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Gerrit van den Berg, Steven M Pincus, Johannes D Veldhuis, Marijke Frölich and Ferdinand Roelfsema

Abstract

We investigated the episodicity of 24-h ACTH and cortisol secretory profiles in 16 patients with Cushing's disease and 25 healthy matched controls, with a recently introduced scale- and modelindependent regularity statistic, approximate entropy (ApEn). The mean (± s.e.m.) ApEn value for plasma ACTH concentrations in Cushing's disease was 1·3817 ± 0·033, and in controls 0·8394 ± 0·049 (P< 10−10); for plasma cortisol concentrations the values were 1·4575 ± 0·052 and 0·8637 ± 0·020 respectively (P<10−10), implying greater irregularity of release for both hormones in Cushing's subjects. The calculated sensitivity and specificity of ApEn for ACTH profiles were 94% and 100% respectively. For cortisol the sensitivity and specificity were both 100%. ApEn was not correlated with sex, age, or the total 24-h secretion rate of ACTH and cortisol in patients and controls. The increased ApEn in patients with Cushing's disease points to an increased disorderliness of ACTH and cortisol secretion compared with healthy controls. In conjunction with the available literature, we hypothesize more generally that autonomous endocrine tumors may be typified by reduced regularity, orderliness, or synchrony of the time structure of hormone release.

European Journal of Endocrinology 136 394–400

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Mark R Postma, Romana T Netea-Maier, Gerrit van den Berg, Jens Homan, Wim J Sluiter, Margreet A Wagenmakers, Alfons C M van den Bergh, Bruce H R Wolffenbuttel, Ad R M M Hermus and André P van Beek

Objective

To assess the influence of long-acting somatostatin analogs (SSTA) after initial pituitary surgery on long-term health-related quality of life (HR-QoL) in relation to disease control in patients with acromegaly.

Design

This is a cross-sectional study in two tertiary referral centers in The Netherlands.

Patients and methods

One hundred and eight patients with acromegaly, in whom transsphenoidal (n=101, 94%) or transcranial (n=7, 6%) surgery was performed. Subsequently, 46 (43%) received additional radiotherapy and 41 (38%) were on postoperative treatment with SSTA because of persistent or recurrent disease at the time of study. All subjects filled in standardized questionnaires measuring HR-QoL. Disease control at the time of study was assessed by local IGF1 SDS.

Results

IGF1 SDS were slightly higher in patients treated with SSTA in comparison with patients without use of SSTA (0.85±1.52 vs 0.25±1.21, P=0.026), but the percentage of patients with insufficient control (IGF1 SDS >2) was not different (17 vs 9%, P=0.208). Patients using SSTA reported poorer scores on most subscales of the RAND-36 and the acromegaly QoL and on all subscales of the multidimensional fatigue inventory-20. A subgroup analysis in patients with similar IGF1 levels (SSTA+, n=26, IGF1 SDS 0.44±0.72 vs SSTA−, n=44, IGF1 SDS 0.41±0.65) revealed worse scores on physical functioning, physical fatigue, reduced activity, vitality, and general health perception across all HR-QoL questionnaires in patients treated with SSTA.

Conclusion

QoL is impaired in association with the need for prolonged postoperative therapy by SSTA in patients with acromegaly despite similar IGF1 levels.

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Pauline Brummelman, Margriet G A Sattler, Linda C Meiners, Martin F Elderson, Robin P F Dullaart, Gerrit van den Berg, Janneke Koerts, Oliver Tucha, Bruce H R Wolffenbuttel, Alfonsus C M van den Bergh and André P van Beek

Objective

The hippocampus and prefrontal cortex (PFC) are important for memory and executive functioning and are known to be sensitive to radiotherapy (RT). Radiation dosimetry relates radiation exposure to specific brain areas. The effects of various pituitary RT techniques were studied by relating detailed dosimetry of the hippocampus and PFC to cognitive performance.

Methods

In this cross-sectional design, 75 non-functioning pituitary macroadenoma (NFA) patients (61±10 years) participated and were divided into irradiated (RT+, n=30) and non-irradiated (RT−, n=45) groups. The RT+ group (who all received 25 fractions of 1.8 Gy; total dose: 45 Gy) consisted of three RT technique groups: three-field technique, n=10; four-field technique, n=15; and five-field technique, n=5. Memory and executive functioning were assessed by standardized neuropsychological tests. A reconstruction of the dose distributions for the three RT techniques was made. The RT doses on 30, 50, and 70% of the volume of the left and right hippocampus and PFC were calculated.

Results

Cognitive test performance was not different between the four groups, despite differences in radiation doses applied to the hippocampi and PFC. Age at RT, time since RT, and the use of thyroid hormone varied significantly between the groups; however, they were not related to cognitive performance.

Conclusion

This study showed that there were no significant differences on cognitive performance between the three-, four-, and five-field RT groups and the non-irradiated patient group. A dose–response relationship could not be established, even with a radiation dose that was higher on most of the volume of the hippocampus and PFC in case of a four-field RT technique compared with the three- and five-field RT techniques.

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Robin P F Dullaart, Gerrit van den Berg, Aafke M van der Knaap, Janneke Dijck-Brouwer, Geesje M Dallinga-Thie, Peter M J Zelissen, Wim J Sluiter and André P van Beek

Objective

GH replacement lowers total cholesterol and low-density lipoprotein cholesterol (LDL-C) in GH-deficient adults, but effects on high-density lipoprotein (HDL) cholesterol (HDL-C) are variable. Both GH and glucocorticoids decrease cholesteryl ester transfer protein (CETP) activity, which is important in HDL metabolism. We determined the extent to which the changes in HDL-C in response to GH replacement are predicted by the −629C>A CETP promoter polymorphism, and questioned whether this association is modified by concomitant glucocorticoid treatment.

Design and methods

A total of 91 GH-deficient adults (63 receiving glucocorticoids) were genotyped for the −629 CETP C>A polymorphism. Fasting serum lipids were measured before and after 1.2±0.4 years of GH treatment (Genotropin, Pfizer Inc., Stockholm, Sweden).

Results

In the whole group, total cholesterol and LDL-C decreased (P<0.05) after GH treatment, but the changes in HDL-C were not significant. In CC carriers receiving glucocorticoids (n=19), HDL-C rose by 0.15±0.25 mmol/l (P=0.02; P<0.03 from unchanged HDL-C in −629 AA+CA carriers on glucocorticoids and from CC homozygotes not receiving glucocorticoids). Multivariate regression analysis showed that individual changes in HDL-C were predicted by the CETP polymorphism (CC versus AA+CC, P=0.006) in glucocorticoid users, independently of baseline HDL-C and other variables including apolipoprotein E4 carrier status; an opposite association with the CETP polymorphism was found in patients not receiving glucocorticoids (P=0.053).

Conclusions

We suggest a common CETP variant-glucocorticoid treatment interaction concerning the effect of GH replacement on HDL-C. This may explain some of the reported variation in the HDL-C response to GH.

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Mark R Postma, Thalijn L C Wolters, Gerrit van den Berg, Antonius E van Herwaarden, Anneke C Muller Kobold, Wim J Sluiter, Margreet A Wagenmakers, Alfons C M van den Bergh, Bruce H R Wolffenbuttel, Ad R M M Hermus, Romana T Netea-Maier and André P van Beek

Objective

To assess the effect of somatostatin analogs (SSAs) on mortality in relation to disease control of acromegaly after pituitary surgery.

Design

A retrospective study in two large tertiary referral centers in The Netherlands.

Methods

Overall, 319 patients with acromegaly in whom pituitary surgery was performed as primary therapy between January 1980 and July 2017 were included. Postoperative treatment with SSA was prescribed to 174 (55%) patients because of persistent or recurrent disease. Disease control at last visit was assessed by IGF1 standard deviation score (SDS). Adequate disease control was defined as IGF1 SDS ≤2. Univariate determinants of mortality and standardized mortality ratios (SMRs) were calculated for groups with and without SSA at any moment postoperatively and at last visit.

Results

In total, 27 deaths were observed. In univariate analysis, determinants of mortality were inadequate disease control (relative risk (RR): 3.41, P = 0.005), surgery by craniotomy (RR: 3.53, P = 0.013) and glucocorticoid substitution (RR: 2.11, P = 0.047). There was a strong trend toward increased mortality for patients who used SSA (RR: 2.01, P = 0.067) and/or dopamine agonists (RR: 2.54, P = 0.052) at last visit. The SMR of patients with adequate disease control who used SSA at any moment postoperatively (1.07, P = 0.785) and at last visit (1.19; P = 0.600) was not increased. Insufficiently controlled patients had a significantly raised SMR (3.92, P = 0.006).

Conclusions

Postoperative use of SSA is not associated with increased mortality in patients with acromegaly who attain adequate disease control. In contrast, inadequate disease control, primary surgery by craniotomy and glucocorticoid substitution are associated with increased mortality.