Professor, Department of Veterinary Clinical Science, The Royal Veterinary College
North Mymms, Hatfield, Hertfordshire, UK
Generally an adrenal tumor (AT) is most effectively treated via surgical removal. This results in the removal of the animal's principle source of cortisol, as the glucocorticoid (GC) secreting sections of the contralateral adrenal gland are invariably atrophic and at least temporarily non-functional. Consequently, GC replacement intra- and post-operatively is essential for a successful recovery. Use of hydrocortisone sodium succinate as a continuous infusion (0.5 mg/kg/hr for 12-24 hours then 0.2 mg/kg/hr for 24 hours) provides adequate GC replacement in the short term post-operative period. Once the animal is eating, oral replacement therapy using cortisone acetate (1mg/kg/12hr, decreasing over two weeks) is usually satisfactory. Cortisone is preferable in this situation as its shorter half life should reduce the time for the contralateral gland to regain GC secreting capacity.
Obviously not all cases of adrenal neoplasia will be appropriate surgical candidates. In those patients were surgery is not an option it may be worth considering palliative therapy with ketoconazole, mitotane or possibly deprenyl.
Pituitary Dependent Hyperadrenocorticism
Although patients with PDH may be treated with bilateral adrenalectomy and a similar replacement regime, the most common method has been long term mitotane (o, pDDD) administration. The essence of this regime is to destroy most of the hyperplastic adrenal cortex. The remaining tissue provides normal plasma cortisol concentrations despite being subjected to almost supraphysiological levels of ACTH.
In other words the animal no longer has the capacity to raise its plasma cortisol level above 20-50 nmol/l. This magnitude of adrenal destruction is essential to achieve significant clinical improvement.
This "chemical adrenalectomy" can be achieved using two different protocols, one aimed at achieving complete and permanent adrenocorticolysis and the other at reducing adrenocortical activity to normal levels through partial adrenocorticolysis. The second protocol has been generally accepted as the favoured method and involves administration of mitotane (25 mg/kg/12hr with food) for five to seven days. During this period water consumption, appetite and general demeanour are closely monitored. If any of these parameters change for more than 12 hours the mitotane therapy is stopped. Animals are evaluated with an ACTH response test 48 hours after the last dose of mitotane. Adrenal destruction is deemed satisfactory when both pre and post ACTH cortisols are similar and below the mid-range for the laboratory's normal basal cortisol concentration. In approximately 15% of cases this may require a second or more courses of daily mitotane.
Once satisfactory adrenal destruction has been achieved it can be maintained by once or twice weekly mitotane administration (25 mg/kg/12hr with food on one or two days per week). Patients can be rechecked with an ACTH response test once every 8-12 weeks to ensure adequate control is being maintained.
Animals treated in this way cannot mount an appropriate stress response to trauma or illness. Consequently, from the start of mitotane therapy prednisolone should always be available and the owners instructed to administer 1-2 mg/kg orally in an emergency while awaiting veterinary attention.
The alternative protocol involves using mitotane on a daily basis for a longer period and attempting to bring about irreversible adrenocorticolysis and subsequently managing patients with glucocorticoid supplementation.
Both protocols have disadvantages. With complete chemical adrenalectomy approximately 30% of patients have sufficiently severe side-effects to justify suspending treatment and the reported relapse rate can be as high as 39%. With the more widely used method of creating and maintaining induction and remission by inducing a selective degree of adrenocorticolysis, the continuous requirement for ACTH stimulation tests along with similar relapse rates makes this regime complicated, involved and often expensive.
As both mitotane protocols could be considered less than ideal, a number of alternative methods of safely and consistently reducing adrenocortical activity in canine PDH have been explored. These have included using different inhibitors of steroidogenesis or ACTH release. However, to date, with ONE exception, these alternative drugs have been either only inconsistently effective or produced side-effects in an unacceptable proportion of patients.
Traditionally the main alternative treatment to mitotane for PDH in the dog has been ketoconazole. More recently three other drugs have been investigated for canine PDH: aminoglutethimide, L-deprenyl (selegiline) and trilostane.
This is an imidazole derivative that interferes with steroid synthesis by inhibiting cytochrome P-450-dependent enzymes. Although it is potentially hepatotoxic, ketoconazole has been effective in a variable proportion of dogs with hyperadrenocorticism. Ketoconazole seems to be better tolerated when the dose is increased gradually. The usual treatment regime starts with a dose of 5mg/kg/12hr for 5-7days and if there are no side-effects (generally GIT related), the dose is increased to 10mg/kg/12hr for 10 to 14 days and an ACTH stimulation test performed at this time.
Satisfactory resolution of clinical signs requires sufficient inhibition of steroidogenesis to insure relatively normal plasma cortisol levels despite the adrenal cortex being subjected to supraphysiological levels of ACTH. In other words the animal no longer has the capacity to raise its plasma cortisol level above 0.7-1.8ug/dl. This level of inhibition of cortisol secretion appears to be essential to achieve significant clinical improvement. Unfortunately over 25% of PDH cases do not respond to ketoconazole and many of the cases that do respond need doses of between 15 and 20mg/kg/12hr.
Furthermore many endocrinologists provide anecdotal evidence of unacceptably high occurrences of side-effects. Consequently the difficulties with unpredictable efficacy along with the inconvenience of twice daily dosing and the substantial cost have limited its widespread use as a satisfactory alternative to mitotane in the treatment of canine PDH.
Aminoglutethimide prevents the conversion of cholesterol to pregnenolone by blocking cholesterol side-chain cleavage. At higher doses it inhibits 11-ß-hydroxylase thereby reducing cortisol, aldosterone and adrenal androgens. Two studies using aminoglutethimide in dogs with PDH had conflicting results. While one showed clinical remission and a tendency towards normalization of several laboratory values, a more recent study demonstrated marked hepatotoxicity with little effect. At least in the author's opinion there is insufficient evidence to justify the use of this drug in the treatment of canine PDH.
Selegiline, l-deprenyl (Anipryl)
Selegiline (or L-deprenyl) is a centrally acting selective and irreversible inhibitor of the enzyme monoamino-oxidase B. The drug theoretically results in increased levels of CNS dopamine. Its main use in humans is in the treatment of Parkinson's disease while in dogs it has been used for the treatment of geriatric cognitive disorders. The use of L-deprenyl for treating canine PDH is premised on the hypothesis that CNS dopamine levels will reduce adenohypophyseal ACTH secretion.
Although two studies in the late 1990s suggested a proportion of dogs with pituitary dependent hyperadrenocorticism may show some improvement in clinical signs, there was no clinicopathological or endocrine evidence to suggest significant changes in these dog's hyperadrenocorticoid status. Subsequently two independent studies investigating the efficacy of L-deprenyl in a total of 21 dogs with pituitary dependent hyperadrenocorticism demonstrated minimal and non-sustainable improvements in clinical signs. This apparent lack of efficacy was supported by no change in both basal and post-ACTH plasma cortisol levels, continuing elevations in the plasma ACTH concentration and persistently elevated urinary corticoid:creatinine ratios in PDH dogs receiving selegiline over a 30-90 day period.8,9 Both investigations concluded the drug couldn't be recommended for the treatment of PDH.
Trilostane is a synthetic, orally active steroid analogue that competitively inhibits 3ß hydroxysteroid dehydrogenase and hence synthesis of several steroids, including cortisol and aldosterone. This competitive inhibition is reversible and seems to be dose-related.
In dogs, peak trilostane concentrations are seen within 1.5 hours of dosing and decrease to baseline values in about 18 hours. Trilostane is variably absorbed after oral administration, at least partly due to its poor water solubility. Absorption may be enhanced by administering the drug with food although this phenomenon has not been investigated in dogs with hyperadrenocorticism.
Trilostane's safety as well as both short and long term efficacy in controlling hyperadrenalism in dogs has been documented in a number of abstracts and four controlled studies utilising a total of 180 dogs with a follow-up period of 180 days or more.
In the four studies 36 of 180 patients were euthanased or died, in 6 trilostane was withdrawn due to perceived adverse effects and 3 cases were lost to follow-up. The mean survival of all trilostane treated dogs in one long-term study was 661 days (Neiger et al 2002). Additionally dogs on trilostane have similar long-term survival to those on mitotane. A preliminary study showed that 58 dogs with PDH on trilostane survived a median of 310 days while 26 dogs on mitotane survived 476 days.
In all four studies the trilostane starting dose was approximately 6 mg/kg/24hr. During the first 180 days, over 50% of all dogs had a change in dose, mostly an increase, resulting in a final dose of between 6.1 and 11.4 mg/kg/24hr in three studies. In one study with a markedly lower post ACTH cortisol concentration as a target, understandably the final trilostane dose was substantially higher at a mean of 18.1 mg/kg (range 5.3 to 48.7 mg/kg).
Trilostane was found to be effective in resolving the signs of PDH in most dogs. In three studies polyuria/polydipsia resolved in 116 of 127 dogs (91%) while polyphagia resolved in 68 of 84 dogs (81%). The time frame for the resolution was variable although marked improvement was noted within 2 months in the majority of cases. Reduction in these clinical signs continued as long as the dogs were maintained on adequate doses of trilostane.
Trilostane resulted in a significant reduction in cholesterol, ALP and ALT although 28 dogs still had an ALP level above the reference range after six months of treatment. A significant decrease in sodium and increase in potassium was also documented with hyperkalaemia recorded in 34 dogs at some time during the period of observation.
Trilostane caused a significant reduction in both the mean basal and post-ACTH cortisol concentrations after 10 days of treatment in all four studies. In one study the post ACTH cortisol concentration decreased to less than 250 nmol/l within one month in 81% of dogs and in another 15% at some time whilst on treatment. These improvements were maintained in the study population for the duration of the trial. In the study targeting lower post ACTH cortisol values all dogs were well or acceptably controlled (post ACTH cortisol < 75 nmol/l and <125 nmol/l respectively) although as mentioned previously, in some dogs these goals were only obtained by marked increases in the daily dose.
It should be noted that in all four studies the "effective" dose of trilostane was, to varying degrees, determined by the demonstration of a significant reduction in the post-ACTH cortisol concentration although the time between dosing and ACTH stimulation testing was not standardised. Recent reports now suggest the duration of trilostane's inhibition of steroid synthesis is relatively short-lived and certainly less than 20 hours. Consequently, as all four studies determined the "effective" trilostane dose on the basis of "acceptable" suppression of post-ACTH cortisol levels sampled up to 24 hours after trilostane's administration, in each investigation there has been some potential for over-estimation of the "appropriate trilostane dose". Some preliminary evidence suggesting, at least in the dog, trilostane also may reduce tissue sensitivity to cortisol, supports this possibility.
Trilostane seems to be well tolerated by most dogs, although mild, self-limiting side effects such as diarrhoea, vomiting and lethargy were noted by 63% of owners in one study. More significantly however in another study acute death was described in two dogs two and four days after starting therapy and another two developed signs and biochemical evidence of hypoadrenocorticism. One of these dogs recovered with appropriate therapy. The other died despite withdrawal of trilostane and administration of appropriate therapy.
The question of how a drug with the capacity to suppress cortisol levels for no more than 20 hours could create clinically significant hypoadrenocorticism remains unanswered. Interestingly anecdotal incidents of acute death shortly after starting trilostane have been noted while a recent report documented the development of bilateral adrenal necrosis in two dogs on trilostane. The likelihood of long-term trilostane treatment leading to increased risk of adrenal necrosis through as a result of ACTH hypersecretion and/or direct effects of trilostane or its metabolites needs to be looked at further.
In summary both trilostane and mitotane seem to be effective in correcting clinical signs and hormonal abnormalities associated with pituitary dependent hyperadrenocorticism in approximately 80-85% of cases. Unfortunately this means a substantial number of affected dogs may not respond to standard medical therapy and in these cases a practical alternative needs to be considered sooner rather than later.
Surgical Alternatives to Mitotane/Trilostane
Investigators at the University of Utrecht have had considerable success using hypophysectomy, however, this is a specialised surgical procedure and not widely available. Additionally, despite apparently complete removal of the adenohyphysis, relapses have been common. Another therapeutic alternative is bilateral adrenalectomy.
Although this procedure has been proposed as a possible treatment some time, reported difficulties in the post-operative management of the adrenalectomised patient has resulted in the technique not achieving widespread acceptance as a feasible alternative to chemical adrenalectomy. However the surgery itself is relatively simple and management of the surgically-induced "panhypoadrenocorticism" is inexpensive and uncomplicated by potential hyperadrenocorticoid relapses. In the author's opinion the reported difficulties with this procedure can be largely overcome by reducing the potential for perioperative glucocorticoid and mineralocorticoid deficiencies with a continuous hydrocortisone infusion at an initial rate of 0.5mg/kg/hr until the animal is taking food and water orally and then changing to a combination of cortisone acetate with or without fludrocortisone for long term replacement therapy. This procedure may be a practical alternative for the treatment of PDH in the dog.