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

BACKGROUND: 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. OBJECTIVES: 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. ANIMALS: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS AND CLINICAL IMPORTANCE: No statistical difference in survival was identified between the PDH and non-PDH groups, and longer survival was associated with higher Gy delivered.

Adrenocorticotropic hormone-producing pituitary adenoma with pituitary apoplexy treated by surgical decompression: a case report.

BACKGROUND: Pituitary-dependent hypercortisolism (PDH) is one of the most common endocrine disorders in veterinary medicine. However, there are few reports on pituitary tumor apoplexy (PTA) in dogs and no reports on its surgical intervention in veterinary medicine. Accordingly, the appropriate treatment is unknown. Herein, a case of PDH and PTA in a dog treated surgically is described. CASE PRESENTATION: A mongrel female dog (spayed; age, 8 years and 8 months; weight, 6.1 kg) with persistently elevated alkaline phosphatase underwent adrenocorticotropic hormone (ACTH) stimulation testing (post-stimulation cortisol: 20.5 µg/dL), abdominal ultrasonography (adrenal gland thickness: left, 5.7 mm; right, 8.1 mm), and brain magnetic resonance imaging (MRI) (pituitary-to-brain ratio [PBR], 0.61) at the referral hospital, resulting in a diagnosis of PDH (day 0). On day 9, the dog visited XXXX for the preparation of pituitary surgery to treat PDH. However, on days 10-15, the dog developed a loss of energy and appetite, bloody diarrhea, vomiting, and a decreased level of consciousness. However, on day 16, the dog's condition recovered. A preoperative MRI scan performed on day 52 (the day of surgery) showed apoplexy in the dorsal pituitary region (PBR, 0.68). Based on the PTA findings, the risks of surgery were described to the owner, and approval was obtained. At the time of trans-sphenoidal surgery, a partial pituitary resection was performed with preservation of the PTA area due to adhesions between the PTA area of the right side of the pituitary and surrounding tissues. The resected pituitary tissue was diagnosed as an ACTH-producing adenoma, with necrotic and hemorrhagic findings. As of day 290, endogenous ACTH and cortisol levels did not exceed the reference range. CONCLUSIONS: The acute signs that occurred on days 10-15 were most likely caused by PTA. Therefore, when signs similar to those detected in acute hypoadrenocorticism are observed in dogs with PDH, it is necessary to include PTA as a differential diagnosis. Trans-sphenoidal surgery may be effective in PDH-affected dogs that develop PTA, but careful attention should be paid to tissue adhesions secondary to hemorrhage that may occur after PTA.

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.

Metabolic profiling of serum from dogs with pituitary-dependent hyperadrenocorticism.

Hyperadrenocorticism (HAC) is one of the most common endocrine diseases in dogs characterized by excessive cortisol production caused by an adrenocorticotropic hormone (ACTH)-secreting tumor, namely pituitary-dependent HAC (PDH) or cortisol-secreting adrenal tumor. Metabolomics presents the ability to identify small molecule metabolites. Thus, the use of metabolomics techniques in canine PDH can provide information about the pathophysiology and metabolic changes in this disease. This study aimed to identify and compare differences in serum metabolites between dogs with PDH and healthy dogs. The metabolomic profile of 20 dogs diagnosed with PDH was compared with 20 healthy dogs using liquid chromatography/mass spectrometry (LC/MS), and metabolite discrimination was performed using partial least squares-discriminant analysis (PLS-DA), the variable important in projection (VIP) and fold changes (FC) group-wise comparisons. The hypergeometric test identified the significantly altered pathways. A total of 21 metabolites were found to be significantly different between the two groups. The major alterations were found in arachidonic and decanoic acid, and phospholipids related to phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylinositol (PI). These metabolites are related to insulin resistance and other complications (i.e. hypertension). Our results indicate that PDH produces changes in serum metabolites of dogs, and the knowledge of these changes can aid to better understanding of pathophysiological processes involved and contribute to potentially detect new biomarkers for this disease.

A case of chronic lymphocytic leukemia masked by Cushing's disease in a dog.

A 12-year-old, 3.5-kg, intact female dog was presented with polyuria, polydipsia, and a pendulous abdomen. Laboratory examinations showed elevated hepatobiliary enzyme levels and neutrophilic leukocytosis. The adrenocorticotropic hormone stimulation test confirmed hyperadrenocorticism (HAC). Trilostane therapy managed the clinical condition and cortisol concentration. However, lymphocytosis and nonregenerative anemia developed after HAC remission. Bone marrow aspiration analysis revealed a lymphoproliferative disorder with a clonal T-cell population. Accordingly, the patient was diagnosed with T-cell chronic lymphocytic leukemia (CLL) and concurrent HAC. Thereafter, chemotherapy was initiated, which improved the lymphocytosis. However, euthanasia was performed because of worsening quality of life at 45 weeks after the first presentation. These results suggested that CLL could be masked by excessive endogenous cortisol and discovered after HAC remission.

Canine adrenocorticotropic hormone-producing sinusoidal neuroendocrine tumor associated with Cushing's disease.

An 18-year-old male Yorkshire Terrier was admitted with a history of neurological signs including dullness and progressive tetraparesis. Physical examination revealed bilaterally symmetrical alopecia and pot-bellied abdomen. Computed tomography and necropsy examination showed a mass across the frontal sinus and cerebral frontal lobe, bilateral adrenocortical hyperplasia, and hepatomegaly. Histopathologically, the tumor lesions consisted of sheets, nests, or cords of small- to medium-sized round-to-polyhedral cells. Adrenal cortex showed bilateral diffuse cellular proliferation, and some hepatocytes showed intracytoplasmic glycogen accumulation. Immunohistochemically, the tumor cells were positive for pancytokeratin, chromogranin-A, neuron-specific enolase, S100, synaptophysin, and thyroid transcription factor-1 but negative for microtubule-associated proein-2 and neurofilament, leading to the diagnosis of neuroendocrine tumor. These tumor cells were also positive for adrenocorticotropic hormone.

Dysregulation of Cortisol Metabolism in Equine Pituitary Pars Intermedia Dysfunction.

Equine Cushing disease [pituitary pars intermedia dysfunction (PPID)] is a common condition of older horses, but its pathophysiology is complex and poorly understood. In contrast to pituitary-dependent hyperadrenocorticism in other species, PPID is characterized by elevated plasma ACTH but not elevated plasma cortisol. In this study, we address this paradox and the hypothesis that PPID is a syndrome of ACTH excess in which there is dysregulation of peripheral glucocorticoid metabolism and binding. In 14 horses with PPID compared with 15 healthy controls, we show that in plasma, cortisol levels and cortisol binding to corticosteroid binding globulin were not different; in urine, glucocorticoid and androgen metabolites were increased up to fourfold; in liver, 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) expression was reduced; in perirenal adipose tissue, 11ß-HSD1 and carbonyl reductase 1 expression was increased; and tissue cortisol levels were not measurably different. The combination of normal plasma cortisol with markedly enhanced urinary cortisol metabolite excretion and dysregulated tissue-specific steroid-metabolizing enzymes suggests that cortisol clearance is increased in horses with PPID. We infer that the ACTH excess may be compensatory and pituitary pathology and autonomous secretion may be a secondary rather than primary pathology. It is possible that successful therapy in PPID may be targeted either at lowering ACTH or, paradoxically, at reducing cortisol clearance.

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.

PITUITARY PARS INTERMEDIA DYSFUNCTION (EQUINE CUSHING'S DISEASE) IN NONDOMESTIC EQUIDS AT MARWELL WILDLIFE: A CASE SERIES. ONE CHAPMAN'S ZEBRA ( EQUUS QUAGGA CHAPMANI) AND FIVE PRZEWALSKI's HORSES ( EQUUS FERUS PRZEWALSKII).

Pituitary pars intermedia dysfunction (PPID), also known as equine Cushing's disease, is widely reported in middle-aged to older domestic equids but to date reported in only one nondomestic equid, the onager ( Equus hemionus onager). This case series reports clinical, hematological, and pathological findings consistent with PPID in two further equid species: one Chapman's zebra ( Equus quagga chapmani) and five Przewalski's horses ( Equus ferus przewalskii). The case series reports basal adrenocorticotropic hormone (ACTH) testing as a method to diagnose and monitor PPID in zoological equids and the use of pergolide mesylate to reduce basal ACTH concentration and reduce clinical signs associated with PPID. Gross and histopathological examinations of the pituitary gland in four of these cases revealed either pars intermedia adenomas or adenomatous hyperplasia, similar to pathological findings in domestic equids affected by PPID. These findings suggest that clinicians working with nondomestic equids should be aware of this condition and consider screening for it routinely, particularly given that improvements in management and veterinary care for exotic animals are resulting in a more aged captive population. Early diagnosis and treatment of PPID may prevent the development of painful clinical sequelae and therefore improve the welfare of zoo equids.

Outcomes of the addition of pasireotide to traditional adrenal-directed treatment for dogs with pituitary-dependent hyperadrenocorticism secondary to macroadenoma: 9 cases (2013-2015).

OBJECTIVE To evaluate clinical signs, endocrine test results, and pituitary tumor size for dogs with medically managed pituitary-dependent hyperadrenocorticism (PDH) and macroadenoma following 6 months of concurrent treatment with pasireotide. DESIGN Prospective case series. ANIMALS 9 client-owned dogs with PDH and macroadenoma in which PDH had been successfully managed with adrenal-directed treatment (trilostane or mitotane). PROCEDURES Dogs were given pasireotide (0.03 mg/kg [0.014 mg/lb], SC, q 12 h) for 6 months, while adrenal-directed treatment was continued. Physical examination, basic clinicopathologic testing, ACTH stimulation testing, and plasma ACTH concentration measurement were performed before (baseline) and 3 and 6 months after treatment began. Measurements of pituitary gland volume and pituitary gland-to-brain ratio were performed via MRI at baseline and 6 months after treatment began. RESULTS No dog developed neurologic abnormalities or signs of adverse effects during the study period. No differences from baseline were identified in clinicopathologic values, ACTH stimulation test results, or plasma ACTH concentration at the 3- or 6-month assessment points. After 6 months of pasireotide treatment, 6 dogs had decreases in MRI-measured values, and 3 had increases. CONCLUSIONS AND CLINICAL RELEVANCE Pasireotide as administered in this study had no noted adverse effects on dogs with PDH and macroadenoma successfully managed with standard treatment. Placebo-controlled, randomized studies are needed to determine whether pasireotide protects from the development of neurologic signs or improves outcome in dogs with pituitary macroadenomas.

Histopathologic Findings in Canine Pituitary Glands.

To optimize the histologic evaluation of hypophysectomy specimens, sections of 207 canine pituitary glands (196 postmortem, 11 hypophysectomy specimens) were reviewed. Adenohypophyseal proliferation was the most common (n = 79) lesion. Proliferative lesions were sparsely to densely granulated; the granules were usually basophilic to chromophobic and periodic acid-Schiff-positive. Adenohypophyseal proliferation was classified as hyperplasia (n = 40) if ≤2 mm diameter with intact reticulin network, as microadenoma (n = 22) for 1-5 mm homogeneous nodules with lost reticulin network, or as macroadenoma (n = 17) for larger tumors. Craniopharyngeal duct cysts were common incidental lesions and the only lesion in 15 dogs. Uncommon diagnoses included lymphoma (n = 4), hemorrhagic necrosis (n = 4), metastatic carcinoma (n = 3), hypophysitis (n = 3), ependymoma (n = 2), craniopharyngioma (n = 2), and 1 case each of metastatic melanoma, pituicytoma, gliomatosis, germ cell tumor, meningioma, and atrophy. The pituitary histologic diagnosis was associated with hyperadrenocorticism (HAC; P < .001) and adrenocortical histologic diagnosis ( P = .025). Both HAC and adrenocortical hyperplasia showed a positive trend with the degree of adenohypophyseal proliferation. The association of adrenocortical hyperplasia with HAC was not significant ( P = .077). Dogs with adenohypophyseal proliferations were older than dogs with normal pituitary glands ( P < .05). Brachycephalic breeds were overrepresented among dogs with pituitary macroadenoma or craniopharyngeal duct cysts, but the association was not statistically significant ( P = .076). Adenohypophyseal hyperplasia was more common than adenoma among postmortem specimens, but was unexpected in >80% of cases. Pituitary macroadenoma was the most common diagnosis in hypophysectomy specimens.

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.

Development of two surgical approaches to the pituitary gland in the Horse.

BACKGROUND: Current treatment of equine pituitary pars intermedia dysfunction (PPID) requires daily oral medication. Minimally invasive surgical palliation of this condition is appealing as a single treatment to alleviate the clinical signs of disease, dramatically improving the welfare of the horse. OBJECTIVE: To develop a surgical approach to the equine pituitary gland, for subsequent treatment of PPID. STUDY DESIGN: A cadaver study to develop methodology and a terminal procedure under anaesthesia in the most promising techniques. ANIMALS AND METHODS: Four surgical approaches to the pituitary gland were investigated in cadaver animals. A ventral trans-basispheniodal osteotomy and a minimally invasive intravenous approach via the ventral cavernous sinus progressed to live horse trials. RESULTS: Technical complications prevented the myeloscopic and trans-sphenopalatine sinus techniques from being successful. The ventral basisphenoidal osteotomy was repeatable and has potential if an intra-operative imaging guidance system could be employed. The minimally invasive approach was repeatable, atraumatic and relatively inexpensive. CONCLUSIONS: A minimally invasive surgical approach to the equine pituitary gland is possible and allows for needle placement within the target tissue. More work is necessary to determine what that treatment might be, but repeatable access to the gland has been obtained, which is a promising step.

Dogs with macroadenomas have lower body temperature and heart rate than dogs with microadenomas.

Pituitary macroadenomas compress the hypothalamus, which partly regulates heart rate and body temperature. The aim of this study was to investigate whether heart rate and/or body temperature could aid in clinically differentiating dogs with macroadenomas from dogs with microadenomas (i.e. small non-compressive pituitary mass). Two groups of dogs diagnosed with pituitary-dependent hyperadrenocorticism (i.e. Cushing's disease) were included. Heart rate and body temperature were collected on initial presentation before any procedure. Dogs with macroadenoma had a significantly lower heart rate and body temperature (P<0.01) compared to dogs with microadenoma. We suggest that the combined cut-off values of 84 beats per minutes and 38.3°C in dogs with Cushing's disease, especially with vague neurological signs (nine of 12 dogs=75%), might help to suspect the presence of a macroadenoma.

An activating mutation in the CRHR1 gene is rarely associated with pituitary-dependent hyperadrenocorticism in poodles.

OBJECTIVES: Pituitary-dependent hyperadrenocorticism is the most common cause of naturally occurring hypercortisolism in dogs. CRHR1 expression in human and dog corticotrophinomas suggested that this gene affects pituitary tumorigenesis. The present study aimed to investigate mutations in the CRHR1 coding region in poodles with pituitary-dependent hyperadrenocorticism. METHODS: Fifty poodles with pituitary-dependent hyperadrenocorticism and 50 healthy poodles were studied. Genomic DNA was amplified by PCR and analyzed by Sanger sequencing. RESULTS: The novel CRHR1 p.V97M mutation was identified in one dog. This valine residue, located in the amino-terminal extracellular domain, exhibits high affinity for its corticotropin-releasing hormone (CRH) ligand. Bioinformatic analysis revealed structural rearrangements in the mutant protein, with a 17% increase in the surface binding affinity between CRHR1 and CRH. In vitro functional studies showed that mutant CRHR1 induced higher ACTH secretion than the wild type after stimulation with human CRH. CONCLUSION: These results suggest that germline activating mutations in CRHR1 may be a rare cause of pituitary hyperadrenocorticism in poodles.

Equine pituitary pars intermedia dysfunction: An international survey of veterinarians' approach to diagnosis, management, and estimated prevalence.

The objectives of the present study were to determine if diagnosis and treatment of equine pituitary pars intermedia dysfunction (PPID) vary by geographic region and to report the prevalence of PPID in horses as observed by veterinarians across locations. An online questionnaire was developed for veterinarians who treat horses. Veterinary associations, especially equine specialty subgroups, were contacted and a survey link was sent to members of each organization. Generalized linear models were used to examine whether the method of diagnosis and treatment of this condition, as well as its reported prevalence, differed by geographic region. Veterinarians from 426 separate clinics in 20 countries returned surveys. Diagnosis of PPID varied by region, but was usually based on clinical signs and an adjunct endocrine test. Horses with PPID were treated medically by 63% of veterinarians and 75% of these used pergolide mesylate as treatment. The median prevalence estimated was 1% and this did not differ by geographic location. Half the veterinarians were caring for 5 or more animals with PPID. Overall, diagnostic approach differed in geographic regions. In general, European veterinarians were more likely than those in North America to diagnose PPID based on clinical signs alone, without using an adjunct laboratory test. Veterinarians reported that cost and management responsibilities were their clients' primary concerns associated with the long-term treatment of this disease, which indicates a need for additional treatment options for PPID.

Les objectifs de la présente étude étaient de déterminer si le diagnostic et le traitement de la dysfonction de l'hypophyse médiale équine (DHME) varient selon la région géographique et signalent la prévalence de la DHME chez les chevaux, comme l'ont observé les vétérinaires dans différentes localisations. Un questionnaire en ligne a été développé pour les vétérinaires qui traitent les chevaux. Les associations vétérinaires, en particulier les sous-groupes de spécialités équines, ont été contactées et un lien pour un sondage a été envoyé aux membres de chaque organisation. Les modèles linéaires généralisés ont été utilisés pour examiner si la méthode de diagnostic et de traitement de cette condition, ainsi que sa prévalence déclarée, différaient selon la région géographique. Les vétérinaires provenant de 426 cliniques distinctes dans 20 pays ont répondu au sondage. Le diagnostic de DHME variait selon la région, mais était généralement basé sur les signes cliniques et un test endocrinien complémentaire. Les chevaux atteints de DHME ont été traités médicalement par 63 % des vétérinaires et 75 % de ceux-ci utilisaient le mésylate de pergolide comme traitement. La prévalence médiane estimée était de 1 % et cela ne différait pas selon la situation géographique. La moitié des vétérinaires prenaient soin de 5 animaux ou plus avec DHME. Dans l'ensemble, l'approche diagnostique différait selon les régions géographiques. En général, les vétérinaires européens étaient plus susceptibles que ceux en Amérique du Nord de diagnostiquer la DHME en se basant uniquement sur les signes cliniques, sans utiliser un test de laboratoire complémentaire. Les vétérinaires ont signalé que les coûts et les responsabilités en matière de gestion étaient les principales préoccupations de leurs clients liées au traitement à long terme de cette maladie, ce qui indique un besoin d'options de traitement supplémentaires pour DHME.(Traduit par Docteur Serge Messier).

An activating mutation in the CRHR1 gene is rarely associated with pituitary-dependent hyperadrenocorticism in poodles

OBJECTIVES: Pituitary-dependent hyperadrenocorticism is the most common cause of naturally occurring hypercortisolism in dogs. CRHR1 expression in human and dog corticotrophinomas suggested that this gene affects pituitary tumorigenesis. The present study aimed to investigate mutations in the CRHR1 coding region in poodles with pituitary-dependent hyperadrenocorticism. METHODS: Fifty poodles with pituitary-dependent hyperadrenocorticism and 50 healthy poodles were studied. Genomic DNA was amplified by PCR and analyzed by Sanger sequencing. RESULTS: The novel CRHR1 p.V97M mutation was identified in one dog. This valine residue, located in the amino-terminal extracellular domain, exhibits high affinity for its corticotropin-releasing hormone (CRH) ligand. Bioinformatic analysis revealed structural rearrangements in the mutant protein, with a 17% increase in the surface binding affinity between CRHR1 and CRH. In vitro functional studies showed that mutant CRHR1 induced higher ACTH secretion than the wild type after stimulation with human CRH. CONCLUSION: These results suggest that germline activating mutations in CRHR1 may be a rare cause of pituitary hyperadrenocorticism in poodles.

Incidencia de enfermedades endocrinas en caninos entre los años 2013-2016 en un hospital veterinario universitario de Chile / Incidence of endocrine diseases in canines between 2013-2016 in a universitary hospital in Chile

It has been shown that there is an association between air pollution and cardiovascular mortality. In bone pathology, studies show that air pollution is associated with a risk of developing osteoporosis and osteoporotic fracture associated with MP2.5 and nitrogen dioxide (NO2 ). The aim of our study was to determine whether or not there is an association between air pollution and osteoporotic disease, associating the incidence of femoral neck fracture in individuals aged 50 years or more and the contamination present in the several cities. Our results showed no statistically significant association between air pollution, evaluated using PM10 and PM2.5 as indicators, and the average annual incidence of osteoporotic hip fracture, comparing the most polluted cities and the less polluted cities of Chile

Clinical Relationship between Cholestatic Disease and Pituitary-Dependent Hyperadrenocorticism in Dogs: A Retrospective Case Series.

BACKGROUND: A high prevalence of cholestatic disease, including gallbladder mucocele (GBM), has been reported in dogs with naturally occurring pituitary-dependent hyperadrenocorticism (PDH). HYPOTHESIS/OBJECTIVES: Differences exist in the clinical features of dogs with PDH and concurrent cholestatic disease, and also is the management of these dogs with trilostane. ANIMALS: Sixty-five client-owned dogs with naturally occurring PDH. METHODS: This was a retrospective, observational case series. Each dog was treated with trilostane for at least 3 months before the study, and had a good clinical response, as determined by owners. Statistical comparisons of clinical signs, results of routine blood tests, basal and post-ACTH cortisol concentration, and optimal trilostane dosage were made after dogs were separated into the following 3 groups by ultrasonographic imaging: normal on ultrasound (NOU) group, cholestasis group, and GBM group. RESULTS: The GBM group had more severe clinical signs and significantly different total serum cholesterol concentration and post-ACTH stimulation cortisol concentration at the time of diagnosis. Dogs that weighed <6 kg had a significantly higher prevalence of cholestatic disease than did the other dogs (P = .003). The optimal trilostane dosages for the GBM and cholestasis groups were 2.5 and 1.5 times the dosage of the NOU group, respectively (P < .001). CONCLUSIONS AND CLINICAL IMPORTANCE: Gallbladder disease associated with cholestatic disease is correlated with PDH in dogs, in both its clinical features and drug management. These findings may be associated with hypercholesterolemia, unidentified genetic factors, and the hydrophobic nature of trilostane.