The Cushing's syndrome     Cushing-Syndrom beim Hund   PDF  (52 KB)


The Cushing's syndrome in dogs can occur in a variety of manifestations. Often, already during the clinical investigation of an animal the suspected diagnosis of Cushing's syndrome is made. The patients show a number of clinical signs of this disease: obesity, polyuria, polydipsia, polyphagia, thinning of the skin, calcinosis cutis, increased panting and muscular atrophy.
In 80 - 85% of the dogs the Cushing's syndrome is triggered by a pituitary tumour and up to 20% of the animals are suffering from a tumour of the adrenal gland. Large breed dogs tend to have tumours of the adrenal gland; smaller breeds of dogs are more affected of pituitary Cushing's syndrome. A clustering of cases of the disease can be found in the dachshund, terriers, poodles and boxers. The average age of the affected animals is > 8 years. To clarify the differential diagnosis over other endocrine disorders a laboratory investigation should be performed. To interpret the different assays and test it is essential to know the control mechanism of the hypothalamohypophyseal axis. 

Hypothalamohypophyseal axis

The hypothalamic-pituitary axis is the central control mechanism for many endocrine systems. During embryogenesis corticotroph cells differentiate in the adenohypophysis. First propiomelanocortin (POMC) is synthesized from which adrenocorticotropic hormone (ACTH) and other peptide hormones (melanotropin, endorphins) incipient.
Additionally somatotroph cells are formed in the adenohypophysis which secrete growth hormone (GH), lactotroph cells, which produce prolactin and thyreotroph (secrete TSH) as well as gonadotroph cells (secrete LH and FSH). The hypothalamus plays a superior role in the regulation of the release and retention of anterior pituitary hormones. Some of the major hormones are CRH (corticotropin-releasing hormone) that stimulates ACTH-secretion, TRH (thyroid-releasing hormone), which activates the release of TSH and GHRF (growth hormone releasing hormone). Peripheral endocrine glands on the other side produce hormones that inhibit, apart from a few exceptions, releasing hormones in the hypothalamus- pituitary system. The secretion of the hypothalamic hormones is a part of a regulatory negative feedback system. 

Stress/cortisol application in a healthy dog

In a healthy animal stress, caused by central neurohormone stimulation, induces the increased release of corticotropin releasing hormone (CRH) in the hypothalamus. Following the pituitary releases ACTH. ACTH affects the adrenal cortex and the cortisolsecretion is increased. When the cortisol level in the blood is elevated, this increase inhibits in the hypothalamus and pituitary gland a further release of CRH and therefore ACTH.

Ongoing stressful situations (such as chronic pain or other chronic diseases) can, in rare cases, reduce the negative feedback and consequently lead to a constant stimulation of the adrenal cortex with an adrenal gland hypertrophy.

Applications of corticosteroids cause a reduction of the CRH- and ACTH-secretion in the hypothalamus and pituitary. As a result the cortisol secretion of the adrenal cortex decreases.

An important factor in this system is the adrenal cortex. In three areas different hormones are produced. The Zona glomerulosa produces mineralocorticoids, the Zona fasciculata glucocorticoids and sex steroids (low) and in the Zona reticularis glucocorticoids (low) and sex steroids (increasingly) are produced. The biosynthesis of cortisols takes place by hydroxylation of cholesterol through various intermediate stages (17 a-hydroxypregnenolon, 17 a-hydroxyprogesteron, desoxycortisol). Another synthesis is the formation of cortisol from progesterone and pregnenolone under the influence of 3-b-hydroxysteroiddehydro-genase (starting point for the Trilostanetherapy). ACTH acts tropic for the Zona fasciculata and Zona reticularis and is the primary regulation hormone for the production of cortisol and androgen in the adrenal cortex. The release of steroids is episodic and follows immediately after the biosynthesis. 

Physiology and pathophysiology of the glucocorticoid effect 

The fundamental task and therefore the effect of the hormone on the target tissue is aimed on an optimal adaptation of the metabolism and organ functions in stressful situations. At the target organs cortisol mediates its effect on nongenomic (direct effects) and genomic mechanisms (delayed onset). Glucocorticoids affect water- and electrolyte balance due to a suppression of the release of ADH (antidiuretic hormone) and increase the glomerular filtration rate.
Physiological corticoid concentrations are important for a maximum dilution of urine. Extreme elevations of glucocorticoids lead to hypertension and hypokalemia (mineralocorticoid effect). Furthermore glucocorticoids affect the glucose metabolism by increasing the gluconeogenesis and thereby increase the protein degradation and lead to a changes in fat metabolism (antiinsulin effect). The catabolic effect of corticosteroids is reflected in an increased glucose production from glucoplastic amino acids.
Long term consequence of the disease is therefore an atrophy of the trunk- and intercostal muscles and the diaphragm. Oxygen intake is impaired and the animals pant constantly. The glycogen synthesis in the liver is increased; leading to a steroidhepatopathy due to a sustained high corticoid level. Misinterpretation with a “fatty liver” in ultrasound investigations can occur.
Due to the effect of glucocorticoids the fat metabolism is changed as well: by stimulating hormone- sensitive lipase free fatty acids are mobilized. With sustained high corticoid levels a redistribution of fat to the abdomen follows and the patient shows the typical pear-shape "pot-bellied” appearance. Patients with a reduced insulin secretion capacity can also develop diabetes mellitus.
Corticosteroids also have an influence on the movement and function of leukocytes and reduce the production of cytokines. Low levels of interleukin II lead to apoptosis (programmed cell death) of lymphocytes with decreased production of antibodies.
Increased corticoid concentrations have also a direct endocrine effect by contributing to the suppression of the concentration of ACTH, TSH and growth hormone; as well as an influence on the hormones in the male and female gonads. In the male animal as a consequence a reduced gonadotropin release decreases the testosterone levels in animals with Cushing's syndrome. In female animals we observe a decreased LH release leading to low oestrogen or progesterone concentration. Amenorrhea or suppressed ovulation can occur as a result.

Influence on other important endocrine organs


detectable change


T4 decreased

gonads (male)

testosterone decreased

gonads (female)

oestrogene/progesterone low

In addition, corticosteroids also have an effect on bone and calcium metabolism. Increased cortisol concentrations require a reduced calcium absorption in the intestine. Accordingly, we see a decrease in bone formation, as well as a decreased synthesis of collagen protein and hyaluronic acid. A frequently in practice observed clinical sign is bilateral symmetrical hair loss caused by a prolonged steroid concentration in the telogenic phase of hair growth. Occasionally, pet owners also report on an altered behaviour of their animal.

Neurological deficiency can be the result of the infiltrative/ compressive growth of a pituitary tumour. Almost 50% of pituitary tumours show a growth trend towards dorsally. Affected areas are the remaining pituitary, hypothalamus, thalamus and finally the third ventricle. Likewise excessively high corticoid concentrations can alter changes in cognitive functions and behaviour in humans and animals. 

Laboratory changes in Cushing's syndrome

altered lab results                                      


stressleucogram (leukocytosis, lymphopenia, monocytosis, eosinopenie)

in almost all animals


in almost all animals

ALT increase

> 90% of animals

AP (heat stable) increase

> 85 % of animals

cholesterol increase

> 50 % of animals

urine - specific gravity UG <1.020

> 50 % of animals


> 50 % of animals

bacterial cystitis (often without sediment)

> 50 % of animals

Which tests help in the diagnosis?

Supportive is first of all a clinical biochemistry-, a haematology- and a urine examination. If the results cast a suspicion of Cushing's syndrome an assay test is the next step.
As the “way-in”-tests the ACTH-stimulationtest, the dexamethasone-screening test and the urine-cortisolcreatinine- ratio test are suitable. The diagnostic significance of these tests varies depending on sensitivity, specificity and prevalence of the disease, so that a pre-selection of the animal is especially important.
Is the diagnosis Cushing's syndrome made, an extended dexamethasone-screening test (additional blood sample after 4 hours) or dexamethasone-inhibition test (application of dexamethasone 0.1 mg / kg body weight) can distinguish whether it is a hypophyseal or adrenal form of the disease. In addition, a measurement of the endogenous ACTH concentration (absolutely necessary: chilled EDTA plasma; immediately centrifuged after sampling) and an ultrasound examination of the adrenal gland can be initiated. Single detection of the basic cortisol concentration is less appropriate, because even affected animals show rather an increase in the daily cortisol concentration as a constant elevated concentration (false negative determination).  

Dexamethasone screening-test / test protocol (good sensitivity and specificity):

1st:  blood collection = basic level
2nd: injection of dexamethasone * 0.01 mg / kg body weight i.m
3rd: blood collection: 8 hours after administration of dexamethasone = suppression level
* UNIVERSITY OF VETERINARY MEDICINE HANOVER recommends in a recent study a dose of 0.02 mg dexamethasone 
An additional blood collection after 4 hours gives an indication of a delayed metabolism and allows the presumption of a pituitary or adrenal form of Cushing's syndrome. 

Interpretation Dexamethasone-screening-test


basic level

suppression after 4 hours

suppression after 8 hours


normal or low (stress?)

< 10 ng/ml or 50% of basic level

< 10 ng/ml

Cushing's syndrome hypophyseal

normal or elevated   

50% of basic level or < 10 ng/ml

> 10 ng/ml

Cushing's syndrome adrenal

normal or elevated

minor suppression < less than 50% of basic level

> 10 ng/ml

Urine cortisol/creatinin-ratio /test protocol (high sensitivity and low specificity):

1st.  collection of morning urine on day 1 = sample1
2nd. collection of morning urine on day 2 = sample 2
3rd.  dose Dexamethasone orally on day 2: 3 x tid 0.1 mg / kg body weight
4th. collection of morning urine on days 3 = sample 3
With the level of the ratio of day 3 it is possible to distinguish between a hypophyseal or adrenal Cushing's syndrome. 

Interpretation urine cortisol/creatinin- ratio

ratio day 1 und 2: < 15x10 -6 there is no indication of Cushing syndrome
ratio day 1 and 2: between 15x10 -6 and 25x10 -6 questionable result 
ratio day 1 and 2:> 25x10 -6 Cushing's Syndrome
ratio day 3 (prerequisite: increase at day 1 and 2)
ratio > 50% of the average value of the first two samples indicate the adrenal form. 
ratio < 50% of the average value of the first two samples indicate the hypophyseal form

Therapy Cushing's syndrome

Drug of choice is Trilostane (Vetoryl®), that inhibits selectively and reversibly the enzyme system 3--hydroxysteroiddehydrogenase and prevents steroid biosynthesis. Therapy recommendation by producer (Janssen):

body weight

initial dosage


3 kg and < 10 kg

30 mg

3- 10 mg/kg

10 kg and < 20 kg

60 mg

3 - 6 mg/kg

20 kg and < 40 kg

120 mg

3 - 6 mg/kg

40 kg

120- 140 mg

3 - 6 mg/kg

The clinical signs of polyuria / polydipsia can already vanish in the first week of therapy. Check-ups by ACTH stimulation test should be performed after 1 week, 3 weeks, 6 weeks, 3 months, 6 months and 12 months after initiation of therapy. Tablets should be given always in the morning and the ACTH test should be performed from 2 to 6 hours after administering of the tablet (University of Zurich).








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