Western Veterinary Conference 2013 EX26 UP-TO-THE-MINUTE UPDATE ON FERRET ADRENAL DISEASE Dan H. Johnson, DVM, Dipl. ABVP (Exotic Companion Mammal) Avian and Exotic Animal Care Raleigh, NC, USA INTRODUCTION Adrenocortical disease (ACD) primarily affects middle-aged to older ferrets with a reported prevalence of up to 25%; however, the incidence of adrenal gland lesions in clinically normal ferrets is likely to be much higher (Chen 2010). Ferret adrenal disease differs from “Cushing’s disease” because adrenal sex steroids are overproduced instead of cortisol as a result of adrenocortical hyperplasia, adenoma, or adenocarcinoma. Neutering, photoperiod, and genetics are believed to play a role in the pathology of adrenocortical disease. CLINICAL SIGNS Adrenal disease typically causes dorsocaudal alopecia in either gender. Pruritis, sexual or aggressive behavior, and a noticeable increase in musky odor can also occur. Affected females may develop vulvar enlargement, and males may present with stranguria or urinary obstruction secondary to prostatic hyperplasia, prostatic cysts, prostatic abscesses, or prostatitis. Additional clinical signs may include estrogen-induced bone marrow toxicity, mammary gland hyperplasia, cystitis, paraurethral or paraprostatic cysts, muscle atrophy, and lethargy. Clinical signs vary depending on which sex hormones are elevated; however, clinical signs do not correlate with the size of the affected gland or degree of adrenal pathology. ETIOLOGY Evidence suggests that neutering (at ANY age) promotes ACD by removing sex hormonal negative feedback on the hypothalamus and leads to overproduction of gonadotropin-releasing hormone (GnRH). In response, the pituitary maintains persistently elevated luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH binds with functional receptors on the adrenal gland, causing it to overproduce sex hormones and inducing hyperplastic and/or neoplastic adrenocortical enlargement. Prolonged photoperiod is also thought to play a role in development of ACD. Ferrets kept indoors under artificial lighting are subjected to unnatural prolonged periods of ‘‘daylight’’ (>8 hours), which is thought to deplete the body’s store of melatonin. As the concentration of this antigonadotropic hormone in blood decreases, there is an increase in GnRH and LH synthesis and release. Finally, a genetic component may also play a role in the etiology of ACD, as one or more tumor suppressor gene aberrances are believed to exist in the highly inbred US ferret population DIAGNOSIS Physical exam findings of symmetrical alopecia, swollen vulva, or palpable mass cranial to the kidney are suggestive of ACD. CBC may reveal anemia in cases with elevated estradiol. Blood chemistry frequently reflects an elevated ALT. Elevations in plasma estradiol, androstenedione, and 17-OH-progesterone are diagnostic (UT ferret adrenal hormone panel; 865-974-5638). Ultrasonography can demonstrate adrenal gland enlargement and distinguish right versus left ACD for surgical planning. Laparotomy permits biopsy with histopathology. TREATMENT The goals of management are to reduce sex steroid production and to provide a normal life span and a good quality of life for the patient. Surgery aims to remove or debulk the tumor (adrenalectomy), whereas medical treatment (hormonal suppression) does not affect the tumor and is not curative. Treatment choice depends on stage of tumor which gland is affected (left vs. right), surgeon’s experience, severity of clinical signs, age of the animal, concurrent diseases, and owner finances. Surgical Surgery is the treatment of choice for adrenocortical disease (ACD, adrenal gland disease, hyperadrenocorticism) in ferrets that are otherwise healthy. For the surgical approach, make a ventral midline incision, extending from the xyphoid as needed to allow a thorough examination of the abdomen. Both adrenal glands should be observed and palpated. They are often embedded in fat and lie at the cranial pole of the kidneys. Normal adrenal glands are whitish pink, 2-3mm wide, and 6-8mm long. Not all diseased adrenal glands are enlarged, and palpation alone is not enough to evaluate for disease. Thus, if the entire gland is not visible, use mosquito hemostats and cotton-tipped applicators to carefully dissect the thin layer of peritoneum and fat surrounding the gland. On the right side, incise the hepatorenal ligament and use it to retract the caudate lobe of the liver cranially. Cysts, yellow-brown discoloration, irregular texture, and enlargement are indications for removal of the gland. If only one adrenal gland is diseased, there is debate as to whether it is best to leave the normal gland, to remove half of it, or to remove it entirely. If both glands are diseased, complete removal of both glands should be attempted. Often the left adrenal is completely removed and the right adrenal is debulked by placing hemostatic clips across it to allow for 5075% removal. Alternatively, the capsule is incised and the glandular contents are shelled out. Subtotal adrenalectomy usually does not result in the need for long-term postoperative steroid therapy. If the right adrenal gland is debulked (less risky than complete removal) signs of ACD may return, necessitating repeat surgery or medical therapy. Removal of the left adrenal gland is usually uncomplicated. The phrenicoabdominal vein (adrenolumbar vein) courses over the ventral surface of the gland. This is ligated at the craniolateral surface of the adrenal gland, and the cranial, lateral, and caudal aspects of the gland are dissected. The gland is elevated and gently undermined, and the phrenicoabdominal vein is traced to the vena cava and inspected for tumor invasion. If no tumor invasion is detected, the vein is ligated and the gland is removed. Right adrenalectomy is often more difficult because of adherence of the gland to the wall of the vena cava and the greater potential for vascular invasion. Magnifying loupes, microsurgical instruments, and vascular clamps are often needed. If the tumor is small, often it can be almost completely freed from the wall of the vena cava with gentle dissection. If so, place hemostatic clips between the gland and the cava and resect the gland. Frequently, however, the gland cannot be freed from the vena cava because of tumor invasion, or it is located mostly on the dorsal aspect of the vessel. For these cases, more advanced surgical techniques may be needed. Partial or total occlusion of the vena cava may be necessary to allow removal of the gland with a portion of the caval wall. Temporary occlusion can be accomplished with a small vascular clamp (neonatal Satinsky clamp) or with oversized braided suture material (e.g. 2-0 Vicryl) tied around the vessel in a “shoelace” knot. The defect in the caval wall can be sutured with 6-0 or smaller monofilament suture. The time that the vena cava is occluded should be limited. Before restoring blood flow, place a piece of gelatin sponge over the suture line. With extensive vascular invasion of the vena cava, resection and anastomosis may be indicated. In some cases, complete ligation of the vena cava may be successful, however predicting whether a ferret will survive complete ligation at surgery is impossible. Approximately 25% of ferrets that undergo complete surgical ligation of the vena cava will experience acute venous hypertension and resultant renal failure. Therefore, surgical procedures that preserve the cava should be attempted before ligation. Research has demonstrated that in most ferrets tested there is collateral circulation branching from the vena cava, through the vertebral sinus, the azygos vein, and back to the vena cava cranial to the ligation. Why some ferrets survive ligation while others do not is unknown. One theory as to why some ferrets survive complete vena cava occlusion is that the adrenal tumor has already created a partial occlusion, allowing for collateral circulation to have gradually developed prior to vena cava ligation. Recently, a technique has been described wherein an ameroid constrictor ring is placed on the vena cava to provide more gradual occlusion. A second surgery is then performed weeks to months later to remove the right adrenal and vena cava segment intact. Cryosurgery, laser surgery, and radiosurgical ablation of the right adrenal gland have been reported. With any of these methods, it may be difficult to evaluate how completely the adrenal tumor has been destroyed. Concerns about thermal damage to the vena cava exist with laser or radiosurgery, but not with cryosurgery. Freezing kills adrenal tumor cells. It also kills caval endothelium, however vessel wall integrity remains intact thanks its elastic structure. After cellular death by freezing, elastic collagen serves as the matrix for new endothelial growth. Some controversy exists about cryosurgery of the adrenal gland as a recent study suggests that the addition of cryosurgery to partial resection has a negative prognostic indicator for long-term survival. Although complete tumor resection is the goal of surgical treatment, partial resection seems to be sufficient to achieve long-term survival, especially for tumors involving the right adrenal gland. Regardless of the method of tumor removal used, a surgical biopsy is recommended in order that histopathology of the tumor can be performed. Medical Melatonin helps to regulate the ferret’s natural breeding season. Melatonin 0.5-1.0 mg/animal every 24 hour by mouth, administered 7-9 hours after sunrise, has been shown to be effective in alleviating clinical signs of alopecia, aggressive behavior, vulvar swelling, and prostatomegaly. The implant form of the drug is approved by the USDA for use in mink, and is commercially available for ferrets in a 5.4mg constant-release implant (Ferretonin, Melatek) that releases melatonin over a 3-4 month period. Possible side effects include lethargy and weight gain. Melatonin can be used alone or in combination with other therapies. The GnRH analog leuprolide acetate (Lupron, TAP Pharmaceuticals)) is a potent inhibitor of LH and FSH. The dose of the 30-day depot formulation is 100-250 micrograms/kg IM q4w until signs resolve, then q4-8w as needed, lifelong. Side effects include dyspnea, lethargy, and irritation at the injection site. Leuprolide acetate was the mainstay of medical therapy for ACD until the introduction several years ago of a longer-acting alternative, deslorelin acetate. Deslorelin acetate 4.7-mg slow-release implants (Suprelorin, Peptech Animal Health, North Ryde, Australia) are commercially available for non-surgical contraception of male dogs in Australia, New Zealand, and some European countries. Deslorelin implants have been evaluated for use in ferrets with ACD, and results are positive (Wagner 2009). Deslorelin 4.7mg implants were legally imported in compliance with FDA guidelines for the past several years, but are now available by prescription in the US, marketed by Virbac under the brand name “Suprelorin F” (Order at http://www.virbacferretsusa.com/ ). As of this writing, the implants are not approved by the FDA, but are legally marketed as an FDA indexed product for use in ferrets only. Extra-label use is prohibited, and the product must not be used in animals intended for use as food for humans or other animals. RECOVERY In most ferrets, clinical signs ACD resolve after adrenal sex hormone levels return to normal. Improvement with medical therapy may be more likely in patients with adrenal hyperplasia or adenoma; less likely in patients with adenocarcinoma. Reduction in vulvar swelling, paraurethral cysts, or prostatic size may be expected within several days. Hair coat typically returns to normal within 2-4 months. PROGNOSIS Prognosis for all treatments varies and depends on tumor type, age of animal, presence of concurrent disease, and mode of treatment. The 1- and 2-year survival rates for ACD are reported to be 98% and 88% respectively. Following unilateral adrenalectomy or subtotal adrenalectomy, monitor for the return of clinical signs; tumor recurrence is common. The reported recurrence rate with development of disease on the contralateral gland following unilateral adrenalectomy is 17%, whereas recurrence following subtotal bilateral adrenalectomy is 15% 7-22 months after surgery. PREVENTION Neutering prevents fatal estrogen-induced bone marrow suppression in jills, reduces aggression in hobs, and decreases the musky odor associated with all ferrets, making them better pets. However, neutering is thought to play an important role in the development of ACD. Alternatives to surgical neutering need to be developed that accomplish the same medical and behavioral goals without predisposing ferrets to ACD. The best hope for such a treatment appears to be deslorelin acetate. Investigators examining the effects of the deslorelin implant and surgical castration on the occurrence of intermale aggression, sexual behavior and play behavior in male ferrets concluded that deslorelin implant is a suitable alternative to surgical castration, and may even be preferred due to the serious medical problems associated with surgical castration in ferrets (Vinkea 2008). Researchers also looked at the effects of deslorelin implantation on plasma testosterone levels, testis size, spermatogenesis, and musky odor in intact ferrets. They concluded that the deslorelin implant effectively prevents reproduction and the musky odor of intact male ferrets and is therefore considered a suitable alternative for surgical castration in male ferrets (Schoemaker 2008). It may be possible to prevent ACD in neutered ferrets through the regular use of deslorelin implants after spay or castration, regardless of the ferret’s age. While this theory has yet to be proven, the concept of using GnRH agonists to prevent ACD in neutered ferrets is widely accepted among ferret veterinarians (Ghys 2011). REFERENCES 1. Simone-Freilicher S. Adrenal disease in ferrets. Vet Clin No Am Exotics 2008; 11(1): 125-137. 2. Chen S. Advanced diagnostic approaches and current medical management of insulinomas and adrenocortical disease in ferrets (Mustela putorius furo). Vet Clin Exot Anim 2010; 13(3): 439-452. 3. Antinoff N, Williams BH. Neoplasia. In: Quesenberry K, Carpenter J, eds. Ferrets, Rabbits, and Rodents: Clinical Medicine and Surgery, 3rd Ed. St. Louis: Elsevier 2012, 105-106. 4. Rosenthal K, Wyre NR. Endocrine diseases, In: Quesenberry K, Carpenter J. Ferrets, Rabbits, and Rodents: Clinical Medicine and Surgery, 3rd Ed. St. Louis: Elsevier, 2012: 86-102. 5. 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