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Yasushi Hara Division of Veterinary Surgery, Nippon Veterinary and Life Science University, Tokyo, JapanCorrespondence: Yasushi HaraDivision of Veterinary Surgery, Nippon Veterinary and Life Science University, 1-7-1 Kyounan-cho, Musashino-shi, Tokyo 180-8602, JapanTel +81 422 31 4151Fax +81 422 33 8836Email hara@nvlu.ac.jpAbstract: Pituitary-dependent hyperadrenocorticism (PDH) is the cause of approximately 80-85% of naturally occurring cases of hyperadrenocorticism(HAC) in canines and is triggered by an adrenocorticotropic hormone (ACTH)-producing pituitary adenoma or hyperplasia of the corticotroph in the pituitary anterior lobe or intermediate lobe. Transsphenoidal surgery(TSS) is an effective treatment that can directly remove pituitary tumors that cause PDH in canines under a single course of general anesthesia. However, careful evaluations of the definitive diagnosis, adenoma size and growth rate, relationship with surrounding tissue, general condition, and neurosurgical procedural skill involved in each case are important to determine TSS suitability. The basic principle is to confirm that the present HAC case is PDH, that is, an ACTH-producing adenoma or the hyperplasia of the corticotroph originating from either the pituitary anterior or intermediate lobe. Evaluations based on endocrinology, particularly plasma ACTH concentration, and imaging diagnosis, particularly MRI is essential for definitive diagnosis. Enlarged pituitary tumors can shorten the post-TSS survival time, increase the recurrence rate of clinical symptoms, and increase the risk for developing permanent central diabetes insipidus. Therefore, complete removal of adenomas of up to Grade IIIA according to the MRI-based classification system is relatively easy to achieve with TSS, and long-term remission and survival can be expected.Keywords: canine, cushing’s syndrome, pituitary-dependent hyperadrenocorticism, transsphenoidal surgery

Case summary: A 7-year-old spayed female domestic shorthair cat weighing 5 kg was referred with polyuria, polydipsia, lethargy, abdominal distension and dermatologic abnormalities. Diabetes mellitus was diagnosed and treatment was started with a diet for diabetic cats and insulin glargine (1 IU q12h SC). Hyperadrenocorticism (HAC) was suspected and diagnosed based on clinical signs, increased urinary cortisol:creatinine ratio, lack of suppression on low-dose dexamethasone suppression test and abdominal ultrasonography demonstrating bilateral adrenal enlargement. Oral cabergoline (10 μg/kg every other day) was initiated. After the second administration of cabergoline, the cat suffered from clinical hypoglycemia and no longer required insulin. One month after insulin withdrawal, blood work and urine analysis results showed normoglycemia, a normal serum fructosamine concentration (244 μmol/l) and normal urine analysis without glycosuria. Diabetic remission persisted until its death 7 months later. In addition, cabergoline treatment was associated with improvement in clinical signs such as lethargy, seborrhea, alopecia and abdominal distension. Relevance and novel information: To our knowledge, this is the first reported case of the use of cabergoline in a cat with HAC, as well as the first reported case of diabetic remission in a cat with HAC after cabergoline treatment. Cabergoline could be an alternative treatment for diabetic cats with pituitary-dependent HAC. Further work should focus on different protocols with greater number of cases. [ABSTRACT FROM AUTHOR]

Serum symmetric dimethylarginine (SDMA) and patterns of urinary protein separated by sodium dodecyl sulfate agarose gel electrophoresis (SDS-AGE) have not been investigated as biomarkers in dogs with ACTH-dependent hyperadrenocorticism (ADHAC). This exploratory prospective study aimed to evaluate SDMA, serum creatinine (sCR), and SDS-AGE in dogs with ADHAC with and without proteinuria (ADHAC-P and ADHAC-nP, respectively). Thirty-five pet dogs classified as ADHAC-P (n =16), ADHAC-nP (n =6) and healthy (n =13) were included. Renal biomarkers were evaluated in all dogs at diagnosis. Baseline concentration of SDMA was not significantly different between the three groups (P = 0.15) whereas sCr was significantly lower in dogs in ADHAC dogs compared to healthy dogs (88.0 µmol/L [70.4–132.6; 79.2–114.4]) whether they had proteinuria or not (P = 0.014 and 0.002, respectively). However, baseline concentrations of sCr and SDMA were not significantly different between dogs with ADHAC-P dogs (SDMA, 8 µg/dL [5–12; 7–9]; sCr, 57.2 µmol/L [35.2–212.2; 52.8–92.4]) and ADHAC-nP dogs (SDMA, 8.5 µg/dL [7–13; 8–10]; sCr, 70.4 µmol/L [61.6–79.2; 61.6–70.4]) (P = 0.35 and P = 0.41, respectively). Proteinuria in dogs with ADHAC-P was mainly of glomerular origin (SDS-AGE pattern: glomerular in 10/16 dogs; mixed glomerular/tubular in four dogs). In our study, SDMA was neither significantly different in dogs with ADHAC whether they were proteinuric or not, nor between ADHAC and healthy dogs. Urinary electrophoresis provides additional information to the UPC and further investigations are needed to determine whether it may help identify dogs with ADHAC-P requiring specific antiproteinuric treatment. • Symmetric dimethylarginine was not lower in dogs with hyperadrenocorticism (HAC). • A glomerular pattern was observed in most proteinuric dogs with HAC. • A non-selective proteinuria was observed in most dogs with HAC. [ABSTRACT FROM AUTHOR]

The incretin glucagon-like peptide 1 (GLP-1) enhances insulin secretion. The aim of this study was to assess GLP-1, glucose and insulin concentrations, Homeostatic Model Assessment (HOMAinsulin sensitivity and HOMAβ-cell function) in dogs with pituitary-dependent hyperadrenocorticism (PDH), and compare these values with those in normal and obese dogs. The Oral Glucose Tolerance Test was performed and the glucose, GLP-1 and insulin concentrations were evaluated at baseline, and after 15, 30, 60 and 120 minutes. Both basal concentration and those corresponding to the subsequent times, for glucose, GLP-1 and insulin, were statistically elevated in PDH dogs compared to the other groups. Insulin followed a similar behaviour together with variations of GLP-1. HOMAinsulin sensitivity was statistically decreased and HOMAβ-cell function increased in dogs with PDH. The higher concentrations of GLP-1 in PDH could play an important role in the impairment of pancreatic β-cells thus predisposing to diabetes mellitus. [ABSTRACT FROM AUTHOR]

Background Maximal aldosterone secretion in healthy dogs occurs 30 minutes postadrenocorticotropin ( ACTH; 5 μg/kg IV) stimulation. The effect of trilostane and mitotane on aldosterone at that time is unknown. Objectives To assess the effect of trilostane and mitotane in dogs with pituitary-dependent hyperadrenocorticism on aldosterone secretory reserve. To determine if aldosterone concentration correlates with electrolyte concentrations. Animals Serum collected from 79 client-owned dogs and 33 stored samples. Methods Client-owned dogs had ACTH stimulation tests with cortisol concentrations measured at 0 and 60 minutes and aldosterone concentrations measured at 0, 30, and 60 minutes. Stored samples had aldosterone concentrations measured at 0 and 60 minutes. Ten historical clinically healthy controls were included. All had basal sodium and potassium concentrations measured. Results The aldosterone concentrations in the mitotane- and trilostane-treated dogs at 30 and 60 minutes post- ACTH were significantly lower than in clinically healthy dogs; no significant difference was detected in aldosterone concentration between 30 and 60 minutes in treated dogs. However, a significantly higher percentage of dogs had decreased aldosterone secretory reserve detected at 30 minutes than at 60 minutes. At 30 minutes, decreased secretory reserve was detected in 49% and 78% of trilostane- and mitotane-treated dogs, respectively. No correlation was detected between aldosterone and serum electrolyte concentrations. Conclusions and Clinical Importance Decreased aldosterone secretory reserve is common in trilostane- and mitotane-treated dogs; it cannot be predicted by measurement of serum electrolyte concentrations. Aldosterone concentration at 30 minutes post- ACTH stimulation identifies more dogs with decreased aldosterone secretory reserve than conventional testing at 60 minutes. [ABSTRACT FROM AUTHOR]

Abstract: Diabetes is often associated with pituitary-dependent hyperadrenocorticism (PDH). Hypercortisolism causes insulin resistance and affects β-cell function. The purpose of this study was to test if daily administration of a long-acting insulin analogue during the first month of anti-PDH treatment can prevent progress to diabetes in these animals. Twenty-six PDH dogs were divided into three groups: one group with glycaemia <5.83mmol/L and two groups with glycaemia >5.83mmol/L and <9.35mmol/L, one of which received insulin detemir during 4months. Dogs with glycaemia <5.83mmol/L and those with glycaemia >5.83mmol/L which received insulin did not develop diabetes. In the non-insulin group, 6/7 dogs developed diabetes after the third month. There is a 13-fold higher risk of diabetes in dogs with glycaemia >5.83mmol/L and no insulin treatment. Administering insulin detemir to dogs with PDH and glycaemia >5.83mmol/L could prevent progression to diabetes. [Copyright &y& Elsevier]

Abstract: Pituitary-dependent hyperadrenocorticism is a common endocrine disorder in dogs in the United States. Once a diagnosis is established, a decision must be made whether or not to pursue treatment, and if so, which medication to use. Historically, mitotane (Lysodren, o,p''-DDD, Bristol-Myers Squibb, New York) has been the most commonly used treatment for medical management. Its use is complicated and comes with many potential side effects, making many practitioners wary of its use. Recently, trilostane has been proven to be an effective treatment of pituitary-dependent hyperadrenocorticism and is approved for use in other countries. Treatment with trilostane is somewhat simpler and the incidence of side effects seems to be less when compared with mitotane therapy. Either treatment can be a safe and effective method of treatment for pituitary-dependent hyperadrenocorticism when the practitioner and client are well educated regarding their use and an appropriate monitoring protocol is used. [Copyright &y& Elsevier]

Abstract: Pituitary-dependent hyperadrenocorticism (PDH) is frequent in dogs. Little is known about its presentation in different age groups and its characteristics. Dividing the population under study (n =107) into three age groups we observed that 11.2% were young, 51.4% adults and 37.4% aged. Using magnetic resonance, pituitary tumours were intra-sellar (IS) in 30.8% and extra-sellar (ES) in 62.6% and the pars intermedia (PI) was affected in 6.5%. ES are predominant in females and IS in males (p <0.0001). In the adult-aged population, the ES and PI are predominant, while in the young, the IS predominate (p <0.0001). ACTH concentration was greater in the ES vs. IS (p <0.05). α-MSH did not present significant differences according to tumour size, showing a negative correlation (r =−0.47; p <0.01) vs. ACTH. Differences in adenoma size according to gender and their age-related frequency of apparition could be because of different origins of the corticotrophinoma. [Copyright &y& Elsevier]

Objective– To describe a case of spontaneous pneumothorax secondary to pulmonary thromboembolism possibly associated with pituitary dependent hyperadrenocorticism. Case Summary– A 7-year-old spayed female Collie weighing 26 kg was referred for evaluation of spontaneous pneumothorax. An exploratory thoracotomy was performed and revealed 2 lung lobes to be diffusely hemorrhagic and they were resected. Histologic examination of multiple sections documented diffuse thromboembolism. A 2–3 cm thrombus was visualized distal to the bifurcation of the pulmonary artery during an echocardiographic examination postoperatively. The dog was discharged to the owner after recovery from surgery. The thrombus had resolved at the 4-week recheck examination. Diagnosis of pituitary dependent hyperadrenocorticism was confirmed based on follow-up endocrine testing. New or Unique Information Provided– This is the first report of pulmonary thromboembolism causing spontaneous pneumothorax in the dog. [ABSTRACT FROM AUTHOR]

Abstract: Pituitary-dependent hyperadrenocorticism (PDH) in dogs is caused by a pituitary corticotroph adenoma. Although PDH is a common disorder in dogs, little is known about the underlying pathogenesis. In the pituitary glands of humans and mice, the pro-opiomelanocortin (POMC)-expressing cell lineages, the corticotrophs and melanotrophs, have a specific marker in common, the T-box transcription factor Tpit (Tbx19), which is obligate for POMC expression. Tpit also regulates the late differentiation of the corticotrophs and melanotrophs, and therefore may contribute to the pathogenesis of the corticotroph adenomas. The aim of this study was to perform an expression and mutation analysis of Tpit in the normal canine pituitary and in corticotroph adenomas. The distribution of the Tpit protein in the pituitary gland was studied with immunohistochemistry and the expression of the gene with RT-PCR. The coding region of Tpit cDNA from 14 dogs with PDH was screened for mutations. Tpit was expressed in corticotroph and melanotroph cells of the normal and adenomatous canine pituitary, and remained present in non-adenomatous corticotrophs of pituitaries from PDH dogs. No tumor-specific mutation in the Tpit cDNA from the corticotroph adenomas was found. However, a missense polymorphism in the highly conserved DNA-binding domain, the T-box, was discovered in one dog. It is concluded that Tpit can be used as a reliable marker for the corticotroph and melanotroph cells in the canine pituitary tissue and that mutations in the Tpit gene are unlikely to play a major role in the pathogenesis of canine corticotroph adenomas. [Copyright &y& Elsevier]

Pituitary-dependent hyperadrenocorticism is a common endocrine disorder in dogs in the United States. Once a diagnosis is established, a decision must be made whether or not to pursue treatment, and if so, which medication to use. Historically, mitotane (Lysodren, o,p’-DDD, Bristol-Myers Squibb, New York) has been the most commonly used treatment for medical management. Its use is complicated and comes with many potential side effects, making many practitioners wary of its use. Recently, trilostane has been proven to be an effective treatment of pituitary-dependent hyperadrenocorticism and is approved for use in other countries. Treatment with trilostane is somewhat simpler and the incidence of side effects seems to be less when compared with mitotane therapy. Either treatment can be a safe and effective method of treatment for pituitary-dependent hyperadrenocorticism when the practitioner and client are well educated regarding their use and an appropriate monitoring protocol is used. [Copyright &y& Elsevier]

To evaluate the degree of pituitary exposure, completeness of hypophysectomy, and perioperative morbidity associated with an alternative paramedian surgical approach and excisional technique for the canine pituitary gland. Experimental imaging, surgical, and endocrinologic study. Nine healthy, purpose-bred Beagle dogs. Surgical landmarks for the pituitary were determined by computed tomography (CT), and then using a ventral paramedian approach medial to the rami of the mandible, the pituitary was exposed and removed en bloc by manipulation and ultrasonic aspiration. Efficacy of the procedure was evaluated using endocrinologic and pathologic observation. CT images allowed the precise location of surgical landmarks for hypophysectomy. Statistically significant decreases in secretion of all measured pituitary hormones except adrenocorticotropic hormone (ACTH) occurred after hypophysectomy. Despite the absence of gross evidence of residual pituitary tissue, immunohistochemical staining revealed residual pituitary cells in the sella turcica of most dogs. CT imaging and a paramedian approach facilitated surgical access to the pituitary gland by a transoral technique; however, use of an ultrasonic aspirator removed all visible pituitary glands but left cellular remnants capable of ACTH secretion in the sella turcica. Although this technique did not result in complete hypophysectomy, clinical use in dogs with pituitary-dependent hyperadrenocorticism is warranted because the goal is not complete hypophysectomy but removal of a pituitary tumor. [ABSTRACT FROM AUTHOR]

Background Trilostane is commonly used in the treatment of dogs with naturally occurring pituitary-dependent hyperadrenocorticism ( PDH). Dose recommendations have varied from the manufacturer and the literature. Hypothesis As body weight increases, dose/kg or dosage/day of trilostane required to control the clinical signs of PDH decreases. Animals 70 dogs with naturally occurring hyperadrenocorticism. Methods Retrospective study. Each dog must have been treated for at least 6 months and should have shown a 'good response' to trilostane, as determined by owners. Statistical comparisons of dose and dosage were made after the dogs were separated into groups weighing <15 or >15 kg; groups weighing ≤10, 10.1-20, 20.1-30, and ≥30 kg; and then groups based on body surface area versus dose/kg and total amount of trilostane required to control the condition. Results There was no significant difference in trilostane dose in mg/kg of body weight or in the total amount of trilostane required daily to control clinical signs, except when the dose for dogs weighing >30 kg was compared with that for the other groups. However, despite lack of statistical significance when comparing groups, there was a significant trend using polynomial regression analysis, suggesting that as body weight increases, the amount of trilostane (mg/kg/dose as well as mg/kg/daily dosage) required to control clinical signs decreases. Conclusions and Clinical Importance Dogs weighing >30 kg, and possibly those weighing >15 kg, might require smaller amounts of trilostane per dose or per day than those weighing less, to control PDH-associated clinical signs. [ABSTRACT FROM AUTHOR]

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., (Copyright © 2021. Published by Elsevier Ltd.)

Case Summary: A 7-year-old spayed female domestic shorthair cat weighing 5 kg was referred with polyuria, polydipsia, lethargy, abdominal distension and dermatologic abnormalities. Diabetes mellitus was diagnosed and treatment was started with a diet for diabetic cats and insulin glargine (1 IU q12h SC). Hyperadrenocorticism (HAC) was suspected and diagnosed based on clinical signs, increased urinary cortisol:creatinine ratio, lack of suppression on low-dose dexamethasone suppression test and abdominal ultrasonography demonstrating bilateral adrenal enlargement. Oral cabergoline (10 μg/kg every other day) was initiated. After the second administration of cabergoline, the cat suffered from clinical hypoglycemia and no longer required insulin. One month after insulin withdrawal, blood work and urine analysis results showed normoglycemia, a normal serum fructosamine concentration (244 μmol/l) and normal urine analysis without glycosuria. Diabetic remission persisted until its death 7 months later. In addition, cabergoline treatment was associated with improvement in clinical signs such as lethargy, seborrhea, alopecia and abdominal distension., Relevance and Novel Information: To our knowledge, this is the first reported case of the use of cabergoline in a cat with HAC, as well as the first reported case of diabetic remission in a cat with HAC after cabergoline treatment. Cabergoline could be an alternative treatment for diabetic cats with pituitary-dependent HAC. Further work should focus on different protocols with greater number of cases., Competing Interests: Conflict of interest: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Transsphenoidal surgery is an option for dogs and cats with functional and nonfunctional pituitary masses or other sellar and parasellar masses. An adrenocorticotropic hormone-secreting tumor causing Cushing disease is the most common clinically relevant pituitary tumor in dogs, and the most common pituitary tumor seen in cats is a growth hormone-secreting tumor causing acromegaly. Transsphenoidal surgery can lead to rapid resolution of clinical signs and provide a cure for these patients. Because of the risks associated with this surgery, it should only be attempted by a cohesive pituitary surgery group with a sophisticated medical and surgical team., (Copyright © 2017 Elsevier Inc. All rights reserved.)