The ACTH stimulation test is validated for the diagnosis of hyperadrenocorticism and for the monitoring of mitotane therapy (Dunn et al 1995).
The ACTH stimulation test demonstrates that Vetoryl reduces cortisol production, and it was assumed to be a valid method of monitoring Vetoryl therapy when the product was first launched (Neiger et al 2002). However, the reliability (correlation with clinical response), repeatability, sensitivity and specificity (for diagnosing over treatment) were never tested (Ramsey 2010).
It has since been shown that there is poor correlation between the post-ACTH stimulation cortisol result and the clinical response of dogs receiving Vetoryl (Wehner et al 2013, Macfarlane et al 2016). This is probably because post-ACTH cortisol does not reflect average daily cortisol.
If ACTH stimulation tests are repeated in the same dog with the same level of clinical control on the same dose of Vetoryl the results may be markedly different (Ramsey et al 2016). This is probably because the suppression of cortisol production by Vetoryl varies in timing day to day.
The post-ACTH stimulation cortisol result may also indicate that a dog is being over treated when in fact it is not (Midence et al 2015). This is because while Vetoryl can induce a temporary over suppression of the cortisol production that ACTH stimulation cannot overcome, this effect may not last for the full inter-dose period. The result is that ACTH stimulation tests lack sufficient specificity for the diagnosis of hypocortisolism in a dog being treated with Vetoryl.
The timing of the ACTH stimulation test relative to the administration of Vetoryl significantly affects the results obtained (Bell et al 2006). However, published target reference ranges are broadly similar (Ramsey, 2010).
In addition, dogs that are unwell because of another condition could have alterations in the post-ACTH stimulation cortisol results because of that condition. This has not been investigated.
Many other methods investigated to date such as the urine cortisol:creatinine ratio, ‘basal’ cortisol, cortisol:ACTH ratio and haptoglobin have not proven to be better than the ACTH stimulation test against which they were compared.
The aim of Vetoryl monitoring is to:
As a result of a shortage of tetracosactide, researchers at the University of Glasgow began to investigate alternative methods of monitoring dogs on Vetoryl treatment whilst continuing to perform ACTH stimulation tests. The researchers developed a standardised questionnaire that provided a semi-quantitative assessment of control. Various alternative monitoring methods and the results of the ACTH stimulation tests were then compared to the results of the questionnaire (Macfarlane et al 2016).
The method that best predicted the results of the owner questionnaire was the cortisol measured just BEFORE Vetoryl administration (now called Pre-Vetoryl Cortisol monitoring) (Macfarlane et al 2016).
The Glasgow results were then communicated to others in the scientific community and a multicentre clinical trial compared the repeatability of Pre-Vetoryl Cortisol monitoring with post-ACTH cortisol tests. The results showed that Pre-Vetoryl Cortisol was considerably more repeatable than post-ACTH cortisol (Ramsey et al 2016). So, a dog on a particular dose of Vetoryl is more likely to have similar result when retested using Pre-Vetoryl Cortisol measurements than using ACTH stimulation tests.
Further work is still on-going in Glasgow, Zurich, Utrecht and Bologna Universities.
Recent data suggest Pre-Vetoryl Cortisol to be superior to the traditional ACTH Stimulation Test for the monitoring of dogs treated with Vetoryl (2017 ALIVE Statement*)
• Pre-Vetoryl Cortisol monitoring is better than ACTH Stimulation Tests done 3 hours after Vetoryl dosing because it is a more reliable predictor of clinical signs
• Pre-Vetoryl Cortisol monitoring is also more repeatable (giving more consistent results), less expensive and easier to perform
• However, it is not fool-proof and clinical judgement still needs to be exercised
Owners should be encouraged to keep good records at home. Direct your clients to the Vetoryl owner website. Here they will be able to keep detailed logs and email them to you directly. However, printed log books can also be ordered by your practice free of charge if the owner is not able to use the online version for any reason.
Initial assessment of patient suitability for this approach should be considered using the coloured boxes below.
Owner’s observations of the dogs well-being should not be overlooked and should form the basis of defining how well a dog is controlled.
The Pre-Vetoryl Cortisol correlates better with clinical control, is more repeatable, less expensive, and easier to perform than ACTH stimulation tests and therefore a more effective monitoring method.
Can I use Pre-Vetoryl Cortisol monitoring in dogs being treated with Vetoryl twice daily?
Yes. All the results so far suggest that Pre-Vetoryl Cortisol monitoring is suitable for dogs treated twice daily. Indeed given that the duration of action of Vetoryl is under 12 hours it is theoretically possible that the performance of Pre-Vetoryl Cortisol monitoring would be better in dogs treated twice daily than those treated once daily.
How do I use PVC in a patient receiving Vetoryl twice daily?
PVC can either be collected prior to the morning or the evening dose - dependent on what best suits the owner and the practice.
If monitoring prior to the morning dose:
The previous evening’s dose should be administered as normal. The PVC appointment should then be booked at the time of, or up to 2 hours after, the dog’s morning dose time. I.e. if the dog is normally dosed at 8 AM the appointment can be booked between 8 AM and 10 AM, but the morning dose of Vetoryl should be delayed until the PVC blood sample is obtained. Once the blood sample has been collected the dog can be fed it’s morning meal and Vetoryl administered.
If monitoring prior to the evening dose:
The patient’s morning dose should be administered as normal. The PVC appointment should then be booked at the time of, or up to 2 hours after, the dog’s evening dose time. I.e. if the dog is normally dosed at 5 PM the appointment can be booked between 5 PM and 7 PM, but the evening dose of Vetoryl should be delayed until the PVC blood sample is obtained. Once the blood sample has been collected the dog can be fed it’s evening meal and Vetoryl administered.
Can I use Pre-Vetoryl Cortisol monitoring in dog with diabetes and hyperadrenocorticism?
Yes. Although the evidence is perhaps a little weaker because fewer dogs have been monitored like this, all the results so far suggest that Pre-Vetoryl Cortisol monitoring is suitable for dogs with diabetes and hyperadrenocorticism.
Can I use Pre-Vetoryl Cortisol monitoring in dogs with adrenal dependent hyperadrenocorticism?
Yes. Although the evidence is perhaps a little weaker because fewer dogs have been monitored like this, all the results so far suggest that Pre-Vetoryl Cortisol monitoring is suitable for dogs with adrenal tumours.
Given that there is so much emphasis placed on using the control of the clinical signs to monitor Vetoryl, why bother with Pre-Vetoryl Cortisol testing?
This sounds like a good idea but there is no way of detecting too little cortisol in an otherwise well dog until it becomes unwell - and hypocortisolism can be dangerous. Another useful feature of Pre-Vetoryl Cortisol measurements is that, in the dog with clinical signs of hyperadrenocorticism, the measurement may aid dose adjustment. In addition, owners may not be entirely reliable and veterinarians may not be overly familiar with this case of hyperadrenocorticism or the condition in general.
Are owners reliable enough?
The majority of owners, especially those committed to treating hyperadrenocorticism, are unlikely to miss signs. It is also possible that by placing more emphasis on their role as the primary monitors of their own dog’s condition, they may be more likely to notice signs sooner. In addition, it is hoped that they may also be more observant of signs of poor control. However some owners are unreliable or do not directly engage with the attending veterinarian. In these circumstances in-clinic assessment and monitoring with Pre-Vetoryl Cortisol should be more frequent if possible.
Direct your clients to the Vetoryl owner website. Here they will be able to keep detailed logs and email them to you directly. However, printed log books can also be ordered by your practice free of charge if the owner is not able to use the online version for any reason.
1) BELL R., NEIGER R., MCGROTTY Y. & RAMSEY I. K. (2006) Study of the effects of once daily doses of Vetoryl on cortisol concentrations and responsiveness to adrenocorticotrophic hormone in hyperadrenocorticoid dogs. Veterinary Record 159: 277-281
2) BURKHARDT W. A., BORETTI F. S., REUSCH C. E. & SIEBER-RUCKSTUHL N. S. (2013) Evaluation of baseline cortisol, endogenous ACTH, and cortisol/ACTH ratio to monitor trilostane treatment in dogs with pituitary-dependent hypercortisolism. Journal of Veterinary Internal Medicine 27: 919-923
3) COOK A. K. & BOND K. G. (2010) Evaluation of the use of baseline cortisol concentration as a monitoring tool for dogs receiving trilostane as a treatment for hyperadrenocorticism. Journal of the American Medical Association 237: 801-805
4) GRIEBSCH C., LEHNER, C., WILLIAMS G. J., FAILING K. & NEIGER R. (2014) Effect of Vetoryl on hormone and serum electrolyte concentrations in dogs with pituitary-dependent hyperadrenocorticism. Journal of Veterinary Internal Medicine 28: 160-165
5) MACFARLANE L., PARKIN T. AND RAMSEY I.K. (2016) Pre-trilostane and 3-hour post-trilostane cortisol to monitor trilostane therapy in dogs. Veterinary Record 179: 597-605
6) MIDENCE J. N., DROBATZ K. J. & HESS, R. S. (2015) Cortisol Concentrations in Well-Regulated Dogs with Hyperadrenocorticism Treated with Vetoryl. Journal of Veterinary Internal Medicine 29: 1529-1533
7) NEIGER, R., RAMSEY I., O'CONNOR J., HURLEY K. J. & MOONEY C. T. (2002) Vetoryl treatment of 78 dogs with pituitary-dependent hyperadrenocorticism. Veterinary Record 150: 799-804
8) RAMSEY I. K. (2010) Trilostane in dogs. Veterinary Clinics of North America: Small Animal Practice 40: 269-283
9) RAMSEY I. K., MACFARLANE L., FRACASSI F., GALAC S. & REUSCH C. (2016) The repeatability of various cortisol measurements in clinically stable dogs with hyperadrenocorticism being treated with Vetoryl (Abstract) European College of Veterinary Internal Medicine Congress, Gotenburg (published in Journal of Veterinary Internal Medicine 17: 737DO - 10.1111/jvim.14600)
10) WEHNER A. GLOECKNER S., SAUTER C., KRUSE D., STOCKHAUS C. & HARTMANN, K. (2013) Association between ACTH stimulation tests, clinical signs, and laboratory parameters in dogs with hyperadrenocorticism treated with Vetoryl. (Abstract) European College of Veterinary Internal Medicine Congress, Liverpool
11) DUNN K. J., HERRTAGE M. E., DUNN J. K. (1995) Use of ACTH stimulation tests to monitor the treatment of canine hyperadrenocorticism Veterinary Record 137(7):161-5
Pre-trilostane and three-hour post-trilostane cortisol to monitor trilostane therapy in dogs. Vet Rec 179: 597-605
Further studies into the use of Pre-Vetoryl Cortisol (perhaps with haptoglobin) are ongoing to develop the optimal monitoring tools for both veterinarians and owners of dogs treated with Vetoryl.
(Agreeing Language In Veterinary Endocrinology - a joint project of the European Society of Veterinary Endocrinology and the Society of Comparative Endocrinology)
Recent data from multiple sources have shown a lack of correlation between ACTH stimulation test results and clinical status of hyperadrenocorticism dogs treated with trilostane.
The ACTH stimulation test has not been shown to accurately indicate trilostane underdosing, overdosing or appropriate dosing.
The ALIVE consensus is therefore that the value of the ACTH stimulation test, as well as the optimal ACTH stimulation test timing and interpretation of results at various times after trilostane administration are not established. Additionally, the basal (post-pill) cortisol does not seem to accurately reflect adrenal reserve.
Recent data suggest pre-pill cortisol just prior to trilostane dosing to be superior to the traditional ACTH stimulation test. Some aspects of this alternative monitoring method, such as the pre-pill timing and number of samples, are still being debated and investigated.
The committee recommends future investigations to focus on developing superior monitoring methods.
For any cortisol measurement to be relied upon, this should be performed by the same laboratory and the laboratory should be conducting regular rigorous quality assurance (e.g. by participating in the ESVE or SCE Laboratory Quality Assurance Scheme). Dogs should also be as calm as possible before sampling.
Regardless of the chosen monitoring method, the ALIVE committee strongly recommends clinicians to pay meticulous attention to the clinical picture of treated patients when making trilostane-dose alteration decisions.