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M Jarfelt, B Lannering, I Bosaeus, G Johannsson and R Bjarnason

Objective: Obesity is frequently reported in patients treated for childhood leukaemia. Obesity, particularly abdominal obesity, is one of the main characteristics of the metabolic syndrome and a risk factor for cardiovascular disease and non-insulin-dependent diabetes mellitus (NIDDM).

Design: All patients treated for acute lymphoblastic leukaemia (ALL) before the onset of puberty in the region of western Sweden, between 1973 and 1985, and in first remission, were included. 35 out of 47 patients aged 20–32 years participated. 19 patients had received cranial radiotherapy, and the median follow-up time was 20 years. The focus of this report was to study body composition and signs of the metabolic syndrome and correlate the findings to spontaneous growth hormone (GH) secretion.

Methods: Body composition was assessed using dual-energy X-ray absorbtiometry (DEXA). We analyzed serum concentrations of insulin, glucose, leptin and lipids.

Results: No patient was obese according to World Health Organization criteria (body mass index, BMI ≥ 30 kg/m2) but one-third were overweight (BMI 25–29.9 kg/m2). The maximal GH peak during 24 h (GHmax) was correlated to percentage of total body fat (r = −0.42; P = 0.017), trunk fat (r = −0.5; P = 0.005) and fat-free mass (r = 0.42; P = 0.017). GHmax was also correlated to s-triglycerides (r = −0.54; P = 0.001), low-density lipoprotein-cholesterol (r = −0.382; P = 0.024) and high-density lipoprotein-cholesterol (r = 0.45; P = 0.007).

Conclusions: We found little effect on BMI but an increased percentage of total body fat, especially trunk fat, and a tendency for an unfavourable lipid profile in adult survivors of childhood leukaemia. These findings were related to low endogenous GH secretion due to cranial irradiation.

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G Götherström, B-Å Bengtsson, I Bosæus, G Johannsson and J Svensson

There are few studies that have determined the effects of long-term GH replacement on bone mineral density (BMD) in GH-deficient (GHD) adults. In this study, the effects of 10 years of GH replacement on BMD were assessed in 87 GHD adults using dual energy X-ray absorptiometry (DEXA). The results show that GH replacement induced a sustained increase in BMD at all the skeletal sites measured.

Introduction: Little is known of the effect of more than 5 years of GH replacement therapy on bone metabolism in GHD adults.

Patients and methods: In this prospective, open-label, single-center study, which included 87 consecutive adults (52 men and 35 women; mean age of 44.1 (range 22–74) years) with adulthood onset GHD, the effect of 10 years of GH replacement on BMD was determined.

Results: The mean initial dose of GH was 0.98 mg/day. The dose was gradually lowered and after 10 years the mean dose was 0.47 mg/day. The mean insulin-like growth factor-I (IGF-I) SDS increased from 1.81 at baseline to 1.29 at study end. The GH replacement induced a sustained increase in total, lumbar (L2–L4) and femur neck BMD, and bone mineral content (BMC) as measured by DEXA. The treatment response in IGF-I SDS was more marked in men, whereas women had a more marked increase in the total body BMC and the total body z-score. There was a tendency for women on estrogen treatment to have a larger increase in bone mass and density compared with women without estrogen replacement.

Conclusions: Ten years of GH replacement in hypopituitary adults induced a sustained, and in some variables even a progressive, increase in bone mass and bone density. The study results also suggest that adequate estrogen replacement is needed in order to have an optimal response in BMD in GHD women.

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D Maiter, R Abs, G Johannsson, M Scanlon, P J Jönsson, P Wilton and M Koltowska-Häggström

Objective: To test the hypothesis whether the effects of GH replacement therapy in adults could be affected by prior pituitary irradiation, the baseline characteristics and response to GH were evaluated in adults with severe GH deficiency (GHD), who had received or not irradiation for the treatment of pituitary adenoma or craniopharyngioma.

Design: Data from 447 patients, who had received radiotherapy (427 in addition to surgery), and 630 patients, who were operated on but not irradiated for their tumour, were retrieved from Pfizer International Metabolic Database (KIMS) and compared at baseline and 1 and 2 years following the onset of GH replacement.

Results: Irradiated and non-irradiated patients exhibited the expected phenotype of GHD at baseline. However, irradiated patients had a greater impairment in the quality of life (QoL), a higher fat mass, lower high-density lipoprotein cholesterol levels and a lower bone mineral content (BMC) than non-irradiated patients. Treatment with GH induced similar changes in both groups. After 1 year of GH replacement, there was an increase in serum IGF-I and fat-free mass, a reduction in fat mass and an improvement in QoL, all changes being equivalent in irradiated and non-irradiated patients. The lipid profile also improved with the irradiated patients showing a better response. These beneficial effects were maintained and the BMC also increased in both groups by the second year of treatment.

Conclusions: This analysis shows that prior irradiation for pituitary adenoma or craniopharyngioma does not compromise the beneficial effects of GH replacement therapy.

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Gudmundur Johannsson, Ragnhildur Bergthorsdottir, Anna G Nilsson, Hans Lennernas, Thomas Hedner and Stanko Skrtic

Background

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.

Objective

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.

Design

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.

Methods

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.

Results

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.

Conclusion

The dual release hydrocortisone tablet with once-daily administration produced a diurnal plasma cortisol profile mimicking the physiological serum cortisol profile.

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Oskar Ragnarsson, Morton G Burt, Ken K Y Ho and Gudmundur Johannsson

Objective

Long-term pharmacological glucocorticoid (GC) therapy leads to skeletal muscle atrophy and weakness. The objective of this study was to investigate whether short-term treatment with GH and testosterone (T) can increase lean mass without major impairment of glucose homoeostasis in patients on GC therapy.

Design, materials and methods

This was a prospective, open-label, randomised, crossover study. Twelve men (age 74±6 years) on chronic GC treatment participated. The effects of 2 weeks' treatment with GH, testosterone and the combination of both on lean body mass (LBM), appendicular skeletal muscle mass (ASMM), extracellular water (ECW), body cell mass (BCM) and plasma glucose concentrations were investigated.

Results

LBM increased significantly after GH (Δ1.7±1.4 kg; P=0.007) and GH+testosterone (Δ2.4±1.1 kg; P=0.003), but not testosterone alone. ASMM increased after all three treatment periods; by 1.0±0.8 kg after GH (P=0.005), 1.7±0.4 kg after GH+testosterone (P=0.002) and 0.8±1.0 kg after testosterone (P=0.018). The increase in ASMM was larger with combined treatment than either GH or testosterone alone (P<0.05). ECW increased significantly after GH+testosterone by 1.5±2.6 l (P=0.038) but not after GH or testosterone alone. BCM increased slightly after single and combined treatments, but the changes were not significant. Fasting glucose increased significantly after GH (Δ0.4±0.4 mmol/l, P=0.006) while both fasting (Δ0.2±0.3 mmol/l, P=0.045) and post glucose-load (Δ1.8±2.3 mmol/l, P=0.023) plasma glucose concentrations increased after GH+testosterone.

Conclusions

GH and testosterone induce favourable and additive body compositional changes in men on chronic, low-dose GC treatment. In the doses used, combination therapy increases fasting and postprandial glucose concentration.

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D S Olsson, M Buchfelder, S Schlaffer, B-Å Bengtsson, K-E Jakobsson, G Johannsson and A G Nilsson

Objective

An important safety issue with GH replacement therapy (GHRT) in hypopituitary patients with a history of a pituitary adenoma is the risk for tumour recurrence or enlargement.

Design

Case–control study.

Subjects and methods

We studied tumour progression rate in 121 patients with hypopituitarism on the basis of non-functioning pituitary adenomas (NFPA) receiving long-term GHRT. A group of 114 NFPA patients not receiving GHRT who were matched in terms of duration of follow-up, gender, age, age at diagnosis and radiotherapy status were used as a control population. The average duration of GHRT was 10±4 years (range 2–17).

Results

In patients with a known residual adenoma, 63% had no detectable enlargement of tumour during the study. In patients who had no visible residual tumour prior to GHRT, 90% did not suffer from recurrence. In total, the 10-year tumour progression-free survival rate in patients with NFPA receiving GHRT was 74%. In the control population not receiving GHRT, the 10-year progression-free survival rate was 70%. Radiotherapy as part of the initial tumour treatment reduced the rate of tumour progression in both GHRT and non-GHRT patients to a similar extent.

Conclusions

The rate of tumour progression was similar in this large group of GHRT patients and the control population not receiving GHRT. Our results provide further support that long-term use of GH replacement in hypopituitarism may be considered safe in patients with residual pituitary adenomas.

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Oskar Ragnarsson, Camilla A M Glad, Ragnhildur Bergthorsdottir, Erik G Almqvist, Eva Ekerstad, Håkan Widell, Bo Wängberg and Gudmundur Johannsson

Objective

Adverse body compositional features and low bone mineral density (BMD) are the characteristic of patients with active Cushing's syndrome (CS). The aim of this study was to evaluate body composition and BMD in women with CS in long-term remission and the influence of polymorphisms in genes affecting glucocorticoid (GC) sensitivity on these end-points.

Design, patients and methods

This was a cross-sectional, case–controlled study, including 50 women previously treated for CS and 50 age and gender-matched controls. Median (interquartile range) remission time was 13 (5–19) years. Body composition and BMD were measured with dual-energy X-ray absorptiometry. Five polymorphisms in four genes associated with GC sensitivity were analysed using TaqMan or Sequenom single-nucleotide polymorphism genotyping.

Results

Patients with CS in remission had increased abdominal fat mass (P<0.01), whereas BMD was not significantly different at any site between patients and controls. In patients, the NR3C1 Bcl1 polymorphism was associated with reduced total (P<0.05) and femur neck BMD (P<0.05). The polymorphism rs1045642 in the ABCB1 gene was associated with increased abdominal fat mass (P<0.05) and decreased appendicular skeletal muscle mass (P<0.05). GC replacement was associated with reduced total BMD (P<0.01), BMD at lumbar spine (P<0.05) and increased abdominal fat (P<0.01).

Conclusion

Ongoing GC replacement therapy together with polymorphisms in two genes related with GC sensitivity is associated with abdominal obesity and adverse skeletal health in patients with CS in long-term remission.

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Casper Hammarstrand, Oskar Ragnarsson, Tobias Hallén, Eva Andersson, Thomas Skoglund, Anna G Nilsson, Gudmundur Johannsson and Daniel S Olsson

Objective

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).

Methods

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.

Results

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.

Conclusion

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.

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C Karlsson, K Stenlof, G Johannsson, P Marin, P Bjorntorp, BA Bengtsson, B Carlsson, LM Carlsson and L Sjostrom

The present study has examined the short- and long-term effects of growth hormone (GH) treatment on the leptin system and energy expenditure. Thirty male individuals with abdominal obesity were randomised to GH or placebo treatment in a 9-month, double-blind study. The dose of GH was 9.5 microg/kg, administered subcutaneously every evening. Serum leptin concentrations were measured by a human leptin RIA. Total RNA was isolated from adipose tissue biopsies and leptin mRNA levels were determined by a semi-quantitative reverse transcriptase-PCR assay. Body composition was determined by potassium-40 and the basal metabolic rate (BMR) was measured by a computerised, ventilated, open-hood system. As compared with placebo, an overall decrease in serum leptin concentrations as assessed by the area under the curve (AUC) (P < 0.05) and an increase in BMR (AUC, P < 0.05) were observed during GH treatment. The overall GH-induced changes were due to marked changes in serum leptin concentrations and BMR after 6 weeks of treatment. After 9 months of GH treatment there was a significant reduction in body fat (BF) while serum leptin concentrations and BMR did not differ from baseline values. Leptin mRNA levels did not change over the study period. We speculate that long-term GH treatment induces a new energy balance steady state with decreased BF stores. The effects of GH on the leptin system is suggested to be of importance for the maintenance of a lower BF mass.

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D S Olsson, M Buchfelder, K Wiendieck, N Kremenevskaja, B-Å Bengtsson, K-E Jakobsson, M Jarfelt, G Johannsson and A G Nilsson

The journal apologizes for an error in Fig. 2 of this article published in the European Journal of Endocrinology 166 1061–1068. The GH-treated group and non-GH-treated group were incorrectly identified. The correct figure is published in full below.

Figure 2
Figure 2

Cox regression of progression-free survival rates adjusted for initial RT, residual tumour after primary treatment and gender in patients treated with and without GHRT. No association between GHRT and tumour progression was found (HR 0.57; CI for GHRT 0.26–1.3; P value=0.17). The 95% CI for each group are indicated by the red and blue colours (GHRT, GH replacement therapy; RT, radiation therapy).