J Vet Intern Med 2005;19:810815

A Comparison of the Survival Times of Dogs Treated with Mitotane or Trilostane for Pituitary-Dependent Hyperadrenocorticism
E.N. Barker, S. Campbell, A.J. Tebb, R. Neiger, M.E. Herrtage, S.W.J. Reid, and I.K. Ramsey
The survival times of 148 dogs treated for pituitary-dependent hyperadrenocorticism were studied using clinical records from 3 UK veterinary centers between 1998 and 2003. Of these animals, 123 (83.1%) were treated with trilostane, while 25 (16.9%) were treated with mitotane. Treatment groups were compared using t-tests and analysis of variance (or their nonparametric equivalents) and chi-square tests. Survival data were analyzed using Kaplan-Meier survival plots and Cox proportional hazard methods. There was no signicant difference between the population attributes from each center or between treatment groups. The median survival time for animals treated with trilostane was 662 days (range 81,971) and for mitotane it was 708 days (range 331,399). There were no signicant differences between the survival times for animals treated with trilostane and those treated with mitotane. In the multivariable model (including drug, center, breed group, weight, diagnostic group, and age at diagnosis), only age at diagnosis and weight were signicantly negatively associated with survival. Importantly, there was no signicant effect of drug choice on survival. Key words: Canine; Cushings disease; Endocrine; Prognosis; Therapy.

pontaneous hyperadrenocorticism (HAC) is one of the most common endocrine diseases of the dog. It results from the overproduction of steroid hormones from the adrenal cortex. The most common cause is a functional pituitary neoplasm, which secretes excessive adrenocorticotropic hormone (ACTH) resulting in overstimulation of the adrenal glands. Pituitary-dependent hyperadrenocorticism (PDH) accounts for approximately 8085% of cases.1,2 The majority of the remaining dogs have functional adrenocortical neoplasms leading to adrenal-dependent hyperadrenocorticism (ADH). The excess adrenocortical hormones can result in a number of nonspecic clinical signs, which are reviewed elsewhere.1 The majority of the clinical signs, while not immediately life threatening, have a considerable impact on the animals quality of life. Therefore, this condition is usually treated and there are no studies on the causes of death in a large series of untreated cases. PDH is mostly treated medically, although surgical options have been described.3 In North America and, until recently, in Europe, HAC is usually treated with mitotane (o,p DDD), an adrenocorticolytic drug. Recent studies from Europe have found trilostane, a competitive 3 -hydroxysteroid dehydrogenase inhibitor, to be an effective alternative in the treatment of canine PDH.4,5 In addition, there have been reports of the treatment of HAC using ketoconazole, selegiline hydrochloride, and aminoglutethimide.68
From the Department of Veterinary Clinical Studies, University of Glasgow, Bearsden Road, Bearsden, Glasgow G61 1QH Scotland (Barker, Campbell, Tebb, Reid, Ramsey); Small Animal Clinic (Internal Medicine), Justus-Liebig Universitat Giessen, Giessen, Germany (Neiger); Department of Clinical Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, UK (Herrtage). This study was previously presented in abstract form at the 47th British Small Animal Veterinary Association Annual Congress, April 14, 2004, Birmingham, UK. Reprint requests: Ian K. Ramsey, Veterinary Clinical Sciences, University of Glasgow Veterinary School, Bearsden Road, Bearsden G61 1QH, UK; e-mail: I.Ramsey@vet.gla.ac.uk. Received September 20, 2004; Revised March 16, 2005; Accepted June 21, 2005. Copyright 2005 by the American College of Veterinary Internal Medicine 0891-6640/05/1906-0004/$3.00/0

Mitotane binds covalently to adrenal proteins before being converted to a reactive metabolite, resulting in the destruction of adrenal tissue. Destruction of the adrenal cortices can be partial or complete, depending on dose and frequency of administration. Complete destruction results in hypoadrenocorticism requiring long-term steroid replacement therapy.9 Partial destruction involves induction and maintenance periods.10 Trilostane is an orally active steroid analogue that acts as a competitive inhibitor of 3 -hydroxysteroid dehydrogenase, interrupting the synthesis of several steroids, including cortisol. To date, there have been no studies published that directly compare the use of mitotane to trilostane in the treatment of canine PDH. The hypothesis of this study was that there was no signicant difference between the survival times of dogs with PDH that had been treated with trilostane and those that had been treated with mitotane.

Materials and Methods

Clinical Cases
The medical records of all dogs that were diagnosed with PDH at three referral-only hospitals, from January 1, 1998, to July 7, 2003, were reviewed. The centers involved were the Queens Veterinary School Hospital of the University of Cambridge (center 1), the Small Animal Hospital of the University of Glasgow (center 2), and the Queen Mother Hospital for Small Animals of the Royal Veterinary College (center 3). A small number of the cases in all the centers were referred from 1st opinion charity practices associated with these institutions; however, their investigation and treatment protocols were no different from other cases referred from private practitioners. These cases included some dogs that had been evaluated in a previous study into the efcacy of trilostane in the treatment of PDH.4 Only animals that had been treated medically for PDH with either mitotane or trilostane and that had sufcient case records available were included. Animals that had not been treated, had been managed surgically, or had been given more than 1 drug for the treatment of HAC were excluded. Data obtained from the records included breed, sex, weight at diagnosis, age at diagnosis, date of diagnosis, treatment given, and date of treatment initiation where recorded. Date of death, date at which point they were lost to follow-up or survival to July 7, 2003, were also recorded. When needed, referring veterinarians and owners were contacted. The results of pretreatment ACTH stimulation tests, lowand high-dose dexamethasone suppression tests (LDDSTs, HDDSTs), endogenous ACTH plasma concentration assays, and abdominal ultra-

Canine Hyperadrenocorticism sonographies were also recorded where these were performed. Animals were grouped into breed categories as dened by the Kennel Club of the United Kingdom (1996): gun dog, hounds, pastoral, terrier, toy, utility, working, and mixed breeds. The numbers of dogs is each group were then directly compared with the registration statistics for 1990 (the median year of birth for the dogs). No comparison was made with the referral populations of the centers, as this was felt to be biased by the activities of other clinic services within the centers. Breed crosses were included into the breed category that was known. Jack Russell Terriers were included in the terrier group.

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tailed t-tests were used to compare the population attributes of the animals on the 2 drug regimens. Survival analysis was performed using a Kaplan-Meier product limit method supplemented by a Cox proportional hazard model to include drug, center, breed group, diagnostic test group, and age and weight at diagnosis as covariates. All analysis was carried out using statistical software.e Signicance was set at the 5% level for all tests. The power of the study to detect a clinically signicant difference between survival rates was calculated using a difference in survival of 90 days (or about 15% of the previously reported median survival time for dogs treated with mitotane).10

Diagnosis
A similar diagnostic protocol was used in each center. Suspicion of HAC was based on history, clinical examination, and routine blood analysis. An ACTH stimulation test was performed as described elsewhere.11 HAC was conrmed by the demonstration of an exaggerated increase in circulating cortisol concentration ( 600 nmol/L, 21.6 g/ dL) 1 hour postintravenous administration of tetracosactide.a A small number of cases were included that had unequivocal clinical signs, biochemical markers, and a 1-hour post-ACTH cortisol concentration 575 nmol/L (20.7 g/dL). In animals with clinical signs and biochemical markers of HAC but without a positive ACTH stimulation test, the diagnosis was conrmed by a more sensitive but less specic test, either by an LDDST that demonstrated an inadequate suppression ( 40 nmol/L, 1.44 g/dL) of cortisol concentration 8 hours after intravenous administration of a low-dose of dexamethasone,b or by an exaggerated increase ( 8.5 nmol/L, 2.83 ng/mL) in circulating 17hydroxyprogesterone (17-OHP) 1 hour postintravenous administration of tetracosactide.12,13 The test that conrmed the diagnosis was recorded for each case for later analysis. PDH was diagnosed by a combination of LDDST, HDDST, endogenous ACTH concentration, and abdominal imaging as previously described elsewhere.2,4,14,15

Results
One hundred forty-eight dogs were identied that tted the inclusion criteria. A number of additional animals that had been identied as having received mitotane or trilostane were excluded due to multidrug therapy (n 8), concurrent radiotherapy (n 3), insufcient data (n 8), and equivocal adrenal function results (n 5). There was a marked difference in the treatment regimens preferred by the different centers. Center 1 treated 20 patients (57.1%) with mitotane and 15 patients (42.9%) with trilostane. Center 2 treated 5 patients (9.4%) with mitotane and 48 patients (90.6%) with trilostane. Center 3 treated 60 patients (100%) with trilostane and none with mitotane. Center 1 treated HAC in 24 patients (68.6%) where it had been conrmed using ACTH stimulation test, 5 patients (14.3%) using LDDST, and 6 patients (17.1%) with 17OHP assays. Center 2 conrmed HAC in 44 patients (83.0%) using ACTH stimulation test, 7 patients (13.2%) with LDDST, and 2 patients (3.8%) with 17-OHP assays. Center 3 conrmed HAC in 50 patients (83.3%) using ACTH stimulation test and 10 patients (16.6%) using LDDST. There were no statistical differences between the dogs seen by each veterinary center when age at diagnosis (P .71), weight at diagnosis (P .29), and reproductive status (P .25) were compared. There were no statistical differences between the populations of dogs in each treatment group when age at diagnosis (P .30), weight at diagnosis (P .57), and reproductive status (P .27) were compared. The number of animals in some of the breed groups was too small to allow meaningful comparison between centers or treatment groups. The median age at diagnosis was 10 years (mean 9.6 years; SD 2.3; range 3.515.2 years). The median weight was 14.45 kg (mean 19.0 kg; SD 12.4; range 358.5 kg). Seventy-ve dogs were male (45 entire, 30 castrated), and 73 dogs were female (20 entire, 53 spayed). Forty-four breeds were represented (the breed group distribution and most frequently seen breeds are listed in Table 1). When breed was recorded (90.5%), there was a higher prevalence of animals in the toy (26.1%) and terrier (21.6%) groups when compared with national registration statistics for 1990 for the toy (20.3%) and terrier (16%) groups. In contrast, gun dogs were relatively underrepresented, with a prevalence of 20.1%, compared with 28.2% of registrations. Yorkshire Terriers and their crosses were the most frequently encountered breed type (20/148; 13.5%). However, in 1990, Yorkshire Terriers were also the most frequently reg-

Treatment Regimen
The same treatment protocol was used for each drug in each center. Mitotane therapy involved an induction period followed by a maintenance dose.11 In the induction period, mitotanec was administered at a dose of 50 mg/kg, up to a limit of 1,000 mg/dog, until polyphagia or polydipsia resolved and the post-ACTH cortisol concentration was less than 120 mmol/L (4.32 g/dL). Following successful induction, a maintenance dose of mitotane was given (initially 50 mg/kg/week). The aim of the therapy was to achieve a postmedication post-ACTH cortisol concentration of 120 mmol/L (4.32 g/dL) at the end of induction and during the maintenance phase, and good clinical response to treatment, ie, reduction/elimination of polyphagia and polydipsia, return of normal coat quality with minimal side effects. The maintenance dose of mitotane was adjusted in frequency or amount to achieve these aims in individual animals. In contrast, trilostane therapy did not involve an induction period. The initial doses of trilostaned were based on body weight and given PO q24h: 520 kg, 60 mg: 2140 kg, 120 mg: 40 kg, 120240 mg.4 The aim of the therapy was to achieve a 4-hour postmedication postACTH cortisol concentration of 40120 mmol/L (1.444.32 g/dL) with good clinical control of the HAC. The initial dose and dose frequency were adjusted accordingly. Dogs that had a postmedication post-ACTH cortisol concentration of 120200 mmol/L (4.327.2 g/ dL) but were responding well to either treatment did not necessarily have their doses adjusted.

Statistics
Population attributes (age at diagnosis and weight) of the 3 centers were compared using analysis of variance (ANOVA) techniques for parametric data, or Kruskal-Wallis for nonparametric data, as appropriate. Categorical data were compared using a chi-square test. Two-

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Table 1. Breed group distribution for all centers. The numbers of the most common breeds within each group are shown.
Breed Group Gun dog, including Number Labrador Irish Setter English Springer Spaniel Dachshund Collie Jack Russell Terrier Staffordshire Bull Terrier Cairn Terrier Yorkshire Terrier Cavalier King Charles Spaniel Bichon Frise Poodle Miniature Schnauzer Boxer Rottweiler 27 9 7 5 8 4 11 7 29 7 5 4 35 20 6 5 10 3 3 14 9 3 14

Hound, including Pastoral, including Terrier, including

Toy, including

Utility, including Working, including Mixed breed

istered breed in the UK, accounting for 9.5% of all dogs registered that year.16 Mitotane was administered to 25 animals (16.9% of those treated). At date of censorship, 17 were dead, 5 were alive, and 3 had been lost to follow-up. The median survival time

for animals treated with mitotane was 708 days (range 33 1,399). Trilostane was administered to 123 animals (83.1% of those treated). At date of censorship, 65 were dead, 54 were alive, and 4 had been lost to follow-up. The median survival time for animals treated with trilostane was 662 days (range 81,971). There was no signicant difference between the survival times for animals treated with trilostane and those treated with mitotane when compared using log rank (P .62) and Wilcoxon (P .81) methods (Fig 1). In the multivariable model (starting with center, breed group, weight, treatment group, diagnostic test group, and age at diagnosis), only the age at diagnosis (hazard ratio 0.81 [condence limits 0.73, 0.90] P .001) and weight (hazard ratio 0.78 [condence limits 0.77, 0.80] P .015) were signicantly negatively associated with survival in the nal model. The 1-year survival fraction for animals on mitotane was 62% and the 2-year survival fraction was 48%. The 1-year survival fraction for animals on trilostane was 68% and the 2-year survival fraction was 47%. The study was, however, underpowered. On the basis of our assumption regarding the effect size and assuming 5% level of signicance and 80% power, over 200 dogs would have been required in each group to state condently that the choice of therapy had no effect on survival. Of the 82 animals that were dead at date of censorship, the cause of death or reason for euthanasia were recorded where possible (Table 2). Of these animals, 9/82 (11.0%) died of causes that were felt to be probably due to the PDH or its treatment. These included signs of space-occupying cranial lesions, conrmed pulmonary embolism (a reported complication of PDH), or suspected hypoadrenocorticism (a reported adverse effect of both mitotane and trilostane therapy). A further 14 (17.0%) died of causes that were felt could have been due to the PDH or its treatment. These

Fig 1. Kaplan-Meier survival curve for both mitotane- and trilostane-treated animals. Dogs alive at the completion of the study and those lost to follow-up were censored.

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Table 2. Reason for death/euthanasia for all 82 dogs that had died by the time of censorship.
Reason for Death/Euthanasia No cause recorded Number Recorded Total 28

Specic cause recorded that is not directly attributable to pituitary-dependent hyperadrenocorticism (PDH) or its treatment Total Respiratory disease (including dyspnea, tracheal collapse) Heart disease (including congestive heart failure, atrial brillation) Renal failure Gastric dilation and volvulus Neoplasia (not central nervous system) Orthopedic disease (including pressure point ulcers, osteo) Pyometritis Diabetes mellitus Pancreatitis Cervical degenerative radiculomyelopathy Anesthetic complication Vague cause recorded that might be attributable to PDH or its treatment Progressive deterioration Old age Collapse Specic cause recorded that is likely attributable to PDH or its treatment Neurological signs Suspected hypoadrenocorticism Pulmonary thromboembolism Total

31 7 6 5 3 3 2 1 1 1 1 1 14 7 4 3 9 7 1 1

Total

included signs of collapse, progressive deterioration, poor quality of life, and what was described as old age. A further 31 (37.8%) dogs died of causes that could not be directly attributable to PDH or its treatment. There are, however, a number of limitations when interpreting cause of death in this study group: 28 (34.1%) of the animals that were dead at censorship did not have a recorded cause of death or reason for euthanasia. Even in those cases where a reason was recorded, it was usually not supported by postmortem examination results. It was felt that there was insufcient reliable data to compare the causes of death between the treatment groups or with the length of survival. However, no trends were apparent on visual inspection of the data.

Discussion
There was a marked difference in the treatment regimen preferred by each center, with one center using trilostane for all of its cases, while another center used mitotane until trilostane became licensed for the treatment of HAC in the UK. However, as there was no geographical variation found when age at diagnosis, weight at diagnosis, and reproductive status were compared, it was concluded that the dogs from each center were derived from the same population and could therefore be combined for further analysis. There was no difference found between each treatment group when age at diagnosis, weight at diagnosis, and reproduc-

tive status were compared. From this, it was concluded that the dogs from each treatment group were derived from the same population. This meant that treatment regimens could be compared in terms of survival parameters. Comparisons between centers and treatment groups in terms of breed were not possible due to the small numbers of animals within some of the breed categories. The dogs in this study tended to be middle to older aged, of medium to small size, although there was a wide weight range. These results agree with previous studies of populations of dogs with PDH. One study reported a mean age of 10.2 years and median weight of 10.3 kg (mean 12.4 8.2 kg; range 1.546.8 kg),10 while another reported a median age of 9 years and a median weight of 12 kg (range 251 kg).9 The same studies also found no sex predisposition. A high incidence of poodles, Dachshunds, and Yorkshire Terriers has been previously reported.9,10 In our study, when the breed group distribution was compared with national registration statistics for 1990 for the toy, terrier, and gun dog groups, it suggested an overrepresentation of toy and terrier breeds, with an underrepresentation of gun dogs.16 In particular, the Yorkshire Terrier was frequently encountered. In 1990, poodles and Dachshunds only comprised 2.7 and 1.9%, respectively, of the dogs registered that year in the UK, while Yorkshire Terriers were most popular (9.5%).17 The differences between study populations are therefore likely to be explained by national variation in breed popularity. No comparison was made with the hospital populations, as these records might be inuenced by referral rates for other conditions. As some animals were alive at the time of censorship for both treatment groups, an element of error is introduced into the median survival times of both mitotane- and trilostane-treated animals. As a greater proportion of animals in the mitotane group (68%) were dead at censorship compared with trilostane (53%), the median survival time for mitotane-treated animals is likely to be a more accurate reection of the true value. However, as the survival times to the date of censorship of the surviving dogs are evenly distributed, it is unlikely that the mean survival gure will change. The power of the study was found to be inadequate to conrm the null hypothesis because the number of mitotane-treated dogs was too low. However, it should be stressed that the median survival time (708 days) and 2year survival fraction (48%) of animals treated with mitotane in this study was found to be similar to previously published results. In a study of 200 dogs with PDH treated with mitotane using a similar protocol, the median survival time was 1.7 years (mean 2.2; range 10 days to 8.2 years) with a 2-year survival of 47%.10 The median survival time (662 days) and 2-year survival fraction (47%) of animals treated with trilostane in this study was found to be greater than previously published results. A previous study had found a median survival time of 549 days for dogs with PDH treated with trilostane.4 However, they noted that this gure was unreliable as very few of their dogs had died at the completion of the study. The retrospective study design was chosen as it was able to encompass the period of time that both trilostane and mitotane were available as the 1st-line treatment for PDH. Due to changes in the prescription regulations in the UK

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around the time of censoring, trilostane is now the sole product licensed for the treatment of PDH in the UK. It therefore has to be used as the 1st-line medical treatment for PDH. Mitotane can only be dispensed following treatment failure with trilostane. A prospective study was therefore not possible. In addition, it would not be possible to do a blinded trial, as the treatment protocols are so different. It was also not possible to compare survival times of treated animals with a no-treatment control group, as it would be unethical to withhold treatment for this disease. There are no published reports by other authors describing the survival parameters of a large population of dogs with PDH that did not undergo any form of therapy. The clinical implications of this study should be assessed by comparison with previous reports. This study used mitotane-induced selective adrenocorticolysis, while others have used nonselective adrenocorticolysis for the treatment of PDH. One study of nonselective adrenocorticolysis with mitotane, where a state of hypoadrenocorticism was induced, reported a 2-year survival fraction of 69%.9 However, they also reported a loss of 11.6% animals (15/129) during the induction period, while death from overdosage for selective adrenocorticolysis was reported to occur in less than 2% of cases.18 Another study reported a median survival time of 30 months for animals with HAC treated with mitotane.19 When those animals that had developed permanent iatrogenic hypoadrenocorticism were excluded from this calculation, the median survival time was reduced to 27 months, suggesting nonselective adrenocorticolysis confers a longer survival time compared with selective adrenocorticolysis. However, while the majority of animals in that study had PDH, animals with ADH were not excluded.19 Surgical treatment for PDH, in the form of hypophysectomy, has been reported in the literature.3 A 2-year survival fraction of 82% for dogs that had undergone hypophysectomy for PDH has been reported, along with a reduction in the recurrence rate of HAC when compared with results obtained following mitotane therapy in the same institution.3 While hypophysectomy can offer a cure for PDH and avoids the potential adverse effects of medical therapy, such as development of signs of cranial-space occupying lesion or iatrogenic hypoadrenocorticism, it does require access to advanced imaging techniques (computer axial tomography, magnetic resonance imaging) and surgical expertise. It was noted in this study that age at diagnosis inuences survival time; the older the animal at diagnosis, the shorter its survival time tended to be. A previously published study found that the majority of animals with PDH did not die because of diseases associated with PDH or its treatment but rather failure of other organs (heart, liver, kidneys, etc), unrelated neoplasia, or geriatric diseases (eg, gradual deterioration, incontinence).10 Another study found that, of the 27 animals that had died by date of censorship, 22.2% had died of causes attributable to HAC or its treatment (n 6), while a further 66.6% could possibly be attributed to HAC (n 18).19 However, the group for which signs could possibly be attributed to HAC included those animals where a reason of euthanasia/death was not recorded, those who died of congestive heart failure, and 2 large-breed dogs with hind-limb weakness. In our study, 11% of animals died or

were euthanatized as a result of clinical signs that were considered likely to be a result of HAC or its treatment and a further 17% may also have been euthanatized as a result of HAC or its treatment. This data must be interpreted with caution, as the assessment of these cases both before euthanasia and at postmortem was very variable. Multivariable analysis in this study also found that weight at survival was signicantly negatively correlated with survival, although to a lesser extent than age at diagnosis. This has not been reported elsewhere in animals treated for PDH medically. Our nding is not surprising, as smaller dogs have been shown to have longer life spans when looking at a general population of dogs.20 As this was a retrospective study, it did not encompass the quality of life of the animals in either treatment group, their response to treatment was not assessed, nor did it assess owner compliance. Previous studies have assessed response to medical therapy.4,10 A total resolution of clinical signs and decrease in pre- and post-ACTH cortisol values to within the normal resting range occurred in 83% of cases of PDH treated with mitotane,10 while in over 70% of dogs with PDH treated with trilostane, their polydipsia/polyuria or polyphagia resolved within the 1st month of treatment, and many of the remaining dogs had a reduction in the severity of clinical signs with dosage adjustment.4 This suggests a comparable efcacy between mitotane and trilostane.

Conclusion
The hypothesis that there was no signicant difference between the survival times of dogs with PDH that had been treated with trilostane and those that had been treated with mitotane could not be rejected. Although the power of this study was limited, by taking previously published survival studies into account, it is unlikely that the choice of therapy (mitotane or trilostane) has a major effect on survival times in dogs with PDH.

Footnotes
a b c d e

Synacthen, Alliance Pharmaceuticals, Chippenham, UK Dexadresson, Intervet UK Ltd, Milton Keynes, UK Lysodren, Bristol-Myers, Canada Vetoryl, Arnolds Veterinary Products, Shrewsbury, UK Minitab; Minitab Inc, State College, PA

Acknowledgments
The authors would like to thank their veterinary and nursing colleagues at the Universities of Cambridge, Glasgow, and London for the dedicated care and management of these cases. Arnolds Veterinary Products partly funded the treatment of some of the trilostane-treated patients.

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Canine Hyperadrenocorticism ACTH concentration and adrenal ultrasonography to distinguish the cause of canine hyperadrenocorticism. J Small Anim Pract 2001;42: 113121. 3. Meij B, Voorhout G, Rijnberk A. Progress in transsphenoidal hypophysectomy for treatment of pituitary-dependent hyperadrenocorticism in dogs and cats. Mol Cell Endo 2002;197:8996. 4. Neiger R, Ramsey IK, OConnor J, et al. Trilostane treatment of 78 dogs with pituitary dependent hyperadrenocorticism. Vet Rec 2002; 150:799804. 5. Ruckstuhl NS, Nett CS, Reusch CE. Results of clinical examinations, laboratory tests, and ultrasonography in dogs with pituitarydependent hyperadrenocorticism treated with trilostane. Am J Vet Res 2002;63:506512. 6. Feldman EC, Bruyette DS, Nelson RW, Farver TB. Plasma cortisol response to ketoconazole administration in dogs with hyperadrenocorticism. J Am Vet Med Assoc 1990;197:7178. 7. Bruyette DS, Ruehl WW. CVT update: L-deprenyl in the treatment of canine pituitary-dependent hyperadrenocorticism. In: Bonagura JD, ed. Current Veterinary Therapy XIII: Small Animal Practice. Philadelphia, PA: WB Saunders; 2000: 364366 8. Perez Alenza MD, Guerrero B, Melian C, et al. Use of amino glutethimide in the treatment of pituitary-dependent hyperadrenocorticism in the dog. J Small Anim Pract 2002;43:104108. 9. Den Hertog E, Braakman JCA, Teske E, et al. Results of nonselective adrenocorticolysis by o,p -DDD in 129 dogs with pituitary dependent hyperadrenocorticism. Vet Rec 1999;144:1217. 10. Kintzer PP, Peterson ME. Mitotane (o,p -DDD) treatment of 200 dogs with pituitary-dependent hyperadrenocorticism. J Vet Int Med 1991;5:182190. 11. Herrtage ME. Canine Hyperadrenocorticism. In: Torrance AG, Mooney CT, eds. Manual of Small Animal Endocrinology, 2nd ed.

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