| 1. |
- Bengtsson, Daniel, 1975-, et al.
(författare)
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Increased Mortality Persists after Treatment of Cushing's Disease: A Matched Nationwide Cohort Study
- 2022
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Ingår i: Journal of the Endocrine Society. - : The Endocrine Society. - 2472-1972. ; 6:6
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Tidskriftsartikel (refereegranskat)abstract
- Context: Whether biochemical remission normalizes life expectancy in Cushing's disease (CD) patients remains unclear. Previous studies evaluating mortality in CD are limited by using the expected number of deaths in the background population instead of the actual number in matched controls. Objective and setting: To study mortality by time-to-event analysis in an unselected nationwide CD patient cohort. Design and participants: Longitudinal data from the Swedish Pituitary Register of 371 patients diagnosed with CD from 1991 to 2018 and information from the Swedish Cause of Death Register were evaluated. Four controls per patient (n = 1484) matched at the diagnosis date by age, sex, and residential area were included. Main outcome measures: Mortality and causes of death. Results: The median diagnosis age was 44 years (interquartile range 32-56), and the median follow-up was 10.6 years (5.7-18.0). At the 1-, 5-, 10-, 15-, and 20-year follow-ups, the remission rates were 80%, 92%, 96%, 91%, and 97%, respectively. Overall mortality was increased in CD patients compared with matched controls [hazard ratio (HR) 2.1 (95% CI 1.5-2.8)1. The HRs were 1.5 (1.02-2.2) for patients in remission at the last follow-up In = 303), 1.7 (1.03-2.8) for those in remission after a single pituitary surgery In = 177), and 5.6 (2.7-11.6) for those not in remission (n = 31). Cardiovascular diseases (32/66) and infections (12/66) were overrepresented causes of death. Conclusions: Mortality was increased in CD patients despite biochemical remission compared to matched controls. The study highlights the importance of careful comorbidity monitoring, regardless of remission status.
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| 2. |
- Bjorvatn Saevik, Åse, et al.
(författare)
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Potential Transcriptional Biomarkers to Guide Glucocorticoid Replacement in Autoimmune Addison's Disease
- 2021
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Ingår i: Journal of the Endocrine Society. - : Endocrine Society. - 2472-1972. ; 5:3
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundNo reliable biomarkers exist to guide glucocorticoid (GC) replacement treatment in autoimmune Addison’s disease (AAD), leading to overtreatment with alarming and persistent side effects or undertreatment, which could be fatal.ObjectiveTo explore changes in gene expression following different GC replacement doses as a means of identifying candidate transcriptional biomarkers to guide GC replacement in AAD.MethodsStep 1: Global microarray expression analysis on RNA from whole blood before and after intravenous infusion of 100 mg hydrocortisone (HC) in 10 patients with AAD. In 3 of the most highly upregulated genes, we performed real-time PCR (rt-PCR) to compare gene expression levels before and 3, 4, and 6 hours after the HC infusion. Step 2: Rt-PCR to compare expression levels of 93 GC-regulated genes in normal versus very low morning cortisol levels in 27 patients with AAD.ResultsStep 1: Two hours after infusion of 100 mg HC, there was a marked increase in FKBP5, MMP9, and DSIPI expression levels. MMP9 and DSIPI expression levels correlated with serum cortisol. Step 2: Expression levels of CEBPB, DDIT4, FKBP5, DSIPI, and VDR were increased and levels of ADARB1, ARIDB5, and POU2F1 decreased in normal versus very low morning cortisol. Normal serum cortisol levels positively correlated with DSIPI, DDIT4, and FKBP5 expression.ConclusionsWe introduce gene expression as a novel approach to guide GC replacement in AAD. We suggest that gene expression of DSIPI, DDIT4, and FKBP5 are particularly promising candidate biomarkers of GC replacement, followed by MMP9, CEBPB, VDR, ADARB1, ARID5B, and POU2F1.
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| 3. |
- Eriksson, Karin, et al.
(författare)
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Gonadotropin Glycoforms Circulating in Women Using Progestins of the Levonorgestrel Family for Contraception
- 2020
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Ingår i: Journal of the Endocrine Society. - : The Endocrine Society. - 2472-1972. ; 4:11
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Tidskriftsartikel (refereegranskat)abstract
- Context: The progestins of the levonorgestrel family are 13-ethylgonane progestins, commonly used for contraception in women. One contraceptive effect of these progestins is inhibition of ovulation, which may be a result of changes in gonadotropin glycosylation patterns. Gonadotropin glycoforms differ in number of glycans and bioactivity: more bioactive low-N-glycosylated glycoforms, diglycosylated luteinizing hormone (LHdi) and triglycosylated follicle-stimulating hormone (FSHtri), and less bioactive fully N-glycosylated glycoforms, LHtri and FSHtetra.Objective: Characterize the glycosylation patterns on the circulating gonadotropin glycoforms in women using 13-ethylgonane progestins for contraception.Design Subjects Main Outcome Measures: Serum samples, collected from 92 healthy women using 13-ethylgonane progestins for contraception, were included. Forty women used progestin-only continuously and 52 used progestins combined with ethinylestradiol (EE) for 3 weeks followed by a hormone-free week. Concentration, sulfonation, and sialylation of each glycoform were determined and compared with follicular phase values of normal menstrual cycles.Results: The progestin-only group had significantly increased serum levels, decreased sulfonation, and increased sialylation of LHdi. The LHdi/FSHtri ratio was increased. The progestin+EE group had significantly decreased gonadotropin glycoform concentrations and decreased sialylation of FSHtri. The progestin+EE effect on sialylation of FSHtri occurred later during the treatment cycle in contrast to the effect on FSHtri concentration.Conclusions: The 2 different progestin treatments induced different effects on the glycan synthesis and concentrations of more bioactive low-glycosylated gonadotropins. Progestin-only treatment increased sialylation and decreased sulfonation of LHdi molecules, contributing to sustained higher levels of bioactive LHdi molecules. Progestin+EE treatment decreased sialylation of FSHtri, contributing to a shorter half-life and decreased levels of bioactive FSHtri.
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| 4. |
- Johansson, Åsa, et al.
(författare)
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Investigating the Effect of Estradiol Levels on the Risk of Breast, Endometrial, and Ovarian Cancer
- 2022
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Ingår i: Journal of the Endocrine Society. - : The Endocrine Society. - 2472-1972. ; 6:8
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Tidskriftsartikel (refereegranskat)abstract
- Background: High levels of estrogen are associated with increased risk of breast and endometrial cancer and have been suggested to also play a role in the development of ovarian cancer. Cancerogenic effects of estradiol, the most prominent form of estrogen, have been highlighted as a side effect of estrogen-only menopausal hormone therapy. However, whether high levels of endogenous estrogens, produced within the body, promote cancer development, has not been fully established.Objective: We aimed to examine causal effects of estradiol on breast, endometrial, and ovarian cancer.Methods: Here we performed a two-sample Mendelian randomization (MR) to estimate the effect of endogenous estradiol on the risk of developing breast, endometrial, and ovarian cancer, using the UK Biobank as well as 3 independent cancer cohorts.Results: Using 3 independent instrumental variables, we showed that higher estradiol levels significantly increase the risk for ovarian cancer (OR = 3.18 [95% CI, 1.47-6.87], P = 0.003). We also identified a nominally significant effect for ER-positive breast cancer (OR = 2.16 [95% CI, 1.09-4.26], P = 0.027). However, we could not establish a clear link to the risk of endometrial cancer (OR = 1.93 [95% CI, 0.77-4.80], P = 0.160).Conclusion: Our results suggest that high estradiol levels promote the development of ovarian and ER-positive breast cancer.
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| 5. |
- Jotanovic, Jelena, et al.
(författare)
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Transcriptome Analysis Reveals Distinct Patterns Between the Invasive and Noninvasive Pituitary Neuroendocrine Tumors
- 2024
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Ingår i: Journal of the Endocrine Society. - : Oxford University Press. - 2472-1972. ; 8:5
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Tidskriftsartikel (refereegranskat)abstract
- Although most pituitary neuroendocrine tumors (PitNETs)/pituitary adenomas remain intrasellar, a significant proportion of tumors show parasellar invasive growth and 6% to 8% infiltrate the bone structures, thus affecting the prognosis. There is an unmet need to identify novel markers that can predict the parasellar growth of PitNETs. Furthermore, mechanisms that regulate bone invasiveness of PitNETs and factors related to tumor vascularization are largely unknown.We used genome-wide mRNA analysis in a cohort of 77 patients with PitNETs of different types to explore the differences in gene expression patterns between invasive and noninvasive tumors with respect to the parasellar growth and regarding the rare phenomenon of bone invasiveness. Additionally, we studied the genes correlated to the contrast enhancement quotient, a novel radiological parameter of tumor vascularization.Most of the genes differentially expressed related to the parasellar growth were genes involved in tumor invasiveness. Differentially expressed genes associated with bone invasiveness are involved in NF-κB pathway and antitumoral immune response. Lack of clear clustering regarding the parasellar and bone invasiveness may be explained by the influence of the cell lineage-related genes in this heterogeneous cohort of PitNETs.Our transcriptomics analysis revealed differences in the molecular fingerprints between invasive, including bone invasive, and noninvasive PitNETs, although without clear clustering. The contrast enhancement quotient emerged as a radiological parameter of tumor vascularization, correlating with several angiogenesis-related genes. Several of the top genes related to the PitNET invasiveness and vascularization have potential prognostic and therapeutic application requiring further research.
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| 6. |
- Ullsten, Sara, et al.
(författare)
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Decreased beta-Cell Proliferation and Vascular Density in a Subpopulation of Low-Oxygenated Male Rat Islets
- 2019
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Ingår i: Journal of the Endocrine Society. - : Endocrine Society. - 2472-1972. ; 3:8, s. 1608-1616
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Tidskriftsartikel (refereegranskat)abstract
- Low-oxygenated and dormant islets with a capacity to become activated when neededmay play a crucial role in the complex machinery behind glucose homeostasis. We hypothesized that low-oxygenated islets, when not functionally challenged, do not rapidly cycle between activation and inactivation but are a stable population that remain low-oxygenated. As this was confirmed, we aimed to characterize these islets with regard to cell composition, vascular density, and endocrine cell proliferation. The 2-nitroimidazole low-oxygenation marker pimonidazole was administered as a single or repeated dose to Wistar Furth rats. The stability of oxygen status of islets was evaluated by immunohistochemistry as the number of islets with incorporated pimonidazole adducts after one or repeated pimonidazole injections. Adjacent sections were evaluated for islet cell composition, vascular density, and endocrine cell proliferation. Single and repeated pimonidazole injections over an 8-hour period yielded accumulation of pimonidazole adducts in the same islets. An average of 30% of all islets was in all cases positively stained for pimonidazole adducts. These islets showed a similar endocrine cell composition as other islets but had lower vascular density and beta-cell proliferation. In conclusion, low-oxygenated islets were found to be a stable subpopulation of islets for at least 8 hours. Although they have previously been observed to be less functionally active, their islet cell composition was similar to that of other islets. Consistent with their lower oxygenation, they had fewer blood vessels than other islets. Notably, beta-cell regeneration preferentially occurred in better-oxygenated islets.
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| 7. |
- Wide, Leif, et al.
(författare)
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Low- and Fully N-Glycosylated Gonadotropins Circulating in Women With Polycystic Ovary Syndrome
- 2021
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Ingår i: Journal of the Endocrine Society. - : ENDOCRINE SOC. - 2472-1972. ; 5:7
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Tidskriftsartikel (refereegranskat)abstract
- Context: A preponderance of basic luteinizing hormone (LH) molecules having elevated bioactivity was detected in the circulation of women with polycystic ovary syndrome (PCOS). Subsequent studies have shown that LH and follicle-stimulating hormone (FSH) both circulate as glycoforms differing in number of glycans: low-N-glycosylated glycoforms, LHdi and FSHtri, with high in vitro bioactivity, and fully glycosylated glycoforms, LHtri and FSHtetra, with high in vivo bioactivity.Objective: This work aims to characterize the glycosylation patterns on circulating gonadotropin glycoforms in women with PCOS.Methods: Serum samples, collected from 8 women with PCOS were included. The concentration, sulfonation, and sialylation of each glycoform were determined and compared with values of serum samples from healthy women: 22 women at follicular phase, 16 at midcycle, and 15 after menopause.Results: All the women with PCOS had higher LHdi serum levels compared with those in the follicular-phase group. Median LHdi and median LHtri levels were significantly elevated in PCOS women. The percentage of LHdi was increased from 37 to 49 and that of FSHtri was decreased from 41 to 33. The LHdi, LHtri, and FSHtetra glycoforms were more sialylated and both LH glycoforms less sulfonated in women with PCOS.Conclusion: All women with PCOS had increased serum levels of LHdi, compared with those in the follicular phase. The percentage of LHdi was increased and that of FSHtri decreased in women with PCOS. The increased LHdi leads to maintenance of the abnormal early follicular development of the polycystic ovary, and the decreased FSHtri contributes to the arrested follicle growth.
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| 8. |
- Wide, Leif, et al.
(författare)
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Thyrotropin N-glycosylation and Glycan Composition in Severe Primary Hypothyroidism
- 2021
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Ingår i: Journal of the Endocrine Society. - : Endocrine Society. - 2472-1972. ; 5:4
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Tidskriftsartikel (refereegranskat)abstract
- Context: In severe primary hypothyroidism (sPH), the serum thyrotropin (TSH) levels are elevated with an increased degree of sialylation. The circulating TSH comprises 2 different TSH glycoforms: TSHdi with 2 and TSHtri with 3 N-glycans and methods have developed to determine their contents of anionic monosaccharides (AMS), that is, sialic acid (SA) and sulfonated N-acetylglactosamine (SU) residues.Objective: Characterize N-glycosylation and glycan composition of circulating TSH molecules and determine the effects during levothyroxine treatment in patients with sPH.Methods: Serum samples were obtained from 25 patients with sPH, from 159 euthyroid individuals, and from 12 women during treatment with levothyroxine for sPH. Degrees of N-glycosylation and concentrations of TSHdi and TSHtri as well as their contents of AMS, SA, and SU residues were determined. Results: The circulating TSH molecules in sPH patients had lower degrees of N-glycosylation, higher degrees of sialylation, and lower degrees of sulfonation than in euthyroid individuals. Levothyroxin restored sialylation and sulfonation of the glycans already at low free thyroxine (FT4) levels, while degree of N-glycosylation was not restored until the FT4 levels were normal.Conclusions: The majority of TSH molecules in severe primary hypothyroidism were less N- glycosylated, more sialylated, and less sulfonated compared with euthyroid individuals. This glycan pattern favors a prolonged half-life in the circulation combined with lower in vitro biopotency at the target cells. During levothyroxine treatment of sPH patients, the sialylation and sulfonation of glycans were restored already at low FT4 levels, while N-glycosylation of TSH was not restored until the FT4 levels were normal.
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| 9. |
- Yuan, Shuai, et al.
(författare)
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Physical Activity, Sedentary Behavior, and Type 2 Diabetes : Mendelian Randomization Analysis
- 2023
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Ingår i: Journal of the Endocrine Society. - : Endocrine Society. - 2472-1972. ; 7:8
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Tidskriftsartikel (refereegranskat)abstract
- Context The causality and pathways of the associations between physical activity and inactivity and the risk of type 2 diabetes remain inconclusive. Objective We conducted an updated mendelian randomization (MR) study to explore the associations of moderate-to-vigorous physical activity (MVPA) and leisure screen time (LST) with type 2 diabetes mellitus (T2DM). Methods Genetic variants strongly associated with MVPA or LST with low linkage disequilibrium were selected as instrumental variables from a genome-wide meta-analysis including more than 600 000 individuals. Summary-level data on T2DM were obtained from the DIAbetes Genetics Replication And Meta-analysis consortium including 898 130 individuals. Data on possible intermediates (adiposity indicators, lean mass, glycemic traits, and inflammatory biomarkers) were extracted from large-scale genome-wide association studies (n = 21 758-681 275). Univariable and multivariable MR analyses were performed to estimate the total and direct effects of MVPA and LST on T2DM. Methylation MR analysis was performed for MVPA in relation to diabetes. Results The odds ratio of T2DM was 0.70 (95% CI, 0.55-0.88; P = .002) per unit increase in the log-odds ratio of having MVPA and 1.45 (95% CI, 1.30-1.62; P = 7.62 x 10(-11)) per SD increase in genetically predicted LST. These associations attenuated in multivariable MR analyses adjusted for genetically predicted waist-to-hip ratio, body mass index, lean mass, and circulating C-reactive protein. The association between genetically predicted MVPA and T2DM attenuated after adjusting for genetically predicted fasting insulin levels. Two physical activity-related methylation biomarkers (cg17332422 in ADAMTS2 and cg09531019) were associated with the risk of T2DM (P < .05). Conclusion The study suggests causal associations of MVPA and LST with T2DM that appear to be mediated by obesity, lean mass, and chronic low-grade inflammation.
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