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I C van Nieuwpoort, M C Vlot, L A Schaap, P Lips and M L Drent

Objective

Human aging is accompanied by a decrease in growth hormone secretion and serum insulin-like growth factor (IGF)-1 levels. Also, loss of muscle mass and strength and impairment of physical performance, ending in a state of frailty, are seen in elderly. We aimed to investigate whether handgrip strength, physical performance and recurrent falls are related to serum IGF-1 levels in community-dwelling elderly.

Design

Observational cohort study (cross-sectional and prospective).

Methods

We studied the association between IGF-1 and handgrip strength, physical performance and falls in participants of the Longitudinal Aging Study Amsterdam. A total of 1292 participants were included (633 men, 659 women). Serum IGF-1 levels were divided into quartiles (IGF-1-Q1 to IGF-1-Q4). Data on falls were collected prospectively for a period of 3 years. All analyses were stratified for age and physical activity and adjusted for relevant confounders.

Results

Men with a low physical activity score in IGF-1-Q1 and IGF-1-Q2 of the younger age group had a lower handgrip strength compared to IGF-1-Q4. In younger more active males in IGF-1-Q2 physical performance was worse. Recurrent fallers were less prevalent in older, low active males with low IGF-1 levels. In females, recurrent fallers were more prevalent in older, more active females in IGF-1-Q2. IGF-1 quartile may predict changes in handgrip strength and physical performance in men and women.

Conclusions

Our results indicate that lower IGF-1 levels are associated with lower handgrip strength and worse physical performance, but less recurrent fallers especially in men. Associations were often more robust in IGF-1-Q2. Future studies on this topic are desirable.

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Christa C van Bunderen, Mirjam M Oosterwerff, Natasja M van Schoor, Dorly J H Deeg, Paul Lips and Madeleine L Drent

Objective

High as well as low levels of IGF1 have been associated with cardiovascular diseases (CVD). The relationship of IGF1 with (components of) the metabolic syndrome could help to clarify this controversy. The aims of this study were: i) to investigate the association of IGF1 concentration with prevalent (components of) the metabolic syndrome; and ii) to examine the role of (components of) the metabolic syndrome in the relationship between IGF1 and incident CVD during 11 years of follow-up.

Methods

Data were used from the Longitudinal Aging Study Amsterdam, a cohort study in a representative sample of the Dutch older population (≥65 years). Data were available in 1258 subjects. Metabolic syndrome was determined using the definition of the US National Cholesterol Education Program Adult Treatment Panel III. CVD were ascertained by self-reports and mortality data.

Results

Levels of IGF1 in the fourth quintile were associated with prevalent metabolic syndrome compared with the lowest quintile (odds ratio: 1.59, 95% confidence interval (CI) 1.09–2.33). The middle up to the highest quintile of IGF1 was positively associated with high triglycerides in women. Metabolic syndrome was not a mediator in the U-shaped relationship of IGF1 with CVD. Both subjects without the metabolic syndrome and low IGF1 levels (hazard ratio (HR) 1.75, 95% CI 1.12–2.71) and subjects with the metabolic syndrome and high IGF1 levels (HR 2.28, 95% CI 1.21–4.28) demonstrated increased risks of CVD.

Conclusions

In older people, high-normal IGF1 levels are associated with prevalent metabolic syndrome and high triglycerides. Furthermore, this study suggests the presence of different pathomechanisms for both low and high IGF1 levels and incident CVD.

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Christa C van Bunderen, Carline J van den Dries, Martijn W Heymans, Anton A M Franken, Hans P F Koppeschaar, Aart J van der Lely and Madeleine L Drent

Objective

Isolated GH deficiency (IGHD) could provide a model to investigate the influence of GH deficiency per se and the effect of GH replacement therapy without the influence from other pituitary hormone deficiencies or their treatment. The aim of this study is to address the questions about differences between IGHD and multiple pituitary hormone deficiencies (MPHDs) in clinical presentation and in responsiveness to GH treatment.

Design

A nationwide surveillance study was carried out to describe the difference in the clinical presentation and responsiveness to GH treatment of patients with IGHD and MPHDs.

Methods

The Dutch National Registry of GH Treatment in Adults was founded in 1998 to gain more insight into long-term efficacy and safety of GH therapy. Out of 2891 enrolled patients, 266 patients with IGHD at the start of GH treatment were identified and compared with 310 patients with MPHDs. Cardiovascular indices will be investigated at baseline and during long-term follow-up, including body composition, lipid profile, glucose metabolism, blood pressure, and morbidity.

Results

Patients with IGHD and MPHDs were demonstrated to be different entities at clinical presentation. Metabolically, patients with MPHDs had a larger waist circumference, lower HDL cholesterol level, and higher triglyceride level. The effect of GH treatment was comparable between patient groups. GH seems to protect against rising lipid levels and blood pressure, even after excluding patients using corresponding concomitant medication. The risk for cardiovascular disease or diabetes mellitus during follow-up was not different between patients with IGHD and MPHDs.

Conclusions

Patients with IGHD had a less impaired metabolic profile than patients with MPHDs at baseline. Influence of other pituitary hormone replacement therapies on the effect of GH treatment is not demonstrated.

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Christa C van Bunderen, Nadège C van Varsseveld, Martijn W Heymans, Anton A M Franken, Hans P F Koppeschaar, Aart J van der Lely and Madeleine L Drent

Objective

The effect of GH deficiency (GHD) on the metabolic profile of acromegaly patients is unclear in patients previously treated for acromegaly, as are the efficacy and safety of GH treatment in this particular group. The aim of the study is to describe the characteristics of patients with severe GHD who were previously treated for acromegaly, and to investigate the effects of long-term GH treatment on cardiovascular risk factors and morbidity, compared with patients who were treated for a nonfunctioning pituitary adenoma (NFPA).

Design

A nationwide surveillance study.

Methods

Sixty-five patients from the Dutch National Registry of Growth Hormone Treatment in Adults with previous acromegaly were compared with 778 patients with previous NFPA. Cardiovascular indices, including body composition, lipid profile, glucose metabolism, blood pressure, and morbidity were investigated.

Results

GHD patients with previous acromegaly had an unfavorable metabolic profile comparable with or more than GHD patients with previous NFPA. GH treatment led to improvement of the lipid profile in both groups, also after excluding patients using lipid-lowering medication. In patients with previous acromegaly, HbA1c levels increased more than in patients with previous NFPA (estimate 0.03, 95% CI 0.002–0.06, P=0.04). The risk for developing cardiovascular diseases was not different between the groups.

Conclusions

The patients with GHD after previous acromegaly have an unfavorable metabolic profile comparable with patients with GHD after previous NFPA. In both groups, the lipid profile improves during GH treatment. Changes in glucose metabolism should be monitored closely. GH treatment in patients with GHD previously treated for acromegaly had no deleterious effect on cardiovascular morbidity.

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I C van Nieuwpoort, C C van Bunderen, L I Arwert, A A M Franken, H P F Koppeschaar, A J van der Lelij, J W R Twisk, M Boers and M L Drent

Objective

The Dutch National Registry of GH Treatment in Adults was established in 1998 as an initiative of the Ministry of Health. The main goals were to gain more insight into long-term efficacy, safety, and costs of GH therapy (GHT) in adult GH-deficient (GHD) patients in The Netherlands.

Methods

Baseline patient characteristics and diagnostic test procedures were evaluated.

Results

Until January 2009 in roughly 10 years, 2891 patients (1475 men and 1416 women, mean age 43.5±16.5 years) were registered. GHD was of childhood-onset (CO) in over 20% of the patients and of isolated in 11%. The most common causes of GHD were pituitary tumors and/or their treatment, craniopharyngiomas, and idiopathic GHD. In 85% of the patients, a GH stimulation test was performed, in the majority an insulin tolerance test (ITT) (49%) or a combined GHRH–arginine test (25%). In 12% of the patients, IGF1 levels were ≤−2 s.d. combined with two or more additional pituitary hormone deficits, and in 2%, it concerned patients with CO-GHD continuing GHT in adulthood. Over the years, the test of first choice shifted from ITT toward GHRH–arginine test.

Conclusion

Nearly, 2900 patients were included in the nationwide surveillance database of the Dutch National Registry of GH Treatment in Adults until January 2009. Baseline patient characteristics are comparable to that reported previously. In 85% of these patients, the diagnosis of GHD was established by provocative testing, particularly an ITT or a combined GHRH–arginine test, with an evident increase in the percentage of GHRH–arginine tests being performed in the last years.

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E B Conemans, L Lodewijk, C B Moelans, G J A Offerhaus, C R C Pieterman, F H Morsink, O M Dekkers, W W de Herder, A R Hermus, A N van der Horst-Schrivers, M L Drent, P H Bisschop, B Havekes, L A A Brosens, K M A Dreijerink, I H M Borel Rinkes, H Th M Timmers, G D Valk and M R Vriens

Objective

Epigenetic changes contribute to pancreatic neuroendocrine tumor (PanNET) development. Hypermethylation of promoter DNA as a cause of tumor suppressor gene silencing is a well-established oncogenic mechanism that is potentially reversible and therefore an interesting therapeutic target. Multiple endocrine neoplasia type 1 (MEN1) is the most frequent cause of inherited PanNETs. The aim of this study was to determine promoter methylation profiles in MEN1-related PanNETs.

Design and methods

Methylation-specific multiplex ligation-dependent probe amplification was used to assess promoter methylation of 56 tumor suppressor genes in MEN1-related (n = 61) and sporadic (n = 34) PanNETs. Differences in cumulative methylation index (CMI), individual methylation percentages and frequency of promoter hypermethylation between subgroups were analyzed.

Results

We found promoter methylation of a large number of potential tumor suppressor genes. CMI (median CMI: 912 vs 876, P = 0.207) was the same in MEN1-related and sporadic PanNETs. We found higher methylation percentages of CASP8 in MEN1-related PanNETs (median: 59% vs 16.5%, P = 0.002). In MEN1-related non-functioning PanNETs, the CMI was higher in larger PanNETs (>2 cm) (median: 969.5 vs 838.5; P = 0.021) and in PanNETs with liver metastases (median: 1036 vs 869; P = 0.013). Hypermethylation of MGMT2 was more frequent in non-functioning PanNETs compared to insulinomas (median: 44.7% vs 8.3%; P = 0.022). Hypermethylation of the Von Hippel–Lindau gene promoter was observed in one MEN1-related PanNET and was associated with loss of protein expression.

Conclusion

Promoter hypermethylation is a frequent event in MEN1-related and sporadic PanNETs. Targeting DNA methylation could be of therapeutic value in MEN1 patients with advanced PanNETs.

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Lutske Lodewijk, Pim J Bongers, Jakob W Kist, Elfi B Conemans, Joanne M de Laat, Carla R C Pieterman, Anouk N A van der Horst-Schrivers, Ciska Jorna, Ad R Hermus, Olaf M Dekkers, Wouter W de Herder, Madeleine L Drent, Peter H Bisschop, Bas Havekes, Inne H M Borel Rinkes, Menno R Vriens and Gerlof D Valk

Objective

Currently, little is known about the prevalence of thyroid tumors in multiple endocrine neoplasia type 1 (MEN1) patients and it is unclear whether tumorigenesis of these thyroid tumors is MEN1-related. The aim of the study was to assess the prevalence of thyroid incidentalomas in MEN1 patients compared with nonMEN1 patients and to verify whether thyroid tumorigenesis is MEN1-related.

Design

A cross-sectional study.

Methods

The study included two groups: patients with MEN1 and a matched non-MEN1 control group without known thyroid disease, who underwent an ultrasound of the neck for the localization of parathyroid adenoma. Ninety-five MEN1 patients underwent ultrasound of the neck and were matched on gender and age with non-MEN1 patients. The prevalence of thyroid incidentalomas described in the ultrasound report was scored. Multinodular goiters, solitary nodes, and cysts were scored as incidentalomas. Presence of nuclear menin expression was evaluated by menin immunostaining of the thyroid tumors.

Results

In the MEN1 group, 43 (45%) patients had a thyroid incidentaloma compared with 48 (51%) in the non-MEN1 group, of which 14 (15%) and 16 (17%), respectively, were solitary nodes. Menin was expressed in the nuclei of all evaluated thyroid tumors.

Conclusions

MEN1 patients do not have a higher prevalence of thyroid incidentalomas compared with primary hyperparathyroidism patients without the diagnosis of MEN1. Menin was expressed in the thyroid tumors of MEN1 patients.