Q & A: Atypical Cushing's Disease in an 11-Month-Old Dog

My patient is a 4-year-F/S Shetland sheepdog who has been treated with melatonin and flax seed oil since she was 11-months-old.  Her main clinical sign was a chronic decrease in appetite, which started at 8-months of age when she had her first heat cycle.

Vaginal smears and cytology at that time was consistent with early estrus. She did not have noticeable bleeding, but she is very "tidy" and licks herself a lot.   No polydipsia or polyuria was noted, and her hair coat has always been completely normal. Results of her physical examination were completely normal.

Two months later, we decided to spay her in case there was any connection between going into heat and the lack of appetite. A CBC and serum chemistry panel done before surgery were both normal. Routine ovariohysterectomy was performed. Examination of the uterus showed that it was more turgid than normal, but it did not show any evidence for pyometra or mucometra.  

After surgery the dog became totally anorexic and vomited multiple time. She was referred to a local internal medicine specialist for workup. Based upon results of abdominal ultrasound, endoscopic exam and intestinal/stomach biopsies, a diagnosis of helicobacter pylori infection and inflammatory bowl disease (IBD) was made.  Treatment with amoxicillin, metronidazole, and a food allergy diet was instituted, which quickly cleared up the intestinal signs and anorexia. 

Because of the finding of bilateral adrenomegaly on abdominal ultrasound, however, an ACTH stimulation test was also performed shortly after surgery. Serum samples for an adrenal panel were submitted to the University of Tennessee Clinical Endocrinology Service Laboratory. 

Atypical Cushing's disease was diagnosed on the basis the finding of a high baseline estradiol concentration (105.1 pg/ml; reference range, 30-69. pg/ml) as well as a high ACTH-stimulated estradiol value (111.1 pg/ml; 28-69 pg/ml). The other sex steroids tested (including 17-hydroyxprogrogesteone) were all within normal limits.  Based on these results, she was started melatonin and flax seed oil for the atypical Cushing's syndrome.  

Now 3 years later, the owner is asking me if her dog really needs the melatonin and flax seed oil.  She has declined the offer of retesting the sex steroid panel on several occasions. The owner says her dog has been normal in every way, except for mild lethargy during the morning after she gives the melatonin.  The owner believes the melatonin is causing sleepiness.

My questions are:

1. Do you think this dog has atypical Cushing's disease? It doesn't appear that she ever had any clinical signs of the disease.
2. If we stop the melatonin, how would we determine the need to go back on the drug?

My Response:

I really must admit that I've heard it all now — diagnosing atypical Cushing's disease in an 11-month old dog with the primary complaints of anorexia, inflammatory bowl disease, and helicobacter!

You cannot base a diagnosis of Cushing's disease — typical or atypical — on the finding of large adrenal glands on an ultrasound exam. This dog was severely ill when the ultrasound and ACTH stimulation test were performed. One would expect a sick dog to have a "stress" response, which would include increased secretion of pituitary ACTH leading to increased cortisol section. With chronic illness and continued stress, bilateral adrenocortical hyperplasia would be an expected finding as cortisol hypersecretion continues.  

Cushing's syndrome (either typical or atypical disease) is a clinical diagnosis and must be based primarily on the dog's clinical features and physical examination findings. Dogs with Cushing's syndrome do NOT have anorexia and vomiting. They have a good to increased appetite, together with polyuria, polydipsia, hair loss, potbelly, and weakness. In my opinion, it was totally inappropriate to even test the dog for atypical Cushing's disease, given the total lack of any clinical features of the disease. Plus, this disease develops in older dogs, not dogs that are less than a year of age.

Bottom line: 

• In any dog with chronic nonadrenal disease, the finding of enlarged adrenal glands with abdominal ultrasonography is not an uncommon finding due to the chronic stress of illness. 
• This finding of "big adrenals" can never be used to confirm a diagnosis of Cushing's syndrome  — be it typical or atypical hyperadrenocorticism. 
• Diagnosis must be based on a combination of the typical clinical features of Cushing's disease together with results of standard pituitary function testing (i.e., low-dose dexamethasone suppression and ACTH stimulation testing).

I agree totally with the owner here. I would stop the melatonin and flax seed oil and monitor the clinical response. Why monitor for hormones when we don't even know what the elevations mean? We see many dogs tested with the sex steroid panel that have high serum estradiol values when the other hormone concentrations are normal.

In fact, I rarely see ANY dog tested that has normal values for estradiol. I can only assume that the labor seen a high incidence of false-positive results.

In support of my clinical experience, a recent research paper published by the head dermatologist at the University of Tennessee, College of Veterinary Medicine showed that serum estradiol concentrations varied considerably in clinically normal dogs (1). They concluded in this study that the finding of high estradiol concentrations alone cannot be used to diagnose atypical Cushing's syndrome, because of the high variability of these hormone results.

References:

Frank LA, Mullins R, Rohrbach BW. Variability of estradiol concentration in normal dogs. Vet Dermatology. 2010; 21:490-493.