Diagnosis, treatment and outcome of pheochromocytoma in a cat.

Pheochromocytoma in cats is a rare clinical condition characterised by the development of a secretory endocrine tumour that arises from the adrenal medulla. An 8-year-old castrated male, domestic shorthair cat was referred for further investigation of a 4-month history of progressive weight loss with normal appetite, polyuria/polydipsia, generalised weakness, and severe hypertension. Sonography and computed tomography of the abdomen disclosed a mass arising from the left adrenal gland. The contralateral adrenal gland was normal in size and shape. Results from a low dose dexamethasone suppression test and measurements of plasma aldosterone concentration and plasma renin activity ruled out a cortisol-secreting tumour and aldosteronoma. The clinical presentation made a sex-steroid secreting tumour unlikely. Increased plasma metanephrine and normetanephrine concentrations prioritised the differential diagnosis of pheochromocytoma. The cat underwent adrenalectomy of the left gland and histopathological diagnosis with immunohistochemical markers confirmed the diagnosis.

Pituitary tumour types in dogs and cats.

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

Endocrine diseases in animals.

BACKGROUND: Several endocrine disorders that affect humans also occur as endocrinopathies in companion animals. Spontaneous endocrine disorders in animals may provide valuable information for their counterparts in human endocrinology. For example, the discovery of progesterone-induced growth hormone production in the mammary gland of dogs may have important consequences for understanding the pathogenesis of breast cancer in women. In addition, the majority of diabetic cats have a type of diabetes mellitus that closely resembles type 2 diabetes mellitus in humans and therefore may serve as an animal model for this disease in humans. This review describes several endocrine diseases in companion animals that are quite similar to those in humans and emphasizes their usefulness as spontaneous animal models for human endocrine disorders.

Urinary corticoid: creatinine ratios in dogs with pituitary-dependent hypercortisolism during trilostane treatment.

BACKGROUND: The adrenocorticotropic hormone (ACTH) stimulation test is used to evaluate trilostane treatment in dogs with hypercortisolism. HYPOTHESIS: The urinary corticoid : creatinine ratio (UCCR) is a good alternative to the ACTH stimulation test to determine optimal trilostane dose. ANIMALS: Eighteen dogs with pituitary-dependent hypercortisolism. METHODS: In this prospective study, the dose of trilostane was judged to be optimal on the basis of resolution of clinical signs of hypercortisolism and results of an ACTH stimulation test. The owners collected urine for determination of UCCR at 2-week intervals for at least 8 weeks after achieving the optimal trilostane dose. RESULTS: The UCCRs were significantly higher before treatment (11.5-202.0 x 10(-6); median, 42.0 x 10(-6)) than at rechecks 2 months after optimal dosing, but they did not decrease below the upper limit of the reference range in the majority of dogs. The UCCRs of 11 dogs that initially were dosed insufficiently (range, 7.5-79.0 x 10(-6); median, 31.0 x 10(-6)) did not differ significantly from UCCRs when the dosage was optimal (8.2-72.0 x 10(-6); median, 33.0 x 10(-6)). Post-ACTH cortisol concentrations did not correlate significantly with UCCRs at rechecks during trilostane treatment. Long-term follow-up indicated that the decrease in UCCR below the upper limit of the reference was associated with hypocortisolism. CONCLUSION AND CLINICAL IMPORTANCE: The UCCR cannot be used as an alternative to the ACTH stimulation test to determine the optimal dose of trilostane, but might be helpful in detecting dogs at risk for developing hypocortisolism during trilostane treatment.

Luteinizing hormone-dependent Cushing's syndrome in a pet ferret (Mustela putorius furo).

Hyperadrenocorticism in ferrets is associated with increased circulating concentrations of adrenal androgens, whereas plasma concentrations of cortisol and ACTH are usually not affected. Here, we report on a 5-year-old castrated male pet ferret (Mustela putorius furo) in which the major presenting signs were polyuria and polyphagia. Routine biochemistry values were within their reference ranges. The urinary corticoid:creatinine ratio (UCCR) was increased and the plasma ACTH concentration was suppressed. Abdominal ultrasonography revealed an enlarged right adrenal gland and atrophy of the left adrenal gland. Administration of hCG resulted in an increase of plasma cortisol and androstenedione concentrations. Based on these findings LH/hCG-dependent hypercortisolism and hyperandrogenism were suspected and treatment was started with a depot GnRH-agonist implant containing 9.4mg deslorelin. Within 3 weeks after placement of the implant all clinical signs had disappeared. Three months later the endocrine parameters had normalized, while abdominal ultrasonography revealed that the right adrenal gland had diminished in size and the left adrenal gland was considered of normal size. No recurrences of clinical signs were seen within 2 years after placement of the deslorelin implant. At that time urinary corticoid and plasma hormone concentrations were within their reference ranges, and no further change in the size of the adrenal glands was seen. In conclusion, this is the first confirmed case of LH-dependent hypercortisolism in a ferret that was treated successfully with a depot GnRH-agonist.

Thyrotropin-releasing hormone-induced growth hormone secretion in dogs with primary hypothyroidism.

Primary hypothyroidism in dogs is associated with increased release of growth hormone (GH). In search for an explanation we investigated the effect of intravenous administration of thyrotropin-releasing hormone (TRH, 10 microg/kg body weight) on GH release in 10 dogs with primary hypothyroidism and 6 healthy control dogs. The hypothyroid dogs had a medical history and physical changes compatible with hypothyroidism and were included in the study on the basis of the following criteria: plasma thyroxine concentration < 2 nmol/l and plasma thyrotropin (TSH) concentration > 1 microg/l. In addition, (99m)TcO(4)(-) uptake during thyroid scintigraphy was low or absent. TRH administration caused plasma TSH concentrations to rise significantly in the control dogs, but not in the hypothyroid dogs. In the dogs with primary hypothyroidism, the mean basal plasma GH concentration was relatively high (2.3+/-0.5 microg/l) and increased significantly (P=0.001) 10 and 20 min after injection of TRH (to 11.9+/-3.5 and 9.8+/-2.7 microg/l, respectively). In the control dogs, the mean basal plasma GH concentration was 1.3+/-0.1 microg/l and did not increase significantly after TRH administration. We conclude that, in contrast to healthy control dogs, primary hypothyroid dogs respond to TRH administration with a significant increase in the plasma GH concentration, possibly as a result of transdifferentiation of somatotropic pituitary cells to thyrosomatotropes.

ACTH-independent hyperadrenocorticism due to food-dependent hypercortisolemia in a dog: a case report.

In addition to adrenocortical tumours, aberrant expression of functional hormone receptors in the adrenal cortex may cause adrenocorticotrophic hormone (ACTH)-independent hyperadrenocorticism. Here we report on a 6 year old Vizsla dog in which ACTH-independent hyperadrenocorticism was associated with meal-induced hypercortisolemia. Diagnosis was based on history, physical findings, biochemical changes, and elevation of the urinary corticoid/creatinine ratio (UCCR) on two consecutive days (11 and 8.3 x 10(-6), reference range <8.3 x 10(-6)). Basal plasma ACTH concentration was found by repeated measurements to be suppressed (<1 ng/L, reference range 5-85 ng/L) and administration of corticotrophin releasing hormone (CRH) resulted in a minor increase (to 6 ng/L), consistent with ACTH-independent hyperadrenocorticism. Ultrasonography and computed tomography revealed two uniformly enlarged adrenal glands. Magnetic resonance imaging of the pituitary area showed a non-enlarged, normally enhancing pituitary gland. Based on these results, expression of functional aberrant adrenocortical receptors was suspected and the possibility of food-dependent hyperadrenocorticism was explored. The UCCR on two separate occasions rose from 11 and 8 x 10(-6) before a meal to 25 and 23 x 10(-6) at 3 h after ingestion of a meal, respectively. There was a corresponding increase in plasma cortisol concentration (from 90 to 150 nmol/L), while plasma ACTH concentration remained low or undetectable. Consistent with the diagnostic criteria for food-dependent hyperadrenocorticism in humans, administration of octreotide completely prevented meal-induced hypercortisolemia. The dog was treated successfully with the cortisol-synthesis-inhibitor trilostane (2h before meal), and at 26 months after the final diagnosis the dog is still in good condition. The combination of (1) low plasma ACTH concentration in the absence of an adrenocortical tumour, (2) an increase of >100% in UCCR after ingestion of a meal, (3) prevention of the meal-induced increase in plasma cortisol concentration by octreotide, and (4) reversal of signs of hypercortisolism by administration of trilostane a few hours before the meal led to the diagnosis of food-dependent hyperadrenocorticism in this dog.

Urinary aldosterone to creatinine ratio in cats before and after suppression with salt or fludrocortisone acetate.

BACKGROUND: The endocrine diagnosis of primary hyperaldosteronism in cats currently is based on an increased plasma aldosterone to renin ratio, which has several disadvantages for use in veterinary practice. OBJECTIVES: To establish a reference range for the urinary aldosterone to creatinine ratio (UACR) and to determine whether oral administration of either sodium chloride or fludrocortisone acetate is effective for use in a suppression test. ANIMALS: Forty-two healthy cats from an animal shelter and 1 cat with primary hyperaldosteronism from a veterinary teaching hospital. METHODS: Morning urine samples for determination of the basal UACR were collected from 42 healthy cats. For the suppression tests, urine samples for the UACR were collected after twice daily oral administration for 4 consecutive days of either sodium chloride, 0.25 g/kg body weight (n = 22) or fludrocortisone acetate, 0.05 mg/kg body weight (n = 15). RESULTS: The median basal UACR was 7.2 x 10(-9) (range, 1.8-52.3 x 10(-9)), with a calculated reference range of < 46.5 x 10(-9). Administration of sodium chloride resulted in adequate salt loading in 10 of 22 cats, but without significant reduction in the UACR. Administration of fludrocortisone resulted in a significant decrease in the UACR (median, 78%; range, 44-97%; P < .001) in healthy cats. In the cat with an aldosterone-producing adrenocortical carcinoma, the basal UACR and the UACR after fludrocortisone administration were 32 x 10(-9) and 36 x 10(-9), respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: Using the UACR for an oral fludrocortisone suppression test may be useful for the diagnosis of primary hyperaldosteronism in cats.

Treating canine Cushing's syndrome: Current options and future prospects.

Naturally occurring hypercortisolism, also known as Cushing's syndrome, is a common endocrine disorder in dogs that can be caused by an adenocorticotrophic hormone (ACTH)-producing pituitary adenoma (pituitary-dependent hypercortisolism, PDH; 80-85% of cases), or by an adrenocortical tumor (ACT; 15-20% of cases). To determine the optimal treatment strategy, differentiating between these two main causes is essential. Good treatment options are surgical removal of the causal tumor, i.e. hypophysectomy for PDH and adrenalectomy for an ACT, or radiotherapy in cases with PDH. Because these options are not without risks, not widely available and not suitable for every patient, pharmacotherapy is often used. In cases with PDH, the steroidogenesis inhibitor trilostane is most often used. In cases with an ACT, either trilostane or the adrenocorticolytic drug mitotane can be used. Although mostly effective, both treatments have disadvantages. This review discusses the current treatment options for canine hypercortisolism, and considers their mechanism of action, efficacy, adverse effects, and effect on survival. In addition, developments in both adrenal-targeting and pituitary-targeting drugs that have the potential to become future treatment options are discussed, as a more selective and preferably also tumor-targeted approach could have many advantages for both PDH and ACTs.

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

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

Pheochromocytomas and paragangliomas in humans and dogs.

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are described in several species. In humans and dogs they have many similarities: the excessive catecholamine release in hormonally active PCC causes similar clinical signs, the frequency of metastasis is similar, and they are histopathologically almost identical. Surgery is curative when PCC and PGL have not metastasized, while only palliative treatment is possible for patients with metastatic disease. Mutations in succinate dehydrogenase subunit B (SDHB) are associated with metastatic behaviour in human PCC/PGL and the same mutation has been described in dogs. The dog might therefore be a suitable model for study of the pathogenesis of metastatic PCC and PGL in humans. Further molecular studies of common tumourigenic pathways and comparative studies of histopathology of human and canine PCC and PGL are warranted.

[Transdermal carbimazole for the treatment of feline hyperthyroidism]. / Carbimazolzalf ter behandeling van hyperthyreoïdie bij de kat.

Orally administered antithyroid drugs are frequently used to treat hyperthyroidism in cats; however, the non-cooperative behaviour of some cats may make it difficult to administer tablets. The aim of this study was to develop a carbimazole ointment for application to the inner pinna of the ear and to test its effectiveness in 13 cats with hyperthyroidism. Laboratory investigations were performed before, and 4, 8, and 12 weeks after start of the treatment. Laboratory data for 9 cats were available at the end of the observation period. The starting dose of carbimazole ointment was 5 mg once daily. If no complications occurred, the dose was increased to 5 mg twice daily from the 6th day onwards. Further dose adjustments were mainly based on the plasma thyroxine (T4) concentration. The median plasma T4 concentration at the end of the observation period (24 nmol/l) was significantly lower than that before treatment (152 nmol/l). The dosage of carbimazole needed to achieve euthyroidism ranged from 4 to 17 mg twice daily. Treatment with carbimazole ointment resulted in disappearance of signs of hyperthyroidism; plasma concentrations of urea and creatinine increased significantly. The results of this study indicate that twice daily administration of carbimazole ointment to the inner pinna of the ear is an effective treatment for hyperthyroidism in cats. This provides the veterinarian with a new and promising treatment option. Because carbimazole ointment has not been registered, according to European law it can only be used for the treatment of hyperthyroidism in cats if other licensed medications have been tried and if there is a therapeutic need.

New Insights in the Functional Zonation of the Canine Adrenal Cortex.

BACKGROUND: Current understanding of adrenal steroidogenesis is that the production of aldosterone or cortisol depends on the expression of aldosterone synthase (CYP11B2) and 11ß-hydroxylase cytochrome P450 (CYP11B1), respectively. However, this has never been studied in dogs, and in some species, a single CYP11B catalyzes both cortisol and aldosterone formation. Analysis of the canine genome provides data of a single CYP11B gene which is called CYP11B2, and a large sequence gap exists near the so-called CYP11B2 gene. OBJECTIVES: To investigate the zonal expression of steroidogenic enzymes in the canine adrenal cortex and to determine whether dogs have 1 or multiple CYP11B genes. ANIMALS: Normal adrenal glands from 10 healthy dogs. METHODS: Zona fasciculata (zF) and zona glomerulosa (zG) tissue was isolated by laser microdissection. The mRNA expression of steroidogenic enzymes and their major regulators was studied with RT-qPCR. Southern blot was performed to determine whether the sequence gap contains a CYP11B gene copy. Immunohistochemistry (IHC) was performed for 17α-hydroxylase/17,20-lyase (CYP17). RESULTS: Equal expression (P = .62) of the so-called CYP11B2 gene was found in the zG and zF. Southern blot revealed a single gene. CYP17 expression (P = .05) was significantly higher in the zF compared with the zG, which was confirmed with IHC. CONCLUSIONS AND CLINICAL IMPORTANCE: We conclude that there is only 1 CYP11B gene in canine adrenals. The zone-specific production of aldosterone and cortisol is probably due to zone-specific CYP17 expression, which makes it an attractive target for selective inhibition of cortisol synthesis without affecting mineralocorticoid production in the zG.

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

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

Hyperadrenocorticism in a dog due to ectopic secretion of adrenocorticotropic hormone.

Spontaneous hyperadrenocorticism in dogs is known to be the result of excessive secretion of adrenocorticotropic hormone (ACTH) by the pituitary gland or excessive autonomous glucocorticoid secretion by an adrenocortical tumor. Here, we report on an 8-year-old German shepherd dog in which ACTH-dependent hyperadrenocorticism was a result of ectopic ACTH secretion and could be related to an abdominal neuroendocrine tumor. Hyperadrenocorticism was diagnosed on the basis of the history, clinical signs, and elevated urinary corticoid/creatinine ratios (UCCRs; 236 and 350 x 10(-6); reference range < 10 x 10(-6)). The UCCR remained elevated (226 x 10(-6)) after three oral doses of dexamethasone (0.1 mg/kg body weight) at 8-h intervals. Ultrasonography revealed two equivalently enlarged adrenal glands, consistent with adrenocortical hyperplasia. Plasma ACTH concentration was clearly elevated (159 and 188 ng/l; reference range 5-85 ng/l). Computed tomography (CT) revealed that the pituitary was not enlarged. These findings were interpreted as indicating dexamethasone-resistant pituitary-dependent hyperadrenocorticism. Transsphenoidal hypophysectomy was performed but within 2 weeks after surgery, there was exacerbation of the clinical signs of hyperadrenocorticism. Plasma ACTH concentration (281 ng/l) and UCCRs (1518 and 2176 x 10(-6)) were even higher than before surgery. Histological examination of the pituitary gland revealed no neoplasia. Stimulation of the pituitary with corticotropin-releasing hormone did not affect plasma ACTH and cortisol concentrations. Treatment with trilostane was started and restored normocorticism. CT of the pituitary fossa, 10 months after hypophysectomy, revealed an empty sella. Hence, it was presumed that there was ectopic secretion of ACTH. CT of the abdomen revealed a mass in the region of the pancreas and a few nodules in the liver. Partial pancreatectomy with adjacent lymph node extirpation was performed and the liver nodules were biopsied. Histological examination revealed a metastasized neuroendocrine tumor. Abdominal surgery was not curative and medical treatment with trilostane was continued. At 18 months after the abdominal surgery, the dog is still in good condition. In conclusion, the combination of (1) severe dexamethasone-resistant hyperadrenocorticism with elevated circulating ACTH levels, (2) definitive demonstration of the absence of pituitary neoplasia, and (3) an abdominal neuroendocrine tumor allowed the diagnosis of ectopic ACTH secretion.

Hypoluteoidism in a bitch.

Hypoluteoidism is characterized by insufficient secretion of progesterone by the corpora lutea during pregnancy. The resulting failure to maintain progesterone concentration above a critical level presumably could lead to fetal resorbtion as well as frank abortion. This report concerns a 2.5-year-old Bernese Mountain dog with a history of two previous pregnancies ending in abortion around Day 50 of pregnancy. The bitch was initially presented 2 days after mating. Physical and gynecological examination revealed no abnormalities. The infectious causes of abortion in the bitch, Brucella canis and herpesvirus, were excluded using serology. On Day 26 after mating, ultrasonography confirmed a pregnancy with at least four living fetuses. During the remaining part of the pregnancy repeated transabdominal ultrasonography and plasma progesterone measurements, using a RIA, were performed. On Day 42, ultrasonography revealed living fetuses but plasma progesterone concentration had decreased to 8.3 nmol/L, which is just above the threshold necessary to maintain a vital pregnancy. Oral treatment with 0.1mg medroxyprogesterone acetate (MPA) per kg body weight, once daily, was started and continued until Day 58 in order to prevent abortion due to progesterone deficiency. The endogenous plasma progesterone concentration decreased further, but pregnancy was maintained. On Day 59 a cesarean section was performed because of dystocia and four living and one dead pup were delivered. One puppy had severe facial malformations and was euthanised. The premature decrease in plasma progesterone concentration while ultrasonography demonstrated that the fetuses were still alive, and the maintenance of pregnancy during administration of MPA, strongly support the diagnosis of hypoluteoidism.

Insulin-like growth factor--phosphatidylinositol 3 kinase signaling in canine cortisol-secreting adrenocortical tumors.

BACKGROUND: Hypercortisolism is a common endocrine disorder in dogs, caused by a cortisol-secreting adrenocortical tumor (AT) in approximately 15% of cases. In adrenocortical carcinomas of humans, activation of the phosphatidylinositol 3 kinase (PI3K) signaling pathway by insulin-like growth factor (IGF) signaling represents a promising therapeutic target. OBJECTIVES: To investigate the involvement of PI3K signaling in the pathogenesis of ATs in dogs and to identify pathway components that may hold promise as future therapeutic targets or as prognostic markers. ANIMALS: Analyses were performed on 36 canine cortisol-secreting ATs (11 adenomas and 25 carcinomas) and 15 normal adrenal glands of dogs. METHODS: mRNA expression analysis was performed for PI3K target genes, PI3K inhibitor phosphatase and tensin homolog (PTEN), IGFs, IGF receptors, IGF binding proteins and epidermal growth factor receptors. Mutation analysis was performed on genes encoding PTEN and PI3K catalytic subunit (PIK3CA). RESULTS: Target gene expression indicated PI3K activation in carcinomas, but not in adenomas. No amino acid-changing mutations were detected in PTEN or PIK3CA and no significant alterations in IGF-II or IGFR1 expression were detected. In carcinomas, ERBB2 expression tended to be higher than in normal adrenal glands, and higher expression of inhibitor of differentiation 1 and 2 (ID1 and ID2) was detected in carcinomas with recurrence within 2.5 years after adrenalectomy. CONCLUSIONS AND CLINICAL IMPORTANCE: Based on these results, ERBB2 might be a promising therapeutic target in ATs in dogs, whereas ID1 and 2 might be valuable as prognostic markers and therapeutic targets.

Effects of aglépristone, a progesterone receptor antagonist, administered during the early luteal phase in non-pregnant bitches.

Aglépristone, a progesterone receptor antagonist, was administered to six non-pregnant bitches in the early luteal phase in order to determine its effects on the duration of the luteal phase, the interestrous interval, and plasma concentrations of progesterone and prolactin. Aglépristone was administered subcutaneously once daily on two consecutive days in a dose of 10 mg/kg body weight, beginning 12 +/- 1 days after ovulation. Blood samples were collected before, during, and after administration of aglépristone for determination of plasma progesterone and prolactin concentrations. The differences in mean plasma concentration of progesterone and of prolactin before, during, and after treatment were not significant. Also, the duration of the luteal phase in the six treated bitches (72 +/- 6 days) did not differ significantly from that in untreated control dogs (74 +/- 4 days ). However, the intervals during which plasma progesterone concentration exceeded 64 and 32 nmol/l were significantly shorter in the six treated bitches than in untreated control dogs. The interestrous interval was significantly shorter in beagle bitches treated with aglépristone (158 +/- 16 days) than in the same group prior to treatment (200 +/- 5 days ). It is concluded that administration of aglépristone during the early luteal phase in the non-pregnant bitch affects progesterone secretion, but not sufficiently to shorten the luteal phase. The shortening of the interestrous interval suggests that aglépristone administered in the early luteal phase influences the hypothalamic-pituitary-ovarian axis.

Termination of mid-gestation pregnancy in bitches with aglepristone, a progesterone receptor antagonist.

Six pregnancies were terminated in mid-gestation with aglépristone, a progesterone receptor antagonist, in 5 beagle bitches in order to determine the effects of aglépristone on plasma concentrations of prolactin and progesterone, the duration of the luteal phase, and the interestrous interval. In addition, the effects of aglépristone on the condition of the uterus and fetuses were examined by ultrasonography. After confirmation of pregnancy by ultrasonography, the dogs received 10 mg, s.c. aglépristone per kg body weight on 2 consecutive days at about 30 d post ovulation. Before, during and after treatment with aglépristone, plasma samples were collected for determination of the concentrations of prolactin and progesterone. The condition of the uterus and fetuses was assessed by ultrasonography the day before and at least 3 times a week for at least 2 wk after aglépristone administration. Termination of pregnancy occurred within 4 to 7 d after the start of aglépristone treatment, which was well tolerated, with no side-effects except slight vaginal discharge. The results of ultrasonographic examination indicated that aglépristone leads to abortion but not to fetal resorption. Elevated plasma concentrations of prolactin were observed during aglépristone treatment, while plasma progesterone levels remained unchanged. Pregnancy termination with aglépristone resulted in premature cessation of luteal function. In addition, the interestrous interval was shortened. The latter effects may be the consequence of actions of the progesterone receptor antagonist at the hypothalamus-pituitary level. In conclusion, aglépristone proved to be a safe and effective abortifacient in mid-gestation in the bitch. The results of the present study also indicated that aglépristone directly or indirectly influences pituitary function.

Urinary corticoid/creatinine ratios in the differentiation between pituitary-dependent hyperadrenocorticism and hyperadrenocorticism due to adrenocortical tumour in the dog.

In a study on the differentiation between pituitary-dependent hyperadrenocorticism (PDH) and hyperadrenocorticism due to adrenocortical tumour (AT), two questions were addressed: 1. Do basal urinary corticoid/creatinine (c/c) ratios have any value in this respect, and 2. what is the reference percentage suppression of the urinary c/c ratios in the high-dose dexamethasone suppression test? Data obtained from 160 dogs with hyperadrenocorticism were analysed. In 49 dogs the diagnosis AT was confirmed by the finding of plasma ACTH concentrations < 40 ng/l, by visualisation of the tumour by ultrasonography and/or computed tomography, and by histological examination of the adrenal tissue obtained at surgery or autopsy. Among the 111 dogs with PDH, there were 31 animals with resistance to dexamethasone suppression, i.e., suppression < 50%. The basal urinary c/c ratios of dogs with PDH and AT did not differ significantly, although urinary c/c ratios > 100 x 10(-6) almost exclusively occurred in association with PDH. Among the dogs with hyperadrenocorticism, the positive predictive value of a basal urinary c/c ratio > 100 x 10(-6) for the diagnosis of PDH was 0.90 (95% CI: 0.74-0.98). Of the 49 dogs with AT, 34 had a urinary c/c ratio after dexamethasone administration higher than the basal urinary c/c ratio. The maximum suppression of the basal urinary c/c ratio in dogs with AT was 43.7%. It is concluded that in dogs with hyperadrenocorticism basal urinary c/c ratios only have predictive value in the differentiation between AT and PDH when the ratio exceeds 100 x 10(-6). The generally accepted criterion of 50% suppression by dexamethasone in the differentiation between PDH and AT is also applicable to the urinary c/c ratio.