Residual endogenous corticosteroid production in patients with adrenal insufficiency

Objective This study aimed at comparing precursors of endogenous corticosteroid production in patients with primary adrenal insufficiency and in secondary adrenal insufficiency. Design Twenty 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 measurements Patients 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/MS Results Compared 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 conce ntrations. 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. Conclusions Adrenal 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

Cardiovascular risk factors in patients with Addison's disease: a comparative study of South African and Swedish patients

BACKGROUND: Patients with Addison's disease (AD) in Scandinavia have an increased risk for premature death due to cardiovascular disease (CVD). Serum lipids are important risk factors for CVD and vascular mortality. Replacement doses of hydrocortisone have historically been higher in Sweden than South Africa. The primary aim was to study the lipid profiles in a large group of patients with AD with the hypothesis that the lipid profile in patients in Sweden would be worse than in South Africa. METHODS: In a cross-sectional study, 110 patients with AD (55 from South Africa, 55 from Sweden) matched for age, gender, ethnicity and BMI were studied. Anthropometric measures, blood pressure, lipids, highly sensitive C-reactive protein (hs-CRP) and adiponectin were studied. RESULTS: All patients were Caucasian and the majority were women N = 36 (65.5%). Mean (standard deviation; SD) ages of the Swedish and South African patients were 52.9 (13.0) and 52.6 (14.4) years and BMI 25.3 (3.2) and 25.8 (4.1) kg/m 2 , respectively. The mean total daily hydrocortisone dose was greater in the Swedish patients than the South African patients, [33.0 (8.1) versus 24.3 (8.0) mg; p<0.0001]. South African patients had higher median (interquartilerange; IQR) triglycerides (TG) [1.59 (1.1-2.46) versus 0.96 (0.74-1.6) mmol/l; p<0.001], total cholesterol (TC) [6.02(1.50) versus 5.13 (0.87) mmol/l; p<0.001], LDL-C [4.43 (1.44) versus 2.75 (0.80) mmol/l; p<0.001] and median hs-CRP [2.15 (0.93-5.45) versus 0.99 (0.57-2.10) mg/L; p<0.003] and lower HDL-C [0.80 (0.40) versus 1.86 (0.46) mmol/l; p<0.001] than the Swedish patients. Approximately 20% of the patients in both cohorts had hypertension and diabetes mellitus. CONCLUSIONS: South African patients with AD have worse lipid profiles and higher hs-CRP compared to their matched Swedish patients, despite lower doses of hydrocortisone. It is uncertain at this time whether these are due to genetic or environmental factors

An oral multiparticulate, modified-release, hydrocortisone replacement therapy that provides physiological cortisol exposure

Objective It is not possible with current hydrocortisone replacement to mimic the diurnal cortisol profile in patients with adrenal insufficiency. Previous attempts with modified-release technology were unsuccessful. Our objective was to develop hydrocortisone formulations that recreate the diurnal cortisol profile using multiparticulate technology. Design and Measurements Screening by in vitro dissolution profiles, pharmacokinetic (PK) testing in dexamethasone-suppressed dogs and humans, and comparison with a reference population. Setting Field laboratories and clinical research facility. Results Formulations were generated using an enteric (delayed release) design configuration with an extended (sustained release) dissolution profile. In vitro dissolution confirmed delayed and sustained hydrocortisone release. However, in dogs and humans, sustained release resulted in reduced bioavailability. A formulation, DIURF-006, was developed that maintained delayed release but omitted the sustained-release functionality. PK characterization of DIURF-006 showed that, despite absence of a sustained-release component, absorption was sufficiently sustained to deliver extended hydrocortisone absorption. In dexamethasone-suppressed volunteers (n = 16) receiving a twice-daily ‘toothbrush’ regimen (20 mg at 23:00 h and 10 mg at 07:00 h), DIURF-006 gave a similar cortisol profile to physiological cortisol levels: DIURF-006 vs physiological, Geomean AUC 5610 vs 4706 h * nmol/l, Geomean Cmax 665 vs 594 nmol/l and Median Tmax 8·5 h vs clock time 08:12 h for peak cortisol. The relative bioavailability of DIURF-006 vs hydrocortisone was 89%, and cortisol levels increased linearly with doses between 5 and 30 mg. Conclusion A multiparticulate oral hydrocortisone formulation with only an enteric coat provides delayed and sustained absorption and when given in a ‘toothbrush’ regimen provides physiological cortisol exposure

Improved Cortisol Exposure-Time Profile and Outcome in Patients with Adrenal Insufficiency: A Prospective Randomized Trial of a Novel Hydrocortisone Dual-Release Formulation.

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, randomized, 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

Acute interaction between hydrocortisone and insulin alters the plasma metabolome in humans

With the aim of identifying biomarkers of glucocorticoid action and their relationship with biomarkers of insulin action, metabolomic profiling was carried out in plasma samples from twenty healthy men who were administered either a low or medium dose insulin infusion (n = 10 each group). In addition, all subjects were given metyrapone (to inhibit adrenal cortisol secretion) +/-hydrocortisone (HC) in a randomised crossover design to produce low, medium and high glucocorticoid levels. The clearest effects of insulin were to reduce plasma levels of the branched chain amino acids (BCAs) leucine/isoleucine and their deaminated metabolites, and lowered free fatty acids and acylcarnitines. The highest dose of hydrocortisone increased plasma BCAs in both insulin groups but increased free fatty acids only in the high insulin group, however hydrocortisone did not affect the levels of acyl carnitines in either group. The clearest interaction between HC and insulin was that hydrocortisone produced an elevation in levels of BCAs and their metabolites which were lowered by insulin. The direct modulation of BCAs by glucocorticoids and insulin may provide the basis for improved in vivo monitoring of glucocorticoid and insulin action

Modified-release hydrocortisone to provide circadian cortisol profiles

Context: Cortisol has a distinct circadian rhythm regulated by the brain's central pacemaker. Loss of this rhythm is associated with metabolic abnormalities, fatigue, and poor quality of life. Conventional glucocorticoid replacement cannot replicate this rhythm. Objectives: Our objectives were to define key variables of physiological cortisol rhythm, and by pharmacokinetic modeling test whether modified-release hydrocortisone (MR-HC) can provide circadian cortisol profiles. Setting: The study was performed at a Clinical Research Facility. Design and Methods: Using data from a cross-sectional study in healthy reference subjects (n = 33), we defined parameters for the cortisol rhythm. We then tested MR-HC against immediate-release hydrocortisone in healthy volunteers (n = 28) in an open-label, randomized, single-dose, cross-over study. We compared profiles with physiological cortisol levels, and modeled an optimal treatment regimen. Results: The key variables in the physiological cortisol profile included: peak 15.5 mu g/dl (95% reference range 11.7-20.6), acrophase 0832 h(95% confidence interval 0759-0905), nadir less than 2 mu g/dl (95% reference range 1.5-2.5), time of nadir 0018 h (95% confidence interval 2339-0058), and quiescent phase (below the mesor) 1943-0531 h. MR-HC 15 mg demonstrated delayed and sustained release with a mean (SEM) maximum observed concentration of 16.6 (1.4) mu g/dl at 7.41 (0.57) h after drug. Bioavailability of MR-HC 5, 10, and 15 mg was 100, 79, and 86% that of immediate-release hydrocortisone. Modeling suggested that MR-HC 15-20 mg at 2300 h and 10 mg at 0700 h could reproduce physiological cortisol levels. Conclusion: By defining circadian rhythms and using modern formulation technology, it is possible to allow a more physiological circadian replacement of cortisol. (J Clin Endocrinol Metab 94: 1548-1554, 2009

Adult Patients with Congenital Adrenal Hyperplasia Have Elevated Blood Pressure but Otherwise a Normal Cardiovascular Risk Profile

Contains fulltext : 96615.pdf (publisher's version ) (Open Access)OBJECTIVE: Treatment with glucocorticoids and mineralocorticoids has changed congenital adrenal hyperplasia (CAH) from a fatal to a chronic lifelong disease. Long-term treatment, in particular the chronic (over-)treatment with glucocorticoids, may have an adverse effect on the cardiovascular risk profile in adult CAH patients. The objective of this study was to evaluate the cardiovascular risk profile of adult CAH patients. DESIGN: Case-control study. PATIENTS AND MEASUREMENTS: In this case-control study the cardiovascular risk profile of 27 adult CAH patients and 27 controls, matched for age, sex and body mass index was evaluated by measuring ambulatory 24-hour blood pressure, insulin sensitivity (HOMA-IR), lipid profiles, albuminuria and circulating cardiovascular risk markers (PAI-1, tPA, uPA, tPA/PAI-1 complex, hsCRP, adiponectin, IL-6, IL-18 and leptin). RESULTS: 24-Hour systolic (126.3 mmHg+/-15.5 vs 124.8 mmHg+/-15.1 in controls, P = 0.019) and diastolic (76.4 mmHg+/-12.7 vs 73.5 mmHg+/-12.4 in controls, P<0.001) blood pressure was significantly elevated in CAH patients compared to the control population. CAH patients had higher HDL cholesterol levels (P<0.01), lower hsCRP levels (P = 0.03) and there was a trend toward elevated adiponectin levels compared to controls. Other cardiovascular risk factors were similar in both groups. CONCLUSION: Adult CAH patients have higher ambulatory blood pressure compared to healthy matched controls. Other cardiovascular risk markers did not differ, while HDL-cholesterol, hsCRP and adiponectin levels tended to be more favorable

Addison's disease symptoms - a cross sectional study in urban South Africa

BACKGROUND: Addison's disease is a potentially life-threatening disorder, and prompt diagnosis, and introduction of steroid replacement has resulted in near normal life-expectancy. There are limited data describing the clinical presentation of Addison's disease in South Africa. It is hypothesised that patients may present in advanced state of ill-health, compared to Western countries. Patients A national database of patients was compiled from primary care, referral centres and private practices. 148 patients were enrolled (97 white, 34 mixed ancestry, 5 Asian and 12 black). METHODS: Demographic and clinical data were elicited using questionnaires. Biochemical data were obtained from folder reviews and laboratory archived results. RESULTS: The majority of the cohort was women (62%). The median and inter-quartile age range (IQR) of patients at enrolment was 46.0 (32.0-61.0) years, with a wide range from 2.8-88.0 years. The median and IQR age at initial diagnosis was 34.0 (20.0-45.0) years (range 0.02-77.0) years, indicating that at the time of enrolment, the patients, on average, were diagnosed with Addison's disease 12 years previously. Hyperpigmentation was observed in 76%, nausea and vomiting occurred in more than 40%, and weight loss was noted in 25%. Loss of consciousness as a presenting feature was recorded in 20 %. with a 95% confidence interval [CI] of (14-28%) and shock occurred in 5% CI (1.5-8.5%). Case-finding was recorded at 3.1 per million. CONCLUSIONS: The usual constellation of hyperpigmentation, nausea, vomiting and weight loss suggests Addison's disease, but a significant proportion present with an advanced state of ill-health and Addisonian crises. A lower prevalence rate, compared to Western countries is suggested