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Canine Cushing's Disease
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CANINE CUSHING’S DISEASE

By Geneva Coats, R.N.

 

Your dog seems tired and irritable, excessively thirsty, has a ravenous appetite, and he is losing his coat. Your veterinarian tells you that many different problems could cause these symptoms, including thyroid disease, diabetes, or Cushing’s disease. You’ve heard of thyroid disease and diabetes. But, what is Cushing’s disease?

 

Cushing’s disease is a set of symptoms that occur when excess cortisol is circulating in the body.  Cortisol is a steroid hormone produced by the adrenal glands, the small glands located next to the kidneys.

 

Your endocrine system consists of several glands that produce hormones, which regulate processes throughout your body. Endocrine glands include the adrenals, pituitary, thyroid, parathyroid, pancreas, ovaries (in females) and testes (in males).  These glands interact with each other in a biofeedback manner to maintain proper hormone levels necessary for health.

The adrenal glands have various effects on metabolism, including regulating water and electrolyte balance, blood pressure control, and producing sex hormones such as testosterone and DHEA, (a precursor of estrogen). Another layer of the adrenal gland produces the nervous system regulators epinephrine and norepinephrine. 

Cortisol (along with epinephrine and norepinephrine) is produced in response to stress, stimulated by the "fight or flight" response. Think of how you feel when you just narrowly avoid a car accident or witness a crime. Your body reacts instinctively in a primal survival response to deal quickly with this threat. Your sympathetic nervous system automatically kicks into overdrive. Your heart pounds, you breathe rapidly. Your hair stands on end. Your stomach is tied up in knots. Your sphincters may relax (OH NO!!) causing incontinence. Your body shunts blood to the extremities so you can RUN away from the dangerous situation or so you can fight off an aggressor. Cortisol is released from the adrenal gland, and this cortisol in turn stimulates the release of glucose from the liver and other cells of the body, so that you will have energy to deal with your stressful situation. Cortisol has potent anti-inflammatory properties and anti-allergy effects. When the immune system is suppressed, however, you then become more susceptible to infection.

Cortisol is necessary for survival, as a mechanism to deal with stress. Normally the body compensates for this stress response with a “rest and relaxation” phase produced by the parasympathetic nervous system. However, if your body is continually producing excess cortisol, you may develop the same symptoms as someone under chronic stress: high blood pressure, elevated blood sugar levels, hunger, thirst, fatigue, irritability, redistribution of fat to the abdomen, thinning of skin and loss of hair, loss of bone mass and muscle mass, and increased susceptibility to infection. Disruption of the calcium-phosphorus balance can result in joint pain and weakening of cartilage.

There are several ways that the adrenal glands are stimulated to produce excess cortisol. If the master gland in the brain (pituitary) is overactive, as with a pituitary tumor, it can stimulate the adrenals to produce too much cortisol. Dr. Harvey Cushing first described a woman with signs and symptoms of this disease in 1912, and in 1932 he was able to link the adrenal overproduction of cortisol to an abnormality in the pituitary. Occasionally, tumors of the thyroid, lung or pancreas can produce similar hormones that overstimulate the adrenal glands. Even rarer is a tumor of the adrenal gland itself.

Due to their potent anti-inflammatory effects, synthetic corticosteroid medications such as prednisone or decadron are often used to treat allergies or arthritis. Prolonged use of these corticosteroids can also produce the symptoms of Cushing’s disease, such as elevated blood sugar levels and impaired immunity which can lead to infection. When taking steroids, your adrenal glands turn off its production of cortisol, due to high levels already detected in your body. For this reason, abrupt withdrawal of steroid medications is never advisable, and dosages are tapered down over several days. Your body needs some time to gradually resume its own production of cortisol. A gradual withdrawal of these medications will allow the natural hormonal balance of the body to become re-established.

 

DIAGNOSTIC TESTS


If your dog presents with Cushing’s symptoms such as excessive thirst, hunger, or thinning coat, your vet will want to rule out other more common conditions with similar symptoms, such as diabetes, thyroid disease, or use of veterinary steroids, before he decides to test for Cushing’s disease. Bottom line, most of the tests for Cushing’s disease are time-consuming, expensive and not reliably diagnostic. Ultrasound of adrenals and kidneys may (rarely) show a tumor. Diagnostic CT or MRI are less commonly used for dogs.

 

Diagnostic lab tests can be done. These tests work by either stimulating the adrenal glands with synthetic Adrenocorticotropic Hormone (ACTH stimulation test), or by suppressing the release of ACTH from the pituitary gland (low dose dexamethasone suppression test or LDDS). Using the stimulation test, one is looking for excessive release of cortisol from the adrenal glands; and using the suppression test, one is looking at whether or not cortisol levels can be completely suppressed for a prolonged period of time.

 

The ACTH stimulation test measures serum cortisol levels before and after injection of the pituitary stimulator hormone. Very high levels can indicate Cushings, although a large percent of affected dogs will have normal findings.

 

The LDDS test can distinguish between pituitary-stimulated Cushing’s disease and adrenal-dependent Cushings’s disease. The dog is injected with the steroid hormone dexamethasone, and levels of cortisol and ACTH are then measured as they decline over an extended period of time. In dogs with Cushing’s disease, the cortisol levels remain high. False positives occur in roughly half the subjects, most likely due to the stress involved in the testing process. A high dose test can also be attempted.


Upon diagnosis, treatment might be surgical to remove a tumor, occasionally radiation therapy is recommended to shrink the tumor, or various medications can be used. The goal of these medications is to control the release of cortisol from the adrenal glands. None of these medications is without serious side effects.

 

MEDICATIONS

 

Anipryl (Selegiline), a drug used to treat canine senility, works in some cases of pituitary over-activity. Anipryl decreases pituitary production of ACTH. It is expensive and only works in about half the patients.

 

Nizoral (Ketoconazole) is an antifungal medication which also blocks the production of cortisol and other steroid hormones.

 

Lysodren (mitotane) is commonly used. It causes erosion of the adrenal cortex. Careful monitoring is necessary as too much erosion of the adrenal cortex can permanently damage the adrenal gland, result in severe deficiency of cortisol. This is the reverse of Cushing’s disease, and is known as Addison’s disease. An Addisonian crisis can be fatal.

 

Vetoryl (Trilostane) suppresses cortisol levels by inhibiting production, not by destroying the gland. It is not currently available in the US but can be obtained with a prescription from two distributors, www.mastersmarketing.com or Arnolds Veterinary Products www.arnolds.co.uk. Trilostane is currently being prescribed by veterinary schools at the University of Pennsylvania, Cornell, and the University of California at Davis. Trilostane is costly. It is short-acting, and does not remain in the body for an extended period of time, so it is important not to miss a dose. Also, Trilostane is not effective for atypical cases caused by high levels of sex hormones (see atypical Cushings’s disease, below)

 

 

ATYPICAL CUSHING’S DISEASE


Some dogs show many of the signs and symptoms of Cushing’s disease, yet have normal circulating cortisol levels on standard Cushing’s tests. This is called “atypical” Cushing’s disease, meaning the disease presents in a manner which is not typical. This is also known as adrenal hyperplasia-like syndrome or hyperestrinism. Some researchers believe that Alopecia X may, at least in some cases, be due to atypical Cushing’s disease.

 

Cushing’s disease symptoms may sometimes be due to excessive levels of cortisol precursors, in particular the sex hormones estradiol (the most potent form of estrogen) and hydroxyprogesterone, a form of progesterone from which cortisol is produced in the body. In addition to cortisol, both estradiol and hydroxyprogesterone are produced by the adrenal glands. Dogs commonly have elevation of progesterone. Increased estradiol occurs frequently, but less so than for progesterone. Testosterone is increased only rarely. Several patterns of hormone increase can occur, so a complete adrenal panel will provide your vet with the most useful information.

 

The University of Tennessee veterinary school is on the forefront of research into alopecia X, Cushing’s and atypical Cushing’s disease. An "adrenal panel" blood test can be sent there for analysis. In a study published earlier this year, UT’s Dr Linda Frank determined that estrogen receptors in hair follicles did not have any affect on hair follicle cycles in dogs. Dr Frank does not believe that Alopecia X in Pomeranians is related to atypical Cushing’s disease. Further, she states that a diagnosis of “atypical” may just mean that testing was inconclusive, although the dog may actually have Cushing’s disease.

 

A retained testicle or ovarian remnant may cause Cushing’s symptoms. Early spay-neuter has also been suspected of playing a role in adrenal imbalance, due to the interplay between the ovaries/testes and the adrenal gland production of sex hormones. Genetic predisposition may play a role in the development of Cushing’s disease.

 

Antiestrogen drugs like Arimidex are now being used with some success to treat atypical Cushing’s cases. Arimidex prevents the conversion of certain male hormones into estradiol.  Lupron, a hormone which suppresses estrogen, and Nolvadex (tamoxifen), an estrogen blocker, have been suggested as possible treatments but are not recommended but the University at this time.

 

Melatonin has been used with some success. Melatonin is a hormone from the pineal gland in the brain. Melatonin controls the timing and release of the female reproductive hormones. Human breast cancer patients often have estrogen-dependent tumors, and high levels of circulating estradiols, along with low levels of melatonin. These breast cancer patients are often prescribed estrogen-blocking drugs such as Lupron, Arimidex and Nolvadex.

 

Dr. Jack Oliver, endocrine specialist at the University of Tennessee, has developed a diagnostic testing and treatment protocol for atypical Cushing’s, which includes the following suggestions (revised 11-13-2008):

 

Where positive test results of increased adrenal activity are present, consider the need for:

  1. Ultrasound to rule out a primary adrenal tumor
  2. Melatonin. Often used as a first treatment, especially if alopecia is present, since it is inexpensive, has few side effects, and is available in health food stores. Typically, a total dose of 3 mg is given every 12 hours for dogs less than 30 lbs; a total dose of 6 mg is given every 12 hours for dogs over 30 lbs. Use regular, not extended release products. Melatonin inhibits estradiol production and effectively lowers cortisol levels.
  3. Melatonin implants. (www.melatek.net) Dose dependent on weight of dog. Effects last 3-4 months. NOTE: Melatonin and flaxseed oil with lignans are used together when estradiol is increased.
  4. Flaxseed oil (FSO) with lignans. The lignans in FSO have phytoestrogenic activity and may compete with estradiol for tissue estrogen receptors with less biological effect. Lignans lower both estradiol and cortisol. Sources include health food stores and internet sites: www.barleans.com or www.vitacoast.com/nsiflaxseedlignans; suggested dose 40 mg every other day for dogs weighing less than 30 lbs, or once daily for dogs weighing over 30 lbs.
  5. Lysodren: may be useful in combination with melatonin and lignans to help lower sex steroid levels other than estradiol. Also useful by itself as the traditional treatment and is very effective in lowering cortisol, progesterone and other sex steroids. Estradiol is not always suppressed by Lysodren.
  6. Trilostane: Available in UK and Europe. Trilostane will INCREASE some sex steroids, Lysodren may be preferable for atypical Cushing’s cases. Care should be used when switching from triolstane to lysodren.
  7. Ketoconazole (Nizoral) May be effective as an alternative treatment for hyperestrinism in dogs, and may also be used in combination with melatonin and lignans.
  8. Anipryl (Selegiline) Alternative treatment which decreases ACTH stimulation from the pituitary.
  9. Specific hyperestrinism treatment such as Arimidex and Aromasin. Kinetic studies are lacking.
  10. Ovarian remnant detection
  11. Retained testicle detection

 

For further information refer to website: www.vet.utk.edu/diagnostic/endocrinology

 

COMPLEMENTARY THERAPIES

 

Phosphatidylserine (PS) is a natural fat produced by the body which maintains proper nervous system function. PS is available as a dietary supplement. Clinical studies have shown that PS raises circulating levels of such hormones as dopamine and melatonin, and reduces levels of ACTH and cortisol. It may have some usefulness in treating Cushing’s disease as well as senility.

 

Some holistic veterinarians prescribe PS for borderline Cushing’s cases or use PS in addition to other therapies.  Other complementary therapies include use of various herbs; Ginkgo biloba, milk thistle, dandelion, rehmannia, turmeric, astragalus, boswellia and ashwagandha. Holistic veterinarians may also recommend purified drinking water, and dietary modifications such as adding antioxidant vitamins E and C, essential fatty acids, probiotics, glucosamine, and CoEnzyme Q10.

 

Always seek the advice of your veterinarian for diagnosis and for forming a treatment plan for your dog.

 

XENOESTROGENS


Hormone disruption is believed to play a major role in many dogs who display Cushing's symptoms. One newer theory involves synthetic environmental estrogenic compounds called "xenoestrogens." These compounds are found in petroleum products, plastics, pesticides and fertilizers....even in some skin creams.  Xenoestrogens are believed to mimic the effects of estrogen in the body, including suppression of melatonin and promotion of estrogen-dependent disorders such as breast cancer, ovarian cancer, and endometriosis. Xenoestrogens may also be responsible for decreased sperm count in males and a host of other problems.
Because they derive from oil, most of these synthetic products are, like steroid hormones, fat-soluble. This means that, rather than leaving the body (as they would if they were water-soluble), these synthetic products accumulate in the fat tissues of the body. Xenoestrogens are everywhere in the modern environment. The effects may be with us for generations to come.


There are many different factors involved in a disease such as Cushing’s, which is characterized by disruption of hormonal pathways. Since the disease is usually caused by tumors, it often occurs in old age. Arriving at the correct diagnosis and treatment involves a process of trial and error. Always consult with your veterinarian for advice regarding your dog’s unique situation.

 

References

 

Hillier, Andrew, BVSc, MACVSc, Dipl ACVD, “Alopecia, is an Endocrine Disorder Responsible?”

Ohio State University, est date 2006

 

Kirzeder, Elizabeth M., Frank, Linda A., Sowers, Kristi D., Rohrbach, Barton W., Donnell, Robert L. ; “Influence of Inflammation and Coat Type on Estrogen Receptor Immunohistochemistry: Veterinary Dermatology, Vol 19, Issue 5; Aug 7, 2008.

 

Oliver, Jack W., DVM, PhD; “Steroid Profiles in the Diagnosis of Canine Adrenal Disorders”;

Proceedings 25th ACVIM Forum, Pp. 471-473, Seattle, WA. 2007

 

Paddock, Lisa; “Atypical Cushing’s Disease”; “”A Cushing’s Primer”; Great Scots Magazine, March-April 2005

 

Schmeck, Heidi; “Complications and Concurrent Disease Associated With Hyperadrenocorticism”; “Hyperadrenocorticism Treatment Options Overview”; Canine Cushings/Autoimmune Care, 2007

 

University of Tennessee, Clinical Endocrinology Service, College of Veterinary Medicine; “Steroid Profiles in the Diagnosis of Atypical Cushing’s Disease”; revised 11-13-2008