Cushing’s syndrome, or hyperadrenocorticism (HAC), can be a frustrating disease for both veterinarians and pet owners to diagnose and manage. The road to diagnosis can be a long and expensive one for clients. (A guide to diagnosing Cushing’s syndrome is available in the 2023 AAHA Selected Endocrinopathies of Dogs and Cats Guidelines.)

Once a diagnosis is obtained, treatment requires lifelong daily medication and frequent monitoring. The costs of medication and monitoring can add up and create a barrier to treatment for some families. Additionally, there has been some debate about the best testing protocols to use for monitoring HAC treatment. Veterinarians should stay up to date on current strategies for monitoring therapy for Cushing’s syndrome so they can maximize quality of life for their patients and clients.

Trilostane provides excellent patient outcomes

The primary goal of treatment for this disease is to control clinical signs, including polyuria and polydipsia, changes in the hair coat or physical appearance of the pet, and excessive panting. With treatment, these clinical signs can be controlled in most patients, leading to a better quality of life for both pet and family.

Trilostane (available as Vetoryl® from Dechra) is the only FDA-approved medical treatment for dogs with both pituitary-dependent and adrenal-dependent Cushing’s syndrome. It is a reversible inhibitor of an enzyme (3ß-hydroxysteroid dehydrogenase) required for steroid synthesis. While it is considered safer than the historically used mitotane, which is cytotoxic to the adrenal gland, there is still a potential for iatrogenic hypoadrenocorticism.

Vetoryl® is available in multiple capsule sizes which can be combined to achieve the necessary dosage. The labeled dose is 2.2–6.7 mg/kg/day, though many veterinarians start at lower doses or twice daily dosing. Many of the authors of the AAHA guidelines start around 1 mg/kg twice daily in their patients. The medication should be administered with food to improve absorption.

Monitoring trilostane therapy: laboratory testing

Regardless of what dosing is used, routine monitoring is essential to ensure their patients have good control of clinical signs while avoiding overdoses that can lead to iatrogenic hypoadrenocorticism.

Monitoring utilizes a combination of pet owner reports of clinical signs, physical examination, and laboratory testing. There are multiple strategies reported in the literature for monitoring Cushing’s syndrome, but there is no consensus on which monitoring protocol is superior.

In general, rechecks are recommended at 10 to 14 days and 30 days after starting trilostane or adjusting the dosage. Once control is achieved, monitoring is recommended every 90 days. The primary goal of the first recheck is to ensure that patients are not being over-suppressed. Dosages may be decreased based on clinical signs and lab testing at this appointment but should not be increased.

At the one-month recheck, medication dosage is increased if clinical signs of HAC are not controlled, but laboratory testing ensures that the patient’s adrenal glands are not over-suppressed and that maintaining the current dose or increasing to a higher dose is safe.

When patients remain uncontrolled, veterinarians should be sure to assess for comorbidities that may have similar clinical signs and/or complicate disease management, such as concurrent diabetes mellitus or urinary tract infections.

ACTH stimulation test

Traditionally, the ACTH stimulation test, performed 3 to 5 hours after medication administration, has been utilized for monitoring cortisol levels. However, the test has never been validated for this use and some studies have shown poor correlation between clinical signs and ACTH stimulation test results.

As the ACTH stimulation test is the gold standard for diagnosing hypoadrenocorticism, it is a good tool to screen for iatrogenic hypoadrenocorticism. An algorithm is available from Dechra to guide veterinarians in monitoring treatment with Vetoryl® using the ACTH stimulation test.

Unfortunately, the cost of repeated testing can quickly add up, especially if being performed twice a month while trying to gain control of the disease. Additionally, cortrosyn, the synthetic ACTH that is used in the test, is sometimes not available.

Pre-pill cortisol measurements

An alternative monitoring strategy utilizes a single cortisol measurement collected prior to pill administration. In a study by Macfarlane et al (2016), pre-pill cortisol measurements were better able to distinguish level of disease control than the ACTH stimulation test and were well-correlated with results of an owner questionnaire assessing clinical control.

This monitoring strategy may reduce the costs of laboratory monitoring, since only a single cortisol level is needed and no cortrosyn is required. However, patients may need additional testing such as electrolyte checks or an ACTH stimulation test if they are showing clinical signs consistent with hypoadrenocorticism.

Additionally, most dogs in the study received once daily trilostane dosing, so more research is needed to see if this testing is as reliable in dogs receiving twice daily dosing.

The essential role of the client in monitoring

Regardless of what laboratory testing protocol is utilized, veterinarians must rely on their clients’ observations of the pet. Clinical signs are the most important factor in determining if a dosage increase is needed.

Client questionnaires are available from Dechra and as part of the 2023 AAHA Selected Endocrinopathies of Dogs and Cats Guidelines. These questionnaires provide an objective way for clients to provide information about their pet’s clinical signs.

Clients should also be educated on the potential for iatrogenic hypoadrenocorticism and stay alert for clinical signs of this condition. If clients note clinical signs of lethargy, vomiting, diarrhea, inappetence, they should stop the medication and schedule a recheck for their pet, as these can be signs that the pet is becoming over-suppressed.

Take home points

While Cushing’s syndrome can pose a diagnostic and therapeutic challenge, most pets do well with treatment. Clinical signs are an essential component of monitoring. Clients must observe their pet carefully and share their observations with their veterinary team to ensure that treatment goals are achieved.

Laboratory monitoring helps to ensure that current doses are safe, and the adrenal glands are not over-suppressed, but should not be the sole factor in deciding to increase patient dosages if there is good clinical control.

References and further reading

1. Bugbee A, Rucinsky R, Cazabon S, et al. 2023 AAHA selected endocrinopathies of dogs and cats guidelines. JAAHA 2023;59: DOI10.5326/JAAHA-MS-7368
2. Treating Cushing’s. Available at https://www.dechra-us.com/management-areas/companion-animals/endocrinology/canine-hyperadrenocorticism/treating-cushings. Accessed November 8, 2023.
3. Monitoring Cushing’s. Available at https://www.dechra-us.com/management-areas/companion-animals/endocrinology/canine-hyperadrenocorticism/monitoring-cushings. Accessed November 8, 2023.
4. Lemetayer J, Blois S. Update on the use of trilostane in dogs. Can Vet J. 2018 Apr;59(4):397-407. PMID: 29606727; PMCID: PMC5855282.
5. Macfarlane L, Parkin T, and Ramsey I. Pre-trilostane and three-hour post-trilostane cortisol to monitor trilostane therapy in dogs. Vet Rec 2016;179(23):597. https://bvajournals.onlinelibrary.wiley.com/doi/ pdf/10.1136/vr.103744