Cause and who is affected
Merck considers the following mechanism likely. Neutering removes negative feedback, so gonadotropins stay high and keep stimulating the adrenal cortex until it grows [1]. The neoplasia chapter adds that, under constantly raised luteinizing hormone, cells of the zona reticularis differentiate into cells able to make estrogen, androstenedione, and hydroxyprogesterone [4].
Neutering age seems not to matter. Merck states that the time of neutering "is no longer thought to play a significant role." The 2010 review notes that European ferrets neutered later also develop the disease. It takes this to mean that neutering itself, not its timing, is the driver [1][2].
The 2020 chapter cites a randomized trial that confirmed the gonadectomy link, though it does not give the trial's size [3]. That chapter also says that outside the United States, most ferrets are not gonadectomized but are chemically neutered with 4.7-mg deslorelin acetate implants. In these ferrets, adrenal disease and prostatic cysts are relatively uncommon [3]. The neoplasia chapter also mentions lower incidence in Europe and points to outdoor housing, natural light cycles, and delayed neutering as possible factors [4].
According to the neoplasia chapter, several studies place the average age at about 4.5 years. The disease has been reported in ferrets under 12 months, and there is no sex predilection [4].
Clinical signs
Merck lists symmetrical alopecia, a swollen vulva in neutered females, return of sexual behavior in neutered males, and pruritus as the most prominent signs [1]. The 2010 review describes hair loss that usually starts at the tail and moves forward to the shoulders and neck [2]. The neoplasia chapter reports bilateral truncal alopecia in about half of affected ferrets and vulvar swelling in up to 90% of affected neutered jills. It adds that the absence of vulvar swelling does not exclude the disease [4].
In males, prostatic enlargement and periprostatic or periurethral cysts can cause stranguria and urinary obstruction. The 2010 review warns that severe prostatomegaly can lead to acute renal failure [1][2]. The 2020 chapter calls adrenal-associated prostatic disease the most frequent cause of urethral obstruction in male ferrets in the United States [3]. That chapter also reviews a six-ferret series of paraurethral cysts. Adrenal hyperplasia or neoplasia was found in five, and the adrenal gland of the sixth was not evaluated [3].
Other reported associations include:
- aggression in males
- occasional mammary enlargement in females
- stump pyometra in spayed females
- hyperestrogenism when the disease goes untreated [1][2][3]
Diagnosis
Examination and imaging
Merck describes the initial diagnosis as presumptive, based on history and physical examination. An enlarged gland may be palpable craniomedial to a kidney, and the left gland is easier to palpate than the right [1]. The 2010 review places the left adrenal in a large fat pad cranial to the left kidney and the right one under a liver lobe [2].
Merck calls ultrasonography the most useful tool for identifying which gland is affected and for checking for an ovarian remnant. It also lists contrast CT as an option [1]. The neoplasia chapter recommends a 14.5-MHz probe for best detail [4].
Imaging has a limit. The neoplasia chapter warns that "functional lesions may be present in normal-sized adrenal glands," so a gland that looks normal on ultrasound does not rule out disease [4].
Hormone testing
The neoplasia chapter states that hyperadrenocorticism in ferrets "is not a form of Cushing's disease" and that cortisol testing is not useful for routine diagnosis [4]. The 2010 review adds that dexamethasone suppression and ACTH stimulation tests are not useful [2].
According to the neoplasia chapter, estrogen, androstenedione, and 17-hydroxyprogesterone are "over 95% predictive" for adrenocortical disease [4]. Merck and the 2020 chapter identify the University of Tennessee as the laboratory that runs the panel [1][3]. None of the cited sources gives reference ranges for the panel.
Differentials and bloodwork
Merck states that hormone elevations cannot separate adrenal disease from an active ovarian remnant [1]. The 2020 chapter says that in spayed ferrets, abdominal ultrasound can help tell the two apart [3]. The neoplasia chapter suggests considering residual reproductive tissue when signs appear in very young spayed females or respond poorly to medical management [4].
The 2010 review reports that CBC and chemistry are usually normal, although ALT may be raised. Occasional anemia, or in severe cases pancytopenia resembling estrogen toxicity, can occur. A packed cell volume below 15% is "associated with a grave prognosis" [2].
Pathology and classification
The cited sources give no formal staging scheme for ferret adrenal disease. The 2010 review states that the hormone elevations can occur with cortical hyperplasia, adenoma, or adenocarcinoma [2]. The neoplasia chapter describes these lesions as a spectrum from hyperplasia to benign or malignant neoplasia. It notes that adenomas and adenocarcinomas cannot be differentiated without histopathology [4]. That chapter reports that the left and right glands are affected about equally often and that about 20% of cases are bilateral [4].
The neoplasia chapter also describes leiomyosarcomas of the adrenal capsule. These very firm masses cannot be differentiated without histopathology and may lead surgeons to remove a normally functioning gland [4].
Surgical treatment
Merck describes left adrenalectomy as fairly easy, with only the phrenicoabdominal vein needing ligation. The right side is harder because the gland is attached to the caudal vena cava and lies close to the liver [1].
The 2010 review says complete right-sided excision is often not possible and that disease can recur in the remaining gland or in residual tissue. It recommends bilateral adrenalectomy when both glands are affected. In males, it recommends drainage with marsupialization of prostatic cysts [2].
When a tumor occludes 50% or more of the vena cava, the neoplasia chapter's authors do not recommend en bloc resection of the vessel. They cite risks of renal failure and death that they consider greater than the risk of death from the adrenal disease itself [4].
The 2020 chapter reports that cystic prostatic hypertrophy usually begins to resolve within 2 to 3 days after surgery [3].
Medical treatment
Deslorelin implant
Merck states that the deslorelin implant is licensed for ferret hyperadrenocorticism. The implant releases the drug continuously. This overrides the pulsatile GnRH signal needed for gonadotropin release and down-regulates pituitary receptors [1]. The 2020 chapter identifies the product as a 4.7-mg deslorelin acetate implant (Suprelorin, Virbac). It describes medical therapy as the usual first-line approach for adrenal-associated prostatic disease [3].
Merck cautions that medical treatment does not affect the tumor itself. Over time the adrenal tissue may begin producing steroids on its own, leading to a loss of efficacy and a return of signs [1].
Merck reports a disease-free period of 16.5 months (range 3 to 30) for the implant, compared with 13.6 months (range 0 to 38) for surgery. It does not give the study design or sample size, and the ranges overlap widely [1]. Merck also cites preliminary data suggesting that using the implant in place of surgical neutering may lower the incidence of adrenal disease [1].
Other drugs
The 2010 review does not mention the deslorelin implant. It names leuprolide acetate as one of the most widely used drugs, given intramuscularly or subcutaneously every 3 to 8 weeks. It notes that most ferrets need treatment for life and that the affected gland usually does not shrink [2].
The 2020 chapter lists depot leuprolide acetate given intramuscularly. It reports that high-dose leuprolide can shrink prostatic tissue within 12 to 48 hours [3].
The 2010 review describes melatonin as promoting hair regrowth and lowering plasma steroids [2]. Anastrozole, flutamide, bicalutamide, and finasteride are also mentioned. The 2020 chapter says the effectiveness and safety of the antiandrogens remain unclear and advises caution in ferrets with liver disease [2][3].
Where the sources disagree
The neoplasia chapter (2012) calls surgery the treatment of choice and generally reserves medical therapy for nonsurgical candidates [4]. The 2010 review says surgery may be preferred if a ferret is otherwise in good health. It says medical therapy is often chosen for older ferrets with concurrent disease or for poor anesthetic and surgical candidates [2]. Merck, citing its disease-free figures, says medical treatment has become preferred [1]. Merck does not describe the study design behind those figures.
Prognosis and monitoring
The neoplasia chapter says a good prognosis appears warranted for all surgically removed lesions, regardless of side, histologic grade, or completeness of excision. It also warns that lesions can occasionally develop later in the contralateral gland, and that a low percentage of highly anaplastic carcinomas metastasize [4].
The 2020 chapter describes the prognosis for prostatic cysts as generally good with aggressive treatment of the adrenal disease. It recommends following cysts by ultrasound and tracking sex-steroid levels and adrenal size [3].
The 2010 review suggests that ferrets aged 3 to 4 years and older have examinations twice a year and yearly bloodwork, which may include an adrenal panel [2].
Points for client conversations, drawn from these sources, include:
- the likelihood of lifelong drug therapy
- the possibility of disease in the other gland
- gradual loss of implant effect
- the emergency risk of urinary obstruction in males [1][2][3][4]
