Treating Cushing’s disease in dogs begins with a confirmed diagnosis of hyperadrenocorticism (HAC) — and from there the decision depends on several variables: the form of disease (pituitary-dependent vs. adrenal-dependent), the size and behaviour of any identified tumour, the dog’s overall health status, and the owner’s capacity for monitoring and follow-up. There is no single universal protocol — but there are well-characterised options, each with a distinct mechanism, monitoring requirement, and risk profile.
This post covers those options in detail: the two primary pharmaceutical approaches, the circumstances in which surgery is the appropriate choice, and the rationale behind the endocrine monitoring that makes safe, effective treatment possible.
Trilostane (Vetoryl)
Trilostane has become the most commonly used pharmaceutical treatment for canine HAC in many countries since receiving regulatory approval for dogs (US: 2008; earlier in Europe). It is indicated for both pituitary-dependent and adrenal-dependent disease.
Mechanism
Trilostane is a competitive inhibitor of 3β-hydroxysteroid dehydrogenase (3β-HSD), an enzyme essential at multiple points in the biosynthetic pathway that converts cholesterol into active steroid hormones including cortisol, aldosterone, and androgens. By blocking 3β-HSD, trilostane reduces the adrenal cortex’s capacity to synthesise cortisol without destroying adrenal tissue — making it a reversible intervention. If the dose is too high or the dog’s cortisol requirements change, the drug can be discontinued and adrenal function will recover.
Dosing and Administration
Trilostane is administered orally with food (absorption is improved when given with a meal). The approved label dose in the US is 2.2–6.7 mg/kg/day, though many clinicians now start considerably lower — around 1 mg/kg twice daily — and titrate upward from there. Because trilostane has a short half-life, twice-daily dosing is preferred by most clinicians for more consistent control across the day. Individual titration is the norm rather than the exception. Capsule sizes are fixed, which means that appropriate dosing for a given dog’s weight requires careful selection among available strengths.
Monitoring
Because trilostane reduces cortisol production, monitoring is centred on ensuring the drug is effective without suppressing cortisol to dangerously low levels. The ACTH stimulation test is the standard monitoring tool.
The typical monitoring schedule:
- 10–14 days after initiation or any dose change: ACTH stimulation test
- 4 weeks after initiation
- 12 weeks after initiation
- Every 3–6 months thereafter once stable
The test is performed 4–6 hours post-pill (when trilostane’s effect on the adrenal gland is near its peak). Target post-stimulation cortisol values vary by protocol but commonly fall in the range of 2–5 µg/dL, reflecting adequate suppression without overcorrection.
An alternative approach — measuring pre-pill cortisol immediately before the next dose — has gained ground in recent research as a simpler and less expensive way to guide dosing. We compare both methods and explain how to read the numbers in our full guide to monitoring trilostane in dogs.
Adverse Effects and Risks
The most important risk with trilostane is excessive cortisol suppression, which manifests as clinical hypocortisolism (lethargy, weakness, inappetence, vomiting, diarrhoea) and electrolyte disturbances. These signs require prompt veterinary assessment and may necessitate glucocorticoid supplementation while the drug effect wanes.
A more serious and less predictable complication is adrenal necrosis: trilostane can, in a subset of cases, trigger irreversible destruction of adrenal tissue rather than simple enzymatic inhibition. The mechanism is not fully understood. The result can be acute adrenal insufficiency, which is a medical emergency. Owners should be briefed to watch for signs of acute collapse, weakness, or gastrointestinal crisis and seek emergency care immediately if these occur.
Prognosis
Dogs with PDH treated with trilostane have a median survival time in published studies of approximately 700–900 days from the start of treatment, with many dogs living considerably longer. Quality of life improvements are typically observed within weeks of initiating therapy as cortisol levels fall.
Mitotane (Lysodren, o,p’-DDD)
Mitotane is the older of the two primary pharmaceutical options, used in veterinary medicine for decades before trilostane became available. It remains a valid and effective option, and in some countries it is the primary agent used.
Mechanism
Unlike trilostane, mitotane is adrenocorticolytic: it selectively destroys the cortisol-producing zones of the adrenal cortex (the zona fasciculata and zona reticularis) through a direct cytotoxic effect. The zona glomerulosa, which produces aldosterone, is more resistant to mitotane and is typically spared at standard doses — though high doses or prolonged use can affect aldosterone production.
Because mitotane causes permanent reduction in adrenocortical mass, it is not reversible in the same way trilostane is. This changes both the risk calculus and the monitoring approach.
Treatment Phases: Induction and Maintenance
Mitotane therapy proceeds in two distinct phases.
Induction involves daily administration — typically at 25–50 mg/kg/day divided with food — with the goal of reducing cortisol output to acceptable levels. Owners monitor for clinical endpoints during induction: reduced water intake and appetite that brings the dog back toward a normal range are the primary signals that induction is working. This phase typically lasts 5–10 days but is highly variable.
Crucially, owners must have oral prednisolone available during induction and instructions on when to administer it. If cortisol suppression occurs too rapidly — or if the dog stops eating or shows signs of weakness — prednisolone provides glucocorticoid cover while treatment pauses.
An ACTH stimulation test is performed at the end of induction. Target post-stimulation cortisol is generally 2–5 µg/dL.
Maintenance follows successful induction: mitotane is given once or twice weekly rather than daily, maintaining the reduction in functional adrenocortical tissue achieved during induction. Regular ACTH stimulation testing (every 3–6 months) continues indefinitely.
Adverse Effects and Risks
Gastrointestinal signs (vomiting, diarrhoea, inappetence) are common during induction and are one reason owners are instructed to monitor closely throughout this phase. Hypocortisolism — too much suppression — requires prednisolone supplementation and temporary dose adjustment. In a small percentage of cases, mitotane damages the zona glomerulosa as well, producing true hypoadrenocorticism (Addison’s disease), which requires lifelong mineralocorticoid replacement.
Surgical Options
Adrenalectomy for Adrenal-Dependent HAC
For dogs with ADH caused by a discrete adrenal tumour, surgical removal of the affected gland is the treatment of choice when the tumour is resectable and the patient is an appropriate surgical candidate. Adrenalectomy offers the possibility of cure rather than ongoing pharmaceutical management — a meaningful distinction, particularly in dogs with adrenal adenomas.
The procedure carries significant surgical complexity. Adrenal tumours are highly vascular, adjacent to major vessels, and in the case of carcinomas may exhibit direct invasion into the caudal vena cava. Pre-operative CT imaging is standard for surgical planning, including assessment of vascular invasion. The perioperative period requires careful glucocorticoid management: the contralateral adrenal gland, suppressed by chronic cortisol excess, cannot immediately compensate after the tumour-bearing gland is removed, and glucocorticoid supplementation must be provided until adrenal recovery is confirmed.
Perioperative morbidity and mortality can nonetheless be significant — adrenalectomy is not a low-risk procedure, and case selection matters. In experienced surgical centres, long-term outcomes for adrenal adenomas are generally very good. Carcinomas carry a more guarded prognosis depending on degree of invasion and whether metastatic disease is present.
Hypophysectomy for Pituitary-Dependent HAC
Transsphenoidal hypophysectomy — surgical removal of the pituitary gland — is the treatment of choice for PDH in human patients and is offered at a small number of specialist veterinary centres. When performed by experienced surgeons, remission rates in dogs are high, and in many cases the procedure is curative.
The procedure is technically demanding, requires advanced neurosurgical capability and intraoperative imaging, and is associated with significant perioperative management requirements including glucocorticoid and thyroid hormone replacement. Availability is limited to specialist referral centres. For owners willing and able to access this option, it merits serious consideration, particularly in younger dogs or those with macroadenomas.
Radiation Therapy
In dogs with pituitary macroadenomas causing neurological signs, radiation therapy may be used to reduce tumour size and relieve compression on adjacent brain structures. Radiation does not rapidly normalise cortisol — it may take weeks to months for the pituitary tumour to respond — and pharmaceutical management of HAC typically continues in parallel. Radiation is primarily a tool for managing the neurological burden of large tumours rather than a primary treatment for cortisol excess.
Monitoring: The Ongoing Commitment
Treating canine HAC is not a one-time intervention — it is an ongoing management commitment. Whichever pharmaceutical approach is chosen, regular endocrine testing is required, doses often need adjustment over time as the disease progresses or the patient’s health status changes, and acute complications can occur even in well-managed cases.
Owners should understand before treatment begins that:
- Regular ACTH stimulation tests are a non-negotiable part of safe management
- Clinical improvement should be visible within weeks of effective therapy (reduced thirst, reduced panting, coat regrowth over months)
- Signs of under-treatment (return of PU/PD, polyphagia) and over-treatment (lethargy, weakness, loss of appetite) both require prompt veterinary contact
- Emergency preparedness — knowing the signs of acute adrenal crisis and having access to emergency care — is part of responsible management
The goal of treatment is not just cortisol suppression but a meaningful return of quality of life — and in most cases, with appropriate management, that goal is achievable.
In the next post, we examine natural supportive approaches: the evidence base for lignans and melatonin in dogs with Cushing’s, what the proposed mechanisms are, and an honest assessment of where the data is strong and where it is limited.
If you’re researching natural supportive options while managing a Cushing’s diagnosis, our sponsors at lignans.com provide detailed information on SDG lignans and melatonin for dogs with hyperadrenocorticism.
The information on this site is educational and not a substitute for veterinary diagnosis or treatment. Always work with a licensed veterinarian for your dog’s care.
Sources
- Merck Veterinary Manual — Cushing Syndrome (Hyperadrenocorticism) in Animals
- MSPCA-Angell — Trilostane Dosing and Monitoring in Dogs
- Today’s Veterinary Practice — Trilostane for Dogs With Hyperadrenocorticism
- AAHA — Monitoring Strategies for Trilostane Therapy in Dogs with Cushing’s Syndrome
- Comparison of Survival Times for Dogs with Pituitary-Dependent Hyperadrenocorticism: Trilostane versus Untreated
- García San José et al. — Survival of dogs with PDH treated twice daily with low doses of trilostane (Veterinary Record, 2022)
- Long-Term Survival of Dogs with Adrenal-Dependent Hyperadrenocorticism: Mitotane vs Twice-Daily Trilostane
- Use of ACTH stimulation tests to monitor the treatment of canine hyperadrenocorticism
- Prognostic factors for outcome after transsphenoidal hypophysectomy in dogs with PDH
- Today’s Veterinary Practice — Cushing’s Disease in Dogs Part 3: Current and Investigative Options for Therapy
