Treating canine hyperadrenocorticism (Proceedings)

Surgical management of hyperadrenocorticism

Hypophysectomy

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. In a recent study looking at 181 dogs undergoing hypophysectomy, 86% were alive at 1 year, 83% at 2 years, 80% at 3 years and 79% at 4 years. Of the 181 dogs, 14 died in the post-operative period (4 weeks). Twelve of 181 had residual disease as determined by persistence of signs, increased urinary cortisol/creatinine ratios and/or cross-sectional imaging. Of the 181, 155 went into remission. Of the 155 dogs, 119 remained in remission. Decreased survival times and shorter remission times were seen with larger pituitary tumors. Additional complications include diabetes insipidus, keratoconjunctivitis sicca and hypothyroidism. Hypothyroidism is permanent but hypocortisolism, diabetes insipidus and keratoconjunctivitus sicca are usually transient.

Adrenalectomy

Unilateral adrenalectomy 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 them a poor surgical candidate. 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. 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 not 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 prior to cessation of glucocorticoids. 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. The surgery itself also 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. Bilateral adrenalectomy has also been performed in dogs with bilateral tumors or PDH. This creates a dog with permanent hypoadrenocorticism and requires life-long glucocorticoid and mineralocorticoid supplementation.

Mitotane

Mitotane has historically been the most commonly used adrenolytic in dogs in the United States. Adrenolytic therapy is recommended for dogs with PDH that is not the result of a pituitary macroadenoma. It is also recommended in dogs with adrenal tumors that are not surgical candidates for whatever reason. Mitotane results in destruction of the cells of the zona fasciculata and zona reticularis. Because it spares the zona glomerulosa, aldosterone synthesis should be spared and electrolyte abnormalities are not typically seen. Absorption is improved with feeding fatty meals. The most common side effects occur early on in treatment and are related to an absolute or relative cortisol deficiency including 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 that are debilitated or diagnosed with concurrent diabetes mellitus or cardiac disease are often induced with 50% of this dose. 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. Appetite is most often first affected. ACTH stimulation tests are performed weekly and at the completion of induction with a goal of post stimulation values below the reference range but detectable. 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 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 mitotane 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 mitotane 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 mitotane and this may be due to failure to administer the medication, poor absorption/potency, incorrect diagnosis, medications that interfere with mitotane, presence of an adrenocortical tumor, a resistant form of the disease or iatrogenic HAC. Mitotane also results in decreased levels of androstenedione, progesterone and 17-OH progesterone so it may be useful in some cases of atypical hyperadrenocorticism when other treatments are ineffective.

Trilostane

Trilostane has been used for the medical management of PDH for many years in Europe where mitotane is not available. 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. It is recommended to give with food but there is no evidence food increases absorption. Trilostane may be associated with fewer episodes of transient and permanent hypoadrenocorticism than mitotane. There have been a few reports of necrosis of the zona fasciculata causing side effects early in administration but side effects are more commonly seen during chronic administration. It can be used to treat PDH and adrenal tumors in dogs. Various dosing regimens are available. The manufacturer recommends initiating therapy at 2.2 mg/kg once or twice daily. Another dosing regimen is 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. Dose ranges for control of signs in dogs is extremely variable from 1.2 to 50 mg/kg/dose with most dogs controlled on 2 to 8 mg/kg/dose. Once daily therapy may be adequate to control signs of HAC in some dogs but twice daily administration may be necessary because the effects of trilostane on cortisol synthesis do not exceed 8 to 20 hours. An ACTH stimulation test is typically done prior to therapy, at 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 2 to 6 hours post pill with measurement of a pre and one hour cortisol. The goal is to keep post stimulation cortisol below the reference range. If cortisol levels are increased, the daily dose is increased by 25 to 50%. If the result is below the reference range the dose is decreased by 25 to 50%. Studies comparing survival times with trilostane vs. mitotane are conflicting. Androstenedione, 17 OH-progesterone and estradiol often increase with this drug and in some cases may contribute to signs of HAC. Trilostane has recently been approved by the FDA for use in dogs and is currently available in the United States.

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 or 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 cortisol below 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 and cortisol levels may even increase in some.

Melatonin

Melatonin is a hormone produced by many organs, including the pineal gland, that is involved in regulation of other physiologic processes within the body including reproduction and sleep patterns. Melatonin also inhibits the enzymes 21-hydroxylase (involved in cortisol synthesis) and aromatase (involved in estradiol synthesis). Melatonin is used most commonly in dogs with atypical hyperadrenocorticism due to increases in estradiol. Atypical hyperadrenocorticism occurs when clinical manifestations (PU, PD, liver enzymes, skin changes, etc) are due to the accumulation of steroid hormones or precursors other than cortisol. Recommended doses are 3 to 6 mg orally twice daily. It may take several weeks to months to see improvement. If twice daily administration appears ineffective, a melatonin implant can be used that is good for approximately 4 months. Monitoring is with improvement in clinical signs and steroid hormone profiles. Melatonin has been used in combination with lignans and mitotane to treat dogs with PDH.

Lignins

Lignins are found in the cell walls of plants. Lignins inhibit 3 beta-hydroxysteroid dehydrogenase (cortisol) and aromatase (estradiol). Lignins are used most commonly with atypical hyperadrenocorticism due to estradiol increases. Give 1 tsp of flaxseed oil with lignins per 25 pounds on food once daily. Alternatively 1000 mg flaxseed oil capsules can be given once daily. The University of Tennessee provides this and additional information regarding steroid profiles and treatment of atypical hyperadrenocorticism on their website:

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

Pituitary irradiation

Pituitary irradiation is recommended for all dogs with PDH and neurologic signs but has also been used to control signs related to hyperadrenocorticism in some dogs without neurologic signs. Following radiation therapy neurologic signs improve in most dogs but signs of hyperadrenocorticism are less consistently controlled. Neurologic and endocrine signs may recur. Medical management of hyperadrenocorticism is often used concurrently when radiation therapy does not control signs of hypercortisolism or for those who relapse. In general the size and severity of neurologic signs correlate with survival and response to irradiation but survival times of 1 to 3 years have been reported.

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