Companion Animal TREATMENT: HYPERADRENOCORTICISM (CUSHING S SYNDROME) IN DOGS

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1 Edward C. Feldman, DVM Diplomate ACVIM (SAIM), Professor Emeritus, Small Animal Internal Medicine University of California Davis, California TREATMENT: HYPERADRENOCORTICISM (CUSHING S SYNDROME) IN DOGS TREATING DOGS FOR NATURALLY OCCURRING CUSHING S SYNDROME The Good The goals in treating dogs afflicted with naturally occurring Cushing s syndrome (pituitary dependent hyperadrenocorticism, PDH; or adrenocortical tumor hyperadrenocorticism, ACT) are to resolve the clinical signs and improve both dog and owner s quality of life. It is critically important, however, for owners to understand their role on the veterinary-owner-patient team. Major decisions are made based on owner observations and are keys to long-term success. Success rates with several forms of treatment have been excellent. Signs resolve in a typical order, with polyphagia being the first sign to improve in most dogs. Owners also note that their dogs begin to be more active and pant less, as polydipsia and polyuria resolve. All these can begin to resolve in just days to a few weeks. Muscle strength and pot belly take longer to resolve and the various skin and hair coat issues may require months. Why is all this important? It has been shown that as these signs resolve, there is parallel improvement in hypertension, susceptibility to infection, proteinuria, and other concerns. The Bad It must be pointed out that some dogs with Cushing s syndrome have severe arthritis, immune-mediated conditions, chronic kidney disease, or other problems masked by their Cushing s syndrome and revealed with therapy. Arthritis can be quite alarming. It is a concern we mention to all owners of dogs with Cushing s syndrome who are >20 kg in weight. The anti-inflammatory effects of cortisol in dogs are striking. For example, the combination of hyperadrenocorticism and pancreatitis is quite unusual. However, after Cushing s has been successfully treated, this inflammatory condition becomes far more common. A few treated dogs have seemed to develop cancer soon after therapy for Cushing s, begging the question of whether the Cushing s had been masking cancer. Similarly, a small percentage of dogs with PDH begin exhibiting clinical signs of a pituitary macro-tumor soon after being treated. Again, was the excess cortisol suppressing tumor-associated inflammation or slowing growth? The Ugly Dogs with severe alopecia, secondary to Cushing s syndrome tend to slowly have return of a hair coat as treatment progresses. Sometimes these dogs develop a puppy coat before developing their normal adult hair coats. Some dogs with PDH, with treatment, actually change hair coat color, with the most common change being that the coat is far darker. Dogs that have what appears to be a partial or full hair coat before treatment may go through a period in which they shed their truncal coats and have severe skin flaking. This can be quite alarming or bothersome to owners. It is our experience, however, that this period of shedding and flaking is associated with excellent response to treatment and is usually followed by return of a full hair coat. However, a puppy coat or change in coat color does happen on occasion. SURGICAL REMOVAL OF ADRENAL AND PITUITARY TUMORS Surgical removal of an autonomously functioning, glucocorticoid-secreting, adrenocortical tumor (ACT), causing hyperadrenocorticism, is the treatment of choice in dogs and cats. This surgery is increasingly being done with laparoscopy. Surgical removal of a pituitary tumor causing hyperadrenocorticism (PDH) is the standard treatment strategy for people. Pituitary surgery has been utilized with dogs and cats with PDH, but only a few veterinary surgeons have been trained in this procedure. It is anticipated that this form of treatment will become standard in the future as expertise is gained. MEDICAL THERAPY USING o,p DDD Background Mitotane (Lysodren, o,p -DDD) is a derivative of the insecticide DDT. Research completed in the 1940 s demonstrated that this drug was an adrenocorticolytic agent (causing cell death and necrosis) of canine adrenal cortices. In most treated dogs, the zona fasciculata and zona reticularis are damaged or destroyed while the mineralocorticoid-producing zona glomerulosa is spared or less damaged. While

2 this drug is relatively ineffective in the treatment of hyperadrenocorticism in people and cats, it is quite effective in dogs with PDH. However, if too little medication is given, hyperadrenocorticism fails to resolve and if too much is given, life threatening hypocortisolism or hypoadrenocorticism (including destruction of the zona glomerulosa; Addison s disease) can occur. The goal in therapy: make the owner happy. In other words, resolving clinical signs is the best measure of success in resolving the biochemical and other issues associated with chronic circulating excesses in cortisol. Induction Protocol Lysodren (o,p DDD) therapy should always be initiated at home, on a Sunday, with the owner administering 25 mg/kg, BID, after feeding their dog. Glucocorticoids are not routinely administered and are not routinely dispensed. Rather, the owner should receive thorough education on the actions of o,p DDD and instructions to begin reducing their dog s food allotment by one-third beginning one or two days before o,p - DDD is begun. In other words, we have owners give their dog one-third of its normal food allotment twice daily, beginning on a Friday or Saturday. This should make the typical polyphagic Cushing s dog even more hungry. NOTE: NO DOG WITH A POOR APPETITE SHOULD EVER RECEIVE THIS DRUG! o,p -DDD administration should be continued twice daily until (1) the dog s daily water consumption approaches 60 ml/kg; (2) the dog simply takes longer to consume a meal and certainly before it develops partial or complete inappetence; (3) vomiting; (4) diarrhea, or (5) unusual listlessness. Any of these signs is an indication that the owner should stop daily o,p DDD therapy and have the dog examined by the veterinarian. The goal is simply to have the owner observe their dog eat. They should stop medication should any reduction in appetite be seen. Anorexia indicates that too much medication has been given or that a new problem has developed. The single most reliable and consistent indicator for stopping the induction phase of therapy is appetite. Any reduction in appetite indicates that the induction phase of therapy has been completed. Decreasing appetite is usually the first evidence of o,p -DDD action, usually noted in 4 to 9 days. Water intake in polydipsic dogs decreases, in more than 90% of dogs, within 5 to 10 days. In all, response takes as few as 3 or as long as 35 days, but the vast majority exhibit response within 4 10 days. Lysodren therapy can be quite successful in eliminating signs of Cushing s. Use of this drug is most effective if there is close communication between owner and veterinarian. Either the veterinarian or a technician should call the owner every day beginning with the second day of therapy. Owners usually become impressed with their veterinarian s concern and begin to observe their dog more closely after several phone calls. We advise our clients to feed their dogs 2 small meals each day. The dog s appetite should be observed prior to every o,p DDD administration. If food is rapidly consumed, medication can be given. If food is consumed slowly, incompletely, or not at all, the medication should not be given until the veterinarian is consulted. Reduction in appetite always indicates the end of therapy s induction phase. In addition to making daily phone calls, the veterinarian should see the dog 8 to 9 days after beginning therapy, sooner if decreased appetite is noted. Owners should bring urine collected from their dog the morning of any examination. At each examination, a thorough history, physical examination, urine specific gravity, a check for glucose in the urine, and an ACTH response test should be performed. Dogs that appear to have responded to the medication (or if the owner is not certain) should have therapy withheld until results of an ACTH response test can be evaluated. The goals of therapy with o,p DDD are to achieve resolution of clinical signs and an ACTH response test that is suggestive of relative hypoadrenocorticism. In our clinic, clinical success with o,p DDD is defined by an owner while biochemical success is indicated by pre- and post ACTH serum cortisol concentrations >1.5 and <5 µg/dl. If the dog with hyperadrenocorticism has a normal or exaggerated response to ACTH following the initial 8 to 9 days of o,p DDD therapy, daily medication should be continued for 3 to 7 additional days (this is quite unusual). ACTH response tests should be repeated every 7 to 10 days until the post-acth plasma cortisol is in the basal cortisol reference range (usually µg/dl). It is important to emphasize that each dog must be treated as an individual. There appears to be no reliable method of predicting the length of time required for a response or the amount of o,p DDD therapy

3 required except to state that most dogs respond in 5 9 days. It is unusual for a dog to require more than 9 consecutive days of o,p DDD. Approximately 10% of dogs with PDH are not polydipsic. They, too, can and should be treated by their owners at home. Absence of polydipsia simply eliminates one of the factors that can be monitored during the initial phases of therapy. Therapy will be based on history, physical examination and ACTH response test results. The most important monitoring guide in these dogs is no different than for polydipsic dogs, it is their appetite. Reduction in appetite in any dog receiving o,p DDD is an indication that the induction phase is completed or that over dosage is imminent. Maintenance Therapy The maintenance phase of therapy with o,p DDD may be initiated once a dog with Cushing s demonstrates a post-acth plasma cortisol in the basal cortisol reference range (usually µg/dl). Lysodren does not affect the pituitary. Therefore, the excessive ACTH secretion associated with PDH continues or becomes exaggerated with therapy. Failure to chronically continue o,p DDD therapy will result in re-growth of the adrenal cortices and return of clinical signs. This recurrence typically takes place within 1 to 12 months of stopping therapy. Maintenance therapy involves choosing an o,p DDD protocol and altering that regimen as required by the dog. Dogs that respond to daily o,p DDD therapy within 5-7 days are usually started on a maintenance schedule of 25 mg/kg/wk of o,p DDD. Those that initially require 7-10 days of therapy are typically given about 35 mg/kg/wk. An ACTH response test is performed 1 and 3 months after beginning the maintenance therapy, and every 3 to 6 months thereafter. If the plasma cortisol concentration after ACTH administration is in the reference range or elevated, the o,p DDD dosage or the frequency of administration is increased. If the post- ACTH plasma cortisol concentration is <1.5 µg/dl (sometimes <2.0 µg/dl) the dose should be decreased. If a dog receiving o,p DDD ever becomes ill, NO o,p DDD should be given. Let me provide an example of long-term treatment and its adjustments. A 20 kg dog has Cushing s and responds after 6 days of o,p -DDD. The dog is then placed on 25 mg/ kg/week (500 mg/week; o,p -DDD is provided as 500 mg tablets). Specifically, the dog is placed on one-fourth tablet (125 mg) orally, after eating, on Mondays, Tuesdays, Thursdays and Fridays. If on a subsequent examination, it is believed that the dog is receiving too much medication (poor appetite, for example) the dose can be reduced to 2-3 doses weekly. However, if the clinical signs begin to recur, if the urine specific gravity is <1.020, or if the post-acth cortisol is >5.5 µg/dl, then the dog should receive medication 5-6 days per week. In either scenario, the dog should be rechecked in 1-3 months and the process repeated. In geographic areas where ACTH is unavailable or prohibitively expensive, dogs with PDH can be treated and monitored long-term with o,p -DDD safely. Owner opinion is key is making dose adjustments. Well controlled dogs usually have home-caught urine that has a specific gravity > If an owner begins to observe recurrence of clinical signs in a pet whose specific gravity is <1.020, increase in dose is likely required. One should also obtain a morning serum cortisol from the dog before it is treated. Cortisol concentrations <1.5 µg/dl would indicate that medication be discontinued for a period. Concentrations above this should be viewed as inconclusive. MEDICAL THERAPY USING KETOCONAZOLE, RETINOIC ACID, CABERGOLINE In addition to its antifungal activity, ketoconazole (Nizoral) has been shown to interfere with gonadal and adrenal steroid synthesis. In comparison to o,p -DDD and trilostane, responses to ketoconazole have been inconsistent, relatively expensive, and rarely employed in the United States. However, in countries where o.p -DDD and trilostane are unavailable, use of ketoconazole, usually in combination with one of these other drugs has been efficacious (Perez-Alenza and Melian, 2016). MEDICAL THERAPY USING TRILOSTANE Background, Action, Efficacy and Safety as Compared with o,p -DDD Trilostane was first synthesized and used in the 1960 s, with generally poor results, for the treatment of hyperadrenocorticism in people. Like the disappointing results with o,p -DDD in people but excellent response in dogs, trilostane has followed a similar path. It began to be used for the treatment of dogs with naturally occurring hyperadrenocorticism in the 1990 s. Since then, a number of studies have been published demonstrating the excellent sensitivity of dogs with naturally occurring hyperadrenocorticism to trilostane. It is now licensed for veterinary use in countries

4 around the world. Trilostane, a synthetic steroid analogue, interferes with the enzyme 3beta-HSD. As an enzyme blocker, trilostane inhibits adrenocortical synthesis of progesterone and its end-products, including cortisol and aldosterone. The advantages of trilostane over o,p -DDD are its efficacy in dogs with either PDH or ATH and that it s use is licensed by many countries. Is the drug more effective than o,p -DDD? Effectiveness in dogs with PDH is similar with either drug, but trilostane is an unequivocally more effective treatment for dogs with ATH. Is trilostane safer than o,p -DDD? Either drug can be under dosed, which results in continuing clinical signs. Either drug can be over dosed, which can result in signs that range from a mild decrease in appetite to severe iatrogenic hypoadrenocorticism, crisis, and death. Since o,p -DDD is cytotoxic, adverse effects are expected persist. Since trilostane is an enzyme blocker, adverse effects would be expected to quickly dissipate. However, adverse side effects have persisted in many trilostane over dosed dogs, and some have had adrenocortical necrosis. It is likely that trilostane is more expensive than o,p -DDD in most countries. Monitoring response to therapy is similar for both. Current Availability, Compounding Pharmacies Trilostane is available commercially as 5, 10, 30, 60, and 120 mg capsules in most countries and marketed under the brand name Vetoryl. Use of trilostane manufactured by compounding pharmacies is not supported by published studies and is not recommended. General Approach Once medication is started (always by owners in the home environment) owners should be phoned every day, just as with o,p -DDD to be certain that serious side effects have not been seen and to remind owners that this drug can be lethal if given in too high a dose. Trilostane-treated dogs should be rechecked after about 7 days of therapy. The protocol we now recommend on days of a scheduled veterinary examination are for the owner to collect a urine sample from their dog that morning. The dog should then be fed and the trilostane administered. Dog and urine should be brought to the veterinarian about 2 hours later. The ACTH response test should be started 2 to 3 hours after trilostane administration and the urine assessed for specific gravity and glucose. From this time forward, the same starting time (post trilostane administration) should be employed for every ACTH stimulation test. The goal in therapy is to have an owner state that their dog is improved in the shortterm (first weeks) and normal in the long-term (after 4 to 8 weeks). To aid in achieving this goal, urine specific gravity should be >1.020 and the post-acth serum cortisol concentration should be between 1.5 and 5.5 µg/dl. If the post-acth serum cortisol concentration is <1.5 µg/dl, the dose given BID should be reduced by about 50%. If the post-acth serum cortisol concentration is >5.5 g/dl, the dose given BID should be increased by ~ 25%. If the post-acth serum cortisol concentration is > 1.5 and < 5.5 g/dl, and the urine is >1.020, continue the dose being given. However, if the post- ACTH serum cortisol concentration is > 1.5 and < 5.5 g/dl, and the urine is <1.020, then the veterinarian should advise the owner that the drug will be more effective given three times daily. Most dogs treated using this protocol have an excellent response and ultimately receive 0.2 to 1.0 mg/kg BID. Goals of Therapy: Dogs with Obvious Signs versus Dogs with Questionable Signs As with o,p -DDD, the use of trilostane should be limited to dogs with obvious clinical signs and appropriate laboratory and imaging results. The goal in therapy: make the owner happy. In other words, resolving clinical signs is the best measure of success in resolving biochemical and other issues associated with chronic circulating excesses of cortisol. If a dog is diagnosed with naturally occurring hyperadrenocorticism, but without owner perceived obvious clinical signs, the diagnosis must be questioned. Cushing s is a clinical syndrome, never solely biochemical. No veterinarian should treat any dog for this condition unless being absolutely convinced that treatment would be recommended if the dog were their personal pet. Also, it can be beneficial to remember that naturally occurring hyperadrenocorticism is a chronic progressive condition. Whenever one is unsure if a particular dog really has this condition, whether a particular dog should be treated, it is best to wait 1 12 months to observe. Dogs with naturally occurring hyperadrenocorticism progressively exhibit worsening signs of polyuria, polydipsia, polyphagia, hair loss, muscle weakness, etc. If such an approach is taken, it is important to understand that progression does not affect treatment success rate, rather, it assures that treatment is employed for the correct condition.

5 Protocol: Initial and Continuing Dose It is recommended that all dogs treated with trilostane begin at about mg/kg, twice daily. The 0.3 to 0.5 mg/kg BID dose is for dogs less than 15 kg and the 0.1 to 0.3 mg/kg BID dose is for dogs weighing more than 20 kg. There is no loading dose or induction phase of treatment with trilostane. In addition, once a satisfactory dose is established, it usually does not change significantly unless the diet or health of the dog changes. The veterinary clinician begins trilostane in a search for the dose and frequency best for the dog being treated. Ideally, the initial dose would be too low and the inadequate response would allow the dose to be progressively raised until that needed by the individual patient is attained. This would also be the best protocol for avoiding serious adverse side effects. Our experience to date is that these low doses are not only beneficial, but the clinical signs of polyuria, polydipsia, polyphagia, panting, and inactivity resolve within weeks in some dogs on these low dose protocols. We recommend that trilostane therapy always be initiated at home, on a Sunday, with the owner administering the BID dose after feeding their dog. The owner should receive thorough information on the actions of trilostane and instructed to begin reducing their dog s food allotment by one-third beginning one or two days before treatment is begun. In other words, we have owners give their dog one-third of its normal food allotment twice daily, beginning on a Friday or Saturday. This should make the typical polyphagic Cushing s dog even more hungry. NOTE: NO DOG WITH A POOR APPETITE SHOULD EVER RECEIVE THIS DRUG! After the first 7 to 10 days of treatment, normal quantities of food should again be given. Trilostane administration should be continued twice daily for about 7-10 days until the first recheck. The owner should be instructed to measure their dog s daily water consumption and to note when it approaches 60 ml/kg/day. Owners should also observe their dog s appetite to determine if the polyphagia is resolving by seeing that their dog simply takes longer to consume a meal. Partial or complete inappetence, vomiting, or diarrhea would indicate that the dog has been over dosed or that a serious concurrent condition has developed. Any worrisome change should lead to the owner stopping therapy and contacting their veterinarian. The goal is simply to have a dog s appetite return to normal. The earliest and single most reliable and consistent indicator for a positive response to therapy is reduction of appetite, often noted within days of starting trilostane. Water intake in polydipsic dogs decreases, in more than 90% of dogs, within 5 to 10 days. In all, response takes a few days or weeks. Ideally, it would require about days to establish an appropriate dose, but improvement has been seen far quicker and more consistently faster than this. Monitoring Laboratory Variables Veterinarians have blood, urine, blood pressure, imaging, and culture testing available. Any test may be of importance in monitoring specific individuals. In general, it is wise to assess BUN, creatinine, sodium and potassium at any recheck, since these parameters could indicate need for reconsidering therapy. Hyperkalemia, hyponatremia, or azotemia should prompt discontinuing treatment. As a dog is treated, veterinarians gain a sense as to what should be assessed, but there is no specific guideline we recommend, aside from recheck every 4 months, once stability is achieved. Monitoring with ACTH Stimulation Timing the Stimulation Test. To support owner observations, veterinary recheck examinations are quite valuable in fine tuning trilostane treatment to the individual. On the morning of the scheduled veterinary recheck, the owner should collect a free-catch urine sample from the dog, feed as usual and administer the trilostane. About 2 hours after trilostane dosing, the dog should be seen by the veterinarian. An ACTH stimulation test should be started 2 to 3 hours after trilostane was given. That time point for starting the stimulation test after trilostane should be used for every subsequent test. In other words, if the test is begun at 2.5 hours, all ACTH stimulation tests for that dog should be started 2.5 hours after trilostane. Trilostane peak effect in most dogs is 2-3 hours after administration. We have not only shown significant reduction in trilostane effect when comparing stimulation tests started 3 versus 9 hours after trilostane, but we have demonstrated significant difference when comparing tests begun 2 versus 4 hours. By 4 hours, trilostane effect begin to dissipate in most dogs and by 9 hours it is likely having little effect. Thus, tests started just an hour or 2 earlier or later can significantly change results obtained. Also, this is the reason for using twice daily dosing initially.

6 Employing Stimulation Test Results to Determine Dose. The ACTH stimulation test result is used to determine trilostane dose. In general, if the post-acth plasma cortisol is about 2 to 5.5 µg/dl, trilostane dose is good. If the cortisol concentration is lower, the dose should be decreased. If the cortisol concentration is higher, the dose of trilostane may need to be increased. If the owner is satisfied with their dog s progress, rather than raise a dose, one may wait and observe. If the owner is still observing clinical signs, even if less pronounced, the dog may benefit from a dose increase. Employing Urinalysis to Determine Frequency of Trilostane Administration. Collected urine should always be assessed for glucose and the other components of a dip-stick. This discussion assumes urine negative for glucose. If positive, the dog has diabetes mellitus and will likely require exogenous insulin. Also, before employing the urine specific gravity as a component for adjusting dose, the post-acth plasma cortisol concentration should be in the range of 2 to 5.5 µg/dl. Once that is achieved, urine specific gravity can be used to determine the best dosing frequency. If the owner is pleased with response to treatment, the stimulation results acceptable and urine specific gravity >1.020, no change in dose or frequency is made. In this scenario, dogs receiving trilostane TID can be tried on BID, those receiving the drug BID can be tried on a once daily regimen. However, if the stimulation results are acceptable (2 to 5.5 µg/dl) but an owner is continuing to observe polyuria and other clinical signs of Cushing s syndrome in a dog whose specific gravity is <1.020, the duration of trilostane effect is likely too brief to resolve the condition. In these dogs, we recommend increasing the frequency while slightly decreasing each dose. If possible, when changing from once to twice daily or twice to three times daily, each dose should be about 10-20% less than currently being employed. About 20% of our long-term trilostane-treated dogs are treated once daily, with about 70% and 10% treated BID or TID, respectively. The Formula for Long-Term Success. A formula for how to determine who needs a dose adjustment and what kind is needed should be heavily tilted to owner opinion. Also, only dogs described as having a ravenous or excellent appetite should be treated. Successful management of Cushing s is always associated with appetite reduction. If a dog has a poor appetite, Cushing s is the least important concern. Owners are best at determining excellent response as opposed to an over or under dosage. Unreliable owners negatively impact treatment success. Use of urinalysis and urine specific gravity is slightly less important. ACTH stimulation test results should be the third and least important determinant, unless results are <1.5 µg/dl, a scenario in which every dog should have their dose reduced. Monitoring without ACTH Stimulation In geographic areas where ACTH is unavailable or prohibitively expensive, dogs with hyperadrenocorticism can still be treated and monitored, long-term, safely. Owner opinion is key is making dose adjustments, together with home-caught urine specific gravity and a morning, pre-treatment, plasma cortisol. Well controlled dogs usually have home-caught urine that has a specific gravity > If an owner begins to observe recurrence of clinical signs in a pet whose specific gravity is <1.020 and the plasma cortisol is >5.5 µg/dl, increase in dose is required. If the specific gravity is <1.020 and the plasma cortisol is µg/dl, increase in frequency is required. SURGERY: ADRENALECTOMY Adrenalectomy may be unilateral for an adrenocortical tumor or bilateral as a mode of therapy for PDH. It is recommended that this surgery be performed by specialists and in facilities capable of handling the potential postoperative complications. Once the diagnosis of hyperadrenocorticism due to an adrenal tumor has been confirmed, attempts should be made to localize the tumor and rule out metastasis or vascular invasion. Methods for tumor localization include abdominal radiographs, ultrasonography, CT scans, and gamma camera imaging. Ultrasonography has proven to be our most valuable and cost effective aid in tumor localization and for detecting vascular invasion or metastasis. If metastasis is suspected, an ultrasound guided biopsy can be performed to confirm this suspicion. Thoracic radiographs should also be evaluated for metastatic disease in the lung parenchyma.