New Treatment Options in Canine Cushing's Syndrome
WSAVA 2002 Congress
Claudia E. Reusch, Dipl ECVIM-CA
Clinic for Small Animal Internal Medicine, University of Zurich
Winterthurerstr, Zurich

Cushing's syndrome (CS) is one of the most common endocrine disorders in dogs. 80 to 85% suffer from pituitary-dependent hyperadrenocorticism (PDH), in the other cases the disease is due to a functional adrenal tumor (FAT). CS is typically found in middle-aged to old dogs. Common breeds include miniature poodle, dachshund, terrier breeds, boxer, beagle. FAT tend to occur more frequently in large breed dogs than PDH.

Most dogs exhibit several, but not all of the typical symptoms. It should be remembered however, that in about 30% of cases PU/PD is the only sign, and about 10% of dogs only show hair coat abnormalities. About 20% of dogs with PDH eventually develop an expanding pituitary tumor, clinical signs include lethargy, behaviour changes, nervousness, anorexia, weight loss, circling, ataxia, disorientation, head pressing, seizures, stupor. Those signs may precede, coincide or follow the diagnosis of hyperadrenocorticism. Screening tests include ACTH stimulation test, low dose dexamethasone test (LDDS), and the urine cortisol:creatinine ratio (UCC). The ACTH stimulation test is a test to investigate adrenal reserve, it is therefore used to rule in or rule out hypoadrenocorticism. It has a relatively low sensitivity, depending on the study it ranges between 60-85%. Specificity ranges between 85-90%. The LDDS test has a high sensitivity (85-95%), however, specificity is lower (70-75%). One of the advantages of the LDDS is that by taking a 3rd blood sample 4 hours after dexamethasone injection it cannot only be used as a screening test, but also as a discrimination test. If there is no suppression, but so-called dexamethasone resistance, either PDH or FAT could be present and other discrimination tests have to be used. The UCC has the highest sensitivity of all screening tests (98%), but specificity is relatively low (20-77%). After diagnosing the presence of CS the next step in the work up is to differentiate between PDH and FAT. For us the test of choice is adrenal ultrasonography. We recently investigated whether dogs with PDH and a small pituitary tumor (microtumor) differ from dogs with clearly visible tumors (macrotumor) with regard to signalment, clinical signs, routine laboratory tests and specific endocrine tests. Dogs with macrotumors had significantly higher body weight than dogs with microtumors, and dogs with macrotumors had far more frequently a dexamethasone resistance than dogs with microtumors. Since about 20% of dogs with PDH develop neurological signs because of expansion of the tumor we recommend CT in all dogs with PDH. In large breed dogs and in dogs with dexamethasone resistance we particularly emphasize its importance.

The standard treatment of pituitary-dependent hyperadrenocorticism (PDH) in dogs has long been mitotane (Lysodren®). Mitotane leads to selective, progressive necrosis of the adrenal cortex, which may be partially or completely destroyed, depending on the treatment protocol. The efficacy of mitotane is favorable and more than 80% of the dogs with PDH have a good to excellent response. Disadvantages of mitotane include potential development of adrenocortical insufficiency, possible drug intolerance, and a relatively high frequency of relapses during therapy. During the last few years, the efficacy of a number of substances with central or peripheral action has been investigated for treatment of PDH. With the exception of ketoconazole, which inhibits synthesis of adrenocortical steroids, efficacy was poor. L-deprenyl was reported to be a safe treatment for PDH in dogs, but it resulted in clinical improvement in only about 20% of dogs. Therefore we do not recommend L-deprenyl as treatment for PDH. Ketokonazole may be used as an alternative drug for the treatment of dogs with PDH as well as for dogs with functional adrenal tumors. However, up to 30% of cases do not show improvement, the drug is relatively expensive and has potential hepatotoxicity. Recently, Trilostane (Modrenal ®) has gained popularity for the treatment of Cushing's syndrome in dogs. Trilostane is an orally administered competitive inhibitor of 3ß-hydroxysteroid-dehydrogenase. This enzyme system mediates the conversion of pregnenolone to progesterone in the adrenal gland. Cortisol, aldosterone and androstenedione are produced from progesterone via various biochemical pathways. Trilostane inhibits the production of progesterone and therefore the synthesis of its end products. We have used Trilostane for more than 2 years now for the treatment of PDH and investigated its efficacy in a prospective study. 82% of our dogs with PDH had a very good response to trilostane. The time required for a noticeable response to trilostane was similar to that of mitotane, with a rapid improvement in PU/PD, polyphagia and activity and a delayed improvement in hair coat, skin condition and abdominal muscle tone. The ACTH stimulation test determines adrenal reserve and is therefore suitable for evaluating the extent of enzyme inhibition during treatment, and to calculate dosage adjustments. Currently we start Trilostane as follows: dogs < 5 kg 30 mg SID, dogs 5-20 kg 60 mg SID, dogs > 20 kg 120 mg SID. Re-evaluations are performed after 1, 3, 6, 13 weeks, 6 months and 12 months, and include history, physical examination and an ACTH stimulation test. It appears to be of importance that the ACTH stimulation test has always to be performed at the same time after drug administration. On the condition that the ACTH stimulation test is performed 2-6 hours after the drug administration the target range of the post ACTH cortisol level is 1-2 µg/dl (27-56 nmol/l). We speculate that in dogs treated with trilostane, steroid precursors, which have accumulated as a result of the enzyme inhibition, have a certain glucocorticoid-like effect. Although the cortisol concentration is low, symptoms of hypocortisolism may be prevented by the precursors. Overdosage is possible, however, due to the short half-life of trilostane and the reversibility of the enzyme inhibition symptoms resolve quickly once treatment is discontinued. Adverse effects seen so far consisted of 1 dog with transient lethargy and 1 dog with anorexia. Frequent adjustments in dosage, both increases and decreases, are required, particularly during the first few weeks of treatment. It is apparent that the effective dosage of trilostane differs markedly among dogs with PDH. This may be due to a significant variation in 3ß-hydroxysteroid dehydrogenase activity in adrenal glands among individuals. However, it appears that stabilization of the response to treatment occurs over a period of time after which adjustments in dosage are seldom necessary. Interestingly we found very distinct changes in the ultrasonographic appearance of the adrenal glands during the study. In almost all dogs, there was a marked increase in the thickness and echogenicity of the outer zone, which was assumed to be the adrenal cortex. Possibly, the increase in thickness of the cortex reflected increased synthesis of precursors due to increased ACTH secretion, as a result of the abolition of the negative feedback normally exerted by cortisol. Studies are under way at our clinic to investigate this.

In large pituitary tumors other treatment modalities have to be used. In humans transspenoidal hypophysectomy is the treatment of choice. In veterinary medicine however, only very few surgeons are able to perform a hypophysectomy, another limitation is that this procedure is limited to tumors up to 1.0 cm in height. For those tumors radiation therapy has proven to be an efficient treatment modality. In Zurich we are currently using a linear accelerator for radiation therapy of large pituitary tumors. The treatment plan is generated by a computer after performing CT scan. Under general anesthesia 12 radiation fractions at 3.5 Gy are given on a Monday, Wednesday, Friday schedule. So far, tolerance of the procedure was very good, and besides focal depigmentation we have not observed any side effects. Most dogs showed improvement of their neurological signs already during radiation, and continued to improve during the following weeks to months. In dogs with less severe neurological signs improvement was faster than in dogs with severe signs. In several of the dogs in which follow-up CT scan were available a clear decrease in size of the pituitary mass was found. Radiation therapy is less effective to control hypercortisolism and the vast majority of the dogs need additional medical treatment.

References

1.  Kaser-Hotz B, Stankeova S, Fidel J, Sumova A, Wergin M, Rohrer C, Achermann R, Gardelle O, Reusch C: Strahlentherapeutische Behandlung von hypophysären Makrotumoren bei 4 Hunden. Kleintierprax, 46, 197-206, 2001.

2.  Reusch CE, Steffen T, Hoerauf A: The efficacy of L-Deprenyl in dogs with pituitary-dependent hyperadrenocorticism. J Vet Intern Med, 13, 291-301, 1999.

3.  Reusch C, Stankeova S, Geissbühler U, Glaus T, Tomsa K, Hörauf A, Kaser-Hotz B: Zusammenhang zwischen computertomographisch ermittelter Hypophysengrösse und dem Auftreten neurologischer Symptome bei Hunden mit Cushing-Syndrom. Kleintierprax 46, 133-139, 2001.

4.  Ruckstuhl N, Nett C, Reusch C: Results of clinical examination, laboratory tests, and ultrasonography in dogs with pituitary-dependent hyperardrenocorticism treated with trilostane. Am J Vet Res, 63, 506-512, 2002.

5.  Théon AP, Feldman EC: Mega-voltage irradiation of pituitary macrotumors in dogs with neurologic signs. J Am Vet Med Assoc, 213, 225-231, 1998.

Speaker Information
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Claudia E. Reusch, Dipl ECVIM-CA
Clinic for Small Animal Internal Medicine
University of Zurich
Winterthurerstr, Zurich


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