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Circadian patterns of serum insulin-like growth factor (IGF) II and IGF binding protein 3 in growth hormone-deficient patients and age- and sex-matched normal subjects

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.

Open access

Prenatal exposure to glucocorticoids and the prevalence of overweight or obesity in childhood

Kristina Laugesen, Henrik Toft Sørensen, Jens Otto L Jorgensen, and Irene Petersen

Objective

Prenatal exposure to excess cortisol can affect postnatal metabolic health by epigenetic mechanisms. We aimed to investigate if prenatal exposure to pharmacological glucocorticoids increases the risk of overweight/obesity in childhood.

Design

A nationwide population registry-based cohort study.

Methods

We identified 383 877 children born in Denmark (2007–2012), who underwent routine anthropometric evaluation at 5–8 years of age. Prenatal exposure to glucocorticoids was divided into systemic and topical glucocorticoids, cumulative systemic dose, and use by trimester. The comparison cohort included children without exposure, born to maternal never-users. Negative control exposures were used to investigate confounding from an underlying disease or unmeasured characteristics. Such exposures included children without glucocorticoid exposure born to maternal users of non-steroidal anti-inflammatory drugs or immunotherapy during pregnancy, maternal former users of glucocorticoids, or paternal users of glucocorticoids during the pregnancy of their partner. We estimated sex-stratified adjusted prevalence ratios (aPR) of overweight/obesity at 5–8 years of age, as epigenetic modifications have shown to be sex-specific.

Results

In the study, 21 246 (11%) boys and 27 851 (15%) girls were overweight/obese at 5–8 years of age. Overall, neither systemic nor topical glucocorticoids were associated with overweight/obesity. In boys, high-dose systemic glucocorticoids was associated with higher prevalence of overweight/obesity vs the comparison cohort (aPR: 1.41 (95% CI: 1.07–1.86), prevalence: 16% vs 11%). Negative control exposures indicated robustness to confounding.

Conclusion

Overweight/obesity might be an adverse effect of prenatal exposure to high-dose systemic glucocorticoids in boys. We found no association for neither prenatal exposure to lower doses of systemic nor topical glucocorticoids. These results merit clinical attention.

Free access

DIAGNOSIS OF ENDOCRINE DISEASE: Prevalence of hypercortisolism in type 2 diabetes patients: a systematic review and meta-analysis

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.

Free access

Inflammatory adipokines contribute to insulin resistance in active acromegaly and respond differently to different treatment modalities

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.

Free access

Hyponatremia and mortality risk: a Danish cohort study of 279 508 acutely hospitalized patients

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.

Free access

Conventional and novel biomarkers of treatment outcome in patients with acromegaly: discordant results after somatostatin analog treatment compared with surgery

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.

Free access

Serum proteome changes in acromegalic patients following transsphenoidal surgery: novel biomarkers of disease activity

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.

Free access

MANAGEMENT OF ENDOCRINE DISEASE: Glucocorticoid-induced adrenal insufficiency: replace while we wait for evidence?

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.

Free access

Apoplexy of microprolactinomas during pregnancy: report of five cases and review of the literature

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

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 the 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 micro-prolactinomas) 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.

Free access

Acute cardiovascular events and all-cause mortality in patients with hyperthyroidism: a population-based cohort study

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.