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Simple Summary: Drugs rarely are aimed at a single target. More frequently, drugs can affect the functioning of multiple systems as a consequence of the different levels of activity of the aimed target or because of the effects caused by drug interactions with the other possible targets. Trilostane is a veterinary drug used for very specific diseases, but the array of possible beneficial effects generated by trilostane could be useful for diseases different from those indicated for the use of this drug. Additionally, although abandoned as a drug to treat diseases in human patients, the use of trilostane in animals to address conditions still needing effective therapies could give trilostane appeal for a new appraisal in disorders common to humans and animals, such as epilepsy, anxiety, and depression. This review of the present evidence suggests that trilostane is a powerful tool to stimulate the production of hormones (steroids), making the brain more resilient to injuries and traumatic events, preventing more negative consequences caused by the triggered neuroinflammatory responses (a consequence common to seizures and, but not only, depression), which definitely could lead to more severe conditions. Trilostane is a drug able to block the synthesis of progesterone from pregnenolone, dependent on the enzyme 3β-hydroxysteroid dehydrogenase/Δ5−4 isomerase. As a consequence of this effect, it is used to treat endocrinological diseases such as Cushing's syndrome, especially in dogs. Because of the modulatory effects of trilostane on the hypothalamic–pituitary–adrenal axis, trilostane administration causes an increase in brain levels of neurosteroids with anticonvulsant properties, as in the case of allopregnanolone. Allopregnanolone is also of interest in curing depression, suggesting that trilostane might represent a tool to address neurological and psychiatric disorders. In this review, we investigated the historical development of this drug and its current use, mechanisms, and possible developments. By searching the literature from 1978 to 2025, we identified 101 papers describing studies with trilostane. Precisely, 55 were about dogs and trilostane, 3 were on cats, and 23 were with other animals. Some studies (15) were also designed with human patients. The main disease treatment with trilostane was hyperadrenocorticism. However, we also found two preclinical papers on trilostane's potential use in psychiatric diseases and three on trilostane's potential use in neurological disorders. Moreover, few clinical and preclinical studies suggested the involvement of neurosteroids modulated by trilostane in different neurological disorders, thus opening a possible new perspective for the use of this drug. [ABSTRACT FROM AUTHOR]

Simple Summary: Hyperadrenocorticism in dogs is a condition characterized by excess cortisol and can disrupt overall health. This study examined its impact on gut bacteria, which is crucial for health. Compared to healthy dogs, the dogs with hyperadrenocorticism had less diverse gut bacteria and an increase in Proteobacteria (Pseudomonadota), Actinobacteria, Bacteroides, Enterococcus, Corynebacterium, Escherichia, and Proteus, alongside a decrease in Firmicutes (Bacillota). These imbalances continued even after treatment, suggesting ongoing health risks. Understanding these gut changes can improve treatments for affected dogs. Hyperadrenocorticism (HAC) is a common endocrine disorder in dogs, which is associated with diverse metabolic abnormalities. We hypothesized that elevated cortisol levels in dogs with HAC disrupt the gut microbiome (GM), and this disruption persists even after trilostane treatment. This study explored GM composition in dogs with HAC. We included 24 dogs, 15 with HAC and 9 healthy controls, and followed up with 5 dogs with HAC who received trilostane treatment. The GM analysis revealed significant compositional changes in dogs with HAC, including reduced microbiome diversity compared to healthy controls, particularly in rare taxa, as indicated by the Shannon index (p = 0.0148). Beta diversity analysis further showed a distinct clustering of microbiomes in dogs with HAC, separating them from healthy dogs (p < 0.003). Specifically, an overrepresentation of Proteobacteria (Pseudomonadota), Actinobacteria, Bacteroides, Enterococcus, Corynebacterium, Escherichia, and Proteus populations occurred alongside a decreased Firmicutes (Bacillota) population. Despite trilostane treatment, gut dysbiosis persisted in dogs with HAC at a median of 41 d post treatment, suggesting its potential role in ongoing metabolic issues. We identified GM dysbiosis in dogs with HAC by examining key bacterial genera, offering insights into potential interventions like probiotics or fecal microbiota transplants for better HAC management. [ABSTRACT FROM AUTHOR]

A 9‐year‐old, entire, female, soft‐coated Wheaten terrier and a 7‐year‐old, male, neutered greyhound were presented for clinical signs suggestive of hyperadrenocorticism (polyuria, polydipsia, and in the first case, polyphagia and weight gain). Adrenocorticotrophic hormone stimulation test and low‐dose dexamethasone suppression test ruled out excessive production of cortisol. Imaging (abdominal ultrasound and computed tomography) revealed an adrenal mass in both cases. Further hormonal testing revealed hyperprogesteronism. In the first case, surgical treatment was not considered due to vascular invasion of the mass, the patient was treated successfully with trilostane and was still stable 18 months later. In the second case, adrenalectomy was performed, and the clinical signs resolved, the dog was stable 10 months later. We report two clinical cases of progesterone‐secreting adrenocortical tumours and their management. [ABSTRACT FROM AUTHOR]

Hyperadrenocorticism (HAC) in dogs is routinely treated with trilostane single-dose (CTG) which is reported to cause adverse reactions. The current retrospective study of several dogs with terminal stage of HAC aimed to compare the clinical, hematological, and biochemical effects of trilostane titration-dose treatment (TTG) with the single-dose treatment (CTG). All clinical cases (n=7) were confirmed on HAC by anamnestic, clinical, hematology, biochemistry, and low-dose dexamethasone suppression test findings, indicative for Cushing’s disease. Two cases were treated with CTG (2.2-6.7 mg/kg, single dose daily) and their treatment was discontinued on the second week due to adverse reactions. The TTG cases were treated for up to 12 weeks (0.5 mg/kg once daily for 7 days, and then with 0.5 mg/kg twice daily for 7 days). Blood samples and clinical checks were performed on 0., 4., and 12. weeks of the treatment. Hemoglobin was non-significantly higher in TTG at 12 weeks. Alanine transaminase was significantly lower in the TTG cases on the 12. week of the treatment (78.04±15.37 U/L) compared to the 0-week (137.81±24.03 U/L), and 4-week samples (131.92±23.36 U/L). No significant differences were observed with the CTG cases. Alkaline phosphatase was significantly lower on 12-week samples in TTG (251.02±93.06) compared to the 4-week (567.94±283.93 U/L), and 0-week samples (1,341.84 U/L). In conclusion, TTG has indicated to have significantly higher tendency to decrease alanine transaminase and alkaline phosphatase, alleviating the negative effects on the liver. The clinical findings were more adverse for the CTG.

Trilostane is a 3β‐hydroxysteroid dehydrogenase/Δ5‐4 isomerase inhibitor able to produce a manyfold increase in brain levels of various neurosteroids, including allopregnanolone. We previously found that treatment with trilostane can slow down epileptogenesis in the kainic acid (KA) model of temporal lobe epilepsy. It is unknown whether trilostane may have a similar effect on the progression of epilepsy severity, as observed in KA‐treated rats. Consequently, we investigated the effects of trilostane (50 mg/kg/day, 1 week) in epileptic rats, given 64 days after KA administration. Seizures were monitored by video‐electrocorticographic recordings before and during the treatment with trilostane or vehicle (sesame oil), and neurosteroid levels were measured in serum and cerebral tissue using liquid chromatography–electrospray tandem mass spectrometry after treatment. Pregnenolone sulfate, pregnenolone, progesterone, 5α‐dihydroprogesterone, and allopregnanolone peripheral levels were massively increased by trilostane. With the only exception of hippocampal pregnenolone sulfate, the other neurosteroids augmented in both the neocortex and hippocampus. Only pregnanolone levels were not upregulated by trilostane. As expected, a significant increase in the seizure occurrence was observed in rats receiving the vehicle, but not in the trilostane group. This suggests that the increased availability of neurosteroids produced a disease‐modifying effect in the brain of epileptic rats. [ABSTRACT FROM AUTHOR]

Hyperadrenocorticism (HAC) in dogs is routinely treated with trilostane single-dose (CTG) which is reported to cause adverse reactions. The current retrospective study of several dogs with terminal stage of HAC aimed to compare the clinical, hematological, and biochemical effects of trilostane titration-dose treatment (TTG) with the single-dose treatment (CTG). All clinical cases (n=7) were confirmed on HAC by anamnestic, clinical, hematology, biochemistry, and low-dose dexamethasone suppression test findings, indicative for Cushing's disease. Two cases were treated with CTG (2.2-6.7 mg/kg, single dose daily) and their treatment was discontinued on the second week due to adverse reactions. The TTG cases were treated for up to 12 weeks (0.5 mg/kg once daily for 7 days, and then with 0.5 mg/kg twice daily for 7 days). Blood samples and clinical checks were performed on 0., 4., and 12. weeks of the treatment. Hemoglobin was non-significantly higher in TTG at 12 weeks. Alanine transaminase was significantly lower in the TTG cases on the 12. week of the treatment (78.04±15.37 U/L) compared to the 0-week (137.81±24.03 U/L), and 4-week samples (131.92±23.36 U/L). No significant differences were observed with the CTG cases. Alkaline phosphatase was significantly lower on 12-week samples in TTG (251.02±93.06) compared to the 4-week (567.94±283.93 U/L), and 0-week samples (1,341.84 U/L). In conclusion, TTG has indicated to have significantly higher tendency to decrease alanine transaminase and alkaline phosphatase, alleviating the negative effects on the liver. The clinical findings were more adverse for the CTG. [ABSTRACT FROM AUTHOR]

Simple Summary: Cushing's syndrome is a common disease in middle-aged and old dogs, characterized by steroid overproduction by the adrenal glands. This steroid excess can be caused by an adrenal tumor (adrenal dependent hypercortisolism) and is associated with systemic hypertension. In people with this disease, it is known that hypertension can be difficult to manage and, sometimes, several drugs are necessary to treat it. However, there are no studies focused on the changes in the blood pressure during treatment in dogs with adrenal-dependent hypercortisolism. In this study, 14 dogs with this disease were followed during the first year of medical treatment or during 1 year after surgery to remove the adrenal tumor (adrenalectomy), and the changes in their blood pressure were evaluated. We observed that blood pressure in medically treated dogs decreased during the study period using, in most cases, a single antihypertensive drug. Also, in those dogs surgically treated, blood pressure normalized three months after surgery, and in one case, antihypertensive medications could be reduced. Thus, when adrenalectomy is performed, it is important to carefully address blood pressure after the procedure as these dogs might require reductions in their antihypertensive treatment. Hypercortisolism in dogs is frequently associated with systemic hypertension (SH). However, there are no studies evaluating the changes in systolic blood pressure (SBP) in dogs with adrenal-dependent hypercortisolism (ADH) during trilostane treatment or after adrenalectomy and their response to antihypertensive treatments. For this reason, the objectives of this study were to evaluate the changes in SBP in dogs with ADH during the first year of trilostane treatment or after adrenalectomy, the relation with clinical control of hypercortisolism and certain laboratory parameters, and the response to antihypertensive drugs. Fourteen dogs newly diagnosed with ADH were prospectively included and evaluated at diagnosis (T0) and 1, 3, 6, and 12 months after (T1, T3, T6, and T12, respectively). Dogs were classified as hypertensive (HT; SBP ≥ 160 mmHg) and non-hypertensive. In HT dogs, benazepril was considered as the first-line drug, and, if necessary, amlodipine was prescribed. The prevalence of SH at T0 was 79%, and it was reduced to 25% at T12. Blood pressure (BP) was not associated with disease control or selected laboratory parameters at any endpoint. Only 22% of dogs with SH needed more than one drug to normalize their SBP. In all dogs surgically treated that were HT at T0, BP normalized at T3. [ABSTRACT FROM AUTHOR]

The spotted scat (Scatophagus argus) is an important ornamental species with sexually biased ornamental values that favor males. Therefore, it makes sense to breed mono-male fingerlings as ornamental fish. The spotted scat has an XX/XY sex determination system; therefore, the first step in producing genetically all-male offspring should be the induction of a fertile sex-reversed XY pseudo-female, which would then be mated with a normal XY male to produce a YY super-male. However, the XY pseudo-female produced by estradiol (E2) treatment failed due to ovarian malformations. Here, male to female sex reversal was induced in spotted scat through a combination of E2 and an androgen inhibitor (trilostane, TR). Spotted scat fingerlings of approximately 2.8–3.5 cm were fed a diet containing both E2 (300 µg/g) and TR (300 µg/g). The fish were treated for 90 days and then fed a normal diet until they reached one year of age, when they were sampled. Twenty-eight treated XY individuals were identified using sex-linked markers. According to their gonadal histological characteristics, these treated XY fish could be divided into three groups: males with testes (n = 21), intersex individuals with ovaries–testes (n = 3), and fully sex-reversed individuals with ovaries (n = 4). All treated XX fish (n = 8) developed into normal females. There were no obvious abnormalities in the ovaries of the XY sex-reversed fish compared to the treated XX fish. Serum 11-ketotestosterone (11-KT) levels were significantly lower in XY-reversed females and treated XX females than in XY males. Compared with XY male fish, the expression of female (42sp50, foxl2, figla, zar1, and zp2) and male (dmrt1, gsdf, amh and cyp11b2) biased genes was up- and down-regulated, respectively, in the gonads of XY-completely sex-reversed fish. Immunohistochemical results indicate that 42Sp50 was expressed in oocytes of XY-partially and completely sex-reversed fish, while strong Gsdf signals were mainly detectable in testicular somatic cells of XY-partially sex-reversed fish and XY male fish. XY females were successfully produced by the combined treatment of E2 and TR in the spotted scat. Their fertility will be tested in the future. [ABSTRACT FROM AUTHOR]

Copyright of Nouveau Praticien Vétérinaire Canine & Féline is the property of EDP Sciences and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

This case report describes a practical approach for diagnosing and treating a 17-month-old Syrian hamster with hyperadrenocorticism based on: history, systemic signs, dermatological lesions, and therapeutic trial. The patient was monitored for 16 weeks while he was treated with trilostane and achieved hair regrowth and the resolution of systemic and demeanour signs.

Abstract A 13‐year‐old spayed female Schnauzer dog with chronic kidney disease (CKD; International Renal Interest Society stage 2, non‐proteinuric, normotensive), diabetes mellitus, hypercortisolism and myxomatous mitral valve degeneration (American College of Veterinary Internal Medicine stage B2) presented with electrolyte imbalance that had progressed to hyperkalaemia and hyponatremia, with a sodium to potassium (Na:K) ratio of 19.6. Cortisol levels after the adrenocorticotropic hormone stimulation test were within the therapeutic range, but aldosterone levels were below the reference range; hence, isolated hypoaldosteronism was diagnosed. After administration of deoxycorticosterone pivalate (DOCP), the electrolyte imbalance improved with a Na:K ratio of 27.7. This is the first report of the management of isolated hypoaldosteronism and hypercortisolism using trilostane and DOCP in a dog. This case highlights the importance of recognizing isolated hypoaldosteronism after long‐term treatment with trilostane in a canine patient with CKD.

IntroductionAdrenocortical carcinoma (ACC) with metastasis has a grave prognosis, and adrenalectomy is associated with a high perioperative mortality rate in dogs. A favorable outcome following trilostane treatment in patients with metastatic ACC confirmed by a decreased size of the adrenal tumor and metastatic lesions has not been reported in dogs.Case descriptionA 12-year-old neutered male Maltese dog was diagnosed with a right adrenal tumor and a hepatic mass. Adrenal-dependent hyperadrenocorticism (ADH) was diagnosed based on clinical signs and an adrenocorticotropic hormone stimulation test (ACTHST). In addition, tests for plasma metanephrine and normetanephrine ruled out a pheochromocytoma. Based on cytology and computed tomography, unresectable metastatic ACC was confirmed. The dog was managed with trilostane due to the presence of distant metastasis. Medical management improved the clinical signs and post-ACTHST cortisol concentrations. One year after the first presentation, the clinical signs and ACTHST test showed a favorable outcome. In addition, computed tomography revealed a decreased size of the right adrenal tumor and resolution of the hepatic mass.ConclusionsTrilostane could be considered as a treatment option for unresectable metastatic ACC. A decrease in tumor size following treatment with trilostane has not been reported in dogs. This case report is the first to demonstrate a favorable outcome of metastatic ACC following trilostane mono therapy for >1 year.

Objective: Epileptogenesis after status epilepticus (SE) has a faster onset in rats treated to reduce brain levels of the anticonvulsant neurosteroid allopregnanolone with the 5α‐reductase inhibitor finasteride; however, it still has to be evaluated whether treatments aimed at increasing allopregnanolone levels could result in the opposite effect of delaying epileptogenesis. This possibility could be tested using the peripherally active inhibitor of 3β‐hydroxysteroid dehydrogenase/Δ5‐4 isomerase trilostane, which has been shown repeatedly to increase allopregnanolone levels in the brain. Methods: Trilostane (50 mg/kg) was administered subcutaneously once daily for up to six consecutive days, starting 10 min after intraperitoneal administration of kainic acid (15 mg/kg). Seizures were evaluated by video‐electrocorticographic recordings for 70 days maximum, and endogenous neurosteroid levels were assessed by liquid chromatography–electrospray tandem mass spectrometry. Immunohistochemical staining was performed to evaluate the presence of brain lesions. Results: Trilostane did not alter the latency of kainic acid‐induced SE onset or its overall duration. When compared to the vehicle‐treated group, rats receiving six daily trilostane injections presented a remarkable delay of the first spontaneous electrocorticographic seizure and subsequent tonic–clonic spontaneous recurrent seizures (SRSs). Conversely, rats treated with only the first trilostane injection during SE did not differ from vehicle‐treated rats in developing the SRSs. Notably, trilostane did not modify neuronal cell densities or the overall damage in the hippocampus. In comparison to the vehicle group, repeated administration of trilostane significantly decreased the activated microglia morphology in the subiculum. As expected, allopregnanolone and other neurosteroid levels were remarkably increased in the hippocampus and neocortex of rats treated for 6 days with trilostane, but pregnanolone was barely detectable. Neurosteroids returned to basal levels after a week of trilostane washout. Significance: Overall, these results suggest that trilostane led to a remarkable increase in allopregnanolone brain levels, which was associated with protracted effects on epileptogenesis. [ABSTRACT FROM AUTHOR]

Adrenal gland disease has been described as a rare disease in pet rabbits and rodents. Hyperadrenocorticism with excessive secretion of corticosteroids is most commonly observed in guinea pigs and hamsters, with dermatologic signs similar to those seen in dogs. Diagnosis is based on clinical signs, diagnostic imaging such as abdominal ultrasound, and determination of the blood hormone concentrations. In guinea pigs, an adrenocorticotrophic hormone stimulation test with the measurement of salivary cortisol or corticosterone concentrations is recommended. The recommended treatment of adrenal disease in guinea pigs and hamsters is oral administration of trilostane or ketoconazole; surgical treatment is also possible., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Copyright of Acta Veterinaria Brasilica is the property of Acta Veterinaria Brasilica and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Nouveau Praticien Vétérinaire Canine & Féline is the property of EDP Sciences and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Nouveau Praticien Vétérinaire Canine & Féline is the property of EDP Sciences and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

A 13‐year‐old spayed female Schnauzer dog with chronic kidney disease (CKD; International Renal Interest Society stage 2, non‐proteinuric, normotensive), diabetes mellitus, hypercortisolism and myxomatous mitral valve degeneration (American College of Veterinary Internal Medicine stage B2) presented with electrolyte imbalance that had progressed to hyperkalaemia and hyponatremia, with a sodium to potassium (Na:K) ratio of 19.6. Cortisol levels after the adrenocorticotropic hormone stimulation test were within the therapeutic range, but aldosterone levels were below the reference range; hence, isolated hypoaldosteronism was diagnosed. After administration of deoxycorticosterone pivalate (DOCP), the electrolyte imbalance improved with a Na:K ratio of 27.7. This is the first report of the management of isolated hypoaldosteronism and hypercortisolism using trilostane and DOCP in a dog. This case highlights the importance of recognizing isolated hypoaldosteronism after long‐term treatment with trilostane in a canine patient with CKD. [ABSTRACT FROM AUTHOR]

BackgroundStandard protocols for adrenocorticotropic hormone (ACTH) stimulation testing (ACTHst) often involve intravenous (IV) injection of corticotropin. ACTH might be unintentionally injected into the perivascular (PV) space.ObjectiveTo compare stimulation test results after IV and PV injections of ACTH.AnimalsTwenty privately owned dogs were studied: 10 healthy and 10 with trilostane-treated naturally occurring hyperadrenocorticism (HAC).MethodsProspective study. Each of 20 dogs underwent 2 ACTHst not

Simple Summary: The medical termination of unwanted pregnancies in dogs is practiced throughout the world for many reasons, including at the request of animal owners. For these procedures, it is advised to use rapidly effective drugs with minimal side effects. In this study, we investigated trilostane, which decreases progesterone levels, for its efficacy in terminating mid-term pregnancies in dogs, as well as potential side effects. Although trilostane is not a standalone alternative for the termination of pregnancy in dogs, it has been determined that its combined use with another medical agent of known efficacy reduces both the abortion time and potential side effects. Further studies investigating an increased frequency of administration rather than the administration dose could contribute to determining the efficacy of trilostane in dogs. Progesterone (P4) is the only hormone needed to maintain pregnancy in dogs. Therefore, a competitive inhibitor of 3β-hydroxysteroid dehydrogenase (3β-HSD) could be a safe and effective option to terminate pregnancy by inhibiting P4 synthesis. To address this hypothesis, we investigated the efficacy of trilostane (TRL), a competitive inhibitor of 3β-HSD, in terminating pregnancy in dogs. Twenty-one dogs between days 30 and 38 of pregnancy were randomly assigned to one of two treatment groups (trilostane (TRL) and aglepristone (AGL)) and an untreated control (CON) group (n = 7 dogs each). Fetal heart rates (FHRs) (measured at 12 h intervals) and serum P4 concentrations (measured at 6 h intervals) were evaluated. The pregnancy termination rates were 0% and 100% in the TRL and AGL groups, respectively. The decrease in the FHR in the TRL and AGL groups was significantly lower than that observed in the CON group. There was a marked decrease in P4 concentrations in the TRL group 6, 54, and 102 h after the initiation of treatment. The luteal expression of StAR appeared to be weaker in the AGL group than the CON group. In conclusion, although a treatment-induced decrease was observed in plasma P4 concentrations, a seven-day TRL treatment alone was not effective in terminating pregnancies. Further studies are needed on the effects of the prolonged administration of TRL with varying doses and frequencies for the termination of mid-term pregnancy in dogs. [ABSTRACT FROM AUTHOR]

A 10-year-old castrated male cat showing behavioral (irritation, prowling, and tumbling) and cutaneous abnormalities such as dermal fragility was diagnosed as hyperadrenocorticism with pituitary macroadenoma, concurrent with insulin dependent diabetes mellitus. Pituitary enlargement (18.0 mm) was observed during magnetic resonance imaging. High endogenous adrenocorticotropic hormone levels (>2,500 pg/ml) were also observed. Although trilostane treatment (5-10 mg/head, daily) was commenced, the clinical signs did not disappear. Insulin and trilostane treatment were discontinued on day 86 after first day of radiation therapy (4 Gy/12 fractions). After radiation therapy, a decreased pituitary tumor size (10.7 mm) was observed on day 301; neurological and dermatological signs exhibited remission. Radiation therapy is the treatment of choice for feline hyperadrenocorticism with pituitary macroadenoma with neurological signs. [ABSTRACT FROM AUTHOR]

Summary: Background Human 3β-hydroxysteroid dehydrogenase type 1 (HSD3B1) is an enzyme associated with steroidogenesis, however its' role in hepatocellular carcinoma (HCC) biology is unknown. Trilostane is an inhibitor of HSD3B1 and has been tested as a treatment for patients with breast cancer but has not been studied in patients with HCC. Methods and Results The expression of HSD3B1 in HCC tumors in 57 patients were examined. A total of 44 out of 57 tumors (77.2%) showed increased HSD3B1 expression. The increased HSD3B1 in tumors was significantly associated with advanced HCC. In vitro, the knockdown of HSD3B1 expression in Mahlavu HCC cells by a short hairpin RNA (shRNA) led to significant decreases in colony formation and cell migration. The suppression of clonogenicity in the HSD3B1-knockdown HCC cells was reversed by testosterone and 17β-estradiol. Trilostane-mediated inhibition of HSD3B1 in different HCC cells also caused significant inhibition of clonogenicity and cell migration. In subcutaneous HCC Mahlavu xenografts, trilostane (30 or 60 mg/kg, intraperitoneal injection) significantly inhibited tumor growth in a dose-dependent manner. Furthermore, the combination of trilostane and sorafenib significantly enhanced the inhibition of clonogenicity and xenograft growth, surpassing the effects of each drug used alone, with no documented additional toxicity to animals. HSD3B1 blockade was found to suppress the phosphorylation of extracellular signal-regulated kinase (ERK). The decreased ERK phosphorylation was reversed by testosterone or 17b-estradiol. Conclusions Trilostane significantly inhibited the growth of HCC by inhibiting HSD3B1 function and augmenting the efficacy of sorafenib. [ABSTRACT FROM AUTHOR]

Mud crab (Scylla paramamosain) has become an important mariculture crab along the southeast coast of China due to its strong adaptability, delicious taste, and rich nutrition. Several vertebrate steroid hormones and their synthesis-related genes and receptors have been found in crustaceans, but there are few reports on their synthesis process and mechanism. 3-beta-hydroxysteroid dehydrogenase (HSD3B) is a member of the Short-chain Dehydrogenase/Reductase (SDR) family, and an indispensable protein in vertebrates' steroid hormone synthesis pathway. In this study, the SpHsd3b gene sequence was obtained from the transcriptome data of S. paramamosain , and its full-length open reading frame (ORF) was cloned. The spatial and temporal expression pattern of SpHsd3b was performed by quantitative real-time PCR (qRT-PCR). SpHsd3b dsRNA interference (RNAi) and HSD3B inhibitor (trilostane) were used to analyze the function of Sp HSD3B. The results showed that the SpHsd3b gene has an 1113 bp ORF encoding 370 amino acids with a 3β-HSD domain. Sp HSD3B has lower homology with HSD3B of vertebrates and higher homology with HSD3B of crustaceans. SpHsd3b was expressed in all examined tissues in mature crabs, and its expression was significantly higher in the testes than in the ovaries. SpHsd3b expression level was highest in the middle stage of testicular development, while its expression was higher in the early and middle stages of ovarian development. RNAi experiment and trilostane injection results showed that Sp HSD3B had regulatory effects on several genes related to gonadal development and steroid hormone synthesis. 15-day trilostane suppression could also inhibit ovarian development and progesterone level of hemolymph. According to the above results, crustaceans may have steroid hormone synthesis pathways like vertebrates, and the Hsd3b gene may be involved in the gonadal development of crabs. This study provides further insight into the function of genes involved in steroid hormone synthesis in crustaceans. • Steroid hormone synthesis pathway-related gene— Hsd3b was identified from Scylla paramamosain. • SpHsd3b knockdown can decrease the expression of gonadal development and steroid hormone synthesis-related genes. • Trilostane can inhibit ovarian development and lower progesterone level of hemolymph. • crustaceans may have steroid hormone synthesis pathways like vertebrate. [ABSTRACT FROM AUTHOR]

BackgroundTrilostane 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.ObjectiveTo compare ACTHst results in dogs being treated for NOH with trilostane when the test is begun 2 versus 4 hours after trilostane administration.AnimalsTwenty-one privately owned dogs with NOH, each treated with trilostane for at least 30 days.MethodsEach 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.ResultsFor 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).ConclusionsResults 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.

Abstract Background Clinical signs and consequences of Cushing's syndrome are likely to impact upon a dog's life. Quantification of this impact on a dog's health‐related quality‐of‐life (HRQoL) could contribute to optimized disease management. Hypothesis/objectives To develop a novel HRQoL tool to aid assessment of dogs with Cushing's syndrome and to evaluate factors that impact upon dogs living with this disease. Animals Two hundred and ten dogs with Cushing's syndrome and 617 dogs without Cushing's syndrome. Methods Cross‐sectional study design. Dog owners answered questions relating to the HRQoL of their dogs which were refined to develop the final tool. The tool was analyzed for reliability, validity, and interpretability, including Cronbach's alpha and principal components analysis. Factors impacting upon the HRQoL of dogs with Cushing's syndrome were assessed using appropriate nonparametric tests. Results The tool was refined from 32 questions to 19 and showed good internal consistency (α = .83). Owners rated questions related to “owner impact” as more important and those related to demeanor as less important. There was a positive correlation between the tool score of dogs with Cushing's syndrome and owner's assessment of their dog's quality‐of‐life (r = .41, P

Hyperadrenocorticism (HAC) is one of the most common endocrinopathies in dogs, caused by excessive synthesis of cortisol. Atypical or occult HAC is a syndrome characterized by the presentation of clinical, biochemical, and imaging alterations compatible with hypercortisolism, but normal results in endocrine tests that are conventionally used for HAC diagnosis. However, these patients present high serum concentrations of precursors or other corticoadrenal hormones. The present study describes the case of an 8 years old female canine, Bichón Frisé, epileptic and treated with phenobarbital, presenting clinical signs associated with HAC, in which the low-dose dexamethasone suppression test and stimulation with ACTH resulted within normal values. The measurement of adrenal steroids, after ACTH stimulation, showed abnormal elevation of estrogen and progesterone, the latter persisting after the patient was spayed. Treatment with trilostane allowed the reduction of progesterone levels and the partial resolution of clinical signs. However, full clinical recovery was only achieved after the diagnosis and treatment of concomitant hypothyroidism. The challenge that represent the diagnosis of atypical HAC highlights the importance of performing and having availability of panels that include measurement of adrenal steroid hormones other than cortisol, as well as considering the occurrence of other concomitant endocrine metabolic diseases

Practical relevance: Diabetes mellitus (DM) is a common feline endocrinopathy, and is often driven by underlying insulin resistance with associated pancreatic beta (β)-cell dysfunction. Although spontaneous hyperadrenocorticism (HAC) with hypercortisolemia (hypercortisolism) is relatively uncommon in cats, it is a well-established cause of insulin resistance and is routinely associated with DM in this species. Clinical challenges: Many of the clinical signs associated with feline HAC are subtle and may be attributed to concurrent DM or the aging process. Failure to recognize HAC in the diabetic cat can impact patient wellbeing and predispose the patient to progressive compromise. Unfortunately, it can be difficult to establish a diagnosis of HAC, as test results may be influenced by poor diabetic regulation, and protocols are different to those used in canine patients. Treatment options depend on the underlying cause, and often require careful, ongoing assessment and modulation of both adrenal function and insulin requirements. However, various approaches have been shown to either improve glycemic control in cats with sustained insulin dependence, or facilitate diabetic remission. Evidence base: This review summarizes the current literature on feline HAC, with a particular focus on cats with concurrent DM. The clinical findings that suggest HAC are discussed, along with an outline of diagnostic options and their limitations. Published outcomes for various medical options, surgical procedures and radiation therapy are provided. The authors also share their thoughts on the safe and effective management of cats with HAC and DM, with an emphasis on the anticipation and recognition of changing insulin requirements. [ABSTRACT FROM AUTHOR]

Neurosteroids can modulate γ‐aminobutyric acid type A receptor‐mediated inhibitory currents. Recently, we discovered that the neurosteroids progesterone, 5α‐dihydroprogesterone, allopregnanolone, and pregnanolone are reduced in the cerebrospinal fluid of patients with status epilepticus (SE). However, it is undetermined whether neurosteroids influence SE. For this reason, first we evaluated whether the inhibitor of adrenocortical steroid production trilostane (50 mg/kg) could modify the levels of neurosteroids in the hippocampus and neocortex, and we found a remarkable increase in pregnenolone, progesterone, 5α‐dihydroprogesterone, and allopregnanolone levels using liquid chromatography tandem mass spectrometry. Second, we characterized the dynamics of SE in the presence of the varied neurosteroidal milieu by a single intraperitoneal kainic acid (KA; 15 mg/kg) injection in trilostane‐treated rats and their controls. Convulsions started in advance in the trilostane group, already appearing 90 minutes after the KA injection. In contrast to controls, convulsions prevalently developed as generalized seizures with loss of posture in the trilostane group. However, this effect was transient, and convulsions waned 2 hours before the control group. Moreover, electrocorticographic traces of convulsions were shorter in trilostane‐treated rats, especially at the 180‐minute (P <.001) and 210‐minute (P <.01) time points. These findings indicate that endogenous neurosteroids remarkably modulate SE dynamics. [ABSTRACT FROM AUTHOR]

Background: Hyperadrenocorticism is an uncommon guinea pig disease, but it is an important rule out for bilateral symmetrical non-pruritic alopecia, polyuria, polydipsia, and other generalized signs of illness. Diagnostic testing options are limited due to lack of reference intervals. Testing is challenging due to daily fluctuations in cortisol, stress, concurrent disease, obtaining sufficient samples, and large/variable adrenal gland size in normal guinea pigs. Case description: A three-and-a-half-year-old female guinea pig (Cavia porcellus) presented for a five-week history of bilateral symmetrical alopecia, polyuria, and polydipsia. Abdominal ultrasound revealed small adrenal glands bilaterally. An ACTH stimulation test revealed markedly elevated cortisol pre- and post-stimulation. Treatment with trilostane was initiated (2-4 mg/kg PO q12h), which resolved the clinical signs after three months with no adverse effects noted. The guinea pig later became refractory to treatment and had lost significant weight, at which time an ultrasound was performed and revealed a right adrenal gland mass. Conclusions: Diagnosing hyperadrenocorticism in guinea pigs is challenging and cases can present similarly to ovarian cysts. Diagnosis can be achieved using a combination of clinical signs, abdominal ultrasound, cortisol testing, and ACTH stimulation testing. Case relevance: This report highlights the need for establishment of reference intervals for traditional screening and differentiating tests, as well as reporting effective therapeutic protocols. [ABSTRACT FROM AUTHOR]

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Approaches to downregulate ovarian function in the sexually mature bitch by applying slow release GnRH agonist implants are hampered by the initial stimulation of folliculogenesis (flare up) and the resulting side effects. The present pilot study was designed to test to what extent these effects can be suppressed by simultaneous treatment with the 3ß-hydroxysteroid-dehydrogenase (HSD3B) blocker trilostane (T). Treatment with T in 6-h intervals completely blocked adrenal cortisol production. However, in parallel and concomitant with the increase of LH, progesterone and estradiol levels increased, ending up in pro-estric steroid levels in two of the three dogs. Hormonal changes were reflected in the respective clinical symptoms. During the whole observation period the course of LH concentrations did not indicate downregulation of pituitary function as a result of treatment with the GnRH-agonist Suprelorin®, 4.7 mg. The incomplete inhibitory effect of T on the follicular production of sex steroids could be explained by an insufficient transfer of T into the follicular compartment or the existence of a HSD3B isoform in the dog ovary different from the adrenal enzyme. Concerning the lack of downregulation and when accounting for published data different pharmacodynamics/pharmacokinetic activities of GnRH-agonists should be taken into account. • Stimulation of ovarian function using a GnRH agonist implant could not be overcome by inhibiting HSD3B activity. • The course of E2, P4 and the clinical symptoms observed in two of the three dogs resemble a normal physiological pattern. • No downregulation of the anterior pituitary function was observed during the whole observation period of 30 days. • When further pursuing this approach the different pharmacodynamics of the GnRH agonists should be taken into account. [ABSTRACT FROM AUTHOR]

Background: Pheochromocytoma (PCC) has poor prognosis and adrenalectomy is hard to be performed, in case of caudal vena cava invasion. The long-term administration of phenoxybenzamine in PCC has not been reported in dogs. Case presentation: A 14-year-old castrated male Poodle dog presented with an abdominal mass. On physical examination, hypertension, increased lens opacity, calcinosis cutis, generalized alopecia, and systolic murmur were observed. Serum chemistry and urinalysis profiles revealed hyperglycemia, hypercholesterolemia, elevated liver enzymes, and glucosuria. Abdominal ultrasonography showed a right adrenal mass with invasion of the caudal vena cava, which was cytologically diagnosed as suspected PCC. An adrenal mass (width × height × length, 28 × 26 × 48 mm3) was found on computed tomography and diagnosed as PCC with increased plasma metanephrines and normetanephrines. An adrenocorticotropin hormone stimulation test showed elevated adrenal hormones (androstenedione, estradiol, progesterone, and 17-OH progesterone) with normal cortisol, compatible with atypical Cushing's syndrome. The dog was managed with trilostane, phenoxybenzamine, and insulin therapy. Glycosylated hemoglobin and fructosamine levels gradually decreased, and hypertension resolved. In the 10-month follow-up period, the liver enzymes levels gradually decreased, and the clinical signs of the dog were well-controlled without deterioration. Conclusions: This case report describes long-term medical management without adrenalectomy of PCC complicated with atypical Cushing's syndrome and DM. [ABSTRACT FROM AUTHOR]

Background: Clinical signs and consequences of Cushing's syndrome are likely to impact upon a dog's life. Quantification of this impact on a dog's health‐related quality‐of‐life (HRQoL) could contribute to optimized disease management. Hypothesis/objectives: To develop a novel HRQoL tool to aid assessment of dogs with Cushing's syndrome and to evaluate factors that impact upon dogs living with this disease. Animals: Two hundred and ten dogs with Cushing's syndrome and 617 dogs without Cushing's syndrome. Methods: Cross‐sectional study design. Dog owners answered questions relating to the HRQoL of their dogs which were refined to develop the final tool. The tool was analyzed for reliability, validity, and interpretability, including Cronbach's alpha and principal components analysis. Factors impacting upon the HRQoL of dogs with Cushing's syndrome were assessed using appropriate nonparametric tests. Results: The tool was refined from 32 questions to 19 and showed good internal consistency (α =.83). Owners rated questions related to "owner impact" as more important and those related to demeanor as less important. There was a positive correlation between the tool score of dogs with Cushing's syndrome and owner's assessment of their dog's quality‐of‐life (r =.41, P < .001). Dogs currently on treatment with trilostane had a statistically better HRQoL (.33, interquartile range [IQR].23–.44) than those not receiving trilostane (.36, IQR.33–.54, P =.04). Conclusions and Clinical Importance: The developed tool quantifies the HRQoL of dogs with Cushing's syndrome and could assist clinicians in the clinical assessment of dogs with Cushing's syndrome. [ABSTRACT FROM AUTHOR]

The pheochromocytoma is a rare neoplastic endocrinopathy that affects the sympathetic nervous system due to the involvement of chromaffin cells in the adrenal medulla that produce catecholamines. Diagnosis usually occurs postmortem due to the difficulty of early diagnosis and the absence of pathognomonic clinical signs. This study reports the case of a 13-year-old female canine patient of the Shih-Tzu breed, weighing 7kg, treated at the Veterinary School Clinic of the Tuiuti University of Paraná, with a history of diagnosed and treated hyperadrenocorticism (HAC), and current complaint of otitis. After complementary exams, the presence of right adrenal gland enlargement with altered echotexture and mass appearance was evidenced, suggesting the performance of a computed tomography for surgical screening and subsequent adrenalectomy. The surgical procedure was performed, and subsequent histopathological examination revealed the presence of a pheochromocytoma. Fifteen days after the procedure, the patient presented a recurrence of clinical signs of HAC, such as polyuria, polydipsia, and polyphagia, which were previously controlled with clinical treatment using trilostane. The administration of trilostane was resumed. Currently, the patient shows an absence of clinical signs and a stable condition. [ABSTRACT FROM AUTHOR]

Background A high prevalence of cholestatic disease, including gallbladder mucocele (GBM), has been reported in dogs with naturally occurring pituitary‐dependent hyperadrenocorticism (PDH). Hypothesis/Objectives Differences exist in the clinical features of dogs with PDH and concurrent cholestatic disease, and also is the management of these dogs with trilostane. Animals Sixty‐five client‐owned dogs with naturally occurring PDH. Methods This was a retrospective, observational case series. Each dog was treated with trilostane for at least 3 months before the study, and had a good clinical response, as determined by owners. Statistical comparisons of clinical signs, results of routine blood tests, basal and post‐ACTH cortisol concentration, and optimal trilostane dosage were made after dogs were separated into the following 3 groups by ultrasonographic imaging: normal on ultrasound (NOU) group, cholestasis group, and GBM group. Results The GBM group had more severe clinical signs and significantly different total serum cholesterol concentration and post‐ACTH stimulation cortisol concentration at the time of diagnosis. Dogs that weighed

The purpose of this study was to propose a standard for differentiation between normal dogs and patients with hyperadrenocorticism (HAC) by measuring skin thickness via ultrasonography in small breed dogs. Significant changes in skin thickness of patients treated with prednisolone (PDS) or patients with HAC treated with trilostane were evaluated. Skin thickness was retrospectively measured on three abdominal digital images obtained from small breed dogs weighing < 15 kg that underwent abdominal ultrasonography. Mean skin thickness of normal dogs was 1.03 ± 0.25 mm (mean ± SD). Both the HAC and PDS groups showed significantly thinner skin than that in the normal group. Seven of the 10 HAC patients treated with trilostane had increased skin thickness. The area under the curve value of 0.807 was based on the receiver operating characteristics (ROC) curve for differentiating normal dogs from HAC patients. Sensitivity was 76% and specificity was 73% when skin thickness was less than the 0.83 mm cutoff value. In conclusion, measurement of skin thickness in small breed dogs by using ultrasonography is likely to provide clinical information useful in differentiating HAC patients from normal dogs. However, exposure to PDS, trilostane, and other conditions may have a significant effect on skin thickness. [ABSTRACT FROM AUTHOR]

OBJECTIVE To evaluate clinical signs, endocrine test results, and pituitary tumor size for dogs with medically managed pituitary-dependent hyperadrenocorticism (PDH) and macroadenoma following 6 months of concurrent treatment with pasireotide. DESIGN Prospective case series. ANIMALS 9 client-owned dogs with PDH and macroadenoma in which PDH had been successfully managed with adrenal-directed treatment (trilostane or mitotane). PROCEDURES Dogs were given pasireotide (0.03 mg/kg [0.014 mg/lb], SC, q 12 h) for 6 months, while adrenal-directed treatment was continued. Physical examination, basic clinicopathologic testing, ACTH stimulation testing, and plasma ACTH concentration measurement were performed before (baseline) and 3 and 6 months after treatment began. Measurements of pituitary gland volume and pituitary gland-to-brain ratio were performed via MRI at baseline and 6 months after treatment began. RESULTS No dog developed neurologic abnormalities or signs of adverse effects during the study period. No differences from baseline were identified in clinicopathologic values, ACTH stimulation test results, or plasma ACTH concentration at the 3- or 6-month assessment points. After 6 months of pasireotide treatment, 6 dogs had decreases in MRI-measured values, and 3 had increases. CONCLUSION AND CLINICAL RELEVANCE Pasireotide as administered in this study had no noted adverse effects on dogs with PDH and macroadenoma successfully managed with standard treatment. Placebo-controlled, randomized studies are needed to determine whether pasireotide protects from the development of neurologic signs or improves outcome in dogs with pituitary macroadenomas. [ABSTRACT FROM AUTHOR]

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Spontaneous hypercortisolism or Cushing's syndrome is a common endocrinopathy in dogs. Pituitary-dependent and adrenal-dependent hypercortisolism each require specific treatment and diagnostic imaging is very helpful in choosing the treatment that is appropriate. The aims and expectations of the treatment need to be established beforehand and discussed with the owner to avoid unexpected disappointments. The clinical signs of pituitary-dependent hypercortisolism caused by a pituitary microadenoma can be managed with the adrenocorticostatic drug trilostane, but the drug will not affect the pituitary tumor. Hypophysectomy is therefore preferred in those dogs that have an enlarged pituitary but are in good clinical condition and have a long life-expectancy. Inoperable pituitary tumors can be treated by radiotherapy. The best treatment in dogs with cortisol-secreting adrenocortical tumors is adrenalectomy. If surgery is not possible, because of vascular invasion or metastatic spread, mitotane is recommended. Treatment with trilostane can be considered but is only palliative: it does not affect the adrenocortical tumor.

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

Background: hypothyroidism is a disease of clinical importance that causes multisystem disorders, which can be confused with other endocrinopathies. Rapid and accurate diagnosis is necessary in order to avoid worsening of the clinical manifestation. The use of drugs in a wrong way can directly imply the difficulty of the diagnostic approach, since they may cause changes in the biochemical profiles, which are of great importance as markers in diseases of animals with low thyroid function. Case: The case reports a German Spitz male, one year old and six months old, neutered, who presented bilateral do not cause itching alopecia, being treated by another professional for endocrine and fungal affections. In this same medical appointment were neglected biochemical and hematological profile exams. The exams that had been performed were skin scrapings, which showed growth of fungi and bacteria, besides the measurement of thyroid hormones as TSH, T4L (T4 free) e T3, and also the low-dose dexamethasone suppression test. Based on the findings the therapy instituted by such professional was the administration of itraconazole (ITL®), levothyroxine sodium (compounded drugs) and trilostane (compounded drugs). With absence of clinical improvement, the guardian came to the hospital veterinary, in search of a second diagnostic opinion, where during the collection of information at the time of the anamnesis the patient presented lethargy, drowsiness and absence of hair on both sides. During the clinical examination, the animal presented mild bradycardia and a slightly diminished rectal temperature; in the dermatological evaluation the presence of pup pelt, cutaneous hyperpigmentation and hair thinning in the abdominal area were noted. From this evaluation, hematological exams were requested, which had altered the presence of lymphocytosis, and biochemical tests, where changes in the cholesterol and triglyceride levels were expected, but they were within the normal range. Hormone measurement showed decreased TSH and T4L levels within the reference range. Thyroid ultrasonography demonstrated a hypoplastic gland, while the assessment of abdominal organs were preserved. Based on this, the new therapy instituted was the increase of levothyroxine sodium (Puran®) dose with the withdrawal of other drugs that were being administered to the patient. Over the course of five months, the tutor returned because of lack of improvement in the condition, where he returned to present symptoms such as drowsiness, apathy and indisposition. Thus, a new battery of tests was requested, where the biochemical and hormonal parameters were within the normal range. Due to TSH being within normal, it was decided to change the medication for another version of human levothyroxine sodium (Synthroid®), which has been presenting satisfactory results so far. Discussion: In cases of patients, even when young, when they present bilateral symmetrical alopecia, complementary exams such as scraping of the skin and hair, trichrome and fungal culture, together with hemogram and biochemical profile, are necessary for discarding of endocrinopathies other than hypothyroidism. Treatments instituted with drugs such as trilostan cause changes in laboratory tests, which may make diagnosis difficult. Treatment with levothyroxine sodium expected in patients with hypothyroidism, and serum TSH and T4L levels should be monitored for evaluation of treatment efficacy. The present study demonstrated that the inadequate treatment made diagnosis difficult due to hematological and biochemical alterations. [ABSTRACT FROM AUTHOR]

Steroidogenic enzymes in placentas shape steroid hormone profiles in the maternal circulation of each mammalian species. These include 3β-hydroxysteroid dehydrogenase/Δ5-4 isomerase (3βHSD) and 17α-hydroxylase/17,20-lyase cytochrome P450 (P450c17) crucial for progesterone and androgen synthesis, respectively, as well as aromatase cytochrome P450 (P450arom) that converts Δ4-androgens to estrogens. 5α-reductase is another important enzyme in equine placentas because 5α-dihydroprogesterone (DHP) sustains pregnancy in the absence of progesterone in the second half of equine pregnancy. DHP and its metabolites decline dramatically days before foaling, but few studies have investigated placental enzyme activity before or at parturition in mares. Thus, key enzyme activities and transcript abundance were investigated in equine placentas at 300 days of gestation (GD300) and post-partum (term). Equine testis was used as a positive control for P450c17 activity. Substrates were incubated with microsomal preparations, together with enzyme inhibitors, and products were measured by liquid chromatography tandem mass spectrometry or radiometric methods (aromatase). Equine placenta expressed high levels of 3βHSD, 5α-reductase and aromatase, and minimal P450c17 activity at GD300 compared with testis (600-fold higher). At foaling, 3βHSD and aromatase activities and transcript abundance were unchanged but 5α-reductase (and P450c17) was no longer detectable (P < 0.05) and transcript was decreased. Trilostane inhibited 3βHSD significantly more in testis than placenta, suggesting possible existence of different 3βHSD isoforms. Equine placentas have significant capacity for steroid metabolism by 5α-reductase, 3βHSD and aromatase but little for androgen synthesis lacking P450c17. Declining pre-partum 5α-reduced pregnane concentrations coincide with selective loss of placental 5α-reductase activity and expression at parturition in horses. [ABSTRACT FROM AUTHOR]

The aim of this study was to describe the incidence and permanence of hypoadrenocorticism associated with trilostane treatment and to assess potential risk factors for hypoadrenocorticism. A retrospective cohort study was conducted using case records for 156 dogs treated with trilostane after a diagnosis of hyperadrenocorticism. Occurrences of hypoadrenocorticism were categorised as either transient or permanent. After initiation of treatment with trilostane, the estimated cumulative incidence of hypoadrenocorticism was 15% by 2 years and 26% by 4.3 years, respectively. Occurrences of hypoadrenocorticism were transient in 14/19 (74%) affected study dogs. The risk of hypoadrenocorticism was not significantly associated with trilostane dose rate and other potential risk factors assessed were not significantly associated with subhazard of hypoadrenocorticism, but effect estimates for most were imprecise. In conclusion, approximately 15% of dogs being treated with trilostane developed hypoadrenocorticism within the first 2 years of treatment and about one quarter became affected by 4 years. However, first occurrences of hypoadrenocorticism were mostly transient. Over the range of dose rates studied, each 1 mg/kg/day increase in trilostane dose rate resulted in, at most, only a small increase in the risk of developing hypoadrenocorticism. [ABSTRACT FROM AUTHOR]

3β-Hydroxysteroid dehydrogenase type 1 (3β-HSD1) is selectively expressed in human placenta, mammary glands and breast tumors in women. Human 3β-HSD2 is selectively expressed in adrenal glands and ovaries. Based on AutoDock 3 and 4 results, we have exploited key differences in the amino acid sequences of 3β-HSD1 (Ser194, Arg195) and 3β-HSD2 (Gly194, Pro195) by designing a selective inhibitor of 3β-HSD1. 2,16-Dicyano-4,5-epoxy-androstane-3,17-dione (16-cyano-17-keto-trilostane or DiCN-AND) was synthesized in a 4-step procedure from androstenedione. In purified 3β-HSD inhibition studies, DiCN-AND competitively inhibited 3β- HSD1 with K i = 4.7 μM and noncompetitively inhibited 3β-HSD2 with a 6.5-fold higher K i = 30.7 μM. We previously reported similar isoenzyme-specific inhibition profiles for trilostane. Based on our docking results, we created, expressed and purified the chimeric S194G-1 mutant of 3β-HSD1. Trilostane inhibited S194G-1 (K i = 0.67 μM) with a noncompetitive mode compared to its 6.7-fold higher affinity, competitive inhibition of 3β-HSD1 (K i = 0.10 μM). DiCN-AND inhibited S194G-1 with a 6.3-fold higher K i (29.5 μM) than measured for 3β-HSD1 (K i = 4.7 μM) but with the same competitive mode for both enzyme species. Since DiCN-AND noncompetitively inhibits 3β-HSD2, which has the Gly194 and Pro195 of 3β-HSD2 in place of the Ser194 and Arg195 in 3β-HSD1, this suggests that Arg195 alone in 3β-HSD1 or S194G-1 is required to bind DiCN-AND in the substrate binding site (competitive inhibition). However, both Ser194 and Arg195 are required to bind trilostane in the 3β-HSD1 substrate site based on its noncompetitive inhibition of S194G-1 and 3β-HSD2. In support of this hypothesis, DiCN-AND inhibited our chimeric R195P-1 mutant noncompetitively with a K i = 41.3 μM (similar to the 3β-HSD2 inhibition profile). Since DiCN-AND competitively inhibited S194G-1 that still contains R195 but noncompetitively inhibited R195P-1 that still contains S194, our data provides strong evidence that the Arg195 being mutated to Pro195 (as present in 3β-HSD2) shifts the inhibition mode from competitive to noncompetitive in 3β-HSD1. This supports the key role of Arg195 in 3β-HSD1 for the high affinity, competitive binding of the trilostane analogs. Our new structure/function information for the design of targeted 3β-HSD1 inhibitors may lead to important new treatments for the prevention of spontaneous premature birth. [ABSTRACT FROM AUTHOR]

Background: Glucocorticoids influence the synthesis and metabolism of catecholamines (epinephrine and norepinephrine) and metanephrines (metanephrine and normetanephrine). The aim of this study was to measure urinary catecholamines and metanephrines in dogs with hypercortisolism before and during trilostane therapy. Urine samples were collected during initial work up and during therapy with trilostane in 14 dogs with hypercortisolism and in 25 healthy dogs. Epinephrine, norepinephrine, metanephrine and normetanephrine were measured using high-pressure liquid chromatography and expressed as ratios to urinary creatinine concentration. Results: Untreated dogs with hypercortisolism had significantly higher epinephrine, norepinephrine, and normetanephrine: creatinine ratios compared to healthy dogs. During trilostane therapy, urinary catecholamines and their metabolites did not decrease significantly. However, dogs with low post-ACTH cortisol concentrations during trilostane therapy had less increased epinephrine, norepinephrine and normetanephrine:creatinine ratios compared to healthy dogs. There was no correlation of urinary catecholamines and their metabolites with baseline or post-ACTH cortisol or endogenous ACTH concentrations during trilostane therapy. Conclusion: Influences between steroid hormones and catecholamines seem to occur, as dogs with hypercortisolism have significantly higher urinary epinephrine, norepinephrine, and normetanephrine:creatinine ratios. Once-daily trilostane therapy does not lead to a significant decrease in catecholamines and their metabolites. Trilostane-treated dogs still have increased urinary epinephrine, norepinephrine and normetanephrine:creatinine ratios during trilostane therapy. [ABSTRACT FROM AUTHOR]

Copyright of Pesquisa Veterinaria Brasileira is the property of Colegio Brasileiro de Patologia Animal - CBPA and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)