Pauline Brummelman

Cognitive functioning in patients treated for nonfunctioning pituitary macroadenoma and the effects of pituitary radiotherapy

Context and objective  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.

Cognitive performance after postoperative pituitary radiotherapy: a dosimetric study of the hippocampus and the prefrontal cortex

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.

Effects of previous growth hormone excess and current medical treatment for acromegaly on cognition.

Eur J Clin Invest 2012; 42 (12): 1317–1324

The effects of two different doses of hydrocortisone on cognition in patients with secondary adrenal insufficiency - Results from a randomized controlled trial

CONTEXT A wide variety in hydrocortisone (HC) substitution dose-regimens are considered physiological for patients with secondary adrenal insufficiency (SAI). 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 1h after first dose ingestion (mean [SD], low dose: 653 [281] nmol/L; high dose: 930 [148] nmol/L; P<0.001). No differences in cognitive performance were found between the two dose regimens. CONCLUSIONS 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.

Hydrocortisone Dose Influences Pain, Depressive Symptoms and Perceived Health in Adrenal Insufficiency: A Randomized Controlled Trial.

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.

Pharmacokinetics of oral hydrocortisone - Results and implications from a randomized controlled trial

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.

Cognition and brain abnormalities on MRI in pituitary patients

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.

Somatosensory function in patients with secondary adrenal insufficiency treated with two different doses of hydrocortisone: Results from a randomized controlled trial

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<0.001). No differences were found in MDT, MPT, MPS and PPT z-scores between the two doses of HC. Furthermore, the number of patients showing sensory abnormalities did not differ between the two different doses. Conclusions The results suggest that the dose of HC has no impact on somatosensory functioning in response to mechanical stimuli in patients with SAI, despite previously found altered subjective pain reports.

Higher hydrocortisone dose increases bilirubin in hypopituitary patients- Results from an RCT

Bilirubin has anti‐oxidative and anti‐inflammatory properties, which may explain its proposed protective effects on the development of cardiometabolic disorders. Glucocorticoids affect heme oxygenase regulation in vitro, which plays a key role in bilirubin production. Effects of variations in glucocorticoid exposure on circulating bilirubin levels in humans are unknown. Here we tested whether a higher hydrocortisone replacement dose affects circulating bilirubin in hypopituitary patients.

Cognitief functioneren bij patiënten die behandeld zijn voor een niet functionerende hypofysemacro-adenoom en de effecten van hypofysebestraling

Niet functionerende hypofysemacro-adenomen (NFA) zijn goedaardige tumoren van de hypofyse die door druk op de oogzenuwen uitval van het gezichtvermogen kunnen geven en tevens kunnen leiden tot verlies van de hypofysefunctie. De aanbevolen behandeling bestaat uit transsfenoïdale chirurgie soms gevolgd door radiotherapie indien er sprake is van een tumorrest of hergroei. De lokale tumorcontrole verbetert sterk door de toepassing van radiotherapie op de hypofyse (Van den Bergh et al., 2007). Naast deze positieve effecten op tumorcontrole, worden er cognitieve veranderingen gevonden in het geheugen en executieve functies (o.a. planning, cognitieve flexibiliteit en inhibitie) bij behandelde hypofysepatiënten (Guinan et L., 1998; Noad et al., 2004; Peace et al., 1997; Peace et al., 1998). Eerdere studies hadden echter als nadeel dat de patiëntenpopulaties heterogeen waren ten aanzien van de hypofyse aandoening en bovendien vaak klein waren.