Canine Hyperadrenocorticism: Diagnostic Protocols and Medical Management

Introduction

Canine hyperadrenocorticism (HAC), commonly termed Cushing's syndrome, refers to the clinical and biochemical abnormalities resulting from chronic glucocorticoid excess. The condition is classified as pituitary-dependent (PDH) in approximately 80 to 85 percent of naturally occurring cases, with the remainder arising from functional adrenocortical tumors (AT). A small subset involves iatrogenic HAC due to exogenous corticosteroid administration. Accurate diagnosis and effective medical management are essential to improve quality of life and survival in affected dogs [1, 2, 3].

Pathophysiology

The hypothalamic-pituitary-adrenal (HPA) axis is governed by corticotropin-releasing hormone (CRH) from the hypothalamus, which stimulates pituitary secretion of adrenocorticotropic hormone (ACTH). ACTH then drives cortisol synthesis and release from the zona fasciculata and zona reticularis of the adrenal cortex. In PDH, a microadenoma or macroadenoma of the pars distalis produces excessive ACTH autonomously, leading to bilateral adrenal hyperplasia and sustained hypercortisolemia. Functional adrenocortical tumors secrete cortisol independent of ACTH feedback, suppressing endogenous ACTH via negative inhibition. Chronic hypercortisolemia induces catabolic effects on protein, carbohydrate, and lipid metabolism, resulting in the classic clinical phenotype.

Clinical Presentation

Typical clinical signs include polydipsia, polyuria, polyphagia, panting, abdominal distention (pot-bellied appearance), hepatomegaly, muscle wasting, truncal alopecia, comedones, pyoderma, and calcinosis cutis. Calcinosis cutis, characterized by dystrophic mineralization of the dermal collagen, can be a painful and debilitating complication. A recent case series described the use of multiwavelength locked system laser therapy for calcinosis cutis in three dogs, suggesting a non-invasive management option [4]. Concurrent conditions such as hypertension, diabetes mellitus, pancreatitis (see Canine Pancreatitis for evidence-based dietary management), and thromboembolism are frequently observed and must be considered in the overall treatment plan.

Diagnostic Protocols

A stepwise diagnostic approach is recommended, comprising initial screening tests to confirm hypercortisolemia followed by discrimination tests to differentiate PDH from AT. The choice of tests depends on clinical suspicion, availability, and patient stability.

Screening Tests

The three most common screening tests are the urine cortisol-to-creatinine ratio (UCCR), the ACTH stimulation test, and the low-dose dexamethasone suppression test (LDDS). Each has distinct performance characteristics.

Table 1: Comparison of Screening Tests for Canine Hyperadrenocorticism

The UCCR is best used as a rule-out test when clinical signs are equivocal. A normal UCCR from two consecutive morning urine samples effectively excludes HAC.

The ACTH stimulation test has been extensively evaluated [5, 6]. Administration of synthetic ACTH (cosyntropin, 5 mcg/kg intravenously) results in measurable increments in serum cortisol. Johnson et al. (2017) demonstrated that perivascular injection should be avoided as it yields lower post-ACTH cortisol concentrations compared to intravenous administration [5]. The test is also employed for monitoring trilostane and mitotane therapy.

The LDDS protocol involves baseline cortisol measurement, followed by 0.01 mg/kg dexamethasone intravenously, with subsequent cortisol measurements at 4 and 8 hours [2, 7]. Suppression of cortisol below a predefined threshold (commonly <1.4 to <1.5 mcg/dL at 8 hours) is considered negative for HAC. Non-suppression indicates HAC, but does not differentiate PDH from AT. Hoffrogge et al. (2020) reported that dental restoration under general anesthesia can transiently alter LDDS results, potentially leading to false-positive outcomes; therefore, testing should be deferred for at least two weeks after such procedures [8].

Discrimination Tests

Once HAC is confirmed, identifying the underlying etiology guides therapy.

Endogenous ACTH concentration: Measurement of endogenous ACTH in plasma is the preferred discrimination test. A suppressed ACTH (<5 pg/mL) strongly suggests an adrenocortical tumor. Elevated ACTH (>20-30 pg/mL) is consistent with PDH. Intermediate values require additional testing.

High-dose dexamethasone suppression test (HDDST): A modified protocol using 0.1 mg/kg dexamethasone intravenously with cortisol measured at 0 and 8 hours. Suppression of serum cortisol by >50% from baseline supports PDH. However, overlap exists, and this test is less commonly employed where ACTH assays are available.

Imaging: Abdominal ultrasonography can identify unilateral adrenal enlargement (suggesting AT) versus bilateral symmetrical hyperplasia (suggesting PDH). Computed tomography (CT) and magnetic resonance imaging (MRI) of the pituitary fossa are used to detect pituitary masses [9, 10, 11, 12]. Dynamic CT of the pituitary gland has been described as a diagnostic tool [12].

Novel approaches: Salivary cortisol measurement has been investigated as a non-invasive alternative. Meunier et al. (2025) demonstrated the feasibility of in-hospital and at-home salivary sampling in healthy dogs and those receiving trilostane therapy for HAC [13]. This method may reduce stress artifacts associated with venipuncture.

Primary care diagnosis: Carvalho et al. (2025) surveyed diagnostic practices among European primary care veterinarians and found considerable variability in the use of screening tests, with ACTH stimulation and LDDS being the most frequently employed [1].

The following Mermaid diagram summarizes the diagnostic algorithm.

flowchart TD
    A["Clinical suspicion: PU/PD, pot-bellied, alopecia"], > B{"Screening test (UCCR, ACTH stim, or LDDS)"}
    B, >|Normal| C["HAC unlikely; consider other causes"]
    B, >|Abnormal| D["Confirms hypercortisolemia"]
    D, > E{"Discriminate PDH vs AT"}
    E, > F["Endogenous ACTH"]
    E, > G["HDDST"]
    E, > H["Imaging (US, CT, MRI)"]
    F, >|Suppressed| I["Adrenal tumor likely"]
    F, >|Elevated| J["Pituitary-dependent likely"]
    I, > K["Surgical adrenalectomy or medical therapy"]
    J, > L["Medical therapy (trilostane, mitotane) or radiotherapy"]

Medical Management

Trilostane

Trilostane is a competitive inhibitor of 3-beta-hydroxysteroid dehydrogenase, blocking the conversion of pregnenolone to progesterone and thereby reducing cortisol synthesis. It is currently the most widely used medical therapy for PDH.

Dosing protocols: Initial dosing typically ranges from 1 to 3 mg/kg once daily. However, twice-daily administration may improve clinical control and reduce adverse effects. Arenas et al. (2013) compared once-daily versus twice-daily trilostane in dogs with PDH and found that twice-daily dosing resulted in more consistent cortisol suppression and fewer episodes of hypoadrenocorticism [14]. In small dogs (<5 kg), low-dose trilostane (as low as 0.5-1 mg/kg twice daily) has been shown to be effective [15].

Monitoring: The ACTH stimulation test is recommended 4-6 hours after trilostane administration, with a target post-ACTH cortisol of approximately 1.5 to 5.5 mcg/dL (or 40-150 nmol/L, depending on laboratory). Burkhardt et al. (2013) evaluated baseline cortisol, endogenous ACTH, and the cortisol/ACTH ratio as monitoring tools; they concluded that none of these singly predicted adequate control as reliably as the ACTH stimulation test [16].

Survival outcomes: García San José et al. (2022) reported favorable survival times in dogs with PDH treated twice daily with low doses of trilostane; median survival exceeded 900 days [17]. For adrenal-dependent HAC, Arenas et al. (2014) compared mitotane and twice-daily trilostane and found no significant difference in survival between treatments, although trilostane was associated with fewer adverse effects [18].

Mitotane (o,p'-DDD)

Mitotane is an adrenocorticolytic agent that causes progressive necrosis of the zonae fasciculata and reticularis while sparing the zona glomerulosa (non-selective adrenocorticolysis). It is used primarily for PDH but also for AT when surgery is not feasible.

Protocol: Induction is typically initiated at 50 mg/kg/day divided into two doses, with dose adjustments based on clinical response and ACTH stimulation results. Maintenance dosing is then reduced (often 50 mg/kg weekly). Den Hertog et al. (1999) reported outcomes in 129 dogs with PDH treated with mitotane: remission was achieved in 85% of cases, but hypoadrenocorticism developed in approximately 10% [19].

Comparison with trilostane: Reine (2012) reviewed the medical management of PDH and concluded that both trilostane and mitotane are effective, but trilostane offers a lower risk of irreversible hypoadrenocorticism and does not require monitoring of electrolyte disturbances as stringently [20]. Clemente et al. (2007) directly compared non-selective adrenocorticolysis with mitotane versus trilostane and found similar efficacy but a significantly higher incidence of adverse gastrointestinal effects with mitotane [21].

Radiotherapy

For dogs with large pituitary macroadenomas causing neurological signs (e.g., stupor, blindness, ataxia), radiotherapy is a valuable option. Gieger et al. (2024) compared stereotactic radiation therapy (SRT) to fractionated radiation therapy (FRT) in 44 dogs with pituitary masses. Both modalities improved neurological signs, but SRT required fewer treatments and was associated with less toxicity [9]. Rapastella et al. (2023) investigated the effect of PDH on survival after radiotherapy; dogs with PDH had a shorter progression-free interval compared to those without overt HAC, likely due to ongoing cortisol excess [10]. Hansen et al. (2019) reported long-term survival with SRT for imaging-diagnosed pituitary tumors, with median survival exceeding 700 days [11]. Théon and Feldman (1998) earlier demonstrated that megavoltage irradiation of pituitary macrotumors alleviates neurological deficits in most patients [22].

Other Agents

Aminoglutethimide is an adrenal steroidogenesis inhibitor that blocks the conversion of cholesterol to pregnenolone. Pérez et al. (2002) reported its use in PDH, but its efficacy was inferior to trilostane and mitotane, and it is no longer recommended as a first-line agent [23].

L-Deprenyl (selegiline) was postulated to reduce pituitary ACTH secretion through dopaminergic modulation. However, Reusch et al. (1999) found it ineffective in controlling clinical signs of PDH, and it is not considered a valid therapeutic option [24].

Management of Adrenal Tumors

When a functional adrenocortical tumor is identified, surgical adrenalectomy is the treatment of choice, provided there is no evidence of vascular invasion or metastasis. Preoperative stabilization with trilostane or mitotane may be beneficial. In inoperable cases, mitotane or trilostane can be used palliatively. Rijnberk et al. (1992) described corticoid production by hyperfunctioning adrenocortical tumors during mitotane treatment, noting that cortisol reduction is achievable [25].

Monitoring and Adverse Effects

Regular reassessment of clinical signs and performance of ACTH stimulation tests are essential. Dogs receiving trilostane should be monitored for signs of hypoadrenocorticism (lethargy, vomiting, diarrhea, collapse). Electrolyte imbalances are less common with trilostane than with mitotane but can occur. Dose adjustments should be made based on post-ACTH cortisol concentrations.

Conclusion

The diagnosis and management of canine hyperadrenocorticism require a systematic approach integrating clinical evaluation, endocrine testing, and imaging. Trilostane is currently the preferred medical therapy for PDH, while mitotane remains a viable alternative, particularly for adrenal tumors. Radiotherapy plays a critical role in managing pituitary macroadenomas with neurological sequelae. Emerging techniques such as salivary sampling may improve diagnostic accuracy and owner compliance. Ongoing research continues to refine therapeutic protocols and enhance long-term outcomes [4, 13, 17, 18, 14].

References

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[22] Théon AP, Feldman EC. Megavoltage irradiation of pituitary macrotumors in dogs with neurologic signs. J Am Vet Med Assoc. 1998. URL: https://pubmed.ncbi.nlm.nih.gov/9676592/

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