Q & A: Managing Dogs with Cushing's Syndrome: Mitotane vs Trilostane?

I had attended your endocrine lectures at the annual meeting of the Minnesota Veterinary Medical Association last month and heard your great talk on how you workup and treat dogs with Cushing's syndrome.

My patient is a 9-year old, FS, Brittany Spaniel, weighing about 20 kg. She has a 6-month history of increased drinking, urination, hunger, and weight gain. 

On her routine blood tests, she had high serum alanine aminotransferase activity (ALT, 152 U/L; reference range, 12-118 U/L), high serum alkaline phosphatase activity (1998 U/L; reference range, 23-212 U/L). The serum cholesterol was also elevated  at 459 mg/dl (reference range, 110-320 mg/dl). I did a serum bile acids test, which was normal.

After I heard your lecture, I did a low-dose dexamethasone suppression test, with the following cortisol results. 

• Cortisol basal sample: 3.3 μg/dl (reference range, 1-5 μg/dl)
• Cortisol 4 hr: 2.2 μg/dl (reference range, 0.0-1.4 μg/dl)
• Cortisol 8 hr: 3.5 μg/dl (reference range, 0.0-1.4 μg/dl)

I know that the lack of cortisol suppression is diagnostic for Cushing's syndrome but the results do not differentiate between pituitary-dependent hyperadrenocorticism and functional adrenal tumor.

The owner is interested in doing an abdominal ultrasound and wants to pursue treatment eventually. So we are planning to set up an appointment for an ultrasound as the next step, but I did have some questions in terms of longer-term outcome for dogs with Cushing's disease. With some of our other suspected cases, the owners have not pursued pituitary-adrenal function testing or treatment due to cost, so I haven't actually had any that I've gone on to treat (I've also only been practicing since July 2010).  

1. If it is an adrenal tumor, you had recommend treating with trilostane for several weeks prior to surgical adrenalectomy, correct? Does this help to minimize post-operative complications?
2. And if they go on to surgery, and it comes back as benign, do most dogs do pretty well after long-term?
3. If the owner cannot afford/does not want to pursue surgery, can they do relatively well on trilostane (provided it isn't a carcinoma)?
4. If pituitary-dependent and treated with trilostane, do dogs do pretty well long-term? I wasn't sure about their long-term prognosis.

Thanks for you time in advance. I really appreciate any insight you're able to give me since again, we haven't really treated many dogs at my clinic.

My Response:

In answer to your questions:

1. Yes, if this dog has an adrenal tumor, I recommend treating with trilostane (Vetoryl, Dechra Animal Health) for 4-6 weeks prior to surgery (1,2). Controlling the high cortisol values prior to surgery helps to minimize post-operative complications, such as thromboembolism, poor wound healing, and infections.
2. If the dog has a benign adrenal tumor which is removed surgically, the dog would be cured (1). Post-operatively, she will go through a period of adrenal insufficiency (remember that the contralateral adrenal cortex is suppressed and will take a few weeks to start working again). During the immediate post-operative period, glucocorticoid supplementation should be initiated. The doses of the daily glucocorticoids should then be slowly tapered over the next 6-8 weeks, when they can generally be discontinued in most dogs.
3. If the owner cannot afford the cost of adrenalectomy or does not want to pursue surgery, most dogs can be controlled relatively well on trilostane (Vetoryl) but will never be cured (1-3). Overall, the prognosis with medical treatment is not as good as surgical treatment. If the dog has adrenal carcinoma, medical treatment will not prevent tumor growth, invasion into the vena cava, or metastasis (1).
4. If the dog has pituitary-dependent hyperadrenocorticism (PDH) and is treated with trilostane (Vetoryl), most dogs do well when treated with either mitotane (Lysodren) or trilostane. Studies have reported that there is no difference in survival between use of either of these drugs (4,5).

Botton line— We need a differentiating test to help guide our treatment recommendations and determine prognosis. Let me know when you have the results of the abdominal ultrasound on this dog.

Follow-up:

The abdominal ultrasound was just done this morning. Both adrenals were at the upper end of normal size —not nodular— and no masses found on either adrenal gland. 

So these imaging results are consistent with pituitary-dependent Cushing's disease, correct?

My Response:

Yes, your dog has PDH and can be treated with either trilostane or mitotane.

Remember to explain to the owner, however, the dog's problem lies in the pituitary gland, not the adrenal glands. Most of these dogs will have small pituitary tumors that tend to grow slowly over time (1,6,7). Others, however, have large pituitary tumors at time of diagnosis and some of these tumors expand more rapidly and can cause compression of the hypothalamus and lead to neurological signs.

Hopefully, your patient will be well-controlled with the medical treatment and will die of old age before the development of a large, invasive pituitary tumor becomes and issue.

References:

1. Melián C, M. Pérez-Alenza, D, Peterson ME. Hyperadrenocorticism in dogs, In: Ettinger SJ (ed): Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat (Seventh Edition). Philadelphia, Saunders Elsevier, 2010; pp. 1816-1840.
2. Ramsey IK. Trilostane in dogs. The Veterinary Clinics of North America Small Animal Practice 2010;40:269-283. 
3. Helm JR, McLauchlan G, Boden LA, et al. A comparison of factors that influence survival in dogs with adrenal-dependent hyperadrenocorticism treated with mitotane or trilostane. Journal of Veterinary Internal Medicine 2011; 25:251-260.  
4. Clemente M, De Andrés PJ, Arenas C, et al. Comparison of non-selective adrenocorticolysis with mitotane or trilostane for the treatment of dogs with pituitary-dependent hyperadrenocorticism. Veterinary Record 2007;161:805-809.
5. Kintzer PP, Peterson ME. Mitotane (o,p'-DDD) treatment of 200 dogs with pituitary-dependent hyperadrenocorticism. Journal of Veterinary Internal Medicine  1991;5:182-90. 
6. Ihle SL. Pituitary corticotroph macrotumors. Diagnosis and treatment. The Veterinary Clinics of North America Small Animal Practice 1997;27:287-297. 
7. Kent MS, Bommarito D, Feldman E, et al. Survival, neurologic response, and prognostic factors in dogs with pituitary masses treated with radiation therapy and untreated dogs. Journal of Veterinary Internal Medicine 2007;21:1027-1033.