Atypical Hypoadrenocorticism In A Cat

My patient is an 8-year old, female DSH cat that has been on oral megestrol acetate (Ovaban) for the last 6 years. This progestin was prescribed by another veterinarian for behavioral problems (i.e., inter-cat aggression, and inappropriate urination). In addition to this cat, two other cats in the household have also been on the drug for the same prolonged period.

This cat presented for signs of anorexia, lethargy, and weight loss of 6-weeks duration, all of which started after the owner abruptly stopped the megestrol in all three cats. Fortunately, the other two cats in the household remain clinically normal after stopping the drug.

In this sick cat, routine blood testing was fairly unremarkable, with normal renal function and serum electrolytes. An abdominal ultrasound revealed a hyperechoic liver (thought to be due to mild hepatic lipidosis secondary to anorexia) and small adrenal glands.

Because of the clinical signs and small adrenals, an ACTH stimulation test was performed by collecting serum for cortisol determination before, 1 and 2 hours after the intravenous injection of 0.125 mg cosyntropin (Cortrosyn). After the ACTH stimulation test was completed, we administered 1 mg of dexamethasone, IM, and the cat ate some food about an hour later.

The results of the ACTH stimulation test showed undetectable serum concentrations of cortisol, both before and after ACTH stimulation. The cat’s appetite is again very poor 2 days after the glucocorticoid injection.

My questions are the following:

1. The low cortisol levels are diagnostic for hypoadrenocorticism. However, there have been no electrolyte abnormalities. Is this atypical hypoadrenocorticism in a cat?
2. If so, is this atypical Addison’s disease caused by the chronic administration of megestrol?
3. Should I continue the glucocorticoids if this cat continues to respond to them?
4. Do I still need to provide mineralocorticoid treatment (Florinef or Percorten) if electrolytes remain normal?

My Response

Is this cat’s hypoadrenocorticism related to the megestrol treatment?
Megestrol acetate (Ovaban, Ovarid, or Megace), a progestational compound that has been widely used in the past for treatment of a variety of feline dermatologic and behavioral disorders, commonly induces severe adrenocortical suppression that is even more profound than that produced by high-dose glucocorticoids (1-4). Such marked adrenocortical suppression develops in cats treated with standard dosages of the drug (2.5 to 5.0 mg every other day) for as little as one to two weeks (1,2).

Progestational agents, such as megestrol acetate, act via the negative feedback effects on the HPA axis to suppress pituitary ACTH secretion, which leads to a “secondary” form of hypoadrenocorticism in cats. The deficient ACTH secretion results in a decrease in glucocorticoid production caused by atrophy of the zona fasciculata and zona reticularis (4,5). The adrenal zona glomerulosa is preserved because ACTH has little stimulatory effect on mineralocorticoid production.

The clinical signs are due to deficiency in glucocorticoid production and so are similar to those observed in cats with primary hypoadrenocorticism (5-8). However the derangements associated with mineralocorticoid deficiency (and subsequent electrolyte disturbances) are absent. Consequently, clinical signs observed are usually less severe than those that develop in cats with primary hypoadrenocorticism.

Is this a case of feline atypical hypoadrenocorticism?
In this cat, this isn't “atypical” hypoadrenocorticism because we know what the cause is — it's drug-induced secondary adrenal atrophy. The subnormal resting and ACTH-stimulated serum cortisol concentrations that develop during treatment will normalize within a few weeks after cessation of megestrol acetate (1,5).

How should this cat be managed?
I’d start this cat on glucocorticoid replacement with oral prednisolone, at the lowest daily dose that will get the cat to feel better. I’d then slowly taper the daily prednisolone dose down to 1.25 to 2.5 mg per day, and then decrease to alternate day therapy (5,6). It may take a few months before all glucocorticoid supplementation can be stopped.

Again, megestrol causes secondary hypoadrenocorticism, with pituitary ACTH suppression. Mineralocorticoid secretion should remain normal, and I would not expect serum electrolyte abnormalities to develop. Therefore, neither fludrocortisone acetate (Florinef) nor desoxycorticosterone pivalate (Percorten-V) should be required in this cat.

My Bottom Line
Megestrol is not a recommended treatment for cats because of the high incidence of adverse effects, including profound adrenal suppression and diabetes mellitus.  Although it does work very well for treatment of a variety of dermatologic conditions (e.g., miliary dermatitis, eosinophilic granulomata) and behavior problems, the disadvantages outweigh the benefits of the drug.

I would never dispense this drug for a cat, unless I had exhausted every other treatment option and believed that this was the only chance to prevent the cat from being euthanized. In that case, you must inform the owners about the high risk of side effects associated with megestrol and other progestational drugs in cats.

References

1. Peterson ME. Effects of megestrol acetate on glucose tolerance and growth hormone secretion in the cat. Research in Veterinary Science 1987;42:354-357.
2. Middleton DJ, Watson AD, Howe CJ, et al. Suppression of cortisol responses to exogenous adrenocorticotrophic hormone, and the occurrence of side effects attributable to glucocorticoid excess, in cats during therapy with megestrol acetate and prednisolone. Canadian Journal of Veterinary Research 1987;51:60-65. 
3. Watson AD, Church DB, Emslie DR, et al. Comparative effects of proligestone and megestrol acetate on basal plasma glucose concentrations and cortisol responses to exogenous adrenocorticotrophic hormone in cats. Research in Veterinary Science 1989;47:374-376. 
4. Chastain CB, Graham CL, Nichols CE. Adrenocortical suppression in cats given megestrol acetate. American Journal of Veterinary Research 1981;42:2029-2035.
5. Peterson ME, Randolph JF, Mooney CT. Endocrine diseases, In: Sherding RG (ed): The Cat: Diagnosis and Clinical Management. (2nd Ed) New York, Churchill Livingstone, 1994;1404-1506.
6. Peterson ME, Baral R. Adrenal gland disorders, In: Little, S.E. (ed), The Cat: Clinical Medicine and Management. Philadelphia, Elsevier Saunders. 2012; 592-610. 
7. Duesberg C, Peterson ME. Adrenal disorders in cats. Veterinary Clinics of North America: Small Animal Practice 1997;27:321-347, 1997.
8. Peterson ME, Greco DS, Orth DN. Primary hypoadrenocorticism in ten cats. Journal of Veterinary Internal Medicine 1989;3:55-58. 

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