Michael E. Herrtage, MA, DVSc, DVR, DVD, DSAM, DECVIM, DECVDI, MRCVS
Tests to Differentiate the Cause of Hyperadrenocorticism
The ability to differentiate between pituitary- and adrenal-dependent hyperadrenocorticism is important in order to provide the most effective method of management for the disease. An accurate test is therefore required to differentiate pituitary from adrenal causes of hyperadrenocorticism.
Plasma ACTH Concentration
The determination of plasma ACTH concentrations in the dog provides a reliable test for differentiating pituitary and adrenal causes of hyperadrenocorticism providing sample handling is meticulous. Dogs with adrenal tumours have very low endogenous ACTH concentrations whereas cases of pituitary-dependent hyperadrenocorticism have high normal or high concentrations.
Diagnostic imaging techniques, particularly abdominal ultrasonography, have also proved sensitive in distinguishing animals with pituitary-dependent hyperadrenocorticism from those with adrenocortical tumours.
High-Dose Dexamethasone Suppression Test
The high-dose dexamethasone suppression test was the most commonly used test for differentiating the cause of hyperadrenocorticism, but is less accurate than abdominal ultrasonography or plasma ACTH measurements.
This test is indicated in those cases where the diagnosis of hyperadrenocorticism has been established by a screening test, but the differentiation of adrenal-dependent and pituitary-dependent hyperadrenocorticism has not been determined. The high dose of dexamethasone inhibits pituitary ACTH secretion through negative feedback in pituitary-dependent hyperadrenocorticism thus suppressing of serum cortisol concentrations by 50% or more by four hours. Adrenocortical tumours are autonomous and thus serum cortisol is not suppressed at four hours.
Approximately 20–30% of pituitary-dependent cases, however, will not suppress with this test. The test does not differentiate adrenocortical adenomas from adrenocortical carcinomas.
Treatment of Pituitary-Dependent Hyperadrenocorticism
Trilostane is a synthetic steroid analogue. It is a competitive inhibitor of 3 β-hydroxysteroid dehydrogenase enzyme system and thus interferes with adrenal steroid biosynthesis. Following oral administration in dogs, peak trilostane concentrations are seen in 1.5 hours and decrease to baseline values in about 18 hours. However, there is considerable individual variability in trilostane concentrations following oral administration due in part to its low water solubility.
Dose: 2–5 mg/kg daily per os, dosage can be adjusted according to response. Treatment should be monitored using the ACTH stimulation test trying to get the post stimulation cortisol down to below 120 nmol/l starting 2 to 4 hours after oral administration. In some individuals trilostane may need to be given twice daily.
Trilostane should be used with caution in dogs with impaired renal function and may cause reversible hypoadrenocorticism in some dogs. Hypoadrenocorticism does occur with over-dosage, but should resolve on withdrawal of the drug.
Pregnant women should wear gloves and all users should wash their hands after handling the drug.
It has been used successfully in a number of cases of HAC. Trilostane is nearly as effective as mitotane in resolving the signs of hyperadrenocorticism in cases of PDH. Up to 10 per cent of cases with PDH may not respond adequately. Mean survival time is 662 to 900 days.
The prevalence of side effects with trilostane is generally considered to be lower than with mitotane. If the various clinical studies are combined then only 16 per cent of dogs treated with trilostane developed adverse effects that may have been attributable to the drug. This figure compares favourably to those reported with mitotane (25 to 42 per cent).
If failure to respond is regarded as an adverse effect then it is probably the most common adverse effect of trilostane administration. In these cases, an increase in the dose (and /or frequency) or a change to an alternative medication (such as mitotane) is indicated.
Another common side effect is an increase in the size of the adrenal glands and a change in the echotexture
The most serious side effect of trilostane that has been identified to date is acute adrenal necrosis. Although deaths are rare, subclinical histopathological evidence of adrenal necrosis is more common. Necrosis of the adrenal cortex cannot be directly explained by the competitive inhibition of steroidogenesis. The development of adrenal necrosis could be due to the hypersecretion of ACTH, which, as well as increasing the size of the adrenals, may also, paradoxically, result in necrosis and haemorrhage of the adrenal glands.
Overdosing with trilostane will result in hypoadrenocorticism. Most cases of hypoadrenocorticism associated with trilostane recover rapidly following temporary cessation of the drug but will continue to require the drug to control the clinical signs of hyperadrenocorticism. Most cases that develop hypoadrenocorticism have typical electrolyte changes (hyponatraemia, hyperkalaemia).
Some clinical studies of trilostane have recorded a mild increase in serum potassium concentrations. Dogs that develop hyperkalaemia but whose cortisol concentrations are adequate do not appear to have a low aldosterone concentrations. The mechanism of action of this hyperkalaemia has not been identified. Any trilostane treated dog with a mild increase in potassium should be checked with an ACTH stimulation test, rather than empirically reducing the dose. Trilostane can then be safely withheld whilst waiting for the results of the test.
Trilostane is associated with vomiting and diarrhoea in some dogs independently of any effects on cortisol concentrations. The best treatment is to administer the tablets with food or to change to an alternative medication.
Mitotane (op'-DDD; Lysodren, Bristol Laboratories) is the treatment of choice for pituitary-dependent hyperadrenocorticism. During its evaluation as an insecticide, mitotane was discovered to have adrenocorticolytic effects. It selectively destroys the zona fasciculata and zona reticularis while tending to preserve the zona glomerulosa.
Mitotane therapy should only be considered once the diagnosis of hyperadrenocorticism has been confirmed. Because of its powerful effects, it should never be used empirically. Before treatment is instigated, the patient's daily water consumption should be measured over at least two consecutive 24-hour periods. If the water intake and appetite are not increased then baseline lymphocyte and eosinophil counts and an ACTH stimulation test, are required to monitor the response to therapy.
Initial treatment. The author prefers to hospitalise the patient for the initial course of treatment, although many clinicians have dogs treated by their owners at home, with the owners doing the necessary monitoring. Mitotane is given orally at a dose rate of 50 mg/kg/day and should be administered with food. Concomitant glucocorticoid treatment is not advised, although if the dog is being treated at home, the owner should be given a small supply of prednisolone tablets. Daily mitotane therapy should be continued until any of the following changes are noted: the water intake of a polydipsic dog drops to below 60 ml/kg/day, the dog takes longer to consume its meal than before treatment or stops eating completely, the dog vomits or has diarrhoea, or the dog becomes listless and depressed.
The initial course of mitotane is then stopped and the dog put on maintenance therapy (see below). The importance of close monitoring of the patient during this period cannot be over-emphasised.
Possible problems that may be encountered during mitotane therapy and their management:
Vomiting or anorexia within the first 3 days of treatment (gastric irritation)
Discontinue mitotane and reassess patient. Divide dose and give 2 to 4 times day
Profound weakness, depression and anorexia usually around 4th or 5th day of treatment
Discontinue mitotane and reassess patient. Check sodium and on the potassium levels and institute prednisolone (0.2 mg/kg/day)
Reassess ACTH stimulation test. Start maintenance therapy with mitotane
Acute onset of neurological signs (due to sudden expansion of the pituitary tumour)
Continue mitotane unless the dog is anorexic, vomiting or depressed. Give prednisolone 2.0 mg/kg/day or dexamethasone 0.1 mg/kg/day and decrease dose slowly once neurological signs have resolved
Failure to resume normal water intake
Recheck urinalysis and blood urea. Reassess ACTH stimulation test. Increase mitotane by 50 per cent if post ACTH cortisol level is greater than 200 nmol/l
Failure to regrow hair
Reassess ACTH stimulation test. Determine baseline T4. Increase mitotane by 50 per cent if post ACTH cortisol level is greater than 200 nmol/l. (If < 120 nmol/L perform a TRH/TSH stimulation test).
Excessive depression or weakness related to weekly maintenance therapy
Reassess patient. Check sodium and potassium levels. Repeat ACTH stimulation test. If cortisol level post ACTH is less than 15 nmol/l reduce maintenance dose or give every other week.
Maintenance therapy. Mitotane is given at a dose of 50 mg/kg/week with food. Cases that are well controlled may sleep for a few hours after the weekly dose and for that reason it is often recommended that the treatment is given in the evening. More profound depression or weakness requires re-evaluation and possibly a reduction of the maintenance dose. Failure to control the polydipsia may require an increased dose of mitotane.
Re-examination. Treated dogs should be re-examined 6–8 weeks after completion of the initial therapy, unless there are any problems. Marked improvement should be noted at this time. The most obvious and rapid response is a reduction in water intake, urine output and appetite and this is usually obvious at the end of the initial course of therapy. Muscle strength and exercise tolerance improve over the first 3–4 weeks. Skin and hair coat changes take longer and the progress is variable. The skin and alopecia may deteriorate markedly before improving; alternatively there may be gradual and noticeable resolution of the dermatological signs. Although improvement should be noted at eight weeks, the skin and haircoat may not return to normal for 3–6 months. A few dogs have dramatic changes in coat colour following successful therapy.
Re-examination every 3–6 months is recommended for the remainder of the animal's life. Relapses and episodes of overdosage do occur and re-assessment of adrenal reserve by ACTH stimulation testing is indicated. Relapses may require a short course of daily mitotane therapy or an increase in the maintenance dosage. Overdosage requires reassessment by an ACTH stimulation test and a reduction of the maintenance dose.
The mean survival time of treated dogs is 30 months with a range of a few days to over seven years.
Other Therapeutic Options for Pituitary-Dependent Hyperadrenocorticism
L-deprenyl (selegiline hydrochloride) is a monoamine oxidase inhibitor that inhibits ACTH secretion by increasing dopaminergic tone to the hypothalamic-pituitary axis. The use of L-deprenyl for treatment of hyperadrenocorticism has been evaluated in dogs. Although the effectiveness of treatment is variable, one major advantage of L-deprenyl is the lack of any severe adverse effects, including iatrogenic hypoadrenocorticism.
Treatment is initiated at a dosage of 1 mg/kg daily. If an inadequate response is seen after two months, the dosage is increased to 2 mg/kg/day. If this dosage also proves ineffective, alternative treatment is required. About 50 per cent of dogs fail to respond adequately to this treatment.
Ketoconazole has a reversible inhibitory effect on glucocorticoid synthesis whilst having minimal effects on mineralocorticoid production. Ketoconazole has been used effectively to control hyperadrenocorticism in dogs. However, ketoconazole is not uniformly efficacious in dogs and between one-third to one-half of all dogs treated fail to respond adequately.
The initial recommended dosage of ketoconazole is 10 mg/kg twice daily for 14 days. Alternatively, treatment is initiated at 5 mg/kg twice daily for the first seven days to assess drug tolerance, then increased to 10 mg/kg. The efficacy of the initial 14-day course of treatment is determined by an ACTH stimulation test.
Bilateral adrenalectomy has been employed successfully but involves the risk of putting an ill animal with a compromised immune system and poor wound healing, through a difficult surgery procedure. Currently, bilateral adrenalectomy appears to be the most successful means of treating feline hyperadrenocorticism. Patients treated by this approach require life-long treatment for hypoadrenocorticism.
Hypophysectomy has been successfully performed in the dog for the treatment of pituitary-dependent hyperadrenocorticism, but the operation is technically difficult.
Treatment of Adrenal-Dependent Hyperadrenocorticism
Dogs diagnosed as having adrenal dependent hyperadrenocorticism carry the best prognosis if the tumour can be removed surgically, although mitotane therapy is also recommended.
Unilateral adrenalectomy requires considerable experience and expertise because of the complex anatomy. The technique is well-described using the paracostal, flank approach. It should only be performed by experienced surgeons as perioperative mortality is high. Postoperative support is important as the contralateral adrenal cortex will be atrophic and unable to respond to the stress. Replacement glucocorticoid therapy may therefore be required for 7–10 days postoperatively. The surgery should only be performed by experienced surgeons and even then there is a high morbidity and mortality rate with perioperative mortality in the order of 30%. The median survival time is around two years with some dogs surviving for longer than four years.
Mitotane and trilostane therapy are effective and relatively safe in dogs with adrenal-dependent hyperadrenocorticism. Dogs with adrenal tumours however, tend to be more resistant to mitotane and trilostane than dogs with pituitary-dependent hyperadrenocorticism. Generally dogs with adrenal-dependent hyperadrenocorticism require higher daily induction doses of mitotane (50–75 mg/kg/day) and a longer period of induction (> 14 days) than dogs with pituitary-dependent hyperadrenocorticism. Frequent monitoring of treatment by ACTH stimulation testing is important to ensure adequate control of the hyperadrenocorticism. Maintenance doses are also generally higher (75–100 mg/kg/week) and again frequent monitoring of the cortisol response to ACTH stimulation is required to maintain optimal control of the disease. Adverse effects of treatment are similar to those described for pituitary-dependent hyperadrenocorticism. Those dogs requiring higher dose rates tend to be more prone to adverse effects. The adrenal tumour and metastatic mass will often reduce in size due the cytotoxic effects of mitotane, but in other cases the tumour will continue to grow despite increasing doses of mitotane. The median survival time is 11 months with a range of a few weeks to more than five years.