Adrenocortical Disease in Ferrets

Introduction

Hyperadrenocorticism is a common and complex clinical condition of pet ferrets (Mustela putorius furo), affecting animals anywhere from 2-3 years of age. The median age is 4.5 years and greater than 80% of ferrets older than 5 years have some degree of adrenal disease.^24,25,32

The prevalence of adrenal disease was between 0.55% to 5.7% in different studies.^10,14 In a recent Japanese retrospective study, the adrenal gland was the most commonly affected organ of the endocrine system (71.2% of endocrine lesions).²⁶ In studies reviewing ferret neoplasms, adrenal tumors were the first or second most common and accounted for 16.7% to 36.6% of cases.^1,10,18 Non-neoplastic lesions or hyperplasia can also cause clinical disease.³²

 

Pathogenesis

Adrenal disease in ferrets is unlike hyperadrenocorticism in dogs, which is due to elevated levels of cortisol. Adrenal disease in ferrets is due to increased production of sex hormones, such as estradiol, androstenedione, and 17α-hydroxyprogesterone.²⁶

While the underlying cause of disease is not completely understood, it is thought that gonadectomy coupled with exposure to a prolonged photoperiod from being housed indoors triggers a “perpetual breeding season” syndrome. Exposure to long days stimulates the production of gonadotropin-releasing hormone (GnRH) by the hypothalamus, which in turn stimulates pituitary gland secretion of luteinizing hormone (LH) and follicle stimulating hormone.¹¹

Neutering removes the critical negative feedback of sex steroid hormones on gonadotropin secretion in the pituitary gland, resulting in persistent stimulation of the adrenal cortex, which possesses LH receptors. Age at diagnosis has been shown to be linearly correlated with age at neutering.^10,26  In one study, the median interval between neutering and adrenocortical disease diagnosis was 3.5 years.²⁶  This theory is supported by the lower incidence of adrenocortical disease in the United Kingdom, where ferrets kept for hunting are left intact and housed outdoors.²⁶ Genetic factors have also been suggested as alterations of specific genes have been found in adrenocortical tumors.⁸

Stimulation of the adrenal glands may lead to adrenal hyperplasia, adrenal adenoma, or even adenocarcinoma.²⁶ Disease may be unilateral (~85%) or bilateral (~15%).³¹ Adrenal adenocarcinoma metastasizes late in the disease process to regional tissues, such as the liver or spleen.²⁶

 

Clinical disease

Signalment

Hyperadrenocorticism occurs most frequently in ferrets 3 years or older, but has been reported in animals as young as 1 year of age (4.5 years of median and > 80% affected ferrets older than 5 years).^24,25,32 There is no obvious gender predisposition.

Clinical signs

Most clinical signs are related to sex steroid hormone secretion, except in rare cases with mechanical compression of adjacent structures or invasion of the caudal vena cava. Some ferrets may exhibit weight loss and reduced activity.^13,26 In rare instances, hyperestrogenism may cause non-regenerative anemia due to bone marrow toxicity in male or female ferrets.²⁶

Dermatologic clinical signs

The most common clinical sign of hyperadrenocorticism in ferrets is progressive alopecia of the tail, tail base, and trunk, which affects more than 90% of ferrets (Fig 1-Fig 4).²⁶ Alopecia may progress until the affected ferret is completely bald (Fig 5).

 

 

 

 

 

Although most affected ferrets show some degree of pruritus, approximately 30% are profoundly pruritic (Fig 6). Pruritus is often localized to the interscapular region and may lead to excoriation and erythema.²⁶ This pruritus has been theorized to be caused by histamine production, another hallmark of ferret adrenocortical disease.¹³ Thinning of the skin and comedones are also mentioned by some authors.¹³ In rare instances, hyperestrogenism may also cause hyperpigmentation of the skin.²⁶

 

Urogenital clinical signs

Vulvar enlargement is seen in up to 90% of spayed females with adrenocortical disease (Fig 2).³² Localized vaginitis with seromucoid discharge is also sometimes present. Around the vulva, the skin might be dark and bruised.

 

 

Male ferrets may present with signs of pollakiuria, stranguria, or even complete urethral obstruction. These findings are caused by prostatomegaly and periurethral cysts in the prostatic area due to androgenic stimulation (Fig 9).²⁶ The prostate may be palpable as a mass dorsal to the bladder on physical examination. In addition, diverticuli of the urethra are possible, resulting in bladder-like cysts.^7,26

 

Some ferrets may exhibit sexual behavior, including mounting, urine marking, and aggression towards people and other ferrets.^26,32 These actions are generally attributed to male ferrets in the literature ^25,26,32 , however behavioral changes can occur in both sexes and these changes may develop before any external signs are observed (C. Johnson-Delaney, written communication, October 2022).

Some ferrets may emit a musky odor that is stronger than normal.^26,32 In rare instances, hyperestrogenism may cause hyperpigmentation of the skin or non-regenerative anemia due to bone marrow toxicity in male or female ferrets.²⁶ Mammary enlargement can also be observed in female ferrets.^19,26

 

Diagnosis

Although clinical signs can be very suggestive of adrenal disease, several differential diagnoses should be excluded. Many ferrets also have concurrent disease that must be identified, such as islet cell neoplasia and/or cardiac disease. Confirmation of the diagnosis mostly relies on diagnostic imaging, which is especially needed if surgical treatment may be considered. Some clinicians also use therapeutic diagnosis as medical treatment is minimally invasive and often less expensive than diagnostic tests.

Table 1. Primary differential diagnoses for ferrets with clinical signs suggestive of hyperadrenocorticism2526
Signalment	Differentials
Female ferrets	Ovarian remnant Ovarian neoplasm (granulosa cell tumor) Non-neutered jill with intact ovaries
Male ferrets	Sertoli cell tumor (intact ferret, +/- cryptorchid) Hypothyroidism
Both genders	Food intolerance/allergy Atopy Infectious skin diseases Seasonal alopecia Pheochromocytoma

Physical examination findings

An enlarged adrenal gland is occasionally palpable, craniomedially to the kidney as a round, firm mass embedded in fat.²⁶ Adrenal glands are usually easier to identify on the left side as the right gland is partially covered by the liver.²⁶ An enlarged prostatic cyst may be palpable as a mass dorsal to the bladder.²⁶

Minimum database

Adrenocortical disease in the ferret rarely causes any significant changes in the complete blood cell count (CBC) or chemistry profile. More commonly, clinical pathology results may suggest concurrent diseases, like insulinoma, however testing may be performed, particularly if surgery is considered. A CBC, or at least hematocrit, may be performed as hyperestrogenism can cause pancytopenia, consisting of mild to moderate non-regenerative anemia, thrombocytopenia, and leukopenia.²⁶ In rare individuals, liver enzymes can be elevated secondary to metastasis.²⁶

Imaging

Survey radiographs are usually unremarkable except in cases of prostatomegaly, where the prostate may appear as a mass lesion dorsal to the bladder (Fig 10). Profound adrenomegaly may also be visible on survey radiographs, however, in most cases, even when the gland is mineralized, radiographs are not diagnostic.

 

Abdominal ultrasound is the most useful diagnostic tool. Experienced ultrasonographers often detect adrenomegaly (width > 3-3.5 mm) or abnormal adrenal architecture in which the gland becomes irregular or widened.^3,21 Distinct nodules are less commonly seen ³, however increased vascularization is frequently observed. With adequate landmarks, both adrenal glands can be identified relatively easily. Typical findings include increased width (> 3.9 mm), rounded appearance, heterogeneous structure, increased echogenicity or mineralization of the gland (Fig 11, Fig 12).^25,26 The adrenal glands of clinically affected ferrets may occasionally appear normal in size and shape, especially early in the disease process. Both glands are affected in about 20% of cases, and the contralateral gland displays no atrophy.^2,25,32 However, ultrasonographic findings do no provide information regarding functionality of the modified gland and sonographically normal adrenal glands may still be surgically and histologically abnormal.^10,26

 

 

Ultrasound can also be used to further evaluate prostatic tissue in male ferrets. During abdominal ultrasound, it is also important to look for potential metastases or potential ovarian remnant in females or cryptorchid testicles in males.

Computed tomography with contrast may be useful to better delineate the enlarged gland, especially in preparation for surgery.²⁶

Hormone analysis

Measurement of serum or plasma hormone levels is also commonly used. The ferret androgen panel typically includes estradiol, androstenedione, and 17α-hydroxyprogesterone. Most affected ferrets will have elevated blood levels of one or more of these steroids, however intact females also show increased hormonal levels during estrus, so this diagnostic test is unable to differentiate adrenal disease from an ovarian remnant.^25,26

Ancillary tests

Uncommonly used tests include a human chorionic gonadotropin stimulation test and the urinary corticoid-creatinine ratio.²⁶ These tests are of limited value in clinical practice because they only differentiate healthy neutered ferrets from neutered ferrets with adrenal disease. Ovarian remnant disease cannot be differentiated.²⁵

Histopathology

Histology of the affected adrenal gland provides a definitive diagnosis. Lesions are most commonly neoplastic with 62% to 92% of adrenal lesions being cortical neoplasms, including 41% carcinomas and 29% adenomas. Cortical hyperplasia accounted for 8% to 19% of lesions in these studies.^1,10,18,27 However, in surgical case studies, carcinomas were only encountered in 10% to 40% of removed adrenal glands.¹⁰

Other adrenal tumors, such as pheochromocytomas, neuroblastomas, leiomyosarcomas, leiomyomas, and spindle cell sarcomas, represent 2% to 8% of adrenal neoplasms.^1,18,24

 

Therapy

If left untreated, adrenocortical disease can cause potentially fatal sequelae, including urethral obstruction in males, bone marrow suppression, tumor-related invasion of the vena cava, and/or regional metastasis to the liver or spleen. In addition, affected ferrets clinically feel unwell and are uncomfortable.

Treatment options include surgery and medical management. The choice depends on many factors, such as the age of the ferret, the presence of concurrent disease, the surgical risk (higher for the right adrenal gland) and/or financial limitations. In one study, the mean disease-free period was higher for ferrets treated with a deslorelin implant (16.5 months) compared with ferrets who underwent surgery (13.6 months).^15,25 Median recurrence time post-surgery was 6 to 7 months in other studies.^10,18,31

Surgical therapy

Adrenalectomy has traditionally been considered the treatment of choice for ferrets determined to be good anesthetic candidates that have a concurrent condition that would benefit from surgery, such as insulinoma. Geriatric ferrets or ferrets with cardiomyopathy are not good candidates for surgical therapy.

Surgical removal of diseased adrenal tissue may be unilateral or partially bilateral. Because of the intimate association between the right adrenal gland and the caudal vena cava, right adrenalectomy is a much more technically demanding procedure (Fig 13-Fig 15). However, a study found that collateral circulation seems to develop when the caudal vena cava is ligated.^4,10 Anecdotal evidence suggests this is less common, with collateral circulation developing before ligation due to an already reduced flow. For this reason, it is wise to confirm the presence of collateral circulation with Doppler ultrasound prior to ligation or risk severe adverse events like kidney failure (C. Johnson-Delaney, written communication, October 2022). Partial resection of the right adrenal gland was found to have a more favorable outcome than complete resection or partial resection combined with cryosurgery.²⁸  In cases where both glands are affected, some authors suggest to remove the entire left gland and part of the right one. This resulted in an Addisonian crisis in 5% of these ferrets, and this complication should be anticipated and discussed with owners. Detailed descriptions of surgical techniques in the ferret can be found elsewhere.^2,12

 

 

 

Perioperative death may occur in 2% to 5.5% of patients and chylous ascites has been described as a postoperative complication of adrenalectomy.²⁹ Ninety-eight percent of ferrets treated surgically survived 1 year post-operatively and 88% survive to 2 years.²⁸

Clinical signs caused by prostatomegaly and pruritus begin to subside within 48 to 72 hours after surgery. All clinical signs may resolve within 2 to 4 months postoperatively, although in one study 5.8% of patients did not improve after surgery.^{2,10,15,25,29} Owners should be informed that recurrence occurs in about 15% to 30% of cases due to development of disease in remaining adrenal tissue.

Excised adrenal tissue may be submitted for histopathological examination, although the exact etiology of the lesions (hyperplasia, adenoma, or adenocarcinoma) was not found to influence  survival time.¹⁰

Medical management

DESLORELIN ACETATE

Deslorelin is a depot GnRH agonist and deslorelin implants (Suprelorin-F, Virbac) are the only drug licensed for treatment of adrenal disease in ferrets. When comparing surgical resection alone with deslorelin acetate implants alone, deslorelin acetate provides a longer disease-free interval based on timing to recurrence of clinical signs.^15,22,25 The continuous release of deslorelin suppresses the release of gonadotropins, overriding the pulsatile release of GnRH needed for the secretion of gonadotropins.²⁵ However, it is essential to acknowledge that this GnRH agonist only moderates clinical signs, it does not cure the disease. Tumor size does not change significantly after implant placement, and in fact, tumor size may continue to increase.³⁰ Additionally, autonomous production of steroids by the adrenal glands may occur over time and result in loss of efficacy of the implant and thus recurrence of clinical signs.²⁵

After placement of the implant, clinical signs may worsen during the first 2 weeks before the suppressive effects begin. Hair regrowth may occur within 4-6 weeks post-implant but may be incomplete in some ferrets. Most ferrets have complete regrowth by 8 weeks post treatment. Within 2 months, plasma levels of steroid hormones decrease. Vulvar swelling and pruritus decrease 10-14 days after treatment, and the vulva returns to a normal appearance by 6 weeks post-treatment.⁶ Clinical recurrence has a median time of 13.7 to 17.6 months in ferrets treated with GnRH implants. So, even if survival time has not been specifically evaluated, it is at least 1 to 2 years based on this data.^10,15,30

 

LEUPROLIDE ACTETATE

Leuprolide acetate 30-day depot (Lupron) may also be used.⁵ In a study using the monthly depot form, median time at recurrence was 3.8 months.^10,18 Most clinical signs (vulvar swelling, pruritus, dysuria, and aggression) diminish within a few days to weeks, but hair regrowth still takes 4 to 8 weeks.⁶

Some ferrets with adrenal disease do not respond to the deslorelin implant, and may instead respond to leuprolide acetate. As leuprolide acetate may begin to work more rapidly than deslorelin, a Lupron dose may be given at the same time an implant is inserted for profoundly uncomfortable ferrets (C. Johnson-Delaney, written communication, October 2022).

 

OTHER TREATMENTS

A single injection of a GnRH vaccine (GonaCon, USDA) was shown to be effective in resolving clinical signs and normalizing serum sex hormone levels within 3 months.¹⁷ This vaccine is used for contraception of wildlife populations (especially deer), but it is not commercially available or labeled for use in ferrets.^17,26

Additional treatments, such as melatonin^20,23, ketoconazole, mitotane, and trilostane have been investigated but are currently discouraged for use in ferrets with adrenal disease.²⁵

Management of prostatic enlargement and paraurethral cysts

Ultrasound-guided aspiration of large prostatic cysts should be performed to improve urethral patency and for cytology and bacterial culture and sensitivity. Prostatic or urethral cysts containing flocculent material should also be aspirated for culture and sensitivity and/or cytology. Preputial cytology may show an increase in cornified epithelial cells in males with hyperadrenocorticism.²²

For medical management of prostatic enlargement, administration of a GnRH agonist is generally advised. Treatment usually leads to improvement of dysuria within a few days.⁵ , however, in some ferrets it may temporarily make prostatic disease worse, and obstruction can occur. Therefore urination must be closely observed.

Visit Urethral Catheterization in Male Ferrets for advice on managing affected males.

In cases of prostatitis, management with antibiotics (e.g. trimethoprim-sulfamethoxazole) and placement of a deslorelin implant was successful in all cases.³⁰

Surgical management, such as omentalization or surgical draining, may also be required in severe cases and has been described.^2,12

Prognosis and complications

Ferrets with adrenal disease may live for several years after diagnosis, depending on factors such as age, concurrent diseases, clinical signs, and extension of neoplasms, usually by local invasion. Rupture of the caudal vena cava invaded by an adrenal tumor has been reported, and prostatic enlargement may lead to life-threatening urinary blockage.²⁶ Although very rare, metastases may also occur. Paraplegia caused by metastases to the spinal cord and vertebral bodies resulted in hindlimb paraplegia in a ferret.⁹

In females, cystic stump pyometra has been reported in spayed jills, and suspected secondary to adrenal disease with increased progesterone levels.¹⁶ Hyperestrogenism-induced anemia may also occur and depending on anemia severity, blood transfusion might be required.¹⁹

 

Prevention

Although neutering is generally required for prevention of hyperestrogenism in jills and reducing the intensity of body odor in hobs, surgical desexing should be avoided as it has been implicated as a causative factor of adrenal disease. Instead chemical neutering using the deslorelin implant is advised. The 4.7-mg implant is effective between 1 and 3 years in females and males.²⁶ Although in many countries, ferrets in the pet trade have undergone early neuter/spay and demusking at 5-6 weeks of age, it may be advantageous to consider deslorelin implantation starting at the age of chronological puberty and maintained throughout the ferret’s life.^25b,26 Uncommonly, benign adverse effects, such as pruritus and scabs, have been observed.²⁶ In the first 2 weeks after placement, temporary estrus may be observed and rare incidence of pseudopregnancy has been reported.²⁶

Although studies evaluating the impact of deslorelin implants on the incidence of adrenal disease are ongoing, the GnRH vaccine was associated with a lesser increase in the size of adrenal glands in jills. It is thus likely that GnRH implants also prevent the development of adrenal disease.^17,26

 

Conclusion

Hyperadrenocorticism is a common and complex clinical condition in the pet ferret. This disease occurs most frequently in middle-aged to older ferrets but has been reported in animals as young as one year of age. Presumptive diagnosis of adrenal disease in the ferret is based on history, clinical signs and diagnostic imaging. Medical therapy using deslorelin implants, though not curative, is recommended. Ferrets may remain asymptomatic for a median of 1-1.5 years. Adrenalectomy may be indicated in case non-responsiveness to medical treatment, although adrenalectomy of the right adrenal gland is challenging.

 

Acknowledgement:  This article is an updated version of a manuscript written by Tracey Ritzman, DVM, DABVP (Avian Practice), DABVP (Exotic Companion Mammal Practice).

 

References