***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: CONTEXT Conventional glucocorticoid replacement therapy fails to mimic the physiological cortisol rhythm , which may have implication s for morbidity and mortality in patients with Addison 's disease . OBJECTIVE The objective of the study was to compare the effects of continuous sc hydrocortisone infusion ( CSHI ) with conventional oral hydrocortisone ( OHC ) replacement therapy . DESIGN , PATIENTS , AND INTERVENTIONS This was a prospect i ve crossover , r and omized , multicenter clinical trial comparing 3 months of treatment with thrice-daily OHC vs CSHI .  From Norway and Sweden , 33 patients were enrolled from registries and clinics . All patients were assessed at baseline and after 8 and 12 weeks in each treatment arm . MAIN OUTCOME MEASURES The morning ACTH level was the primary outcome measure . Secondary outcome measures were effects on metabolism , health-related quality of life ( HRQoL ) , sleep , and safety . RESULTS CSHI yielded normalization of morning ACTH and cortisol levels , and 24-hour salivary cortisol curves resembled the normal circadian variation . Urinary concentrations of glucocorticoid metabolites displayed a normal pattern with CSHI but were clearly altered with OHC . Several HRQoL indices in the vitality domain improved over time with CSHI . No benefit was found for either treatments for any subjective ( Pittsburgh Sleep Quality Index question naire ) or objective ( actigraphy ) sleep parameters . CONCLUSION CSHI safely brought ACTH and cortisol toward normal circadian levels without adversely affecting glucocorticoid metabolism in the way that OHC did . Positive effects on HRQoL were noted with CSHI , indicating that physiological glucocorticoid replacement therapy may be beneficial and that CSHI might become a treatment option for patients poorly controlled on conventional therapy Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Objective The objective was to assess the long-term safety profile of dual-release hydrocortisone ( DR-HC ) in patients with adrenal insufficiency ( AI ) . Design R and omised , open-label , crossover trial of DR-HC or thrice-daily hydrocortisone for 3 months each ( stage 1 ) followed by two consecutive , prospect i ve , open-label studies of DR-HC for 6 months ( stage 2 ) and 18 months ( stage 3 ) at five university clinics in Sweden . Methods Sixty-four adults with primary AI started stage 1 , and an additional 16 entered stage 3 . Patients received DR-HC 20–40 mg once daily and hydrocortisone 20–40 mg divided into three daily doses ( stage 1 only ) . Main outcome measures were adverse events ( AEs ) and intercurrent illness ( self-reported hydrocortisone use during illness ) . Results In stage 1 , patients had a median 1.5 ( range , 1–9 ) intercurrent illness events with DR-HC and 1.0 ( 1–8 ) with thrice-daily hydrocortisone . AEs during stage 1 were not related to the cortisol exposure-time profile . The percentage of patients with one or more AEs during stage 1 ( 73.4 % with DR-HC ; 65.6 % with thrice-daily hydrocortisone ) decreased during stage 2 , when all patients received DR-HC ( 51 % in the first 3 months ; 54 % in the second 3 months ) . In stages 1–3 combined , 19 patients experienced 27 serious AEs , equating to 18.6 serious AEs/100 patient-years of DR-HC exposure . Conclusions This long-term prospect i ve trial is the first to document the safety of DR-HC in patients with primary AI and demonstrates that such treatment is well tolerated during 24 consecutive months of therapy Context Hyporituitarism in adults is known to be associated with deleterious effects on body composition , lipid profile and quality of life ( QoL ) . This was attributed to GH deficiency . The potential role of glucocorticoid overreplacement had never been investigated . Objective To investigate whether reduction in glucocorticoid replacement dose to more physiological one could ameliorate the “ AO-GHD”-attributed symptomatology in patients with hypopituitarism . Design Eleven patients with panhypopituitarism taking 20–30 mg/day of hydrocortisone , but on no GH replacement  were switched to 10–15 mg of hydrocortisone daily . Both basally and 6–12 months later , their body mass index , body composition by dual-energy X-ray absorptiometry , lipid profile , and the score of quality of life , QOL-AGHDA were measured . Results Within 6–12 months of lower hydrocortisone dose , subjects lost an average of 7.1 kg of total body fat and 4.1 kg of abdominal fat . No changes were seen in lean body mass , bone mineral content and HOMA-IR . Plasma total cholesterol and triglyceride concentrations decreased significantly ( < 0.05 ) and the QoL improved ( P = 0.018 ) . Conclusions Our pilot study suggests that decreasing the glucocorticoid replacement dose to ~15 mg/day is beneficial in terms of patients ’ body composition , lipid profile and quality of life CONTEXT Concerns about the safety and efficacy of diabetes interventions persist , in part because r and omized clinical trials ( RCTs ) have not measured their effect on patient-important outcomes , ie , death and quality of life ( morbidity , pain , function ) . OBJECTIVE To systematic ally determine the extent to which ongoing and future RCTs in diabetes will ascertain patient-important outcomes . DATA SOURCES On November 10 , 2007 , we search ed primary RCT registries Clinical Trials.gov ( http://www . clinical trials.gov ) , International St and ard R and omized Controlled Trial Number Register ( http://is rct n.org ) , and Australian New Zeal and Clinical Trials Registry ( http://www.anzctr.org.au ) . STUDY SELECTION We identified phase 2 through 4 RCTs  enrolling patients with diabetes . Of 2019 RCTs , 1054 proved eligible . We r and omly sample d 50 % of the eligible RCTs ( 527 of 1054 ) and selected 436 registered since registration became m and atory ( 2004 ) . DATA EXTRACTION Pairs of review ers working independently collected study characteristics and determined the outcomes measured and their type ( physiological outcomes , surrogate outcomes thought to reflect an increased risk for patient-important outcomes , and patient-important outcomes ) . RESULTS Of the 436 registered RCTs included in this analysis , 24 ( 6 % ) had not started enrollment , 109 ( 25 % ) were actively enrolling , and 303 ( 69 % ) had completed enrollment . Primary outcomes were patient-important outcomes in only 78 of 436 RCTs ( 18 % ; 95 % confidence interval [ CI ] , 14%-22 % ) , physiological and laboratory outcomes in 69 of 436 ( 16 % ; 95 % CI , 13%-20 % ) , and surrogate outcomes in 268 of 436 ( 61 % ; 95 % CI , 57%-66 % ) . Patient-important outcomes were reported as primary or secondary outcomes in 201 of 436 ( 46 % ; 95 % CI , 41%-51 % ) . In multivariate analysis , large trials ( odds ratio [ OR ] , 1.10 ; 95 % CI , 1.02 - 1.19 for every additional 100 patients ) and trials of longer duration ( OR , 1.03 ; 95 % CI , 1.01 - 1.06 for every additional 30 days ) were more likely while parallel design RCTs ( OR , 0.15 ; 95 % CI , 0.05 - 0.44 ) and type 2 diabetes trials ( OR , 0.23 ; 95 % CI , 0.09 - 0.61 ) were less likely to assess patient-important outcomes as a primary outcome . CONCLUSION In this sample of registered ongoing RCTs in diabetes , only 18 % included patient-important outcomes as primary outcomes CONTEXT Patients with treated adrenal insufficiency ( AI ) have increased morbidity and mortality rate . Our goal was to improve outcome by developing a once-daily ( OD ) oral hydrocortisone dual-release tablet with a more physiological exposure-time cortisol profile . OBJECTIVE The aim was to compare pharmacokinetics and metabolic outcome between OD and the same daily dose of thrice-daily ( TID ) dose of conventional hydrocortisone tablets . DESIGN AND SETTING We conducted an open , r and omized , two-period , 12-wk crossover multicenter trial with a 24-wk extension at five university hospital centers . PATIENTS The trial enrolled 64 adults with primary AI ; 11 had concomitant diabetes mellitus ( DM ) . INTERVENTION The same daily dose of hydrocortisone was administered as OD dual-release or TID . MAIN OUTCOME MEASURE We evaluated cortisol pharmacokinetics . RESULTS Compared with conventional TID , OD provided a sustained serum cortisol profile 0 - 4 h after the morning intake and reduced the late afternoon and the 24-h cortisol exposure . The mean weight ( difference = -0.7 kg , P = 0.005 ) , systolic blood pressure ( difference = -5.5 mm Hg , P = 0.0001 ) and diastolic blood pressure ( difference : -2.3 mm Hg ; P = 0.03 ) , and glycated hemoglobin ( absolute difference = -0.1 % , P = 0.0006 ) were all reduced after OD compared with TID at 12 wk . Compared with TID , a reduction in glycated hemoglobin by 0.6 % was observed in patients with concomitant DM during OD ( P = 0.004 ) . CONCLUSION The OD dual-release tablet provided a more circadian-based serum cortisol profile . Reduced body weight , reduced blood pressure , and improved glucose metabolism were observed during OD treatment . In particular , glucose metabolism improved in patients with concomitant DM Assessment of patients on steroid replacement therapy  is important to avoid the consequences of overtreatment such as osteoporosis . The aim of this prospect i ve study is to evaluate the severity and the etiology of osteopenia in 24 patients ( 15 women , 9 men ) with Addison 's disease receiving 30 mg hydrocortisone . Mean age of patients was 55 15 years .  Osteoporosis , diagnosed by the measurement of bone mineral density ( BMD ) at the level of lumbar spine and right hip , was found in 58 % of patients , i.e. in 10 women and 4 men . The latter had normal testosterone levels while seven women had an early menopause , the etiology of their Addison 's disease being autoimmune . Three were on hormonotherapy .  Correlations were found between BMD in the femoral neck and hip and the dose of hydrocortisone  ( mg/m(2)/day ; mg/kg/day ) , the duration of treatment and 24 hr-cortisoluria/g creatinine . Multivariate analysis shows that 24-hr cortisoluria/g creatinine is a good predictor of BMD values . Thus , osteoporosis is frequent in Addison 's disease and cortisoluria could be a useful tool to predict this complication OBJECTIVE Individuals with primary adrenal insufficiency ( PAI ) or congenital adrenal hyperplasia ( CAH ) receive life-long glucocorticoid ( GC ) replacement therapy . Current daily GC doses are still higher than the reported adrenal cortisol production rate . This GC excess could result in long-term morbidities such as osteoporosis . No prospect i ve trials have investigated the long-term effect of GC dose changes in PAI and CAH patients . METHODS This is a prospect i ve and longitudinal study including 57 subjects with PAI ( 42 women ) and 33 with CAH ( 21 women ) . Bone mineral density ( BMD ) was measured by dual energy X-ray absorptiometry at baseline and after 2 years . Subjects were divided into three groups ( similar baseline characteristics ) depending on changes in daily hydrocortisone equivalent dose ( group 1 : unchanged 25.2±8.2 mg ( mean±S.D. , n=50 ) ; group 2 : increased 18.7±10.3 to 25.9±12.0 mg ( n=13 ) ; group 3 : decreased 30.8±8.5 to 21.4±7.2 mg ( n=27 ) ) . RESULTS Subjects in group 1 showed normal lumbar and femoral Z-scores which were unchanged over time . Group 2 subjects showed a significant decrease in femoral neck Z-scores over time ( -0.15±1.1 to -0.37±1.0 ( P<0.05 ) ) , whereas group 3 subjects showed a significant increase in lumbar spine and hip Z-scores ( L1-L4 : -0 
    Output:
    
There was no significant association between dose and type of  GC  and the incidence of adrenal crises .
The effect on bone mineral density was heterogeneous .
Extended-/dual-release , and continuous subcutaneous forms of GC may be associated with higher QoL scores .