Canine hyperadrenocorticism (HAC) is a common endocrine disease that can be successfully managed with trilostane. Trilostane therapy for canine HAC should only be initiated in patients with compatible clinical signs and not solely based on HAC-associated laboratory abnormalities.
Following are the top 5 indicators to monitor in canine HAC patients receiving trilostane therapy according to the author.
1. Resolution of Clinical Signs
In addition to the classic signs of canine HAC (ie, polyuria, polydipsia, polyphagia, panting, alopecia, pot-bellied appearance), other less obvious clinical signs that detract from quality of life may include lethargy, muscle wasting, and weakness. At diagnosis, all clinical signs affecting the patient should be identified and their severity quantified. This can be achieved via a standardized questionnaire with numeric or other scale-based measures (eg, mild, moderate, severe) that is completed by the pet owner and confirmed by the clinician after evaluation. After initiation of trilostane treatment, the same questionnaire should be completed at each recheck to gauge resolution of clinical signs and identify any signs of potential adrenal oversuppression.
Owners often notice an improvement in polyuria and polydipsia and increased activity or energy after 1 to 2 weeks of therapy, although complete resolution of signs may require ≥1 month. Resolution of panting and polyphagia can be variable and may never be completely achieved. Owners should be informed that dermatologic signs may take 3 to 6 months to resolve.
Control of clinical signs should be assessed and the dosage adjusted if indicated.
2. Signs of Oversuppression or Addisonian Crisis
Transient oversuppression of the adrenal axis involves temporary excessive steroidogenic enzyme inhibition, in which, decreasing the trilostane dose or ceasing trilostane therapy typically results in adrenal axis recovery. Although generally transient, cortisol production may be suppressed long-term (eg, weeks to years1) in some patients; thus, ensuring recovery of the adrenal axis (eg, resolution of clinical signs, rebound of resting cortisol and/or adrenocorticotropic hormone [ACTH] stimulation levels) prior to resuming trilostane therapy is critical. Complete adrenal necrosis is an infrequent but potentially life-threatening complication of trilostane therapy that may result in acute hypoadrenocortical crisis (ie, Addisonian crisis), thus requiring emergency stabilization with prolonged or permanent glucocorticoid and mineralocorticoid supplementation.
Owners should be counseled about signs of adrenal axis oversuppression and/or onset of Addisonian crisis; however, some dogs receiving trilostane therapy may display transient, mild, self-limiting clinical signs (eg, lethargy, decreased appetite2) at the onset of therapy. Distinguishing transient oversuppression, Addisonian crisis, and/or transient, mild, and self-limiting drug effects at the onset of therapy may be difficult. Owners should be advised to monitor for GI signs (eg, vomiting, diarrhea, anorexia), lethargy, collapse, and any other nonspecific clinical signs. If signs are observed, trilostane therapy should be stopped and dexamethasone (0.15 mg/kg PO) administered; dexamethasone should be dispensed prior to initiation of trilostane therapy. Owners should then seek immediate veterinary care, at which time physical examination, a minimum database (eg, CBC, serum chemistry profile, urinalysis), cortisol testing (ie, resting cortisol/ACTH stimulation test), and supportive care are indicated.
The estimated cumulative incidence of hypoadrenocorticism in a study of trilostane-treated dogs was 15% by 2 years and 26% by 4.3 years.3 Of the dogs that developed hypoadrenocorticism, 74% were transient in nature and 26% were permanent.
3. Cortisol Levels
Cortisol testing is necessary during trilostane therapy to determine whether therapy can be safely continued or if a dose increase can be safely done, depending on the assessment of the patient. Cortisol testing should not be used to determine whether the patient is clinically well-controlled; rather, clinical signs should be assessed. Cortisol testing is recommended 10 to 14 days after initiation of trilostane therapy, after any dose alteration, and 1 month, 3 months, and every 3 to 6 months after a dose has been established.
ACTH stimulation testing is recommended 4 to 6 hours after trilostane administration. Owners should be advised to administer the morning trilostane dose with food each day, including the day of the recheck examination. The author, based on anecdotal experience, considers a post-ACTH stimulation level >1.6 µg/dL to indicate safe continuation of therapy in a clinically well-controlled dog showing no signs of illness, whereas the package insert for trilostane recommends a threshold of ≥1.45 µg/dL.4 In clinically well-controlled patients that show no signs of illness but for which ACTH stimulation testing shows oversuppression of the adrenal axis (post-ACTH cortisol level <1.6 µg/dL), trilostane may be stopped, the dosage decreased, or an ACTH stimulation test performed later in the administration interval (often ≈9 hours postadministration). In some patients, cortisol levels may increase later in the administration interval and demonstrate recovery of the adrenal axis, indicating a suitable dosage.5 If signs are undercontrolled and persistent and if an ACTH stimulation test excludes oversuppression, the dose or frequency (eg, daily dose divided into 2 doses) may be increased. In sick patients with low cortisol levels following ACTH stimulation testing, trilostane therapy should be stopped and supportive care administered as needed.
An alternative to ACTH stimulation testing is measurement of cortisol at the end of the administration interval, just prior to trilostane administration (ie, “prepill” cortisol; see Analyzing Prepill Cortisol Levels). ACTH stimulation testing is still recommended in sick dogs that show signs of oversuppression, and prepill cortisol is most useful in clinically well-controlled dogs in which oversuppression of cortisol is not suspected.
Analyzing Prepill Cortisol Levels
In clinically well dogs in which clinical signs are well controlled and prepill cortisol levels are as follows:
<2 µg/dL: An ACTH stimulation test should be performed (or the dose decreased).
>2 µg/dL: It is likely safe to continue the current dose.
In clinically well dogs with persistent clinical signs of HAC and prepill cortisol levels are as follows:
<2 µg/dL: History and clinical signs should be re-evaluated and an ACTH stimulation test should be performed.
>2 and <5 µg/dL: An ACTH stimulation test can be considered before increasing the dose, or doses being given once daily can be split and given twice daily; increasing the dose can be considered if cortisol levels are >3 μg/dL.
>5 µg/dL: It is likely safe to increase or split the dose.
4. Serum Electrolytes
Monitoring serum electrolytes is recommended during therapy. Trilostane inhibits 3β-hydroxysteroid dehydrogenase, which inhibits the production of cortisol and, to a lesser extent, mineralocorticoids (eg, aldosterone). The electrolyte levels (specifically sodium and potassium) of patients receiving trilostane therapy often remain within the normal reference range; however, sodium may decrease slightly, and potassium may increase slightly as compared with baseline values at diagnosis. Electrolytes should be assessed at recheck examinations when cortisol testing is being conducted and especially after every dose alteration. Monitoring of electrolytes is particularly crucial when trilostane is concurrently administered with medications that interfere with aldosterone production (eg, potassium-sparing diuretics, ACE inhibitors, angiotensin-receptor blockers [eg, telmisartan]) because the additive inhibitory effects on aldosterone can increase the risk for electrolyte derangements.
5. Signs Consistent with Macroadenoma Syndrome
Macroadenoma syndrome develops in dogs with pituitary-dependent HAC when the pituitary tumor begins to grow and applies pressure to surrounding structures in the brain. Neurologic signs associated with macroadenoma syndrome occur in ≈10% to 30% of dogs with pituitary-dependent HAC, with most cases showing signs after initiation of therapy.6 The most common signs are behavior changes (eg, dullness, restlessness, loss of interest in normal activities, disorientation, pacing) and decreased appetite. Initial or mild signs may be dismissed as changes associated with normal aging but may be suggestive of pituitary macroadenoma. Advanced imaging is necessary for antemortem diagnosis of pituitary macroadenoma, and treatment most commonly involves radiation therapy, although some case reports have described treatment with hypophysectomy.1,6,7
Conclusion
Trilostane can be an efficacious treatment option for canine hyperadrenocorticism, but appropriate monitoring during therapy is essential for success.