Association between anemia and vitamin D deficiency in German seniors : A retrospective data analysis.

BACKGROUND: Anemia and deficiency of vitamin D (VDD) are frequently seen in seniors and an association is suspected. Approximately one third of the German population is affected by VDD, with a rising prevalence among seniors. AIM: To analyze the association between anemia and VDD among German seniors aged ≥ 60 years. METHODS: Retrospective cross-sectional data analysis (n = 4008) in a nationwide working laboratory medical center (January-December 2019). Study parameters included amongst others: hemoglobin (Hb), calcifediol (25D) and calcitriol (1.25D), glomerular filtration rate (GFR) to assess the kidney disease outcomes quality initiative (KDOQI) state. The inclusion criteria were age ≥ 60 years, normal C­reactive protein (CRP) and leucocyte levels. RESULTS: The 25D was estimated in 4008 patients and 1.25D only in 411 patients. Mean age 75 years (± 8.61 years; 60-99 years) with 30.6% males; mean GFR 62 ml/min/1.73 m3 (± 22.74); 20% of patients were anemic, 35% were deficient for 25D (< 50 nmol/l), with men > women (p = 0.014). Linear regression analysis revealed a significant effect of 25D values < 30 nmol/l on hemoglobin in males of KDOQI I-III and females of KDOQI I-IV (R2 = 0.052; p = 0.005; and R2 = 0.124; p < 0.001, respectively). For 1.25D a weak but significant effect on hemoglobin independent of KDOQI was only seen in women (R2 = 0.200; p = 0.005). CONCLUSION: In this cohort deficiency of 25D and 1.25D was significantly associated with hemoglobin independent of renal function only in women but not in men.

Relationship between Contingent Negative Variation and afterimage duration in migraine patients.

Background: Abnormalities in electrocortical parameters and persistence of afterimage after visual stimulation are known to occur in migraine patients. The results of studies on Contingent Negative Variation (CNV) and afterimage persistence in migraine patients suggest a link between these two phenomena and a connection to the pathomechanism of migraine. Objectives: To date, no studies have investigated both afterimage duration and CNV parameters in the same subjects. The aim of this study was to investigate the relationship between the early component of CNV (iCNV) and the duration of the afterimage in migraine patients. Methods: Sixty seven migraine patients from the headache center of the University of Rostock Medical Center were examined for iCNV amplitude, iCNV habituation and afterimage duration. The subjects also completed questionnaires developed for this study and the MIDAS (Migraine Disability Assessment) questionnaire. Results: Associations were found between iCNV amplitude and afterimage duration and between habituation capacity and afterimage duration. A deficit in habituation capacity correlated with a significantly prolonged afterimage duration. Increased iCNV amplitude and prolonged afterimage duration were also significantly correlated. Conclusion: Conclusions about the pathophysiology of migraine can be drawn from the results of this study. The results support the hypothesis of cortical hyperexcitability as a consequence of a low pre-activation level, which may be a possible contributory cause of migraine. Furthermore, they allow assessment of whether the afterimage examination, which is easier and quicker to perform than the CNV examination, can be used as a diagnostic tool or as a parameter to monitor the course of therapy in people with migraine.

Glucocorticoid replacement therapy for primary and secondary adrenal insufficiency and their impact on cognition.

Patients with adrenal insufficiency (AI) are treated with conventional or modified-release glucocorticoid (GC) replacement therapy (GRT). Although current GRT regimens aim to mimic the physiological circadian pattern of cortisol secretion, temporary phases of hypo- and hypercortisolism are common. There is good evidence that prolonged phases of hypo- or hypercortisolism are associated with impaired cognitive functioning. However, little is known about cognitive functioning in patients with AI regarding the effects of dosage and duration of glucocorticoid replacement therapy. There is also little data available comparing the effects of GC therapy on patients with primary and secondary forms of AI as well as with respect to different formulas. This Mini-Review gives an overview of the current studies on GRT for primary and secondary AI and their impact on cognition. Strengths and weaknesses of the studies and their Implications for clinical daily routine are discussed with a special emphasis on practical considerations for the treating endocrinologist.

Poor quality of life and sleep in patients with adrenal insufficiency-another cause of increased mortality?

BACKGROUND: Patients with adrenal insufficiency (AI) are treated with glucocorticoid replacement therapy (GRT). Although current glucocorticoid regimens aim to mimic the physiological circadian rhythm of cortisol secretion, temporary phases of hypo- and hypercortisolism are common undesired effects which lead to a variety of consequences like increased cardiovascular risk and premature mortality. Additionally, poor quality of life (QoL) and impaired sleep have been reported. However, little is known about these topics regarding the effects of daily dosage, duration of therapy, and patients with different forms of AI (primary, PAI, and secondary, SAI). METHODS: In this study, 40 adults with AI substituted with hydrocortisone (HC) and 20 matched healthy controls completed questionnaires evaluating depressive symptoms, subjective health status, quality of sleep and daytime sleepiness. Furthermore, demographic data, dosage of HC, duration of therapy and co-medication were evaluated. Patients were compared in different groups. RESULTS: Patients assessed general health significantly worse than controls; likewise, daytime sleepiness was reported significantly more often. Depressive symptoms differed significantly in the two groups but did not reach clinically relevant scores. There was no difference between patients with PAI and SAI. High dosage of hydrocortisone had negative impact on mental health but not on sleep quality or daytime sleepiness. CONCLUSIONS: The present data highlight that poor QoL and impaired sleep are still severe and underrated issues in current GRT and might be additional factors for premature mortality in patients with AI. Some AI patients reach normal or near-normal self-assessed QoL and sleep, even despite unphysiological replacement.

Dual-release hydrocortisone and its benefits on cognitive function and quality of sleep.

PURPOSE: Patients with adrenal insufficiency are usually treated with conventional hydrocortisone replacement therapy which fails to mimic the circadian rhythm of cortisol secretion. Dual-release hydrocortisone (DR-HC) resembles the daily normal cortisol profile improving metabolic parameters and quality of life. However, currently little is known about its impact on cognitive function. Aim of this study was to evaluate cognitive function and well-being in DR-HC treated patients compared to healthy controls and conventional HC treatment. METHODS: Twenty adults with adrenal insufficiency treated with DR-HC (Plenadren®) underwent 10 neuropsychological tests, evaluating cognitive functions. Furthermore, demographic data, quality of life, symptoms of depression, and quality of sleep were evaluated by well-established questionnaires. Patients were compared by diagnosis (PAI/SAI) and dose (≥20 mg). In addition, eighteen DR-HC treated adults were compared to eighteen matched conventionally treated adults. RESULTS: With respect to diagnosis patients with PAI performed significantly better on intellectual abilities (p = 0.038) and on executive functioning (p = 0.026) and reported a significant longer time to fall asleep (p = 0.026). Regarding DR-HC dosage, there were no significant differences in cognitive functions. Patients on high dose reported a better subjective quality of sleep (p = 0.028) than patients on low dose. In comparison to conventional HC treatment, patients with DR-HC tended to show better results in executive functioning (p = 0.099). CONCLUSION: Patients with PAI reached better results in several cognitive functions and had a worse quality of sleep than patients with SAI. Our data suggest a positive impact of DR-HC on quality of sleep. DR-HC may be better for executive functioning.

Improved cognitive function after kidney transplantation compared to hemodialysis.

End-stage renal disease is associated with chronic stress that in turn may result in endocrine changes, affect cognitive, and physical capacities and increase the risk for cardiovascular events. The objective of this study was to evaluate and characterize possible stress parameters and compare cognitive function in those patients. Physiological and biochemical stress parameters as well as cognitive function were assessed in 17 hemodialysis and 18 renal transplant patients and both groups were compared. Serum cortisol and interleukin-6 levels were elevated in both groups but showed no significant difference. Cholesterol and low-density lipoprotein levels were significantly higher in patients following renal transplantation. While heart rate variability was comparable in both groups, most cognitive tests showed better results in renal transplant patients. We showed that: (1) cognitive function may improve following renal transplantation; (2) standard biochemical stress parameters are not useful to discriminate stress in patients with chronic kidney disease; and (3) heart rate variability is unaltered in this setting.

Impaired attention in patients with adrenal insufficiency - Impact of unphysiological therapy.

Patients with adrenal insufficiency (AI) are treated with glucocorticoid (GC) replacement therapy. Although current GC regimens aim to mimic the physiological circadian rhythm of cortisol secretion, temporary phases of hypo- and hypercortisolism are common undesired effects. Both conditions may lead to impairment in cognitive functioning. At present, little is known about cognitive functioning in patients with AI, especially regarding the effects of dosage and duration of glucocorticoid replacement therapy. There is also little data available comparing the effects of GC therapy on patients with primary (PAI) and secondary (SAI) forms of AI. In this study 40 adults with AI (21 PAI, 19 SAI) substituted with hydrocortisone (HC) and 20 matched healthy controls underwent 10 different neuropsychological tests evaluating memory, executive functioning, attention, psychomotricity and general intellectual ability. Furthermore demographic data, dosage of HC, duration of therapy and co-medication were evaluated. Patients were compared in groups with regard to diagnosis, dosage and duration of therapy. Patients showed worse performance than controls in attention, though patients with PAI and SAI seemed to be equally impaired. There were no limitations in intellectual abilities or memory function. High dosage of HC was found to impair attention, visual-motoric skills and executive functioning while the duration of therapy showed no significant impact on cognitive functions. In conclusion, our study showed that AI patients on HC replacement therapy reveal significant cognitive deficits concerning attention. There was no difference between patients with PAI and SAI. Furthermore, high dosage seems to have a negative impact especially on executive functioning.

The corticosteroid prednisolone increases amygdala and insula reactivity to food approach signals in healthy young men.

Short- and long-term treatment with glucocorticoids is widely used in clinical practice and frequently induces features of iatrogenic Cushing syndrome, such as abdominally centered weight gain. Despite decades of glucocorticoids usage, the mechanisms underlying these side effects are still only partly understood. One possibility is that glucocorticoids impact subcortical (hypothalamus, amygdala, insula) and cortical (orbitofrontal and cingulate cortex) brain regions involved in appetite regulation and reward processing. In the present study, we used functional magnetic resonance imaging (fMRI) to study the acute effects of a prednisolone infusion on reactivity of brain reward systems to food stimuli. Twenty healthy normal-weight men were tested in a randomized, double-blind, cross-over study. After an overnight fast and infusion of either 250 mg prednisolone or placebo (always administered between 8 and 9 A M), fMRI scans were taken while presenting food and object pictures in a Go/NoGo (GNG) task. At home, participants were asked to register what they had eaten. On the following morning they came back to the lab and had a supervised ad libitum breakfast at a standardized buffet. Food-Go in contrast to Object-Go pictures yielded increased blood oxygen level dependent (BOLD) activity in hippocampus, amygdala, orbitofrontal cortex, insula and anterior cingulate cortex. Prednisolone increased activation in the bilateral amygdala and right insula for approach-associated food pictures. The buffet test did not reveal significant differences in calorie consumption or preferences of different macronutrients. However, prednisolone-induced insula reactivity to Food-Go images was associated with greater caloric intake, both at home and in the standardized buffet. In sum, we observed a specific effect of prednisolone on the BOLD response of the amygdala and insula to approach-associated food stimuli. As these brain areas have previously been implicated in hedonic eating, the present pattern of results may reflect an increased anticipated reward value of food modulated by glucocorticoids. These effects might potentially drive increased food intake and weight gain under prolonged glucocorticoid treatment.

[Diagnosis and Management of Adrenal Insufficiency]. / Diagnostik und Therapie der Nebenniereninsuffizienz.

Adrenal insufficiency is a potentially life-threatening endocrine disorder. Therefore, it is very important to detect the symptoms in sufficient time and treat effectively to avoid acute adrenal insufficiency. This article provides an insight into diagnostically procedures and therapeutically specific aspects of this rare endocrine disease.

FKBP5 methylation as a possible marker for cortisol state and transient cortisol exposure in healthy human subjects.

Current glucocorticoid replacement regimens, in adrenal insufficiency, fail to mimic the physiological cortisol secretion, thereby fostering serious side effects. AIM: To experimentally evaluate the impact of CpG methylation within the FKBP5 gene as a possible short- and long-term marker for cortisol exposure in humans. MATERIALS & METHODS: An ACTH-stimulation test was carried out and methylation status of the FKBP5 gene in leukocytes was determined. RESULTS: A negative correlation between basal levels of methylation and serum cortisol was observed. Individual changes in FKBP5 methylation after 24 h correlated with cortisol responses. CONCLUSION: Considering previous studies conducted with murine leucocytes, FKBP5 methylation may be suitable as a long-term biomarker, rather than acute glucocorticoid exposure, also in humans.

Life-threatening endocrine emergencies during pregnancy - management and therapeutic features.

Endocrine emergencies during pregnancy may be life-threatening events for both mother and fetus. Besides pregnancy-associated endocrine disorders, several pre-existing endocrinopathies such as type-1 diabetes and Grave's disease or adrenal failure may acutely deteriorate during pregnancy. Since "classical" signs are often modified by pregnancy, early diagnosis and management may be hampered. In addition, laboratory tests show altered physiologic ranges and pharmacologic options are limited while therapeutic goals are mostly tighter than in the non-pregnant patient. Though subclinical endocrinopathies are more frequent and worth consideration due to their related adverse sequelae, this article focuses on endocrine emergencies complicating pregnancy.

Self-management in adrenal insufficiency - towards a better understanding.

Patients with adrenal insufficiency (AI) require life-long glucocorticoid (GC) replacement treatment and dose adjustment in stress situations to prevent life-threatening adrenal crises. Herein this study we evaluated the patients' healthcare situation and their knowledge on AI, comparing various aspects to a prior survey in 209 physicians. Using a questionnaire, we conducted a comprehensive survey among 33 AI patients who were treated at the endocrine outpatient clinics of two University Hospitals in Germany. The majority of AI patients (97%) named their treating physician as main source for information. Overall, 89.7% of interviewees were satisfied with their medical treatment; however, about 1/3 reported controversies with healthcare professionals regarding GC replacement in various situation. Two thirds of AI patients increased their substitution dose temporarily within the last 12 months. However, not all patients had an emergency ID, and only 64.5% an emergency kit. None of the interviewed patients identified the need for adjustment in all given situations correctly. Almost 80% of patients did not correctly identify all symptoms of GC over- and under-replacement. Interestingly, we found no significant differences between patients and physicians regarding specific aspects of GC replacement. We showed that: (i) AI patients have some knowledge gaps on modalities and adequacy of GC replacement therapy; (ii) long-term management of patients with AI remains a challenge requiring an experienced specialist; and (iii) further education of physicians as primary source of information is necessary. Additional education may help AI patients to empower them to adequate self-treatment.

Increased Cardiovascular Risk in Patients with Adrenal Insufficiency: A Short Review.

Cardiovascular disease (CVD) is the most common cause of death in the world. Recent studies have shown an association between adrenal insufficiency (AI) and increased cardiovascular risk (CVR). Patients with AI receive glucocorticoid (GC) replacement therapy which can lead to varying levels of blood cortisol. It was shown that these imbalances in blood cortisol may lead to a higher prevalence of coronary heart disease, major adverse coronary events, and increased mortality. GC substitution is essential in the treatment of AI without which the disease has been shown to be fatal. The most frequently used GC formula for replacement therapy is hydrocortisone (HC). There is no uniform opinion on hydrocortisone replacement therapy. Alternative GC such as prednisolone is also in use. Overreplacement of GC may lead to adverse effects including obesity, high blood pressure, and hyperglycaemia. Outcome may vary between primary and secondary AI mainly due to differences in the renin-angiotensin-aldosterone system (RAAS). Furthermore, decreased blood levels of cortisol may lead to a compensatory secretion of inflammatory mediators such as Interleukin-1 (IL-1), Interleukin-6 (IL-6), and/or tumor-necrosis factor (TNF). Physicians and patients should be properly educated about the increased risk of CVD in patients with AI.

Prevalence and Predictors of Overweight and Obesity in Patients with Pituitary Dysfunctions.

BACKGROUND: Patients with hypothalamic-pituitary disorders (HPD) may be of increased risk to develop overweight and obesity, thereby fostering cardiovascular events. However, it remains unclear if patients with pituitary dysfunctions per se have an increased risk of becoming obese. OBJECTIVE: The objective of this study was to evaluate prevalence and to identify possible predictors of overweight and obesity in patients with pituitary dysfunctions. METHODS: A total of 121 out-patients having various causes for HPD were assessed for height and body weight; body mass index (BMI) was calculated and correlated with clinical features. Patients were divided into various subgroups depending on underlying conditions and therapeutic modalities. RESULTS: Most of the HPD patients were overweight or obese with males being significantly more affected. Of interest, patients with macroadenomas suffered significantly more often from overweight and obesity than individuals with microadenomas (73.4% vs. 43.5%, p= 0.006). Increased BMI (≥25 kg/m2) tended to be more common in patients with prolactinomas (70.0%), hormone deficiencies (76.1%) and hormone replacement therapies (76.6%) than in a healthy population. CONCLUSION: In conclusion, we showed that patients with HPD: (i) frequently suffer from overweight and obesity; (ii) prevalence of overweight and obesity however is comparable to that in the general population; (iii) only patients with macroadenomas seem to have a significantly higher risk; (iv) hormone deficiencies and hormonal replacement therapy may foster weight gain and (v) radiation and surgical tumour therapy per se do not seem to be additional risk factors for weight gain.

Prednisolone increases neural reactivity to negative socio-emotional stimuli in healthy young men.

Exogenous glucocorticoids are known to trigger affective changes, but these are highly variable across individuals. A better understanding of how synthetic glucocorticoids impact the processing of negative emotions in the human brain might help to predict such changes. In the present functional magnetic resonance imaging (fMRI) study, we sought to uncover the slow effects of a synthetic glucocorticoid infusion on the neural response to socio-emotional scenes using a within-participant, double-blind, placebo-controlled design. In two separate sessions, 20 young males were given either an intravenous prednisolone dose (250mg) or placebo in a cross-over, randomized order. Four hours later, they were scanned while viewing drawings of persons in a neutral or negative emotional situation. On the next morning participants provided a blood sample for serum cortisol measurement, which served as a manipulation check. Prednisolone strongly suppressed morning cortisol, and heightened brain reactivity to emotional stimuli in left amygdala, left caudate head, right inferior frontal gyrus, bilateral supplementary motor area, and right somatosensory cortex. Amygdala reactivity was related to lower self-reported fatigue and higher irritability in the prednisolone condition. Moreover, prednisolone blunted inferior frontal and amygdala connectivity with other regions of the emotion-processing neural circuitry. Our results suggest specific brain pathways through which exogenous glucocorticoids may labilize affect.

Exploring the Impact of Short- and Long-Term Hydrocortisone Replacement on Cognitive Function, Quality of Life and Catecholamine Secretion: A Pilot Study.

Hydrocortisone (HC) substitution is essential in the treatment for patients with adrenal insufficiency (AI). Current replacement regimens however only incompletely mimic the physiological circadian rhythm of cortisol secretion, thereby resulting in subclinical temporary hypo- and hypercortisolism. Several studies point toward impairment of cognitive functions under these conditions, in part due to affected catecholamine secretion. Aim of this study was to evaluate the influence of long-term versus short-term HC replacement therapy on the adrenomedullary system and cognitive functions. Fourteen patients with primary or secondary AI were divided into two groups, depending on the duration of disease and HC replacement therapy (<15 years). All subjects underwent standardized neurocognitive testing; in addition, cortisol and catecholamine levels as well as physiological parameters and quality of life (QoL) were assessed. Patients with HC replacement therapy ≥15 years (n = 7) received significantly higher equivalent glucocorticoid doses than those with a shorter lasting therapy (n = 7; p = 0.048). Neuropsychological tests, QoL, physiological parameters, and cortisol levels did not differ significantly between both groups. Of note, norepinephrine levels were significantly lower in patients on short-term HC replacement therapy (p = 0.025). However, there were no significant differences in catecholamines with respect to the underlying pathophysiology, gender, or age. Irrespective of the duration of use, male patients scored significantly better for single aspects of QoL, whereas females performed significantly better in the attention test. Overall, we showed that duration of cortisol replacement therapy may have an impact on catecholamine release, but does not seem to affect cognitive functions and QoL.