State of the union: Ferret adrenocortical disease (Proceedings)

Adrenocortical disease (ACD, adrenal gland disease, hyperadrenocorticism) is a common malady affecting middle-aged to older ferrets with no sex predilection. ACD can affect ferrets under a year old. First reported in ferrets in 1987, the prevalence of ACD is reported to range from 0.55% to 25%. Ferret adrenal disease is different from human, canine, and feline hyperadrenocorticism because in ferrets adrenal sex hormones are overproduced instead of cortisol. Estradiol, 17-hydroxyprogesterone, or one or more of the plasma androgens may be increased as a result of adrenocortical hyperplasia, adenoma, or adenocarcinoma. The adrenal cortex of the ferret is divided into three layers: zona glomerulosa (outermost), which produces aldosterone; the middle (zona fasciculata) which produces cortisol; and the inner (zona reticularis) which produces androgens. Hyperadrenocorticism can therefore be divided into three syndromes: hyperaldosteronism (the most common form in cats, but also reported in a ferret); hypercortisolism (true "Cushing's disease", the most common form in dogs and man); and hyperandrogenism (the most common form in ferrets). Excess androgen levels are produced by ferrets with ACD by cells under the influence of luteinizing hormone (LH). Androgens can be further metabolized to estrogens by the action of aromatase enzymes by cells under the influence of follicle stimulating hormone. ACD in ferrets may therefore result in excesses of androgens or estrogens, and the clinical signs will vary according to which sex steroid(s) are present. The current theory is that neutering and long-photoperiod interact such that the ferret hypothalamus stays under continuous stimulation, and produces unregulated amounts of gonadotropin releasing hormone (GNRH). This, in turn, stimulates the pituitary to produce continuously high levels of LH and FSH. By the continuous stimulation of LH and FSH, adrenal androgen producing cells are thought to become hyperplastic, and through continued stimulation to progress from hyperplastic, to adenoma, and eventually adenocarcinoma.

Clinical signs

Adrenal disease is most commonly characterized by hair loss in both sexes and by vulvar enlargement in females. Pruritus, sexual or aggressive behavior, and a noticeable increase in musky odor may occur. Affected 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 /paraprostatic cysts, muscle atrophy, and lethargy. Clinical signs may vary depending on which sex hormones are elevated, and clinical signs do not always correlate with the size of the affected gland or the degree of adrenal pathology. In some cases, clinical signs caused by the space-occupying or catabolic effects of the neoplastic process may be seen. It has been reported that approximately 85% of ferrets with hyperadrenocorticism have enlargement of one adrenal gland, and that the other 15% have the disease bilaterally. The most important differential diagnosis for a ferret with signs of ACD is a non-ovariectomized female or a female with an active ovarian remnant. In intact female ferrets, or those with ovarian remnants, treatment with 1000 U of human chorionic gonadotropin, repeated 2 weeks apart will reduce the vulva size. Ultrasonography may help to differentiate these conditions, or exploratory surgery may be required. Severe alopecia and pruritus in a ferret has been seen due to food allergy.

Etiology

The underlying cause of the pathologic changes in the adrenal glands of ferrets with ACD is unknown. There is growing evidence that neutering plays a role. Most ferrets with adrenocortical disease have been neutered before six weeks of age, and the disease rarely occurs in sexually intact ferrets. In the prepubescent gonadectomized ferret, lack of negative gonadal hormonal feedback on hypothalamic gonadotropin-releasing hormone (GnRH) leads to a persistently elevated luteinizing hormone (LH) and follicle-stimulating hormone (FSH). High LH may induce hyperplastic and/or neoplastic adrenocortical enlargement via functional LH receptors. LH binds with these receptors, causing the adrenal gland to overproduce sex hormones. It is thought that the ferret adrenal gland can do this because nests of undifferentiated gonadal cells have been carried with the adrenal glands during embryological development.

There is a debate as to whether neutering has to take place at an early age for ACD to occur. In the US, ferrets are neutered at an early age (4-5weeks), whereas ferrets in the Netherlands are typically neutered after physical maturity. Ferrets in both countries tend to develop adrenal disease about 3.5 years after neutering. In Great Britain and Australia, on the other hand, ferrets typically remain intact, and adrenal disease is rarely reported. This suggests that neutering promotes ACD in ferrets, and that the age at neutering does not.

Husbandry conditions (including diet and photoperiod) of ferrets in the US, where adrenal disease is common, differs from that in Europe and Australia, and this also may play a role in the prevalence of ferret adrenal disease. For example, in Great Britain where ACD is uncommon, ferrets are usually kept outdoors, and are thus exposed to natural photoperiod. In the US, where ACD is very common, ferrets are usually kept indoors and are exposed to a relatively uniform, long photoperiod. This difference suggests that photoperiod may also play role in the development of ACD.

A genetic predisposition in US ferrets is suspected as the ferret population in the US is more inbred than that in Great Britain. About 80% of all ferrets in the US come from one breeding farm, and this has been blamed for the high occurrence of ACD in the US. However, in the Netherlands, where breeding stock are widely distributed, the prevalence ACD is similar to that in the US. One could therefore conclude that inbreeding or a particular breeding facility cannot be blamed. Genetics could still play a role in ACD, however, because it has been shown that the protein marker GATA-4 is expressed in cases of ferret adrenocortical adenomas and carcinomas, but is not present in cases of adrenal hyperplasia. One or more tumor suppressor gene aberrances may exist in the US ferret population. In fact, it has been proposed that the progression of adrenal gland tumors is not under pituitary control, but rather under the control of an abnormal tumor suppressor gene, because the pituitary of affected ferrets has a low density of gonadotropin-positive cells.

Diagnosis

A diagnosis of ACD in ferrets is usually made on the basis of classic clinical signs, findings on abdominal radiographs or ultrasound, CBC values, and blood chemistry analysis. Physical exam findings of symmetrical alopecia, a swollen vulva, or palpable mass cranial to the kidney are suggestive. CBC is usually normal, but anemia can be present with elevated estradiol. Blood chemistry frequently reflects an elevated ALT. Elevations in plasma estradiol, androstenedione, and 17-hydroxyprogesterone are most diagnostic. The University of Tennessee has the only validated test for use on ferrets. The adrenocorticotropic hormone (ACTH) stimulation test and the dexamethasone suppression test cannot be used to diagnose adrenal disease in ferrets. Ultrasonography can be useful for demonstrating adrenal gland enlargement, and is the diagnostic test of choice by many practitioners. Ultrasonography is also used to distinguish right versus left ACD for surgical planning prior to adrenalectomy. Laparotomy allows the glands to be assessed directly, and permits biopsy with histopathology.

Treatment

The goal of management should be to provide the ferret a normal life span and a good quality of life. In general, there are two treatment options: surgery and medicine. Both treatment methods are aimed at reducing sex steroid production. Surgery aims to remove or debulk the tumor (adrenalectomy), whereas medical treatments do not affect the tumor and are not curative. The decision as to which form of treatment is appropriate is multifactorial; which gland is affected (left vs. right), surgeon's experience, severity of clinical signs, age of the animal, concurrent diseases, and finances should be considered.

Surgical

Adrenalectomy is the treatment of choice for ferrets that are otherwise healthy and free of high-risk concurrent illness. In most ferrets the clinical signs resolve after the diseased adrenal gland has been removed. A CBC and plasma chemistry analysis should be performed prior to surgery in order to evaluate for abnormalities. Hypoglycemia may be detected as a result of insulin-secreting tumors (insulinoma), which are a common concurrent finding.

For the surgical approach, make a ventral midline incision, extending from the xyphoid as needed to allow a thorough examination of the abdomen. Systematically evaluate all organs; liver disease, splenomegaly, lymphoma, and gastric foreign bodies are common. Islet cell tumors are found in approximately 25% of patients with adrenal neoplasia. In male ferrets, carefully palpate the prostate gland for cystic enlargement. In females, inspect the ovarian and uterine stumps. Take biopsies of abnormal tissues.

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. 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 perform leave the normal gland, to remove half of it, or to remove it entirely. If both glands are diseased, complete removal of one gland and partial removal of the other is indicated. Often the left adrenal is completely removed and the right adrenal is debulked by placing hemostatic clips across it to allow for 50-75% removal. Alternatively, the capsule is incised 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. However, frequently 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 cava, resection and anastomosis of the cava may be needed. 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 at least some collateral circulation to have gradually developed prior to vena cava ligation. Recently, a technique had 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, radiosurgical ablation, and alcohol injection 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. However, cryosurgery of blood vessels is safe. Freezing kills tumor tissue and blood vessel endothelium, but vessel wall integrity remains intact thanks to the elastic structure of the vessel wall. After cellular death by freezing, this elastic collagen serves as the matrix for new endothelial growth. Some controversy exists about cryosurgery of the adrenal gland in ferrets, however, as recent work suggests that cryosurgery of the adrenal gland may actually worsen long-term prognosis. Injection of pure ethanol into the affected adrenal has been anecdotally reported to work well by several respected clinicians. Like cryosurgery, this method causes cellular necrosis, but there is no data whatsoever as to its efficacy or safety, and this method cannot be recommended until such time as that data is available. Regardless of the method of tumor removal used, a surgical biopsy is recommended in order that histopathology of the tumor can be performed.

Complete removal of all adrenal tissue is difficult and usually unnecessary. Removal of both glands rarely causes iatrogenic adrenal insufficiency ("Addison's disease"), requiring close monitoring and medical management. If both glands are surgically treated, administer post-operative prednisone 0.25-0.5 mg/kg PO every 12 hours for 1 week, then gradually taper the dose over 1-2 weeks. Total or sub-total bilateral adrenalectomy may necessitate long-term post-operative treatment with glucocorticoids. The dosage is titrated to the individual, and tapered to the lowest dosage interval necessary to prevent clinical signs. If concurrent insulinoma is found, then treatment with corticosteroid therapy should be accompanied by diet change, assisted feeding, and diazoxide therapy.

Some ferrets have accessory adrenal tissue and can be completely weaned off of exogenous steroids if carefully monitored. However, some ferrets experience Addisonian symptoms (lethargy, weakness, anorexia) even with prednisone therapy, and require treatment with mineralocorticoids. Signs typically begin within days to weeks post-operatively. Fludrocortisone acetate 0.05-0.10 mg/kg every 24 hours PO (or divided every 12 hours PO) or deoxycorticosterone pivalate (DOCP) 2 mg/kg intramuscularly every 21 days are used. Carefully monitor electrolyte status and renal function post-operatively.

Medical

Medical management is aimed at reducing the clinical signs of adrenal disease rather than curing the condition. None of the medical therapies used in ferrets are effective in all individuals. Medical treatment is not curative, must be administered lifelong, and has no effect on adrenal tumor size or potential metastasis. Consider medical management if the owner cannot afford surgery or if a ferret is a poor surgical candidate. Medical management can be offered in cases where tumors cannot be completely resected and in cases where adrenal disease has recurred following surgery.

Androgen receptor blockers reverse the signs of disease but do not inhibit growth of an abnormal adrenal gland. They act at receptor sites (such as those in the prostate) to block the actions of androgens. Androgen receptor blockers are used in human medicine to treat men with benign prostatic hyperplasia and prostatic carcinoma. They are effective in some but not all ferrets, and are indicated mostly in male ferrets. Flutamide (Eulexin, Schering, Kenilworth, NJ) inhibits androgen uptake and binding in target tissues, and is used in the treatment of androgen-responsive prostatic tumors in humans. It has been used to reduce the size of prostatic tissue and treat alopecia in ferrets with adrenal disease. Flutamide is given at 5-10 mg/kg every 12-24 hours PO. It has no effect on tumor growth or metastasis. Side effects may include gynecomastia and hepatic injury. Liver enzyme concentrations should be monitored during its use. Flutamide therapy is expensive and may be cost prohibitive for some patients. Bicalutamide (Casodex, AstraZeneca, Wilmington, DE) competitively inhibits the action of androgens at receptors, but leads to increased levels of estrogen and testosterone when used alone, so must be used in conjunction with leuprolide acetate. Bicalutamide is administered 5mg/kg every 24 hours PO until signs resolve, then for one week on/one week off indefinitely. Pregnant women should avoid contact with this drug.

Androgen formation blockers prevent the formation of dihydrotestosterone (DHT). Finasteride (Proscar or Propecia, Merck, Whitehouse Station, NJ) 5 mg/ferret every 24 hours by mouth l lowers the levels of DHT by blocking 5-alpha reductase, the enzyme that converts testosterone to dihydrotestosterone (DTH), the key hormone involved in prostate enlargement.

Aromatase inhibitors specifically inhibit aromatase, the enzyme that catalyzes the final step in estrogen production. Anastrazole (Arimidex, AstraZeneca, Wilmington, DE) is given 0.10 mg/kg by mouth every 24 hours until signs resolve, then for one week on/one week off indefinitely. It is a nonsteroidal aromatase inhibitor that blocks the conversion of adrenally-generated androstenedione to estrone, and then to estradiol in peripheral tissues. Anastrazole inhibits estrogen production and decreases plasma estradiol. Pregnant women should also avoid contact with this drug.

GnRH analogs are widely used in human medicine to treat prostatic cancer, endometriosis, and breast cancer. Analogs may be GnRH agonist or GnRH antagonists. GnRH agonists initially have the same stimulatory action a GnRH, however when administered long-term, they suppress gonadotropin release and downregulate receptors in the hypothalamus. Leuprolide acetate (Lupron Depot, TAP Pharmaceuticals, Lake Forest, IL) is a GnRh analog. Adrenal disease has been successfully treated using leuprolide acetate. It is a potent inhibitor of gonadotropin secretion, and it acts to suppress LH and FSH and to downregulate their receptor sites. It is available in 1- or 4-month depot formulations. It alleviates the dermal and reproductive organ signs of disease in ferrets. The one month formulation appears to be more consistently effective. The dose is 100-250 micrograms/kg IM q4w until signs resolve, then q4-8w as needed, lifelong. Larger ferrets may require the higher dose range. Leuprolide has no effect on adrenal tumor growth or metastasis. Side effects include dyspnea, lethargy, and local injection site irritation. Anecdotal evidence suggests that leuprolide is more effective in alleviating clinical signs in patients with hyperplasia or adenomas; adenocarcimonas may be less likely to respond.

Another GnRH-analogue is deslorelin acetate (Suprelorin, Peptech Animal Health, North Ryde, Australia) is commercially available for non-surgical contraception of male dogs in Australia, New Zealand, and some European countries. Deslorelin slow-release implants have been evaluated for use in ferrets with ACD, and the results are very positive. Deslorelin implants appear to reverse the signs of adrenal disease for up to two years. Like leuprolide, deslorelin does not appear to affect adrenal tumor growth or metastasis. Once the drug becomes commercially available in the US it is likely to become the drug of choice for ferret ACD.

Melatonin is the primary hormone produced by the pineal gland. Melatonin is directly involved in activating (in the spring/summer) and terminating (fall/winter) the ferret's natural breeding season. As day length decreases in the fall, higher levels of melatonin are released during the dark hours. When ferrets are exposed to the dark for more than 12 hours/day, the pineal gland maintains a high circulating melatonin concentration that in turn suppresses release of GnRH and subsequently inhibits the release of pituitary LH and FSH. This suppresses the breeding season and causes the ferret to put on its winter coat and increase body fat. Melatonin is an appetite stimulant. 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. Improvement may be more likely in patients with adrenal hyperplasia or adenoma; less likely in patients with adenocarcinoma. Melatonin has no effect on adrenal tumor growth or metastasis. 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 that releases melatonin over a 3-4 month period. Implants can be placed using a distraction treat (e.g. Nutrical) or general anesthesia. Possible side effects include lethargy and weight gain. Lethargy in some cases can be profound and severe. In general, the response to melatonin is better in the fall and winter than during the spring or summer. Melatonin is an inexpensive treatment option that can be used alone or in combination with other therapies for ferret adrenal disease.

Recovery

Response to therapy is usually evidenced by resolution of clinical signs, particularly regrowth of hair, regression of vulvar swelling, and reduction in the size of urogenital cysts or prostatic tissue. Urogenital signs usually resolve with days of surgery. Monitor serum glucose concentrations following adrenalectomy since many ferrets have concurrent insulinomas and develop post-op hypoglycemia.

Following unilateral adrenalectomy or subtotal adrenalectomy, monitor for the return of clinical signs; tumor recurrence is common. Clinical signs typically develop one year or more postoperatively, but may recur as soon as several months. In ferrets with bilateral adrenalectomy, monitor for the development of Addison's disease by performing periodic evaluation of serum electrolytes. Ferrets with hypoadrenocorticism may present with hypothermia and coma, hyperkalemia, hyponatremia, and a sodium potassium ratio below 25:1. Affected ferrets will show a dramatic response to aggressive fluid therapy, glucocorticoid and mineralocorticoid replacement, and supportive care measures. Prednisolone, fludrocortisone, dexamethasone, deoxycorticosterone pivalate (DOCP) are used at published dosages. Since concurrent insulinoma common, ferrets should receive regular fasted glucose checks.

Prognosis

In most ferrets, the associated clinical signs resolve after the affected gland(s) have been removed. 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. Later complications of surgical treatment include recurrence of adrenal tumor because of metastasis (rare), or the development of an adrenocortical tumor in the remaining gland. Response to medical therapy varies with tumor type, however dermal signs generally improve over several weeks to several months, while urogenital signs only take several days to weeks to resolve.

Prognosis for all treatments varies and depends on tumor type, age of animal, presence of concurrent disease, and mode of treatment. If the effects of the adrenal disease are only cosmetic (alopecia), then the prognosis for life is good. The prognosis worsens if prostatic disease, bone marrow suppression, or tumor-related mechanical interference with the vena cava develops, or if the tumor metastasizes. Ferrets with adrenal hyperplasia or adenoma often live 2 years or more, even with no treatment. Of course, dermal and/or urogenital signs generally worsen without therapy. The 1- and 2-year survival rates for ACD are reported to be 98% and 88% respectively. 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

Premature neutering may play a role in the etiology of ferret adrenal disease, and there is some evidence to suggest that neutering after 6 months of age may decrease the incidence of adrenal disease in ferrets. However, one analysis of 1274 ferrets in the Netherlands, where ferrets are generally neutered at 12-18 months of age, found that the interval between the age of neutering and the onset of adrenal disease is almost exactly the same as that in the US. Therefore, it appears that neutering alone sets the stage for later development of hyperadrenocorticism, as opposed to the age at which neutering occurs.

Neutering ferrets prevents fatal estrogen-induced bone marrow suppression in jills, reduces aggression in hobs, and decreases the musky odor associated with all ferrets, making ferrets better pets. Alternatives to surgical neutering need to be developed that accomplish the same medical and behavioral goals without predisposing ferrets to hyperadrenocorticism. The best hope for such a treatment appears to be deslorelin. Early tests indicate that deslorelin can block the LH surge believed to be a contributing factor in ACD. In a similar manner, giving leuprolide by injection each winter between (January and mid-February in the northern hemisphere) has been shown to block the LH surge that occurs in the spring, and anecdotal evidence suggests that it, too, may be an effective preventive for ACD.

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