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
nce a diagnosis of hyperadrenocorticism (HAC) has been
made, treatment decisions are influenced by many factors
including etiology of HAC, client financial constraints, the level
of commitment involved in treatment, and a consideration of
the risk/benefit ratio of the treatment compared with the con-
sequences associated with the disease.
Three main categories of options are available for the treat-
ment of pituitary-dependent and adrenal-dependent HAC
(PDH and ADH) in dogs: medical, surgical, and radiation
Department of Clinical Studies, Ontario Veterinary College,
University of Guelph, Guelph, Ontario N1C 1G9.
Address all correspondence to Dr. Julie Lemetayer; e-mail:
julie.lemetayer@hotmail.com
Use of this article is limited to a single copy for personal study.
Anyone interested in obtaining reprints should contact the
CVMA office (hbroughton@cvma-acmv.org) for additional
copies or permission to use this material elsewhere.
adverse effects while alleviating clinical signs associated with
HAC, including polyuria-polydipsia (PUPD), polyphagia,
haircoat and skin changes, truncal obesity, muscle weakness,
and alopecia (1). Ideally, it should also improve deleterious
physiological consequences of HAC including hypertension,
thromboembolism, and proteinuria.
Trilostane is a synthetic steroid that selectively inhibits the
enzyme 3b-hydroxysteroid dehydrogenase (3b-HSD) in the
adrenal cortex. This inhibition blocks the conversion of preg-
nenolone to progesterone (2), thereby inhibiting the production
of glucocorticoids and, to a lesser extent, mineralocorticoids
and sex hormones.
Trilostane has been used in dogs with HAC for almost 20 y,
and a veterinary approved product was first marketed in Canada
in 2009. Control of clinical signs is gradual and variable among
studies. Reports of good control ranged from , 50% to 100%
of treated dogs after few weeks of treatment (3–13). However,
after several months of treatment, partial to complete control of
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
reported to occur in 0% to 40% of cases (3–13).
A recent article reported that 26 dogs with untreated PDH
had shorter mean survival times (506 d) than 17 dogs that were
treated with trilostane at 1 to 3 mg/kg body weight (BW) once
(q24h) or twice a day (q12h), whose median survival time was
COM PTE R E N DU
not reached at the end of the study (14). This study suggests
that withholding treatment for dogs with PDH could increase
the risk of death. Therefore, it suggests a positive effect of trilo-
stane in dogs with PDH. However, the cause of death in many
of the untreated dogs was either unknown or did not seem to
be related to their HAC. In addition, the retrospective nature
of that study makes it difficult to accurately compare untreated
dogs with dogs treated with trilostane.
Similar efficacy, similar or even longer survival times, and
similar or lower rates of adverse effects have been reported
with trilostane compared to mitotane in both PDH and ADH
(13,15–18). Longer survival was found when trilostane was
compared to mitotane in a non-selective adrenolytic protocol
(18). However, the veterinary literature is lacking large prospec-
tive, randomized, controlled studies comparing trilostane and
mitotane therapy to determine which is the superior treatment
for dogs with HAC.
Many research articles detailing the use of trilostane in dogs
with HAC have been published. This article will summarize
the pharmacology of trilostane as well as the latest research on
trilostane treatment in canine HAC.
Pharmacology
Trilostane is a competitive inhibitor of 3b-HSD. This block-
ade is reversible and appears to be dose-related (19). 3b-HSD
converts pregnenolone to progesterone, and dehydroepian-
drosterone (DHEA) to androstendione. The enzymatic action
of 3b-HSD is thus essential for the synthesis of cortisol and all
other steroids including mineralocorticoids, sex steroids, and
other glucocorticoids. Inhibition of progesterone production
reduces the synthesis of cortisol in the zona fasciculata of the
adrenal glands. It also decreases the production of aldosterone
in the zona glomerulosa and production of androstendione
in the zona reticularis. In contradiction with a previous study
(20), a later study did not find an effect of trilostane on DHEA
concentration. This suggests that there might be more than one
form of the enzyme 3b-HSD present in dogs, with a variable
effect of trilostane on each isoenzyme (21). However, the first
study was in vivo while the second study was in vitro (21). This
could account for the different results between the 2 studies.
Trilostane may also inhibit the enzymes 11b-hydroxylase
and 11b-hydroxysteroid dehydrogenase (11b-HSD) in dogs
(20,22). 11b-HSD catalyzes the conversion of physiologically
active cortisol to inactive cortisone.
Pharmacokinetic studies in healthy dogs showed that maximal
plasma concentration of trilostane occurs 1.7 to 3.8 h following
administration and plasma concentration returns to baseline
by about 12 h [Vetoryl (trilostane) 2015 drug insert, Dechra
Veterinary Products, Pointe-Claire, Quebec]. Studies in dogs
with HAC have shown that trilostane’s activity can even be
considerably shorter than 12 h in some dogs (23,24).
398
Dose
Trilostane is now supplied in 5-, 10-, 30-, 60-, and 120-mg
capsules (Vetoryl). Currently, the manufacturer’s initial dose rec-
ommendation for trilostane is 2.2 to 6.6 mg/kg BW, PO, q24h
based on body weight and capsule size. Previous label instruc-
tions for trilostane recommended initial dosing by body weight
categories (, 5 kg, 30 mg; 5 to 20 kg; 60 mg; and . 20 kg;
120 mg; q24h). One study compared this dosing approach with
dosing at 2 to 5 mg/kg BW, q24h. The study found that there
was comparable clinical improvement and decrease in cortisol
in both dosing groups, but a lower risk of side effects was associ-
ated with mg/kg BW dosing (25).
The use of compounded capsules, if necessary based on the
patient size, should be considered carefully. If compounded
doses are necessary, only the licensed trilostane product should
be used, and compounding should be performed by trained
pharmacists. A study evaluating trilostane products purchased
from 8 compounding pharmacies found that actual concentra-
tions in compounded capsules varied from 39% to 152.6% of
the label claim. Additionally, dissolution of the compounded tri-
lostane was lower in 20% of tested products (26). The potential
variation in strength and dissolution of compounded trilostane
could have negative impacts on management of patients with
HAC. With the advent of licensed 5 mg and 10 mg capsules,
the use of compounded capsules is rarely necessary.
Studies in dogs with HAC treated with trilostane reported a
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).
However, these studies had very different study designs. While
most studies were prospective clinical trials, a few were retro-
spective studies (6,7,13) which carry more risk of selection bias,
misclassification, and information bias than prospective studies.
The number of dogs included varied from 9 to 78 with differ-
ences in dog breeds and body weight (3–13,19). The number of
dogs can affect statistical results with higher risk of type 2 errors
in smaller populations (3,8,9,11,13). Dogs . 25 to 30 kg, and
possibly also dogs . 15 kg, have been found to require a lower
dose/kg BW of trilostane to control clinical signs compared
with dogs weighing # 15 kg (5,10,27). Studies which only
included dogs , 15 kg (3,9) or which segregated the smallest
dogs (, 10 kg) to 1 group (7) had higher risk of bias. In addi-
tion, the diagnosis of HAC in dogs with supportive clinical
and biochemical changes varied from a single confirmatory
test (4–8,13) to at least 2 confirmatory tests (3,9–12). These
tests consisted of 1 to 2 urine cortisol to creatinine ratio(s)
(UCCR), an adrenocorticotropic hormone (ACTH) stimula-
tion test, and/or a low dose dexamethasone suppression test.
Studies which used fewer tests to confirm the diagnosis of HAC
were more likely to include dogs that were falsely diagnosed
with HAC.
The most notable differences among studies were the time
the ACTH stimulation test was performed after administra-
tion of trilostane and the definition of good disease control.
Following administration of trilostane, the ACTH stimulation
test was either performed variably within the day (4,5,9), 2 to
6 h later (3,7), 3 to 4 h later (11), 3 h later (12), 2 to 4 h later
(6), 4 to 6 h later (8,10), or 8 to 12 h later (8,10,13). The
CVJ / VOL 59 / APRIL 2018
upper limit of the acceptable post-ACTH cortisol concentra-
tion range varied from 69 nmol/L (3) to 250 nmol/L (4) a few
hours after administration of trilostane. In some studies, the
trilostane dose was mostly changed based on the results of the
ACTH stimulation test (3,5,7). In other studies, the trilostane
dose was left unchanged in dogs with high (and in some cases
low) post-ACTH stimulation cortisol concentration as long as
clinical signs were controlled (6,8,9,11,12).
Besides these differences in study design that could explain
the wide differences in doses among the studies, some inter-
individual variability could also be due to the low water solu-
bility of trilostane, and thus variable absorption of the drug
(15). In addition, it could be due to a variation in the 3b-HSD
activity in the dogs’ adrenal glands, or variable conversion into
active metabolites such as ketotrilostane (21). It is worth not-
ing that to enhance absorption, trilostane should be given with
food, including on the days recheck ACTH stimulation tests
are being conducted.
In studies describing the use of trilostane q24h (Table 1)
(3–9), the initial dose ranged from 1.0 to 20 mg/kg BW, q24h
with a mean dose of 2.9 to 6.4 mg/kg BW, q24h. The final trilo-
stane dose varied from 0.8 to 50 mg/kg BW, q24h with a mean
dose of 2.8 to 19 mg/kg BW, q24h. However, as explained, the
duration of cortisol suppression after a dose of trilostane is often
less than 12 h. Therefore, several studies have examined the use
and clinical efficacy of trilostane q12h for treatment of PDH
and ADH (Table 2) (7–13).
In studies describing the use of trilostane q12h, the initial
dose ranged from 0.5 to 7.5 mg/kg BW, q12h, with a mean
dose of 0.78 to 3.1 mg/kg BW, q12h. The final trilostane dose
varied from 0.21 to 9.05 mg/kg BW, q12h, with a mean dose of
1.43 to 3.75 mg/kg BW, q12h. Among the studies reported in
Table 2, 10 out of 180 dogs (5.6%) required trilostane 3 times
a day to successfully control their clinical signs (11,12).
In dogs treated with trilostane either q24h or q12h, frequent
dose adjustments were necessary to control the disease (3–13).
In these studies, clinical signs in dogs treated with trilostane
q24h improved in . 75% of cases at 6 mo (3–9). However, the
rates of improvement were variable and 1 study reported only
42% of the total cases (5/12 dogs) had complete resolution of
clinical signs at 6 mo (8). Among studies reporting treatment
with trilostane q12h, 67% to 100% of dogs were well-controlled
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-
lostane q24h and in 69% to 100% of the dogs treated with
trilostane q12h.
Among the 11 studies listed in Tables 1 and 2, adverse effects
were reported in 35/264 (13%) cases with q24h treatment and
in 34/180 (19%) cases with q12h treatment. In both q12h
and q24h treatment groups, most adverse effects were mild or
moderate and included mild electrolyte abnormalities without
clinical signs, transient decrease in appetite, vomiting, diarrhea,
and lethargy.
To date, 3 studies have directly compared the efficacy of
q24h versus q12h trilostane treatment in dogs with HAC.
Augusto et al (7) concluded that dogs treated either q24h or
q12h showed similar improvement in clinical scores. In this
CVJ / VOL 59 / APRIL 2018
retrospective study, control of the clinical signs and cortisol
concentrations was seen sooner in the q12h treatment group.
The mean final dose was 7.6 mg/kg BW per day in the q24h
group and 5.4 mg/kg BW per day in the q12h group (2.7 mg/kg
BW, q12h). Reports of adverse effects, which were documented
as mild to moderate in severity, were more common in the
R E V I E W A R T I C LE
q12h versus the q24h treatment group. However, animals
given trilostane q24h had a 15% increased chance of treatment
discontinuation although no clear explanation to explain the
difference was identified.
Cho et al (9) found fewer adverse effects with low dose (0.5 to
1 mg/kg BW) trilostane administered q12h compared with
30 mg/dog given q24h (6 to 12 mg/kg BW per day) in dogs
, 5 kg BW. While 100% success in controlling clinical signs
and cortisol concentrations was seen in both groups at 24 wk
after initiation of trilostane treatment, improvement occurred
more slowly in the q12h group. The mean final daily dose
required for control of HAC was much lower in the q12h group
compared with the q24h treatment group (2.9 mg/kg BW per
day in the q12h group and 7.1 mg/kg BW per day in the q24h
group). Additionally, results suggested fewer adverse effects in
the q12h versus the q24h treatment group (9).
Arenas et al (8) compared dogs with PDH that were treated
with trilostane either q12h or q24h. The mean final dose was
4.6 mg/kg BW per day in the q24h group and 4.7 mg/kg BW
per day in the q12h group (2.4 mg/kg BW). This study found
that more dogs in the q12h group had complete resolution of
clinical signs than in the q24h group (69% had complete clini-
cal recovery at 6 mo in the q12h group and 42% in the q24h
group). While clinical response was more prevalent in the q12h
treatment group, there was no significant difference in the mean
post-ACTH cortisol concentration between groups. Both pro-
tocols were safe and generally well-tolerated.
Based on these studies, it appears that use of trilostane q12h,
often given at total daily doses that are lower than the manu-
facturer’s recommendations, results in a safe and effective treat-
ment for dogs with HAC. When using a twice-daily treatment
protocol, it is recommended to start at doses of 0.5 to 1 mg/kg
BW, q12h, with a maximum initial dose of 30 mg/dog for dogs
. 30 kg. Indeed, complete control of clinical signs and cortisol
concentrations can be achieved in some dogs using a very low
dose of trilostane (12).
Monitoring
Choosing the best monitoring protocol in HAC dogs undergo-
ing treatment can be challenging. The ACTH stimulation test is
currently the gold standard test used to monitor the response to
treatment of dogs with HAC. However, there are some limita-
tions to this test which will be discussed later. It is recommended
that the ACTH stimulation test be conducted at 10 to 14 d
after initiating trilostane or changing doses, then at 1, 3, and
subsequently every 3 to 6 mo after the trilostane dose becomes
stable (15). It is generally accepted that clinical signs and cor-
tisol concentrations continue to improve in some dogs in the
first month after starting trilostane therapy (12). Therefore, the
ACTH stimulation test performed after 10 to 14 d of onset of
therapy should be used only to ensure that there is no e­ xcessive
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
cortisol concentrations and clinical signs is not expected at 10 to
14 d after starting therapy, and the dose should not be increased
at this time or hypoadrenocorticism could result (15).
Use of synthetic ACTH [Cortrosyn (cosyntropin) and
Synacthen (tetracosactrin or tetracosactide)] for ACTH stimu-
lation tests has been reported for diagnosing and monitoring
HAC in dogs. However, the potency of both drugs has not been
compared. Samples for cortisol measurement are obtained at
0 and 60 min after IV or IM injection of standard non-absorbed
products. Both IV and IM administration of cosyntropin
produce similar ACTH-stimulated cortisol concentrations in
healthy dogs and in dogs with HAC (1,28). Doses of 1 mg/kg
BW and 5 mg/kg BW of cosyntropin were also recently found to
produce similar results when reassessing dogs with HAC treated
with mitotane or trilostane. Therefore, the lower dose appears
to be a safe and more cost-effective way to use synthetic ACTH
for monitoring HAC in dogs undergoing treatment. However,
the same study found a significant difference between the
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
HAC (29).
Use of depot tetracosactide (250 mg total dose or 5 mg/kg
BW, IM) was evaluated in healthy dogs and in dogs with HAC
(30,31). However, since peak cortisol is only obtained 180 min
after IM injection, it is recommended to collect blood samples
at 0 and 180 min for cortisol measurement (30,31).
Only 1 small study evaluated the use of compounded ACTH
in 5 healthy dogs and found no difference in serum cortisol con-
centrations at 60 min for 4 compounded products (32). While
compounded ACTH preparations may be less expensive, they
are not recommended because their potency and the time that
maximal concentration of cortisol occurs may vary significantly
among formulations, even potentially from bottle to bottle at a
specific compounding pharmacy (33).
There is currently no standardization regarding the time
when an ACTH stimulation test should be performed, nor the
optimal cortisol concentration target range. The manufacturer
recommends that the ACTH stimulation test be performed
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
of trilostane treatment. Reported times include 2 to 6 h (3,7),
3 to 4 h (11), 3 h (12), 2 to 4 h (6), 4 to 6 h (8,10), or 8 to 12 h
(8,10,13) after administration of trilostane. Post-ACTH cortisol
concentrations vary with the time interval between dosing and
testing (11). One study demonstrated that a difference of only
2 h between the time the ACTH stimulation test was started
significantly changed the post-ACTH serum cortisol concentra-
tions (34). An ACTH stimulation test should therefore always
be started at or about the same time after trilostane administra-
tion in each individual patient. The lowest cortisol concentra-
tions usually occur 2 to 4 h after trilostane administration (35),
so if the goal of the ACTH stimulation is to determine the
cortisol concentration when trilostane is maximally effective, an
ACTH stimulation test should be performed during this time
interval.
The literature reports various optimal target cortisol con-
centrations for dogs undergoing treatment of HAC. Neiger
et al (4) found that good clinical control of PDH was usually
associated with post-ACTH cortisol concentrations of 20 to
250 nmol/L, regardless of the time of the test. Others have
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
, 150 nmol/L (9,11,12,36), for control of HAC. The authors
of the present article recommend targeting a post-ACTH
­cortisol concentration , 150 nmol/L. However, if good clinical
control is achieved when post-ACTH cortisol concentrations
are , 250 nmol/L, the dose can remain unchanged. It is worth
mentioning that cortisol concentration can be affected by the
assay methodology and can vary among laboratories (37).
Therefore, the cut-offs reported in the literature may be dif-
ficult to apply directly to data from another laboratory. Ideally,
laboratory specific cut-offs should be used.
There is a lack of clear recommendations of how to adjust
the trilostane dose when dogs have well-regulated HAC, but
low cortisol concentrations before and after ACTH stimula-
tion. One recent study examined a small group of dogs with
well-regulated HAC and cortisol concentrations , 55 nmol/L
before and after ACTH stimulation performed 3 to 6 h after
trilostane was administered. A second ACTH stimulation test
revealed that the dogs had significantly increased cortisol con-
centrations 9 to 12 h after the dose of trilostane was given (38).
The authors suggested that a second ACTH stimulation test
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.
In animals with low pre- and post-ACTH cortisol concentra-
tions (, 40 to 55 nmol/L), the authors of the present article
recommend that the trilostane dose be decreased or discontinued
(especially if cortisol ­concentration is , 30 nmol/L). If trilostane
is discontinued, it should be restarted at a lower dose only after
COM PTE R E N DU
an ACTH stimulation test shows that hypocortisolemia has
resolved.
Despite the study findings previously discussed, it remains
unclear whether the ACTH stimulation test is the best method
for monitoring treatment with trilostane (23). In some dogs,
the results of the ACTH stimulation test do not parallel the
control of clinical signs in dogs treated for HAC in both q12h
and q24h treatments (8,12).
Neiger et al (4) proposed that the administration of exog-
enous ACTH during stimulation testing may override the revers-
ible inhibition of cortisol synthesis by trilostane, particularly as
the concentration of the drug decreases, such that the results of
the ACTH stimulation test may be inaccurate. Another possible
explanation would be that the action of trilostane is too short in
these dogs to fully control their clinical signs. The frequency of
administration may need to be increased in these dogs. Lastly,
undiagnosed concurrent diseases could mimic some of the
clinical signs associated with uncontrolled HAC. For instance,
a persistence of PUPD in dogs with early chronic kidney disease
may be falsely interpreted as clinical signs of uncontrolled HAC.
Measuring multiple cortisol concentrations over time, while
expensive and time consuming, may be more accurate than a
stimulation test.
Investigators have assessed other possible options for monitor-
ing treatment response in dogs with HAC. These have included
the UCCR (5,11,12,39), the baseline cortisol (40,41) with or
without combination with an endogenous ACTH and the corti-
sol/ACTH ratio (6,42), the pre-trilostane cortisol concentration
alone or in combination with the 3 h post-trilostane cortisol
concentration (43). In many of these studies, results of these
ancillary tests have been evaluated to determine whether they are
predictive of the ACTH stimulation test results, and therefore
if they could be less expensive monitoring tools. The UCCR,
baseline cortisol, endogenous ACTH, and cortisol/ACTH
ratio have not been found to be very reliable for this purpose.
However, as described, the ACTH stimulation test has its own
limitations making it challenging to assess utility of these other
tests for the monitoring of HAC.
Macfarlane et al (43) evaluated the utility of measuring a
pre-trilostane cortisol concentration (considered peak cortisol
concentration) and a 3-hour post-trilostane cortisol concentra-
tion (considered trough cortisol concentration). In this study,
the pre-trilostane cortisol concentration as well as the 3-hour
post-trilostane cortisol concentration better reflected the level
of clinical control in dogs with uncontrolled HAC than did
the post-ACTH cortisol concentration performed 3 h after
trilostane administration. Clinical control was determined
by detailed questionnaires filled by the owners. However,
94/110 tests (85%) were performed on dogs receiving q24h
trilostane treatment; the results may be different with q12h tri-
lostane treatment.
404
Efficacy of trilostane
Clinical signs of HAC, such as PUPD, polyphagia, or lethargy,
improve gradually over the first months of treatment in most
dogs treated with trilostane q12h or q24h (Tables 1 and 2).
Resolution of dermatological abnormalities can take several
more months after starting trilostane (7).
Trilostane is effective for both PDH and ADH. In ADH
cases, it can be used as a short-term treatment for the control
of cortisol concentrations in preparation for adrenalectomy, or
as a long-term medical therapy (8,11,12). Similar survival times
but fewer side effects were reported with trilostane compared to
mitotane in the treatment of HAC due to ADH (8).
The typical laboratory abnormalities associated with HAC,
such as increase in liver enzymes, hypercholesterolemia, low
urine specific gravity, secondary hyperparathyroidism and
increased phosphorus concentration have all improved with
trilostane treatment (3,7,9,44–46).
Along with the typical clinical signs associated with HAC,
this disorder can also create severe physiological abnormalities.
Sequelae of HAC can include hypertension, proteinuria, hyper-
coagulability, immunosuppression, insulin resistance, and soft
tissue calcification including calcinosis cutis, muscle wasting,
and cranial cruciate rupture (1). Over half of HAC patients
have hypertension at the time of diagnosis, and hypertension
does not resolve in many dogs treated with trilostane, even
after a year of treatment (13,45,46). Persisting hypertension
could be explained by the fact that after trilostane treatment is
initiated, plasma renin activity increases (6), which may lead
to activation of the renin-angiotensin-aldosterone system and
renal vasoconstriction. Proteinuria, as determined by the urinary
protein-to-creatinine ratio, improves over time with trilostane
treatment, but some dogs remain proteinuric after a year of
treatment (45,46). However, hypercoagulability, as measured
by thromboelastographic variables, increased platelet count and
fibrinogen concentration, did not improve following trilostane
treatment in dogs with PDH over 6 mo (46). The persistence
of these physiologic abnormalities associated with HAC may be
due to the serum cortisol concentration still exceeding physi-
ological concentrations during a certain period of the day, even
when trilostane is administered twice daily (45).
Hyperadrenocorticism is associated with calcium dysregula-
tion that can lead to the development of calcium-oxalate uro-
liths, soft tissue mineralization, such as calcification of the skin
(calcinosis cutis), or perihilar bronchial mineralization. Dogs
with HAC have higher parathyroid hormone and phosphate
concentrations than healthy dogs, and these abnormalities
improve in some dogs with HAC following treatment with
trilostane (44). Some patients had resolution of calcinosis cutis
with trilostane treatment (4,47).
Little information is available on the use of trilostane in
dogs with concurrent HAC and diabetes mellitus. Excessive
cortisol concentration causes insulin resistance, making it more
difficult to regulate diabetes mellitus in dogs with concurrent
uncontrolled HAC (1). Insulin resistance is expected to at least
partially improve with trilostane treatment, and therefore,
careful monitoring of blood glucose concentration is needed in
dogs treated for both disorders. In a small study of 8 dogs with
CVJ / VOL 59 / APRIL 2018
diabetes mellitus and HAC, insulin requirements and fructos-
amine concentrations were not consistently reduced during
trilostane treatment for HAC (48). However, the number of
dogs included in the study was small and results may have been
different if a larger population had been used. Interestingly, and
likely only coincidentally, 10% of 103 dogs treated with trilo-
stane developed diabetes mellitus after trilostane was initiated in
1 retrospective study (40% of them within the first 4 mo after
starting trilostane) (49).
Safety of trilostane
Trilostane has a relatively low incidence of adverse effects, espe-
cially when low doses are used. Adverse effects were reported
in 35/264 (13%) dogs undergoing q24h treatment and in
34/180 (19%) dogs receiving q12h treatment in a total of
11 studies (3–13). Reported adverse effects include anorexia,
lethargy, vomiting, diarrhea, and other events typical of a hypo-
adrenal state (hyperkalemia, hyponatremia, and hypovolemic
shock) which may or may not be associated with adrenal necrosis
and hemorrhage. Chronic trilostane use is also associated with
the development of diffuse and/or nodular hyperplasia (50),
enlargement (up to 60% of the original size) and change of
echotexture of the adrenal glands on ultrasound (3). This may
be secondary to the increased endogenous ACTH concentration
that is noted with trilostane treatment (51).
Although more frequent with higher doses, adverse reactions
to trilostane can occur with any dose and any frequency. These
include adverse reactions in dogs treated with trilostane doses
, 1 mg/kg BW, q12h (12), suggesting that factors other than
dose or frequency of administration may contribute to the
development of adverse effects. For instance, since trilostane is
metabolized by the liver and excreted in bile and urine, its use
is not recommended in dogs with liver or renal insufficiency
as dose accumulation may occur. Other factors could include
a particularly good absorption of the drug in some individuals,
as well as individual or breed susceptibility to the effect of tri-
lostane (21). Another possibility is that some dogs could have
been wrongly diagnosed with HAC.
Although in theory the effects of trilostane as an enzyme
inhibitor should be rapidly reversible, prolonged adrenocortical
suppression can occur, and cases of permanent hypoadrenocorti-
cism or adrenal necrosis following trilostane therapy have been
described (5,6,10). In most of the described cases, prolonged
iatrogenic hypoadrenocorticism occurred after several months
of treatment (5,10). However, 2 dogs developed prolonged
hypoadrenocorticism or isolated hypocortisolism following
short courses (3 and 13 d) of trilostane given at 2 to 5 mg/kg
BW, q24h (52,53). Based on a study performed in rats, adrenal
degeneration in this species is likely caused by the effect of
increased ACTH concentration on the adrenal glands rather
than the direct effect of trilostane on the adrenal glands (54).
Periodic monitoring of electrolyte concentrations during tri-
lostane treatment is also recommended since both hyperkalemia
and hyponatremia are common (40). However, most dogs have
mild electrolyte derangements and ACTH stimulation testing
is typically not indicative of hypoadrenocorticism. The mecha-
nism of mild hyperkalemia or other electrolyte changes in dogs
CVJ / VOL 59 / APRIL 2018
treated with trilostane is unknown. Usually trilostane inhibits
the production of glucocorticoids more than the production of
mineralocorticoids. However, it is possible that in some dogs,
trilostane may more effectively block the synthesis of miner-
alocorticoids than glucocorticoids (11,12,55). If electrolyte
changes are observed with trilostane treatment, a careful client
R E V I E W A R T I C LE
interview to help detect clinical signs of hypoadrenocorticism
and an ACTH stimulation test are recommended. It is possible
that a short episode of hypocortisolemia (although not enough
to induce clinical signs) may not be detected by the ACTH
stimulation test (35).
Use in alopecia X
Alopecia X is a form of canine adult-onset alopecia that mainly
affects nordic breeds such as the Alaskan malamute, chow chow,
keeshond, Pomeranian, Samoyed, and Siberian husky, and also
other breeds including the miniature poodle. This form of alo-
pecia resembles the alopecia seen with HAC but other clinical
signs of HAC, such as PUPD and polyphagia, are absent and
traditional tests to diagnose HAC (low dose dexamethasone
suppression test and ACTH stimulation) are normal. Despite
these findings, trilostane has been shown to be effective in the
treatment of alopecia X. Currently, there are few data regard-
ing the treatment of alopecia X. The doses used in 3 published
studies were highly variable (56–58).
The first effective reported doses for treatment of alopecia X
in Pomeranians and miniature poodles ranged from , 6 to
. 23 mg/kg BW, q24h. Some dogs were treated with pulse
therapy (2 to 3 treatments per wk) after initial stabilization
(57). Three Alaskan malamutes were successfully treated in
another study with doses of 3 to 3.6 mg/kg BW, q12h (58).
The frequency of administration was reduced to twice weekly
after initial stabilization. More recently, successful treatment
has also been reported with a dose of 1 mg/kg BW, q12h in
Pomeranians (56). Alopecia X has been postulated to be due to
increased concentration of 17-hydroxyprogesterone (17-OHP).
However, values of 17-OHP have been found to further increase
during successful treatment with trilostane (57).
In conclusion, there have been many studies published in the
past few years contributing to a better understanding of the use
of trilostane in dogs. One of the most clinically relevant findings
that has been recently reported is the use of significantly lower
doses, often given twice daily, which have effectively controlled
HAC in dogs with fewer side effects.
Further study of the use of trilostane in dogs with HAC
is needed to answer some ongoing clinical questions. First,
the results of an ACTH stimulation test, which is the current
gold standard test for monitoring the effect of treatment with
trilostane, do not always correlate with clinical signs, making
it challenging to monitor dogs undergoing treatment. Second,
there is no consensus on the optimal post-ACTH serum corti-
sol concentration, the ideal timing of sampling after trilostane
administration, or the appropriate starting dose and frequency.
Overall, trilostane is an effective and safe method of treating
PDH and ADH in many dogs, and is also reported to be effec-
tive in the treatment of alopecia X. However, it is important
to note that trilostane might not correct physiological changes
405
 associated with HAC, including hypertension and proteinuria,
and these conditions may require specific therapy. CVJ
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Book Review
Compte rendu de livre
Equine Laminitis
Belknap JK, ed. Wiley-Blackwell, Oxford, United Kingdom.
2017. 455 pp. ISBN: 9781-1199-4471-3.
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
anatomy of the foot, the underlying physiology and pathophysi-
ology of all three forms of laminitis (sepsis-associated, endocri-
nopathic, and supporting limb); and the role of the lamellar
basal epithelial cell (LBEC). Crucially, this text manages to
integrate recent research findings with chapters describing the
experimental models of laminitis, the hemodynamic and inflam-
matory aspects of disease, and the role of endocrine and meta-
bolic dysregulation with practical, clinically applicable chapters
on the diagnosis and management of horses with this condition.
The flow between these seemingly diametrically opposed aspects
of laminitis is seamless and easy to follow as a reader.
The clinical portion of the book is extensive and comprehen-
sive. Clearly identified sections written by multiple authors cover
the clinical presentation, diagnostic evaluation, and medical
CVJ / VOL 59 / APRIL 2018
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treatment of the laminitic patient. There are additional sections
on digital support and stabilization of the distal phalanx; treat-
ment — encompassing discussions on the use of casts, dorsal
hoof wall resections, and well-balanced chapters on contentious
issues such as deep digital flexor tendon tenotomy and raising
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
textbook which is beautifully balanced between research and
clinical applicability. As such, it should not be pulled out
when faced with a laminitic horse and expected to deliver a
step-by-step guide to management. It is easy to read, and after
thoughtful consumption can be retrieved and re-examined when
faced with a clinical case, or shown to an owner to illustrate a
difficult concept. Overall this is a textbook which has a place
on the shelf of all veterinary practices that do any amount of
equine clinical work.
Reviewed by James L. Carmalt, MA, VetMB, MVetSc, PhD,
FRCVS, DABVP(Eq), DAVDC(Eq), DACVSMR(Eq), DACVS,
Professor — Equine Surgery, Western College of Veterinary
Medicine, University of Saskatchewan, Canada.
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