Biology subjects

Arlt, W.

Publications and source records attributed to Arlt, W..

4 recordsLinked to original sources

bioRxiv2019

11β-Hydroxysteroid Dehydrogenase Type 1 inhibition in Idiopathic Intracranial Hypertension: a double-blind randomized controlled trial.

Treatment options for idiopathic intracranial hypertension are limited. The enzyme 11{beta}-hydroxysteroid dehydrogenase type 1 has been implicated in regulating cerebrospinal fluid secretion, and its activity is associated with alterations in intracranial pressure in idiopathic intracranial hypertension. We assessed therapeutic efficacy, safety and tolerability, and investigate indicators of in vivo efficacy of the 11{beta}-hydroxysteroid dehydrogenase type 1 inhibitor AZD4017 compared to placebo in idiopathic intracranial hypertension. A multicenter, UK, 16-week phase II randomized, double-blind, placebo-controlled trial of 12-weeks treatment with AZD4017 or placebo was conducted. Women aged 18 to 55 years with active idiopathic intracranial hypertension (>25cmH2O lumbar puncture opening pressure and active papilledema) were included. Participants received 400mg twice daily of oral AZD4017 compared to matching placebo over 12-weeks. The outcome measures were initial efficacy, safety and tolerability. The primary clinical outcome was lumbar puncture opening pressure at 12 weeks analysed by intention-to-treat. Secondary clinical outcomes were symptoms, visual function, papilledema, headache and anthropological measures. In vivo efficacy was evaluated in the central nervous system and systemically. 31 subjects (mean age 31.2 (SD=6.9) years and BMI 39.2 (SD=12.6) kg/m2) were randomized to AZD4017 (n=17) or placebo (n=14). At 12 weeks, lumbar puncture pressure was lower in the AZD4017 group (29.7 cmH2O) compared with placebo (31.3 cmH2O), but the difference between groups was not statistically significant (mean difference: -2.8, 95% confidence interval: -7.1-1.5; p=0.2). An exploratory analysis assessing mean change in lumbar puncture pressure within each group found a significant decrease in the AZD4017 group (mean change: -4.3 cmH2O (SD=5.7); p=0.009) but not in the placebo group (mean change: -0.3 cmH2O (SD=5.9); p=0.8). AZD4017 was safe, with no withdrawals related to adverse effects. Nine transient drug-related adverse events were reported. One serious adverse event occurred in the placebo group (deterioration requiring shunt surgery). In vivo biomarkers of 11{beta}-hydroxysteroid dehydrogenase type 1 activity (urinary glucocorticoid metabolites, hepatic prednisolone generation and CSF cortisone to cortisol ratios) demonstrated significant enzyme inhibition. This is the first phase 2 randomized controlled trial in idiopathic intracranial hypertension evaluating a novel therapeutic target. AZD4017 was safe, well-tolerated and inhibited 11{beta}-hydroxysteroid dehydrogenase type 1 activity in vivo. Possible clinical benefits were noted in this small cohort. A longer, larger study would now be of interest.

clinical trials↗

bioRxiv2019

Increased risk of infections in Addison’s disease and congenital adrenal hyperplasia: a primary care database cohort study

ContextMortality and infection-related hospital admissions are increased in patients with primary adrenal insufficiency (PAI). However, the risk of primary care-managed infections in patients with PAI is unknown.\n\nObjectiveTo estimate infection risk in PAI due to Addisons disease (AD) and congenital adrenal hyperplasia (CAH) in a primary care setting.\n\nDesignRetrospective cohort study using UK data collected from 1995 to 2018.\n\nMain outcome measuresIncidence of lower respiratory tract infections (LRTIs), urinary tract infections (UTIs), gastrointestinal infections (GIIs), and prescription counts of antimicrobials in adult PAI patients compared to unexposed controls.\n\nResultsA diagnosis of PAI was established in 1580 AD patients (mean age 51.7 years) and 602 CAH patients (mean age 35.4 years). All AD patients and 42% of CAH patients were prescribed glucocorticoids, most frequently hydrocortisone in AD (82%) and prednisolone in CAH (50%). AD and CAH patients exposed to glucocorticoids, but not CAH patients without glucocorticoid treatment, had a significantly increased risk of LRTIs (adjusted incidence rate ratio AD 2.11 [95% confidence interval 1.64-2.69], CAH 3.23 [1.21-8.61]), UTIs (AD 1.51 [1.29-1.77], CAH 2.20 [1.43-3.34]), and GIIs (AD 3.80 [2.99-4.84], CAH 1.93 [1.06-3.52]). This was mirrored by increased prescription of antibiotics (AD 1.73 [1.69-1.77], CAH 1.77 [1.66-1.89]) and antifungals (AD 1.89 [1.74-2.05], CAH 1.91 [1.50-2.43]).\n\nConclusionsThere is an increased risk of infections and antimicrobial use in PAI in the primary care setting at least partially linked to glucocorticoid treatment. Future studies will need to address whether more physiological glucocorticoid replacement modes could reduce this risk.\n\nPrecisUsing data from 1580 AD patients and 602 CAH patients collected in a UK primary care database from 1995 to 2018, we identified increased risk of infections and antimicrobial prescription counts.

epidemiology↗

bioRxiv2019

Alternative pathway androgen biosynthesis and human fetal female virilization

Androgen biosynthesis in the human fetus proceeds through the adrenal sex steroid precursor dehydroepiandrosterone, which is converted towards testosterone in the gonads, followed by further activation to 5-dihydrotestosterone in genital skin, thereby facilitating male external genital differentiation. Congenital adrenal hyperplasia due to P450 oxidoreductase deficiency results in disrupted dehydroepiandrosterone biosynthesis, explaining undervirilization in affected boys. However, many affected girls are born virilized, despite low circulating androgens. We hypothesized that this is due to a prenatally active, alternative androgen biosynthesis pathway from 17-hydroxyprogesterone to 5-dihydrotestosterone, which bypasses dehydroepiandrosterone and testosterone, with increased activity in congenital adrenal hyperplasia variants associated with 17-hydroxyprogesterone accumulation. Here we employ explant cultures of human fetal organs (adrenal, gonads, genital skin) from the major period of sexual differentiation and show that alternative pathway androgen biosynthesis is active in the fetus, as assessed by liquid chromatography-tandem mass spectrometry. We found androgen receptor expression in male and female genital skin using immunohistochemistry and demonstrated that both 5-dihydrotestosterone and adrenal explant culture supernatant induce nuclear translocation of the androgen receptor in female genital skin primary cultures. Analyzing urinary steroid excretion by gas chromatography-mass spectrometry, we show that neonates with P450 oxidoreductase deficiency produce androgens through the alternative androgen pathway during the first weeks of life. We provide quantitative in vitro evidence that the corresponding P450 oxidoreductase mutations predominantly support alternative pathway androgen biosynthesis. These results indicate a key role of alternative pathway androgen biosynthesis in the prenatal virilization of girls affected by congenital adrenal hyperplasia due to P450 oxidoreductase deficiency.\n\nSIGNIFICANCEIn the classic androgen biosynthesis pathway, testosterone is converted to 5-dihydrotestosterone, a step crucially required for normal male genital virilization. Congenital adrenal hyperplasia (CAH) due to P450 oxidoreductase deficiency (PORD) is an inborn disorder that disrupts classic androgen biosynthesis. However, some affected girls present with severe genital virilization at birth. We hypothesized that this is explained by a prenatally active, alternative biosynthesis pathway to 5-dihydrotestosterone. We show that adrenals and genital skin cooperate to produce androgens via the alternative pathway during the major period of human sexual differentiation and that neonates with PORD still produce alternative pathway androgens during the first weeks of life. This indicates that alternative pathway androgen biosynthesis drives prenatal virilization in CAH due to PORD.

developmental biology↗

bioRxiv2019

The Endocrine and Metabolic Response in Male Survivors of Major Trauma

ContextSurvival rates after severe injury are improving, but complication rates and outcomes are variable. ObjectiveThis cohort study addressed the lack of longitudinal data on the steroid response to major trauma and during recovery. DesignWe undertook a prospective, observational cohort study from time of injury to six months post-injury at a major UK trauma centre and a military rehabilitation unit, studying patients within 24 hours of major trauma (estimated New Injury Severity Score (NISS) >15). Main outcome measuresWe measured adrenal and gonadal steroids in serum and 24-h urine by mass spectrometry, assessed muscle loss by ultrasound and nitrogen excretion, and recorded clinical outcomes (ventilator days, length of hospital stay, opioid use, incidence of organ dysfunction and sepsis); results were analysed by generalized mixed-effect linear models. FindingsWe screened 996 multiple injured adults, approached 106, and recruited 95 eligible patients; 87 survived. We analysed all male survivors <50 years not treated with steroids (N=60; median age 27 [interquartile range 24-31] years; median NISS 34 [29-44]). Urinary nitrogen excretion and muscle loss peaked after one and six weeks, respectively. Serum testosterone, dehydroepiandrosterone and dehydroepiandrosterone sulfate decreased immediately after trauma and took two, four and more than six months, respectively, to recover; opioid treatment delayed dehydroepiandrosterone recovery in a dose-dependent fashion. Androgens and precursors correlated with SOFA score and probability of sepsis. ConclusionThe catabolic response to severe injury was accompanied by acute and sustained androgen suppression. Whether androgen supplementation improves health outcomes after major trauma requires further investigation. PrecisA cohort study in male survivors of major trauma revealed acute and sustained androgen suppression and protein catabolism including muscle loss. Serum androgens correlated with probability of sepsis.

physiology↗