Adrenal Associated Endocrinopathy in the Domestic Ferret

(Click on thumbnails to download full-sized images.)
Ferret with AAE (80K). Note the classic pattern of hair loss over the flanks and trunk, sparing the head, neck, and feet. (Photo courtesy of Dr. Erik Stauber, Washington State College of Veterinary Medicine.)
Normal anatomy of the ferret adrenal glands (33K). The left adrenal gland (seen on the right side of the photo as the animal is positioned on his back) is easily found at the cranial pole of the kidney. The right adrenal gland is found beneath the caudate lobe of the liver, which is retracted in this photo. Note that the right adrenal gland sits on top of the caudal vena cava, necessitating care in removal.
Clinical presentation of an adrenal carcinoma at surgery in the left adrenal gland of a ferret (32K). The more pale mass cranial to the pole of the kidney (the more caudal, darker red structure) is the enlarged adrenal gland. (Photo courtesy of Dr. X. Li and Dr. J. Fox, Dept of Comparative Medicine, Massachusetts Institute of Technology.)

"Doc, why is my ferret going bald?" This is easily the most often asked question in ferret medicine, and a question that most ferret practioners hear on a daily basis.

Alopecia, or hair loss, is the most common sign of a very prevalent syndrome in American ferrets known as adrenal-associated endocrinopathy, or AAE. (The disease may also be referred to as hyperadrenocorticism in the ferret, but as discussed below, NOT Cushing's disease.)

AAE is caused by the presence of a proliferative lesion within the adrenal cortex, the region which is responsible for secreting a number of important hormones. The adrenal cortex secretes steroids that regulate mineral balances in the body, steroids that moderate the "fight or flight" syndrome and our responses to stress, and also secretes small amounts of sex steroids, such as estrogen. It is this last hormone, estrogen, which results in all of the signs of AAE in the ferret.

Estrogen is a hormone which is normally produced in the ovary of females, the testis of males (in small amounts) and the adrenal glands of both sexes (also in small amounts). At normal levels, estrogen regulates many parts of the reproductive cycle in both males and females ferret; however, in excessive amounts, estrogen can cause serious, even life-threatening health problems in ferrets.

The source of the hyperestrogenism in affected animals is a proliferative lesion in one (or in approximately 15% of cases, both) adrenals. (Please note: The term "proliferative lesion" is preferable to adrenal "cancer" or even the less objectionable term adrenal "tumor", as only about half of these lesions are true neoplasms, the rest being nodules of adrenocortical hyperplasia.)

Clinical signs exhibited by ferrets with AAE include a spectrum of cutaneous, reproductive, or behavioral symptoms, all related to high serum levels of estrogen and/or its precursors. Cutaneous signs are most commonly observed by owners and are characterized by bilaterally symmetric alopecia beginning over the tailhead and progressing forward along the body, generally sparing the head, neck, and distal extremities (see picture, below). Reproductive abnormalities include swelling of the vulva vaginal discharge, and stump pyometra in spayed females, and dysuria in males as a result of cystic prostatic disease, secondary to hyperestrogenism and squamous metaplasia of glandular epithelium. Behavioral abnormalities include increased mounting behavior or aggression in both males and females, and marking behavior in males. Longstanding cases may show mild anemia and petechiation (small hemorrhages) as a result of estrogen's suppressive effect on the bone marrow, muscle wasting, and other non-specific signs such as lethargy and posterior paresis.

In most cases, diagnosis is based on clinical signs. Complete blood counts and chemistry panels will be within normal limits in the vast majority of animals, except in longstanding cases in which anemia or decreased platelet numbers may be seen. As the elevated hormone in AAE is estrogen, not cortisol, practitioners should be aware that serum cortisol is rarely if ever elevated, and diagnostic testing for Cushing's disease will be of little or no diagnostic value. While serum levels of estradiol may be measured at commercial labs, elevation of estradiol precursors or intermediates are responsible for clinical signs in many cases, and estradiol measurements may be within normal ranges. A new blood panel is available at the Department of Endocrinology at the University of Tennessee College of Veterinary Medicine which measures not only levels of serum estradiol but six other intermediates. Although the test is extremely sensitive (resulting in positive diagnosis in over 90% of cases) it is expensive and takes several weeks to complete, and should be reserved for cases in which clinical signs are marginal.

The most effective treatment of AAE is surgical removal of the affected adrenal gland. Exploratory laparotomy often reveals unilateral enlargement of one or both adrenal glands beyond the normal 3-5 mm. For unknown reasons, over 80% of proliferative adrenal lesions are located in the left adrenal gland. In approximately 15% of cases, lesions are bilateral. Unilateral adrenalectomy results in a cessation of clinical signs and hair regrowth in the majority of cases. Hair regrowth should begin within 2-6 weeks, or may be delayed until the next shedding cycle. However, in animals in with bilateral disease, hair regrowth may be shortlived, or not seen at all. In these cases, hemiadrenalectomy of the remaining adrenal gland should be strongly considered. Recently, a protocol was published in Modern Ferret for corticosteroid replacement in animals having undergone bilateral adrenalectomy by Dr. Joseph Bock. Bilateral adrenalectomy may be required in cases in which bilateral adrenocortical carcinomas develop. While much more research is required in this area, the possibility of exogenous maintenance of adrenalectomized ferrets now gives added hope in the treatment of adrenal neoplasia in ferrets.

From the pathologist's viewpoint, a review of 104 adrenal glands (removed from ferrets exhibiting clinical signs of AAE) that I did several years ago yielded some very interesting findings. Approximately 45% of the lesions were benign hyperplasia, 45% carcinoma, and 10% adenoma. Followup on the cases of adrenal malignancy revealed that these neoplasms metastasize late in the course of disease -- in fact, a ferret is more likely to die from vascular hemorrhage as a result of tumor necrosis in a large adrenal malignancy than as a result of metastatic disease. Translated into clinical terms, the prognosis for a malignant adrenocortical neoplasm, if removed early in the course of disease, is little different than that of a benign neoplasm.

Medical treatment of hyperadrenocorticism is reserved only for those animals who present a poor surgical risk, as it is generally symptomatic.  while it may promote hair regrowth and lessen lethargy in affected animals, it generally does nlittle to stop the growth of potentially malignant neoplasms in affected animals. A recent review of medical therapies for ferret with AAE was posted by Dr. Charles Weiss.

Adrenal-associated endocrinopathy is a very common, and very treatable disease in the ferret. The diagnosis and treatment of this condition is something with which every ferret practitioner must be familiar. Every bald ferret is a ferret that you can help.