Performing an ACTH Stimulation Test in Dogs Treated with Fludrocortisone (Florinef)

Fludrocortisone acetate (Florinef), a drug used as mineralocorticoid replacement in dogs with primary hypoadrenocorticism (Addison's disease) 

Thanks for your last post on "Confirming the Diagnosis of Addison's Disease after Treatment of an Adrenal Crisis." I found it to very helpful in managing these dogs in my practice. However, after reading it, I have 2 questions:

1. Are you at all concerned about the glucorticoid effect of fludrocortisone (Florinef) and its effect on the hypothalamic-pituitary-adrenal (HPA) axis?
2. Will fludrocortisone cross-react in the cortisol assay to falsely elevate the measured cortisol result? I've read that the cross reaction is limited to 6% or less — is that correct?
3. How long would I have to stop this drug before I do an ACTH stimulation test in a dog suspected of having Addison's disease?

My Response:

All of your questions are good ones. When we consider mineralocorticoid replacement for dogs with Addison's disease, we have two choices — fludrocortisone acetate (Florinef), administered orally on a daily basis, or desoxycorticosterone pivalate (Percorten-V) generally administered by injection every 3-5 weeks (1-3).

Fludrocortisone acetate is a synthetic adrenocortical steroid that has potent mineralocorticoid and glucocorticoid activities. Compared to cortisol, this drug has 125-times the mineralocorticoid activity and has 10-times the glucocorticoid activity. In this regard, fludrocortisone is very different than desoxycorticosterone pivalate, which is a pure mineralocorticoid agent and possesses no glucocorticoid activity.

The potent glucocorticoid activity of fludrocortisone explains why some dogs will develop polyuria and other signs of iatrogenic Cushing's syndrome, especially when on high daily doses of the drug. It also is the reason why many dogs treated with fludrocortisone do not require additional daily prednisone or prednisolone supplementation.

Because of its glucocorticoid activity, fludrocortisone will indeed cross-react in the cortisol assay to a some extent, as you noted. But even more importantly, it can suppress the HPA axis, especially when given in large doses (4,5), and may lead to a lowering of the basal cortisol concentration and blunting of the cortisol response to ACTH stimulation.

Ideally, we would do the ACTH stimulation test early in the course of the disease, before the dog has been treated for more than a few days with fludrocortisone but especially before the drug dosage has been increased to high daily levels. In these dogs, I simply withhold the drug for 24 hours prior to doing the ACTH stimulation test. That time interval will allow most of the drug to be eliminated so we don't have to worry about measuring the fludrocortisone in the cortisol assay.

If a dog has been on long-term and high-dose fludrocortisone therapy, it is always a good idea to switch to Percorten-V therapy for their mineralocorticoid supplementation for a month or two prior to ACTH stimulation testing. Because Percorten doesn't have any glucocorticoid activity, this might allow the HPA to recover if it has been chronically suppressed by the high-dose fludrocortisone therapy.

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, 2013;in press.
4. Otte C, Jahn H, Yassouridis A, et al. The mineralocorticoid receptor agonist, fludrocortisone, inhibits pituitary-adrenal activity in humans after pre-treatment with metyrapone. Life sciences 2003;73:1835-1845. 
5. Karamouzis I, Berardelli R, Marinazzo E, et al. The acute effect of fludrocortisone on basal and hCRH-stimulated hypothalamic-pituitary-adrenal (HPA) axis in humans. Pituitary 2013;16:378-385. 

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