, skin problems, and congestive heart failure.
Cushing’s disease affects primarily middle-aged and older dogs. The majority (about 85 percent) of Cushing’s disease cases are caused by tumors of the pituitary gland; these are usually benign (adenomas). About 15 percent of Cushings cases are caused by tumors of the adrenal gland, half of which are benign and half malignant (carcinomas).
In pituitary-dependent hyperadrenocorticism (PDH), tumors cause the pituitary gland to overproduce adrenocorticotropic hormone (ACTH), which signals the adrenal glands to release cortisol. The average age at diagnosis with PDH is 10 years, and the most commonly affected breeds are Poodles, Dachshunds, Beagles, German Shepherds, Boxers, Boston Terriers, Labrador Retrievers, and terriers, with 75 percent of patients weighing less than 44 pounds.
With adrenal-dependent Cushing's, the adrenal tumor itself secretes excessive cortisol. The average age for diagnosis with adrenal tumors is 11 years, with Poodles, German Shepherds, Dachshunds, Labrador Retrievers, and terriers predominating. About half of all cases occur in dogs weighing more than 44 pounds, and females may be more commonly affected.
Girl, a Miniature Schnauzer, has lived with Cindy Bright of Indiana, Pennsylvania, since her first owner passed away in 2006. Girl is famous for eating anything (including toads, dehydrated or living), and at 27 pounds, she was seriously overweight.
By February 2008, Girl’s symptoms included excessive thirst and urination, overeating, urinary incontinence, and occasional hyperexcitement or aggression. She was diagnosed with PDH and began taking Vetoryl (trilostane), a drug that was not approved in the U.S. until 2009 for the treatment of both pituitary- and adrenal-dependent Cushing’s, but which has been used in the U.K. since 2001. Bright imported the drug from the U.K. (something that could be accomplished with a prescription and by filling out a form to obtain permission from the FDA).
Today Girl is doing well, and her weight is a normal 19 pounds. Her occasional health setbacks tend to follow dietary indiscretions, such as her consumption of a 6-pack of English muffins that someone set outside the basement freezer and her indulgence in wild rabbit droppings, which Bright describes as Girl’s "caviar." Girl suffered a serious bout of pancreatitis in 2010. “Life is like walking the tightrope,” Bright says. “One slip and it’s difficult to get everything back on course.”
Like Girl, all dogs with Cushing’s disease require careful monitoring. Depending on the drug used to control symptoms, even minor changes in condition or behavior can signal major problems, and conscientious caregivers keep a close eye on anything that seems unusual or different.
In Springfield, Vermont, Kathy Mason’s beagle, Chance, was diagnosed with PDH at 8 years old. He was originally treated with Anipryl, which was not effective, and then switched to Lysodren (mitotane). “After about two years of good bloodwork,” says Mason, “Chance went into an Addisonian crisis. We thought we were going to lose him, but he survived and stayed Addisonian for the rest of his life. It was so much easier to treat. He passed away in January, five years post diagnosis, at the age of 14 years old.”
While most pituitary tumors are microscopic, 10 to 20 percent are larger than 10 millimeters (3/8 inch) in diameter. Called macrotumors or macroadenomas, almost all are benign, but about half are large enough to compress the brain and cause neurological symptoms such as listlessness, poor appetite, confusion, walking in circles, or seizures. Most dogs are diagnosed with Cushing’s at least six months before neurological symptoms develop. Breeds with short noses, such as Boxers and Pugs, tend to have the largest pituitary tumors.
Most dogs with pituitary tumors are treated with medication because their tumors are considered inoperable. However, a new surgical technique allows some tumors to be removed (see New Treatment for Pituitary-Dependent Cushing’s Disease, WDJ March 2011. Another option for large pituitary tumors is radiation therapy, which is expensive ($3,000 to $5,000 in the Los Angeles area) and can have adverse side effects such as skin and hair loss, hearing loss, or problems with tear production in the eyes. Although successful in 70 percent of cases, further treatment for Cushing’s is usually required, and tumors treated with radiation are likely to recur. Survival time is not increased if neurological problems are severe.
Three years ago Maggie, a 12-year-old black Labrador Retriever/hound mix in Atlanta, Georgia, developed a voracious appetite, drank incredibly large amounts of water, and began raiding the trash. Her owner, Kristin Boggs, took Maggie to their veterinarian, who suspected Cushing’s.
“Usually Cushing’s is pituitary-based,” she says, “but instead of assuming this, my vet ordered an ultrasound test. He had once before seen a case of Cushing’s that was caused by an adrenal tumor. Sure enough, Maggie had a large tumor on her adrenal gland.”
The solution was to remove the entire gland. Maggie’s surgery took place at a special internal medicine veterinary clinic, where a post-surgical nurse attended her through the night.
“Maggie came through with flying colors, despite an incision almost the full length of her belly,” says Boggs. “She’s a tough old girl. Thankfully the tumor was benign. After a few weeks of medication to balance her cortisol levels, she was back to normal. I am so thankful that our vet recognized the possibility of this less common adrenal cause of Cushing’s and that we got the ultrasound done.”
In Toledo, Ohio, Linda Boyle’s Springer Spaniel, Cody, was diagnosed with Cushing’s disease at age 11 in 2005 after developing a suddenly ravenous appetite and gaining weight. Cody’s ultrasound exam revealed tumors on both adrenal glands.
“A bilateral adrenalectomy is very risky,” says Boyle, “but it worked well for Cody. He became an Addison’s dog because his body no longer produced any cortisol at all, but he lived another two years with good quality of life before passing away from what we believe was pneumonia.”
Because Cushing’s patients tend to have high blood pressure and poor healing ability, several months of medical therapy may be needed to strengthen the patient prior to surgery. After surgery, prednisone or other corticosteroids may be required for a few months until the dog’s ability to produce cortisol recovers, and some dogs may need mineralocorticoid replacement as well. In a survey of 63 dogs who had surgery, 4 (6 percent) had inoperable tumors and were euthanized; 18 (29 percent) died during surgery or soon after because of complications; and the average post-surgical life span for the remaining 41 dogs was 46 months.
As this article goes to press, Maggie’s Cushing's symptoms have returned, caused by a new tumor on her remaining adrenal gland.
“I can't believe this has happened to us again,” says Boggs. “It's an exact repeat of what we went through three years ago. We don't know if the tumor is malignant or benign, as we don’t feel extensive surgery at her age (15 ½) is reasonable. My vet and I have decided to treat her with trilostane and see how she does. My priority now is that she is happy and comfortable.”
Cushing’s disease isn’t always easy to diagnose. Routine test results that can point toward Cushing’s include:
- High or very high alkaline phosphatase (ALP, ALKP, SAP). Although this is a “liver enzyme,” marked elevation is associated with cortisol. It does not indicate liver disease if other liver enzymes such as ALT (alanine aminotransferase) are normal.
- Increased neutrophils and decreased lymphocytes (stress leukogram).
- Elevated cholesterol and triglycerides due to abnormal fat mobilization.
- Fasting hyperglycemia due to insulin resistance.
- Liver enzymes may be mildly elevated.
- Dilute urine (low specific gravity) due to excessive drinking.
- Protein in urine (microalbuminuria or proteinuria).
- X-rays may show an enlarged liver and occasionally calcium deposits in the skin (calcinosis cutis, which feel like rocks and cause itching).
Cushing’s disease is associated with bladder, skin, and other infections due to the immunosuppressive effects of cortisol. Because of urine dilution, bladder infections may not be apparent on urinalysis, so cultures may be needed to detect infection. Approximately 20 percent of dogs with Cushing’s have an inapparent bladder infection.
Confirming the diagnosis can be challenging, especially as false positives are common in dogs with nonadrenal illness. The following tests are commonly used:
- Urine Cortisol:Creatinine Ratio (UCCR) is a screening test only. A negative result rules out Cushing’s, but anything that increases stress can cause a positive result, so further testing is required if the result is positive. The test is best done on urine samples caught at home so that the stress of the vet visit doesn’t influence results.
- Low Dose Dexamethasone Suppression (LDDS), considered the most accurate for diagnosing Cushing’s, takes eight hours in the hospital. A baseline blood cortisol level is measured, then a tiny dose of dexamethasone (corticosteroid) is injected. In a normal dog, blood cortisol levels drop after 8 hours. Blood samples are sometimes checked after four hours, as this can help classify the form of Cushing’s. About 95 percent of dogs with Cushing’s test positive, but false positives are also common, and the more severe a nonadrenal illness, the more likely a false positive result. This test is preferred if an adrenal tumor is suspected.
- ACTH Stimulation: No longer recommended for diagnosis, as its sensitivity is poor, its cost is high, and it cannot differentiate between pituitary and adrenal forms. This test is more specific than LDDS, however, meaning that strongly positive results definitely indicate Cushing’s disease, and false positives are unusual, but false negatives are common, particularly when the cause is an adrenal tumor. This test is useful for monitoring treatment, and it is the only test that can be used for dogs currently taking corticosteroids. A low-normal or blunted response indicates iatrogenic Cushing’s (see below). This may be the preferred test if symptoms are mild, for it is better to miss the diagnosis than get a false positive.
Test results must be considered in combination with symptoms. A dog with at least three of the typical signs plus a positive test is considered to have Cushing’s, but a dog with no signs but maybe high ALP and a positive test may not, in which case it’s best to take a wait-and-see approach. If signs are present but test results are negative, consider retesting in three to six months or test for atypical Cushing’s (see Atypical Cushing's below).
None of the tests are reliable for dogs with a known nonadrenal illness.
Classifying the type of Cushing’s disease as pituitary or adrenal helps determine which treatment is best. The endogenous ACTH level is felt by many to be the most accurate method of identifying the type of Cushing’s, but this test is difficult to run, as serum must remain frozen during transport to the lab. Dogs with pituitary tumors have high ACTH levels, while those with adrenal tumors will have low or no measurable ACTH.
LDDS may be used for classification when a 4-hour sample is drawn. If the 8-hour sample is > 30 nmol/L and the 4-hour sample is < 30, or both are less than half of the baseline sample, the pituitary form is likely.
The high dose dexamethasone suppression (HDDS) test is similar to LDDS, but a high dose of dexamethasone is used. This test is done only on dogs already known to have Cushing’s. Dogs with a pituitary tumor will show suppression in circulating cortisol levels 75 percent of the time, but those with adrenal tumors never show suppression.
Adrenal tumors can be seen on ultrasound 30 to 50 percent of the time. An adrenal tumor is suspected whenever one adrenal gland is observed to be enlarged while the other is not visible. If they have not spread, adrenal tumors should be removed, if possible, but surgery is difficult and usually requires a specialist.
Two normal or large adrenal glands indicate the pituitary form of Cushing’s, although enlarged adrenal glands are also often seen in cases of nonadrenal disease due to the chronic stress of the illness. An MRI or CT scan can detect pituitary tumors and determine their size. Two-thirds of dogs with tumors greater than 10 millimeters initially will develop neurological signs and may benefit from immediate radiation therapy, even before signs are seen.
A study published in 2012 found that giving insulin to dogs with Cushing's who also have elevated glucose levels can prevent the development of diabetes. The study was done on dogs diagnosed with Cushing's who had glucose levels between 5.83 and 9.35 mmol/L (105-168 mg/dL). See Low dose of insulin detemir controls glycaemia, insulinemia and prevents diabetes mellitus progression in the dog with pituitary-dependent hyperadrenocorticism.
The best treatment for Cushing’s disease depends on the severity of symptoms, type of Cushing’s, risk of adverse effects, and cost factors. Medical therapy is used to control clinical signs, but it does not cure the disease. It is not likely to prolong life but does improve the dog’s quality of life, and sometimes the owner’s as well, such as when excessive drinking leads to incontinence and accidents in the house. Not treating is also a viable option, particularly if symptoms are minimal.
If the dog suffers from a concurrent medical condition, it is important to treat and stabilize that illness if possible before treating for Cushing’s. Treatment for dogs with concurrent nonadrenal illness, such as diabetes, is complex and beyond the scope of this article.
■ Mitotane (Lysodren®), which is used for both pituitary and adrenal Cushing’s, was the only treatment available until recent years.
Mitotane is convenient and relatively inexpensive, but it has potentially severe side effects. A chemotherapy drug, it works by selectively eroding the two inner layers of the adrenal cortex that produce cortisol while tending to preserve the outer layer that makes aldosterone. If too much is eroded, the result is a cortisol deficiency.
About 30 percent of dogs treated with mitotane develop short-term reactions. When this happens, mitotane is discontinued and the dog is treated with prednisone until the adrenal glands recover. The destruction may be permanent, requiring treatment for atypical (or sometimes typical) Addison’s. Mitotane’s risk of a permanent or life-threatening Addisonian reaction is considered 2 to 5 percent.
Mitotane is given once or twice a day during the "induction" phase to induce erosion of the adrenal glands. It must be given with food or it will not be absorbed. Mitotane should not be used for dogs who don’t have a good appetite; a poor appetite indicates that something else is going on that must be diagnosed and addressed prior to beginning Cushing’s therapy.
During the induction phase, caregivers should notify their veterinarians as soon as their dog experiences any appetite reduction, decrease in water consumption, diarrhea, vomiting, lethargy, or listlessness. It is important to watch for these signs starting around the third day of treatment. These symptoms indicate that the end of the induction has been reached and it’s time for an ACTH stimulation test. Induction time is variable, usually between 7 and 14 days, but some patients require just two to three days and others can take as long as six weeks, especially if they are taking other drugs that interact with Lydsodren, such as phenobarbital or insulin. If there is no response, dosage can be increased or mitotane can be reformulated in an oil base to increase absorption, or the drug trilostane can be used instead.
When the ACTH test and clinical signs indicate that sufficient adrenal erosion has taken place, daily use (induction phase) is stopped and lifelong maintenance treatment once or twice a week is begun. The ACTH test can be repeated after about a month, then one to four times a year thereafter.
If vomiting, diarrhea, appetite loss, or listlessness occur at any time during treatment, the dog may need a prednisone “antidote” pill, which should produce improvement within 30 minutes to two hours. Your veterinarian will probably prescribe prednisone and discontinue mitotane for a couple of weeks after that, before resuming at a lower dose. If there is no improvement, something else is causing the symptoms.
About half the dogs treated with mitotane relapse at some point and require a second round of induction, and their maintenance dose may have to be increased.
Marked improvement should be seen within six to eight weeks of starting the maintenance dose, with a full reversal of clinical signs after four to six months of treatment. Usually the first improvements are more normal water consumption, urination, and appetite, and the last is hair regrowth. Muscle strength and exercise tolerance improve over the first three to four weeks.
Mitotane can be used to treat adrenal Cushing’s, but a higher dosage is needed, resulting in more adverse reactions. The average survival time in this case is 16 months.
A study published in 2011 entitled Low-Dose, Twice-Daily Trilostane Treatment for Dogs with Hyperadrenocorticism found that giving smaller doses of Trilostane twice a day worked equally well while causing fewer side effects. The duration of adrenal inhibition in most dogs from Trilostane is much less than 24 hours
Dogs were given 0.21 to 1.1 mg/kg (0.1 to 0.5 mg/lb) every 12 hours. The total daily dose was 0.2 to 1 mg/lb (compared to the recommended starting dosage of 1 to 3 mg/lb). About 40 percent of dogs did not require a dosage increase. After one year of treatment, the mean dosage required was 1.7 mg/kg (0.8 mg/lb), twice daily, or 1.1 mg/kg (0.5 mg/lb), 3 times daily.
A later study, A comparison of once and twice daily administration of trilostane to dogs with hyperadrenocorticism., found that twice-daily administration of trilostane achieved a faster and more effective control for comparable daily doses.
■ Trilostane (Vetoryl®), used to treat both pituitary and adrenal Cushing’s disease, inhibits the enzyme 3-beta-hydroxysteroid dehydrogenase, which is involved in the production of several steroids, including cortisol.
Because this drug can block aldosterone as well as cortisol in some dogs, it carries increased risk of side effects such as dehydration, weakness, and electrolyte changes (low sodium and high potassium). It is important to stop the medication if this occurs, and some dogs may need fluid support.
For reasons that are not understood, trilostane occasionally causes acute adrenal gland necrosis, which can occur within days of starting the drug or after several months. The condition is unpredictable and is not dose-dependent. It requires prompt treatment with fluid therapy, glucocorticoids, and mineralocorticoids or it can be fatal (Addisonian crisis). This complication is permanent and irreversible, and lifelong supplementation of both mineralocorticoids and glucocorticoids will be necessary (i.e., treatment for typical Addison’s).
A study published in 2012 found that larger dogs may need less trilostane for their weight in order to control Cushing's disease.
"Dogs weighing > 66 lb (30 kg) required less trilostane to control their clinical signs. The results did not achieve statistical significance, but a trend suggested that as body weight increased, the relative amount of trilostane needed to control signs decreased. The researchers also found that only 11% of dogs required more than 3 mg/kg/dose to control their disease—the manufacturer's recommended initial dose is 3 to 6 mg/kg once daily. . . . Additionally, study data suggest that the initial dosage recommendation of 3 to 6 mg/kg/day be reconsidered." (Bigger dogs may need less trilostane to control hyperadrenocorticism)
Conclusions: "Dogs weighing >30 kg [66 pounds], and possibly those weighing >15 kg [33 pounds], might require smaller amounts of trilostane per dose or per day than those weighing less, to control PDH-associated clinical signs."
See the following articles for more information:
Trilostane is given once or twice a day with food (which increased absorption). Side effects may be less common when given twice a day. Starting dosage is 1 to 3 mg per pound of body weight daily. Starting at the low end of that range is safest, even though the suggested starting dosage in the product brochure is higher.
Close monitoring in the beginning and after any dose adjustment is essential. Discontinue trilostane and contact your veterinarian immediately if signs of intolerance are seen. Common side effects include mild lethargy, vomiting, diarrhea, and appetite reduction, especially in the beginning. Most reactions are minor and are reversed by decreasing the dose or discontinuing therapy, but serious or fatal Addisonian reactions are also possible. Side effects should be followed by electrolyte and ACTH testing. Once symptoms resolve, the drug can be restarted at 50 percent dose reduction.
Most dogs show decreases in drinking, urination, and appetite within one week, but some may take two months or longer. Trilostane controls clinical signs in dogs with adrenal tumors, but will not slow tumor growth.
Trilostane may be safer than mitotane, as side effects tend to be less severe and most are reversible. The risk of a permanent or life-threatening Addisonian reaction from trilostane is considered to be 2 to 3 percent. Cost is its main disadvantage, though monitoring costs may be less than with mitotane. Baseline cortisol levels measured 4 to 6 hours after trilostane administration may provide adequate monitoring without the need for ACTH stimulation tests.
Trilostane seems to predispose dogs to increased adrenal toxicity from mitotane, so it’s best to wait at least a month in between if switching to mitotane. When changing from another drug to trilostane, wait a couple of weeks or until clinical signs recur. This drug is not recommended for dogs with liver or kidney disease.
■ Ketoconazole (Nizoral®) is used to treat both adrenal and pituitary Cushing’s. This antifungal medication suppresses adrenal hormones in about 80 percent of dogs as a side effect.
A low dose is used for a week; then, if no side effects are seen, a higher maintenance dose is used. It is not possible to induce Addison’s disease with ketoconazole, so monitoring tests aren’t needed, other than after a month or so to determine if the medication is working.
Side effects can include vomiting and diarrhea, but no “antidote pill” is needed. Just discontinue until side effects go away, then restart at a lower dose.
Ketoconazole’s disadvantages are that it must be given twice a day indefinitely and its effect may be mild or temporary. This drug may reduce clinical signs in up to 30 percent of dogs with adrenal tumors, but side effects are common.
■ L-Deprenyl (Anipryl® or selegiline) is used to treat pituitary Cushing’s only. It is also used to treat canine cognitive dysfunction.
L-Deprenyl works by inhibiting ACTH secretion via high dopamine levels in the intermediate pituitary area, where 30 percent of pituitary tumors are located, and may work only for dogs with such tumors. This drug has no serious side effects, but approximately 5 percent of patients experience minor nausea, restlessness, or reduced hearing. It cannot induce Addison’s disease, and no monitoring is required.
Because it’s difficult to determine whether the drug is working, and it may take considerable time to take effect, few veterinarians report good results. However, because some dogs improve and its safety margin is high, it may be worth trying in dogs with mild symptoms that are progressing slowly. L-Deprenyl can be combined with mitotane or trilostane for dogs with cognitive dysfunction, and it may increase the dog’s activity level and quality of life.
A very small percentage of Cushing’s cases result from medical treatments for other conditions, such as the use of prednisone or other corticosteroid medications to control allergies, arthritis, or autoimmune conditions. This is called "iatrogenic" (doctor-caused) Cushing’s. In these cases, the Cushing's is treated by gradual discontinuation of the corticosteroid drugs (if the drugs are withdrawn too quickly, an Addisonian crisis can result). Patients can take as long as three months to recover after corticosteroid drugs are stopped.
Also known as Alopecia X, pseudo-Cushing’s has been called growth-hormone-responsive alopecia, adrenal sex hormone imbalance, castration-responsive dermatosis, and congenital adrenal hyperplasia. It is identified by symmetrical alopecia (hair loss) on the trunk of the body, thighs, or neck, along with darkening of the skin where hair is lost. The coat’s color may change as well, but it doesn’t cause itching.
Pseudo-Cushing's is seen in young dogs (ages 1 to 5) with plush coats, such as Pomeranians, Poodles, Samoyeds, Alaskan Malamutes, and Siberian Huskies. Pseudo-Cushing’s is thought to be a mild form of pituitary-dependent hyperadrenocoriticism.
Dogs with this disorder may respond to castration, methyltestosterone, melatonin, growth hormone supplementation, or one of the drugs used to treat Cushing’s disease. One study showed that 90 percent of dogs treated with trilostane responded within 8 weeks.
Because the diagnosis and treatment of Cushing’s disease can be confusing, expensive, and fraught with adverse side effects, many caregivers turn to alternative or complementary therapies.
For those who prefer treatments that have been proven in double-blind, placebo-controlled clinical trials, unconventional therapies are themselves fraught with peril. Product testimonials and anecdotal reports don’t prove anything, and by turning first to an herbal preparation or glandular extract, one might deny the patient an opportunity for effective treatment. Online reviews of nutritional supplements or herbal preparations range from reports about dogs that appear to be cured to heartbreaking stories of dogs whose condition deteriorated rapidly. Success stories are often not documented by laboratory test results, leaving readers to wonder whether the dogs that improved so dramatically actually had Cushing’s.
At the same time, the cost of veterinary tests, surgery, or prescription drugs for a dog are sometimes simply prohibitive. Because drugs can only relieve symptoms and cannot cure Cushing’s disease or slow its progression, there is little harm in trying alternatives if your dog’s quality of life is not impacted.
For some, the decision to pursue nutritional and alternative treatments is philosophical. Holistic veterinarians look at Cushing’s disease and every other canine illness from a different perspective than do conventionally trained veterinarians. They are likely to try holistic or natural treatments first and turn to symptom-suppressing conventional therapies later instead of the other way around.
Phosphatidylserine (PS), a phospholipid derived from lecithin, has been demonstrated to have a natural cortisol-suppressive effect on the adrenal glands. It can also help with cognitive dysfunction. Oral PS is available both by itself and in many combination supplements.
Elizabeth Knight, of Portland, Oregon, had some success using PS to treat her Welsh Corgi, Jasper, who was diagnosed with Cushing’s at age 11 and lived for two more years. “Two substances worked very well for us. For quite a while phosphatidylserine helped him a great deal with restlessness. And a Chinese herbal formula, Si Miao San, also helped with his restlessness and thirst. His polydispia and polyuria (excessive drinking and urination), pacing, and panting were controlled fairly well. I would say they helped about 80 percent.” Knight suspects that Jasper also had canine dementia.
In their book Herbs for Pets, Greg Tilford and Mary Wulff recommend herbal therapy to support organs and systems that are subjected to additional stress because of the disease. “Dandelion root, burdock, garlic, and nettle are good choices for supporting an overtaxed liver and digestive system and to help replace potassium that is lost as a result of increased urination. Adaptogenic herbs such as Siberian ginseng or astragulus help buffer adrenal response to stress.” They also recommend avoiding licorice, borage leaf, and other herbs that stimulate adrenal activity.
Susannah Blanchard of Wilmington, North Carolina, turned to holistic treatments when her 10-year-old Shih Tzu, Bandit, was diagnosed with pituitary-based Cushing’s. “At that time,” she says, “the conventional treatment was Lysodren [mitotane], but I had a really hard time putting him on something that could induce Addison's disease and was almost restrictively expensive. So I researched and found Cushex, a blend of homeopathic and herbal ingredients from PetAlive/Native Remedies. We moved around some, and every new vet who saw Bandit was amazed that he had a Cushing’s diagnosis. I credit the Cushex for keeping his coat rather thick with none of the thinning that generally accompanies Cushing’s disease. Bandit lived another five years and passed away last June at age 15. Only in the last few months of his life did his coat and tailfeathers start to visibly thin out.”
(Editor's note: Bandit’s initial diagnosis was never confirmed by later testing; it’s possible that his original symptoms were caused by something other than Cushing’s.)
Another plant-based product is Vitex Plus (formerly called Canine Cush X) from the English company Hilton Herbs. Medical herbalist Hilary Self, the director of Hilton Herbs, created the formula nine years ago for dogs with Cushing’s caused by adrenal adenoma. “However,” she says, “a virtually identical product formulated for equine Cushing's disease, which is caused by pituitary adenoma, has proved to be equally successful. I would anticipate that it would work equally as well in dogs with pituitary adenoma.”
The formula is added to the dog’s meals. “Symptoms usually respond within three weeks,” Self says. “The supplement is by no means a cure, but it has proved to be beneficial to many dogs. It has enabled many owners to either delay having to use the conventional drugs or even reduce a drug’s dosage over a period of months if the dog is already on it. If the dog is on medication, it is vital for the dog’s veterinarian to carry out regular blood tests to measure the response.”
Glandular supplements can also support the adrenal glands. “I think highly of Standard Process glandular products,” says Anita Moore, DVM, of Anne Arundel County, Maryland. “SP Canine Adrenal Support contains ‘functional foods,’ which are ingredients that have shown to benefit various organs and tissues in the body. It helps normalize adrenal function, making it appropriate for dogs with both Cushing’s and Addison’s disease. It doesn’t cure either illness, but it may help improve symptoms, as it has done with some of my patients.”
Cushing's disease can cause loss of lean muscle and muscle atrophy. Physical therapy may be beneficial in canine steroid myopathy. Supplementation with oral L-carnitine (50 mg/kg [25 mg/lb] twice a day) and coenzyme Q10 (100 mg daily) may be beneficial in alleviating muscle weakness, according to one veterinary site.
Diets for dogs with Cushing’s disease should be high in protein, which can help to combat muscle wasting as well as being good for the skin and immune system. Fat should be moderately low, as Cushing’s predisposes dogs to hyperlipidemia (elevated cholesterol and triglycerides) and pancreatitis.
There is a lot of outdated information on the web about Cushing’s dogs needing a low-fiber, low-purine diet. It all appears to come from a single source, which references the third edition of Small Animal Clinical Nutrition (Lewis, et al, 1987). The newer fourth edition (Hand, et al, 2000), however, has no reference to purines, nor does it make any sense to restrict purines for dogs with Cushing’s.
The newer edition of Small Animal Clinical Nutrition also suggests that a diet “lower in fat (less than 12 percent dry matter) and moderate in crude fiber (8 to 17 percent DM) . . . may aid in weight loss and control of mild hyperglycemia . . . in dogs with glucocorticoid-induced carbohydrate intolerance” as well as hyperlipidemia. Some of this reasoning is questionable, but the point is that it no longer recommends a low-fiber diet.
Dogs with Cushing’s are predisposed to the development of calcium oxalate bladder stones, due to elevated calcium in their urine. Avoid giving excessive calcium, which might be a contributing factor. Feeding a low-oxalate diet with other modifications, such as avoiding vitamin C, might be helpful (see Calcium Oxalate Kidney and Bladder Stones, WDJ May 2010). Keeping your dog well hydrated and allowing frequent urination can also help prevent stone formation. Make sure fresh water is available at all times.
It is not unusual for dogs with Cushing’s disease to graduate from holistic therapies to conventional treatments or to take both at the same time. Three years ago Stacy McDaniel of Kingman, Arizona, noticed that her Husky/Malamute, Mascara, was gaining weight, drinking, and panting more than other dogs. In addition, Mascara had a voracious appetite and was greedy and protective of her food. (She lives with four other Husky/Malamutes.)
“The closest holistic vet I could find was 100 miles away in Las Vegas, Nevada,” says McDaniel. “Mascara was placed on Energetix BioBalancer vitamins [no longer available], Rehmannia (a Chinese herb), melatonin spray, and essential oils. I also used selegiline [Anipryl]. Most Cushing’s dogs have a thyroid problem, and Mascara was placed on thyroid medication. This combination seemed to work, and every follow-up test was within the appropriate range until she was tested in February 2011.”
That’s when Mascara’s medication was changed from Anipryl to Lysodren (mitotane). “What a difference,” she says. “Masc even acted different. She was like a puppy again, playing and jumping. I was initially terrified of Cushing’s, but I now understand it and have respect for the treatments that are available. Mascara will always be on her medication. Without it she would die an early death due to the havoc excess cortisol wreaks on the body. I am all about the quality of life for my dogs, and right now, she has an amazing life.”
What if your dog has all of the symptoms of Cushing’s – excessive drinking, urination, and appetite, pot belly, skin problems, elevated alkaline phosphatase, etc. – but the tests say no?
Veterinary endocrinologists at the University of Tennessee in Knoxville (UTK) have been investigating this phenomenon. They found that many dogs have elevated steroid intermediates (also called steroid precursors or “sex steroids”) with normal cortisol. They call this condition “atypical Cushing’s disease,” or “adrenal hyperplasia-like syndrome.” It has been suggested that cases of atypical Cushing’s disease may be caused by a problem in the steroid production pathway. Elevated steroid intermediates have been linked to sudden acquired retinal degeneration syndrome (SARDS), which causes sudden blindness in dogs.
These steroid intermediate hormones include 17-hydroxyprogesterone (also called 17-OH progesterone or 17-OHP), progesterone, androstenedione, estradiol, and aldosterone. UTK developed a steroid hormone profile test to measure these hormones both before and after ACTH stimulation. Steroid hormone profiling is indicated when other tests of adrenal function are negative (ACTH Stimulation and LDDS), but the dog still exhibits signs of Cushing’s.
One or more of these steroid intermediate hormones are increased in affected patients, both before and after ACTH stimulation. Estradiol does not respond to either ACTH or dexamethasone, while 17-OHP shows an exaggerated response to ACTH administration in cases of both atypical and typical Cushing’s.
Atypical Cushing’s can be either pituitary or adrenal. Dogs with atypical pituitary-dependent Cushing’s usually have an enlarged liver, hepatopathy (liver abnormalities), and enlargement of both adrenal glands, along with increased levels of endogenous ACTH. Dogs with the adrenal form will also have an enlarged liver and elevated liver enzymes, but in this case only one adrenal gland will be enlarged (the other may be atrophied), and endogenous ACTH levels will be decreased.
Both forms cause the usual clinical signs of Cushing’s disease, including bloodwork changes and haircoat problems. If aldosterone is elevated, it can cause hypertension (high blood pressure), high sodium, and low potassium leading to muscle weakness.
In some cases, adrenal tumors can secrete other steroids besides cortisol, and cortisol levels may be normal. Ultrasound is recommended to confirm whether a tumor is present before beginning treatment. If a tumor is found, surgical removal is recommended, especially since noncortisol-secreting adrenal tumors are almost always carcinomas. If that is not possible, mitotane (Lysodren) is the next choice, although it will not affect estradiol levels, and these types of noncortisol-secreting adrenal tumors tend to respond poorly to medical treatment. Trilostane is not recommended, as it can cause increases in intermediate steroid hormones.
Elevated estradiol, called hyperestrinism or hyperestrogenism, causes many of the same signs as elevated cortisol does. In dogs with hyperestrinism, ACTH stimulation and LDDS tests are usually normal for cortisol, thyroid function is normal or controlled, and liver problems are frequent and typical (very high alkaline phosphatase, enlarged liver, and other liver abnormalities). Symptoms frequently include excessive drinking and urination, along with haircoat problems. Panting may also be present. A skin biopsy will suggest endocrine abnormalities.
According to “Treatment Option Considerations” for atypical Cushing’s on the University of Tennessee’s web site, melatonin may be used as an initial treatment, particularly when alopecia (hair loss) is present. Melatonin decreases cortisol and sometimes estradiol levels as well. Their recommended melatonin dosage is 3 mg twice a day for dogs weighing less than 30 lbs, and 6 mg twice a day for dogs over 30 lbs. Melatonin implants lasting three to four months can also be used.
Lignans, a type of phytoestrogen, are also recommended. Lignans may also inhibit enzymes involved in the production of estradiol, so a combination of melatonin and lignans may be used to treat hyperestrinism. The University of Tennessee’s suggested lignan dosage is 10 to 40 milligrams daily of flax hull (SDG) lignan or HRM lignan for small to large dogs. Do not use flax seed oil as the lignan content is low and flax oil can increase triglycerides.
Lysodren (mitotane) can be combined with melatonin and lignans to help lower sex steroid levels other than estradiol, along with suppressive effect on cortisol level. Another document on the University of Tennessee’s website states that “Mitotane will likely be effective if the source of estradiol is the adrenal tissues” (adrenal tumor). Lysodren may be preferred for treatment of atypical Cushing’s, as Trilostane treatment frequently results in increased estadiol and other intermediate hormone levels.
Or is there another explanation?
Caroline Levin, a registered nurse who has been researching SARDS in dogs for years, has a different name for atypical Cushing's. She calls it adrenal fatigue or exhaustion, caused by the adrenal glands becoming too tired to make sufficient cortisol.
Levin says, “When adrenal glands become exhausted they increase production of adrenal estrogen. This is an overwhelming pattern in SARD dogs. Ninety to 98 percent of dogs tested have elevated estrogen and/or other sex hormones — in other words they have adrenal exhaustion.
“Increased estrogen causes signs that closely resemble those of excess cortisol,” continues Levin, “including fatigue, confusion, depression, incontinence, irritability, seizures, and darkening of the skin. Elevated estrogen raises liver/pancreas enzymes (serum amylase/alkaline phosphatase), cholesterol, and triglycerides. Elevated estrogen also results in kidney degeneration, bone marrow and immunoglobulin suppression (anemia, cancer, infections, GI upset), increased histamine activity (allergies/itching), and thyroid binding.”
Even slightly elevated estrogen in combination with symptoms such as lethargy, confusion, panting, excessive appetite, and incontinence is significant, according to Levin. Prolonged exposure to excess estrogen decreases quality of life and can cause gradual damage to internal organs such as the kidneys, liver, and brain.
In addition to problems caused by estrogen, Levin says, “Elevated levels of hormone precursors, such as progesterones and androgens, cause impaired glucose tolerance (high blood glucose levels), obesity, increased body core temperature (heat intolerance/panting), increased hunger, aggression, thick coats, acne (small flesh-colored bumps), and bald patches. Severely depleted cortisol can result in loss of appetite, vomiting, abdominal pain, diarrhea, weakness, organ failure, and death.”
As an alternative to the full steroid hormone profile offered by the University of Tennessee, Levin suggests a faster, less expensive test for adrenal exhaustion: the Endocrine/Immune panel at National Veterinary Diagnostics Services (Levin has no affiliation with either facility). This test measures total estrogen (not just estradiol), cortisol, T3 and T4 thyroid levels, and IgA, IgG, and IgM immunoglobulin levels.
Most dogs with adrenal exhaustion show low cortisol levels, though they may rise to the challenge of an ACTH stimulation test. A small minority may appear to have elevated cortisol, but elevated adrenal estrogen and elevated cortisol do not occur at the same time. “Under chronic stress,” Levin explains, “some dogs will produce an inactive hormone isomer called 11-epi-cortisol. Others are unable to convert deoxycortisol, a precursor hormone, into cortisol. Neither 11-epi-cortisol nor deoxycortisol can be differentiated from cortisol on tests, causing these dogs to appear to have normal or even high cortisol levels.”
Practitioners familiar with this treatment start with injections of dexamethasone (0.8 to 1.0 mg per 20 pounds of body weight) and Vetalog (0.062 to 0.125 mg per 20 pounds). These injections are followed by oral medications, which are given on an ongoing basis:
- Medrol, beginning 3 days after injections: 1 mg or less per 10 pounds (up to 40 pounds) of body weight daily. Most dogs over 40 pounds also do well on 4 mg per day. Rarely will a dog need 5 to 6 mg.
- Levothyroxine (thyroid supplement): 0.1 mg per 10 pounds body weight twice a day. This is given even to dogs whose thyroid levels are in the low-normal range (T4 less than 2.0).
- Dogs with severe IgA deficiency (IgA < 60 mg) may be unable to absorb oral corticosteroids and other medications, and may require repeated injections of Dexamethasone and Vetalog at 2 to 3 week intervals instead. Sulfasalazine (10 mg per pound twice a day) may be prescribed as an alternative to ongoing injections if IgA is less than 60.
Levin also recommends reducing stress as much as possible. She believes that melatonin and particularly mitotane interfere with cortisol production, which she perceives as the underlying problem.
With appropriate treatment, improvement in mood and energy level may be seen within two to four weeks, but it can take three to nine months before other signs, such as elevated sex hormones, obesity, heat intolerance, and coat changes to improve. Other signs, especially food-seeking behavior, may persist even with treatment, especially in dogs that have been subject to elevated estrogen levels for a long time.
According to Levin, prompt treatment following onset of SARDS can restore vision in more than 20 percent of cases. Other conditions that can be linked to adrenal exhaustion that may respond to treatment include poorly controlled diabetes or pancreatitis (because elevated estrogen raises glucose, cholesterol, triglyceride, and lipase levels); poorly controlled epilepsy (elevated estrogen reduces seizure threshold and increases nerve cell transmissions); poorly controlled inflammatory bowel disease (IBD) or allergies (elevated estrogen suppresses immunoglobulin levels and increases histamine levels); and poorly controlled Cushing’s disease or atypical Cushing’s.
While these theories are considered controversial and are not accepted by most conventional veterinarians, many dogs do well with the unconventional approach, especially those with SARDS. Some dogs may do well with the more conventional treatment, particularly if an adrenal or pituitary tumor is the underlying cause, or when estrogen is not elevated and SARDS is not a factor.
Update: I've heard of two supplements, both with support from some veterinarians, designed to help dogs with adrenal disorders: DOGtorRx from Pet Equinox and Adrenal Harmony Gold from Pet Wellbeing. I have not received direct feedback about either product. If anyone tries it, I would appreciate it if you would let me know how it works for your dog.
University of Tennessee Clinical Endocrinology Service
See Treatment Considerations for additional information.
Resources for SARD-dog owners, (503) 631-3491
National Veterinary Diagnostics Services, 281-661-4292,
- Canine Vitex Plus from Hilton Herbs. (866) 929-0636
- Cushex Drops by PetAlive, by Native Remedies. (877) 289-1235
I've heard that Vetoryl (Trilostane) may be prohibitively expensive, especially for larger dogs. Compounding pharmacies may be able to provide the drug less expensively, but quality is key. See Pharmacy Compounding Accreditation Board for a list of accredited compounding pharmacies by state. Also see Pharmaceutical evaluation of compounded trilostane products for a study showing that compounded products can vary considerably in the amount of trilostane they actually contain.
Online Support Groups:
- Cushing's Disease (Hyperadrenocorticism) See "Related Articles" on right side of page
- Canine Cushing's Disease by Kate Connick
- Cushing's Disease in Dogs (Hyperadrenocorticism) by Dr. Cary Buckman
- Cushing's Disease in Dogs: Recommended Diagnostic Protocols and Treatment Options by Mark E. Peterson, DVM, ACVIM
- Canine Cushing’s Syndrome: Diagnosis and Treatment Part 1: Typical, Atypical, and Pseudo-Cushing’s Disease
- Canine Hyperadrenocorticism, Diabetes Mellitus, or Both?
- Cushing's Disease In Your Dog -hyperadrenocorticism- What Happened And What You Need To Do
- Chapter 118, Hyperadrenocorticism, from the Textbook of Veterinary Internal Medicine, S. J. Ettinger and E. C. Feldman, editors, 1995 (includes results of adrenal surgery on page 1565)
- Insights into Veterinary Endocrinology: Hyperadrenocorticism (Cushing's syndrome)
- What's the Best Protocol for ACTH Stimulation Testing in Dogs and Cats?
- Evaluation of the use of baseline cortisol concentration as a monitoring tool for dogs receiving trilostane as a treatment for hyperadrenocorticism
- False-positive and -negative results in diagnosis of canine hyperadrenocorticism
- Steroid Profiles in the Diagnosis of Canine Adrenal Disorders (UTK)
- Diagnostic Laboratory Insight with Regard to Adrenal Disease (UTK)
- Trilostane: A therapeutic consideration for canine hyperadrenocorticism
- Vetoryl® Capsules (trilostane product brochure)
- Treatment Option Considerations: Steroid Profiles in the Diagnosis of Atypical Cushing’s Disease (UTK)
- Evaluation of twice-daily lower-dose trilostane treatment administered orally in dogs with naturally occurring hyperadrenocorticism.
- Comparing therapies for canine hyperadrenocorticism
Blog posts by Dr. Mark E. Peterson, veterinary endocrinologist:
- Calculating the Dose for the Dexamethasone Suppression Test
- Why Precise Dose Calculation is Critical for Low Dose Dexamethasone Suppression Testing
- Low-Dose, Twice-Daily Trilostane Treatment for Dogs with Hyperadrenocorticism
- Hypertension and Proteinuria: Frequent Complications of Cushing's Disease in Dogs
- Hyperadrenocorticism (Cushing's syndrome)
- Protocol for ACTH Stimulation Testing to Monitor Dogs on Trilostane Therapy: Timing, Feeding, and ACTH Preparation All Matter
- Trilostane, Prednisone, and ACTH Stimulation Testing in Dogs with Cushing's Disease
- More melatonin and dog cancer
- Phosphatidylserine (PS) as a potential nutraceutical for canine brain aging: A review
- Iso-Phos (phosphatidylserine) from Thorne Research
- Si Miao San