An analysis of treatment and therapy options for the management of Cushing's disease in dogs, or canine pituitary dependent hyperadrenocorticism.
February 17, 2016|
Issue: March/April 2016
DVM, Diplomate ACVIM
David Bruyette, DVM, Diplomate ACVIM, is the medical director at VCA West Los Angeles Animal Hospital and President and CEO of Veterinary Diagnostic Investigation and Consultation. He was an assistant professor and head of internal medicine at Kansas State University and director of its Analytical Chemistry Laboratory. Dr. Bruyette received his DVM from University of Missouri and completed an internship at Purdue University and residency in internal medicine at University of California–Davis. He then became a staff internist at West Los Angeles Veterinary Medical Group and member of the Department of Comparative Medicine at Stanford University.
Read Articles Written by David Bruyette
Canine pituitary dependent hyperadrenocorticism (PDH), also known as Cushing’s disease, is a common endocrine disorder in older dogs. This disorder is caused by a pituitary adenoma (PA) that secretes inappropriate amounts of adrenocorticotropic hormone (ACTH), which results in bilateral adrenal hyperplasia and disorderly and excessive production of cortisol by the adrenal gland.
Read the first 2 articles of this series:
- (November/December 2015)
- Part 2: Diagnostic Approach (January/February 2016)
Therapeutic Approaches to Cushing’s Disease
In humans, while pituitary surgery is considered first-line treatment for patients with Cushing’s disease,1 medical therapy now plays a more important role in the armamentarium available to patients if surgery is not successful.2,3 Repeat surgery, bilateral adrenalectomy, and pituitary radiation are also frequently employed.1
In dogs, medical management is far more common than surgical approaches and generally involves the use of medications directed toward reducing adrenal glucocorticoid production.4,5 However, recent work on newer medical and surgical therapies and emerging treatments provides the clinician with multiple therapeutic options.
Medical treatments can be classified based on their mechanism of action and categorized as (Table 1):
- Adrenal-directed steroidogenesis inhibitors or adrenolytics
- Centrally acting agents
- Glucocorticoid receptor blockers.
In dogs, o,p’-DDD, also known as mitotane (Lysodren, bms.com), trilostane (Vetoryl, dechra .com), and ketoconazole (in many countries outside of the U.S.), are the most commonly used agents for canine Cushing’s disease, although several other agents have been used or are under investigation (Table 2).
Mitotane is a potent adrenocorticolytic agent derived from the insecticide dichlorodiphenyltrichloroethane (DDT). The goal of mitotane therapy is to achieve both pre- and post-cortisol measurements in the normal resting range (2–6 mcg/dL).
Pharmacodynamics. The drug causes progressive necrosis of the zona fasciculata and zona reticularis of the adrenal gland and, at higher doses, may also cause necrosis of the zona glomerulosa. Other effects of mitotane include fatty degeneration, centrilobular atrophy, and congestion of the liver.
Healthy dogs with and without hyperadrenocorticism (HAC) are usually quite resistant to the effects of the drug, but some may show adverse effects, such as gastric irritation, hypoadrenocorticism, and, very occasionally, neurologic signs.
Initial Therapy. Mitotane therapy is begun at a dose of 50 mg/kg, divided, Q 12 H.6,7 In dogs with significant nonadrenal illness, the dose of mitotane may be reduced by 50% and adjusted upward based on clinical and hormonal response. Administering the drug with food improves its gastrointestinal absorption. At induction doses, mitotane is typically administered for 5 to 10 days, until water consumption decreases to less than 100 mL/kg/day. At this point, the dog should be reevaluated and an ACTH stimulation test performed.
In patients that are not demonstrating polydipsia, or those in which water consumption cannot be monitored or polydipsia is due to another underlying disease (eg, diabetes mellitus), mitotane should be administered for a maximum of 5 to 7 days prior to ACTH stimulation testing.
Mitotane should be discontinued immediately if decreased appetite, depression, diarrhea, or vomiting is observed.
Maintenance Therapy. Maintenance therapy (50 mg/kg Q 7–10 days or 25 mg/kg Q 3 days) is started once the ACTH stimulation test demonstrates adequate suppression (pre- and post-cortisol measurements of ≥ 3 and ≤ 5 mcg/dL, respectively) and prednisone therapy (if necessary) has been discontinued (see Role of Prednisone). Failure to use maintenance therapy results in regrowth of the adrenal cortex and recurrence of clinical signs.
Efficacy of maintenance therapy is monitored by ACTH stimulation tests 1 month after initiation of maintenance therapy and every 3 to 4 months thereafter. The total weekly dose of mitotane required for long-term maintenance is quite variable (26–330 mg/kg/week), but therapy should always begin with the recommended initial dosage; then titrated to effect based on subsequent ACTH stimulation test results. If clinical signs return in conjunction with elevated cortisol concentrations post ACTH stimulation, the patient can be managed with higher, or more frequent, maintenance doses or a return to the induction protocol outlined in Initial Therapy.
Role of Prednisone. Glucocorticoids were typically administered in combination with mitotane therapy for many years, but it is no longer common to administer these drugs concurrently. However, prednisone therapy (0.2–0.5 mg/kg/day) should be initiated in patients with clinical signs of hypocortisolemia until results of the ACTH stimulation test are known.
A small supply of prednisone should be made available to the owner in the event of overdose of mitotane. However, dexamethasone can be used preferentially for emergency situations because it does not interfere with measurement of serum cortisol concentrations.
Treatment Considerations. Reasons for mitotane treatment failure include:
- Incorrect diagnosis
- Presence of an adrenal tumor (although some adrenal tumors do respond well)
- Loss of drug potency due to poor storage or compounding of mitotane
- Need for a higher dose or duration of treatment in some dogs.
Note that phenobarbital enhances the metabolism of mitotane, leaving it ineffective. Therefore, patients with Cushing’s disease and idiopathic epilepsy should be treated with other anticonvulsant drugs (eg, potassium bromide, levetiracetam).
Median survival time of 200 dogs treated with mitotane was 2.2 years (range, 10 days–8.2 years).6
Trilostane is a synthetic, hormonally inactive steroid analogue, which is a competitive inhibitor of the 3-beta-hydroxysteroid dehydrogenase system.
Pharmacodynamics. Trilostane blocks synthesis of adrenal steroids, including cortisol and aldosterone.8-14 It is rapidly absorbed orally (peak concentrations within 1.5 H), although suppression of plasma cortisol concentrations is short lived (< 20 H).
Trilostane is well tolerated in most dogs. Adverse effects are usually mild and self-limiting, and include diarrhea, vomiting, and lethargy in up to 63% of treated dogs.8,9 However, the percentage of dogs that develop adverse events is much lower when they are treated with current recommended (lower) starting doses. There have been anecdotal reports of acute death shortly after initiating trilostane treatment.
Initial Therapy. Current recommendations for trilostane use specify administration of an initial dose of 1 to 2 mg/kg Q 12 to 24 H. This dose is then increased or decreased based on evaluation of ACTH stimulation test results.15-17 Trilostane should be administered with food, including the days that ACTH stimulation tests are performed, to aid in absorption. Whenever possible the brand name preparation (Vetoryl, dechra.com) should be used to avoid inconsistencies in dose seen when using compounded medications.
ACTH stimulation testing should be performed 10, 30, and 90 days after initiation of treatment; then 30 days after each dose adjustment.18-21 While samples for testing can be collected either 4 or 6 H after drug administration, it is important that the same sampling time—4 or 6 H—always be maintained for a specific patient.
Maintenance Therapy. Hormonal end points are post cortisol concentrations less than 6 to 9 mcg/dL, in conjunction with remission of clinical signs. In patients that fail to reach clinical remission with continued elevations in post ACTH cortisol concentrations, the dose of trilostane should be increased by 25% and the pet retested in 7 to 10 days. If post ACTH cortisol concentrations demonstrate adequate hormonal control but clinical signs persist, twice daily dosing may be indicated. If you are switching from once daily to twice daily dosing, the once daily dose should be split in half and administered Q 12 H. For example, if the patient was initially on 60 mg Q 24 H, the dose would be changed to 30 mg Q 12 H.
Compared with higher doses administered Q 24 H, twice daily therapy, at a starting dose of 1 to 3 mg/kg, may:
- Result in good control of clinical signs, with less risk of adverse effects
- Be more effective at consistently controlling hypercortisolemia throughout the day
- Be appropriate as a starting dose in dogs with diabetes and other related complications of Cushing’s disease.22-26
Treatment Considerations. Occasionally, dogs receiving trilostane have developed hypoadrenocorticism, which is generally glucocorticoid deficient only, although dogs with evidence of mineralocorticoid deficiency have been reported. Trilostane-induced hypoadrenocorticism is generally reversible but, in rare cases, this may take several months, most likely due to adrenocortical necrosis. See Consider This Case, for a case example of trilostane therapy in a dog with PDH.
Mitotane Versus Trilostane for Canine Cushing’s Disease
Studies have compared trilostane and mitotane therapy in dogs with PDH or adrenal tumors.27-31 In a retrospective study of dogs treated with either mitotane (n = 25) or trilostane (n = 123), long-term survival was not statistically different between the groups. Median survival in the mitotane group was 708 days (range, 33–1399) and, in the trilostane group, 662 days (range, 8–1971). Of the dogs that died in this study, 11% died due to causes attributed to the underlying PDH, and a further 17% died of causes that may have been related to underlying PDH. In 38% of cases, cause of death could not be directly attributed to PDH and, in 34%, the cause of death was unknown.31
While ketoconazole was used more frequently in the past,32,33 its use now is generally in countries where mitotane and trilostane are not available, or when these agents have failed to correct hypercortisolism or resulted in adverse reactions. Its systemic use has recently been restricted or banned in several countries due to potential of significant hepatotoxicity in humans.
Pharmacodynamics. Specifically, ketoconazole has been shown to inhibit cholesterol side-chain cleavage enzyme, which converts cholesterol to pregnenolone, 17-alpha-hydroxylase, and 17,20-lyase—which convert pregnenolone into androgens—and 11-beta-hydoxylase, which converts 11-deoxycortisol to cortisol.
Efficacy. One study examined the safety and efficacy of ketoconazole in 48 dogs with PDH.34 Data collected from each record included signalment, clinical signs, results of ACTH stimulation tests before and after treatment with ketoconazole (10 mg/kg PO Q 12 H), serum alkaline phosphatase (ALP) and alanine aminotransferase (ALT) activities, dosage of ketoconazole, clinical response, and survival time.
Forty-three of 48 dogs (90%) had evidence of clinical improvement during the treatment period. In all dogs, treatment with ketoconazole resulted in significantly lower serum cortisol concentrations before and after ACTH stimulation testing; 69% (33/48) of serum cortisol concentrations measured after ACTH stimulation were within the basal resting range. Serum ALP and ALT activities significantly decreased after treatment with ketoconazole.
Prognosis. Survival time after diagnosis of PDH ranged from 2 to 61 months (mean, 26.9 months; median, 25 months).34 Another study evaluating ketoconazole found that after diagnosis, 50% of the dogs died approximately 1.8 to 2 years (range, 0.6–3) after starting therapy.35
Additional Therapeutic Options
Several other adrenal steroidogenesis inhibitors have been used in humans and, at times, in dogs (Table 2).36,37
A 10-year-old castrated male cocker spaniel was referred for evaluation of severe polyuria and polydipsia (PU/PD) of 3 months duration.
On physical examination no significant abnormalities were detected, with the exception of mild hepatomegaly. The skin and hair coat appeared to be normal.
Previous laboratory analysis, including a complete blood count and serum biochemical profile, was unremarkable, with the exception of a urine specific gravity (USG) of 1.010 and positive urine culture for Escherichia coli. The pet was treated with enrofloxacin (5 mg/kg Q 24 H) for 10 days; however, no change in the PU/PD was observed.
An ACTH stimulation test was performed, with a resting cortisol and 1-hour post cortisol results of 2.7 and 14.8 mcg/dL, respectively. These results were considered normal for the laboratory.
HAC was still considered to be the most likely differential cause for the PU/PD, despite the previously normal ACTH stimulation test, given the signalment, history, and clinical signs.
A low-dose dexamethasone suppression test (LDDS) was performed following IV administration of 0.01 mg/kg of dexamethasone. The resting cortisol, 4-hour post LDDS, and 8-hour post LDDS results were 5.1 (reference range, 1.4–5 mcg/dL), 1.2, and 4.6 mcg/dL, respectively.
The elevated 8-hour cortisol (reference range, < 1.4 mcg/dL), in combination with greater than 50% suppression in cortisol concentrations seen at 4 hours, was diagnostic of PDH.
Treatment options were discussed with the referring veterinarian and treatment with trilostane (Vetoryl) was recommended, starting with 2 mg/kg PO Q 24 H in the morning.
The owner was instructed to:
- Administer the medication with food to enhance gastrointestinal absorption
- Monitor the animal’s water consumption, urination, appetite, and activity level
- Observe for any adverse reactions, such as vomiting and diarrhea.
A recheck examination consisting of a physical examination and ACTH stimulation test with monitoring of electrolytes was scheduled 10 days following the start of medication.
At the time of the recheck examination, the owners reported a marked reduction in the PU/PD. An ACTH stimulation test was performed 4 hours post administration of trilostane, with pre and post ACTH cortisol concentrations 2.2 and 5.4 mcg/dL, respectively, indicating adequate adrenal suppression. Determination of electrolytes with an in-house chemistry analyzer was performed and sodium and potassium concentrations were within normal limits.
Due to the laboratory results, along with the observed improvement in clinical signs, the current dose of trilostane was continued and the pet scheduled for a recheck examination in 4 weeks.
During the subsequent recheck examination, the owners reported that the pet was more active, with normal water consumption and urination. A morning urine sample collected by the owner demonstrated a USG of 1.028. Electrolytes were within normal limits. The pre and post cortisol concentrations were 1.4 and 4.8 mcg/dL, respectively, indicating continued adequate adrenal suppression. The dose of trilostane was maintained and the pet scheduled for a recheck examination in 3 months.
Three- and 6-Month Rechecks
Three and 6 months later the pet was clinically normal. One episode of vomiting and diarrhea had occurred at 4.5 months, but the patient responded to the use of a bland diet, and clinical signs resolved in 24 hours, with no adjustments made to the treatment protocol. At the 3- and 6-month recheck examinations, electrolyte concentrations were within normal limits and post ACTH cortisol concentrations were less than 4.2 and 5 mcg/dL, respectively. The dose of trilostane was maintained and the pet scheduled for a recheck examination in 3 to 4 months.
This case illustrates several important points regarding Cushing’s disease and its treatment with trilostane. The referring veterinarian had 3 questions regarding this patient’s presentation and diagnostic results:
- The lack of clinical signs of Cushing’s disease other than PU/PD
- The normal initial ACTH stimulation test
- The finding of normal serum ALP on the initial laboratory evaluation.
PU/PD may be the only clinical sign of HAC. Dermatologic abnormalities, such as bilateral symmetric endocrine alopecia and pyoderma, need not be present.
ACTH Stimulation Test
Up to 15% to 20% of dogs with HAC have a normal ACTH stimulation test upon initial evaluation of the pituitary–adrenal axis. When faced with a patient that has clinical signs indicative of HAC but a normal ACTH stimulation test, consider LDDS to establish a diagnosis or rule out HAC. Conversely, up to 10% of dogs have an initially normal LDDS; therefore, if LDDS is used as the initial screening test and a normal test result is obtained, consider an ACTH stimulation test.
Serum ALP Results
Up to 20% of dogs do not have an elevated ALP in response to either exogenous or endogenous steroid excess, likely due to lack of the gene encoding for the steroid inducible isoenzyme.
The target hormonal goal for the ACTH stimulation test is considered a post ACTH cortisol of less than 9.1 mcg/dL. Together with improvement in clinical signs, this level of adrenal suppression indicates appropriate dosing with trilostane. In our hands, up to 80% of patients obtain clinical and hormonal improvement with once daily dosing.
Recent work on somatostatin and dopaminergic receptor changes in humans and dogs with Cushing’s disease has opened the door to targeted therapy of pituitary tumors. Such therapies not only result in decreased ACTH production but a reduction in tumor size. Several agents have been studied or are in clinical trials (Table 3).
The monoamine oxidase B inhibitor selegiline (L-deprenyl), which raises concentrations of dopamine in the brain, has been used to treat hyperadrenocorticism in dogs.43 The medication appears effective in 20% to 30% of patients with pars intermedia disease, with few side effects.44 Currently, it is used in PDH patients in which the cost of monitoring ACTH stimulation tests and electrolytes prohibits treatment with adrenal enzyme blockers or adrenolytics.
Several groups have described the successful use and complications associated with administration of transsphenoidal hypophysectomy (TSH) in dogs with PDH.45-47
Recently, Mamelak and colleagues described a technique for transsphenoidal removal of pituitary adenomas in 26 dogs with PDH using a high definition video telescope.47 Pituitary tumors were removed using a modified transoral transsphenoidal approach, and localization of the sella was performed by drilling pilot holes in the basisphenoid bone, followed by computed tomography. Sustained tumor control and hormonal remission based on normalized ACTH and urine cortisol creatinine ratio (UCCR) measurements were observed in 20/21 (95%) of dogs one year post surgery.
Tumor Size. In the study by Mamelak and colleagues,47 all dogs had tumors with pituitary height/brain area (P/B) ratios greater than 0.32 and a median P/B ratio of 0.73. Median tumor volume was 820 mm3, which is 9 times larger than the median volume of 89 mm3 reported by Hanson and colleagues, whose study reported mean tumor height of 6 mm, mean width of 6.2 mm, and mean height of 5.4 mm, with a median P/B ratio of 0.3. Forty-three percent of the dogs had a normal P/B ratio.45
Interestingly, Hanson and colleagues concluded that pituitary size (height) was the most significant predictor of postoperative survival and mortality.45 In those studies, initial remission of PDH occurred in 85% of dogs, with relapse in 28% by 3 years. Similarly, Hara and colleagues evaluated outcomes in 25 dogs that underwent TSH using the protocol of Meij and colleagues.46 Median P/B ratio was 0.38 (range, 0.24–0.71), and 24% of dogs had a normal P/B ratio.
Survival. Surgical experience is likely an important variable in dogs undergoing TSH. In the study by Hanson and colleagues, survival at 1, 2, 3, and 4 years were 86%, 83%, 80%, and 79% in 181 patients, respectively.45 Disease free intervals (DFIs) were 90%, 77%, 72%, and 68%, respectively.
In the study by Hara and colleagues, initial remission was attained in 84% of dogs, with 12% relapsing within 4 years. Survival rates at 1, 2, 3, and 4 years was 92%, 81%, 81%, and 81%, respectively.46 No data on DFIs were reported.
In the study by Mamelak and colleagues, 1-year survival was 81%, with all 5 deaths occurring within the first 5 days, with 100% of the surviving dogs in remission at 3 months and 95% in remission at 1 year. To date, 7 dogs have survived greater than 2 years and 1 dog greater than 3 years.47
Further Investigation. Continued experience with surgery to remove pituitary tumors in both dogs and cats is important to not only improve survival and DFIs but also facilitate continued collection of tumor tissue, allowing for additional studies on pathogenesis of this disease and novel therapies for both humans and pets.
The most commonly used treatments in the management of PDH are mitotane and trilostane. Most clinicians prefer the use of trilostane, given similar efficacy and fewer side effects when compared with mitotane, especially at the lower dosages currently being recommended. In the future, expanded use of TSH and medications that are pituitary—rather than adrenal—directed should help increase survival and improve the quality of life of patients diagnosed with PDH.
ACTH = adrenocorticotropic hormone; ALP = alkaline phosphatase; ALT = alanine aminotransferase; a-MSH = alpha-melanocyte stimulating hormone; DDT = dichlorodiphenyltrichloroethane; DFI = disease free interval; EGFR = epidermal growth factor receptor; HAC = hyperadrenocorticism; LDDS = low-dose dexamethasone suppression; PA = pituitary adenoma; P/B = pituitary height/brain area; PDH = pituitary dependent hyperadrenocorticism; POMC = proopiomelanocortin; PU/PD = polyuria/polydipsia; SSR = somatostatin receptor; TSH = transsphenoidal hypophysectomy; UCCR = urine cortisol creatinine ratio; USG = urine specific gravity
Read More on Cushing’s Disease in Dogs
•Part 1: An Overview
•Part 2: Diagnostic Approach
- Nieman L, Biller B, Findling J, et al. Treatment of Cushing’s syndrome: An endocrine society clinical practice guideline. J Clin Endocrinol Metab 2015; 100(8):2807–2831.
- Cuevas-Ramos D, Fleseriu M. Treatment of Cushing’s disease: A mechanistic update. J Endocrinol 2014: 223:R19-R39.
- Lau D, Rutledge C, Aghi M. Cushing’s disease: Current medical therapies and molecular insights guiding future therapies. Neurosurg Focus 2015; 38(2):1-10.
- de Bruin C, Meij BP, Kooistra HS, et al. Cushing’s disease in dogs and humans. Horm Res 2009; 71:140-143.
- Braddock JA. Medical treatment of hyperadrenocorticism in the dog. Aust Vet J 2003; 81(1-2):31-33.
- Kintzer P, Peterson M. Mitotane (o,p’-DDD) treatment of 200 dogs with pituitary-dependent hyperadrenocorticism. J Vet Intern Med 1999; 5:182-190.
- den Hertog E, Braakman J, Teske E, et al. Results of non-selective adrenocorticolysis by o, p’-DDD in 129 dogs with pituitary dependent hyperadrenocorticism. Vet Rec 1999; 144:12-17.
- Ruckstuhl NS, Nett CS, Reusch CE. Results of clinical examinations, laboratory tests, and ultrasonography in dogs with pituitary-dependent hyperadrenocorticism treated with trilostane. Am J Vet Res 2002; 63(4):506-512.
- Neiger R, Ramsey I, O’Connor J, et al. Trilostane treatment of 78 dogs with pituitary-dependent hyperadrenocorticism. Vet Rec 2002; 150(26):799-804.
- Braddock JA, Church DB, Robertson I, et al. Trilostane treatment in dogs with pituitary-dependent hyperadrenocorticism. Aust Vet J 2003; 81(10):600-607.
- Wenger M, Sieber-Ruckstuhl NS, Müller C, et al. Effect of trilostane on serum concentrations of aldosterone, cortisol, and potassium in dogs with pituitary-dependent hyperadrenocorticism. Am J Vet Res 2004; 65(9):1245-1250.
- Sieber-Ruckstuhl N, Boretti F, Wenger M, et al. Cortisol, aldosterone, cortisol precursor, androgen and endogenous ACTH concentrations in dogs with pituitary-dependent hyperadrenocorticism treated with trilostane. Dom Anim Endocrinol 2006; 31:63-75.
- Bell R, Neiger R, McGrotty Y, Ramsey IK. Study of the effects of once daily doses of trilostane on cortisol concentrations and responsiveness to adrenocorticotrophic hormone in hyperadrenocorticoid dogs. Vet Rec 2006; 159(9):277-281.
- Sieber-Ruckstuhl NS, Boretti FS, Wenger M, et al. Serum concentrations of cortisol and cortisone in healthy dogs and dogs with pituitary-dependent hyperadrenocorticism treated with trilostane. Vet Rec 2008; 163(16):477-481.
- Feldman EC, Kass PH. Trilostane dose versus body weight in the treatment of naturally occurring pituitary-dependent hyperadrenocorticism in dogs. J Vet Intern Med 2012; 26(4):1078-1080.
- Cho KD, Kang JH, Chang D, et al. Efficacy of low- and high-dose trilostane treatment in dogs (< 5 kg) with pituitary-dependent hyperadrenocorticism. J Vet Intern Med 2013; 27(1):91-98.
- Fracassi F, Corradini S, Floriano D, et al. Prognostic factors for survival in dogs with pituitary-dependent hypercortisolism treated with trilostane. Vet Rec 2015; 176(2):49-54.
- Reid LE, Behrend EN, Martin LG, et al. Effect of trilostane and mitotane on aldosterone secretory reserve in dogs with pituitary-dependent hyperadrenocorticism. J Vet Intern Med 2014; 28(2):443-450.
- Griebsch C, Lehnert C, Williams GJ, et al. Effect of trilostane on hormone and serum electrolyte concentrations in dogs with pituitary-dependent hyperadrenocorticism. J Vet Intern Med 2014; 28(1):160-165.
- Burkhardt WA, Boretti FS, Reusch CE, et al. Evaluation of baseline cortisol, endogenous ACTH, and cortisol/ACTH ratio to monitor trilostane treatment in dogs with pituitary-dependent hypercortisolism. J Vet Intern Med 2013; 27(4):919-923.
- Cook AK, Bond KG. Evaluation of the use of baseline cortisol concentration as a monitoring tool for dogs receiving trilostane as a treatment for hyperadrenocorticism. JAVMA 2010; 237(7):801-805.
- Alenza DP, Arenas C, Lopez ML, Melian C. Long-term efficacy of trilostane administered twice daily in dogs with pituitary-dependent hyperadrenocorticism. JAAHA 2006; 42(4):269-276.
- Feldman EC. Evaluation of twice-daily lower-dose trilostane treatment administered orally in dogs with naturally occurring hyperadrenocorticism. JAVMA 2011; 238(11):1441-1351.
- Augusto M, Burden A, Neiger R, Ramsey I. A comparison of once and twice daily administration of trilostane to dogs with hyperadrenocorticism. Tierarztl Prax Ausg K Kleintiere Heimtiere 2012; 40(6):415-424.
- Arenas C, Melián C, Pérez-Alenza MD. Long-term survival of dogs with adrenal-dependent hyperadrenocorticism: A comparison between mitotane and twice daily trilostane treatment. J Vet Intern Med 2014; 28(2):473-480.
- Braun C, Boretti FS, Reusch CE, et al. Comparison of two treatment regimens with trilostane in dogs with pituitary-dependent hyperadrenocorticism. Schweiz Arch Tierheilkd 2013; 155(10):551-558.
- Arenas C, Melián C, Pérez-Alenza MD. Evaluation of 2 trilostane protocols for the treatment of canine pituitary-dependent hyperadrenocorticism: Twice daily versus once daily. J Vet Intern Med 2013; 27(6):1478-1485.
- Reine NJ. Medical management of pituitary-dependent hyperadrenocorticism: Mitotane versus trilostane. Top Companion Anim Med 2012; 27(1):25-30.
- Helm JR, McLauchlan G, Boden LA, et al. A comparison of factors that influence survival in dogs with adrenal dependent hyperadrenocorticism treated with mitotane or trilostane. J Vet Intern Med 2011; 25(2):251-260.
- Clemente M, De Andrés PJ, Arenas C, et al. Comparison of non-selective adrenocorticolysis with mitotane or trilostane for the treatment of dogs with pituitary-dependent hyperadrenocorticism. Vet Rec 2007; 161(24):805-809.
- Barker EN, Campbell S, Tebb AJ, et al. A comparison of the survival times of dogs treated with mitotane or trilostane for pituitary-dependent hyperadrenocorticism. J Vet Intern Med 2005; 19(6):810-815.
- Peterson ME. Medical treatment of canine pituitary-dependent hyperadrenocorticism (Cushing’s disease). Vet Clin North Am Small Anim Pract 2001; 31(5):1005-1014.
- Feldman E, Bruyette D, Nelson R. Plasma cortisol response to ketoconazole administration in dogs with hyperadrenocorticism. JAVMA 1990; 197:71-78.
- Lien YH, Huang HP. Use of ketoconazole to treat dogs with pituitary-dependent hyperadrenocorticism: 48 cases (1994-2007). JAVMA 2008; 233(12):1896-1901.
- Castillo V, Gomez N, Lalia J, et al. Cushing’s disease in dogs: Cabergoline treatment. Res Vet Sci 2008; 85(1):26-34.
- Daniel E, Newell-Price J. Steroidogenesis enzyme inhibitors in Cushing’s syndrome. Eur J Endocrinol 2015; 17:263-280.
- Fleseriu M, Petersenn S. Medical therapy for Cushing’s disease: Adrenal steroidogenesis inhibitors and glucocorticoid receptor blockers. Pituitary 2015; 18:245-252.
- Pérez AM, Guerrero B, Melián C, et al. Use of aminoglutethimide in the treatment of pituitary-dependent hyperadrenocorticism in the dog. J Small Anim Pract 2002; 43(3):104-108.
- Orth DN, Peterson ME, Drucker WD. Plasma immunoreactive proopiomelanocortin peptides and cortisol in normal dogs and dogs with Cushing’s syndrome: Diurnal rhythm and responses to various stimuli. Endocrinol 1988; 122(4):1250-1262.
- Dodam JR, Kruse-Elliott KT, Aucoin DP, Swanson CR. Duration of etomidate-induced adrenocortical suppression during surgery in dogs. Am J Vet Res 1990; 51(5):786-788.
- Kruse-Elliott KT, Swanson CR, Aucoin DP. Effects of etomidate on adrenocortical function in canine surgical patients. Am J Vet Res 1987; 48(7):1098-1100.
- Bertagna X, Pivonello R, Fleseriu M. LCI699, a potent 11 beta-hydroxylase inhibitor, normalizes urinary cortisol in patients with Cushing’s disease: Results from a multicenter, proof-of-concept study. J Clin Endocrinol Metab 2014; 99(4):1375-1383.
- Bruyette D. Canine pituitary-dependent hyperadrenocorticism: A spontaneous animal model for neurodegenerative disorders and their treatment with L-deprenyl. In Yu P, Tipton K, Boulton A (eds): Current Neurochemical and Pharmacological Aspects of Biogenicamines. Prog Brain Res 1995; 106:207-215.
- Peterson ME. Medical treatment of canine pituitary-dependent hyperadrenocorticism (Cushing’s disease). Vet Clin North Am Small Anim Pract 2001; 31(5):1005-1014, viii.
- Hanson JM, Teske E, Voorhout G, et al. Prognostic factors for outcome after transsphenoidal hypophysectomy in dogs with pituitary-dependent hyperadrenocorticism. J Neurosurg 2007; 107(4):830-840.
- Hara Y, Teshima T, Taoda T, et al. Efficacy of transsphenoidal surgery on endocrinological status and serum chemistry parameters in dogs with Cushing’s disease. J Vet Med Sci 2010; 72(4):397-404.
- Mamelak AN, Owen TJ, Bruyette D. Transsphenoidal surgery using a high definition video telescope for pituitary adenomas in dogs with pituitary dependent hypercortisolism: Methods and results. Vet Surg 2014; 43(4):369-379.
- Castillo V, Theodoropoulou M, Stalla J, et al. Effect of SOM230 (pasireotide) on corticotropic cells: Action in dogs with Cushing’s disease. Neuroendocrinol 2011; 94:124-136.
- Robben JH, van den Brom WE, Mol JA. Effect of octreotide on plasma concentrations of glucose, insulin, glucagon, growth hormone, and cortisol in healthy dogs and dogs with insulinoma. Res Vet Sci 2006; 1:25-32.
- Pivonello R, Ferone D, De Herder W, et al. Dopamine receptor expression and function in corticotroph pituitary tumors. J Clin Endocrinol Metab 2004; 89:2452-2462.
- Petrossians P, Thonnard A, Beckers A. Medical treatment in Cushing’s syndrome: Dopamine agonists and cabergoline. Neuroendocrinol 2010; 92:116-119.
- Bondioni S, Angioni A, Corbetta S. Effect of 9-cis retinoic acid on dopamine d2 receptor expression in pituitary adenoma cells. Exp Biol Med 2008; 233(4):439-446.
- Giraldi F, Ambrogio A, Andrioli M. Potential role for retinoic acid in patients with Cushing’s disease. J Clin Endocrinol Metab 2012; 97(10):3577-3583.
- Castillo V, Giacomini D, Páez-Pereda M. Retinoic acid as a novel medical therapy for Cushing’s disease in dogs. Endocrinol 2006; 147(9):4438-4444.
- Fukuoka H, Cooper O, Ben-Shlomo A, et al. EGFR as a therapeutic target for human, canine, and mouse ACTH-secreting pituitary adenomas. J Clin Invest 2011; 121:4712-4721.
What is the best treatment for Cushing's disease in dogs? ›
The only way to "cure" Cushing's disease is to remove the adrenal tumor if the disease is adrenal-dependent and the tumor hasn't spread, says Stohlman. However, because of the complexity and risks of the surgery, most cases are treated with medication.What investigations may be required to aid in the diagnosis and management of Cushing's syndrome? ›
Urine and blood tests.
Urine and blood samples will be sent to a laboratory to be analyzed. Your doctor might also recommend other specialized tests that involve measuring cortisol levels before and after using hormone medications to stimulate or suppress cortisol.
In general, a dog with untreated Cushing's can actually live as long as a treated dog, but will likely have more side effects (over time) from the disease if not treated.How long can a dog live with Cushing's disease with treatment? ›
According to the American Kennel Club the average survival time for a dog with Cushing's is about two years, with only 10 percent living beyond the four-year mark.What is the best natural treatment for Cushing's disease in dogs? ›
A combination of Melatonin and Lignans offer an excellent natural treatment for both Cushing's and Atypical Cushing's disease in dogs. In fact, supplementing with melatonin and lignans helps your dog's system return to normal.What are the final stages of Cushings disease in dogs? ›
As the disease progresses, dogs lose muscle and become weak. Owners might notice a thinning of the skin, lesions on the skin, and hair loss on the flanks, neck, and perineum. Obesity and lack of energy are also symptoms.Which is the single first-line of treatment of a Cushing syndrome case? ›
Surgery is the first-line treatment in patients with Cushing's syndrome (CS), but preoperative medical therapy (PMT) is often given, in order to control cortisol excess and correct severe comorbidities prior to the surgical procedure (1, 2).What is the first-line treatment for Cushing's syndrome? ›
Essential Points. The Endocrine Society recommends that the first-line treatment for endogenous Cushing's syndrome be the removal of the tumor unless surgery is not possible or unlikely to address the excess cortisol.What are the 3 components of Cushing's triad? ›
Cushing's triad refers to a set of signs that are indicative of increased intracranial pressure (ICP), or increased pressure in the brain. Cushing's triad consists of bradycardia (also known as a low heart rate), irregular respirations, and a widened pulse pressure.Are dogs in pain with Cushing's disease? ›
Most dogs with Cushing's are not in any pain and their symptoms can be easily managed through medication. Dogs that have developed the condition due to a tumor on the adrenal gland may require the tumor to be surgically removed as these tumors are aggressive.
How do dogs feel when they have Cushing's disease? ›
The increased appetite is a direct result of elevated levels of cortisol, which stimulate appetite. Lethargy (drowsiness or lack of activity) and a poor hair coat are also common in pets with hyperadrenocorticism. "Many dogs with Cushing's disease develop a bloated or pot-bellied appearance."What causes death in dogs with Cushing's? ›
Glands near the kidneys produce cortisone necessary for health. Unbalanced levels are unhealthy and can cause illness and even death. Too little and sudden death can occur, too much results in Cushing syndrome. Too much cortisone over a long period of time can also result in death.Should I walk my dog with Cushing's disease? ›
Dogs with Cushing's disease can benefit from daily exercise. You may need to start small and build up to a more rigorous activity, but gentle, daily exercise can help control weight gain and sustain energy in a Cushing's dog.Do dogs with Cushings get aggressive? ›
Aggression, increased pursuance of food and water, exercise intolerance, lethargy, and difficulty moving around in their day-to-day environments (navigating stairs, going up onto elevated surfaces, etc.) are some of the behavior changes commonly seen in dogs afflicted by Cushing's disease.What happens if I don't treat my dogs Cushings disease? ›
If Cushing's disease is left untreated, dogs tend to become progressively lethargic and weak. They have an increased susceptibility to contracting infections (particularly urinary infections) and the skin is slow to heal after any injury.What foods should dogs avoid with Cushing's disease? ›
First and foremost, avoid feeding your dog table scraps and treats that are fatty or high in sugar, and instead follow your veterinarian's recommendations to find the right Cushing's disease diet for your dog.Is raw food good for dogs with Cushing's? ›
It is thought that dogs who suffer from Cushing's disease (hyperadrenocorticism), hyperthyroidism and diabetes may also be at risk. In terms of treatment there is every reason to continue raw feeding since this is the easiest food for your dog to digest.What does melatonin do for dogs with Cushings? ›
“What I use melatonin most commonly for is the treatment of Cushing's disease,” Morgan says. The supplement helps the body block the uptake of increased cortisone caused by a benign tumor on the pituitary gland, she says. Cushing's disease can also be caused by a tumor on an adrenal gland.How does Cushing's cause death? ›
Vascular disease is the main cause of death in CS patients (2, 4, 8, 12, 14). Indeed, the risk of cardiovascular and cerebrovascular events is greater in patients with active CS as compared with the general population and persists during long-term follow-up, even after remission has been achieved (7, 14).What are the 4 underlying causes of Cushing's syndrome? ›
Cushing's syndrome can be caused by overuse of cortisol medication, as seen in the treatment of chronic asthma or rheumatoid arthritis (iatrogenic Cushing's syndrome), excess production of cortisol from a tumor in the adrenal gland or elsewhere in the body (ectopic Cushing's syndrome) or a tumor of the pituitary gland ...
What is the treatment of choice for Cushing's disease? ›
Treatment of choice for classic Cushing disease is transsphenoidal surgery by an experienced neurosurgeon. The goal of surgery is to remove the adenoma, preserving as much pituitary function as possible. The more extensive the mass and the resulting resection, the greater the risk for loss of pituitary function.What is the most common psychiatric manifestation of Cushing syndrome? ›
Depression is the most prevalent psychiatric disturbance in Cushing's syndrome. A major depressive syndrome is seen in 50%–70% of the cases .How long does it take to reverse Cushing's syndrome? ›
If treatment removes the source of excess cortisol, most of the symptoms of Cushing's syndrome disappear within 12 months. Osteoporosis begins to improve within six months and continues to improve over several years.How quickly does Cushing's progress? ›
Because Cushing's progresses slowly and gradually, in most cases, it can go unrecognised for quite some time, sometimes resulting in depression. Looking back, many patients realise that there were clues to the condition two or more years before they were referred to an endocrinologist.How do you reverse Cushing's disease naturally? ›
Slow down with the salt. Excess cortisol from Cushing's syndrome can increase blood pressure, leading to hypertension. Avoid processed foods packed with sodium, which contributes to high blood pressure. Focus on fruits, vegetables, and reduced-sodium soups, dressing, and spreads.What 3 signs and symptoms are present in Cushing's reflex? ›
The Cushing reflex classically presents as an increase in systolic and pulse pressure, reduction of the heart rate (bradycardia), and irregular respiration.What are the investigations of Cushing syndrome? ›
Diagnosis of Cushing's syndrome is based on a review of your medical history, physical examination and laboratory tests, which help to determine the presence of excess levels of cortisol. Often X-ray exams of the adrenal or pituitary glands are useful for locating tumors.What is the most important nursing intervention when caring for a patient with Cushing's syndrome? ›
Limiting fluid intake is important in preventing circulatory overload. Encourage the client to have low sodium and high potassium diet. Too much sodium in the diet promotes fluid retention and weight gain. There should be an adequate potassium in the diet since the elevation of cortisol level causes hypokalemia.Does Cushing's affect dogs eyes? ›
Cushing's disease in dogs is associated with a number of ophthalmologic abnormalities, including corneal abnormalities (such as corneal degeneration and ulceration), keratoconjunctivitis sicca, lipemia of the aqueous humor and/or retina, and hypertensive chorioretinopathy.What happens if Vetoryl doesnt work? ›
Without a constant supply of Vetoryl, cortisol production will increase and your dog may start to display symptoms of Cushing's once more.
Do dogs with Cushing's have anxiety? ›
The symptoms of Cushing's disease in dogs are similar to some of the side effects human patients experience when taking steroids. Symptoms of Cushing's disease in dogs may include: Restlessness, which may include senior dog anxiety at night.What age is considered old for most dogs? ›
Small dogs are considered senior citizens of the canine community when they reach 11-12 years of age. Their medium-sized friends become seniors at 10 years of age. Their larger-sized colleagues are seniors at 8 years of age. And, finally, their giant-breed counterparts are seniors at 7 years old.Why do dogs tremble Cushings? ›
Turning off the adrenal gland results in too little cortisol production. Too little cortisol production leads to a myriad of clinical signs including weakness, vomiting, lethargy, shaking, and even total collapse.How long can a dog live on trilostane? ›
Survival times of dogs treated with trilostane or Lysodren are similar (about 600-900 days).How can I help my dog with Cushing's disease? ›
Most veterinarians treat both adrenal- and pituitary-dependent Cushing's disease with medication. The only way to "cure" Cushing's disease is to remove the adrenal tumor if the disease is adrenal-dependent and the tumor hasn't spread, says Stohlman.Can Cushings in dogs cause neurological problems? ›
Most of the time, these tumors are small and benign, yet they produce a hormone that stimulates the adrenal glands to produce cortisol. Uncommonly, these tumors are very large and can result in neurological problems in your pet.What is the best food to feed a dog with Cushing's disease? ›
Dogs with Cushing's do best on a diet based on a highly digestible protein. Protein helps to prevent muscle wasting, a common side effect of Cushing's disease. Some examples of highly digestible protein sources include egg whites, beef, chicken, lamb, salmon, and organ meats.Should you treat an older dog with Cushing's disease? ›
Usually treatment for Cushing's is not even recommended unless the dog has clinical signs because treatment does not necessarily change their overall life span - it just keeps them from being polyuric (urinating a lot), polydypsic (drinking a lot), losing their hair, etc.Should you withhold water from a dog with Cushings? ›
You must continually monitor your dog's food and water intake. Both should return to a normal level. Water intake should be less than 1 ounce per pound (66 ml per kilogram) of body weight per day, but do not limit the water if your dog needs to drink more.When is it time to put a dog down with Cushings? ›
- Abnormal thirst levels in your dogs.
- High urination levels.
- A sudden increase in appetite.
- Thinning of fur coat due to hair fall.
- A rapid increase in the weight of your pet.
- Your pet is out of breath and panting at fairly low activity levels.
- Low level of energy.
How long can a senior dog live with Cushings? ›
According to the American Kennel Club the average survival time for a dog with Cushing's is about two years, with only 10 percent living beyond the four-year mark. That said, it's important to remember that most cases of Cushing's disease are diagnosed in elderly dogs.What is the prognosis for a dog with Cushing's disease? ›
The prognosis for most dogs with Cushing's disease is excellent, particularly those patients that are diagnosed prior to the onset of complications such as insulin resistance and kidney issues. Most patients can be adequately managed for years by an experienced doctor and routine follow up.What happens if you stop giving your dog Vetoryl? ›
If VETORYL Capsules are discontinued or not given as directed, excess cortisol production can resume and the signs of hyperadrenocorticism can return.Can a dog live a normal life with Cushing's disease? ›
Usually, a dog can live an active, normal life with medication to treat the condition, though they'll need it for the rest of their life. Drugs are best for dogs with Cushing's syndrome caused by the pituitary gland or for those with a tumor on their adrenal gland that can't be removed with surgery.What foods should you avoid with Cushing's disease? ›
Slow down with the salt
Excess cortisol from Cushing's syndrome can increase blood pressure, leading to hypertension. Avoid processed foods packed with sodium, which contributes to high blood pressure. Focus on fruits, vegetables, and reduced-sodium soups, dressing, and spreads.
Pituitary gland tumor.
The most common cause of Cushing's disease (85% - 90% of all cases) is a tumor of the pituitary gland (which is located at the base of the brain). The tumor may be either benign (harmless) or malignant (cancerous).
First and foremost, avoid feeding your dog table scraps and treats that are fatty or high in sugar, and instead follow your veterinarian's recommendations to find the right Cushing's disease diet for your dog.What foods help Cushings? ›
Cushing syndrome can lead to high blood glucose, so try to limit foods that can cause a rise in blood sugar. Examples of foods to focus on eating include vegetables, fruits, whole grains, and fish. Cut back on sodium. Cushing syndrome is also associated with high blood pressure (hypertension).Does Cushing's in dogs cause leg weakness? ›
Does Cushing's Disease cause hind leg weakness in dogs? Hind leg weakness in dogs with Cushing's Disease is common. In Cushing's excessive cortisol causes muscles to weaken which can make it difficult for a dog with Cushing's to stand up unassisted or climb the stairs.What vitamins are good for Cushing's disease? ›
Vitamin D and calcium supplements are recommended for people receiving long-term corticosteroids. Potassium. Potassium levels are low in individuals with Cushing's syndrome, and low potassium levels are a significant determinant of cardiovascular complications in this population.
What are the neurological signs of Cushing's disease in dogs? ›
About 20% of dogs with PDH eventually develop an expanding pituitary tumor, clinical signs include lethargy, behaviour changes, nervousness, anorexia, weight loss, circling, ataxia, disorientation, head pressing, seizures, stupor.How much water should a dog with Cushing's drink? ›
You must continually monitor your dog's food and water intake. Both should return to a normal level. Water intake should be less than 1 ounce per pound (66 ml per kilogram) of body weight per day, but do not limit the water if your dog needs to drink more.Can dogs live comfortably with Cushing's disease? ›
The ultimate age for a dog to survive with Cushing's is approximately three years. However, in some cases there is a survival rate of two years. Dogs with the disease can have a good quality of life if they're closely monitored by a vet.How does melatonin help dogs with Cushings? ›
“What I use melatonin most commonly for is the treatment of Cushing's disease,” Morgan says. The supplement helps the body block the uptake of increased cortisone caused by a benign tumor on the pituitary gland, she says. Cushing's disease can also be caused by a tumor on an adrenal gland.