Canine and feline adrenal gland diseases (Proceedings)

Background

Canine Hyperadrenocorticism (Canine Cushing's syndrome) is one of the more common endocrinopathies encountered in small animal practice; ranking behind only hypothyroidism and diabetes mellitus. The resultant hypercotisolemia has many far-reaching pathophysiologic effects on many organ systems; including the kidney, (polyuria, hyposthenuria and compensatory polydipsia, hypercalciuria), liver (gluconeogenesis, glycogenolysis, histologically-hepatic lipidosis and glycogen deposition), pancreas (insulin antagonism-approximately 10% of affected canines develop overt diabetes mellitus), skeletal muscle (increased protein catabolism-resulting in muscle weakness and myasthenia), skeleton (osteopenia-due to increased protein catabolism and negative calcium balance), adipose tissue (redistribution of fat deposits, increased lipolysis-resulting in hepatic lipidosis), immune system (blunted inflammatory and immune response-increased susceptibility to infection) and blood cells (neutrophilia, lymphopenia, eosinopenia and erythrocytosis).

Approximately 85% of affected canines suffer from PDH (pituitary-dependent hyperadrenocorticism->90% of these patients have pituitary tumors; either microadenomas {80%}or macroadenomas {10%}. The remaining (15%) cushingoid patients have functional adrenal tumors (FAT). By utilizing various diagnostic modalities (urine cotisol/creatinine ratio-as a screening test, low-dose dexamethasone suppression test {LDDST}, endogenous ACTH assay, high dose dexamethasone suppression test {HDDST} and imaging techniques {abdominal ultrasonography, abdominal/pituitary CT/MRI}, the diagnosis and type of hyperadrenocorticism can be determined on a vast majority of suspected canine patients.

Due to financial constraints and the fear of increased morbidity/mortality by the pet owners, hypophysectomies are rarely performed. This surgical procedure carries with it the added burden of having to supplement the patient (on a life-long basis) with replacement hormones due to the loss of TSH, ACTH, STH and possibly vasopressin. Even adrenalectomies are not commonly performed (even in specialty practices), because these patients are poor surgical risks (obesity, poor healing tendencies, hypertension, poor immune response to potential infections, etc.).

Objective

To review the various medical treatment options available to small animal practioner in the management of Canine Hyperadrenocorticism and to discuss their various advantages and disadvantages.

Review of medications

Mitotane (O,P'DDD) {Lysodren}

Since 1973 when a rational protocol for the medical treatment of Canine Hyperadrenocorticism was firsrt published, mitotane has been the mainstay for the medical management of PDH and selected cases of FAT and has been used by this author for >33 years in over 650 cases. The drug, a dervitive of DDT is a potent adrenolytic agent, producing marked, progressive necrosis of the zona fasiculata and zona reticularis of the adrenal cortex. Later studies demonstrated that in prolonged high doses, mitotane causes necrosis of the zona glomerulosa with subsequent mineralocoid depletion. The key approach to successful use of this agent is be conservative and slowly convert the patient from hypercortisolemia to eu or mild hypocortisolemia. The clincian should realize that the disease took many months to develop and lowering the plasma cortisol levels is not a STAT clinical situation.

Mitotane is administered in two distinct phases: 1) a loading dose phase (usually 10-14 days; sometimes 21 days are required) and 2) a maintainence phase usually administered 1-3x/week for the rest of the dog's life. The most accepted loading dosage is: 50mg/kg in divided dosages (with food) although this author cosiders the dog's age, renal and hepatic function, body composition, attitude and appetite before arriving at a starting dosage. Often it is best to begin at 35-40 mg/kg divided and take one's time. Parameters to be carefully checked 1) appetite (usually a reduction of the often ravenous appetite is detected in 8-10 days) 2) cessation of polyuria/polydipsia (<60ml/kg/day). When the above phenomena occur daily mitotane administration is stopped and the dog undergoes an ACTH stimulatoin test. If the post ACTH level of plasma cortisol is 1-5 micrograms/dl, the patient is begun on maintence therapy (25-50 mg/kg/wk) and the patient is rechecked on a quarterly basis (CBC biochemistry panel, electrolytes and ACTH stimulation test). Because of this author's conservative dosing protocol and respect for mitotane's side effects (nausea, vomition diarrhea, severe anorexia, ataxia, CNS signs due rapidly expanding pituitary macroadenoma, decreased Na:K ratio etc.) administration of glucocorticoids along with the drug is almost never done Utilizing mitotane in the above manner has resulted in satisfying clincal results (suvivals of of 450->900 days in this author's experience).

Ketoconazole {Nizoral}

Ketoconazole is a broad-spectrum antimycotic imidazole derivative first approved for the treatment of systemic fungal infections. At higher doses ketoconazole inhibits steroidogenesis, causing a reduction of androgen and cortisol secretion. The above phenomena has led to the use of this drug in the management of humans with disseminated prostatic carci noma, precocious puberty, hirsutism and Cushing's syndrome.

Ketoconazole has been used in the mangement of Canine Hyperarenocorticism in many settings with variable results. The drug is usually begun at a dose of 5 mg/kg bid for 1 week. If no side effects are encountered (anorexia,icterus), the dose is increased to 10 mg/kg bid for 14 days. At this point the patient should undergo an ACTH stimulation test and the same criteria used to assess the efficacy of mitotane apply to ketoconazole. If the post ACTH level exceeds 7 micrograms/dl, the dose may be increased to 15 mg/kg bid for 10-14 days and a second ACTH stimulation test is performed. Some patients require 20 mg/kg bid to reduce plasma cortisol levels.

Disadvantages of ketoconazole therapy include: 1) the need to administer the drug bid for the rest of the life of the animal, 2) the excessive expense of this therapeutic protocol, 3) potential side effects which are dose and time dependent (anorexia, vomition, diarrhea and hepatopathy/jaundice). 4) 25-30% of canine patients will not respond to this agent despite escalating dosage..

Ketoconazole may be a therapeutic considerations in 1) dogs that will not tolerate mitotane (very rare in this author's experience), 2) to rapidly lower plasma cortisol levels in dogs with a FAT prior to unilateral adrenalectomy and 3) in dogs with a large locally invasive and non-resectable FAT.

Trilostane {Vetoryl, UK}

Trilostane is the drug of choice in in the UK for the medical management of Canine Hyperadrenocorticism and is the "hot new kid on the block" especially in the nightly ACVIM chatlines. It is NOT FDA-approved in the USA, although it can be obtained in "bootlegged" formulations by a few on-line drug supply houses. Trilostane is a synthetic steroid with no inherent hormonal activity and exerts its effects as a competitive ihibitor of the 3-beta hydroxysteroid dehydrogenase enzyme system. The above physiologic activities result in the blockage of synthesis of glucocorticoids and mineralocoids in the adrenal cortex. This process is completely reversible upon cessation of the drug. Trilostane is contraindicated in dogs with primary renal and hepatic disease as well as in female dogs that are pregnant, lactating or to be utilized for breeding.

The beginning dosages for trilostane are as follows: < 5 kg-not recommended, 5-20 kg-60 mg., 20-40 kg-120 mg., >40 kg.-120-140 mg. The patient should be rechecked (physical examination, CBC, electrolytes, biochemical panel, ACTH stimulation test) at 10-14 days, 4-6 weeks, 12-16 weeks and quarterly thereafter. The ACTH response test should be ideally run 4-6 hours after trilostane administration. The same criteria apply to trilostane therapy as compared to mitotane therapy with respect to the ACTH response test.

The general efficacy of trilostane appears to be inferior to that of mitotane (ameloiration of ployuria/polydipsia ~70%, compared to ~85%, regrowth of hair coat and reversal of calcinosis cutis ~60%, compared to 80%).

Although initially touted as being almost devoid of side effects, trilostane can cause lethargy, vomition, depression and anorexia, and lowered Na: K ratios (signs of adrenal insufficiency) in 10-15% of treated dogs. Additional complications include: sudden, unexplained death (usually within the first few days after initiating therapy), acute pancreatitis and CNS signs due a rapidly expanding pituitary macroadenoma.

The advantage of trilostane when compared to mitotane is a reduced overall incidence of side effects. Disadvantages include: 1) the drug is not FDA approved (this may cause legal problems, especially if the patient experiences sudden unexplained death-ALWAYS have the pet owner sign a release form advising he or she that trilostane is an investigational drug and is NOT FDA approved). 2) it can be difficult to obtain, 3) it is much more expensive than mitotane 4) it has to be given everyday for the rest of the dog's life (sometimes bid in some patients) 5) it can cause side effects.

In this country trilostane appears to be useful in those dogs that cannot tolerate mitotane or those dogs that have adrenal tumors and are poor surgical candidates.

L-Deprenyl {Anipryl}

L-Deprinyl (selegiline) is a monoamine oxidase inhibitor (MAO) and inbibits ACTH secretion by increasing dopamine concentrations in the hypothalamic-pituitary axis. One of the hypotheses of PDH in the dog is a decreased concentration of this neurotransmitter resulting in supraphysiologic secretion of ACTH. L-deprenyl is licensed for treatment of Canine PDH and geriatric senility in the USA. When it was first marketed, Anipryl was touted to be a safe efficacious alternative to mitotane, however multiple clinical trials by a variety of researchers have demonstrated minimal reduction of plasma cortisol levels in only 20% of treated dogs. The recommended initial dose of L-deprenyl is 1 mg/kg daily. If little or no response is seen after 2 months the dose is doubled. If after an additional 2 months, the clinical signs have not abated, alternative therapy should be employed. Since l-depenyl is degraded to amphetamine and metamphetamine, it is contraindicated in dogs with hypertension, congestive heart disease, renal disease and diabetes mellitus.

Because of its low efficacy, expense, the threat of inducing hypertension and the need for daily administration, use of L-deprinyl cannot be advocated by this author in the management of Canine PDH.

Bromocriptine {Parlodel}

Bromocriptine is an agent that increases dopamine concentrations in the brain, which may result in transient reduction of ACTH secretion by the adenohypophysis. Previous research has documented its ineffectiveness in Canine PDH patients.

Cyproheptadine {Periactin}

Cyproheptadine is an agent that exhibits anti-serotonin, anti-histaminicand anti-cholinergic properties. It was first FDA approved for humans in the treatment of urticaria and used extensively by veterinarians as an appetite stimulant in anorectic dogs and cats. Because it is thought that excessive serotonin secretion may result in excessive ACTH secretion, a serotonin blocker like cyprohepatadine may blunt ACTH secretion/release. In multiple clincal studies in dogs with PDH, the ability of cyproheptadine to induce amelioration of clinical signs was < 10%. Cyprohepatine has been use by this author with succes in combinaion with lowered doses of mitotane (~20 mg/kg, daily and then weekly) in a few selected PDH dogs that were deemed to be too debiltated to receive higher doses of mitotane. The dose of cyproheptadine ranged from 4-8 mg bid.

Summary

Although the clinician today has multiple therapeutic options in the medical management of Canine PDH, it appears that the "old standby" mitotane when used consevatively offers the advantages of efficacy, convenience of administration and reasonable cost to the pet owner. The patient should be thoroughly evaluated and the diagnosis solidly confirmed. It is imperative that firm client communication be established and frequent serial re-evaluations be conducted.

References

Alenza DP 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 et al. A comparison of the survival times of dogs treated with mitotane or trilostane for pituitary-dependent hyperadrenocorticism.J Vet. Int. Med. 2005 Nov.-Dec; 19(6):810-5.

Sieber-Ruckstuhl, NS et al, Cortisol, aldosterone, cortisol precursor, androgen and endogenous ACTH concentrtions in dogs with pituitary-dependent hyperadrenocorticism treated with trilostane. Domest. Anim. Endocrinology, 2006 Jul, 31 (1) 63-75.

Questions

1. Which therapeutic agent is cytotoxic to the adrenal cortex?

      a. Trilostane

      b. Ketoconazole

      c. Mitotane X

      d. Bromocriptine

2. Which therapeutic agent may be associated with the develpoment of hypertension?

      a. Cyproheptadine

      b. L-deprenyl X

      c. Mitotane

      d. Ketoconazole

3. Which therapeutic agent may be utilized as a short-term therapy to ameliorate clinical signs prior to surgical adrenalectomy in dogs with FAT?

      a. Ketoconazole X

      b. Cyproheptadine

      c. Bromocriptine

      d. L-deprenyl