Adrenal Gland Disease in Ferrets
What is adrenal gland disease of ferrets?
This disease is associated with overproduction of sex steroid hormones by the adrenal gland. The body contains two adrenal glands, left and right. These glands are situated in front of each kidney.
Based on microscopic appearance and function, each gland has two basic parts: the adrenal cortex and the adrenal medulla. The adrenal medulla is responsible for producing hormones like adrenaline that are responsible for the fright response. The cortex has three separate layers. The outer layer is responsible for hormones related to water and sodium balance. The inner two cortical layers are the body’s primary producers of cortisol (the natural form of cortisone), which helps with stress responses, and sex steroids like estrogens and testosterones.
Adrenal gland disease is an abnormal growth of cells of the adrenal cortex. This abnormality can be diagnosed microscopically as hyperplasia (a very benign increased number of cells), adenoma (a benign tumor of cells), or an adenocarcinoma (cancer of the cells). In all cases, the abnormal tissue secretes excessive sex steroids.
Affected ferrets can be of either sex but are usually at least 3 years of age. The average age for adrenal gland disease to affect a ferret is about 4 years of age. It seems to be more common in ferrets that are spayed and neutered early in life (before their first heat cycle), although the disease has been seen in intact male and female ferrets.
I have researched adrenal gland disease and I keep reading about Cushing’s disease. Is this the same disease as in ferrets?
No. Dogs, cats, humans, and hamsters are prone to tumors of the pituitary gland or adrenal gland that will overproduce cortisol. This can be called Cushing’s disease or Cushing’s syndrome. This particular syndrome does not involve sex steroids and is entirely different from the condition in ferrets in the way it affects the animal and treatment.
What does the typical ferret with adrenal gland disease look like?
Alopecia (hair loss) is the most common clinical sign. Any ferret missing hair on the tail, rump, flanks and chest is a strong candidate for adrenal disease. Remaining hair may pull out painlessly. There are ferrets that may lose hair in late winter or early spring that resolves without treatment. Alopecia may recur again the following year. Usually if this happens two or more years in a row, the hair will eventually fail to re-grow. There are some males who will seasonally lose hair on the tail and have it re-grow. This may be normal and not a sign of adrenal gland disease.
Itchiness is seen in over one-third of ferrets with adrenal gland disease. While itchiness usually occurs with hair loss, many cases of adrenal gland disease have been confirmed wherein severe itch occurred without hair loss. Severe itch may be the only sign of adrenal gland disease.
Adrenal gland disease in females commonly presents with a swollen vulva. In fact, over 70% of female ferrets with adrenal disease have a swollen vulva. There may be a discharge from the vulva and the skin may appear bruised. In a spayed, age-appropriate female ferret, vulvar enlargement is typically caused by adrenal gland disease.
Male ferrets may develop adrenal gland disease related prostate enlargement, infection or cysts. Male ferrets with trouble urinating should be evaluated for adrenal gland disease. A life-threatening urinary obstruction may occur in a male ferret with adrenal gland disease. Rarely, urinary obstruction has been seen in female ferrets with adrenal gland disease.
In neutered ferrets, return to sexual behavior (aggression, courtship behavior with females) can be noted occasionally. In males and females that have been spayed or neutered, a thicker skin and increased musky odor may be seen.
Lethargy is common in chronic or severe cases. Hyperactivity is seen uncommonly. Rear leg weakness is a common, non-specific sign seen in adrenal gland disease and many common diseases in the ferret.
Ferrets with adrenal gland disease commonly have other problems as well. While the typical ferret with adrenal gland disease is not overtly ill, it is possible to see signs related to other conditions. Lethargy, rear leg weakness, hypersalivation and pawing at the face are common with pancreatic tumors called insulinomas ( hyperlink). Trouble breathing, cough, lethargy or abdominal enlargement may be present with heart disease. Vomiting or chronic malaise and weight loss can be associated with viral infections, inflammatory bowel disease, chronic stomach infections, hairballs, or lymphatic cancer. Weight loss can be seen in very chronic, uncontrolled adrenal gland disease, but if it happens in a ferret who has just recently started showing hair loss or itch, concurrent diseases should be suspected.
What diagnostic tests should I expect my veterinarian to recommend to confirm the diagnosis and help decide how to treat my ferret?
Making a clinical diagnosis of adrenal gland disease is often quite straightforward. Probably over 90% of ferrets with hair loss have adrenal gland disease. Very few illnesses make ferrets itch. Itching in the absence of fleas is likely adrenal gland disease.
Swollen vulva in spayed female indicates adrenal gland disease until proven otherwise. In a very young ferret (less than 1.5 yrs of age), your veterinarian may want to rule out that a remnant of the ovary exists despite the prior spay. However, ovarian remnant syndrome is quite unusual.
Males with trouble urinating and no urinary stones on radiographs (x-rays) usually have adrenal pathology.
While diagnosis of adrenal gland disease can often be made based on clinical signs and physical examination, hormonal assays are available to aid in confirmation of diagnosis. Pathology from adrenal gland disease in ferrets is due to increased androgens and/or estrogens produced by the adrenal gland(s). Hormonal assays that have been validated for the ferret are hard to find. The University of Tennessee Diagnostic Lab has a panel of hormones offered to aid in diagnosis of this disease in ferrets. In 96% of ferrets with adrenal gland disease, this panel will show some abnormality. A normal panel doesn’t rule out the diagnosis of adrenal gland disease.
A complete blood cell count is indicated in any ferret with suspected adrenal disease. Anemia (low red cells) is uncommonly associated with adrenal gland disease. Profound anemia is associated with a very poor prognosis. The white cell count is usually normal except in rare cases of bone marrow suppression.
Serum chemistry tests are often normal. However, failure to perform serum chemistries may result in missing concurrent conditions such as insulinoma.
Radiographs (x-rays) are not helpful in the diagnosis. Abdominal radiographs may demonstrate an enlarged spleen but this is common in many ferret diseases. All affected ferrets should have chest radiographs. Co-existing heart disease (cardiomyopathy) is common in adrenal gland disease. Any question about heart size should be further evaluated with an ultrasound of the heart (echocardiogram). Adrenal cancer rarely metastasizes (spreads to distant sites) but in the rare instances where adrenal adenocarcinoma has spread to the lungs, a chest radiograph may show lung nodules.
Ultrasound examination of the chest and abdomen are excellent ancillary tests. As stated above, an ultrasound to evaluate for heart disease is recommended in all cases where heart disease is suspected. If surgery is to be considered, heart disease MUST be ruled out. Most cases of peri-operative mortality in adrenal disease are associated with heart disease and heart failure.
Abdominal ultrasound can help identify the size and internal architecture of each adrenal gland. This knowledge is helpful when planning surgical therapy and in monitoring certain forms of medical therapy. In planning therapy, it is useful to know which adrenal gland (or both) is enlarged.
What causes adrenal gland disease in ferrets?
Like most disease of cells, we don’t know the cause of adrenal gland disease in ferrets. In all likelihood, adrenal gland disease is caused and/or promoted by multiple causes. The most likely factors that are involved in causing or predisposing to this disease are genetics, early age spay/neuter, photoperiod length, and housing in large groups.
Genetic causes of adrenal gland neoplasia are thought to exist. In Europe, adrenal gland disease is less common than in the U.S. The ferrets that enter the pet trade in the U.S. are considered to be of limited genetic stock and therefore inbred. There is ongoing research into the role of genetics, including evaluation of a gene linked to multiple endocrine neoplasias in humans.
Spaying or neutering at an early age has been long theorized to contribute to this condition. This may be related to gonadal cells in the adrenal capsule. It may relate to not experiencing the initial breeding season of life after early age neuter and spay. There may be an association between the age at neuter or spay and the age of development of adrenal disease.
It has been demonstrated that ferrets who have more than 8 hours of daylight per day have increased levels of circulating sex steroid production stimulators called gonadotropes. Since the adrenal gland has significant numbers of gonadotrope receptors, repeated stimulation of the adrenal gland to produce sex steroids may be involved in the development of hyperplastic and neoplastic lesions of the adrenal cortex.
In the UK, when ferrets were housed outside, fed raw carnivore diets, and kept individually and not in large groups, the incidence of adrenal disease was quite rare. Since their adaptation to house pets and the increase in social grouping and the increased photoperiod related to living indoors, adrenal gland disease incidence has increased.
Research into treatments based on these theories is continuing. However, it is likely that until it can be proven what role, if any, each of these factors has in causing adrenal disease, it is likely we will continue to try to treat this disease rather than prevent it.
My ferret has been diagnosed with adrenal gland disease. What are the treatment options?
There are four options available to veterinarians for treatment of adrenal gland disease:
- Surgical therapy
- Medical therapy
- Benign neglect
- Euthanasia
In cases of chronic disease, bone marrow suppression, profound anemia, and urinary obstruction are options. If you cannot afford or don’t want to pursue aggressive therapy, euthanasia is a viable option.
In cases where alopecia is the only clinical sign and the quality of life is unaffected, benign neglect is a viable option. This is an easier choice in the female versus the male, since urinary obstruction is rare in the female.
Ultimately the choice of therapy should be based on a number of factors including
- Age
- Type of clinical sign(s) present
- Sex
- Presence or absence of co-morbid conditions
- Which adrenal gland appears to be affected (or both)
- The number and type of prior abdominal surgical procedures
- The experience and comfort level of the surgeon
- The availability of magnification, microsurgical instrumentation, and blood donors.
- Your desire for a cure
- Your willingness and ability to invest financially and emotionally in medical or surgical therapy
- Your willingness to risk intra-operative complications (usually with right sided gland removal)
- Your willingness to risk post-operative complications (usually with bilateral gland removal)
Medical treatment in ferret adrenal gland disease will not cure the disease, will not reduce the growth of tumor, and will not reduce the risk of a malignant tumor spreading. However, medical therapy has its uses and some advantages over surgical therapy. Risk of therapy is minimal in most cases.
Recommended medical therapy for adrenal disease in the ferret includes the following medications:
- Gonadotropin-releasing hormone blockers
- Androgen receptor blockers
- Anti-androgen drugs
- Aromatase inhibitors, and
- Melatonin
GnRH analogs can be used to treat adrenal gland disease. The most common GnRH analog used is leuprolide acetate (Lupron®) 30 day depot injection. Lupron attaches to the GnRH receptor and causes a spike in LH secretion. Interestingly though, after that LH surge, prolonged exposure to Lupron causes a reduction in LH secretion.
Lupron is commonly dosed using the 30-day depot injection at 100-200 mcg. Injections are given monthly. In areas of the world where Lupron is not readily available, other GnRH analogs (deslorelin acetate (Suprelorin®, goserelin (Zoladex® ) may be available. Recent studies showed that the effects of 3 mg deslorelin implants were similar to effects of leuprolide acetate depot injection.
In the presence of excessive androgens, some ferrets may benefit from androgen receptor blockers. Flutamide (Eulexin®) and bicalutamide (Casodex®) have been used in ferrets. Androgen receptor blockers are purported to bind competitively to the testosterone receptors on the prostate gland. There is anecdotal evidence that these medications may be of some use in some ferrets with adrenal gland disease. There are no controlled studies on either drug in ferret adrenal disease, but flutamide has been used extensively in ferret behavioral research.
Finasteride is an antiandrogen. It inhibits the enzyme 5-alpha-reductase, and inhibits conversion of testosterone to its biologically active form (dihydrotestosterone). There are no controlled studies on the use of this drug in ferrets.
The final step in estrogen formation is catalyzed by the enzyme aromatase. Anastrozole (Arimidex®) is an aromatase inhibitor that has anecdotal success in some ferrets with adrenal gland disease.
Melatonin is a hormone produced by the pineal gland. Photoperiod (the amount of light exposure per day) has a large role in regulating melatonin secretion. High circulating melatonin levels are purported to reduce secretion of GnRH. The exact mechanism of action of melatonin in the treatment of adrenal gland disease in ferrets is unknown. Melatonin implants (2.7mg and 5.4mg) are available commercially and have growing anecdotal evidence of a positive effect in ferret adrenal gland disease. Colorado State’s Matthew Johnston, VMD is currently working on a large scale study of these implants. Based on preliminary reports, melatonin implants can be an effective medical therapy for ferret adrenal disease.
How do I know if medical therapy is working?
In most cases, the success or failure of medical therapy can be judged clinically. Resolution of clinical signs (with the possible exception of complete regrowth of hair) should be evident.
If pre-treatment hormone assays are available, post treatment assays should show reduction of pre-treatment elevations in cases where a GnRH analog or melatonin is used.
If breakthrough clinical signs are noted (e.g., vulvar enlargement), one must consider adjunctive therapies or repeating prior pulse therapy (e.g. Lupron or melatonin). Clinical signs may lag behind hormone elevations by 1 month or more, so monitoring of hormone levels at regular intervals during therapy may be indicated.
What are the surgical options for adrenal gland disease in ferrets?
The first step in surgical treatment for adrenal gland disease is a complete pre-operative diagnostic evaluation for co-existing illnesses. This testing should be a complete blood cell count, serum chemistries (including a fasted blood sugar) and a chest x-ray.
Ferrets are very hardy surgical patients and can handle a multitude of surgical procedures during one laparotomy. All ferret abdominal surgical patients should receive intravenous fluid support, thermal support and a multi-faceted approach to pain and anesthesia. Proper magnification, instrumentation and lighting are extremely important in adrenal gland removal. In some cases, transfusion may be needed so having a ferret available as a donor is ideal.
Surgical procedures to remove an adrenal gland are different between the left and right gland. The left gland is relatively easy to remove. Blood supply to the gland is uncomplicated and exposure of the gland is simplified by its position away from major structures. Left sided adrenal gland removal is complicated only when there is massive enlargement of the gland – especially if this large mass has invaded a blood vessel. While there may be times when this surgery requires removal of part or the entire left kidney or major surgical risk, the left sided surgery is usually an uncomplicated one.
The right adrenal gland is tucked under the liver and usually is intimately attached to the large vein in the abdomen called the caudal vena cava (CVC). Tumors of the right adrenal gland are commonly found to be attached to the liver or invading the CVC. Due to the intimate relationship between the gland and the CVC, right-sided adrenal gland removal is a complicated procedure that requires a patient, experienced surgeon with proper instrumentation, magnification and lighting. Right-sided gland removals often involve removal of part of the liver or part of the CVC. Due to these factors, intra- and post-operative complications are much more common in right-sided surgeries than left-sided surgeries.
Surgical procedures that have been used to minimize the intra-operative complications of right sided surgery include using metal clips to isolate the tumor from the CVC, carbon dioxide laser, and even cryosurgery (freezing). Your veterinarian will discuss what options he or she recommends for the surgery.
In cases where the adrenal gland disease exists on the left side only, surgical therapy is often simple and easy. Surgical removal of the left adrenal gland can be curative in these cases. However, remember we do not know the exact mechanism of what causes this disease. Some ferrets will have a recurrence of adrenal gland disease 6 to 12 months following successful and appropriate therapy.
To lessen the chance of recurrence, it may be recommended that the larger side be removed and that 50% to 60% of the other side also be removed – even if it looks normal at surgery. This procedure is called a “subtotal bilateral adrenalectomy.” It carries with it a risk of temporary reduction in adrenal gland function (called Addison’s disease of hypoadrenocorticism) necessitating treatment with oral medicine or monthly injections. Subtotal adrenalectomy patients can still have recurrent disease but the time between surgery and recurrence is usually longer than one sided adrenalectomy, and recurrences can again be treated surgically or medically.
In cases where both glands are abnormal, one must decide whether to proceed with subtotal bilateral adrenalectomy, bilateral TOTAL adrenalectomy, or to remove the larger tumor and depend on medical therapy for further control of clinical signs. Bilateral total adrenal gland removal is being recommended more often by experienced surgeons. Recurrent disease is still possible, but far more unusual than with other procedures. However, a significant number (perhaps 25-60% or more) may require therapy for hypoadrenocortism. This is usually a lifelong therapy that is not inexpensive and requires monthly blood tests to monitor therapy. Untreated hypoadrenocorticism can be fatal.
When is a ferret not a good surgical candidate for adrenalectomy?
Older ferrets (over 7 to 8 years old) and those with untreated or uncontrolled heart disease are not good surgical candidates. Ferrets that have treated and controlled cardiac disease are at a greater risk for complications and peri-operative complications including death, but well-controlled cardiac patients have been reported to do well with adrenalectomy. A ferret with advanced lymphatic cancer may not benefit from surgical therapy.
Almost all other ferrets are good surgical candidates. However, the decision for medical versus surgical therapy must rest with the owner who will have to deal with the complications or failures of whatever choice they make.
Should I get the adrenal gland biopsied after removal?
From a prognostic standpoint, it makes sense to get a histopathologic diagnosis after surgery. Since the same patient commonly has different biopsy diagnoses in left and right adrenal glands, it is recommended that all tissue removed be sent to the pathologist for biopsy.
When can I expect clinical signs to resolve after surgery?
In one study of adrenalectomy in ferrets, clinical signs resolved within 2 to 6 weeks. In less than 10% of the ferrets, alopecia worsened 2 to 3 weeks after surgery but hair subsequently return completely.
http://www.veterinarypartner.com/Content.plx?P=A&C=189&A=2512&S=5