This practical guide for vets outlines options for monitoring dogs on trilostane therapy for Cushing's syndrome. It is informed by published papers, ALIVE project (European Society of Veterinary Endocrinology) and experience. It covers the use of pre-pill cortisol, ACTH stimulation testing, and importance of correlation with clinical signs when considering change to treatment of hyperadrenocorticism. There is also guidance about additional testing and other considerations where clinical signs have not responded despite apparent control of cortisol levels.
General Guidance on Monitoring for Trilostane Treatment
ALIVE (Aligning language in veterinary endocrinology) states the goals of treatment of Cushing’s syndrome are to:
- Improve quality of life
- Reduce/eliminate clinical signs
- Reduce longer term complications and mortality
This is achieved by eliminating the source of either ACTH or autonomous adrenal hormone excess, or at least controlling excess adrenal hormone secretion. Treatment should only be considered if there are compatible clinical signs and the diagnosis is confirmed with endocrine testing.
Samples for monitoring should be sent to an external laboratory participating in a quality assurance scheme (e.g. ESVE or SCE- programme) and using validated assays for the species and interpretative guidelines. When following trends, it is important for the sample to be analysed in the same laboratory with the same methodology.
Manufacturer recommended treatment and monitoring schedule
Monitoring dogs on trilostane therapy
The most important aspect is the clinical response at home. The ALIVE project strongly recommends that clinicians ALWAYS interpret results of clinicopathological and hormone testing in conjunction with the clinical picture when making decisions about treatment.
Quality of life assessment
Encouraging owners to keep a diary of clinical signs can be helpful as changes can be subtle, or you can recommend the use of a monitoring tool such as CushQoL-pet (Dechra/RVC) quality of life questionnaire for more objective monitoring and to assess for trends. The following have not been shown to be helpful in monitoring the response to treatment:
- Urine specific gravity has not been shown to discriminate between adequately vs underdosed dogs.
- UCCR monitoring has also not been shown to discriminate between adequately vs underdosed dogs.
Pre-pill cortisol prior to trilostane administration
- Data suggests that a pre-pill cortisol, just prior to trilostane administration, is superior to traditional ACTH stimulation testing
- The ideal testing window is 2 hrs before or after the normal time trilostane is administered. Bearing in mind that for the latter, the pill must not be given until after the blood sample is collected. If the dog is on twice daily medication, this test can be performed before either dose is due.
- If the value is very low an ACTH stimulation test may also be recommended depending upon the circumstances.
- Some aspects of this alternative monitoring protocol, including timing and number of samples, are still being debated and investigated.
- A basal post-pill cortisol does not accurately reflect adrenal reserve.
- This protocol is only suitable for calm, well, and unstressed dogs.
ACTH stimulation test
- Has been used traditionally to monitor response to treatment and adrenal reserve capacity.
- Several studies have shown a lack of correlation between ACTH stimulation testing and clinical status of dogs with Cushing’s syndrome treated with trilostane
- An ACTH stimulation test might not accurately indicate trilostane underdosing, overdosing or appropriate dosing
- The ALIVE project concluded that optimal timing for ACTH stimulation is not established, but recommends sampling 60 minutes post-ACTH administration in dogs.
- Recommendations for the timing of an ACTH stimulation test for monitoring response to trilostane vary from 2-4 hrs post pill to 4-6 hours post-pill, and it is best to check with your submitting laboratory.
- Interpretation is based upon the post-ACTH cortisol levels, not the baseline / pre-stimulation cortisol.
Consider an ACTH stimulation test when:
- There is concern that trilostane has resulted in idiosyncratic adrenal necrosis causing hypoadrenocorticism e.g. pre-pill cortisol <40nmol/l, dog unwell or where there is concern about transient hypocortisolaemia as a result of too tight control
- There is concern there might be escape from trilostane suppression of excess adrenal hormone secretion, e.g. test prior to administration of the next dose to see if more frequent dosing is indicated.
Interpretation of pre-pill cortisol concentration during trilostane treatment
- Target range for pre-pill cortisol is 40-138nmol/L (+/-15%) which indicates adequate control in association with improved clinical signs.
- Pre-pill cortisol <40nmol/L can indicate excessive suppression, but should be correlated with clinical signs. Consider stopping trilostane and performing an ACTH stimulation test to assess adrenal reserve.
- Pre-pill cortisol >138nmol/L (+/- 15%) can indicate underdosing, but should be correlated with clinical signs.
ACTH stimulation testing during trilostane treatment
- Timing post-trilostane should be discussed with your laboratory e.g. 2-4 hrs post-trilostane
- Target range varies from laboratory to laboratory, this is an example.
- Target post-ACTH cortisol >50nmol/l and <200nmol/l (ideally <120nmol/l)
- Post-ACTH cortisol <50nmol/l could indicate excessive suppression, correlate with clinical signs and consider dose reduction or stopping trilostane if dog is unwell
- Post-ACTH cortisol >200nmol/l can indicate underdosing, correlate with clinical signs and consider dose increase or increased frequency of administration if on once daily therapy.
When clinical signs remain despite cortisol levels indicating adequate control
Sometimes, your patient may continue to have clinical signs despite cortisol levels indicating adequate control. Clinical signs associated with Cushing’s syndrome improve at different rates, with polyphagia, PU/PD and lethargy resolving more quickly once cortisol concentrations are controlled, compared with skin and coat changes which can take months. Some signs, such as calcinosis cutis, can require more specific treatment.
If clinical signs persist, then it would be pertinent to evaluate dose rate and/or frequency of administration (once vs twice daily therapy) and consider an adjustment of one or both of these. For example, persistent clinical signs of Cushing’s syndrome on once daily therapy could indicate trilostane-escape and improvement might be obtained with a move to twice daily therapy. The starting dose of trilostane is recommended to be 2mg/kg/24hr or 1mg/kg every 12hrs. However, often a significant increase in total daily dose may be required to achieve remission of clinical signs e.g. 5-7mg/kg/24hrs and significantly higher doses (>10mg/kg/day) are also reported.
The duration of effect of trilostane can also be affected by the rate of absorption after oral administration, the efficacy of absorption, the rate of metabolism and clearance of the drug and potentially the effect of pituitary ACTH excess secretion over-riding trilostane inhibition of adrenal cortisol production.
It is important to consider that ongoing clinical signs might be unrelated to hyperadrenocorticism and could indicate a need for more extensive investigation, e.g. other causes of PU/PD, other causes of skin disease, possible malabsorptive conditions affecting trilostane absorption.
References
Braddock JA, Church DB, Robertson ID, Watson AD. Trilostane treatment in dogs with pituitary-dependent hyperadrenocorticism. Aust Vet J. 2003 Oct;81(10):600-7. doi: 10.1111/j.1751-0813.2003.tb12498.x. PMID: 15080470.
Arenas Bermejo C, Pérez Alenza D, García San José P, Llauet L, Pérez-López L, Melián C, C Feldman E. Laboratory assessment of trilostane treatment in dogs with pituitary-dependent hyperadrenocorticism. J Vet Intern Med. 2020 Jul;34(4):1413-1422. doi: 10.1111/jvim.15830. Epub 2020 Jun 13. PMID: 32533623; PMCID: PMC7379015.
Macfarlane L, Parkin T, Ramsey I. Pre-trilostane and three-hour post-trilostane cortisol to monitor trilostane therapy in dogs. Vet Rec. 2016 Dec 10;179(23):597. doi: 10.1136/vr.103744. Epub 2016 Nov 1. PMID: 27803375; PMCID: PMC5256409.