Content uploaded by Christopher John Scudder
Author content
All content in this area was uploaded by Christopher John Scudder on Jun 05, 2015
Content may be subject to copyright.
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
>10mm, although classication 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 specic 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 10mg, 30mg, 60mg and 120mg 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.
Companion Animal.Downloaded from magonlinelibrary.com by 195.195.217.140 on May 28, 2015. For personal use only. No other uses without permission. . All rights reserved.
MEDICINE
Companion animal
|
April 2015, Volume 20 No 4 231
© 2015 MA Healthcare Ltd
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 10mg 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 28mmol/l
excluded excessive suppression in 97% of dogs, and four to six
hour post-trilostane administration serum cortisol concentrations
above 36mmol/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
>120mmol/l was an indicator of inadequate control, and four to
six hours post-trilostane administration below 80mmol/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 >28mmol/l. A
trilostane dose increase should be considered if a patient continues
to exhibit clinical signs consistent with hyperadrenocorticism and
basal cortisol is >28mmol/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.
Companion Animal.Downloaded from magonlinelibrary.com by 195.195.217.140 on May 28, 2015. For personal use only. No other uses without permission. . All rights reserved.
MEDICINE
232 Companion animal
|
April 2015, Volume 20 No 4
© 2015 MA Healthcare Ltd
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 30mg 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 signicant 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.
Companion Animal.Downloaded from magonlinelibrary.com by 195.195.217.140 on May 28, 2015. For personal use only. No other uses without permission. . All rights reserved.
MEDICINE
Companion animal
|
April 2015, Volume 20 No 4 233
© 2015 MA Healthcare Ltd
age maintenance weekly dose of mitotane in one study of 184 dogs
was 71mg/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 100mg/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 signicant 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 signicantly 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 efcacy 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
Companion Animal.Downloaded from magonlinelibrary.com by 195.195.217.140 on May 28, 2015. For personal use only. No other uses without permission. . All rights reserved.
MEDICINE
234 Companion animal
|
April 2015, Volume 20 No 4
© 2015 MA Healthcare Ltd
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 decits 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 rened 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
Companion Animal.Downloaded from magonlinelibrary.com by 195.195.217.140 on May 28, 2015. For personal use only. No other uses without permission. . All rights reserved.
MEDICINE
Companion animal
|
April 2015, Volume 20 No 4 235
© 2015 MA Healthcare Ltd
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 inuenced 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 prole 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
Companion Animal.Downloaded from magonlinelibrary.com by 195.195.217.140 on May 28, 2015. For personal use only. No other uses without permission. . All rights reserved.
MEDICINE
236 Companion animal
|
April 2015, Volume 20 No 4
© 2015 MA Healthcare Ltd
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 4Gy (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 dened 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
Companion Animal.Downloaded from magonlinelibrary.com by 195.195.217.140 on May 28, 2015. For personal use only. No other uses without permission. . All rights reserved.
MEDICINE
Companion animal
|
April 2015, Volume 20 No 4 237
© 2015 MA Healthcare Ltd
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 dened 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 benets 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.
References:
Alenza DP, Arenas C, Lopez ML, Melian C (2006) Long-term efcacy of trilostane
administered twice daily in dogs with pituitary-dependent hyperadrenocorticism.
J Am Anim Hosp Assoc 42: 269–76
Anderson CR, Birchard SJ, Powers BE, Belandria GA, Kuntz CA, Withrow SJ
(2001) Surgical treatment of adrenocortical tumors: 21 cases (1990-1996). J Am
Anim Hosp Assoc 37: 93–7
Andrade N, Rivas LR, Milovancev M, Radlinsky MA, Cornell K, Schmiedt C.
(2014) Intercostal approach for right adrenalectomy in dogs. Vet Surg 43:
99–104
Arenas C, Melián C, Pérez-Alenza MD (2013) Evaluation of 2 trilostane protocols
for the treatment of canine pituitary-dependent hyperadrenocorticism: Twice
daily versus once daily. J Vet Intern Med 27: 1478–85
Arenas C, Melián C, Pérez-Alenza MD (2014) Long-term survival of dogs with
adrenal-dependent hyperadrenocorticism: a comparison between mitotane and
twice daily trilostane treatment. J Vet Intern Med 28: 473–80
Axlund TW, Behrend EN, Sorjonen DC, Simpson ST, Kemppainen RJ (2005) Ca-
nine hypophysectomy using a ventral paramedian approach. Vet Surg 34: 179–89
Barker EN, Campbell S, Tebb AJ (2005) A comparison of the survival times of dogs
treated with mitotane or trilostane for pituitary-dependent hyperadrenocorticism.
J Vet Intern Med 19: 810–5
Barrera JS, Bernard F, Ehrhart EJ, Withrow SJ, Monnet E (2013) Evaluation of
risk factors for outcome associated with adrenal gland tumors with or without
invasion of the caudal vena cava and treated via adrenalectomy in dogs: 86 cases.
J Am Vet Med Assoc 242: 1715–21
Behrend EN (2015) Canine hyperadrenocorticism. In: Feldman EC, Nelson RW,
Reusch CE, Scott-Moncriedd JCR, eds. Canine and Feline Endocrinology. 4th
edn. Elsevier Saunders, St Louis, MO: 377–452
Behrend EN, Kooistra HS, Nelson R, Reusch CE, Scott-Moncrieff JC (2013)
Diagnosis of spontaneous canine hyperadrenocorticism: 2012 ACVIM consensus
statement (small animal). J Vet Intern Med 27: 1292–304
Bertoy EH, Feldman EC, Nelson RW, Dublin AB, Reid MH, Feldman MS (1996)
One-year follow-up evaluation of magnetic resonance imaging of the brain in
dogs with pituitary-dependent hyperadrenocorticism. J Am Vet Med Assoc 208:
1268–73
Biller BMK, Grossman AB, Stewart PM et al (2008) Treatment of adrenocorticotro-
pin-dependent Cushing’s syndrome: a consensus statement. J Clin Endocrinol
Metab 93: 2454–62
Burkhardt WA, Boretti FS, Reusch CE, Sieber-Ruckstuhl NS (2013) Evaluation
of baseline cortisol, endogenous ACTH, and cortisol/ACTH ratio to monitor
trilostane treatment in dogs with pituitary-dependent hypercortisolism. J Vet
Intern Med 27: 919–23
Clemente M, De Andrés PJ, Arenas C, Melián C, Morales M, Pérez-Alenza MD
(2007) Comparison of non-selective adrenocorticolysis with mitotane or trilos-
tane for the treatment of dogs with pituitary-dependent hyperadrenocorticism.
Vet Rec 161: 805–9
Cook AK, Bond KG (2010) Evaluation of the use of baseline cortisol concentration
as a monitoring tool for dogs receiving trilostane as a treatment for hyperadreno-
corticism. J Am Vet Med Assoc 237: 801–805
Cook AK, Spaulding KA, Edwards JF (2014) Clinical ndings in dogs with inciden-
tal adrenal gland lesions determined by ultrasonography: 151 cases (2007-2010).
J Am Vet Med Assoc 244: 1181–5
Daley CA, Zerbe CA, Schick RO, Powers RD (1993) Use of metyrapone to treat
pituitary-dependent hyperadrenocorticism in a cat with large cutaneous wounds.
J Am Vet Med Assoc 202: 956–60
Dow SW, LeCouteur RA, Rosychuk RAW, Powers BE, Kemppainen RJ, Gillette EL
(1990) Response of dogs with functional pituitary macroadenomas and macro-
carcinomas to radiation. J Small Anim Pract 31: 287–94
Duesberg C, Peterson ME (1997) Adrenal disorders in cats. Vet Clin North Am
Small Anim Pract 27: 321–347
KEY POINTS
Following a diagnosis of hyperadrenocorticism, pituitary-dependent and
adrenal-dependant disease should be differentiated from each other,
because of the different treatment options available.
Surgical intervention is the only treatment modality to provide
disease cure, by removing the tumour, but patients undergoing
hypophysectomy or bilateral adrenalectomy will require life-long
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.
Companion Animal.Downloaded from magonlinelibrary.com by 195.195.217.140 on May 28, 2015. For personal use only. No other uses without permission. . All rights reserved.
MEDICINE
238 Companion animal
|
April 2015, Volume 20 No 4
© 2015 MA Healthcare Ltd
Duesberg CA, Nelson RW, Feldman EC, Vaden SL, Scott-Moncrieff CR (1995)
Adrenalectomy for treatment of hyperadrenocorticism in cats: 10 cases (1988-
1992). J Am Vet Med Assoc 207: 1066–70
Essex HE, Astrarabadi TM (1953) Transbuccal hypophysectomy in the dog. Ann
Surg 138: 143–4
Feldman E (2008) Evaluation of twice-daily, lower-dose trilostane treatment admin-
istered orally in dogs with naturally occurring hyperadrenocorticism. J Am Vet
Med Assoc 238: 1441–51
Feldman EC, Nelson RW (2004) Canine hyperadrenocorticism (Cushing’s Syn-
drome). In: Feldman EC, Nelson RW, eds. Canine and Feline Endocrinology and
Reproduction. 3rd edn. Saunders, St Louis, MO: 252–439
Fracassi F, Corradini S, Floriano D et al (2014) Prognostic factors for survival in
dogs with pituitary-dependent hypercortisolism treated with trilostane. Vet Rec
176: 49. doi: 10.1136/vr.102546
Fulmer BR (2007) Diagnosis and management of adrenal cortical carcinoma. Curr
Urol Rep 8: 77–82
Galac S, Kooistra HS, Voorhout G et al (2005) Hyperadrenocorticism in a dog due
to ectopic secretion of adrenocorticotropic hormone. Domest Anim Endocrin 28:
338–48
Galac S, Buijtels JJ, Kooistra HS (2009) Urinary corticoid: creatinine ratios in dogs
with pituitary-dependent hypercortisolism during trilostane treatment. J Vet
Intern Med 23: 1214–9
Goossens MM, Feldman EC, Theon AP, Koblik PD (1998) Efcacy of cobalt 60
radiotherapy in dogs with pituitary-dependent hyperadrenocorticism. J Am Vet
Med Assoc 212: 374–6
Graves TK (2010) Hypercortisolism in cats (feline Cushing’s syndrome). In Ettinger
SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine. 7th edn. Elsevier
Saunders, St Louis, MO: 1840–7
Hanson JM, van ‘t Hoofd MM, Voorhout G, Teske E, Kooistra HS, Meij BP. (2005)
Efcacy of transsphenoidal hypophysectomy in treatment of dogs with pituitary-
dependent hyperadrenocorticism. J Vet Intern Med 19: 687–94
Hanson JM, Teske E, Voorhout G, Galac S, Kooistra HS, Meij BP (2007) Prog-
nostic factors for outcome after transsphenoidal hypophysectomy in dogs with
pituitary-dependent hyperadrenocorticism. J Neurosurg 107: 830–40
Helm JR, McLauchlan G, Boden LA et al (2011) A comparison of factors that inu-
ence survival in dogs with adrenal-dependent hyperadrenocorticism treated with
mitotane or trilostane. J Vet Intern Med 25: 251–60
Henry RW, Hulse DA (1982) Transoral hypophysectomy with mandibular symphysi-
otomy in the dog. Am J Vet Res 43: 1825–9
den Hertog E, Braakman JC, Teske E, Kooistra HS, Rijnberk A (1999) Results of
non-selective adrenocorticolysis by o,p’-DDD in 129 dogs with pituitary-depend-
ent hyperadrenocorticism. Vet Rec 144: 12–17
Hoenig M (2002) Feline hyperadrenocorticism—where are we now? J Feline Med
Surg 4: 171–4
Ihle S (1997) Pituitary corticotroph macrotumors. Diagnosis and treatment. Vet
Clin North Am Small Anim Pract 27: 287–96
Kaltsas GA, Nomikos P, Kontogeorgos G, Buchfelder M, Grossman AB (2005)
Clinical review: Diagnosis and management of pituitary carcinomas. J Clin
Endocrinol Metab 90: 3089–99
Kelly DF (2007) Transsphenoidal surgery for Cushing’s disease: a review of success
rates, remission predictors, management of failed surgery, and Nelson's Syn-
drome. Neurosurg Focus 23(3): E5
Kenny, PJ, Scudder C, Keyte SV, et al (2015) Experiences of a newly established
hypophysectomy Clinic for treatment of feline hypersomatotropism. J Vet Intern
Med 29: 449–50
Kent MS Bommarito D, Feldman E, Theon AP (2007) Survival, neurologic
response, and prognostic factors in dogs with pituitary masses treated with radia-
tion therapy and untreated dogs. J Vet Intern Med 21: 1027–33
Kintzer PP, Peterson ME (1991) Mitotane (o,p’-DDD) treatment of 200 dogs with
pituitary-dependent hyperadrenocorticism. J Vet Intern Med 5: 182–90
Kipperman BS, Feldman EC, Dybdal NO, Nelson RW (1992) Pituitary tumor size,
neurologic signs, and relation to endocrine test results in dogs with pituitary-
dependent hyperadrenocorticism: 43 cases (1980–1990). J Am Vet Med Assoc
201: 762–7
Kooistra HS, Galac S (2010) Recent advances in the diagnosis of Cushing’s syn-
drome in dogs. Vet Clin North Am Small Anim Pract 40: 259–67
Kyles AE, Feldman EC, de Cock HE et al (2003) Surgical management of adrenal
gland tumours with and without associated tumor thrombi in dogs: 40 cases, J
Am Vet Med Assoc 223: 654–62
Lang JM, Schertel E, Kennedy S, Wilson D, Barnhart M, Danielson B (2011)
Elective and emergency surgical management of adrenal gland tumors: 60 cases
(1999-2006). J Am Anim Hosp Assoc 47: 428–35
Lien YH, Huang HP (2008) Use of ketoconazole to treat dogs with pituitary-
dependent hyperadrenocorticism: 48 cases (1994–2007). J Am Vet Med Assoc
233: 1896–901
Lo AJ, Holt DE, Brown DC, Schlicksup MD, Orsher RJ, Agnello KA (2014)
Treatment of aldosterone-secreting adrenocortical tumors in cats by unilateral
adrenalectomy: 10 cases (2002–2012). J Vet Intern Med 28: 137–43
Loli P, Berselli ME, Tagliaferri M (1986) Use of ketoconazole in the treatment of
Cushing’s syndrome. J Clin Endocrinol Metab 63: 1365–71
Loose DS, Kan PB, Hirst MA, Marcus RA, Feldman D (1983) Ketoconazole blocks
adrenal steroidogenesis by inhibiting cytochrome P450-dependent enzymes. J
Clin Invest 71: 1495–9
Lorenz MD (1982) Diagnosis and medical management of canine Cushing’s syn-
drome: a study of 57 consecutive cases. J Am Anim Hosp Assoc 18: 707–16
Mariani CL, Schubert TA, House RA et al (2013) Frameless stereotactic radiosur-
gery for the treatment of primary intracranial tumours in dogs. Vet Comp Oncol:
[early view]. DOI: 10.1111/vco.12056
Massari F, Nicoli S, Romanelli G, Buracco P, Zini E (2011) Adrenalectomy in dogs
with adrenal gland tumors: 52 cases (2002-2008). J Am Vet Med Assoc 239:
216–21
Mayer MN, Greco DS, LaRue SM (2006) Outcomes of pituitary tumor irradiation
in cats. J Vet Intern Med 20: 1151–4
Mayer UK, Glos K, Schmid M, Power HT, Bettenay SV, Mueller RS (2008) Adverse
effects of ketoconazole in dogs – a retrospective study. Vet Dermatol 19: 199–208
Mayhew PD, Culp WT, Hunt GB et al (2014) Comparison of perioperative morbid-
ity and mortality rates in dogs with noninvasive adrenocortical masses undergoing
laparoscopic versus open adrenalectomy. J Am Vet Med Assoc 245: 1028–35
Meij BP, Voorhout G, Van den Ingh TS, Hazewinkel HA, Van’t Verlaat JW (1997)
Transsphenoidal hypophysectomy in beagle dogs: evaluation of a microsurgical
technique. Vet Surg 26: 295–309
Meij BP, Voorhout G, van den Ingh TS, Hazewinkel HA, Teske E, Rijnberk A (1998)
Results of transsphenoidal hypophysectomy in 52 dogs with pituitary-dependent
hyperadrenocorticism. Vet Surg 27: 246–61
Meij BP, Voorhout G, Van Den Ingh TS, Rijnberk A (2001) Transsphenoidal hypo-
physectomy for treatment of pituitary-dependent hyperadrenocorticism in 7 cats.
Vet Surg 30: 72–86
Meij B, Voorhout G, Rijnberk A (2002) Progress in transsphenoidal hypophysectomy
for treatment of pituitary-dependent hyperadrenocorticism in dogs and cats. Mol
Cell Endocrinol 197: 89–96
Melian C, Perez-Alenza MD, Peterson ME (2010) Hyperadrenocorticism in dogs.
In: Ettinger S, Feldman E, eds. Textbook of Veterinary Internal Medicine. 7th edn.
Saunders, St Louis, MO: 1816–40
Mellett Keith AM, Bruyette D, Stanley S (2013) Trilostane therapy for treatment
of spontaneous hyperadrenocorticism in cats: 15 cases (2004-2012). J Vet Intern
Med 27: 1471–1477
Moore LE, Biller DS, Olsen DE (2000) Hyperadrenocorticism treated with me-
tyrapone followed by bilateral adrenalectomy in a cat. J Am Vet Med Assoc 217:
691–4
Naan EC, Kirpensteijn J, Dupré GP, Galac S, Radlinsky MG (2013) Innovative
approach to laparoscopic adrenalectomy for treatment of unilateral adrenal gland
tumors in dogs. Vet Surg 42: 710–5
Neiger R, Witt AL, Noble A, German AJ (2004) Trilostane therapy for treatment of
pituitary-dependent hyperadrenocorticism in 5 cats. J Vet Intern Med 18: 160–4
Nelson RW, Feldman EC, Smith MC (1988) Hyperadrenocorticism in cats: seven
cases (1978-1987). J Am Vet Med Assoc 193: 245–50
Ramsey IK (2010) Trilostane in dogs. Vet Clin North Am Small Anim Pract 40:
269–83
Rijnberk A, Belshaw B (1988) An alternative protocol for the medical management
of canine pituitary-dependent hyperadrenocorticism. Vet Rec 122: 486–8
Ritzel K, Beuschlein F, Mickisch A (2013) Clinical review: Outcome of bilateral
adrenalectomy in Cushing’s syndrome: a systematic review. J Clin Endocrinol
Metab 98: 3939–48
Scavelli TD, Peterson ME, Matthiesen DT (1986) Results of surgical treatment for
hyperadrenocorticism caused by adrenocortical neoplasia in the dog: 25 cases
(1980-1984). J Am Vet Med Assoc 189: 1360–4
Schwartz P, Kovak JR, Koprowski A, Ludwig LL, Monette S, Bergman PJ (2008)
Evaluation of prognostic factors in the surgical treatment of adrenal gland tumors
in dogs: 41 cases (1999-2005). J Am Vet Med Assoc 232: 77–84 Schwedes CS
(1997) Mitotane (o, p‘-DDD) treatment in a cat with hyperadrenocorticism. J
Small Anim Pract 38: 520–4
Seth M, Drobatz KJ, Church DB, Hess RS (2011) White blood cell count and the
sodium to potassium ratio to screen for hypoadrenocorticism in dogs. J Vet Intern
Med 25: 1351–6
Skelly BJ, Petrus D, Nicholls PK (2003) Use of trilostane for the treatment of pitui-
tary-dependent hyperadrenocorticism in a cat. J Small Anim Pract 44: 269–72
Théon AP, Feldman EC (1998) Megavoltage irradiation of pituitary macrotumors in
dogs with neurologic signs. J Am Vet Med Assoc 213: 225–31
Valentin SY, Cortright CC, Nelson RW et al (2013) Comparison of diagnostic tests
and treatment options for feline hyperadrenocorticism: A retrospective review of
32 cases. J Vet Intern Med 27: 688
Valentin SY, Cortright CC, Nelson RW et al (2014) Clinical ndings, diagnostic test
results, and treatment outcome in cats with spontaneous hyperadrenocorticism:
30 cases. J Vet Intern Med 28: 481–7
van Sluijs FJ, Sjollema BE, Voorhout G, van den Ingh TS, Rijnberk A (1995) Results
of adrenalectomy in 36 dogs with hyperadrenocorticism caused by adreno-corti-
cal tumour. Vet Q 17: 113–6
Veytsman I, Nieman L, Fojo T (2009) Management of endocrine manifestations and
the use of mitotane as a chemotherapeutic agent for adrenocortical carcinoma. J
Clin Oncol 27: 4619–29
Weiss LM (1984) Comparative histologic study of 43 metastasizing and nonmetasta-
sizing adrenocortical tumors. Am J Surg Pathol
8: 163–9
Wood FD, Pollard RE, Uerling MR, Feldman EC (2007) Diagnostic imaging nd-
ings and endocrine test results in dogs with pituitary-dependent hyperadrenocor-
ticism that did or did not have neurologic abnormalities: 157 cases (1989-2005).
J Am Vet Med Assoc 231: 1081–5
Companion Animal.Downloaded from magonlinelibrary.com by 195.195.217.140 on May 28, 2015. For personal use only. No other uses without permission. . All rights reserved.
