Contributors: David Bruyette, Ian Ramsey, Samuel Fowlie

 Species: Canine   |   Classification: Diseases

Introduction Pathogenesis Diagnosis Treatment Outcomes Further Reading


  • Relatively common endocrine disease.
  • Cause: syndrome resulting from excessive production or administration of glucocorticoids.
  • Signs: polydipsia, polyuria, polyphagia, alopecia, lethargy.
  • Diagnosis: screening lab tests and dynamic tests of adrenal function.
  • Treatment: trilostane, mitotane.
  • Prognosis: good with adequate monitoring.
    Print out owner factsheet on Cushing's disease (hyperadrenocorticism) Cushing's disease (hyperadrenocorticism) to give to your client.

Age Predisposition

  • Middle to old age.

Breed Predisposition

Pituitary-dependent hyperadrenocorticism

Adrenal-dependent hyperadrenocorticism

  • No specific breed predilection except that larger breeds are probably over-represented.

Cost Considerations

  • Can be quite expensive to treat and requires life-long therapy and monitoring.

Special Risks

  • Poor wound healing - avoid surgery until stabilized if possible.



  • Iatrogenic associated with prolonged corticosteroid therapy.
  • For pathophysiology see adrenal pathophysiology Adrenal: anatomy and physiology.
  • Failure of negative feedback on ACTH release.
  • Functional pituitary tumor (corticotrophic adenoma).
  • Functional adrenal tumor - usually unilateral with 50% benign, 50% malignant.


  • Glucocorticoids profoundly affect carbohydrate, protein and fat metabolism.
  • Glucocorticoids also modify inflammatory and immune responses.
  • Excessive glucocorticoids cause:


  • Increased gluconeogenesis.
  • Increased glycogen stores.
  • Induce certain enzymes.


  • Increased protein catabolism → muscle wasting and weakness.


  • Microscopic osteopenia associated with increased PTH, increased protein catabolism and negative calcium balance. Dogs with hyperadrenocorticism do not get clinically detectable osteoporosis (cf humans).


  • Increased protein catabolism → thin skin, poor wound healing, poor scar formation, cessation of hair growth.


  • Erythrocytosis.
  • Decrease in circulating lymphocytes and eosinophils.
  • Increase in circulating neutrophils.


  • Increased glomerular filtration rate or interference with ADH release or action → polyuria → polydipsia.
  • Increased calcium excretion.

Immune system

  • Reduced inflammatory response.
  • Reduced immune response.


  • Increased lipolysis.
  • Redistributed fat deposits.

Genital system

  • Reduced gonadotrophins → anestrus in bitch/testicular atrophy in dog.


  • Months → years.


Presenting Problems

  • Polydipsia and polyuria.
  • Polyphagia - scavenge for food.
  • Abdominal distension - 'pot belly'.
  • Lethargy.
  • Poor exercise tolerance.

Client History

  • Insidious onset over many months or years.

Clinical Signs

  • Palpable liver enlargement.
  • Muscle wasting/weakness Hyperadrenocorticism muscle atrophy.
  • Skin: thin and inelastic, striae, superficial veins visible, comedones, calcinosis cutis Calcinosis cutis superficial , excessive bruising, poor wound healing, breakdown of scars Calcinosis cutis.
  • Hair: bilaterally symmetrical non-pruritic alopecia affecting flanks, trunk and neck first, and feet and tail late Hyperadrenocorticism Hyperadrenocorticism collie 01 Hyperadrenocorticism collie 02 Alopecia (flank) collie.
  • Anestrus/testicular atrophy.
  • Hair: becomes lighter in color and finer in texture.
  • Myotonia (mainly seen in poodles for reasons that are unknown).

Diagnostic Investigation


Hormone assay

  • Basal cortisol assays are of little value as these frequently lie within the normal range in dogs with hyperadrenocorticism.
  • Diagnosis requires adrenal function testing with:
    • ACTH stimulation test ACTH stimulation test :
      • Exaggerated cortisol response to ACTH suggestive of hyperadrenocorticism.
        This test is less sensitive that the low dose dexamethasone suppression test (particularly important to remember that a negative result does not exclude hyperadrenocorticism - particularly when caused by an adrenal tumor).
    • Low-dose dexamethasone suppression test Low-dose dexamethasone suppression test :
      • Failure of cortisol suppression following dexamethasone administration suggests hyperadrenocorticism.
        This test is more affected by non-adrenal gland disease than the ACTH stimulation test.
  • Differentiation of adrenal and pituitary dependent disease can be aided by:
    • ACTH assay ACTH Assay :
      • ACTH normal or increased in pituitary-dependent disease.
    • High-dose dexamethasone suppression test High-dose dexamethasone suppression test :
      • Cortisol concentrations in cases with adrenal neoplasia (and some pituitary neoplasms) fail to suppress following HDDST.
      • This test has largely been superceded by ACTH assay and imaging techniques.

2-D Ultrasonography

  • Liver Ultrasonography: liver to look for hepatic metastases or local invasion (adrenal tumors).
  • Adrenals Ultrasonography: adrenal gland to identify bi-/uni-lateral enlargement.
  • Finding a unilateral adrenal mass, particularly if adrenal architecture is abnormal, is highly suggestive of adrenal-dependent disease.
  • Bilateral adrenal enlargement points towards a diagnosis of pituitary-dependent disease.



  • Specific gravity Urinalysis: specific gravity decreased: 1.010-1.018.
    Can be increased with water deprivation.
  • Active sediment, ie protein Urinalysis: protein and inflammatory cells Urinalysis: white blood cell may be present with urinary tract infection (UTI) but may not due to anti-inflammatory effects of glucocorticoids.
  • Urine protein: creatinine ratio increased in 30% of cases that do not have UTI (thought to be associated with hypertension Hypertension rather than a specific glomerulonephropathy).
  • Glycosuria Urinalysis: glucose if concurrent diabetes mellitus.
  • Urine cortisol:creatinine ratio Urine cortisol:creatinine ratio increased.
  • This test is useful as a screening test for hyperadrenocorticism but ratio is increased in many dogs with non-adrenal gland disease.


  • Abdomen Radiography: abdomen Liver hepatomegaly (Cushings disease) - radiograph lateral :
    • Pot-bellied appearance.
    • Liver enlargement.
    • Calcinosis cutis and soft tissue mineralization.
    • Adrenal enlargement/calcification with tumor Adrenal mass - radiograph.
    • Distended bladder/cystic calculi.
  • Thorax Radiography: thorax Lung interstitial pattern (close-up) - radiograph Lung interstitial pattern - radiograph lateral :
    • Interstitial lung pattern.
    • Tracheal and bronchial calcification.
    • Pulmonary mineralization.
    • Osteoporosis of the thoracic spine.
    • Calcinosis cutis and soft tissue mineralisation.
    • Pulmonary metastases from adrenocortical carcinoma.
    • Congestive heart failure (rare).
    • Pulmonary thromboembolism (rare).
    • Skull: sinus venography for large pituitary tumors.


Gross Autopsy Findings

Pituitary-dependent hyperadrenocorticism

Adrenal-dependent hyperadrenocorticism

  • 15-20% cases caused by benign or malignant (50% each) unilateral or bilateral adrenal tumors.
  • Adenomas are small, well-circumscribed tumors that are not locally invasive.
  • Carcinomas are larger, locally invasive, hemorrhagic and necrotic. In the right adrenal gland they frequently invade the phrenicoabdominal vein and caudal vena cava and metastasize to the liver, lung and kidney.


Standard Treatment

  • There is no standard treatment for hyperadrenocorticism. All published studies on these drugs have been controlled and unblinded. National differences in the products that are authorized for use, the severity of the illness, the experience of the veterinarian, client preferences and patient's response will all play a role in determining which treatment is selected. No treatment modality currently available, or likely to be so in the near future, is perfect.


  • See also Trilostane Trilostane.
  • Reversibly inhibits 3-beta hydroxysteroid dehydrogenase enzyme system, thereby decreasing synthesis of cortisol and aldosterone.
  • Positive results reported with use of trilostane in several large multicenter trials. Trilostane is authorized in the UK for the treatment of hyperadrenocorticism.
  • Well tolerated: less side effects than mitotane. Efficacy similar to mitotane.
  • Dose: 2-5 mg/kg orally once daily, using the lower dosage range in small dogs. Dose adjustment after first 4 weeks of therapy according to clinical signs and serum cortisol values.
  • Clinical reassessment after 10 days of therapy. Pre-trilostane cortisol monitoring Pre-trilostane cortisol monitoring performed 4 weeks and 12 weeks after starting therapy, then every 3 months while stable.


  • See also mitotane Mitotane.
  • Selectively destroys zona fasciculata and reticularis with relative sparing of the zona glomerulosa.
  • Induction: 50 mg/kg (to maximum of 1 g/dog) PO SID (given with food to improve absorption), usually for 7-14 days treatment, until:
    Either Water consumption returns to normal (<50 ml/kg/day).
    Or Dog takes longer to eat food.
    Or Side effects develop.
  • Repeat ACTH stimulation test; if post-ACTH [cortisol] <100 nmol/l start maintenance therapy.
  • Maintenance: weekly dosing at weekly dose equal to initial daily dose.
  • Dogs with adrenal neoplasia may also be treated with mitotane but generally these animals require longer induction periods and higher maintenance doses (mean 102 mg/kg/week in one study) than animals with pituitary-dependent disease.


  • Studies in America initially suggested that mono-amine oxidase inhibitors, eg selegilene Selegiline hydrochloride may be effective in some cases of pituitary dependent hyperadrenocorticism.
  • Subsequent studies refuted this suggestion. Some clinical improvement may be noted (especially lethargy may get better) but endocrine tests do not change. Improvement in lethargy may be related to central action of drug.
  • It has not been licensed for the treatment of hyperadrenocorticism in the UK.
  • Animals are treated at 1 mg/kg for 1 month and if there is no clinical improvement then dose should be increased to 2 mg/kg for a further month.
  • Life-long therapy would be required.

Radiation therapy

  • See also radiation therapy Radiotherapy.
  • For pituitary macroadenoma.
  • Requires careful planning.
  • Likely to improve neurological signs - but consider concurrent medical therapy.


  • Technically difficult procedure with procedure-related mortality estimated at 30-60%. Even in institutions with a lower mortality rate the morbidity is still significant.
  • Intensive care facilities are mandatory before undertaking this operation.
  • Consider pre-operative stabilization with mitotane, trilostane or ketoconazole to minimize risk of wound breakdown and other complications associated with hyperadrenocorticism. Mitotane may make the tumor more friable.
  • Should not be undertaken unless full extent of tumor is determined with ultrasound, CT or MRI prior to surgery.
  • Unilateral for adrenal tumor.
    Bilateral adrenalectomy for PDH is not recommended in the dog and carries risk of post-operative crisis of hypoadrenocorticism.


  • See also ketoconazole Ketoconazole.
  • Suppresses steroidogenesis.
  • Dose: 5 mg/kg BID for 7 days, then 10 mg/kg BID for 7-14 days, then 15 mg/kg BID if necessary.
    Essential to monitor hepatic function throughout therapy.Less useful than trilostane due to hepatopathy.


  • Technically very difficult. Limited availability in Europe.
  • Critical post-operative phase.

If concurrent diabetes mellitus

  • Attempt stabilization of diabetes Diabetes mellitus with insulin before giving mitotane/trilostane.



  • Clinical signs should be monitored.
  • Clinical assessment after 10 days of treatment. Pre-trilostane cortisol monitoring performed at 4 weeks, 12 weeks and then every 3 months following start of treatment and after each dose adjustment. Test should be performed 24 h after last Trilostane dose if on once daily dosing or after 12 h if on twice daily dosing. Ideally performed first thing in the morning. A good client history focusing on clinical signs and a thorough clinical examination are very important.
    • Ideally cortisol levels should be between 40 and 138 nmol/L with no clinical signs.
    • If <40 nmol/L consider reducing the dose of trilostane or stopping if clinically unwell.
    • If >138 nmol/L consider dose increase or splitting daily dose in two for twice daily dosing.
  • See Pre-trilostane cortisol monitoring Pre-trilostane cortisol monitoring for further information.
  • Repeated every 3 months.
  • Trilostane is absorbed better if given with food.


  • [Eosinophil] and [lymphocyte] if no polydipsia.
  • ACTH stimulation test: post-treatment [cortisol]:
  • Ideally <120 nmol/l with no stimulation following ACTH administration.
  • If <15 nmol/l, consider reducing frequency and/or dose of mitotane.
  • If >200 nmol/l, consider increasing dose or frequency of mitotane.
  • Mitotane side-effects Mitotane ; most problems transient.


  • Clinical signs should be monitored and care taken to check for ketoconazole side effects Ketoconazole.
  • ACTH stimulation test: post-treatment [cortisol]:
    • Ideally <120 nmol/l with no stimulation following ACTH administration.
    • If <15 nmol/l, consider reducing frequency and/or dose of ketoconazole.
    • If >200 nmol/l, consider increasing dose or frequency of ketoconazole.

Subsequent Management


Management of hypocortisolism

Treatment comparatively safe in most dogs which show complete reversal of clinical signs.

  • Risk of development of hypoadrenocorticism Hypoadrenocorticism in dogs with persistently low cortisol levels post-treatment.
  • If adverse signs, stop mitotane/trilostane/ketoconazole, repeat ACTH stimulation test and reassess case.



  • Generally good - most treated animals have a good quality of life.

Expected Response to Treatment

  • Water intake drops rapidly.
  • Other clinical signs should resolve over weeks to months.

Reasons for Treatment Failure

  • Owner refuses treatment (cost may be a factor).
  • Adrenal tumor non-operable and not responsive to medical therapy.

Further Reading


Refereed papers

  • Recent references from PubMed and VetMedResource.
  • Ramsey I & Ristic J (2007) Diagnosis of canine hyperadrenocorticism. In Practice 29 (8), 446-454 VetMedResource.
  • Ramsey I & Neiger R (2007) Treatment of canine hyperadrenocorticism. In Practice 29 (9), 512-519 VetMedResource.
  • Bell R, Neiger R, McGrotty Y & Ramsey I K (2006) Study of the effects of once daily trilostane administration on cortisol concentrations and ACTH responsiveness in hyperadrenocorticoid dogs. Vet Rec 159 (9), 277-281 PubMed.
  • Ramsey I (2006) Treatment of canine hyperadrenocorticism. UK Vet 11 (2), 27-32 VetMedResource.
  • Ramsey I (2006) Diagnosis of canine hyperadrenocorticism. UK Vet 11 (1), 21-28 MAGOnlineLibrary.
  • Ramsey I (2006) Pathophysiology of hyperadrenocorticism. UK Vet 10 (8), 31-37.
  • Barker E, Campbell S, Tebb A, Neiger R, Herrtage M E & Ramsey I K (2005) A comparison of the survival times of dogs treated for hyperadrenocorticism with trilostane or mitotane. J Vet Intern Med 19 (6), 810-815 PubMed.
  • Ramsey I K, Tebb A, Harris E, Evans H & Herrtage M E (2005) Hyperparathyroidism in dogs with hyperadrenocorticism. JSAP 46 (11), 531-536 PubMed.
  • Tebb A J, Arteaga A, Evans H & Ramsey I K (2005) Canine hyperadrenocorticism: effects of trilostane on parathyroid hormone, calcium and phosphate concentrations. JSAP 46 (11), 537-542 PubMed.
  • Wenger M, Sieber-Ruckstuhl N S, Muller C & Reusch C E (2004) Effect of trilostane on serum concentrations of aldosterone, cortisol, and potassium in dogs with pituitary-dependent hyperadrenocorticism. Am J Vet Res 65 (9), 1245-1250 PubMed.
  • Neiger R (2003) Treatment of canine hyperadrenocorticism (Cushing's Disease) with trilostane. UK Vet (2) 19-22.
  • Neiger R, Ramsey I K, O'Connor J, Hurley K & Mooney C T (2002) Trilostane treatment of 78 dogs with pituitary dependent hyperadrenocorticism. Vet Rec 150 (26), 799-804 PubMed.
  • Ruckstuhl N S, Nett C S & Reusch C E (2002) Results of clinical examinations, laboratory tests, and ultrasonography in dogs with pituitary-dependent hyperadrenocorticism treated with trilostane. Am J Vet Res 63 (4), 506-512 PubMed.
  • Gould S M, Baines E A, Mannion P A, Evans H & Herrtage M E (2001) Use of endogenous ACTH concentration and adrenal ultrasonography to distinguish the cause of canine hyperadrenocorticism. JSAP 42 (3), 113-121 PubMed.
  • Frank L A, DeNovo R C, Kraje A C et al (2000) Cortisol concentrations following stimulation of healthy and adrenopathic dogs with two doses of tetracosactrin. JSAP 41 (7), 308-311 PubMed.
  • Reusch C E, Steffen T & Hoerauf A (1999) The efficacy of L-Deprenyl in dogs with pituitary-dependent hyperadrenocorticism. J Vet Intern Med 13 (4), 291-301 PubMed.
  • Zerbe C A et al (1999) The Hypothalamic-Pituitary-Adrenal Axis and Pathophysiology of Hyperadrenocorticism. Comp Contin Educ Pract Vet 21 (12), 1134-1137 VetMedResource.
  • Hess R S, Kass P H & Ward C R (1998) Association between hyperadrenocorticism and development of calcium-containing uroliths in dogs with urolithiasis. JAVMA 212 (12), 1889-1891 PubMed.
  • Théon A P & Feldman E C (1998) Megavoltage irradiation of pituitary macrotumors in dogs with neurologic signs. JAVMA 213 (2), 225-231 PubMed.
  • Thuróczy J, van Sluijs F J, Kooistra H S et al (1998) Multiple endocrine neoplasms in a dog - corticotrophic tumor, bilateral adrenocortical tumors, and pheochromocytoma. Vet Q 20 (2), 56-61 VetMedResource.
  • Angles J M, Feldman E C, Nelson R W et al (1997) Use of urine cortisol-creatinine ratio versus adrenocorticotropic hormone stimulation testing for monitoring mitotane treatment of pituitary-dependent hyperadrenocorticism in dogs. JAVMA 211 (8), 1002-1004 PubMed.
  • Dunn K J (1996) Complications associated with the diagnosis and management of canine hyperadrenocorticism. In Practice 19 (5), 246-52 VetMedResource.
  • Grooters A M, Theisen S K et al (1996) Ultrasonographic characteristics of the adrenal glands in dogs with PDH - comparison with normal dogs. JVIM 10 (3), 110-115 PubMed.
  • Bertoy E H, Feldman E C, Nelson R Wet al (1995) MRI of the brain of dogs with recently diagnosed but untreated pituitary dependent hyperadrenocorticism. JAVMA 206 (5), 651-656 PubMed.
  • van Sluijs F J, Sjollema B E, Voorhout G, van der Ingh T S G A M & Rijnberk A (1995) Results of adrenalectomy in 36 dogs with hyperadrenocorticism​ caused by adrenocortical tumor. Vet Q 17 (3), 113-116 PubMed.
  • Kintzer P P & Peterson M E (1994) Mitotane treatment of 32 dogs with cortisol-secreting adrenocortical neoplasms. JAVMA 205 (1), 54-61 PubMed.
  • Kintzer P P & Peterson M E (1991) Mitotane (o,p'-DDD) treatment of 200 dogs with pituitary-dependent hyperadrenocorticism. J Vet Intern Med 5 (3), 182-190 PubMed.

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