Ferret Adrenal Disease

 

Tumors of the adrenal gland in ferrets can cause excess secretion of sex hormones, thus affecting many organs in the body. Unfortunately, this is a relatively common problem in middle aged and older ferrets. Even though most of these tumors are not malignant, they can cause significant disease if left untreated.

This disease goes by several names in addition to the one in the title of this page:

  • ADG- adrenal gland disease
  • AGN- adrenal gland neoplasia
  • ACD- adrenal cortical disease
  • AEE- adrenal associated endocrinopathy
  • FADC- ferret adrenal disease complex

FADC is probably the most accurate description, because as is the case with so many diseases, as we advance our knowledge over the decades, and develop more sophisticated diagnostic tools, we realize that most diseases are much more complex than originally envisioned. It is human nature to try to make things simple so they are easier to understand. This does not apply to most diseases we encounter in animals.

Dogs and cats get a problem similar to this, although it acts and is treated differently. In dogs and cats it is due to an excess secretion of cortisone, not sex hormones. In these species it is called Cushing’s disease.

At the very end of this page is a video of part of a surgery to remove cancerous adrenal glands and cancerous nodules on the pancreas.

The adrenal gland is small, so click on photos to enlarge them.

This page contains graphic photos from surgery and necropsy of diseased ferrets.


 

Physiology

 

This disease involves reproductive hormones. In a normal ferret, a hormone from the hypothalmus in the brain, called gonadotropin-releasing hormone (GnRH),  is released in larger amounts, usually due to an increase in daylight. This causes stimulation of luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the pituitary gland.

These hormones stimulate the release of estrogen and testosterone from the gonads and adrenal glands (important point in neutered pets that have no gonads). A very sensitive negative feedback loop maintains just the right amount of estrogen and testosterone. This sensitive balance is upset in adrenal disease of ferrets.

In the medical treatment section we will discuss a drug called Lupron. This drug binds with receptors on the GnRH molecules and lessens its effects on the pituitary.

Cause

 

The exact reason this tumor arises is not completely unknown. It is seen more often in the U.S. than in Great Britain, where different breeding and husbandry practices are utilized. It is speculated that diet, exposure to sunlight, and neutering are all factors, with neutering being the most important one.

Ferrets breed seasonally, causing variation in melatonin release with varying daylight. Less daylight means more melatonin and a thick haircoat. This higher level of melatonin eventually exerts a negative feedback on the release of the sex hormones estrogen and testosterone. When ferrets are spayed and neutered the negative feedback is disrupted, more of these sex hormones are secreted than is normal, and clinical signs develop.

The three main types of adrenal lesion encountered are:

  • Benign nodular hyperplasia that occurs 56% of the time
  • Benign adrenocortical adenoma that occurs 16 % of the time
  • Malignant adrenocortical adenocarcinoma that occurs 26% of the time
  • A combination of the above

Anatomy

 

The adrenal glands are small glands located just in front of the kidneys. The left gland is embedded in fat just in front of the kidney, the right one is located deeper in the abdomen and under one of the liver lobes. The left adrenal gland is the one affected in almost all cases, which is advantageous surgically as you will learn.

The arrow points to a normal left adrenal gland of a ferret. It is quite small and buried in fat in front of the kidneys. Click on the photo to enlarge.

Ferret-AdrenalFat

A close up to show how tiny it can be when normal

Ferret-AdrenalCloseup

Here is another one at the top of the hemostat on the left. This one is inflamed, typical of an this gland with adrenal disease

Cushings-FerretAdrenal1

The tip of this hemostat shows an inflamed adrenal gland. Note the large vein underneath it, called the adrenolumbar vein  This vessel makes this surgery intricate. You can see the adrenolulmbar vein (horizontal blue line) in this picture below the adrenal gland. This is what will be ligated when we show surgery pictures later.

Rocky Walker 21218 Ferret Gastric tumor Blood supply to mildly inflamed left adrenal

Other much more inflamed and enlarged left adrenal glands

Cushings-FerretAdrenal3

necropsy of Ash, the ferret with insulinoma kidney on right adrenal to left of kidney at cranial end

When a diseased left adrenal gland is not removed surgically it might eventually get extremely enlarged and cause substantial illness. The left 2/3 of this picture is a diseased adrenal gland. The right 1/3 of this picture is the kidney, showing just how large this adrenal gland became as this ferret aged. The adrenal gland is so diseased that it is literally rutpturing, as can be seen toward the top left of the gland.

The right adrenal gland is under the right lobe of the liver, adjacent or attached to the vena cava (VC). The vena cava is the major return of all the blood from the back of the body to the heart. The liver has to be pulled away to visualize the adrenal gland.

Ferret-LiverCoveringAdrenal

When you pull the liver lobe forward you can see the enlarged right adrenal gland to the right of the arrow. You can also see how the adrenal gland is adhered to the vena cava, which makes surgery to remove a diseased right adrenal gland problematic, to say the least.

Ferret-AdrenalNormalRIghtVC

A different view of the right adrenal gland and its close association to the liver and vena cava (VC)

Ferret-RightAdrenalVC

In this picture we have both right (on the bottom) and left (on the top) adrenal glands of the same ferret. The white arrow in the lower left of this picture points to a normal right adrenal gland. It is very small because it is normal. On the left, above this right adrenal gland, is a lobe of the liver (L) that has to be pulled forward during surgery in order to get access to the right adrenal gland. The posterior vena cava is the large blue vein running horizontally. The abnormal left adrenal gland can be visualized to the left of the arrow on the top right.

Sometimes the tumor on the right side gets greatly enlarged. Here is is intertwined with the right kidney and the  vena cava (vertical blue line to the right of the tumor).

Ferret-LargeRtAdrenal6

Here is a different angle of this same tumor showing just how large it is

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Physiology

 

These small but very important glands have numerous roles you can learn more about in our Cushing’s page It gets very detailed, so be prepared to learn some anatomy and physiology before you return back here to learn about adrenal disease in ferrets.

The adrenal tissue in ferrets normally secretes several sex hormones. The important ones are:

  • 17 – OHP (17 alpha hydroxyprogesterone)
  • androstenedione
  • DHEa (dehydroepiandrosterone sulfate)

It is postulated that these hormones are secreted from the adrenal glands after chronic stimulation from follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary gland. Indoor housing of ferrets, leading to more light than ferrets in the wild, is postulated to also stimulate release of LH, along with gonadotropin releasing hormone (GnRH) from the pituitary gland. The end result of this hormone imbalance is excess secretion of estrogen in females and testosterone in males. This causes the vulva to enlarge in females, and a return to male sexual behavior in the male. The enlarged vulva is easy to see, which might be the reason we diagnose this problem more often in female ferrets.

A special lab in Tennessee can check for excess amounts of these hormones on a blood panel, an important help in the diagnosis of this disease.  A ferret can have normal values on this test, yet still have adrenal gland disease. This is why we always follow the tenets of the diagnostic process.

 

Symptoms

 

Hair loss

The most common symptom of adrenal disease in ferrets is hair loss, sometimes with itchiness (pruritis). Itchiness due to adrenal disease an also be present with no hair loss. The most likely spots for hair loss are the tail area and rear legs. Hair loss in dogs and cats is almost always caused by a different problem. This hair loss occurs in over 80% of the ferrets with this disease.

Some ferrets with adrenal disease do not show any symptoms, while others exhibit varying degrees of hair loss and even enlarged vulvas in spayed females. The hair loss can be seasonal, can come and go, but eventually it progresses to almost complete baldness.  It has been observed that mast cell tumors in ferrets can also cause hair loss.

This is typical of the hair loss that can occur

Alopecia

It can sometimes be more extreme as the seasons progress

 

Difficulty urinating (stranguria)

Male ferrets sometimes have difficulty urinating in addition to hair loss. Even if they are neutered there might be a return to normal sexual behavior. There might also be lethargy, a decrease in appetite and weight loss.

In male ferrets cysts can occur in the small amount of prostatic tissue they have. They can also get a bacterial prostatitis causing these symptoms. This can cause difficulty in urination, which can affect the kidneys if it progresses. On rare occasion this problem can progress to complete inability to urinate due to the enlarged prostatic tissue.  Inability to urinate is a medical emergency, and needs immediate attention to save the kidneys and prevent the bladder from rupturing.

A urinary bladder that is so distended that a pet cannot urinate is diagnosed on palpation during a physical exam. It is confirmed with a radiograph, as in this cat that cannot urinate. If we run a blood panel on this animal we will see what is called post renal azotemia, a sign the kidneys are shutting down. Our kidney page has much more detail on this.

distendedbladder

This is the necropsy picture of a severely distened bladder in a ferret that did not make it.

Ferret-DistendedBladderNecropsy

When a ferret is presented in this state we have to immediately catheterize them. You can see the tip of the catheter at the arrow as it is in the lumen of the urinary bladder. The catheter was placed through the tip of the penis, and gently pushed past the pelvic urethra and into the bladder. You can see all of this if you enlarge the photo below.

Ferret-LateralRadCatheter

Radiopaque dye was put into the urinary bladder to make sure there was no rupture

Note also the unique shape of the tip of the penis in the ferret. It has a bone in it (just like the dog) called the os penis. The tip of the os penis in the ferret is curved, and the opening is very small, making catheterization difficult.

Ferret-Penis

Stones in the urethra and bladder can also cause stranguria, so we cannot always assume adrenal disease is the cause of a ferret that is straining to urinate or cannot urinate.

These are what stones look like in a ferret urethra

Ferret-UrethralStones

Thes are the stones after removal from the urethra

Ferret-BladderStones

Male ferrets with adrenal disease might also return to typical male sexual behavior or mounting, whether it is a female or a male they are mounting. Aggression can occur, and seems to occur more in ferrets with malignant adrenal disease (adenocarcinoma).

Swollen vulva

In years past, before all ferrets were routinely spayed, an enlarged vulva in a sick ferret was a sign of a ferret that did not mate when it was in heat. Being an induced ovulator, meaning jills would only release eggs from their ovaries when they mated, jills that did not mate would secrete an excess of estrogen for a long period of time.

This excess estrogen was toxic to the bone marrow, and would cause a severe life-threatening anemia that few would survive from. The technical term was aplastic anemia. When we had a sick unspayed ferret with an enlarged vulva we would run a blood panel. The anemia would show up as  severely low RBC’s (red blood cells), HGB (hemoglobin) or HCT (hematocrit).

Our lab runs a special blood panel for small mammals like ferrets

Ferret-SmallMammalProfile

This ferret has a hematocrit (HCT) of 15.5 %, typical of a ferret with aplastic anemia. It should be at least 43% at this lab.

Ferret-AdrenalCBC

Now that all ferrets are spayed and neutered upon purchase in the United States, we no longer see this type of anemia. When we have a ferret with an enlarged vulva we know it is most likely due to adrenal disease, especially if hair loss is present also. Retained ovarian tissue form a spay can cause this on rare occasion.

The arrow points to an enlarged vulva typical in females with adrenal disease

 

Lethargy and muscle atrophy

Occasional symptoms might include lethargy and muscle atrophy. Abdominal muscle atrophy can also cause the pot-bellied appearance seen in Cushing’s disease of dogs.

Sometimes the muscle atrophy is severe, and is also caused in conjunction with other common ferret diseases, notably cancer in the intestines or lymph nodes. The bulge on the left at the back end of this ferret is the right kidney.

Ferret-HairLossMuscleWasting

Diagnosis

 

Signalment

This tends to be a disease of neutered male and female ferrets with an average age of 3 years. It be seen earlier and later than these age groups.

Symptoms

Although enlarged adrenal glands can be palpated during an examination, this is not usually the case. A large number of adrenal tumors are confirmed during routine exploratory surgery, especially if the ferret exhibits the typical pattern of hair loss and an enlarged vulva in the female, or straining to urinate in the male. Exploratory surgery is a common way to verify the diagnosis and correct the problem. During this surgery we routinely check other organs for problems, especially the pancreas for tumor nodules that might be an insulinoma.

Physical Exam

This might reveal pale gums and heart murmur if there is a significant anemia. If the adrenal gland is on the left (most cases), and it is large enough, it might be possible to feel it during abdominal palpation.

We perform a complete physical exam on all our patients. This is particularly important due to their propensity to get other diseases besides adrenal gland disease. This ferret has an enlarged submandibular lymph node. Unfortunately, in the case it was malignant cancer called lymphosarcoma.

Ferret-EnlargedSubMandLN

We have a detailed page that talks about lymph nodes

Adrenal Panel

Sex hormone assays are very helpful in the diagnosis also, particularly to rule out other diseases. Pioneer work on these hormones was done at the University of Tennessee, and it is where we send all of our hormone tests on ferrets. You learned about these hormones in the physiology section above.

A special blood sample can be performed to check hormone levels. This test can be used if the typical symptoms of hair loss and enlarged vulva or urine straining are not particularly prevalent. This sample is sent to a special laboratory that takes several weeks to report their results.

Ferret-AdrenalProfile

This is their results based on 3,000 ferrets  with confirmed adrenal disease, on how much of an increase (the abnormal column) is needed above the normal column to be considered positive for ferret adrenal disease. They also noted that all 3 tests need to be run because on occasion estradiol was normal in a ferret that has adrenal disease.

Ferret-AdrenalPanelNormals

This is how they report a sample back to us

This adrenal panel needs to be interpreted with regard to time of the year in the northern hemisphere, because even neutered ferrets can have seasonal variations in these hormones. This emphasizes the importance of the diagnostic process in making a diagnosis of this disease, and using clinical signs along with ultrasound, surgery,  and biopsy findings, to confirm a diagnosis.

Radiology

Radiographs are usually unhelpful in this diagnosis since it is difficult to see the adrenal glands. On occasion, due to size or calcification, we can get an indication the adrenal glands are enlarged on a radiograph.

This normal radiograph shows two overlapping kidneys (K) in the middle of the abdomen. The adrenal glands are located just to the left of these glands. They are not routinely visible on radiographs.

Can you see the the large whitish area on this radiograph that could indicate a greatly enlarged adrenal gland?

Ferret-LargeRtAdrenal1

Ferret-HugeRightAdrenalRad

Do you see the calcification in the area of the right adrenal gland?

Ferret-LargeRtAdrenal

Ferret-HugeRightAdrenal

Ultrasound

Ultrasound is what is needed to visualize the adrenal glands in ferrets, and also dogs and cats in most cases. Ferret adrenal glands can be tiny, which is why we always call our radiologist to perform this test.

Radiologist are specialists in this area, and perform many dozens of ultrasounds on a daily basis. Their skill is extraordinary. Our radiologist, Dr. Ann Reed, is very experienced with ferrets, and is the only one we trust to perform our ultrasounds.

This ferret is having an ultrasound performed on its abdomen

Ferret-AdrenalUS3

Ferret-AdrenalUS1

Ferret-AdrenalUS2

With ultrasound we can measure the size of the adrenal gland and determine if it is enlarged

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Surgical Treatment

 

These ferrets sometimes come in very ill, and need medical stabilizing before we can proceed further. At this point in the exam we do not know what an individual ferret has, so we correct basic problems like dehydration, hypothermia, negative nitrogen balance, nausea, and hypoglycemia before proceeding further.

Most ill ferrets are treated with IV fluids to correct dehydration. The IV catheter also allows administration of medication without having to inject into the muscle.

Ferret-sickferret

The primary method of treating adrenal disease in ferrets is surgical removal of the gland. The problem can occur on either the right or left adrenal gland (or both). In the overwhelming number of cases the problem is in the left gland only. Eventually, both glands are commonly involved. After surgery to remove the affected gland vulvar swelling decreases and hair growth starts within 1-2 months and returns to normal at 6 months in most cases.

The left gland is much easier to work with because it is in a fat pad above the left kidney. The right gland is much more difficult to approach because it is under a lobe of the liver and is attached to the posterior vena cava, the main vein that returns blood from the back end of the body to the heart. You saw that in the pictures at the beginning of this page.

In most surgeries we remove the diseased left gland, leaving the right gland alone.  Complete removal of both glands can cause serious complications. Sometimes removal of only one of the glands can cause a problem if the remaining gland cannot make up for the loss. If that is the case we might cause something similar to a disease called hypoadrenocorticism.

We take the same precautions in ferret adrenal gland surgery as we do in all pets. First we perform a pre anesthetic blood panel to check the internal organs. If everything is in order we perform a pre-anesthetic physical exam, and then carefully go through our checklist prior to anesthetizing our patient.

This is a sterile abdominal surgery, and our surgeon starts the pre-surgical process by using special soap to clean his hands

_D2A8630

While our patient is being anesthetized our surgeon is already in our surgical suite setting up instruments. Our surgeon is ready to start before our patient is at a proper plane of anesthesia. Once the anesthetist gives the green light the surgery starts immediately. We want our surgeon waiting for his patient, not the other way around.  All of this is to minimize anesthetic time.

OVH-rabbit-3

OVH-rabbit-2

 In ferret surgery we have to pay particular attention to low body temperature (hypothermia) and low blood sugar (hypoglycemia). They are placed next to special hot water bottles throughout the procedure.

Our patients are carefully monitored to detect any abnormality before it becomes a problem. This early warning system is important in such a small animal that is ill and undergoing anesthesia and major surgery.

This machine monitors:

Temperature

Heart Rate

Heart rhythm

Oxygen saturation

Carbon dioxide level

Respiratory rate

Surgery-Monitor

In addition to our monitoring equipment our anesthetist stays “hands on” in monitoring important physiologic parameters. We use a special stethoscope (called an esophageal stethoscope) that is passed down the esophagus and can give us a clear sound of the heart

Rabbit-femurfx-9

Rabbit-femurfx27

Once our patient is draped we are ready to proceed

OVH-rabbit-4

We make our incision in a particular location in the center of the abdomen, called a ventral mid line incision. In this picture our surgeon has incised through the skin, and is pointing to the muscle layer he will be going through to gain entrance into the abdomen. It is important that we go through this particular area because this is the area that will be able to hold the sutures we use to sew the muscles back together, and thus prevent a hernia.

Ferret-AdrenalIncision

Ferrets are little guys, so their surgical anatomy is small. In some surgical cases we use magnifying loops to help identify structures

GPig-EyeSx-11

The pictures you previously saw of the adrenal glands were enlarged to allow easier visualization. The picture below is from an actual surgery. The white arrow points to the diseased adrenal gland that is held at the tip of the hemostat running vertically. The other hemostat to the left is clamping off the blood supply to the adrenal gland, including the adrenolumbar vein you saw earlier .

The white arrow points to the suture that remains once the gland is removed.

In many surgeries we use hemoclips to tie off the blood supply to the adrenal gland

Ferret-Adrenal2

We sometimes use the laser on the larger glands to aid in hemostasis (control of bleeding). This is of great important in such a small animal because large tumors like the can bleed excessively

Ferret-Adrenal6

Ferret-Adrenal5

Ferret-Adrenal4

During the surgery and immediately after we monitor body temperature to prevent hypothermia.

We also check the blood sugar level when the procedure is finished and before the ferret is completely awake. Their veins are small and difficult to find, so it is much easier to do it when the ferret is still groggy from the anesthesia.

We test the blood sugar level right in the surgical suite so we can plan our post operative care

Here is our little friend nice and cozy right after her surgery. She has been given a pain injection and is being monitored closely.

We continue to monitor temperature and blood glucose as our patient recovers

Ferret-Adrenal3PostOp

Whenever we perform an exploratory surgery (called a laparotomy) on an animal we check other internal organs for disease. This is especially important in ferrets due to their propensity for having other diseases. This is a picture of an enlarged spleen found during a routine adrenal gland surgery.

Ferret-Splenectomy1

We knew there was an enlarged spleen in this ferret because we could palpate it during an examination. This enlarged spleen was verified by a radiograph. The black arrows outline the enlarged spleen. A kidney (K) is also visible overlying the spleen.

This spleen was biopsied to determine whether this was a normal enlargement, called hypersplenism, or whether it was cause by cancer. This picture shows cautery of the spleen after a small biopsy was taken.

We have a very detailed page on spleen disease if you want to learn more.

Another very important organ to check in ferrets is the pancreas due to a disease called insulinoma. In this disease the pancreas secretes too much insulin, the opposite of sugar diabetes (diabetes mellitus).

Our surgeon is carefully palpating the intestines to check for intestinal cancer, and also the pancreas (the peach colored semi-circular area in the center of the intestines) for nodules that could indicate insulinoma

Ferret-Adrenal8

This ferret had a cyst on one of its liver lobes

 

Now that you know how we perform this surgery lets look at an abbreviated video of a ferret with an adrenal gland tumor and an insulinoma. You will also get a chance to see how we make a bloodless incision with the laser.

Medical Treatment

 

Much of the information on medical therapy for animals is anecdotal, and ferrets are no exception. With the ready availability of information on the Internet, the number of ferret organizations, along with the propensity for people to sell you most anything, people with sick ferrets can be desperate to try anything and will use medications that are unproven, and sometimes can make a condition worse. Our first goal as veterinarians when treating any animal is “first do no harm”.

Lupron

One of the best medications used to treat this condition is called Lupron, originally used to treat testicular cancer in men and endometriosis in women.

Lupron (Leuprolide) is a GnRH analog (remember the physiology section above) that minimizes the secretion of the sex hormones from the adrenal gland. Lupron does this by suppressing the production of FSH and LH from the pituitary gland. This decreases levels of estrogen and testosterone, and symptoms diminish.  It will decrease symptoms but not the size of the tumor.

It is usually given as an injection that lasts several months at least, all depending on the dose. We titrate the dose based on symptoms, age, weight, blood results, body condition score, and client compliance. Some ferrets exhibit a swelling at the injection site. This is of no cause for alarm and will usually resolve.

We have maintained ferrets on Lupron successfully for many years, so it has become a mainstay of our medical management after the left adrenal gland is removed. Long term effects of the chronic use of this drug are unknown. In some cases we also use only medical therapy, particularly if a ferret is not a good surgical candidate due to age or other conditions that are so common in ferrets.

Adrenal tumors are so common in the United States that some veterinarians that work with large numbers of ferrets even use Lupron as a protective plan with the following criteria:

Indoor ferrets that are exposed to unnatural photoperiods- give 1 mg Lupron Depot 4-month every 6-8 months starting at 4-8 months of age.

Outdoor ferrets exposed to natural photoperiods- 1 mg Lupron Depot 4-month annual in Feb or March in North America starting at 4-8 months of age.

Viadur, a 1-year Leuprolide implant is planned for the future.

Miscellaneous drugs with potential

The following medications have been used with varying success on adrenal disease in ferrets. Much more work needs to be done before we can recommend them routinely. There is concern that long term use of them can cause damage to organs like the kidneys. No long terms studies have been performed. They should be used when Lupron is not working, and adrenal profile hormones and ultrasounds should be performed every 3 months to monitor their effects, both good and bad.

Mitotane

This is one of the primary drugs used to treat dogs with Cushing’s. It is sometimes in conjunction with Lupron. It seems to show variable success only with cortical adenomas, and does not help adenocarcinomas. Its seems to work by chemically reducing the size of the affected adrenal gland. If a ferret has insulinoma at the same time, which is not uncommon, mitotane can cause hypoglycemia (low blood sugar) and a ferret can become comatose.

It is sometime used as pulse therapy, and symptoms of hair loss sometimes return after stopping mitten. As general rules, this drug, or in combination with Lupron, is only used on older ferrets with both adrenal glands affected and also a poor candidate for surgery due to other diseases occurring at the same time.

Deslorelin

This drug is a synthetic GnRH analog, and is used currently to reduce testosterone in dogs as a contraceptive. When given as a injection it is slow release and has helped reduce the typical symptoms of ferret adrenal disease.

Melatonin

Melatonin inhibits the release of GnRH, suppressing the amount of LH and FSH released into the bloodstream. It theoretically helps regulate hormonal control in a ferrets normal circadian rhythm of light and dark. It is in the form of a long acting injection or daily oral medication.

Melatonin can be used to stimulate hair regrowth, it does not suppress the adrenal tumor. If used prior to a physical exam it can mask symptoms, and cause the adrenal gland to become even larger before surgical removal.

It can cause lethargy, and should not be used in smaller ferrets. Ferrets can develop a tolerance. It should be used as an adjunct to Lupron.

Casodex

This oral drug blocks binding sites to testosterone. It will help minimize symptoms of adrenal disease, especially straining in the male ferret. It needs to be used one week on, one week off, for life. More information is needed before we can recommend this drug.

Arimidex

This oral drugs interferes with the enzyme pathway that converts testosterone to estrogen. It should not be used with Casodex since the two drugs will negate each other.

Prognosis

Most ferrets that have this surgery regain hair growth and do well for years. Even though most adrenal tumors are benign, recurrence can occur. A tumor can appear in the adrenal gland that is not removed at the time of  surgery, and symptoms can recur.