Adrenal Disease in Domestic Ferrets: An Overview
Lauren W. Johnson, DVM; Juliet Gladden, DVM; and Kenneth S. Latimer, DVM, PhD
Class of 2007 (Johnson), Department of Small Animal Medicine and Surgery (Gladden), and Department of Pathology (Latimer), College of Veterinary Medicine, The University of Georgia Athens, GA 30602-7388
Introduction
Adrenal disease is one of the most commonly diagnosed clinical conditions among domestic ferrets (Mustela putorius furo) in the United States. This disease is most often seen in middle age to older ferrets,12 wherein most ferrets in this age group are diagnosed with adrenal disease. It is unclear whether or not there is a sexual predilection for adrenal disease in ferrets. Clinical signs may include lethargy, alopecia, vulvar enlargement in females, aggression, and return to male sexual behavior in neutered males.
Adrenal disease in ferrets is different than that seen in dogs, cats, and humans. In dogs, cats and humans, adrenal disease is associated with hyperadrenocorticism, characterized by elevated cortisol concentrations. In dogs, hyperadrenocorticism is more commonly associated with a pituitary tumor. In ferrets, adrenal disease is associated with elevation of sex hormone concentrations that usually are derived from a functional adrenal tumor or nodular adrenal hyperplasia. In some European research articles, adrenal disease in ferrets also is referred to as adrenal associated endocrinopathy (AAE) due to the multifaceted nature of the disease and its dissimilarity to hyperadrenocorticism in dogs.
This article presents a brief overview of adrenal disease in the ferret. Key information is presented relating to possible etiology, clinical signs, disease diagnosis, and treatment.
Etiology
There are several proposed predisposing factors for the high incidence of adrenal disease in ferrets including early spaying and neutering, genetics, diet, alteration of UV light intake, and alteration in daily light cycles.
Early spay and neuter - In the United States, ferrets are neutered as early as 6 weeks of age,2,4 whereas early spay and neuter are not as common in other countries. Studies done to identify the presence of adrenal disease in sexually intact ferrets in the Netherlands showed a prevalence of 0.55%4 which suggests a correlation between adrenal disease and early spay or neutering.
Since the adrenal glands and the gonads are in close proximity during early development, undifferentiated gonadal cells may migrate in the embryo with the adrenal gland cells. These undifferentiated cells may later become functional steroidogenic cells.5,12 Current research studies have identified gonadal steroidogenic cells in adrenal tumors using markers such as inhibin-a, GATA-4 and estrogen.5
Surgical removal of the gonads is thought to reduce the appropriate negative feedback mechanism on the hypothalamic-pituitary axis. Thus, the functional gonadal cells secrete hormones in excess. Over time, the excess hormonal secretion, lack of negative feedback control, and an increase in lutenizing hormone (LH) stimulation likely leads to neoplastic transformation of these aberrant adrenal cells.
Genetics - Other reports do not indicate as high an incidence of disease in ferrets that are spayed and neutered at an early age that. Therefore, this observation suggests that there may also be a genetic basis for disease.1 In the United States, ferrets also are highly inbred or derived from a limited gene pool.
Diet - Another predisposing factor that hasn't been thoroughly evaluated is diet. In the United States, ferrets typically are fed a diet of either dry cat food or specially formulated diets for ferrets. In some European countries, ferrets are fed whole prey. Some researchers theorize that the higher incidence of adrenal disease in ferrets in the U.S. may attribute to the diet, however, the specific difference in foods has not been identified.
While many theories exist about the etiology of adrenal disease in the ferret, a single, specific cause has not been identified. Perhaps a combination of factors may be involved in the development of adrenal disease in this species.
Clinical Signs
The four most common clinical signs associated with adrenal disease in ferrets are alopecia, lethargy, muscle atrophy, and vulvar enlargement in females.1 Other reported clinical signs of disease include aggression, pruritus, return to male sexual behavior (neutered males), and stranguria (males). One or more of these clinical signs may be present in ferrets diagnosed with adrenal disease.
Alopecia - Typical of endocrine-associated disease, ferrets commonly present with bilaterally symmetrical alopecia. Alopecia may be localized just proximal to the tail, on the dorsum, on the ventrum, or on the dorsal surface of the feet. However, alopecia may involve any portion of the ferret's body.1 Pruritus may or may not be associated with the alopecia.1
Ferrets commonly undergo a seasonal alopecia in which the hair re-grows at the end of the season. In ferrets with adrenal disease, however, the alopecia is secondary to elevated concentrations of circulating hormones (estradiol and other androgens) that suppress the anagen hair phase. Therefore, only follicles in the telogen phase remain.3 Ferrets commonly undergo a seasonal alopecia in which the hair re-grows at the end of the season. In ferrets with adrenal disease, however, the alopecia is secondary to elevated concentrations of circulating hormones (estradiol and other androgens) that suppress the anagen hair phase. Therefore, only follicles in the telogen phase remain.3
Return to male sexual behavior - Neutered male ferrets that exhibit a return to male sexual behavior are most often observed attempting to mate with spayed female and, occasionally, male ferrets.1
Stranguria in male ferrets - Stranguria in male ferrets is associated with a prostatic or periurethral cyst that occludes the urethra. Affected ferrets often will be presented for acute urinary obstruction. In ferret with adrenal disease, the prostatic tissue surrounding the urethra becomes swollen under the influence of sex hormones and contributes to cyst formation.1 Female ferrets may have an enlarged, swollen vulva which also is due to high circulating concentrations of sex hormones. Increased vulvar discharge provides an ideal medium for bacterial growth, increasing susceptibility to concurrent urinary tract infection.
Abdominal palpation - Abnormal adrenal glands are rarely palpated on physical examination. Splenomegaly, however, is a common finding in all ferrets; this finding may be coincidental in ferrets with adrenal disease.
Diagnosis
A presumptive diagnosis of adrenal disease in ferrets may be made based upon the medical history, clinical signs of disease, and pertinent findings during physical examination.1 However, it also is important to remember that sexually intact females in estrus or females with retained ovarian remnants may demonstrate similar signs of disease. Definitive diagnosis of hyperadrenocorticism in ferrets may require laboratory testing, abdominal ultrasonography, endoscopy, exploratory laparotomy, and histology (Fig. 1).
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| Figure 1. Medical illustration of the anatomical location of the adrenal glands in the ferret (Mustela putorius furo). The histologic section at right shows the three zones of the normal adrenal cortex and the medulla (Image courtesy of Drs. Kenneth S. Latimer and Ashley L. Ayoob © 2000). |
Complete Blood Cell Count and Biochemical Profile - The complete blood cell count (CBC) and biochemical profile may provide supportive evidence for a diagnosis of adrenal disease. Anemia or pancytopenia may be present on the CBC. The anemia, if present, is most likely due to estrogen toxicosis with myelosuppression. Increased activity of alanine aminotransferase (ALT) may be observed on the biochemical profile. Increased ALT activity is due to increased hepatocellular permeability. The ACTH stimulation and dexamethasone suppression tests currently used to diagnose canine hyperadrenocorticism are ineffective in establishing a disease diagnosis in ferrets because ferret adrenal disease is rarely associated with elevated concentrations of cortisol.
Sex hormone diagnostic panel - A diagnostic an adrenal panel to quantitate selected sex hormones in ferrets is available through the University of Tennessee < http://www.vet.utk.edu/diagnostic/endocrinology/ >. This panel of tests quantitates estradiol, androstenedione and 17-hydroxyprogesterone concentrations, which are the most commonly elevated sex hormones in adrenal disease of ferrets (Fig. 2).9 This diagnostic panel has consistently identified ferrets with adrenal disease.
Abdominal ultrasonography - Abdominal ultrasonographic imaging allows the practitioner to visualize the adrenal glands and the remainder of the abdominal cavity for any concurrent problems (ferrets may commonly have multiple endocrinopathy or concurrent neoplastic disease that may involve the pancreas, spleen, or internal lymph nodes). One study has reported that echogenicity and echotexture are not valid criteria to detect of adrenal disease. However, adrenal gland thickness is the deciding factor to determine whether or not an adrenal gland is abnormal.14 The reported ultrasonographic normal values for length and thickness, respectively, of ferret adrenal glands is 5.4-9.8 mm by 2.3-3.6 mm for the left adrenal gland and 5.8-10.5 mm by 2.2-3.8 mm for the right adrenal gland.14 In general, any adrenal gland measuring > 4mm in thickness is abnormal. To provide "maximal diagnostic information," ultrasonography should be performed within ~1 to 3 days of surgery. Any prolonged length of time between ultrasonographic examinations may fail to reveal the extent of continued growth of an adrenal mass that may be expected at surgery.14
One study reported that only one adrenal gland was affected in 84% of diseased ferrets. Furthermore, the left adrenal gland was involved most frequently.1 On histopathologic examination of affected adrenal glands, adrenocortical adenoma was diagnosed most commonly.10 In some ferrets, adrenal gland hyperplasia or adrenocortical carcinoma may be found. In one report, in 100% of the ferrets that exhibited a return to male behavior, an adrenal carcinoma was diagnosed on histopathology.
Endoscopy, exploratory laparotomy and histology - Direct visualization of the adrenal glands per se requires endoscopy or exploratory laparotomy. If abnormal adrenal tissue is observed, a definitive diagnosis can only be achieved with incisional or excisional biopsy and histologic evaluation. Histologic evaluation is essential to classify the type of adrenal disease, distinguish hyperplastic from neoplastic lesions, and differentiated between benign and malignant neoplasms. Adrenal lesions are more varied in ferrets than in other mammalian species and are frequently a diagnostic challenge even to the most skilled diagnostic pathologists. Immunohistochemical staining may be of benefit in identifying malignant neoplasms (Fig. 3).
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Figure 3. The histologic appearance of adrenal lesions in ferrets may be difficult to distinguish. The four plates above represent 1. Normal adrenal gland, 2. Adrenocortical nodular hyperplasia, 3. Adrenocortical adenoma, and 4. Adrenocortical carcinoma. Immunohistochemical expression of proliferating cell nuclear antigen (PCNA) is absent in the normal adrenal gland (1), mild to moderate in adrenocortical nodular hyperplasia (2) and adrenocortical adenoma (3), and intense in adrenocortical carcinoma (4) (Image courtesy of Drs. Kenneth S. Latimer and Ashley L. Ayoob © 2000). |
Treatment
| Note:
Treatment of animals should only be performed by a licensed veterinarian.
Veterinarians should consult the current literature and current pharmacological
formularies before initiating any treatment protocol. |
Surgical removal of the affected adrenal gland or debulking is the treatment method of choice. The left adrenal gland is more easily resected because of its anatomical location. When the right adrenal gland is affected, complete surgical excision is difficult due to the close and intimate association of the gland with the vena cava (Fig. 4). In this instance, reoccurrence of disease is possible and the incidence of surgical complications may increase. However, a cure may be achieved with successful removal of the affected gland. Complete adrenalectomy in ferrets generally has a favorable prognosis. In ferrets with malignant adrenal tumors such as adrenocortical carcinoma, development of distant metastasis is rare and the prognosis is similar to that for benign tumors.
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Figure 4. Medical illustration of the anatomical location of the left and right adrenal glands of the ferret based on a ventral view as seen during midline abdominal laparotomy. The right adrenal gland (left side of illustration) is intimately associated with the caudal aspect of the vena cava (large blue vessel). The left adrenal gland (right side) is more easily resected (Image courtesy of Drs. Kenneth S. Latimer and Ashley L. Ayoob © 2000). |
Although surgical removal of the affected adrenal gland usually is the treatment of choice, there are several medical treatment options for owners who chose not to pursue surgery. These options regarding medical therapy are briefly presented below.
Administration of leuprolide and melatonin may help reduce clinical signs of disease in affected ferrets but do not permanently resolve the adrenal disease. Leuprolide (Lupron, TAP Pharmaceuticals, Deerfield, IL) is a GnRH analog that effectively reduces the amount of circulating estrogen and androgens by suppressing the pituitary gland's production of FSH and LH.6 A single injection of leuprolide may temporarily reduce the ferret's clinical signs of disease, but repeated injections of this drug may be necessary for long-term disease management. This treatment option may be useful in ferrets that are poor risks for anesthesia and surgery due to age or a concurrent medical condition.6
Melatonin is another drug that has been investigated as a treatment for adrenal disease in ferrets. Although its mechanism of action has not been elucidated, melatonin is thought to reduce GnRH secretion by the pituitary gland. Currently, experimental studies are being performed to critically evaluate this drug's efficacy in the treatment of adrenal disease in ferrets.
Mitotane (Lysodren, Bristol Myers Squibb, Princeton, NJ) is a drug that is commonly used to treat dogs with hyperadrenocorticism (Cushing's disease) and has been previously tried in ferrets. Administration of this drug results in the destruction of adrenal cortical cells. Mitotane is not commonly recommended for treatment of adrenal disease in ferrets because of its unpredictable response, lack of selectivity for the estrogen secreting cells adrenocortical cells, and low margin of safety.
Anastrozole (Arimidex, Zeneca Pharmaceuticals, Wilmington, DE) is an aromatase inhibitor that inhibits the production of estrone and estradiol from their precursor molecules.8 Ferrets often have increased concentrations of several different sex hormones in addition to or independently of estrogen. In these affected individuals, anastrozole is ineffective. This drug is relatively expensive and, therefore, is not commonly used to treat adrenal disease in ferrets.
In summary, leuprolide is used most commonly for the medical management of adrenal disease in ferrets. It may reduce the clinical signs of disease but will not cure the underlying cause of the condition. Medical treatment of adrenal disease may be a trial and error process; one ferret may respond better than another to a leuprolide treatment regimen.
Conclusion
It is important for practicing veterinarians to be aware of updated information pertaining to the diagnosis and treatment of adrenal disease in ferrets. Adrenal disease in ferrets is a common clinical condition that may be diagnosed by clinical signs and judicious laboratory testing. Adrenal disease may respond well to both surgical and medical treatment. Clinical signs may completely resolve shortly after appropriate treatment. References
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Acknowledgement
"Busted" by Bruce H. Williams, DVM, DAVCP, is a watercolor of his ferret Cosmo from his website Pathology of the Domestic Ferret and is used with permission. |
