Clinical features and long-term management of cats with primary hypoadrenocorticism using desoxycorticosterone pivalate and prednisolone.

BACKGROUND: Primary hypoadrenocorticism (PH) is rare in cats and knowledge about treatment is sparse. OBJECTIVE: To describe cats with PH with a focus on long-term treatment. ANIMALS: Eleven cats with naturally occurring PH. METHODS: Descriptive case series with data on signalment, clinicopathological findings, adrenal width, and doses of desoxycorticosterone pivalate (DOCP) and prednisolone during a follow-up period of >12 months. RESULTS: Cats ranged from 2 to 10 years (median 6.5); 6 cats were British Shorthair. Most common signs were reduced general condition and lethargy, anorexia, dehydration, obstipation, weakness, weight loss, and hypothermia. Adrenal glands on ultrasonography were judged small in 6. Eight cats could be followed for 14 to 70 months (median: 28). Two were started on DOCP doses ≥2.2 mg/kg (2.2; 2.5) and 6 < 2.2 mg/kg (1.5-2.0 mg/kg, median 1.8) q28 days. Both high-dose cats and 4 low-dose cats needed a dose increase. Desoxycorticosterone pivalate and prednisolone doses at the end of the follow-up period were 1.3 to 3.0 mg/kg (median: 2.3) and 0.08 to 0.5 mg/kg/day (median: 0.3), respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: Desoxycorticosterone pivalate and prednisolone requirements in cats were higher than what is currently used in dogs; thus, a DOCP starting dose of 2.2 mg/kg q28 days and a prednisolone maintenance dose of 0.3 mg/kg/day titrated to the individual need seems warranted. Small adrenal glands (width < 2.7 mm) on ultrasonography in a cat suspected of hypoadrenocorticism can be suggestive of the disease. The apparent predilection of British Shorthaired cats for PH should be further evaluated.

Corticotropin-stimulated steroid profiles to predict shock development and mortality in sepsis: From the HYPRESS study.

RATIONALE: Steroid profiles in combination with a corticotropin stimulation test provide information about steroidogenesis and its functional reserves in critically ill patients. OBJECTIVES: We investigated whether steroid profiles before and after corticotropin stimulation can predict the risk of in-hospital death in sepsis. METHODS: An exploratory data analysis of a double blind, randomized trial in sepsis (HYPRESS [HYdrocortisone for PRevention of Septic Shock]) was performed. The trial included adult patients with sepsis who were not in shock and were randomly assigned to placebo or hydrocortisone treatment. Corticotropin tests were performed in patients prior to randomization and in healthy subjects. Cortisol and precursors of glucocorticoids (17-OH-progesterone, 11-desoxycortisol) and mineralocorticoids (11-desoxycorticosterone, corticosterone) were analyzed using the multi-analyte stable isotope dilution method (LC-MS/MS). Measurement results from healthy subjects were used to determine reference ranges, and those from placebo patients to predict in-hospital mortality. MEASUREMENTS AND MAIN RESULTS: Corticotropin tests from 180 patients and 20 volunteers were included. Compared to healthy subjects, patients with sepsis had elevated levels of 11-desoxycorticosterone and 11-desoxycortisol, consistent with activation of both glucocorticoid and mineralocorticoid pathways. After stimulation with corticotropin, the cortisol response was subnormal in 12% and the corticosterone response in 50% of sepsis patients. In placebo patients (n = 90), a corticotropin-stimulated cortisol-to-corticosterone ratio > 32.2 predicted in-hospital mortality (AUC 0.8 CI 0.70-0.88; sensitivity 83%; and specificity 78%). This ratio also predicted risk of shock development and 90-day mortality. CONCLUSIONS: In this exploratory analysis, we found that in sepsis mineralocorticoid steroidogenesis was more frequently impaired than glucocorticoid steroidogenesis. The corticotropin-stimulated cortisol-to-corticosterone ratio predicts the risk of in-hospital death. Trial registration Clinical trial registered with www. CLINICALTRIALS: gov Identifier: NCT00670254. Registered 1 May 2008, https://clinicaltrials.gov/ct2/show/NCT00670254 .

[Therapy of primary hypoadrenocorticism in dogs with low dose desoxycorticosterone pivalate]. / Therapie des primären Hypoadrenokortizismus beim Hund mit niedrig dosiertem Desoxycorticosteronpivalat.

OBJECTIVE: Since 2016 the only approved drug for the treatment of primary hypoadrenocorticism (Addisons disease) in dogs in Germany is desoxycorticosterone pivalate (DOCP), namely Zycortal®. The initial dose recommended by the manufacturer is 2.2 mg/kg. Our own experience and select publications raise the suspicion that a distinctly lower initial dose would be sufficient. Mainly cost reduction motivates for dose reduction and with it comes a higher owner motivation and compliance. It was the objective of our retrospective study to show that an initial dose of 1.5 mg/kg DOCP is sufficient for controlling canine hypoadrenocorticism. MATERIAL AND METHODS: Dogs with primary hypoadrenocorticism were included if the initial starting dose was 1.5 mg/kg DOCP subcutaneously. The first, second and the last known dose of DOCP were documented. Electrolyte concentrations at the time of diagnosis as well as 10-14 days after the first injection, on the day of the second injection as well as at the last known injection were recorded. A dog was considered medically well-regulated when clinically healthy, sodium and potassium concentrations within the reference ranges, and when the responsible veterinarian did not recommended a dose alteration. RESULTS: All 13 included dogs were clinically healthy after the first or second injection. One dog received 1.6 mg/kg DOCP as last documented dose, all other dogs received ≤ 1.5 mg/kg (median: 1.3, range: 0.4-1.6) DOCP. Eleven dogs were injected once monthly, 2 dogs received injections every 60 days. The dogs were followed at least 7 months (median: 20 months, range: 7-26 months). CONCLUSION AND CLINICAL RELEVANCE: We were able to show that a starting dose of 1.5 mg/kg DOCP (Zycortal®) is sufficient for controlling primary hypoadrenocorticism in dogs. Adjustments of the dose are needed in some dogs. Regular measurement of electrolyte concentrations 10 days after treatment initiation and at the monthly DOCP injection is required for a correct disease management with DOCP.

Randomised clinical non-inferiority trial comparing two formulations of desoxycortone pivalate for the treatment of canine primary hypoadrenocorticism.

BACKGROUND: This clinical trial compared two formulations of desoxycortone pivalate (DOCP) for treating the mineralocorticoid deficit in dogs with primary hypoadrenocorticism (PH). METHODS: At veterinary clinics in the USA and France, dogs with PH (n=152) were randomised (3:1) to receive approximately monthly treatments with either the test product, Zycortal (Dechra), administered subcutaneously (n=113), or the control product, Percorten-V (Novartis Animal Health), administered intramuscularly (n=39), both at an initial dose of 2.2 mg/kg DOCP. Treatment administrators were unblinded; veterinarians assessing clinical signs were blinded; owners were blinded until at least day 90, the primary end point. Veterinarians assessed treatment outcome based on all of the following: clinical signs; sodium concentrations; potassium concentrations. Dogs received concurrent glucocorticoid therapy throughout the trial. Non-inferiority was assessed using a generalised linear mixed model to compare success rates between groups. RESULTS: Success rates at day 90 were similar between groups (per-protocol population at day 90: Zycortal 87/101, 86.2 per cent, Percorten-V 29/34, 85.1 per cent). Zycortal was non-inferior to Percorten-V as the upper limit of the 95 per cent CI for the difference between groups was 13.6 per cent. Polydipsia and polyuria were the most common clinical observations. CONCLUSION: Both products, in combination with glucocorticoid therapy, were safe and effective in treating PH.

Evaluation of a low-dose desoxycorticosterone pivalate treatment protocol for long-term management of dogs with primary hypoadrenocorticism.

BACKGROUND: Lowering the dose of desoxycorticosterone pivalate (DOCP) for the treatment of dogs with primary hypoadrenocorticism (PH) decreases costs and could lead to increased owner motivation to treat their affected dogs. OBJECTIVE: To evaluate the efficacy of a low-dose DOCP treatment protocol in dogs with PH. ANIMALS: Prospective study, 17 client-owned dogs with naturally occurring PH (12 newly diagnosed, 5 previously treated with fludrocortisone acetate [FC]). METHODS: Dogs with newly diagnosed PH were started on 1.5 mg/kg DOCP SC; dogs previously treated with FC were started on 1.0-1.8 mg/kg DOCP SC. Reevaluations took place at regular intervals for a minimum of 3 months and included clinical examination and determination of serum sodium and potassium concentrations. The DOCP dosage was adjusted to obtain an injection interval of 28-30 days and to keep serum electrolyte concentrations within the reference interval. RESULTS: Median (range) follow-up was 16.2 months (4.5-32.3 months). The starting dosage was sufficient in all but 2 dogs and had to be significantly decreased after 2-3 months to a median dosage (range) of 1.1 mg/kg (0.7-1.8). Dogs 3 years of age or younger needed significantly higher dosages compared to older dogs. None of them, however, needed the 2.2 mg/kg DOCP dosage, recommended by the manufacturer. CONCLUSIONS AND CLINICAL IMPORTANCE: A starting dosage of 1.5 mg/kg DOCP is effective in controlling clinical signs and serum electrolyte concentrations in the majority of dogs with PH. An additional dose reduction often is needed to maintain an injection interval of 28-30 days. Young and growing animals seem to need higher dosages.

Investigation of THDOC effects on pathophysiological signs of Alzheimer's disease as an endogenous neurosteroid: inhibition of acetylcholinesterase and plaque deposition.

Alzheimer's disease (AD) is an advanced neurodegenerative disorder greatly accompanied by acetylcholinesterase (AChE) activation and amyloid plaque deposition. Tetrahydrodeoxycorticosterone (THDOC) is an endogenous neurosteroid that is reduced in AD patient according to previous results. It has neuroprotective effects and plays important role in neurological diseases. By considering AChE role in AD, this study investigated THDOC effects on catalytic and non-catalytic functions of the enzyme. Inhibitory effect of THDOC on hydrolytic activity of AChE was confirmed by in vitro assay (IC50 = 5.68 µM). Molecular docking analysis revealed THDOC bound tightly to the catalytic site of enzyme and inhibited substrate binding. According to in vivo experiments, neurosteroid administration causes inhibition of hyper-activated AChE in hippocampus related to rat model of AD. Staining of hippocampus tissue by plaque specific dye approved THDOC reduced plaque numbers and size in AD rats. Histological and immunoblotting experiments showed neurosteroid administration improved neurodegeneration and neuronal damages in AD rats that lead to improved spatial learning ability. Overall this study suggests, THDOC is an endogenous regulator for AChE. By considering pathophysiological and molecular similarities between AD and animal model, our results highlight THDOC as a potential therapeutic strategy in patients suffering from AD or similar cognitive disorders (Fig. 6, Ref. 28). Keywords: tetrahydrodeoxycorticosterone, acetylcholinesterase, non-catalytic function, amyloid plaque deposition, nucleus basalis of Meynert lesioned rats, neurodegeneration.

Altered Serum Thyrotropin Concentrations in Dogs with Primary Hypoadrenocorticism before and during Treatment.

BACKGROUND: Thyrotropin (TSH) can be increased in humans with primary hypoadrenocorticism (HA) before glucocorticoid treatment. Increase in TSH is a typical finding of primary hypothyroidism and both diseases can occur concurrently (Schmidt's syndrome); therefore, care must be taken in assessing thyroid function in untreated human patients with HA. OBJECTIVE: Evaluate whether alterations in cTSH can be observed in dogs with HA in absence of primary hypothyroidism. ANIMALS: Thirty dogs with newly diagnosed HA, and 30 dogs in which HA was suspected but excluded based on a normal ACTH stimulation test (controls) were prospectively enrolled. METHODS: cTSH and T4 concentrations were determined in all dogs and at selected time points during treatment (prednisolone, fludrocortisone, or DOCP) in dogs with HA. RESULTS: cTSH concentrations ranged from 0.01 to 2.6 ng/mL (median 0.29) and were increased in 11/30 dogs with HA; values in controls were all within the reference interval (range: 0.01-0.2 ng/dL; median 0.06). There was no difference in T4 between dogs with increased cTSH (T4 range 1.0-2.1; median 1.3 µg/dL) compared to those with normal cTSH (T4 range 0.5-3.4, median 1.4 µg/dL; P=0.69) and controls (T4 range 0.3-3.8, median 1.8 µg/dL; P=0.35). After starting treatment, cTSH normalized after 2-4 weeks in 9 dogs and after 3 and 4 months in 2 without thyroxine supplementation. CONCLUSIONS AND CLINICAL RELEVANCE: Evaluation of thyroid function in untreated dogs with HA can lead to misdiagnosis of hypothyroidism; treatment with glucocorticoids for up to 4 months can be necessary to normalize cTSH.

HYPOALDOSTERONISM IN A MATSCHIE'S TREE KANGAROO (DENDROLAGUS MATSCHIEI).

A 20-yr-old female Matschie's tree kangaroo (Dendrolagus matschiei) was diagnosed with hypoaldosteronism, a rare condition in which the body fails to produce normal amounts of the mineralocorticoid aldosterone. Aldosterone plays a key role in body salt homeostasis, increasing sodium reabsorption and promoting excretion of potassium. Hypoaldosteronism resulted in decreased appetite, lethargy, and weight loss in conjunction with hyponatremia, hyperkalemia, and hypercalcemia in this tree kangaroo. The animal was successfully managed with mineralocorticoid replacement using desoxycorticosterone pivalate. To the authors' knowledge this is the first report of hypoaldosteronism in a tree kangaroo and one of the few reports in the veterinary literature in any species.

Perioperative Management and Outcome of Bilateral Adrenalectomy in 9 Dogs.

OBJECTIVE: To report perioperative care, postoperative management, and long-term outcomes in dogs undergoing bilateral adrenalectomy. STUDY DESIGN: Retrospective case series. ANIMALS: Dogs undergoing bilateral adrenalectomy from 2008 to 2013 (n=9). METHODS: Data retrieved from the record, when available, included signalment, preoperative clinical signs, laboratory data, diagnostic imaging, blood pressure measurement, preoperative treatment for adrenal gland disease, intraoperative procedures, treatments and complications, postoperative treatment and diagnostics during hospitalization, diagnostics and management following discharge, histopathologic diagnosis, and survival. RESULTS: Seven dogs underwent concurrent bilateral adrenalectomy and 2 dogs had staged adrenalectomy. Surgery was uncomplicated in most cases. All dogs received IV dexamethasone SP intraoperatively. Eight dogs received intramuscular desoxycorticosterone pivalate intraoperatively. Histopathology revealed adrenocortical adenoma (7 dogs), adrenocortical carcinoma (4), pheochromocytoma (6), and adrenocortical atrophy (1). One dog died perioperatively and the remainder died due to unrelated causes. Postoperative management of hypoadrenocorticism included oral prednisone and intramuscular desoxycorticosterone pivalate (6 dogs), oral prednisone and fludrocortisone (1), and oral fludrocortisone alone (1). The median survival time in dogs surviving to hospital discharge was 525 days (range 67-966 days). No dogs developed metastatic disease or died due to signs of hypoadrenocorticism. CONCLUSION: Based on the cases reported here, the perioperative mortality in dogs undergoing bilateral adrenalectomy may be lower than previously reported. Management of postoperative hypoadrenocorticism is both achievable and straightforward.

Successful treatment of a cat with primary hypoadrenocorticism and severe hyponatremia with desoxycorticosterone pivalate (DOCP).

A 6-year-old, castrated male Siamese cat was diagnosed with primary hypoadrenocorticism, confirmed by an adrenocorticotopic hormone (ACTH) stimulation test documenting both hypocortisolism and hypoaldosteronism. The cat was successfully treated using a combination of prednisolone and desoxycorticosterone pivalate (DOCP). This case demonstrates that DOCP can be used successfully as mineralocorticoid supplementation in cats with hypoadrenocorticism and may have a longer therapeutic duration than that in dogs.

Traitement réussi d'un chat atteint d'hypoadrénocorticisme primaire et d'hyponatrémie à l'aide de pivalate de désoxycorticostérone (DOCP). Un diagnostic d'hypoadrénocorticisme primaire a été posé pour un chat Siamois castré âgé de 6 ans et confirmé par un test de stimulation de l'hormone adrénocorticotope (ACTH) qui a documenté l'hypocortisolisme et l'hypoaldostéronisme. Le chat a été traité avec succès à l'aide d'une combinaison de prednisolone et de pivalate de désoxycorticostérone (DOCP). Ce cas démontre que le DOCP peut être utilisé avec succès en tant que supplément de minéralocorticoïdes chez les chats atteints d'hypoadrénocorticisme et peut présenter une durée thérapeutique plus longue que chez les chiens.(Traduit par Isabelle Vallières).

Generalized vitiligo in a dog with primary hypoadrenocorticism.

BACKGROUND: Vitiligo is presumed to be an autoimmune disorder in the dog; primary adrenal insufficiency (Addison's disease) is associated with immune-mediated destruction of the adrenal cortex. HYPOTHESIS/OBJECTIVES: In this case report we describe a dog with primary hypoadrenocorticism that developed generalized vitiligo. CASE REPORT: A 4-year-old spayed female cross-bred dog developed signs of Addison's disease and this was confirmed by biochemical testing; the dog was treated with fludrocortisone acetate and then desoxycorticosterone pivalate. Three months after the diagnosis, the dog developed depigmentation of the whole hair coat and of several focal areas of the skin. Histopathological findings were consistent with vitiligo. CONCLUSIONS AND CLINICAL IMPORTANCE: Dogs with immune-mediated disease may develop other manifestations of immune-mediated disease, including a combination of Addison's disease and vitiligo. The cause in this case was not determined.

Coronary slow flow accompanying exertional blurred vision and effects of corticosteroids.

Background Various pathophysiological mechanisms such as microvascular and endothelial dysfunction, small vessel disease, diffuse atherosclerosis, and inflammation have been held responsible in the etiology of coronary slow flow. It is also thought to be a reflection of a systemic slow-flow phenomenon in the coronary arterial tree. Case Report A 44-year-old man presented with chest pain causing fatigue, together with blurred vision for the last 2 years, which disappeared after resting. He had used corticosteroid therapy for facial paralysis 1 month ago. Coronary slow flow was detected in all 3 major coronary arteries on coronary angiography. TIMI measurements for the left anterior descending artery, circumflex, and right coronary artery were 64, 72, and 55, respectively. In fundus fluorescein angiography, retinal vascularity was normal, the arm-to-retina circulation time was 21.8 s, and the arteriovenous transit time was 4.3 s. In the early arteriovenous phase, choroidal filling was long, with physiological patchy type. Diltiazem 90 mg/day and acetylsalicylic acid 100 mg/day were given. His chest pain and visual symptoms disappeared after medical treatment. Conclusions Physicians should be aware that glucocorticoids might cause an increase in the symptoms of coronary slow flow and some circulation problems, which might lead to systematic symptoms.

Hypoadrenocorticism (Addison's disease) in a Hoffmann's two-toed sloth (Choloepus hoffmanni).

A 22-yr-old, captive-born, presumed female Hoffmann's two-toed sloth (Choloepus hoffmanni) presented in respiratory distress with severe dehydration and symptoms of hypotension. During treatment, dysphagia was noted and oral examination revealed enlarged palatine tonsils and mucosal plaques. Bloodwork showed a decreased sodium:potassium ratio, a low baseline cortisol, a decreased adrenocorticotropin response test, and a blunted aldosterone stimulation test. All values were compared to a healthy male Hoffmann's two-toed sloth at the same facility. Despite aggressive medical management and treatment for hypoadrenocorticism, the sloth was found deceased. Necropsy revealed abdominal effusion, multifocal plaques throughout the upper gastrointestinal tract, and testes. Histopathology showed marked adrenal cortical atrophy and intranuclear mucosal inclusions in the gastrointestinal tract; advanced molecular techniques did not uncover any viral etiologies. This is the first reported case of hypoadrenocorticism in a sloth.

Use of plasma renin activity to monitor mineralocorticoid treatment in dogs with primary hypoadrenocorticism: desoxycorticosterone versus fludrocortisone.

BACKGROUND: Measurement of plasma renin activity (PRA) is the gold standard for monitoring mineralocorticoid treatment in humans with primary hypoadrenocorticism (PH). OBJECTIVES: To compare PRA in dogs with newly diagnosed PH, dogs with diseases mimicking PH, and healthy dogs, and evaluate measurement of PRA to monitor therapeutic effects in dogs with PH treated with different mineralocorticoids. ANIMALS: Eleven dogs with newly diagnosed PH (group 1), 10 dogs with diseases mimicking PH (group 2), 21 healthy dogs (group 3), 17 dogs with treated PH (group 4). METHODS: In group 1, PRA was measured before treatment and at different times after initiating treatment. In groups 2 and 3, PRA was measured at initial presentation only. In group 4, no baseline PRA was obtained but PRA was measured once or every 1-6 months during treatment. Mineralocorticoid treatment consisted of fludrocortisone acetate (FC) or desoxycorticosterone pivalate (DOCP). RESULTS: Plasma renin activity before treatment was increased in dogs with PH compared to normal dogs and dogs with diseases mimicking PH with median activity of 27, 0.8, and 1.0 ng/mL/h, respectively. In dogs with PH, PRA decreased and normalized with mineralocorticoid treatment using DOCP but not with FC. In dogs treated with DOCP, PRA was lower than in dogs treated with FC. Plasma sodium concentrations were higher and potassium concentrations were lower with DOCP treatment compared to FC treatment. CONCLUSION AND CLINICAL IMPORTANCE: Plasma renin activity is a reliable tool for monitoring mineralocorticoid treatment. DOCP treatment more effectively suppresses PRA compared to FC in dogs with PH.

Beyond T and DHT - novel steroid derivatives capable of wild type androgen receptor activation.

While androgen deprivation therapy (ADT) remains the primary treatment for metastatic prostate cancer (PCa), castration does not eliminate androgens from the prostate tumor microenvironment, and residual intratumoral androgens are implicated in nearly every mechanism by which androgen receptor (AR)-mediated signaling promotes castration-resistant disease. The uptake and intratumoral (intracrine) conversion of circulating adrenal androgens such as dehydroepiandrosterone sulfate (DHEA-S) to steroids capable of activating the wild type AR is a recognized driver of castration resistant prostate cancer (CRPC). However, less well-characterized adrenal steroids, including 11-deoxcorticosterone (DOC) and 11beta-hydroxyandrostenedione (11OH-AED) may also play a previously unrecognized role in promoting AR activation. In particular, recent data demonstrate that the 5α-reduced metabolites of DOC and 11OH-AED are activators of the wild type AR. Given the well-recognized presence of SRD5A activity in CRPC tissue, these observations suggest that in the low androgen environment of CRPC, alternative sources of 5α-reduced ligands may supplement AR activation normally mediated by the canonical 5α-reduced agonist, 5α-DHT. Herein we review the emerging data that suggests a role for these alternative steroids of adrenal origin in activating the AR, and discuss the enzymatic pathways and novel downstream metabolites mediating these effects. We conclude by discussing the potential implications of these findings for CRPC progression, particularly in context of new agents such as abiraterone and enzalutamide which target the AR-axis for prostate cancer therapy.

Neurosteroids modulate epileptiform activity and associated high-frequency oscillations in the piriform cortex.

Allotetrahydrodeoxycorticosterone (THDOC) belongs to a class of pregnane neurosteroidal compounds that enhance brain inhibition by interacting directly with GABAA signaling, mainly through an increase in tonic inhibitory current. Here, we addressed the role of THDOC in the modulation of interictal- and ictal-like activity and associated high-frequency oscillations (HFOs, 80-500 Hz; ripples: 80-200 Hz, fast ripples: 250-500 Hz) recorded in vitro in the rat piriform cortex, a highly excitable brain structure that is implicated in seizure generation and maintenance. We found that THDOC: (i) increased the duration of interictal discharges in the anterior piriform cortex while decreasing ictal discharge duration in both anterior and posterior piriform cortices; (ii) reduced the occurrence of HFOs associated to both interictal and ictal discharges; and (iii) prolonged the duration of 4-aminopyridine-induced, glutamatergic independent synchronous field potentials that are known to mainly result from the activation of GABAA receptors. Our results indicate that THDOC can modulate epileptiform synchronization in the piriform cortex presumably by potentiating GABAA receptor-mediated signaling. This evidence supports the view that neurosteroids regulate neuronal excitability and thus control the occurrence of seizures.