High Doses Of Hydrocortisone Research Articles

Clinical profile and growth pattern of children with congenital adrenal hyperplasia attending endocrine clinic, in a tertiary care center, South India

Background: Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders that result from the deficiency of one of several enzymes involved in the steroidogenic pathway for cortisol or aldosterone biosynthesis. Glucocorticoid replacement therapy, though largely effective in managing crises and limiting virilization, is far from perfect. Aims and Objectives: The aims and objectives of the study are to study the clinical profile and association between type of disease and glucocorticoid dosage with the growth of children with CAH attending pediatric and endocrinology outpatient department in a tertiary care hospital. Materials and Methods: This is a prospective observational study. All children who were newly diagnosed and old cases of CAH were consecutively recruited. Background details of the patient including sociodemographic data were obtained by a structured pro forma. Medical history and details of treatment were obtained from previous records. Patients were then followed up 6 monthly for 1 year and height and height velocity were obtained. Results: This study included 33 children (23 salt wasting [SW] and 10 simple virilizing [SV] CAH). Mean age was 6.3 ± 4.3 years. Among SW CAH, while 83.3% of male babies presented with adrenal crises while only 20% of the female babies went for a crisis, because most of them were diagnosed by the presence of ambiguous genitalia. Among SV patients, all females presented with ambiguous genitalia and males presented with precocious puberty. The overall height standard deviation was 0.8 ± 1.2 with a greater growth faltering in those taking higher doses of hydrocortisone. Growth was compromised more in SW CAH than in SV CAH. Conclusion: Growth in CAH is less compared to normal population and many factors including glucocorticoid dose and type of disease determine the growth and final height.

FRI254 Unconventional Pre-operative Management Of Congenital Adrenal Hyperplasia

Abstract Disclosure: M.A. Ortiz-Rivera: None. L.N. Madera Marin: None. A. Rosado-Burgos: None. L. El Musa Penna: None. W. Medina-Torres: None. L.R. Sepulveda-Garcia: None. L.A. Gonzalez-Rodriguez: None. M. Ramirez-Vick: None. M. Alvarado-Santiago: None. A.J. Grana Santini: None. M. Feliciano-Emmanuelli: None. Management of classic salt-wasting congenital adrenal hyperplasia [CAH] warrants suppression of the hypothalamic-pituitary-adrenal axis through glucocorticoid and mineralocorticoid supplementation. Preferred glucocorticoid replacement is generally hydrocortisone [HC] 3 times daily but caring for these patients often involves unconventional choices of glucocorticoid preparation regimens tailored to meet patient needs. A 41-year-old female with history of long-standing poorly controlled classic salt-wasting CAH associated to secondary amenorrhea and hypothyroidism, presenting with bilateral myelolipomas was consulted to our service for pre-op optimization. She underwent evaluation by Urology due to worsening right-sided back pain for which an abdominal-pelvic CT was performed showing large bilateral adrenal gland lesions (left mass measuring 11.5 x 10.3 x 10.6 cm and right mass measuring 8.1 x 10.4 x 7.7 cm) consistent with adrenal myelolipomas. Endocrine surgeon favored adrenalectomy due to mass effect brought about by massive adrenal growth secondary to inadequate therapeutic regime. Patient had been lost to follow-up after transitioning from pediatric to adult Endocrinology and was managed by her primary care physician who kept her on an unmodified therapeutic regime. During a pharmacy shortage of HC, she was switched from HC 25 mg TID to 5 mg daily. Furthermore, use of fludrocortisone 0.1 mg daily had been inadvertently halted in the past year. There had been progressive skin hyperpigmentation since the age of 20, significant hirsutism and salt cravings which made her add soy sauce to meals. At the age of 12 a vaginoplasty was performed, with menstrual periods ceasing at age 15. Physical examination was remarkable for grave voice, broad shoulders, bronze skin and coarse terminal hairs on chin, upper lip, sides of face and upper back. Hormonal workup revealed a direct renin > 300 pg/mL (nl 3.6 – 81.6), ACTH 463 pg/mL (nl 0.00 – 46.00), androstenedione > 10 ng/mL (nl 0.6 – 3.10), total testosterone [TT] 419 ng/dL (nl 13 – 53) and 17-hydroxyprogesterone [17-OHprog] > 20 ng/mL (nl 0.20 – 2.6). Frequent increases in medication dosing, up to HC 20mg TID and fludrocortisone 0.1mcg BID, did not attain adequate hormonal control. Dexamethasone 0.25 mg was then added at bedtime and the patient was finally able to achieve restoration of menses, resolution of salt cravings and hormonal profile control with decreases in renin to 23.02 pg/mL, androstenedione to < 0.30 ng/mL, TT to 11 ng/dL and 17-OHprog to 3.15 ng/mL. Alternative treatment strategies are sometimes warranted to achieve control of CAH. In this patient with prominent androgen excess and amenorrhea who failed to meet goals on high doses of hydrocortisone and fludrocortisone, combination therapy with a small dose of long-acting glucocorticoid at bedtime achieved the desired goal. Presentation: Friday, June 16, 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.

Sleep patterns in patients treated for non-secreting intra- and parasellar tumors: A self-report case-control study.

In this study we evaluate sleep patterns of patients treated for non-secreting intra- and parasellar tumors and age- and sex-matched healthy controls. We conducted a self-report cross-sectional case-control study with 104 patients treated for non-secreting intra- and parasellar tumors and 1800 healthy controls in an 1:8 matching. All subjects answered the Munich ChronoType Questionnaire, whereas patients were provided the Pittsburgh Sleep Quality Index, the Epworth Sleepiness Scale, the Short-Form 36 Health survey, the Beck Depression Inventory and the State-Trait Anxiety Inventory additionally. Patients treated for non-secreting intra- and parasellar tumors go to bed earlier, fall asleep earlier, need less time to prepare to sleep but also to get up. Additionally, they lie and sleep longer. The subgroup analysis showed that patients with secondary adrenal insufficiency compared to controls experienced shorter daily light exposure and longer sleep latency. Higher hydrocortisone dose (>20mg) was associated with worse score in global, physical and mental health, shorter time to prepare to sleep, earlier sleep onset and longer sleep duration. Our study shows that patients treated for non-secreting intra- and parasellar tumors, even if successfully treated, experience altered sleep patterns compared to controls. We suggest that managing clinicians should enlighten these possible sleep alterations to their patients and use specific questionnaires to document sleep disturbances. Additionally, when treating patients surgically, especially by transcranial approach, damaging the suprachiasmatic nucleus should be avoided. Furthermore, circadian hydrocortisone replacement therapy ideally with dual-release hydrocortisone - if possible, in a dose not more than 20mg daily - that resembles physiological cortisol levels more closely may be beneficial and could improve sleep patterns and sleep-related quality of life.

Primary adrenal insufficiency - Addison's disease

Introduction and purpose&#x0D; Addison's syndrome is defined as primary adrenal insufficiency, the symptoms of which result from hormonal deficiencies: glucocorticosteroids, mineralocorticosteroids and androgens. Currently, autoimmunity is considered the most common cause of Addison's Syndrome. Antibodies are most often directed against the enzymes 21-hydroxylase and 17-hydroxylase involved in steroidogenesis.&#x0D; The aim of the study is to present a typical clinical course, diagnostic path and current therapeutic options of Addison's syndrome.&#x0D; Description of the state of knowledge&#x0D; Currently, in developed countries, the number of cases is 100-140 people per million people. Initially, Addison's syndrome runs secretly. The clinical picture is closely correlated with the degree of adrenal cortex destruction. The most common symptoms include hypotonia, weight loss, weakness, salt craving, gastrointestinal disorders, and hyperpigmentation of the skin and mucous membranes. In extreme cases, adrenal crisis may develop, characterized by rapid clinical deterioration with hypotension, fever, vomiting, dehydration, and loss of consciousness.&#x0D; Diagnostics uses the measurement of the concentration of morning cortisol and corticotropin (ACTH) in the blood, and in doubtful situations, additionally a stimulation test using synthetic ACTH.&#x0D; Summary&#x0D; A diagnosis of Addison's syndrome requires end-of-life hormonal substitution. For this purpose, hydrocortisone or prednisone and fludrocortisone are used. In stressful situations, the doses of glucocorticoids should be adequately increased. Patients with adrenal crisis require intensive fluid resuscitation to restore intravascular volume, correct hypoglycemia and electrolyte disturbances, and administer rapidly high doses of hydrocortisone.

Addison crisis related psychosis

IntroductionAddison’s disease (AD) is a rare disorder of the adrenal glands which causes deficiency of cortisol and aldosterone. It presents with a variety of symptoms, including neuropsychiatric manifestations. We discuss the case of a patient who exhibited psychotic symptoms in clear consciousness and no other clinical sign of AD.ObjectivesTo investigate the association between AD and neuropsychiatric symptoms; to make clinicians aware of psychotic manifestations of AD as first presentation.MethodsCase Presentation of a patient with psychosis and AD. A review of the literature was conducted in PubMed using the following keywords: Addison’s disease, Addison crisis, psychosis, psychotic, neuropsychiatricResultsA 32-year-old alert male patient presented with delusions of persecution, auditory hallucinations and mild psychomotor agitation after a stressful life event. Lab tests showed hyponatremia (132 mEq/L). Patient exhibited rapid clouding of consciousness after admission and further lab results showed low levels of cortisol. He was therefore started treatment with high doses of hydrocortisone with good response. A close association between AD and psychiatric manifestations was indicated by the literature review, especially in males and those with thyroid dysfunction comorbidity. These include a wide range of symptoms, such as apathy, catatonia, anxiety, depression, lethargy, delirium, cognitive disorder, irritability, behavioural disorders, agitation, delusions, hallucinations, and rarely psychotic symptoms in clear consciousness. The aetiopathogenetic mechanism involves electrolyte disturbances, cortisole deficiency and increase in endogenous endorphinesConclusionsClinicians should be alert of the manifestation of AD with psychiatric symptoms ;patients with AD should be informed of the risk for Addison crisis after stress.DisclosureNo significant relationships.

Susceptibility to Adrenal Crisis Is Associated With Differences in Cortisol Excretion in Patients With Secondary Adrenal Insufficiency.

ObjectiveTo compare cortisol pharmacokinetics and pharmacodynamics mapped through several glucocorticoid sensitive pathways in patients on hydrocortisone substitution with or without an adrenal crisis.DesignA post-hoc analysis of a previously conducted randomized controlled trial in patients with secondary adrenal insufficiency examining the effects of 2 weight-adjusted hydrocortisone doses.MethodsComparisons were primarily made on a hydrocortisone dose of 0.2-0.3 mg/kg/day for plasma cortisol and cortisone, 24-hour urinary steroid profile, the glucocorticoid sensitive tryptophan-kynurenine pathway, the renin-angiotensin-aldosterone system and aspects of quality of life. Variables of interest were also analyzed on the hydrocortisone dose of 0.4-0.6 mg/kg/day.ResultsOut of 52 patients, 9 (17%) experienced at least one adrenal crisis (AC+ group) and 43 did not develop an adrenal crisis (AC- group) during an observation period of 10 years. 24-hour urinary excretion of cortisol and cortisone were lower in the AC+ group (0.05 [IQR 0.03; 0.05] vs. 0.09 [0.05; 0.12] µmol/24h, P=0.01and 0.13 [0.10; 0.23] vs. 0.24 [0.19; 0.38] µmol/24h, P=0.04, respectively). No differences in pharmacokinetics of cortisol were observed. Kynurenine concentrations were higher in the AC+ group (2.64 [2.43; 3.28] vs. 2.23 [1.82; 2.38] µmol/L, P=0.03) as was general fatigue (Z-scores 1.02 [-0.11; 1.42] vs. -0.16 [- 0.80; 0.28], P=0.04). On the higher hydrocortisone dose urinary excretion of cortisol and cortisone was still significantly lower between the AC- and AC + group. The differences in glucocorticoid sensitive variables disappeared.ConclusionPatients susceptible to an adrenal crisis demonstrated differences in cortisol and cortisone excretion as well as in pharmacodynamics when compared to patients who did not experience an adrenal crisis, suggesting a biological predisposition in certain patients for the development of an adrenal crisis.

Effects of hydrocortisone-presensitized sugammadex on recovery from neuromuscular blockade induced by rocuronium: a rodent in vivo study.

BackgroundSugammadex is a specific antagonist of aminosteroidal neuromuscular blocking agents with 1:1 binding to guest molecules. Sugammadex can also bind to other drugs having a steroid component in its chemical structure. In this in vivo experiment, we investigated the differences in the recovery of rocuronium-induced neuromuscular blockade using sugammadex pre-exposed with two different concentrations of hydrocortisone.MethodsThe sciatic nerves and tibialis anterior muscles of 30 adult Sprague–Dawley rats were prepared for the experiment. The sciatic nerves were stimulated using a train-of-four (TOF) pattern with indirect supramaximal stimulation at 20 s intervals. After 15 min of stabilization, a 250 μg loading dose and 125 μg booster doses of rocuronium were serially administered until > 95% depression of the first twitch tension of TOF stimulation (T1) was confirmed. The study drugs were prepared by mixing sugamadex with the same volume of three different stock solutions (0.9% normal saline, 10 mg/ml hydrocortisone, and 100 mg/ml hydrocortisone). The recovery of rats from neuromuscular blockade was monitored by assessing T1 and the TOF ratio (TOFR) simultaneously until T1 was recovered to > 95% and TOFR to > 0.9.ResultsIn the group injected with sugammadex premixed with a high concentration of hydrocortisone, statistically significant intergroup differences were observed in the recovery progression of T1 and TOFR (P < 0.050).ConclusionsWhen sugammadex was pre-exposed to a high dose of hydrocortisone only, recovery from neuromuscular blockade was delayed. Delayed recovery from neuromuscular blockade is not always plausible when sugammadex is pre-exposed to steroidal drugs.

Cortisol Dose-Dependently Impairs Migration and Tube-like Formation in a Trophoblast Cell Line and Modulates Inflammatory and Angiogenic Genes.

Several stimuli can change maternal hormone levels during pregnancy. These changes may affect trophoblastic cells and modulate the development of the embryo and the placental tissue itself. Changes in cortisol levels are associated with impaired trophoblast implantation and function, in addition to other pregnancy complications. This study aims to analyze the effects of low and high doses of cortisol on an extravillous trophoblast cell line, and the effects of various exposures to this hormone. SGHPL-4 cells were treated with cortisol at five doses (0–1000 nM) and two exposures (continuous: 24 h/day; and intermittent: 2 h/day). In intermittent treatment, cortisol acted mainly as an anti-inflammatory hormone, repressing gene expression of kinin B1 receptors, interleukin-6, and interleukin-1β. Continuous treatment modulated inflammatory and angiogenic pathways, significantly repressing angiogenic factors and their receptors. Cortisol affected cell migration and tube-like structures formation. In conclusion, both continuous and intermittent exposure to cortisol repressed the expression of inflammatory genes, while only continuous exposure repressed the expression of angiogenic genes, suggesting that a sustained increase in the levels of this hormone is more harmful than a high short-term increase. Cortisol also impaired tube-like structures formation, and kinin receptors may be involved in this response.

A High-Dose Cortisol Receptor Antagonist for the Management of Severe Hyperglycemia in a Patient With an Adrenocortical Carcinoma

The management of functional adrenocortical carcinoma (ACC) is challenging as it involves treating the underlying endocrinological abnormalities such as hypercortisolism. Competitive glucocorticoid receptor antagonist such as mifepristone (Korlym®) can be used to treat dysglycemia secondary to hypercortisolism. A 59-year-old male was admitted for dizziness and lightheadedness. Past medical history was significant for hypertension, and obesity. During evaluation, patient was found to have a random blood glucose of 663 mg/dL and a hemoglobin A1c of 14.4% with a previous of 5.8%. After admission, patient required 62.9 units of IV insulin over 9 hours to stabilize blood glucose. Due to the high insulin requirement and clinical presentation, a concern for hypercortisolism was considered and workup revealed an 8am cortisol level of 28.3 mcg/dL, and dexamethasone suppression test with cortisol of 50.4 mcg/dL, dexamethasone level 209 ng/dL and ACTH of <5 pg/mL. Patient was discharged on glargine 40 units SC BID and aspart 10 units SC TID AC. Seventeen days after discharge, patient was admitted with hyperglycemia (233 mg/dL), hypokalemia (2.5 mg/dL), abdominal pain, nausea, and vomiting. CT of abdomen revealed a 9.3 x 10.8 x 9 cm retroperitoneal mass arising from the left adrenal. Patient was started on mifepristone (Korlym®) 600mg PO daily while inpatient as his acute hyperglycemia was insufficiently controlled for consideration to open adrenalectomy. Within 24 hours of starting therapy, patient’s insulin requirement was de-escalated, and euglycemia was maintained for 20 days until surgery. Postoperative pathology demonstrated a 12.1cm resected tumor consistent with adrenocortical carcinoma. No clinical signs of adrenal insufficiency occurred postoperatively despite not stopping mifepristone (Korlym®) prior to surgery. Discussion: Adrenocortical carcinomas (ACC) are rare malignancies with an annual incidence of 0.7–2 cases per million population. They carry a poor prognosis with 5-year survival between 16–47%. The clinical presentation varies on the functional activity of these tumors and approximately 60% of them are cortisol secreting. The management of functioning-ACCs is challenging. Our patient presented with hyperglycemia secondary to hypercortisolism that was recurrent and difficult to control. He was started on mifepristone (Korlym®), a FDA approved potent competitive glucocorticoid receptor antagonist for the treatment of dysglycemia secondary to all forms of Cushing disease. In our patient, mifepristone provided a significant and rapid glycemic control, requiring to decrease the dose of insulin. Conclusion: This case demonstrates a safe and acute use of mifepristone (Korlym®) without initial titration in an inpatient monitored setting making this medication a viable option for management and optimization of hyperglycemia secondary to hypercortisolism.This research was supported (in whole or in part) by HCA Healthcare and/or an HCA Healthcare affiliated entity. The views expressed in this publication represent those of the authors and do not necessarily express the official views of the HCA Healthcare or any of its affiliated entities.

Kongenitalna adrenalna hiperplazija

Congenital adrenal hyperplasia is a disease in which a gene mutation, which is inherited in an autosomal recessive manner, causes a disorder in the synthesis of enzymes that create glucocorticoids, mineralocorticoids, or sex steroids from adrenal cholesterol. The incidence of the classic form of the disease ranges from 1:14000 to 1:18000 births. In the majority of cases, the disease is caused by mutations in the CYP21A2 gene that participates in the synthesis of the 21 Alpha-hydroxylase. Due to the lack of enzymes, the synthesis of cortisol is blocked with the accumulation of sex hormones. The classic form of the disease, or a simple virilizing form in which patients lose salt, is diagnosed in the infant period. In the non-classical or mild form of the disease, with late-onset, patients may be asymptomatic or with a milder form of virilization postnatally. The diagnosis is made based on 17-hydroxyprogesterone levels, in order to determine the deficiency of the 21 Alpha-hydroxylase enzyme. Common complications of the disease are adrenal crisis, hypoglycemia, infertility, and premature entry into puberty. Prenatal therapy is referred to as experimental treatment, while the basis of care is hydrocortisone replacement. In severe forms of the disease, patients are unable to produce enough cortisol in response to stress from gastroenteritis, surgery, trauma, or fever, requiring higher doses of hydrocortisone. In certain cases of genital uncertainty, surgical treatment is necessary. A multidisciplinary team of experts is necessary for adequate surveillance of the disease, in both childhood and adulthood.

Hydrocortisone as a Potential Treatment of Savage Ovary Syndrome: A Rare Case from Syria

Advances in Medical, Dental and Health Sciences,2020,3,3,49-51.DOI:10.5530/amdhs.2020.3.12Published:October 2020Type:Case ReportAuthors:Dema Adwan Author(s) affiliations:Dema Adwan* Damascus University Gynecology and Obstetrics Hospital, SYRIA. Abstract:A 32-year old woman with a secondary amenorrhea for 5 years presented to my clinic (April 2019), previously had been treated as a premature ovarian failure patient and put on HRT. With further investigation, FSH Levels were high at the menopausal range, whereas the AMH levels and antral follicles count were within normal ranges and found to be age-compatible, These findings, as well as the failure of ovaries to respond to exogenous gonadotropins, helped to set the diagnosis of Savage Ovary Syndrome, which is also known as Insensitive Ovary Syndrome (IOS). Written informed consent was obtained from the patient for publication of this case report and accompanying images" Patient was convinced to be treated empirically with a high dose of Hydrocortisone and the result was the patient well responded as a normal spontaneous menstruation happened. The analysis of FSH and estradiol induces normal values and the return of the functional activity of the ovary to the formation of multiple ovarian bilateral follicle and give an echo feature similar to the ovarian hyper stimulatory syndrome with an increase the thickness of the endometrium. This case shows the importance of further studying patients with secondary amenorrhea and high levels of gonadotropins and not to treat them all as premature ovary insufficiency patients, just like our patient was firstly treated for a long time. Furthermore, the case highlights the potential benefit of the treatment of Savage Ovary Syndrome patients with Hydrocortisone. Keywords:Antral follicles, Gonadotropin, Infertility, Insensitive ovary, Resistant ovarian syndrome, Secondary amenorrheaView:PDF (535.52 KB)

Cortisol regulates insulin-like growth-factor binding protein (igfbp) gene expression in Atlantic salmon parr

The growth hormone (Gh)/insulin-like growth-factor (Igf)/Igf binding protein (Igfbp) system regulates growth and osmoregulation in salmonid fishes, but how this system interacts with other endocrine systems is largely unknown. Given the well-documented consequences of mounting a glucocorticoid stress response on growth, we hypothesized that cortisol inhibits anabolic processes by modulating the expression of hepatic igfbp mRNAs. Atlantic salmon (Salmo salar) parr were implanted intraperitoneally with cortisol implants (0, 10, and 40 μg g−1 body weight) and sampled after 3 or 14 days. Cortisol elicited a dose-dependent reduction in specific growth rate (SGR) after 14 days. While plasma Gh and Igf1 levels were unchanged, hepatic igf1 mRNA was diminished and hepatic igfbp1b1 and -1b2 were stimulated by the high cortisol dose. Plasma Igf1 was positively correlated with SGR at 14 days. Hepatic gh receptor (ghr), igfbp1a, -2a, -2b1, and -2b2 levels were not impacted by cortisol. Muscle igf2, but not igf1 or ghr, levels were stimulated at 3 days by the high cortisol dose. As both cortisol and the Gh/Igf axis promote seawater (SW) tolerance, and particular igfbps respond to SW exposure, we also assessed whether cortisol coordinates the expression of branchial igfbps and genes associated with ion transport. Cortisol stimulated branchial igfbp5b2 levels in parallel with Na+/K+-ATPase (NKA) activity and nka-α1b, Na+/K+/2Cl--cotransporter 1 (nkcc1), and cystic fibrosis transmembrane regulator 1 (cftr1) mRNA levels. The collective results indicate that cortisol modulates the growth of juvenile salmon via the regulation of hepatic igfbp1s whereas no clear links between cortisol and branchial igfbps previously shown to be salinity-responsive could be established.

Health-related quality of life in patients with non-functioning pituitary adenoma: a special focus on hydrocortisone replacement dose.

Patients with non-functioning pituitary adenomas (NFPA) suffer from pronounced impairments in physical and mental measures that result in an impairment of health-related quality of life (HRQOL). The role of secondary adrenal insufficiency (SAI) and especially the one of the hydrocortisone (HC) replacement dose on the HRQOL seems to be conflicting. The primary aim of this study is to assess the HRQOL in patients with NFPA in terms of presence of SAI and in patients without SAI and the secondary to explore the impact of treatment parameters such as daily HC dose. In a cross-sectional study we evaluated parameters of HRQOL in 95 patients with NFPA of the Endocrine Outpatient Unit of the Max Planck Institute of Psychiatry in Munich using standardized questionnaires like Short Form (SF-36), Beck's Depression Inventory (BDI), State-Trait Anxiety Inventory (STAI), Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI) and a self-constructed questionnaire about medical history. We could not find any significant difference between patients with and without SAI in the standardized questionnaires in terms of HRQOL. We could show that higher doses of HC were negatively correlated with HRQOL measured by SF-36 global health score regardless of using BDI or STAI in the block (β = - 0.397; p = 0.021, β = - 0.390; p = 0.016, respectively). NFPA patients with SAI do not have a worse HRQOL than patients with NFPA and intact corticotropic axis. We could show that higher doses of HC are associated with an impaired HRQOL measured by SF-36 global and physical health score, whereas mental health score is not significantly influenced by the HC dose.

Severe Leptospirosis with Pulmonary Hemorrhage; The Role of Intravenous Hydrocortisone

Leptospirosis is an endemic zoonosis caused by spirochetes of the genus Leptospira that typically occurs in tropical regions. Pulmonary hemorrhage which is the frequent cause of mortality in leptospirosis is either underdiagnosed or only discovered at autopsy. In this paper, we present a 23 year old male presenting with five days history of fever with anuria, dyspnea and hemoptysis. Leptospira IgM was positive. Chest Xray and HRCT scan showed diffuse bilateral infiltrates with pulmonary hemorrhage. Patient was treated with antibiotics, renal replacement therapy and steroids. However, methylprednisolone was unavailable thus, a high dose of hydrocortisone was used as an alternative. Leptospirosis has an immune phase which damages the endothelium affects organs like the liver, kidneys, heart, lungs and meninges. Immunomodulation with high-dose steroids may be used. Methylprednisolone is the ideal steroid given and is proven to weaken the inflammatory response and ameliorate the adverse effect of immune mediated response. In our case, a hydrocortisone equivalent of methylprednisolone was used which was unconventional but is cheaper and more available. Early recognition is important as administration of corticosteroid in addition to broad-spectrum antibiotics and early supportive care can lead to successful treatment, shortened hospital stays, reduction of morbidity and mortality. Thus, targeting the pulmonary involvement of leptospirosis with methylprednisolone equivalent hydrocortisone has demonstrated to be effective as evidenced by our patient’s response. Hence, it can be used to treat Leptospirosis with pulmonary hemorrhage at a lesser cost which is more practical to use in areas with limited resources.

Perioperative Glucocorticoid Therapy for Patients with Adrenal Insufficiency: Dosing Based on Pharmacokinetic Data.

Perioperative glucocorticoid therapy for patients with adrenal insufficiency (AI) is currently based on anecdotal reports, without supporting pharmacokinetic data. We determined the half-life, clearance, and volume of distribution of 2 consecutive intravenously (IV)-administered doses of hydrocortisone (15 or 25 mg every 6 hours) to 22 dexamethasone-suppressed healthy individuals and used the data to develop a novel protocol to treat 68 patients with AI who required surgical procedures. Patients received 20 mg of hydrocortisone orally 2 to 4 hours before intubation and were started on 25 mg of IV hydrocortisone every 6 hours for 24 hours and 15 mg every 6 hours during the second day. Nadir cortisol concentrations were repeatedly measured during that period. In healthy individuals, cortisol half-life was longer when the higher hydrocortisone dose was administered (2.02 ± 0.15 vs 1.81 ± 0.11 hours; P < 0.01), and in patients with AI, the half-life was longer than in healthy individuals given the same hydrocortisone dose. In both populations, the cortisol half-life increased further with the second hormone injection. Prolongation of cortisol half-life was due to decreased hydrocortisone clearance and an increase in its volume of distribution. Nadir cortisol levels determined throughout the 48 postoperative hours were within the range of values and often exceeded those observed perioperatively in patients without adrenal dysfunction. Cortisol pharmacokinetics are altered in the postoperative period and indicate that lower doses of hydrocortisone can be safely administered to patients with AI undergoing major surgery. The findings of this investigation call into question the current practice of administering excessive glucocorticoid supplementation during stress.

Lipopolysaccharide Stress Induces Cryptic Exon Splice Variants of the Human Glucocorticoid Receptor.

Glucocorticoids are widely used in the treatment of numerous inflammatory conditions, including sepsis. Unfortunately, patient response to glucocorticoid therapy can be inconsistent. Variations in the human glucocorticoid receptor (hGR) may contribute to the differential patient response. We screened for hGR variants in the buffy coats of burn patients and peripheral blood mononuclear cells (PBMCs) treated with lipopolysaccharide. Three novel splice variants containing cryptic exons were upregulated in the PBMCs after lipopolysaccharide exposure at 3 and 13 h with the greatest observed expression at 3 h. Luciferase assays revealed that two of the isoforms had no significant activity in comparison with the reference hGR when stimulated with hydrocortisone. The third isoform had an augmented response that was greater than the reference hGR at a high cortisol dose. This shows that PBMCs are able to produce variant hGR isoforms in response to stress. Furthermore, lipopolysaccharide stress appears to induce these hGR variants, potentially by influencing mRNA splicing. In the future, identifying hGR expression profiles may be a key component in individually tailoring a patient's treatment to sepsis and injury.

Residual endogenous corticosteroid production in patients with adrenal insufficiency.

ObjectiveThis study aimed at comparing precursors of endogenous corticosteroid production in patients with primary adrenal insufficiency and in secondary adrenal insufficiency.DesignTwenty patients with primary adrenal insufficiency and matched controls and 19 patients with secondary adrenal insufficiency participated in this ancillary analysis of two different studies.Patients and measurementsPatients with primary adrenal insufficiency were on stable hydrocortisone and fludrocortisone therapy. Patients with secondary adrenal insufficiency received two different doses of hydrocortisone in a randomized crossover study. Main outcome measures were concentrations of precursors of cortisol and aldosterone measured by LC‐MS/MSResultsCompared to controls, progressively lower concentrations of the glucocorticoid precursors 11‐deoxycortisol, 11‐deoxycorticosterone and corticosterone concentrations were found in patients with secondary adrenal insufficiency on lower hydrocortisone dose, secondary adrenal insufficiency on higher hydrocortisone dose and primary adrenal insufficiency, respectively. Half of the primary adrenal insufficient patients showed evidence of residual endogenous cortisol or aldosterone synthesis, as determined by quantifiable 11‐deoxycortisol, 11‐deoxycorticosterone and corticosterone concentrations. In secondary adrenal insufficient patients with higher endogenous cortisol production, as indicated by 11‐deoxycortisol concentrations above the median, no increased cortisol exposure was observed both by plasma pharmacokinetic parameters and 24‐hour free cortisol excretion in urine.ConclusionsAdrenal corticosteroid production is likely to continue during treatment in a considerable percentage of patients with both primary and secondary adrenal insufficiency. In patients with secondary adrenal insufficiency, this synthesis appears to be sensitive to the dose of hydrocortisone. However, the residual corticosteroid concentrations were quantitatively low and its clinical significance remains therefore to be determined.

274-LB: The Anti-inflammatory Effects of Insulin and Hydrocortisone Combination in Obese Subjects

Glucocorticoids have been used as the major class of anti-inflammatory agents for over 60 years. However, they have well known side effects including weight gain, adiposity, muscle loss, osteoporosis and diabetogenicity. We have recently described the induction of specific pro-inflammatory genes by a single large dose of hydrocortisone (HC) in normal weight subjects. Since our group discovered the anti-inflammatory actions of insulin, we have now hypothesized that a combination of insulin with a high dose of a HC may neutralize the proinflammatory effects of HC and offer a safe anti-inflammatory combination. Eight obese subjects (BMI:31-46 kg/m2, age: 29-63 years, 3 females) were randomized into a cross over study to be injected in two separate visits (a week apart) with 300 mg of HC (?60 mg prednisolone) intravenously with or without an infusion of 2U/h of insulin with 5% dextrose for 8 hours. HC injection alone induced a significant anti-inflammatory effect including suppression of CCR-2 (by 54±8%), IL-4 (by 68±14%) and TNF-α (by 35±10%) expression in mononuclear cells (MNC). However, the HC injection also induced an increase in the expression of HMG-B1, TLR2, TLR4, TLR9, JNK-1 and RANK-L (by 43±12%, 57±9%, 62±17%, 69±15%, 89±19% and 61±11% over the baseline, respectively, P&amp;lt;0.05 for all). Plasma glucose and FFA concentrations also increased significantly following the HC injection alone. Insulin infusion along with the HC injection further suppressed the expression of CCR-2, TNF-α and IL-4 in MNC and completely inhibited the HC induced increases in FFA concentrations and in HMG-B1, TLR-2, TLR-9 and RANK-L expression (p&amp;lt;0.05 vs. HC alone). In addition, insulin infusion not only inhibited the HC induced increases in JNK-1 and TLR4 expression but also suppressed levels below baseline (by 27±14% and 22±10%, p&amp;lt;0.001 vs. HC alone). Thus, the infusion of insulin at a low dose with a high dose of HC or other corticosteroids may constitute an ideal anti-inflammatory cocktail in the in- patient setting. Disclosure P. Dandona: Advisory Panel; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Intarcia Therapeutics, Inc., Merck &amp; Co., Inc., Novo Nordisk Inc., Sanofi. Research Support; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk Inc., Sanofi. H. Ghanim: None. M. Batra: None. K. Green: None. S. Abuaysheh: None. R. Katkar: None.

Temporal profiles of cortisol accumulation and clearance support scale cortisol content as an indicator of chronic stress in fish.

The development of chronic stress indicators for fish is of great interest, but appropriate non-invasive methods are lagging those used in terrestrial vertebrates. Here, we explore the possibility that levels of the stress hormone cortisol in scales could be used as a chronic stress indicator. Three experiments were conducted to assess the temporal profiles of cortisol rise and fall in plasma and scales of goldfish (Carassius auratus) in response to stressors of varying intensity and duration. Results show that a single acute air emersion stressor does not influence scale cortisol content. In contrast, relative to plasma levels, the fall in scale cortisol content following a high-dose cortisol implant is delayed by at least 8 days, and the rise and fall in scale cortisol content in response to unpredictable chronic stress are delayed by at least 7 days. Also, scale cortisol content is spatially heterogeneous across the body surface of goldfish. Overall, since high and sustained circulating cortisol levels are needed to influence scale cortisol content and the rates of cortisol accumulation and clearance are much slower in scales than in plasma, our results show that scales can provide an integrated measure of cortisol production and serve as a chronic stress indicator.