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Summary In July 2017, a 35-year-old woman was referred to our care for treatment of a large pituitary mass with an unusually high growth rate. She presented with right-sided ptosis and diplopia (n. III palsy), increasing retrobulbar pain and vertigo. Although laboratory investigations were consistent with acromegaly, she exhibited no clear phenotypic traits. During transsphenoidal surgery aimed at biopsy, typical adenomatous tissue was encountered, upon which it was decided to proceed to debulking. Histopathological analysis demonstrated a poorly differentiated plurihormonal Pit-1-positive adenoma with focal growth hormone (GH) and prolactin positivity, positive SSTR2 staining and a Ki-67 of 20–30%. Postoperative magnetic resonance imaging (MRI) examination revealed a large tumour remnant within the sella invading the right cavernous sinus with total encasement of the internal carotid artery and displacement of the right temporal lobe. As a consequence, she was treated additionally with radiotherapy, and a long-acting first-generation somatostatin analogue was prescribed. Subsequently, the patient developed secondary hypocortisolism and diabetes mellitus despite adequate suppression of GH levels. In September 2019, her symptoms recurred. Laboratory evaluations indicated a notable loss of biochemical control, and MRI revealed tumour progression. Lanreotide was switched to pasireotide, and successful removal of the tumour remnant and decompression of the right optic nerve was performed. She received adjuvant treatment with temozolomide resulting in excellent biochemical and radiological response after three and six courses. Symptoms of right-sided ptosis and diplopia remained. Evidence for systemic therapy in case of tumour progression after temozolomide is currently limited, although various potential targets can be identified in tumour tissue. Learning points Poorly differentiated plurihormonal Pit-1-positive adenoma is a potentially aggressive subtype of pituitary tumours. This subtype can express somatostatin receptors, allowing treatment with somatostatin analogues. A multidisciplinary approach involving an endocrinologist, neurosurgeon, pituitary pathologist, neuroradiologist, radiation oncologist and medical oncologist is key for the management of patients with aggressive pituitary tumours, allowing the successful application of multimodality treatment. Temozolomide is first-line chemotherapy for aggressive pituitary tumours and carcinomas. Further development of novel targeted therapies, such as peptide receptor radionuclide therapy (PRRT), vascular endothelial growth factor (VEGF) receptor-targeted therapy, tyrosine kinase inhibitors, mammalian target of rapamycin (mTOR) inhibitors and immune checkpoint inhibitors, is needed.

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.

CONTEXT AND OBJECTIVE This study aimed at comparing pharmacokinetics of two different doses of hydrocortisone (HC) in patients with secondary adrenal insufficiency (SAI). DESIGN, SETTING AND PATIENTS Forty-six patients with SAI participated in this randomized double-blind crossover study. INTERVENTION Patients received two different doses of HC (0.2-0.3mg HC/kg body weight/day and 0.4-0.6mg HC/kg body weight/day). MAIN OUTCOME MEASURES One- and two-compartment population models for plasma free cortisol, plasma total cortisol and salivary cortisol were parameterized. The individual pharmacokinetic parameters clearance (CL), volume of distribution (Vd), elimination half-life (t1/2), maximum concentration (Cmax), and area under the curve (AUC) were calculated. RESULTS The one-compartment models gave a better description of the data compared to the two-compartment models. Weight-adjusted dosing reduced variability in cortisol exposure with comparable AUCs between weight groups. However, there was large inter-individual variation in CL and Vd of plasma free cortisol, plasma total cortisol and salivary cortisol. As a consequence, AUC24h varied more than 10 fold. Cortisol exposure was increased with the higher dose, but this was dose proportional only for free cortisol concentrations and not for total cortisol. CONCLUSIONS Cortisol concentrations after a doubling of the dose were only dose proportional for free cortisol. HC pharmacokinetics can differ up to 10-fold inter-individually and individual adjustment of treatment doses may be necessary. Doubling of the HC dose in fast metabolizers (patients that showed relative low AUC and thus high clearance compared to other patients), does not result in significantly enhanced exposure during large parts of the day and these patients may need other management strategies.

ContextThyroid dysfunction is thought to be associated with stillbirth. Therefore, thyroid function is often recommended in the diagnostic investigations for stillbirth.ObjectiveWe aimed to evaluate the added value of thyroid function testing in the diagnostic investigations for stillbirth.Design and patientsA nationwide multicentre prospective cohort study in 1025 women who suffered stillbirth >20 weeks of gestation performed between 2002 and 2008. In each woman, an extensive diagnostic work-up was performed, including placental examination and autopsy. TSH and FT4 values below the 25th percentile or above the 975th percentile according local laboratory reference values were regarded as abnormal. Women with a history of thyroid disease were evaluated separately.Main outcome measuresThyroid function abnormalities in women with stillbirth.ResultsOf 1025 included women, 21 had a history of thyroid disease (2%). In the 875 with TSH and FT4 results and no history of thyroid disease, 10% had hypothyroxinemia, 46% subclinical hypothyroidism, 16% overt hypothyroidism and 15% subclinical hyperthyroidism. Women with a subclinical hyperthyroidism more often had a foetal death caused by foetal hydrops: 23% vs 29% (adjusted OR 103, 95% CI 25-42).ConclusionsWomen with a stillbirth had a slightly higher prevalence of overt hypothyroidism, subclinical hypothyroidism and hypothyroxinaemia compared to previous studies on thyroid dysfunction in pregnant women. Given the absence of a strong associations with the cause of stillbirth, and no demonstrated beneficial effects of treating thyroid dysfunction in these women, routine screening after stillbirth is not justified.

Background: There is a major lack of randomized controlled trials (RCTs) evaluating the effects of hydrocortisone (HC) substitution therapy in patients with secondary adrenal insufficiency. Therefore, we evaluated the effects of two different replacement doses of HC on health-related quality of life (HRQoL) in a RCT. Methods: This RCT with a double-blind cross-over design was performed at the University Medical Center Groningen. Forty-seven patients (29 men, age 51 ± 14 years, range 19-73 years) with secondary adrenal insufficiency participated. Patients received both a lower and a higher dose of HC (0.2-0.3 and 0.4-0.6 mg/kg body weight/day) for 10 weeks in random order. HRQoL was assessed with a daily mood and symptom checklist (Patient Health Questionnaire-15 [PHQ-15], Generalized Anxiety Disorder-7 [GAD-7], Patient Health Questionnaire-9 [PHQ-9]) and with questionnaires assessing general well-being (RAND 36-Item Health Survey [RAND-36]), mood (Hospital Anxiety and Depression Scale [HADS]) and fatigue (Multidimensional Fatigue Inventory-20 [MFI-20]). ClinicalTrials.gov identifier: NCT01546922. Results: Patients receiving the higher dose of HC reported significantly fewer symptoms of depression (p = 0.016 and p = 0.045 for HADS and PHQ-9, respectively), less general and mental fatigue (p = 0.004 and p = 0.003, respectively, both MFI-20), increased motivation (p = 0.021, MFI-20), better physical functioning (p = 0.041), better general health (p = 0.013) and more vitality (p = 0.025) (all RAND-36). In addition, while on the higher dose, fewer somatic symptoms (p = 0.022) and less pain (p < 0.001) (both PHQ-15) were experienced. Conclusions: On the higher dose of HC, patients reported a better HRQoL on various domains as compared to the lower dose of HC. The fact that a higher dose of HC may improve patient well-being should be taken into consideration when individualizing the HC substitution dose.

Context: A wide variety in hydrocortisone (HC) substitution dose-regimens are considered physiological for patients with secondary adrenal insufficiency (SAD. However, it is likely that cognition is negatively influenced by higher cortisol exposure to the brain.Objective: To examine the effects of a high physiological HC dose in comparison to a low physiological HC dose on cognition.Design and setting: This study was a randomized double blind cross-over study at the University Medical Center Groningen. This study is registered with ClinicalTrials.gov, number NCT01546922.Patients: Forty-seven patients (29 males, 18 females; mean [SD] age, 51 [14] years, range 19-73) with SAI participated.Intervention(s): Patients randomly received first a low dose of HC (0.2-0.3 mg/kg body weight/day) during 10 weeks followed by a high dose (0.4-0.6 mg/kg body weight/day) for another 10 weeks, or vice versa. HC substitution was given in three divided doses with the highest dose in the morning.Main outcome measure(s): Cognitive performance (memory, attention, executive functioning and social cognition) of patients was measured at baseline and after each treatment period using a battery of 12 standardized cognitive tests.Results: The higher dose of HC resulted in significantly higher systemic cortisol exposure for example measured at 1 h after first dose ingestion (mean [SD], low dose: 653 [281] nmol/L; high dose: 930 [148] nmol/L; PConclusions: No negative influence on memory, attention, executive functioning and social cognition was observed after 10 weeks of treatment with a higher physiological dose of HC in patients with SAI when compared to a lower dose. (C) 2015 Elsevier Ltd. All rights reserved.

Purpose: The extent to which cognitive dysfunction is related to specific brain abnormalities in patients treated for pituitary macroadenoma is unclear. Therefore, we compared brain abnormalities seen on Magnetic Resonance Imaging (MRI) in patients treated for nonfunctioning pituitary macroadenoma (NFA) with or without impairments in cognitive functioning.Methods: In this cross-sectional design, a cohort of 43 NFA patients was studied at the University Medical Center Groningen. White matter lesions (WMLs), cerebral atrophy, (silent) brain infarcts and abnormalities of the temporal lobes and hippocampi were assessed on pre-treatment and post-treatment MRI scans. Post-treatment cognitive examinations were performed using a verbal memory and executive functioning test. We compared our patient cohort with large reference populations representative of the Dutch population.Results: One or more impairments on both cognitive tests were frequently observed in treated NFA patients. No treatment effects were found with regard to the comparison between patients with and without impairments in executive functioning. Interestingly, in patients with one or more impairments on verbal memory function, treatment with radiotherapy had been given more frequently (74% in the impaired group versus 40% in the unimpaired group, P = 0.025). Patients with or without any brain abnormality on MRI did not differ in verbal memory or executive functioning.Conclusions: Brain abnormalities on MRI are not observed more frequently in treated NFA patients with impairments compared to NFA patients without impairments in verbal memory or executive functioning. Conversely, the absence of brain abnormalities on MRI does not exclude impairments in cognition. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

Background and purpose: To assess and compare brain abnormalities on Magnetic Resonance Imaging (MRI) in non-functioning pituitary macro-adenoma (NFA) patients treated with or without postoperative radiotherapy (RT).Material and methods: In 86 NFA patients, treated between 1987 and 2008 at the University Medical Center Groningen, white-matter lesions (WMLs), cerebral atrophy, brain infarctions and abnormalities of the temporal lobes and hippocampi were assessed on pre- and-post-treatment MRI scans in patients treated with (n = 47) or without RT.Results: The median MRI follow-up time for RT patients was 10 (range 1-22) years and 5 (range 1-21) years in patients treated without RT. In RT patients the cumulative incidence of WMLs was significantly lower compared to patients treated without RT (log-rank test RR 0.49, 95% CI 0.25-0.97, p =.042). The cumulative incidences of cerebral atrophy, brain infarctions, abnormalities of the temporal lobes and hippocampi, and the severity of WMLs and cerebral atrophy ratings were not significantly different between the two treatment groups.Conclusions: Brain abnormalities on MRI are not observed more frequently in NFA patients treated with RT compared to patients treated with surgery-alone. Furthermore, RT was not associated with an increased severity of WMLs and cerebral atrophy ratings in this cohort of NFA patients. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

BACKGROUND Low cortisol levels are associated with several functional pain syndromes. In patients with secondary adrenal insufficiency (SAI), the lack in endogenous cortisol production is substituted by the administration of oral hydrocortisone (HC). Our previous study showed that a lower dose of HC led to an increase in reported subjective pain symptoms. Whether different doses of HC substitution alter somatosensory functioning in SAI patients has not been established yet. METHODS In this randomized double blind cross-over trial, forty-six patients with SAI participated. Patients randomly received either first a lower dose (0.2-0.3 mg HC/kg body weight/day) for 10 weeks followed by a higher dose (0.4-0.6 mg HC/kg body weight/day) for another 10 weeks, or vice versa. After each treatment period, blood samples were drawn and somatosensory functioning was assessed by determining the mechanical detection threshold (MDT), mechanical pain threshold (MPT), mechanical pain sensitivity (MPS) and the pain pressure threshold (PPT), according to the Quantitative Sensory Testing (QST) battery by the German Network on Neuropathic Pain. RESULTS The administration of the higher dose of HC resulted in significantly higher levels of cortisol (mean [SD] 748 [245] nmol/L) than the lower dose (537 [250] nmol/L, P

Background Although there is convincing evidence for the association between small for gestational age (SGA) and socioeconomic status (SES), it is not known to what extent explanatory factors contribute to this association. Aim To examine to what extent risk factors could explain educational inequalities in SGA. Study design In this study fully completed data were available for 3793 pregnant women of Dutch origin from a population-based cohort (ABCD study). Path-analysis was conducted to examine the role of explanatory factors in the relation of maternal education to SGA. Results Low-educated pregnant women had a higher risk of SGA offspring compared to the high-educated women (OR 1.98, 95% CI 1.35–2.89). In path-analysis, maternal cigarette smoking and maternal height explained this association. Maternal age, hypertension, chronic disease, late entry into antenatal care, neighborhood income, underweight, environmental cigarette smoking, drug abuse, alcohol use, caffeine intake, fish intake, folic acid intake, anxiety, and depressive symptoms did not play a role in the association between maternal education and SGA birth. Conclusion Among a large array of potential factors, the elevated risk of SGA birth among low-educated women appeared largely attributable to maternal smoking and to a lesser extent to maternal height. To reduce educational inequalities more effort is required to include low-educated women especially in prenatal intervention programs such as smoking cessation programs instead of effort into reducing other SGA-risk factors, though these factors might still be relevant at the individual level.

The objective of this study is first to examine the relation of maternal education and growth velocity during the first year of life and early childhood (1–5 years). The second objective is to determine the potential explanatory role of standardized birth weight, maternal smoking during pregnancy, maternal prepregnancy body mass index (BMI), and infant feeding practice in this relation. We used longitudinal growth data of 1,684 participants with Dutch ethnicity participating in a population-based cohort study (Amsterdam Born Children and their Development study). Growth velocity of weight and of weight-for-length were calculated by subtracting the weight and weight-for-length standard deviation scores (SDS), respectively of two time periods. In the first year of life, children with low-educated mothers had an increase in SDS of 0.26 (95 % confidence interval (CI) 0.08–0.45) for weight compared to children with high-educated mothers. In early childhood, children with low-educated mothers had a 0.27 SDS (95 % CI 0.11–0.42) increase for weight-for-length, compared to children with high-educated mothers. Using path analysis, these inequalities could partly be explained by maternal smoking, duration of breastfeeding, maternal age, and maternal BMI. Conclusion: Children with low-educated mothers had an increased weight gain during the first year of life and an increased weight-for-length gain in early childhood compared to children with high-educated mothers. Although underlying mechanisms were not completely clarified, an optimal duration of breastfeeding, cessation of maternal smoking, and reduction of maternal BMI seem to reduce these educational inequalities in early growth and possible adverse consequences of accelerated growth.

Bestraling is veilig bij behandeling voor goedaardige hypofysetumor. Patienten die met bestraling (radiotherapie) zijn behandeld voor een goedaardige tumor in de hypofyse vertoonden geen grote verschillen in late effecten ten opzichte van vergelijkbare patienten die niet bestraald waren. Hiervoor onderzocht Margriet Sattler patienten met een niet-functionerend hypofyse-adenoom, acromegalie of de ziekte van Cushing. Dat deze patienten geen aantoonbare schade oplopen, pleit voor deze behandeling, aldus de promovenda. Zij onderzocht de incidentie van secundaire tumoren, mortaliteit, cerebrovasculaire ziekte en radiologische afwijkingen van de hersenen, en van cognitie en seksueel functioneren als aspect van kwaliteit van leven van patienten die zijn behandeld voor hypofysetumoren. De behandeling voor een hypofysetumor bestaat meestal uit een operatie, eventueel gevolgd door radiotherapie en/of hormoononderdrukkende medicatie. Sattler bestudeerde de late effecten van radiotherapie in een grote groep patienten met een hypofysetumor. Er waren nog weinig vergelijkende studies verricht betreffende de late effecten onder bestraalde en niet bestraalde hypofysepatienten. Volgens de promovenda is het risico op late effecten van de radiotherapie klein met de radiotherapietechnieken die zijn toegepast in de laatste decennia en dit zal naar verwachting nog lager worden met de moderne en meer geavanceerde radiotherapietechnieken. Ze concludeert dat in de meeste patienten met een hypofysetumor die nadat opereren niet meer mogelijk is nog steeds ziekteactiviteit hebben, de voordelen van radiotherapie opwegen tegen het kleine risico op ernstige late effecten. Margriet Sattler studeerde Geneeskunde aan de Rijksuniversiteit Groningen en volgde haar opleiding tot radiotherapeut-oncoloog in het Universitair Medisch Centrum Groningen (UMCG). Zij verrichtte haar promotieonderzoek bij de afdelingen Radiotherapie en Endocrinologie van het UMCG.

ObjectiveThe 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.MethodsIn 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.ResultsCognitive 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.ConclusionThis 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.

Objectives: To illustrate the importance of recognizing symptoms of severe hypercortisolism in the intensive care unit and key emergency measures to reduce this extreme hypercortisolism.Design: Case report.Setting: Intensive care unit in a university hospital.Patient: A 55-yr-old woman was admitted to the intensive care unit with multiorgan failure after perforation of the sigmoid. Recent-onset hypertension, spontaneous hypokalemia, and diabetes mellitus suggested severe Cushing's syndrome as the underlying disease. Markedly increased serum cortisol (5900 nmol/L) and adrenocorticotropic hormone (302 ng/L) levels were found, highly suggestive for ectopic adrenocorticotropic hormone secretion. Imaging studies failed to unequivocally establish a solitary source of ectopic adrenocorticotropic hormone secretion. The deteriorating condition of the patient urged rapid intervention.Interventions: Etomidate was infused continuously to reduce endogenous adrenal cortisol secretion. Subsequently, a rescue bilateral adrenalectomy was undertaken.Measurements and Results: Etomidate effectively reduced the cortisol level. Serial blood samples were obtained during the bilateral adrenalectomy. Plasma adrenocorticotropic hormone markedly decreased immediately after resection of the right adrenal gland. Histopathological examination revealed a tumor of the right adrenal gland identified as a pheochromocytoma and hyperplasia of the left adrenal gland, but no signs of malignancy. The patient recovered slowly.Conclusion: This case illustrates that severe hypercortisolism is a medical emergency and that specific and prompt combined medical and surgical intervention can be life-saving. (Crit Care Med 2010; 38:1598-1601)

ObjectiveGH 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 methodsA 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).ResultsIn the whole group, total cholesterol and LDL-C decreased (Pn=19), HDL-C rose by 0.15±0.25 mmol/l (P=0.02; PCETP 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).ConclusionsWe 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.

Purpose: To demonstrate the benefit of immediate postoperative radiotherapy in residual nonfunctioning pituitary adenoma (NFA) in perspective to the need for hormonal substitution and life expectancy.Methods and Materials: Retrospective cohort analysis of 122 patients, operated for NFA between 1979 and 1998. Recurrence was defined as regrowth on computed tomography or magnetic resonance imaging. The occurrence of hormonal deficiencies was defined as the starting date of hormonal substitution therapy.Results: Seventy-six patients had residual NFA after surgery and received immediate postoperative radiotherapy (Group 1); three patients developed a recurrence, resulting in a 95% local control rate at 10 years. Twenty-eight patients had residual NFA after surgery, but were followed by a wait-and-see policy (Group 2). Sixteen developed a recurrence, resulting in a local control rate of 49% at 5 years and 22% at 10 years (p Conclusions: Immediate postoperative radiotherapy provides a marked improvement of local control among patients with residual NFA compared with surgery alone, without an additional deleterious effect on pituitary function and life expectancy. (c) 2007 Elsevier Inc.

Despite adequate glycemic control, pregnancy outcome of women with type 1 diabetes (T1D) is still unfavorable as compared to healthy women. In a rat-model of T1D under normoglycemic conditions, adverse pregnancy outcome was also observed, which was associated with aberrant immunological adaptations to pregnancy. Because similar processes may occur in women with T1D we studied the systemic immune response in non-pregnant and pregnant women with and without T1D. The systemic immune response was assessed by using flow cytometry to evaluate the number and activational status of subpopulations of lymphocytes, Natural Killer cells and monocytes in peripheral blood of non-pregnant and pregnant women with and without T1D. An increased white blood cell count, an increased Th1/Th2 ratio, increased Natural Killer cell expression of CD335 and enhanced activation of intermediate and non-classical monocytes was observed in pregnant women with T1D vs. healthy pregnant women. Also, the pregnancy outcome (i.e. incidence of preterm delivery and macrosomia) of women with T1D was unfavorable as compared to healthy women. This study showed that in T1D, the immunological adaptations to pregnancy are disturbed. In addition to hyperglycemia, these different immunological adaptations may be responsible for the greater frequency of complications in pregnant women with T1D.

Summary OBJECTIVE As described originally, Nelson’s syndrome is characterized by grossly elevated ACTH concentrations, a sellar mass and skin hyperpigmentation emerging in the course of Cushing’s disease after bilateral adrenalectomy. No detailed studies have defined whether the mechanisms directing ACTH secretion differ in Nelson’s syndrome and untreated Cushing’s disease. PATIENTS AND METHODS To address this pathophysiological issue, we studied nine patients fulfilling the criteria of Nelson’s syndrome receiving glucocorticoid and mineralocorticoid replacement; nine patients with untreated pituitary-dependent Cushing’s disease and nine gender- and age-matched controls. ACTH release was appraised by monitoring plasma ACTH concentrations in blood samples collected every 10 min for 24 h. ACTH secretion rates and endogenous decay were quantified by multiparameter deconvolution analysis. The orderliness of the ACTH release process was delineated by the approximate entropy (ApEn) statistic. Diurnal variation in ACTH secretion was appraised by cosinor analysis. RESULTS Basal ACTH secretion was increased sixfold and pulsatile secretion ninefold in patients with Nelson’s syndrome compared with Cushing’s disease ( P ≤ 0·01 and P ≤ 0·001, respectively). The increase in pulsatile secretion was due to an eightfold augmentation of burst mass. Event frequency was comparable in both patient groups (32 ± 1 vs. 28 ± 2 pulses/24 h), and higher than in normal controls (22 ± 1 pulses/24 h, P < 0·0001). Paradoxically, the consistency of subordinate patterns of serial ACTH release, albeit disrupted in active Cushing’s disease, was normal in Nelson’s syndrome ( P = 0·014). Normal ACTH secretory-process regularity in Nelson’s syndrome was attributable to a more reproducible (lower ApEn) succession of ACTH secretory-burst mass denoting more uniform amplitude evolution over 24 h ( P = 0·007, Nelson vs. Cushing). However, the quantifiable regularity of serial interburst intervals (waiting times) was unexpectedly elevated in Nelson’s syndrome ( P = 0·022). Nelson patients maintained a significant diurnal rhythm in ACTH release, which was marked by a 15-fold greater amplitude ( P = 0·0018 vs. Cushing’s) and a 4-h acrophase (maximum) delay ( P = 0·037 vs. control). CONCLUSION The present detailed analyses delineate marked ACTH secretory-burst mass amplification and (amplitude-independent) anomalous regularity of successive pulse size and timing in Nelson’s syndrome compared with Cushing’s disease or controls. We postulate that the foregoing novel distinctions are due to unique tumoural secretory properties, concurrently required glucocorticoid replacement and/or hypothalamic injury associated with prior radiotherapy in Nelson’s syndrome.

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), 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

Item does not contain fulltext PURPOSE: To assess and compare the incidence of stroke and stroke subtype in pituitary adenoma patients treated with postoperative radiation therapy (RT) and surgery alone. METHODS AND MATERIALS: A cohort of 462 pituitary adenoma patients treated between 1959 and 2008 at the University Medical Center Groningen in The Netherlands was studied. Radiation therapy was administered in 236 patients. The TOAST (Trial of ORG 10172 in Acute Stroke Treatment) and the Oxfordshire Community Stroke Project classification methods were used to determine causative mechanism and anatomic localization of stroke. Stroke incidences in patients treated with RT were compared with that observed after surgery alone. Risk factors for stroke incidence were studied by log-rank test, without and with stratification for other significant risk factors. In addition, the stroke incidence was compared with the incidence rate in the general Dutch population. RESULTS: Thirteen RT patients were diagnosed with stroke, compared with 12 surgery-alone patients. The relative risk (RR) for stroke in patients treated with postoperative RT was not significantly different compared with surgery-alone patients (univariate RR 0.62, 95% confidence interval [CI] 0.28-1.35, P=.23). Stroke risk factors were coronary or peripheral artery disease (univariate and multivariate RR 10.4, 95% CI 4.7-22.8, P

Much remains to be understood about the socioeconomic inequalities in hypertension that continue to exist. We investigated the association of socioeconomic status with blood pressure and prehypertension in childhood. In a prospective cohort, 3024 five- to six-year–old children had blood pressure measurements and available information on potential explanatory factors, namely birth weight, gestational age, smoking during pregnancy, pregnancy-induced hypertension, familial hypertension, maternal body mass index, breastfeeding duration, domestic tobacco exposure, and body mass index. The systolic and diastolic blood pressures of children from mid-educated women were 1.0-mm Hg higher (95% CI, 0.4–1.7) and 0.9-mm Hg higher (95% CI, 0.3–1.4), and the blood pressures of children with low-educated women were 2.2-mm Hg higher (95% CI, 1.4–3.0) and 1.7-mm Hg higher (95% CI, 1.1–2.4) compared with children with high-educated women. Children with mid- (odds ratio, 1.50; 95% CI, 1.18–1.92) or low-educated mothers (odds ratio, 1.80; 95% CI, 1.35–2.42) were more likely to have prehypertension compared with children with high-educated mothers. Using path analyses, birth weight, breastfeeding duration, and body mass index were determined as having a role in the association of maternal education with offspring blood pressure and prehypertension. The socioeconomic gradient in hypertension appears to emerge from childhood as the results show a higher blood pressure and more prehypertension in children from lower socioeconomic status families. Socioeconomic disparities could be reduced by improving 3 factors in particular, namely birth weight, breastfeeding duration, and body mass index, but other factors might also play a role.

In untreated acromegaly patients, decreased cognitive functioning is reported to be associated with the degree of growth hormone (GH) and IGF-1 excess. Whether previous GH excess or current medical treatment for acromegaly specifically affects cognition remains unclear. The aim of this study was to compare cognitive functioning of patients who are treated for acromegaly with patients with non-functioning pituitary adenomas (NFA). In addition, we assessed the influence of prolonged medical treatment after initial transsphenoidal surgery on cognition.In this cross-sectional study, 74 patients participated, who were treated for acromegaly (n = 50; median [interquartile range] age: 53 [45-65] years) or NFA (n = 24; age: 63 [59-70] years). The NFA patients were selected for a high likelihood of normal GH secretion based on an IGF-1 z-score within the normal range (-2) and zero or one axis substituted. Of the acromegaly patients, 28 had achieved remission, while 22 were biochemically controlled with long-acting somatostatin analogues and/or pegvisomant. Memory and executive functioning were assessed by the 15 Words Test and the Ruff Figural Fluency Test, and reported as z-scores.The total patient group scored significantly poorer than the reference population on memory and executive functioning (P0·001). However, cognitive test performance was not significantly different between acromegaly patients with a persistent disease, acromegaly patients in remission and NFA patients.The total patient group scored worse compared with reference populations. We found no association between previous GH excess and cognition. In addition, current medical treatment for GH excess in acromegaly was not related to memory and executive functioning.

OBJECTIVE: Socioeconomic status (SES) is adversely associated with perinatal outcomes. This association is likely to be mediated by tobacco exposure. However, previous studies were limited to single perinatal outcomes and devoted no attention to environmental tobacco exposure. Therefore, this study aimed firstly to explain the role of maternal smoking in the association between maternal education and preterm birth (PTB), low birth weight (LBW) and small for gestational age (SGA), and secondly to explain whether environmental tobacco smoke mediates these associations further. STUDY DESIGN: This study was nested in a population-based cohort study in the Netherlands, the Amsterdam Born Children and their Development (ABCD) study. Analyses were done in a sample of 3821 pregnant women of Dutch origin, using logistic regression analysis. RESULTS: Least educated women, who were more often smoking and exposed to environmental tobacco smoke, had a significantly higher risk of PTB (OR 1.95 [95% CI: 1.19-3.20]), LBW (OR 2.41 [95% CI: 1.36-4.27]) and SGA (OR 1.90 [95% CI 1.32-2.74]) than highly educated women. The mediating effect of smoking in the least educated women was 43% for PTB, 55% for LBW and 66% for SGA. Environmental tobacco smoke did not explain these associations further. After adjustment for maternal smoking, the association between lower maternal education and pregnancy outcomes was no longer significant. CONCLUSIONS: Smoking explains to a considerable extent the association between lower maternal education and adverse perinatal outcomes. Therefore, tobacco-interventions in lower educated women should be primarily focussed on maternal smoking to reduce PTB, LBW, and SGA. Additional attention to environmental tobacco exposure does not seem to reduce educational inequalities in perinatal outcomes.

Background Socioeconomic inequalities in cardiovascular disease are pervasive, yet much remains to be understood about how they originate. The objective of this study was to explore the relations of socioeconomic status to lipid and glucose metabolism as indicators of cardiovascular health in 5–6 year olds. Additionally to explore the explanatory role of maternal factors, birth outcome, and child factors. Methods In 1308 5–6 year old ethnic Dutch children from the ABCD cohort study, lipids (cholesterol, LDL, HDL, triglycerides), glucose and C-peptide were measured after an overnight-fast. Results There were no differences in cholesterol, HDL, LDL, and triglycerides between socioeconomic groups, as indicated by maternal education and income adequacy. However, children of low educated mothers had on average a higher glucose (β = 0.15; 95% confidence interval (CI) 0.03 – 0.27), logC-peptide (β = 0.07; 95% CI 0.04 – 0.09), and calculated insulin resistance (HOMA-IR) (β = 0.15; 95% CI 0.08 – 0.22) compared to children of high educated mothers. Only childhood BMI partly explained these differences (models controlled for age, height, and sex). Conclusions The socioeconomic gradient in cardiovascular risk factors seems to emerge in early childhood. In absence of underlying mechanisms these empirical findings are relevant for public health care and further explanatory research.

This study aimed firstly to investigate the contribution of maternal 25(OH) vitamin D to the association of maternal education and small-for-gestational-age birth weight (SGA) and secondly to examine whether the contribution of 25(OH) vitamin D differs by overweight, season, and maternal smoking. Logistic regression analysis was carried out in this study, using data of 2,274 pregnant women of Dutch ethnicity from the ABCD study, a population-based cohort study in the Netherlands. Maternal 25(OH) vitamin D was measured in early pregnancy. Stratified analyses were conducted for overweight, season of blood sampling, and smoking. Low-educated women had lower 25(OH) vitamin D levels compared to high-educated women, and women in the lowest 25(OH) vitamin D quartile had a higher risk of SGA offspring. In addition, low-educated women had a higher risk of SGA offspring (OR 1.95 [95% CI: 1.20-3.14]). This association decreased with 7% after adjustment for 25(OH) vitamin D (OR 1.88 [95% CI 1.16-3.04]). In stratified analyses, adjustment for 25(OH) vitamin D resulted in a decrease in OR of about 17% in overweight women and about 15% in women who conceived in wintertime. 25(OH) vitamin D appears to be a modifiable contributor to the association between low maternal education and SGA offspring, particularly in overweight women and women who conceived in the winter period. In those women, increasing the intake of vitamin D, either through dietary adaptation or through supplementation in order to achieve the recommendation, could be beneficial

Cognitive deterioration is reported in patients with a nonfunctioning pituitary macroadenoma (NFA) and after pituitary radiotherapy. However, reported results are inconsistent and are potentially confounded by different underlying pituitary disorders. The aim of this study was to examine cognitive functions in patients previously treated for NFA with or without radiotherapy.Verbal memory was assessed with the Dutch equivalent to the Rey Auditory Verbal Learning Test (15 Words Test, 15 WT). Executive functioning was examined using the Ruff Figural Fluency Test (RFFT). We compared our patient cohort with large reference populations representative of the Dutch population.Eighty-four patients (62±10 years) who underwent transsphenoidal surgery 8.6±6.3 years earlier participated. Patients who underwent radiotherapy (n=39) were compared to those who received surgery alone (n=45). All patients were on stable hormonal replacement therapy.The total patient group scored significantly below the reference sample on all 15 WT z-scores (95%CI): short-term memory, -0.3 (-0.5 to -0.1); total memory, -0.8 (-1.1 to -0.5); learning score, -0.3 (-0.5 to -0.1); delayed memory, -0.8 (-1.1 to -0.5), all P0.01. The total patient group scored significantly below the reference sample on RFFT z-scores (95%CI): unique designs, -0.7 (-0.9 to -0.5) and perseverative errors, -0.5 (-0.8 to -0.2), both P0.001. Patients who underwent radiotherapy showed no significant differences on cognition when compared to those who received surgery alone.Patients with NFA score significantly worse on cognition compared to reference populations. Radiotherapy does not appear to have a major influence on cognition.

SLEEP PROBLEMS OCCUR AT ALL AGES AND MAY HAVE A SUBSTANTIAL IMPACT ON EVERYDAY FUNCTIONING. ACCORDING TO PREVIOUS STUDIES, 20% TO 40%1–4 of children experience sleep problems. Sleep plays an important role in normal development and everyday functioning,5 and sleep problems can lead to significant morbidity, such as behavior problems,6–7 depressive symptoms,8 more anxiety in adulthood,9 impaired neurobehavior functioning,10 poorer child-parent and peer relations, and hyperactivity.11 Because of these potential serious effects, valid assessment of sleep habits in school-aged children is essential. Many sleep studies in children have used different instruments, hampering a direct comparison of results. Also, psychometric properties (reliability, validity) of these instruments have not always been reported. To examine sleep in Dutch children, an internationally used and valid pediatric sleep instrument, the Child Sleep Habits Questionnaire (CSHQ), was translated. The CSHQ was developed in the US and has been used in several other countries, e.g., China and Italy.2,12 Its main goal is to identify sleep problems and the need for further diagnostic investigation. The CSHQ was designed as a screening tool for sleep difficulties in children aged 4 to 10 years, based on the International Classification of Sleep Disorders pediatric diagnoses.13 Acceptable to good reliability and validity have been demonstrated in American and Chinese populations.13–14 The aim of the present study was to translate the CSHQ into Dutch and to assess its reliability and structural validity in a large community-based sample of school-aged children, which differs in sociocultural background compared with the populations in which the CSHQ has been used.

Sleep disorders can lead to significant morbidity. Information on sleep in healthy children is necessary to evaluate sleep disorders in clinical practice, but data from different societies cannot be simply generalized. The aims of this study were to (1) assess the prevalence of sleep disturbances in Dutch healthy children, (2) describe sleep habits and problems in this population, (3) collect Dutch norm data for future reference, and (4) compare sleep in children from different cultural backgrounds. A population-based descriptive study was conducted using the Children’s sleep habits questionnaire and the sleep self-report. One thousand five hundred seven proxy-reports and 262 self-reports were analyzed. Mean age was 8.5 years (95% confidence interval, 8.4–8.6), 52% were boys. Sleep problems in Dutch children were present in 25%, i.e., comparable to other populations. Sleep habits were age-related. Problem sleepers scored significantly higher on all scales. Correlations between parental and self-assessments were low to moderate. Dutch children had significantly more sleep disturbances than children from the USA and less than Chinese children. Cognitions and attitudes towards what is considered normal sleep seem to affect the appraisal of sleep, this probably accounts partly for cultural differences. For a better understanding of cultural influences on sleep, more information on these determinants and the establishment of cultural norms are mandatory.

Purpose: To assess the influence of different treatment modalities on long-term health-related quality of life (HR-QoL) and cognitive problems among patients who had been treated for nonfunctioning pituitary adenoma (NFA).Methods and Materials: Eighty-one patients (49 men and 32 women, aged 55 +/- 10 years) with a minimal follow-up -period of I year after treatment for NFA participated in this cross-sectional study. Sixty-two patients were initially treated by transsphenoidal surgery and 19 by craniotomy. Subsequently, 45 of these 81 subjects (56%) received additional radiotherapy (RT) after surgery because of a tumor remnant or regrowth. All subjects filled in standardized questionnaires measuring HR-QoL, depression, fatigue, and cognitive problems.Results: Patients who underwent additional RT more frequently underwent a craniotomy and were younger at surgery, but not at entering this study. They also used more hormonal substitution. Most HR-QoL domains showed a similar score in patients who underwent RT when compared with patients who did not receive RT. However, vitality and physical functioning proved to be better in RT subjects, and RT subjects also had better scores for depression and physical and mental fatigue (all p Conclusion: Postoperative RT in patients with NFA is not associated with reduced quality of life or cognition when compared with surgery alone. (C) 2007 Elsevier Inc.