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Treating canine Cushing’s syndrome: Current options and future prospects

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... Il trilostano è uno steroide sintetico che inibisce in modo competitivo l'enzima 3β-idrossisteroido deidrogenasi (3βHSD), il quale è necessario per la sintesi di tutti gli ormoni surrenalici e in particolare del cortisolo (Figura 1). 1 Inibendo la produzione di cortisolo, si riduce/viene a mancare il feedback negativo a livello ipofisario con conseguente aumento compensatorio dell'ACTH plasmatico. 2 Il trilostano è registrato per il trattamento sia del PDH che dell'ADH, ma la maggior parte degli studi sull'utilizzo di tale farmaco sono stati eseguiti su cani con PDH. 3 Il trilostano viene assorbito rapidamente dal tratto gastroenterico, in particolare quando assunto con l'alimento, pertanto viene sempre consigliata la somministrazione contestualmente al pasto. 4 A differenza di quanto consigliato circa 10-15 anni fa, il dosaggio di partenza che oggi viene utilizzato è molto più basso, anche se esiste una marcata variabilità sul dosaggio di partenza tra i vari studi presenti in letteratura. ...
... 6,[9][10][11][12]14 La terapia in singola dose giornaliera risulta comunque un'alternativa valida e in questo caso il dosaggio di partenza dovrebbe essere di 1-2 mg/kg una volta al giorno. 3 Dopo l'inizio della terapia, un'adeguata dose di trilostano porta a miglioramenti clinici evidenti, quali: miglioramento/risoluzione di astenia e letargia, riduzione di poliuria, polidipsia e polifagia. È necessario un periodo di tempo maggiore (anche mesi) per osservare dei miglioramenti a livello di cute e pelo, in particolare se vi è la presenza di calcinosis cutis. ...
... te nei pazienti di età più giovane con HC, dovrebbe essere effettuato un controllo tramite tomografia computerizzata (TC) o risonanza magnetica (RM) dopo circa un anno di trattamento con trilostano in modo da rivalutare le dimensioni ipofisarie (Figura 2). 3 Nei cani con ADH la chirurgia è la terapia d'elezione considerando che questi tumori sono prevalentemente maligni ed il trilostano non ne impedisce la crescita o la diffusione metastatica. La terapia medica è prettamente di tipo palliativo e riduce efficacemente i segni clinici, con risultati paragonabili a quelli ottenuti su cani con PDH. ...
Article
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The differentiation between pituitary-dependent and adrenal-dependent hypercortisolism is essential to determine the optimal treatment strategy. Currently, trilostane is the medical therapy of choice for hypercortisolism. Trilostane allows the control of clinical signs in most of the cases without, however, leading to the resolution of the hypercortisolism. To date, trilostane treatment includes two possible monitoring methods, the ACTH stimulation test and the “prepill cortisol” concentration. Both monitoring methods have advantages and disadvantages. The aim of this review is to investigate the possible therapeutic options available to date and those still object of study for the medical treatment of canine hypercortisolism. Particular attention will be given to trilostane therapy and therapeutic monitoring.
... Contudo, como a medicação age por menos de 12 horas na maioria dos cães, e o pico de ação é ao redor de 2 a 4 horas após a administração, o uso duas vezes por dia (em latim, bis in die [bid]) está associado a melhor controle da doença e menor incidência de efeitos colaterais. 75 O trilostano deve ser administrado sempre junto de uma refeição, dada sua natureza lipossolúvel. 1 Há uma tendência de animais de grande porte precisarem de doses menores para controle do HAC, ao passo que animais de pequeno porte têm tendência a precisar de doses maiores para alcançar um controle satisfatório da doença. ...
... Recentemente, foi proposto um método alternativo de monitoramento da terapia com trilostano pelo fato de o TEACTH jamais ter sido validado para esse fim e de o ACTH sintético, além de oneroso, não estar sempre disponível nas rotinas clínicas. 75 No entanto, esse método ainda não está completamente aceito e tem sido tema de grande debate na comunidade endocrinológica internacional. A proposta é o emprego do cortisol basal pré-pílula (pré-administração de trilostano) ou a mensuração do cortisol basal 3 horas após a administração do trilostano. ...
... Além disso, o fato de não avaliar a reserva adrenal pelo TEACTH não garante que um paciente com um cortisol pré-pílula ou 3 horas pós-trilostano dentro da faixa alvo terá capacidade de secretar mais cortisol se desafiado por episódio de estresse. 75 No entanto, na falta de ACTH sintético ou diante de incapacidade de o tutor arcar com o custo do teste, esse protocolo alternativo é uma opção para garantir a segurança do tratamento. ...
... In this study, we tested two drugs to determine if they could prevent or reduce chronic stress in a wild species: house sparrows (Passer domesticus). Diazepam acts on GABA receptors in the brain to decrease anxiety and thereby change the perception of stress (Licata and Rowlett, 2008), and mitotane acts at the adrenal cortex to reduce the body's ability to mount an HPA response (Sanders et al., 2018). ...
... Not only is mitotane not effective in all species, but also it can lead to death in some individuals (Breuner et al., 2000). On the other hand, mitotane is an approved drug for human medicine to treat adrenocortical carcinomas (Ardolino et al., 2020) and has been used to treat Cushing's syndrome in humans (Tritos and Biller, 2020) and pet dogs (Sanders et al., 2018). Reports indicate that 5% (Puglisi et al., 2020) to 30% (Baudry et al., 2012) . of human patients discontinue therapy because of adverse side-effects. ...
... Reports indicate that mitotane is teratogenic (Tritos and Biller, 2020), so it is probably advisable to cease mitotane treatment several months prior to initiating long-term captive breeding programs. Critically, most human and dog studies administer mitotane for months to years (Sanders et al., 2018;Puglisi et al., 2020). Adverse effects of a few injections to ease the transition to captivity, as in this study, are not known but unlikely to be as severe as reported in the human and canine clinical literature. ...
Article
Wild animals brought into captivity frequently experience chronic stress and typically need a period of time to adjust to the conditions of captivity (restraint, artificial lighting, altered diet, human presence, etc.), to which they may never fully acclimate. Changes in mass, the hypothalamic–pituitary–adrenal axis and heart rate parameters have been observed over the first week in newly captive house sparrows (Passer domesticus). In this study, we tested the effects of two drugs, diazepam and mitotane, in preventing the chronic stress symptoms caused by captivity, compared with oil-injected control animals. Diazepam is an anxiolytic that is widely prescribed in humans and other animals and has been shown in some cases to reduce physiological stress. Mitotane is an agent that causes chemical adrenalectomy, reducing the body’s capacity to produce glucocorticoid hormones. Our mitotane treatment did not cause the expected change in corticosterone concentrations. Baseline corticosterone was higher after a week in captivity regardless of the treatment group, while stress-induced corticosterone did not significantly increase above baseline after a week in captivity in any treatment group. However, mitotane treatment did have some physiological effects, as it reduced the resting heart rate and the duration of the heart rate response to a sudden noise. It also prevented the increase in nighttime activity that we observed in control animals. There was no effect of diazepam on corticosterone, resting heart rate, activity or heart rate response to a sudden noise, and no effect of either treatment on the sympathetic vs parasympathetic control of the resting heart rate. Together, these data suggest that mitotane, but not diazepam, can have a modest impact on helping house sparrows adapt to captive conditions. Easing the transition to captivity will likely make conservation efforts, such as initiating captive breeding programs, more successful.
... Corticotroph adenomas are pituitary adenomas from the TPIT lineage that express ACTH. Corticotroph adenomas can excessively secrete ACTH, which results in PDH, also known as Cushing's disease (Sanders et al., 2018). ...
... The more recent study by Benchekroun et al. suggests that POMC processing is altered especially in large pituitary tumours in dogs, and is related to decreased expression of the PC1/3 enzyme (Benchekroun et al., 2018). The therapeutic management of dogs with PDH has been recently reviewed elsewhere (Sanders et al., 2018). In short, pituitary-targeted treatment options include surgical removal (transsphenoidal hypophysectomy) or radiotherapy. ...
... Because hypophysectomy and radiotherapy are not widely available and include risks, dogs are often treated medically. Medical treatment of dogs with PDH is currently aimed at regulating cortisol levels with the adrenal steroidogenesis inhibitor trilostane (Ramsey, 2010;Sanders et al., 2018). Pituitary-targeted medical treatment options, such as the somatostatin analogue pasireotide (Castillo et al., 2011;Lottati and Bruyette, 2018), or the vitamin A1 metabolite retinoic acid (Castillo et al., 2006), have shown some promise in experimental treatment of dogs with PDH. ...
Article
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Pituitary tumours are common in dogs and are being increasingly recognized in cats. Pituitary tumours are usually classified as adenomas and should only be classified as carcinomas when there is evidence of metastatic spread of the tumour, which is rare. Despite the benign nature of most pituitary tumours, they can still compress or invade neighbouring tissues. Pituitary tumours can be functional (hormonally active) or non-functional (hormonally silent). The aim of this review was to provide an overview of the different pituitary tumour types in dogs and cats that have been reported in the literature. In dogs, the most common pituitary tumour type is the corticotroph adenoma, which can cause pituitary-dependent hypercortisolism. In cats, the most common pituitary tumour is the somatotroph adenoma, which can cause hypersomatotropism, and the second-most common is the corticotroph adenoma. A lactotroph adenoma has been described in one dog, while gonadotroph, thyrotroph and null cell adenomas have not been described in dogs or cats. Hormonally silent adenomas are likely underdiagnosed because they do not result in an endocrine syndrome. Tools used to classify pituitary tumours in humans, particularly immunohistochemistry for lineage-specific transcription factors, are likely to be useful to classify canine and feline pituitary tumours of unknown origin. Future studies are required to better understand the full range of pituitary adenoma pathology in dogs and cats and to determine whether certain adenoma subtypes behave more aggressively than others. Currently, the mechanisms that underlie pituitary tumorigenesis in dogs and cats are still largely unknown. A better understanding of the molecular background of these tumours could help to identify improved pituitary-targeted therapeutics.
... A leggyakoribb klinikai tünetek a polyuria-polydipsia (PU/PD), polyphagia, elhízás, májmegnagyobbodás, lihegés, izomsorvadás, progresszív szimmetrikus szőrhullás, magas vérnyomás és megnagyobbodott hastérfogat, elvékonyodott bőr, hyperpigmentáció, calcinosis cutis és inzulinrezisztens diabetes mellitus (3,5,19). Egy tanulmány szerint a hyperadrenocorticismusban szenvedő betegeknél négyszer nagyobb az esély a thrombosis kialakulására (24). ...
... A kutya 692 nappal később elpusztult, a boncolás során az aortában és az a. pulmonalisban találtak thrombust. Az agyalapi mirigy daganata, méretétől függően idegrendszeri tüneteket is okozhat, úgy mint levertség, viselkedésváltozás, szűk helyek keresése, a fej falhoz támasztása, látásromlás, ataxia (3,5,19,25). Egy tanulmányban az agyalapi mirigy nagy méretű daganata és a catalepsia kialakulása között találtak összefüggést (21). ...
... A kezelés lényege az élettani kortizolszint elérése és az esetleges kompreszszió miatt kialakult idegrendszeri tünetek megszüntetése vagy mérséklése (19). A gyógyszeres kezelés egyik módja a trilosztán-tartalmú készítmények adása. ...
Article
Full-text available
Background: Hypercortisolism is one of the most common endocrine disease in dogs. It could have peripheral or central aetiology. The central hypercortisolism is caused by adrenocorticotropic hormone dependent pituitary gland adenoma in most cases. According to another grading system, P/B ratio is a good method to distinguish microtumours from macrotumours. Treatment includes conservative and/or radiotherapy and surgery. Materials and Methods, Results and Discussion: An 8-year-old female boxer was presented for evaluation with the signs of PU/PD and weight loosing. Preoperative examination included minimal data-based and special test (ACTH, LDDS, HDDS, MRI, CT), which confirmed the diagnosis of the central Cushing disease. Preoperative 3D-planning was performed based on the DICOM images from CT and MRI. During the first surgery, intensive bleeding was observed, thus we postponed the intervention. During the second surgery the tumorous pituitary gland was removed without complication. Histopathology showed microadenoma. During 3 days hospitalization strict blood and urine control was performed in every hour. Supplementation therapy was started with prednisolone, desmopressin and thyroxine. 11 days later the dog was dull, depressed and had a stiff gait. Control MRI showed myelitis of spinal cord between C1-C5. The CSF showed signs of septic meningoencephalitis but the CSF bacteriological test did not confirmed any microorganism. Antibiotic was given for 7 days intravenously and at the end of the treatment the symptoms were resolved. 100 days after the surgery, control MRI showed the intact and empty sella turcica. After the MRI prednisolone and desmopressin was tapered and stopped. After almost 1 year follow-up the dog is fine, has gained her weight back and again vivacious. The authors highlight the importance of the detailed perioperative monitoring and the preoperative 3D-planning, which could help in the presurgical visualization and intraoperative navigation.
... A leggyakoribb klinikai tünetek a polyuria-polydipsia (PU/PD), polyphagia, elhízás, májmegnagyobbodás, lihegés, izomsorvadás, progresszív szimmetrikus szőrhullás, magas vérnyomás és megnagyobbodott hastérfogat, elvékonyodott bőr, hyperpigmentáció, calcinosis cutis és inzulinrezisztens diabetes mellitus (3,5,19). Egy tanulmány szerint a hyperadrenocorticismusban szenvedő betegeknél négyszer nagyobb az esély a thrombosis kialakulására (24). ...
... A kutya 692 nappal később elpusztult, a boncolás során az aortában és az a. pulmonalisban találtak thrombust. Az agyalapi mirigy daganata, méretétől függően idegrendszeri tüneteket is okozhat, úgy mint levertség, viselkedésváltozás, szűk helyek keresése, a fej falhoz támasztása, látásromlás, ataxia (3,5,19,25). Egy tanulmányban az agyalapi mirigy nagy méretű daganata és a catalepsia kialakulása között találtak összefüggést (21). ...
... A kezelés lényege az élettani kortizolszint elérése és az esetleges kompreszszió miatt kialakult idegrendszeri tünetek megszüntetése vagy mérséklése (19). A gyógyszeres kezelés egyik módja a trilosztán-tartalmú készítmények adása. ...
Article
Full-text available
SUMMARY Background: Hypercortisolism is one of the most common endocrine disease in dogs. It could have peripheral or central aetiology. The central hypercortisolism is caused by adrenocorticotropic hormone dependent pituitary gland adenoma in most cases. According to another grading system, P/B ratio is a good method to distinguish microtumours from macrotumours. Treatment includes conservative and/or radiotherapy and surgery. Materials and Methods, Results and Discussion: An 8-year-old female boxer was presented for evaluation with the signs of PU/PD and weight loosing. Preoperative examination included minimal data-based and special test (ACTH, LDDS, HDDS, MRI, CT), which confirmed the diagnosis of the central Cushing disease. Preoperative 3D-planning was performed based on the DICOM images from CT and MRI. During the first surgery, intensive bleeding was observed, thus we postponed the intervention. During the second surgery the tumorous pituitary gland was removed without complication. Histopathology showed microadenoma. During 3 days hospitalization strict blood and urine control was performed in every hour. Supplementation therapy was started with prednisolone, desmopressin and thyroxine. 11 days later the dog was dull, depressed and had a stiff gait. Control MRI showed myelitis of spinal cord between C1-C5. The CSF showed signs of septic meningoencephalitis but the CSF bacteriological test did not confirmed any microorganism. Antibiotic was given for 7 days intravenously and at the end of the treatment the symptoms were resolved. 100 days after the surgery, control MRI showed the intact and empty sella turcica. After the MRI prednisolone and desmopressin was tapered and stopped. After almost 1 year follow-up the dog is fine, has gained her weight back and again vivacious. The authors highlight the importance of the detailed perioperative monitoring and the preoperative 3D-planning, which could help in the presurgical visualization and intraoperative navigation.
... The goal of treatment of hyperadrenocorticism is to decrease the excessive production of either ACTH or cortisol by surgery, radiotherapy and/or pharmacotherapy. 21,22 Pharmacotherapy was the only possible option for a suspected case of ACTH-dependent hyperadrenocorticism without an accurate aetiologic diagnosis. Several drugs exist and are classified into pituitary-targeting drugs (pasireotide, cabergoline, retinoic acid, etc.) and adrenaltargeting drugs (trilostane, mitotane, ketoconazole, etc.). ...
... Several drugs exist and are classified into pituitary-targeting drugs (pasireotide, cabergoline, retinoic acid, etc.) and adrenaltargeting drugs (trilostane, mitotane, ketoconazole, etc.). 21,22 As only ketoconazole had previously been administered to bottlenose dolphins and was effective in a previous case of hyperadrenocorticism, 2 this drug was the treatment of choice in this case. Moreover, ketoconazole efficacy is recognised in the treatment of ACTH-dependent hyperadrenocorticism in dogs. ...
... Moreover, ketoconazole efficacy is recognised in the treatment of ACTH-dependent hyperadrenocorticism in dogs. 13,21 Ketoconazole is a synthetic imidazole derivative, originally developed as an antifungal agent, and administered to dolphins for that purpose. 12 Ketoconazole inhibits several cytochrome P450 enzymes involved in steroidogenesis, 21 but also in the metabolism of many xenobiotics like CYP3A. ...
Article
A 35-year-old female Atlantic bottlenose dolphin (Tursiops truncatus) presented with lethargy, dysorexia, obesity and locomotor difficulties. An abnormal deposition of fat and superficial skin lesions was observed. Laboratory findings showed lymphopenia and eosinopenia associated with hypercholesterolemia. Endocrinological assessment revealed chronically increased serum cortisol values associated with increased plasma adrenocorticotrophic hormone (ACTH) concentration. ACTH-dependent hypera- drenocorticism, also known as Cushing’s syndrome, was strongly suspected. The bot- tlenose dolphin was treated with ketoconazole (2.3 mg/kg every 12 hours) and prednisone (0.03 mg/kg every 48 hours), which resulted in an improvement in clinical signs, except for obesity. Long-term treatment with ketoconazole and prednisone did not cause any adverse effects. However, the authors recommend avoiding concurrent hor- monal treatment with altrenogest as it might cause a relapse of hyperadrenocorticism or drug–drug interaction with ketoconazole. Endocrinopathies are rare in cetaceans but this case highlights the importance of considering hyperadrenocorticism as a differential diagnosis in dolphins with obesity and skin lesions.
... The goals of treating hypercortisolism in dogs would optimally be to eliminate the source of either ACTH or autonomous cortisol excess, achieve normocortisolism, eliminate the clinical signs, reduce long-term complications and death, and improve the quality of life. 4 Achieving these treatment goals require definitive treatments, such as transsphenoidal hypophysectomy or radiotherapy for PDH, and adrenalectomy in the case of CPAT. 4 PDH and CPAT are generally differentiated using a combination of imaging modalities, such as abdominal ultrasonography and MRI, and hormonal testing. 5,6 In veterinary medicine, the first choice of hormone test to differentiate PDH from CPAT is the highdose dexamethasone suppression test (HDDST). ...
... 4 Achieving these treatment goals require definitive treatments, such as transsphenoidal hypophysectomy or radiotherapy for PDH, and adrenalectomy in the case of CPAT. 4 PDH and CPAT are generally differentiated using a combination of imaging modalities, such as abdominal ultrasonography and MRI, and hormonal testing. 5,6 In veterinary medicine, the first choice of hormone test to differentiate PDH from CPAT is the highdose dexamethasone suppression test (HDDST). ...
Article
Full-text available
Background Hyperadrenocorticism (HAC) is a common endocrine disorder in dogs; however, there are no reports on the use of the corticotropin-releasing hormone test (CRHT) to differentiate between pituitary-dependent hyperadrenocorticism (PDH) and cortisol-producing adrenal tumors (CPATs), both causative of HAC. Objectives To evaluate the usefulness of CRHT as a tool to differentiate between PDH and CPAT in dogs and to determine the reference intervals for CRHT in healthy, PDH, and CPAT dogs. Animals Dogs diagnosed with PDH (n = 21), CPAT (n = 6), and healthy beagle dogs (n = 33). Methods This prospective study included dogs with a definitive diagnosis of PDH and CPAT and healthy beagle dogs, in which CRHT was performed, were prospectively evaluated. We investigated the correlations of CRHT (endogenous adrenocorticotropic hormone [ACTH] concentration, endogenous ACTH concentration [EAC], and poststimulation ACTH concentration [PAC]) with pituitary-to-brain ratio (PBR) (in PDH) and with indices of adrenal ultrasonography (smaller and larger adrenal gland dorsoventral thickness in PDH and CPAT). Results For EAC, the area under the curve (AUC) was 0.95, with a cutoff value of 26.3 pg/mL (sensitivity: 90.62%, specificity: 87.50%). The AUC for PAC was 0.96 with a cutoff value of 54.5 pg/mL (sensitivity: 100.00%, specificity: 66.67%). The 95% reference interval for CRHT in healthy (control) dogs ranged 5.00 to 79.8 pg/mL (1.10-17.57 pmol/L) for EAC, and 1.92 to 153.42 pg/mL (0.42-33.78 pmol/L) for PAC. There was no significant correlation between PBR and CRHT, nor adrenal size and CRHT. Conclusions and Clinical Importance CRHT appears to be a rapid and reliable test for differentiating PDH from CPAT in dogs.
... According to its origin, Cushing's syndrome (CS) in dogs generally is classified as pituitary (ACTH-dependent) or adrenal (ACTH-independent). 1 An additional source of pituitary ACTH (ectopic ACTH secretion syndrome) originating from a neuroendocrine neoplasm is also a reported cause of ACTH-dependent CS in dogs. [2][3][4][5] Typically, adrenal CS results from a cortisol-secreting adrenocortical tumor (adenoma or carcinoma), 6 and, exceptionally, from expression of aberrant adrenal receptors such as the glucose-dependent insulinotropic peptide (GIP) receptor which is involved in food-dependent hypercortisolism. ...
... ACTH-dependent CS in dogs classically results from a functional pituitary adenoma (corticotropinoma) or, exceptionally, from a neuroendocrine tumor (ectopic ACTH syndrome). 1 In humans, in addition to the previously mentioned etiologies, pheochromocytoma and PBMAH also have been reported as the cause of clinical or subclinical CS caused by ectopic ACTH production. 17 To our knowledge, apart from a recent report of a case with pheochromocytoma, PBMAH has not been reported to cause CS by ectopic ACTH production in dogs. ...
Article
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A 13-year-old Labrador retriever was diagnosed with Cushing's syndrome (CS) caused by primary bilateral nodular adrenocortical hyperplasia with adrenocorticotropic hormone (ACTH) expression. The pituitary origin of CS was ruled out by suppression of plasma ACTH concentration and absence of a proliferative lesion on histological evaluation of the pituitary gland using periodic acid-Schiff (PAS) staining, reticulin staining, and immunostaining for ACTH. A pheochromocytoma also was found at necropsy examination. On histological evaluation of both adrenal glands, at the junction of the fascicular and glomerular zones, multiple cell clusters distributed in both hyperplastic adrenal cortices expressed ACTH, whereas the pheochromocytoma cells did not. These results indicate that a disease similar to primary bilateral macronodular adrenocortical hyperplasia in humans also occurs in dogs, with intra-adrenocortical expression of ACTH, glucocorticoids excess, and clinical signs of CS. Therefore, the term ACTH-independent could be inappropriate in some cases of bilateral adrenocortical hyperplasia and suppressed plasma ACTH concentration in dogs.
... Persistent cortisol excess from the adrenal cortex leads to combined gluconeogenic, lipolytic, lipogenic, protein catabolic, and anti-inflammatory effects on many organs 3,4 . HAC is suspected when dogs show clinical symptoms like polyuria, polydipsia, polyphagia, central obesity, hepatomegaly, panting, muscle atrophy, progressive bilateral alopecia, and systemic hypertension 5 . Abdominal distention, often described as the "potbellied" or pendulous abdomen, is also a classic symptom and the cumulative result of increased abdominal organ weight and decreased abdominal muscle strength due to the catabolic effects of cortisol 6 . ...
... Alterations in the number of leukocytes with increased serum cortisol concentration characterized by neutrophilia, monocytosis, lymphopenia, and eosinopenia are termed "stress leukogram" and are popularly recognized in many species, including dogs 14 . Mild erythrocytosis may occasionally be noted in dogs with HAC, owing to ventilatory problems, or in females because of androgenic stimulation of the bone marrow 5 . Dyslipidemia, such as an increase in serum total cholesterol and triglyceride levels, is common in dogs with HAC 13,15 . ...
Article
A 6-month-old female beagle dog, assigned to the low-dose group in a toxicity study, was evaluated for compound toxicity, and spontaneous hyperadrenocorticism was suspected. The animal had an externally apparent distended abdomen on clinical examination upon arrival. Pre-dose clinical pathology showed slightly higher erythroid parameters and stress leukogram on hematology; plasma biochemistry showed higher total protein, gamma-glutamyl transferase, total cholesterol, and triglyceride levels than the reference data. On necropsy, a prominent increase in adipose tissues of the subcutis and abdomen and increased weight of the adrenal gland and liver were observed. Histopathology revealed diffuse hyperplasia of adrenocortical cells in the zona fasciculata and reticularis, cortical atrophy of the thymus, and abundant glycogen accumulation in the hepatocytes. These findings were incidental and not test-substance-related. Electron microscopy of the adrenocortical cells in the zona fasciculata revealed decreased typical translucent lipid droplets, increased electron-dense lipid droplets, and abundant smooth endoplasmic reticulum and lysosomes. Additionally, increased numbers of various sizes and forms of mitochondria with tubular, vesicular, or lamellar cristae compared to that of normal animals were observed. These ultrastructural characteristics of the adrenocortical cells suggested hyperfunction. The pre-dose plasma cortisol levels were slightly higher than those of other females assigned to the toxicity study, while plasma adrenocorticotropic hormone levels were within the normal range. These findings indicate that hyperadrenocorticism is a possible cause of the systemic changes in this case.
... Both PDH and csACT can be treated by surgically removing the causative tumor. Because surgery is not without risks and not suitable for every patient, dogs with Cushing's syndrome are often treated with the steroidogenesis inhibitor trilostane (2). Although trilostane can effectively reduce the clinical signs associated with hypercortisolism, it does not inhibit tumor growth (3). ...
Article
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Canine Cushing's syndrome (hypercortisolism) can be caused by a pituitary tumor (pituitary-dependent hypercortisolism; PDH) or a cortisol-secreting adrenocortical tumor (csACT). For both cases, non-invasive biomarkers that could pre-operatively predict the risk of recurrence after surgery would greatly impact clinical decision making. The aim of this study was to determine whether circulating microRNAs (miRNAs) can be used as diagnostic (presence of PDH or csACT) and/or prognostic (disease recurrence, histological grade) non-invasive biomarkers for canine Cushing's syndrome. After a pilot study with 40 miRNAs in blood samples of healthy dogs (n = 3), dogs with PDH (n = 3) and dogs with a csACT (n = 4), we selected a total of 20 miRNAs for the definitive study. In the definitive study, these 20 miRNAs were analyzed in blood samples of healthy dogs (n = 6), dogs with PDH (n = 19, pre- and post-operative samples) and dogs with a csACT (n = 26, pre-operative samples). In dogs with PDH, six miRNAs (miR-122-5p, miR-126-5p, miR-141-3p, miR-222-3p, miR-375-3p and miR-483-3p) were differentially expressed compared to healthy dogs. Of one miRNA, miR-122-5p, the expression levels did not overlap between healthy dogs and dogs with PDH (p = 2.9x10−4), significantly decreased after hypophysectomy (p = 0.013), and were significantly higher (p = 0.017) in dogs with recurrence (n = 3) than in dogs without recurrence for at least one year after hypophysectomy (n = 7). In dogs with csACTs, two miRNAs (miR-483-3p and miR-223-3p) were differentially expressed compared to healthy dogs. Additionally, miR-141-3p was expressed significantly lower (p = 0.009) in dogs with csACTs that had a histopathological Utrecht score of ≥ 11 compared to those with a score of <11. These results indicate that circulating miRNAs have the potential to be non-invasive biomarkers in dogs with Cushing's syndrome that may contribute to clinical decision making.
... for more articles like this and to become a subscriber synthesis of cytoskeleton-stabilising protein vascular endothelial cadherin), leading to the reduction of vasogenic oedema generated by the mass effect. 20 Although clinical remission can be also observed in the idiopathic vestibular syndrome, 11 the recurrence of vestibular signs with the reincorporation of trilostane (rapid start action, hours) 21 allows the establishment of a direct role of this drug in the neurological signs of this patient. learning points ► The diagnosis of pituitary carcinoma should include recognition of systemic or cerebral metastasis. ...
Article
Metastatic pituitary carcinoma and central vestibular syndrome originating in the thalamus are not common disorders in dogs. An 11-year-old Maltese dog with pituitary-dependent hypercortisolism presented signs of central vestibular dysfunction after trilostane treatment. Interestingly, the patient showed remission of vestibular signs after drug withdrawal, but twoweeks later, with a new administration of trilostane, these signs reappeared after 48 hours. Postmortem, two neoplasms were found: one in the pituitary gland and the other in the thalamus, both with intense positivity for adrenocorticotropic hormone. Findings were conclusive of a functional corticotropic pituitary carcinoma with thalamic metastasis. Altogether, the vestibular dysfunction in this case was attributed to the effect of the mass in the thalamus, and the remission and reappearance of vestibular signs were associated with the level and the effect of cortisol, which depend on the trilostane therapy. Consequently, thalamic metastasis should be considered as a differential diagnosis in dogs with central vestibular dysfunction.
... Es konnte kein Zusammenhang zwischen dem Vorkommen einer Introduction Spontaneous hypercortisolism (HC), one of the most common endocrinopathies in dogs, induces a state of immunosuppression which increases susceptibility to infections. 11,13,15,36 As a result, dogs with HC often develop bacteriuria, comparable to dogs under long-term therapy with glucocorticoids or immunocompromised dogs. 12,16,37,38 According to current veterinary guidelines, the presence of bacteria in the urine determined by a positive bacterial culture, together with clinical signs (pollakisuria, dysuria, periuria, stranguria, hematuria), is defined as sporadic bacterial cystitis. ...
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Introduction: Dogs with hypercortisolism are predisposed to developing bacteriuria associated either with clinical signs of cystitis or without clinical signs (subclinical bacteriuria). Based on current guidelines, dogs with subclinical bacteriuria should not be treated with antibiotics because there is no evidence that treatment improves outcome and because unnecessary treatments should be avoided. Before these guidelines were published in 2019, dogs with hypercortisolism and bacteriuria were commonly treated with antibiotics irrespective of clinical signs. Comprehensive data on the frequency of bacterial cystitis, subclinical bacteriuria and the outcome of antimicrobial treatment in dogs with hypercortisolism is sparse. The aims of this study were to investigate dogs with hypercortisolism for the presence of bacterial cystitis and subclinical bacteriuria, to address the pathogens involved, and to assess the outcome of antibiotic treatment. Dogs newly diagnosed with hypercortisolism between 2005 and 2015 from which a urine bacterial culture was available were included. Statistical analysis was performed with non-parametric tests. Of the 161 client-owned dogs included, 29 (18%) showed bacteriuria, which was subclinical in 24 (83%) cases. Escherichia coli was the most commonly isolated pathogen (58%). Bacteriuria was not associated with sex or neutering status. In 14 dogs, follow-up data was available, of which 13 (93%) were treated with antimicrobials for 14 to 28 days. Follow-up bacterial culture (1 to 118 days after cessation of therapy) was negative in 10 (77%) treated dogs; a negative follow-up culture was not associated with gender, age or duration of treatment. Bacteriuria persisted in three treated dogs and the one untreated dog. The prevalence of positive bacterial urinary culture in dogs with hypercortisolism was lower than previously reported. In the majority of dogs, bacteriuria was subclinical. Most dogs had a negative bacterial culture result after antimicrobial treatment; however, more resistant bacteria were detected in persistently positive urine.
... In humans, Cushing's disease usually is caused by a microadenoma and selective surgical removal of the adenoma is considered the treatment of choice, leaving unaffected pituitary tissue in situ. 1 In dogs, microadenomas usually are treated medically, whereas enlarged pituitary glands more frequently are treated by surgery, radiation therapy, or both. [2][3][4] The aim of pituitary surgery in dogs is generally complete hypophysectomy because it is difficult to recognize unaffected pituitary tissue during surgery. 5,6 Transsphenoidal hypophysectomy has been reported as an effective treatment for pituitary neoplasia in dogs. ...
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Background Electrolyte abnormalities, especially hypernatremia, are frequent complications after transsphenoidal hypophysectomy in dogs with pituitary-dependent hypercortisolism. Objectives To describe electrolyte abnormalities after transsphenoidal hypophysectomy and to investigate possible associations between postoperative hypernatremia and clinical and surgical variables as well as with postoperative outcome. Animals One hundred and twenty-seven client-owned dogs. Methods Dogs with pituitary corticotroph adenomas that underwent transsphenoidal hypophysectomy were retrospectively included. Plasma sodium and potassium concentrations were measured −2, +2, +8, +24, and +48 hours from hypophysectomy. Clinical (breed, age, body weight, skull type, urinary cortisol/creatinine ratio, percentage of suppression to dexamethasone) and surgical variables (duration of anesthesia and surgery, pituitary dimensions) were compared to the development of hypernatremia. Results Postoperative hypernatremia developed in 46.5% (57/127) of dogs and hyponatremia in 6.3% (8/127). Plasma sodium concentration increased after surgery and peaked at 8 hours after surgery, normalizing after 24 to 48 hours. Plasma potassium concentration increased without exceeding the reference limit. No significant associations were found between clinical and surgical variables and hypernatremia, or between hypernatremia and postoperative death, long-term survival or recurrence. Surgery time was significantly longer in dogs that developed persistent diabetes insipidus (P = .02) and persistent diabetes insipidus occurred more frequently in dogs with enlarged pituitary glands (P = .01). Conclusion and Clinical Importance Hypernatremia remains a frequent postoperative complication after transsphenoidal hypophysectomy but did not appear to have an impact on postoperative outcome. No predisposing factor to postoperative hypernatremia was identified. Variations in plasma potassium concentrations do not seem to influence postoperative outcome.
... In contrast, high, or very high; serum eACTH concentration are expected in conditions such secondary hypercortisolism (pituitary-dependent hypercortisolism -PDH) (BEHREND et al., 2013), primary hypoadrenocorticism (LATHAN et al., 2014), and due to trilostane medical treatment of Cushing´s syndrome (TESHIMA et al., 2009). Distinguish PDH from ADH is imperative while defining therapeutic goals (SANDERS et al., 2018). The same is true when primary and secondary hypoadrenocorticism are considered. ...
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Endogenous adrenocorticotrophic hormone (eACTH) measurement is useful in hypercortisolism and hypoadrenocorticism investigation; however, since the hormone is highly unstable, blood samples require proper processing and storage, as well as shipping is often a step limiting since few laboratories offer this assay in Brazil. The aim of this note was to compare overnight dog´s eACTH preanalytical stability when frozen samples were shipped in dry ice (DI), or with recyclable ice bars (RIB). A total of 56 paired samples for eACTH measurement were analyzed. Blood samples were properly handled, plasma aliquots transferred into plastic microtubes, and stored at -80ºC. The fifty-six paired samples were overnight shipped in two thermic isolated boxes with DI or involved by RIB. Despite there was a high correlation between results from both shipping methods (r Spearman = 0.958, P<0.001), the Wilcoxon matched-pairs rank test showed that the shipping method may influence results (P<0.001). However, this difference does not affect results interpretation. By this way, when DI shipping was not possible, RIB shipping may represent a risk to eACTH preanalytical stability.
... Other or adjunctive treatment options include the steroidogenesis inhibitor trilostane, which will only reduce the clinical signs of hypercortisolism and has no effect on tumour growth, and the adrenocorticolytic agent mitotane, which can cause considerable side-effects. 2 Reported recurrence rates after adrenalectomy vary between 12% and 38%, [3][4][5] which can be caused by metastases or regrowth of the ACT. ...
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Hypercortisolism is caused by a cortisol‐secreting adrenocortical tumour (ACT) in approximately 15‐20% of cases in dogs. Little is known about which molecular markers are associated with malignant behaviour of canine ACTs. The objective of this study was to identify molecular markers of prognosis, which could be useful to refine prognostic prediction and to identify potential treatment targets. Cortisol‐secreting ACTs were included from 40 dogs, of which follow‐up information was available. The ACTs were classified as low risk of recurrence tumours (LRT; n = 14) or moderate‐high risk of recurrence tumours (MHRT; n = 26), based on the novel histopathological Utrecht score. Normal adrenals (NAs) were included from 11 healthy dogs as reference material. The mRNA expression of 14 candidate genes was analysed in the 40 ACTs and in 11 NAs with quantitative RT‐PCR. The genes' expression levels were statistically compared between NAs, LRTs and MHRTs. Univariate and multivariate analyses were performed to determine the association of the genes' expression levels with survival. Seven genes were differentially expressed between NAs and ACTs, of which pituitary tumour‐transforming gene‐1 (PTTG1) and topoisomerase II alpha (TOP2A) were also differentially expressed between LRTs and MHRTs. In survival analyses, high expression levels of Steroidogenic factor‐1 (SF‐1), PTTG1 and TOP2A were significantly associated with poor survival. In conclusion, we have identified several genes that are part of the molecular signature of malignancy in canine ACTs. These findings can be used to refine prognostic prediction, but also offer insights for future studies on druggable targets. This article is protected by copyright. All rights reserved.
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O Linfedema é constituído por um acúmulo de fluido no espaço intersticial, caracterizado por um edema que sucede ao distúrbio do sistema linfático.A tumefação a princípio é mole e pode estar determinada a região do corpo que apresenta uma disfunção linfática superficial e, apenas em raras ocorrências, atinge o sistema linfático profundo. O edema pode desaparecer durante o repouso, no entanto, frequentemente evoluem podem se tornar maiores e firmes, decorrente da fibrose reativa. Este trabalho apresenta um relato de caso sobre linfedema localizado em membros posteriores e com atrofia/hipoplasia de linfonodos poplíteos de um cão macho, com 4 meses de idade no diagnóstico, além de características clínicas e laboratoriais de um linfedema primário. O animal foi acompanhado durante o período de 2 anos onde se evidenciou um fibroedema, provocando uma rigidez da textura da derme e do tecido subcutâneo e predisposição a infecções bacterianas secundárias.
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The objective of the study was to describe the clinical, imaging, surgical and histological findings in a dog with Rathke's cleft cyst of the pituitary gland. A 6‐year‐old, female, neutered Staffordshire bull terrier was presented with an acute onset of abnormal behaviour. Magnetic resonance imaging of the skull showed a pituitary mass of 12.9 mm (height) × 8.8 mm (width) × 10.2 mm (length) with a pituitary height/brain area value of 0.73 (reference <0.31). Magnetic resonance imaging findings were suggestive of pituitary apoplexy or neoplasia. Transsphenoidal hypophysectomy was performed and a cystic mass was removed. Histopathology revealed a Rathke's cleft cyst lined by a layer of pseudo‐stratified ciliated columnar epithelial cells and mucin‐secreting goblet cells with remnant pituitary tissue with positive immunostaining against adrenocorticotropic hormone, alpha melanocyte and growth hormone in the periphery. Rathke's cleft cyst should be included in the differential diagnosis of pituitary masses in the dog, and transsphenoidal hypophysectomy is an effective treatment.
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Hypercortisolism is a common endocrinopathy in dogs; however, in a few cases, bilateral functional adrenocortical adenomas cause spontaneous disease, and thrombotic events are considered uncommon complications. The aim of this report was to describe a case of bilateral adrenocortical adenoma in a dog with hyperadrenocorticism associated with distal aortic and iliac thrombosis, with emphasis on clinical and pathological aspects. A 15-year-old spayed female Dachshund with a previous clinical history of hyperadrenocorticism presented with acute bilateral hindlimb paraparesis. A vertebral thoracolumbar radiography was performed and did not present any evidence of intervertebral disk disease or vertebral abnormalities; however, abdominal ultrasound and vascular Doppler evaluation revealed bilateral adrenal enlargement in addition to an aortic and external iliac artery thrombus. The animal was euthanized. At necropsy, both adrenal glands were enlarged by well-demarcated neoplastic nodules in the parenchyma, and a thrombus caudal to the abdominal aorta bifurcation within the external iliac arteries that extended to the left external iliac artery was noted. Histological evaluation revealed a well-differentiated neoplastic proliferation of cortical epithelial cells, consistent with bilateral adenoma, and muscular necrosis in the pelvic limbs was also observed. Bilateral functional adrenocortical adenoma; although, very rare, should be considered as a cause of hypercortisolism, and aortic thrombosis in dogs should be considered as a possible consequence.
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Background: Twice daily low trilostane doses have proven to be effective to manage canine Cushing's syndrome. However, survival and prognostic factors in dogs treated with this protocol have not been evaluated. The aim of the study was to evaluate survival and prognostic factors, including systolic blood pressure (SBP) at diagnosis, in dogs with pituitary-dependent hypercortisolism (PDH) treated with low trilostane doses. Methods: Medical records of 91 dogs newly diagnosed with PDH initially treated with 0.2-1.1 mg/kg of trilostane twice daily were retrospectively included. Survival times were calculated using the Kaplan-Meier estimator. Univariable and multivariable analysis were performed using the Cox proportional hazard regression analysis. Results: Overall, median survival was 998 days (range 26-1832 days, 95% confidence interval = 755-1241 days). In the multivariable analysis, age (hazard ratio [HR] = 1.337, p < 0.001), presence of calcinosis cutis (HR = 5.271, p < 0.001), body condition score (BCS) ≤3/9 (HR = 8.100, p < 0.001) and higher platelet count (HR = 1.002, p = 0.022) were negatively correlated with survival. SBP was not associated with survival. Conclusions: Low-dose trilostane treatment twice daily provides slightly longer survival than previously reported for dogs with PDH treated once or twice daily at higher doses. Older age, presence of calcinosis cutis, low BCS and higher platelet count, but not systemic hypertension, are predictive of poorer prognosis in dogs with PDH.
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Objective To describe the surgical technique and report the outcomes of adrenalectomy and thrombus removal with kidney preservation by renal venotomy in a population of dogs with adrenal tumors and vascular invasion into the renal vein (RV) and caudal vena cava (CVC). Study design Short case series. Animals Five client‐owned dogs that underwent adrenalectomy. Methods Dogs with adrenal tumors and vascular invasion into the RV and CVC were retrospectively enrolled in this multi‐institutional study. Renal venotomy was performed at the time of adrenalectomy for tumor thrombus removal. Recorded data included signalment, clinical signs and results of laboratory testing, physical examination findings, diagnostic imaging results, surgical technique, surgical time, surgical complications, and outcome. Results Tumor thrombus was removed by renal venotomy in five dogs. In one dog with an ectopic adrenal tumor located ventral to the left kidney, the thrombus was occluding 90% of caval flow, and a small caval venotomy was required to remove it. Kidney preservation was achieved in all dogs. No significant intraoperative or postoperative complications occurred, and all dogs were discharged 3 to 4 days postoperatively. Median surgical time was 125 minutes (range, 80‐210). At the end of the study, four dogs were alive without signs of recurrence, while one dog died of a suspected pulmonary embolism at 510 days. Median follow‐up was 510 days (range, 279‐890). Conclusion Renal venotomy is feasible for thrombectomy in dogs with adrenal tumors and RV invasion and allowed for the preservation of the kidney in this case series, thus limiting perioperative morbidity.
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El objetivo de este trabajo fue resaltar la importancia del diagnóstico de la causa del síndrome de Cushing, en un paciente canino macho, de 12 años de edad, con carcinoma cortical adrenal, que llega a la consulta por presentar signos clínicos compatibles con Síndrome de Cushing. Los resultados de la estimulación con ACTH sintética (Synacthen 0.25 mg®) arrojaron un aumento en el cortisol basal (10.8 µg/dl) y pos-estimulación (28.4 µg/dl). La ecografía abdominal reveló la glándula adrenal izquierda de forma redondeada y aumentado de tamaño (3.3 x 3.4 cm), compatible con neoplasia adrenal. El tratamiento de elección fue la adrenalectomía de la glándula adrenal izquierda por abordaje abdominal en la línea media y posterior envío a histopatología para su evaluación, el cual confirmó un carcinoma cortical adrenal. La adrenalectomía en estos casos aumenta la supervivencia, mejorando así la calidad de vida del paciente.
Chapter
Metabolic disease is high on the differential diagnosis list with crusting of frictional surfaces. Canine hypothyroidism is the most frequently diagnosed and misdiagnosed endocrinopathy. It is due to a deficiency in thyroid hormone, commonly due to immunemediated lymphocytic thyroiditis. Treatment of hypothyroidism involves the use of oral levothyroxine supplementation. Hyperthyroidism is one of the most common endocrinopathies affecting older cats and is usually due to either adenomatous hyperplasia of the thyroid or a single thyroid adenoma. Endogenous canine hypercortisolism is a relatively common endocrinopathy that usually affects older dogs. Feline hypercortisolism is a rare condition with infrequent dermatologic manifestations that are usually associated with iatrogenic rather than naturally occurring hypercortisolism. It is important to keep in mind that dermatohistopathologic findings are suggestive of an endocrine disease but are not pathognomonic. Skin changes due to abnormalities in sex hormones are rare and can be caused by abnormalities in the adrenal glands or gonadal organs.
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Background: The use of adrenocorticotropic hormone stimulation test as method to monitor efficacy of trilostane treatment of hypercortisolism (HC) in dogs has been questioned. Objectives: To evaluate and compare 12 methods with which to monitor efficacy of trilostane treatment in dogs with HC. Animals: Forty-five client-owned dogs with HC treated with trilostane q12h. Methods: Prospective cross-sectional observational study. The dogs were categorized as well-controlled, undercontrolled, and unwell through a clinical score obtained from an owner questionnaire. The ability to correctly identify trilostane-treatment control of dogs with HC with the following variables was evaluated: before trilostane serum cortisol (prepill), before-ACTH serum cortisol, post-ACTH serum cortisol, plasma endogenous ACTH concentrations, prepill/eACTH ratio, serum haptoglobin (Hp) concentration, serum alanine aminotransferase (ALT), gamma-glutamyl transferase (γGT) and alkaline phosphatase activity, urine specific gravity, and urinary cortisol : creatinine ratio. Results: Ninety-four re-evaluations of 44 dogs were included; 5 re-evaluations of 5 unwell dogs were excluded. Haptoglobin was significantly associated with the clinical score (P < .001) and in the receiver operating characteristic analysis, Hp cutoff of 151 mg/dL correctly identified 90.0% of well-controlled dogs (specificity) and 65.6% of undercontrolled dogs (sensitivity). Alanine aminotransferase (P = .01) and γGT (P = .009) were significantly higher in undercontrolled dogs. Cutoff of ALT and γGT greater than or equal to 86 U/L and 5.8 U/L, respectively, were significantly associated with poor control of HC by trilostane. Conclusions and Clinical Importance: Of all the 12 variables, Hp, and to a lesser degree ALT and γGT, could be considered additional tools to the clinical picture to identify well-controlled and undercontrolled trilostane-treated dogs.
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Hyperadrenocorticism is a medical condition caused by the increase in cortisol production by the cortex of the adrenal gland. Although infrequently described in most animal species, its naturally occurring form, called Cushing's syndrome, is the most prevalent endocrinopathy in dogs. Cushing's syndrome is also present in humans and might be confused with the pseudo‐Cushing's syndrome (PCS), rarely described in animals. PCS shares many of the clinical and biochemical features of Cushing's syndrome. However, the hypercortisolemia seen is usually idiopathic and, in some circumstances, associated with psychological disruptions. This report describes PCS‐like disorder in two marmosets Callithrix aurita that were exposed to environmental changes, suggesting stress as the main cause of the process and reviewing the mechanisms involved in the pathogeny of the two syndromes.
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Context Cushing’s disease (CD) due to ACTH-secreting pituitary tumors can be a management challenge. Objective To better understand the outcomes of stereotactic radiosurgery (SRS) for CD and define its role in management. Design International, multicenter, retrospective cohort analysis. Setting Ten medical centers participating in the International Gamma Knife Research Foundation (IGKRF). Patients Patients with CD with greater than 6 months endocrine follow-up. Intervention SRS using Gamma Knife radiosurgery. Main outcome measures The primary outcome was control of hypercortisolism (defined as normalization of free urinary cortisol). Radiologic response and adverse radiation effects were recorded. Results 278 patients met inclusion criteria, with mean follow-up of 5.6 years (0.5-20.5 years). Twenty-two patients received SRS as a primary treatment for CD. Mean margin dose was 23.7 Gy. Cumulative initial control of hypercortisolism was 80% at 10 years. Mean time to cortisol normalization was 14.5 months. Recurrences occurred in 18% with initial cortisol normalization. Overall, the rate of durable control of hypercortisolism was 64% at 10 years, and 68% among patients who received SRS as a primary treatment. Adverse radiation effects included hypopituitarism (25%) and cranial neuropathy (3%). Visual deficits were related to treatment of tumor within the suprasellar cistern (P=0.01), while both visual (P<0.0001) and non-visual cranial neuropathy (P=0.02) were related to prior pituitary irradiation. Conclusions SRS for CD is well-tolerated and frequently results in control of hypercortisolism. However, recurrences can occur. SRS should be considered for patients with persistent hypercortisolism after pituitary surgery and as a primary treatment in those unfit for surgery. Long-term endocrine follow-up is essential after SRS.
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Chimeric somatostatin/dopamine compounds such as BIM-23A760, an sst2/sst5/D2 receptors-agonist, have emerged as promising new approaches to treat pituitary adenomas. However, information on direct in vitro effects of BIM-23A760 in normal and tumoral pituitaries remains incomplete. The objective of this study was to analyze BIM-23A760 effects on functional parameters (Ca²⁺ signaling, hormone expression/secretion, cell viability and apoptosis) in pituitary adenomas (n = 74), and to compare with the responses of normal primate and human pituitaries (n = 3–5). Primate and human normal pituitaries exhibited similar sst2/sst5/D2 expression patterns, wherein BIM-23A760 inhibited the expression/secretion of several pituitary hormones (specially GH/PRL), which was accompanied by increased sst2/sst5/D2 expression in primates and decreased Ca²⁺ concentration in human cells. In tumoral pituitaries, BIM-23A760 also inhibited Ca²⁺ concentration, hormone secretion/expression and proliferation. However, BIM-23A760 elicited stimulatory effects in a subset of GHomas, ACTHomas and NFPAs in terms of Ca²⁺ signaling and/or hormone secretion, which was associated with the relative somatostatin/dopamine-receptors levels, especially sst5 and sst5TMD4. The chimeric sst2/sst5/D2 compound BIM-23A760 affects multiple, clinically relevant parameters on pituitary adenomas and may represent a valuable therapeutic tool. The relative ssts/D2 expression profile, particularly sst5 and/or sst5TMD4 levels, might represent useful molecular markers to predict the ultimate response of pituitary adenomas to BIM-23A760.
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The adrenocorticotropic hormone (ACTH) is a pituitary hormone derived from a larger peptide, the proopiomelanocortin (POMC), as are the MSHs (α-MSH, β-MSH, and γ-MSH) and the β-LPH-related polypeptides (Figure 1A). ACTH drives adrenal steroidogenesis and growth of the adrenal gland. ACTH is a 39 amino acid polypeptide that binds and activates its cognate receptor [melanocortin receptor 2 (MC2R)] through the two regions H6F7R8W9 and K15K16R17R18P19. Most POMC-derived polypeptides contain the H6F7R8W9 sequence that is conserved through evolution. This explains the difficulties in developing selective agonists or antagonists to the MCRs. In this review, we will discuss the clinical aspects of the role of ACTH in physiology and disease, and potential clinical use of selective ACTH antagonists.
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Somatostatin analog treatment is first line medical treatment in patients with acromegaly. This drug is currently mainly administered by monthly depot preparations of octreotide and lanreotide. With the innovative transient permeability enhancer, a technology enabling the absorption of drug molecules via transient opening of the tight junctions of the gut epithelium, it is possible to achieve therapeutic octreotide levels after oral ingestion. The present review summarized the preclinical work and the recently reported phase I and III study on oral octreotide capsules in patients with acromegaly. Maintenance of control in 155 participating patients was achieved in 65% at the end of core period. Once controlled on oral octreotide, the response was maintained to the end of the extension phase in 85%. Side effects were comparable to currently available preparations. There was a profound suppression of growth hormone levels, and significant symptom reduction. Currently available parental somatostatin analogs are generally well tolerated and are able to achieve longstanding biochemical control in patients with somatostatin sensitive tumors. Potential advantages of an oral alternative is the lack injection-related side effects, but there will be an ongoing need for a very strict compliance with the 2 daily dose regimen and fasting around drug administrations. A second phase III study is currently being conducted. The potential place in the treatment of acromegaly is discussed.
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Background: Although pituitary-dependent hyperadrenocorticism (PDH) is one of the most common endocrinopathies in dogs, the effects of withholding treatment on survival time in dogs with PDH remain unclear. Hypothesis/objectives: The purpose of this study was to clarify the effects of treatment in dogs with PDH by comparing survival times between dogs treated with trilostane and untreated dogs. Animals: Forty-three dogs diagnosed with PDH at a primary-care hospital in Japan between June 2009 and January 2014. Methods: Retrospective cohort study. The medical records of dogs with PDH treated with trilostane (n = 17) or left untreated (n = 26) were reviewed retrospectively. Survival analysis at 2 years after diagnosis of PDH was performed. Results: Median survival time for the trilostane group was not reached (95% confidence interval [CI], 443 days-not applicable) and was significantly longer than the 506 days (95% CI, 292-564 days; P = .016) for the untreated group. Multivariate Cox proportional hazards analysis (including age at diagnosis, basal cortisol concentration at diagnosis, and treatment group) only identified assignment to the untreated group (hazard ratio, 5.01; 95% CI, 1.63-15.44) as associated with increased mortality. Conclusions and clinical importance: The results of this retrospective cohort study suggest that withholding treatment for dogs with PDH might be associated with a higher risk of death. This represents the largest study to date to report survival times of untreated dogs with PDH.
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Introduction: Cushing’s disease (CD) is caused by a corticotroph adenoma of the pituitary gland that secretes excess adrenocorticotropic hormone (ACTH) causing increased morbidity and mortality. Surgery is the treatment of choice, but is not always successful. Alternatives include radiotherapy, adrenal surgery, and pharmaceutical therapy. The latter is increasingly gaining momentum due to the recent development of compounds that reduce hypercortisolaemia or its symptoms, acting through different mechanisms. Areas covered: In this article, the authors provide a complete overview of the treatment options for Cushing´s disease, including adrenal-directed, tumor-targeted, and peripheral therapies that are currently used or in development, and discuss their potential advantages and limitations. Expert Opinion: Considering the lack of long-term remission in up to half of the patients after surgery, and the delayed response to radiotherapy along with potential side effects, there is a strong need for an effective pharmaceutical treatment. Pasireotide, mifepristone, ketoconazole and metyrapone have been approved by regulatory authorities but their use remains limited due to considerable costs and side effects. Research in this field has focused recently on the improvement of pre-existing drugs and the development of safe new ones. However, few approaches aim at targeting the source of the disease, the ACTH-secreting adenoma.
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It is recommended that trilostane therapy of canine hyperadrenocorticism is monitored using an ACTH stimulation test, however this has never been validated. Three cortisol concentrations (pre-trilostane, 3-hour posttrilostane and 1-hour post-ACTH stimulation) were compared to a clinical score obtained from an owner questionnaire. There were 110 sets of 3 cortisol measurements and questionnaires obtained from 67 trilostane treated dogs. Questionnaire results were used to classify each dog as well or unwell. Well dogs were then categorised as having excellent, moderate or poor hyperadrenocorticism control, using thresholds produced by 14 independent veterinarians. Correlation co-efficients were used to compare the three cortisol concentrations to the owner score and the Kruskal Wallis and Mann-Whitney U tests were used to compare the three cortisol concentrations between categories of control. Cortisol cut-off values between significantly different categories were determined using ROC curves. Pre-trilostane and 3-hour post-trilostane cortisol were better correlated to the owner score and had cut-offs to differentiate between categories of control that had superior sensitivity and specificity results, than the post-ACTH cortisol. Iatrogenic hypoadrenocorticism was not detected in any unwell dog. This study shows that the pre-trilostane and 3-hour post-trilostane cortisol are potentially better monitoring methods than the ACTH stimulation test.
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Purpose: Endogenous Cushing's syndrome (CS) is a rare disease that results from exposure to high levels of cortisol; Cushing's disease (CD) is the most frequent form of CS. Patients with CS suffer from a variety of comorbidities that increase the risk of mortality. Surgical resection of the disease-causing lesion is generally the first-line treatment of CS. However, some patients may not be eligible for surgery due to comorbidities, and approximately 25 % of patients, especially those with CD, have recurrent disease. For these patients, adrenal steroidogenesis inhibitors may control cortisol elevation and subsequent symptomatology. CS is rare overall, and clinical studies of adrenal steroidogenesis inhibitors are often small and, in many cases, data are limited regarding the efficacy and safety of these treatments. Our aim was to better characterize the profiles of efficacy and safety of currently available adrenal steroidogenesis inhibitors, including drugs currently in development. Methods: We performed a systematic review of the literature regarding adrenal steroidogenesis inhibitors, focusing on novel drugs. Results: Currently available adrenal steroidogenesis inhibitors, including ketoconazole, metyrapone, etomidate, and mitotane, have variable efficacy and significant side effects, and none are approved by the US Food and Drug Administration for CS. Therefore, there is a clear need for novel, prospectively studied agents that have greater efficacy and a low rate of adverse side effects. Efficacy and safety data of current and emerging adrenal steroidogenesis inhibitors, including osilodrostat (LCI699) and levoketoconazole (COR-003), show promising results that will have to be confirmed in larger-scale phase 3 studies (currently ongoing). Conclusions: The management of CS, and particularly CD, remains challenging. Adrenal steroidogenesis inhibitors can be of major interest to control the hypercortisolism at any time point, either before or after surgery, as discussed in this review.
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Adrenocorticotropin (ACTH) acts via a highly selective receptor that is a member of the melanocortin receptor subfamily of type 1 G protein-coupled receptors. The ACTH receptor, also known as the melanocortin 2 receptor (MC2R), is unusual in that it is absolutely dependent on a small accessory protein, melanocortin receptor accessory protein (MRAP) for cell surface expression and function. ACTH is the only known naturally occurring agonist for this receptor. This lack of redundancy and high degree of ligand specificity suggests that antagonism of this receptor could provide a useful therapeutic aid and a potential investigational tool. Clinical situations in which this could be useful include (1) Cushing’s disease and ectopic ACTH syndrome – especially while preparing for definitive treatment of a causative tumor, or in refractory cases, or (2) congenital adrenal hyperplasia – as an adjunct to glucocorticoid replacement. A case for antagonism in other clinical situations in which there is ACTH excess can also be made. In this article, we will explore the scientific and clinical case for an ACTH antagonist, and will review the evidence for existing and recently described peptides and modified peptides in this role.
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Background: Transsphenoidal hypophysectomy is one of the treatment strategies in the comprehensive management of dogs with pituitary-dependent hypercortisolism (PDH). Objectives: To describe the influence of pituitary size at time of pituitary gland surgery on long-term outcome. Animals: Three-hundred-and-six dogs with PDH. Methods: Survival and disease-free fractions were analyzed and related to pituitary size; dogs with and without recurrence were compared. Results: Four weeks after surgery, 91% of dogs were alive and remission was confirmed in 92% of these dogs. The median survival time was 781 days, median disease-free interval was 951 days. Over time, 27% of dogs developed recurrence of hypercortisolism after a median period of 555 days. Dogs with recurrence had significantly higher pituitary height/brain area (P/B) ratio and pre-operative basal urinary corticoid-to-creatinine ratio (UCCR) than dogs without recurrence. Survival time and disease-free interval of dogs with enlarged pituitary glands was significantly shorter than that of dogs with a non-enlarged pituitary gland. Pituitary size at the time of surgery significantly increased over the 20-year period. Although larger tumors have a less favorable prognosis, outcome in larger tumors improved over time. Conclusions and clinical importance: Transsphenoidal hypophysectomy is an effective treatment for PDH in dogs, with an acceptable long-term outcome. Survival time and disease-free fractions are correlated negatively with pituitary gland size, making the P/B ratio an important pre-operative prognosticator. However, with increasing experience, and for large tumors, pituitary gland surgery remains an option to control the pituitary mass and hypercortisolism.
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Background: Stereotactic radiosurgery (SRS) and stereotactic radiotherapy (SRT) are highly conformal, high-dose radiation treatment techniques used to treat people and dogs with brain tumors. Objectives: To evaluate the response to SRS- and SRT-treated tumors using volume and perfusion variables and to measure the survival times of affected dogs. Animals: Prospective study of 34 dogs with evidence of brain tumors undergoing stereotactic radiosurgery (SRS) or stereotactic radiotherapy (SRT). Methods: Computed tomography and MRI imaging were used to calculate tumor volume and perfusion at baseline, and at 3 months and 6 months after treatment. Survival analysis was performed to evaluate treatment efficacy. Results: Mean tumor volume significantly declined from baseline to the first recheck by -0.826 cm(3) (95% CI: -1.165, -0.487) (P < .001); this reduction was maintained at the second recheck. Blood flow and blood volume declined significantly in the tumor after treatment. Median survival was 324 days (95% CI: 292.8, 419.4), and 4 dogs survived longer than 650 days. Neither actual tumor volume (hazard ratio = 1.21, P = .19) nor the change in tumor volume from the baseline (hazard ratio = 1.38, P = .12) significantly affected the hazard of death because of the tumor. Conclusions and clinical importance: Stereotactic radiosurgery and SRT are effective treatments for reducing tumor volume, blood flow, and blood volume. Treated dogs surviving for more than 1 year are more likely to die from other causes than of their primary brain tumor. SRS and SRT should be considered for noninvasive treatment of intracranial brain tumors.
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Background: Current understanding of adrenal steroidogenesis is that the production of aldosterone or cortisol depends on the expression of aldosterone synthase (CYP11B2) and 11β-hydroxylase cytochrome P450 (CYP11B1), respectively. However, this has never been studied in dogs, and in some species, a single CYP11B catalyzes both cortisol and aldosterone formation. Analysis of the canine genome provides data of a single CYP11B gene which is called CYP11B2, and a large sequence gap exists near the so-called CYP11B2 gene. Objectives: To investigate the zonal expression of steroidogenic enzymes in the canine adrenal cortex and to determine whether dogs have 1 or multiple CYP11B genes. Animals: Normal adrenal glands from 10 healthy dogs. Methods: Zona fasciculata (zF) and zona glomerulosa (zG) tissue was isolated by laser microdissection. The mRNA expression of steroidogenic enzymes and their major regulators was studied with RT-qPCR. Southern blot was performed to determine whether the sequence gap contains a CYP11B gene copy. Immunohistochemistry (IHC) was performed for 17α-hydroxylase/17,20-lyase (CYP17). Results: Equal expression (P = .62) of the so-called CYP11B2 gene was found in the zG and zF. Southern blot revealed a single gene. CYP17 expression (P = .05) was significantly higher in the zF compared with the zG, which was confirmed with IHC. Conclusions and clinical importance: We conclude that there is only 1 CYP11B gene in canine adrenals. The zone-specific production of aldosterone and cortisol is probably due to zone-specific CYP17 expression, which makes it an attractive target for selective inhibition of cortisol synthesis without affecting mineralocorticoid production in the zG.
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Stress-induced increases in neonatal corticosterone demonstrate a unique shift from ACTH independence to ACTH dependence between postnatal day 2 (PD2) and day 8 (PD8) in newborn rats. This shift could be due to the binding of a bioactive, non-­immunoreactive plasma ligand to the adrenocortical melanocortin 2 receptor (MC2R) (ACTH receptor). A potent MC2R antagonist would be useful to evaluate this phenomenon in the neonate. Therefore, we investigated the acute corticosterone response to ACTH(1–39) injection in rat pups pretreated with newly developed MC2R antagonists (GPS1573 and GPS1574), which have not been tested in vivo. The doses used in vivo were based on their in vitro potency, with GP1573 being more potent than GPS1574. GPS1573 (PD2 and PD8), GPS1574 (PD2 only), or vehicle were injected intraperitoneally (ip) 10 min before baseline sampling. Then, 0.001 mg/kg of ACTH(1–39) was injected ip, and subsequent blood samples obtained for the measurement of plasma corticosterone. Pretreatment of PD2 pups with GPS1573 demonstrated augmentation, rather than inhibition, of the corticosterone response to ACTH. In PD8 pups, pretreatment with 0.1 mg/kg GPS1573, but not 4 mg/kg, augmented the corticosterone response to ACTH. Pretreatment with GPS1574 attenuated the plasma corticosterone response to ACTH at 30 min in PD2 pups. The activity of these two compounds in vivo do not match their potency in vitro, with GPS1573 leading to a small augmentation of the corticosterone response to ACTH in vivo while GPS1574 resulted in inhibition.
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The effects of trilostane, a 3 beta-hydroxysteroid dehydrogenase inhibitor on basal cortisol concentrations and the results Of ACTH stimulation tests in dogs with pituitary-dependent hyperadrenocorticism were investigated. in eight of nine dogs trilostane suppressed the concentration of cortisol below the lower limit of the reference range (<50 nmol/l) for a mean (sd) of 3.5 (2.3) hours during the day, but for no longer than 13 hours. In another 10 dogs, there was a clear difference between the Post ACTH cortisol concentrations observed four and 24 hours after the administration of trilostane. Furthermore, in the six dogs whose clinical signs were poorly controlled the post-ACTH concentrations observed four and 24 hours after the administration of trilostane were always higher than the equivalent cortisol concentrations in the four dogs whose clinical signs were controlled. A short duration of drug action may be responsible for the failure of some dogs to respond adequately to once daily trilostane administration.
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Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis. Discrimination between ACCs and adrenocortical adenomas (ACAs) remains challenging, with as current golden standard the Weiss score, consisting of several histopathological characteristics. However, new markers like Ki67, a marker for proliferation, and the staining of reticulins, are promising, not only as it comes to identifying malignancy, but also as prognostic markers in patients with ACC. Currently, surgery is still the only curative treatment for ACC. Mitotane, an adrenolytic drug, is used in the adjuvant setting and in case of metastatic or advanced disease. Patients with progressive disease are frequently treated with mitotane, alone or in combination with etoposide, doxorubicine and cisplatin. Radiotherapy is indicated in selected cases. The low response rates and high toxicity of the systemic therapies emphasize the need for markers that enable the identification of responders and non-responders. Consequently, research is focusing on predictive factors varying from the expression of DNA repair genes to clinical patient characteristics. Subgroups of ACC with different prognosis have been identified based on transcriptome characteristics. As a conclusion from large molecular studies, ACCs appear to harbor many abnormalities compared to ACAs. Altered pathways driving ACC pathogenesis include the IGF, TP53 and the Wnt signaling pathway, allowing these as new potential targets for medical therapy. However, despite efforts in preclinical and clinical studies investigating efficacy of targeting these pathways, most of novel therapies appear to be effective in only a subset of patients with ACC. New treatment concepts are therefore urgently needed.
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Background There are no clear treatment guidelines for dogs with clinically well-regulated hyperadrenocorticism in which serum cortisol concentrations before and after an ACTH stimulation test performed 3–6 hours after trilostane administration are < 2.0 μg/dL.Objective To determine if serum cortisol concentrations measured before (Pre1) and after (Post1) ACTH stimulation at 3–6 hours after trilostane administration are significantly lower than cortisol concentrations measured before (Pre2) and after (Post2) ACTH stimulation 9–12 hours after trilostane administration, in a specific population of dogs with clinically well-regulated hyperadrenocorticism and Pre1 and Post1 <2 μg/dL.AnimalsThirteen client-owned dogs with clinically well-regulated hyperadrenocorticism and Pre1 and Post1 serum cortisol concentrations <2.0 μg/dL 3–6 hours after trilostane administration.Methods Prospective study. Dogs had a second ACTH stimulation test performed 9–12 hours after trilostane administration, on the same day of the first ACTH stimulation test. Cortisol concentrations before and after ACTH stimulation were compared using a paired t-test.ResultsCortisol concentrations before (1.4 ± 0.3 μg/dL) and after the first stimulation (1.5 ± 0.3 μg/dL, mean ± SD) were significantly lower than cortisol concentration before the second stimulation (3.3 ± 1.6 μg/dL, P = .0012 each). Cortisol concentration before the first stimulation was also significantly lower than cortisol concentration after the second stimulation (5.3 ± 2.4 μg/dL, P = .0001).Conclusions and clinical importanceIn dogs with clinically well-regulated, trilostane-treated, hyperadrenocorticism, and cortisol concentrations <2 μg/dL before and after the first stimulation, a second ACTH stimulation test performed 9–12 hours after treatment can result in higher cortisol concentrations that could support continued trilostane treatment.
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Introduction: Endogenous Cushing's syndrome (CS) is characterized by chronic overproduction of cortisol and is associated with increased mortality and morbidity. It can be caused by a pituitary adenoma, ectopic adrenocorticotropic hormone (ACTH) production or primary adrenal disease. Successful tumor-directed surgery is the keystone treatment. When surgery is unsuccessful, contraindicated or in case of acute disease, pharmacotherapy is indicated to treat hypercortisolism. Areas covered: In this review, pharmacotherapeutic options for CS will be covered discussing the different possible targets, that is: i) inhibition of ACTH secretion; ii) suppression of steroidogenesis; and iii) blockade of cortisol effects at tissue level. Preclinical and clinical studies will be discussed considering mono- and combination therapy, taking into account efficacy, toxicity and mechanism of action. Per CS entity, future directions of pharmacotherapies will be addressed. Expert opinion: The number of medical treatment options for CS has increased in the past years. In contrast to decades ago, prospective trials are now being performed focusing on pituitary-directed drugs like pasireotide, the glucocorticoid receptor blocker mifepristone and 'new generation' steroid synthesis inhibitors. Future studies will focus on tumor-shrinking effects of neuromodulatory drugs, the optimal order and combination of pharmacotherapy, long-term efficacy and safety and new targets for medical treatment of CS.
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Background Transsphenoidal hypophysectomy is an effective treatment for dogs with pituitary-dependent hypercortisolism (PDH). However, long-term recurrence of hypercortisolism is a well-recognized problem, indicating the need for reliable prognostic indicators.Objectives The aim of this study was to evaluate the prognostic value of perioperative plasma ACTH and cortisol concentrations for identifying recurrence of hypercortisolism after transsphenoidal hypophysectomy.AnimalsA total of 112 dogs with PDH that underwent transsphenoidal hypophysectomy met the inclusion criteria of the study.Methods Hormone concentrations were measured preoperatively and 1–5 hours after surgery. Both absolute hormone concentrations and postoperative concentrations normalized to preoperative concentrations were included in analyses. The prognostic value of hormone concentrations was studied with Cox's proportional hazard analysis.ResultsMedian follow-up and disease-free period were 1096 days and 896 days, respectively. Twenty-eight percent of patients had recurrence, with a median disease-free period of 588 days. Both absolute and normalized postoperative cortisol concentrations were significantly higher in dogs with recurrence than in dogs without recurrence. High ACTH 5 hours after surgery, high cortisol 1 and 4 hours after surgery, high normalized ACTH 3 hours after surgery, high normalized cortisol 4 hours after surgery and the random slope of cortisol were associated with a shorter disease-free period.Conclusions and clinical importanceIndividual perioperative hormone curves provide valuable information about the risk of recurrence after hypophysectomy. However, because no single cutoff point could be identified, combination with other variables, such as the pituitary height/brain area (P/B) ratio, is still needed to obtain a good estimate of the risk for recurrence of hypercortisolism after hypophysectomy.
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Pasireotide is the first medical therapy officially approved for the treatment of adult patients with Cushing's disease (CD) who experienced a failure of pituitary surgery or are not candidates for surgery and require medical therapeutic intervention. The current study aimed at investigating the effects of long-term treatment with pasireotide (up to 24 months) on tumor mass in a group of patients with CD, participating to a phase III study. Fourteen CD patients entered the phase III clinical trial CSOM230B2305 at Naples Center, and eight (seven women, one man, aged 38.9 ± 17.6 years), including seven with a microadenoma and one with a macroadenoma, received treatment with pasireotide at the dose of 600-1200 µg bid for at least 6 months, and were considered for the analysis of the study. These eight patients were subjected to the evaluation of pituitary tumor volume by pituitary MRI, together with the evaluation of urinary cortisol levels, at baseline and every 6 months for the entire period of treatment. Pasireotide treatment induced full disease control in 37.5 % and partial disease control in 37.5 % after 6 months, whereas full and partial disease control after 12 months was obtained in 28.6 % and in 57.1 % of patients, respectively. A significant (>25 %) reduction in tumor volume was found in 62.5 % and in 100 % of patients, after 6 and 12 months, respectively. In particular, after 6 months, a slight tumor shrinkage (between 25.1 and 50 %) was observed in 25 %, moderate (50.1-75 %) in 25 %, and marked (>75 %) in 12.5 % of patients, whereas after 12 months, a slight tumor shrinkage was observed in 43 %, moderate in 14 %, and marked in 43 % of patients. In 25 % of patients (two patients), a marked tumor shrinkage was recorded, with tumor mass disappearance in one case; this tumor shrinkage was associated to rapid and sustained biochemical remission up to 24 months of continuous pasireotide treatment. These two cases represent the first cases with a documentation of such a notable effect of pasireotide on tumor mass. Pasireotide induces significant tumor shrinkage in 62.5 % of patients after 6 months and in 100 % of patients after 12 months, and occasionally induces a radiological disappearance of the tumor. This evidence supports and strengthens the role of pasireotide as medical treatment specifically addressed to patients with CD, particularly in those who had unsuccessful pituitary surgery, or are not candidates for surgery.
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Pituitary-dependent hypercortisolism (PDH) is one of the most frequent endocrinopathies in dogs, but prognostic factors are largely unknown. The aim of this retrospective case series study was to determine the prognostic value of different clinical and clinicopathological variables evaluated in dogs newly diagnosed with PDH that were subsequently treated with trilostane. Medical records from one referral centre were evaluated. Eighty-five dogs with PDH were included. The median survival time was 852 days (range 2-3210 days); 60/85 (70 per cent) and 25/85 (29 per cent) dogs survived more than one and three years, respectively. In multivariable model analysis the length of survival of older dogs (HR 1.24, 95% CI 1.09 to 1.40) and dogs with higher serum phosphate concentrations (HR 1.35, 95% CI 1.01 to 1.81) was shorter. Serum phosphate concentrations were above the reference range in 37/85 (44 per cent) of animals. Clinical signs, liver enzymes, serum cortisol concentrations of the endocrine tests, proteinuria, systolic hypertension, the presence of concomitant disorders, and the frequency of trilostane administration were not associated with survival time. Hyperphosphataemia is a common finding in dogs with newly diagnosed PDH and represents a negative prognostic factor.
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Cushing's disease (CD) is a rare condition in which hypercortisolemia is secondary to excessive ACTH release from a pituitary corticotroph adenoma. CD is associated with significant morbidity and mortality, and a safe therapy that effectively targets the pituitary tumor is still lacking. Retinoic acid (RA) and dopamine agonists (DAs) have recently been considered as monotherapy in CD patients, and satisfactory results have been reported, albeit in a limited number of patients. Given the permissive role of RA on the dopamine receptor type-2 (DRD2), the aim of present study was to see whether a combination of 9-cis RA and the DA bromocriptine (Br) might represent a possible treatment for CD. Here we show that 9-cis RA induces a functional DRD2 in the pituitary corticotroph cell line AtT20, and increases cell sensitivity to Br via a mechanism only partially related to corticotroph-to-melanotroph transdifferentiation. In addition, 9-cis RA and Br act synergistically to modulate cell viability, with favorable implications for clinical use. In nearly 45% of corticotropinoma-derived primary cultures, the combined administration of 9-cis RA and Br lowered the steady-state level of the ACTH precursor proopiomelanocortin (POMC) more efficiently than either of the drugs alone. In conclusion, the effects of a combination of 9-cis RA and Br on ACTH synthesis/secretion and cell viability in AtT20, and on POMC transcriptional activity in human corticotropinomas might represent a suitable starting point for assessing the potential of this treatment regimen for ACTH-secreting pituitary adenomas. This study thus has potentially important implications for novel therapeutic approaches to Cushing's disease.
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A 13 yr old castrated male vizsla was referred to the authors' institute because of polyuria, polydipsia, polyphagia, and weight loss. Pituitary-dependent hypercortisolism (PDH) was diagnosed by hormone testing and adrenal and pituitary imaging. Computed tomography (CT) revealed a pituitary mass measuring 21 mm in width. Medical therapy was initiated with trilostane. Despite adequate control of the hypercortisolemia, the polyuria and polydipsia persisted and the dog developed neurologic signs due to the pituitary mass effect. Pituitary transsphenoidal debulking surgery was performed and immunocytochemistry confirmed a corticotroph adenoma. The dog survived for 13 mo after surgery. Postmortem examination revealed an empty fossa without pituitary remnants and the presence of a malignant pheochromocytoma in the right adrenal gland. This case report demonstrates, for the first time, that a large pituitary adenoma in the dog may be treated successfully by pituitary surgery.
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Somatostatin (SRIF), an inhibitory polypeptide with two biologically active forms SRIF-14 and SRIF-28, inhibits growth hormone (GH), prolactin (PRL), thyrotropin (TSH), and adrenocorticotropin (ACTH) secretion in the anterior pituitary gland. Somatostatin also has an anti-proliferative effect inducing cell-cycle arrest and apoptosis. Such actions are mediated through five G-protein coupled somatostatin receptors (SSTR); SSTR1 to SSTR5. In GH-secreting adenomas, SSTR2 expression predominates, and somatostatin receptor ligands (SRLs; octreotide and lanreotide) directed to SSTR2 are presently the mainstays of medical therapy. However, about half of patients show incomplete biochemical remission, but the definition of resistance per se remains controversial. We summarize here the determinants of SRL resistance in acromegaly patients, including clinical, imaging features as well as molecular (mutations, SSTR variants and polymorphisms), and histopathological (granulation pattern, and proteins and receptor expression) predictors. The role of SSTR5 may explain the partial responsiveness to SRLs in patients with adequate SSTR2 density in the cell membrane. In patients with ACTH-secreting pituitary adenomas, i.e. Cushing disease (CD), SSTR5 is the most abundant receptor expressed and tumors show low SSTR2 density due to hypercortisolism-induced SSTR2-down regulation. Clinical studies with pasireotide, a multireceptor-targeted SRL with increased SSTR5 activity, lead to approval of pasireotide for treatment of patients with CD. Other SRL delivery modes (oral octreotide), multireceptor-targeted SRL (somatoprim) or chimeric compounds targeting dopamine D2 receptors and SSTR2 (dopastatin) are briefly discussed.
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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. CONCLUSIONS 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. © 2018, American Veterinary Medical Association. All rights reserved.
Article
The purpose of this study was to determine the therapeutic and/or adverse effects of radiation therapy (RT) against pituitary tumors in dogs with pituitary-dependent hypercortisolism, as monitored by frequent post-RT detailed MRI examinations, clinical signs, and changes in hormone concentrations. Nine dogs with an adrenocorticotropic hormone (ACTH)-secreting pituitary mass diagnosed by magnetic resonance imaging (MRI) underwent RT for 4weeks (total of 48Gy in 4-Gy fractions). Pituitary height/brain area (P/B) value, clinical signs, basal plasma ACTH concentrations, serum cortisol concentrations (pre- and post-ACTH stimulation test) and adverse effects of RT were evaluated before and post-RT. The P/B value was significantly lower in all nine dogs post-RT. One dog lacking any neurological signs demonstrated no change in clinical signs pre and post-RT. Out of 8 dogs which exhibited neurological signs pre-RT, half of them demonstrated complete resolution of their signs, whereas the other half showed transient resolution. In all animals with recurrence of neurological signs, pituitary tumor regrowth was not observed; however, MRI revealed moderate to severe pituitary hemorrhage. Late adverse effect (bilateral otitis media) was observed in three of nine dogs post-RT. RT did not induce any significant changes in the dogs' basal plasma ACTH concentration and pre- and post-ACTH serum cortisol concentrations. In conclusion, RT is effective to reduce pituitary size and the mass effect, but does not appear to affect blood hormone concentrations, necessitating additional medical treatment against hypercortisolism. Periodic MRI imaging post-RT enables early detection of adverse effects of RT.
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Hypercortisolism is one of the most commonly diagnosed endocrinopathies in dogs, and new targeted medical treatment options are desirable. Steroidogenic factor-1 (SF-1), an orphan nuclear hormone receptor, is a key regulator of adrenal steroidogenesis, development, and growth. In pituitary-dependent hypercortisolism (PDH), high plasma ACTH concentrations increase the transcriptional activity of SF-1. In adrenal-dependent hypercortisolism, SF-1 expression is significantly greater in dogs with recurrence after adrenalectomy than in those without recurrence. Inhibition of SF-1 could therefore be an interesting treatment option in canine spontaneous hypercortisolism. We determined the effects of 3 SF-1 inverse agonists, compounds IsoQ A, #31, and #32, on cortisol production, on the messenger RNA (mRNA) expression of steroidogenic enzymes and SFs, and on cell viability, in primary adrenocortical cell cultures of 8 normal adrenal glands and of 3 cortisol-secreting adrenocortical tumors (ATs). To mimic PDH, the normal adrenocortical cell cultures were stimulated with ACTH. The results show that only compound #31 inhibited cortisol production and SF-1 target gene expression in non-ACTH-stimulated and ACTH-stimulated normal adrenocortical cells but did not affect cell viability. In the AT cell cultures, the effects of #31 on cortisol production and target gene expression were variable, possibly caused by a difference in the SF-1 mRNA expressions of the primary tumors. In conclusion, inhibition of SF-1 activity shows much promise as a future treatment for canine hypercortisolism.
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Objective: To describe a technique for tumor thrombectomy by phrenicoabdominal venotomy in dogs with adrenal neoplasia and suspected caval invasion and to report complications and outcomes associated with the procedure. Study design: Retrospective case series. Animals: Eight client-owned dogs with invasive adrenal tumors. Methods: Medical records of dogs diagnosed with adrenal tumors with extension of thrombus into the phrenicoabdominal vein (PAV) and vena cava were reviewed. Cases where phrenicoabdominal venotomy without cavotomy for thrombus resection was performed were included. Data collected from the medical records included signalment, clinical signs, physical examination findings, diagnostic imaging results, preoperative laboratory testing, surgical technique, surgical and postoperative complications and outcome. Results: Phrenicoabdominal venotomy was successful in removal of vena caval thrombosis in 7 of 8 dogs. In one case, an attempt was made to remove a large vena caval thrombus through a distended PAV resulting in fragmentation of the thrombus and the need to extend the incision into the vena cava. In all dogs, complete removal of tumor thrombus was achieved. Two dogs died in the perioperative period, one from cardiopulmonary arrest and a second from bronchopneumonia and pancreatitis. The remaining 6 dogs were discharged from the hospital. Conclusion: Thrombectomy through a phrenicoabdominal venotomy may obviate the need for a cavotomy in a subset of dogs with invasive adrenal neoplasia.
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Background and purpose: To further the development of new agents for the treatment of adrenocortical carcinoma (ACC), we characterized the molecular and cellular mechanisms of cytotoxicity by the adrenalytic compound ATR-101 (PD132301-02). Experimental approach: We compared the effects of ATR-101, PD129337, and ABC transporter inhibitors on cholesterol accumulation and efflux, on cortisol secretion, on ATP levels, and on caspase activation in ACC-derived cell lines. We examined the effects of these compounds in combination with methyl-β-cyclodextrin or exogenous cholesterol to determine the roles of altered cholesterol levels in the effects of these compounds. Key results: ATR-101 caused cholesterol accumulation, ATP depletion, and caspase activation within 30 minutes after addition to ACC-derived cells, whereas PD129337 did not. Suppression of cholesterol accumulation by methyl-β-cyclodextrin or exogenous cholesterol, prevented ATP depletion and caspase activation by ATR-101. ATR-101 blocked cholesterol efflux and cortisol secretion, suggesting that it inhibited ABCA1, ABCG1, and MDR1 transporters. Combinations of ABCA1, ABCG1, and MDR1 inhibitors were also cytotoxic. Combinations of ATR-101 with inhibitors of ABCG1, MDR1, or mitochondrial functions had increased cytotoxicity. Inhibitors of steroidogenesis reduced ATP depletion by ATR-101, whereas U18666A enhanced cholesterol accumulation and ATP depletion together with ATR-101. ATR-101 repressed ABCA1, ABCG1, and IDOL transcription by mechanisms that were distinct from the mechanisms that caused cholesterol accumulation. Conclusions and implications: Inhibition of multiple ABC transporters and the consequent accumulation of cholesterol mediated the cytotoxicity of ATR-101. Compounds that replicate these effects in tumours are likely to be useful in the treatment of ACC.
Article
Objectives: To evaluate the feasibility and efficacy of hypofractionated stereotactic volumetric-modulated arc radiotherapy in treating canine adrenal tumours with vascular invasion. Methods: A single-arm clinical study was performed. The dogs underwent total body computed tomography, brain and abdomen magnetic resonance imaging and endocrine assay. Adrenal masses were classified as cortisol-secreting adrenal tumour or non-secreting adrenal tumour. Radiotherapy treatments were delivered by hypofractionated stereotactic volumetric-modulated arc radiotherapy via a linear accelerator. The overall survival was estimated by the Kaplan-Meier method. The overall response and radio-toxicity effects were determined. Results: Nine dogs were enrolled. Three dogs were affected by cortisol-secreting adrenal tumours and the remaining dogs had non-secreting adrenal tumours. The prescribed doses ranged from 30 to 45 Gy in three or five consecutive daily fractions. The median overall survival time was 1030 days, and the overall mean reduction of the diameter and volume were ~32 and 30% respectively. The endocrine profile normalised in two dogs with cortisol-secreting adrenal tumours. Radio-toxicities were mild and self-limiting. Seven deaths were recorded during the follow-up period and two dogs were censored. Clinical significance: Hypofractionated stereotactic volumetric-modulated arc radiotherapy should be considered as a feasible and effective therapeutic option for adrenal tumours with vascular invasion.
Article
Objectives: To estimate prevalence and risk factors for diagnosis with hyperadrenocorticism in dogs attending primary-care veterinary practices in the UK from 2009 to 2014. Methods: Cases were identified by searching the de-identified electronic patient records from UK primary-care veterinary practices participating in the VetCompass Programme. Results: The estimated prevalence for hyperadrenocorticism diagnosis in dogs was 0·28% (95% confidence interval: 0·25 to 0·31). Multivariable logistic regression analysis revealed four associated risk factors: breed, breed-relative bodyweight, age and insurance status. The bichon frise had 6·5 times the odds (95% CI: 3·5 to 12·1, P<0·001) of hyperadrenocorticism compared with crossbreds. Dogs weighing more than or equal to their breed mean had 1·7 times the odds (95% CI: 1·3 to 2·3, P<0·001) of hyperadrenocorticism compared with dogs weighing less than the breed mean. Dogs aged 12·0 years and above showed 5·7 times the odds (95% CI: 3·7 to 8·7, P<0·001) of hyperadrenocorticism compared with dogs aged 6·0 to 8·9 years. Insured dogs had 4·0 times the odds (95% CI: 2·8 to 5·6, P<0·001) of hyperadrenocorticism compared with non-insured dogs. Clinical significance: This is the first epidemiological report of a non-referral hospital population of dogs diagnosed with hyperadrenocorticism in the UK and describes important breed, age and bodyweight associations with this disorder which may improve diagnosis and enhance understanding of the underlying pathophysiology.
Article
ATR-101 is a novel, oral drug candidate currently in development for the treatment of Adrenocortical Cancer (ACC). ATR-101 is a selective and potent inhibitor of acyl-coenzyme A:cholesterol O-acyltransferase 1 (ACAT1), an enzyme located in the endoplasmic reticulum (ER) membrane that catalyzes esterification of intracellular free cholesterol. We aimed to identify mechanisms by which ATR-101 induces adrenocortical cell death. In H295R human adrenocortical carcinoma cells, ATR-101 decreases the formation of cholesteryl esters and increases free cholesterol levels, demonstrating potent inhibition of ACAT1 activity. Caspase-3 levels and TUNEL-positive cells are increased by ATR-101 treatment, indicating activation of apoptosis. Exogenous cholesterol markedly potentiates the activity of ATR-101, suggesting that excess free cholesterol that cannot be adequately esterified increases caspase-3 activation and subsequent cell death. Inhibition of calcium release from the ER or the subsequent uptake of calcium by mitochondria reverses apoptosis induced by ATR-101. ATR-101 also activates multiple components of the Unfolded Protein Response (UPR), an indicator of ER stress. Targeted knockdown of ACAT1 in an adrenocortical cell line mimicked the effects of ATR-101, suggesting that ACAT1 mediates the cytotoxic effects of ATR-101. Finally, in vivo treatment of dogs with ATR-101 decreased adrenocortical steroid production and induced cellular apoptosis that was restricted to the adrenal cortex. Together, these studies demonstrate that inhibition of ACAT1 by ATR-101 increases free cholesterol, resulting in dysregulation of ER calcium stores that result in ER stress, the UPR, and ultimately apoptosis.
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Adrenocortical carcinoma (ACC) is a rare malignancy that harbors a dismal prognosis in advanced stages. Mitotane is approved as an orphan drug for treatment of ACC and counteracts tumor growth and steroid hormone production. Despite serious side effects, mitotane has been clinically used for decades. Elucidation of its unknown molecular mechanism of action appears essential to develop better ACC therapies. Here, we set out to identify the molecular target of mitotane and altered downstream mechanisms by combining expression genomics and mass spectrometry technology in the NCI-H295 ACC model cell line. Pathway analyses of expression genomics data demonstrated activation of endoplasmic reticulum (ER) stress and profound alteration of lipid-related genes caused by mitotane treatment. ER-stress marker CHOP was strongly induced and the two upstream ER-stress signalling events XBP1-mRNA splicing and eIF2α phosphorylation were activated by mitotane in NCI-H295 cells but to a much lesser extent in four non-steroidogenic cell lines. Lipid mass spectrometry revealed mitotane-induced increase of free cholesterol, oxysterols and fatty acids specifically in NCI-H295 cells as cause of ER-stress. We demonstrate that mitotane is an inhibitor of Sterol-O-Acyl-Transferase 1 (SOAT1) leading to accumulation of these toxic lipids. In ACC tissue samples we show variable SOAT1 expression correlating with the response to mitotane treatment. In conclusion, mitotane confers adrenal specific cytotoxicity and down regulates steroidogenesis by inhibition of SOAT1 leading to lipid-induced ER-stress. Targeting of cancer specific lipid metabolism opens new avenues for treatment of ACC and potentially other types of cancer.
Article
Adrenocortical carcinoma (ACC) is a rare malignancy known for high rates of local recurrence, though the benefit of postoperative radiation therapy (RT) has not been established. In this study of grossly resected ACC, we compare local control of patients treated with surgery followed by adjuvant RT to a matched cohort treated with surgery alone. We retrospectively identified patients with localized disease who underwent R0 or R1 resection followed by adjuvant RT. Only patients treated with RT at our institution were included. Matching to surgical controls was on the basis of stage, surgical margin status, tumor grade, and adjuvant mitotane. From 1991 to 2011, 360 ACC patients were evaluated for ACC at the University of Michigan (Ann Arbor, MI). Twenty patients with localized disease received postoperative adjuvant RT. These were matched to 20 controls. There were no statistically significant differences between the groups with regard to stage, margins, grade, or mitotane. Median RT dose was 55 Gy (range, 45-60 Gy). Median follow-up was 34 months. Local recurrence occurred in 1 patient treated with RT, compared with 12 patients not treated with RT (P=.0005; hazard ratio [HR] 12.59; 95% confidence interval [CI] 1.62-97.88). However, recurrence-free survival was no different between the groups (P=.17; HR 1.52; 95% CI 0.67-3.45). Overall survival was also not significantly different (P=.13; HR 1.97; 95% CI 0.57-6.77), with 4 deaths in the RT group compared with 9 in the control group. Postoperative RT significantly improved local control compared with the use of surgery alone in this case-matched cohort analysis of grossly resected ACC patients. Although this retrospective series represents the largest study to date on adjuvant RT for ACC, its findings need to be prospectively confirmed. Copyright © 2015 Elsevier Inc. All rights reserved.
Article
The majority of prostate cancer (PCa) cases are diagnosed as a localized disease. Definitive treatment, active surveillance or watchful waiting are employed as therapeutic paradigms. The current standard of care for the treatment of metastatic PCa is either medical or surgical castration. Once PCa progresses in spite of castrate androgen levels it is termed ‘castration-resistant prostate cancer’ (CRPC). Patients may even exhibit rising PSA levels with possible bone, lymph node or solid organ metastases. In 2010, the only agent approved for the treatment of CRPC was docetaxel, a chemotherapeutic agent. It is now known that cells from patients with CRPC express androgen receptors (AR) and remain continuously influenced by androgens. As such, treatments with novel hormonal agents that specifically target the biochemical conversion of cholesterol to testosterone have come to the forefront. The use of cytochrome P450c17 (CYP17A1) inhibitor underlies one of the most recent advances in the treatment of CRPC. Abiraterone acetate (AA) was the first CYP17A1 inhibitor approved in the United States. This review will discuss CRPC in general with a specific focus on AA and novel CYP17A1 inhibitors. AA clinical trials will be reviewed along with other novel adjunct treatments that may enhance the effectiveness of abiraterone therapy. Furthermore, the most recently identified CYP17A1 inhibitors Orteronel, Galeterone, VT-464, and CFG920 will also be explored.
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Objective: To describe the clinicopathologic features of a cohort of dogs with adrenocortical masses that underwent laparoscopic adrenalectomy and to compare perioperative morbidity and mortality rates in these dogs with rates for dogs that underwent open adrenalectomy for resection of similarly sized (maximal diameter, ≤ 5 cm) adrenocortical masses. Design: Retrospective case series. Animals: 48 client-owned dogs that underwent laparoscopic (n = 23) or open (25) adrenalectomy for noninvasive tumors (ie, tumors that did not invade the vena cava or other surrounding organs). Procedures-Medical records were reviewed. History, clinical signs, physical examination findings, clinicopathologic findings, imaging results, and surgical variables were recorded. A 3- or 4-port approach was used for laparoscopic adrenalectomy. Surgical time, perioperative complications, postoperative and overall hospitalization times, and perioperative deaths were recorded and compared between groups. Results: The surgical method for 1 dog was converted from a laparoscopic to an open approach. Perioperative death occurred in no dogs in the laparoscopic group and 2 dogs in the open adrenalectomy group. Surgical time was shorter for laparoscopic (median, 90 minutes; range, 40 to 150 minutes) than for open (median, 120 minutes; range, 75 to 195 minutes) adrenalectomy. Laparoscopic adrenalectomy was associated with shorter hospitalization time and more rapid discharge from the hospital after surgery, compared with the open procedure. Conclusions and clinical relevance: With careful patient selection, laparoscopic adrenalectomy was associated with a low complication rate and low conversion rate for resection of adrenocortical masses as well as shorter surgical and hospitalization times, compared with open adrenalectomy.
Article
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.AnimalsTwenty-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.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).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.
Article
Treatment of adrenal-dependent hyperadrenocorticism (ADH) involves either surgical resection of the adrenal tumor or medical therapy. For many years, mitotane has been considered the medical treatment of choice for dogs with ADH. The aim of this study was to determine survival and prognostic factors for dogs with ADH treated with mitotane and trilostane. Twenty-six dogs with ADH were included in the study. Fourteen dogs were treated with mitotane and 12 dogs were treated with trilostane. Medical records were reviewed. Epidemiologic factors, signalment, clinicopathologic abnormalities, endocrine test results, and treatment protocols were evaluated to identify potential predictive factors of overall survival time. Survival times of dogs treated with mitotane (median, 15.6 months) or trilostane (median, 14.0 months) were not significantly different. Using univariate analysis, age and postadrenocorticotropic hormone cortisol concentrations were inversely correlated with survival time. The multivariate model also identified weakness at presentation as a negative prognostic indicator. The type of medical treatment (mitotane versus trilostane) does not influence survival time in dogs with ADH; therefore, trilostane, a drug with less frequent and milder adverse effects, might be used as the primary medical treatment when adrenalectomy cannot be performed.
Article
Maximal aldosterone secretion in healthy dogs occurs 30 minutes postadrenocorticotropin (ACTH; 5 μg/kg IV) stimulation. The effect of trilostane and mitotane on aldosterone at that time is unknown. To assess the effect of trilostane and mitotane in dogs with pituitary-dependent hyperadrenocorticism on aldosterone secretory reserve. To determine if aldosterone concentration correlates with electrolyte concentrations. Serum collected from 79 client-owned dogs and 33 stored samples. Client-owned dogs had ACTH stimulation tests with cortisol concentrations measured at 0 and 60 minutes and aldosterone concentrations measured at 0, 30, and 60 minutes. Stored samples had aldosterone concentrations measured at 0 and 60 minutes. Ten historical clinically healthy controls were included. All had basal sodium and potassium concentrations measured. The aldosterone concentrations in the mitotane- and trilostane-treated dogs at 30 and 60 minutes post-ACTH were significantly lower than in clinically healthy dogs; no significant difference was detected in aldosterone concentration between 30 and 60 minutes in treated dogs. However, a significantly higher percentage of dogs had decreased aldosterone secretory reserve detected at 30 minutes than at 60 minutes. At 30 minutes, decreased secretory reserve was detected in 49% and 78% of trilostane- and mitotane-treated dogs, respectively. No correlation was detected between aldosterone and serum electrolyte concentrations. Decreased aldosterone secretory reserve is common in trilostane- and mitotane-treated dogs; it cannot be predicted by measurement of serum electrolyte concentrations. Aldosterone concentration at 30 minutes post-ACTH stimulation identifies more dogs with decreased aldosterone secretory reserve than conventional testing at 60 minutes.
Article
The effects of trilostane on key hormones and electrolytes over 24 hours in dogs with pituitary-dependent hyperadrenocorticism (PDH) are unknown. 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. Nine dogs (mean age 9.3 ± 0.67 years, mean weight 31.9 ± 6.4 kg) with confirmed PDH. 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. 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. 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.
Article
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. 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. Thirty-two client-owned dogs diagnosed with PDH between 2008 and 2010 and treated with trilostane either BID or SID. 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. 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. 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.
Article
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.