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1.
  • Söderqvist, Gunnar, et al. (författare)
  • Metabolism of estrone sulfate by normal breast tissue : Influence of menopausal status and oral contraceptives
  • 1994
  • Ingår i: Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier BV. - 0960-0760. ; 48:2-3, s. 221-224
  • Tidskriftsartikel (refereegranskat)abstract
    • The metabolism of [ 3 H]estrone sulfate ([ 3 H]E 1 S) was studied in normal breast tissue from 10 premenopausal women without oral contraceptives (OC), in 12 OC users and in 9 untreated postmenopausal women. [ 3 H]E 1 S was converted into estrone ([ 3 H]E 1 ) and estradiol-17β ([ 3 H]E 2 ) by tissue samples from all three groups of women, with only minor formation of other unconjugated compounds. The rate of [ 3 H]E 2 formation was significantly higher in premenopausal women without OC than in postmenopausal women. Among premenopausal women, OC users had a significantly lower rate of total hydrolysis and of [ 3 H]E 1 formation than non-users. The rate of total hydrolysis of [ 3 H]E 1 S in normal breast tissue from all three groups of women was similar to that in muscle, but the rate of [ 3 H]E 2 formation was ten times higher. Both total hydrolysis rate and rate of [ 3 H]E 2 formation were significantly lower in normal breast tissue than in breast carcinoma and in normal and neoplastic endometrium. The specific ability of normal breast tissue to convert E 1 S into the terminal biologically active estrogen E 2 may be important for estrogenic stimulation of the breast in subjects with low circulating E 2 levels. The lower rate of E 1 formation in OC users may reflect an inhibitory effect of the progestagen compound in such preparations.
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  • Akner, Gunnar, 1953-, et al. (författare)
  • Subcellular distribution of the glucocorticoid receptor and evidence for its association with microtubules
  • 1995
  • Ingår i: Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier BV. - 0960-0760 .- 1879-1220. ; 52:1, s. 1-16
  • Forskningsöversikt (refereegranskat)abstract
    • The cellular distribution of the glucocorticoid receptor (GR) has not yet been firmly established. The extensive literature indicates that GR is present both in the cytoplasm and the cell nucleus, however, some studies have failed to detect cytoplasmic GR. It is still controversial as to whether GR is randomly diffusing in the cytoplasm and nucleus, or if the GR-distribution is organized or controlled in some way, which may be of importance for the transduction of glucocorticoid effects to cells. There is evidence that both non-activated and activated GR is associated with the plasma membrane, a number of cytoplasmic organelles and the nucleus. Both morphological and biochemical evidence show that GR is associated with microtubules during different stages of the cell cycle, i.e. GR co-localizes, co-purifies and co-polymerizes with tubulin. This indicates that GR is structurally linked to the intracellular MT-network which may be of importance in the mechanism of action of glucocorticoid hormones. The literature in this field is reviewed including the reported data on subcellular GR-localization.
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  • DONOVAN, M, et al. (författare)
  • The cellular retinoic acid binding proteins
  • 1995
  • Ingår i: The Journal of steroid biochemistry and molecular biology. - 0960-0760. ; 53, s. 459-
  • Tidskriftsartikel (refereegranskat)
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  • Loinder, Kristina, 1963-, et al. (författare)
  • The nuclear receptor corepressor (N-CoR) modulates basal and activated transcription of genes controlled by retinoic acid
  • 2003
  • Ingår i: Journal of Steroid Biochemistry and Molecular Biology. - 0960-0760 .- 1879-1220. ; 84:1, s. 15-21
  • Tidskriftsartikel (refereegranskat)abstract
    • Variation in cell morphology and function is caused by differentiation. In myeloid differentiation, retinoid signaling, acting through heterodimers consisting of retinoic acid receptor and retinoid X receptor (RAR/RXR) plays a crucial part. The RAR/RXR heterodimers bind to naturally occurring response elements in the promoter regions of target genes, deciding whether the gene is to be transcribed or not. In the absence of the RAR-specific ligand all trans retinoic acid, RAR/RXR heterodimers are associated with the nuclear receptor corepressor N-CoR or the related SMRT.Here we show, using Western, far-Western and Northern blot techniques, that when the human monocytic cell line THP-1 is allowed to differentiate into macrophage-like cells the expression of N-CoR is down-regulated both at the protein and at the mRNA level. To investigate how this affects the transcriptional activity of retinoic acid response element (RARE)-controlled genes, we performed transient transfection experiments in THP-1 and CV-1 cells. The results indicate that N-CoR functions not merely as a repressor of basal transcription, but rather as a modulator of both basal and ligand-activated transcription of genes controlled by RAR/RXR heterodimers in a dose-dependent manner.
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  • Ritzen, EM, et al. (författare)
  • Estrogens and human growth
  • 2000
  • Ingår i: The Journal of steroid biochemistry and molecular biology. - 0960-0760. ; 74:5, s. 383-386
  • Tidskriftsartikel (refereegranskat)
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  • Wu, Xuxia, et al. (författare)
  • Expression of Bcl-2, Bcl-x, Mcl-1, Bax and Bak in human uterine leiomyomas and myometrium during the menstrual cycle and after menopause
  • 2002
  • Ingår i: Journal of Steroid Biochemistry and Molecular Biology. - 0960-0760 .- 1879-1220. ; 80:1, s. 77-83
  • Tidskriftsartikel (refereegranskat)abstract
    • To investigate the expression of Bcl-2, Bcl-x, Mcl-1, Bax and Bak proteins in human uterine leiomyomas and homologous myometrium during the menstrual cycle and after menopause.The expression of Bcl-2, Bcl-x, Mcl-1, Bax and Bak in leiomyomas (n=24) and myometrial samples (n=22) from women with leiomyomas was measured by immunohistochemistry and Western blot. Measured by immunohistochemistry, a significant difference between leiomyomas and myometrium was observed only for the Bax protein, in tissues obtained from women in the secretory phase of the menstrual cycle. The Bcl-2 staining was more abundant in leiomyomas than in myometrium only in tissues obtained in the proliferative phase of the cycle. Bcl-2 was more abundant in leiomyomas from women of fertile age than in leiomyomas from menopausal women. No significant differences were observed for the Bcl-x or Bak proteins, whereas the Mcl-1 protein was significantly less abundant in secretory phase leiomyomas than in leiomyomas from menopausal women. Western blot analysis based on pools of tissue extracts from the different groups essentially confirmed the data obtained by immunohistochemistry. Bcl-2 family proteins are expressed in leiomyomas and myometrium in different phases related to and influenced by gonadal steroids. These proteins are suggested to interact with each other in the regulation of programmed cell death, apoptosis, but their specific role in growth control of uterine leiomyomas remains to be investigated.
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  • Abdel-Khalik, Jonas, et al. (författare)
  • Bile acid biosynthesis in Smith-Lemli-Opitz syndrome bypassing cholesterol: Potential importance of pathway intermediates.
  • 2021
  • Ingår i: The Journal of steroid biochemistry and molecular biology. - : Elsevier BV. - 1879-1220 .- 0960-0760. ; 206
  • Tidskriftsartikel (refereegranskat)abstract
    • Bile acids are the end products of cholesterol metabolism secreted into bile. They are essential for the absorption of lipids and lipid soluble compounds from the intestine. Here we have identified a series of unusual Δ5-unsaturated bile acids in plasma and urine of patients with Smith-Lemli-Opitz syndrome (SLOS), a defect in cholesterol biosynthesis resulting in elevated levels of 7-dehydrocholesterol (7-DHC), an immediate precursor of cholesterol. Using liquid chromatography - mass spectrometry (LC-MS) we have uncovered a pathway of bile acid biosynthesis in SLOS avoiding cholesterol starting with 7-DHC and proceeding through 7-oxo and 7β-hydroxy intermediates. This pathway also occurs to a minor extent in healthy humans, but elevated levels of pathway intermediates could be responsible for some of the features SLOS. The pathway is also active in SLOS affected pregnancies as revealed by analysis of amniotic fluid. Importantly, intermediates in the pathway, 25-hydroxy-7-oxocholesterol, (25R)26-hydroxy-7-oxocholesterol, 3β-hydroxy-7-oxocholest-5-en-(25R)26-oic acid and the analogous 7β-hydroxysterols are modulators of the activity of Smoothened (Smo), an oncoprotein that mediates Hedgehog (Hh) signalling across membranes during embryogenesis and in the regeneration of postembryonic tissue. Computational docking of the 7-oxo and 7β-hydroxy compounds to the extracellular cysteine rich domain of Smo reveals that they bind in the same groove as both 20S-hydroxycholesterol and cholesterol, known activators of the Hh pathway.
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  • Alexanderson, Camilla, 1978, et al. (författare)
  • A single early postnatal estradiol injection affects morphology and gene expression of the ovary and parametrial adipose tissue in adult female rats.
  • 2010
  • Ingår i: The Journal of steroid biochemistry and molecular biology. - : Elsevier BV. - 1879-1220 .- 0960-0760. ; 122:1-3, s. 82-90
  • Tidskriftsartikel (refereegranskat)abstract
    • Events during early life can affect reproductive and metabolic functions in adulthood. We evaluated the programming effects of a single early postnatal estradiol injection (within 3h after birth) in female rats. We assessed ovarian and parametrial adipose tissue morphology, evaluated gene expression related to follicular development and adipose tissue metabolism, and developed a non-invasive volumetric estimation of parametrial adipose tissue by magnetic resonance imaging. Estradiol reduced ovarian weight, increased antral follicle size and number of atretic antral follicles, and decreased theca interna thickness in atretic antral follicles. Adult estradiol-injected rats also had malformed vaginal openings and lacked corpora lutea, confirming anovulation. Estradiol markedly reduced parametrial adipose tissue mass. Adipocyte size was unchanged, suggesting reduced adipocyte number. Parametrial adipose tissue lipoprotein lipase activity was increased. In ovaries, estradiol increased mRNA expression of adiponectin, complement component 3, estrogen receptor alpha, and glucose transporter 3 and 4; in parametrial adipose tissue, expression of complement component 3 was increased, expression of estrogen receptor alpha was decreased, and expression of leptin, lipoprotein lipase, and hormone-sensitive lipase was unaffected. These findings suggest that early postnatal estradiol exposure of female rats result in long-lasting effects on the ovary and parametrial adipose tissue at adult age.
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  • Almokhtar, Mokhtar, et al. (författare)
  • Motor neuron-like NSC-34 cells as a new model for the study of vitamin D metabolism in the brain.
  • 2016
  • Ingår i: Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier BV. - 0960-0760 .- 1879-1220. ; 158, s. 178-188
  • Tidskriftsartikel (refereegranskat)abstract
    • Vitamin D-3 is a pro-hormone, which is sequentially activated by 25- and 1 alpha-hydroxylation to form 25-hydroxyvitamin D-3 [25(OH)D-3] and 1 alpha,25-dihydroxyvitamin D-3 [1 alpha,25(OH)2D(3)], respectively. Subsequent inactivation is performed by 24-hydroxylation. These reactions are carried out by a series of CYP450 enzymes. The 25-hydroxylation involves mainly CYP2R1 and CYP27A1, whereas 1 alpha-hydroxylation and 24-hydroxylation are catalyzed by CYP27B1 and CYP24A1, respectively, and are tightly regulated to maintain adequate levels of the active vitamin D hormone, 1 alpha,25(OH)(2)D-3. Altered circulating vitamin D levels, in particular 25(OH)D-3, have been linked to several disorders of the nervous system, e.g., schizophrenia and Parkinson disease. However, little is known about the mechanisms of vitamin D actions in the neurons. In this study, we examined vitamin D metabolism and its regulation in a murine motor neuron-like hybrid cell line, NSC-34. We found that these cells express mRNAs for the four major CYP450 enzymes involved in vitamin D activation and inactivation, and vitamin D receptor (VDR) that mediates vitamin D actions. We also found high levels of CYP24A1-dependent 24,25-dihydroxyvitamin D-3 [24,25(OH)(2)D-3] production, that was inhibited by the well-known CYP enzyme inhibitor ketoconazole and by several inhibitors that are more specific for CYP24A1. Furthermore, CYP24A1 mRNA levels in NSC-34 cells were up-regulated by 1 alpha,25(OH)(2)D-3 and its synthetic analogs, EB1089 and tacalcitol. Our results suggest that NSC-34 cells could be a novel model for the studies of neuronal vitamin D metabolism and its mechanism of actions.
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  • Amzaleg, Y., et al. (författare)
  • Estrogens and selective estrogen receptor modulators differentially antagonize Runx2 in ST2 mesenchymal progenitor cells
  • 2018
  • Ingår i: Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier BV. - 0960-0760 .- 1879-1220. ; 183, s. 10-17
  • Tidskriftsartikel (refereegranskat)abstract
    • Estrogens attenuate bone turnover by inhibiting both osteoclasts and osteoblasts, in part through antagonizing Runx2. Apparently conflicting, stimulatory effects in osteoblast lineage cells, however, sway the balance between bone resorption and bone formation in favor of the latter. Consistent with this dualism, 17 beta-estradiol (E2) both stimulates and inhibits Runx2 in a locus-specific manner, and here we provide evidence for such locus specific regulation of Runx2 by E2 in vivo. We also demonstrate dual, negative and positive, regulation of Runx2-driven alkaline phosphatase (ALP) activity by increasing E2 concentrations in ST2 osteoblast progenitor cells. We further compared the effects of E2 to those of the Selective Estrogen Receptor Modulators (SERMs) raloxifene (ral) and lasofoxifene (las) and the phytoestrogen puerarin. We found that E2 at the physiological concentrations of 0.1-1 nM, as well as ral and las, but not puerarin, antagonize Runx2-driven ALP activity. At >= 10 nM, E2 and puerarin, but not ral or las, stimulate ALP relative to the activity measured at 0.1-1 nM. Contrasting the difference between E2 and SERMs in ST2 cells, they all shared a similar dose-response profile when inhibiting preosteoclast proliferation. That ral and las poorly mimic the locus-and concentration-dependent effects of E2 in mesenchymal progenitor cells may help explain their limited clinical efficacy.
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  • Ankarberg-Lindgren, Carina, 1963, et al. (författare)
  • High-sensitivity quantification of serum androstenedione, testosterone, dihydrotestosterone, estrone and estradiol by gas chromatography-tandem mass spectrometry with sex- and puberty-specific reference intervals.
  • 2018
  • Ingår i: The Journal of steroid biochemistry and molecular biology. - : Elsevier BV. - 1879-1220 .- 0960-0760. ; 183, s. 116-124
  • Tidskriftsartikel (refereegranskat)abstract
    • Androgen and estrogen determinations serve as important diagnostic markers in a variety of clinical conditions. However, one challenge is to enhance assay sensitivity for determination in the lowest range, such as in prepubertal children. We here present a recently developed gas chromatography-tandem mass spectrometry (GC-MS/MS) method for determination of androstenedione (A4), dihydrotestosterone (DHT), testosterone (T), estrone (E1), and estradiol (E2) in children, which we have compared with the sensitive radioimmunoassays; E2 extraction-RIA and T-RIA.Steroids were extracted in ethyl acetate n-hexane solution from serum spiked with isotopically labeled internal standard and derivatized sequentially with pentafluorobenzyl bromide, pentafluorobenzyl hydroxylamine and pentafluoropropionic acid anhydride and analyzed by GC-MS/MS using a triple quadrupole mass spectrometer operated in negative chemical ionization mode. Leftover routine samples (n=414) were used to evaluate the concordance between GC-MS/MS and RIAs and the validity of GC-MS/MS for pediatrics; of these samples, 101 were from seemingly healthy children. Pubertal stage was recorded for reference interval evaluation.Lower limit of detection for A4, T, DHT, E1, and E2 were 0.1nmol/L, 0.1nmol/L, 27pmol/L, 9pmol/L, and 2pmol/L, respectively. Good agreement was found between GC-MS/MS and T-RIA (r=0.98) as well as between GC-MS/MS and E2 extraction-RIA (r=0.98, for E2 concentrations above 14pmol/L). In boys, T and DHT increased significantly from prepuberty throughout pubertal development, and in girls the same increase was observed for E1 and E2. The greatest increase in A4 for both genders, as well as E1 and E2 in boys and T and DHT in girls, occurred in mid to late puberty.We report the development of a GC-MS/MS method sensitive enough to accurately determine serum levels of androgens and estrogens in children.
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  • Asnake, Solomon, 1985-, et al. (författare)
  • Species differences in ligand interaction and activation of estrogen receptors in fish and human
  • 2019
  • Ingår i: Journal of Steroid Biochemistry and Molecular Biology. - : Pergamon Press. - 0960-0760 .- 1879-1220. ; 195
  • Tidskriftsartikel (refereegranskat)abstract
    • Estrogen receptor (ER) sequences vary between species and this suggests that there are differences in the ligand-specificity, leading to species-specific effects. This would indicate that it is not possible to generalize effects across species. In this study, we investigated the differences in activation potencies and binding affinities of ER´s alpha (α) and beta (β) in human, zebrafish and sea bream to elucidate species differences in response to estradiol, estrone, estriol and methyltestosterone. In vitro analysis showed that estradiol had the highest activity for all the ER´s except for human ERβ and seabream ERβ2. Alignment of the ligand binding domain and ligand binding pocket (LBP) residues of the three species showed that different residues were involved in the LBPs which led to differences in pocket volume, affected binding affinity and orientation of the ligands. By combining in silico and in vitro results, it was possible to identify the ligand specificities of ER´s. The results demonstrated that the human ER´s show lower resolution in ligand-dependent activation, suggesting higher promiscuity, than the zebrafish and seabream ER´s. These results show species-specificity of ER´s and suggest that species-specific differences must be taken into consideration when studying different exposure scenarios.
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  • Björk, Anne, et al. (författare)
  • Variations in the vitamin D receptor gene are not associated with measures of muscle strength, physical performance, or falls in elderly men : Data from MrOS Sweden
  • 2019
  • Ingår i: Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier BV. - 0960-0760 .- 1879-1220. ; 187, s. 160-165
  • Tidskriftsartikel (refereegranskat)abstract
    • The vitamin D receptor (VDR) has been proposed as a candidate gene for several musculoskeletal phenotypes. However, previous results on the associations between genetic variants of the VDR with muscle strength and falls have been contradictory. The MrOS Sweden survey, a prospective population-based cohort study of 3014 elderly men (mean age 75 years, range 69-81) offered the opportunity to further investigate these associations. At baseline, data were collected on muscle strength and also the prevalence of falls during the previous 12 months. Genetic association analysis was performed for 7 Single Nucleotide Polymorphisms (SNPs), covering the genetic region surrounding the VDR gene in 2924 men with available samples of DNA. Genetic variations in the VDR were not associated with five different measurements of muscle strength or physical performance (hand grip strength right and left, 6 m walking test (easy and narrow) and timed-stands test). However, one of the 7 SNPs of the gene for the VDR receptor, rs7136534, was associated with prevalence of falls (33.6% of the AA, 14.6% of the AG and 16.5% of the GG allele). In conclusion, VDR genetic variants are not related to muscle strength or physical performance in elderly Swedish men. The role of the rs7136534 SNP for the occurrence of falls is not clear.
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  • Brunius, Carl, et al. (författare)
  • Feeding dried chicory root to pigs decrease androstenone accumulation in fat by increasing hepatic 3 beta hydroxysteroid dehydrogenase expression
  • 2012
  • Ingår i: Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier BV. - 0960-0760 .- 1879-1220. ; 130, s. 90-95
  • Tidskriftsartikel (refereegranskat)abstract
    • The present study investigated the in vivo effect of chicory root on testicular steroid concentrations and androstenone metabolizing enzymes in entire male pigs. Furthermore, the effect on skatole and indole concentrations in plasma and adipose tissue was investigated. The pigs were divided into two groups; one receiving experimental feed containing 10% dried chicory root for 16 days before slaughter, the control group was fed a standard diet. Plasma, adipose and liver tissue samples were collected at slaughter. Plasma was analyzed for the concentration of testosterone, estradiol, insulin-like growth factor 1 (IGF-1), skatole and indole. Adipose tissue was analyzed for the concentration of androstenone, skatole and indole, while the liver tissue was analyzed for mRNA and protein expressions of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), sulfotransferase 2A1 and heat-shock protein 70 (HSP70). The results showed that the androstenone concentrations in the adipose tissue of chicory fed pigs were significantly (p < 0.05) lower and indole concentrations were higher (p < 0.05) compared to control fed pigs. Moreover the chicory root fed pigs had increased mRNA and protein expression of 3 beta-HSD and decreased HSP70 expression (p < 0.05). Testosterone and IGF-1 concentrations in plasma as well as skatole concentrations in adipose tissue were not altered by dietary intake of chicory root. It is concluded that chicory root in the diet reduces the concentration of androstenone in adipose tissue via induction of 3 beta-HSD, and that these changes were not due to increased cellular stress. (C) 2012 Elsevier Ltd. All rights reserved.
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  • Brönnegård, Mikael, et al. (författare)
  • Lack of evidence for estrogen and progesterone receptors in human adipose tissue.
  • 1994
  • Ingår i: The Journal of steroid biochemistry and molecular biology. - 0960-0760. ; 51:5-6, s. 275-81
  • Tidskriftsartikel (refereegranskat)abstract
    • We have previously presented data indicating the absence of estrogen and progesterone receptors from human adipose tissue by the use of specific antibodies (Abbott) as well as specific ligands. In addition, specific estrogen and progesterone cRNA probes did not hybridize to any mRNA species in either abdominal or gluteal/femoral adipose tissue as demonstrated by solution hybridization and Northern blot. In order to demonstrate even extremely small quantities of gene products we have now used the Polymerase chain reaction-technique to study estrogen- and progesterone receptor gene expression. Sequences corresponding to each specific cDNA were demonstrated indicating small amounts of estrogen- and progesterone receptor mRNA not detected by RNA/RNA or RNA/TNA (total nucleic acids) hybridization assays. The estrogen receptor-regulated gene pS2, however, was not induced by estrogens in human adipose tissue in contrast to a significant increase in pS2 mRNA levels after estrogen exposure to the estrogen receptor(+) cell line MCF7. From these results we conclude that estrogen- and progesterone receptors are absent from human adipose tissue and that the extremely low level of transcription of the corresponding genes is not sufficient to allow translation of the message into functional proteins.
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  • Bärebring, Linnea, et al. (författare)
  • Serum cortisol and vitamin D status are independently associated with blood pressure in pregnancy
  • 2019
  • Ingår i: Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier BV. - 0960-0760. ; 189:May, s. 259-264
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim was to study if serum cortisol during pregnancy was associated with blood pressure and development of gestational hypertensive disorders. Additionally, associations between 25-hydroxyvitamin D (25OHD) and cortisol, including confounding effects and interactions in their relation to blood pressure were investigated. In total, 1413 pregnant women from the prospective Swedish GraviD cohort were included. Serum was collected in the first (T1) and third trimester (T3) and analyzed for 25OHD by liquid chromatography mass spectrometry and cortisol using an electro-chemiluminescence immunoassay. The main outcome measures were T1 blood pressure and development of gestational hypertensive disorders (gestational hypertension or preeclampsia). Gestational hypertensive disorders were defined as new onset hypertension, with or without proteinuria, after gestational week 20. Mean ± SD cortisol increased significantly from T1 to T3 (312 ± 123 vs. 659 ± 201 nmol/L, p < 0.001) and this increase was influenced by ethnicity. Serum concentrations of cortisol and 25OHD correlated in both T1 (B = 0.35, p < 0.001) and T3 (B = 0.30, p < 0.001). Cortisol and 25OHD were positively associated with T1 blood pressure, and there were non-significant trends for associations with gestational hypertensive disorders. Cortisol and 25OHD did not display any confounding effect or effect modification in their relationships with blood pressure. In conclusion, there was a positive correlation between serum cortisol and 25OHD in both early and late pregnancy. Both cortisol and 25OHD were positively associated with early pregnancy blood pressure. These results imply that the two hormones might be on different paths in their relationship with blood pressure. © 2019
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