Pituitary-dependent Hypercortisolism Research Articles

Challenges of transsphenoidal pituitary surgery in severe brachycephalic dogs.

Transsphenoidal hypophysectomy is the standard surgical technique for the excision of pituitary neoplasms. Anatomy may be more obscured in brachycephalic skull types due to the crowding of soft tissue and osseous structures. We describe the unique challenges to approach the sphenoid bone and localize the correct burr hole site in severe brachycephalic dogs. A single institution retrospective case series of brachycephalic dogs with pituitary-dependent hypercortisolism (PDH). Preoperative computed tomography enabled 3D-, and cross-sectional reconstruction to plan and dry-practice the position of the ideal burr hole in relation to the sella turcica, pterygoid hamular processes, and hard palate. Rostral burring of the caudal hard palate obscuring the direct sphenoid approach necessitated adaptations to the original transsphenoidal hypophysectomy procedure. Postoperative outcomes and complications with respect to those seen in mesocephalic dogs are described. Ten brachycephalic dogs including French Bulldogs (n = 9) and a single Dogue de Bordeaux were included. All dogs were diagnosed with PDH and had preoperative advanced imaging performed on the skull. All but one dog had an enlarged pituitary gland, with a median pituitary/brain value of 0.5 (range 0.21-0.9). A total of 11 transsphenoidal hypophysectomy procedures were performed in these 10 dogs. Rostral extension of the soft palate incision into the hard palate was performed to access the burr hole site on the sphenoid bone. Major complications included aspiration pneumonia (n = 1), severe gastroesophageal reflux (n = 1), and central nervous signs (=1). All dogs survived until discharge, with a median time to follow-up of 618 days (range 79-1,669 days). Seven dogs experienced long-term remission of PDH. Brachycephalic dogs undergoing transsphenoid al hypophysectomy benefit from meticulous presurgical planning and extension of the approach into the caudal hard palate. Advanced surgical skills can render a good outcome in a technically challenging environment.

Effect of pituitary-dependent hypercortisolism on the survival of dogs treated with radiotherapy for pituitary macroadenomas.

Radiotherapy (RT) is an effective treatment for dogs presented with neurologic signs caused by pituitary tumors. However, its impact on the outcome of concurrent pituitary-dependent hypercortisolism (PDH) is controversial. Determine whether dogs with PDH have longer survival after pituitary RT compared with dogs with nonhormonally active pituitary masses and to evaluate whether clinical, imaging, and RT variables affect survival. Ninety-four dogs divided into 2 groups: PDH and non-PDH, based on the presence of hypercortisolism. Forty-seven dogs were allocated to the PDH group and 47 to the non-PDH group. Retrospective cohort study in which clinical records of dogs undergoing RT for pituitary macroadenomas between 2008 and 2018 at 5 referral centers were retrospectively evaluated. Survival was not statistically different between PDH and non-PDH groups (median survival time [MST], 590 days; 95% confidence interval [CI], 0-830 days and 738 days; 95% CI, 373-1103 days, respectively; P = .4). A definitive RT protocol was statistically associated with longer survival compared with a palliative protocol (MST 605 vs 262 days, P = .05). The only factor statistically associated with survival from multivariate Cox proportional hazard analysis was total radiation dose (Gy) delivered (P < .01). No statistical difference in survival was identified between the PDH and non-PDH groups, and longer survival was associated with higher Gy delivered.

Clinical features of muscle stiffness in 37 dogs with concurrent naturally occurring hypercortisolism.

Severe muscle stiffness (SMS) in dogs with hypercortisolism (HC) is uncommon. To evaluate signalment, presentation, treatments, and long-term outcomes of dogs with concurrent HC and SMS. Thirty-seven dogs. Medical records of dogs with HC and concurrent SMS were recruited from 10 institutions. Clinical information, test results, therapeutic responses, and survival times were reviewed. All 37 dogs with HC and SMS had pituitary-dependent hypercortisolism (PDH); 36/37 weighed <20 kg. Signs and test results were typical of PDH aside from SMS, initially diagnosed in all 4 limbs in 9, pelvic limbs of 22, and thoracic limbs of 6 dogs. Hypercortisolism and SMS were diagnosed together in 3 dogs; HC 1-36 months before SMS in 23; SMS 1-12 months before HC in 11. Mitotane or trilostane, given to control HC in 36/37 dogs, improved or resolved HC signs in 28; SMS did not resolve, remaining static or worsening in 31/36 dogs, mildly improving in 5/19 dogs given additional therapies. Progression of SMS included additional limbs in 10 dogs and the masticatory muscles of 2. The median survival time from diagnosis of SMS was 965 days (range, 8-1188). Concurrent SMS and HC is uncommon, possibly affecting only dogs with PDH. Development of SMS might occur before or after diagnosis of HC. Apart from SMS, the clinical picture and survival time of these dogs seem indistinguishable from those of dogs with HC in general. However, while muscle weakness usually resolves with HC treatment SMS does not.

Re-evaluation of the low-dose dexamethasone suppression test in dogs.

This study aims to re-evaluate the low-dose dexamethasone suppression test 8-hour cortisol cut-point for the diagnosis of hypercortisolism in dogs using a solid-phase, competitive chemiluminescent enzyme immunoassay. Twenty-seven client-owned dogs with naturally occurring hypercortisolism and 30 healthy control dogs were prospectively recruited. Performance of the low-dose dexamethasone suppression test was assessed using sensitivity, specificity and a receiver operating characteristic curve compared to a clinical diagnosis of hypercortisolism including response to treatment. Twenty-four dogs were diagnosed with pituitary-dependent hypercortisolism and three with adrenal-dependent hypercortisolism. In 30 healthy control dogs, 8-hour post-dexamethasone cortisol concentrations ranged from 5.5 to 39 nmol/L. A receiver operating characteristic curve curve constructed from the 8-hour post-dexamethasone cortisol concentrations of hypercortisolism and control dogs demonstrated that the most discriminatory cut-point was more than 39 nmol/L with sensitivity of 85.2% (95% confidence interval, 67.5% to 94.1%) and specificity of 100% (95% confidence interval, 88.7% to 100.0%) and an area under the curve of 0.963. The optimal cut-point of more than 36 nmol/L proposed by this study is similar to the currently accepted 8-hour cortisol concentration cut-point for diagnosing hypercortisolism when using a solid-phase, competitive chemiluminescent enzyme immunoassay.

Evaluation of the ACTH stimulation test using a low dose of a depot formulation in healthy dogs and in dogs with untreated Cushing's syndrome

The sensitivity of the adrenocorticotropic hormone (ACTH) stimulation test to detect Cushing's Syndrome (CS) using a depot formulation needs to be evaluated. The aims of this study were to propose a reference interval (RI) for cortisol values 1-hour after administration of a low-dose of depot ACTH in healthy dogs, and to evaluate the sensitivity of this test to detect CS, differentiating among types of CS based on ultrasound findings.Forty-one healthy dogs (20 males, 21 females) were prospectively included. Additionally, 90 dogs with CS (31 males, 59 females) were retrospectively included. Dogs with CS were ultrasonographically classified as follows: 44 dogs with symmetrical adrenomegaly consistent with pituitary-dependent hypercortisolism (PDH), 8 dogs with unilateral adrenomegaly and atrophy of the contralateral adrenal gland or unilateral or bilateral adrenomegaly with malignancy features consistent with adrenal-dependent hypercortisolism (ADH), 34 dogs with equivocal adrenal asymmetry (EAA) and 4 dogs with normal adrenal thickness.In healthy dogs, lower and upper limit of the 95% RI for 1-hour post-ACTH cortisol concentration and their 90% confidence intervals, were 4.4 (2.7–5.8) μg/dl and 18.4 (16.5–20.0) μg/dl, respectively. Post-ACTH cortisol concentration was above the RI in 90.0% (ci95%, 76.1–100) of dogs with CS. An elevated post-ACTH cortisol concentration was detected in 95.5% (ci95%, 76.1–100) of dogs with PDH, 62.5% (ci95%, 46.1–78.9) of dogs with ADH and 88.2% (ci95%, 69.1–100) of dogs with EAA. The sensitivity of the ACTH stimulation test using a low-dose of depot ACTH in high in dogs with CS.

Assessment of selegiline and trilostane combined therapy efficacy for canine pituitary-dependent hypercortisolism treatment: A pilot randomized clinical trial

Canine pituitary-dependent hypercortisolism (PDH) management with trilostane usually demands lifelong therapy. The greater the dose needed, the greater the risk of side effects. Selegiline therapy has been previously described but not commonly used for PDH treatment. The present work aimed to assess the efficacy of selegiline and trilostane combined therapy for canine PDH treatment. Fifteen client-owned dogs diagnosed with spontaneous PDH were enrolled. The patients were treated with trilostane (Tri group, n = 8, initial dose of 0.5 mg/kg, PO, q12h), or with trilostane and selegiline (Tri + Sel group, n = 7, initial trilostane dose of 0.5 mg/kg, PO, q12h and selegiline 1 mg/kg, PO, q24h). Dogs underwent clinical examination, serum biochemical analysis, urinalysis, abdominal ultrasound, and eACTH and post-ACTH cortisol measurements on treatment days zero (D0), 30 (D30), 90 (D90), and 180 (D180). There was a lack of adverse effects due to the combined therapy. Both groups showed a similar clinical response and lower post-ACTH cortisol levels at the study's end. There was no significant difference in trilostane dosage at D180 between groups. There was no documented increase in either right or left adrenal gland thickness in the Tri + Sel group in contrast with patients in the Tri group. However, there was no statistical difference between the groups regarding eACTH at D0 and D180. Patients in the Tri + Sel group achieved better serum triglycerides control at the end of the study. The association of selegiline with trilostane might be a feasible therapy for canine PDH; however, its eventual advantages need larger studies.

Survival of dogs with pituitary-dependent hyperadrenocorticism treated twice daily with low doses of trilostane.

Twice daily low trilostane doses have proven to be effective to manage canine Cushing's syndrome. However, survival and prognostic factors in dogs treated with this protocol have not been evaluated. The aim of the study was to evaluate survival and prognostic factors, including systolic blood pressure (SBP) at diagnosis, in dogs with pituitary-dependent hypercortisolism (PDH) treated with low trilostane doses. Medical records of 91 dogs newly diagnosed with PDH initially treated with 0.2-1.1mg/kg of trilostane twice daily were retrospectively included. Survival times were calculated using the Kaplan-Meier estimator. Univariable and multivariable analysis were performed using the Cox proportional hazard regression analysis. Overall, median survival was 998 days (range 26-1832 days, 95% confidence interval=755-1241 days). In the multivariable analysis, age (hazard ratio [HR]=1.337, p<0.001), presence of calcinosis cutis (HR=5.271, p<0.001), body condition score (BCS) ≤3/9 (HR=8.100, p<0.001) and higher platelet count (HR=1.002, p=0.022) were negatively correlated with survival. SBP was not associated with survival. Low-dose trilostane treatment twice daily provides slightly longer survival than previously reported for dogs with PDH treated once or twice daily at higher doses. Older age, presence of calcinosis cutis, low BCS and higher platelet count, but not systemic hypertension, are predictive of poorer prognosis in dogs with PDH.

Circulating MicroRNAs as Non-invasive Biomarkers for Canine Cushing's Syndrome.

Canine Cushing's syndrome (hypercortisolism) can be caused by a pituitary tumor (pituitary-dependent hypercortisolism; PDH) or a cortisol-secreting adrenocortical tumor (csACT). For both cases, non-invasive biomarkers that could pre-operatively predict the risk of recurrence after surgery would greatly impact clinical decision making. The aim of this study was to determine whether circulating microRNAs (miRNAs) can be used as diagnostic (presence of PDH or csACT) and/or prognostic (disease recurrence, histological grade) non-invasive biomarkers for canine Cushing's syndrome. After a pilot study with 40 miRNAs in blood samples of healthy dogs (n = 3), dogs with PDH (n = 3) and dogs with a csACT (n = 4), we selected a total of 20 miRNAs for the definitive study. In the definitive study, these 20 miRNAs were analyzed in blood samples of healthy dogs (n = 6), dogs with PDH (n = 19, pre- and post-operative samples) and dogs with a csACT (n = 26, pre-operative samples). In dogs with PDH, six miRNAs (miR-122-5p, miR-126-5p, miR-141-3p, miR-222-3p, miR-375-3p and miR-483-3p) were differentially expressed compared to healthy dogs. Of one miRNA, miR-122-5p, the expression levels did not overlap between healthy dogs and dogs with PDH (p = 2.9x10−4), significantly decreased after hypophysectomy (p = 0.013), and were significantly higher (p = 0.017) in dogs with recurrence (n = 3) than in dogs without recurrence for at least one year after hypophysectomy (n = 7). In dogs with csACTs, two miRNAs (miR-483-3p and miR-223-3p) were differentially expressed compared to healthy dogs. Additionally, miR-141-3p was expressed significantly lower (p = 0.009) in dogs with csACTs that had a histopathological Utrecht score of ≥ 11 compared to those with a score of <11. These results indicate that circulating miRNAs have the potential to be non-invasive biomarkers in dogs with Cushing's syndrome that may contribute to clinical decision making.

Pituitary tumour types in dogs and cats

Pituitary tumours are common in dogs and are being increasingly recognized in cats. Pituitary tumours are usually classified as adenomas and should only be classified as carcinomas when there is evidence of metastatic spread of the tumour, which is rare. Despite the benign nature of most pituitary tumours, they can still compress or invade neighbouring tissues. Pituitary tumours can be functional (hormonally active) or non-functional (hormonally silent). The aim of this review was to provide an overview of the different pituitary tumour types in dogs and cats that have been reported in the literature. In dogs, the most common pituitary tumour type is the corticotroph adenoma, which can cause pituitary-dependent hypercortisolism. In cats, the most common pituitary tumour is the somatotroph adenoma, which can cause hypersomatotropism, and the second-most common is the corticotroph adenoma. A lactotroph adenoma has been described in one dog, while gonadotroph, thyrotroph and null cell adenomas have not been described in dogs or cats. Hormonally silent adenomas are likely underdiagnosed because they do not result in an endocrine syndrome. Tools used to classify pituitary tumours in humans, particularly immunohistochemistry for lineage-specific transcription factors, are likely to be useful to classify canine and feline pituitary tumours of unknown origin. Future studies are required to better understand the full range of pituitary adenoma pathology in dogs and cats and to determine whether certain adenoma subtypes behave more aggressively than others. Currently, the mechanisms that underlie pituitary tumorigenesis in dogs and cats are still largely unknown. A better understanding of the molecular background of these tumours could help to identify improved pituitary-targeted therapeutics.

Urinary vanillylmandelic acid:creatinine ratio in dogs with pheochromocytoma

Pheochromocytoma diagnosis in dogs is challenging because biochemical tests are not always available. In humans, urinary vanillylmandelic acid (VMA) is part of a pheochromocytoma biochemical diagnostic profile, whereas its diagnostic accuracy is currently unknown in dogs with pheochromocytoma. Prospectively, VMA was determined by HPLC and expressed as the ratio with respect to urinary creatinine (VMA:C). The diagnostic accuracy of the VMA:C ratio was evaluated by analyzing the receiver operating characteristic (ROC) curve in 10 healthy dogs, 8 dogs with pituitary-dependent hypercortisolism, 8 dogs with adrenal-dependent hypercortisolism, and 7 dogs with pheochromocytoma. The pheochromocytoma diagnosis was confirmed by histology and immunohistochemistry in all tumors. The VMA:C ratio was significantly higher in dogs with pheochromocytoma (158 [53.4 to 230.8] × 10−3) than in dogs with adrenal-dependent hypercortisolism (48.1 [24.3 to 144.9] × 10−3; P < 0.05), dogs with pituitary-dependent hypercortisolism (37.5 [32 to 47.1] × 10−3; P < 0.001), and healthy dogs (33.8 [13.3 to 87.9] × 10−3; P < 0.001). When using a VMA:C ratio >58.2 × 10−3 for pheochromocytoma diagnosis, a sensitivity of 85.7% and a specificity of 88.4% were obtained. Nevertheless, when using a cut-off ratio of 4 times the median VMA:C ratio determined in healthy dogs, there was no overlap (100% specificity). The area under the ROC curve indicated that the VMA:C ratio test could be used to discriminate between dogs with and without pheochromocytoma, what leads to the conclusion that it is useful for pheochromocytoma diagnosis in dogs.

Feline plasma adrenocorticotropic hormone: validation of a chemiluminescent assay and concentrations in cats with hypercortisolism, primary hypoadrenocorticism and other diseases.

The aims of this study were to validate a commercially available chemiluminescent assay for measurement of feline plasma adrenocorticotropic hormone concentration (ACTH), to determine the normal reference interval (RI) of plasma ACTH in healthy cats, to assess plasma ACTH in cats with naturally occurring hypercortisolism (HC), primary hypoadrenocorticism (PH) and other diseases (OD), and to evaluate the effect of aprotinin on plasma ACTH degradation. Forty healthy cats, 10 with HC, 11 with PH and 30 with OD, were included. The chemiluminescent enzyme immunometric assay was evaluated by measurement of intra-assay precision, interassay precision and linearity. The RI for plasma ACTH in healthy cats was established using robust methods. Plasma ACTH of samples collected with and without aprotinin, stored at 4°C and assayed over a 6-day period, was measured. The intra-assay coefficients of variance (CVs) ranged from 2.7% to 4.3% and interassay CVs from 3.3% to 10.7%. Dilution studies showed excellent accuracy (R2 >0.99). The RI for plasma ACTH in healthy cats was 32-370 pg/ml. Plasma ACTH was not significantly different between healthy cats and the OD group. Cats with pituitary-dependent hypercortisolism (PDH) and PH had significantly higher plasma ACTH than the other groups. Plasma ACTH did not show significant differences when samples collected with and without aprotinin were compared. The Immulite chemiluminescent assay is a valid technique for measuring plasma ACTH in cats and the RI of plasma ACTH is quite wide. Owing to the low overlap between healthy or OD cats and cats with HC or PH, the measurement of plasma ACTH appears to be useful and should be included in the diagnostic work-up when HC or PH are suspected. Furthermore, the measurement of plasma ACTH may be an accurate test for differentiating PDH from adrenal-dependent hypercortisolism.

Vestibular dysfunction due to thalamic metastasis of a corticotropic carcinoma in a dog

Metastatic pituitary carcinoma and central vestibular syndrome originating in the thalamus are not common disorders in dogs. An 11-year-old Maltese dog with pituitary-dependent hypercortisolism presented signs of central vestibular dysfunction...

Circulating neurohormone imbalances in canine sudden acquired retinal degeneration syndrome and canine pituitary-dependent hypercortisolism.

BackgroundSudden acquired retinal degeneration syndrome (SARDS) has clinical similarity to pituitary‐dependent hypercortisolism (PDH) in dogs. Some studies have identified a greater frequency of SARDS in seasons with reduced daylight hours. Neurohormone imbalances contribute to retinal lesions in other species, warranting further study in dogs with SARDS.HypothesisDysregulation of circulating melatonin concentration is present in dogs with SARDS but not in dogs with PDH.AnimalsFifteen client‐owned dogs with spontaneous SARDS (median time of vision loss 18 days), 14 normal dogs, and 13 dogs with confirmed PDH.ProceduresProspective case‐control study. ELISA on samples (obtained in the morning) for measurement of plasma melatonin and dopamine, serum serotonin, urine 6‐sulfatoxymelatonin (MT6s), and creatinine. Statistical analysis was performed using 1‐way ANOVA, Spearman correlation and receiver operator characteristic area under the curve analysis.ResultsThere were no significant differences in circulating melatonin, serotonin or dopamine concentrations between the 3 groups, although the study was underpowered for detection of significant differences in serum serotonin. Urine MT6s:creatinine ratio was significantly higher in dogs with PDH (4.08 ± 2.15 urine [MT6s] ng/mL per mg of urine creatinine) compared with dogs with SARDS (2.37 ± .51, P < .01), but not compared with normal dogs.Conclusions and Clinical RelevanceWe have identified neurohormone differences between dogs with SARDS and PDH.

Melanocortin 2 receptor antagonists in canine pituitary-dependent hypercortisolism: in vitro studies

Canine hypercortisolism is most often caused by an ACTH-secreting pituitary adenoma (pituitary-dependent hypercortisolism; PDH). An interesting target for a selective medical treatment of PDH would be the receptor for ACTH: the melanocortin 2 receptor (MC2R). In this study we investigated whether two peptide compounds, BIM-22776 (#776) and BIM-22A299 (#299), are effective MC2R antagonists in vitro. Their effects on cortisol production and mRNA expression of steroidogenic enzymes, MC2R and melanocortin 2 receptor accessory protein (MRAP) were evaluated in primary adrenocortical cell cultures (n = 8) of normal canine adrenal glands. Cortisol production stimulated by 50 nM ACTH was dose-dependently inhibited by #299 (inhibition 90.7 ± 2.3% at 5 μM) and by #776 (inhibition 38.0 ± 5.2% at 5 μM). The ACTH-stimulated mRNA expression of steroidogenic enzymes, MC2R and MRAP was significantly inhibited by both compounds, but most potently by #299. These results indicate that canine primary cell culture is a valuable in vitro system to test MC2R antagonists, and that these compounds, but especially #299, are effective MC2R antagonists in vitro. To determine its efficacy in vivo, further studies are warranted. Antagonism of the MC2R is a promising potential treatment approach in canine PDH.

The mRNA expression of PTTG1 is a strong prognostic indicator for recurrence after hypophysectomy in dogs with corticotroph pituitary adenomas

Pituitary-dependent hypercortisolism (PDH) is a common endocrinopathy in dogs, but the promotors and initiators of the tumourigenesis of corticotroph pituitary adenomas remain unknown. Based on human data, we investigated mRNA expression of pituitary tumour transforming gene 1 (PTTG1) with quantitative RT-PCR in canine corticotroph pituitary adenomas. PTTG1 was overexpressed in adenomas approximately 3-fold. A strong association was observed between PTTG1 expression and disease-free interval; dogs with high PTTG1 expression had a significantly (4 times; P=0.02) shorter disease-free interval than dogs with low PTTG1 expression. This paper shows that PTTG1 expression is a negative prognosticator in relation to disease-free interval and recurrence in dogs undergoing transsphenoidal hypophysectomy as treatment for PDH.

Immunohistochemical Evaluation of Canine Pituitary Adenomas Obtained by Transsphenoidal Hypophysectomy.

Hypophysectomy specimens from 16 dogs with pituitary adenoma were evaluated with periodic acid-Schiff (PAS), reticulin, and immunohistochemistry for adrenocorticotrophic hormone (ACTH), melanocyte stimulating hormone (MSH), growth hormone (GH), and Ki-67. The reticulin network was obliterated in all adenomas. One adenoma expressed ACTH and GH. Eight corticotroph adenomas were basophilic to chromophobic, and PAS- and ACTH-positive. Seven melanotroph adenomas were distinguished from corticotroph adenomas by expression of MSH. Pituitary-dependent hypercortisolism was diagnosed in 5 of 8 dogs with corticotroph and 4 of 7 with melanotroph adenoma. Pituitary height/brain area (P/B) ratio was elevated in all dogs. Previous canine hypophysectomy studies suggested that melanotroph adenomas were larger and carried a worse prognosis than corticotroph adenomas; however, in this study, corticotroph adenomas in comparison to melanotroph adenomas were larger (median P/B ratio: 1.06 versus 0.76), more proliferative (median Ki-67 index: 9.47% versus 1.99%), and associated with shorter survival (median: 300 versus 793 days). Recommended immunohistochemistry for PAS-positive pituitary adenomas includes ACTH and MSH to distinguish corticotrophs from melanotrophs and Ki-67 for proliferation index.

Pituitary size alteration and adverse effects of radiation therapy performed in 9 dogs with pituitary-dependent hypercortisolism

The purpose of this study was to determine the therapeutic and/or adverse effects of radiation therapy (RT) against pituitary tumors in dogs with pituitary-dependent hypercortisolism, as monitored by frequent post-RT detailed MRI examinations, clinical signs, and changes in hormone concentrations. Nine dogs with an adrenocorticotropic hormone (ACTH)-secreting pituitary mass diagnosed by magnetic resonance imaging (MRI) underwent RT for 4weeks (total of 48Gy in 4-Gy fractions). Pituitary height/brain area (P/B) value, clinical signs, basal plasma ACTH concentrations, serum cortisol concentrations (pre- and post-ACTH stimulation test) and adverse effects of RT were evaluated before and post-RT.The P/B value was significantly lower in all nine dogs post-RT. One dog lacking any neurological signs demonstrated no change in clinical signs pre and post-RT. Out of 8 dogs which exhibited neurological signs pre-RT, half of them demonstrated complete resolution of their signs, whereas the other half showed transient resolution. In all animals with recurrence of neurological signs, pituitary tumor regrowth was not observed; however, MRI revealed moderate to severe pituitary hemorrhage. Late adverse effect (bilateral otitis media) was observed in three of nine dogs post-RT. RT did not induce any significant changes in the dogs' basal plasma ACTH concentration and pre- and post-ACTH serum cortisol concentrations.In conclusion, RT is effective to reduce pituitary size and the mass effect, but does not appear to affect blood hormone concentrations, necessitating additional medical treatment against hypercortisolism. Periodic MRI imaging post-RT enables early detection of adverse effects of RT.

TRH-induced secretion of adrenocorticotropin and cortisol in dogs with pituitary-dependent hypercortisolism

Background: In dogs, spontaneous Cushing’s syndrome is most often pituitary-dependent and caused by hypersecretion of adrenocorticotropic hormone (ACTH), resulting in increased adrenocortical glucocorticoid secretion similar to horses. In horses with Cushing’s syndrome (or pituitary pars intermedia dysfunction [PPID]) a thyrotropin-releasing hormone (TRH) stimulation test can be used for diagnosis, as TRH administration results in increased circulating ACTH and cortisol concentrations in affected horses.Objective: The aim of this study was to investigate the effect of TRH administration on the circulating ACTH and cortisol concentrations in dogs with pituitary-dependent hypercortisolism (PDH).Methods: Ten clinically normal control dogs and 10 dogs with PDH, all client owned, underwent a TRH stimulation test with measurement of plasma concentrations of ACTH and cortisol, before and after intravenous administration of 10 μg TRH/kg bodyweight.Results: Plasma ACTH concentration did not rise significantly after TRH stimulation, neither in PDH dogs nor in clinically normal dogs. In contrast, the plasma cortisol concentration did increase significantly after TRH stimulation in both groups (p = .003 in PDH and p < .001 in control). Immunohistochemistry of normal adrenal glands demonstrated the presence of TRH receptors in the whole adrenal cortex.Conclusions: The results of this study demonstrate that the TRH stimulation test should be rejected as a tool to diagnose PDH in dogs. The observed TRH-induced increase in plasma cortisol concentration without a significant rise in plasma ACTH concentration may be explained by a direct effect of TRH on adrenocortical cells mediated by adrenocortical TRH receptors.

Steroidogenic factor-1 inverse agonists as a treatment option for canine hypercortisolism: in vitro study

Hypercortisolism is one of the most commonly diagnosed endocrinopathies in dogs, and new targeted medical treatment options are desirable. Steroidogenic factor-1 (SF-1), an orphan nuclear hormone receptor, is a key regulator of adrenal steroidogenesis, development, and growth. In pituitary-dependent hypercortisolism (PDH), high plasma ACTH concentrations increase the transcriptional activity of SF-1. In adrenal-dependent hypercortisolism, SF-1 expression is significantly greater in dogs with recurrence after adrenalectomy than in those without recurrence. Inhibition of SF-1 could therefore be an interesting treatment option in canine spontaneous hypercortisolism. We determined the effects of 3 SF-1 inverse agonists, compounds IsoQ A, #31, and #32, on cortisol production, on the messenger RNA (mRNA) expression of steroidogenic enzymes and SFs, and on cell viability, in primary adrenocortical cell cultures of 8 normal adrenal glands and of 3 cortisol-secreting adrenocortical tumors (ATs). To mimic PDH, the normal adrenocortical cell cultures were stimulated with ACTH. The results show that only compound #31 inhibited cortisol production and SF-1 target gene expression in non–ACTH-stimulated and ACTH-stimulated normal adrenocortical cells but did not affect cell viability. In the AT cell cultures, the effects of #31 on cortisol production and target gene expression were variable, possibly caused by a difference in the SF-1 mRNA expressions of the primary tumors. In conclusion, inhibition of SF-1 activity shows much promise as a future treatment for canine hypercortisolism.

The Influence of Pituitary Size on Outcome After Transsphenoidal Hypophysectomy in a Large Cohort of Dogs with Pituitary-Dependent Hypercortisolism.

BackgroundTranssphenoidal hypophysectomy is one of the treatment strategies in the comprehensive management of dogs with pituitary‐dependent hypercortisolism (PDH).ObjectivesTo describe the influence of pituitary size at time of pituitary gland surgery on long‐term outcome.AnimalsThree‐hundred–and‐six dogs with PDH.MethodsSurvival and disease‐free fractions were analyzed and related to pituitary size; dogs with and without recurrence were compared.ResultsFour weeks after surgery, 91% of dogs were alive and remission was confirmed in 92% of these dogs. The median survival time was 781 days, median disease‐free interval was 951 days. Over time, 27% of dogs developed recurrence of hypercortisolism after a median period of 555 days. Dogs with recurrence had significantly higher pituitary height/brain area (P/B) ratio and pre‐operative basal urinary corticoid‐to‐creatinine ratio (UCCR) than dogs without recurrence. Survival time and disease‐free interval of dogs with enlarged pituitary glands was significantly shorter than that of dogs with a non‐enlarged pituitary gland. Pituitary size at the time of surgery significantly increased over the 20‐year period. Although larger tumors have a less favorable prognosis, outcome in larger tumors improved over time.Conclusions and Clinical ImportanceTranssphenoidal hypophysectomy is an effective treatment for PDH in dogs, with an acceptable long‐term outcome. Survival time and disease‐free fractions are correlated negatively with pituitary gland size, making the P/B ratio an important pre‐operative prognosticator. However, with increasing experience, and for large tumors, pituitary gland surgery remains an option to control the pituitary mass and hypercortisolism.