Hyperadrenocorticism in ferrets (Proceedings)

Adrenal disease is one of the most common and serious disorders facing pet ferrets in the United States today, and is emerging as a common disease entity in other parts of the world as well. Ongoing research provides more clues to the etiology of adrenal disease, and is helps to direct therapeutic choices as well. Some insight into short and long-term prevention strategies is now available.

Ferrets belong to the Mustelidae family, in the group of medium-sized carnivores that includes skunks, mink, otters and badgers. Ferrets are sexually mature at 6-9 months, and are seasonal breeders, breeding twice yearly. Ferrets are induced ovulators. Mating produces a surge of luteinizing hormone (LH), which is followed by ovulation and pregnancy. Hormonal feedback from the gonads ends the breeding season.1

Peak sex hormone levels that occur at puberty and during the breeding season "set the gonadostat" at the hypothalamus and pituitary gland. This sensitivity to fluctuating hormone levels controls the intact ferret's hormonal feedback system.

Recent work has determined that ferret adrenal tissue has LH receptors as well, allowing it to produce sex steroids, even in the absence of gonadal tissue.

In the spayed or castrated ferret, sex hormones still cycle annually, but to a lesser degree. Blood levels of sex hormones in all ferrets, intact or otherwise rise at the onset of breeding season, and peaks in late December or January in males, and January to March in the female.2

The difference between intact and early spay/neuter ferrets is that in intact ferrets, seasonal gonadal production of sex steroids is followed by breeding, then LH surge followed by downregulation of the hormone pathway. In early spay/neuter ferrets, the adrenal gland produces sex steroids, and breeding does not occur to shut the system down. In some cases, sex hormones are produced all year long at levels similar to those in normal intact ferrets during the breeding season.

Therefore, removal of the gonads apparently interrupts the normal feedback system present in the intact ferret. While the exact mechanism remains uncertain, elevated blood levels of LH and GnRH upregulate sex hormone production from the adrenal gland. The adrenal gland apparently responds by becoming hyperplastic, and ultimately neoplasia. A number of things are unclear about the mechanism of the development of adrenal disease in ferrets, including why GnRH analogues such as Luprolide acetate (Lupron, TAP Pharmaceuticals, Inc. Deerfield, IL USA) depress the production of sex steroids in the ferret.2

As an interesting side note, Johnson-Delaney and Oliver observed that 1-2 weeks of elevated ambient temperature (greater than 80 F) can also cause both intact and neutered ferrets to spontaneously cycle out of season (unpublished data).

Dr. Michelle Hawkins is currently pursuing a theory that development of adrenal disease in ferrets may have a genetic component. In humans, the appearance of neoplasia within two or more endocrine organs is almost always genetic in origin and is termed multiple endocrine neoplasia syndrome (MENS). Affected tissues often progress from hyperplasia to neoplasia, and organs most commonly involved include the parathyroid gland, pancreas, pituitary gland, adrenal gland, thyroid and thymic tissues.3

History and Physical Examination Findings

History and physical examination findings include varying degrees of bilaterally symmetrical alopecia, thinning of the skin, pruritus, increased aggression, dysuria, enlarged prostate in the male and enlarged vulva in the female ferret. Enlarged prostate is linked to dysuria and prostatitis. In theory, increased estrogen levels may contribute to bone marrow aplasia and anemia in ferrets, but the author has been unable to confirm or document this.

Work up of ferrets with suspected adrenal disease includes complete blood count (CBC) and chemistry panel, including measurement of fasting blood glucose, radiographs and possibly ultrasound. Ferrets with anemia should undergo evaluation of the bone marrow, especially in those with splenomegaly which may indicate extra-medullary hematopoiesis and a much more severe clinical picture.

Measurement of adrenal hormones is useful in ferrets where the diagnosis of adrenal disease is uncertain, but it should be kept in mind that hormone levels in ferrets with adrenal disease fluctuate.

Diagnosis is through clinical symptoms, measurement of adrenal hormones, ultrasound and exploratory laparotomy.

Treatment of Adrenal Disease in Ferrets

Treatment options are divided into surgical intervention and palliative medical management, and often include both. Adrenalectomy is a common procedure in ferrets, varies as to level of difficulty and outcome, and is often complicated by the presence of concurrent disease or general debilitation. The author has found that age at time of surgery is much less of a prognosticator than general condition at the time of surgery. In other words, a 7-year-old otherwise healthy ferret with acute onset of adrenal symptoms is often a better surgical candidate than the 4 year old with long-term symptoms and evidence of concurrent disease.

Disease can be present in one or both glands. Identification of abnormal glands is usually by visual inspection, and abnormal glands can be enlarged, cystic, rounded in appearance, discolored or with increased vasculature. Left glands are often buried in perirenal fat and must be carefully dissected for visual examination. Removal of the left adrenal gland is straightforward and usually uncomplicated. Removal of the right gland, however, is significantly more difficult due to close association of the gland with the caudal vena cava. Debate exists on the best protocol for adrenalectomy of the right adrenal gland. Options described include simple surgical debulking, laser or cryosurgery used as a primary modality or in conjunction with surgical debulking, and venous surgery including disruption or ligation of the vena cava. Complete removal of the right gland is most likely achieved with the use of vascular clamps and venotomy techniques. Interestingly enough, even ferret undergoing so called complete bilateral adrenalectomy seldom need long term cortico- and mineralocorticoid supplementation, suggesting failure to remove the complete gland, or the presence of ectopic adrenal tissue. Without retrospective studies of long-term survival rates of ferrets undergoing right adrenalectomy with various techniques, choice of technique is largely surgeon's preference.

The author preferred surgical technique is aggressive surgical debulking. Under no circumstances should laparotomy be performed unless the surgeon is prepared to perform right adrenalectomy and handle complications that might occur following manipulation of the vena cava. Practitioners who are not comfortable doing so should refer the case rather than subject the patient to an incomplete surgery.

Surgical debulking of the affected gland tissue will effectively slow the progress of the disease by decreasing tumor mass and therefore sex steroid production. However, a new clinical study has shown that without additional suppression of sex hormone production, the survival rate of ferrets treated with surgery alone was less than survival rate of those treated with Lupron alone. However, the most statistically effective treatment at this time appears to be surgical debulking in conjunction with administration of Lupron. (Delaney unpublished data).

It should be mentioned that another distinct advantage to surgery as part of treatment of adrenal disease is the opportunity to diagnose and address other concurrent conditions through biopsy of the pancreas, gastrointestinal tract and lymph nodes. The author estimates that nearly 40% of ferrets undergoing adrenalectomy are found to have other abnormalities detected at the time of surgery, such as gastric foreign bodies, enlarged gastrointestinal lymph nodes, hepatic cysts, pancreatic nodules and/or other abnormalities.

Palliative medical management includes suppressive drugs acting at the level of the central nervous system, such as leuprolide acetate depot, a synthetic GnRH analogue. The 30-day depot formulation of leuprolide acetate has been shown via measurement of sex hormones to effectively downregulate sex steroid production in intact ferrets during the breeding season, and effects last for approximately 30 days. The three month formulation was effective in male ferrets for 75-90 days, but only effective in some female ferrets for 60-75 days.2

Melatonin has also been utilized for the treatment of adrenal disease, but earlier studies did not correlate clinical signs such as hair regrowth with measurement of adrenal hormones. A recent study in December 2006 demonstrated significant hair regrowth in ferrets given oral melatonin once daily for a year. However, 60% of ferrets experienced a relapse of clinical signs at 8 months of therapy. Levels of some hormones were seen to decrease at least early on in the study, but all steadily increased over the study period.

It should be kept in mind that medical therapy is palliative only, and there is no evidence that medical therapy slows the progression of disease or prevents tumor growth. In the melatonin study, adrenal size increased during the treatment period, as would be expected in the natural course of the disease.

Of great interest is recent work by Dr. Schoemaker on the use of desorelin implants for treatment of adrenal disease, and as an alternative to surgical alteration. This drug is not currently available in the United States.5

References

1. O'Malley B. Ferrets. In: Clinical Anatomy and Physiology of Exotic Species. Elsevier Limited. 2005; 237-261.

2. Johnson-Delaney C. Ferret adrenal disease: 2006 perspective. ExoticDVM 8(3), 2006; 31-34.

3. Hawkins M. possible influence of heredity on multiple endocrine neoplasms in ferrets. ExoticDVM 8(3). 2005; 35-37.

4. Ramer J, Benson K, Morrisey J, et al. Effects of melatonin administration on the clinical course of adrenocortical disease in domestic ferrets. JAVMA 229(11) 2006; 1743-1748

5. Schoemaker N. Everything you wanted to know about adrenal disease in ferrets. Proc N Am Vet Conference 2008, 1863-1866.