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Treatment of canine and feline hyperadrenocorticism: trilostane and the alternatives

Authors:
  • Southfields Veterinary Specialists
  • Small Animal Specialist Hospital, Sydney, Australia

Abstract and Figures

The common causes of hyperadrenocorticism (HAC) are pituitary ACTH-secreting corticotroph tumours, known as pituitary-dependent hyperadrenocorticism, and cortisol-secreting adrenal tumours. The only licensed medical treatment in the UK is trilostane. This treatment improves the clinical signs of HAC in the majority of cats and dogs. There are a number of alternative treatment options that are available for use in non-responders or as first-line treatment instead of trilostane. After a diagnosis of HAC is made, each option should be discussed with clients. This article discusses medical, surgical and radiotherapy options that should be considered to create an individualised treatment plan for each patient and owner.
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MEDICINE
230 Companion animal
|
April 2015, Volume 20 No 4
© 2015 MA Healthcare Ltd
Treatment of canine and
feline hyperadrenocorticism:
trilostane and the alternatives
The common causes of hyperadrenocorticism (HAC) are pituitary ACTH-secreting
corticotroph tumours, known as pituitary-dependent hyperadrenocorticism, and
cortisol-secreting adrenal tumours. The only licensed medical treatment in the UK is
trilostane. This treatment improves the clinical signs of HAC in the majority of cats and
dogs. There are a number of alternative treatment options that are available for use in
non-responders or as first-line treatment instead of trilostane. After a diagnosis of HAC
is made, each option should be discussed with clients. This article discusses medical,
surgical and radiotherapy options that should be considered to create an individualised
treatment plan for each patient and owner. 10.12968/coan.2015.20.4.230
Mr Christopher Scudder BVSc MVetMed MRCVS. Veterinary Researcher, RVC and Mr Patrick Kenny
BVSc Dip ACVIM (Neurology) DipECVN FHEA MRCVS, Head of Neurology and Neurosurgery, RVC at
Department of Clinical Science and Services, Royal Veterinary College, North Mymms, UK. Dr Stijn
Niessen DVM PhD DipECVIM-CA MRCVS, Co-Head of Small Animal Internal Medicine, RVC. Diabetes
Research Group, Medical School, University of Newcastle, Newcastle, Tyne and Wear, UK
Key words: Pituitary | Adrenal | Hyperadrenocorticism | Cushing’s syndrome | Hypophysectomy | Adrenalectomy
T
he common causes of hyperadrenocorticism (HAC)
are pituitary ACTH-secreting corticotroph tumours,
known as pituitary-dependent hyperadrenocorticism
(PDH), and cortisol-secreting adrenal tumours (ATs)
which can either be adenomas or carcinomas. There are rare re-
ports of dogs having ectopic ACTH syndrome caused by non-pi-
tuitary ACTH-secreting tumours, and food-dependent HAC. The
common clinical signs of hyperadrenocorticism (HAC) are poly-
dipsia, polyuria, polyphagia and panting (Behrend et al, 2013). The
American College of Veterinary Internal Medicine has published a
consensus statement on the diagnosis of HAC in dogs, and there
are many excellent reviews on this topic (Kooistra and Galac,
2010; Melian et al, 2010; Behrend et al, 2013; Behrend, 2015).
Pituitary tumours are the cause of HAC in 75 to 85% of canine
and feline HAC cases, and it is most commonly caused by an adeno-
ma (Hoenig, 2002; Kooistra and Galac, 2010; Valentin et al, 2013).
Pituitary tumours can be categorised in several ways, for instance mi-
cro- or macro-, functional or non-functional and adenoma or carcino-
ma. Macroadenomas often protrude out of the bony indentation that
houses the pituitary at the base of the brain, the sella turcica, and are
>10mm, although classication based on a cut-off size of 10mm has
questionable utility in veterinary medicine (Meij et al, 2002; Wood et
al, 2007). In addition to the common clinical signs of HAC, pituitary
macroadenomas may cause central blindness or neurological disease,
secondary to a space-occupying lesion effect (Goossens et al, 1998;
Wood et al, 2007). There are a number of different treatment options
for PDH and ATs, and clinicians should individualise treatment ac-
cording the specic presentation of the animal and preference of the
owner. The age of the animal at diagnosis and long-term costs are
some of the factors that should be considered.
Medical Management
Trilostane (Vetoryl, Dechra, Shrewsbury, UK) has been shown to
be extremely useful in the management of PDH. One of mecha-
nism of actions is the inhibition of 3-β hydroxysteroid dehydro-
genase, an essential enzyme during steroidogenesis in the adre-
nal gland. Trilostane has been shown to impressively improve the
clinical signs of HAC in 86% and between 67 to 100% of cats
and dogs, respectively (Ramsey, 2010; Mellett Keith et al, 2013).
Trilostane is sold as 10mg, 30mg, 60mg and 120mg hard cap-
sules, is recommended by many as a preferred treatment modality,
and is the only licensed drug to treat canine HAC in the UK.
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Trilostane is rapidly absorbed from the gastrointestinal tract after
oral administration, and bioavailability is improved when given with
food. Peak serum concentrations of trilostane and the primary active
metabolite, keto-trilostane, occur 30 to 90 minutes after oral admin-
istration, and peak serum cortisol reduction occurs between four to
six hours after administration (Vetoryl datasheet, Dechra, Shrews-
bury, UK). A starting dose of 2–5mg/kg/day is recommended, and
the addition of a 10mg capsule to the product range has made pre-
scription of these doses more practical (Ramsey, 2010).
Patient monitoring is performed as recommended by the data-
sheet, and dose alterations prescribed gradually to achieve control
of clinical signs and biochemical control. The monitoring of trilos-
tane-treated hyperadrenocorticoid dogs is challenging if the supply
of synthetic ACTH is restricted. Recent studies have investigated
the use of serum cortisol and serum cortisol to endogenous plasma
ACTH ratio to monitor patients during trilostane therapy (Cook
and Bond, 2010; Burkhardt et al, 2013). Serum cortisol, measured
two to three hours post-trilostane administration, above 28mmol/l
excluded excessive suppression in 97% of dogs, and four to six
hour post-trilostane administration serum cortisol concentrations
above 36mmol/l excluded excessive cortisol suppression in 98%
of dogs (Cook and Bond, 2010; Burkhardt et al, 2013). Three-
hour post-trilostane administration serum cortisol concentration
>120mmol/l was an indicator of inadequate control, and four to
six hours post-trilostane administration below 80mmol/l excluded
inadequate control in 95% of dogs (Cook and Bond, 2010; Bur-
khardt et al, 2013). However, the authors of the study concluded
that endogenous ACTH or serum cortisol to endogenous ACTH
concentrations did not adequately distinguish between excessively,
adequately, and inadequately controlled dogs and should not be
used instead of an ACTH stimulation test to monitor trilostane
therapy (Burkhardt et al, 2013). One attractive alternative to meas-
uring serum cortisol would be the measurement of urine cortisol
or corticoid to creatinine ratios (UCCR). However, the majority of
hyperadrenocorticoid dogs treated with trilostane for two months
did not achieve normalisation of their UCCR, possibly because of
the measurement of cortisol precursors that continue to be synthe-
sised during trilostane therapy (Galac et al, 2009). Therefore, the
UCCR test cannot be used as a monitoring tool for trilostane treat-
ment. The authors recommend basal serum cortisol and electrolyte
concentrations are measured if a patient becomes unwell during
therapy, and medication is temporarily discontinued while await-
ing results. The patient can be prescribed 0.2mg/kg prednisolone
and receive supportive care if sick enough to require hospitalisa-
tion. A lymphocyte count could be performed while awaiting the
endocrine test results as patients are highly unlikely to have hy-
poadrenocorticism if their lymphocyte count is <0.75x10^9/l (Seth
et al, 2011). The patient should restart trilostane at half the previ-
ous dose when clinically well and basal cortisol is >28mmol/l. A
trilostane dose increase should be considered if a patient continues
to exhibit clinical signs consistent with hyperadrenocorticism and
basal cortisol is >28mmol/l, but a slow and gradual dose increase
should be prescribed.
A proportion of dogs do not respond completely during once-
daily trilostane therapy. Twice- or three times daily therapy could
be prescribed on a trial basis based on the rationale that trilostane
may not induce cortisol reduction for 24 hours. Twice-daily therapy
is generally well tolerated and often improves the clinical signs of
dogs affected by PDH and AT (Alenza et al, 2006; Feldman, 2008;
Arenas et al, 2013). There are several disadvantages of trilostane
for the management of HAC. Although HAC is typically a disease
of the older dog, long-term use can prove expensive, especially in
large dogs and those diagnosed at a young age. Dose adjustments
and frequent blood test monitoring can add to the long-term nan-
cial cost for owners. Adverse drug effects are common, occurring
in 10 to 40% of patients treated either one or twice daily. (Alenza
et al, 2006; Arenas et al, 2013). Side effects are typically mild, and
include gastrointestinal upset and lethargy, which may improve fol-
lowing dose reduction. However, rare cases of iatrogenic adrenal
necrosis and subsequent hypoadrenocorticism have been report-
ed. These are thought to be related to the increased endogenous
ACTH levels causing increased adrenal blood ow, causing in turn
a higher chance of adrenal haemorrhage, given the fragile nature of
adrenal vessels. Trilostane treatment also leaves the inciting cause
17-hydroxy pregnenolone
17-hydroxy progesterone
11-deoxycortisol
Cortisol
Dehydroepiandrosterone
Androstenedione
Estrone Testosterone
Estradiol
Desmolase
3ß hydroxysteroid
dehydrogenase
21 hydroxylase
11ß hydroxylase
Aldosterone
synthase
3ß hydroxysteroid
dehydrogenase
21 hydroxylase
11ß hydroxylase
3ß hydroxysteroid
dehydrogenase
17 ketoreductase
aromatase
aromatase
17 ketoreductase
17
α
hydroxylase
17
α
hydroxylase
17, 20 lyase
17, 20 lyase
Cholesterol
Pregnenolone
Progesterone
Deoxy-corticosterone
Corticosterone
Aldosterone
Figure 1. Adrenal gland steroid hormone biochemical pathways.
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untouched. The possibility that a pituitary tumour could continue
to grow, and cause secondary space-occupying disease, should be
a consideration at the time of diagnosis.
There is a general paucity of information regarding using
trilostane to treat feline HAC. The rst report was in 2003,
which described a good clinical response to 30mg twice-daily
trilostane therapy, and this dose appeared to be well tolerated
(Skelly et al, 2003). Three subsequent case series report the
response to trilostane therapy in ve, nine and 15 cats (Neiger
et al, 2004; Mellett Keith et al, 2013; Valentin et al, 2014).
Therapy was typically well tolerated and associated with good
long-term survival in many cases. However, up to 90% of fe-
line HAC patients have concurrent diabetes mellitus, which is
likely secondary to cortisol-induced insulin resistance (Graves,
2010). Trilostane therapy reduced insulin requirements in 6/9
diabetic HAC cats in one study, and this was only a 36% reduc-
tion, while another study reported insulin doses were not re-
duced in any of the ve diabetic HAC cats treated (Neiger et al,
2004; Mellett Keith et al, 2013). As insulin dose decrease has
been considered an indicator of response to HAC treatment,
unchanged insulin requirement suggests inadequate control of
hypercortisolaemia, or permanent exocrine pancreatic disease
(Valentin et al, 2014).
The Veterinary Medicines Regulations allows UK veterinarians
to prescribe medications for use other than the authorised use if
there are no licenced products or if the licenced product is unsuit-
able. Prescription of a non-licenced product should be considered
if a patient experiences signicant adverse drug effects or the li-
cenced product is ineffective at controlling the disease. Veterinary
surgeons should consider the reliability of the original diagnosis
of HAC before prescription of an alternative medication, because
nearly 90% of hyperadrenocorticoid dogs experience rapid clinical
improvement during trilostane treatment.
Mitotane (Lysodren, HRA Pharma UK and Ireland Limited,
London, UK) is a prescription-only medicine licensed for the
symptomatic treatment of advanced adrenal corticol carcinoma in
humans. The complete mechanism of action of mitotane is un-
known, however it is primarily adrenolytic, by induction of free
radicals, and inhibits 11β hydroxylase and desmolase in the adre-
nal gland, thereby reduce steroid synthesis (Figure 1) (Veytsman et
al, 2009). This drug successfully improves clinical signs of HAC
in up to 87% of dogs and 50% of cats, but mitotane-associated
side-effects occur in up to 42% dogs, and clinical relapse following
dose adjustments is common (Lorenz, 1982; Nelson et al, 1988;
Kintzer and Peterson, 1991; Schwedes, 1997). The common side-
effects are gastrointestinal signs (vomiting, anorexia and diarrhoea)
or weakness. Mitotane can be used for two different treatment
strategies: it can be given life-long with gradual dose adjustment to
effect, or for a short period of time for the induction of permanent
hypoadrenocorticism. Mitotane can be considered for patients
who do not respond to, or experience adverse drug effects during,
trilostane therapy, and for those with metastatic AT.
Life-long therapy is prescribed as an initial ‘loading-phase typi-
cally over eight days, followed by a ‘maintenance phase’. The aver-
Figure 3. Dorsal view of a T2-weighted intra-cranial MRI to show the location of
the optic chiasm and pituitary gland. Optic chiasm compression could be caused
by a pituitary macroadenoma.
Optic chiasm
Pituitary
Pituitary
enlargement
Figure 2. Use of contrast-enhanced T1-weighted MRI to aid diagnosis of a pituitary enlargement in a dog with hyperadrenocorticism; (a)
pre-contrast enhanced T1-weighted intra-cranial MRI; (b) post-gadolinium contrast enhanced T1-weighted intra-cranial MRI.
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age maintenance weekly dose of mitotane in one study of 184 dogs
was 71mg/kg, but relapse of clinical signs was common using this
protocol, with around 50% of dogs experiencing clinical relapse
within the rst year of therapy, and the loading phase may need to
be repeated in this scenario (Kintzer and Peterson, 1991).
Adrenolytic protocols require giving higher doses of mitotane
daily (typically doses of 50 to 100mg/kg/day given in three or four
doses per day) for 25 consecutive days (Rijnberk and Belshaw,
1988; Feldman and Nelson, 2004; Clemente et al, 2007). Con-
current glucocorticoid and mineralocorticoid supplementation is
started on day three of therapy. These ‘higher-dose’ protocols have
been successful at achieving control of HAC-associated clinical
signs, and have a median survival time of 720 days and three year
survival fraction of 60% (den Hertog et al, 1999; Clemente et al,
2007). The potential side effects of these protocols, expense of
treatment of hypoadrenocorticism (particularly in the USA), and
risk of fatal consequences of poorly-treated hypoadrenocorticism,
has caused some clinicians to discourage its use (Behrend, 2015).
The adrenolytic protocols have a reported mortality rate of 5 to
10% within the rst 25 days of therapy, although these gures may
over-estimate the risk, as some of the patients had signicant con-
current disease at the time of diagnosis; 10 to 40% of incidence of
gastrointestinal upset; and 30 to 40% incidence of disease relapse
(den Hertog et al, 1999; Clemente et al, 2007).
The use of mitotane in cats has been discouraged due to the
feline sensitivity to chlorinated hydrocarbons and reports of seri-
ous side-effects and poor response to treatment (Duesberg and
Peterson, 1997; Nelson et al, 1988). There are reports of mitotane
therapy achieving clinical control of feline HAC, however trilos-
tane appears to be a more advantageous medical management op-
tion in cats (Schwedes, 1997).
Trilostane versus mitotane studies have been reported. Pos-
sibly the most applicable study to the UK veterinary surgeon is
the study by Barker et al (2005), which reported median survival
times of 662 days and 708 days for trilostane treated and life-long
mitotane therapy treated PDH respectively. Twice-daily trilostane
appeared to have a more favourable outcome for the treatment of
PDH compared to a mitotane adrenolytic protocol, having median
survival times of 900 days and 720 days, respectively (Clemente et
al, 2007). Both trilostane and mitotane have been used to treat AT
and no study to date has reported signicantly different survival
times for either drug (Helm et al, 2011; Arenas et al, 2014).
Several prognostic factors have been proposed when using
trilostane or mitotane therapy. Older age and heavier weight are
negative prognostic factors reported in several studies; higher
one hour post-ACTH serum cortisol, weakness at presentation,
hyperphosphataemia and severity of clinical signs have also been
reported as negative prognostic indicators (Kintzer and Peterson,
1991; Barker et al, 2005; Clemente et al, 2007; Arenas et al, 2014;
Fracassi et al, 2014).
There are a small number of studies reporting use of alterna-
tive drugs to manage HAC. Ketoconazole is likely to have several
cortisol synthesis-inhibiting mechanisms of action, including gen-
eral inhibition of P450 enzymes and 11β hydroxylase (Loose et
al, 1983; Loli et al, 1986). However, its efcacy is underwhelm-
ing, especially in light of better medical options being available,
despite some reports suggesting it to be relatively effective, with
improvement of HAC-associated clinical signs in 43 of 48 dogs
and survival times comparable to mitotane and trilostane (median
survival 810 vs 622 to 852 days, respectively) (Barker et al, 2005;
Lien and Huang, 2008; Fracassi et al, 2014). Idiosyncratic keto-
conazole-induced hepato- and other toxicity appear to be rare, but
therapy is commonly associated with gastrointestinal upset (Lien
and Huang, 2008; Mayer et al, 2008).
Metyrapone inhibits the conversion of 11-deoxycortisol to
cortisol, and successfully improved HAC clinical signs prior to
A
B
C D
Pituitary
fossa
Sutured soft
palate
Figure 4. (a) Photograph of a dog with pituitary-dependent hyperadrenocorti-
cism; (b) The same dog under general anaesthesia placed in sternal recum-
bency and head placed in a surgical head brace to maintain an elevated head
position; (c) The soft palate has been incised and retracted. The pituitary fossa
has been exposed after burring the basisphenoid and presphenoid bones; (d)
The soft palate has been closed using absorbable suture material.
Figure 5. (a) Photograph of a cat with a diagnosis of pituitary-dependent hy-
peradrenocorticism; (b) Contrast enhanced computed tomography of the same
cat showing pituitary enlargement; (c) Photomicograph showing haematoxylin
and eosin staining of the pituitary tissue collected during the hypophysectomy
surgery of the same cat. The cells are polygonal and exhibit the eosinophilic
cytoplasm that is typical of corticotropes.
B
Pituitary enlargement
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bilateral adrenalectomy in two cats, but reports in dogs are lack-
ing (Daley et al, 1993; Moore et al, 2000).
In summary, trilostane is the medical management option of
choice for the UK veterinarian, and mitotane is an appropriate
second line therapy. Other medical management options are of-
ten either less effective or more frequently associated with detri-
mental side-effects.
Surgical Management
Hypophysectomy
Hypophysectomy (surgical extirpation of the hypophysis/pitui-
tary gland) is the only curative procedure for PDH. Around 75%
of patients achieve long-term cure, but the remainder of patients
experience disease recurrence or residual disease post-surgery
(Hanson et al, 2005). Surgical debulking of larger pituitary tu-
mours can improve or resolve neurological decits caused by
compression of the adjacent brain (Figures 2 and 3 reveal the
location of the pituitary gland and relationship to the adjacent
brain and optic nerves). This treatment option is available in the
UK; it should be performed by an experienced surgeon in a facil-
ity capable of providing the intensive intra- and post-operative
care required by these patients. Although a nancial investment
is required up front, subsequent medical management (hormonal
replacement) over the long term is comparatively less expensive.
Both factors are of relevance when considering younger animals
diagnosed with hyperadrenocorticism. Additionally, there is a
reasonable chance (approximately 20%) that without surgery the
pituitary tumour will grow large enough to cause clinical signs
and shortened life span (Kipperman et al, 1992; Bertoy et al,
1996; Ihle, 1997; Kent et al, 2007).
Hypophysectomy is by no means a new procedure: the rst ca-
nine hypophysectomy was performed in 1886, and later rened by
Aschner in 1912. Since these early reports, there have been sev-
eral techniques described, including the transbuccal approach (Es-
sex and Astrabadi, 1953), transoral approach following mandibular
symphysiotomy (Henry and Hulse, 1982), and ventral paramedian
approach between the larynx and mandibular ramus (Axlund et al,
2005). These techniques have been largely superseded by the tran-
soral approach described by Meij et al (1997; 2001). The patient is
positioned in sternal recumbency and the head elevated with mouth
open. The skull-base is accessed by a soft palate incision and the
bone ventral to the hypophyseal fossa is removed using a rotating
burr (Meij et al, 1998). The approach is guided by referencing bony
landmarks and reconstructions of pre-operative computed tomogra-
phy images. When the pituitary gland is exposed, the dura mater is
incised and the pituitary gland extirpated using ne surgical tools.
The skull defect is closed using either bone wax or collagen sponge,
and the soft palate is closed using absorbable suture material in two
layers (Figure 4). Medical care of the patient during the intra- and
post-operative period centres on glycaemic and free-water control, in-
itially cortisol and later also thyroxine supplementation. A two-week
course of broad-spectrum bacteriocidal antibiotics is prescribed,
because the surgery is performed transorally. Cortisol and thyroxine
supplementation are life-long and titrated to effect. The hypothala-
mus synthesises vasopressin, which is normally transported to the
posterior pituitary via the hypothalamic-neurohypophyseal tract.
Desmopressin (DDAVP) is prescribed to manage free-water control
but, depending on the exact location of the pituitary stalk excision,
remaining neurones in the hypothalamic-neurohypophyseal tract
may be able to release vasopressin. Around 80% of patients can be
weaned off desmopressin over the weeks to months following sur-
gery, however 20% develop permanent central diabetes insipidus
and require life-long desmopressin therapy (Hanson et al, 2005).
Insulin therapy is titrated to effect and can often be reduced or
Figure 6. (a) Ultrasound image of an enlarged adrenal gland. The
gland has the characteristic ‘peanut’ shape but is enlarged at the
cranial aspect; (b) A sagittal image of contrast-enhanced abdominal
computed tomography identifying an enlarged adrenal gland; (c) A
dorsal image of contrast-enhanced abdominal computed tomogra-
phy. This is the same adrenal gland as in 4b, showing the relation-
ship of the adrenal gland to the kidneys and caudal vena cava.
Figure 4. ??????
Adrenal
Gland
Adrenal
Gland
Vena
cava
Adrenal
Gland
Kidney
A
B
C
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discontinued as hypercortisolaemia-induced insulin-resistance re-
solves, if patients are diabetic at the time of presentation.
The acute surgical mortality rate of humans who had Cush-
ing’s disease and were treated by transphenoidal adenomectomy
was 0 to 1.9%; remission rates were between 69 to 98% and were
associated with tumour size and invasiveness (Kelly, 2007). Post-
operative basal cortisol was a predictor of disease remission in
this review. A report of 150 canine hypophysectomy surgeries for
the treatment of PDH described an 8% post-operative mortality
rate, with the majority of these patients being in the early cohort
following the development of their hypophysectomy clinic (Han-
son et al, 2005). Their one-, two-, three- and four-year estimated
survival rates were 84%, 76%, 72% and 68%, respectively. Sur-
vival and disease-free fraction was lower in patients with pituitary
height to brain area ratio >0.31, and a later study from the same
group described older age, larger pituitary size and increased ba-
sal plasma ACTH concentration as risk factors for post-operative
survival (Hanson et al, 2007). Pre-operative urine cortisol to cre-
atinine ratio was a predictor for disease recurrence, and post-op-
erative urine cortisol to creatinine ratio measured six to 10 weeks
after surgery was a predictor for disease remission and survival.
Feline hypophysectomy has been described in two case series,
and the techniques used are similar to canine hypophysectomy
(Figure 5). In the rst, hypophysectomy was performed on seven
hyperadrenocorticoid cats: two died within two weeks of surgery,
and the remaining ve achieved disease remission (Meij et al,
2001). A more recent abstract reported the treatment of twelve
cats with hypersomatotropism and diabetes mellitus by hypophy-
sectomy: two cats died perioperatively; of the surviving ten cats,
seven went into complete diabetic remission, and three into par-
tial remission (Kenny et al, 2015).
Keratoconjunctivitis sicca (KCS) and persistent diabetes in-
sipidus can occur after canine and feline hypophysectomy sur-
gery. KCS affects a third of dogs post-operatively and although
the majority completely recover, 20% of these dogs have persist-
ently low tear production (Hanson et al, 2005).
Hormone supplementation and monitoring of thyroxine is
needed, since pituitary adenomectomy without total hypophy-
sectomy is rarely possible.
In summary, hypophysectomy provides a surgical alternative
to medical palliation of PDH. Around 75% of treated patients
achieve disease cure without recurrence. Life-long post-oper-
ative hormone supplementation is required and should be dis-
cussed with owners considering this option.
Adrenalectomy
Bilateral adrenalectomy (BA) is the treatment of choice for bi-
lateral AT. BA is more widely available than is hypophysectomy,
and should be considered as a possible option for the treatment
of PDH. There are cases of ectopic ACTH production causing
HAC in humans and a single case report exists of this disease in
dogs; BA or medical management are appropriate in these cases
if the primary tumour cannot be found or excised (Galac et al,
2005; Biller et al, 2008). Ventral midline abdominal, intercostal/
ank and laparoscopic techniques have been described for per-
forming adrenalectomy (Massari et al, 2011; Barrera et al, 2013;
Naan et al, 2013; Andrade et al, 2014). Patients will need life-long
glucocorticoid and mineralocorticoid supplementation, and to be
monitored in a similar manner to a patient with naturally occur-
ring hypoadrenocorticism. As hypoadrenocorticism is more easily
managed than hyperadrenocorticism, this remains an attractive
alternative.
A recent systemic review of BA for human AT revealed low
surgical mortality (3%) and a good rate of resolution of clinical
signs, but 43% of patients died due to thromboembolic disease
(such as stroke or myocardial infarction), progressive disease
or other cause within 12 months following surgery (Ritzel et al,
2013). A case series of eight cats that underwent BA for PDH has
been described (Duesberg et al, 1995). Three of the eight cats
died within three weeks of surgery from complications that could
have been attributed to HAC induced disease and surgical com-
plications. The clinical signs of the remaining ve cats resolved
by four months post-surgery, but some cats continued to require
insulin therapy. There are case reports of bilateral adrenalectomy
in dogs, but to the authors’ knowledge a large case-series has not
been reported (Anderson et al, 2001; Hanson et al, 2007; Lang
et al, 2011).
Unilateral adrenalectomy is the treatment of choice in
patients with AT, and may be followed by chemotherapy in
patients with metastatic disease (Figure 6 reveals the adrenal
enlargement). Table 1 summarises the ndings of studies
reporting case series of adrenalectomy in patients having AT.
There are a number of different prognostic factors and survival
times reported, and it should be noted that different surgical
techniques, surgical expertise and post-operative care protocols
will have inuenced outcomes. There are no large case series of
unilateral adrenalectomy for the treatment of feline AT, though
a recent case series of 10 cats that underwent adrenalectomy
for adrenal-dependent hyperaldosteronism revealed good post-
operative recovery. Two of these 10 cats were euthanized due
to consequences of surgery, and the remaining eight cats had
good long-term survival (Lo et al, 2014). Although these cats will
have a different metabolic derangement prole to cats having
AT, this study suggests that it is possible to perform unilateral
adrenalectomy safely in this species.
In summary, adrenalectomy is the treatment of choice for AT.
Patients undergoing bilateral adrenalectomy will require life-long
management of hypoadrenocorticism.
Radiotherapy
Radiotherapy is considered an effective second line therapy for
human PDH. Radiotherapy is prescribed for human patients un-
suitable for hypophysectomy, or for those who experience disease
persistence following hypophysectomy. Radiotherapy improves
survival in patients with pituitary masses, and the response to ra-
diotherapy and survival following treatment is negatively correlated
with the ratio of tumour size to brain height (Theon et al, 1998;
Kent et al, 2007).
Fractionated external beam radiotherapy has been used to treat
canine pituitary macroadenomas since 1985. The rst report of ra-
diotherapy improving the neurological disease caused by a PDH
macrotumour was in 1990 (Dow et al, 1990). Dogs received 10
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236 Companion animal
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Table 1. Summaries of studies of adrenalectomy in dogs with cortisol-secreting adrenal tumours
Reference Number
enrolled
Procedure/ disease Survival Complications (number of patients) Prognostic factors
Post-op
Died
Intra-op
Pancreatitis
CVR
Renal
GIT
Other
Scavelli et
al, 1986
25 dogs All unilateral; 24 ventral
midline, 1 paracostal,
11 adenomas, 14
carcinomas
Adenoma: 3 survive >
24 months; carcinoma:
2 survive > 24 months
12 1 7 1 1 Negative: possible AT
carcinoma
van Sluijs et
al, 1995
36 dogs 33 unilateral and 3
bilateral
40% probability of
survival at 1 200 days
10 3 1 6
Anderson
et al, 2001
21 dogs 18 unilateral and 3
bilateral; 4 adenomas
and 20 carcinomas
Adenoma MST not
reached; if carcinoma
patient survived first 14
days, survival time 992
days
5 1 1 1 1 1 None
Kyles et al,
2003
40 dogs 37 unilateral and 3
bilateral 28 AT, 11 pheo,
1 no diagnosis
MST not reached for
adrenalectomy alone;
MST c. 6–8 months
for adrenalectomy and
thrombectomy
9 4 1 8 1 3 5
Schwartz et
al, 2008
41 dogs Unilateral
adrenalectomy; 19
carcinoma 14 adenoma
MST carcinoma was 230
days; MST adenoma
687.5 days
4 2 3 5 10 Negative: pre-operative
hypokalaemia, azotaemia,
kidney disease
Lang et al,
2011
60 dogs 59 unilateral and 1
bilateral; 15 adenoma,
26 carcinoma, 6
hyperplasia
If survive peri-operative
period: 492 days
7 21 7 Negative: acute adrenal
haemorrhage; each 1 mm
increase in tumour size
increased perioperative
mortality by 7.9%
Massari et
al, 2011
52 dogs 25 adenomas, 18
carcinomas, 7 pheo, 1
other
All-dog survival was 953
days
1 1 4 2
Negative: tumour size >5,
metastatic disease, vein
thrombosis
Barrera et
al, 2013
86 dogs 14 adenoma and 45
carcinoma, 27 pheo
All adenoma patients
survived; MST
carcinoma 48 months;
MST pheo not reached
22 53 8 31 6 31 12 Negative: presence of
extensive vena cava
thrombus, but not tumour
type
Mayhew et
al, 2014
48 dogs 19 adenoma and 27
carcinoma
Short-term follow-up
only
2 1 6 1
AT = Adrenal tumour; CVR = Cardiovascular/respiratory; GIT = gastro-intestinal; MST = median survival time; op = operation;
pheo = pheochromocytoma.
fractions of 4Gy (40 Gy total dose) over 22 days. Neurological
status improved within three months and pituitary tumour volume
reduced by 50% every six months for at least one year. Side effects
were regional hair depigmentation, reduced hearing or deafness,
keratoconjunctivitis sicca, and temporary vestibular syndrome;
one dog started to seizure 17 months later and another developed
unilateral trigeminal neuropathy nearly 30 months later. However,
biochemical control of PDH following radiotherapy has been poor,
and continued medical management has been necessary (Goos-
sens et al, 1998; Theon et al, 1998). Fractionated radiotherapy can
improve the diabetic control of cats with PDH, but, as in dogs, does
not lead to normalisation of cortisol secretion (Mayer et al, 2006).
Stereotactic radiosurgery, performed by delivering a single dose
of radiotherapy to a dened target area, has been performed in dogs
with pituitary neoplasia, but the ability of this treatment to control
canine PDH is not yet known (Mariani et al, 2013). Stereotactic
radiosurgery for PDH has been reported in two cats. One cat was
receiving concurrent trilostane and experienced clinical improve-
ment within nine months after radiosurgery; the other cat was eu-
thanised two months after treatment due to suspected abdominal
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neoplasia. Larger studies are needed to understand the role that
radiosurgery could have in the management of PDH.
In summary, radiotherapy can play a limited role in the man-
agement of hyperadrenocorticism. It appears most useful to shrink
the pituitary tumour, but seems less useful to achieve hormonal
normalisation.
Malignant neoplasms
Pituitary carcinomas are rare; adenomas are most commonly en-
countered. They are dened by metastatic behaviour rather than by
invasive or histopathology characteristics in human endocrinology
(Kaltsas et al, 2005). The treatment of humans affected by pitui-
tary carcinomas is mainly palliative. The incidence of this type of
tumour in veterinary species in not known, nor is the most appro-
priate treatment protocol. Treatment would likely involve a combi-
nation of surgery, radiotherapy and medical treatments including
cytotoxic chemotherapy, in an attempt to improve quality of life.
However, euthanasia should be considered if the patient’s quality
of life does not improve in response to therapy.
Adrenal tumour invasion and/or metastatic disease are used to
differentiate adrenal cortical adenomas from carcinoma in human
pathology, and an adrenal mass ≥2cm is likely to be malignant in
canine medicine (Cook et al, 2014). In the absence of these fea-
tures, the Weiss system, which assesses nine different histopatho-
logical features, is commonly used in human pathology to assess
adrenal tumour malignancy (Weiss, 1984). Adrenal carcinomas
should be excised if possible, because this is positively correlated
with survival in humans (Fulmer, 2007). Metastatic disease is a
negative prognostic factor, and adjuvant treatment with mitotane or
mitotane plus cytotoxic chemotherapy may improve survival further
(Helm et al, 2011).
The opinion of the authors is that veterinary patients are prob-
ably best monitored for the development of metastatic disease and
receive treatment if/when this disease occurs. Cytotoxic chemo-
therapy typically has disappointing success as the primary and sole
therapy for adrenal cortical neoplasia, and the benets of adjuvant
chemotherapy without metastatic disease do not outweigh possible
side-effects.
In summary, surgical excision of malignant AT is an appropriate
treatment option and can prove very satisfactory if performed at a
time prior to metastatic disease. Malignant PDH is fortunately rare.
Conclusion
Trilostane is a good treatment option for many patients suffering
from hyperadrenocorticism, but there is more to consider than
trilostane treatment after a diagnosis of HAC has been made. Cli-
nicians should encourage owners to invest in differentiating PDH
from AT. Additionally, the full range of treatment options should be
discussed, so that therapy is tailored to the individual patient and
owner rather than the recommendation of a single therapy for all
patients.
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KEY POINTS
Following a diagnosis of hyperadrenocorticism, pituitary-dependent and
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Surgical intervention is the only treatment modality to provide
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management of hypoadrenocorticism.
Radiotherapy is an appropriate treatment for patients experiencing
neurological consequences of a growing pituitary macroadenoma, but
does not offer good hormonal control.
Pituitary carcinomas are rare and associated with a poor prognosis.
Adrenal carcinomas are a common cause of adrenal-dependent
hyperadrenocorticism and early intervention is likely to improve survival.
Patient and owner characteristics will help identify the best option, and
may include age of the animal and long-term financial impact of all
options.
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... De las alteraciones adrenales reconocidas en felinos, el hiperadrenocorticismo (HAC) se ha reportado con mayor frecuencia (Duesberg et al, 1997). Las causas más comunes del HAC incluyen tumores pituitarios y tumores adrenales (Scudder et al, 2015). Los signos clínicos son en su mayoría poliuria, polidipsia, polifagia, abdomen péndulo, debilidad muscular, letargia y obesidad (Duesberg et al, 1997), aunque puede haber pérdida de peso debida a los efectos catabólicos del exceso de cortisol (Lowe et al., 2008). ...
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El hiperadrenocorticismo felino es una endocrinopatía poco frecuente, caracterizada por niveles elevados de cortisol en sangre. Puede ser causado por afecciones primarias de la hipófisis o de las glándulas adrenales. Los signos clínicos de esta patología incluyen poliuria, polidipsia, polifagia y dermatopatías. La edad promedio de presentación es de 10 años y suele asociarse a otros desórdenes endocrinos, principalmente la diabetes mellitus. El diagnóstico se basa en pruebas de función adrenal y diagnóstico por imagen. La terapia instaurada puede ser médica, quirúrgica o una combinación de las dos.
... Alguns atuam nas glândulas adrenais inibindo a esteroidogênese, há os que atuam diretamente no tumor e por fim aqueles cuja função é de bloquear os receptores dos glicocorticoides (Constanzo & Picó, 2012). Temos como opções o Mitotano, o Etomidato e o Trilostano, sendo ele a melhor opção terapêutica para HAC em felinos (Martinez & Roca, 2009;Scudder et al., 2015). O trilostano foi o tratamento de escolha para o presente relato, já que ele inibe a enzima 3-β-hidroxiesteroide-desidrogenase (3β-HAD), responsável pela conversão da pregnenolona em progesterona, inibindo a conversão da progesterona em cortisol e aldosterona (Neiger et al., 2004;Skelly et al., 2003). ...
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O Hiperadrenocorticismo (HAC) é uma doença endócrina consequente da exposição excessiva ao cortisol podendo ser decorrente da alteração funcional das glândulas adrenais ou da administração crônica de glicocorticóides. Essa patologia em felinos é rara e acomete, em maioria, diabéticos de meia idade a idade avançada. No presente relato o caso descrito é de um felino, macho, pelo curto brasileiro, com 16 anos, com pré diagnóstico de Diabetes Melittus e manifestando, dentre outros, os seguintes sintomas: prostração, vômito, palidez das mucosas, dilatação abdominal e pele delgada e sem elasticidade. O volume abdominal e a condição da pele associados a diabetes descompensada sugeriram a possibilidade de diagnóstico, com confirmação final mediante o Teste de Supressão com Dexametasona. Foi estabelecido terapia com o uso do Trilostano, que se mostrou eficaz no controle da patologia. O objetivo do relato de caso é mostrar que o hiperadrenocorticismo também acomete felinos, sendo uma das causas a diabetes na espécie.
... The hyperadrenocorticism (HAC), or Cushing's syndrome (CS) is an endocrine disease diagnosed in dogs associated with excessive endogenous glucocorticoid by pituitary or adrenal neoplasm, by iatrogenic (IHAC) induced by oral, parenteral or topical by excessive glucocorticoids administrations (Parry 2012, Bhavani et al. 2015, Scudder & Niessen 2015. The effects of clinical and laboratory manifestations vary among animals, due to the individual differences in cortisol sensitivity (Peterson 2007, Ramsey & Ristic 2007, Behrend et al. 2013, where the majority of dogs with HAC presenting hypercoagulability (Pace et al. 2013, Rose et al. 2013) and hyperalbunemia (Chen et al. 2016). ...
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The hyperadrenocorticism (HAC), or Cushing's syndrome (CS) is an endocrine disease diagnosed in dogs associated with excessive endogenous glucocorticoid by pituitary or adrenal neoplasm, by iatrogenic (IHAC) induced by excessive administration of oral glucocorticoids, parenteral or topical. These changes are identified by physical examination, no specific laboratory tests (blood counts, urinalysis, lipid profile, alkaline phosphatase dosage and liver function profiles) and confirmed by specific tests. Clinical and laboratory manifestations vary among animals due to individual differences in cortisol sensitivity, with the absence or presence of clinical and laboratory signs. Given the importance of this disease in the clinic for dogs, and systemic effects produced, this paper studied 21 dogs were tested by ACTH stimulation for HAC. Dogs that had some consistent factor for HAC, as recurrent urinary tract infections, cholesterol or triglycerides after fasting for 12 high hours or alkaline phosphatase levels above the normal range without presenting liver and bone disease, underwent stimulation test adrenocorticotropic hormone (ACTH-adrenocorticotropic hormone) synthetic dose 0.25 mg / dog. Dogs with cortisol results after stimulation with ACTH, above 20 mcg / dL, had a confirmed diagnosis of hyperadrenocorticism. Of the 21 dogs studied, 7 were diagnosed for HAC, these eight dogs were positive for some hematozoa six with monoinfection by Anaplasma platys and a dog had multiple parasitic infection, A. platys and Mycoplasma canis. Hematologic findings showed three dogs with anemia, four with thrombocytopenia, two with thrombocytosis, two with leukocytosis six with eosinopenia seven neutrophilic six with lymphopenia five with monocytopenia, with monocyte, seven dogs had neutrophil rod (a left shift ), six with hyperproteinaemia (Table 1). Only a positive dog HAC did not breed. The results of biochemical evaluation showed eight with alkaline phosphatase elevation. None of the observed hematological changes were positive correlation, although only dogs with alkaline phosphatase above 984 U / L are positive (100%) for HAC. This work aimed to present the importance of the absence of clinical and laboratory signs specific to HAC, because as immunosuppressive disease allows the presence of concomitant diseases, making diagnosis difficult. Dogs with elevated alkaline phosphatase levels (> 984 U / L) should be investigated for the diagnosis of HAC.
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Pituitary-dependent hypercortisolism (PDH) is one of the most frequent endocrinopathies in dogs, but prognostic factors are largely unknown. The aim of this retrospective case series study was to determine the prognostic value of different clinical and clinicopathological variables evaluated in dogs newly diagnosed with PDH that were subsequently treated with trilostane. Medical records from one referral centre were evaluated. Eighty-five dogs with PDH were included. The median survival time was 852 days (range 2-3210 days); 60/85 (70 per cent) and 25/85 (29 per cent) dogs survived more than one and three years, respectively. In multivariable model analysis the length of survival of older dogs (HR 1.24, 95% CI 1.09 to 1.40) and dogs with higher serum phosphate concentrations (HR 1.35, 95% CI 1.01 to 1.81) was shorter. Serum phosphate concentrations were above the reference range in 37/85 (44 per cent) of animals. Clinical signs, liver enzymes, serum cortisol concentrations of the endocrine tests, proteinuria, systolic hypertension, the presence of concomitant disorders, and the frequency of trilostane administration were not associated with survival time. Hyperphosphataemia is a common finding in dogs with newly diagnosed PDH and represents a negative prognostic factor.
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Corticotroph macrotumors are found in a subset of dogs with pituitary-dependent hyperadrenocorticism (PDH). In addition to clinical signs of hypercortisolism, affected dogs also may exhibit various neurologic abnormalities. Results of endocrine testing of dogs with macrotumors and PDH are not consistently different than results from dogs with microtumors and PDH; thus, the only way to confirm the diagnosis of a pituitary macrotumor is with CT scanning or MR imaging. Currently, radiation therapy is the treatment of choice for dogs with a pituitary macrotumor and PDH, but response to treatment is variable.
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Objective: To determine the prevalence of and clinical features associated with incidental adrenal gland lesions (IAGLs) discovered during abdominal ultrasonography in dogs. Design: Retrospective case series. Animals: 151 dogs with an IAGL and 400 control dogs. Procedures: Reports of ultrasonographic examinations of the abdomen of dogs performed during a 3.5-year period were reviewed. Adrenal glands were classified as having an IAGL if a nodule or mass was described or the width of either gland was ≥ 10 mm. For dogs with an IAGL, information regarding signalment, concurrent disorders, and outcome was obtained from the medical record. Findings were compared with those in a control population of 400 dogs examined during the same period. Results: An IAGL was detected in 151 of 3,748 (4%) dogs. Dogs with an IAGL were significantly older (median age, 11.25 years) and heavier (median body weight, 21 kg [46.2 lb]) than the control population (median age, 9.5 years; median body weight, 14 kg [30.8 lb]). Malignant tumors were reported in 6 of 20 (30%) dogs that underwent adrenal glandectomy or necropsy and had a maximum IAGL dimension that ranged from 20 to 46 mm; benign lesions all had a maximum dimension < 20 mm. Various coincidental conditions were reported in dogs with an IAGL, including nonadrenal gland malignant neoplasia in 43 (28.5%) dogs. Conclusions and clinical relevance: IAGLs were more likely in dogs ≥ 9 years of age. On the basis of this small data set, malignancy should be suspected for IAGLs ≥ 20 mm in maximum dimension.
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Treatment of adrenal-dependent hyperadrenocorticism (ADH) involves either surgical resection of the adrenal tumor or medical therapy. For many years, mitotane has been considered the medical treatment of choice for dogs with ADH. The aim of this study was to determine survival and prognostic factors for dogs with ADH treated with mitotane and trilostane. Twenty-six dogs with ADH were included in the study. Fourteen dogs were treated with mitotane and 12 dogs were treated with trilostane. Medical records were reviewed. Epidemiologic factors, signalment, clinicopathologic abnormalities, endocrine test results, and treatment protocols were evaluated to identify potential predictive factors of overall survival time. Survival times of dogs treated with mitotane (median, 15.6 months) or trilostane (median, 14.0 months) were not significantly different. Using univariate analysis, age and postadrenocorticotropic hormone cortisol concentrations were inversely correlated with survival time. The multivariate model also identified weakness at presentation as a negative prognostic indicator. The type of medical treatment (mitotane versus trilostane) does not influence survival time in dogs with ADH; therefore, trilostane, a drug with less frequent and milder adverse effects, might be used as the primary medical treatment when adrenalectomy cannot be performed.
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Spontaneous hyperadrenocorticism (HAC) is rare in cats. Clinical findings, diagnostic test results, and response to various treatment options must be better characterized. To report the clinical presentation, clinicopathologic findings, diagnostic imaging results, and response to treatment of cats with HAC. Cats with spontaneous HAC. Retrospective descriptive case series. Thirty cats (15 neutered males, 15 spayed females; age, 4.0-17.6 years [median, 13.0 years]) were identified from 10 veterinary referral institutions. The most common reason for referral was unregulated diabetes mellitus; dermatologic abnormalities were the most frequent physical examination finding. Low-dose dexamethasone suppression test results were consistent with HAC in 27 of 28 cats (96%), whereas ACTH stimulation testing was suggestive of HAC in only 9 of 16 cats (56%). Ultrasonographic appearance of the adrenal glands was consistent with the final clinical diagnosis of PDH or ADH in 28 of 30 cats (93%). Of the 17 cats available for follow-up at least 1 month beyond initial diagnosis of HAC, improved quality of life was reported most commonly in cats with PDH treated with trilostane. Dermatologic abnormalities or unregulated diabetes mellitus are the most likely reasons for initial referral of cats with HAC. The dexamethasone suppression test is recommended over ACTH stimulation for initial screening of cats with suspected HAC. Diagnostic imaging of the adrenal glands may allow rapid and accurate differentiation of PDH from ADH in cats with confirmed disease, but additional prospective studies are needed.
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To describe an intercostal (IC) approach to the right adrenal (RA) gland in dogs. Cadaveric study and case series. Dogs with right adrenal (RA) tumors (n = 11) and normal canine cadavers (6). Cadavers had an IC (n = 3) or paracostal (3) approach to the RA. The relative spatial position of the RA to the incision was evaluated. Medical records (June 2007-December 2012) of dogs that had an IC approach to the RA were reviewed. Perioperative data were recorded and described. In cadavers, the RA was closer to the cranial aspect of the surgical incision after an IC approach compared with a paracostal approach. The IC approach for right adrenalectomy was successfully performed in 11 dogs (6 adrenocortical carcinomas, 4 pheochromocytomas, and 1 osteosarcoma) with a mean anesthesia duration of 242 minutes and mean surgical of 144 minutes. Dogs had vascular invasion into the phrenicoabdominal vein (n = 11) and caudal vena cava (6). There were no significant intra- or postoperative complications. One dog was euthanatized intraoperatively. Median survival time for all dogs was 786 days. The IC approach for right adrenalectomy offers superior exposure of the RA compared with a paracostal approach.