Gudmundur Johannsson, Ragnhildur Bergthorsdottir, Anna G Nilsson, Hans Lennernas, Thomas Hedner and Stanko Skrtic
Endogenous plasma cortisol levels have a well-defined circadian rhythm. The aim of this project is to develop a once daily oral dual-release formulation for cortisol replacement therapy that mimics the diurnal variation in the plasma cortisol profile.
To determine single-dose plasma pharmacokinetics and dose-proportionality of oral 5 and 20 mg dual-release hydrocortisone tablets in healthy volunteers. In addition, the effect of food intake was investigated for the 20 mg dose.
A randomised, controlled, two-way cross-over, double-blind, phase I study of oral hydrocortisone (modified (dual) release; 5 and 20 mg) with an open food-interaction arm.
The single dose pharmacokinetic studies were performed with betamethasone suppression. The two first study days were blinded and randomised between morning administration of 5 and 20 mg tablet in a fasting state. The third day was open with a 20 mg tablet taken 30 min after a high-calorie, high-fat meal. The plasma samples were assayed using both a validated LC–MS/MS and an immunoassay. The plasma pharmacokinetic variables were calculated using non-compartmental data analysis.
The time to reach a clinically significant plasma concentration of cortisol (>200 nmol/l) was within 20 min and a mean peak of 431 (s.d. 126) nmol/l was obtained within 50 min after administration of the 20 mg tablet. Plasma cortisol levels remained above 200 nmol/l for around 6 h thereafter and all plasma concentrations 18–24 h after intake were below 50 nmol/l. In the fed state the time to reach 200 nmol/l was delayed by 28 and 9 min based on LC–MS/MS and immunoassay, respectively. The 5 and 20 mg tablets produced an increase in plasma exposure of cortisol that was not fully dose proportional.
The dual release hydrocortisone tablet with once-daily administration produced a diurnal plasma cortisol profile mimicking the physiological serum cortisol profile.
Camilla A M Glad, Edna J L Barbosa, Helena Filipsson Nyström, Lena M S Carlsson, Staffan Nilsson, Anna G Nilsson, Per-Arne Svensson and Gudmundur Johannsson
GH-deficient (GHD) adults have reduced serum concentrations of IGF1. GH replacement therapy increases serum IGF1 concentrations, but the interindividual variation in treatment response is large and likely influenced by genetic factors. This study was designed to test the hypothesis that single-nucleotide polymorphisms (SNPs) in genes within the GH signaling pathway influence the serum IGF1 response to GH replacement.
Design and methods
A total of 313 consecutive GHD adults (58.1% men; mean age 49.7 years) were studied before and after 1 week, 6 months, and 1 year of GH treatment. GH dose was individually titrated to normalize serum IGF1 levels. Six SNPs in the GH receptor (GHR) and the GH signaling pathway (JAK2, STAT5B, SOCS2, and PIK3CB) genes were selected for genotyping. The GHR exon 3-deleted/full-length (d3/fl) polymorphism was analyzed using tagSNP rs6873545.
After 1 week of GH replacement, homozygotes of the fl-GHR showed a better IGF1 response to GH than carriers of the d3-GHR (P=0.016). Conversely, homozygotes of the minor allele of PIK3CB SNP rs361072 responded better than carriers of the major allele (P=0.025). Compared with baseline, both SNPs were associated with the IGF1 response at 6 months (P=0.041 and P=0.047 respectively), and SNP rs6873545 was further associated with the IGF1 response at 1 year (P=0.041).
Our results indicate that common genetic variants in the GH signaling pathway may be of functional relevance to the response to GH replacement in GHD adults.
Casper Hammarstrand, Oskar Ragnarsson, Tobias Hallén, Eva Andersson, Thomas Skoglund, Anna G Nilsson, Gudmundur Johannsson and Daniel S Olsson
Patients with secondary adrenal insufficiency (AI) have an excess mortality. The objective was to investigate the impact of the daily glucocorticoid replacement dose on mortality in patients with hypopituitarism due to non-functioning pituitary adenoma (NFPA).
Patients with NFPA were followed between years 1997 and 2014 and cross-referenced with the National Swedish Death Register. Standardized mortality ratio (SMR) was calculated with the general population as reference and Cox-regression was used to analyse the mortality.
The analysis included 392 patients (140 women) with NFPA. Mean ± s.d. age at diagnosis was 58.7 ± 14.6 years and mean follow-up was 12.7 ± 7.2 years. AI was present in 193 patients, receiving a mean daily hydrocortisone equivalent (HCeq) dose of 20 ± 6 mg. SMR (95% confidence interval (CI)) for patients with AI was similar to that for patients without, 0.88 (0.68–1.12) and 0.87 (0.63–1.18) respectively. SMR was higher for patients with a daily HCeq dose of >20 mg (1.42 (0.88–2.17)) than that in patients with a daily HCeq dose of 20 mg (0.71 (0.49–0.99)), P = 0.017. In a Cox-regression analysis, a daily HCeq dose of >20 mg was independently associated with a higher mortality (HR: 1.88 (1.06–3.33)). Patients with daily HCeq doses of ≤20 mg had a mortality risk comparable to patients without glucocorticoid replacement and to the general population.
Patients with NFPA and AI receiving more than 20 mg HCeq per day have an increased mortality. Our data also show that mortality in patients substituted with 20 mg HCeq per day or less is not increased.
Anna G Nilsson, Ragnhildur Bergthorsdottir, Pia Burman, Per Dahlqvist, Bertil Ekman, Britt Edén Engström, Oskar Ragnarsson, Stanko Skrtic, Jeanette Wahlberg, Heinrich Achenbach, Sharif Uddin, Claudio Marelli and Gudmundur Johannsson
To investigate the long-term safety and tolerability of a once-daily, dual-release hydrocortisone (DR-HC) tablet as oral glucocorticoid replacement therapy in patients with primary adrenal insufficiency (AI).
Prospective, open-label, multicenter, 5-year extension study of DR-HC conducted at five university clinics in Sweden.
Seventy-one adult patients diagnosed with primary AI who were receiving stable glucocorticoid replacement therapy were recruited. Safety and tolerability outcomes included adverse events (AEs), intercurrent illness episodes, laboratory parameters and vital signs. Quality of life (QoL) was evaluated using generic questionnaires.
Total DR-HC exposure was 328 patient-treatment years. Seventy patients reported 1060 AEs (323 per 100 patient-years); 85% were considered unrelated to DR-HC by the investigator. The most common AEs were nasopharyngitis (70%), fatigue (52%) and gastroenteritis (48%). Of 65 serious AEs reported by 32 patients (20 per 100 patient-years), four were considered to be possibly related to DR-HC: acute AI (n = 2), gastritis (n = 1) and syncope (n = 1). Two deaths were reported (fall from height and subarachnoid hemorrhage), both considered to be unrelated to DR-HC. From baseline to 5 years, intercurrent illness episodes remained relatively stable (mean 2.6–5.4 episodes per patient per year), fasting plasma glucose (0.7 mmol/L; P < 0.0001) and HDL cholesterol (0.2 mmol/L; P < 0.0001) increased and patient-/investigator-assessed tolerability improved. QoL total scores were unchanged but worsening physical functioning was recorded (P = 0.008).
In the first prospective study evaluating the long-term safety of glucocorticoid replacement therapy in patients with primary AI, DR-HC was well tolerated with no safety concerns observed during 5-year treatment.
Daniel S Olsson, Penelope Trimpou, Tobias Hallén, Ing-Liss Bryngelsson, Eva Andersson, Thomas Skoglund, Bengt-Åke Bengtsson, Gudmundur Johannsson and Anna G Nilsson
Hypopituitarism has been associated with increased mortality. The excess mortality may be due to untreated growth hormone (GH) deficiency but also due to various underlying disorders. We therefore analysed mortality in patients with only one underlying disorder, non-functioning pituitary adenoma (NFPA), with and without GH replacement therapy (GHRT).
Design and method
Patients with NFPA in the western region of Sweden, 1997–2011, were identified through the National Patient Registry and cross-referenced with several National Health Registries. All patient records were reviewed. Standardised mortality ratios (SMRs) with 95% confidence intervals (CIs) were calculated using the general population as reference. Cox-regression models were performed to identify predictors of mortality.
A total of 426 NFPA patients with 4599 patient-years were included, of whom 207 had used GHRT and 219 had not received GHRT. Median (range) follow-up in patients with and without GHRT was 12.2 (0–25) and 8.2 (0–27) years, respectively. Other pituitary hormone deficiencies were more frequent in the GHRT group than those in the non-GHRT group. SMR was 0.65 (95% CI, 0.44–0.94; P = 0.018) for the GHRT group and 1.16 (0.94–1.42; P = 0.17) for the non-GHRT group. Direct comparison between the groups showed reduced mortality among those who were GH replaced (P = 0.0063). The SMR for malignant tumours was reduced in the GHRT-group (0.29; 0.08–0.73; P = 0.004) but not in untreated patients.
Selection bias explaining some of the results cannot be excluded. However, NFPA patients with GHRT had reduced overall mortality compared with the general population, and death due to malignancy was not increased. This suggests that long-term GHRT is safe in adult patients selected for treatment.
Edna J L Barbosa, Camilla A M Glad, Anna G Nilsson, Helena Filipsson Nyström, Galina Götherström, Per-Arne Svensson, Isabela Vinotti, Bengt-Åke Bengtsson, Staffan Nilsson, Cesar Luiz Boguszewski and Gudmundur Johannsson
GH deficiency (GHD) in adults is associated with an altered serum lipid profile that responds to GH replacement therapy (GHRT). This study evaluated the influence of polymorphisms in genes related to lipid metabolism on serum lipid profile before and after 1 year of GHRT in adults.
Design and methods
In 318 GHD patients, total cholesterol (TC) serum concentrations, LDL-C, HDL-C, and triglycerides (TG) were assessed. Using a candidate gene approach, 20 single nucleotide polymorphisms (SNPs) were genotyped. GH dose was individually titrated to obtain normal serum IGF1 concentrations.
At baseline, the minor alleles of cholesteryl ester transfer protein (CETP) gene SNPs rs708272 and rs1800775 were associated with higher serum TC and apolipoprotein E (APOE) gene SNP rs7412 with lower TC concentrations; CETP SNPs rs708272, rs1800775, and rs3764261 and apolipoprotein B (APOB) gene SNP rs693 with higher serum HDL-C; APOE SNP rs7412, peroxisome proliferator-activated receptor gamma (PPARG) gene SNP rs10865710 with lower LDL-C, and CETP SNP rs1800775 with higher LDL-C; and APOE/C1/C4/C2 cluster SNP rs35136575 with lower serum TG. After treatment, APOB SNP rs676210 GG genotype was associated with larger reductions in TC and LDL-C and PPARG SNP rs10865710 CC genotype with greater TC reduction. All associations remained significant when adjusted for age, sex, and BMI.
In GHD adults, multiple SNPs in genes related to lipid metabolism contributed to individual differences in baseline serum lipid profile. The GH treatment response in TC and LDL-C was influenced by polymorphisms in the APOB and PPARG genes.