| 1. |
- Bridel, Claire, et al.
(författare)
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Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology : A Systematic Review and Meta-analysis
- 2019
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149 .- 2168-6157. ; 76:9, s. 1035-1048
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Forskningsöversikt (refereegranskat)abstract
- Importance Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date.Objectives To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions.Data Sources PubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC.Study Selection Studies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex.Data Extraction and Synthesis Individual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept.Main Outcome and Measure The cNfL levels adjusted for age and sex across diagnoses.Results Data were collected for 10 059 individuals (mean [SD] age, 59.7 [18.8] years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n = 2795), dementias and predementia stages (n = 4284), parkinsonian disorders (n = 984), and HC (n = 1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. The cNfL overlapped in most clinically similar diagnoses except for FTD and iHIV, which segregated from other dementias, and PD, which segregated from atypical parkinsonian syndromes.Conclusions and Relevance These data support the use of cNfL as a biomarker of neuroaxonal damage and indicate that age-specific and sex-specific (and in some cases disease-specific) reference values may be needed. The cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.
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| 2. |
- Adeyinka, Adewale, et al.
(författare)
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Comparative cytogenetic and DNA flow cytometric analysis of 242 primary breast carcinomas
- 2003
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Ingår i: Cancer Genetics and Cytogenetics. - 0165-4608. ; 147:1, s. 62-67
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Tidskriftsartikel (refereegranskat)abstract
- The cytogenetic and DNA flow cytometric findings in 242 breast carcinomas were compared. The combined use of both techniques improved the detection of abnormal cell populations from 65% by cytogenetic analysis alone and 59% by DNA flow cytometric analysis alone to 84%. Informative and comparable cytogenetic and flow cytometric data were obtained for 155 tumors. Among these 155 tumors, there was good concordance (64%) between the estimates of genomic changes by the two methods. Most discrepancies were among the DNA-diploid cases, where cytogenetic analysis detected small genomic changes. There were, however, also some exceptions in which large genomic changes detected by one method were missed by the other. Of the specific breast cancer-associated cytogenetic aberrations subjected to separate correlation analysis, polysomy for chromosome 20 was significantly associated with a high S-phase fraction, whereas loss of the long arm of chromosome 16 and/or the presence of a der(1;16) were significantly associated with a low S-phase fraction. Our data show that cytogenetic and DNA flow cytometric analyses of breast carcinomas give largely comparable results, and that combining data from both methods significantly improves the information obtained by either technique used alone on the genetic abnormalities in these tumors.
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| 3. |
- Agnarsson, Hjalmar Ragnar, et al.
(författare)
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The impact of glucocorticoid replacement on bone mineral density in patients with hypopituitarism before and after 2 years of growth hormone replacement therapy.
- 2014
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 99:4, s. 1479-1485
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Tidskriftsartikel (refereegranskat)abstract
- Context: Patients with hypopituitarism have reduced bone mineral density (BMD) and increased fracture risk. Objective: The aim of this study was to analyze the effects of glucocorticoid (GC) replacement on BMD before and after two years of growth hormone (GH) therapy in hypopituitary patients. The main hypothesis was that patients on GC replacement demonstrate greater improvement in BMD when treated with GH. Design: This was a post hoc analysis of data from a prospective single centre study. Patients: Data on 175 adult patients with hypopituitarism and verified GH deficiency due to non-functioning pituitary adenoma were analyzed. Ninety-eight (56%) were GC insufficient, receiving a mean±SD hydrocortisone equivalent dose of 20.9±5.0 mg/day. Main outcome measure: BMD before and after two years of GH replacement therapy, measured by using dual-energy X-ray absorptiometry. Results: BMD at baseline did not differ between GC sufficient and insufficient patients, neither at lumbar spine nor femur neck. After two years on GH replacement BMD increased in both groups. After adjustment for weight, age, gender, free T4 concentrations, change in IGF-I levels and sex hormone treatment, GC sufficiency was associated with greater increase in BMD at femur neck (ΔT-score in GC insufficient patients 0.09±0.46, in GC sufficient patients 0.19±0.43; P<0.05) but not at lumbar spine. Conclusions: GH replacement therapy for 2 years increased BMD in hypopituitary patients. In contrast to our hypothesis, GC insufficient patients receiving near physiological doses of hydrocortisone do not show a greater therapeutic response to GH therapy than their GC sufficient counterparts.
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| 4. |
- Andela, C. D., et al.
(författare)
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MECHANISMS IN ENDOCRINOLOGY Cushing's syndrome causes irreversible effects on the human brain: a systematic review of structural and functional magnetic resonance imaging studies
- 2015
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Ingår i: European Journal of Endocrinology. - : Oxford University Press (OUP). - 0804-4643 .- 1479-683X. ; 173:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cushing's syndrome (CS) is characterized by excessive exposure to cortisol, and is associated with both metabolic and behavioral abnormalities. Symptoms improve substantially after biochemical cure, but may persist during long-term remission. The causes for persistent morbidity are probably multi-factorial, including a profound effect of cortisol excess on the brain, a major target area for glucocorticoids. Objective: To review publications evaluating brain characteristics in patients with CS using magnetic resonance imaging (MRI). Methods: Systematic review of literature published in PubMed, Embase, Web of Knowledge, and Cochrane databases. Results: Nineteen studies using MRI in patients with CS were selected, including studies in patients with active disease, patients in long-term remission, and longitudinal studies, covering a total of 339 unique patients. Patients with active disease showed smaller hippocampal volumes, enlarged ventricles, and cerebral atrophy as well as alterations in neurochemical concentrations and functional activity. After abrogation of cortisol excess, the reversibility of structural and neurochemical alterations was incomplete after long-term remission. MRI findings were related to clinical characteristics (i.e., cortisol levels, duration of exposure to hypercortisolism, current age, age at diagnosis, and triglyceride levels) and behavioral outcome (i.e., cognitive and emotional functioning, mood, and quality of life). Conclusion: Patients with active CS demonstrate brain abnormalities, which only partly recover after biochemical cure, because these still occur even after long-term remission. CS might be considered as a human model of nature that provides a keyhole perspective of the neurotoxic effects of exogenous glucocorticoids on the brain.
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| 5. |
- Andersson, Agnes, et al.
(författare)
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Headache Before and After Endoscopic Transsphenoidal Pituitary Tumor Surgery: A Prospective Study
- 2022
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Ingår i: Journal of Neurological Surgery Part B-Skull Base. - : Georg Thieme Verlag KG. - 2193-6331 .- 2193-634X. ; 83:suppl. 2
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Tidskriftsartikel (refereegranskat)abstract
- Objective Headache is a common symptom among patients with pituitary tumors, as it is in the general population. The aim of the study was to investigate headache as a symptom in patients with pituitary tumors before and 6 months after endoscopic transsphenoidal surgery (TSS). Design This is a prospective observational cohort study. Setting This study was conducted at university tertiary referral hospital. Participants A total of 110 adult patients underwent endoscopic TSS for pituitary tumors. Main Outcome Measures The Migraine Disability Assessment (MIDAS) questionnaire was used before and 6 months after surgery for the assessment of headache. Clinical variables with potential influence on headache were analyzed. Results Sixty-eight (62%) patients experienced headaches at least once during the 3 months before surgery. Thirty (27%) patients reported disabling headache before surgery, with younger age being an independent associated factor ( p <0.001). In patients with disabling headache before surgery, the median (interquartile range) MIDAS score improved from 78 (27-168) to 16 (2-145; p =0.049), headache frequency decreased from 45 (20-81) to 14 (4-35) days ( p =0.009), and headache intensity decreased from 6 (5-8) to 5 (4-7) ( p =0.011) after surgery. In total, 16 of the 30 (53%) patients reported a clinically relevant improvement and five (17%) a clinically relevant worsening. Four (5%) patients developed new disabling headache. No predictor for postoperative improvement of headache was identified. Conclusion In this prospective study, the results show that disabling headache improves following endoscopic TSS in a subset of patients with pituitary tumors. However, no predictive factors for improvement could be identified.
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| 6. |
- Arason, Adalgeir, et al.
(författare)
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Genome-wide search for breast cancer linkage in large Icelandic non-BRCA1/2 families
- 2010
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 12:4, s. R50-
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Tidskriftsartikel (refereegranskat)abstract
- Chromosomes 2p, 6q and 14q are candidate sites for genes contributing together to high breast cancer risk. A polygenic model is supported, suggesting the joint effect of genes in contributing to breast cancer risk to be rather common in non-BRCA1/2 families. For genetic counselling it would seem important to resolve the mode of genetic interaction.
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| 7. |
- Arlien-Soborg, Mai C., et al.
(författare)
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Acromegaly management in the Nordic countries: A Delphi consensus survey
- 2024
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Ingår i: Clinical Endocrinology. - : WILEY. - 0300-0664 .- 1365-2265.
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveAcromegaly is associated with increased morbidity and mortality if left untreated. The therapeutic options include surgery, medical treatment, and radiotherapy. Several guidelines and recommendations on treatment algorithms and follow-up exist. However, not all recommendations are strictly evidence-based. To evaluate consensus on the treatment and follow-up of patients with acromegaly in the Nordic countries.MethodsA Delphi process was used to map the landscape of acromegaly management in Denmark, Sweden, Norway, Finland, and Iceland. An expert panel developed 37 statements on the treatment and follow-up of patients with acromegaly. Dedicated endocrinologists (n = 47) from the Nordic countries were invited to rate their extent of agreement with the statements, using a Likert-type scale (1-7). Consensus was defined as >= 80% of panelists rating their agreement as >= 5 or <= 3 on the Likert-type scale.ResultsConsensus was reached in 41% (15/37) of the statements. Panelists agreed that pituitary surgery remains first line treatment. There was general agreement to recommend first-generation somatostatin analog (SSA) treatment after failed surgery and to consider repeat surgery. In addition, there was agreement to recommend combination therapy with first-generation SSA and pegvisomant as second- or third-line treatment. In more than 50% of the statements, consensus was not achieved. Considerable disagreement existed regarding pegvisomant monotherapy, and treatment with pasireotide and dopamine agonists.ConclusionThis consensus exploration study on the management of patients with acromegaly in the Nordic countries revealed a relatively large degree of disagreement among experts, which mirrors the complexity of the disease and the shortage of evidence-based data.
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| 8. |
- Arlien-Soborg, Mai C., et al.
(författare)
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Acromegaly management in the Nordic countries: A Delphi consensus survey
- 2024
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Ingår i: CLINICAL ENDOCRINOLOGY. - : WILEY. - 0300-0664 .- 1365-2265.
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveAcromegaly is associated with increased morbidity and mortality if left untreated. The therapeutic options include surgery, medical treatment, and radiotherapy. Several guidelines and recommendations on treatment algorithms and follow-up exist. However, not all recommendations are strictly evidence-based. To evaluate consensus on the treatment and follow-up of patients with acromegaly in the Nordic countries.MethodsA Delphi process was used to map the landscape of acromegaly management in Denmark, Sweden, Norway, Finland, and Iceland. An expert panel developed 37 statements on the treatment and follow-up of patients with acromegaly. Dedicated endocrinologists (n = 47) from the Nordic countries were invited to rate their extent of agreement with the statements, using a Likert-type scale (1-7). Consensus was defined as >= 80% of panelists rating their agreement as >= 5 or <= 3 on the Likert-type scale.ResultsConsensus was reached in 41% (15/37) of the statements. Panelists agreed that pituitary surgery remains first line treatment. There was general agreement to recommend first-generation somatostatin analog (SSA) treatment after failed surgery and to consider repeat surgery. In addition, there was agreement to recommend combination therapy with first-generation SSA and pegvisomant as second- or third-line treatment. In more than 50% of the statements, consensus was not achieved. Considerable disagreement existed regarding pegvisomant monotherapy, and treatment with pasireotide and dopamine agonists.ConclusionThis consensus exploration study on the management of patients with acromegaly in the Nordic countries revealed a relatively large degree of disagreement among experts, which mirrors the complexity of the disease and the shortage of evidence-based data.
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| 9. |
- Arlien-Søborg, Mai C., et al.
(författare)
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Acromegaly management in the nordic countries : a Delphi consensus survey
- 2024
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Ingår i: Clinical Endocrinology. - : John Wiley & Sons. - 0300-0664 .- 1365-2265.
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Acromegaly is associated with increased morbidity and mortality if left untreated. The therapeutic options include surgery, medical treatment, and radiotherapy. Several guidelines and recommendations on treatment algorithms and follow-up exist. However, not all recommendations are strictly evidence-based. To evaluate consensus on the treatment and follow-up of patients with acromegaly in the Nordic countries.Methods: A Delphi process was used to map the landscape of acromegaly management in Denmark, Sweden, Norway, Finland, and Iceland. An expert panel developed 37 statements on the treatment and follow-up of patients with acromegaly. Dedicated endocrinologists (n = 47) from the Nordic countries were invited to rate their extent of agreement with the statements, using a Likert-type scale (1−7). Consensus was defined as ≥80% of panelists rating their agreement as ≥5 or ≤3 on the Likert-type scale.Results: Consensus was reached in 41% (15/37) of the statements. Panelists agreed that pituitary surgery remains first line treatment. There was general agreement to recommend first-generation somatostatin analog (SSA) treatment after failed surgery and to consider repeat surgery. In addition, there was agreement to recommend combination therapy with first-generation SSA and pegvisomant as second- or third-line treatment. In more than 50% of the statements, consensus was not achieved. Considerable disagreement existed regarding pegvisomant monotherapy, and treatment with pasireotide and dopamine agonists.Conclusion: This consensus exploration study on the management of patients with acromegaly in the Nordic countries revealed a relatively large degree of disagreement among experts, which mirrors the complexity of the disease and the shortage of evidence-based data.
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| 10. |
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| 11. |
- Bengtsson, Daniel, 1975-, et al.
(författare)
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Long-Term Outcome and MGMT as a Predictive Marker in 24 Patients With Atypical Pituitary Adenomas and Pituitary Carcinomas Given Treatment With Temozolomide
- 2015
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Ingår i: Journal of Clinical Endocrinology & Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 100:4, s. 1689-1698
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Tidskriftsartikel (refereegranskat)abstract
- Context/Objective: Locally aggressive pituitary tumors (LAPT) and pituitary carcinomas respond poorly to conventional therapy and cytotoxic drugs. Temozolomide (TMZ) is an oral alkylating drug with good tolerability, approved for treatment of malignant gliomas. The experience of its use in pituitary tumors is limited. Design and Setting: We report on 24 patients with aggressive pituitary tumors (16 LAPTs, 8 carcinomas) treated with TMZ for a median of 6 months (range 1-23). Follow-up ranged from 4 to 91 months with a median of 32.5 months. 19/24 tumors were hormone secreting (PRL 9, ACTH 4, GH 4, GH/PRL 2). Ki-67 was 2-50% in LAPTs, and 5-80% in carcinomas. Main Outcome: Response to TMZ and the association with tumor expression of O6-methylguanine DNA methyltransferase (MGMT), MLH1, MSH2, and MSH6, examined by immunohistochemistry. Results: Complete tumor regression occurred in two carcinomas and persisted at follow-up after 48 and 91 months, respectively. Partial regress of tumor mass ranging from 35% to 80% occurred in 5 LAPTs and 2 carcinomas. Another patient with LAPT had a 71% decrease in prolactin levels without change in tumor volume. Three LAPTs could not be evaluated. Median MGMT staining was 9% (5-20%) in responders vs 93% (50-100%) in nonresponders. Loss of MSH2 and MSH 6 was observed in a single patient who had a rapid development of resistance to TMZ. Conclusions: This study shows that TMZ is a valuable treatment option for patients with uncontrolled pituitary tumors. The data suggest that tumoral MGMT staining below 50% is associated with a high likelihood of treatment response.
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| 12. |
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| 13. |
- Bergthorsdottir, Ragnhildur, 1971, et al.
(författare)
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Increased risk of hospitalization, intensive care and death due to covid-19 in patients with adrenal insufficiency : a Swedish nationwide study
- 2024
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Ingår i: Journal of Internal Medicine. - : John Wiley & Sons. - 0954-6820 .- 1365-2796. ; 295:3, s. 322-330
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Tidskriftsartikel (refereegranskat)abstract
- Background: Patients with adrenal insufficiency (AI) have excess morbidity and mortality related to infectious disorders. Whether patients with AI have increased morbidity and mortality from COVID-19 is unknown.Methods: In this linked Swedish national register-based cohort study, patients with primary and secondary AI diagnosis were identified and followed from 1 January 2020 to 28 February 2021. They were compared with a control cohort from the general population matched 10:1 for age and sex. The following COVID-19 outcomes were studied: incidence of COVID-19 infection, rates of hospitalization, intensive care admission and death. Hazard ratios (HR) with 95% confidence intervals (95% CI) adjusted for socioeconomic factors and comorbidities were estimated using Cox regression analysis.Results: We identified 5430 patients with AI and 54,300 matched controls: There were 47.6% women, mean age was 57.1 (standard deviation 18.1) years, and the frequency of COVID-19 infection was similar, but the frequency of hospitalization (2.1% vs. 0.8%), intensive care (0.3% vs. 0.1%) and death (0.8% vs. 0.2%) for COVID-19 was higher in AI patients than matched controls. After adjustment for socioeconomic factors and comorbidities, the HR (95% CI) was increased for hospitalization (1.96, 1.59–2.43), intensive care admission (2.76, 1.49–5.09) and death (2.29, 1.60–3.28).Conclusion: Patients with AI have a similar incidence of COVID-19 infection to a matched control population, but a more than twofold increased risk of developing a severe infection or a fatal outcome. They should therefore be prioritized for vaccination, antiviral therapy and other appropriate treatment to mitigate hospitalization and death.
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| 14. |
- Bergthorsdottir, Ragnhildur, 1971, et al.
(författare)
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Visceral Fat and Novel Biomarkers of Cardiovascular Disease in Patients With Addison's Disease: A Case-Control Study
- 2017
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Ingår i: Journal of Clinical Endocrinology & Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 102:11, s. 4264-4272
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Tidskriftsartikel (refereegranskat)abstract
- Context: Patients with Addison's disease (AD) have increased cardiovascular mortality. Objective: To study visceral fat and conventional and exploratory cardiovascular risk factors in patients with AD. Subjects: Patients (n = 76; n = 51 women) with AD and 76 healthy control subjects were matched for sex, age, body mass index (BMI), and smoking habits. Main outcome measures: The primary outcome variable was visceral abdominal adipose tissue (VAT) measured using computed tomography. Secondary outcome variables were prevalence of metabolic syndrome (MetS) and 92 biomarkers of cardiovascular disease. Results: The mean 6 standard deviation age of all subjects was 53 6 14 years; mean BMI, 25 6 4 kg/ m2; and mean duration of AD, 17 6 12 years. The median (range) daily hydrocortisone dose was 30 mg (10 to 50 mg). Median (interquartile range) 24-hour urinary free cortisol excretion was increased in patients vs controls [359 nmol (193 to 601 nmol) vs 175 nmol (140 to 244 nmol); P, 0.001]. VAT did not differ between groups. After correction for multiple testing, 17 of the 92 studied biomarkers differed significantly between patients and control subjects. Inflammatory, proinflammatory, and proatherogenic risk biomarkers were increased in patients [fold change (FC),.1] and vasodilatory protective marker was decreased (FC, < 1). Twenty-six patients (34%) vs 12 control subjects (16%) fulfilled the criteria for MetS (P = 0.01). Conclusion: Despite higher cortisol exposure, VAT was not increased in patients with AD. The prevalence of MetS was increased and several biomarkers of cardiovascular disease were adversely affected in patients with AD.
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| 15. |
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| 16. |
- Chantzichristos, Dimitrios, 1976, et al.
(författare)
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Identification of human glucocorticoid response markers using integrated multi-omic analysis from a randomized crossover trial.
- 2021
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Ingår i: eLife. - 2050-084X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Glucocorticoids are among the most commonly prescribed drugs, but there is no biomarker that can quantify their action. The aim of the study was to identify and validate circulating biomarkers of glucocorticoid action.In a randomized, crossover, single-blind, discovery study, 10 subjects with primary adrenal insufficiency (and no other endocrinopathies) were admitted at the in-patient clinic and studied during physiological glucocorticoid exposure and withdrawal. A randomization plan before the first intervention was used. Besides mild physical and/or mental fatigue and salt craving, no serious adverse events were observed. The transcriptome in peripheral blood mononuclear cells and adipose tissue, plasma miRNAomic, and serum metabolomics were compared between the interventions using integrated multi-omic analysis.We identified a transcriptomic profile derived from two tissues and a multi-omic cluster, both predictive of glucocorticoid exposure. A microRNA (miR-122-5p) that was correlated with genes and metabolites regulated by glucocorticoid exposure was identified (p=0.009) and replicated in independent studies with varying glucocorticoid exposure (0.01 ≤ p≤0.05).We have generated results that construct the basis for successful discovery of biomarker(s) to measure effects of glucocorticoids, allowing strategies to individualize and optimize glucocorticoid therapy, and shedding light on disease etiology related to unphysiological glucocorticoid exposure, such as in cardiovascular disease and obesity.The Swedish Research Council (Grant 2015-02561 and 2019-01112); The Swedish federal government under the LUA/ALF agreement (Grant ALFGBG-719531); The Swedish Endocrinology Association; The Gothenburg Medical Society; Wellcome Trust; The Medical Research Council, UK; The Chief Scientist Office, UK; The Eva Madura's Foundation; The Research Foundation of Copenhagen University Hospital; and The Danish Rheumatism Association.NCT02152553.
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| 17. |
- Ding, Yuan C, et al.
(författare)
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A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers
- 2012
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research. - 1055-9965 .- 1538-7755. ; 21:8, s. 1362-1370
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers.METHODS: IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers.RESULTS: Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 (HR, 1.43; 95% confidence interval (CI), 1.06-1.92; P = 0.019) and BRCA2 mutation carriers (HR, 2.21; 95% CI, 1.39-3.52, P = 0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class II mutations than class I mutations (class II HR, 1.86; 95% CI, 1.28-2.70; class I HR, 0.86; 95%CI, 0.69-1.09; P(difference), 0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR, 2.42; P = 0.03).CONCLUSION: The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class II mutation carriers.Impact: These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers.
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| 18. |
- Einarsdottir, Margret, et al.
(författare)
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High Mortality Rate in Oral Glucocorticoid Users: A Population-Based Matched Cohort Study
- 2022
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Ingår i: Frontiers in Endocrinology. - : Frontiers Media SA. - 1664-2392. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveThe aim of the study was to investigate all-cause and disease-specific mortality in a large population-based cohort of oral glucocorticoid (GC) users. MethodsThis was a retrospective, matched cohort study. Information on dispensed prescriptions was obtained from the Swedish Prescribed Drug Register. The cause of death was obtained from the Swedish Cause-of-Death Registry. Patients receiving prednisolone >= 5 mg/day (or equivalent dose of other GC) for >= 21 days between 2007-2014 were included. For each patient, one control subject matched for age and sex was included. The study period was divided into 3-month periods and patients were divided into groups according to a defined daily dose (DDD) of GC used per day. The groups were: Non-users (0 DDD per day), low-dose users (>0 but <0.5 DDD per day), medium-dose users (0.5-1.5 DDD per day) and high-dose users (>1.5 DDD per day). Hazard ratios (HRs), unadjusted and adjusted for age, sex and comorbidities, were calculated using a time-dependent Cox proportional hazard model. ResultsCases (n=223 211) had significantly higher all-cause mortality compared to controls (HR adjusted for age, sex and comorbidities 2.08, 95% confidence interval 2.04 to 2.13). After dividing the cases into subgroups, adjusted HR was 1.31 (1.28 to 1.34) in non-users, 3.64 (3.51 to 3.77) in low-dose users, 5.43 (5.27 to 5.60) in medium-dose users and, 5.12 (4.84 to 5.42) in high-dose users. The highest adjusted hazard ratio was observed in high-dose users for deaths from sepsis 6.71 (5.12 to 8.81) and pulmonary embolism 7.83 (5.71 to 10.74). ConclusionOral GC users have an increased mortality rate compared to the background population, even after adjustment for comorbidities. High-dose users have an increased risk of dying from sepsis, and pulmonary embolism compared to controls. Whether the relationship between GC exposure and the excess mortality is causal remains to be elucidated.
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| 19. |
- Einarsdottir, Margret, et al.
(författare)
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High prescription rate of oral glucocorticoids in children and adults: a retrospective cohort study from Western Sweden.
- 2020
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Ingår i: Clinical endocrinology. - : Wiley. - 1365-2265 .- 0300-0664. ; 92:1, s. 21-28
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Tidskriftsartikel (refereegranskat)abstract
- Glucocorticoids (GCs) are a cornerstone in treating various common and uncommon diseases. The aim of this study was to estimate the prevalence of GC use in terms of doses associated with risk of tertiary adrenal insufficiency in adults and children, and treatment indications.This was a retrospective cohort study. Information on dispensed prescriptions was obtained from the Swedish Prescribed Drug Register. Patients with prescriptions of prednisolone (or equivalent dose of other GCs) ≥5 mg daily for ≥21 days between 2007-2014 were included. Information on concurrent diseases was obtained from the Swedish National Patient Register and the Västra Götaland Regional Healthcare Database.Of 1,585,335 inhabitants in Västra Götaland County, 223,211 were included in the study (women 55.6%). Mean age was 48 ± 24 years. Period prevalence of oral GC use during the 8-year study period was 14.1%. The highest prevalence (27.4%) was in men aged 80-89 years and lowest (7.5%) in men 10-19 years of age. The period prevalence in children 0-9 years of age was 10.6%. COPD and asthma were the most common indications for treatment (17.2%) followed by allergy (12.5%), and malignant neoplasms (11.5%). Allergy was the most frequent indication (20.5%) in children and adolescents.Between 2007-2014, every seventh inhabitant in western Sweden received a GC prescription at doses associated with risk of developing tertiary adrenal insufficiency. These findings illustrate the importance of awareness of the potential development of tertiary adrenal insufficiency in both pediatric and adult patients.
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| 20. |
- Einarsdottir, Margret, et al.
(författare)
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Impact of chronic oral glucocorticoid treatment on mortality in patients with COVID-19: analysis of a population-based cohort.
- 2024
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Ingår i: BMJ Open. - 2044-6055. ; 14:3
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Tidskriftsartikel (refereegranskat)abstract
- While glucocorticoid (GC) treatment initiated for COVID-19 reduces mortality, it is unclear whether GC treatment prior to COVID-19 affects mortality. Long-term GC use raises infection and thromboembolic risks. We investigated if patients with oral GC use prior to COVID-19 had increased mortality overall and by selected causes.Population-based observational cohort study.Population-based register data in Sweden.All patients infected with COVID-19 in Sweden from January 2020 to November 2021 (n=1 200 153).Any prior oral GC use was defined as ≥1GC prescription during 12 months before index. High exposure was defined as ≥2GC prescriptions with a cumulative prednisolone dose ≥750mg or equivalent during 6 months before index. GC users were compared with COVID-19 patients who had not received GCs within 12 months before index. We used Cox proportional hazard models and 1:2 propensity score matching to estimate HRs and 95% CIs, controlling for the same confounders in all analyses.3378 deaths occurred in subjects with any prior GC exposure (n=48806; 6.9%) and 14850 among non-exposed (n=1 151 347; 1.3%). Both high (HR 1.98, 95% CI 1.87 to 2.09) and any exposure (1.58, 1.52 to 1.65) to GCs were associated with overall death. Deaths from pulmonary embolism, sepsis and COVID-19 were associated with high GC exposure and, similarly but weaker, with any exposure. High exposure to GCs was associated with increased deaths caused by stroke and myocardial infarction.Patients on oral GC treatment prior to COVID-19 have increased mortality, particularly from pulmonary embolism, sepsis and COVID-19.
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| 21. |
- Einarsdottir, Margret Jona, et al.
(författare)
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Intermittent high-dose glucocorticoid treatment does not cause adrenal insufficiency in patients with diffuse large B-cell lymphoma - a prospective study.
- 2023
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Ingår i: Acta haematologica. - 1421-9662.
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Tidskriftsartikel (refereegranskat)abstract
- Glucocorticoid (GC) treatment suppresses the hypothalamic-pituitary-adrenal axis and can cause GC-induced adrenal insufficiency. In this study we investigated the incidence of GC-induced adrenal insufficiency in patients receiving intermittent short-term high-dose oral GC treatment for newly diagnosed diffuse large B-cell lymphoma. Cosyntropin stimulation test was used to assess adrenal function at study entry (baseline), at 2 months (before the 5th cycle), and 6 months from baseline (3 months after the last cycle). Ten patients were included (40% women). Mean age was 61 years. The mean (range) plasma morning cortisol was 407 (320-530) nmol/L at baseline, 373 (260-610) nmol/L at 2 months, and 372 (230-520) nmol/L 6 months from baseline. All patients had normal response to cosyntropin stimulation at baseline as well as 2 and 6 months from baseline. Thus, none of the patients developed biochemically verified adrenal insufficiency. Therefore, short-term high-dose GC therapy, a commonly used adjuvant treatment in patients with malignant hematological diseases, does not seem to down-regulate the hypothalamic-pituitary-adrenal axis.
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| 22. |
- Einarsdottir, Margret, et al.
(författare)
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Undiagnosed adrenal insufficiency as a cause of premature death in glucocorticoid users.
- 2024
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Ingår i: Endocrine connections. - 2049-3614. ; 13:4
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Tidskriftsartikel (refereegranskat)abstract
- It is unknown whether glucocorticoid (GC)-induced adrenal insufficiency may cause premature mortality in GC users. We conducted a retrospective cohort study to investigate if undiagnosed and undertreated GC-induced adrenal insufficiency is a contributor to premature death in GC users.Information on dispensed prescriptions in West Sweden from 2007 to 2014 was obtained from the Swedish Prescribed Drug Register. Cause of death was collected from the Swedish Cause of Death Register. Of 223,211 patients who received oral GC prescriptions, 665 died from sepsis within 6 months of their last prescription. Three hundred of these patients who had died in hospital were randomly selected for further investigation. Medical records were initially reviewed by one investigator. Furthermore, two additional investigators reviewed the medical records of patients whose deaths were suspected to be caused by GC-induced adrenal insufficiency.Of 300 patients (121 females, 40%), 212 (75%) were prescribed GC treatment at admission. The mean age was 76 ± 11 years (range 30-99). Undiagnosed or undertreated GC-induced adrenal insufficiency was considered a probable contributor to death by at least two investigators in 11 (3.7%) patients. In five of these 11 cases, long-term GC therapy was abruptly discontinued during hospitalization. Undiagnosed or undertreated GC-induced adrenal insufficiency was considered a possible contributing factor to death in a further 36 (12%) patients.GC-induced adrenal insufficiency is an important contributor to premature death in GC users. Awareness of the disorder during intercurrent illness and following cessation of GC treatment is essential.
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| 23. |
- Ekstrand, Elise, et al.
(författare)
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Metabolic Effects of Cortisone Acetate vs Hydrocortisone in Patients With Secondary Adrenal Insufficiency.
- 2020
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Ingår i: Journal of the Endocrine Society. - : The Endocrine Society. - 2472-1972. ; 4:12
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Tidskriftsartikel (refereegranskat)abstract
- Pharmacokinetic properties of cortisone acetate (CA) and hydrocortisone (HC) differ because CA needs to be converted into cortisol to become active.This work analyzed the metabolic consequences of switching CA to an equivalent daily dose of HC in patients with secondary adrenal insufficiency (SAI).This was a post hoc analysis from a prospective study including individuals with hypopituitarism receiving growth hormone replacement. Data were collected before and after a switch from CA to an equivalent dose of HC (switch group). Two control groups were included: patients continuing CA replacement (CA control group) and adrenal-sufficient hypopituitary patients (AS control group).The analysis included 229 patients: 105, 31, and 93 in the switch, CA control, and AS control groups, respectively. After the change from CA to HC, increases in mean body weight (1.2 kg; P<.05), waist circumference (2.9 cm; P<.001), body fat measured by dual-energy x-ray absorptiometry (1.3 kg; P<.001), and glycated hemoglobin (0.3%; P<.05) were recorded in the switch group. The increase in mean waist circumference was greater than in the AS control group (0.9 cm; P<.05). Mean body fat increased in the switch group but not in the CA control group (-0.7 kg; P<.05).A switch from CA to an equivalent dose of HC was associated with a worsened metabolic profile, suggesting that HC has a more powerful metabolic action than CA based on the assumption that 20 mg HC equals 25 mg CA.
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| 24. |
- Espiard, Stéphanie, et al.
(författare)
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Improved Urinary Cortisol Metabolome in Addison's disease: a Prospective Trial of Dual-Release Hydrocortisone.
- 2021
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 106:3, s. 814-825
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Tidskriftsartikel (refereegranskat)abstract
- Oral once-daily dual-release hydrocortisone (DR-HC) replacement therapy has demonstrated an improved metabolic profile compared to conventional 3-times-daily (TID-HC) therapy among patients with primary adrenal insufficiency. This effect might be related to a more physiological cortisol profile, but also to a modified pattern of cortisol metabolism.To study cortisol metabolism during DR-HC and TID-HC.Randomized, 12-week, crossover study.DC-HC and same daily dose of TID-HC in patients with primary adrenal insufficiency (n=50) versus healthy subjects (n=124) as control.Urinary corticosteroid metabolites measured by gas chromatography/mass spectrometry on 24-hour urinary collections.Total cortisol metabolites decreased during DR-HC compared to TID-HC (P < 0.001) and reached control values (P = 0.089). During DR-HC, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity measured by tetrahydrocortisol+5α-tetrahydrocortisol/tetrahydrocortisone ratio was reduced compared to TID-HC (P < 0.05), but remained increased versus controls (P < 0.001). 11β-HSD2 activity measured by urinary free cortisone/free cortisol ratio was decreased with TID-HC versus controls (P < 0.01) but normalized with DR-HC (P = 0.358). 5α- and 5β-reduced metabolites were decreased with DR-HC compared to TID-HC. Tetrahydrocortisol/5α-tetrahydrocortisol ratio was increased during both treatments, suggesting increased 5β-reductase activity.The urinary cortisol metabolome shows striking abnormalities in patients receiving conventional TID-HC replacement therapy with increased 11β-HSD1 activity that may account for the unfavorable metabolic phenotype in primary adrenal insufficiency. Its change towards normalization with DR-HC may mediate beneficial metabolic effects. The urinary cortisol metabolome may serve as a tool to assess optimal cortisol replacement therapy.
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| 25. |
- Esposito, Daniela, et al.
(författare)
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Androgen deficiency in hypopituitary women: its consequences and management
- 2024
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Ingår i: REVIEWS IN ENDOCRINE & METABOLIC DISORDERS. - 1389-9155 .- 1573-2606.
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Forskningsöversikt (refereegranskat)abstract
- Women with hypopituitarism have various degrees of androgen deficiency, which is marked among those with combined hypogonadotrophic hypogonadism and secondary adrenal insufficiency. The consequences of androgen deficiency and the effects of androgen replacement therapy have not been fully elucidated. While an impact of androgen deficiency on outcomes such as bone mineral density, quality of life, and sexual function is plausible, the available evidence is limited. There is currently no consensus on the definition of androgen deficiency in women and it is still controversial whether androgen substitution should be used in women with hypopituitarism and coexisting androgen deficiency. Some studies suggest beneficial clinical effects of androgen replacement but data on long-term benefits and risk are not available. Transdermal testosterone replacement therapy in hypopituitary women has shown some positive effects on bone metabolism and body composition. Studies of treatment with oral dehydroepiandrosterone have yielded mixed results, with some studies suggesting improvements in quality of life and sexual function. Further research is required to elucidate the impact of androgen deficiency and its replacement treatment on long-term outcomes in women with hypopituitarism. The lack of transdermal androgens for replacement in this patient population and limited outcome data limit its use. A cautious and personalized treatment approach in the clinical management of androgen deficiency in women with hypopituitarism is recommended while awaiting more efficacy and safety data.
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