Dual-release Hydrocortisone Research Articles

Conventional steroids vs. dual-release hydrocortisone on metabolic, cardiovascular and bone outcomes in adrenal insufficiency: a 10-year study.

Adrenal insufficiency (AI) is characterized by increased mortality compared to general population, mainly due to cardiovascular disease. Conventional glucocorticoid (GC) replacement therapy has a role in determining the increased mortality risk. Primary outcome of the current study was to evaluate the impact of 10 years of conventional GCs and DR-HC on body weight changes in treatment-naïve patients with AI. Secondary outcomes were changes from baseline to 5 and 10 years in anthropometric and metabolic profile, insulin sensitivity, cardiovascular and bone parameters. We prospectively randomised 42 patients to conventional GCs (cortisone acetate or hydrocortisone) and 44 to DR-HC (1:1). Anthropometric, metabolic, cardiovascular and bone parameters were evaluated at baseline and after 5 and 10 years of follow-up. This trial is registered at ClinicalTrials.gov NCT06260462. At 10 years of follow-up, patients with conventional GCs had significantly higher values ​​of BMI (p=0.031), waist circumference (p=0.047), systolic blood pressure (p=0.039), total and LDL cholesterol (p=0.041 and p=0.042), HbA1c (p=0.040), HOMA-IR (p=0.006), AUC2h of glucose (p<0.001), thickness of the interventricular septum in diastole and of the posterior wall (both p<0.001) and significantly lower values ​​of oral disposition index (p=0.001) and ISI-Matsuda (p<0.001), lumbar spine T score (p=0.036) and femoral neck Z score (p=0.026), compared to patients treated with DR-HC. In patients with treatment-naïve AI, 10 years of conventional GC treatment is associated with a worsening of metabolic, insulin-sensitivity, cardiac and bone outcomes, while DR-HC had no impact on them achieving a lower risk of developing comorbidities.

Impact of 10 years of conventional steroids vs dual-release hydrocortisone on metabolic, cardiovascular, and bone outcomes in treatment-naive patients with adrenal insufficiency

Impact of 10 years of conventional steroids vs dual-release hydrocortisone on metabolic, cardiovascular, and bone outcomes in treatment-naive patients with adrenal insufficiency

Metabolic impact of dual-release hydrocortisone in patients with congenital adrenal syndrome: a retrospective study

Metabolic impact of dual-release hydrocortisone in patients with congenital adrenal syndrome: a retrospective study

Monitoring adrenal insufficiency through salivary steroids: a pilot study.

Various glucocorticoid replacement therapies (GRTs) are available for adrenal insufficiency (AI). However, their effectiveness in restoring glucocorticoid rhythm and exposure lacks adequate biochemical markers. We described the diurnal salivary cortisol (SalF) and cortisone (SalE) rhythm among different GRTs and analysed the associations between saliva-derived parameters and life quality questionnaires. Control subjects (CSs, n = 28) and AI patients receiving hydrocortisone (HC, n = 9), cortisone acetate (CA, n = 23), and dual-release hydrocortisone once (DRHC-od, n = 10) and twice a day (DRHC-td, n = 6) collected 9 saliva samples from 07:00 to 23:00. Patients compiled Pittsburgh Sleep Quality Index, Hospital Anxiety and Depression Scale, and Addison disease-specific quality-of-life questionnaires. SalE and SalF were measured by liquid chromatography-mass spectrometry. Exposure was monitored using SalE for HC and DRHC and SalF for CA. Area under the curve (AUC) was computed. Different GRTs were compared by Z-scores calculated from saliva-derived parameters. Questionnaire results predictors were evaluated with multiple regression analysis. Compared with controls, all GRTs resulted in glucocorticoid overexposure in the morning. Hydrocortisone, CA, and DRHC-td caused overexposure also in afternoon and evening. Compared with other treatments, CA determined increased Z-score-07:00 (P < .001), DRHC-td determined increased Z-score-AUC07:00→14:00 (P = .007), and DRHC-od induced lower Z-score-AUC14:00→23:00 (P = .015). Z-scores-AUC14:00→16:00 ≥ .619 best predicted questionnaire scores. None of the GRTs mimics normal glucocorticoid rhythmicity and exposure. SalE, SalF, and Z-score may be useful markers for monitoring and comparing different GRTs. Excess glucocorticoid in early afternoon best associated with depressive symptoms and worse life and sleep quality.

Exploring sexual function in adrenal insufficiency: findings from the Dual RElease hydrocortisone versus conventionAl glucocorticoid replaceMent therapy in hypocortisolism (DREAM) trial.

Data on sexual function in patients with adrenal insufficiency are scarce and largely controversial. To investigate sexual dysfunction in patients with primary and secondary adrenal insufficiency and the effects of switching to once-daily dual-release hydrocortisone on sexual function in outcome assessors blinded, randomized, multicenter, active comparator clinical trial. Eighty-nine adrenal insufficiency patients on conventional, multiple daily doses of glucocorticoid replacement, enrolled in the Dual RElease hydrocortisone versus conventionAl glucocorticoid replaceMent in hypocortisolism (DREAM) trial, were randomly assigned to continue their therapy or to switch to an equivalent dose of dual-release hydrocortisone. Sixty-three patients (34 women) consented to sex steroid measurements and questionnaires completion for quality of life (Addison's disease-specific quality-of-life questionnaire) and sexual function evaluation (female sexual function index for women, International Index of Erectile Function-Erectile Function for men) at baseline and 24weeks after randomization. At baseline, sexual dysfunction was observed in 41% of women and 59% of men with adrenal insufficiency. In both sexes, no associations were found between sexual function and hormone levels, whereas Addison's disease-specific quality-of-life questionnaire total and fatigue domain scores positively correlated with total female sexual function index and International Index of Erectile Function-Erectile Function scores. At 24weeks, there was no significant difference either in sexual function or sex steroid levels between study groups. In the dual-release hydrocortisone group, the variation in the female sexual function index desire domain score was positively associated with the change in Addison's disease-specific quality-of-life questionnaire's symptom domain score (ρ=0.478, p=0.045). Sexual dysfunction is common in adrenal insufficiency patients and is likely explained by multiple factors. dual-release hydrocortisone treatment is not directly associated with sexual function improvement, but an indirect effect mediated by quality-of-life amelioration cannot be excluded.

Dual-release hydrocortisone improves body composition and the glucometabolic profile in patients with secondary adrenal insufficiency

PurposeStudies have suggested improved metabolic profiles in patients with adrenal insufficiency treated with dual-release hydrocortisone (DR-HC) compared with conventional hydrocortisone (C-HC). This study investigates the effect of DR-HC compared with C-HC treatment on five health variables: diurnal salivary cortisol/cortisone, body composition, bone health, glucose metabolism, lipids, and blood pressure.MethodsProspective study of 27 participants (24 men) with secondary adrenal insufficiency with measurements during stable C-HC and 16 weeks after treatment switch to DR-HC.OutcomesDiurnal salivary-cortisol/cortisone, body composition assessed by Dual-Energy X-ray absorptiometry scan, bone status indices (serum type I N-terminal procollagen [PINP], collagen type I cross-linked C-telopeptide [CTX], osteocalcin, receptor activator kappa-B [RANK] ligand, osteoprotegerin, and sclerostin), lipids, haemoglobin A1c (HbA1c), and 24-hour blood pressure.ResultsAfter the switch to DR-HC, the diurnal salivary-cortisol area under the curve (AUC) decreased non-significantly (mean difference: −55.9 nmol/L/day, P = 0.06). The salivary-cortisone-AUC was unchanged. Late-evening salivary-cortisol and cortisone were lower (−1.6 and −1.7 nmol/L, P = 0.002 and 0.004). Total and abdominal fat mass (−1.5 and −0.5 kg, P = 0.003 and 0.02), HbA1c (−1.2 mmol/mol, P = 0.02), and osteocalcin decreased (−7.0 µg/L, P = 0.03) whereas sclerostin increased (+41.1 pg/mL, P = 0.0001). The remaining bone status indices, lipids, and blood pressure were unchanged.ConclusionThis study suggests that switching to DR-HC leads to lower late-evening cortisol/cortisone exposure and a more favourable metabolic profile and body composition. In contrast, decreased osteocalcin with increasing sclerostin might indicate a negative impact on bones.Clinical trial registrationEudraCT201400203932

Effects of Dual-Release Hydrocortisone on Bone Metabolism in Primary and Secondary Adrenal Insufficiency: A 6-Year Study.

Patients with primary (PAI) and secondary adrenal insufficiency (SAI) experience bone metabolism alterations, possibly due to excessive replacement. Dual-release hydrocortisone (DR-HC) has shown promising effects on several parameters, but bone metabolism has seldom been investigated. We evaluated the long-term effects of once-daily DR-HC on bone in PAI and SAI. Patients on immediate-release glucocorticoid therapy were evaluated before and up to 6 years (range, 4-6) after switching to equivalent doses of DR-HC, yielding data on bone turnover markers, femoral and lumbar spine bone mineral density (BMD), and trabecular bone score (TBS). Thirty-two patients (19 PAI, 18 female), median age 52 years (39.4-60.7), were included. At baseline, osteopenia was observed in 38% of patients and osteoporosis in 9%, while TBS was at least partially degraded in 41.4%. Higher body surface area-adjusted glucocorticoid doses predicted worse neck (P < .001) and total hip BMD (P < .001). Longitudinal analysis showed no significant change in BMD. TBS showed a trend toward decrease (P = .090). Bone markers were stable, albeit osteocalcin levels significantly varied. PAI and SAI subgroups behaved similarly, as did patients switching from hydrocortisone or cortisone acetate. Compared with men, women exhibited worse decline in TBS (P = .017) and a similar trend for neck BMD (P = .053). After 6 years of chronic DR-HC replacement, BMD and bone markers remained stable. TBS decline is more likely due to an age-related derangement of bone microarchitecture rather than a glucocorticoid effect. Our data confirm the safety of DR-HC replacement on bone health in both PAI and SAI patients.

SAT302 Circulating And Urinary Metabolites Associated With Total Exposure Of Cortisol And Cortisol Time Profile

Abstract Disclosure: J. McQueen: None. T. Garner: None. D. Chantzichristos: None. O. Ragnarsson: None. R. Bergthorsdottir: None. S. Skrtic: None. A. Stevens: None. G. Johannsson: None. The detrimental effects of excess cortisol exposure are well known, but the disruption of the circadian rhythm itself has also been associated with cardiometabolic and mental disorders. The aim of this study was to better understand these outcomes by identifying metabolites associated with total exposure of cortisol and cortisol time profile separately. This was a hypothesis-generating study using a randomized, two-armed, 12-week cross-over study comparing once-daily (OD) dual-release hydrocortisone tablet treatment with the same daily dose of thrice-daily (TID) conventional immediate-release hydrocortisone tablet treatment. Eighteen patients with primary adrenal insufficiency, who performed a full 24h in-house pharmacokinetic (PK) serum cortisol and urinary free cortisol (UFC) profiling, were included. The total exposure of cortisol was calculated by the area under the curve (AUC) of the observed cortisol concentration over 24h. To describe the variability of the cortisol time profile, the lag-1 autocorrelation (AUTO) of the cortisol concentration was calculated. Metabolites in serum and urine were analyzed using gas and liquid chromatography-mass spectrometry (GC-MS, LC-MS). Analyses were performed in negative and positive mode, and with targeted and untargeted approach. The relationship between AUC, AUTO and expression of metabolites was assessed using a Bayesian generalized linear model. The total exposure of cortisol was 20% higher during TID treatment. The AUTO was lower, reflecting a larger variability during TID compared to OD. In both serum and urine, a total of 775 metabolites were significantly associated with AUC and 479 with AUTO; 206 metabolites were overlapping and thus associated with both total exposure and the time profile. Serum GC-MS identified 55 metabolites correlated with AUC and 24 with AUTO. Among them, 12 metabolites were uniquely correlated with AUTO. Pathway analysis of these metabolites showed a high impact on the taurine and hypotaurine metabolism, and the primary bile acid biosynthesis. Pathway analysis on metabolites uniquely correlated with AUTO, identified in serum using LC-MS, also showed an impact on the primary bile acid biosynthesis, as well as the cysteine and methionine metabolism. Urinary metabolomics identified 21 metabolites correlated with AUC and 2 with AUTO. Pathway analysis of the metabolites in urine uniquely correlated with AUC, showed an impact on the ascorbate and aldarate metabolism, as well as the synthesis and degradation of ketone bodies. Our study identified circulating and urinary metabolites uniquely correlated with total exposure of cortisol and cortisol time profile, respectively. The study results therefore support that the total exposure and the time profile of cortisol may have different metabolic effects. The outcome of the study may be a step towards identifying novel biomarkers of the action of cortisol. Presentation: Saturday, June 17, 2023

Bone safety of dual-release hydrocortisone in patients with autoimmune primary adrenal insufficiency.

Conventional glucocorticoids (C-GC) replacement regimens have a detrimental effect on skeletal health in patients with adrenal insufficiency (AI), ultimately leading to an increased fracture risk. The novel dual-release hydrocortisone (DR-HC) formulations are characterized by a more favourable safety profile on various clinical endpoints. Data comparing the impact of C-GC and DR-HC on bone, however, are scarce. Twenty-seven patients with autoimmune primary AI (PAI; 13 treated with C-GC and 14 treated with DR-HC) were evaluated to compare bone-related parameters between the two treatment groups. No significant differences between the two treatments groups were observed with respect to bone turnover markers. Patients treated with C-GC showed a lower bone mineral density (BMD) at lumbar spine (LS; 0.791 ± 0.195 vs. 0.942 ± 0.124 g/cm2, p=0.025) and at femoral neck (FN; 0.633 ± 0.114 vs. 0.716 ± 0.088 g/cm2, p=0.045). Moreover, they were characterized by a lower trabecular bone score (TBS; 1.236 ± 0.035 vs. 1.383 ± 0.030, p=0.004) and by a higher mean number of vertebral fractures per patient (0.75 vs. 0 fractures, p=0.002). TBS was the best predictor of fracture risk, with a pseudo-R2 of 0.593; moreover, at mediation analysis, it was able to fully explain the observed detrimental effect of C-GC, compared to DR-HC, on fracture risk. These results suggest that DR-HC is associated with less bone-related complications compared to C-GC in patients with PAI. Moreover, TBS seems to play a pivotal role in the mediation of the relationship between glucocorticoid treatment regimens and fracture risk.

Tissue Glucocorticoid Metabolism in Adrenal Insufficiency: A Prospective Study of Dual-release Hydrocortisone Therapy.

Patients with adrenal insufficiency (AI) require life-long glucocorticoid (GC) replacement therapy. Within tissues, cortisol (F) availability is under the control of the isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD). We hypothesize that corticosteroid metabolism is altered in patients with AI because of the nonphysiological pattern of current immediate release hydrocortisone (IR-HC) replacement therapy. The use of a once-daily dual-release hydrocortisone (DR-HC) preparation, (Plenadren®), offers a more physiological cortisol profile and may alter corticosteroid metabolism in vivo. Prospective crossover study assessing the impact of 12 weeks of DR-HC on systemic GC metabolism (urinary steroid metabolome profiling), cortisol activation in the liver (cortisone acetate challenge test), and subcutaneous adipose tissue (microdialysis, biopsy for gene expression analysis) in 51 patients with AI (primary and secondary) in comparison to IR-HC treatment and age- and BMI-matched controls. Patients with AI receiving IR-HC had a higher median 24-hour urinary excretion of cortisol compared with healthy controls (72.1 µg/24 hours [IQR 43.6-124.2] vs 51.9 µg/24 hours [35.5-72.3], P = .02), with lower global activity of 11β-HSD2 and higher 5-alpha reductase activity. Following the switch from IR-HC to DR-HC therapy, there was a significant reduction in urinary cortisol and total GC metabolite excretion, which was most significant in the evening. There was an increase in 11β-HSD2 activity. Hepatic 11β-HSD1 activity was not significantly altered after switching to DR-HC, but there was a significant reduction in the expression and activity of 11β-HSD1 in subcutaneous adipose tissue. Using comprehensive in vivo techniques, we have demonstrated abnormalities in corticosteroid metabolism in patients with primary and secondary AI receiving IR-HC. This dysregulation of pre-receptor glucocorticoid metabolism results in enhanced glucocorticoid activation in adipose tissue, which was ameliorated by treatment with DR-HC.

Bone metabolism and dual-release Hydrocortisone: results from a real-life study

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

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.

Benefits of dual-release hydrocortisone treatment on central adiposity and health-related quality of life in secondary adrenal insufficiency

PurposePatients with secondary adrenal insufficiency (SAI) have an increased morbidity and an impaired health-related quality of life (HRQoL), which seems to primarily depend on the sub-optimal replacement of hypoadrenalism with standard glucocorticoid (GC) therapy, and on the inadequate correction of other associated pituitary deficiencies. A dual-release hydrocortisone (DR-HC) formulation has shown to exert positive effects on morbidity and HRQoL, mainly in patients with primary adrenal insufficiency. We assessed the variations of anthropometric and metabolic parameters and HRQoL in patients with SAI after switching from cortisone acetate (CA) or hydrocortisone (HC) to DR-HC.MethodsTwenty-one patients (17 M, 4 F) treated with CA (n = 16; 25 mg/day twice a day) or HC (n = 5; 20 mg/day three times a day), were evaluated for waist circumference, BMI, fasting glucose, HbA1c, insulin, HOMA-IR index, serum lipids, electrolytes, blood pressure and HRQoL at baseline, at 3, 6 and 12 months after switching from CA/HC to DR-HC.ResultsThe study showed a significant reduction of waist circumference and BMI (p = 0.04, for both), after 3 and 6months of DR-HC treatment, respectively. No significant changes were observed for fasting glucose, insulin, HOMA-IR index, HbA1c, total cholesterol, triglycerides, LDL cholesterol, electrolytes, and blood pressure. However, HDL cholesterol significantly decreased (p = 0.003). An improvement of AddiQoL total score was observed during DR-HC treatment (p = 0.01), mainly for the category “emotions”. No predictors resulted for these changes.ConclusionDR-HC treatment provides some benefits in patients with SAI, reducing central adiposity and improving HRQoL; however, worsening of HDL cholesterol is observed during treatment with DR-HC.

Bone metabolism and dual-release Hydrocortisone: results from a real-life study

Bone metabolism and dual-release Hydrocortisone: results from a real-life study

Long-term outcomes of conventional and novel steroid replacement therapy on bone health in primary adrenal insufficiency

Steroids affect bone health causing osteoporosis and fractures. The study aims to compare dual-release hydrocortisone (DR-HC) and conventional steroids on bone metabolism in patients with primary adrenal insufficiency (PAI). Thirty-five patients with PAI on conventional steroids (group A) and 35 patients switched to DR-HC (group B), consecutively referred at our hospital, were evaluated at baseline and after 18, 36 and 60 months of treatment. After 60 months of follow-up, patients in group A had a significant increase in body mass index (p = 0.004) and waist circumference (WC) (p = 0.026) and a significant decrease in osteocalcin (p = 0.002), bone alkaline phosphatase (p = 0.029), lumbar spine bone mass density (BMD) T and Z scores (p < 0.001 and p = 0.001, respectively) and vertebral fractures rate (p = 0.021) than baseline. By contrast, patients in group B had a significant decrease in WC (p = 0.047) and increase in bone alkaline phosphatase (p = 0.019), lumbar spine BMD T score (p = 0.032), femoral neck BMD T and Z scores (p = 0.023 and p = 0.036, respectively) than baseline. Long-term conventional steroid replacement therapy is associated with a decrease in BMD, notably at lumbar spine, and increase in vertebral fractures rate. By contrast, DR-HC treatment is associated with improvement of BMD.

Improved urinary cortisol metabolome in addison disease: A prospective trial of dual-release hydrocortisone

CONTEXT: Oral once-daily dual-release hydrocortisone (DR-HC) replacement therapy has demonstrated an improved metabolic profile compared to conventional 3-times-daily (TID-HC) therapy among patients with primary adrenal insufficiency. This effect might be related to a more physiological cortisol profile, but also to a modified pattern of cortisol metabolism. OBJECTIVE: This work aimed to study cortisol metabolism during DR-HC and TID-HC. DESIGN: A randomized, 12-week, crossover study was conducted. INTERVENTION AND PARTICIPANTS: DC-HC and same daily dose of TID-HC were administered to patients with primary adrenal insufficiency (n = 50) vs healthy individuals (n = 124) as controls. MAIN OUTCOME MEASURES: Urinary corticosteroid metabolites were measured by gas chromatography/mass spectrometry at 24-hour urinary collections. RESULTS: Total cortisol metabolites decreased during DR-HC compared to TID-HC (P < .001) and reached control values (P = .089). During DR-HC, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity measured by tetrahydrocortisol + 5α-tetrahydrocortisol/tetrahydrocortisone ratio was reduced compared to TID-HC (P < .05), but remained increased vs controls (P < .001). 11β-HSD2 activity measured by urinary free cortisone/free cortisol ratio was decreased with TID-HC vs controls (P < .01) but normalized with DR-HC (P = .358). 5α- and 5β-reduced metabolites were decreased with DR-HC compared to TID-HC. Tetrahydrocortisol/5α-tetrahydrocortisol ratio was increased during both treatments, suggesting increased 5β-reductase activity. CONCLUSIONS: The urinary cortisol metabolome shows striking abnormalities in patients receiving conventional TID-HC replacement therapy, with increased 11β-HSD1 activity that may account for the unfavorable metabolic phenotype in primary adrenal insufficiency. Its change toward normalization with DR-HC may mediate beneficial metabolic effects. The urinary cortisol metabolome may serve as a tool to assess optimal cortisol replacement therapy.

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A Prospective Cross-Over Study of Tissue Glucocorticoid Metabolism in Patients With Adrenal Insufficiency: The Effects of Dual-Release Hydrocortisone Therapy

Background: Patients with adrenal insufficiency (AI) require life-long glucocorticoid (GC) replacement therapy. Within tissues, cortisol (F) availability is under the control of the isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD). We hypothesize that GC metabolism is altered in patients with AI due to the non-physiological pattern of current immediate-release hydrocortisone (IR-HC) replacement therapy. The use of once-daily dual-release hydrocortisone (DR-HC) preparation (Plenadren®) offers a more physiological cortisol profile and may alter GC metabolism in vivo.Study Design and Methods: Prospective cross-over study assessing impact of 12 weeks of DR-HC on tissue GC metabolism (using urinary steroid metabolomics, serum cortisol generation curves and adipose tissue biopsies) in 51 patients with AI (primary and secondary) and compared to age-and BMI-matched controls. Results: Patients with AI (n=51) receiving immediate-release HC (IR-HC) had a higher median 24-hour excretion of urinary cortisol compared to healthy controls [72.1µg/24hrs (IQR 43.6–124.2) vs 51.85 (35.5–72.3), p=0.02],with a lower global activity of 11β-HSD2 and higher activity of 5-alpha reductase. Following the switch from IR-HC to DR-HC therapy, there was a significant reduction in urinary F and total GC metabolite excretion, which was most significant in the evening on diurnal urine sampling. There was an increase in global 11β-HSD2 activity. Hepatic 11β-HSD1 activity was not significantly altered post-DR-HC but there was a significant reduction in gene expression of 11β-HSD1 in subcutaneous adipose tissue. Conclusion: Using comprehensive in-vivo techniques we have demonstrated significant abnormalities in glucocorticoid metabolism in patients with AI. This is driven by dysregulation in the pre-receptor enzyme activity controlling tissue-specific GC availability, which can be improved following treatment with DR-HC.

Dual-release hydrocortisone and its benefits on cognitive function and quality of sleep.

Patients with adrenal insufficiency are usually treated with conventional hydrocortisone replacement therapy which fails to mimic the circadian rhythm of cortisol secretion. Dual-release hydrocortisone (DR-HC) resembles the daily normal cortisol profile improving metabolic parameters and quality of life. However, currently little is known about its impact on cognitive function. Aim of this study was to evaluate cognitive function and well-being in DR-HC treated patients compared to healthy controls and conventional HC treatment. Twenty adults with adrenal insufficiency treated with DR-HC (Plenadren®) underwent 10 neuropsychological tests, evaluating cognitive functions. Furthermore, demographic data, quality of life, symptoms of depression, and quality of sleep were evaluated by well-established questionnaires. Patients were compared by diagnosis (PAI/SAI) and dose (≥20 mg). In addition, eighteen DR-HC treated adults were compared to eighteen matched conventionally treated adults. With respect to diagnosis patients with PAI performed significantly better on intellectual abilities (p = 0.038) and on executive functioning (p = 0.026) and reported a significant longer time to fall asleep (p = 0.026). Regarding DR-HC dosage, there were no significant differences in cognitive functions. Patients on high dose reported a better subjective quality of sleep (p = 0.028) than patients on low dose. In comparison to conventional HC treatment, patients with DR-HC tended to show better results in executive functioning (p = 0.099). Patients with PAI reached better results in several cognitive functions and had a worse quality of sleep than patients with SAI. Our data suggest a positive impact of DR-HC on quality of sleep. DR-HC may be better for executive functioning.

Switching From Immediate-Release to Fractionated Dual-Release Hydrocortisone May Improve Metabolic Control and QoL in Selected Primary Adrenal Insufficiency Patients.

ObjectiveThe use of once-daily dual-release HC (DR-HC) in primary adrenal insufficiency (PAI) is often associated with benefits in metabolic parameters when compared to immediate-release HC (IR-HC). In this study, we evaluated the effects on clinical, biochemical and metabolic parameters of switching from IR-HC to lower-dose DR-HC given both in once and fractionated daily doses.MethodsTwenty autoimmune-PAI subjects were included. Patients on 30 mg/day divided in three doses IR-HC regimen (group A) were switched to DR-HC 25 mg/day given in two daily doses (20 mg in the morning and 5 mg at 2.00 p.m.); patients on 25 mg/day divided in two doses IR-HC regimen (group B) were switched to DR-HC 20 mg once daily. Biochemical and metabolic parameters, BMI and quality of life (QoL) were evaluated at the baseline and six months after the switch.ResultsOur small non-randomized study with short follow up showed significant benefits in both group A and group B without any apparent side-effects. After the switch to DR-HC, a significant decrease in adrenocorticotropic hormone (ACTH), HbA1c, total cholesterol, triglycerides, LDL, cholesterol, BMI as well as a significant improvement in QoL, were observed in both groups. At 6 months, ACTH levels were lower in group A while HbA1C and total cholesterol were lower in group B.ConclusionThe DR-HC is a valid and effective therapeutic strategy to improve the metabolic control and the QoL in PAI. The reduction of ACTH levels with DR-HC regimens reflects a better biochemical control of PAI, obtained by using a lower dose and more physiological HC formulation. Both once-daily and fractionated daily doses of DR-HC showed advantages compared with IR-HC formulation.