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- Falhammar, Henrik, et al.
(author)
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Increased cardiovascular and metabolic morbidity in patients with 21-hydroxylase deficiency : a Swedish population-based national cohort study
- 2015
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In: The Journal of Clinical Endocrinology & Metabolism. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 0021-972X. ; 100:9, s. 3520-3528
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Journal article (peer-reviewed)abstract
- CONTEXT: Congenital adrenal hyperplasia (CAH) is lethal in its most severe forms if not treated with glucocorticoids. However, glucocorticoids may increase the risk of cardiovascular and metabolic morbidity. OBJECTIVE: This study aimed to study cardiovascular and metabolic morbidity in CAH. DESIGN, SETTING, AND PARTICIPANTS: Patients with CAH due to 21-hydroxylase deficiency (n = 588; >80% with known CYP21A2 mutations) were compared with controls matched for sex, year, and place of birth (n = 58 800). Data were obtained by linking national population-based registers. Subgroup analyses were performed regarding sex, clinical severity (salt wasting, simple virilizing, nonclassic), CYP21A2 genotype (null, I2 splice, I172N, P30L), and stratified by the introduction of neonatal screening, age groups, and nonobesity. MAIN OUTCOME MEASURES: To study cardiovascular and metabolic morbidity in CAH. RESULTS: In CAH, both any cardiovascular and metabolic disorders (OR [odds ratio], 3.9; 95% CI [confidence interval], 3.1-5.0), and cardiovascular disease (OR, 2.7; 95% CI, 1.9-3.9) were increased. Separate analyses of the individual diseases showed higher frequencies in CAH of hypertension, hyperlipidemia, atrial fibrillation, venous thromboembolism, obesity, diabetes (mainly type 2), obstructive sleep disorder, thyrotoxicosis, and hypothyroidism. Similar results were seen in the stratified groups. On the subgroup level, females were generally more affected (especially I172N and the nonclassic group), as were males with the null genotype. CONCLUSIONS: CAH was associated with excess cardiovascular and metabolic morbidity but the mechanism is not certain as the glucocorticoids were not assessed. Hypothyroidism and obesity may be an effect of close observation. However, more severe conditions were presumably detected equally in patients and controls. Screening for diabetes and other metabolic disorders that increase cardiovascular risk is important.
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- Falhammar, Henrik, et al.
(author)
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Increased mortality in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency
- 2014
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In: The Journal of Clinical Endocrinology & Metabolism. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 0021-972X .- 1945-7197.
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Journal article (peer-reviewed)abstract
- Context: Reports on mortality in patients with congenital adrenal hyperplasia (CAH) are lacking. Objective: To study mortality and causes of death in CAH. Design, Setting and Participants: We studied patients with CAH (21-hydroxylase deficiency, n=588; CYP21A2 mutations known, >80%), and compared them with controls (n=58800). Data were derived through linkage of national population-based registers. Main Outcome Measures: Mortality and causes of death. Results: The mean age of death was 41.2±26.9 years in CAH patients and 47.7±27.7 years in controls (P<0.001). Among CAH patients 23 (3.9%) had deceased compared to 942 (1.6%) of controls. The hazard ratio (and 95% confidence interval) of death was 2.3(1.2-4.3) in CAH males and 3.5(2.0-6.0) in CAH females. Including only patients born 1952-2009, gave similar total results but only patients with salt-wasting or with unclear phenotype had an increased mortality. The causes of death in CAH patients were adrenal crisis (42%), cardiovascular (32%), cancer (16%), and suicide (10%). There were seven additional deaths in CAH individuals with incomplete or reused personal identification number that could not be analyzed using linkage of registers. Of the latter all except one were deceased before the introduction of neonatal screening in 1986 and most of them in the first weeks of life, probably in an adrenal crisis. Conclusions: CAH is a potentially lethal condition and was associated with excess mortality due to adrenal crisis. The salt-wasting phenotype seemed to have worse outcome also in children and adults due to adrenal crisis and not only before the introduction of neonatal screening.
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- Strandqvist, Anna, et al.
(author)
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Suboptimal psychosocial outcomes in patients with congenital adrenal hyperplasia : epidemiological studies in a nonbiased national cohort in Sweden
- 2014
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In: The Journal of Clinical Endocrinology & Metabolism. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 0021-972X .- 1945-7197.
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Journal article (peer-reviewed)abstract
- Context: Congenital adrenal hyperplasia (CAH), CYP21A2 deficiency, results in cortisol and aldosterone deficiency and increased production of androgens, with a good genotype phenotype correlation. Objective: To study psychosocial outcomes in relation to clinical severity, CYP21A2 genotype, in men and women. Design: An epidemiological study with a matched cohort control design. Setting: All known CAH patients in Sweden. Participants: 588 patients, >95% with known severity of CAH; 100 controls per patient matched for sex, year and place of birth. Main outcome and measures: Proxies for quality of life were selected: level of education, employment, income, sick-leave, disability pension, marriage and children. Results: Women with salt-wasting (SW) CAH had completed primary education less often (OR 0.3), not explained by neonatal salt-crisis or hypoglycemia since the men did not differ from controls. Men and women in the less severe I172N genotype group were more likely to have an academic education (OR 1.8) SW women were more likely to have an income in the top 20 percentile (OR 2.0 ). Both men and women had more disability pension (OR 1.5) and sick leave (OR 1.7). The men more often had long lasting employment (OR 3.1). Men were more often (OR 1.6) while women were less often married (OR 0.7). Patients had children less often (OR 0.3). Conclusions: This study shows important outcome differences regarding education, employment, marriage and fertility depending on sex and severity of CAH. The mechanisms behind this and the increased risk for sick leave or disability pension in both men and women should be identified to improve medical and psychological care.
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- Abrahamsson, Annelie, et al.
(author)
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Estradiol, Tamoxifen, and Flaxseed Alter IL-1 beta and IL-1Ra Levels in Normal Human Breast Tissue in Vivo
- 2012
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In: Journal of Clinical Endocrinology and Metabolism. - : Endocrine Society. - 0021-972X .- 1945-7197. ; 97:11, s. E2044-E2054
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Journal article (peer-reviewed)abstract
- Introduction: Sex steroid exposure increases the risk of breast cancer by unclear mechanisms. Diet modifications may be one breast cancer prevention strategy. The proinflammatory cytokine family of IL-1 is implicated in cancer progression. IL-1Ra is an endogenous inhibitor of the proinflammatory IL-1 alpha and IL-1 beta. less thanbrgreater than less thanbrgreater thanObjective: The objective of this study was to elucidate whether estrogen, tamoxifen, and/or diet modification altered IL-1 levels in normal human breast tissue. less thanbrgreater than less thanbrgreater thanDesign and Methods: Microdialysis was performed in healthy women under various hormone exposures, tamoxifen therapy, and diet modifications and in breast cancers of women before surgery. Breast tissue biopsies from reduction mammoplasties were cultured. less thanbrgreater than less thanbrgreater thanResults: We show a significant positive correlation between estradiol and in vivo levels of IL-1 beta in breast tissue and abdominal sc fat, whereas IL-1Ra exhibited a significant negative correlation with estradiol in breast tissue. Tamoxifen or a dietary addition of 25 g flaxseed per day resulted in significantly increased levels of IL-1Ra in the breast. These results were confirmed in ex vivo culture of breast biopsies. Immunohistochemistry of the biopsies did not reveal any changes in cellular content of the IL-1s, suggesting that mainly the secreted levels were affected. In breast cancer patients, intratumoral levels of IL-1 beta were significantly higher compared with normal adjacent breast tissue. less thanbrgreater than less thanbrgreater thanConclusion: IL-1 may be under the control of estrogen in vivo and may be attenuated by antiestrogen therapy and diet modifications. The increased IL-1 beta in breast cancers of women strongly suggests IL-1 as a potential therapeutic target in breast cancer treatment and prevention.
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- Agnarsson, Hjalmar Ragnar, et al.
(author)
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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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In: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 99:4, s. 1479-1485
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Journal article (peer-reviewed)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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8. |
- Ahmed, Fozia, et al.
(författare)
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Role of Estrogen and Its Receptors in Adipose Tissue Glucose Metabolism in Pre- and Postmenopausal Women
- 2022
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : ENDOCRINE SOC. - 0021-972X .- 1945-7197. ; 107:5, s. E1879-E1889
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Tidskriftsartikel (refereegranskat)abstract
- Context: Reduced estrogen levels in postmenopausal women predispose them to metabolic side effects, including insulin resistance and type 2 diabetes; however, the cellular mechanisms are not well understood.Objective: This work aimed to study the expression of estrogen receptors in adipose tissue from pre- and postmenopausal women and the effects of estradiol (E2) on glucose uptake of adipocytes.Methods: Subcutaneous (SAT) and visceral adipose tissue (VAT) obtained from pre- and postmenopausal women (19-51 and 46-75 years old, respectively) were used to measure gene expression of ESR1 and ESR2. SAT tissue was incubated with E2, and glucose uptake and estrogen receptor levels were measured. Polymorphisms in ESR1 and ESR2 were addressed in public databases to identify single nucleotide polymorphisms associated with metabolic traits.Results: ESR2 expression was lower in pre- vs postmenopausal women, corresponding to lower ESR1:ESR2 gene expression ratio in postmenopausal women. In premenopausal women, the expression of ESR1 was higher in VAT than in SAT. In both pre- and postmenopausal women, ESR2 expression was lower in VAT than in SAT. In late, but not pre- or early postmenopausal women, E2 reduced glucose uptake and GLUT4 protein and increased expression of ESR2. ESR1 polymorphisms were associated with weight, body fat distribution, and total cholesterol, and ESR2 polymorphisms were associated with total cholesterol and triglyceride levels and with body fat percentage.Conclusion: E2 inhibits glucose utilization in human adipocytes in late postmenopausal women. Changes in glucose utilization over time since menopause may be explained by a lower ESR1:ESR2 ratio. This can have clinical implications on the timing of estrogen treatment in postmenopausal women.
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