Managing Addison's Dogs with Concurrent, Uncontrolled Diabetes

I have a 10-year old male Terrier dog named Scooter who now weighs in at 11 pounds (5 kg). He was originally diagnosed diabetes mellitus that we could not get regulated with Vetsulin, even at doses as high as 8 units twice daily. 

Scooter was subsequently diagnosed with with pituitary-dependent Cushing's disease and was treated with mitotane (Lysodren). Once we got the Cushing's disease under control, his daily insulin requirements fell to 3 units twice a day, and the diabetes was well regulated based on glucose curves done at my vet's hospital. However, after a few months of treatment with mitotane, it was apparent that Scooter had been severely overdosed with the medicine, which resulted in complete adrenal insufficiency and threw him into a severe Addison's crisis. It was a near death experience for him, but he has pulled threw and is now doing much better off of the mitotane and on treatment for his iatrogenic Addison's disease. 

Now we have spent the last 3 months trying to stabilize his iatrogenic Addison's disease and concurrent diabetes. Currently, he is on 2.5 mg of fludrocortisone (Florinef) twice day along with 1.25 mg of prednisone twice daily. The Florinef dose has had to be gradually increased to keep his serum electrolytes (sodium and potassium) within their proper ratio and ranges. Based on his last blood test, we may have to increase it yet again, since his serum potassium remains slightly high. 

To make matters even worse, his diabetes is now completely out of control, as evidenced by his intense thirst and excessive urinations with heavy amount of glucose in the urine. Serial blood glucose monitored done at my veterinarian's clinic confirms that the blood glucose readings remain very high throughout the day. We have gradually increased the insulin dose back up to 7 units twice daily, but it just doesn't seem to be working at all at this point. 

What do you recommend that I do? We need to get the Addison's disease controlled but as we have raised the doses of the Florinef and prednisone, Scooter's diabetes is getting worse! My vet has suggested that I transition Scooter from the Florinef tablets to Percorten injections in order to stabilize his serum electrolytes. He also told me that the Florinef contains some steroid activity which may be contributing to his high insulin doses.  Is the steroid in Florinef any less hard on him than the prednisone?   

Any advice would be greatly appreciated. 

My Response: 

With Scooter, we need to address both his poorly-regulated Addison's disease and his uncontrolled diabetes, as well as the increased thirst (polydipsia) and urination (polyuria). There is a lot going on with Scooter, so let's take one problem at a time.

Mineralocorticoid replacement: Florinef vs. Percorten-V? 
For mineralocorticoid replacement for dogs with Addison's disease, either oral fludrocortisone acetate (Florinef) or injectable desoxycorticosterone pivalate (DOCP; Percorten-V) can be used successfully (1-3).

In your dog, however, I would definitely make the switch to Percorten-V. Some dog's just don't respond very well to treatment with Florinef, and it's not uncommon for dogs to require increasing doses of daily Florinef over time to control the serum electrolyte concentrations (1-3). With high doses of Florinef, this can lead to signs of increased thirst and urination, and may also lead to problems with management of diabetes, as you are seeing in Scooter.

Since you are having problems controlling the serum electrolytes, I'd recommend starting with the label dose of 2.2 mg/kg, injected every 25-30 days (4). If this drug works to stabilize the serum sodium and potassium levels (and I expect that it will), then we can try to gradually lower the Percorten dosage after a few weeks to months (e.g., I generally try reducing the dose by 10% or so each month). Many dogs will maintain normal serum electrolyte levels on doses between 1-1.5 mg/kg per month, and a few will even need less (1,5).

Glucocorticoid supplementation in Addison's disease
Now let's next turn to your dog's glucocorticoid needs. Dogs with Addison's disease, either spontaneous or iatrogenic (that is, drug-induced, as it was in Scooter), will require replacement glucocorticoids (e.g., prednisone or prednisolone) in addition to the mineralocorticoid supplementation (1-3). Some dogs will do fine without any glucocorticoid supplementation, but the vast majority of dogs will feel better with a small daily dose of glucocorticoid administered daily. Since we know that these dogs cannot secrete normal amounts of cortisol, it certainly makes a great deal of sense to use low-dose glucocorticoid replacement.

Unfortunately, many dogs with Addison's disease are treated with too much glucocorticoid. Remember that our goal with glucocorticoid supplementation is to provide the same amount of steroid that the dogs would normally produce if their adrenals had not failed.

For dogs, the daily glucocorticoid maintenance dose for prednisone is only 0.1-0.2 mg/kg/day (3), so that calculates out to only 0.5-1.0 mg per day for Scooter, quite a bit lower that what you are currently giving (2.5 mg per day). That would certainly be enough to cause an increased thirst by itself, but would also contribute to glucocorticoid-induced insulin resistance, making the diabetes uncontrollable despite the higher insulin doses.

Therefore, we should try to lower the prednisone dosage first down to 1.0 mg once daily (or divided). If he is doing well clinically (i.e., normal appetite and no vomiting), then the dose can be lowered even further, down to 0.5 mg per day. Prednisone or prednisolone are available in 1-mg tablets, as well as an oral solution, making it possible to administer these smaller dosages (6,7).

Florinef also contains significant glucocorticoid activity
In addition to the fact that Addison's dogs are commonly overdosed with prednisone, it's very important to realize that fludrocortisone acetate also possesses moderate glucocorticoid activity, as well as having marked mineralocorticoid potency (2,3). By comparison, fludrocortisone has 10-times the glucocorticoid activity and 125-times the mineralocorticoid activity of cortisol, the glucocorticoid hormone secreted by the adrenal gland. In this regard, fludrocortisone is very different than Percorten-V, which possess no glucocorticoid activity (2,3).

For the dog with Addison's disease, a glucocorticoid is a glucocorticoid —it makes no difference to Scooter if this glucocorticoid activity comes from prednisone or from the Florinef.  This potent glucocorticoid activity of fludrocortisone explains why some dogs will develop polydipsia and polyuria, common side effects associated with higher-dose glucocorticoid treatment in dogs (8). This is another reason why we need to get Scooter off of the Florinef and switch to the Percorten-V.

Glucocorticoid-induced insulin resistance
In all likelihood, the reason for Scooter's poorly controlled diabetes is related to insulin resistance associated with glucocorticoid excess (9,10). By stopping the Florinef and providing mineralocorticoid replacement with Percorten-V instead, we will remove one source of excess glucocorticoid. Lowering his daily prednisone dose will also help.

As we remove the cause of the insulin resistance, the dose of insulin will again fall. You should monitor Scooter closely during this period to ensure that insulin overdosage and hypoglycemia do not occur, and lower the insulin dose as needed.

Don't forget to rule out urinary tract infections
Finally, don't forget that diabetic dogs, no matter what the cause, will commonly develop urinary tract infections. Think about it: a bladder full of sugar-laden urine is a perfect breeding ground for bacteria to thrive! Such urinary tract infections will also commonly contribute to insulin resistance (9,10) but can also lead to kidney failure, if the infection ascends from the bladder up to the kidneys.

For this reason, I always recommend checking a complete urinalysis and urine culture in all dogs (and cats) with insulin resistance. However, even if the diabetes is well-controlled, I still recommend doing a urinalysis with culture twice yearly in all of my diabetic patients.

References: 

1. Kintzer PP, Peterson ME. Treatment and long-term follow-up of 205 dogs with hypoadrenocorticism. J Vet Intern Med 1997;11:43-49. 
2. Church DB. Canine hypoadrenocorticism In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;156-166.
3. Kintzer PP, Peterson ME. Canine hypoadrenocorticism In: Bonagura JD, Twedt DC, eds. Kirk's Current Veterinary Therapy, Volume XV. Philadelphia: Saunders Elsevier, 2014; pp 233-237.  
4. Lynn RC, Feldman EC, Nelson RW. Efficacy of microcrystalline desoxycorticosterone pivalate for treatment of hypoadrenocorticism in dogs. DOCP Clinical Study Group. J Am Vet Med Assoc 1993;202:392-396. 
5. Bates JA, Shott S, Schall WD. Lower initial dose desoxycorticosterone pivalate for treatment of canine primary hypoadrenocorticism. Aust Vet J 2013;91:77-82. 
6. Peterson ME: Treating small-breed Addison's dogs with low doses of prednisone or prednisolone. Animal Endocrine Clinic blog, December 14, 2013. 
7. Plumb, DC. Plumb's Veterinary Drug Handbook. Seventh Edition, Wiley-Blackwell. 2011.
8. 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;1816-1840.
9. Hess RS. Insulin resistance in dogs. Vet Clin North Am Small Anim Pract 2010;40:309-316. 
10. Peterson ME. Diagnosis and management of insulin resistance in dogs and cats with diabetes mellitus. Vet Clin North Am Small Anim Pract 1995;25:691-713.  

Treating Small-Breed Addison's Dogs with Low Doses of Prednisone or Prednisolone

My 4-year old Toy Poodle was diagnosed with atypical Addison's disease about 6 weeks ago. She weighs 11.8 lbs and is taking 1.25 mg of prednisolone per day. She is not receiving any mineralocorticoid supplementation (i.e., Florinef or Percortin-V) for now since her serum sodium and potassium levels are in the normal range. We will continue to monitor that because we know that that might change and mineralocorticoids will have to be added to her treatment.

For her glucocorticoid needs, we are using a 5-mg tablet of prednisolone that we cut into quarters to administer a 1.25-mg dose each day. This is extremely tricky, and there is probably never a day that she gets an exact dose because the tablets do not cut without some crumbling.

So I have two main questions:

1. First, my dog has developed a ravenous appetite and finishes her meals very quickly. Normally, she has a picky appetite. I know that you generally recommend giving these dogs a much lower dosage, and that a lower dosage would be better for her overall health since she will be on this daily dosage for the rest of her life. Should her prednisolone dosage be lowered to help with the appetite issue? 
2. Second, is there any other tablet or form of prednisolone that would be easier for us to administer to her so that she gets the proper amount each day? The 5-mg tablet just isn't working very well for us. 

Thank you for your help.

My Response:

The glucocorticoid replacement dose I use for prednisone or prednisolone in dogs with Addison's disease is 0.1-0.2 mg/kg/day. So at 11.8 pounds (5.4 kg), that calculates out to be only 0.5 mg/day, up to a maximum dose of 1.0 mg/day. So if you are giving your small dog 1.25 mg/day, that means you are giving too much of the drug. That would certainly be enough to induce iatrogenic Cushing's disease, as reflected by the increased appetite.

In dogs, prednisone is converted to prednisolone within the body. So basically, these two glucocorticoids can be used interchangeably.

I would try to lower the daily prednisone/prednisolone dose down to 0.5 mg each day. Administrating too much glucocorticoid will cause increased hunger (as you see in your dog).  Overdosage of prednisone, prednisolone or any other glucocorticoid can also lead to lethargy, weight gain, enlargement of the abdomen, muscle atrophy, and muscle weakness. Decreasing the dose of the prednisone or prednisolone should help prevent any of these problems.

Fig. 1: Prednisone is available as a 1-mg tablet

Fig 2: PrediapredOral prednisolone
liquid (1 mg/mL) 

Prednisone tablets are available as 1-mg and 2.5-mg sizes, which can be helpful in dosing small to medium-sized dogs (Figure 1).

In addition, both prednisone and prednisolone are available as a syrup/oral liquid or solution, available as a 1 mg/mL concentration (Figure 2).  Examples of liquid prednisolone products include Pediapred® (Celltech Pharm); Millipred® (Laser); Orapred® (Sciele); Veripred® 20 Hawthorn); and Flo-Pred® (Taro). For prednisone, Intensol® Concentrate (Roxane) oral solution is available.

All of these formulations are human-labeled products so your veterinarian may not be familiar with them. Your local pharmacy will know about them, however.

Either way, I'd get either the 1-mg tablets and give half a tablet a day. Or use a liquid formulation (1 mg/mL) and give 0.5 mg (1/2 mL per day).

References:

1. Plumb, DC. Plumb's Veterinary Drug Handbook. Seventh Edition, Wiley-Blackwell. 2011.

Tapering the Glucocorticoid Dose in Dogs with Addison's Disease

My dog is a 2-year old, male Saint Bernard., weighing almost 145 pounds (75 kg). He was just diagnosed with Addison's disease and was treated with an intramuscular injection of Percorten-V (65 mg) and started on oral prednisone (30 mg per day —15 mg in AM and 15 mg in PM). 

As my veterinarian and I are learning more about treating Addison's disease in dogs, we realize that he is now suffering from cortisol overload. His current signs include lethargy, frequent urinations and incontinence, and excessive hunger and thirst. 

After reading your work, we know that we should lower his daily prednisone dose, probably down to 5 mg per day. Considering that he hasn't been on it for even a week, I've started to taper the dose fairly rapidly. His appetite remains fine but he now has some diarrhea. 

Here is how we've begun lowering the daily prednisone dosage: 

• Day 1-4: 15 mg twice a day (AM and PM)
• Day 5-6: 15 mg in AM, none at night 
• Day 7: 10 mg in AM, none at night  

Can I just give him 10 mg today and begin just 5 mg tomorrow? Or is that too much danger without tapering? 

My Response: 

You should be fine to lower the dose to 5 mg per day now. Remember that a 5-mg dose is the human replacement dose, so we are still giving the amount that you or I would need to survive. So even for your large breed dog, that will still be plenty!

As far as how fast to taper, you can base that on his appetite. As long as he is eating well without vomiting, you should be fine to taper the dose down, especially since he has also received the mineralocorticoid supplementation (i..e, Percoten-V).

You might want to check his serum chemistry panel and electrolytes soon, just to ensure that the serum sodium and potassium are back within the reference range limits.

Follow-up Question: 

I have lowered the prednisone dose to 5 mg once daily in the AM, which he has been on for the last week. He seemed fine for the first few days on this new dose (good appetite, no vomiting or diarrhea), but more recently he has been pretty lethargic.  

Could this be because he only gets prednisone once a day? Can I experiment and give a divided dosage, with 2.5 mg in the AM and another 2.5 mg in the PM? 

Follow-up Response: 

Yes, dividing the dose of the prednisone may help and certainly can't hurt.

Remember, however, that dogs with Addison's disease have both glucocorticoid and mineralocorticoid deficiencies. Some of his lethargy could be related to the fact that his mineralocorticoid dosage might need to be adjusted.

Therefore, it's important to have his serum chemistry panel and electrolytes rechecked. After the first injection of the Percorten-V, I recommend rechecking the serum electrolytes at 10-14 days and then again at 25-30 days, just before the second injection.

References:

1. Kintzer PP, Peterson ME. Treatment and long-term follow-up of 205 dogs with hypoadrenocorticism. J Vet Intern Med 1997;11:43-49. 
2. Church DB. Canine hypoadrenocorticism In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;156-166.

How to Adjust the Glucocorticoid Dose in Dogs Treated for Addison's Disease

Zoe, a female Rat Terrior with Addison's disease

Zoe is a 4-year-old 17.5 lb (8.0 kg) female Rat Terrier who was diagnosed with Addison’s disease 7 months ago. She receives Percorten injections every 28 days, along with 5 mg of prednisone daily.

She is active and playful but is always famished. Her water intake has also increased on the medication, but she isn't showing any incontinence.

My major concern is that she has lost her hair on all four legs and belly, and now it is progressing up her shoulders, hind quarters, and to her head!

Her lab tests are within normal range according to her vet, who wants to take a wait and see approach. I thought she may be getting too much prednisone, but my vet is afraid to cut back for fear of her ”crashing” and developing an adrenal crisis.

Any thoughts on this? Zoe could sure use the help before all the other dogs start teasing her!

My Response:

Based on the clinical features of increased appetite, increased thirst, and hair loss, it is most likely that Zoe is being overdosed with the prednisone and has developed iatrogenic Cushing's syndrome (glucocorticoid excess).

In support of that, the daily maintenance dose of prednisone or prednisolone in dogs with Addison's disease is only 0.1-0.2 mg per kg per day. So at 8 kg (Zoe's body weight), that calculates out to 0.8 mg to 1.6 mg per day. This is only 15-30% of the dose that she is now receiving every day. When you think about that, it's no wonder that she is showing signs of glucocorticoid (prednisone) excess!

Remember that the adrenal glands in dogs with Addison's disease have failed so we must replace the missing hormones. These dogs will require lifelong replacement with both a mineralocorticoid (e.g., Percoten-V) and glucocorticoid (e.g., prednisone) hormone.  Both the mineralocorticoids and glucocorticoid dosages must be individualized for that particular dog.

The dosage of the mineralocorticoids can best be determined by monitoring the serum electrolyte concentrations (sodium, chloride, and potassium); the dosage is increased to decreased, as needed to normalize the circulating electrolyte concentrations.

Prednisone (or prednisolone), a common glucocorticoid used to treat dogs with Addison's disease, is ideally started at physiological dosages (0.1-0.2 mg/kg/day). This dosage should be adjusted up or down as needed, as some dogs show exquisite sensitivity to the adverse prednisone’s effects. The amount of prednisone that enhances the dog’s well-being (normal activity level and appetite) but prevents side effects (increased thirst, panting, polyphagia, hair loss) may be very small.

If a dog's serum electrolytes are normal on Percorten replacement therapy, dogs with Addison's disease aren't going to develop serious adrenal crisis, even if the prednisone dosage is lowered too much for a day or two.

My Bottom Line: 

Your dog is receiving too much glucocorticoid supplementation. With time, even a mild overdose will lead to signs of iatrogenic Cushing's syndrome, which may include hair loss, increased thirst and urination, and increased appetite. I'd taper the dose down to 1 mg per day over the next couple of weeks. The prednisone is available as a 1-mg tablet, which would make dosing much more convenient.

If the hair loss doesn't resolve after two to three months, I'd recommend that your veterinarian check a serum thyroid panel. Some dog's with Addison's disease will also develop concurrent hypothyroidism, which commonly leads to hair loss in dogs.

References:

1. Church DB. Canine hypoadrenocorticism. In: Mooney CT, Peterson ME, eds. BSAVA  Manual of Canine and Feline Endocrinology. 3rd ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2004; 172-180.
2. Kintzer PP, Peterson ME. Treatment and long-term follow-up of 205 dogs with hypoadrenocorticism. J Vet Intern Med 1997;11:43-49.
3. Klein SC, Peterson ME. Canine hypoadrenocorticism: part I. Can Vet J 2010;51:63-69.
4. Klein SC, Peterson ME. Canine hypoadrenocorticism: part II. Can Vet J 2010;51:179-184.

Air Travel with a Dog with Addison’s Disease

I have a 10-year old, 25 kg, female lab who was diagnosed with Addison’s disease about 5 years ago. She has been well-controlled on oral Florinef (0.3 mg, twice daily) and prednisone (2.5 mg, once daily).

I am moving from Canada (Nova Scotia) to Europe and do not want to leave her behind, if it is at all possible.  Do you think that I could fly her to Europe with me or that is not an option?

 I'll do whatever you recommend and feel is best for my dog!

My Response: 

As you have proven in your dog, primary hypoadrenocorticism (Addison's disease) is a readily treatable disease with an excellent prognosis, provided that proper monitoring and treat­ment is maintained for life. Dogs on adequate maintenance therapy should expect to lead rela­tively healthy lives, with no obvious impairment to exercise or other usual activities (1,2).

Therefore, if your dog's Addison's disease is well-controlled, flying should not be a problem. Before you go, I'd repeat a serum chemistry profile, which should include tests for kidney function (urea nitrogen and creatinine) as well as serum electrolytes (sodium, potassium). We want to make sure that her Addison's disease is perfectly regulated the day she leaves for her new home in Europe.

However, it is vitally important remember that these dogs have no adrenocortical reserve and cannot secrete additional cortisol in times of stress, like normal animals would be expected to do. Therefore, any non­adrenal illness or stressful event (such as air travel) needs to be matched with an appropriate increase in the amount of gluco­corticoid administered.

So what does that mean in practical terms for your dog? Because of the stress of the air travel, however, I would recommend that you increase the glucocorticoid supplementation (i.e., the prednisone) on the day that you travel. You are giving a relatively low maintenance dose of prednisone now (0.1 mg/kg/day). I'd recommend that you double this daily dose on the day you travel and continue the higher dose (as needed) for 2-3 days once you arrive.

References:

1. Kintzer PP, Peterson ME. Treatment and long-term follow-up of 205 dogs with hypoadrenocorticism. J Vet Intern Med 1997;11:43-49. 
2. Church DB. Canine hypoadrenocorticism In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;156-166.

Managing Urinary Incontinence in Dogs Treated for Addison's Disease

I am the owner of Abbie, a 55 pound (25 kg) female spayed dog with Addison’s disease. She was diagnosed in January of this year; Abbie has been treated with daily prednisone (1.5 mg/day), as well as an intramuscular injection of Desoxycorticosterone pivalate (DOCP; Percorten-V, Novartis) given every 3 weeks (1.8 mg/kg).

All of Abbie's clinical signs have resolved but our problem is that she now has an ongoing issue with urinary incontinence. I just do not know whether this is due to too much or not enough prednisone or DOCP. We have tried increasing the prednisone dose for a day but it doesn't appear to help. Her routine serum chemistry panel done this week was normal with a sodium:potassium ratio of 35 (serum sodium, 149 mEq/L; serum potassium, 4.2 mEq/L).

This has been a rough ride for Abbie and us. There is not a lot of literature I can find. I would appreciate ANY helpful suggestions you may have.

My Response:

You don't mention if Abbie is drinking and urinating more or if she is only showing urinary incontinence.  Many dogs treated for Addison's disease will develop polyuria and polydipsia (increased thirst and urination) secondary to the drug they receive (1-3). Some of those dogs will develop an overflow incontinence (i.e., the bladder overfills and the dogs will leak urine, especially overnight when they haven't been walked for a few hours).

Why do dogs treated for Addison's disease develop a increased thirst and urination?
In dogs, treatment with any form of glucocorticoid (e.g., prednisone, prednisolone, methyprednisonlone, cortisone, dexamethasone) can lead to a form of nephrogenic diabetes insipidus (3). In simple terms, this means that the kidneys loose the ability to concentrate the urine, and this can result in large volumes of urine being produced.

To avoid this complication, it's very important not to give too much of any of these glucocorticoids — for prednisone or prednisolone, the maintenance dosage to replace the missing glucocorticoid hormones is about 0.1 mg/kg/day (or about 2.5 mg/day in Abbie) (1).  So, for Abbie, her dosage of 1.5 mg per day is not at all high, in fact, you might think that raising it could help — unfortunately, it could make her feel better if she is deficient, but giving more glucocorticoid will never help polyuria or urinary incontinence.

Treatment or control of polyuria, polydipsia or incontinence in dogs treated for Addison's disease
Unfortunately, some dogs (like Abbie) are simply overly sensitive to the "correct" dosages of glucocorticoid which are being given. Management of these dogs can be complicated, but may include one or more of the following steps (3):

1. Stopping all salt supplementation (if the dog is receiving any NaCl supplementation).

2.  Reducing the glucocorticoid dosage or stopping administration completely, if possible. Many dogs will do fine getting prednisone every 2 or 3 days. In some dogs, glucocorticoids can be discontinued without any ill effects and mineralocorticoid replacement alone will adequately control signs of hypoadrenocorticism.

3.  If glucocorticoid is required to prevent signs of hypoadrenocorticism, the glucocorticoid can be switched from prednisone or prednisolone to either cortisone acetate or methyprednisonolone (Medrol).

Cortisone acetate is a synthetic steroid that has equipotent glucocorticoid and mineralocorticoid activity (1,4). Therefore, it will provide more mineralocorticoid activity than other synthetic glucocorticoids, such as prednisone or prednisolone. In addition, its shorter half-life and lower overall activity means it is less likely to create polyuria or polydipsia. Generally, a daily dose of approximately 1.0 mg/kg provides adequate glucocorticoid coverage (1).

Methyprednisonolone (Medrol), the 6-methyl derivative of prednisolone, is also associated with less polyuria than that seen with prednisone or prednisolone (3). The daily maintenance dosage for this glucocorticoid is similar to prednisolone (0.2 mg/kg).

4. If all of the above fails, one can reduce the monthly dosage of DOCP and evaluate the effect.

5. Finally, if on Florinef instead of DOCP, then a switch to Percorten-V may solve the problem (obviously, this is not the case for Abbie).

Urinary incontinence without any increase in thirst
If Abbie's thirst is completely normal, however, it certainly is possible that she has estrogen-responsive incontinence (not uncommon in spayed female dogs) or a urinary tract infection (5,6). If you haven't already done so, I'd recommend that your veterinarian do a complete urinalysis and urine culture. If an infection is found, administration of an appropriate antibiotic may cure the incontinence.

References and Suggested Reading:

1. Church DB. Canine hypoadrenocorticism In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;156-166.
2. Kintzer PP, Peterson ME. Treatment and long-term follow-up of 205 dogs with hypoadrenocorticism. J Vet Intern Med 1997;11:43-49.
3. Nichols R, Peterson ME. Investigation of polyuria and polydipsia In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;215-220.
4. Plumbs DC. Plumb's Veterinary Drug Handbook. Seventh edition. Wiley-Blackwell; 2011.
5. Forsee KM, Davis GJ, Mouat EE, et al. Evaluation of the prevalence of urinary incontinence in spayed female dogs: 566 cases (2003-2008). J Am Vet Med Assoc. 2013;242(7):959-962.  
6. Stöcklin-Gautschi NM, Hässig M, Reichler IM, et al. The relationship of urinary incontinence to early spaying in bitches. J Reprod Fertil (Suppl) 2001;57:233-236. 

Interpreting the ACTH Stimulation Test in Dogs with Suspected Addison's Disease

I am hoping you may be able to offer me some insight/information about testing for hypoadrenocorticism (Addison's disease) in dogs.

I have a 3-year old male neutered German Shorthaired Pointer. Since April, Luke has been steadily losing weight despite no changes in his diet. He has also seemed "off" (slightly lethargic, just not himself) and had slight changes in gait from time to time. He then would seem better and back to his normal self.

In November, he began having chronic diarrhea and losing weight at a much more rapid pace. He has now last 20 pounds, going down from 85 to 65 lbs. He has had an ultrasound, exocrine pancreatic insufficiency test, full tick panel, fecal tests, serum thyroid tests, and complete blood count and serum chemistry panel. No clinically significant abnormalities have been detected in any these tests.

He had no response to treatment with Panacur, Proviable, or Flagyl. He responded to high-dose prednisone, but then when we tapered the dose, his clinical signs returned. He was off prednisone for 3 days before doing the first ACTH stimulation test, which came back out of range:

• Basal cortisol: 1.2 μg/dl (Reference range, 1.0-6.5 μg/dl)
• ACTH-stimulated cortisol:  3.6 μg/dl (Reference range, 6.5-18.0 μg/dl)

We waited 3 weeks to do the second ACTH stimulation test which came in within the normal range. These results were as follows:

• Basal cortisol: 1.3 μg/dl  
• ACTH-stimulated cortisol:  9.5 μg/dl  

Based on this information, is it possible he has Addison's disease? Or is the fact that his stimulated cortisol value came back within the normal range on the second test just an indication that the prednisone was affecting the results in the first ACTH stimulation test?

I have been doing a lot of research on this because he seems to have many symptoms that match up with Addison's disease. Some things I've read have said that it is possible in atypical Addison's disease to have varying test results. Other things have disagreed. This is why I am trying to contact someone who specializes in this field. In your experience, is this something you have encountered?

I really appreciate any insight you may be able to give me. Thank you for your time.

My Response:

Causes of Hypoadrenocorticism in Dogs
In dogs, as in man, hypoadrenocorticism can be classified into primary and secondary subtypes (1-6). With primary hypoadrenocorticism, the primary disease process is in the adrenal glands themselves. In secondary hypoadrenocorticism, the problem lies in the pituitary gland where ACTH is secreted; with secondary forms of the disease, the cortisol secretion goes down because of too little ACTH secretion from the pituitary gland.

The most common cause of secondary hypoadrenocorticism is iatrogenic (induced inadvertently by the veterinarian) resulting from overly rapid discontinuation of long-term and/or high-dose glucocorticoid therapy. Very rare spontaneous or natural causes in the dog include pituitary or hypothalamic lesions (e.g., large destructive pituitary tumors) or idiopathic isolated ACTH deficiency.

In addition to primary Addison's disease or hypoadrenocorticism  (the failure of the adrenal glands to produce both glucocorticoid and mineralocorticoid hormones), and secondary (which is the failure of the pituitary gland to secrete ACTH, a hormone which stimulates the adrenal glands), a third type of hypoadrenocorticism has been described — "atypical" Addison's disease (7-9). This is a confusing term, which I believe can and should not be avoided because it really does not describe a definitive diagnosis.

Almost all of these dogs diagnosed with atypical Addison's can be classified into primary or secondary forms of the disease with proper diagnostic testing (10-11). In addition to ACTH stimulation testing, this may include  determination of circulating ACTH concentrations (the pituitary hormone). In some dogs, repeating the ACTH stimulation test and measuring the basal and ACTH-stimulated concentrations of aldosterone, a mineralocorticoid hormone is helpful.  Properly classifying the dogs into primary and secondary subtypes helps us better predict the needs for long-term treatment.

In  this dog, there is no reason to go any further because the last ACTH stimulation test completely rules out all forms of Addison's disease — primary, secondary, and atypical hypoadrenocorticism (see below).

ACTH Stimulation Testing
In normal dogs, administration of a dose of ACTH generally produces a rise in serum cortisol to values greater than 6 μg/dl. In contrast, dogs with hypoadrenocorticism (typical or atypical Addison's disease) have an absent or blunted response to ACTH administration. Basal and post-ACTH serum cortisol concentrations are less than 1 μg/dl in over 75% of dogs and less than 2 μg/dl in virtually all dogs with primary hypoadrenocorticism (1-6).

Although the post-ACTH serum cortisol concentration may be as high as 2 to 3 μg/dl in a few dogs with naturally occurring secondary hypoadrenocorticism (due to pituitary ACTH deficiency), the great majority of these dogs also have ACTH-stimulated cortisol concentrations of less than 2 μg/dl.

When borderline results occur (post ACTH cortisol concentrations between 2 and 6 μg/dl), the first thing that one must consider is the recent use of glucocorticoids, which would act through the negative-feedback effect to suppress circulating ACTH and cause temporary and mild atrophy of the adrenal cortical cells that secrete cortisol. That is likely what happened in your dog.

My Bottom Line

So in your dog, the first ACTH stimulation test is borderline for Addison's, but the cortisol response is high enough to make it unlikely. Remember that the dose given for Addison's disease would only be between 2.5-5 mg per day (around 0.1 mg/kg/day), so anything higher than that dose would suppress pituitary ACTH secretion and could lead to blunting of the cortisol response.

In accord with that, his second ACTH stimulation test done 3 weeks later is completely normal, totally excluding Addison's disease.

It's time to look for another disease. Consider an abdominal ultrasound or endoscopy next to better define your dog's gastrointestinal disease.

References:

1. Church DB. Canine hypoadrenocorticism. In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. 3rd ed. Quedgeley, Gloucester: British Small Animal Veterinary Assoc, 2004; 172-180.
2. Feldman EC, Nelson RW. Hypoadrenocorticism (Addison’s disease). In: Canine and Feline Endocrinology and Reproduction, 3rd ed. Philadelphia: Saunders, 2004; 394-439.  
3. Kintzer PP, Peterson ME. Primary and secondary canine hypoadrenocorticism. Veterinary Clinics of North American Small Animal Practice 1997;27:349-357. 
4. Peterson ME, Kintzer PP, Kass PH. Pretreatment clinical and laboratory findings in dogs with hypoadrenocorticism: 225 cases (1979-1993). Journal of the American Veterinary Medical Association 1996; 208: 85-91.
5. Klein SC, Peterson ME. Canine hypoadrenocorticism: part I. Canadian Veterinary Journal 2010;51:63-69.
6. Klein SC, Peterson ME. Canine hypoadrenocorticism: part II. Canadian Veterinary Journal 2010;5:179-184.
7. Bartges JW, Nielson DL. Reversible megaesophagus associated with atypical primary hypoadrenocorticism in a dog. Journal of the American Veterinary Medical Association 1992; 201: 889-891.
8. Lifton SJ, King LG, Zerbe CA. Glucocorticoid deficient hypoadrenocorticism in dogs: 18 cases (1986-1995).  Journal of the American Veterinary Medical Association1996;209:2076-2081. 
9. Sadek D, Schaer M. Atypical Addison’s disease in the dog: A retrospective survey of 14 cases. J Am Anim Hosp Assoc 1996;32:159-163. 
10. Mueller C, Boretti FS, Wenger M, et al. Investigation on the aldosterone concentration before and after ACTH application in 44 dogs with hypoadrenocorticism. Kleintierpraxis 2007;52:216-224.
11. Insights into Veterinary Endocrinology Blog. Atypical Addison's Disease in Dogs with Gastrointestinal Signs. April 14, 2011.