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Jens Sandahl Christiansen and Jens Otto Lunde Jørgensen

Abstract.

Growth hormone deficiency in adults is associated with psychosocial maladjustment, reduced muscle strength, and reduced exercise capacity. Body composition is significantly altered, with increased fat and decreased muscle volume as compared with healthy subjects. Kidney function is subnormal. Epidemiological data suggest premature mortality owing to cardiovascular disease in hypopituitary patients. Short-term GH treatment trials have shown improved psychosocial performance, normalization of body composition, increased muscle strength, improved exercise capacity, increased cardiac performance, and normalization of kidney function. Thus GH replacement therapy in GH-deficient adults exhibits potential long-term beneficial effects. A number of important questions have to be addressed before long-term GH replacement therapy in GH-deficient adults can be considered on a routine basis.

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Kristina Laugesen, Jens Otto Lunde Jørgensen, Irene Petersen and Henrik Toft Sørensen

Objective

Glucocorticoid treatment of inflammatory disorders is associated with significant adverse effects related to glucocorticoid excess as well as adrenal insufficiency. This necessitates awareness of its use. We therefore investigated trends in systemic glucocorticoid use as well as morbidity and comedications among users.

Design

Cross-sectional drug utilisation study.

Methods

We conducted a population-based study of 926,314 users of systemic glucocorticoids (oral and injectable formulations) from 1999 to 2014 using Danish nationwide registries. We computed annual prevalence and incidence of systemic glucocorticoid use and prevalence of comedications and morbidity. Further, we assessed the annual amount of disease-modifying drug use.

Results

Of the 926,314 users of systemic glucocorticoids, 54% were female and median age at first-time use was 55 years. The annual prevalence was ≈ 3%, while the incidence was ≈ 1.4/100 person years (p-y). Both figures remained constant from 1999 to 2014. In the elderly, the annual prevalence was 6.7–7.7% (60–79 years of age) and 9.7–11% (≥80 years of age). Incidence increased among persons aged ≥80 years from 3.0/100 p-y in 1999 to 3.6/100 p-y in 2014. Concomitantly, the annual amount of for example methotrexate, azathioprine and tumour necrosis factor (TNF)-alpha agents increased and new biological agents emerged. The most frequent comedications were antibiotics (49%), cardiovascular drugs (38%) and NSAIDs (37%).

Conclusions

Our findings confirm a widespread use of systemic glucocorticoids, especially in the elderly, which prevails despite increased use of disease-modifying drugs. The continuously prevalent use of glucocorticoid use constitutes a challenge for the endocrine community.

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Poul Frølund Vestergaard, Mette Hansen, Jan Frystyk, Ulrick Espelund, Jens S Christiansen, Jens Otto Lunde Jørgensen and Sanne Fisker

Objective

Senescent changes in body composition and muscle strength are accompanied by reduced production of GH and IGF1, but the causal relationship remains elusive. We speculate that serum bioactive IGF1, measured by the IGF1 kinase receptor activation assay, is closer related to human physiological ageing than total IGF1 measured by immunoassay.

Design

We conducted a cross-sectional study in 150 adult males and females, between 20 and 70 years. After an overnight fasting, serum levels of bioactive IGF1, total IGF1 and IGF-binding protein 1 (IGFBP1) and IGFBP3 were assessed. Furthermore, body composition and muscle strength was measured.

Results

Total IGF1 levels were higher in females (P=0.048). Bioactive IGF1 were identical in males and females (P=0.31), decreasing with age. Total IGF1 tended to decrease more with age compared with bioactive IGF1 (−1.48 vs −0.89 percent/year, P=0.052). Total body fat (TBF) was lower and BMI was higher in males (P<0.001 and P=0.005), and both increased with age. Knee extension and elbow flexion force were higher in males (P=0.001 and P=0.001), but decreased with age in both genders.

 Total but not bioactive IGF1 was positively correlated to TBF, knee extension and muscle function in males. In multiple linear regression, only age predicted total IGF1, whereas age and IGFBP1 predicted bioactive IGF1.

Conclusions

Bioactive IGF1 tends to decrease to a lesser extent than total IGF1 with age and was not correlated with measures of body composition or muscle strength. Therefore, levels of circulating bioactive IGF1 does not appear to be a better biomarker of physiological ageing than total IGF1.

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Mette Søgaard, Dóra Körmendiné Farkas, Vera Ehrenstein, Jens Otto Lunde Jørgensen, Olaf M Dekkers and Henrik Toft Sørensen

Objective

The association between thyroid disease and breast cancer risk remains unclear. We, therefore examined the association between hypothyroidism, hyperthyroidism and breast cancer risk.

Design

This was a population-based cohort study.

Methods

Using nationwide registries, we identified all women in Denmark with a first-time hospital diagnosis of hypothyroidism or hyperthyroidism, 1978–2013. We estimated the excess risk of breast cancer among patients with hypothyroidism or hyperthyroidism compared with the expected risk in the general population, using standardized incidence ratios (SIRs) as a measure of risk ratio. Breast cancer diagnoses in the first 12 months following diagnosis of thyroid disease were excluded from the calculations to avoid diagnostic work-up bias.

Results

We included 61 873 women diagnosed with hypothyroidism and 80 343 women diagnosed with hyperthyroidism. Median follow-up time was 4.9 years (interquartile range (IQR): 1.8–9.5 years) for hypothyroidism and 7.4 years (IQR: 3.1–13.5 years) for hyperthyroidism. Hyperthyroidism was associated with a slightly increased breast cancer risk compared with the general population (SIR: 1.11, 95% CI: 1.07–1.16), which persisted beyond 5 years of follow-up (SIR: 1.13, 95% CI: 1.08–1.19). In comparison, hypothyroidism was associated with a slightly lower risk of breast cancer (SIR: 0.94, 95% CI: 0.88–1.00). Stratification by cancer stage at diagnosis, estrogen receptor status, age, comorbidity, history of alcohol-related disease and clinical diagnoses of obesity produced little change in cancer risk.

Conclusions

We found an increased risk of breast cancer in women with hyperthyroidism and a slightly decreased risk in women with hypothyroidism indicating an association between thyroid function level and breast cancer risk.

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Birgitte Nellemann, Britt Christensen, Kristian Vissing, Line Thams, Peter Sieljacks, Mads Sørensen Larsen, Jens Otto Lunde Jørgensen and Søren Nielsen

Objective

Very low density lipoprotein triglyceride (VLDL–TG) and free fatty acids (FFA) constitute a substantial proportion of human energy supply both at rest and during exercise. Exercise acutely decreases VLDL–TG concentration, and VLDL–TG clearance is increased after an exercise bout. However, the effects of long-term training are not clear.

Design

The aim was to investigate long-term effects of training by direct assessments of VLDL–TG and palmitate kinetics and oxidation in healthy lean men (n=9) at rest, before and after a 10-week training program, compared with a non-training control group (n=9).

Methods

VLDL–TG kinetics were assessed by a primed constant infusion of [1-14C]VLDL–TG, and VLDL–TG oxidation by specific activity (14CO2) in expired air. The metabolic study days were placed 60–72 h after the last exercise bout.

Results

Palmitate kinetics and oxidation were assessed by a 2 h constant infusion of [9,10-3H]palmitate. In the training group (n=9), maximal oxygen uptake increased significantly by ≈20% (P<0.05), and the insulin sensitivity (assessed by the hyperinsulinemic–euglycemic clamp) improved significantly (P<0.05). Despite these metabolic improvements, no changes were observed in VLDL–TG secretion, clearance, or oxidation or in palmitate kinetics.

Conclusion

We conclude that 10 weeks of exercise training did not induce changes in VLDL–TG and palmitate kinetics in healthy lean men.

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Jens Juel Christiansen, Sanne Fisker, Claus Højbjerg Gravholt, Paul Bennett, Birgit Svenstrup, Marianne Andersen, Ulla Feldt-Rasmussen, Jens Sandahl Christiansen and Jens Otto Lunde Jørgensen

Objective and design: Compared with their male counterparts, healthy females secrete more growth hormone (GH) and those with GH-deficiency have lower insulin-like growth factor I (IGF-I) levels and are less responsive to GH substitution. To test whether this gender difference is related to sex hormones we measured androgen status and IGF-I related parameters in 38 hypopituitary women (mean (range) age 41.5 (20–58) years) during continued GH substitution as compared with a control group of 38 healthy women matched for age and menopausal status. Twenty six patients were studied twice: with estrogen replacement and after 28 days of estrogen discontinuation in a randomised design.

Results: The patients were androgen deficient compared with controls (median, range), dehydroepiandrosterone sulphate (DHEAS): 185 (99–7800) nmol/l vs 4400 (820–13 000) nmol/l, P = < 0.001; androstenedione: 0.5 (0.1–7.1) nmol/l vs 4.3 (1.6–8.8) nmol/l, P = < 0.001; dihydrotestosterone (DHT): 0.13 (0.09–0.54) nmol/l vs 0.55 (0.09–0.89) nmol/l, P = < 0.001; testosterone: 0.28 (0.09–1.56) nmol/l vs 1.1 (0.71–2.24) nmol/l, (P = < 0.001); free testosterone: 0.004 (0.001–0.030) nmol/l vs 0.016 (0.001–0.030) nmol/l, P = < 0.001. The circulating levels of IGF-I, IGF-II, IGF-binding protein 1 (IGFBP-1), and IGFBP-3 did not differ between patients and controls. The subgroup of patients receiving hydrocortisone (HC) replacement (n = 24) had significantly lower levels of androgens (suppressed by 80–100%) as well as IGF-I and IGFBP-3 as compared with the patients not receiving HC. IGF-I was correlated to free testosterone in patients (r = 0.57, P = 0.0005) as well as controls (r = 0.43, P = 0.008), and free testosterone was a significant positive predictor of IGF-I. Estrogen discontinuation induced an increase in IGF-I (167 ± 15 vs 206 ± 14 μg/l, P = 0.005 and IGFBP-3 (3887 ± 139 vs 4309 ± 138 μg/l, P = 0.0005). Estrogen discontinuation was associated with a significant increase in median (range) free testosterone (0.004 (0–0.02) vs 0.0065 (0–0.03) nmol/l, P = 0.001) and a significant decrease in median (range) sex-hormone binding globulin (SHBG; 93 (11–278) vs 55.5 (20–142) nmol/l, P = 0.001). ΔIGF-I correlated with ΔSHBG (r = −0.45 P = 0.033) and ΔIGFBP-3 (r = 0.67 P = < 0.001). In a regression model ΔE2, Δtestosterone, ΔSHBG and ΔIGFBP-3 explained 93% of the variation in ΔIGF-I.

Conclusions: Androgen levels are low in hypopituitary women and free testosterone correlates with IGF-I. Discontinuation of estrogen replacement in these patients induces elevations in IGF-I as well as free testosterone, and ΔIGF-I correlated positively with Δfree testosterone. These effects may contribute to the gender differences observed in the GH–IGF axis in healthy adults as well as in the responsiveness of hypopituitary patients to GH substitution.

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Jens Juel Christiansen, Claus Højbjerg Gravholt, Sanne Fisker, Niels Møller, Marianne Andersen, Birgit Svenstrup, Paul Bennett, Per Ivarsen, Jens Sandahl Christiansen and Jens Otto Lunde Jørgensen

Objective: In female adrenal insufficiency, dehydroepiandrosterone (DHEA) secretion is impaired and circulating androgen levels are severely reduced. We wanted to analyse the acute effects of physiological DHEA substitution on substrate metabolism.

Design: We studied nine females with adrenal insufficiency after 9 days of oral DHEA replacement (50 mg/day) in a double-blind, placebo-controlled crossover study.

Methods: Whole body and regional substrate metabolism was assayed in the basal state and during a euglycemic hyperinsulinemic glucose clamp by means of isotope dilution techniques (glucose, phenyl-alanine, tyrosine), indirect calorimetry and in situ lipolysis (microdialysis technique).

Results: DHEA treatment normalized the levels of all androgens. Basal and insulin-stimulated total energy expenditure and rates of protein, lipid and glucose oxidation were unaffected by DHEA. Whole body turnover of glucose and protein were also unaffected by DHEA. Forearm breakdown of protein was reduced by insulin to the same extent after placebo and DHEA. Insulin sensitivity as expressed by the glucose infusion rate during the euglycemic clamp was similar after placebo and DHEA. Finally, the interstitial release of glycerol in adipose tissue was not significantly influenced by DHEA.

Conclusions: Short-term oral DHEA replacement in women with adrenal insufficiency was not associated with measurable changes in total or regional substrate metabolism.

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Anne Lene Dalkjær Riis, Troels Krarup Hansen, Steffen Thiel, Claus Højbjerg Gravholt, Signe Gjedde, Lars Christian Gormsen, Jens Otto Lunde Jørgensen, Jørgen Weeke and Niels Møller

Background: Recent studies have indicated the existence of causal links between the endocrine and immune systems and cardiovascular disease. Mannan-binding lectin (MBL), a protein of the innate immune system, may constitute a connection between these fields.

Methods: To test whether thyroid hormone regulates MBL levels, we studied eight patients with Graves’ hyperthyroidism before and after methimazole therapy, eight healthy subjects before and after short-term experimental hyperthyroidism, and eight hypothyroid patients with chronic auto-immune thyroiditis before and after L-thyroxine substitution.

Results: In all hyperthyroid patients, MBL levels were increased – median (range), 1886 ng/ml (1478–7344) – before treatment and decreased to 954 ng/ml (312–3222) after treatment (P = 0.01, paired comparison: Wilcoxon’s signed ranks test). The healthy subjects had MBL levels of 1081 ng/ml (312–1578). Administration of thyroid hormones to these persons induced mild hyperthyroidism and increased MBL levels significantly to 1714 ng/ml (356–2488) (P = 0.01). Two of the eight hypothyroid patients had undetectably low levels of MBL both before and after L-thyroxine substitution. The other six hypothyroid patients had decreased levels of MBL of 145 ng/ml (20–457) compared with 979 ng/ml (214–1533) after L-thyroxine substitution (P = 0.03, paired comparison: Wilcoxon’s signed ranks test).

Conclusion: Our data show that thyroid hormone increases levels of MBL. MBL is part of the inflammatory complement system, and this modulation of complement activation may play a role in the pathogenesis of a number of key components of thyroid diseases.

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Esben T Vestergaard, Niels Møller, René Frydensbjerg Andersen, Søren Rittig and Jens Otto Lunde Jørgensen

Objective

Acyl ghrelin, which is the endogenous ligand for the growth hormone secretagogue receptor, potently stimulates pituitary growth hormone release, and to some degree adrenocorticotropic hormone and prolactin. Ghrelin is also orexigenic and has recently been shown to stimulate renal sodium absorption in rodent models. Increased thirst sensation has been observed as a side effect of acyl ghrelin administration in some human studies. The objective of this clinical trial was to investigate the direct effects of acyl ghrelin on thirst sensation and sodium excretion in hypopituitary patients.

Design

Hypopituitary patients on stable replacement with hydrocortisone and growth hormone were investigated in two double-blind and placebo-controlled crossover studies. The patients received a 5-h intravenous infusion of acyl ghrelin (5 pmol/kg/min in the first study and 1 pmol/kg/min in the second study). Thirst sensation was measured on a Visual Analog Scale (VAS). In the second study plasma osmolality, vasopressin, copeptin, water intake, diuresis and urinary excretion of sodium and creatinine were measured.

Results

In the initial study, acyl ghrelin (5 pmol/kg/min) increased thirst sensation (time × treatment analysis of variance for the effect of acyl ghrelin infusion P = 0.003). In the second study acyl ghrelin (1 pmol/kg/min) also increased thirst (P = 0.04) but did not affect urinary excretion of either sodium or water.

Conclusions

We demonstrate that acyl ghrelin infusion increases thirst sensation, without affecting sodium excretion or diuresis in human subjects.

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Katharina Schilbach, Christina Gar, Andreas Lechner, Shiva Sophia Nicolay, Laura Schwerdt, Michael Haenelt, Jakob Dal, Jens-Otto Lunde Jørgensen, Sylvère Störmann, Jochen Schopohl and Martin Bidlingmaier

Objective

Growth hormone (GH) nadir (GHnadir) during oral glucose tolerance test (OGTT) is an important tool in diagnosing acromegaly, but data evaluating the need to adjust cut-offs to biological variables utilizing today's assay methods are scarce. We therefore investigated large cohorts of healthy subjects of both sexes to define normal GHnadir concentrations for a modern, sensitive, 22 kD-GH-specific assay.

Design

Multicenter study with prospective and retrospective cohorts (525 healthy adults: 405 females and 120 males).

Methods

GH concentrations were measured by the IDS-iSYS immunoassay after oral application of 75 g glucose.

Results

GHnadir concentrations (µg/L) were significantly higher in lean and normal weight subjects (group A) compared to overweight and obese subjects (group B); (males (M): A vs B, mean: 0.124 vs 0.065, P = 0.0317; premenopausal females without estradiol-containing OC (OC-EE) (FPRE): A vs B, mean: 0.179 vs 0.092, P < 0.0001; postmenopausal women (FPOST): A vs B, mean: 0.173 vs 0.078, P < 0.0061). Age, glucose metabolism and menstrual cycle had no impact on GHnadir. However, premenopausal females on OC-EE (FPREOC) exhibited significantly higher GHnadir compared to all other groups (all P < 0.0001). BMI had no impact on GHnadir in FPREOC (A vs B, mean: 0.624 vs 0.274, P = 0.1228).

Conclusions

BMI, sex and OC-EE intake are the major determinants for the GHnadir during OGTT in healthy adults. Using a modern sensitive GH assay, GHnadir concentrations in healthy subjects are distinctly lower than cut-offs used in previous guidelines for diagnosis and monitoring of acromegaly.