A retrospective cohort study of 122 dogs treated for hypercortisolism: low-dose dexamethasone suppression test sensitivity and comparative outcomes in response to mitotane or trilostane

[Estudo de coorte retrospectivo de 122 cães que receberam tratamento para hipercortisolismo: sensibilidade do teste de supressão por baixa dose de dexametasona e comparação entre os desfechos em relação ao mitotano ou ao trilostano]

ABSTRACT

Spontaneous hypercortisolism (HC), a prevalent endocrinopathy among elderly dogs, is mainly confirmed by the low dexamethasone dose suppression test (LDDST). However, its diagnostic sensitivity in Brazil is anecdotally reported low compared with published literature. Medical treatment with mitotane was the rule over decades in Brazil but has been progressively substituted by trilostane, an argued safer drug. This work evaluated the LDDST sensitivity and medical treatment efficacy of trilostane and mitotane in dogs treated for HC in Southern Brazil. The retrospective cohort study included 122 dogs treated with trilostane (58.2%) or mitotane (41.8%). Pituitary-dependent HC cases were overrepresented (81.96%). Treatment outcomes (P=0.61) and survival (P=0.16) were similar in response to mitotane or trilostane, with good clinical control achieved in 72.5% and 62.4% of dogs respectively. The LDDST sensitivity in this population was considered lower (77.8%) than reported in the literature with a cutoff of 1.4 µg/dL for 8-hour post-dexamethasone cortisol; however, a suggested 0.8µg/dL cutoff significantly (P=0.01) increased the test sensitivity to 85.2%. Mitotane should still be considered as a medical treatment option for canine HC. Individually reducing the LDDST cutoff in patients with well-documented clinical Cushing´s syndrome diagnosis could be worthwhile.

Keywords:
Cushing´s syndrome; hyperadrenocorticism; diagnostic test; false-negative; survival

RESUMO

Hipercortisolismo espontâneo (HC), uma endocrinopatia prevalente entre cães idosos, é confirmado pelo teste de supressão de dose baixa de dexametasona (TSBDD). No entanto, relatos sugerem baixa sensibilidade do teste no Brasil comparado à literatura. Tratamento médico com mitotano, regra durante décadas no Brasil, foi progressivamente substituído pelo trilostano, considerado mais seguro. Objetivou-se avaliar a sensibilidade do TSBDD e comparar eficácia do tratamento médico com trilostano ou mitotano em cães tratados para HC no sul do Brasil. O estudo de coorte retrospectivo incluiu 122 cães tratados com trilostano (58,2%) ou mitotano (41,8%). Casos de HC-pituitário dependentes foram mais frequentes (81,96%). Resposta terapêutica (P=0,61) e sobrevivência (P=0,16) foram semelhantes em resposta ao mitotano ou trilostano, com bom controle clínico em 72,5% e 62,4% dos cães, respectivamente. A sensibilidade do TSBDD foi inferior (77,8%) à relatada na literatura com ponto de corte de 1,4µg/dL para cortisol oito horas pós-dexametasona; no entanto, a adoção de um ponto de corte de 0,8µg/dL aumentou significativamente (P = 0,01) a sensibilidade para 85,2%. Mitotano ainda deve ser considerado como uma opção de tratamento médico para HC canino. A redução individual do ponto de corte do TSBDD em pacientes com diagnóstico clínico de HC bem documentado pode ser útil.

Palavras-chave:
síndrome de Cushing; hiperadrenocorticismo; testes diagnósticos; falso-negativo; sobrevida

INTRODUCTION

Spontaneous hypercortisolism (HC), also known as Cushing´s syndrome (previously named hyperadrenocorticism) is the most prevalent endocrinopathy in dogs (Pöppl et al., 2016), which might compromise animals’ quality of life if not diagnosed and treated properly (Schofield et al., 2019a). The most common complaints reported by owners are polyuria, polydipsia, polyphagia, swollen abdomen, bilateral alopecia, muscle weakness, and lethargy (Bishop and Lathan, 2015; Bennaim et al., 2019a; Martins et al., 2019). Some breeds are more predisposed to the disease, as well as certain age groups (Behrend, 2015; Carotenuto et al., 2015). Pituitary-dependent HC (PDH) is the most common presentation in spontaneous cases, representing 80-85% of cases, followed by the adrenal-dependent HC (ADH) variant, representing 15-20% of the cases (Behrend et al., 2013; Bennaim et al., 2019a). In both cases, the hypothalamic-pituitary-adrenal axis is upregulated and irresponsive to negative feedback due to the pituitary secretion of ACTH by a pituitary adenoma, or ACTH-independent cortisol secretion by an adrenal tumor (Behrend, 2015). Sub-diagnostic Cushing´s syndrome (SDCS) is a clinical syndrome in which a dog appears to have HC. Yet, the results of dynamic testing of pituitary-adrenal function fall into “appropriate” reference intervals (Agreeing…, 2019). The SDCS has been previously referred to as atypical or occult hyperadrenocorticism in veterinary literature (Behrend and Kennis, 2010; Frank et al., 2015).

A detailed clinical examination and, a minimal database (complete blood count, serum biochemistry, and urine analysis) and imaging, are crucial to evaluate these patients further and define better endocrine tests to achieve an accurate diagnosis of the disease, and choose a suitable treatment (Behrend et al., 2013; Bennaim et al., 2019a). The low dexamethasone dose suppression test (LDDST) has been considered the gold standard dynamic endocrine test to confirm HC diagnosis since it allows the decreased response demonstration of the hypothalamic-pituitary-adrenal axis to negative feedback by glucocorticoids (Kooistra and Galac, 2010; Behrend et al., 2013; Behrend, 2015; Bennaim et al., 2019b). Despite being described as a high-sensitivity test, with an 85 to 100% reported sensitivity in different studies (Behrend et al., 2013; Bennaim et al., 2019b), clinicians often face false-negative results in Brazil. Thus, the ACTH stimulation test (ACTHST) has been used to explore HC diagnosis further, despite being considered a test with lower sensitivity, it shows higher specificity when compared to the LDDST (Peterson, 2007; Bishop and Lathan, 2015; Bugbee et al., 2023).

Over the years, mitotane, an adrenocorticolityc drug, was considered the gold standard for the medical treatment of both PDH and ADH (Braddock, 2003; Galac, 2005; Behrend, 2015; Sanders et al., 2018). However, in the past two decades, the competitive steroidogenic inhibitor trilostane has been available worldwide, and its safety and efficacy documented for both PDH (Barker et al., 2005; Reine, 2007; Ramsey, 2010; Sanders et al., 2018; Schofield et al., 2020a, Golinelli et al., 2020) and ADH (Arenas et al., 2014) have turned trilostane the first choice for HC treatment in dogs around the world (Bugbee et al., 2023).

This study aimed to describe a dog´s population medically treated for HC with mitotane or trilostane, assess the sensitivity of two cut-off values for 8-hour post-dexamethasone (8hPD) serum cortisol during the LDDST and compare treatment efficacy and survival in response to mitotane or trilostane.

MATERIALS AND METHODS

Retrospective cohort study. Data from patients with HC diagnosis were searched in the Veterinary Endocrinology and Metabolism Service (SEMV) database of the Veterinary Clinics Hospital from the Federal University of Rio Grande do Sul (HCV-UFRGS) and from a private endocrinology service (PetEndocrine®) in Porto Alegre, RS, Brazil.

To be eligible for inclusion, cases should meet the following criteria: 1) registered HC diagnosis, 2) dynamic endocrine tests at diagnosis available, 3) to have been treated with mitotane or trilostane, 4) follow-up information regarding treatment, and 5) proper clinical data registration. Concomitant diabetes mellitus diagnosis was an exclusion criterion.

Clinical records were reviewed in detail and relevant data were inserted into Excel spreadsheets for exploratory data analysis and descriptive statistics. Based on the ultrasonographic appearance of the adrenal glands, pituitary imaging when available, and LDDST profile, patients were classified as HPD, HAD, or sub-diagnosed Cushing´s syndrome (SDCS) if they were treated with trilostane or mitotane despite negative results in cortisol measurements during the LDDST and ACTHST.

Owners of the selected dogs were contacted by phone to verify patients´ survival as well as their opinion about the degree of control achieved with the treatment, being assigned a score from one to three, being 1) poor control, 2) regular control, and 3) satisfactory control, based on the clinical improvement presented by the patients considering the dogs' clinical signs, such as polyuria, polydipsia, polyphagia, disposition to activities, coat aspect and abdomen size response to treatment, according to the owners' reports.

The LDDST results in HC-treated dogs were used to assess the test sensibility with the traditional 8hPD serum cortisol cut-off of 1.4 µg/dL and to estimate the sensibility of an arbitrarily defined lower cut-off of 0.8 µg/dL. Fisher´s exact test was applied to evaluate the response grade to each treatment and sensibility against each cut-off. For survival analysis, data were expressed in months between diagnosis and death, or diagnosis to the phone call date for the live patients (censored dogs). The data were analyzed in the program Prisma GraphPad 6.0 and P-values < 0.05 were considered statistically significant.

RESULTS

One hundred twenty-two dogs diagnosed with HC between 2007 and 2016 met the inclusion criteria. The mean age at diagnosis was 10.18 ± 2.56 years and most patients were female, 80/122 (65.5%). Neutered status was documented in 68% of the females and 78% of the males. Fig. 1 presents the distribution histogram of the patient´s age at testing.

Figure 1
Histogram of the age distribution of animals in years at diagnosis.

Regarding breed distribution, 35 (29.5%) were Poodles, 21 (17.21%) were Dachshunds, 14 (11.47%) were mixed breed dogs, and eight (6.5%) were Yorkshire Terriers. The others belonged to breeds such as Pincher and Schnauzer (5.74% each breed), Lhasa Apso and Shih Tzu (4.92% each breed), Bichon Frisé (4.1%), Labrador Retriever (3.27%), Beagle and Maltese (2.46% each breed), Cocker Spaniel (1.64%), and French Bulldog, Scottish Terrier, Dogo Argentino and American Staffordshire Terrier (0.82% each). These breeds were mostly classified as small breeds (body weight < 10kg) in 60.7%, while medium breeds (body weight between 10-20kg) were documented in 27%, and large breeds (body weight >20kg) in 12.3%.

Of the 122 dogs in the study, 81 (66.4%) had been submitted to the LDDST for HC diagnosis. Sixty-three out of 81 were positive for HC applying the standard 1.4 µg/dL 8hPD serum cortisol cut-off value for an HC-positive diagnosis, representing a 77.8% sensitivity. Results were compared with a smaller arbitrary suggested cut-off of 0.8µg/dL. Of the 81 HC-treated dogs exposed to the LDSTT for diagnosis, 68 had an 8-hour post-dexamethasone > 0.8 resulting in improved test sensitivity (85.2%). Fig. 2 represents the relationship between true positives and false negatives against each cut-point for serum cortisol 8hPD. Of the 18 dogs with HC that tested negative in the LDDST, 15 (83.3%) were further submitted to the ACTHST to confirm the diagnosis. The ACTHST was performed as the primary dynamic test in 41 (33.6%) of the dogs.

Figure 2
Graphic representation of true positives and false negatives according to the traditional 1.4 µg/dL 8-hour post-dexamethasone cut-off or a suggested alternative cut-off of 0.8µg/dL. Adoption of the lower cut-off significantly increased the low-dose dexamethasone suppression test sensibility from 77.8% to 85.2% (P = 0.0132).

Pituitary-dependent HC was diagnosed in 101/122 (81.96%) dogs, 12/122 (9.83%) as ADH due to functional adrenocortical neoplasia, and 6/122 (5.73%) were diagnosed as SDSC. Three dogs (2.46%) were diagnosed with concomitant PDH and adrenal neoplasia. Fig. 3 represents the HC subtypes identified in this study. Gender distribution was equal between males and females with SDCS even as neutered status, which was documented in 2/3 in both genders.

Figure 3
Identified subtypes of hypercortisolism in a population of 122 dogs treated with mitotane or trilostane.

Trilostane was considered the first medical treatment choice for 71 (58.2%) patients; however, 3/71 (4.22%) were changed for mitotane therapy over time. According to the HC subtype, trilostane was the first drug choice in 63/101 (62.4%) of the dogs with PDH, 4/12 (33.3%) of the dogs with ADH, 3/6 (50%) of the dogs with SDCS, and 1/3 (33.3%) of the dogs with concomitant PDH and ADH.

In contrast, mitotane was the first choice for 51 patients (41.8%) being substituted for trilostane in the future in 4/51 (7.84%). According to the HC subtype, mitotane was the first drug choice in 38/101 (37.6%) of the dogs with PDH, 8/12 (66.7%) of the dogs with ADH, 3/6 (50%) of the dogs with SDCS, and 2/3 (66.7%) of the dogs with concomitant PDH and adrenal neoplasia.

Of the dogs that took trilostane, 47/71 (66.2%) had good control throughout the disease, 15/71 (21.1%) had moderate control, and 9/71 (12.6%) had poor control, according to the owners. Of the dogs that took Mitotane, 37/51 (72.5%) had good control throughout the disease, 8/51 (15.7%) had moderate control, and 6/51 (11.7%) had poor control. Fig. 4 shows the percentages of the degree of control presented with the use of each of the treatments over time. There was no statistical difference between treatments and outcomes (P = 0.6137).

Figure 4
Distribution of hypercortisolism degree of control in the opinion of the dog owners according to the treatment adopted (mitotane or trilostane) over time.

Of the seven dogs that switched treatment throughout therapy, there was only one ADH case (changed trilostane for mitotane) and the others were PDH cases switching therapy due to poor control and financial issues on the original prescribed therapy. Tab. 1 summarizes data regarding the drug choice and reported outcomes in the population studied.

The median survival of patients treated with mitotane was 36 months, five months more than those treated with trilostane (31 months). However, there was no significant difference (P = 0.16) between survival in both groups due to the therapeutic option chosen. Fig. 5 shows the Kaplan-Maier plot of patients’ survival comparing mitotane vs. trilostane treatment.

Table 1
Medical treatment was applied to a population of 122 dogs with hypercortisolism according to disease classification and reported outcomes

	Trilostane (n=71)	Mitotane (n=51)	Shifted	IHA
Disease Classification
PDH (n = 101)	63 (62.4%)	38 (37.6%)	6 (5.9%)	6 (5.9%)
ADH (n = 12)	4 (33.3%)	8 (66.6%)	1 (8.3%)	1 (8.3%)
SDCS (n = 6)	3 (50%)	3 (50%)	-	-
PDH + AN (n=3)	1 (33.3%)	2 (66.6%)	-	-
Disease Control
Good	47 (66.2%)	37 (72.5%)	-	7 (8.3%)
Moderate	15 (21.1%)	8 (15.7%)	-	-
Poor	9 (12.6%)	6 (11.7%)	7 (46.7%)	-
IHA	5 (7.04%)	2 (3.92%)	-	-
Survival (months)	31 (4 - 95)	36 (9 - 90)	NA	NA

• PDH: pituitary-dependent hypercortisolism, ADH: adrenal-dependent hypercortisolism, SDSC: sub-diagnostic Cushing´s syndrome, AN: adrenal neoplasia, IHA: iatrogenic hypoadrenocorticism, NA: not applicable.

Figure 5
Kaplan-Maier plots of patients’ survival according to the hypercortisolism treatment chosen (Mitotane x Trilostane) in a population of 122 dogs.

DISCUSSION

Trilostane or mitotane use was not associated with survival or disease control outcomes in the studied population. This finding agrees with previous studies comparing both therapies for PDH and ADH (Barker et al., 2005; Ramsey, 2010; Arenas et al., 2014; Behrend, 2015) reinforcing treatment options should be properly discussed with dog owners regarding the risks and benefits of each medical treatment (Sanders et al., 2018; Golinelli et al., 2020). Despite trilostane being considered a safer drug compared with mitotane (Ramsey, 2010; Schofield et al., 2020a; Bugbee et al. 2023) many patients can show poor trilostane response, or eventually develop hypoadrenocorticism over time (King and Morton, 2017). In contrast, mitotane can be a very efficient drug due to its adrenocorticolytic activity (Barker et al., 2005); however, without proper prescription care by the veterinarian and owner compliance, this therapy guards an enormous potential for life-threatening complications due to hypoadrenocorticism development (Braddock, 2003; Sanders et al., 2018). With either mitotane or trilostane, many visits and veterinarian follow-ups will be needed to tailor the dose to the patient's needs. Thus, guidance on possible serious side effects with both drugs should be made clear (Behrend, 2015).

Trilostane was found to be 67% to 100% effective in resolving the various clinical signs of HC over 3 to 6 months (Ramsey, 2010). In contrast, mitotane was effective in approximately 80% of HPD cases (Barker et al., 2005). In one study, the median survival time of dogs with ADH treated with mitotane was similar to that of dogs treated with trilostane twice daily despite the latter needing more often reviews compared with dogs treated with mitotane after six months (Arenas et al., 2014). Despite mitotane's potential to prevent adrenal tumor growth, decrease it, or even induce complete necrosis it would be reasonable to expect a longer survival time in mitotane-treated ADH dogs and, logically, mitotane should be a better option for dogs with ADH (Braddock, 2003; Behrend, 2015); however, present evidence supports long-life trilostane treatment for dogs with ADH which cannot be exposed to adrenalectomy (Arenas et al., 2014; Sanders et al., 2018; Bugbee et al., 2023). It is reasonable to conclude that mitotane is at least as safe and effective as trilostane in controlling the clinical signs of most canine cases, as documented in our study.

Untreated HC is usually a progressive disorder with a poor prognosis (Mooney, 2009). Our median survival time from treatment with mitotane or trilostane was nearly three years and 10% of dogs survive up to four years, results similar to those previously published by Barker et al. (2005) comparing trilostane and mitotane efficacy in canine PDH and by Fracassi et al. (2014) in trilostane-treated PDH dogs. Arenas et al. (2014) observed a mean survival time of 15 months in dogs with ADH, treated with trilostane or mitotane. However, several studies documented smaller mean survival rates than those observed in our study in response to trilostane treatment (Schofield et al. 2020a, 2021a) and there is evidence for smaller twice-daily trilostane treatment regimen being associated with better outcomes (Feldman, 2011), increased survival (San José et al. 2022) and reduced risk for hypoadrenocorticism (King and Morton, 2017). However, death probability is greater according to age at diagnosis, as well as pituitary macroadenomas and adrenal carcinomas guard a poorer prognosis compared with pituitary microadenomas and adrenocortical adenomas (Arenas et al., 2014; Fracassi et al., 2014; Behrend, 2015; Schofield et al. 2020a, 2021a; San José et al., 2022). Hyperphosphatemia (Fracassi et al., 2014), calcinosis cutis, low body condition score, and higher platelet count (San José et al., 2022) were previously associated with poorer prognosis.

Despite what could be considered one study’s limitation, clinical response to mitotane or trilostane evaluated utilizing the patient´s history and owner’s opinion was considered the gold standard in a study evaluating different HC trilostane therapy monitoring strategies in dogs (Macfarlane et al., 2016). Ideally, mitotane therapy should be monitored with regular ACTHST assessments (Braddock, 2003; Behrend, 2015), while the better hormone test (i.e. pre-trilostane basal cortisol, 3-hour post-trilostane basal cortisol, and post-ACTH cortisol) is still polemic (Macfarlane et al., 2016; Golinelli et al., 2021). Moreover, time from trilostane administration and ACTHST performance impact results (Midence et al., 2015). Trilostane reaches maximum blood concentrations within 1.5-2 h after administration and concentrations return to baseline levels after 10-18 h. The duration of cortisol suppression is variable, but in most dogs, cortisol concentrations remain suppressed for less than 13 hours (Ramsey, 2010). Those limitations regarding hormone test results to assess treatment efficacy could generate information bias. Notwithstanding, we also recognize that owners’ opinions are not free of bias.

The mean age at diagnosis of the patients in this study is well documented in the literature and almost all dogs with HC are older than 6 years (Behrend et al., 2013; Behrend, 2015, Bennaim et al., 2019a). Dogs with ADH tend to be older (Peterson, 2007; Arenas et al., 2014; Behrend, 2015) as well as dogs with SDCS were older than dogs with PDH in a study (Frank et al., 2015). Notwithstanding, no age differences were observed concerning the origin of the HC in this study, potentially due to the sparse number of patients with ADH and SDCS. There is no clear sex predilection in dogs with PDH, ADH, or SDCS; however, female sex, and neuter status for both males and females seemed overrepresented in different studies (Carotenuto et al., 2019; Bennaim et al., 2019a) as documented in this cohort.

Likewise, HC occurs equally in purebred and mixed-breed dogs (Behrend et al., 2013; Carotenuto et al., 2019; Bennaim et al., 2019a), although numerous breeds are commonly mentioned to be at increased risk including breeds overrepresented in this study such as Poodles and Dachshunds (Behrend, 2015). Most dogs in our study were classified as PDH, 60% small breed dogs, and 27% considered medium breed (10-20kg). These results agree with previous data showing near 75% of the PDH dogs weighed <20 kg while almost 50% of dogs with ADH weighed >20 kg (Behrend et al., 2013; Behrend, 2015). However, a study showed no differences in Cushing´s syndrome clinical signs between heavier (>20kg) and lighter (<20kg) dogs (Bennaim et al., 2019c)

The concomitance of pituitary and adrenal tumors and bilateral adrenal tumors are rare, and represent a diagnostic challenge (Greco et al., 1999). Adrenal tumors may have different origins (cortex vs. medulla). They may or may not cause hormonal disturbances, including upregulated secretion of mineralocorticoids, glucocorticoids, sexual hormones, and catecholamines, as well as adrenal cortex function loss leading to hypoadrenocorticism (van Bokhorst et al., 2023). Given this heterogeneity, and to avoid classification bias, a few cases that attend the criteria for PDH diagnosis in our study were classified only as PDH with adrenal tumors.

The LDDST evaluates the ability of the hypothalamic-pituitary-adrenal cortex axis to respond to glucocorticoid-induced negative feedback and the interpretation of its results may help distinguish HC origin (Behrend et al., 2013). PDH is considered ACTH-dependent, while ADH is an ACTH-independent disease; therefore, cortisol suppression after dexamethasone in a dog with Cushing´s syndrome argues in favor of a pituitary origin (Bennaim et al., 2019a). Isolated adrenal ultrasound evaluation supports proper differentiation between HPD and HAD in 56% of the cases (Melián et al., 2021), and associated LDDST results increase the probability of an accurate differential diagnosis (Agreeing…, 2019). The high-dose dexamethasone suppression test was most used to differentiate the cause of HC in the past, but its accuracy has been questioned, the same for the LDDST (Bennaim et al., 2019b). Endogenous ACTH concentration may discriminate between PDH and ADH and the results can be further supported by pituitary and adrenal imaging techniques (Behrend et al., 2013; Behrend 2015; Melián et al., 2021). The ability to differentiate between pituitary-dependent and adrenal-dependent HAC may have important implications for choosing the most effective treatment; however, as with screening tests, no single differentiation test is 100% accurate (Behrend et al., 2013; Sanders et al., 2018).

The sensitivity and specificity of a given diagnostic test depend on the pretest disease probability in tested individuals. Well-documented Cushing´s syndrome clinical signs, physical exam abnormalities, and compatible abnormalities in complementary exams (CBC, serum biochemistry, urine analysis, and abdominal ultrasound evaluation) are considered the basic indications to perform dynamic adrenal function tests in dogs (Behrend et al., 2013). The patient´s clinical characterization may have a high sensitivity and specificity for HC diagnosis (Schofield et al., 2020c, 2021b). The HC awareness by owners and veterinarians was claimed to cause suspected dogs to be tested earlier in response to more subtle patient presentations and discrete clinical signs. However, hormone measurement technology has evolved, and each laboratory should provide its reference range results instead of adopting literature in their results reports. This may promote higher false-negative results in the LDSST despite its sensitivity varying from 85% to 100% (Behrend et al., 2013; Bennaim et al., 2019b).

The present study observed that a reduction in the 8hPD serum cortisol cutoff was associated with increased test sensitivity from 78% to 85%, a result comparable with the published literature. According to ESVE´s ALIVE Project (ESVE), in an ideal world, a patient should be treated only after the HC confirmation by a positive result in a dynamic test. Therefore, patients with a well-characterized Cushing´s syndrome sufficient to consider HC medical treatment would benefit from individually defined serum cortisol post-dexamethasone cutoffs to increase the LDSST sensitivity. In contrast, increasing sensitivity by reducing the cutoff value would further reduce the LDDST specificity, which is already considered poor ranging from 44% to 95% (Behrend et al., 2013; Bennaim et al., 2019b). Unfortunately, one of our study limitations was that the LDSTT specificity (true negatives) was not determined, since the analysis of the charts was restricted to cases with HC exposed to treatment only (i.e. assumed to be positive) and did not include tested dogs considered negative.

The ACTHST is often applied for HC confirmation as observed in our results; and despite identifying the disorder, it does not distinguish between adrenal or pituitary dependence (Behrend, 2015). Moreover, the ACTHST is considered a less sensitive (overall sensitivity 57% to 95%) test, especially for ADH diagnosis (57% to 63%, against 80% to 92% for PDH); however more specific (59% to 95 %) (Behrend et al., 2013; Bennaim et al., 2019b). The SDCS entity is considered a consequence of the present inaccuracy in the endocrine test cutoffs (Frank et al., 2015; Agreeing, 2019) therefore, post-ACTH cortisol cutoffs for HC diagnosis should also be a matter of debate.

CONCLUSIONS

Demographic and epidemiologic features of dogs with HC in southern Brazil are comparable with the worldwide case series described, including patients’ mean age, overrepresented breeds, and sex, with the tendency for neutered patients to be more often affected. Trilostane and mitotane efficacy were comparable in promoting good clinical control in most dogs of this cohort, as similar survival, and complication occurrence rates. Despite nowadays mitotane being an expensive and hard-to-find drug in the Brazilian market, it still represents an effective treatment alternative for many dogs with HC and should be demystified by younger veterinarians. Clinical decisions in treating a dog with Cushing´s syndrome with medical treatment in sub-diagnostic cases may represent a therapeutic trial, a practice not fully supported by the ESVE. In this way, increasing test sensitivity by adopting smaller serum cortisol cut-off values in dynamic adrenal function tests would be helpful to avoid the need for further testing and diagnostic expenses in cases with a high HC suspicion, especially when HC treatment seems urgent.

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Publication Dates

• Publication in this collection
  14 July 2025
• Date of issue
  Jul-Aug 2025

History

• Received
  04 July 2024
• Accepted
  24 Oct 2024