Pituitary-dependent Hyperadrenocorticism Research Articles

Relationship of serum leptin concentration with pituitary-dependent hyperadrenocorticism and cholestatic disease in dogs.

ObjectivesTo measure serum leptin concentration in dogs with pituitary‐dependent hyperadrenocorticism and varying degrees of cholestatic disease and determine whether serum levels differed between dogs with pituitary‐dependent hyperadrenocorticism and those with gall bladder mucocoele.Materials and MethodsClient‐owned healthy dogs (n=20), dogs diagnosed with gall bladder mucocoele (n=20) and dogs diagnosed with pituitary‐dependent hyperadrenocorticism (n=60) were enrolled. Only dogs of normal body condition score were included. Dogs with pituitary‐dependent hyperadrenocorticism were divided into three groups according to the severity of cholestatic disease: normal gall bladder (n=20), cholestasis (n=20) and gall bladder mucocoele (n=20). Serum leptin levels were measured using sandwich enzyme‐linked immunosorbent assay.ResultsSerum concentrations of leptin were similar between dogs with gall bladder mucocoele and those with pituitary‐dependent hyperadrenocorticism accompanied by gall bladder mucocoele; these concentrations were significantly higher than those in healthy control dogs. In dogs with pituitary‐dependent hyperadrenocorticism, circulating leptin concentration significantly increased with the severity of cholestasis: higher in the cholestasis group than the normal gall bladder group and higher in the gall bladder mucocoele group than the cholestasis group.Clinical SignificanceElevated circulating leptin concentration was associated with canine pituitary‐dependent hyperadrenocorticism and gall bladder mucocoele. Homeostatic imbalance of leptin concentration might be associated with severity of cholestatic disease in pituitary‐dependent hyperadrenocorticism.

Diagnostic utility of clinical and laboratory test parameters for differentiating between sudden acquired retinal degeneration syndrome and pituitary-dependent hyperadrenocorticism in dogs.

To identify discriminating factors, using clinical ophthalmic examination findings and routine laboratory testing, that differentiate dogs with early sudden acquired retinal degeneration (SARDS; vision loss <6weeks' duration), age- and breed-matched control dogs, and dogs with pituitary-dependent hyperadrenocorticism (PDH). Client-owned dogs: 15 with SARDS with <6weeks duration of vision loss, 14 age- and breed-matched control dogs, and 13 dogs with confirmed PDH. Dogs underwent ophthalmic examination, electroretinography (ERG) fundus photography, and spectral-domain optical coherence tomography (SD-OCT) in addition to physical examination, urinalysis, serum biochemistry, complete blood count, and adrenocorticotrophic hormone (ACTH) stimulation testing. Statistical analysis was performed using receiver operating curve area under the curve analysis, principal component analysis with sparse partial least squares analysis, and one-way ANOVA. Dogs with SARDS all had absent vision and ERG a- and b-waves. SD-OCT demonstrated that dogs with SARDS had significantly thicker inner retina, thinner outer nuclear layer, and thicker photoreceptor inner/outer segment measurements than either controls or dogs with PDH. Discriminating laboratory parameters between dogs with SARDS and PDH with high specificity included post-ACTH serum cortisol (<19.3μg/dL), AST:ALT ratio (>0.343), and urine specific gravity (>1.030). We have identified significant discriminators between SARDS and PDH. This work provides the basis for future studies that could identify and examine dogs with SARDS prior to vision loss, which may extend the potential therapeutic window for SARDS.

The interpretive contribution of the baseline serum cortisol concentration of the ACTH stimulation test in the diagnosis of pituitary dependent hyperadrenocorticism in dogs.

BackgroundCurrent recommendation for performing the ACTH stimulation test (ACTHST) for diagnosis of hyperadrenocorticism (HAC) advocates the collection of baseline serum cortisol concentration (BC), but no references for interpretation of its results exist.ObjectiveEvaluate the contribution of BC of the ACTHST to the diagnosis of HAC.AnimalsFifty‐four dogs were evaluated for suspected HAC at a referral hospital.MethodsRecords of dogs that had been evaluated by ACTHST for suspected HAC were reviewed. Receiver operator characteristics (ROC) analyses were used to assess the performance of BC, post‐stimulation serum cortisol concentrations (PC), post‐to‐baseline cortisol concentration difference (DeltaC) and quotient (RatioC) for the diagnosis of HAC by comparing the area under the ROC curve (AUC) of PC to each of the other tests.ResultsThe AUC of PC (95% confidence interval [CI]: 0.92; 95% CI, 0.81‐0.98) was significantly higher than AUCs of BC (0.70; 95% CI, 0.56‐0.82; P = .01) and RatioC (0.55; 95% CI, 0.41‐0.69; P < .001), and was not significantly different from AUC of DeltaC (0.86; 95% CI, 0.74‐0.94; P = .09). An optimal cutoff value of 683 nmol/L (24.8 μg/dL) for PC yielded a sensitivity of 86% and a specificity of 94%, respectively, and a cutoff value of 718 nmol/L (26.0 μg/dL) yielded a specificity of 100% with of 81% sensitivity for the diagnosis of pituitary‐dependent HAC.Conclusion and Clinical ImportanceThe PC had good discriminatory ability for the diagnosis of HAC. It was comparable to DeltaC, whereas BC and RatioC were ineffective. Current recommendations to collect samples for BC appear redundant.

Adrenocortical Challenge Response and Genomic Analyses in Scottish Terriers With Increased Alkaline Phosphate Activity.

Scottish terriers (ST) frequently have increased serum alkaline phosphatase (ALP) of the steroid isoform. Many of these also have high serum concentrations of adrenal sex steroids. The study's objective was to determine the cause of increased sex steroids in ST with increased ALP. Adrenal gland suppression and stimulation were compared by low dose dexamethasone (LDDS), human chorionic gonadotropin (HCG) and adrenocorticotropic hormone (ACTH) response tests. Resting plasma pituitary hormones were measured. Steroidogenesis-related mRNA expression was evaluated in six ST with increased ALP, eight dogs of other breeds with pituitary-dependent hyperadrenocorticism (HAC), and seven normal dogs. The genome-wide association of single nucleotide polymorphisms (SNP) with ALP activity was evaluated in 168 ST. ALP (reference interval 8–70 U/L) was high in all ST (1,054 U/L) and HAC (985 U/L) dogs. All HAC dogs and 2/8 ST had increased cortisol post-ACTH administration. All ST and 2/7 Normal dogs had increased sex steroids post-ACTH. ST and Normal dogs had similar post-challenge adrenal steroid profiles following LDDS and HCG. Surprisingly, mRNA of hydroxysteroid 17-beta dehydrogenase 2 (HSD17B2) was lower in ST and Normal dogs than HAC. HSD17B2 facilities metabolism of sex steroids. A SNP region was identified on chromosome 5 in proximity to HSD17B2 that correlated with increased serum ALP. ST in this study with increased ALP had a normal pituitary-adrenal axis in relationship to glucocorticoids and luteinizing hormone. We speculate the identified SNP and HSD17B2 gene may have a role in the pathogenesis of elevated sex steroids and ALP in ST.

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, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) expression was reduced; in perirenal adipose tissue, 11β-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.

Canine hyperadrenocorticism associations with signalment, selected comorbidities and mortality within North American veterinary teaching hospitals.

To describe a large population of dogs with a diagnosis of hyperadrenocorticism at the time of death in North American veterinary teaching hospitals, and to identify comorbid conditions associated with hyperadrenocorticism. Retrospective cohort study of 1519 dogs with hyperadrenocorticism from a population of 70,574 dogs reported to the Veterinary Medical Database. Signalment, presence or absence of hyperadrenocorticism, aetiology of hyperadrenocorticism (if described), frequency of select comorbidities and causes of death were evaluated in dogs with and without hyperadrenocorticism. Hyperadrenocorticism was more frequent in females. Neutering was associated with a minor, but significant, increase in the odds of hyperadrenocorticism. Hyperadrenocorticism was the presumed cause of death of 393 (25∙9%) of affected dogs. When aetiology was specified (527 dogs, corresponding to 34∙7% of the cases), pituitary-dependent hyperadrenocorticism [387 (73∙4%) out of 527 dogs] was more common than functional adrenocortical tumour [136 (25∙8%) out of 527 dogs). Hyperadrenocorticism was over-represented in certain expected (miniature poodle, dachshund) and unexpected (Irish setter, bassett hound) breeds compared with the population at large. Of the select comorbidities investigated, dogs with hyperadrenocorticism were at increased risk for concurrent diabetes mellitus, urinary tract infection, urolithiasis, hypertension, gall bladder mucocoele and thromboembolic disease compared with dogs without hyperadrenocorticism. Hyperadrenocorticism is significantly associated with certain comorbid conditions but is not a major cause of mortality in affected dogs. Documented patterns now provide targets for prospective clinical research.

Adenoma de hipófise em uma gata com hiperadrenocorticismo

Background : : : : Feline Cushing’s syndrome (FCS) is a disorder of excessive cortisol secretion by the adrenal glands and is rare in cats. The most frequently observed clinical signs are polyuria, polydipsia, and polyphagia which are also consistent with diabetes mellitus . These diabetic cats are often insulin resistants. The dexamethasone suppression test is considered the test of choice for the diagnosis of hyperadrenocorticism. The majority of cats with naturally occurring Cushing’s syndrome have pituitary-dependent hyperadrenocorticism and it is caused by functional microadenoma or macroadenoma pituitary. Computed tomography or magnetic resonance imaging is helpful in diagnosis of pituitary tumors. Treatments of pituitary-dependent hyperadrenocorticism include surgery of the pituitary or adrenals, radiation of the pituitary, and medical therapies. Bilateral adrenalectomy continues to represent the best long-term therapeutic strategy until hypophysectomy becomes more widely available. This paper reports a cat with macroadenoma pituitary causing hiperadrenocorticism and insulin resistance. Case : A 12-year-old female castrated Brazilian shorthair cat was referred to the veterinary due to polyuria, polydipsia, weight loss and polyphagia. The presence of hyperglycemia (blood glucose >250 mg/dl), glucosuria and elevated fructosamine concentration revealed diabetes mellitus . Insulin therapy was introduced but the glycemia was poorly controlled despite the high dose of insulin. Concomitant disease was suspected. Abdominal ultrasonography revealed bilaterally enlarged adrenals. The dexamethasone suppression test showed pituitary-dependent hyperadrenocorticism. Computed tomography or hypophysectomy wasn‘t available. Medical therapy with mitotane was introduced but anorexia and vomiting developed. Bilateral adrenalectomy was performed without complications and histological evaluation of adrenal revealed hyperplasia. After surgery, treatment with mineralcorticoids and glucocorticoids was introduced. The cat had resolution of clinical signs and insulin requirements were decreased. According to the owner, three weeks after surgery, the cat showed abnormal behavior, compulsive walking and circling. The cat died eight months after bilateral adrenalectomy. A complete necropsy was performed and histopathological examination confirmed the pituitary macroadenoma. Discussion : Insulin resistance should be suspected in diabetic cat if control of glycemia is poor despite the high insulin dosage. Clinical signs related to poorly controlled diabetes mellitus are common in cats with hyperadrenocorticism. Hyperadrenocorticism can cause severe insulin resistance and it is often associated with a pituitary macrotumor. Pituitary tumors may lead to hypercotisolism. Bilateral adrenalectomy is a viable alternative to transphenoidal hypophysectomy for treatment of feline pituitary-dependent hyperadrenocorticism when hypophysectomy is not available. Neurological signs can be a result of pituitary tumors and they can get worse after the adrenalectomy because of the enlargement of the tumor. Despite of clinical signs, the cat had improved in response to the bilateral adrenalectomy and had a good quality of life during eight months after surgery.

Granulosa Cell Tumor Associated with Occult Hyperadrenocorticism in a Yorkshire Terrier Bitch

Background: Hyperadrenocorticism (HAC), is considered a set of symptoms due to excessive exposure to cortisol. Naturally occurring HAC is most often related to pituitary tumors (pituitary-dependent HAC - PDH). Occult HAC, is referred as a clinical picture highly consistent with HAC; however, routine screening tests are negative. In addition, one or more steroids are elevated following administration of adrenocorticotrophic hormone (ACTH). Ovarian granulosa cell tumors, can produce steroids leading to paraneoplastic syndromes. The objective of this study was to report an unpublished case of ovarian granulosa cell tumor associated with occult hyperadrenocorticism in a Yorkshire Terrier.Case: A 13-year-old intact female dog, Yorkshire Terrier, was brought for consultation with slight weight loss, polyuria, polydipsia, irregular estrous cycles, increased abdominal volume and thin coat. On physical examination the animal was gasping and presented severe periodontal disease, bulging abdomen, alopecia and skin hyperpigmentation. Complete blood count presented no changes; however, serum biochemistry evaluation highlighted hyperalbuminemia, hypertriglyceridemia, alkaline phosphatase increased activity, and urinary specific gravity and creatinine below reference values. On abdominal ultrasonography left adrenal gland measured 2.08 cm x 1.08 cm and the right adrenal gland measured 2.11 cm x 0.84 cm, indicating bilateral adrenomegaly compatible with PDH. In the hypogastric abdomen, a large heterogeneous hypoechogenic mass was also observed, with areas of cystic cavities, measuring 5.80 cm x 7.30 cm. A low dose dexamethasone suppression test (LDDST) was performed, due to PDH suspicion. The test did not confirm HAC, suspecting, then, to be a case of occult/atypical HAC. Due to the strong clinical suspicion, and owner financial problems for further investigated occult HAC, trilostane treatment was initiated. Approximately one month after starting treatment, an ACTH stimulation test (AST) for cortisol and 17-hydroxyprogesterone (17-OHP) determination was performed, revealing high values for both hormones. Exploratory laparotomy was indicated due to the tumor image on hypogastric region visualized on abdominal ultrasonography. A cranial pole mass of the left ovary measuring 8.5 x 7.0 x 4.5 cm, of friable consistency and brownish color, was removed through ovariohysterectomy. A granulosa cell tumor on left ovary, as well as leiomyoma and cystic endometrial hyperplasia in the uterus, became clear through histopathological examination. Trilostane treatment was sustained after surgery. Few weeks later, the patient presented a clinical picture suggestive of hypoadrenocorticism, associated with a low sodium:potassium ratio (25:1), and AST results (basal and post-ACTH cortisol) below reference range, confirming Addisonian´ crises. The patient deceives within two days.Discussion: Granulosa cell tumors can produce estrogen and progesterone, as well as other steroids, leading to paraneoplastic syndromes with peculiar clinical presentations. Steroids transport in plasma occurs via specific carrier proteins. Increased production of other steroid hormones may result in higher concentration of free cortisol, thus leading to clinical manifestations of hypercortisolism. As 17-OHP is one of the precursors in cortisol synthesis and has been shown elevated on AST, it can be assumed that altered steroid hormone levels due to the granulosa cell tumor interfered on cortisol biodisponibility, leading to HAC signs. Dexamethasone suppression test results indicated that pituitary-adrenal axis was responsive to negative feedback. The Addisonian crises after tumor removal indicate that the main source for systemic excessive cortisol effects was the eminent steroid secretion by the granulosa cell tumor.

Acquired Skin Fragility Syndrome and Diabetes Mellitus Secondary to Hyperadrenocorticism in a Cat

Background: Acquired skin fragility syndrome is a rare disorder which affects adult to senior cats with no history of skin trauma. Acquired skin fragility syndrome and diabetes mellitus, unlike the dog, are highly associated to feline hyperadrenocorticism (HAC) and, often, undiagnosed, what may accentuate the skin lesions and cause management complications. This report aimed to describe a case of acquired skin fragility syndrome and diabetes mellitus secondary to spontaneoushyperadrenocorticism in a cat, focusing on the chronic dermatological signs and their management, as well as on the treatment of the primary disease.Case: An approximately 7 year-old male mixed breed feline was admitted to the University Veterinary Hospital of an Institution with a history of polyphagia, polyuria and polydipsia, and skin ulcers on the trunk and in the cervical region about 2 months after onset and difficult to heal. Laboratory examinations indicated leukocytosis with lymphopenia, decreased urine specific gravity, glycosuria and hyperglycemia. The fasting plasma glucose level, the dexamethasone suppression test and the bilateral adrenal gland enlargement, visualized by ultrasonography, revealed diabetes mellitus and spontaneous hyperadrenocorticism, respectively. Histological skin findings indicated feline acquired skin fragility syndrome. Skin wound treatment through cleaning, protection and antibiotic therapy, and administration of insulin and trilostane were performed. After 6 months of trilostane therapy, adrenocorticotropic hormone (ACTH) stimulation test was performed, which demonstratednormal cortisol values 4 h after administration, which allowed maintenance of the dosage. After 12 months of the diagnosis of skin fragility syndrome and diabetes mellitus secondary to HAC, the patient did not present new skin lesions, fasting glycemia was within the reference values without insulin therapy and maintained only the prescription of trilostane.Discussion: The pituitary-dependent hyperadrenocorticism was the cause of the skin fragility syndrome, and it could be confirmed by the dexamethasone suppression test and the ultrasonography, which demonstrated bilateral adrenal gland enlargement. Healing of the wounds caused by the acquired skin fragility syndrome as well as the absence of new lesions may occur if the primary cause is found and treated adequately. Signs of polyuria, polydipsia and polyphagia verified inthe patient of this report are nonspecific and allow the suspicion of both diabetes mellitus and hyperadrenocorticism. The return of glycemia to basal levels and the interruption of insulin demonstrated that diabetes mellitus was transient and secondary to hyperadrenocorticism. Therefore, it is indicated in situations similar to the clinical condition described in thepatient of this report, to perform tests for diabetes mellitus and HAC. Trilostane can reduce the clinical signs of hyperadrenocorticism, but sometimes maintenance of insulin therapy is needed. The use of the drug improved the skin lesions in the cat of the current report and also allowed for the interruption of insulin administration. Those skin lesions which areof spontaneous occurrence and persistent, with no previous history of trauma and that do not respond to treatment, may alert clinicians to investigate underlying causes of non-dermatological origin and guide owners through the likely slow skin lesions healing until diagnosis and adequate therapeutic response of the primary disease.Keywords: Cushing disease, feline, skin, trilostane, wound healing.

Preoperative medical treatment in Cushing's syndrome: frequency of use and its impact on postoperative assessment: data from ERCUSYN.

Surgery is the definitive treatment of Cushing's syndrome (CS) but medications may also be used as a first-line therapy. Whether preoperative medical treatment (PMT) affects postoperative outcome remains controversial. (1) Evaluate how frequently PMT is given to CS patients across Europe; (2) examine differences in preoperative characteristics of patients who receive PMT and those who undergo primary surgery and (3) determine if PMT influences postoperative outcome in pituitary-dependent CS (PIT-CS). 1143 CS patients entered into the ERCUSYN database from 57 centers in 26 countries. Sixty-nine percent had PIT-CS, 25% adrenal-dependent CS (ADR-CS), 5% CS from an ectopic source (ECT-CS) and 1% were classified as having CS from other causes (OTH-CS). Twenty per cent of patients took PMT. ECT-CS and PIT-CS were more likely to receive PMT compared to ADR-CS (P < 0.001). Most commonly used drugs were ketoconazole (62%), metyrapone (16%) and a combination of both (12%). Median (interquartile range) duration of PMT was 109 (98) days. PIT-CS patients treated with PMT had more severe clinical features at diagnosis and poorer quality of life compared to those undergoing primary surgery (SX) (P < 0.05). Within 7 days of surgery, PIT-CS patients treated with PMT were more likely to have normal cortisol (P < 0.01) and a lower remission rate (P < 0.01). Within 6 months of surgery, no differences in morbidity or remission rates were observed between SX and PMT groups. PMT may confound the interpretation of immediate postoperative outcome. Follow-up is recommended to definitely evaluate surgical results.

Decrease of nitric oxide and increase in diastolic blood pressure are two events that affect renal function in dogs with pituitary dependent hyperadrenocorticism.

Hyperadrenocorticism is a frequent disease in dogs. The excess of circulating cortisol affects different organs and metabolic pathways, producing severe adverse effects that endanger the animal’s life. Among these effects, hypertension and renal damage can be mentioned. A group of 20 dogs with pituitary dependent hyperadrenocorticism (PDH) and 12 control dogs were used to study the following parameters: cortisol and nitric oxide (NO nit/nit) concentrations, diastolic and systolic blood pressure, renal artery resistance index by Doppler ultrasound, the rate of glomerular filtration by radio-renogram excretion and the presence of proteins in urine. Dogs with PDH showed a significantly lower NO nit/nit (P<0.0001) than the controls and this correlated with high values of diastolic and systolic pressure (r = -0.87; P<0.0001 and r = -0.81; P<0.0001 respectively). Most dogs (80%) are hypertensive mainly due to an increase in diastolic pressure, which correlated positively with the UPC (r = 0.8; P<0.001) and negatively with the glomerular rate of filtration (r = -0.58; P=0.007). Systolic pressure only increased in 60% of the cases and did not correlate with the mentioned variables. In PDH the decrease of NO affects blood pressure. The diastolic pressure would seem to have the greatest impact on the kidneys, therefore its evaluation and control are important to avoid and/or control renal damage.

Effects of Oral Prednisone Administration on Serum Cystatin C in Dogs.

BackgroundOral administration of glucocorticoid alters serum cystatin C (sCysC) concentration in humans.ObjectiveTo determine if oral administration of prednisone alters sCysC in dogs without pre‐existing renal disease.AnimalsForty six dogs were included: 10 dogs diagnosed with steroid responsive meningitis arteritis (SRMA; group A), 20 dogs diagnosed of pituitary‐dependent hyperadrenocorticism (PDH; group B), and 16 healthy control dogs (group C).MethodsRetrospective observational study. SRMA diagnosed dogs were administered prednisone 4 mg/kg/24 h PO 7 days, reducing the dose to 2 mg/kg/24 h 7 days before medication withdrawal. In group A, sampling was performed at days 0, 7, 14 and a final control at day 21. Blood and urine samples were collected in the 3 groups, and in group A, sampling was performed at all time points (days 1, 7, 14, and 21).ResultsIn group A, sCysC was significantly higher at day 7 compared to the control group (0.4 ± 0.04 mg/L vs. 0.18 ± 0.03 mg/L mean ± SEM respectively P < 0.01); sCysC values decreased to basal at day 14 when the dose was decreased and after 1 week of withdrawal of prednisone (0.27 ± 0.03 mg/L for group A at day 14 and 0.15 ± 0.02 mg/L at day 21; P > 0.05). Dogs with PDH included in group B did not have significant differences in sCysC (0.22 ± 0.03 mg/L) compared to control (P > 0.05).Conclusions and Clinical ImportanceOral administration of prednisone unlike altered endogenous glucocorticoid production, increases sCysC in dogs in a dose‐dependent fashion.

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.

Concurrent hyperadrenocorticism and diabetes mellitus in dogs

Hyperadrenocorticism (HAC) and diabetes mellitus (DM) are two diseases that can occur concurrently in dogs. The objective of this study was to evaluate the coexistence of HAC and DM, and the risk factors involved that could contribute to the development of DM in dogs with HAC. A total of 235 dogs with HAC were studied and, according to their fasting glycemia, they were divided into three groups: <5.6mmol/L, between 5.6 and 10.08mmol/L and >10.08mmol/L. The following parameters were evaluated: age, gender, cause of HAC, body condition, glycemia, total cholesterol, triglycerides, urinary cortisol:creatinin ratio (UCCR) and survival time. A 13.61% concurrence of HAC and DM was observed. Dogs with a fasting glycemia >5.6mmol/L, with dislipemia, with Pituitary-Dependent Hyperadrenocorticism, UCCR >100×10−6 and non-castrated females showed a higher risk of developing DM. The development of DM in dogs with HAC reduces the survival time.

Urine protein electrophoresis study in dogs with pituitary dependent hyperadrenocorticism during therapy with trilostane

ABSTRACT: Hyperadrenocorticism is one of the most common endocrine disorders in dogs. Regarding to the kidneys, chronic hypercortisolemia can cause damage to the glomerulus, and evolve into chronic kidney disease. This study evaluated nine normotensive dogs with pituitary dependent hyperadrenocorticism, before and after therapy with trilostane, during the follow-up period of six months, in order to investigate the development of pathological proteinuria by quantitative (urinary protein-to-creatinine ratio) and qualitative (urinary protein electrophoresis) methods, and also to monitor its intensity over the course of the disease and therapy. The main renal lesion detected in dogs with hyperadrenocorticism was in the tubular segment, evidenced by the prevalence of urinary protein bands of lower molecular weight, indicating the lack absorption of these proteins in the proximal segment of the nephron. Low molecular weight proteins persisted throughout the follow-up. Regarding the future of routine veterinary medical clinic in the care of patients with hyperadrenocorticism, the assessments of proteinuria determinations by the urinary protein-to-creatinin ratio and urinary protein electrophoresis, according to the results obtained in this study, can add more information about the renal damage in these animals, and contribute to the prognosis.

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

BackgroundA high prevalence of cholestatic disease, including gallbladder mucocele (GBM), has been reported in dogs with naturally occurring pituitary‐dependent hyperadrenocorticism (PDH).Hypothesis/ObjectivesDifferences exist in the clinical features of dogs with PDH and concurrent cholestatic disease, and also is the management of these dogs with trilostane.AnimalsSixty‐five client‐owned dogs with naturally occurring PDH.MethodsThis 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.ResultsThe 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 ImportanceGallbladder 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.

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.

Lack of Ubiquitin Specific Protease 8 (USP8) Mutations in Canine Corticotroph Pituitary Adenomas.

PurposeCushing’s disease (CD), also known as pituitary-dependent hyperadrenocorticism, is caused by adrenocorticotropic hormone (ACTH)-secreting pituitary tumours. Affected humans and dogs have similar clinical manifestations, however, the incidence of the canine disease is thousand-fold higher. This makes the dog an obvious model for studying the pathogenesis of pituitary-dependent hyperadrenocorticism. Despite certain similarities identified at the molecular level, the question still remains whether the two species have a shared oncogenetic background. Recently, hotspot recurrent mutations in the gene encoding for ubiquitin specific protease 8 (USP8) have been identified as the main driver behind the formation of ACTH-secreting pituitary adenomas in humans. In this study, we aimed to verify whether USP8 mutations also play a role in the development of such tumours in dogs.MethodsPresence of USP8 mutations was analysed by Sanger and PCR-cloning sequencing in 38 canine ACTH-secreting adenomas. Furthermore, the role of USP8 and EGFR protein expression was assessed by immunohistochemistry in a subset of 25 adenomas.ResultsNone of the analysed canine ACTH-secreting adenomas presented mutations in the USP8 gene. In a subset of these adenomas, however, we observed an increased nuclear expression of USP8, a phenotype characteristic for the USP8 mutated human tumours, that correlated with smaller tumour size but elevated ACTH production in those tumours.ConclusionsCanine ACTH-secreting pituitary adenomas lack mutations in the USP8 gene suggesting a different genetic background of pituitary tumourigenesis in dogs. However, elevated nuclear USP8 protein expression in a subset of tumours was associated with a similar phenotype as in their human counterparts, indicating a possible end-point convergence of the different genetic backgrounds in the two species. In order to establish the dog as a useful animal model for the study of CD, further comprehensive studies are needed.

Comparison of Survival Times for Dogs with Pituitary-Dependent Hyperadrenocorticism in a Primary-Care Hospital: Treated with Trilostane versus Untreated.

BackgroundAlthough pituitary‐dependent hyperadrenocorticism (PDH) is one of the most common endocrinopathies in dogs, the effects of withholding treatment on survival time in dogs with PDH remain unclear.Hypothesis/ObjectivesThe purpose of this study was to clarify the effects of treatment in dogs with PDH by comparing survival times between dogs treated with trilostane and untreated dogs.AnimalsForty‐three dogs diagnosed with PDH at a primary‐care hospital in Japan between June 2009 and January 2014.MethodsRetrospective cohort study. The medical records of dogs with PDH treated with trilostane (n = 17) or left untreated (n = 26) were reviewed retrospectively. Survival analysis at 2 years after diagnosis of PDH was performed.ResultsMedian survival time for the trilostane group was not reached (95% confidence interval [CI], 443 days–not applicable) and was significantly longer than the 506 days (95% CI, 292–564 days; P = .016) for the untreated group. Multivariate Cox proportional hazards analysis (including age at diagnosis, basal cortisol concentration at diagnosis, and treatment group) only identified assignment to the untreated group (hazard ratio, 5.01; 95% CI, 1.63–15.44) as associated with increased mortality.Conclusions and Clinical ImportanceThe results of this retrospective cohort study suggest that withholding treatment for dogs with PDH might be associated with a higher risk of death. This represents the largest study to date to report survival times of untreated dogs with PDH.

Carbenoxolone Disodium Treatment for Canine Pituitary-Dependent Hyperadrenocorticism.

Pituitary-dependent hyperadrenocorticism (PDH) is mainly caused by pituitary corticotroph tumors in dogs. A characteristic feature of corticotroph tumors is their resistance to negative feedback by glucocorticoids. In some animal species, including dogs, the aberrant expression of 11β-hydroxysteroid dehydrogenase (11HSD), a cortisol metabolic enzyme, is observed in corticotroph tumors. We previously reported that carbenoxolone (CBX), an inhibitor of 11HSD, suppressed ACTH secretion from the pituitary gland, and decreased cortisol concentrations in healthy dogs. Therefore, the aim of this study was to investigate the therapeutic effects of CBX on dogs with PDH. Six dogs with PDH were treated with 60 to 80 mg/kg/day of CBX for 6 weeks, followed by trilostane, which is a commonly used agent for canine PDH. CBX treatment led to a gradual decrease in both basal and in corticotropic releasing hormone (CRH)-stimulated plasma ACTH concentrations and CRH-stimulated serum cortisol concentrations, without side effects. However, basal and stimulated ACTH and cortisol concentrations remained higher than those of healthy dogs, and clinical symptoms such as polydipsia and polyuria were not ameliorated. After a 2-week wash-out interval, trilostane was administered for 2 weeks. Although basal plasma ACTH concentrations were higher after trilostane treatment than CBX treatment, polydipsia and polyuria resolved in all six dogs. The reason for the lack of improvement in polydipsia and polyuria with CBX treatment is unclear. Other mechanisms, in addition to a partial decrease in ACTH secretion, are likely to be involved. In conclusion, this is the first study to report the in vivo effects of CBX in dogs with PDH. The findings suggest that CBX inhibits ACTH secretion from canine pituitary tumors, resulting in lower cortisol concentrations.