Cushing's Disease (Hyperadrenocorticism) in Dogs

Synthesized from Multiple Veterinary Sources

1. Definition & Terminology

2. Etiology & Classification

3. Epidemiology

• Overall prevalence: ~0.20% in general practice; up to 1.46% at specialist referral centers
• Mean age at diagnosis: 9.8 ± 2.5 years (middle-aged to older dogs)
• Sex predisposition: Females > males (OR 1.85); neutered animals at higher risk (OR 2.54)
• Breed predisposition: Standard Schnauzer (OR 58.1), Fox Terrier (OR 20.33), Poodle, Dachshund, Boxer, Boston Terrier, Beagle
• Study population: 21,281 client-owned dogs across 5 veterinary centers in Italy

4. Clinical Signs

5. Pathophysiology

• Gluconeogenesis → hyperglycemia, insulin resistance
• Protein catabolism → muscle wasting, poor wound healing, thin skin
• Immunosuppression → susceptibility to infections (UTI, pyoderma, fungal infections)
• Mineralocorticoid effect (at high levels) → sodium/water retention → hypertension, PU/PD
• Lipid metabolism → hepatic lipidosis, hypercholesterolemia, hepatomegaly

6. Diagnosis

Step 1 — Screening Tests (confirm hypercortisolism)

Key point (Lathan 2023): A flatline post-ACTH stimulation result (<2 µg/dL) confirms hypoadrenocorticism, but not all dogs with naturally occurring Cushing's syndrome (NOCS) have elevated post-ACTH results. LDDST is preferred for diagnosis.

Step 2 — Differentiation Tests (PDH vs. ACT)

Routine Clinicopathological Findings

• CBC: Stress leukogram (neutrophilia, lymphopenia, eosinopenia, monocytosis), erythrocytosis
• Chemistry: Elevated ALP (most consistent — often >5× ULN), elevated ALT, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, hypokalemia (occasionally)
• UA: Low specific gravity, proteinuria, glucosuria (if diabetic), bacteriuria (secondary UTI common despite lack of pyuria due to immunosuppression)

7. Treatment

A. Medical Management (most common approach)

Trilostane (preferred first-line)

• Mechanism: Competitive inhibitor of 3β-hydroxysteroid dehydrogenase → blocks cortisol and aldosterone synthesis
• Dose: 1–2 mg/kg SID or BID; titrate based on ACTH stimulation test (target post-ACTH cortisol 1.45–9.1 µg/dL / 40–250 nmol/L)
• Monitoring: ACTH stimulation test at 10–14 days, 4 weeks, then every 3–6 months
• Adverse effects: Adrenal insufficiency (overdose), reversible adrenal necrosis, hypotension, hyperkalaemia
• Advantage over mitotane: Simpler dosing, reversible mechanism, less systemic toxicity

Mitotane (o,p'-DDD) — alternative

• Mechanism: Adrenocorticolytic drug → selective destruction of zona fasciculata/reticularis (induction) or total adrenocortical destruction (high-dose)
• Induction (PDH): 25–50 mg/kg/day PO with food until loss of PU/PD, typically 7–10 days; concurrent monitoring for hypoadrenocorticism
• Maintenance: ~50 mg/kg/week
• Monitoring: ACTH stimulation test (target post-ACTH cortisol 1–5 µg/dL)
• Adverse effects: GI signs (anorexia, vomiting, diarrhea), life-threatening addisonian crisis, neurological signs
• Use for ACT: High-dose protocol (75–100 mg/kg/day) — greater risk of complete adrenal destruction
• Reine 2007: Mitotane use is "complicated and comes with many potential side effects, making many practitioners wary of its use"

Ketoconazole

• Mechanism: Inhibits adrenal and gonadal steroidogenesis (P450 enzymes)
• Dose: 5–15 mg/kg BID
• Use: Less effective; considered second-line; useful when trilostane/mitotane unavailable
• Adverse effects: Hepatotoxicity, GI signs

L-Deprenyl (Selegiline)

• Mechanism: MAO-B inhibitor → dopaminergic → suppresses ACTH secretion
• Use: Mild, early PDH only; poor responder rate vs. other drugs; no longer commonly recommended

B. Surgical Treatment

C. Radiation Therapy

• Indicated for pituitary macroadenomas (>1 cm) causing neurological signs
• Does not directly reduce cortisol but shrinks tumor mass
• Rapastella et al. 2023 [PMID 37218395]: Concurrent hypercortisolism affects survival in dogs treated with radiotherapy for pituitary macroadenomas — combined medical + radiation is preferred

8. Complications & Comorbidities

• Diabetes mellitus: Insulin resistance → concurrent DM in ~10% of Cushing's cases; resolves with successful treatment
• Pulmonary thromboembolism: Hypercoagulable state; can be fatal
• Hypertension: Common; may require antihypertensive therapy (amlodipine)
• Recurrent infections: UTI most common; also pyoderma, demodicosis
• Calcinosis cutis: Mineralization of skin; can be severely pruritic
• Respiratory signs: Panting, exercise intolerance; radiographic abnormalities documented (Mendonça 2024)
• QT interval instability: Cardiac arrhythmia risk documented (Vila et al. 2023 [PMID 35575953])

9. Prognosis

• PDH (medically managed): Median survival ~2 years with trilostane or mitotane; quality of life significantly improved with treatment
• ACT (adrenalectomy): Adenoma — good prognosis; carcinoma — guarded, metastasis possible
• Macroadenoma with neurological signs: Poor without combined pituitary-directed therapy
• Untreated Cushing's: Progressive deterioration, diabetes, infections, thromboembolic disease

10. Emerging / Future Treatments

• Pituitary-targeting drugs: Pasireotide (somatostatin analogue), cabergoline (dopamine agonist) — reduce ACTH from tumor
• Novel steroidogenesis inhibitors: Levoketoconazole, osilodrostat — under investigation in dogs
• Machine learning screening: Yoo et al. 2026 [PMID 41431376] demonstrated ML-assisted screening improves early detection accuracy

Key References by Source