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.

The 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 micro-or macro-, functional or nonfunctional 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 classification based on a cut-off size of 10 mm 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 specific 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 dehydrogenase, an essential enzyme during steroidogenesis in the adrenal 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 capsules, is recommended by many as a preferred treatment modality, and is the only licensed drug to treat canine HAC in the UK.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, ketotrilostane, occur 30 to 90 minutes after oral administration, and peak serum cortisol reduction occurs between four to six hours after administration (Vetoryl datasheet, Dechra, Shrews-bury, UK).A starting dose of 2-5 mg/kg/day is recommended, and the addition of a 10 mg capsule to the product range has made prescription 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 trilostanetreated 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;Burkhardt 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 measuring 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 synthesised during trilostane therapy (Galac et al, 2009).Therefore, the UCCR test cannot be used as a monitoring tool for trilostane treatment.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 0.2 mg/kg prednisolone and receive supportive care if sick enough to require hospitalisation.A lymphocyte count could be performed while awaiting the endocrine test results as patients are highly unlikely to have hypoadrenocorticism 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 financial 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 following dose reduction.However, rare cases of iatrogenic adrenal necrosis and subsequent hypoadrenocorticism have been reported.These are thought to be related to the increased endogenous ACTH levels causing increased adrenal blood flow, causing in turn a higher chance of adrenal haemorrhage, given the fragile nature of adrenal vessels.Trilostane treatment also leaves the inciting cause 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.

Figure 1: Adrenal gland steroid hormone biochemical pathways
There is a general paucity of information regarding using trilostane to treat feline HAC.The first 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 five, 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 feline 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% reduction, while another study reported insulin doses were not reduced in any of the five 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 unsuitable.
Prescription of a non-licenced product should be considered if a patient experiences significant adverse drug effects or the licenced 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 adrenal 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' typically over eight days, followed by a 'maintenance phase'.The average 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 first 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).Concurrent 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 first 25 days of therapy, although these figures may over-estimate the risk, as some of the patients had significant 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 trilostane appears to be a more advantageous medical management option in cats (Schwedes, 1997).
Trilostane versus mitotane studies have been reported.Possibly 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.Twicedaily 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 significantly 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 alternative drugs to manage HAC.Ketoconazole is likely to have several cortisol synthesis-inhibiting mechanisms of action, including general inhibition of P450 enzymes and 11β hydroxylase (Loose et al, 1983;Loli et al, 1986).However, its efficacy is underwhelming, 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 ketoconazole-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 bilateral adrenalectomy in two cats, but reports in dogs are lacking (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 detrimental side-effects.

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 deficits 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 facility capable of providing the intensive intra-and post-operative care required by these patients.Although a financial 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 first ca-nine hypophysectomy was performed in 1886, and later refined 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 transoral 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 preoperative computed tomogra-phy images.When the pituitary gland is exposed, the dura mater is incised and the pituitary gland extirpated using fine 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, initially 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 hypothalamus synthesises vasopressin, which is normally transported to the posterior pituitary via the hypothalamicneurohypophyseal 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 hypothalamicneurohypophyseal tract may be able to release vasopressin.Around 80% of patients can be weaned off desmopressin over the weeks to months following surgery, 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 discontinued as hypercortisolaemia-induced insulinresistance resolves, 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 basal 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 postoperative 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 first, hypophysectomy was performed on seven hyperadrenocorticoid cats: two died within two weeks of surgery, and the remaining five achieved disease remission (Meij et al, 2001).A more recent abstract reported the treatment of twelve cats with hypersomatotropism and diabetes mellitus by hypophysectomy: 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 insipidus can occur after canine and feline hypophysectomy surgery.KCS affects a third of dogs post-operatively and although the majority completely recover, 20% of these dogs have persistently low tear production (Hanson et al, 2005).
Hormone supplementation and monitoring of thyroxine is needed, since pituitary adenomectomy without total hypophysectomy 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-operative 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, 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 five 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 findings 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 influenced 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 profile 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 radiotherapy 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 first report of radiotherapy improving the neurological disease caused by a PDH macrotumour was in 1990 (Dow et al, 1990).Dogs received 10 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 (Goossens 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 defined 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 improvement within nine months after radiosurgery; the other cat was euthanised two months after treatment due to suspected abdominal 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 defined by metastatic behaviour rather than by invasive or histopathology characteristics in human endocrinology (Kaltsas et al, 2005).The treatment of humans affected by pituitary 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 ≥2 cm 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 probably 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 benefits 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.Clinicians 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.

Figure 2 .
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.

Figure 3 :
Figure 3: Dorsal view of a T2-weighted intracranial MRI to show the location of the optic chiasm and pituitary gland.Optic chiasm compression could be caused by a pituitary macroadenoma.

Figure 4 .
Figure 4. (a) Photograph of a dog with pituitary-dependent hyperadrenocorticism; (b) The same dog under general anaesthesia placed in sternal recumbency 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 .
Figure 5. (a) Photograph of a cat with a diagnosis of pituitary-dependent hyperadrenocorticism; (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.

Figure 6 .
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 tomography.This is the same adrenal gland as in 4b, showing the relationship of the adrenal gland to the kidneys and caudal vena cava.

Table 1 .
Summaries of studies of adrenalectomy in dogs with cortisol-secreting adrenal tumours