[Hypercorticism during streptozotocin diabetes and mifepristone administration: the role of cyclic adenosine monophosphate]. / Giperkortitsizm pri streptozototsinovom diabete i vvedenii mifepristona: rol' tsiklicheskogo adenozinmonofosfata.

It was studed basal and ACTH-stimulated production of cyclic adenosine monophosphate (cAMP) and corticosteroid hormones (progesterone and corticosterone) in rat adrenals in vitro under streptozotocin diabetes, in conditions of mifepristone administration and their combination. It was shown that in streptozotocin diabetes animals, both the basal and adrenocorticotropic hormone (ACTH) stimulated cAMP production significantly increased; this was accompanied by the increase in basal and ACTH-stimulated progesterone and corticosterone production in rat adrenals in vitro. Repeated administration of mifepristone to control and diabetic rats caused an increase mainly in ACTH-stimulated production of the main glucocorticoid hormone, corticosterone, without additional changes in the cAMP level. The results obtained suggest activation of two mechanisms of steroidogenesis enhancement in experimental animals. In rats with streptozotocin diabetes, both basal and ACTH-stimulated activity of all stages of steroidogenesis increase, which is mediated by the increased formation of cAMP as second messenger mediating the ACTH action on adrenocortical cells. Prolonged administration of mifepristone to control and diabetic rats resulted in increased activity of only late stages of steroidogenesis with predominant elevation of synthesis of physiologically active hormone corticosterone without additional changes in cAMP production level.

Investigation of adrenal and thyroid gland dysfunction in dogs with ultrasonographic diagnosis of gallbladder mucocele formation.

Gallbladder mucocele formation is an emerging disease in dogs characterized by increased secretion of condensed granules of gel-forming mucin by the gallbladder epithelium and formation of an abnormally thick mucus that can culminate in obstruction of the bile duct or rupture of the gallbladder. The disease is associated with a high morbidity and mortality and its pathogenesis is unknown. Affected dogs have a significantly increased likelihood of concurrent diagnosis of hyperadrenocorticism, hypothyroidism, and hyperlipidemia. Whether these endocrinopathies represent coincidental primary disease processes that exacerbate gallbladder mucocele formation in predisposed dogs or reflect a concurrent disruption of endocrine and lipid metabolism is unclear. In this study, we investigated a hypothesis that dogs with gallbladder mucocele formation would have a high prevalence of occult and atypical abnormalities in adrenal cortical and thyroid gland function that would suggest the presence of endocrine disruption and provide deeper insight into disease pathogenesis. We performed a case-control study of dogs with and without ultrasonographic diagnosis of gallbladder mucocele formation and profiled adrenal cortical function using a quantitative mass spectrometry-based assay of serum adrenal-origin steroids before and after administration of synthetic cosyntropin. We simultaneously profiled serum thyroid hormone concentrations and evaluated iodine sufficiency by measurement of urine iodine:creatinine ratios (UICR). The studies were complemented by histological examination of archival thyroid tissue and measurements of thyroid gland organic iodine from dogs with gallbladder mucocele formation and control dogs. Dogs with gallbladder mucocele formation demonstrated an exaggerated cortisol response to adrenal stimulation with cosyntropin. A prevalence of 10% of dogs with gallbladder mucocele formation met laboratory-based criteria for suspect or definitive diagnosis of hyperadrenocorticism. A significantly greater number of dogs with gallbladder mucocele formation had basal serum dehydroepiandrosterone (DHEAS) increases compared to control dogs. A high percentage of dogs with gallbladder mucocele formation (26%) met laboratory-based criteria for diagnosis of hypothyroidism, but lacked detection of anti-thyroglobulin antibodies. Dogs with gallbladder mucocele formation had significantly higher UICRs than control dogs. Examination of thyroid tissue from an unrelated group of dogs with gallbladder mucocele formation did not demonstrate histological evidence of thyroiditis or significant differences in content of organic iodine. These findings suggest that dogs with gallbladder mucocele formation have a greater capacity for cortisol synthesis and pinpoint DHEAS elevations as a potential clue to the underlying pathogenesis of the disease. A high prevalence of thyroid dysfunction with absent evidence for autoimmune thyroiditis suggest a disrupted thyroid hormone metabolism in dogs with gallbladder mucocele formation although an influence of non-thyroidal illness cannot be excluded. High UICR in dogs with gallbladder mucocele formation is of undetermined significance, but of interest for further study.

Síndrome de Cushing ectópico: descripción de 9 casos / Ectopic Cushing syndrome: Report of 9 cases

Introducción: El síndrome de Cushing ectópico (SCE) es una entidad rara debida a la secreción de ACTH por tumores extrahipofisarios. Su baja frecuencia dificulta la adquisición de experiencia en su manejo. El objetivo de este trabajo es describir a los pacientes con SCE atendidos en el servicio de Endocrinología en un hospital de tercer nivel en un periodo de 15 años. Métodos: Se trata de un estudio retrospectivo de los datos clínicos, bioquímicos y radiológicos, tratamiento recibido, y evolución de los pacientes con SCE atendidos entre los años 2000 y 2015. Resultados: Se incluyeron 9 pacientes (6 mujeres) con una edad media de 47 años. El síndrome clínico se desarrolló en un tiempo inferior a 3 meses en todos los casos excepto en uno, y la mayoría presentaba edemas, hiperpigmentación y/o hipopotasemia. La media del cortisol libre urinario y de la ACTH fue de 2.840μg/24h y 204pg/ml, respectivamente. El origen ectópico se confirmó por la combinación de pruebas dinámicas no invasivas y estudios radiológicos en la mayoría de los casos. El tumor responsable pudo identificarse en 8 casos y 7 presentaban diseminación metastásica. El tratamiento primario consistió en cirugía en un caso, cirugía más terapia sistémica en 3 y quimioterapia en otros 3. En 4 pacientes fue necesaria la suprarrenalectomía bilateral para controlar el hipercortisolismo. Tras un seguimiento medio de 40 meses, 3 habían fallecido, 5 permanecían vivos y en uno se había perdido el seguimiento. Conclusiones: Se confirma que el SCE abarca un amplio espectro de tumores de diferente agresividad y naturaleza. Habitualmente el origen ectópico del síndrome de Cushing puede sospecharse y confirmarse en la mayoría de los casos sin necesidad de pruebas invasivas. Tanto el control del hipercortisolismo como del tumor requieren múltiples modalidades terapéuticas, siendo recomendable el manejo multidisciplinar

Introduction: Ectopic Cushing's syndrome (ECS) is a rare condition caused by ACTH secretion by extrapituitary tumors. Its low frequency makes it difficult to acquire experience in its management. The aim of this study was to describe patients with ECS seen at the endocrinology department of a tertiary hospital over 15 years. Methods: This was a retrospective study of the clinical, biochemical and radiographic data, treatment, and course of patients with ECS seen from 2000 to 2015. Results: Nine patients (6 of them female) with a mean age of 47 years were included in the study. The clinical syndrome developed in less than 3 months in all cases but one, and most patients also had edema, hyperpigmentation and/or hypokalemia. Mean urinary free cortisol and ACTH levels were 2,840μg/24h and 204pg/mL respectively. The ectopic origin was confirmed by a combination of dynamic non-invasive tests and radiographic studies in most cases. The tumor responsible could be identified in 8 cases, and 7 patients had metastatic dissemination. Primary treatment was surgery in one patient, surgery combined with systemic therapy in 3, and chemotherapy in the other 3 patients. Bilateral adrenalectomy was required in 4 patients to control hypercortisolism. After a mean follow-up of 40 months, 3 patients died, 5 were still alive, and one had been lost to follow-up. Conclusions: Our study confirms that ECS covers a wide spectrum of tumors of different aggressiveness and nature. The ectopic origin of Cushing's syndrome can usually, be suspected and confirmed in most cases without the need for invasive tests. Control of both hypercortisolism and the tumor requires multiple treatment modalities, and multidisciplinary management is recommended

Alterations in sympathetic nerve traffic in genetic haemochromatosis before and after iron depletion therapy: a microneurographic study.

AIMS: Haemochromatosis (HH) displays a number of circulatory alterations concurring at increase cardiovascular risk. Whether these include sympathetic abnormalities in unknown. METHODS AND RESULTS: In 18 males with primary HH (age: 42.3 ± 10.4 years, mean ± SD), clinic and beat-to-beat blood pressure (BP, Finapres), heart rate (HR, EKG), and muscle sympathetic nerve activity (MSNA, microneurography) traffic were measured in the iron overload state and after iron depletion therapy. Haemochromatosis patients displayed elevated serum iron indices while other haemodynamic and metabolic variables were superimposable to ones seen in 12 healthy subjects (C). Muscle sympathetic nerve activity was significantly greater in HH than C (64.8 ± 13.3 vs. 37.8 ± 6.7 bs/100 hb, P < 0.01). Iron depletion caused a significant reduction in serum ferritin, transferrin saturation, and MSNA (from 64.8 ± 13.3 to 39.2 ± 9.2 bs/100 hb, P < 0.01) and a significant improvement in baroreflex-MSNA modulation. This was paralleled by a significant increase in the high-frequency HR variability and by a significant reduction in the low-frequency systolic BP variability components. Before after iron depletion therapy, MSNA was significantly and directly related to transferrin saturation, liver iron concentration, and iron removed, while the MSNA reductions observed after the procedure were significantly and inversely related to the baroreflex-MSNA increases detected after iron depletion. In C, all variables remained unchanged following 1 month observation. CONCLUSION: These data provide the first evidence that in HH iron overload is associated with an hyperadrenergic state and a baroreflex alteration, which are reversed by iron depletion. These findings underline the importance of iron overload in modulating sympathetic activation, possibly participating at the elevated cardiovascular risk reported in HH.

Diabetes Mellitus-Associated Functional Hypercortisolism Impairs Sexual Function in Male Late-Onset Hypogonadism.

Functional hypercortisolism is generated by conditions able to chronically activate hypothalamic-pituitary-adrenal axis and has been proven to have a negative role in several complications. However, no study has evaluated the possible influence of diabetes mellitus-associated functional hypercortisolism on male hypogonadism and sexual function. We aimed to identify any association of hypothalamic-pituitary-adrenal axis dysregulation measures with testosterone and sexual function in men simultaneously affected by diabetes mellitus and late-onset hypogonadism. Fifteen diabetes mellitus and late-onset hypogonadism subjects suffering from functional hypercortisolism and fifteen diabetes mellitus and late-onset hypogonadism subjects who were free of functional hypercortisolism were retrospectively reviewed. Clinical, hormonal, and sexual parameters were considered. Hypercortisolemic subjects showed higher values of body mass index, waist, and glycated hemoglobin and lower ones of testosterone compared to normocortisolemic ones. All sexual parameters, except for orgasmic function, were significantly worse in hypercortisolemic than in normocortisolemic subjects. Hypercortisolemic patients showed higher values of cortisol after dexamethasone and urinary free cortisol as well as a lesser ACTH response after corticotropin releasing hormone test (ACTH area under curve) compared to normocortisolemic ones. No significant association was found at Poisson regression analysis between hormonal and sexual variables in normocortisolemic patients. In hypercortisolemic subjects, negative and significant associations of cortisol response after corticotropin releasing hormone (cortisol area under curve) with erectile function (ß: -0.0008; p: 0.015) and total international index of erectile function score (ß: -0.0006; p: 0.001) were evident. This study suggests for the first time the impairing influence of the dysregulated hypothalamic-pituitary-adrenal axis on sexual function in diabetes mellitus-associated late-onset hypogonadism.

Influence of iatrogenic hypercorticoidism induced by long-term application of dexamethasone on power of muscular contraction of white rats.

Research objective consisted in detection of nature of the changes of the myothermiс and the ergometric parameters of the contraction of the forward tibial muscle of rats in the course of performing of the tiring work at the saturation of an organism by therapeutic doses of dexamethasone. Method: The experiments were performed on sexually mature rats-females (200-220 g), divided into control (n = 10) and experimental (n = 60) groups. The animals of experimental group received dexamethasone (D, KRKA, Slovenia) in a dose of 0,25 mg/kg (intraperitoneal, 1 time in 2 days) during from 10 to 60 days. On anesthetized animals (sodium thiopental, 100 mg/kg) with the use of myothermia and ergographia the nature of change of power of the muscle's contraction in the course of the performance of the tiring work (3 six-second tetanus with external loading of 80 g) was studied. Restults: At the initial stage of the development of iatrogenic hypercorticoidism (after 5-20 injections of D) the initial value of the external work of the muscle in comparison with the control is significantly lower (for 30-52%) and the temperature cost of the unit of the work (TCMW), on the contrary, - is higher (for 26-82%). On the end of the 2-month period of application of D the initial values of the power parameters of the muscle came back to control level. During the performance of the tiring tetanus in animal experimental groups the decline of the external work of the muscle is greater (69-73%) compared with the control (55%). This effect does not depend of the number of injections of D, which indicates about a high pathophysiological activity of glucocorticoid concerning working capacity of the muscle. At expressed fatigue the TCMW always increases from 104% (5 injections of D) to 230% (20 injections); at control animals the effect of the tiring work on TCMW is significantly weaker (28%). At long-term application of D (2 months) the described effect of the preparation is weakened, though remains accurately expressed. Conclusion: The obtained data are considered from the point of view of formation at the hypercorticoidizm of the pathophysiological mechanism - the increase of power cost of muscular work. The revealed effect of D can be the cornerstone of the formation of the number of the pathophysiological mechanisms in neuromuscular system including causing the development of the myopathy at the hypercorticoidizm.

[AMPLITUDE-FREQUENCY'S DEPENDENCE OF M-RESPONSE OF THE SKELETAL MUSCLE OF RATS WITH EXPERIMENTAL HYPERCORTICOIDIZM].

In experiments over the mature white female rats the influence of the hypercorticoidizm (simulated by daily parenteral injection of hydrocortisone in a dose of 3 mg/kg/days for 30 days) on some parameters of the M-response of the forward tibial muscle with a different frequency of stimulation of the low-tibial nerve is studied. It is established that the hypercorticoidizm is followed by lengthening of the chronaxia of the forward tibial muscle at its indirect irritation (by 69 per cent), deterioration of stability of M-response's generation, lengthening of the latent period (by 30 per cent) and to reduction of amplitude (by 29 per cent) of single M-responses against increase in frequency of polyphase potentials (to 35 per cent). At animals with hypercorticoidizm in the range of low frequencies of nerve's stimulation (10-30 imp/s) periodic generation of higher-amplitude M-responses, than at control, against their low initial amplitude was observed, which can testify in a favor of an initial partial blocking of synapses. The hypercorticoidizm was followed more expressed, in comparison with control, decreasing of M-responses' amplitude in the process of increasing in frequency of low-tibial nerve's stimulation, decreasing in frequency of nerve's stimulation on achievement which inverse relationship between M-responses' amplitude and frequency of nerve's irritation was established.

Quantitative CT assessment of bone mineral density in dogs with hyperadrenocorticism.

Canine hyperadrenocorticism (HAC) is one of the most common causes of general osteopenia. In this study, quantitative computed tomography (QCT) was used to compare the bone mineral densities (BMD) between 39 normal dogs and 8 dogs with HAC (6 pituitary-dependent hyperadrenocorticism [PDH]; pituitary dependent hyperadrenocorticism, 2 adrenal hyperadrenocorticism [ADH]; adrenal dependent hyperadrenocorticism) diagnosed through hormonal assay. A computed tomogaraphy scan of the 12th thoracic to 7th lumbar vertebra was performed and the region of interest was drawn in each trabecular and cortical bone. Mean Hounsfield unit values were converted to equivalent BMD with bone-density phantom by linear regression analysis. The converted mean trabecular BMDs were significantly lower than those of normal dogs. ADH dogs showed significantly lower BMDs at cortical bone than normal dogs. Mean trabecular BMDs of dogs with PDH using QCT were significantly lower than those of normal dogs, and both mean trabecular and cortical BMDs in dogs with ADH were significantly lower than those of normal dogs. Taken together, these findings indicate that QCT is useful to assess BMD in dogs with HAC.

Involvement of glucagon-like peptide 1 in the glucose homeostasis regulation in obese and pituitary-dependent hyperadrenocorticism affected dogs.

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 (HOMA insulin sensitivity and HOMA ß-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. HOMA insulin sensitivity was statistically decreased and HOMA ß-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 ß-cells thus predisposing to diabetes mellitus.

Clinical features of hyperadrenergic postural tachycardia syndrome in children.

BACKGROUND: Hyperadrenergic postural tachycardia syndrome (POTS) is the main phenotype of POTS. The aim of this study was to present our single-center experience of hyperadrenergic POTS in children and adolescents. METHODS: Thirty-seven patients who met the diagnostic criteria for POTS were enrolled in our study. Their orthostatic serum norepinephrine levels were determined by high-performance liquid chromatography. In a retrospective analysis, based on clinical and serum norepinephrine criteria, we analyzed the clinical features of POTS cases between the POTS-alone group and the hyperadrenergic POTS group. RESULTS: Nineteen patients (51.35%) met the diagnostic criteria for hyperadrenergic POTS and 18 patients were assigned to the POTS-alone group. Compared with the POTS-alone patients, dizziness, headache and tremulousness were more frequent in patients with hyperadrenergic POTS (P < 0.05). During the tilt table test, children with hyperadrenergic POTS had a greater increment of systolic blood pressure and heart rate than POTS-alone patients. CONCLUSION: Patients with hyperadrenergic POTS should be identified and differentiated from those with neuropathic POTS. Hyperadrenergic POTS in children and adolescents should be considered when POTS patients suffer from frequent dizziness, headache, and tremulousness. In head-up tilt testing, children and adolescents with hemodynamic characteristics of hyperadrenergic POTS had greater increments of systolic blood pressure and heart rate.

Comparison of adrenocorticotropic hormone stimulation test results started 2 versus 4 hours after trilostane administration in dogs with naturally occurring hyperadrenocorticism.

BACKGROUND: Trilostane medical treatment of naturally occurring hyperadrenocorticism (NOH) in dogs is common, as is use of the adrenocorticotropic hormone (ACTH) stimulation test (ACTHst) in monitoring response to treatment. There is uncertainty regarding when the ACTHst should be started relative to time of trilostane administration. OBJECTIVE: To compare ACTHst results in dogs being treated for NOH with trilostane when the test is begun 2 versus 4 hours after trilostane administration. ANIMALS: Twenty-one privately owned dogs with NOH, each treated with trilostane for at least 30 days. METHODS: Each dog had 2 ACTHst completed, 1 started 2 hours and the other 4 hours after trilostane administration. The second test was started no sooner than 46 hours and no later than 74 hours after the first. RESULTS: For all 21 dogs, the mean post-ACTH serum cortisol concentration from tests started 2 hours after trilostane administration (5.4 ± 3.7 µg/dL) was significantly lower (P = .03) as compared with results from the tests started 4 hours after administration (6.5 ± 4.5 µg/dL). CONCLUSIONS: Results of ACTHst started at different times yield significantly different results. Dogs with NOH, treated with trilostane, and monitored with ACTHst results should have all of their subsequent ACTHst tests begun at or about the same time after trilostane administration.

Desmopressin test in the diagnosis and follow-up of cyclical Cushing's disease / El test de la desmopresina en el diagnóstico y seguimiento de la enfermedad de Cushing cíclica

OBJECTIVE: To assess the utility of the desmopressin (DDAVP) test in the diagnosis and follow-up of a cyclical Cushing's disease (CCS) case. MATERIAL AND METHODS: Laboratory tests included morning and midnight serum cortisol levels, 24 h urine free cortisol excretion, midnight salivary cortisol levels, serum cortisol levels after low (1 mg) and high (8 mg) dexamethasone, plasma ACTH and serum cortisol levels after DDAVP. Magnetic resonance imaging (MRI) was used to assess the presence of a pituitary adenoma. The resected tumor specimen was studied by histological, immunohistochemical and cell biology techniques. RESULTS: A patient was referred to our unit with a diagnosis of Cushing's syndrome (CS) for further evaluation and treatment. However, no biochemical evidence of hypercortisolism was observed in the follow-up evaluations. Furthermore, the typical features of CS fluctuated throughout this period. A consistent positive response to the DDAVP stimulation test was observed during the diagnostic work-up, even when overt clinical features of CS were not apparent, raising suspicion for CCS. After two years of follow-up a definitive diagnosis of hypercortisolism was established. An MRI scan revealed a pituitary adenoma, as the source of ACTH production. After transphenoidal surgery, clinical signs of CS resolved and the response to DDAVP became negative. DDAVP induced a significant increase in ACTH levels in cultured pituitary adenoma cells, consistent with the in vivo DDAVP test results. CONCLUSIONS: Our case illustrates the utility of the DDAVP test in the evaluation of patients with suspected CCS. The DDAVP test could facilitate the management of CCS by shortening the time of diagnosis

OBJETIVO: Evaluar la utilidad de la prueba de la desmopresina (DDAVP) en el diagnóstico y seguimiento de un caso de enfermedad de Cushing cíclica (ECC). MATERIAL Y MÉTODO: Se realizaron mediciones de cortisol sérico diurno y nocturno, cortisol libre en orina de 24 h, cortisol en saliva nocturno, cortisol sérico tras dosis elevadas y bajas de dexametasona, ACTH plasmática y cortisol tras la DDAVP, y resonancia magnética (RM) para valorar la presencia de un adenoma hipofisario. El tumor extirpado fue analizado mediante técnicas histológicas, inmunohistoquímicas y de biología celular. RESULTADOS: Se presenta una paciente enviada a nuestra unidad con el diagnóstico de síndrome de Cushing (SC) para evaluación más completa y tratamiento. No obstante durante un periodo de seguimiento de 2 años no se encontró evidencia alguna de hipercortisolismo en los análisis realizados en nuestro laboratorio. Durante este tiempo, la paciente mostró fluctuaciones de los síntomas y signos típicos del SC. De manera interesante, la prueba de DDAVP mostró hiperrespuesta de cortisol y ACTH en todas las evaluaciones. La exploración por RM mostró un adenoma hipofisario que tras extirpación resultó ser positivo para ACTH. El SC se resolvió tras la cirugía y la respuesta a la prueba de DDAVP desapareció en las evaluaciones de seguimiento posquirúrgico. Se incubaron muestras del tumor mostrando este un aumento en la secreción in vitro de ACTH. CONCLUSIONES: Este caso ilustra la utilidad de la prueba de DDAVP en la evaluación de pacientes con sospecha de SCC. Esta prueba podría facilitar el manejo del SCC acortando el tiempo de diagnóstico

Clinical findings, diagnostic test results, and treatment outcome in cats with spontaneous hyperadrenocorticism: 30 cases.

BACKGROUND: Spontaneous hyperadrenocorticism (HAC) is rare in cats. Clinical findings, diagnostic test results, and response to various treatment options must be better characterized. OBJECTIVES: To report the clinical presentation, clinicopathologic findings, diagnostic imaging results, and response to treatment of cats with HAC. ANIMALS: Cats with spontaneous HAC. METHODS: Retrospective descriptive case series. RESULTS: Thirty cats (15 neutered males, 15 spayed females; age, 4.0-17.6 years [median, 13.0 years]) were identified from 10 veterinary referral institutions. The most common reason for referral was unregulated diabetes mellitus; dermatologic abnormalities were the most frequent physical examination finding. Low-dose dexamethasone suppression test results were consistent with HAC in 27 of 28 cats (96%), whereas ACTH stimulation testing was suggestive of HAC in only 9 of 16 cats (56%). Ultrasonographic appearance of the adrenal glands was consistent with the final clinical diagnosis of PDH or ADH in 28 of 30 cats (93%). Of the 17 cats available for follow-up at least 1 month beyond initial diagnosis of HAC, improved quality of life was reported most commonly in cats with PDH treated with trilostane. CONCLUSIONS AND CLINICAL IMPORTANCE: Dermatologic abnormalities or unregulated diabetes mellitus are the most likely reasons for initial referral of cats with HAC. The dexamethasone suppression test is recommended over ACTH stimulation for initial screening of cats with suspected HAC. Diagnostic imaging of the adrenal glands may allow rapid and accurate differentiation of PDH from ADH in cats with confirmed disease, but additional prospective studies are needed.

Effect of trilostane on hormone and serum electrolyte concentrations in dogs with pituitary-dependent hyperadrenocorticism.

BACKGROUND: The effects of trilostane on key hormones and electrolytes over 24 hours in dogs with pituitary-dependent hyperadrenocorticism (PDH) are unknown. OBJECTIVES: To determine the plasma concentration of cortisol, endogenous adrenocorticotropic hormone (ACTH), aldosterone, sodium, potassium, and ionized calcium concentrations, and plasma renin activity over a 24-hour period after administration of trilostane to dogs with well-controlled PDH. ANIMALS: Nine dogs (mean age 9.3 ± 0.67 years, mean weight 31.9 ± 6.4 kg) with confirmed PDH. METHODS: Prospective study. Thirty days after the first administration of trilostane, blood samples were taken at -30, 0 (baseline), 15, 30, 60, and 90 minutes, and 2, 3, 4, 6, 8, 12, 16, 20, and 24 hours after administration of trilostane and plasma concentration of cortisol, endogenous ACTH, aldosterone, sodium, potassium, ionized calcium, and renin activity were determined. RESULTS: Cortisol concentrations decreased significantly (P < .001) 2-4 hours after trilostane administration. From baseline, there was a significant (P < .001) increase in endogenous ACTH concentrations between hours 3-12, a significant increase (P < .001) in aldosterone concentration between hours 16-20, and a significant (P < .001) increase in renin activity between hours 6-20. Potassium concentration decreased significantly (P < .05) between hours 0.5-2. CONCLUSION AND CLINICAL IMPORTANCE: Treatment with trilostane did not cause clinically relevant alterations in plasma aldosterone and potassium concentration. Results suggest that in dogs with PDH, the optimal time point for an ACTH-stimulation test to be performed is 2-4 hours after trilostane dosing. Future studies are necessary to establish interpretation criteria for a 2- to 4-hour postpill ACTH-stimulation test.

Serum adipokine concentrations in dogs with naturally occurring pituitary-dependent hyperadrenocorticism.

BACKGROUND: An excess of intra-abdominal fat is observed frequently in dogs with hyperadrenocorticism (HAC). Adipokine dysregulation is a possible cause of complications related to visceral obesity, but little information is available on adipokine in dogs with naturally occurring HAC. OBJECTIVES: To examine the differences in the circulating adipokines concentrations in overweight dogs with and without pituitary-dependent HAC (PDH). ANIMALS: Thirty healthy dogs and 15 client-owned dogs with PDH. METHODS: Case-controlled observational study, which enrolled 15 overweight dogs diagnosed with PDH and 30 otherwise healthy dogs of similar body condition score. Nine of 15 dogs with PDH were treated with low-dose trilostane twice daily and reassessed after treatment. RESULTS: The serum leptin (P < .0001) and insulin (P < .0001) concentrations were significantly higher in the PDH group (leptin, 22.8 ± 8.8 [mean ± SD]; insulin, 9.1 ± 6.1) than the healthy group (leptin, 4.9 ± 3.7; insulin, 1.9 ± 0.9). However, there were no significant differences in the adiponectin, resistin, tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, IL-10, and IL-18 levels between the 2 groups. In the PDH group, the serum cortisol concentrations had a linear association with the leptin concentrations, and there were significant decreases in the leptin (P = .0039) and insulin (P = .0039) levels after trilostane treatment. However, the leptin and insulin levels remained higher after trilostane treatment than in healthy control dogs with similar body condition score. CONCLUSIONS AND CLINICAL IMPORTANCE: Hypercortisolemia in dogs with PDH might upregulate the circulating leptin levels. However, a large population-based study will be necessary to determine whether the upregulation of leptin is involved directly with the complications caused by HAC.

Disorders of hemostasis in overt and subclinical hypercortisolism.

Glucocorticoids are a group of hormones of a particular impact on hemostasis. Epidemiological studies show an approximately severalfold greater incidence of thromboembolic events in hypercortisolemic patients compared to those without hormonal disorders. The prothrombotic action of this steroid class is caused by both the direct impact of hypercortisolism on the activation of coagulation and the inhibition of fibrinolysis, as well as, the pathology of hemostasis due to metabolic disorders, which occur in this endocrinopathy. The aim of this study was to discuss the hemostasis abnormalities that occur in patients with overt and subclinical hypercortisolism with a particular emphasis on plasmatic coagulation, endogenous anticoagulation system, homocysteine and proinflammatory cytokines.

Evaluation of 2 trilostane protocols for the treatment of canine pituitary-dependent hyperadrenocorticism: twice daily versus once daily.

BACKGROUND: Trilostane is the drug of choice to treat pituitary-dependent hyperadrenocorticism (PDH) in dogs, but there is still controversy about which protocol best controls the clinical signs and results of adrenal functioning test. OBJECTIVES: To compare the efficacy of twice daily (BID) versus once daily (SID) trilostane administration and to compare the safety of both protocols in the treatment of dogs with PDH. ANIMALS: Thirty-two client-owned dogs diagnosed with PDH between 2008 and 2010 and treated with trilostane either BID or SID. METHODS: In this prospective randomized study, 2 trilostane protocols were evaluated on the basis of the owner's perception of clinical signs, on the results of laboratory tests, and on the results of the ACTH stimulation test in dogs with PDH. Dogs were followed up for a period of 1 year. RESULTS: During the study, more dogs in the BID group had complete clinical recovery than in the SID group. However, there was no significant difference in the mean post-ACTH cortisol concentration between groups. Basal cortisol concentration at 6 months was higher in animals treated SID compared with animals treated BID. Mean total daily doses of trilostane used to control PDH, as well as adverse effects observed in the course of the study, in both groups were not statistically different. CONCLUSION AND CLINICAL IMPORTANCE: Adverse effects were mild using either protocol of treatment. Using trilostane BID might increase the number of dogs with a good clinical response compared with using trilostane SID.

Diagnosis of spontaneous canine hyperadrenocorticism: 2012 ACVIM consensus statement (small animal).

This report offers a consensus opinion on the diagnosis of spontaneous canine hyperadrenocorticism. The possibility that a patient has hyperadrenocorticism is based on the history and physical examination. Endocrine tests should be performed only when clinical signs consistent with HAC are present. None of the biochemical screening or differentiating tests for hyperadrenocorticism are perfect. Imaging can also play a role. Awareness of hyperadrenocorticism has heightened over time. Thus, case presentation is more subtle. Due to the changes in manifestations as well as test technology the Panel believes that references ranges should be reestablished. The role of cortisol precursors and sex hormones in causing a syndrome of occult hyperadrenocorticism remains unclear.

Trilostane therapy for treatment of spontaneous hyperadrenocorticism in cats: 15 cases (2004-2012).

BACKGROUND: Medical treatment with trilostane improves clinical signs, causes unclear insulin requirement changes, and variable survival times in cats. OBJECTIVES/HYPOTHESIS: To characterize the long-term efficacy of trilostane in treating cats with hyperadrenocorticism (HAC). ANIMALS: Fifteen client-owned cats with spontaneous HAC. METHODS: Multicenter descriptive retrospective study with a search performed on all medical records for cats diagnosed with spontaneous HAC. RESULTS: Clinical signs (13 of 15 cats) and ACTH stimulation testing results (13 of 15) improved with trilostane therapy. Diabetes mellitus was reported in 9/15 cases. Insulin requirements decreased by 36% within 2 months in 6/9 diabetic cats. Median survival time was 617 days for all cats (range 80-1,278 days). Complications included weight loss, urinary tract infections, chronic kidney disease, seizures, and recurrent pancreatitis. Hypocortisolemia was documented in 1 case. Cause of death occurred as a result of nonadrenal or nondiabetic illnesses (renal failure, seizures [caused by hypoglycemia or unknown]), or lymphoma. CONCLUSIONS AND CLINICAL IMPORTANCE: Trilostane ameliorates clinical signs of HAC in cats, is tolerated well in the long term, and can lead to improved regulation of diabetes.