Cushing's Disease In Your Dog - Hyperadrenocorticism - What Happened And What You Need To Do
What Happened - And What You Need To Do
Ron Hines DVM PhD
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Cushing's Disease, hypothyroidism and diabetes are the most common hormone problem that veterinarians see in older dogs. And of the three, Cushing's Disease is the most complicated and difficult to treat.
The disease has been known for a very long time. Dr. Harvey Cushing first took note of its peculiar symptoms in a young woman he was treating in 1912. (ref) Vets and physicians still call it Cushing's Disease because its scientific name, hyperadrenocorticism, is such a tongue-twister to pronounce.
diagnose this disease in pets more and more frequently. It is unclear
if this is because it has become more common, or if we are just looking
for it more than we once did.
Here is the basic problem: The adrenal glands of your pet are producing too much of certain hormones called corticosteroids (cortisone, cortisol). All the problems that you are seeing in your dog are the result of too much of these hormones circulating in its body.
There are two possible reason your pet’s adrenal glands are over-producing corticosteroid hormones. The first would be a tumor located within one of the adrenal glands itself. However, a second, and more common cause would be a tumor located in your pet’s pituitary gland, located just below its brain. We think that about 85% of the cases of Cushing's disease veterinarians see in dogs are due to tumors within the pituitary gland. This form is called pituitary-dependent Cushing’s (= PD, PDA or PDC form). In almost all the other 15%, the tumor is located in one or both of the adrenal glands. These 15% are called the Adrenal-Dependent form (= AT, ADH form) of Cushing's disease.
Hormone (corticosteroid) production in your pet’s adrenal glands is under the control of its pituitary gland. When it feels it is necessary, your pet’s pituitary gland signals the adrenals to produce more hormone by releasing its own hormone, ACTH (= corticotrophin), into the blood stream. When a functioning tumor is present in the pituitary, it releases more ACTH than it should – like a faulty thermostat that runs your air conditioning system continuously.
Tumors, whether located in the pets pituitary or adrenal glands, are usually a type called adenomas. They are slow-growing and generally do not spread (metastasize) or threaten life in themselves. When they are located in the pet's adrenal glands, some of these tumors can produce hormones other than cortisol in excess as well. (ref)
Cushing's Syndrome is a disease of middle-aged and elderly pets. Affected dogs are as young as 5, but the average age at diagnosis is about 10-11 years. (ref) Tumors located in the adrenal glands tend to affect dogs a bit older than this (11-12 yrs). Adrenal tumors seem more common in the large breeds and pituitary tumors more common in small breeds.
Breeds that seem a bit more prone to Cushing's disease include Yorkshire terriers, poodles, beagles dachshunds, staffordshires, Jack Russells, boxers and Boston terriers. But any dog can develop the syndrome. Female dogs are, perhaps, slightly more prone to the problem.
It is helpful to understand some of the functions of corticosteroids to understand the symptoms your pet is experiencing.
The Normal Role Of Corticosteroids In Your Pet
Animals and people cannot live without a normal level of corticosteroids in their body.
It is important in mobilization of body fat reserves and in maintaining normal blood sugar (glucose) levels. It does this by increasing glucose formation in your pet’s liver.
It is essential to the function of your pets immune system. However, when too much is present, it depresses immunity and increases susceptibility to infection.
It suppresses inflammation throughout the body.
It is a basic regulator of the metabolic process in all cells of the body.
In abnormally high levels, it slows bone formation and the absorption of calcium.
In abnormally high levels, it delays wound healing,
At normal levels, it supports muscle and ligament health; but at increased levels, it causes muscle, connective tissue and ligamental weakness.
It is important in maintaining bone health, regulating calcium uptake and excretion as well as maintaining bone density.
In abnormally high amounts, cortisol thins the pet’s skin and increases hair shed leading to baldness. It can even cause deposits of calcium to form in the skin.
Corticosteroids increases circulation within your pet’s kidneys (glomerular filtration rate). Abnormally high levels cause pets to drink and urinate excessively.
Normal levels of corticosteroid are necessary for proper brain function. In humans, excess levels are associated with mood swings and loss of acuity. This probably occurs in our pets as well.
Your pet’s adrenal glands have two major layers. The inner one (medulla) plays no part in Cushing’s disease. The mid-portion of the outer one layer, the adrenal cortex, produces all the corticosteroid (zona fasciculata).
The amount of corticosteroid your pet’s adrenal glands produce is constantly rising and falling depending on the pituitary gland’s assessment of the pets immediate needs. These "orders" are sent from the pituitary to the adrenals through the bloodstream in the form of the messenger chemical, ACTH (corticotrophin) which is , itself, a hormone.
What Signs Might I See If My Pet Has Cushing’s Disease ?
Cushing's is a disease that comes on very gradually – so you are quite likely to ignore the subtle early changes or attribute them to something else, and your vet may do the same. This slow progress is due to the slow rate at which these tumors grow.
One of the most common early signs of Cushing's disease is increased thirst and urination. Females pets are more likely to have accidents in the house and owners often tell me they have to fill their pet's water bowl again and again or that their dog has begun crying to be let out to pee during the night. Sometimes the problem is mistaken for a urinary tract infection or the beginnings of senility.
Another common symptom is weight gain. Increased cortisone levels increase the pet’s appetite as well as its tendency to retain fluids. It also causes the pet’s liver to grow larger. This, plus cortisone's relaxation of the pet’s abdominal ligaments, often lead to a pot-bellied appearance. At the same time, muscle shrinkage leads to spindly legs. All this makes it harder for your pet to get about, jump up on the bed, and climb stairs. You might mistakenly think the problem is arthritis. You might also mistake the panting and shortness of breath brought on by muscle weakness for a heart problem.
Many of these pets have poor or sparse hair coats due to skin changes caused by the excess of cortisol hormone – particularly on their trunk and flanks. When hair loss occurs, it is symmetrical (the same on both sides of the body).
Cortisol's effect on the pet’s immune system may make it more susceptible to skin, ear and urinary tract infections. Even some of the cases of demodectic mange that occur in non-juvenile dogs probably have Cushing's disease as their underlying cause. (ref)
Many pets with Cushing's disease are just not themselves. They have low energy levels and lack the zest for life that they once had. A similar effect occurs in humans with the disease. (ref) Pets with Cushing's disease may also be more susceptible to blood clots. (ref)
Hypertension (high blood pressure) in these elderly dogs may be a sign of Cushing's disease - It is know to be in humans.
But please do remember that many diseases of mature dogs that are unrelated to Cushing's disease, produce all or some of the symptoms I have listed and that it is unlikely that your pet will exhibit all the signs I have listed even when Cushing's is the underlying problem. So let your veterinarian make the decision as to what your pet’s underlying health issue really is.
What Might Make My Veterinarian Suspicious That My Pet Has Cushing’s Disease ?
Besides these signs you might have noticed at home, your veterinarian may notice other things on a routine exam that would bring Cushing's disease to mind:
Your vet might palpate (feel) an enlarged liver in your pet’s abdomen or be perplexed as to why previously treated infections have returned.
If the pet was presented because of a poor hair coat, finding no evidence of skin parasites or infection to account for it might bring endocrine gland problems to mind.
But it is the routine laboratory tests that vets run that would be most likely to ring alarms.
Many of these pets were brought in for urinary problems or peeing in the house. When the vet examines the urine of mature pets, he/she might wonder if Cushing's disease might explain why the urine is so dilute in the absence of evidence of infection, kidney disease or diabetes.
Such a situation, or vague symptoms reported by you, will probably lead your vet to suggest we send off some common blood counts and blood chemistry determinations.
When those test results are sent back, a very common finding in cushinoid dogs is an elevated blood alkaline phosphatase (ALP, ALKP) level.
A normal or low BUN and Creatinine level eliminates most kidney problems as a cause for the pet’s excessive thirst and, if their blood glucose level is normal, that eliminates the possibility of diabetes as well. (But it is not that unusual for pets to have Cushing's, diabetes and other health problems going on at the same time ! (ref))
It is common for dogs with Cushing's disease to have an increased number of neutrophils in their circulation as well as a lowered level of thyroid hormone (T-4). Their blood sugar level may be moderately increased as well if they are in a diabetic or pre-diabetic state. (You can go here to see what the normal blood values are in your pet.)
If your veterinarian ran x-rays, the vet might have confirmed that an enlarged liver was the cause of your pets increased girth (width) and ,on rare occasion, calcium deposits will be seen in locations where they should not be (skin, kidneys, adrenals, etc).
But again, none of the finding I listed are, in themselves, enough to make a definite diagnosis of Cushing's disease. They are all common finding in many diseases that adult pets suffer from.
What More Specific Tests Will My Veterinarian Want To Run To Be Sure ?
So your veterinarian will have to perform more specific, more complicated (and more costly) tests to decide if it is really Cushing's that underlies your pet’s health problems. It is not an easy task or something that can be done quickly and it always takes two or more different tests for your veterinarian to be reasonably sure.
Your veterinarian's first goal is to rule out the possibility of Cushing's, the next is to positively identify its presence and the third is to determine if the problem is in the pet’s pituitary gland or its adrenal glands. The diagnosis is easier in some pets than in others. In many cases, tests must be repeated and in others, results of two or more different tests do not agree.
The Most Common Screening Tests For Cushing's Disease
None of these screening tests are perfect and much controversy revolves around interpretation of their results. (ref)The pet's endocrine system is in constant flux and most of the tests are only short snapshots in time. (There is probably also genetic variation in how pets responds to compounds used in these tests and to elevated cortisol itself (ref)
Once your veterinarian is suspicious that Cushing's is the problem, the next step is to use one or more of these tests to confirm the diagnosis and , when possible, to distinguish pituitary-dependent (=PA,PDH) from adrenal-dependent (=ADH) hyperadrenocorticism.
Urine cortisol:creatinine ratio
The urine cortisol:creatinine ratio (UC:Cr) test is the simplest, least expensive test to rule out, or rule in, the possibility of Cushing’s disease in your dog. (ref) Dogs with normal UC:Cr values are highly unlikely to have Cushing’s disease. Those with abnormally high values need further testing because dogs with abnormal UC:Cr values do not all have Cushing’s disease.
Cortisol (cortisones) are continuously being shed in your pet’s urine. How much is present in a given amount of urine at any single time, depends on how dilute your pets urine is, as well as the level of those compounds in your pet's blood. Creatinine levels in your pet's blood remain rather constant and at a more stable level in its urine as well (urine creatinine). So by measuring how much urine cortisol is present in relation to how much creatinine is present, veterinarians get an indication as to how much cortisol was present in your pets blood stream when that particular urine was formed.
Urine for this test should be collected at home in the early morning (although a few vets still prefer a mixed, 24-hour sample). Do not bring your pet to the animal hospital – collect the urine at home. The stress of a car ride can be sufficient to alter the results in some pets. If your pet is emotional, let it calm down a few days after its last vet visit before you collect the sample. (ref)
Your veterinarian will send the pet’s urine sample to a national testing laboratory. If the UC:Cr value is reported back as normal, your pet probably does not have Cushing's disease. But only one dog in 4 or 5 that have an abnormally high (= positive) value actually do have Cushing's disease. That is because gastrointestinal, urinary tract, liver and heart diseases - as well as simple stress can also make your pet’s UC:Cr value go up.
Low Dose Dexamethasone Suppression Test = (LDDS)
If your pet’s Urine cortisol:creatinine test was abnormal or suspicious, this second test should be run. For it, your pet will have to spend the entire day at the animal hospital.
Dexamethasone is a synthetic compound similar to your pet’s own natural cortisol. When it is injected, your pet’s pituitary gland should mistake it for cortisol and inform (thru decreased ACTH release) the pet’s adrenal glands that no more cortisol needs to be produced. In normal dogs, this causes a drop in their natural blood cortisol levels. If the level of blood cortisol remains high after the dexamethasone is given, one of two things are happening: Either, your pet’s pituitary gland has a pituitary tumor that continues to produce ACTH, or your pet has an adrenal tumor that continues to produce cortisol.
The laboratory test can tell the difference between the pet’s own cortisol and the dexamethasone that was give and will report back if the natural cortisol level dropped normally after the injection, by how much and for how long.
This test will detect most of the pets that have Cushing's disease. However, certain medications (phenobarbital, phenytoin, spironolactone, tetracycline and perhaps others) can cause this test to fail. (ref) Also, some pituitary tumors retain some sensitivity to dexamethasone, which can also trick the test.
Some veterinarians rely on the 4-hour LDDS test sample to tell if the tumor is in the pituitary gland (PDH,PA) or adrenal gland (ADH,AT) (The odds are in their favor because about 85% are in the pituitary) Others insist on running the High Dose Dexamethasone Suppression test (HDDS) to more positively locate the tumor. I generally let my laboratory chemists (Antech) make that call because I trust their judgment.
Opinions vary as to the accuracy of this test. Some veterinarians feel it gives too many false-positives and is not as accurate as the ACTH stimulation test. (ref) Others put great faith it its results. If there is any doubt in you or your vet's mind as to the significance of the results, or if your pet fails to benefit later from its medications, have them run the ACTH stimulation test as well. Test with "cliff hanger" results need to be repeated. (I know these tests are expensive and a hassle, but Cushing's medications can be quite toxic and I do not want your pet taking them without a definite need).
Measurement Of The Amount Of Cortisol In Your Pets Hair - Hair Analysis
I explained to you that traditional Cushing’s disease is due to persistently high body cortisol hormone levels.
I also mention that the major drawback of simply checking to see if you pet's cortisol levels are too high is that its cortisol blood level is in constant flux (always changing) depending on the needs of the moment.
But your pet’s hair forms over a period of months – not hours. It also contains small amounts of cortisol that entered the hair shafts as the hair was forming. Chemists can now accurately determine the amount of cortisol trapped in those hair shafts. That could be an even better indication of the extent of the problem - if one exits.
The test has been most often used to detect the long term high cortisol levels of chronic stress in humans and research animals. In theory at least, it should also be above normal in dogs with Cushing’s disease.
In 2013 veterinarians at the Veterinary College in Vienna, Austria reported that dogs with Cushing’s disease did, in fact, have elevated levels of cortisol in their hair coat. You can read their report here. However, this same year, another group of veterinarians in Bologna, Italy found the test considerably less accurate. Read their study here. So I can not tell you yet how accurate a hair test will be in determining if your pet has Cushing’s disease. (We know that in humans, it can be of considerable help [ref]) We do know that exposure to water and bathing lowers the amount of cortisol in hair – the more you bath you dog, the lower its hair cortisol levels are likely to be. (ref) Cortisol is quite oil soluble (lipotrophic). So the amount of oil in your dog’s hair coat or its breed could also influence the amount of cortisol in its hair as might many other factors. (ref) Cortisol might also be destroyed by sunlight (ref1, ref2 ) Never-the-less, Accu-Metrics/Viaguard of Toronto, Canada offers a pet hair analysis for cortisol as a screening test for Cushing’s disease in dogs (It is for sale for $99 on Amazon.com, view). Only time will tell how valuable this test is, what hair is best sampled, and how the results stack up with low dose dexamethasone suppression test and urine cortisol:creatinine ratio results. I would be quite interested in getting feedback from you if you decide to have this test performed on your pet and subsequently have a dexamethasone suppression test run as well. (If you do have the hair test performed, it might be prudent to first clip a small area over the neck and let the hair there regrow without exposure to water, licking, hair-care products or medications. Once a sufficient amount has regrown – then send that off for analysis. [ref])
I have asked the Company for guidance, but have not heard back from them as of this writing.
ACTH Stimulation Test (= cosyntropin, tetracosactide or Synacthen test)
At one time, this was the most common way veterinarians identified dogs with Cushing’s disease. But with the common availability of the LDDS, it has become a less common diagnostic tool for Cushing's disease due to its expense, and the time involved in running it.
I mentioned that ACTH is the hormone that your pet’s pituitary gland normally releases to stimulate the pet's adrenal glands to produce cortisol. If your veterinarian injects a synthetic form of ACTH (Cosyntropin, Cortrosyn) into your pet, normal adrenal glands will respond by producing additional amounts of cortisol. But dogs with Cushing’s disease respond by producing even more (a exaggerated amount) than a normal pituitary/adrenal system would.
This test is not fool-proof either. There are a few non-adrenal diseases that can cause an abnormally high ACTH test. Also, the ACTH test is more accurate in identifying dogs with pituitary tumors than those with tumors of the adrenal gland. When the test result is not clear cut, your vet may suggest repeating it; or he/she may ask that the lab determine the levels of some similar hormones that may have shown a more dramatic spike after the injection (progesterone, 17-hydroxyprogesterone, androstenedione).
High Dose Dexamethasone Suppression Test
Vets usually suggest this test when they already know that your pet has Cushing's disease, but do not yet know if the tumor is in the pets pituitary gland or its adrenal gland. It is performed similarly to the LDDS test – but a larger amount of dexamethasone is give.
If the tumor is in the adrenal glands, blood cortisol levels will not drop after the injection because the tumors have broken loose from the control of pituitary ACTH. If the tumor is in the pituitary gland, in theory, high doses of dexamethasone should suppress ACTH production and lower blood cortisol. Unfortunately this theory does not hold up as well in practice as we would like. It appears that 20-30% of pituitary tumors fail to suppress the body's ACTH in response to the dexamethasone - tumors come in endless variation.
Since Cushing’s disease is a result of high blood cortisol levels, one might think that simply measuring your pets blood cortisol level would tell you if it had Cushing's disease.
However, the blood cortisol level in your pet varies greatly throughout the day and a single sample is unlikely to tell your veterinarian much.
Endogenous ACTH Level
This is another test that is seldom run in pets because of its difficulty. Elevated endogenous (= made in the pet's own body) blood ACTH would signify a malfunctioning pituitary gland. However, ACTH is a very fragile compound and it is difficult to transport it intact to central commercial laboratories capable of running the assay. Where it can be accurately run, as at universities, it is a very valuable test.
Abdominal Ultrasound Imaging
In the 15 or so percent of dogs whose Cushing's disease is due to an adrenal tumor, an ultrasound examination of the pets abdomen might detect the tumor. Adrenal glands can be hard to see on ultrasound, and many of the tumors are too small to see. So the veterinarian who performs this examination must be quite skilled in visualizing these difficult-to-see organs. Tumors of the right adrenal are considerably harder to see than tumors of the left. When only one adrenal gland contains tumors, that gland may be obviously larger than its normal or shrunken partner.
Ultrasound examination is a painless procedure. Although it is not always successful, when it is, it very helpful in distinguishing between the pituitary (PDH, PA ) and the adrenal (AT, ADH) forms of Cushing’s disease. So when it locates a functional adrenal tumor, it is a real help to your veterinarian in developing the best treatment plan for your pet.
The presence of an adrenal tumor is, in itself, not sufficient to warrant surgery. Dexamethasone suppression and ACTH stimulation tests must also support the diagnosis of a adrenal tumor that is actually producing cortisol. Some of them don't. (ref)
Other Forms Of Imaging
MRIs, or Cat Scan studies might also locate the tumor when high dose dexamethasone tests are inconclusive. These procedures are more accurate than ultrasound in detecting adrenal gland abnormalities. Occasionally, they detect calcified lesions within tumorous adrenal glands or liver enlargement - both common in Cushing's.
These techniques can also be used to examine your pet’s pituitary gland. However, only very large pituitary tumors are likely to be discovered in this way – most, when present, are quite small.
You or your veterinarian may still decide that an MRI of your pet’s pituitary gland is desirable. If a tumor can be seen and it is quite large (a “macro-tumor”) it might indicate that it has, or soon will, press on other portions of the pet's brain. These tumors can be removed – however, the surgery is delicate and expensive and some of the pituitary gland's other vital processes will likely be destroyed in the process. It is not a procedure I recommend to my clients. (Read on for more information on that surgery)
If expense is not a factor, periodic MRIs will tell you how fast the tumor is growing (most grow quite slowly). Pets with Cushing's disease are in the autumn season of their lives. Many are frail and, like elderly folks, they don't like to be hastled. They must not wiggle during these procedures and I hesitate in putting them through the stress of repeated, optional tests that require anesthetics - particularly when it does not add to your treatment options.
Why Is Cushing's Disease Such A Tough Problem For My Vet To Handle ?
Besides responding to your pets ever-changing stress needs for cortisol , the pituitary gland of all animals is known to produce signaling hormones in rhythms and cycles. Its processes ebb and flow like the tides. Some do this on a daily basis, some monthly, some annually or at even longer intervals. These are called biological rhythms. (Melatonin plays an important role in many of these processes).
There are no studies in dogs that I know of; but in humans at least, some cases of pituitary-based Cushing's also cycle. (ref)
So Cushing's tests that might be negative at one point could, conceivably, be positive at another and vice versa, and drug doses that were adequate at one point could be too small or too large at another point. It can be quite frustrating - like shooting at a moving target.
Another point of consternation (worry) is the potential toxicity of the two mainline drugs used to treat this condition and the common ineffectiveness of the less-toxic ones. Many vets hesitate to treat suspected early Cushing's cases because of the bad experiences they have encountered with these medications in the past.
The high cost of repeated sophisticated testing is also an important decision factor for most pet owners.
The inaccessibility of the pituitary gland and the lack of veterinary centers offering refined surgery or other techniques to selectively remove tumors from the pituitary are also quite exasperating.
Do I really Have To Have All These Tests Run?
If a low dose dexamethasone test result is strongly suggestive of Cushing's disease (and your pet is ill) , it is acceptable to have your vet place your pet on appropriate medications and see how it does - we already know that about 85% of these dogs have a tumor in their pituitary gland.
Here is the risk in doing that: If your pet is one of the other 15% that have the tumor in their adrenal glands, there may be an option to remove it surgically, curing the dog. The other problem is that those 15% which are in the adrenal glands are occasionally malignant and by the time you get around to doing further tests, such a tumor might be inoperable. Also, dogs in this 15% often need a much higher dose of medication than dogs with pituitary gland tumors.
What Are The Treatment Options For My Pet ?
There are four commonly used drugs to treat Cushing's disease in the United States: Lysodren (= mitotane or o.p’-DDD), Trilostane (= Vetoryl), Ketoconazole (= Nizoral) and L-Deprenyl (= Anipryl, Eldepryl, selegiline).
All drugs used to treat Cushing's disease vary in their effectiveness in one pet versus another. This is probably due to individual variations in metabolism of the drugs between pets and to differences in the characteristics of the pituitary tumor between pets.
Some vets delay or do not treat suspected mild cases because of their experiences with the side effects of lysodren. (their thoughts are: many of these pets are elderly and frail with multiple health problems and they might pass away first from something else other than Cushing's) Not all dogs need immediate treatment. A survey in 2001 found that over 50% of specialist would not treat a dog that had minimal signs, no mater what the pet's Cushing's test results were. (ref) I personally would not treat a dog if the sole or major complaints were a sparse hair coat or infertility. I would suggest medications if I suspected that a pet's markedly elevated blood pressure, recurrent serious infections, severe muscle weakness, diabetes or nerve-related problems were due to Cushing's disease. Other vets would treat more aggressively based on their personal experience and the resources at hand. (ref)
It is also important that other health problems your pet may have be stabilized as best as possible before Cushing's treatment begins. Heart problems need to be stabilized with appropriate medications, low thyroid function (hypothyroidism) needs to be corrected, diabetic dogs need to be stabilized with insulin and the problems associated with chronic kidney disease need to be addressed.
If you live in an isolated part of the World or simply prefer reading the textbooks that most veterinarians rely on in treating Cushing's disease, click here and here. For a physician’s perspective on treatment and diagnosis , go here or here.
Lysodren (= mitotane or o.p’-DDD)
The generic name of this medication is mitotane. It has been used the longest to treat Cushing's disease in dogs. It is relatively inexpensive.
Lysodren has the potential to cause serious side effects. Dogs receiving it need to be closely monitored through periodic blood tests and owner observation. Many vets suggest a repeat of the pet’s ACTH stimulation test a month or so after beginning lysodren and twice a year thereafter.
If response is inadequate after about two weeks, the dose may need to be increased. It takes 4-6 months for all of the signs of Cushing's disease to dissipate when lysodren is successful. However, your pets water consumption and urination habits should return to normal much faster than that. Hair is often the slowest thing to return to normal.
It is not
unusual for the pets required dose to change over time.
Side effects, due to lysodren are quite common. They include loss of appetite, vomiting, diarrhea, mopiness and incoordination. These side effects are usually due to an excessive or rapid drop in the pets cortisol levels (too much drug) and they can be fatal. If you use lysodren, have your veterinarian dispense an appropriate dose of prednisone tablets or injection to give in emergencies when the vet might be unavailable (if a 24-hour veterinary emergency center is not close by).
Your veterinarian may begin with a more substantial daily dose (a loading or induction dose) than that required for long-term maintenance of your pet - just to get the disease under control.
The first 7 – 14 days of treatment with lysodren is its“induction period”. During this period, it is generally given twice a day. It is only well-absorbed if fatty food is present in your pets stomach, so feed the dog when you medicate it. (ref) At the end of this period, your veterinarian may suggest another ACTH stimulation test to see if the dog’s adrenal glands are now working properly. (A good sign you should see is a reduction in your pets thirst and appetite to what it was prior to its illness.) Lack of interest in food all together is more likely a sign of lysodren toxicity or another concurrent medical problem.
Most vets suggest you begin this loading period when you are not preoccupied with life’s many distractions and when you are certain that your favorite veterinarian will not be out-of-pocket. The lysodren dose for every dog must be individually tailored and carefully monitored – particularly when beginning treatment. This is because there is always the danger that too much adrenal tissue will be destroyed. Your veterinarian will only see your pet occasionally, it is up to you to be watchful and vigilant.
Once your veterinarian is reasonably certain that the lysodren has decreased your pets adrenal cortisol secretions to normal levels, the vet may reduce your pets dose frequency – perhaps to once or twice a week.
Contact your veterinarian immediately if any of the side effect I mentioned earlier occur (or if anything worrisome occurs). Individual veterinarians make many modifications in the procedure I have described based on their personal experiences. If your veterinarian suggest a lysodren regimen or protocol that differs from mine – follow your veterinarian's instructions ! .
Trilostane (Vetoryl, Modrenal)
Trilostane is a relatively new option for pet owners in the USA. It has been used longer in the UK (It was licensed by the US FDA in 2009 for canine Cushing's). It works equally well for pituitary (PA, PDH) and adrenal (AT, ADH) Cushing's cases. It is, perhaps, somewhat safer than Lysodren and its success rate is about equal to Lysodren. (ref)
Its effects are quite similar to lysodren although it does not appear to be as severe in its effects on adrenal tissue as lysodren is. It should not be given when your pet’s kidney or liver tests are abnormal or when certain heart medications have been administered in the recent past. It seems to work best when the suggested daily dose is divided and given every 8-12 hours with food (no more than one calculated total daily dose per day).
Positive signs that the medication is working include increased activity, more exercise tolerance, decreased thirst and urination and less panting. Negative reactions to look for include vomiting, lack of energy, listlessness, diarrhea and loss of appetite. These signs do often go away or lessen with time or dose adjustment, but always bring them to your veterinarian’s attention immediately.
Pre-marketing research indicated that trilostaine should be less capable of producing the occasional (and even irreversible) adrenal gland damage (Addisonian reaction) than Lysodren. This now appears to be untrue. So dogs on trilostane need to be just as closely monitored as those on lysodren, so I suggest that prednisone tablets or injectable corticosteroids always be available at home for emergencies (if a 24-hour veterinary emergency center is not close by).
As with lysodren, the drug must be begun cautiously and ACTH stimulation tests need to be run periodically to judge the drug's effectiveness.
Although trilostane must be given more frequently and at a higher cost, it is an alternative for dogs that do not tolerate lysodren well.
If you contemplate switching your pet from lysodren to trilostane, it is, perhaps, safest if a month passes after stopping the lysodren before beginning the trilostane.
There is some recent data that, in some situations, trilostane (and probably lysodren as well) might make pituitary tumors grow more rapidly. (ref) (In humans, a somewhat similar phenomenon is called [chemical] Nelson's Syndrome) Trilostane can also cause adrenal glands to increase in size.
Anipryl (= L-Deprenyl, levodeprenyl, Eldepryl, Carbex, selegiline)
The powerful potential side effects of lysodren led veterinarians to look for alternative medications to treat Cushing's disease. One of these, l-deprenyl (Anipryl), became available in 1997 as a spin-off of human Parkinson disease research. (Veterinarians also use Anipryl to treat canine senility = canine cognitive dysfunction syndrome)
When Anipryl has any benefit, it is only effective if the root of your dog’s Cushing's problem is a pituitary tumor. It is not a very effective drug if your pet’s problem is caused by adrenal gland tumors. This medication works by regulating dopamine, a signaling (neuro-transmitting) chemical in your dog’s brain and pituitary gland. When dopamine levels are high, portions of the pituitary gland stop send ACTH signal messages to your pets adrenal glands telling them to produce cortisol.
Anipryl has much fewer and less serious side effects than lysodren. Perhaps 5% of the pets receiving it will experience gastrointestinal upsets, restlessness, disorientation or occasional hearing problems.
Veterinarians generally dispense a daily dose for two month, gradually increasing the dose if the initial dose is not sufficient. There are some drug interactions that need to be avoided. (certain mange dips, antidepressants, incontinence drugs, certain narcotics and narcotic patches, etc.)
it seems that Anipryl is an effective alternative to lysodren therapy
in only 20 –40% of canine Cushing's patients. Some theorize that
it only helps when pituitary gland tumors are located in areas sensitive
Ketoconazole is an anti fungal drug that also has effects on the endocrine gland system. It is generally not the first choice of veterinarians or physicians in Cushing's disease treatment - but it is occasionally given when other drugs are ineffective or produce too many side effects.
About half of the dogs with Cushing's disease seem to benefit from the drug. However, improvements seen on ketoconazole are often incomplete or temporary. When it works, It seems about equally effect for pituitary (PA, PDH) and the adrenal (AT, ADH) forms of Cushing's.
Generally, the pet is observed for a week or two on a low dose of ketoconazole and, if it tolerates it well and does not cause vomiting or diarrhea, the dose is gradually increased. An ACTH stimulation test is desirable after a month or two on the medication to see if it is actually helping.
It, and Anipryl, are not my first choices in treating Cushing's. But other vets reported quite good results using it. (ref)
Are There Other Medications That Might Possibly Help?
Retinoic acid is a compound similar to vitamin A. Some research has found that administering this compound reduced the size of pituitary tumors in Cushing’s cases in dogs. They found its efficacy (effects) about the same as ketoconazole. (ref) (do not give excessive amounts of OTC vitamin A to your pet, in excessive amounts, it is toxic)
Cabergoline, like Anipryl, interferes with the pituitary’s dopamine system. It has been used to treat a disease caused by other types of pituitary tumors (prolactinomas and those that secrete growth hormone) in humans. It was reported to be useful in about 40% of Cushing's cases in dogs, (ref) - although in humans, it seems to loose its effectiveness over time. (ref)
Mifepristone is the same compound found in certain “morning after” pills. Another ability of this drug is to make the body resistant to the effects of cortisol. So it has been used to counteract the effects of excessive cortisol produced by the adrenal tumor (AT) form of Cushing’s disease. It could, conceivably, be helpful in the 15% of dogs in which tumors are located in the adrenal gland but which were found to be inoperable for one reason or another.
Medications directly targeting the cancerous pituitary cells
It initially appeared that thiazolidinedione compounds, or drugs with similar actions might control Cushing's disease without the side effects of current medications. (ref) Although the work looked promising at the time, later trials showed that the tumor cells resumed their excess ACTH production after about 6 month. (This was the same star-crossed compound, rosiglitazone, sold in the US for diabetes.(Avandia)
Are There Holistic, Homeopathic Or Other Non-traditional Treatments That Might Help My Pet?
Whenever you are dealing with an incurable disease in humans or pets, for which no easy treatments exist, an opportunity opens for hucksters to market worthless, unproven or scientifically untested remedies. The fact that the symptoms of Cushing's can wax and wane without treatment and the difficulty of being 100% certain in ones diagnosis makes evaluation of these products all the more difficult. For example, a British vet reports superb cure rates using a mixture of grain alcohol, acorns and "essence" of ACTH. (ref)
I am a product of Texas A&M University, Illinois rural practicality and the NIH, so I do not believe in homeopathy or any other "alternative" , "complementary" or mystical technique that cannot be scientifically explained. If these things have any benefits, it is in offering solace to grieving owners desperate to do something - anything - for the pet they love so dearly. There is nothing wrong with that. Besides, your pet keys off of your emotions - it worries when you worry ; and that worry, tension and stress elevate cortisol in your pet as well as in you. (ref)
Melatonin is a hormone that pulses during the day in the blood of humans and animals. It also rises in 24 hour cycles that help establish hormone rhythms in many endocrine glands. It is also a powerful antioxidant. It is secreted by the pineal gland at the front of the brain. It reaches its highest levels at night. It is commonly sold as a sleep aid.
Laboratory experiments have found that low levels of melatonin stimulate the growth of certain types of breast and prostate cancer cells while adding melatonin to these cells seems to slow their growth.
It has been suggested by endocrine specialists at the University of Tennessee veterinary school that melatonin might help dogs with Cushing’s disease, (ref) and there are human studies that indicate it may slow the growth of endocrine tumors as well. (ref 1, ref 2) (I would not rely on melatonin as the primary treatment for Cushing's disease.)
Lignans and Ligands are not the same thing. Lignans are a type of plant estrogen (phytoestrogens) and antioxidants, while ligands are compounds that bind to metal atoms. It is confusing because they have both been suggested as having a role in Cushing’s disease. (ref)
Lignans are also suggested by the University of Tennessee as a therapy for “atypical” Cushing’s disease. Two forms are available at health food stores.
I know of no controlled studies of either melatonin or lignan use to treat Cushing's disease in dogs.
As with most neutraceuticals, there is probably no harm in adding either compound to another, well-thought-out, treatment plan.
Are There Traditional Non-Drug Treatment Options?
Surgery For Adrenal Gland Tumors
If your veterinarian can identify discrete tumor(s) in one of your pet’s adrenal glands (the uncommon form of Cushing's), that gland might be removed successfully through surgery (adrenalectomy). It is ticklish surgery and would need to be performed at a veterinary surgical center by a specialist in the procedure.
This surgery is not commonly attempted. First, in most canine Cushing’s cases, the tumor(s) are in the pituitary gland. Secondly, the tumors in many adrenal cases are small, diffuse, and impossible to see. Thirdly, the tumors are sometimes malignant and have already spread to other locations. And lastly, these tumors are usually diagnosed at an advanced age.
Postoperative complications after this surgery are common. This is because the normal remaining adrenal gland has often shrunken and lost its ability to produce the pet’s required amount of cortisol. Sometimes, a post surgical period on prednisone gives the remaining adrenal gland time to recover.
It is also possible to attempt to destroy these tumors (and the rest of the pet’s adrenal glands) with high doses of lysodren. Dogs that have had this done, accidentally or on purpose then have the Addison's problem and will need supplemental prednisone and, possibly, a second hormone replacement (Florinef, percorten-V) for the rest of their lives. (ref)
Surgery For Pituitary Gland Tumors
Your pet’s pituitary gland is located in an extremely inaccessible location - just below its brain. It is surrounded by an intricate and fragile network of blood vessels (Circle of Willis), that can easily be torn, leading to fatal hemorrhage. Surgical removal of pituitary tumors in cases of Cushing’s disease is routinely done in humans. Pituitary surgery is a much less common procedure in pets and, when it is attempted, the entire anterior portion of the gland is usually removed (hypophysectomy). This is because the small size of most pets limits the surgeon’s field of view and because the tumors are often very small (the gland must be approached through the pet's open mouth).
Because veterinarians generally remove all of the anterior portion, following this surgery , there is a danger your pet will be left hypothyroid, deficient in cortisol (Addisonian) and, possibly, also with a rare form of diabetes (Diabetes Insipidus).
At the NIH I did this surgery in rodents, whose tiny size made the procedure even more challenging. It is not something I would recommend often for an elderly house pet. Perhaps with advances in microsurgery and robotics it will become a less daunting procedure. Today, the technique is a last hope for large, space-occupying, pituitary tumors that are causing neurological signs in pets. To get an idea of the difficulty working in this area, if you wish, you can look at some gruesome photos here.
If this procedure is attempted, the tumor must be discrete and visible on MRIs and your pet’s general health would need to be adequate.
The vet school in Utrecht, Netherlands seems to have had the most success with this surgery. (see Meij prior ref and 2nd ref). They believe that even after their surgery, enough functional pituitary cells remain to supply enough ACTH for your pet’s adrenals to produce adequate cortisol. (I am told that almost half of the pets in the Netherlands have health insurance vs 2% in the US, however, as of this writing, even US-written policies, such as VIP say thay will pay these costs anywhere in the World)
Radiation therapy, similar to cancer treatments in humans, is an option for certain pets with the pituitary tumor form of Cushing’s disease. Radiation will destroy pituitary tumors. The problem with the technique is the collateral damage that inevitably occurs in pets and people. (ref)
It is best reserved for large pituitary tumors that are compressing nearby portions of the brain and causing things like blindness, seizures, personality changes and difficulty getting about. In these cases, it is a valid alternative to surgery (hypophysectomy). The primary symptoms of Cushing’s disease rarely disappear after radiation therapy, but the tumors usually shrink and their local effects on the surrounding brain tissue often lessen as well.(ref)
What Is The Outlook For My Pet?
Cushing’s disease is not, in itself, a painful condition. The most important thing is that your pet be happy in its autumn years - and you are a better judge of that than your veterinarian. If your pet can still do the activities with you that give you both pleasure, you can just accept the diagnosis or you can ask your veterinarian to prescribe some of the less severe, but unproven treatments. Some owners confuse the normal declines and loss of organ capacity that come with aging for symptoms of Cushing’s disease and it can be very hard for veterinarians to sort them out as well. Many cases really do need to be treated – but not all of them do.
When, in the future, owners and veterinarians have access to more precise surgery and better targeted drugs, that will change. I only write these articles from time to time; but new discoveries are made every day. My best advice now is to try to find a veterinarian whose philosophy matches your own and let them suggest treatment decisions.
Cases of Cushing’s disease that are not treated may progress to heart, liver pancreatic, kidney and neurological problems. The rate at which that occurs is very unpredictable and differs with every pet and its particular tumor. Many of these tumors are very slow-growing. You can judge the speed with which the disease is progressing by observing how your pet behaves over the 6-8 months since its diagnosis. That pretty much establishes the diseases’ slope or curve.
Elevated blood cortisol makes dogs with Cushing’s disease more susceptible to infections. So they need extra attentive care, good nutrition and a low-stress, monotonous life. The most dangerous time is the first six months after treatment begins. None of the treatments we have, actually restore healthy pituitary/adrenal function, but once that six months period has passed, dogs with the disease may live several more good-quality years.
Accidental (Iatrogenic )Cushing's
The same signs we see in pets with a malfunctioning pituitary-adrenal gland system (Cushing’s) can be caused by giving pets too much cortisol-like medication for too long a time.
Many common veterinary medications contain corticosteroid ingredient (cortisone, hydrocortisone, prednisone, prednisolone, dexamethasone, triamcinolone, etc.). These medications are very important in veterinary medicine; but given them in large doses or over long periods, can cause “accidental”( = iatrogenic) Cushing's disease.
Corticosteroids, given for short periods by your veterinarian, can be life saving. When your veterinarian prescribes them for longer periods, it is usually because there is no other treatment option available. For many sick pet, the mild to moderate Cushing's-like side effects of periodic, or intermittent corticosteroid use are preferable to the pain and debility of the condition being treated. But never give more than is absolutely necessary and be mindful of the side effects they might cause (many of these steroid treatments are for autoimmune or allergic diseases) .
Even topically applied, beclomethasone, betamethasone and budesonide, steroids have, on rarer occasions, caused Cushing's-like symptoms.
When iatrogenic Cushing's disease occurs , the compounds should not be stopped suddenly. Usually, when they are gradually withdrawn, the pet’s adrenal glands and pituitary will return to normal function.
Although it is generally not required, an ACTH stimulation test can distinguish between true Cushing’s disease and the Cushing's-like symptoms of steroid over use.
Monitoring Progress -The Key To Successful Treatment
A steady and balanced amount of blood cortisol is critical to the life of all animals. Both lysodren and trilostane have the ability to abruptly lower the pet’s blood cortisol to dangerously low levels, particularly when the correct dose is just being established or the pet is under additional stress.
Cushing's is a progressive disease as well, so your pet’s medication dosages will need to be periodically adjusted over time through visual observation, blood chemistry and occasional ACTH tests. It may turn out that periodic urine cortisone: creatinine testing (UC:Cr) or hair analysis will be helpful in monitoring your pet’s condition - but this is still uncertain.
Given two pets with the same severity of Cushing's, the ones that receive this attention and careful monitoring are the ones that are likely to survive the longest. Laboratory tests can be helpful in adjusting doses, but drinking normal amounts of water, a steady healthy weight and appetite, improved skin and hair coat and a happy active life tell us more about your pet’s treatment success than any laboratory test can.
A study was published in 2010 that indicated that blood cortisol levels could be used to judge the effectiveness of your pet's medicine, rather than more expensive and complicated repeat ACTH tests. You can read that article here.
Why Is Cushing's Syndrome Such A Difficult Disease For My Vet To Treat ?
If you have read this far, you already know a lot of reasons for that. Pituitary and adrenal tumors also come in endless variations. Only through extensive testing and experimenting with various medications and doses, can your vet know the potentials of the tumors affecting your dog. That takes a lot of time, thought and it incurs a lot of expense.
The symptoms of Cushing’s disease are highly variable and they overlap with many common diseases of older pets. It is often only after extended treatment of another condition that the possibility of an underlying Cushing’s problem comes to mind.
The fact that the common laboratory tests for Cushing’s disease often straddle the fence or disagree with one another is exasperating.
The lack of proven medications that directly target the problem without serious side effects is as frustrating to veterinarians as it is to you.
This is why there is so much controversy as to when and how to treat your pet. If any vet was truly satisfied with his/her protocol, all vets around the World would quickly jump on board. Widely different treatment and diagnostic plans in medicine mean that no one is entirely satisfied with their method of treatment.
What Is An Addisonian Reaction?
Some 57 years before Dr. Cushing's described his strange case, a British physician, Thomas Addison, noticed a particular bronze skin color, severe weakness, vomiting and a craving for salt in some of his patients. This was later understood to be due to a situation the exact opposite of Cushing’s syndrome.
In pets and humans, Addison’s disease occurs when there is insufficient cortisol in the body. The disease occurs naturally in some dogs, particularly standard poodles, westies and Portuguese water dogs. But it can also be caused by lysodren and trilostane and surgical or radiation treatments aimed at curing or controlling Cushing's disease.
Sometimes it occurs when the dose of lysodren or trilostane is too high. But sometimes it is just an individual (idiosyncratic, quirky) reaction to what should have been the correct therapeutic dose.
Such a situation can be life threatening. It is why one must always be careful in adjusting the doses of these drugs and why you should always have emergency prednisone tablets or injection on hand at home (if you do not live near a 24 hour veterinary emergency center). A common sign of an Addisonian crisis is vomiting and weakness. In such cases, get your pet to a veterinarian immediately. Orally administered prednisone takes 30 minutes to 2 hours to have an effect, but many of these dogs need intravenous fluids and other specialized care immediately. They may also be unable to swallow oral medications safely. So please don’t attempt to handle such a problem alone if that can in any way be avoided.
Most of these crises are temporary and occur during periods of high stress or dose adjustments. But they are occasionally permanent – requiring steroid supplementation for the rest of the pet’s life.
There are also veterinarians who feel that destruction of the pet's adrenal glands is preferable to adrenal gland over-production of cortisol because the medications used to control Addison's disease are more predictable than the ones used to control Cushing's disease.
My Veterinarian Thinks My Pet Might Have "Atypical Cushing's Disease" - What Is That ?
Veterinarians have always been perplexed by a percentage of dogs that have one or more symptoms that are often seen in Cushing’s disease but test negative for Cushing’s on the low dose dexamethasone stimulation test, the ACTH stimulation test and the urine cortisol:creatinine ratio test.
These pets, with evidently normal cortisol levels, were labeled by some veterinarians as having Atypical Cushing’s Disease. That was an unfortunate choice of words, because in human medicine, Atypical Cushing's Disease refers to the opposite situation, higher than normal blood cortisol and positive ACTH/Dexamethasone test results but few or no disease signs (ref) or a situation where tumors in other areas of the body (often the lungs) raise blood cortisol levels. (ref)
Veterinarians rely on physicians for most key discoveries and we need to speak in the same medical language if we are going to interact effectively. It is a bit like saying that ice is atypical water - technically true but unenlightening.
The pituitary gland of your pet is a vast hormone-producing factory - the "master gland" (9 pituitary hormones known as of this writing) - it and your pet’s adrenal glands have cells that are "plastic" or multi-potential and have the capacity to produce many hormones and hormone-like compounds as well. (ref1 ref2) There is no doubt in my mind that these processes can go wrong at many different points, producing many different steroid-hormones other than cortisol which might cause symptoms similar to Cushing’s disease in your pet. But, to my way of thinking, if your pet’s signs are not due to elevated blood cortisol, your pet does not have Cushing's disease - typical, atypical or otherwise. What it has is another of the many hormonal problem that involve the pituitary-adrenal axis. Neutered ferrets suffer similar excess adrenal hormone problems. Rather than call them Atypical Cushing's cases, veterinarians call them "Adrenal-associated endocrinopathies". (ref) Adding to the complexity, neutering your dog also permanently affects its pituitary-adrenal axis. (ref)
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