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Basics ⬇

Basics

Definition

  • Spontaneous hyperadrenocorticism (HAC) is a disorder caused by excessive production of cortisol by the adrenal cortex.
  • Iatrogenic HAC results from excessive exogenous administration of glucocorticoids of any form or by any route.
  • In either instance, clinical signs are due to deleterious effects of elevated circulating glucocorticoid concentrations on multiple organ systems.

Pathophysiology

  • Approximately 80–85% of cases of naturally occurring HAC are due to bilateral adrenocortical hyperplasia resulting from pituitary corticotroph tumors or hyperplasia with oversecretion of ACTH.
  • In the remaining 15–20% of cases, cortisol-secreting adrenocortical neoplasia is present; approximately one-half of these are malignant.
  • Rarely caused by ectopic ACTH secretion from a non-pituitary tumor.
  • Iatrogenic HAC results from excessive administration of exogenous glucocorticoids.

Systems Affected

  • The degree to which each system is involved varies considerably; signs referable to one system may predominate or several systems may be involved to a comparable degree.
  • Signs referable to the urinary tract or skin often predominate.
  • Endocrine/Metabolic-hyperglycemia; diabetes mellitus occurs in 10%.
  • Cardiovascular-hypertension (usually mild).
  • Gastrointestinal-polyphagia.
  • Hemic/Lymphatic/Immune-stress leukogram; immunosuppression; mild erythrocytosis and thrombocytosis.
  • Hepatobiliary-hepatopathy due to glycogen deposition; increased serum ALP activity due to production of corticosteroid-induced isoenzyme.
  • Neuromuscular-muscle weakness; CNS signs including anorexia, ataxia, disorientation and, uncommonly, seizures if pituitary macroadenoma present.
  • Renal/Urologic-polyuria/polydipsia in 90% of cases; proteinuria; UTI common.
  • Reproductive-testicular atrophy and anestrus.
  • Respiratory-panting; pulmonary thromboembolism possible due to a hypercoagulable state.
  • Skin-bilaterally symmetric alopecia common; comedones; hyperpigmentation; recurrent pyoderma.

Genetics

No genetic basis known.

Incidence/Prevalence

  • No exact figures available.
  • Considered one of most common endocrine disorders in dogs.

Signalment

Species

Dog

Breed Predilections

Poodle, dachshund, Boston terrier, German shepherd dog, and beagle.

Mean Age and Range

Generally a disorder of middle-aged to old animals; pituitary-dependent HAC (PDH) can very rarely be seen in dogs as young as 1 year.

Predominant Sex

No predilection for PDH in dogs; possible predilection for female dogs to have an adrenal tumor.

Signs

General Comments

  • Severity varies greatly, depending on duration and severity of cortisol excess.
  • In some cases, the physical presence of the neoplastic process (pituitary or adrenal) contributes.

Historical and Physical Examination Findings

Polyuria and polydipsia, polyphagia, pendulous abdomen, increased panting, hepatomegaly, hair loss, cutaneous hyperpigmentation, thin skin, muscle weakness, obesity, lethargy, muscle atrophy, comedones, bruising, testicular atrophy, anestrus, calcinosis cutis, facial nerve palsy.

Causes

  • Pituitary-dependent-adenoma most common; adenocarcinomas rare; anterior pituitary involved in approximately 80% of cases, intermediate lobe in remaining cases; exact incidence of pituitary macroadenomas (i.e., >1 cm diameter) unknown, may be 10–25%.
  • Adrenal tumor-adenoma or carcinoma (50/50).
  • Ectopic ACTH secretion-rare.
  • Iatrogenic-due to glucocorticoid administration.

Risk Factors

  • None known for spontaneous disease.
  • Presence any condition that leads to exogenous glucocorticoid administration is a risk factor for iatrogenic HAC.

Diagnosis ⬆ ⬇

Diagnosis

Differential Diagnosis

  • Depends on clinical and laboratory abnormalities displayed.
  • Includes hypothyroidism, sex hormone dermatoses, Alopecia X, sex hormone-secreting tumors, acromegaly, diabetes mellitus, hepatopathies, renal disease, and other causes of polyuria/polydipsia.

CBC/Biochemistry/Urinalysis

  • Hemogram may show eosinopenia, lymphopenia, leukocytosis, neutrophilia, erythrocytosis and/or thrombocytosis.
  • Serum chemistry may show high liver enzymes, cholesterol, and total CO2; alkaline phosphatase activity high in approximately 90% and ALP elevations are proportionately greater than that for ALT; hyperglycemia common but only about 10% of dogs with HAC have concurrent diabetes mellitus.
  • Urinalysis may reveal low specific gravity, proteinuria, hematuria, pyuria and/or bacteriuria.

Other Laboratory Tests

  • Endocrine testing required in dogs with history, clinical signs, and laboratory abnormalities suggestive of HAC.
  • Do not perform testing for HAC in sick dogs unless clinical signs consistent with HAC are present.
  • Screening tests are designed to determine if HAC is present or not.
  • Once a diagnosis of HAC is made, a differentiation test should be performed to determine if PDH or AT is present; differentiation provides information crucial to therapeutic decisions and an accurate prognosis.
  • Differentiation tests should never be performed before a diagnosis of HAC is made via screening tests.
  • See Appendix II for table of endocrine test protocols.
  • To convert cortisol concentration in nmol/L to µg/dL, divide by 27.6.
  • All cortisol concentrations below used for illustration purposes; check with your own laboratory for its normal ranges and cut-off values.

Screening Tests

Urine Cortisol:Creatinine Ratio (UC:Cr)

  • Urine cortisol excretion increases as a reflection of augmented adrenal secretion of the hormone, whether PDH or AT present.
  • An elevated UC:Cr is a sensitive marker of HAC, present in 90–100% of affected dogs.
  • Should be measured in a sample collected at home when the pet not stressed.
  • False-positive results common; only about 20% of dogs with an elevated UC:Cr have HAC.
  • A normal ratio makes the diagnosis of HAC very unlikely (10% chance).
  • Elevated ratio consistent with a diagnosis of HAC, but since the chance of a false-positive result is great, an ACTH stimulation test or low-dose dexamethasone suppression test must always be done to confirm the presence of HAC.

Low-Dose Dexamethasone Suppression Test

  • Lack of suppression 8 hours after an injection of a low dose of dexamethasone consistent with a diagnosis of HAC.
  • Sensitivity approximately 95% in dogs.
  • In dogs, there is a relatively high chance of a false-positive result, up to 50%, if non-adrenal illness is present.
  • Lack of suppression at 4 hours but with full suppression at 8 hours is technically not consistent with HAC but is suspicious for its presence; further testing warranted.
  • With certain results, the LDDST may also serve as a differentiation test; if the 8-hour sample is >30 nmol/L, the result is consistent with HAC; if, in addition, there is suppression to <30 nmol/L at 4 h post-dexamethasone (i.e., an “escape” at 8 hours post-dexamethasone) or the 4- and/or 8-h post-dexamethasone samples are <50% of baseline, the results are consistent with PDH; if criteria for PDH not met, chances are still approximately 50/50 for PDH versus AT.
  • If baseline values close to 30 nmol/L or suppression just at 50%, presence of PDH should be confirmed by other means.
  • A protocol exists in Europe where a minimum of two morning urine samples are collected and then dexamethasone is administered (3 doses over 24 h) for differentiating purposes and another urine sample is collected. The protocol reportedly has high sensitivity and specificity. However, the cortisol assay used is proprietary and not commercially available. The accuracy of the protocol using cortisol assays commercially available in the United States has not been established, and, thus, the method is not recommended for use in the United States and Canada.

ACTH Stimulation Test

  • A response greater than normal is consistent with a diagnosis of spontaneous HAC.
  • Overall sensitivity of the test approximately 80%; for PDH, sensitivity is approximately 87%, while for HAC due to an AT, sensitivity is approximately 61%.
  • More specific in dogs than the LDDST (only 15% chance of a false-positive result with non-adrenal illness).
  • Can never differentiate between PDH and AT.
  • Only test that can diagnose iatrogenic HAC; a diagnosis is made with a history of glucocorticoid exposure by any route, presence of consistent clinical signs and a post-ACTH cortisol concentration below the reference range.
  • Cortrosyn is the recommended form of ACTH to use; if using compounded ACTH, collect samples before and at 1 and 2 hours post-ACTH administration so peak response not missed.

Differentiating Tests

High-Dose Dexamethasone Suppression Test

  • Two responses consistent with PDH; if there is suppression to <30 nmol/L at 4 and/or 8 hours post-dexamethasone or the 4- and/or 8-h post-dexamethasone samples are <50% of baseline, PDH is present.
  • If baseline values close to 30 nmol/L or suppression just at 50%, presence of PDH should be confirmed by other means.
  • Can never confirm presence of an AT; if criteria for diagnosis of PDH not met, there is a 50/50 chance the patient has PDH or an AT.

Endogenous ACTH Concentration

  • Requires only a single blood sample but special handling needed.
  • In patients with PDH, endogenous ACTH (eACTH) concentration is normal to increased; with AT, eACTH concentration is below normal.
  • Can be used to confirm the presence of an AT.
  • A gray zone exists in the results; if the patient's eACTH concentration falls into this zone, results not diagnostic.
  • With repeat testing when the original concentration measured is in the gray zone (about 15% chance), approximately 96% have definitive differentiation.
  • There is no way to predict when eACTH concentration will be in the gray zone.

Imaging

  • Abdominal radiographs may differentiate PDH from AT; approximately 40–50% of canine ATs are visualized; adrenal mineralization is highly suspicious for the presence of an AT.
  • Chest radiographs indicated in patients with an AT to check for metastases.
  • Ultrasonography, CT, and MR-useful for differentiating PDH from AT and for staging AT; abdominal ultrasonography can never be used as a screening test as bilateral adrenal enlargement may be seen due to chronic non-adrenal illness; AT can be small and may be difficult to see with ultrasonography; vena caval, hepatic or renal invasion is an indicator of malignancy; adrenal atrophy can be difficult to determine with ultrasonography.
  • CT and MRI-often useful for demonstrating pituitary macroadenomas.
  • Since radiation therapy, a treatment modality required for a pituitary macroadenoma, is more effective for smaller tumors, some authors advocate routine pituitary imaging in all dogs when PDH diagnosed; follow-up and treatment recommendations vary depending on tumor size.

Diagnostic Procedures

Adrenal biopsy (usually performed on AT obtained via adrenalectomy) often needed to differentiate benign vs. malignant tumor.

Pathologic Findings

  • PDH-gross examination reveals normal-to-enlarged pituitary and bilateral adrenocortical enlargement.
  • Microscopically, pituitary adenoma, adenocarcinoma, or corticotroph hyperplasia of pars distalis or pars intermedia and adrenocortical hyperplasia.
  • AT-gross examination reveals variable-sized adrenal mass, atrophy of contralateral gland (rarely bilateral tumors), and metastasis in some patients with adrenal carcinoma; invasion into vena cava or vena caval thrombosis may be seen with malignant tumors.
  • Microscopically, see adrenocortical adenoma or carcinoma.
  • With any form HAC, general changes of cortisol excess may be seen such as cutaneous atrophy and glomerulopathy.

Treatment ⬆ ⬇

Treatment

Appropriate Health Care

Dictated by severity of clinical signs, patient's overall condition, and any complicating factors (e.g., diabetes mellitus, pulmonary thromboembolism).

Nursing Care

Variable as above.

Activity

No alteration of activity necessary.

Diet

Usually no need to alter; use appropriate diet if diabetes mellitus concurrent.

Client Education

  • If using medical therapy, life-long therapy required.
  • If adverse reaction to mitotane or trilostane occurs-discontinue drug, give prednisone, and have veterinarian reevaluate next day; if no response to prednisone noted in a few hours, veterinarian should evaluate immediately.

Surgical Considerations

  • Hypophysectomy-described, but generally not available in the United States.
  • Bilateral adrenalectomy not used for treatment of PDH in dogs
  • Surgery is the treatment of choice in dogs with adrenocortical adenomas and small carcinomas unless the patient is a poor surgical risk or the client refuses surgery.
  • Appropriate personnel and facilities are required as adrenalectomy is a technically demanding surgery and intensive postoperative management is required.
  • Removal of tumor and vena caval thrombi can be performed; surgery not expected to be curative in such cases, but long-term survival can be achieved, e.g., >1 year.
  • Depending on patient status, medical control of HAC may be desirable prior to surgery, if possible.

Medications ⬆ ⬇

Medications

Drug(s) Of Choice

Mitotane

  • Mitotane (o,p';-DDD, Lysodren) is one of two main drugs used for medical management of PDH in dogs; selectively destroys glucocorticoid-secreting cells of the adrenal cortex; may be drug of choice for medical management of AT since it may destroy tumor cells as well as control cortisol secretion.
  • PDH-give an initial loading dose of 40–50 mg/kg divided twice daily; evaluate efficacy with ACTH stimulation test after 8 days or sooner if decreased appetite, vomiting, diarrhea, listlessness or decreased water intake (<60 mL/kg/day) noted; goal is for both basal and post-ACTH cortisol concentration to be in ideal range of 30–150 nmol/L; continue induction with repeat testing as necessary until adequate response seen, then initiate maintenance therapy at 50 mg/kg/week divided into two to three doses; dosage adjustments based on ACTH stimulation testing (maintain basal and post-ACTH cortisol levels within ideal range); if serum cortisol concentration pre- or post-ACTH <30 nmol/L, stop administering mitotane and administer physiologic doses prednisone (0.1 mg/kg q12h); cannot administer prednisone within 12 hours before ACTH stimulation test; perform ACTH stimulation tests every 7–14 days initially; cortisol secretion usually recovers in weeks to a couple months but can take longer; once cortisol concentration is in ideal range, discontinue prednisone and begin maintenance therapy; if had been on maintenance therapy when became cortisol deficient, restart maintenance at 25% lower dose; if relapse occurs at any time while on maintenance therapy, as indicated by cortisol levels above ideal range, dose adjustment required; if post-ACTH serum cortisol concentration 150–300 nmol/L, increase maintenance dose 25% and reevaluate in 4 weeks; if post-ACTH serum cortisol concentration >300 nmol/L, reload for 5–7 days and do an ACTH stimulation test; continue loading until cortisol concentration is in ideal range, then reinitiate weekly maintenance dose at approximately 50% higher dose.
  • AT-goal of mitotane use is low-to-non-detectable (i.e., <30 nmol/L) basal and post-ACTH cortisol concentrations; starting dose 50–75 mg/kg divided daily; perform ACTH stimulation test after 10–14 days to evaluate efficacy or sooner if decreased appetite, vomiting, diarrhea, listlessness or decreased water intake (<60 mL/kg/day) noted; induction typically requires higher doses and is of longer duration than for treatment of PDH; dose should be increased by 50 mg/kg/day every 10–14 days if control has not been achieved as judged by an ACTH stimulation test; if adverse effects develop due to mitotane, administration should continue at highest tolerable dose; once control achieved, maintenance therapy should begin at 75–100 mg/kg/wk divided into 2–3 doses; if cortisol levels pre- and post-ACTH rise into normal resting range (i.e., 10–160 nmol/L), increase maintenance dose 50%; if cortisol levels rise above normal resting range pre- and post-ACTH, reload until control achieved and increase weekly maintenance dose approximately 50%; during induction and maintenance, since goal is to create glucocorticoid insufficiency, give prednisone at 0.2 mg/kg/day.
  • Aldosterone deficiency possible secondary to mitotane therapy; if occurs, likely patient will have permanent complete adrenocortical insufficiency; treatment for hypoadrenocorticism should be initiated.

Trilostane

  • Trilostane (Vetoryl) is approved for use in Europe and the United States; efficacy for treatment of PDH high, comparable to mitotane; survival of dogs with PDH is same for dogs treated with mitotane or trilostane; inhibits adrenocortical enzyme 11--hydroxysteroid dehydrogenase and maybe others, thereby suppressing production of progesterone and its end-products, including cortisol and aldosterone.
  • Initial dose is 2.2–6.7 mg/kg PO q24h or divided q12h; if minor side effects are seen (i.e., anorexia, vomiting, diarrhea), stop the drug for 3–5 days and then restart q48h for 1 week before continuing with initial dosing scheme; an ACTH stimulation test should be performed beginning 4–6 hours post-pill at 10–14 days, 30 days, and 90 days after being on a full dose; if at the 10–14 day recheck any improvement is seen, do not increase the dose even if cortisol concentrations above ideal but wait until the 30 day recheck and change the dose then if needed. If post-ACTH cortisol concentration is <40 nmol/L and the patient feels well, stop the trilostane for 48–72 hours and then either restart at a lower dose, or, ideally, an ACTH stimulation test should be performed and trilostane not reinstituted until cortisol secretion has recovered; if the post-ACTH cortisol concentration is 40–150 and clinical signs have resolved, the dose should continue as is; if the post-ACTH cortisol concentration is 150–250 nmol/L, increase the trilostane dose if clinical signs are present or, if the clinical signs have resolved, leave as is but monitor carefully for signs of recurrence; if the post-ACTH serum cortisol concentration is >250 nmol/L, increase once-daily dose or twice-daily therapy should be used; the same dose given once-daily should be divided and given twice (e.g., if giving 60 mg once daily then give 30 mg q12h); if post-ACTH serum cortisol concentration is 40–150 nmol/L but clinical signs are continuing, use twice-daily therapy; once the dog's clinical condition and dose have stabilized, an ACTH stimulation test should be performed every 3–6 months and serum potassium concentration measured to check for hyperkalemia.
  • Since trilostane can suppress aldosterone secretion, an Addisonian crisis can occur; adrenocortical necrosis secondary to trilostane administration may be more common than previously believed; hypocortisolemia secondary to trilostane administration usually resolves within 48–72 hours of discontinuation of drug administration, but temporary suppression of weeks to months and even permanent suppression can occur.
  • Can be used to treat AT and will control clinical signs, at least transiently, but not the drug of choice; for AT, mitotane is the drug of choice as it is truly chemotherapeutic and may kill tumor cells.

l-Deprenyl

  • l-Deprenyl (selegiline hydrochloride) FDA approved for treatment of PDH; decreases pituitary ACTH secretion by increasing dopaminergic tone in the hypothalamic-pituitary axis, thus decreasing serum cortisol concentrations; indicated only for treating uncomplicated PDH; not recommended for dogs with concurrent illnesses such as diabetes mellitus; cannot be used to treat AT; initiate therapy with 1 mg/kg daily and increase to 2 mg/kg/day after 2 months if response inadequate; if higher dose also ineffective, give alternative therapy; no objective monitoring; assessment of efficacy based on subjective evaluation of remission of clinical signs.
  • Efficacy questionable; one study found 20% efficacy and another judged L-deprenyl ineffective.
  • Adverse effects such as anorexia, lethargy, vomiting, and diarrhea uncommon (<5% of dogs) and usually mild; disadvantages include need for lifelong daily administration and medication expense.

Ketoconazole

Ketoconazole (10 mg/kg PO q12h initially; up to 20 mg/kg PO q12h in some dogs) inhibits enzymes responsible for cortisol synthesis; indicated for dogs unable to tolerate mitotane at doses necessary to control HAC; may be useful for palliation of clinical signs of HAC in dogs with AT; monitoring done by performance of ACTH stimulation tests with same goals as for mitotane; efficacy approximately 50% or less; adverse effects include anorexia, vomiting, diarrhea, lethargy, thrombocytopenia and idiosyncratic hepatopathy.

Contraindications

  • Do not use nonsteroidal anti-inflammatory agents in dogs with uncontrolled HAC.
  • Drugs that increase blood pressure or coagulation should be used with caution.

Precautions

  • Side effects of mitotane not uncommon; mild in most dogs; include lethargy, weakness, anorexia, vomiting, diarrhea, ataxia, and iatrogenic hypoadrenocorticism.
  • Side effects more common in dogs with AT given high doses of mitotane.
  • For mitotane, use with caution in patients with renal insufficiency and primary hepatic disease.
  • Side effects of ketoconazole seem to be less common; include anorexia, vomiting, diarrhea, thrombocytopenia, and hepatopathy.
  • For ketoconazole, use with caution in patients with primary hepatic disease or thrombocytopenia; effect on breeding ability unknown.
  • Side effects of l-deprenyl uncommon.
  • Side effects of trilostane include anorexia, lethargy, vomiting and diarrhea; may occur in approximately 60% of patients; Addisonian crisis and adrenocortical necrosis have been reported.
  • For trilostane, use with caution in patients with renal insufficiency and primary hepatic disease; contraindicated in pregnancy.
  • For all drugs, if using on a diabetic patient, careful monitoring needed; insulin needs can decrease rapidly with control of HAC.

Alternative Drug(s)

Radiation therapy required for animals with pituitary macroadenomas; ACTH levels may take several months to decrease; control HAC with above drugs in the interim.

Follow-Up ⬆ ⬇

Follow-Up

Patient Monitoring

Response to therapy-use periodic ACTH stimulation testing to assess mitotane, ketoconazole, or trilostane efficacy (see above for details); once on maintenance mitotane therapy, test at 1, 3, and 6 months and every 3–6 months thereafter or if clinical signs of HAC recur; adequacy of any necessary mitotane reloading period is checked with an ACTH stimulation test before higher maintenance mitotane dose initiated; adequacy of ketoconazole or trilostane dose checked with an ACTH stimulation test after any dose alteration; with trilostane, ACTH stimulation test should be performed starting 4–6 hours post-pill, while with mitotane and ketoconazole, post-pill timing does not matter; clinical signs of HAC resolve several days to months after control achieved; evaluate efficacy of l-deprenyl therapy solely on the basis of resolution of clinical signs of HAC.

Prevention/Avoidance

For prevention of recurrence, regular administration of medications with appropriate follow-up required.

Possible Complications

  • Hypertension
  • Proteinuria
  • Recurrent infection
  • Urinary calculi (calcium oxalate)
  • Diabetes mellitus
  • Pulmonary thromboembolism
  • Neurologic signs secondary to a pituitary macroadenoma

Expected Course and Prognosis

  • Untreated HAC-generally a progressive disorder with a poor prognosis.
  • Treated PDH-usually a good prognosis; median survival time with mitotane or trilostane treatment approximately 2 years; at least 10% survive 4 years; dogs living longer than 6 months tend to die of causes unrelated to HAC.
  • Macroadenomas and neurologic signs-poor-to-grave prognosis; macroadenomas with no or mild neurologic signs-fair-to-good prognosis with radiation and medical therapy.
  • Adrenal adenomas-usually good-to-excellent prognosis; small carcinomas (not metastasized) fair-to-good prognosis overall, good-to-excellent with surgical resection.
  • Large carcinomas and AT with widespread metastasis-generally poor-to-fair prognosis, but impressive responses to high doses of mitotane occasionally seen.

Miscellaneous ⬆

Miscellaneous

Associated Conditions

Neurologic signs in dogs with large pituitary tumors; glucose intolerance or concurrent diabetes mellitus; pulmonary thromboembolism; increased incidence of infections, especially urinary tract and skin; hypertension; proteinuria/glomerulopathy.

Pregnancy/Fertility/Breeding

N/A

Synonyms

Cushing's disease; Cushing's syndrome

Abbreviations

  • ACTH = adrenocorticotropic hormone
  • ALP = alkaline phosphatase
  • ALT = alanine aminotransferase
  • AT = adrenal tumor
  • CNS = central nervous system
  • CT = computed tomography
  • eACTH = endogenous ACTH
  • HAC = hyperadrenocorticism
  • HDDST = high-dose dexamethasone-suppression test
  • LDDST = low-dose dexamethasone-suppression test
  • MRI = magnetic resonance imaging
  • PDH = pituitary-dependent hyperadrenocorticism
  • UC:Cr = urine cortisol:creatinine ratio
  • UTI = urinary tract infection

Internet Resources

www.dechra.com: good information on use of trilostane.

Author Deborah S. Greco

Consulting Editor Deborah S. Greco

Acknowledgment The author and book editors acknowledge the prior contribution of Ellen Behrend.

Client Education Handout Available Online

Suggested Reading

Behrend EN, Kemppainen RJ. Diagnosis of canine hyperadrenocorticism. Vet Clin North Am 2001, 31:985–1003.

Braddock JA, Church DB, Robertson ID, et al. Inefficacy of selegiline in treatment of canine pituitary-dependent hyperadrenocorticism. Aust Vet J 2004, 82:272–277.

Braddock JA, Church DB, Robertson ID, et al. Trilostane treatment in dogs with pituitary-dependent hyperadrenocorticism. Aust Vet J 2003, 81:600–607.

Feldman EC, Nelson RW. Canine hyperadrenocorticism (Cushing's syndrome). In: Feldman EC, Nelson RW, eds., Feline and Canine Endocrinology and Reproduction, 3rd ed. Philadelphia: Saunders, 2004, pp. 252–357.

Kintzer PP, Peterson ME. Mitotane treatment of cortisol secreting adrenocortical neoplasia: 32 cases (1980–1992). J Am Vet Med Assoc 1994, 205:54–61.

Kintzer PP, Peterson ME. Mitotane (o,p';-ddd) treatment of 200 dogs with pituitary-dependent hyperadenocorticism. J Vet Intern Med 1991, 5:182–190.

Vaughn MA, Feldman EC, Hoar BR, Nelson RW. Evaluation of twice-daily, low-dose trilostane treatment administered orally in dogs with naturally occurring hyperadrenocorticism. J Am Vet Med Assoc 2008, 232:1321–1328.