In 1932, brain surgeon Dr. Harvey Cushing published a scientific paper about 12 patients with a particular tumor of the pituitary gland. This gland is a small structure at the base of the brain that we now know is central to the regulation of a great number of hormones throughout the body. He noted that the patients all displayed a set of symptoms that later became called Cushing’s syndrome. Some time later, veterinarians began to recognize a similar disease, primarily in dogs, and though some of the more classic symptoms in people are not as commonly noted in dogs, there are many signs in common.
When I was in veterinary school we all learned that if something came up in two different lectures, you better wake up because it’s important. To give you an idea of how complicated this disease can be, in my veterinary training we received lectures on Cushing’s disease no less than five different times. For that reason, we’ll make this a brief overview and not a graduate-level course in canine Cushing’s disease or Cushing’s syndrome.
Let’s start by looking at some anatomy and hormone control. In people, adrenal glands are located right on top of each kidney. The adrenal glands produce a number of different hormones, which are chemical messengers that act on various body tissues to cause a wide variety of effects. In Cushing’s syndrome, the hormone at the root of all of the clinical signs is cortisol.
The adrenal glands have a number of layers. The innermost layer, the medulla, produces adrenalin when stimulated by the sympathetic nervous system. You are familiar with this hormone; it causes your heart rate to go up when you are excited or frightened.
Three outer layers are part of the adrenal cortex. One of these produces aldosterone to regulate blood salt levels. Two other layers produce cortisol and androgens (sex hormones). Unlike the medulla, with its direct nerve connections, hormone production in all three of the layers of the cortex is controlled by stimulating hormones produced by the pituitary gland.
One of the stimulating hormones is ACTH (adrenocorticotropic hormone). As the name implies, it causes cells in the adrenal cortex to produce and release cortisol into the bloodstream, where it is then delivered to cells throughout the body.
How important is cortisol? Everyone needs cortisol. Without it we can’t handle any physiologic stress, things ranging from infection to lack of sleep to running to catch the bus. An animal without enough cortisol will die. However, whether you are a human or a dog, too much cortisol isn’t good either. In Cushing’s disease, blood cortisol levels are elevated for too long a period and problems develop.
Loss Of Control
There’s an important nerve center in the brain, the hypothalamus, sometimes called the master gland. It coordinates many different body functions, one of which is being able to deal with stress. Sensing input from a number of sources, including the current level of circulating cortisol, it acts like a thermostat to set the blood level of cortisol. If the hypothalamus determines that the level of cortisol is insufficient, it releases a signal that travels to the pituitary gland in the form of corticotropin-releasing hormone (CRH) that tells the pituitary to release ACTH. If the level is sensed as adequate, CRH is not released. Thus, a stimulating “loop” is created based on a system of negative feedback. As cortisol levels rise, the stimulation for more cortisol is inhibited, and as cortisol levels drop, the stimulation increases
In Cushing’s syndrome, regulation is generally lost from one of two situations. The most common is pituitary-dependent hyperadrenocorticism (PDH), which is caused by the growth of a pituitary adenoma (tumor) that produces ACTH without “listening” to the signals from the hypothalamus. Many of these tumors are microscopic and are not visible on any form of imaging, such as a MRI. Roughly 85 percent of canine cases result from this type of tumor. In the second form, the cells of the adrenal cortex become cancerous and start to release cortisol, independently of any control from the pituitary. In both cases, normal negative feedback is lost.
Signs And Diagnosis Of Cushing’s Disease In Dogs
Once control is lost, a continued high level of cortisol results in the typical and fairly dramatic signs we see in Cushing’s syndrome, including polydipsia (excess thirst), polyphagia (almost uncontrolled hunger), polyuria (excess urination), abdominal enlargement (pot belly), alopecia (hair loss), panting, muscle weakness, lethargy, poor wound healing and chronic infections.
Signs develop slowly, often over a period of months to years, and many owners think that what is happening is simply “my dog is just getting old.” Most dogs exhibit only a few of the external signs of the disease, and diagnosis often requires a bit of “clinical suspicion.” Internally, the high cortisol levels cause changes in the blood count, serum chemistries and urinalysis results, changes that further support a clinical diagnosis.
Diagnosis of Cushing’s disease starts with recognizing that a dog has some of the clinical signs and laboratory changes. Additional testing can include taking X-rays of the abdomen to look at the size and shape of internal organs, or for calcification in the region of the adrenal glands, which is often linked to an adrenal tumor. An abdominal ultrasound is very helpful, allowing the doctor to examine the adrenal glands and other organs that might be affected. Finding one large adrenal gland and one small one might also indicate an adrenal tumor. If both glands are enlarged, a pituitary-dependent condition might exist.
Direct testing of the adrenal glands involves injecting a drug and measuring the amount of cortisol that the glands produce. The dexamethasone suppression test will cause a dog’s cortisol production to shut down for a few hours, whereas a dog with Cushing’s will often continue to produce the hormone. For an ACTH stimulation test, the drug stimulates the glands and most normal dogs will produce more cortisol after stimulation, but only within a given range. Dogs with Cushing’s often produce too much cortisol when tested this way. There is no worry that either type of test will make things worse. In either case, a short period of more or less cortisol is not dangerous to the patient.
When talking about signs and test results, why do we say “often?” Because there is no particular sign or test available that is diagnostic for 100 percent of Cushing’s cases. For this reason, your veterinarian may need to perform a series of tests and combine the information with all the other data to arrive at a diagnosis.
Treating Dogs With Cushing’s Disease
Once your dog is diagnosed with Cushing’s disease, what do you do? The decision to treat a dog with Cushing’s is one that should be made only after thorough consultation with your veterinarian. Not all dogs with Cushing’s need to be treated, and some don’t need to be treated right this minute.
The most common treatments involve giving the dog oral medications. This is a life-long situation, as none of the drugs will cure the patient. One drug recently approved for use in dogs is called trilostane. It prevents the production of cortisol in the adrenal glands by blocking one of the enzymes that converts a precursor molecule into cortisol. This medication must be given daily. Another drug, selegiline is also approved for use in Cushing’s, but only for the pituitary-dependent form.
Though not approved for use in dogs and technically “off-label,” the drug with the longest history of use for the treatment of Cushing’s disease is mitotane, a chemical that kills cells in the adrenal gland. You can think of it as a chemical scalpel, carving away part of the enlarged glands each time it is given.
Each of the treatments has its own set of problems and risks. Every case requires individual planning and adjustment, and side effects from the drugs can be life-threatening. With mitotane, the most common treatment regimen begins with an induction period where a dose is given daily for about seven days. As soon as any of the clinical signs change (even a little bit), the drug is stopped and an ACTH stimulation test is performed. Your veterinarian is looking to see that the adrenal glands are no longer overproducing cortisol. This is followed by a maintenance dose given once or twice weekly. Follow-up testing should be done on a regular basis. For trilostane, a similar schedule is followed, except there is no induction period; you start with the daily or twice daily dosing immediately.
There’s more to this condition in terms of other testing and other treatments that your veterinarian will have to consider. After all, if canine Cushing’s disease were all this neat and simple, it wouldn’t take five lectures in veterinary school and countless hours after graduation to understand all of the subtleties, additional rarer forms of the disease, and different tests and treatments that now exist. Hopefully you now have some of the basics to begin to understand one of the most common endocrine (hormone) diseases encountered in our canine companions.