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Jens Otto L. Jørgensen, Werner F. Blum, Niels Møller, Michael B. Ranke, and Jens S. Christiansen

Abstract.

Knowledge of the circadian patterns of serum IGF-I I and the large molecular weight IGF binding protein, IGFBP-3 might, apart from its physiological relevance, be of clinical interest, inasmuch as measurements of these parameters are being introduced into the evaluation of GH deficiency. We therefore evaluated the 24-h (08.00-08.00 h) patterns of serum IGF-II and IGFBP-3 in 8 GH-deficient patients who were studied during three periods when receiving 1. GH (2 IU) at 20.00 h; 2. GH (2 IU) at 08.00 h and 3. no GH. For comparison, 10 age- and sex-matched untreated healthy subjects were studied once under similar conditions. The serum IGF-II levels of the patients were relatively stable over the 24-h periods, yielding mean levels which were significantly lower during no GH: 553±78 (evening GH), 554±54 (morning GH), and 429±65 μg/l (no GH). The mean IGF-II level in the normal subjects was 635±29 μg/l, which was significantly higher than in either patient study. Similarly, stable 24-h levels of IGFBP-3 were recorded in all studies. The mean IGFBP-3 level of the patients was significantly lower when they received no GH, and the mean level in the healthy subjects was higher than in any of the patient studies: 1853±301 (no GH), 2755 ± 317 (evening GH), 2904±269 (morning GH), and 3856±186 μg/l (healthy subjects). However, minute but significant changes over time, characterised by slight decrements at night, were observed for both parameters in several of the studies. Nevertheless, since both IGF-II and IGFBP-3 display rather stable 24-h levels in the individual, it is concluded that measurements of these parameters in evaluation of growth retardation can be based on a single daytime sample.

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Nicoleta C Olarescu, Thor Ueland, Kristin Godang, Rune Lindberg-Larsen, Jens Otto L Jørgensen, and Jens Bollerslev

Background

Active acromegaly is associated with insulin resistance, but it is uncertain whether inflammation in adipose tissue is a contributing factor.

Aim

To test if GH/IGF1 promotes inflammation in adipocytes, and if this is relevant for systemic insulin resistance in acromegaly. Furthermore, to investigate the effect of treatment modalities (transsphenoidal surgery (TS), somatostatin analogs (SAs), and pegvisomant (PGV)) on glucose metabolism and inflammatory biomarkers in acromegaly.

Methods

The in vitro effects of GH/IGF1 on gene expression of adipokines in human adipocytes were investigated. Body composition, glucose metabolism, and circulating adipokines (adiponectin (AD), high-molecular weight AD (HMWAD), leptin, vascular endothelial growth factor-A (VEGF-A), monocyte chemotactic protein 1 (MCP1), and thioredoxin (TRX)) were measured in 37 patients with active acromegaly before and after treatment.

Results

In vitro GH, but not IGF1, increased VEGF and MCP1 in human adipocytes. In all treatment groups, body fat increased and IGF1 decreased to the same extent. Fasting glucose decreased in the TS (P=0.016) and PGV (P=0.042) groups, but tended to increase in the SA group (P=0.078). Insulin and HOMA-IR decreased in both TS and SA groups, while the PGV group showed no changes. Serum VEGF and MCP1 decreased significantly in the TS group only (P=0.010, P=0.002), while HMWAD increased with PGV treatment only (P=0.018). A multivariate analysis model identified the changes in GH and VEGF as predictors of improvement in HOMA-IR after treatment (R 2=0.39, P=0.002).

Conclusions

i) GH directly promotes inflammation of human adipocytes by increasing VEGF and MCP1 levels; ii) glucose metabolism and inflammation (VEGF and MCP1) improve to some extent after treatment, despite an increase in adipose tissue mass; and iii) the decrease in insulin resistance after therapy in acromegaly depends, to some extent, on treatment modalities.

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Emmanuelle Kuhn, Alexandra A Weinreich, N R Biermasz, Jens Otto L. Jorgensen, and Philippe Chanson

Abstract

Context: Prolactinomas frequently cause amenorrhoea, galactorrhoea and infertility and require dopamine agonist (DA) treatment to normalize prolactin levels and hence restore ovulation. The vast majority of female patients harbour microprolactinomas in whom DA treatment is usually discontinued at the time of pregnancy diagnosis, and surveillance is generally limited as symptomatic growth is considered very rare.

Case Descriptions: We report five cases of women harbouring a microprolactinoma in whom symptomatic pituitary apoplexy occurred during pregnancy. Only one necessitated surgery during pregnancy, while the others were treated conservatively by reintroducing DAs in three. A systematic literature review found reports of four additional cases among 20 cases of prolactinomas (both macro- and microprolactinomas) complicated by apoplexy during pregnancy.

Conclusion: During pregnancy, pituitary apoplexy may occur in pre-existing microprolactinomas, causing tumour enlargement and headache, which may be self-limiting but may require intervention by re-initation of dopamine agonists or surgery. Our literature review confirms that this clinical event is rare; nevertheless, physicians managing pregnant patients with microprolactinomas must be aware that symptomatic pituitary apoplexy may incidentally occur in all trimesters of pregnancy and require prompt radiological, endocrine and ophthalmological assessment and treatment.

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Charlotte Steffensen, Alberto M Pereira, Olaf M Dekkers, and Jens Otto L Jørgensen

Objective

Type 2 diabetes (T2D) and Cushing’s syndrome (CS) share clinical characteristics, and several small studies have recorded a high prevalence of hypercortisolism in T2D, which could have therapeutic implications. We aimed to assess the prevalence of endogenous hypercortisolism in T2D patients.

Design

Systematic review and meta-analysis of the literature.

Methods

A search was performed in SCOPUS, MEDLINE, and EMBASE for original articles assessing the prevalence of endogenous hypercortisolism and CS in T2D. Data were pooled in a random-effect logistic regression model and reported with 95% confidence intervals (95% CI).

Results

Fourteen articles were included, with a total of 2827 T2D patients. The pooled prevalence of hypercortisolism and CS was 3.4% (95% CI: 1.5–5.9) and 1.4% (95 CI: 0.4–2.9) respectively. The prevalence did not differ between studies of unselected patients and patients selected based on the presence of metabolic features such as obesity or poor glycemic control (P = 0.41 from meta-regression). Imaging in patients with hypercortisolism (n = 102) revealed adrenal tumors and pituitary tumors in 52 and 14% respectively.

Conclusions

Endogenous hypercortisolism is a relatively frequent finding in T2D, which may have therapeutic implications.

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Kristine Z Rubeck, Michael Madsen, Caroline Marie Andreasen, Sanne Fisker, Jan Frystyk, and Jens Otto L Jørgensen

Context

Control of disease activity in acromegaly is critical, but the biochemical definitions remain controversial.

Objective

To compare traditional and novel biomarkers and health status in patients with acromegaly treated with either surgery alone or somatostatin analog (SA).

Design and methods

Sixty-three patients in long-term remission based on normalized total IGF1 levels after surgery alone (n=36) or SA (n=27) were studied in a cross-sectional manner. The groups were comparable at diagnosis regarding demographic and biochemical variables. Each subject underwent 3 h of serum sampling including a 2-h oral glucose tolerance test (OGTT). Health status was measured by two questionnaires: EuroQoL and Acrostudy (Patient-assessed-Acromegaly symptom questionnaire (PASQ)).

Results

Total and bioactive IGF1 (μg/l) levels were similar (total: 185±10 (SA) versus 171±8 (surgery) (P=0.28); bioactive: 1.9±0.2 vs 1.9±0.1 (P=0.70)). Suppression of total and free GH (μg/l) during OGTT was blunted in the SA group (total GHnadir: 0.59±0.08 (SA) versus 0.34±0.06 (surgery) (P=0.01); free GHnadir: 0.43±0.06 vs 0.19±0.04 (P<0.01)). The insulin response to OGTT was delayed, and the 2-h glucose level was elevated during SA treatment (P=0.02). Disease-specific health status was better in patients after surgery (P=0.02).

Conclusions

i) Despite similar and normalized IGF1 levels, SA treatment compared with surgery alone was associated with less suppressed GH levels and less symptom relief; ii) this discordance may be due to specific suppression of hepatic IGF1 production by SA; iii) we suggest that biochemical assessment during SA treatment should include both GH and IGF1.

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Diana Cruz-Topete, Britt Christensen, Lucila Sackmann-Sala, Shigeru Okada, Jens Otto L Jorgensen, and John J Kopchick

Context

Transsphenoidal adenomectomy is the primary treatment for acromegaly. However, assessment of the therapeutical outcome remains problematic since the existing biomarkers of disease activity frequently show discordant results.

Objective

To discover novel serum biomarkers of disease activity in acromegalic patients before and after surgery.

Design

Serum samples of eight newly diagnosed acromegaly patients before and after transsphenoidal surgery were analyzed for proteomic changes by two-dimensional gel electrophoresis. Protein spots displaying statistically significant changes, pre- versus post-surgery, were identified by mass spectrometry (MS), tandem MS (MS/MS), and western blot analysis.

Results

Six protein spots displaying decreased intensities after surgery were identified as transthyretin (two isoforms), haptoglobin α2, β-hemoglobin, and apolipoprotein A-1 (two isoforms). One protein spot, identified as complement C4B precursor, was increased after the surgery.

Conclusions

Seven serum protein spots were differentially expressed following surgery in acromegalic patients. The identified proteins represent potential novel biomarkers to assess the effectiveness of surgical treatment in acromegalic individuals. Future studies will validate the use of the identified proteins as biomarkers of disease activity after medical treatment of acromegaly.

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Olaf M Dekkers, Erzsébet Horváth-Puhó, Suzanne C Cannegieter, Jan P Vandenbroucke, Henrik Toft Sørensen, and Jens Otto L Jørgensen

Objective

Several studies have shown an increased risk for cardiovascular disease (CVD) in hyperthyroidism, but most studies have been too small to address the effect of hyperthyroidism on individual cardiovascular endpoints. Our main aim was to assess the association among hyperthyroidism, acute cardiovascular events and mortality.

Design

It is a nationwide population-based cohort study. Data were obtained from the Danish Civil Registration System and the Danish National Patient Registry, which covers all Danish hospitals. We compared the rate of all-cause mortality as well as venous thromboembolism (VTE), acute myocardial infarction (AMI), ischemic and non-ischemic stroke, arterial embolism, atrial fibrillation (AF) and percutaneous coronary intervention (PCI) in the two cohorts. Hazard ratios (HR) with 95% confidence intervals (95% CI) were estimated.

Results

The study included 85 856 hyperthyroid patients and 847 057 matched population-based controls. Mean follow-up time was 9.2 years. The HR for mortality was highest in the first 3 months after diagnosis of hyperthyroidism: 4.62, 95% CI: 4.40–4.85, and remained elevated during long-term follow-up (>3 years) (HR: 1.35, 95% CI: 1.33–1.37). The risk for all examined cardiovascular events was increased, with the highest risk in the first 3 months after hyperthyroidism diagnosis. The 3-month post-diagnosis risk was highest for atrial fibrillation (HR: 7.32, 95% CI: 6.58–8.14) and arterial embolism (HR: 6.08, 95% CI: 4.30–8.61), but the risks of VTE, AMI, ischemic and non-ischemic stroke and PCI were increased also 2- to 3-fold.

Conclusions

We found an increased risk for all-cause mortality and acute cardiovascular events in patients with hyperthyroidism.

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Louise Holland-Bill, Christian Fynbo Christiansen, Uffe Heide-Jørgensen, Sinna Pilgaard Ulrichsen, Troels Ring, Jens Otto L Jørgensen, and Henrik Toft Sørensen

Objective

We aimed to investigate the impact of hyponatremia severity on mortality risk and assess any evidence of a dose–response relation, utilizing prospectively collected data from population-based registries.

Design

Cohort study of 279 508 first-time acute admissions to Departments of Internal Medicine in the North and Central Denmark Regions from 2006 to 2011.

Methods

We used the Kaplan–Meier method (1 – survival function) to compute 30-day and 1-year mortality in patients with normonatremia and categories of increasing hyponatremia severity. Relative risks (RRs) with 95% CIs, adjusted for age, gender and previous morbidities, and stratified by clinical subgroups were estimated by the pseudo-value approach. The probability of death was estimated treating serum sodium as a continuous variable.

Results

The prevalence of admission hyponatremia was 15% (41 803 patients). Thirty-day mortality was 3.6% in normonatremic patients compared to 7.3, 10.0, 10.4 and 9.6% in patients with serum sodium levels of 130–134.9, 125–129.9, 120–124.9 and <120 mmol/l, resulting in adjusted RRs of 1.4 (95% CI: 1.3–1.4), 1.7 (95% CI: 1.6–1.8), 1.7 (95% CI: 1.4–1.9) and 1.3 (95% CI: 1.1–1.5) respectively. Mortality risk was increased across virtually all clinical subgroups, and remained increased by 30–40% 1 year after admission. The probability of death increased when serum sodium decreased from 139 to 132 mmol/l. No clear increase in mortality was observed for lower concentrations.

Conclusions

Hyponatremia is highly prevalent among patients admitted to Departments of Internal Medicine and is associated with increased 30-day and 1-year mortality risk, regardless of underlying disease. This risk seems independent of hyponatremia severity.

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Kristina Laugesen, Leonie H A Broersen, Simon Bøggild Hansen, Olaf M Dekkers, Henrik Toft Sørensen, and Jens Otto L Jorgensen

Glucocorticoids are, besides non-steroidal anti-inflammatory drugs, the most widely used anti-inflammatory medications. Prevalence studies indicate substantial use of both systemic and locally acting agents. A recognised adverse effect of glucocorticoid treatment is adrenal insufficiency, which is highly prevalent based on biochemical testing, but its clinical implications are poorly understood. Current evidence, including randomised trials and observational studies, indicates substantial variation among patients in both risk and course of glucocorticoid-induced adrenal insufficiency, but both are currently unpredictable. Oral and intra-articular formulations, as well as long-term and high-dose treatments, carry the highest risk of glucocorticoid-induced adrenal insufficiency defined by biochemical tests. However, no route of administration, treatment duration, or dose can be considered without risk. More research is needed to estimate the risk and temporal pattern of glucocorticoid-induced adrenal insufficiency, to investigate its clinical implications, and to identify predictors of risk and prognosis. Randomized trials are required to evaluate whether hydrocortisone replacement therapy mitigates risk and symptoms of glucocorticoid-induced adrenal insufficiency in patients discontinuing glucocorticoid treatment. This review aims to provide an overview of the available evidence, pointing to knowledge gaps and unmet needs.

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Johanne Marie Holst, Erzsébet Horváth-Puhó, Rikke Beck Jensen, Mariane Rix, Kurt Kristensen, Niels Thomas Hertel, Olaf M Dekkers, Henrik Toft Sørensen, Anders Juul, and Jens Otto L Jørgensen

Objective

Cushing’s syndrome (CS) affects all age groups, but epidemiologic data in young patients are very limited. We therefore examined the incidence, prevalence and hospital morbidity of CS in children and adolescents.

Design

In a nationwide cohort study, we included all Danish citizens aged 0–20 years from 1977 to 2012. Data were obtained from the Danish National Patient Registry using the International Classification of Diseases (ICD) codes and the Danish Civil Registration System. The diagnosis and treatment were validated by means of individual patient charts. Incidence rate of CS patients aged 0–20 years at diagnosis were computed (standardized to the age and sex distribution of the Danish population). The patients were followed for a maximum of 36 years. Standardized incidence ratios (SIRs) of different hospital-recorded outcomes based on the ICD codes in patients with CS compared to the general population were assessed.

Results

We identified a total of 40 pediatric patients with CS, yielding an annual incidence of 0.89 cases/106 population (95% confidence interval (CI) = 0.63–1.16). The median age at the time of diagnosis was 13.8 years (interquartile range: 10.5–18.2 years), 58% were female and 70% had adrenocorticotropic hormone-producing pituitary adenomas. During follow-up, CS patients (excluding three malignant cases) were at increased risk of being diagnosed with infections (SIR: 3.24, 95% CI: 1.05–7.54) and infertility (SIR: 4.56, 95% CI: 1.48–10.63). The three patients with an adrenocortical carcinoma died shortly after diagnosis, but mortality was not increased in the remaining patients.

Conclusions

CS is rare in the pediatric population. The risk of morbidity related to infections and infertility is elevated and merits further attention.