S. Galac

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.

Prognostic factors for outcome after transsphenoidal hypophysectomy in dogs with pituitary-dependent hyperadrenocorticism

OBJECT The aim of this study was to determine prognostic factors for outcome after transsphenoidal hypophysectomy in dogs with pituitary-dependent hyperadrenocorticism (PDH). METHODS One veterinary neurosurgeon performed transsphenoidal hypophysectomies in 181 dogs with PDH over a 12-year period. Survival analysis was performed with the Kaplan-Meier method. Prognostic factors were analyzed with the univariate Cox proportional hazard analysis followed by stepwise multivariate analysis. The log-rank test was used to assess disease-free fractions in three groups categorized according to early postoperative urinary corticoid/creatinine (C/C) ratios. RESULTS Multivariate analysis revealed that old age, large pituitary size, and high preoperative concentrations of plasma adrenocorticotropic hormone were associated with an increased risk of PDH-related death. In addition, large pituitary size, thick sphenoid bone, high C/C ratio, and high concentration of plasma alpha-melanocyte-stimulating hormone (alpha-MSH) before surgery were associated with an increased risk of disease recurrence in the dogs that went into remission after hypophysectomy. Disease-free fractions were significantly higher in dogs with postoperative urinary C/C ratios in the lower normal range (< 5 x 10(-6)) than in dogs with postoperative C/C ratios in the upper normal range (5-10 x 10(-6)). CONCLUSIONS The results of this study indicate that pituitary size, sphenoid bone thickness, plasma alpha-MSH concentration, and preoperative level of urinary cortisol excretion are predictors of long-term remission after transsphenoidal hypophysectomy for PDH in dogs. Urinary C/C ratios measured 6 to 10 weeks after surgery can be used as a guide for predicting the risk of tumor recurrence.

Aldosterone-to-Renin and Cortisol-to-Adrenocorticotropic Hormone Ratios in Healthy Dogs and Dogs with Primary Hypoadrenocorticism

In dogs with primary hypoadrenocorticism, hypocortisolism and hypoaldosteronism usually are present, but these deficiencies also may occur in isolated forms. The diagnosis is commonly made by measuring plasma cortisol concentration before and after stimulation with ACTH, thereby ignoring aldosterone. In search of an alternative approach that would include assessment of glucocorticoid and mineralocorticoid production, 2 pairs of endocrine variables were measured: (1) plasma concentration of cortisol and ACTH, and (2) plasma aldosterone concentration and plasma renin activity. In addition, the cortisol-to-ACTH ratio (CAR) and the aldosterone-to-renin ratio (ARR) were calculated. Reference intervals were established in a population of 60 healthy dogs. In these dogs, CAR ranged from 1.1 to 26.1 and ARR ranged from 0.1 to 1.5. The variables were compared with those of 22 dogs with spontaneous primary hypoadrenocorticism. Plasma concentration of cortisol and ACTH in both groups of dogs overlapped, whereas CAR did not. Similarly, plasma aldosterone concentration and plasma renin activity overlapped, whereas ARR did not. These observations indicate that measurement of these endogenous variables (in one blood sample) allows the specific diagnoses of primary hypocortisolism and primary hypoaldosteronism.

Effects of trilostane on the pituitary-adrenocortical and renin-aldosterone axis in dogs with pituitary-dependent hypercortisolism.

The medical records of 63 dogs with pituitary-dependent hypercortisolism (PDH) before and during treatment with trilostane were reviewed retrospectively. The correct trilostane dosage in dogs with PDH was based on the resolution of clinical signs and the results of an adrenocorticotropic hormone (ACTH) stimulation test. The mean (+/-SD) dose rate of trilostane to achieve good clinical control was 2.8+/-1.0mg/kg bodyweight. Trilostane treatment resulted in a significant decline in basal plasma cortisol concentrations. The median plasma ACTH concentration (39 pmol/L, range 7-132 pmol/L; n=60) at the optimal trilostane dosage time was significantly higher (P<0.001) than before treatment (13 pmol/L, range 2-102 pmol/L). These values did not overlap with plasma ACTH concentrations (range 212-307 pmol/L) of five PDH dogs with trilostane-induced hypocortisolism. The median cortisol/ACTH ratio in well-controlled dogs (0.23, range 0.03-2.5; n=46) was significantly lower (P<0.001) than before treatment (2.59, range 0.27-13.25). Trilostane treatment resulted in an insignificant decrease in plasma aldosterone concentration (PAC), but the median plasma renin activity (PRA) at the time the trilostane dosage was considered optimal (265 fmol/L/s, range 70-3280 fmol/L/s; n=18) was significantly higher (P<0.001) than prior to treatment (115 fmol/L/s, range 15-1330 fmol/L/s). Similarly, the median PAC/PRA ratio during trilostane treatment (0.16, range 0.003-0.92; n=17) was significantly lower (P<0.001) than before treatment (median 0.44, range 0.04-1.33). Trilostane affected both the hypothalamic-pituitary-adrenocortical and the renin-aldosterone axes. The results also suggested that basal plasma ACTH concentration may be used to detect trilostane overdosage.

Primary hyperaldosteronism: Expanding the diagnostic net

Practical relevance Primary hyperaldosteronism is probably the most common adrenocortical disorder in cats. As in humans, it is often unrecognised, which excludes a potentially large number of cats from appropriate treatment. Patient group Affected cats present at a median age of 13 years (range 5–20 years). A breed or sex predilection has not been documented. The excessive secretion of mineralocorticoids usually leads to hypokalaemia and/or systemic arterial hypertension. Most affected cats present with muscular weakness and/or ocular signs of arterial hypertension. Diagnostics In any cat presenting with hypokalaemia and/or arterial hypertension, other potential causes should be excluded. The ratio of plasma aldosterone concentration to plasma renin activity (aldosterone:renin ratio) is currently the best screening test for feline primary hyperaldosteronism. Diagnostic imaging is required to differentiate between adrenocortical neoplasia and bilateral hyperplasia, and to detect any distant metastases. Clinical challenges The differentiation between adrenocortical neoplasia and bilateral hyperplasia is imperative for planning optimal therapy, but the limited sensitivity of diagnostic imaging may occasionally pose a problem. For confirmed unilateral primary hyperaldosteronism, unilateral adrenalectomy is the treatment of choice, and offers an excellent prognosis, but potentially fatal intra- and postoperative haemorrhage is a reported complication and risk factors have yet to be identified. Evidence base Only a few case reports are available on which to base the optimal diagnostic and therapeutic approach to feline primary hyperaldosteronism. This article reviews the physiology of aldosterone production and the pathophysiology of primary hyperaldosteronism, and summarises the currently available literature on the feline disease. Practical suggestions are given for the diagnostic investigation of cats with suspected primary hyperaldosteronism.

Innovative approach to laparoscopic adrenalectomy for treatment of unilateral adrenal gland tumors in dogs

Objective To report a technique for, and short-term outcome of unilateral laparoscopic adrenalectomy in dogs positioned in sternal recumbency without abdominal support. Study Design Experimental and prospective clinical study. Animals Healthy dogs (n = 5) and dogs with unilateral adrenal gland tumor (n = 9). Methods Anesthetized dogs were positioned in sternal recumbency with 2 cushions placed under the dog to elevate the chest and pelvic area so that the abdomen was not in contact with the surgical table allowing gravitational displacement of the abdominal viscera. Three 5-mm portals were located in the paralumbar fossa. Adrenal glands were carefully dissected and surrounding tissues sealed and cut using a vessel-sealing device. A retrieval bag or part of a surgical glove finger was used to remove the adrenal gland from the abdomen. Surgical time and complications were recorded, and short-term outcome assessed. Results Adrenal glands in normal dogs and unilateral adrenal tumors (8 left, 1 right) not involving the caudal vena cava in affected dogs were successfully removed laparoscopically. There were no major intraoperative complications. Of the dogs with adrenal tumors, 1 dog died within 24 hours of surgery from unrelated causes. Eight dogs recovered within 1 day and were discharged within 72 hours. Surgical times ranged from 42 to 117 minutes and were significantly shorter than those reported previously. Conclusions Positioning anesthetized dogs in sternal recumbency with the abdomen suspended to facilitate gravitational displacement of the abdominal viscera improves access to, and visibility of, the adrenal gland for laparoscopic removal.OBJECTIVE To report a technique for, and short-term outcome of unilateral laparoscopic adrenalectomy in dogs positioned in sternal recumbency without abdominal support. STUDY DESIGN Experimental and prospective clinical study. ANIMALS Healthy dogs (n = 5) and dogs with unilateral adrenal gland tumor (n = 9). METHODS Anesthetized dogs were positioned in sternal recumbency with 2 cushions placed under the dog to elevate the chest and pelvic area so that the abdomen was not in contact with the surgical table allowing gravitational displacement of the abdominal viscera. Three 5-mm portals were located in the paralumbar fossa. Adrenal glands were carefully dissected and surrounding tissues sealed and cut using a vessel-sealing device. A retrieval bag or part of a surgical glove finger was used to remove the adrenal gland from the abdomen. Surgical time and complications were recorded, and short-term outcome assessed. RESULTS Adrenal glands in normal dogs and unilateral adrenal tumors (8 left, 1 right) not involving the caudal vena cava in affected dogs were successfully removed laparoscopically. There were no major intraoperative complications. Of the dogs with adrenal tumors, 1 dog died within 24 hours of surgery from unrelated causes. Eight dogs recovered within 1 day and were discharged within 72 hours. Surgical times ranged from 42 to 117 minutes and were significantly shorter than those reported previously. CONCLUSIONS Positioning anesthetized dogs in sternal recumbency with the abdomen suspended to facilitate gravitational displacement of the abdominal viscera improves access to, and visibility of, the adrenal gland for laparoscopic removal.

Animal models of adrenocortical tumorigenesis

Over the past decade, research on human adrenocortical neoplasia has been dominated by gene expression profiling of tumor specimens and by analysis of genetic disorders associated with a predisposition to these tumors. Although these studies have identified key genes and associated signaling pathways that are dysregulated in adrenocortical neoplasms, the molecular events accounting for the frequent occurrence of benign tumors and low rate of malignant transformation remain unknown. Moreover, the prognosis for patients with adrenocortical carcinoma remains poor, so new medical treatments are needed. Naturally occurring and genetically engineered animal models afford a means to investigate adrenocortical tumorigenesis and to develop novel therapeutics. This comparative review highlights adrenocortical tumor models useful for either mechanistic studies or preclinical testing. Three model species - mouse, ferret, and dog - are reviewed, and their relevance to adrenocortical tumors in humans is discussed.

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.

Expression of the ACTH receptor, steroidogenic acute regulatory protein, and steroidogenic enzymes in canine cortisol-secreting adrenocortical tumors

Studies of human adrenocortical tumors (ATs) causing Cushings syndrome suggest that hypersecretion of cortisol is caused by altered expression of steroidogenic enzymes and that steroidogenesis can only be maintained when there is expression of the ACTH receptor (ACTH-R). Here we report the screening for the mRNA expression of the ACTH-R, steroidogenic acute regulatory protein (StAR), cholesterol side-chain cleavage enzyme, 3β-hydroxysteroid dehydrogenase, 21-hydroxylase (all in 38 cortisol-secreting ATs), 17α-hydroxylase, and 11β-hydroxylase (both in 28 cortisol-secreting ATs). Real-time PCR (RT-PCR) was applied in all samples and was compared with that in normal canine adrenal glands. Messenger-RNA encoding StAR, steroidogenic enzymes, and ACTH-R were present in both normal adrenal glands and cortisol-secreting ATs. The amounts of mRNA encoding StAR and enzymes of the steroidogenic cluster needed for cortisol production did not differ significantly between either adenomas or carcinomas and normal adrenal glands. The amount of mRNA encoding ACTH-R was significantly lower in carcinomas than in normal adrenal glands (P = 0.008). In conclusion, RT-PCR analysis revealed no overexpression of StAR and steroidogenic enzymes in canine cortisol-secreting ATs. Significant downregulation of ACTH-R in carcinomas might be associated with the malignant character of the AT.

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.