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

BACKGROUND: 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. MATERIALS AND METHODS: A randomized double-blind cross-over study (ClinicalTrials.gov, number NCT01546992) was performed in 47 patients with secondary adrenal failure [10-week exposure to a higher hydrocortisone dose (0·4-0·6 mg/kg body weight) vs. 10 weeks of a lower hydrocortisone dose (0·2-0·3 mg/kg body weight)]. RESULTS: Plasma total bilirubin was increased by 10% from 7 to 8 µM in response to the higher hydrocortisone dose (P = 0·033). This effect was inversely related to age (P = 0·042), but was unaffected by sex, obesity and (replacement for) other hormonal insufficiencies. The higher hydrocortisone dose also resulted in lower alkaline phosphatase (P = 0·006) and aspartate aminotransferase activities (P = 0·001). CONCLUSION: Bilirubin is modestly increased in response to higher glucocorticoid exposure in humans, in conjunction with lower alkaline phosphatase and aspartate aminotransferase activities, which are supposed to represent biomarkers of a pro-inflammatory state and enhanced liver fat accumulation.

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.

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

BACKGROUND: 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. DESIGN: 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. RESULTS: The total patient group scored significantly poorer than the reference population on memory and executive functioning (P < 0·001). However, cognitive test performance was not significantly different between acromegaly patients with a persistent disease, acromegaly patients in remission and NFA patients. CONCLUSION: 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.

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. DESIGN: 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. PATIENTS: 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. RESULTS: 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 P<0.01. 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 P<0.001. Patients who underwent radiotherapy showed no significant differences on cognition when compared to those who received surgery alone. CONCLUSION: Patients with NFA score significantly worse on cognition compared to reference populations. Radiotherapy does not appear to have a major influence on cognition.

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.

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.

Effects of Hydrocortisone on the Regulation of Blood Pressure: Results From a Randomized Controlled Trial.

CONTEXT: Cardiovascular risk is increased in patients with secondary adrenal insufficiency, which may be ascribed to an unfavorable metabolic profile consequent to a relatively high hydrocortisone replacement dose. OBJECTIVE: We determined the effects of a higher versus a lower glucocorticoid replacement dose on blood pressure (BP), the renin-angiotensin-aldosterone system, 11ß-hydroxysteroid dehydrogenase enzyme activity and circulating (nor)metanephrines. DESIGN, SETTING, AND PATIENTS: Forty-seven patients with secondary adrenal insufficiency from the University Medical Center Groningen participated in this randomized double-blind crossover study. INTERVENTIONS: Patients randomly received 0.2-0.3 mg hydrocortisone/kg body weight followed by 0.4-0.6 mg hydrocortisone/kg body weight, or vice versa, each during 10 weeks. MAIN OUTCOME MEASURE(S): BP and regulating hormones were measured. RESULTS: The higher hydrocortisone dose resulted in an increase in systolic BP of 5 (12) mm Hg (P = .011), diastolic BP of 2 (9) mm Hg (P = .050), and a median [interquartile range] drop in plasma potassium of -0.1 [-0.3; 0.1] nmol/liter (P = .048). The higher hydrocortisone dose led to decreases in serum aldosterone of -28 [-101; 9] pmol/liter (P = .020) and plasma renin of -1.3 [-4.5; 1.2 ] pg/mL (P = .051), and increased the ratio of plasma and urinary cortisol to cortisone (including their metabolites) (P < .001 for all). Furthermore, on the higher dose, plasma and urinary normetanephrine decreased by -0.101 [-0.242; 0.029] nmol/liter (P < .001) and -1.48 [-4.06; 0.29] µmol/mol creatinine (P < .001) respectively. CONCLUSIONS: A higher dose of hydrocortisone increased systolic and diastolic BP and was accompanied by changes in the renin-angiotensin-aldosterone system, 11ß-hydroxysteroid dehydrogenase enzyme activity, and circulating normetanephrine. This demonstrates that hydrocortisone dose even within the physiological range affects several pathways involved in BP regulation.

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.

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.

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.