Adrenal Disease

What is Adrenal Disease and How Can We Treat It?

Author: Katt Crouch

 Healthy Adrenal Glands

To understand how Adrenal Disease works, we first need to understand how the adrenal glands work when they are healthy.

Normally, the hypothalamus sends signals to the pituitary gland, which then in turn sends signals to the adrenal glands and gonads (testicles or ovaries) telling them to produce sex hormones – testosterone and estrogen (as well as other important hormones). Adrenal glands also produce sex hormones, but in much smaller quantities than the gonads. NORMALLY, the gonads produce the bulk of the sex hormones – let’s use Testosterone from the testicles (blue burst, “T”) for the purposes of simplifying this discussion (but remember, this happens in females as well and there are many different hormones involved in addition to Testosterone).

a

1

The testicles produce testosterone, which then travels through the blood stream and has many different effects in the body. One of these effects is to send a negative feedback signal – when the testosterone in the blood is high enough it tells the hypothalamic-pituitary system “STOP – we have enough testosterone.” The hypothalamic-pituitary system then stops signaling the testicles and adrenal glands, which allows them to take a “break” from pumping out Testosterone.

When testosterone is low, this negative feedback signal stops and the hypothalamus turns the signals back on (see Figure 1).

2

The hypothalamus-pituitary system thus acts like a thermostat, turning the adrenal glands and testicles UP or DOWN based on how high or low the hormone levels are.

3

Neutered Ferrets

When you remove the testicles (or ovaries in females) by neutering your ferret, there will be significantly less sex hormone – testosterone – made. This low testosterone is sensed by the hypothalamus tells the pituitary to send a big “MAKE HORMONES” signal to the testicles AND adrenal glands. However, there are no testicles to produce testosterone, so the “ON” signal remains ON and in full force – and STILL the body remains low in testosterone. As a result, that signal gets turned up even more. Meanwhile, the poor adrenal gland is bombarded with a massive “make hormones” signal and tries madly to compensate. The adrenals are forced to try to produce enough testosterone for themselves and the missing testicles.

4

When ANY organ is forced to be overactive like this, it will undergo hyperplasia and/or hypertrophy – which means that it increases the number and size of cells. More cells mean it can make more hormone to keep up with the increased workload demand. In time, the cells begin to multiply more than needed and with the abnormal growth and signals, they become PRE-cancerous. There’s more cells, and often those cells are each producing more hormone than a normal cell. Carcinoma In-Situ is a tumor or cancer, that is NOT yet malignant – but that has the capacity to become malignant. At this point we now see enlarged glands and may see TUMORS in the glands that are producing abnormal amounts of hormones (which lead to the symptoms of adrenal disease). These tumors are NOT malignant at first. However, given enough time under the continued stress of perpetual “ON” signals from the pituitary, and with continued abnormal cell growth, the tumors can become malignant and invade other tissues. A tumor is NOT malignant UNTIL it invades other tissues – that is the medical definition of a malignant cancer.

The Adrenal Disease Symptoms that we see in ferrets are caused by the hormones, not the “cancer.” [When the tumors on the gland become malignant and invasion and metastasis happen, you are then dealing with malignant cancer, which is a more complicated problem.] As the adrenal gland grows, it becomes more and more abnormal. Eventually it can produce several hormones in excess of what the body actually needs. These excess hormones cause many of the symptoms that we identify as typical Adrenal Disease symptoms. For example, one hormone made by the adrenal gland called DHEAS has been implicated in hair loss and prostate enlargement (which in turn causes urinary blockage). Excess estrogen is thought to also stop hair growth, contributing to the alopecia (balding) seen in adrenal ferrets. Other effects of hormone imbalances include bone disease, muscle wasting, weakened immune system, depression, irritability, and aggression, among other symptoms.

5

Surgery

All of the signals we have discussed are being transmitted throughout the blood stream in the body, which means that BOTH of the adrenal glands are under the same stress from the increased “ON” signals. This means that typically BOTH glands will undergo the aforementioned process of abnormal cell growth and abnormal hormone production. The process occurs at different rates in different cells, so tumors might become apparent in one gland sooner than the other in the same way that tumors might show up in different spots on one gland at different times. Some vets recommend surgery to treat adrenal disease. This may temporarily stop the symptoms of Adrenal Disease (by removing one half of the source of excess hormones), and the surgery is reported to have a high success rate, however it does not solve the underlying problem and long-term survival and recurrence data is limited.

Removing ONE gland does not at all stop the stressful “ON” signals that the second gland is still receiving and additionally, when you remove that gland you also remove the hormones it made…which means less negative feedback…which means MORE stress on the remaining gland. The single remaining adrenal gland now has to compensate for the missing gonads AND the missing adrenal gland… At this point, it is really only a matter of time until disease starts to appear in the remaining gland. Removing ONE gland may remove the tumor in THAT gland, but it will by no means produce a cure of the underlying problem.

6

Another downfall to surgery is that the removal of adrenal glands from a ferret is a very risky procedure. The adrenal glands lay along very important blood vessels which make them difficult to remove and the risk of bleeding during the operation is high. The right adrenal gland sits alongside the inferior vena cava, the major vein that returns blood from the lower body to the heart. If the vena cava is cut during surgery, the ferret can bleed to death in a matter of seconds. Additionally, any time you put an animal under anesthesia there is an inherent level of risk involved. While some find this risk acceptable for the outcomes, most vets and ferret owners are moving towards less invasive treatment options.

Removing BOTH glands is not a good option. The adrenal glands are very important organs that produce many vital hormones that your ferrets’ bodies need to function. With decreased adrenal signals, Addison’s Disease will develop; with NO adrenal function at all, Nelson’s Disease will develop as the Pituitary becomes the main player receiving increased “ON” signals. Removing both glands is just trading one disease for another much more complicated and dangerous disease.

7

Lupron and Deslorelin/Suprelorin Acetate Implant

So if we don’t want to risk surgery, what else can we do? The ROOT of the problem is that there are not sufficient signals telling the Hypothalamus and Pituitary to STOP sending “ON” signals to the gonads (testicles/ovaries) and adrenal glands. This is where the GnRH agonists Lupron and the Deslorelin Acetate (Suprelorin) Implant come in. These do not get rid of the abnormal cells in the glands but they do, in a way, address the underlying issue. Lupron and Deslorelin are both hormones that work to turn down the Pituitary’s signals. (The way they do this is complex, so we will not go into detail, but long-story short they make the pituitary gland insensitive to the “ON” signals from the hypothalamus). When we turn down this “ON” signal from the pituitary, we remove the constant over-stimulation on the adrenal glands – they are no longer constantly being bombarded with “MAKE HORMONE” signals. If the glands were not yet too diseased, this removal of over-stimulation can actually allow the adrenal glands to return to a more normal activity level and any tumors present may actually shrink or even disappear. Indeed, there have been many reports of adrenal gland shrinkage in ferrets receiving the Deslorelin/Suprelorin implant. [Why Deslorelin works so much better than Lupron we don’t really know; they are nearly identical hormones – it is likely the constant hormone release of the implant that makes the difference.] Now of course, not all of the diseased glands and tumors will shrink – typically by the time the ferret is showing symptoms the gland is too diseased to reverse the damage. The abnormal cells remain and if they contain the right (or rather, wrong) genetic mutations from their aberrant growth, then they will continue to grow abnormally. However, without the constant “ON” signal from the pituitary, the growth will slow VERY significantly, AND the hormone over-production will slow if not stop, causing symptoms to improve and disease progression to slow.

8

Of course as with any medication, Lupron and Deslorelin are not without their own risks. Lupron is an injection that must be given monthly – if it is not given consistently, the disease will continue to progress. The monthly injections are often costly, but it is important that the timing of the injections be consistent or breakthrough disease may occur, enabling the condition of the adrenal glands to further degrade.

Deslorelin/Suprelorin is also expensive, but is usually more cost-effective in the long run, and more convenient, as the implant only needs to be given twice a year. While it was originally stated that the implant only needed to be given once a year, most ferret owners are finding that for active adrenal disease the implant must be given every 6-9 months. Any less often and the ferret will begin to experience breakthrough symptoms. Rather than wait for breakthrough disease to occur, it is typically recommended to stay ahead of the disease and give any ferret with diagnosed adrenal disease a new implant every 6-9 months.

Some ferrets have been known to have reactions to the implant, though this is relatively uncommon and removal of the implant typically stops any adverse effects (at which point other treatment options should be discussed). It is also important to recognize that the hormonal changes seen in adrenal disease may mask other underlying diseases, particularly insulinoma. This means that in some ferrets, receiving treatment for adrenal disease may unmask undiagnosed insulinoma or, rarely, make diagnosed insulinoma worse. This can put a ferret at risk of an insulinomic seizure if their BG is not under good control prior to receiving treatment. On the other hand however, many ferrets with diagnosed insulinoma see significant improvements after their Adrenal Disease is treated. In fact, some ferret owners have reported that ferrets in which they previously were unable to control their BG became stable after treating the ferrets for adrenal disease.

Overall, the risks of Lupron and the Deslorelin/Suprelorin implant are very low. These treatments are highly effective and can provide your ferret with a significantly improved quality of life for years to come. Many studies have found Deslorelin to be comparable, if not more effective, than surgery in terms of symptom improvement and post-treatment survival, and with significantly reduced risks.

As a ferret owner, it is up to you to determine which treatment you will choose for your Adrenal ferret. It is important to discuss the different treatment options for Adrenal Disease with your vet, and to do your own research on each option. Thoroughly weigh out the pros and cons of each option, and talk to other ferret owners about their experience. In the end, only you can make this decision for your ferret.

 

 

References

(2012). Suprelorin EMA. Annex I: Summary of Product Characteristics. 1-36.

Johnson-Delaney, C. (2006). Update of ferret adrenal disease: Etiology, diagnosis, and treatment. Association of Avian Veterinarians. 69-74.

Johnson-Delaney, C. (2004). Medical therapies for ferret adrenal disease. Seminars in Avian and Exotic Pet Medicine. 13 (1): 3-7.

Lennox, A., Wagner, R. (2012). Comparison of 4.7mg Deslorelin implants and surgery for the treatment of adrenocortical disease in ferrets. Journal of Exotic Pet Medicine. 21, 332-335.

Lewington, J. (2007). Chapter 14, Endocrine Diseases. Ferret Husbandry, Medicine, and Surgery, 2e.(356-370). Philadelphia, PA: Saunders.

Schoemaker, N., van der Hage, M., Flik, G., Lumeji, J., Rijnberk, A. Morphology of the pituitary gland in ferrets (Mustela putoris furo) with hyperadrenocorticism. Journal of Comparative Pathology. 69-82.

Prohaczik, A., Kulcsar, M., Huszenicza, G. (2009). Deslorelin treatment of hyperoestrogenism in neutered ferrets (Mustela putorius furo): a case report. Veterinari Medicina. 54 (2), 89-95.

Wagner, R., Miller, L., Finkler, M. (2011). Updates on Adrenal Disease: GnRH Agonists and GnRH Vaccine Studies. 2011 Symposium International Ferret Congress.