Treating canine hyperadrenocorticism (Proceedings)

Hypophysectomy

Surgery is performed for dogs with pituitary and adrenal-dependent disease. In the United States there is limited experience with hypophysectomy for pituitary tumors but outside the United States this surgery has been performed with good results. The mortality rate can approach 10% but most dogs obtain a complete remission for several years. In addition to perioperative mortality, diabetes insipidus may occur but is usually transient. Bilateral adrenalectomy has also been performed in dogs with PDH. This creates a dog with permanent hypoadrenocorticism and requires life long glucocorticoid and mineralocorticoid treatment.

Adrenalectomy

Surgery is the treatment of choice for adrenal tumors. An exception might be made for tumors that have metastasized or dogs with concurrent disease that would make surgery an unnecessary risk. This emphasizes the need for a thorough staging process prior to surgery. Complete removal of a functional cortisol producing tumor will result in a cure. Benign adenomas would be more likely to be cured by surgery than adenocarcinomas. Because the contralateral adrenal is often atrophied, glucocorticoids (dexamethasone, hydrocortisone) are given the day of surgery and continued after surgery. Once dogs have recovered and can take oral medications, oral glucocorticoids are given. Glucocorticoids are tapered over several weeks. Mineralocorticoids are no typically required but given as needed. A few dogs develop evidence of a transient, mild mineralocorticoid deficiency that resolves in 48 to 72 hours and does not necessarily require treatment. For more moderate or prolonged hyponatremia and hyperkalemia temporary use of mineralocorticoids is recommended. An ACTH stimulation can be performed the day after surgery to assess for complete removal of the tumor and absence of metastatic disease. ACTH stimulation tests are also performed by some when on low doses of glucocorticoids to assess return to function of the remaining adrenal gland. It may take several months for the contralateral adrenal gland to function normally. Another concern in these patients is thromboembolic disease. Dogs with HAC are hypercoagulable for reasons stated previously. The surgery itself predisposes them to thromboembolism (anesthesia, hypotension, recumbency, vascular occlusion/stasis). For this reason it is advised to give plasma at a dose of 6 to 10 ml/kg prior to surgery as a source of antithrombin III. It is also recommended to initiate heparin therapy prior to surgery. The prognosis is good for dogs that survive the perioperative period.

Lysodren

Lysodren continues to be the most commonly used adrenolytic in dogs. It is the first line of therapy recommended for PDH that is not the result of a pituitary macroadenoma. It is also recommended in dogs with ACH that are not surgical candidates for whatever reason. Lysodren results in destruction of the cells of the zona fasciculata and zona reticularis. It spares the zona glomerulosa to some extent so aldosterone synthesis may be spared and electrolyte abnormalities are not typically seen. Absorption is improved with feeding, particularly of fatty meals. The most common side effects are related to an absolute or relative cortisol deficiency and include lethargy, anorexia, vomiting and diarrhea. A hepatopathy can occur on rare occasions with this drug. Dogs are typically induced with 50 mg/kg/day divided into 2 doses. Dogs with diabetes mellitus and cardiac disease are often induced with a lower dose of 25 mg/kg/day divided. Most dogs are induced in 5 to 9 days. Induction is assumed complete with any change in water consumption, appetite, onset of lethargy, vomiting or diarrhea. ACTH stimulation tests are performed weekly and at the completion of induction with a goal of post stimulation values below the reference range. Glucocorticoid supplementation (0.5 mg/kg/day of prednisone) is recommended if lethargy, vomiting or diarrhea develop. Once signs have resolved the prednisone is tapered over several days. Mineralocorticoid deficiency is uncommon with treatment but suggests more extensive destruction of the adrenal gland. In these dogs, permanent glucocorticoid and mineralocorticoid therapy may be necessary. Once induction is completed dogs are placed on 25 to 50 mg/kg divided into 2 to 3 doses during the week. An ACTH stimulation test is checked at 1 and 3 months after induction or when signs recur. In a stable dog on lysodren therapy full blood work, a urinalysis and ACTH stimulation test should be performed every 4 to 6 months. Initial adjustments are typically made by altering the number of days the lysodren is given, not the dose per day. Occasionally dogs require high daily doses or have to be induced again. Some dogs fail to respond to lysodren and this may be due to failure to administer the medication, poor absorption/potency, incorrect diagnosis, medications that interfere with lysodren, presence of an adrenocortical tumor, a resistant form of the disease or iatrogenic HAC. Lysodren also results in decreased levels of androstenedione, progesterone and 17-OH progesterone so it may be useful in some cases of atypical hyperadrenocorticism when melatonin and lignins are ineffective.

Trilostane

Trilostane is a competitive inhibitor of 3-beta hydroxysteroid dehydrogenase, an enzyme necessary for the formation of aldosterone, cortisol and androgens in the adrenal gland. There have been reports of necrosis of the adrenal gland zona fasciculate primarily) as a result of its use but typically adrenal glands actually become more enlarged due to lack of feedback. It is recommended it be given with food but there is no evidence food increases absorption. Trilostane has been associated with fewer episodes of hypoadrenocorticism than lysodren and is believed by some to be better tolerated. It can be used to treat PDH and ACH in dogs. There are 10, 30, 60 and 120 mg capsules. Various dosing regimens are available including 15 mg once to twice daily for dogs less than 5 kg, 30 mg once to twice daily for dogs 5 to 20 kg, 60 mg in the am and 30 mg in the pm for dogs 20 to 40 kg and 60 mg twice daily for dogs greater than 40 kg. Once daily therapy may be adequate to control signs of HAC and cortisol levels in the majority of dogs but twice daily may be beneficial to those not controlled by once daily. This is because the effects of orally administered trilostane on cortisol synthesis do not exceed 20 hours. ACTH stimulation tests are done prior to therapy, 2 weeks, 1 month, 2 months and 4 months into therapy and then every 4 to 6 months for stable patients. The test should be done 4 to 6 hours post pill with measurement of a pre and one hour cortisol. The goal is to keep post stimulation cortisol within the reference range. If they are above then the daily dose is increased by 25 to 50%. If the result is below the reference range then the dose is decreased by 25 to 50%. Dogs given trilostane can experience temporary and permanent hypoadrenocorticism but with less frequency than seen with lysodren. Hypoadrenocorticism is more frequently seen with chronic administration of trilostane vs. more acute administration of lysodren. Currently, trilostane therapy is more expensive than lysodren. Studies comparing survival times with trilostane vs. lysodren are conflicting. 17-OH progesterone, androstenedione and estradiol often increase with this drug and in some cases may contribute to signs of HAC. Both trilostane and lysodren should be used cautiously in dogs with hepatic or renal disease and when switching from trilostane to lysodren a washout period of one month or evidence of adrenal function on stimulation testing is recommended. Trilostane is currently not available in the United States so a petition from the FDA must be obtained for each 90 day supply. Trilostane is currently available through compounding pharmacies but the products are not what is manufactured by the parent company and thus have not necessarily been evaluated for safety and efficacy. The company that produces trilostane expects FDA approval this year. There is speculation that once the drug is approved in the US, cost of maintenance therapy will be similar to lysodren. To petition the FDA you must write a letter and send it to:

U.S. Food and Drug Administration

Center for Veterinary Medicine

Attn: Mike Zimmerman

7519 Standish Place

MPN-4, RM-109, HFV-235

Rockville, MD 20855

Ph: (240)276-9202

Fax: (240)276-9241

Additional information, including what information should be in the letter, can be found at the FDA website.

Ketoconazole

Ketoconazole inhibits steroid synthesis by interfering with 17-alpha-hydroxylase and 11-beta hydroxylase enzymes in the cortisol synthetic pathway. It should be given with food. Ketoconazole is typically given to dogs with adrenal tumors that are not treated surgically, to stabilize dogs prior to surgery, to dogs that do not tolerate other oral formulations and as a screening test for hyperadrenocorticism. This drug can cause intestinal upset so it is initially given at 5 mg/kg BID. If well tolerated after one week it is increased to 10 mg/kg BID for one week then an ACTH stimulation test is performed. Again the goal is to keep the post stimulation within the reference range. Often doses over 15 mg/kg BID are required to control clinical signs and hypercortisolemia. Melatonin and lignins can be used to decrease the dose of ketoconazole required (see below). Twenty to 25% of dogs fail to respond to ketoconazole. Intestinal irritation and hepatotoxicity are fairly common side effects.

Melatonin

Melatonin inhibits the enzymes 21-hydroxylase (involved in cortisol synthesis) and aromatase (involved in estradiol synthesis). Recommended doses are 3 to 6 mg orally twice daily. If twice daily administration appears ineffective, a melatonin implant can be used that is good for approximately 4 months.

Lignins

Lignins inhibit 3 beta-hydroxysteroid dehydrogenase (cortisol) and aromatase (estradiol). Give 1 tsp of flaxseed oil with lignins per 25 pounds on food once daily. Alternatively 1000 mg flaxseed oil capsule can be given once daily. The University of Tennessee provides this and additional information regarding steroid profiles and treatment of atypical hyperadrenocorticism on its website:

http://www.vet.utk.edu/diagnostic/endocrinology/treatment.shtml

Pituitary Irradiation

Pituitary irradiation is recommended for all dogs with PDH and neurologic signs due to a macroadenoma. Radiation therapy is primarily used to control neurologic signs. Dogs that have received radiation therapy often still require medical management. In general the size and severity of neurologic signs correlate with survival and response to irradiation but median survival times of 1 to 2 years have been reported.

References

Feldman EC, Nelson RW Canine and Feline Endocrinology and Reproduction. 3rd ed. Saunders. Pp 251-353.

Ettinger SJ, Feldman EC. Textbook of Veterinary Internal Medicine. 6th ed. Elsevier. Pp 1592 – 1611.

Clemente M, De Andres PJ, et al. Comparison of non-selective adrenocorticolysis with mitotane or trilostane for the treatment of dogs with pituitary-dependent hyperadrenocorticism. Vet Rec. 2007 Dec 15; 161(24):805-9.

Reusch CE, Sieber-Ruckstuhl N, et al. Histologic evaluation of the adrenal glands of seven dogs with hyperadrenocorticism treated with trilostane. Vet Rec. 2007 Feb 17;160(7):219-24.

Bell R, Neiger R, et al. Study of the effects of once daily doses of trilostane on cortisol concentrations and responsiveness to adrenocorticotropic hormone in hyperadrenocorticoid dogs. Vet Rec. 2006 Aug 26;159(9):277-81.

Alenza DP, Arenas C, et al. Long-term efficacy of trilostane administered twice daily in dogs with pituitary-dependent hyperadrenocorticism. J Am Anim Hosp Assoc. 2006 Jul-Aug;42(4):269-76.

Barker EN, Campbell S, et al. A comparison of the survival times of dogs treated with mitotane or trilostane for pituitary-dependent hyperadrenocorticism. J Vet Intern Med. 2005 Nov-Dec;19(6):810-5.