Exogenous Glucocorticoid Administration Research Articles

6529 The Risk of Hypophysitis Following Treatment With Relatlimab+Nivolumab Appears Higher Than Expected

Abstract Disclosure: N. Chamorro-Pareja: None. A.T. Faje: None. K.K. Miller: Stock Owner; Self; Bristol-Myers Squibb. Hypophysitis is a recognized complication of immune checkpoint inhibitor therapy; the risk of developing hypophysitis in patients receiving nivolumab (an anti-programmed death-ligand 1 [anti-PD-1]) is estimated to be < 1%. Relatlimab is a human monoclonal antibody targeting lymphocyte activation gene 3 (LAG-3) recently approved in combination with nivolumab for the treatment of unresectable or metastatic melanoma. The risk of hypophysitis as a complication of relatlimab therapy is not well-defined. Objective: To examine the prevalence, identify risk factors, and characterize the clinical presentation of hypophysitis in patients receiving relatlimab+nivolumab. Methods: 159 patients received relatlimab+nivolumab at the Mass General Brigham health care system between 6/2015 and 11/2023. Twenty-seven patients were excluded because they were either diagnosed with adrenal insufficiency (AI) before receiving relatlimab+nivolumab or AI was secondary to other factors, primarily exogenous glucocorticoid administration, leaving a total of 122 patients. The medical records of these patients, including provider encounters, laboratory results, medication records, and radiologic images were reviewed. Data are presented as mean ± SD. Results: Central AI was diagnosed in 10 patients (7.5% of the cohort) after relatlimab+nivolumab administration. The mean age was 64.5±13.8 vs. 67.1±14.4 in patients with AI vs. patients without AI (p= 0.58). Sixty percent of patients in the AI group were male compared to 53% of patients without AI (p= 0.68). The development of AI was not related to the cumulative dose of relatlimab+nivolumab (mean number of cycles 6.4±3.2 vs. 4.9±5.0, p=0.35). The most common presenting symptoms of AI were fatigue, anorexia, nausea, and vomiting. No patients were diagnosed with additional anterior pituitary hormone deficiencies, though not all patients were evaluated for these diagnoses; none had diabetes insipidus. Nine patients had MRIs performed after the diagnosis of central AI; 7 of these patients had pre-treatment MRIs for comparison. Diffuse pituitary enlargement was seen on MRI after initiation of relatlimab+nivolumab in 3 patients up to 8 weeks prior to the diagnosis of hypopituitarism. All patients had persistent hypopituitarism at the most recent evaluation. Conclusions: This study is the first cohort analysis of hypophysitis in patients treated with relatlimab+nivolumab. A significant portion of patients were diagnosed with central AI, presumptively due to hypophysitis given the lack of an identifiable alternative etiology. Although the clinical phenotype of these patients paralleled published studies analyzing anti-PD-1 monotherapy, combination treatment with relatlimab+nivolumab appeared to confer a significantly higher risk of developing hypophysitis. Presentation: 6/3/2024

Does exogenous glucocorticoid administration during pregnancy precipitate the timing of labor? A scoping review.

To investigate whether synthetic (s) glucocorticoids (GCs) administrated between 24th and 34th gestational weeks in pre-term labor, might precipitate labor, studies upon sGCs administration were reviewed. Physiology of endogenous glucocorticoids-related increase in fetal-maternal circulation and its association with labor, followed by a scoping review with studies on exogenous sGCs administrated for fetal lung maturation and the timing of labor were included. Methodology of systematic reviews was followed. MEDLINE, Cochrane library and Google Scholar databases were searched till October 2023, for original studies investigating administration of sGCs in pregnancies risking pre-term labor. Duplicates were removed and 1867 abstracts were excluded as irrelevant. Six controlled and four non-controlled studies were included. The index group consisted of 6001 subjects and 7691 controls in the former, while in the latter the index group consisted of 2069 subjects. In three out of the six controlled studies, gestational age at labor was significantly lower in sGCs-treated women than in controls, while in three studies gestational age at labor was lower in sGCs-treated women than in controls with a trend of statistical significance . In one study, gestational age at labor was significantly lower in controls than in sGCs-treated women. In the non-controlled studies, the majority of women delivered less than one week from the day of sGCs administration. In this scoping review, studies lack homogeneity. However, in the controlled studies, a pattern of earlier labor emerges among sGCs-treated pregnant women. The use of multiple courses of ante-natal sGCs appears to be associated to precipitated labor. Their use should be carefully weighed. Carefully designed trials should examine this still open scientific query.

THU621 Mifepristone In Exogenous Cushing's Syndrome

Abstract Disclosure: S. Priyadarshan: None. D.O. Blavo: None. Introduction: Cushing’s syndrome is characterized by elevated cortisol levels in the body and is associated with significant morbidity and mortality. It can be broadly divided into endogenous and exogenous Cushing’s depending on etiology. Endogenous (body-produced) Cushing’s is diagnosed using Late Night Salivary Cortisol(LNSC), Dexamethasone Suppression Test(DST), or 24-hr Urinary-Free Cortisol(UFC) and after ruling out exogenous glucocorticoid administration. Hyperglycemia and weight gain are two of the many manifestations of Cushing’s that have hitherto proven to be a challenge to treat. Mifepristone is a glucocorticoid receptor antagonist that was recently FDA-approved for treating endogenous Cushing’s syndrome following the breakthrough SEISMIC trial. Literature regarding the utility of Mifepristone in exogenous Cushing’s has been limited since its approval. This case aims to fill that void. Case: A 35-year-old female with past medical history of rheumatoid arthritis was referred to endocrinology for further evaluation due to complaints of weight gain, dorso-cervical fat pad, abdominal striae, bruising of her right breast, and hirsutism requiring her to shave twice a week. She had previously been on prednisone 10mg-20mg daily for 2-3years for rheumatoid arthritis and was later weaned off due to her developing bruising, perioral abscess and dorsocervical fat pad. She was hospitalized for pneumonia later that year and discharged with dexamethasone. Her baseline weight at the time had been around 380lbs and she had a rapid weight gain over the next few weeks with a peak of 467lbs, associated with facial swelling and shortness of breath. For this, a DST was done per her primary provider among other labs and showed a cortisol level of 0.5mcg/dL(n<2mcg/dL). At the endocrine clinic, she had an extensive workup done including renin, aldosterone, plasma metanephrines, LH/FSH levels which all returned within normal limits. A1c was elevated at 6.7%(n <5.7%) and she was started on Metformin 1000mg BID. She had a repeat DST which suppressed cortisol appropriately however her midnight salivary cortisol was elevated. She was diagnosed with exogenous Cushing’s syndrome and started treatment with Mifepristone at 300mg daily. Her only side effect was mild nausea that later resolved. In 4 months, she had already lost 50lbs since her initial visit and HbA1c was down to 5.8. The dose was subsequently increased in increments up to 1200mg. In 7 months since starting Mifepristone, her weight was down to 312lbs, a total of 164lbs down from her initial weight. Her HbA1C was 4.6, down from her initial value of 6.7. Conclusion: This case is an excellent example of the effectiveness of Mifepristone in achieving glycemic control and weight reduction in Cushing’s syndrome with minimal side effects. More specifically, it serves to illustrate its utility in exogenous Cushing’s syndrome. Presentation: Thursday, June 15, 2023

Effects of Exogenous Glucocorticoid Infusion on Appetitic Center Development in Postnatal Dairy Bull Calves.

The objective of this study was to determine the effects of exogenous glucocorticoid administration on leptin concentrations and brain development markers, such as protein and hypothalamic gene expression, in dairy bull calves. Within 4 h of parturition, Holstein bulls were intravenously infused with either a low cortisol dose (LC; n = 9, 3.5 µg/kg of body weight (BW)), high cortisol dose (HC; n = 9, 7.0 µg/kg BW), or control (CON; n = 9, saline) dose, with a 2nd infusion 24 h postpartum. Jugular blood was collected prior to infusion and daily until the calves were euthanized (day 5). Cerebrospinal fluid (CSF) from the third ventricle and adipose (omental, perirenal, and mesenteric) and hypothalamic tissue were collected. The blood and CSF samples were analyzed for leptin concentrations. The data were analyzed using SAS. Serum (p = 0.013) and CSF (p = 0.005) leptin concentrations in HC- and LC-treated calves were decreased compared with CON-treated calves. Leptin protein expression was decreased (p < 0.044) in perirenal and omental adipose tissue of LC-treated calves compared with CON-treated calves. Gene abundance of brain-derived neurotrophic factor and fibroblast growth factors 1 and 2 were decreased (p < 0.006) in HC- and LC-treated calves compared with CON-treated calves. In summary, cortisol administered to dairy bull calves reduced leptin concentrations, decreased leptin protein expression in perirenal and omental adipose tissue, and altered gene expression in hypothalamic tissue.

Prolonged glucocorticoid administration affects oocyte morphology in cats (Felis catus) undergoing an ovarian stimulation protocol

While captivity-related stress and the associated rise in baseline glucocorticoid (GC) concentrations have been linked to ovarian quiescence in some felid species, no study has examined the effects of elevated GC on oocyte quality. This study examined the effects of exogenous GC administration on the ovarian response and oocyte quality of domestic cats after an ovarian stimulation protocol. Entire mature female cats were divided into treatment (n = 6) and control (n = 6) groups. Cats in the GC treatment (GCT) group were given 1 mg kg−1 oral prednisolone daily from Day 0–45. All cats (n = 12) were given 0.088 mg kg−1 day−1 progesterone orally from Day 0–37, before treatment with 75 IU eCG im to induce follicular growth on Day 40, followed by 50 IU hCG im 80 h later to induce ovulation. Cats were ovariohysterectomised 30 h after the hCG treatment. Blood samples were collected on Days 0, 10, 30 and 40 (prior to eCG treatment), 80 h after eCG treatment, and on Day 45 for cortisol, glucose, prednisolone, oestradiol, and progesterone analysis. Cortisol concentrations did not differ between treatment groups throughout the study. Mean glucose concentrations were higher in the GCT cats (P = 0.004). Prednisolone was undetectable in all samples. Oestradiol and progesterone concentrations confirmed that the eCG treatment stimulated follicular activity and ovulation in all cats. Following ovariohysterectomy, the ovarian responses were graded (1 = excellent, 4 = poor) and oocytes retrieved from the oviducts. Each oocyte was given a total oocyte score (TOS: using an 9-point scale, 8 = best) based on four parameters: oocyte morphology, size, ooplasm uniformity and granularity, and zona pellucida (ZP) thickness and variation. Ovulation was confirmed in all cats, with a mean of 10.5 ± 1.1 ovulations per cat. Ovarian mass, ovarian response, number of ovulations, and oocyte recovery did not differ between groups. Oocyte diameter did not differ between the groups, but the ZP was thinner in the GCT group (3.1 ± 0.3 μm vs. 4.1 ± 0.3 μm, P = 0.03). The TOS was similar between treatment and control cats, but the ooplasm grade was lower (1.5 ± 0.1 vs. 1.9 ± 0.1, P = 0.01) and there was a tendency for ZP grade to be poorer (0.8 ± 0.1 vs. 1.2 ± 0.2; P = 0.08) in the treatment group. In conclusion, the GC treatment resulted in morphological changes to oocytes collected following ovarian stimulation. Whether these changes would affect fertility warrants further investigation.

Impact of Glucocorticoids on Cardiovascular System—The Yin Yang Effect

Glucocorticoids are not only endogenous hormones but are also administered exogenously as an anti-inflammatory and immunosuppressant for their long-term beneficial and lifesaving effects. Because of their potent anti-inflammatory property and ability to curb the cytokines, they are administered as lifesaving steroids. This property is not only made use of in the cardiovascular system but also in other major organ systems and networks. There is a fine line between their use as a protective anti-inflammatory and a steroid that could cause overuse-induced complications in major organ systems including the cardiovascular system. Studies conducted in the cardiovascular system demonstrate that glucocorticoids are required for growth and development and also for offering protection against inflammatory signals. Excess or long-term glucocorticoid administration could alter cardiac metabolism and health. The endogenous dysregulated state due to excess endogenous glucocorticoid release from the adrenals as seen with Cushing's syndrome or excess exogenous glucocorticoid administration leading to Cushing's-like condition show a similar impact on the cardiovascular system. This review highlights the importance of maintaining a glucocorticoid balance whether it is endogenous and exogenous in regulating cardiovascular health.

PSAT052 Iatrogenic Cushing's Syndrome With a Remote History of Synthetic Glucocorticoid Use in the Setting of a CYP3A4 Inhibitor – Location Matters

Abstract Introduction The most common cause of Cushing's syndrome is iatrogenic due to the exogenous administration of glucocorticoids (GCs). Exogenous GCs disrupt the hypothalamic-pituitary-adrenal (HPA) axis by reducing ACTH production, thereby suppressing cortisol production by the adrenal gland. The degree of HPA axis suppression and recovery varies by the formulation, dose, duration, frequency, timing, and location of GC administration. It is also well known that the clearance of GCs is delayed by inhibitors of cytochrome P450 (CYP) 3A4 isoenzyme. Here we report a case in which a patient on cobicistat developed iatrogenic Cushing's syndrome (ICS) even with a remote history of GC use. Clinical Case A 34-year-old male with Human Immunodeficiency Virus (HIV) on cobicistat and a history of a motor vehicle accident was referred for evaluation of ICS. The patient was started on triamcinolone epidural injections after the accident and developed a ruddy face, weight gain, posterior neck fat redistribution, and purple abdominal striae. He received a total of nine injections over three months at an unknown dose with the last injection being given two years ago. His symptoms improved after stopping the regimen. He received no GCs again until four months prior to presentation when he completed a 4 mg methylprednisolone taper and the cushingoid phenotype returned. Biochemical workup was consistent with HPA axis suppression: morning cortisol &amp;lt;0.5 mcg/dL (4-22 mcg/dL), ACTH &amp;lt;5 pg/mL (6-50 pg/mL), and DHEAS 18 mcg/dL (106-464 mcg/dL). Synthetic glucocorticoid screen was positive for methylprednisolone 5.3 mcg/dL (n &amp;lt;0.10 mcg/dL) and triamcinolone 0.29 mcg/dL (n &amp;lt;0.1 mcg/dL). The patient denied any surreptitious GC use. We concluded the patient still had unmetabolized triamcinolone even after two years due to drug interactions from cobicistat, which is a CYP3A4 inhibitor. Moreover, epidural triamcinolone has the longest half-life, 523 hours, compared to oral or intraarticular injections. Clinical Lesson: GCs are primarily metabolized in the liver by CYP3A4. Very few cases have been reported with the use of cobicistat and the cushingoid phenotype typically appears within 3-6 months of the GC use. However, our patient had detectable triamcinolone and return of ICS two years after epidural injections. It is not enough to know whether a patient received GCs; it is also essential to know how it was given and the location of the injection as the half-lives vary depending on said location. This case reinforces the importance of pharmacovigilance and performing a thorough medication reconciliation, as even a remote history of steroid use in the setting of CYP3A4 inhibitors could lead to ICS. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Chronic clomipramine treatment reverses depressogenic-like effects of a chronic treatment with dexamethasone in rats.

Corticosteroids are widely used in medicine, for their anti-inflammatory and immunosuppressive actions, but can lead to troubling psychiatric side-effects. In fact, corticosteroids can induce many symptoms and syndromes, for example, mood disorders, anxiety and panic disorder, suicidal thinking and behavior. Furthermore, chronic stress and the administration of exogenous glucocorticoids are reported to induce affective changes in humans and rodents that relate to depressive state. Animal models are highly useful tools for studying the depression etiology. Face validity, construct validity, and predictive validity are the main criteria to evaluate animal depression models. The present study aimed to investigate the behavioral, cognitive, and biochemical effects of a chronic administration of DEX on Wistar rats. Wistar rats were administered daily with DEX (1.5 mg/kg, i.p., 21 days) or saline, the clomipramine treatment (2 mg/kg, i.p.) was realized just after the DEX injections for 21 days. DEX induced changes were evaluated by: forced swimming, novelty suppressed feeding, saccharin preference, open field, Morris water maze, and oxidative stress state in the brain. Results showed that chronic DEX administration conduct to a range of depression-related behavioral traits, including anhedonia, despair, weight loss, anxiety-like behavior, and cognitive impairments, which fill the face validity criterion. The DEX induced behavioral changes may result from the massive production of oxidative stress agents. This sustains the etiological hypothesis claiming that hyper-circulating glucocorticoid resulting from HPA dysfunction induces damage in certain neural structures related to depressive disorder, essentially the hippocampus. The antidepressant treatment has restored the behavioral state of rats which fills the predictive validity criterion.

Effects of Exogenous Glucocorticoid Administration on Appetitic Center Brain Development in Dairy Bull Calves

Abstract The objective of study was to determine the effects of exogenous cortisol on leptin concentrations and appetitic center development of perinatal dairy bull calves. Holstein bull calves (n = 27) were weighed and randomly assigned to treatments within 4 h of parturition (d0). Each calf was intravenously infused with either a low cortisol (LC; n = 9, 3.5 ug/kg of BW), high cortisol (HC; n = 9, 7.0 ug/kg of BW), or a sham infusion control (CON; n = 9, similar volume of saline). Each calf was administered a second infusion (half dose) of its respective treatment 24 h postpartum. All calves were housed similarly and fed milk replacer (28% CP, 20% fat) three times daily. Blood was collected via jugular venipuncture before infusion and from d 0–5 of age. At 5 d of age, calves were euthanized via sodium pentobarbital overdose. Cerebral-spinal fluid (CSF) from the third ventricle of the brain, hypothalamus, and adipose tissue (AT; omental, perirenal, and mesenteric) were collected. Blood and CSF samples were analyzed for leptin concentrations via a validated RIA. Adipose tissue samples were analyzed via western blotting for leptin and glucocorticoid receptor (GR) expression and normalized to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) expression. Hypothalamus samples were analyzed via qRT-PCR for genes associated with neuronal growth factors and normalized to the average of two housekeeping genes. All data were analyzed via ANOVA or repeated measures analysis using appropriate models (SAS Institute Inc., Cary, NC). Serum and CSF leptin concentrations were decreased (P &amp;lt; 0.013) in HC and LC compared to CON. Leptin protein expression was decreased (P &amp;lt; 0.044) in perirenal and omental AT of LC calves compared to CON. Hypothalamic expression of BDNF, FGF1, and FGF2 were decreased (P &amp;lt; 0.006) in HC and LC compared to CON. In summary, exogenous cortisol administered to calves at birth reduced leptin concentrations and altered appetitic control center development of the brain.

Effects of Exogenous Glucocorticoid Administration on Feed Intake in Beef Cattle

Abstract Calves (n = 63) from Angus crossbred cows were weighed and randomly assigned to treatments within 4 h of parturition (d 0). Each calf was intravenously infused with either a low cortisol [LC; n = 22, 3.5 µg hydrocortisol sodium succinate/kg body weight (BW)], high cortisol (HC; n = 20, 7.0 µg/kg BW), or a sham infusion control (CON; n = 21, similar volume of saline). Each calf was administered a second infusion of its respective treatment 24 h postpartum. Blood was collected via jugular venipuncture before infusion and daily from d 0–17 of age and analyzed for leptin concentrations using a validated radioimmunoassay. Animal BW was collected every 14 d from d 0 until the end of the study. Heifers (n = 31; 367±4 d of age) and steers (n = 32; 385±4 d of age) entered a Growsafe system to measure feed intake (FI) and were allowed a 2-wk adjustment period to a commercial ration (1.27 Mcal NEm/kg and 15.8% CP and 0.45 Mcal NEg/kg and 13.8% CP, respectively; DM basis). Heifer body condition score (BCS) was collected at the beginning and end of the trial. Heifers were fed for 70 d and steers until they obtained a 12th rib back fat (BF) thickness of 1.15 cm. Data were analyzed via ANOVA or repeated measures using appropriate models of SAS. Serum leptin concentrations observed a treatment by day interaction (P = 0.0028), in which HC and LC were decreased compared to CON from d 2–17 of age. Calf birth BW and adjusted 205-d BW did not differ (P &amp;gt; 0.056) between treatments. Heifer BW gain, BCS change, and number of feed events were increased (P = 0.001) in LC compared to HC and CON. Steers did not differ between treatments (P &amp;gt; 0.080) in BW, BW gain, or BF thickness. However, LC steers observed greater daily FI (P = 0.047) and tended to have greater final BW (P = 0.080). In summary, exogenous cortisol administered to calves at parturition reduced leptin concentrations and improved FI of beef steers during a feeding trial.

The Case of a Glucocorticoid-Induced Myopathy &amp; Myasthenia Gravis Combination: Is There a Border?

Introduction: Glucocorticoid-induced myopathy is the sign of Cushing’s syndrome in 83%, but can also be consequence of exogenous administration of glucocorticoids. The patients with the compromised neuromuscular system (for example, because of myasthenia gravis) have a higher risk of this complication. Differential diagnosis of glucocorticoid-induced myopathy is challenging. Clinical case. A 77-year woman complained of difficulty in the act of breathing, swallowing, weakness in the limbs, inability to self-service, ptosis. Due to the growing complaints the patient was hospitalized to ICU. From anamnesis: She was diagnosed with myasthenia gravis 2 months ago. The presence of autoantibodies to the nicotine acetylcholine receptor was confirmed. Pyridostigmine bromide 60 mg/day, Methylprednisolone 20 mg/day were prescribed for 5 days. The patient noted some improvement. After the next neurologist’s examination the dose of Methylprednisolone was doubled. (It is not known for certain whether the doctor wanted to reduce the dose and the patient misunderstood.) She noted some worsening: weakness and speech difficulties increased. She returned to the previous dose after 3 days, but there was no improvement. Objectively: hypersthenic body type, BMI 39 kg/m2, predominant deposition of adipose tissue in the abdomen and face. Breathing without a ventilator. BP 250/100 mm Hg, heart rate 87 BPM. Laboratory tests revealed hyperkalemia of 8.76 mmol/l (3.5–5), creatinine of 481 mmol/l (44–124), hyperglycemia of 16 mmol/l. Glucocorticoid-induced myopathy was suspected, the administration of methylprednisolone was cancelled. The improvement of the condition was noted in 3 days. Blood pressure, glycaemia, levels of potassium and creatinine returned to normal. A biopsy of muscle revealed: atrophy of type I and II muscle fibers. There were no signs of necrosis, regeneration or inflammation. Thereby the diagnosis of glucocorticoid-induced myopathy was confirmed. Conclusion. Glucocorticoid-induced myopathy may look like a decompensation of neuromuscular disease. Since there are no accurate diagnostic tests nowadays the main argument of diagnosis is the paradoxical reaction after increasing the dose of glucocorticoids as well in this case. Even a short period of use of these drugs can lead to the development of side effects. It is necessary to regularly monitor the dynamics of the condition of such patients.

60 Effects of exogenous glucocorticoid administration on leptin concentrations in perinatal dairy bull calves

Abstract Previous studies suggest a relationship between leptin and cortisol immediately postpartum is linked to improved feedlot efficiency on cattle exposed to perinatal stressors. The objective of the current study was to determine the effects of exogenous cortisol administration on circulating leptin concentrations in perinatal dairy bull calves. Within four hours of parturition, Holstein bull calves were randomly assigned to treatments and intravenously infused with low cortisol (LC; n =9, 3.5 ug/kg of cortisol), high cortisol (HC; n = 9, 7.0 ug/kg of cortisol), or a sham infusion control (CON; n = 9, similar volume of saline). Calves were housed similarly and fed milk replacer (28% CP, 20% fat) three times daily. Blood collections were performed via jugular venipuncture using Z/9mL serum collection tubes (Sarstedt, Newton, NC) from d 0 to 5 of age. Serum samples were incubated for 1 h at room temperature then overnight at 4°C, centrifuged at 1800 x g at 4°C for 20 minutes, serum decanted, and stored long term at -20°C until analysis. At 5 d of age, calves were euthanized utilizing an overdose of sodium pentobarbital (Schering-Plough Animal Health, Union, NJ) and cerebral-spinal fluid (CSF) from the third ventricle of the brain was collected and stored at -80°C until analysis. All samples were analyzed for leptin concentrations via a previously-validated radioimmunoassay. Serum leptin concentrations were analyzed via repeated measures of ANOVA and CSF leptin concentrations via the GLM procedure of SAS (SAS Institute Inc., Cary, NC, USA). Serum leptin concentrations of HC and LC were decreased (P = 0.013) compared to CON, and d 0 was decreased (P &amp;lt; 0.001) compared to all other days of age. Cerebral-spinal fluid leptin concentrations of HC and LC were decreased (P = 0.005) compared to CON. In summary, exogenous cortisol administered to perinatal dairy bull calves reduced leptin concentrations in serum and CSF.

59 Effects of exogenous glucocorticoid administration on leptin concentrations in perinatal dairy bull calves

Abstract Previous studies suggest a relationship between leptin and cortisol immediately postpartum is linked to improved feedlot efficiency on cattle exposed to perinatal stressors. The objective of the current study was to determine the effects of exogenous cortisol administration on circulating leptin concentrations in perinatal dairy bull calves. Within four hours of parturition, Holstein bull calves were randomly assigned to treatments and intravenously infused with low cortisol (LC; n = 9, 3.5 ug/kg of cortisol), high cortisol (HC; n = 9, 7.0 ug/kg of cortisol), or a sham infusion control (CON; n = 9, similar volume of saline). Calves were housed similarly and fed milk replacer (28% CP, 20% fat) three times daily. Blood collections were performed via jugular venipuncture using Z/9mL serum collection tubes (Sarstedt, Newton, NC) from d 0 to 5 of age. Serum samples were incubated for 1 h at room temperature then overnight at 4°C, centrifuged at 1800 x g at 4°C for 20 minutes, serum decanted, and stored long term at -20°C until analysis. At 5 d of age, calves were euthanized utilizing an overdose of sodium pentobarbital (Schering-Plough Animal Health, Union, NJ) and cerebral-spinal fluid (CSF) from the third ventricle of the brain was collected and stored at -80°C until analysis. All samples were analyzed for leptin concentrations via a previously-validated radioimmunoassay. Serum leptin concentrations were analyzed via repeated measures of ANOVA and CSF leptin concentrations via the GLM procedure of SAS (SAS Institute Inc., Cary, NC, USA). Serum leptin concentrations of HC and LC were decreased (P = 0.013) compared to CON, and d 0 was decreased (P &amp;lt; 0.001) compared to all other days of age. Cerebral-spinal fluid leptin concentrations of HC and LC were decreased (P = 0.005) compared to CON. In summary, exogenous cortisol administered to perinatal dairy bull calves reduced leptin concentrations in serum and CSF.

Glucocorticoids in T cell development, differentiation and function.

Glucocorticoids (GCs) are small lipid hormones produced by the adrenals that maintain organismal homeostasis. Circadian and stress-induced changes in systemic GC levels regulate metabolism, cardiovascular and neural function, reproduction and immune activity. Our understanding of GC effects on immunity comes largely from administration of exogenous GCs to treat immune or inflammatory disorders. However, it is increasingly clear that endogenous GCs both promote and suppress T cell immunity. Examples include selecting an appropriate repertoire of T cell receptor (TCR) self-affinities in the thymus, regulating T cell trafficking between anatomical compartments, suppressing type 1 T helper (TH1) cell responses while permitting TH2 cell and, especially, IL-17-producing T helper cell responses, and promoting memory T cell differentiation and maintenance. Furthermore, in addition to functioning at a distance, extra-adrenal (local) production allows GCs to act as paracrine signals, specifically targeting activated T cells in various contexts in the thymus, mucosa and tumours. These pleiotropic effects on different T cell populations during development and immune responses provide a nuanced understanding of how GCs shape immunity.

Glucocorticoid and mineralocorticoid receptor activation modulates postnatal growth.

During early development, stress or exogenous glucocorticoid (GC) administration reduces body mass in vertebrates, and this is associated with the glucocorticoid receptor (GR) activation. Although GCs also activate the mineralocorticoid receptor (MR), the physiological significance of MR activation on early developmental growth is unknown. We tested the hypothesis that activation of both GR and MR are required for postnatal growth suppression by GCs. Differential regulation of GR and MR activation was achieved by using ubiquitous GR- (GRKO) and MR- (MRKO) knockout zebrafish (Danio rerio) in combination with exogenous cortisol treatment. MR activation increased protein deposition in zebrafish larvae and also upregulated lepa and downregulated lepr transcript abundance. Cortisol treatment reduced body mass and protein content in the WT, and this corresponded with the upregulation of muscle proteolytic markers, including murf1 and redd1 by GR activation. The combined activation of MR and GR by cortisol also upregulated the gh and igf1 transcript abundance, and insulin expression compared to the WT. However, cortisol-mediated reduction in body mass and protein content required the activation of both MR and GR, as activation by GR alone (MRKO + cortisol) did not reduce the larval protein content. Collectively, our results indicate that MR activation favors protein deposition and GR activation stimulates proteolysis, while their combined activation is involved in cortisol-mediated growth suppression. Overall, this work provides insight into the physiological significance of MR activation in regulating protein deposition during early development at a systems level.

Hypothesis: Metabolic targeting of 5-aminolevulinate synthase by tryptophan and inhibitors of heme utilisation by tryptophan 2,3-dioxygenase as potential therapies of acute hepatic porphyrias

Metabolic targeting of liver 5-aminolevulinate synthase (5-ALAS) by inhibition of heme utilisation by tryptophan (Trp) 2,3-dioxygenase (TDO) or the use of tryptophan is proposed as a therapy of acute hepatic porphyrias. 5-ALAS, the rate-limiting enzyme of heme biosynthesis, is under negative feedback control by a small regulatory heme pool in the hepatic cytosol. Acute porphyric attacks, precipitated by fasting, certain hormones and some drugs, involve induction of 5-ALAS secondarily to depletion of the above pool, and the resultant elevation of 5-ALA levels initiates the abdominal and neurological symptoms of attacks. By utilising the regulatory heme, cytosolic TDO undermines the feedback control, thus allowing 5-ALAS induction to occur, e.g. upon glucocorticoid induction of TDO during fasting (starvation) and exogenous glucocorticoid administration. Currently, glucose therapy is the preferred strategy for reversing moderate attacks induced by fasting (calorie restriction), with more severe attacks being treated by intravenous heme preparations. Reversal of fasting-induced attacks by glucose is explained by the previously demonstrated reversal of increased heme utilisation by TDO. Inhibitors of this utilisation are therefore potential therapeutic targets in acute attacks and also for maintenance of a symptomless state. Existing TDO inhibitors other than glucose include allopurinol, nicotinamide and recently developed potent inhibitors such as LM10 used in cancer therapy. Based on studies in rats, the hypothesis predicts that the safety or otherwise of drugs in the hepatic porphyrias is determined by their ability to inhibit TDO utilisation of heme under basal conditions or after glucocorticoid induction or heme activation of TDO, in parallel with reciprocal changes in 5-ALAS induction. Tryptophan is also proposed as a potential therapy of acute attacks either alone or as an adjunct to the recently proposed 5-ALAS1 gene silencing. Trp increases heme biosynthesis by enhancing 5-ALA dehydratase activity and, based on a Trp-5-ALA model presented herein, Trp offers several advantages over heme therapy, namely rapid conversion of 5-ALA into heme, a greatly enhanced heme availability, a near complete inhibition of 5-ALAS induction, assumed rapid clearance of 5-ALA and hence accelerated resolution of symptoms of attacks, and finally provision of the neuroprotective metabolite kynurenic acid to neutralise the neurological symptoms. The hypothesis also addresses heme regulation in species lacking the TDO free apoenzyme and its glucocorticoid induction mechanism and proposes detailed assessment of heme biosynthesis in these species. Detailed proposals for testing the hypothesis are presented.

Steroids and laminitis - the value of evidence over anecdote.

Veterinary RecordVolume 185, Issue 3 p. 79-81 Research Steroids and laminitis – the value of evidence over anecdote David Rendle, Corresponding Author David Rendle daverendle@me.com Rainbow Equine Hospital, Malton, North Yorkshire, UKemail: daverendle@me.comSearch for more papers by this author David Rendle, Corresponding Author David Rendle daverendle@me.com Rainbow Equine Hospital, Malton, North Yorkshire, UKemail: daverendle@me.comSearch for more papers by this author First published: 20 July 2019 https://doi.org/10.1136/vr.l4730Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume185, Issue3July 2019Pages 79-81 RelatedInformation

Selective vulnerability of dorsal raphe-medial prefrontal cortex projection neurons to corticosterone-induced hypofunction.

Glucocorticoid hormones and serotonin (5-HT) are strongly associated with the development and treatment of depression, respectively. Glucocorticoids regulate the function of serotonergic neurons in the dorsal raphe nucleus (DR), which are the major source of 5-HT to the forebrain. DR 5-HT neurons are electrophysiologically heterogeneous, though whether this phenotypic variation aligns with specific brain functions or neuropsychiatric disease states is largely unknown. The goal of this work was to determine if chronic exogenous glucocorticoid administration differentially affects the electrophysiological profile of DR neurons implicated in the regulation of emotion versus visual sensation by comparing properties of cells projecting to medial prefrontal cortex (mPFC) versus lateral geniculate nucleus (LGN). Following retrograde tracer injection into mPFC or LGN, male Sprague-Dawley rats received daily injections of corticosterone (CORT) for 21days, after which whole-cell patch clamp recordings were made from retrogradely labeled DR neurons. CORT-treatment significantly increased the action potential half-width of LGN-projecting DR neurons, but did not significantly affect the firing frequency or excitatory postsynaptic currents of these cells. CORT-treatment significantly reduced the input resistance, evoked firing frequency, and spontaneous excitatory postsynaptic current frequency of mPFC-projecting DR neurons, indicating a concurrent reduction of both intrinsic excitability and excitatory drive. Our results suggest that the serotonergic regulation of cognitive and emotional networks in the mPFC may be more sensitive to the effects of glucocorticoid excess than visual sensory circuits in the LGN and that reduced 5-HT transmission in the mPFC may underlie the association between glucocorticoid excess and depression.

Spinal Epidural lipomatosis due to adrenal cortisol secreting adenoma in a 14 year old girl - a case report

Background: Spinal epidural lipomatosis (SEL) is an excessive fat deposition within the epidural space of spinal canal leading to compression of nervous structures and neurological manifestations. Exogenous glucocorticoid administration is the major cause of symptomatic SEL. The reported patient had SEL related to endogenous Cushing syndrome which is among few reported cases in the literature. Case presentation: A 14 year girl with features of Cushing syndrome had severe back pain and magnetic resonance imaging of spine showed SEL. Subsequently, computed tomography of abdomen showed right adrenal adenoma.The patient underwent adrenalectomy which improved her signs of hypercortisolism and SEL. Conclusion: In view of severe neurological deficits and therapeutic consequences, SEL should be considered in all patients with Cushing syndrome who present with symptoms of spinal cord compression. Correction of underlying endocrinopathy is imperative in management of SEL.

Feline obesity and diabetes: a One Health perspective.

Abstract There is increasing awareness of obesity and diabetes mellitus in cats that parallels the 'epidemic' of obesity and type 2 diabetes in humans. Likewise, understanding of the pathophysiology and management of feline obesity and diabetes has developed alongside and draws from human medicine. As in human medicine, overweight and obesity are associated with the development with diabetes; however, there are other genetic and environmental influences that contribute to this risk, some of which are shared. In cats, the body condition score appears to be a good diagnostic tool. It is reliable in the hands of owners and is likely to reflect visceral adiposity. However, the diagnostic label of feline obesity should be considered against the rate of success of any intervention, owner perspectives and impact on cat quality of life, as well as risk of future disease. The classification of human diabetes is evolving towards one that is more closely linked to disease outcome and therefore management. Consideration could be given to classifying the diabetes of hypersomatotropism and that associated with exogenous glucocorticoid administration in cats, separately in veterinary medicine. Rather regarding feline obesity and diabetes as models of human disease, a closer interdisciplinary 'One Health' approach between veterinary and human medicine is warranted to advance research and clinical care in this field.