Cushing's in dogs. Signs of Cushing's syndrome in dogs and treatment methods

The endocrine system is one of the biggest mysteries of our body. Almost all biochemical processes occurring in the body are tied to the endocrine glands, and the slightest change in hormone levels often leads to irreversible consequences. If we talk about the field of veterinary medicine, the most common disorder is Cushing's syndrome. In dogs, this disorder most often occurs in old age, and today we will look in detail at what it is and how it can be dealt with. This article is for informational purposes only; in any case, you should consult a doctor to make a diagnosis and choose a treatment regimen.

What is it in dogs

This is a pathology that is not as rare as we would like. The violation consists in the fact that the animal’s pituitary gland begins to secrete cortisol in excessively increased quantities. This is a very important hormone, which is a powerful natural remedy for resisting stress. We will not dwell on the mechanism of action of this hormone on the body; we will only say that this substance mobilizes all reserves to withstand the negative influences of the external environment.

It seems like a complete benefit, why, when describing this mechanism, do we talk about Cushing’s syndrome in dogs? The fact is that the amounts of the hormone that begin to be released into the blood are excessive even for an elephant. And the pituitary gland, which is supposed to control the amount of hormone produced, is completely switched off from this process. Because of this, your pet faces extremely unpleasant consequences.

Negative consequences

Cushing's syndrome in dogs leads to changes in the animal's behavior. Mental disorders are clearly manifested. The dog is tormented by constant, exhausting thirst. This creates a high load on the kidneys, and in addition, leads to excess urine production. This disorder can easily lead to death, and quite quickly. The reason for this is easily explained from a physiological point of view. The body is in a mobilized state, which means it wears out several times faster. In veterinary practice, there are examples when the state of the body of a three-year-old dog suffering from this disease is identical in wear and tear to the body of a 13-15 year old dog.

Main symptoms

Let's now talk about how you can suspect Cushing's syndrome in dogs. First of all, owners pay attention to the increased appetite. The animal begins to gain weight very quickly. At the same time, you may notice extreme thirst and very frequent urination. The animal cannot tolerate it for long and, despite the increased number of walks, still pees at home.

In fact, this disease does not appear out of nowhere, but gradually develops, and the symptoms get worse. The dog becomes weak and lethargic, drowsy, but shows an excellent appetite. The abdomen sags due to weakness of the abdominal muscles. Very rapid fatigue is observed. Baldness is gradually added. Large areas of skin remain completely hairless. Most often these are areas on the body, but not on the head or paws. There is no itching. Without treatment, diabetes mellitus develops very quickly against the background of this disease.

Causes of the disease

In fact, veterinarians have several theories as to why dogs suffer from this hormonal disorder. However, the main cause is a tumor affecting the adrenal glands. Most often, doctors try to correct this condition with surgery or medications, which also have their side effects. However, this is not the only reason that can cause Cushing's syndrome in dogs. The photo shows us the external changes that occur in sick animals, but below we will return to the symptoms.

Another cause may be a pituitary adenoma. Therefore, both the pituitary gland and the adrenal glands will need to be examined. However, having discovered a tumor, the doctor is only beginning his work. It is also necessary to determine whether we are dealing with a benign or malignant lesion, and only then predict the course of treatment.

Predisposition

There are certain breeds in which this disease occurs more often than in others. Thus, boxers and terriers of all types are at risk. This also includes dachshunds, beagles, poodles and basset hounds. Most often, adults who are 7-10 years old are susceptible to this disease. At this age, doctors can only maintain the condition of the body as much as possible. However, Cushing's syndrome is also diagnosed at a fairly young age - in dogs less than two years old. The disease is very dangerous because it affects all organs and systems at once, and therefore, without proper treatment, there is a high probability of death of the animal, as well as a serious reduction in life expectancy with adequate treatment.

Survey

It is essential to reliably confirm Cushing's syndrome in dogs. Diagnosis of this disease is very difficult; not all clinics are able to provide the necessary conditions for this. First of all, the doctor must examine the animal and take the necessary tests. A clinical and biochemical blood test, as well as a urine test, in which it is important to check protein levels, will be indicative.

To clarify the picture, the doctor may prescribe an x-ray, which will show enlargement of the liver or mineralization of the adrenal glands. It is necessary to perform an ultrasound to exclude an adrenal tumor. Correct diagnosis should not only confirm Cushing's syndrome in dogs. The symptoms that will be treated in the next stage may be vague, which means it is extremely important to find the source of the problem.

Treatment

This is a difficult and responsible moment. At this stage, the doctor must choose the most appropriate therapy. Restoring cortisol levels and supporting the functioning of all organs and systems is the main task that has faced him since he was diagnosed with Cushing's syndrome. In dogs, treatment can be done in two ways.

The first way is surgical. It is not indicated for all animals, but only for those who have an adrenal tumor. In the case of the animal, everything is even more complicated, and the adrenal glands are simply removed and the animal is prescribed lifelong hormonal treatment.

The second way is medication. In this case, hormone therapy is used to normalize cortisol levels. This is the drug "Mitotane". Reception begins with a dosage of 50 mg per day per 1 kg of weight. The daily dose is divided into 2-3 doses. Treatment lasts two weeks. The animal's condition is monitored using a blood test. When cortisol in the blood decreases to acceptable levels, you need to switch to a dosage of the drug 50 mg/kg once a week.

The second option, which is often prescribed by doctors, is First of all, it is prescribed to those animals who also develop fungal skin damage against the background of Cushing's syndrome. Take this drug in the first week - 10 mg per 1 kg of weight (in two doses). The second week, increase the dosage to 20 mg per 1 kg of weight (also in two doses). Finally, the third week of treatment involves a daily dosage of 30 mg per 1 kg of weight.

How to determine the effectiveness of treatment

The primary guidelines will be blood tests, ultrasound and x-rays. However, there are indicators that the owner himself can evaluate. This is primarily a reduction in the amount of water consumed by the dog. However, it must be taken into account that the animal may develop complications during the therapy. This is vomiting and increased weakness, lethargy and refusal to eat. Such symptoms may indicate concomitant disorders and diseases. Therefore, to get a clearer picture, it is necessary to conduct laboratory tests.

Treatment results

What can we hope for if such patients are diagnosed with Cushing's syndrome? These questions are often asked by owners and veterinarians. It must be said that the described disease is only partially treatable. Most often, life expectancy, even after successful therapy, does not exceed 2-3 years. This is due to the fact that Cushing's syndrome is a systemic disease that affects all organs and systems and causes a number of irreversible changes. These are the musculoskeletal, cardiovascular and nervous systems. At the same time, this disease reduces the body's resistance to various infections, and also provokes a significant increase in blood pressure.

Authors): N. A. Ignatenko, Candidate of Veterinary Sciences, Member of the European Society of Dermatology, Member of the European Society of Endocrinologists, Kiev / N. Ignatenko DVM, PhD, Member of ESVD, ESVE, Kiev
Magazine: №6 - 2012

Abbreviations: ACTH - adrenocorticotropic hormone, CRH - corticoliberin, ADH - antidiuretic hormone, CBC - complete blood count, ALT - alanine aminotransferase, TSH - thyroid-stimulating hormone, US - ultrasound, CPV - caudal vena cava, CT - computed tomography, MRI - magnetic resonance imaging tomography, MAO – monoamine oxidase.

Introduction

Hyperadrenocorticism is a persistent, chronic increase in cortisol levels in the blood. The term "Cushing's syndrome" is often used to define this disease, but this definition refers to a set of clinical and chemical disorders caused by chronic exposure to excessive levels of glucocorticoids. While the definition of “Cushing's disease” refers only to those cases of Cushing's syndrome in which we are talking about pituitary hyperadrenocorticism caused by excessive secretion of ACTH by the pituitary gland. Although pituitary hyperadrenocorticism is the most common disorder in dogs, the term Cushing's syndrome is used for ease of description.

Physiology of the adrenal cortex and pathophysiology of the disease

Cortisol is synthesized in the adrenal cortex, which synthesizes more than thirty types of hormones that have varying degrees of clinical significance. Hormones are usually divided into three groups: mineralocorticoids (playing an important role in water metabolism), glucocorticoids, which stimulate gluconeogenesis, and sex hormones. The structure of the adrenal gland is shown schematically in Fig. 1. Cortisol is produced in the zona fasciculata and zona reticularis of the adrenal cortex.

Fig. 1: Schematic representation of the adrenal gland

The process of cortisol secretion by the adrenal glands is regulated to a greater extent by adrenocorticotropic hormone (ACTH), produced by the anterior pituitary gland, which, in turn, is controlled by the hypothalamic corticotropin-releasing hormone (CRH). CRH is secreted by neurons in the anterior lobe of the paraventricular nucleus in the hypothalamus. Cortisol has a direct negative effect on the pituitary gland and hypothalamus, reducing the secretion of ACTH and CRH. These feedback mechanisms regulate plasma cortisol levels, as shown in Figure 2.

Rice. 2 Scheme of regulation of the secretion of cortisol, ACTH and CRH

The causes of hyperadrenocorticism in dogs can be:

1. Pituitary tumors that secrete excessive amounts of ACTH and sooner or later lead to adrenal hyperplasia (in 80-85% of cases in dogs);

2. Adenoma or adenocarcinoma of the adrenal cortex, autonomously producing excessive amounts of cortisol;

3. Iatrogenic hyperadrenocorticism caused by excessive long-term use of glucocorticoids (systemic and local).

Pituitary hyperplasia caused by excessive CRH secretion has also been described in humans, as well as various non-hypothalamic and non-pituitary tumors that can secrete ACTH in excess, but these disorders have not been described in dogs.

Occurrence

Hyperadrenocorticism is a disease of middle-aged and elderly dogs. Hyperadrenocorticism of adrenal origin occurs in older animals with a mean age of 11–12 years (range, 7–16 years). Pituitary hyperadrenocorticism can occur earlier, on average at 7-9 years (range of occurrence: 2 to 12 years). Cushing's syndrome can develop in any breed, but Dachshunds, Poodles, Jack Russell Terriers and Staffordshire Terriers are most commonly predisposed to it. Large breed dogs (weighing more than 20 kg) are more likely to develop adrenal tumors. It is believed that pituitary hyperadrenocorticism does not have a gender predisposition, and hyperadrenocorticism of adrenal origin occurs in bitches in 60-65% of cases.

Clinical picture

The clinical picture will be characteristic of excess cortisol in the body. Most often, dog owners come to the clinic whose animals suffer from symptoms of polydipsia-polyuria, polyphagia, increasing abdominal volume, decreased exercise tolerance, alopecia, thinning of the skin, possible appearance of comedones, and calcification of the skin. Prolonged anestrus in females and atrophy of the testes in males can also be observed. It should be noted that symptoms are rare in hyperadrenocorticism, and their presence should raise doubts in the examiner's mind that the dog has hyperadrenocorticism. These symptoms include itching, poor appetite, pain, lameness, vomiting and diarrhea. Clinical symptoms are understandable if we remember the role of cortisol in the body and its effect on organs and systems (Table 1)

Table 1 Effect of excess cortisol on organs and systems of the body and clinical manifestations

the effect of glucocorticoids on various organs and systems of the body	clinical manifestations
increased gluconeogenesis, stimulates the synthesis of certain enzymes, increased glycogen deposition	"steroid diabetes" hepatomegaly
increased protein catabolism, inhibition of amino acid transport into muscle cells and other cells (with the exception of the liver).	muscle wasting and weakness, thin dry skin, long wound healing, scarring osteoporosis
disruption of the action of ADH at the level of the renal collecting tubules due to cortisol; increased glomerular filtration rate	polydipsia-polyuria
Suppression of the immune system, especially T cells, steroid lyphocytolysis	With temperature drop, slower wound healing lymphopenia
Negative feedback from the pituitary gland suppresses the secretion of gonadotropic hormones in the pituitary gland.	anestrus, testicular atrophy

However, the pathomechanism of the development of certain clinical signs is not always clear. Thus, polyphagia is associated with the direct effect of corticosteroids, but it is typical for dogs and is not observed in humans. The mechanism of development of skin calcification, which is observed in dogs with hyperadrenocorticism, has not been fully studied.

In some cases, animals may develop neurological signs: depression, suppression of learned behavior, ataxia, anisocoria, which are associated with the growth of a pituitary tumor. Sometimes animals with Cushing's syndrome may develop myotonia, characterized by active muscle contractions. They can be observed on all four limbs or only on the hind limbs.

Fig. 3, 4, 5 Dog with extensive skin calcification due to hyperadrenocorticism

Figure 6. Thinning and dry skin of the ventral abdominal wall in a dog with hyperadrenocorticism.

Laboratory indicators

The most characteristic changes in blood tests are a stress leukogram with lymphopenia. Excess corticosteroids can lead to a delay in the differentiation of eosinophils in the bone marrow, resulting in eosinopenia;

Steroid lymphocytolysis leads to lymphopenia;

The stimulatory effects of cortisol on the bone marrow can lead to increased red blood cell and platelet counts;

Neutrophilia and monocytosis are a consequence of a decrease in the marginal standing of lymphocytes in the capillaries.

In a biochemical blood test, the most significant is the increase in alkaline phosphatase, which can exceed the normal limit by 5-40 times. This parameter is species specific in dogs, since only in dogs both endogenous and exogenous glucocorticoids induce the production of a specific hepatic isoenzyme of alkaline phosphatase. However, an increase in alkaline phosphatase can occur not only with hyperadrenocorticism, but also with some tumor processes, diabetes mellitus, anticonvulsant therapy, and diseases of the liver and biliary tract.

The main abnormalities in biochemistry and CBC are presented in Table 2.

table 2

Laboratory indicators for hyperadrenocorticism in dogs (E. Torrance, K. Mooney “Endocrinology of small animals”)

Clinical blood test:

Lymphopenia (<1,5х10 9 /л)

Eosinopenia (< 0,2 х10 9 /л)

Neutrophilia

Monocytosis

erythrocytosis

Biochemical analysis:

Increased alkaline phosphatase levels

Increase in ALT

Increased fasting glucose levels

Reduced urea levels in the blood

Increased cholesterol levels in the blood

Lipemia

Increased bile acid levels

Decreased thyroid hormone levels

Decreased response to TSH stimulation

Analysis of urine:

Specific gravity of urine < 1,015

Glucosuria (< 10% случаев), Инфекция мочевыводящего тракта)

Additional research methods

Of the additional visual research methods, the most common in practice are radiography and ultrasound (ultrasound). An x-ray of the chest cavity may show mineralization of the wall of the trachea and bronchi, a metastatic process in the lungs due to adenocarcinoma of the adrenal glands. An X-ray of the abdominal cavity is characterized by an enlarged liver and overstretching of the abdominal wall - a “pot-bellied appearance” (Fig. 7). Other findings may include adrenal mineralization, skin calcification, bladder stones, and osteoporosis.

Fig 7 Plain radiograph of a dog with Cushing's syndrome

With the improvement of modern ultrasound equipment, the area of such small organs as the adrenal glands is becoming accessible. It is difficult to conduct research on dogs with deep chests and animals that are overweight. The right adrenal gland is visualized worse than the left. The right adrenal gland is located craniomedial to the right kidney (between the cranial pole of the kidney and the SPV), the location of the left adrenal gland varies craniomedial to the left kidney (in the midline next to the aorta). Dimensions - 12-33x3-7 mm. The schematic location of the adrenal glands is shown in Fig. 8:

Fig 8 Diagram of the location of the adrenal glands

Ultrasound examination can also detect the presence of metastases in the case of adenocarcinoma of the adrenal glands, but does not allow differentiating benign or malignant changes in the adrenal glands in the absence of metastasis.

CT and MRI have been increasingly used in modern veterinary diagnostics in recent years, despite the high cost of the study. They can detect pituitary tumors, tumors and adrenal hyperplasia, but are not yet widely available diagnostic methods.

Confirmatory diagnostic studies

A preliminary diagnosis of Cushing's syndrome is made based on characteristic clinical and laboratory signs, as well as visual examination methods. However, the diagnosis can only be confirmed by conducting specialized tests. Elevated basal cortisol levels are not sufficient to diagnose Cushing's syndrome. During stress and other diseases, cortisol may increase, so the diagnostic value of this parameter is important only in dynamic tests (with ACTH or a small dexamethasone test). I would like to dwell on this in more detail.

ACTH stimulation test

The ACTH stimulation test is the best test for the differential diagnosis of spontaneous and iatrogenic hyperadrenocorticism. The latter, which occurs during long-term treatment with glucocorticoids, cannot be detected by other tests, including the small dexamethasone test. However, the ACTH test does not allow differentiating hyperadrenocorticism of adrenal and pituitary origin. An ACTH test is indispensable for monitoring the treatment of Cushing's syndrome.

Sample protocol:

2. Administration of 0.25 mg of synthetic ACTH intravenously or intramuscularly. For dogs< 5кг – 0,125мг.

3. Taking a second blood sample 30-60 minutes after intravenous administration of ACTH and 60-90 minutes after intramuscular administration.

The administration of corticosteroids should be stopped at least one day before the test. The interpretation is shown in Fig. 9.

Cortisol levels before and after stimulation may be different. Test results are considered positive if cortisol levels rise > 600 nmol/L following ACTH stimulation in dogs with characteristic clinical signs. Cortisol levels < 450 nmol/l after stimulation is considered normal for an animal that does not have hyperadrenocorticism.

Fig 9 Change in cortisol level after ACTH test

Disadvantages of a provocative test with ACTH: the test does not allow to differentiate pituitary hyperadrenocorticism and adrenal (adrenal origin). It may give false positive results.

Suppression test with low doses of dexamethasone

A highly sensitive test, it allows to detect pituitary hyperadrenocorticism in 90-95% of cases and in 100% of hyperadrenocorticism of adrenal origin. It is impossible to diagnose iatrogenic hyperadrenocorticism and monitor the effectiveness of therapy.

Sample protocol:

1. Taking a blood sample to determine basal cortisol levels.

2. Injection of dexamethasone 0.01 mg/kg IV (when performing the test, do not forget that a 0.4% dexamethasone solution contains about 3 mg per ml of active dexamethasone)

3. Determination of cortisol levels after 3-4 hours and after 8 hours

Interpretation of results: a cortisol concentration of more than 40 nmol/l after 8 hours suggests confirmation of the diagnosis of hyperadrenocorticism.

Urinary cortisol/creatinine ratio

Sample protocol.

Urine is collected in the morning to determine cortisol and creatinine levels. It is preferable to do it at home so that the animal does not experience stress.

Interpretation.

A cortisol/creatinine ratio > 10x10 -6 is typical for dogs with hyperadrenocorticism. However, this diagnostic method is more exclusionary than confirmatory: if an animal has a ratio<10х10 -6 \, то гиперадренокортицизм исключается. Если соотношение выше, то мы не можем поставить диагноз гиперадренокортицизм, поскольку проба отличается невысокой специфичностью. Соотношение может повышаться при заболеваниях, не связанных с надпочечниками. Поэтому в случае ее повышения рекомендовано проведение либо малой дексаметазоновой пробы, либо пробы с АКТГ.

Endocrinological tests also include high-dose dexamethasone sampling and endogenous ACTH testing. However, it must be remembered that these tests are not carried out to diagnose and monitor the treatment of hyperadrenocorticism; they can only be used to differentiate hyperadrenocorticism of pituitary and adrenal origin.

Treatment

Because the disease progresses slowly and many owners view polyphagia as a sign of health, some people wonder if their animal really needs lifelong, expensive treatment that can cause unwanted side effects. In addition, a decrease in the blood level of such a powerful anti-inflammatory agent as cortisol can lead to exacerbation of chronic infections: arthritis, itching due to pyoderma, etc. These aspects must be discussed with dog owners before starting treatment. And yet, treatment of Cushing's syndrome allows you to prolong the animal's life, significantly improving its quality, so the veterinarian should recommend treatment. The only rare exception may be animals with severe renal failure. The choice of treatment is determined by the cause of the disease, the experience and capabilities of the doctor. However, it must also be remembered that treatment is not prescribed to an animal in doubtful cases, in the absence of a characteristic clinical picture, only on the basis of laboratory tests.

Surgery.

If we consider hyperadrenocorticism as a paraneoplastic syndrome resulting from a tumor of the adrenal glands or pituitary gland, then it would be logical to remove the tumor to solve the problem.

However, operations on the pituitary gland require complex operating techniques; they are successfully performed only in highly specialized clinics of the University of Utrecht, the Netherlands. Their results indicate an 86% success rate of surgical intervention with a survival time of more than two years in 80% of patients. The disadvantages are: the lack of wide possibility of using the method, the high cost of the operation, possible postoperative complications: transient diabetes insipidus, the need for lifelong replacement therapy with cortisone and thyroxine. A more effective and safe method is drug therapy.

Surgical removal of the adrenal glands is performed in cases of hyperadrenocorticism caused by an adrenal tumor. The surgical technique is less complex than removal of a pituitary tumor, but requires a highly qualified surgeon. The anesthetic risks associated with the increased likelihood of thromboembolism in dogs with hyperadrenocorticism and the importance of intensive postoperative monitoring should be taken into account. Mortality in the first two weeks of the postoperative period can be up to 78%, so drug therapy remains the main method of choice. The recommended drugs are mitotane and trilostane.

Mitotane is a dichlorodiphenyldichloroethane (DDD) cytotoxic drug that selectively destroys the zona fasciculata and reticularis of the adrenal cortex, structurally similar to the insecticide DDT. Fat soluble, must always be given to the animal with food. There are two regimens for taking mitotane. In the first scheme, the goal is partial destruction of the adrenal cortex, in the second – complete destruction, followed by lifelong replacement therapy with glucocorticoids and mineralocorticoids.

Protocol of the first regimen: Initial dosage – 25 mg/kg daily with meals in 2 divided doses. Take daily until symptoms of polydipsia-polyuria and polyphagia disappear. If side effects occur: vomiting, diarrhea, lethargy, apathy, ataxia, immediately stop taking the drug. Maintenance dosage: 2 mg/kg x 2 times a week. The first ACTH test is after 7 days.

In the second regimen, mitotane is used at a higher dosage with lifelong replacement therapy. Side effects during treatment with mitotane can occur in 30% of cases. In case of an overdose of the drug, hypoadrenocorticism may develop.

Trilostane is a reversible competitive inhibitor of 3β-hydroxysteroid dehydrogenase,

blocking the synthesis of steroids in the adrenal glands. Dosage recommended by the manufacturer: 3-6 mg/kg 1 time per day with food. Dosages recommended by Nelson, Feldman, Wenner: max 2.5 mg once daily, or 1.0-2.5 mg twice daily. The dosage is selected individually for each patient. Treatment control: the first test with ACTH is after 7-14 days of treatment, the test is carried out 4-6 hours after administering the drug. The goal is a cortisol level of 50-120 (250) nmol/l. If necessary, the dose is gradually increased, then control tests with ACTH are carried out after 10, 30, 90 days and every 4-6 months. Possible side effects: depression, loss of appetite, electrolyte disturbances - reversible. If they occur, it is necessary to stop giving the drug, perform an ACTH test, and if the cortisol dose is reduced below 20 nmol/l, replacement therapy with corticosteroids is carried out.

A comparative analysis of the life expectancy of dogs with pituitary hyperadrenocorticism when taking mitotane and trilostane showed the following.

Mitotan - average life expectancy - 708-720 days.

Trilostane - average life expectancy when taken once a day - 662-900 days; when taken twice a day: 662-930 days. The longer life expectancy in animals given trilostane twice daily may be due to the fact that the half-life of trilostane is 10 hours, and a single dose is not sufficient for all animals to compensate for Cushing's syndrome.

As an alternative treatment for hyperadrenocorticism, treatment with ketoconazole has been described. , which, in addition to its antifungal effect, has an inhibitory effect on the synthesis of steroids. R. Feldman points to the lack of effect on treatment with ketoconazole in 20-25% of animals, linking it with impaired absorption of the drug into the intestine. The drug is prescribed at a dosage of 5 mg/kg x2 times a day for 7 days. In the absence of changes in appetite and polydipsia, the dosage is increased to 10 mg/kg. After 2 weeks, treatment is monitored with an ACTH test; if ineffective, the dose is increased (maximum up to 20 mg/kg twice a day). Side effects include: anorexia, vomiting, diarrhea, hepatopathy and the development of jaundice. The author recommends its use only if there are no other options and possibilities for treating hyperadrenocorticism.

L-deprenyl (selegenil hydrochloride) is an MAO type B inhibitor used to treat Parkinson's disease. It is believed that it inhibits ACTH secretion by increasing dopanergic tone through the hypothalamic-pituitary connection. Recommended dose: 1 mg/kg 1 time per day. In case of lack of effectiveness, it is recommended to increase the dose to 2 mg/kg. Treatment monitoring is not carried out, since ACTH tests do not show a significant decrease in cortisol levels. Bryette indicated treatment failure in 50% of animals.

Fig.10, 11 Dachshund with hyperadrenocorticism before the start of treatment and six months after the start of treatment with trilostane

Summary

Cushing's syndrome is the most common endocrine pathology in middle-aged and elderly dogs. In 80-85% of cases, this is pituitary hyperadrenocorticism. The most characteristic symptoms are polydipsia-polyuria, polyphagia, sagging of the abdominal wall and an increase in the contours of the abdomen, weakness, shortness of breath, and exercise intolerance. Diagnosis of the disease is complex, including, in addition to routine clinical examination, biochemistry and CBC, a provocative test with ACTH or a suppressive test with low doses of dexamethasone. Determination of basal cortisol levels is not diagnostically valuable and is used only as a step in the tests described above. Treatment of the disease prolongs the life of sick animals, improving its quality. When discussing treatment options with the owner, it is imperative to inform the owner about the advantages and disadvantages, possible side effects of all methods and medications. Drug therapy is more often used. The most effective drugs for treating hyperadrenocorticism in dogs are mitotane and trilostane. Their use should be accompanied by regular monitoring to avoid the development of unwanted side effects and iatrogenic hypoadrenocorticism. The use of alternative methods of drug therapy (ketoconazole, selegenil, etc.) is not recommended.

Literature

1. E. Feldman, R. Nelson “Endocrinology and reproduction of dogs and cats.” - Moscow "Sofion". - 2008

2. Torrance E. D., Mooney K. T. Endocrinology of small domestic animals. A practical guide. – M.: Aquarium, 2006.

3. Astrid Wehner Vorlesung Hyperadrenokortizismus. -fuer Studenten MTK LMU.

4. Mooney C. T., Peterson M. E. Canine and Feline Endocrinology. - BSAVA, 2004.

5. Rational pharmacotherapy of diseases of the endocrine system and metabolic disorders. / Ed. I. I. Dedova, G. A. Melnichenko. – St. Petersburg: Litera, 2006.

6. Kirk's modern course of veterinary medicine. /Trans. from English - M.: Aquarium - Print LLC, 2005.

The dog’s body is a unique system in which many biochemical processes occur that determine the level of physical and intellectual development of the dog.

The state of hormonal levels depends on the proper functioning of the internal secretion organs, which, in turn, ensures the dog’s good health, its psycho-emotional development and is responsible for the animal’s life expectancy. But, unfortunately, a malfunction of your pet’s endocrine system can cause such a complex disease as Cushing’s syndrome in dogs.

What is the syndrome?

This disease is often found in animals over seven years of age, but sometimes young dogs can also get sick.

In order for the dog’s blood clotting system to function properly, blood pressure to be normal, and it to cope with inflammation, the animal’s adrenal glands produce the hormone cortisol. Due to the fact that in critical situations, when excited or frightened, a dog’s blood releases a large amount of this substance, it is also called the stress hormone.

But the adrenal glands cannot “manage” cortisol on their own - the command to produce the hormone is given to them by the pituitary gland, which regulates its concentration in the body. If the pituitary gland ceases to control the level of cortisol, then an increase in its content in the blood becomes the cause of Cushing's syndrome in dogs.

Veterinarians divide this pathology into:

Cushing's disease occurs as a result of damage to the pituitary gland by an adenoma;
caused by the appearance of adenoma or carcinoma of the adrenal glands in dogs;
Iatrogenic hyperadrenocorticism - occurs as a result of long-term use of hormonal drugs.

Thus, we see that the causes of the disease are problems with the adrenal glands or pituitary gland in the dog.

Some breeds have a special predisposition to the occurrence of this syndrome, so owners of terriers, beagles, boxers, and shepherds need to carefully monitor the well-being of their pets and periodically do tests to detect this pathology.

Symptoms

Cushing's syndrome in dogs has quite striking manifestations, when faced with them, veterinarians may suspect the presence of this disease in your pet. The dog’s owners will also notice such characteristic signs as:

pathological thirst;
very frequent urination, in which the dog cannot wait to go for a walk and pees at home;
excessive appetite;
apathy and weakness;
weakening of the abdominal muscles and sagging;
hair loss not accompanied by itching;
Impaired coordination and behavior of the dog.

Since Cushing's disease is a systemic disease, that is, affecting almost all organs and systems, it is accompanied by many different symptoms and causes various complications. Complications of the disease include: diabetes mellitus, osteoporosis, arterial hypertension, disorders of the reproductive organs.

Diagnostics

If the disease is already in an advanced stage, then external signs will be visible to the naked eye. The main ways to diagnose Cushing's syndrome are:

clinical blood test;
determination of biochemical blood parameters;
urine analysis with protein determination;
tests with the administration of dexamethasone and adrenocorticotropic hormone.

In order to identify tumors on the dog's adrenal glands, an ultrasound scan of the abdominal organs is performed. If there is a suspicion of a pituitary tumor, it is advisable to give the animal a CT or MRI to confirm or refute these concerns.

Treatment

Depending on which organ was damaged as the cause of Cushing's syndrome, treatment of this disease can be conservative or surgical.

If a tumor of the adrenal gland is detected, then surgical intervention is possible, during which the adrenal gland is removed. If problems are detected with both adrenal glands, both organs are removed, and to correct the dog’s hormonal levels, she is prescribed lifelong medication.

Standard drug therapy is carried out using proven drugs:

The hormonal drug Mitotane reduces cortisol levels. The initial dose is 50 mcg of medication per kilogram of animal weight. Taking this amount of medication can be divided into 2-3 times a day. After two weeks, a control blood test is done and if the veterinarian notes a decrease in cortisol to normal levels, then the drug is given to the dog once a week at the same dose.
Another popular method in veterinary practice is treatment with Ketoconazole. This drug is especially indicated for those dogs whose disease has caused skin fungus. During treatment, the dose is gradually increased: 1 week - 10 mcg per 1 kilogram of weight (in 2 doses per day), 2 week - 20 mcg/1 kg, 3 week - 30 mcg/1 kg.

With a correct diagnosis and well-chosen treatment, the owner almost immediately notices the effect of the therapy - the dog stops “drinking in basins”, and its general condition improves. If the pet’s condition worsens during treatment, then most likely this is caused by complications of the disease.

To monitor treatment and find the causes of deterioration, the veterinarian prescribes repeated tests and instrumental studies.

If the syndrome is iatrogenic, hormonal therapy must be discontinued. But withdrawal must be carried out gradually, carefully reducing the dose of the medication and monitoring the dog’s condition through testing.

Animal life forecast

From this we can conclude that the life prognosis for a dog with this syndrome will not be very optimistic - even with timely treatment, it can live for about three years.

Do not despair if your pet has been diagnosed with this serious problem, because care, proper treatment and good care will prolong the dog’s life for several more years and give you the joy of communicating with it.

endocrinologist

Introduction
Cushing's syndrome is perhaps the most interesting problem in veterinary endocrinology. The interest lies in overcoming the difficulties associated with the treatment of this endocrinopathy in dogs in our country.
The disease itself and the problems of its treatment will be discussed in this article.

What it is?
Let's start with a definition.
Cushing's syndrome is a pathological condition of the body caused by prolonged excess levels of cortisol in the blood. This means that cortisol is the culprit in Cushing's syndrome. What is this substance?
Cortisol is a steroid hormone that is involved in most metabolic processes.
But, perhaps, its main property is to protect the body from adverse effects. We can say that it is a stress hormone. It allows the body to survive negative influences with minimal losses. How does this happen?
Cortisol helps maintain blood pressure, accelerates blood clotting, and has a powerful anti-inflammatory effect.
But most importantly, it mobilizes the body's energy reserves to combat hostile influences. That is, it stimulates the use of fat reserves and proteins to maintain normal or increased concentrations of glucose (the main source of energy) in the blood.

Cortisol is secreted by the adrenal glands. These are two small endocrine glands, which, as the name implies, are located near each kidney.
The adrenal glands are not normally independent organs; their activity is regulated by the pituitary gland, a structure of the brain.
The pituitary gland releases adrenocorticotropic hormone (ACTH) into the blood, which, acting on the adrenal glands, stimulates their work. Without going into details, we can say that there is something like a vertical “pituitary gland - adrenal glands”. In this vertical there is a so-called negative feedback mechanism, which allows you to keep the concentration of cortisol in normal values. When the concentration of cortisol reaches a certain level required by the body, it interacts with the pituitary gland and inhibits the release of ACTH into the blood. The ACTH concentration decreases, which means the adrenal glands stop being stimulated and produce less cortisol.

With Cushing's syndrome, this mechanism is disrupted, and cortisol begins to be released excessively and uncontrollably into the blood. This can happen for two reasons:

if one or both adrenal glands are affected by a tumor capable of uncontrolled hormone secretion
if the pituitary gland has a tumor (usually an adenoma) that secretes excess amounts of ACTH.

In both cases, the concentration of cortisol in the blood will be constantly increased. That is, the biochemical picture that occurs during stress will be simulated.
A situation arises in which the body spends months and years fighting against adverse effects that actually do not exist. Of course, this will deplete the body’s energy reserves, which will lead to disruption of metabolic processes, and therefore disruption of the functioning of a variety of organ systems. As a result, Cushing's syndrome leads to “burnout” of the body.

Who is sick?
If we talk about small pets, Cushing's syndrome is extremely rare in cats and, at the same time, is one of the most common endocrine diseases of dogs.
Dogs older than middle age get sick.
Cushing's syndrome can occur in any breed of dog, but is more common in dachshunds, terriers, small poodles and boxers.

What does it look like?
Cushing's syndrome begins unnoticed and develops gradually, symptom by symptom.
With a detailed clinical picture, the usual complaints voiced by the owners of an animal with Cushing's syndrome look something like this.

the most common complaints are excessive thirst and urination
in second place in popularity is the deterioration of the quality of the coat and the appearance of extensive bald patches. Hairless areas are distributed symmetrically, localized in the body, tail and neck.
quite soon after the first signs of the disease appear, bitches go into estrus
animals become less mobile
the physique changes: fat loss from subcutaneous fat occurs, muscles atrophy. Due to weakness of the abdominal wall muscles, the abdomen increases in volume and sags.

The result is a thin dog with a voluminous belly and extensive bald spots.
A doctor who has an understanding of Cushing's syndrome can most often suspect this disease based on the patient's appearance.
But only the appearance and history told by the animal owner are not enough to make a diagnosis, even if everything is obvious.
Why? Because treatment for Cushing's syndrome is not easy, not cheap and not safe. This means that before starting treatment, taking into account these three “Ns”, we need to be sure that we are treating Cushing’s syndrome.

Diagnostics
As soon as Cushing's syndrome is suspected, we begin to conduct additional diagnostic methods, which include clinical and biochemical blood tests.
These studies provide additional indirect evidence of Cushing's syndrome. And when enough evidence has been collected, we resort to specific tests, that is, tests that prove the presence of the disease.
Basically, if you think about it, the first thing that comes to mind when we suspect Cushing's syndrome is to measure the concentration of cortisol in the patient's blood. In theory, it should be higher than normal, because, as we remember, Cushing’s syndrome develops precisely due to a long-term persistent increase in the concentration of cortisol in the blood.
But cortisol levels can increase not only when the pituitary gland or adrenal glands are damaged. It can also increase against the background of some other diseases and under some other conditions. Therefore, simply measuring baseline cortisol levels in the blood is not an appropriate test.

To confirm Cushing's syndrome, so-called functional tests are recommended.
Tests that evaluate adrenal function (whether it is excessive or normal).
The most common are the low-dose dexamethasone test and the ACTH test. The essence of the tests is that in addition to determining the base level of cortisol, its concentration is also determined after the administration of dexamethasone or the drug ACTH. And by how its concentration in the blood changes after the use of these drugs, one judges whether there is pathological excess work of the adrenal glands or not.

Once Cushing's syndrome is confirmed, you should try to find out where the pathological focus is localized - in the pituitary gland or in the adrenal glands.
A small dose of dexamethasone test (small dexamethasone test) can provide some information on this issue. But more valuable are visual diagnostic methods (methods that allow you to see the adrenal glands and pituitary gland in one way or another).
We have an ultrasound scan of the adrenal glands at our disposal. We can evaluate the ultrasound structure of the organ, compare the right and left adrenal glands and suggest, in conjunction with other additional studies, how likely it is that one of the adrenal glands is affected by a tumor.
Unfortunately, computed tomography and magnetic resonance imaging are not yet available to us. These are quite informative types of organ visualization, which make it possible to accurately identify neoplasms in the pituitary gland or adrenal glands and assess the extent of their spread.
I think that after some time such research will be easily accessible to domestic veterinary medicine.

Treatment
The choice of treatment for Cushing's syndrome primarily depends on the location of the pathological focus - the pituitary gland or the adrenal glands.
If the tumor affects one of the adrenal glands and no metastases are found in the lungs and liver, then the method of choice is to remove the affected adrenal gland. In this case, the approach is relatively simple.

The situation is somewhat more complicated when the cause of Cushing's syndrome is a pituitary adenoma.
That is, formally everything is not complicated. For this form of Cushing's syndrome, the use of drugs that suppress the production of cortisol by the adrenal glands is recommended. But in reality, purchasing these drugs is a big problem. They are not supplied to the domestic market, and their price is very high. Therefore, in order to choose drug treatment, you need to be able to purchase the drug abroad (Germany, USA, Canada) and have enough money to purchase it. Several patients are treated this way in our clinic. But, unfortunately, not everyone can purchase the drugs mentioned above.
There are two ways left. Use alternative methods of drug treatment or resort to surgery.
Alternative treatment methods refer to the use of drugs whose effectiveness is low or unproven. It seems to me wrong to recommend drugs with low effectiveness and a high probability of side effects or simply zero effectiveness. Therefore, I resort to using these drugs extremely rarely.

Surgical treatment for Cushing's syndrome caused by damage to the pituitary gland involves removing both adrenal glands.
Considering that the adrenal glands synthesize vital hormones, namely mineralo- and glucocorticoids, their removal should involve further replacement therapy. That is, you will need to take some of the missing hormones for life. These hormones include mineralcorticoids and glucocorticoids, which are easy to take.
It seems that surgical removal of both adrenal glands (adrenalectomy) today may be the most suitable treatment for Cushing's syndrome in our country. That is why we are trying to practice adrenalectomy (removal of the adrenal glands).
This operation is not indicated for every animal suffering from Cushing's syndrome. Before recommending surgical treatment, the benefits of it and the degree of risk of complications are weighed. And the choice is not always made in favor of surgical treatment. This is due to the fact that, as a rule, animals suffering from Cushing’s syndrome are very old and by that time have some diseases that are more important than Cushing’s syndrome.

In conclusion, it should be said that the treatment of Cushing's syndrome in small domestic animals in our country faces certain difficulties, quite serious, but completely surmountable.
And finding the optimal solution to existing problems is one of the priority tasks facing us.

Hormonal system In dogs, the structure is no less complex than in humans. It also reacts sensitively to any changes in the body and, under certain circumstances, can lead to serious pathologies.

The most common disease associated with the hormonal system is hyperadrenocorticism in dogs, or Cushing's syndrome. This pathology develops due to an excess of a hormone such as cortisol in the animal’s plasma. This substance slows down metabolic processes, which leads to intestinal disorders, increased blood pressure and other complications in the dog.

Description of the pathology

This disease appears in dogs after they have been The pituitary gland begins to produce cortisol in excess. This hormone is very important. Normally, it is a means of protection against stress. In emergency situations, thanks to it, the animal’s body is fully mobilized to protect itself from the external environment.

That is, the body needs cortisol, but not in the quantities produced by the gland in Cushing's syndrome. The pituitary gland ceases to control the process of hormone production. As a result, the animal develops various disorders:

Mental and behavioral disorders.
Constant thirst and frequent urination. At the same time, urine has such a pungent odor that it is almost impossible to be near it.

In severe cases, this disease can lead to the death of the pet. The cause of death lies in the wear and tear of the body, which has been in a state of complete mobilization for a long time.

When autopsying young animals that died from Cushion's syndrome, veterinarians note that the condition of the internal organs is equivalent to dogs that died of old age.

Reasons for development and varieties

Despite the fact that scientists have been trying for many years to identify possible causes of the disease, their complete clarification is still far away. In some cases, veterinarians simply cannot determine the cause that caused malfunction of the pituitary gland.

Nevertheless, scientists have identified several of the most common causes of pathology:

Hormonally active tumors in the pituitary gland.
Glandular tumors affecting the adrenal cortex.
Incorrect drug treatment using steroid drugs.
Significant age of the animal.
Overweight.
Genetic reasons.

Scientists have also identified several forms of this disease. The division into forms is determined by the reasons for the development of pathology.

Cushing's disease. In dogs, symptoms of this pathology appear when tumors appear in the pituitary gland: adenoma or hyperplasia. This form of the disease is the most common and is detected in 80% of cases.
Cushing's syndrome. It is also often called glucosteroma. The cause of this pathology is dysfunction of the adrenal cortex caused by a tumor. Because of it, a large amount of glucocorticoids are released into the blood, which disrupt the functioning of the pituitary gland.
Iatrogenic Itsenko-Cushing syndrome. This form of pathology develops as a reaction to the excessive introduction of hormonal agents such as prednisolone and dexamethasone into the animal’s body. Typically, these medications are prescribed to dogs for serious colds and allergic reactions. This type of disease goes away quickly after stopping the medications.

If symptoms of Cushing's disease appear after starting treatment with hormonal drugs, then the supply of these drugs should not be abruptly interrupted. It is necessary to gradually reduce the daily dosage of the drug until the symptoms disappear completely.

Symptoms

Hyperadrenocorticism develops slowly, so it may not manifest itself for a long time. In this case, the disease can only be detected through a laboratory blood test to determine the level of cortisol in the blood.

Clinical manifestations appear in the later stages of the disease. The following symptoms appear:

The dog develops extreme thirst.
The dog urinates frequently but little by little.
The coat becomes dry and brittle. Increased loss is observed. First, the hair falls out in clumps in the abdominal area, and later it can become completely bald.
The animal is depressed and tries to move less.
The abdominal muscles weaken, causing it to sag.
The fat layer becomes thinner. At the same time, muscle atrophy occurs.
The cyclical nature of sexual behavior is disrupted. Males don’t want to mate, and females go out of heat.

Dogs with Cushing's disease may experience mental health problems, but this is rare. Much more often, sick pets get tired quickly and move little. They have a significant decrease in reflexes.

Sometimes animals exhibit involuntary convulsive movements. Typically, cramps affect the hind legs.

A blood test of sick pets gives the following picture:

The number of lymphocytes is reduced. Cells are destroyed under the influence of steroid hormones.
Thrombocytosis.
Increase in the number of neutrophils.
Alkaline phosphatase is increased.

Veterinarians are rarely able to make an accurate diagnosis based on symptoms alone. Therefore, sick animals are subjected to additional research methods.

Diagnostics

To clarify a preliminary diagnosis, veterinarians resort to various diagnostic methods. The most commonly used are ultrasound and x-ray.

The latter is needed to detect salt deposits on the mucous membranes of the trachea and bronchi. In addition, X-ray examination can reveal an enlarged liver and a distended abdominal wall. These are characteristic symptoms of Cushing's syndrome.

Ultrasounds are typically used to examine the adrenal glands. Using ultrasound, doctors can evaluate the condition of the glands and determine the presence or absence of tumors.

Various tomographs are used to use the pituitary gland and hypothalamus.

An ACT test is required. First, the dog's blood cortisol level is determined, and then an injection with ACTH is given. After 60 minutes, the cortisol level is re-determined. The disease is confirmed if the hormone level after injection exceeds 600 nmol/l.

Treatment

If the disease was caused by a tumor of any gland, then it is completely impossible to cure the dog. However, treatment makes it possible to prolong the pet’s life and relieve it of some pathological symptoms.

The choice of one or another treatment strategy is determined by the results of the study and the reasons that caused the pathology. Thus, therapeutic assistance is provided only to animals with clearly visible symptoms.

If the dog was diagnosed based on laboratory test data, but there are no symptoms of pathology, then therapy is not carried out, since it can significantly accelerate the development of the disease and worsen the animal’s well-being.

As an emergency measure, veterinarians may perform surgery. We are talking about removing the tumor. Most often it is removed along with the gland.

It is worth noting that when the pituitary gland is damaged, operations are not performed in our country. Veterinarians have too little experience in this area. In addition, surgery on the pituitary gland has the following negative aspects:

It costs a lot.
There are very few qualified specialists, so the result of the intervention is unpredictable.
Lifelong hormonal therapy after surgery.
There is a high risk of diabetes in the animal.

Veterinarians operate on the adrenal glands much more readily, since the operation is less complicated. Despite this, many animals die after surgery, and survivors experience various hormonal disorders and complications.

Due to the high risks of surgery, drug therapy remains the best treatment option.

Most often, the drug Mitotan is used to stabilize the condition of a four-legged patient. It destroys tumor cells in the adrenal cortex.

This drug should be used according to the following regimen:

The medicine is added exclusively to the feed.
At the beginning of the course, the dosage does not exceed 12 mg of the drug per kg of weight.
Treatment continues until the symptoms of the pathology disappear.
After the symptoms disappear, the medicine is continued to be given to the animal along with food at a dose of 2 mg/kg once every few days.

Mitotane prolongs the life of an animal by several years. However, this medication should be taken for life.

Sometimes Mitotane is replaced with Trilostane. The latter drug acts differently: it suppresses the production of hormones in the adrenal glands.

Trilostane is given to dogs at 6 mg per kg of body weight once a day. After two weeks of therapy, the level of cortisol in the blood is assessed, and the dosage is adjusted upward or downward.

Other drugs can be used for therapeutic purposes, however, their effectiveness is low, so today there are simply no alternatives to Trilostane and Mitotane.

In recent years, veterinarians have begun to use radiation therapy to treat hyperadrenocorticism in dogs. This technique shows good results, but is not yet widely available, since the mechanism of such therapy has not yet been sufficiently developed.

Prevention

In most cases, this pathology is detected in older dogs. Given the insufficient knowledge of the etiology of tumors of the pituitary gland and adrenal glands, the development of effective preventive methods seems impossible.

To prevent Cushing's disease, veterinarians advise dog owners to regularly examine their pets. In this case, it will be possible to promptly identify the pathology and begin its treatment, which will prolong the life of the pet.

Treatment for Cushing's syndrome is very expensive and does not provide guaranteed results. Therefore, if the dog is elderly, veterinarians suggest that the owners euthanize the pet. And here each person himself decides the fate of his four-legged friend.

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