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Ferret Adrenal Gland Disease

Karen L. Rosenthal, DVM, MS, University of Pennsylvania

Exotic Animal Medicine

|November 2007|Peer Reviewed

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Definition
• Multisystemic clinical disease caused by abnormally high circulating concentrations of adrenal gland hormones including, but not limited to estrogen, DHEAS, 17-OH-progesterone, androstenedione, and uncommonly cortisol
• Since cortisol is rarely elevated, this is not described as Cushing's disease but rather as ferret adrenal gland disease
• Genetic implications are unknown but are speculated as a cause
• One of the most common endocrine diseases in pet ferrets; true prevalence is unknown
• Common in North America but also reported in the United Kingdom, Europe, Australia, and New Zealand

Signalment
• Usually seen in middle-aged to older ferrets (3 to 7 years of age) but can be seen in ferrets as young as 1 year of age
• No sex predilection

Causes
Unknown. Speculation includes genetics, early neuter and spay, lack of correct light/dark cycle, diet

Risk Factors
• Researchers have tried to link early neutering and spaying with an increased risk for adrenal gland disease, but ferrets that are spayed or neutered later in life have also been reported to develop this disease. Early spaying and neutering causes an abnormal reaction to LH/FSH, leading to enlargement of the adrenal gland and release of hormones.
• Lack of a proper light/dark cycle-usually too much light-leads to alteration in melatonin concentrations and thus possibly to abnormal adrenal gland development.
• Decades of in-breeding may have led to a genetic disposition to adrenal gland disease.
• Some have speculated that diet alterations from the wild-type diet could contribute to adrenal gland disease in pet ferrets.

Pathophysiology/Signs
• Both unilateral and bilateral adrenal gland disease can be present. Adrenal glands can be described as being hyperplastic or as having adenomas or adenocarcinomas. Pituitary lesions have never been reported. The abnormal adrenal glands can produce one or more hormones in excessive quantities. It is impossible to predict which hormones will be elevated in which patient. Signs vary, depending on which hormones are produced.
• The most common sign of adrenal gland disease is hair loss associated with normal-appearing skin. Hair may be lost symmetrically along the flanks and tail and proceed along the body wall cranially, or it may fall out in no specific pattern.
• Females usually have an enlarged vulva.
• Animals are pruritic in about 30% of cases.

• An unknown percentage (probably ≤ 10%) of male ferrets will develop an enlarged prostate, sometimes accompanied by bacterial prostatitis. Severe prostate enlargement precludes urination and is considered an emergency equivalent to that in a "blocked" cat.
• Some ferrets become sexually aggressive to other ferrets or humans.
• In my experience, bone marrow suppression may occur but is very rare-first the red blood cell line becomes suppressed and then other lines might follow. Bone marrow suppression is theorized to be caused by increased estrogen.
• Most cases of ferret adrenal gland disease cause only cosmetic changes: hair loss and an enlarged vulva. Pruritus is more of a quality-of-life issue. Prostate disease and bone marrow suppression are the only truly life-threatening aspects of this disease but the incidence rate of these complications is unknown. Certainly, adrenal gland disease left untreated could become life threatening. Adrenal glands tumors can localize, metastasize or potentially, but rarely, invade distant tissue. Time frame for metastasis is unknown. Since adrenal gland disease is often a disease of older ferrets, the patient may develop another older-ferret condition that is more life threatening. It is very important for the clinician to recognize that some ferrets with adrenal gland disease can live out their life span with no serious complicating aspects of this problem, as treatment may be expensive and risky for the patient.
• Owners usually report hair loss, behavior changes, or difficulty urinating in males with prostate disease; females have an enlarged vulva (which ordinarily would be very small if the animal has been spayed) and pruritus with no outward signs of dermatologic causes. All are considered to be cases of adrenal gland disease until proven otherwise.

Diagnosis

Definitive Diagnosis
• Elevated adrenal gland hormones
• Abdominal ultrasonography revealing abnormal adrenal glands
• Exploratory surgery with removal and histopathologic evidence of abnormal adrenal glands

Differential Diagnoses
• Hair loss and pruritus: ectoparasites, dermatophytosis
• Enlarged vulva: unspayed female, ovarian remnant

Laboratory Findings
• CBC usually normal
• Very rare: nonregenerative anemia due to bone marrow suppression
• Biochemistry panel: usually normal
• Urinalysis: usually normal; pyuria, bacteriuria, mucus may be present with prostate disease

Imaging
• Whole-body radiographs are usually normal
• Enlarged and/or mineralized adrenal gland very rarely visualized
• Prostate disease may be accompanied by an enlarged bladder; enlarged prostate rare on radiographs
• Ultrasonography can reveal enlarged adrenal glands and determine if prostatic disease is present

Postmortem Findings
• Enlarged adrenal glands
• Possible invasion of the right adrenal gland into the vena cava
• Metastasis rare, even in adrenal gland adenocarcinoma

Treatment

Outpatient
• Medical treatment is usually done on an outpatient basis
• Used only for non-life-threatening cases
• Response varies
• Medications do not seem to stop growth of the adrenal gland; medications are only palliative
• Some medications are specifically designed to decrease size of prostate

Inpatient/Surgery
• Surgical removal of diseased adrenal glands
• All diseased tissue must be removed for "cure"
• Left adrenal gland usually easier to remove
• Right adrenal gland difficult to remove if attached to or invading the vena cava; in some cases, the only way to remove all of the right adrenal gland is to remove pieces of the wall of the vena cava or to remove a section of it
• If all adrenal gland tissue is removed in cases of bilateral disease, supplements may be needed, including prednisone and a mineralocorticoid
• Removing the right adrenal gland is technically difficult and not recommended for inexperienced surgeons; even ultrasonic investigation may not identify the degree of difficulty associated with removal of the right adrenal gland
• If all adrenal gland tissue cannot be removed, some patients will need a second surgery; some owners choose medical treatment if signs recur
• A recently studied approach includes surgery coupled with a lifelong leuprolide

Activity
No restriction needed

Client Education
Distribute information on how to watch for early signs of adrenal gland disease, which can be an article on the practice Web site or an information sheet given out at annual visits.

Medications

Leuprolide
- GnRH agonist
- Blocks effects of LH/FSH on receptors
- Given as monthly or every few months as an IM injection
- Does not work in all cases; resistance can occur
- No known contraindications, precautions, or interactions
- Expensive for long-term use
Arimidex
- Aromatase inhibitor
- Blocks effects of estrogen
- Used in human breast cancer
- Given PO once a day
- Does not work in all cases; resistance can occur
- No known contraindications, precautions, or interactions
- Expensive for long-term use
Flutamide
- Pure androgen blocker
- Used mainly to reduce prostate size in early prostate disease
- Can be used in ferrets with other signs of adrenal gland disease
- Given PO once or twice daily
- Does not work in all cases; resistance can occur
- No known contraindications, precautions, or interactions
- Expensive for long-term use
Melatonin
- Unknown method of action
- Newest form of medical treatment
- Can be given PO or as a pellet implanted under the skin
- Can reduce endogenous cortisol concentrations to a dangerous level; caution is essential if used in ferrets with concurrent insulinoma

Follow-up

Patient Monitoring
• Signs will recur if treatment is failing.
• Adrenal gland hormone concentrations can be measured, but this is done only if there is a question of disease return.
• Annual or twice-yearly visits are recommended.
• Medical treatment is lifelong.

Prevention
• No known preventative measures, although some are under investigation
• Some speculate that lifelong leuprolide administration starting at an early age may prevent the disease; however, no peer-reviewed publications support this concept, the cost may be prohibitive for a disease a ferret may never develop, and there is reason to believe-if ferrets are like other animals-that long-term administration of foreign proteins may lead to reaction and resistance

Complications
Removal of the vena cava for invasive right adrenal gland disease can lead to renal disease and/or death.

Course
Onset can be insidious; ferrets can live for years if only cosmetic signs are present.

In General

Relative Cost
• Diagnostic workup: $$$-$$$$
• Medical treatment (depends on how long the ferret lives): $$-$$$$$
• Surgical treatment: $$$$

Prognosis
• If only cosmetic changes: excellent-no change in lifespan
• If life-threatening: depends on how ferret responds to treatment

Future Considerations
• New drug classes may expand treatment options.
• Further work into cause may lead to prevention.


FERRET ADRENAL GLAND DISEASE • Karen L. Rosenthal

Suggested Reading
Correlation between age at neutering and age at onset of hyperadrenocorticism in ferrets. Shoemaker NJ, Schuurmans M, Moorman H, et al. JAVMA 216:195-197, 2000.
Cystic prostatic disease associated with adrenocortical lesions in the ferret (Mustela putorius furo). Coleman GD, Chavez MA, Williams BH. Vet Pathol 35:547-549, 1998.
Evaluation of plasma androgen and estrogen concentrations in ferrets with hyperadrenocorticism. Rosenthal KL, Peterson ME. JAVMA 209:1097-1102, 1996.
Ferret abdominal surgical procedures. I. Adrenal gland and pancreatic beta-cell tumors. Wheeler J, Bennett RA. Compend Contin Educ Pract Vet 21:815-822, 1999.
Hyperadrenocorticism associated with adrenocortical tumor or nodular hyperplasia of the adrenal gland in ferrets: 50 cases (1987-1991). Rosenthal KL, Peterson ME, Quesenberry KE, et al. JAVMA 203:271-275, 1993.
Leuprolide acetate treatment of adrenocortical disease in ferrets. Wagner RA, Bailey EM, Schneider JF, et al. JAVMA 218:1272-1274, 2001.
Medical therapies for ferret adrenal disease. (Therapeutics). Johnson-Delaney CA. Sem Avian Exotic Pet Med. 13:3-7, 2004.
Retrospective review of the ultrasonographic features of adrenal lesions in 21 ferrets. Besso JG, Tidwell AS, Gliatto JM. Vet Radiol Ultrasound 41:345-352, 2000.

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