Review Article  Compte rendu

Update on the use of trilostane in dogs

Julie Lemetayer, Shauna Blois

Abstract — Many articles published in the past few years have contributed to a better understanding of the use
of trilostane in dogs. Trilostane is a competitive inhibitor of 3b-hydroxysteroid dehydrogenase, the enzyme essential
for synthesis of cortisol and all other steroids. Trilostane is reported to be safe and effective in the treatment of
pituitary-dependent hyperadrenocorticism (HAC), adrenal-dependent HAC, and alopecia X. While trilostane
controls most of the clinical signs associated with HAC, abnormalities such as hypertension, hypercoagulability,
and proteinuria may persist despite therapy. Because the duration of cortisol suppression after a dose of trilostane
is often less than 12 hours, many dogs with HAC could benefit from low dose trilostane treatment every 12 hours.
Many controversies regarding trilostane still exist. This review provides a comprehensive commentary on trilostane’s
indications, mode of action, dose, monitoring, efficacy, and adverse effects.

Résumé —Mise à jour sur l’utilisation du trilostane chez les chiens. De nombreux articles publiés au cours
des dernières années ont contribué à une meilleure compréhension de l’utilisation du trilostane chez les chiens. Le
trilostane est un inhibiteur compétitif de la 3b-hydroxystéroïde déshydrogénase, l’enzyme essentiel pour la synthèse
du cortisol et de tous les autres stéroïdes. On signale que le trilostane est sûr et efficace pour le traitement de
l’hyperadrénocorticisme pituitaire (HAC), le HAC adrénal et l’alopécie X. Bien que le trilostane maîtrise la plupart
des signes cliniques associés au HAC, des anomalies comme l’hypertension, l’hypercoagulabilité et la protéinurie
peuvent persister malgré la thérapie. Parce que la durée de la suppression du cortisol après une dose de trilostane
est souvent de moins de 12 heures, plusieurs chiens atteints de HAC pourraient bénéficier d’un traitement à faible
dose de trilostane toutes les 12 heures. Il subsiste encore beaucoup de controverse concernant le trilostane. Cet
examen fournit un commentaire exhaustif sur les indications, le mode d’action, la dose, la surveillance, l’efficacité
et les effets secondaires du trilostane.
(Traduit par Isabelle Vallières)
Can Vet J 2018;59:397–407

Introduction therapy. The optimal medical treatment should have minimal

O
adverse effects while alleviating clinical signs associated with
nce a diagnosis of hyperadrenocorticism (HAC) has been
HAC, including polyuria-polydipsia (PUPD), polyphagia,
made, treatment decisions are influenced by many factors
haircoat and skin changes, truncal obesity, muscle weakness,
including etiology of HAC, client financial constraints, the level
and alopecia (1). Ideally, it should also improve deleterious
of commitment involved in treatment, and a consideration of
physiological consequences of HAC including hypertension,
the risk/benefit ratio of the treatment compared with the con-
thromboembolism, and proteinuria.
sequences associated with the disease.
Trilostane is a synthetic steroid that selectively inhibits the
Three main categories of options are available for the treat-
enzyme 3b-hydroxysteroid dehydrogenase (3b-HSD) in the
ment of pituitary-dependent and adrenal-dependent HAC
adrenal cortex. This inhibition blocks the conversion of preg-
(PDH and ADH) in dogs: medical, surgical, and radiation
nenolone to progesterone (2), thereby inhibiting the production
of glucocorticoids and, to a lesser extent, mineralocorticoids
Department of Clinical Studies, Ontario Veterinary College, and sex hormones.
University of Guelph, Guelph, Ontario N1C 1G9. Trilostane has been used in dogs with HAC for almost 20 y,
Address all correspondence to Dr. Julie Lemetayer; e-mail: and a veterinary approved product was first marketed in Canada
julie.lemetayer@hotmail.com in 2009. Control of clinical signs is gradual and variable among
Use of this article is limited to a single copy for personal study. studies. Reports of good control ranged from , 50% to 100%
Anyone interested in obtaining reprints should contact the of treated dogs after few weeks of treatment (3–13). However,
CVMA office (hbroughton@cvma-acmv.org) for additional after several months of treatment, partial to complete control of
copies or permission to use this material elsewhere. clinical signs occurred in . 75% of cases in published studies

CVJ / VOL 59 / APRIL 2018 397

 (3–13). Adverse effects are generally mild or moderate and are Dose
reported to occur in 0% to 40% of cases (3–13). Trilostane is now supplied in 5-, 10-, 30-, 60-, and 120-mg
A recent article reported that 26 dogs with untreated PDH capsules (Vetoryl). Currently, the manufacturer’s initial dose rec-
had shorter mean survival times (506 d) than 17 dogs that were ommendation for trilostane is 2.2 to 6.6 mg/kg BW, PO, q24h
treated with trilostane at 1 to 3 mg/kg body weight (BW) once based on body weight and capsule size. Previous label instruc-
(q24h) or twice a day (q12h), whose median survival time was tions for trilostane recommended initial dosing by body weight
COM PTE R E N DU

not reached at the end of the study (14). This study suggests categories (, 5 kg, 30 mg; 5 to 20 kg; 60 mg; and . 20 kg;
that withholding treatment for dogs with PDH could increase 120 mg; q24h). One study compared this dosing approach with
the risk of death. Therefore, it suggests a positive effect of trilo- dosing at 2 to 5 mg/kg BW, q24h. The study found that there
stane in dogs with PDH. However, the cause of death in many was comparable clinical improvement and decrease in cortisol
of the untreated dogs was either unknown or did not seem to in both dosing groups, but a lower risk of side effects was associ-
be related to their HAC. In addition, the retrospective nature ated with mg/kg BW dosing (25).
of that study makes it difficult to accurately compare untreated The use of compounded capsules, if necessary based on the
dogs with dogs treated with trilostane. patient size, should be considered carefully. If compounded
Similar efficacy, similar or even longer survival times, and doses are necessary, only the licensed trilostane product should
similar or lower rates of adverse effects have been reported be used, and compounding should be performed by trained
with trilostane compared to mitotane in both PDH and ADH pharmacists. A study evaluating trilostane products purchased
(13,15–18). Longer survival was found when trilostane was from 8 compounding pharmacies found that actual concentra-
compared to mitotane in a non-selective adrenolytic protocol tions in compounded capsules varied from 39% to 152.6% of
(18). However, the veterinary literature is lacking large prospec- the label claim. Additionally, dissolution of the compounded tri-
tive, randomized, controlled studies comparing trilostane and lostane was lower in 20% of tested products (26). The potential
mitotane therapy to determine which is the superior treatment variation in strength and dissolution of compounded trilostane
for dogs with HAC. could have negative impacts on management of patients with
Many research articles detailing the use of trilostane in dogs HAC. With the advent of licensed 5 mg and 10 mg capsules,
with HAC have been published. This article will summarize the use of compounded capsules is rarely necessary.
the pharmacology of trilostane as well as the latest research on Studies in dogs with HAC treated with trilostane reported a
trilostane treatment in canine HAC. wide variation in the dose necessary to control the disease, from
0.42 to 50 mg/kg BW per day (3–13,19,23) (Tables 1 and 2).
Pharmacology However, these studies had very different study designs. While
Trilostane is a competitive inhibitor of 3b-HSD. This block- most studies were prospective clinical trials, a few were retro-
ade is reversible and appears to be dose-related (19). 3b-HSD spective studies (6,7,13) which carry more risk of selection bias,
converts pregnenolone to progesterone, and dehydroepian- misclassification, and information bias than prospective studies.
drosterone (DHEA) to androstendione. The enzymatic action The number of dogs included varied from 9 to 78 with differ-
of 3b-HSD is thus essential for the synthesis of cortisol and all ences in dog breeds and body weight (3–13,19). The number of
other steroids including mineralocorticoids, sex steroids, and dogs can affect statistical results with higher risk of type 2 errors
other glucocorticoids. Inhibition of progesterone production in smaller populations (3,8,9,11,13). Dogs . 25 to 30 kg, and
reduces the synthesis of cortisol in the zona fasciculata of the possibly also dogs . 15 kg, have been found to require a lower
adrenal glands. It also decreases the production of aldosterone dose/kg BW of trilostane to control clinical signs compared
in the zona glomerulosa and production of androstendione with dogs weighing # 15 kg (5,10,27). Studies which only
in the zona reticularis. In contradiction with a previous study included dogs , 15 kg (3,9) or which segregated the smallest
(20), a later study did not find an effect of trilostane on DHEA dogs (, 10 kg) to 1 group (7) had higher risk of bias. In addi-
concentration. This suggests that there might be more than one tion, the diagnosis of HAC in dogs with supportive clinical
form of the enzyme 3b-HSD present in dogs, with a variable and biochemical changes varied from a single confirmatory
effect of trilostane on each isoenzyme (21). However, the first test (4–8,13) to at least 2 confirmatory tests (3,9–12). These
study was in vivo while the second study was in vitro (21). This tests consisted of 1 to 2 urine cortisol to creatinine ratio(s)
could account for the different results between the 2 studies. (UCCR), an adrenocorticotropic hormone (ACTH) stimula-
Trilostane may also inhibit the enzymes 11b-hydroxylase tion test, and/or a low dose dexamethasone suppression test.
and 11b-hydroxysteroid dehydrogenase (11b-HSD) in dogs Studies which used fewer tests to confirm the diagnosis of HAC
(20,22). 11b-HSD catalyzes the conversion of physiologically were more likely to include dogs that were falsely diagnosed
active cortisol to inactive cortisone. with HAC.
Pharmacokinetic studies in healthy dogs showed that maximal The most notable differences among studies were the time
plasma concentration of trilostane occurs 1.7 to 3.8 h following the ACTH stimulation test was performed after administra-
administration and plasma concentration returns to baseline tion of trilostane and the definition of good disease control.
by about 12 h [Vetoryl (trilostane) 2015 drug insert, Dechra Following administration of trilostane, the ACTH stimulation
Veterinary Products, Pointe-Claire, Quebec]. Studies in dogs test was either performed variably within the day (4,5,9), 2 to
with HAC have shown that trilostane’s activity can even be 6 h later (3,7), 3 to 4 h later (11), 3 h later (12), 2 to 4 h later
considerably shorter than 12 h in some dogs (23,24). (6), 4 to 6 h later (8,10), or 8 to 12 h later (8,10,13). The

398 CVJ / VOL 59 / APRIL 2018

upper limit of the acceptable post-ACTH cortisol concentra- retrospective study, control of the clinical signs and cortisol
tion range varied from 69 nmol/L (3) to 250 nmol/L (4) a few concentrations was seen sooner in the q12h treatment group.
hours after administration of trilostane. In some studies, the The mean final dose was 7.6 mg/kg BW per day in the q24h
trilostane dose was mostly changed based on the results of the group and 5.4 mg/kg BW per day in the q12h group (2.7 mg/kg
ACTH stimulation test (3,5,7). In other studies, the trilostane BW, q12h). Reports of adverse effects, which were documented
dose was left unchanged in dogs with high (and in some cases as mild to moderate in severity, were more common in the

R E V I E W A R T I C LE
low) post-ACTH stimulation cortisol concentration as long as q12h versus the q24h treatment group. However, animals
clinical signs were controlled (6,8,9,11,12). given trilostane q24h had a 15% increased chance of treatment
Besides these differences in study design that could explain discontinuation although no clear explanation to explain the
the wide differences in doses among the studies, some inter- difference was identified.
individual variability could also be due to the low water solu- Cho et al (9) found fewer adverse effects with low dose (0.5 to
bility of trilostane, and thus variable absorption of the drug 1 mg/kg BW) trilostane administered q12h compared with
(15). In addition, it could be due to a variation in the 3b-HSD 30 mg/dog given q24h (6 to 12 mg/kg BW per day) in dogs
activity in the dogs’ adrenal glands, or variable conversion into , 5 kg BW. While 100% success in controlling clinical signs
active metabolites such as ketotrilostane (21). It is worth not- and cortisol concentrations was seen in both groups at 24 wk
ing that to enhance absorption, trilostane should be given with after initiation of trilostane treatment, improvement occurred
food, including on the days recheck ACTH stimulation tests more slowly in the q12h group. The mean final daily dose
are being conducted. required for control of HAC was much lower in the q12h group
In studies describing the use of trilostane q24h (Table 1) compared with the q24h treatment group (2.9 mg/kg BW per
(3–9), the initial dose ranged from 1.0 to 20 mg/kg BW, q24h day in the q12h group and 7.1 mg/kg BW per day in the q24h
with a mean dose of 2.9 to 6.4 mg/kg BW, q24h. The final trilo- group). Additionally, results suggested fewer adverse effects in
stane dose varied from 0.8 to 50 mg/kg BW, q24h with a mean the q12h versus the q24h treatment group (9).
dose of 2.8 to 19 mg/kg BW, q24h. However, as explained, the Arenas et al (8) compared dogs with PDH that were treated
duration of cortisol suppression after a dose of trilostane is often with trilostane either q12h or q24h. The mean final dose was
less than 12 h. Therefore, several studies have examined the use 4.6 mg/kg BW per day in the q24h group and 4.7 mg/kg BW
and clinical efficacy of trilostane q12h for treatment of PDH per day in the q12h group (2.4 mg/kg BW). This study found
and ADH (Table 2) (7–13). that more dogs in the q12h group had complete resolution of
In studies describing the use of trilostane q12h, the initial clinical signs than in the q24h group (69% had complete clini-
dose ranged from 0.5 to 7.5 mg/kg BW, q12h, with a mean cal recovery at 6 mo in the q12h group and 42% in the q24h
dose of 0.78 to 3.1 mg/kg BW, q12h. The final trilostane dose group). While clinical response was more prevalent in the q12h
varied from 0.21 to 9.05 mg/kg BW, q12h, with a mean dose of treatment group, there was no significant difference in the mean
1.43 to 3.75 mg/kg BW, q12h. Among the studies reported in post-ACTH cortisol concentration between groups. Both pro-
Table 2, 10 out of 180 dogs (5.6%) required trilostane 3 times tocols were safe and generally well-tolerated.
a day to successfully control their clinical signs (11,12). Based on these studies, it appears that use of trilostane q12h,
In dogs treated with trilostane either q24h or q12h, frequent often given at total daily doses that are lower than the manu-
dose adjustments were necessary to control the disease (3–13). facturer’s recommendations, results in a safe and effective treat-
In these studies, clinical signs in dogs treated with trilostane ment for dogs with HAC. When using a twice-daily treatment
q24h improved in . 75% of cases at 6 mo (3–9). However, the protocol, it is recommended to start at doses of 0.5 to 1 mg/kg
rates of improvement were variable and 1 study reported only BW, q12h, with a maximum initial dose of 30 mg/dog for dogs
42% of the total cases (5/12 dogs) had complete resolution of . 30 kg. Indeed, complete control of clinical signs and cortisol
clinical signs at 6 mo (8). Among studies reporting treatment concentrations can be achieved in some dogs using a very low
with trilostane q12h, 67% to 100% of dogs were well-controlled dose of trilostane (12).
at 6 mo (7–13). Between 2 to 4 mo, the cortisol was within
the target range in 57% to 100% of the dogs treated with tri- Monitoring
lostane q24h and in 69% to 100% of the dogs treated with Choosing the best monitoring protocol in HAC dogs undergo-
trilostane q12h. ing treatment can be challenging. The ACTH stimulation test is
Among the 11 studies listed in Tables 1 and 2, adverse effects currently the gold standard test used to monitor the response to
were reported in 35/264 (13%) cases with q24h treatment and treatment of dogs with HAC. However, there are some limita-
in 34/180 (19%) cases with q12h treatment. In both q12h tions to this test which will be discussed later. It is recommended
and q24h treatment groups, most adverse effects were mild or that the ACTH stimulation test be conducted at 10 to 14 d
moderate and included mild electrolyte abnormalities without after initiating trilostane or changing doses, then at 1, 3, and
clinical signs, transient decrease in appetite, vomiting, diarrhea, subsequently every 3 to 6 mo after the trilostane dose becomes
and lethargy. stable (15). It is generally accepted that clinical signs and cor-
To date, 3 studies have directly compared the efficacy of tisol concentrations continue to improve in some dogs in the
q24h versus q12h trilostane treatment in dogs with HAC. first month after starting trilostane therapy (12). Therefore, the
Augusto et al (7) concluded that dogs treated either q24h or ACTH stimulation test performed after 10 to 14 d of onset of
q12h showed similar improvement in clinical scores. In this therapy should be used only to ensure that there is no e­ xcessive

CVJ / VOL 59 / APRIL 2018 399

 Table 1.  Summary of clinical studies using once daily dosing of trilostane in dogs with hyperadrenocorticism.
Reference numbers 3 4 5
Country Switzerland UK Australia
Year of publication 2002 2002 2003
Number of dogs with PDH 11 78 30
COM PTE R E N DU

Number of dogs with ADH 0 0 0

Starting dose, range in mg/kg BW, q24h 3.9 to 9.2 1.8 to 20.0 2.7 to 12.0
Starting dose, mean in mg/kg BW, q24h NS 5.9 NS
Monitoring 1, 3 to 4, 6 to 7, 12 to 16, 10 d, 1, 3, 6 mo, and then 10 d, 1, 3, then every 3 mo
24 to 28 wk every 3 to 6 mo thereafter
Target cortisol in nmol/L 27 to 69 20 to 250 25–75 for tight control and
75–125 for acceptable control
Time of sampling 2 to 6 h NS, most within a few hours NS
ACTH stimulation test protocol 0.25 mg of tetracosactide IM, NS 5 mg/kg of tetracosactrin IV,
post-ACTH cortisol 60 min later post-ACTH cortisol 60 min later
Dose changes Increased in 5/11 (45%), Increased in 24/78 (31%), NS
decreased in 3/11 (27%) decreased in 9/78 (11%)

Withdrawals None Discontinuation of trilostane None, but 2 dogs had trilostane
in 2 dogs for prolonged hypoAC discontinued for reasons
unrelated to the medication
Final dose, range in mg/kg BW, q24h 4.1 to 15.6 NS 5.0 to 50.0
Final dose, mean in mg/kg BW, q24h NS 7.3 19
Number of dogs with clinical 9/11 (82%) at 6 mo 60/78 (77%) at 1 mo. Clinical improvement in all
improvement Improvement alopecia in dogs at 3 mo
24/39 dogs (62%) at 3 mo


Number of dogs in target cortisol range NS 59/73 (81%) at 1 mo 9/30 (30%) at 1 mo,
17/30 (57%) at 3 mo,
23/29 (79%) at 6 mo
Number of dogs with adverse effects 2/11 (18%), mild 15/78 (19.2%). 2 dogs with No adverse effects for . 6 mo.
hypoAC (1 died). 13 dogs 4/30 (13.3%) dogs had signs
with minor adverse effects of hypoAC after . 12 mo of
treatment
Survival All alive at the end of the study 26 dogs dead at the end of the 5 dogs dead or euthanized for
study, with 9 of unknown cause. causes unrelated to PDH
1 dog due to hypoAC. 2 deaths
shortly after starting treatment
Other comments 

BW — body weight; NS — not stated; PDH — pituitary-dependent hyperadrenocorticism; ADH — adrenal-dependent hyperadrenocorticism; HypoAC —
hypoadrenocorticism; ACTH — adrenocorticotropic hormone.

suppression of cortisol concentrations. Complete control of products. Both IV and IM administration of cosyntropin
cortisol concentrations and clinical signs is not expected at 10 to produce similar ACTH-stimulated cortisol concentrations in
14 d after starting therapy, and the dose should not be increased healthy dogs and in dogs with HAC (1,28). Doses of 1 mg/kg
at this time or hypoadrenocorticism could result (15). BW and 5 mg/kg BW of cosyntropin were also recently found to
Use of synthetic ACTH [Cortrosyn (cosyntropin) and produce similar results when reassessing dogs with HAC treated
Synacthen (tetracosactrin or tetracosactide)] for ACTH stimu- with mitotane or trilostane. Therefore, the lower dose appears
lation tests has been reported for diagnosing and monitoring to be a safe and more cost-effective way to use synthetic ACTH
HAC in dogs. However, the potency of both drugs has not been for monitoring HAC in dogs undergoing treatment. However,
compared. Samples for cortisol measurement are obtained at the same study found a significant difference between the
0 and 60 min after IV or IM injection of standard non-absorbed 2 doses in dogs suspected of having HAC. Therefore a dose of

400 CVJ / VOL 59 / APRIL 2018

 6 7 8 9
Netherlands UK Spain South Korea
2008 2012 2013 2013
63 47 16 7

R E V I E W A R T I C LE
0 12 0 0
2.0 to 4.0 3.3 to 9.5 1.0 to 6.6 6 to 13.3
NS 6.4 2.9 NS
3 wk then every 3 wk until 9 to 12 d, 1, 3, 6 mo 7d, 1, 3, 6 mo, 1 y 2 wk, 1, 2, 3, 4, 6 mo
stable, then every 3 mo
30–190 40 to 120 55 to 248 55 to 150

2–4 h 2 to 6 h 8 to 12 h NS
0.25 mg of tetracosactide IV, NS 0.25 mg of tetracosactide IM, 0.25 mg of tetracosactide IV,
post-ACTH cortisol 90 min later post-ACTH cortisol 60 min later post-ACTH cortisol 60 min later
Increased in 22/63 and decreased NS In 12/16 dogs (75%). 9 increased, Dose increased 12 times from
in 4/63 at 3 wk 2 decreased, 1 increased and 4th to 16th wk in total
decreased
None 29/59 (49%). No withdrawals due 2/16 (13%). Changed to None
to severe side effects of trilostane q12h treatment

0.8–5.8 3.2 to 12 1.0–11.5 3.3 to 10.9
2.8 7.6 4.6 7.1
60/63 (95%) Resolution of many clinical signs 5/13 complete (38%) and 2/7 (29%) at 1 mo, 5/7 (71%) 3 mo,
in all dogs at 3 mo. Improvement 3/13 (23%) partial response at 7/7 (100%) 4 and 6 mo
of the skin only at 6 mo 1 mo, 5/12 (42%) complete or
5/12 (42%) partial response
at 6 mo
60/63 (95%) NS 5/13 (38%) at 1 mo, 9/12 (75%) 5/7 (71%) at 4 wk, 7/7 (100%) at
at 6 mo 2 mo, 5/7 (71%) between 2 and
6 mo, 7/7 (100%) at 6 mo
5/63 (7.9%). HypoAC including 1/59 (1.7%), mild 6/16 (37.5%), mild 2/7 (29%), transient hypoAC
2 dogs with permanent hypoAC


All alive at the end of the study All alive at the end of the study All alive at the end of the study All alive at the end of the study



Comparison q24h versus q12h Comparison q24h versus q12h Comparison q24h versus q12h
treatment. Only dogs . 10 kg in treatment treatment
q12h group. 8 centres. q24h and
q12h groups studied over 2 separate
time periods

5 mg/kg BW is still recommended when being used to diagnose compounded ACTH preparations may be less expensive, they
HAC (29). are not recommended because their potency and the time that
Use of depot tetracosactide (250 mg total dose or 5 mg/kg maximal concentration of cortisol occurs may vary significantly
BW, IM) was evaluated in healthy dogs and in dogs with HAC among formulations, even potentially from bottle to bottle at a
(30,31). However, since peak cortisol is only obtained 180 min specific compounding pharmacy (33).
after IM injection, it is recommended to collect blood samples There is currently no standardization regarding the time
at 0 and 180 min for cortisol measurement (30,31). when an ACTH stimulation test should be performed, nor the
Only 1 small study evaluated the use of compounded ACTH optimal cortisol concentration target range. The manufacturer
in 5 healthy dogs and found no difference in serum cortisol con- recommends that the ACTH stimulation test be performed
centrations at 60 min for 4 compounded products (32). While 4 to 6 h after trilostane is administered. Studies report variable

CVJ / VOL 59 / APRIL 2018 401

 Table 2.  Summary of clinical studies using multiple-daily dosing of trilostane in dogs with hyperadrenocorticism.
Reference numbers 10 11 12
Country Spain USA USA
Year of publication 2006 2008 2011
Number of dogs with PDH 44 18 38
COM PTE R E N DU

Number of dogs with ADH 0 4 9

Starting dose, range in mg/kg BW, q12h 1.2 to 7.5 0.5 to 2.5 0.21 to 1.1
Starting dose, mean in mg/kg BW, q12h 3.1 1.4 0.86
Monitoring 7 d, 1, 3, 6 mo, then every 1 to 2 wk, 1 to 2, 2 to 4 mo 1 to 2, 6 to 7, 15 to 17, 24 to
6 mo (up to 3.5 y) 28 wk
Target cortisol in nmol/L 28 to 138 at 4 to 6 h and , 150 40 to 150
27 to 248 at 8 to 12 h
Time of sampling 4 to 6 h at 7 d, then 8 to 12 h 3 to 4 h 3 h
ACTH stimulation test protocol 5 mg/kg of tetracosactide IV, 0.25 mg of cosyntropin IM, 0.25 mg of cosyntropin IM,
post-ACTH cortisol 60 min later post-ACTH cortisol 60 min later post-ACTH cortisol 60 min later
Dose changes Increased in 19/44 (43%), both 10 increased at 4 to 8 wk, 18 increased at 1 to 2 wk,
increased and decreased in 5 increased at 8 to 16 wk 17 increased at 6 to 7 wk,
10/44 (23%), and decreased 1 increased 1 2 decreased at
in 5/44 (11%) 15 to 17 wk, 1 progressively
increased over 4 mo
Withdrawals 5 for economic reasons. 4 dogs had surgery for ADH 2 no response, 2 dogs with signs
Discontinuation of trilostane in of hypoAC, 9 dogs had surgery for
5 dogs for prolonged hypoAC ADH
Final dose, range in mg/kg BW, q12h 1.3 to 9.05 at 6 mo 1.1 to 2.8 0.21 q12h to 10 q8h
Final dose, mean in mg/kg BW, q12h 3.75 at 6 mo 1.7 NS
Number of dogs receiving q8h treatment 0 3 7
Number of dogs with clinical efficacy 22/36 at 3 mo (61%), 20/30 at 15/22 (68%) improved at 9/9 ADH (100%) and
6 mo (67%), 19/24 at 1 y (79%) 4 to 8 wk, 16/18 (89%) 15/38 PDH (39%) good at
at 8 to 16 wk 6 to 7 wk, 24/28 (86%)
PDH good at 6 mo
Number of dogs in target cortisol range 25/36 (69%) at 3 mo 14/16 (88%) at 8 to 16 wk 7/9 (78%) and 15/38 (39%) at
6 to 7 wk
Number of dogs with adverse effects 11/44 (25%), mild in 3, mild to 2/22 (9%), severe 5/47 (10.6%), moderate in 4,
moderate in 4, severe in 4 severe in 1
Survival 930 d, 29 dogs still alive at the All alive at the end of the study 1 dog euthanized for large
end of the study pituitary mass

Other comments




BW — body weight; NS — not stated; PDH — pituitary-dependent hyperadrenocorticism; ADH — adrenal-dependent hyperadrenocorticism; HypoAC —
hypoadrenocorticism; ACTH — adrenocorticotropic hormone.

timing for performance of ACTH stimulation for monitoring tions usually occur 2 to 4 h after trilostane administration (35),
of trilostane treatment. Reported times include 2 to 6 h (3,7), so if the goal of the ACTH stimulation is to determine the
3 to 4 h (11), 3 h (12), 2 to 4 h (6), 4 to 6 h (8,10), or 8 to 12 h cortisol concentration when trilostane is maximally effective, an
(8,10,13) after administration of trilostane. Post-ACTH cortisol ACTH stimulation test should be performed during this time
concentrations vary with the time interval between dosing and interval.
testing (11). One study demonstrated that a difference of only The literature reports various optimal target cortisol con-
2 h between the time the ACTH stimulation test was started centrations for dogs undergoing treatment of HAC. Neiger
significantly changed the post-ACTH serum cortisol concentra- et al (4) found that good clinical control of PDH was usually
tions (34). An ACTH stimulation test should therefore always associated with post-ACTH cortisol concentrations of 20 to
be started at or about the same time after trilostane administra- 250 nmol/L, regardless of the time of the test. Others have
tion in each individual patient. The lowest cortisol concentra- suggested target post-ACTH cortisol concentrations of , 70

402 CVJ / VOL 59 / APRIL 2018

 7 8 9 13
UK Spain South Korea Spain
2012 2013 2013 2014
25 16 9 0

R E V I E W A R T I C LE
5 0 0 12
1.5 to 2.9 1.25 to 2.75 0.5 to 1 NS
2.2 1.8 0.78 3
9 to 12 d, 1, 3, 6 mo 7 d, 1, 3, 6 mo, 1 y 2 wk, 1, 2, 3, 4, 6 mo 7 d, 1, 3, 6 mo, then every 3 mo

40 to 120 55 to 138 at 4 to 6 h and 55 to 150 , 248
55 to 248 at 8 to 12 h
2 to 6 h 4 to 6 h at 7 d, then 8 to 12 h NS 8 to 12 h
NS 0.25 mg of tetracosactide IM, 0.25 mg of tetracosactide IV, 0.25 mg of tetracosactide IM,
post-ACTH cortisol 60 min later post-ACTH cortisol 60 min later post-ACTH time NS
NS In 11/16 dogs (69%). 5 increased, Dose increased twice and 4 increased at 1 mo, 3 increased
6 increased and decreased decreased 5 times in total at 3, 6, and 12 mo



4/30 (13%). No withdrawn due None None None
to severe side effects of trilostane

1.4 to 4.4 1.4 to 4.45 0.9 to 1.9 NS
2.7 2.35 1.43 NS
0 0 0 0
Resolution of many clinical 8/11 complete (73%) and 2/9 (22%) at 1 mo, 4/9 (44%) 8/12 (67%) at 1 mo, then
signs in all dogs at 9 to 12 d. 2/11 (18%) partial response at 3 mo, 8/9 (89%) 4 mo, 9/12 (75%) at 3, 6, and 12 mo
Improvement skin only at 3 mo 1 mo, 11/16 (69%) complete or 9/9 (100%) 6 mo
3/16 (19%) partial response at 6 mo
NS 7/11 (64%) at 1 mo, 9/16 (56%) 0/9 (0%) at 4 wk, 7/9 (78%) at 8/12 (67%) at 1 mo, then
at 6 mo 4 mo, 9/9 (100%) at 6 mo 9/12 (75%) at 3, 6 and 12 mo
5/30 (17%), mild to moderate 7/16 (44%), mild None 4/12 (33%), mild in 3, severe in 1

All alive at the end of the study All alive at the end of the study All alive at the end of the study Mean survival of 17.7 1/2 4.2 mo
(range: 3.3 to 55.0 mo; median,
14.0 mo)
Comparison q24h versus q12h Comparison q24h versus Comparison q24h versus Comparison trilostane q12h versus
treatment. Only dogs . 10 kg q12h treatment q12h treatment mitotane
in q12h group. 8 centers. q24h
and q12h groups studied over
2 separate time periods

to 75 nmol/L (3,5), between 40 and 120 nmol/L (15), or There is a lack of clear recommendations of how to adjust
, 150 nmol/L (9,11,12,36), for control of HAC. The authors the trilostane dose when dogs have well-regulated HAC, but
of the present article recommend targeting a post-ACTH low cortisol concentrations before and after ACTH stimula-
­cortisol concentration , 150 nmol/L. However, if good clinical tion. One recent study examined a small group of dogs with
control is achieved when post-ACTH cortisol concentrations well-regulated HAC and cortisol concentrations , 55 nmol/L
are , 250 nmol/L, the dose can remain unchanged. It is worth before and after ACTH stimulation performed 3 to 6 h after
mentioning that cortisol concentration can be affected by the trilostane was administered. A second ACTH stimulation test
assay methodology and can vary among laboratories (37). revealed that the dogs had significantly increased cortisol con-
Therefore, the cut-offs reported in the literature may be dif- centrations 9 to 12 h after the dose of trilostane was given (38).
ficult to apply directly to data from another laboratory. Ideally, The authors suggested that a second ACTH stimulation test
laboratory specific cut-offs should be used. performed later in the day could support continued treatment

CVJ / VOL 59 / APRIL 2018 403

 with the same trilostane dose, although further study is needed. Efficacy of trilostane
In animals with low pre- and post-ACTH cortisol concentra- Clinical signs of HAC, such as PUPD, polyphagia, or lethargy,
tions (, 40 to 55 nmol/L), the authors of the present article improve gradually over the first months of treatment in most
recommend that the trilostane dose be decreased or discontinued dogs treated with trilostane q12h or q24h (Tables 1 and 2).
(especially if cortisol ­concentration is , 30 nmol/L). If trilostane Resolution of dermatological abnormalities can take several
is discontinued, it should be restarted at a lower dose only after more months after starting trilostane (7).
COM PTE R E N DU

an ACTH stimulation test shows that hypocortisolemia has Trilostane is effective for both PDH and ADH. In ADH
resolved. cases, it can be used as a short-term treatment for the control
Despite the study findings previously discussed, it remains of cortisol concentrations in preparation for adrenalectomy, or
unclear whether the ACTH stimulation test is the best method as a long-term medical therapy (8,11,12). Similar survival times
for monitoring treatment with trilostane (23). In some dogs, but fewer side effects were reported with trilostane compared to
the results of the ACTH stimulation test do not parallel the mitotane in the treatment of HAC due to ADH (8).
control of clinical signs in dogs treated for HAC in both q12h The typical laboratory abnormalities associated with HAC,
and q24h treatments (8,12). such as increase in liver enzymes, hypercholesterolemia, low
Neiger et al (4) proposed that the administration of exog- urine specific gravity, secondary hyperparathyroidism and
enous ACTH during stimulation testing may override the revers- increased phosphorus concentration have all improved with
ible inhibition of cortisol synthesis by trilostane, particularly as trilostane treatment (3,7,9,44–46).
the concentration of the drug decreases, such that the results of Along with the typical clinical signs associated with HAC,
the ACTH stimulation test may be inaccurate. Another possible this disorder can also create severe physiological abnormalities.
explanation would be that the action of trilostane is too short in Sequelae of HAC can include hypertension, proteinuria, hyper-
these dogs to fully control their clinical signs. The frequency of coagulability, immunosuppression, insulin resistance, and soft
administration may need to be increased in these dogs. Lastly, tissue calcification including calcinosis cutis, muscle wasting,
undiagnosed concurrent diseases could mimic some of the and cranial cruciate rupture (1). Over half of HAC patients
clinical signs associated with uncontrolled HAC. For instance, have hypertension at the time of diagnosis, and hypertension
a persistence of PUPD in dogs with early chronic kidney disease does not resolve in many dogs treated with trilostane, even
may be falsely interpreted as clinical signs of uncontrolled HAC. after a year of treatment (13,45,46). Persisting hypertension
Measuring multiple cortisol concentrations over time, while could be explained by the fact that after trilostane treatment is
expensive and time consuming, may be more accurate than a initiated, plasma renin activity increases (6), which may lead
stimulation test. to activation of the renin-angiotensin-aldosterone system and
Investigators have assessed other possible options for monitor- renal vasoconstriction. Proteinuria, as determined by the urinary
ing treatment response in dogs with HAC. These have included protein-to-creatinine ratio, improves over time with trilostane
the UCCR (5,11,12,39), the baseline cortisol (40,41) with or treatment, but some dogs remain proteinuric after a year of
without combination with an endogenous ACTH and the corti- treatment (45,46). However, hypercoagulability, as measured
sol/ACTH ratio (6,42), the pre-trilostane cortisol concentration by thromboelastographic variables, increased platelet count and
alone or in combination with the 3 h post-trilostane cortisol fibrinogen concentration, did not improve following trilostane
concentration (43). In many of these studies, results of these treatment in dogs with PDH over 6 mo (46). The persistence
ancillary tests have been evaluated to determine whether they are of these physiologic abnormalities associated with HAC may be
predictive of the ACTH stimulation test results, and therefore due to the serum cortisol concentration still exceeding physi-
if they could be less expensive monitoring tools. The UCCR, ological concentrations during a certain period of the day, even
baseline cortisol, endogenous ACTH, and cortisol/ACTH when trilostane is administered twice daily (45).
ratio have not been found to be very reliable for this purpose. Hyperadrenocorticism is associated with calcium dysregula-
However, as described, the ACTH stimulation test has its own tion that can lead to the development of calcium-oxalate uro-
limitations making it challenging to assess utility of these other liths, soft tissue mineralization, such as calcification of the skin
tests for the monitoring of HAC. (calcinosis cutis), or perihilar bronchial mineralization. Dogs
Macfarlane et al (43) evaluated the utility of measuring a with HAC have higher parathyroid hormone and phosphate
pre-trilostane cortisol concentration (considered peak cortisol concentrations than healthy dogs, and these abnormalities
concentration) and a 3-hour post-trilostane cortisol concentra- improve in some dogs with HAC following treatment with
tion (considered trough cortisol concentration). In this study, trilostane (44). Some patients had resolution of calcinosis cutis
the pre-trilostane cortisol concentration as well as the 3-hour with trilostane treatment (4,47).
post-trilostane cortisol concentration better reflected the level Little information is available on the use of trilostane in
of clinical control in dogs with uncontrolled HAC than did dogs with concurrent HAC and diabetes mellitus. Excessive
the post-ACTH cortisol concentration performed 3 h after cortisol concentration causes insulin resistance, making it more
trilostane administration. Clinical control was determined difficult to regulate diabetes mellitus in dogs with concurrent
by detailed questionnaires filled by the owners. However, uncontrolled HAC (1). Insulin resistance is expected to at least
94/110 tests (85%) were performed on dogs receiving q24h partially improve with trilostane treatment, and therefore,
trilostane treatment; the results may be different with q12h tri- careful monitoring of blood glucose concentration is needed in
lostane treatment. dogs treated for both disorders. In a small study of 8 dogs with

404 CVJ / VOL 59 / APRIL 2018

diabetes mellitus and HAC, insulin requirements and fructos- treated with trilostane is unknown. Usually trilostane inhibits
amine concentrations were not consistently reduced during the production of glucocorticoids more than the production of
trilostane treatment for HAC (48). However, the number of mineralocorticoids. However, it is possible that in some dogs,
dogs included in the study was small and results may have been trilostane may more effectively block the synthesis of miner-
different if a larger population had been used. Interestingly, and alocorticoids than glucocorticoids (11,12,55). If electrolyte
likely only coincidentally, 10% of 103 dogs treated with trilo- changes are observed with trilostane treatment, a careful client

R E V I E W A R T I C LE
stane developed diabetes mellitus after trilostane was initiated in interview to help detect clinical signs of hypoadrenocorticism
1 retrospective study (40% of them within the first 4 mo after and an ACTH stimulation test are recommended. It is possible
starting trilostane) (49). that a short episode of hypocortisolemia (although not enough
to induce clinical signs) may not be detected by the ACTH
Safety of trilostane stimulation test (35).
Trilostane has a relatively low incidence of adverse effects, espe-
cially when low doses are used. Adverse effects were reported Use in alopecia X
in 35/264 (13%) dogs undergoing q24h treatment and in Alopecia X is a form of canine adult-onset alopecia that mainly
34/180 (19%) dogs receiving q12h treatment in a total of affects nordic breeds such as the Alaskan malamute, chow chow,
11 studies (3–13). Reported adverse effects include anorexia, keeshond, Pomeranian, Samoyed, and Siberian husky, and also
lethargy, vomiting, diarrhea, and other events typical of a hypo- other breeds including the miniature poodle. This form of alo-
adrenal state (hyperkalemia, hyponatremia, and hypovolemic pecia resembles the alopecia seen with HAC but other clinical
shock) which may or may not be associated with adrenal necrosis signs of HAC, such as PUPD and polyphagia, are absent and
and hemorrhage. Chronic trilostane use is also associated with traditional tests to diagnose HAC (low dose dexamethasone
the development of diffuse and/or nodular hyperplasia (50), suppression test and ACTH stimulation) are normal. Despite
enlargement (up to 60% of the original size) and change of these findings, trilostane has been shown to be effective in the
echotexture of the adrenal glands on ultrasound (3). This may treatment of alopecia X. Currently, there are few data regard-
be secondary to the increased endogenous ACTH concentration ing the treatment of alopecia X. The doses used in 3 published
that is noted with trilostane treatment (51). studies were highly variable (56–58).
Although more frequent with higher doses, adverse reactions The first effective reported doses for treatment of alopecia X
to trilostane can occur with any dose and any frequency. These in Pomeranians and miniature poodles ranged from , 6 to
include adverse reactions in dogs treated with trilostane doses . 23 mg/kg BW, q24h. Some dogs were treated with pulse
, 1 mg/kg BW, q12h (12), suggesting that factors other than therapy (2 to 3 treatments per wk) after initial stabilization
dose or frequency of administration may contribute to the (57). Three Alaskan malamutes were successfully treated in
development of adverse effects. For instance, since trilostane is another study with doses of 3 to 3.6 mg/kg BW, q12h (58).
metabolized by the liver and excreted in bile and urine, its use The frequency of administration was reduced to twice weekly
is not recommended in dogs with liver or renal insufficiency after initial stabilization. More recently, successful treatment
as dose accumulation may occur. Other factors could include has also been reported with a dose of 1 mg/kg BW, q12h in
a particularly good absorption of the drug in some individuals, Pomeranians (56). Alopecia X has been postulated to be due to
as well as individual or breed susceptibility to the effect of tri- increased concentration of 17-hydroxyprogesterone (17-OHP).
lostane (21). Another possibility is that some dogs could have However, values of 17-OHP have been found to further increase
been wrongly diagnosed with HAC. during successful treatment with trilostane (57).
Although in theory the effects of trilostane as an enzyme In conclusion, there have been many studies published in the
inhibitor should be rapidly reversible, prolonged adrenocortical past few years contributing to a better understanding of the use
suppression can occur, and cases of permanent hypoadrenocorti- of trilostane in dogs. One of the most clinically relevant findings
cism or adrenal necrosis following trilostane therapy have been that has been recently reported is the use of significantly lower
described (5,6,10). In most of the described cases, prolonged doses, often given twice daily, which have effectively controlled
iatrogenic hypoadrenocorticism occurred after several months HAC in dogs with fewer side effects.
of treatment (5,10). However, 2 dogs developed prolonged Further study of the use of trilostane in dogs with HAC
hypoadrenocorticism or isolated hypocortisolism following is needed to answer some ongoing clinical questions. First,
short courses (3 and 13 d) of trilostane given at 2 to 5 mg/kg the results of an ACTH stimulation test, which is the current
BW, q24h (52,53). Based on a study performed in rats, adrenal gold standard test for monitoring the effect of treatment with
degeneration in this species is likely caused by the effect of trilostane, do not always correlate with clinical signs, making
increased ACTH concentration on the adrenal glands rather it challenging to monitor dogs undergoing treatment. Second,
than the direct effect of trilostane on the adrenal glands (54). there is no consensus on the optimal post-ACTH serum corti-
Periodic monitoring of electrolyte concentrations during tri- sol concentration, the ideal timing of sampling after trilostane
lostane treatment is also recommended since both hyperkalemia administration, or the appropriate starting dose and frequency.
and hyponatremia are common (40). However, most dogs have Overall, trilostane is an effective and safe method of treating
mild electrolyte derangements and ACTH stimulation testing PDH and ADH in many dogs, and is also reported to be effec-
is typically not indicative of hypoadrenocorticism. The mecha- tive in the treatment of alopecia X. However, it is important
nism of mild hyperkalemia or other electrolyte changes in dogs to note that trilostane might not correct physiological changes

CVJ / VOL 59 / APRIL 2018 405

 associated with HAC, including hypertension and proteinuria, 22. Teshima T, Matsumoto H, Kumagai T, Kurano M, Koyama H.
Expression of 11beta-hydroxysteroid dehydrogenase isoforms in canine
and these conditions may require specific therapy. CVJ
adrenal glands treated with trilostane. Vet J 2014;200:452–455.
23. Bell R, Neiger R, McGrotty Y, Ramsey IK. Study of the effects of once
References daily doses of trilostane on cortisol concentrations and responsiveness
  1. Behrend EN, Kooistra HS, Nelson R, Reusch CE, Scott-Moncrieff to adrenocorticotrophic hormone in hyperadrenocorticoid dogs. Vet
JC. Diagnosis of spontaneous canine hyperadrenocorticism: 2012 Rec 2006;159:277–281.
24. Feldman E, Vaughn M, Nelson R. Duration of trilostane effectiveness in
COM PTE R E N DU

ACVIM consensus statement (small animal). J Vet Intern Med 2013;

27:1292–1304. dogs with naturally occurring hyper-adrenocorticism. Proc Annu Meet
  2. Potts GO, Creange JE, Hardomg HR, Schane HP. Trilostane, an orally Am Coll Vet Intern Med 2007;21:597–597.
active inhibitor of steroid biosynthesis. Steroids 1978;32:257–267. 25. Braun C, Boretti FS, Reusch CE, Sieber-Ruckstuhl NS. Comparison of
  3. Ruckstuhl NS, Nett CS, Reusch CE. Results of clinical examinations, two treatment regimens with trilostane in dogs with pituitary-dependent
laboratory tests, and ultrasonography in dogs with pituitary-dependent hyperadrenocorticism. Schweiz Arch Tierheilkd 2013;155:551–558.
hyperadrenocorticism treated with trilostane. Am J Vet Res 2002; 26. Cook AK, Nieuwoudt CD, Longhofer SL. Pharmaceutical evaluation
63:506–512. of compounded trilostane products. J Am Anim Hosp Assoc 2012;48:
  4. Neiger R, Ramsey I, O’Connor J, Hurley KJ, Mooney CT. Trilostane 228–233.
treatment of 78 dogs with pituitary-dependent hyperadrenocorticism. 27. Feldman EC, Kass PH. Trilostane dose versus body weight in the treat-
Vet Rec 2002;150:799–804. ment of naturally occurring pituitary-dependent hyperadrenocorticism
  5. Braddock JA, Church DB, Robertson ID, Watson AD. Trilostane treat- in dogs. J Vet Intern Med 2012;26:1078–1080.
ment in dogs with pituitary-dependent hyperadrenocorticism. Aust Vet 28. Frank LA, DeNovo RC, Kraje AC, Oliver JW. Cortisol concentrations
J 2003;81:600–607. following stimulation of healthy and adrenopathic dogs with two doses
  6. Galac S, Buijtels JJ, Mol JA, Kooistra HS. Effects of trilostane on of tetracosactrin. J Small Anim Pract 2000;41:308–311.
the pituitary-adrenocortical and renin-aldosterone axis in dogs with 29. Aldridge C, Behrend EN, Kemppainen RJ, et al. Comparison of 2 doses
pituitary-dependent hypercortisolism. Vet J 2008;183:75–80. for ACTH stimulation testing in dogs suspected of or treated for hyper-
  7. Augusto M, Burden A, Neiger R, Ramsey I. A comparison of once and adrenocorticism. J Vet Intern Med 2016;30:1637–1641.
twice daily administration of trilostane to dogs with hyperadrenocorti- 30. Ginel PJ, Sileo MT, Blanco B, Garfia B, Quintavalla F. Evaluation of
cism. Tierarztl Prax K H 2012;40:415–424. serum concentrations of cortisol and sex hormones of adrenal gland
  8. Arenas C, Melian C, Perez-Alenza MD. Evaluation of 2 trilostane origin after stimulation with two synthetic ACTH preparations in
protocols for the treatment of canine pituitary-dependent hyperad- clinically normal dogs. Am J Vet Res 2012;73:237–241.
renocorticism: Twice daily versus once daily. J Vet Intern Med 2013; 31. Sieber-Ruckstuhl NS, Burkhardt WA, Hofer-Inteeworn N, et al. Cortisol
27:1478–1485. response in healthy and diseased dogs after stimulation with a depot
  9. Cho KD, Kang JH, Chang D, Na KJ, Yang MP. Efficacy of low- formulation of synthetic ACTH. J Vet Intern Med 2015;29:1541–1546.
and high-dose trilostane treatment in dogs (, 5 kg) with pituitary-­ 32. Kemppainen RJ, Behrend EN, Busch KA. Use of compounded adreno-
dependent hyperadrenocorticism. J Vet Intern Med 2013;27:91–98. corticotropic hormone (ACTH) for adrenal function testing in dogs.
10. Alenza DP, Arenas C, Lopez ML, Melian C. Long-term efficacy of J Am Anim Hosp Assoc 2005;41:368–372.
trilostane administered twice daily in dogs with pituitary-dependent 33. Petersen M. What ACTH preparations should be used for stimulation
hyperadrenocorticism. J Am Anim Hosp Assoc 2006;42:269–276. testing? Insights into Veterinary Endocrinology 2011. Available from:
11. Vaughan MA, Feldman EC, Hoar BR, Nelson RW. Evaluation of twice- http://endocrinevet.blogspot.com//2011/03/what-acth-preparations-
daily, low-dose trilostane treatment administered orally in dogs with should-be-used.html Last accessed February 13, 2018.
naturally occurring hyperadrenocorticism. J Am Vet Med Assoc 2008; 34. Bonadio CM, Feldman EC, Cohen TA, Kass PH. Comparison of
232:1321–1328. adrenocorticotropic hormone stimulation test results started 2 versus
12. Feldman EC. Evaluation of twice-daily lower-dose trilostane treatment 4 hours after trilostane administration in dogs with naturally occurring
administered orally in dogs with naturally occurring hyperadrenocorti- hyperadrenocorticism. J Vet Intern Med 2014;28:1239–1243.
cism. J Am Vet Med Assoc 2011;238:1441–1451. 35. Griebsch C, Lehnert C, Williams GJ, Failing K, Neiger R. Effect of
13. Arenas C, Melian C, Perez-Alenza MD. Long-term survival of dogs trilostane on hormone and serum electrolyte concentrations in dogs
with adrenal-dependent hyperadrenocorticism: A comparison between with pituitary-dependent hyperadrenocorticism. J Vet Intern Med 2014;
mitotane and twice daily trilostane treatment. J Vet Intern Med 2014; 28:160–165.
28:473–480. 36. McGrotty YL, Arteaga A, Knottenbelt CM, Ramsey IK, Eckersall PD.
14. Nagata N, Kojima K, Yuki M. Comparison of survival times for dogs Haptoglobin concentrations in dogs undergoing trilostane treatment
with pituitary-dependent hyperadrenocorticism in a primary-care hos- for hyperadrenocorticism. Vet Clin Pathol 2005;34:255–258.
pital: Treated with trilostane versus untreated. J Vet Intern Med 2017; 37. Cohen J, Ward G, Prins J, Jones M, Venkatesh B. Variability of cortisol
31:22–28. assays can confound the diagnosis of adrenal insufficiency in the criti-
15. Ramsey IK. Trilostane in dogs. Vet Clin North Am Small Anim Pract cally ill population. Intensive Care Med 2006;32:1901–1905.
2010;40:269–283. 38. Midence JN, Drobatz KJ, Hess RS. Cortisol concentrations in well-
16. Barker EN, Campbell S, Tebb AJ, et al. A comparison of the survival regulated dogs with hyperadrenocorticism treated with trilostane. J Vet
times of dogs treated with mitotane or trilostane for pituitary-dependent Intern Med 2015;29:1529–1533.
hyperadrenocorticism. J Vet Intern Med 2005;19:810–815. 39. Galac S, Buijtels JJ, Kooistra HS. Urinary corticoid: Creatinine ratios
17. Helm JR, McLauchlan G, Boden LA, et al. A comparison of factors that in dogs with pituitary-dependent hypercortisolism during trilostane
influence survival in dogs with adrenal-dependent hyperadrenocorti- treatment. J Vet Intern Med 2009;23:1214–1219.
cism treated with mitotane or trilostane. J Vet Intern Med 2011;25: 40. Woolcock AD, Bugbee AC, Creevy KE. Evaluation of baseline cortisol
251–260. concentration to monitor efficacy of twice-daily administration of trilo-
18. Clemente M, De Andres PJ, Arenas C, Melian C, Morales M, Perez- stane to dogs with pituitary-dependent hyperadrenocorticism: 22 cases
Alenza MD. Comparison of non-selective adrenocorticolysis with mito- (2008–2012). J Am Vet Med Assoc 2016;248:814–821.
tane or trilostane for the treatment of dogs with pituitary-dependent 41. Cook AK, Bond KG. Evaluation of the use of baseline cortisol concen-
hyperadrenocorticism. Vet Rec 2007;161:805–809. tration as a monitoring tool for dogs receiving trilostane as a treatment
19. Neiger R, Lehnert C. Treatment of canine hyperadrenocorticism for hyperadrenocorticism. J Am Vet Med Assoc 2010;237:801–805.
(Cushing’s disease) with trilostane. Tierarztl Prax K H 2004;32: 42. Burkhardt WA, Boretti FS, Reusch CE, Sieber-Ruckstuhl NS. Evaluation
193–198. of baseline cortisol, endogenous ACTH, and cortisol/ACTH ratio to
20. Sieber-Ruckstuhl NS, Boretti FS, Wenger M, Maser-Gluth C, monitor trilostane treatment in dogs with pituitary-dependent hyper-
Reusch CE. Cortisol, aldosterone, cortisol precursor, androgen and cortisolism. J Vet Intern Med 2013;27:919–923.
endogenous ACTH concentrations in dogs with pituitary-dependant 43. Macfarlane L, Parkin T, Ramsey I. Pre-trilostane and three-hour
hyperadrenocorticism treated with trilostane. Domest Anim Endocrinol post-trilostane cortisol to monitor trilostane therapy in dogs. Vet Rec
2006;31:63–75. 2016;179:597.
21. Ouschan C, Lepschy M, Zeugswetter F, Mostl E. The influence of 44. Tebb AJ, Arteaga A, Evans H, Ramsey IK. Canine hyperadrenocorticism:
trilostane on steroid hormone metabolism in canine adrenal glands and Effects of trilostane on parathyroid hormone, calcium and phosphate
corpora lutea-an in vitro study. Vet Res Commun 2012;36:35–40. concentrations. J Small Anim Pract 2005;46:537–542.

406 CVJ / VOL 59 / APRIL 2018

45. Smets PM, Lefebvre HP, Meij BP, et al. Long-term follow-up of renal 52. Gojska-Zygner O, Lechowski R, Zygner W. Canine iatrogenic persistent
function in dogs after treatment for ACTH-dependent hyperadreno- hypoadrenocorticism after short-term treatment of hyperadrenocorti-
corticism. J Vet Intern Med 2012;26:565–574. cism with trilostane — A case report. Vet Arhiv 2011;81:699–705.
46. Park FM, Blois SL, Abrams-Ogg ACG, et al. Hypercoagulability and 53. Ramsey IK, Richardson J, Lenard Z, Tebb AJ, Irwin PJ. Persistent
ACTH-dependent hyperadrenocorticism in dogs. J Vet Intern Med isolated hypocortisolism following brief treatment with trilostane. Aust
2013;27:1136–1142. Vet J 2008;86:491–495.
47. Fialkovicova M, Mardzinova S, Karasova M, et al. Therapy of canine 54. Burkhardt WA, Guscetti F, Boretti FS, et al. Adrenocorticotropic hor-

R E V I E W A R T I C LE
hyperadrenocorticism (Cushing’s syndrome). Case report (abstract). mone, but not trilostane, causes severe adrenal hemorrhage, vacuoliza-
Magy Allatorvosok 2012;134:271–279. tion, and apoptosis in rats. Domest Anim Endocrinol 2011;40:155–164.
48. McLauchlan G, Knottenbelt C, Augusto M, Helm J, McGrotty Y, 55. Reid LE, Behrend EN, Martin LG, et al. Effect of trilostane and mito-
Ramsey I. Retrospective evaluation of the effect of trilostane on insulin tane on aldosterone secretory reserve in dogs with pituitary-dependent
requirement and fructosamine concentration in eight diabetic dogs with hyperadrenocorticism. J Vet Intern Med 2014;28:443–450.
hyperadrenocorticism. J Small Anim Pract 2010;51:642–648. 56. Sanches M, Jerico M, Januario E. Steroid hormone panel test and
49. Rochel D, Siliart B, Friol A, Jaillardon L. Trilostane drug safety surveil- trilostane and melatonin therapy in pomeranian dogs with alopecia X.
lance: A retrospective study of 103 cases. Proc Ann Meet Eur Assoc Vet Proc Ann Meet Am Coll Vet Intern Med 2016;30:1451.
Pharmacol Ther 2015;38:33–33. 57. Cerundolo R, Lloyd DH, Persechino A, Evans H, Cauvin A. Treatment
50. Reusch CE, Sieber-Ruckstuhl N, Wenger M, Lutz H, Perren A, of canine Alopecia X with trilostane. Vet Dermatol 2004;15:285–293.
Pospischil A. Histological evaluation of the adrenal glands of seven 58. Leone F, Cerundolo R, Vercelli A, Lloyd DH. The use of trilostane for
dogs with hyperadrenocorticism treated with trilostane. Vet Rec 2007; the treatment of alopecia X in Alaskan malamutes. J Am Anim Hosp
160:219–224. Assoc 2005;41:336–342.
51. Witt AL, Neiger R. Adrenocorticotropic hormone levels in dogs with
pituitary-dependent hyperadrenocorticism following trilostane therapy.
Vet Rec 2004;154:399–400.

Book Review
Compte rendu de livre

Equine Laminitis treatment of the laminitic patient. There are additional sections
on digital support and stabilization of the distal phalanx; treat-
Belknap JK, ed. Wiley-Blackwell, Oxford, United Kingdom. ment — encompassing discussions on the use of casts, dorsal
2017. 455 pp. ISBN: 9781-1199-4471-3. hoof wall resections, and well-balanced chapters on contentious
issues such as deep digital flexor tendon tenotomy and raising

T his book is a complete anthology of equine laminitis; tak-

ing the reader from the historical reports of disease to the
modern understanding of the condition. It explores the normal
the heels of horses with chronic laminitis, as well as a good sec-
tion on the prevention of laminitis.
This is not a handbook or a “how-to” text. It is a well-written
anatomy of the foot, the underlying physiology and pathophysi- textbook which is beautifully balanced between research and
ology of all three forms of laminitis (sepsis-associated, endocri- clinical applicability. As such, it should not be pulled out
nopathic, and supporting limb); and the role of the lamellar when faced with a laminitic horse and expected to deliver a
basal epithelial cell (LBEC). Crucially, this text manages to step-by-step guide to management. It is easy to read, and after
integrate recent research findings with chapters describing the thoughtful consumption can be retrieved and re-examined when
experimental models of laminitis, the hemodynamic and inflam- faced with a clinical case, or shown to an owner to illustrate a
matory aspects of disease, and the role of endocrine and meta- difficult concept. Overall this is a textbook which has a place
bolic dysregulation with practical, clinically applicable chapters on the shelf of all veterinary practices that do any amount of
on the diagnosis and management of horses with this condition. equine clinical work.
The flow between these seemingly diametrically opposed aspects
of laminitis is seamless and easy to follow as a reader. Reviewed by James L. Carmalt, MA, VetMB, MVetSc, PhD,
The clinical portion of the book is extensive and comprehen- FRCVS, DABVP(Eq), DAVDC(Eq), DACVSMR(Eq), DACVS,
sive. Clearly identified sections written by multiple authors cover Professor — Equine Surgery, Western College of Veterinary
the clinical presentation, diagnostic evaluation, and medical Medicine, University of Saskatchewan, Canada.

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