| 1. |
- Rodanaki, Maria, 1987-, et al.
(author)
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A Randomized Trial of the Effect of a GnRH Analogue Injection on Ghrelin Levels in Girls
- 2022
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In: Hormone Research in Paediatrics. - : S. Karger. - 1663-2818 .- 1663-2826. ; 95:5, s. 442-451
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Journal article (peer-reviewed)abstract
- Introduction: Ghrelin concentrations decline during puberty by an unclear mechanism. Acylated ghrelin (AG) is unstable in sampling tubes, but no standardized sampling protocol exists. We hypothesized that ghrelin levels decrease as a consequence of increased gonadotropin-releasing hormone (GnRH) signalling and that the addition of a protease inhibitor to sampling tubes preserves the AG levels.Methods: In this randomized, placebo-controlled, cross-over study, 13 girls with suspected central precocious puberty were included. They performed an adjusted GnRH stimulation test twice and were given Relefact LHRH (R)(100 mu g/m(2)) or saline in a randomized order. Blood was sampled repeatedly for 150 min for the analysis of hormone concentrations. Oestradiol levels were only measured at baseline. The protease inhibitor 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF) was added to the sampling tubes. Specific ELISA kits were used for the analysis of AG and desacylated ghrelin (DAG) levels.Results: Neither AG nor DAG levels changed after GnRH analogue injection in comparison to saline. The addition of AEBSF preserved AG levels (650.1 +/- 257.1 vs. 247.6 +/- 123.4 pg/mL, p < 0.001) and decreased DAG levels (51.9 [12.5-115.7] vs. 143.5 [71.4-285.7] pg/mL, p < 0.001). Both AG and DAG levels were inversely associated with insulin levels (r = -0.73, p = 0.005, and r = -0.78, p = 0.002, respectively). AG levels were inversely associated with oestradiol levels (rho = -0.57, p = 0.041).Conclusion: Ghrelin levels do not decrease following a pharmacological dose of a GnRH analogue in the short term in girls. Addition of a protease inhibitor to the sampling tubes decreases AG degradation, resulting in preserved AG and decreased DAG levels. (C) 2022 The Author(s). Published by S. Karger AG, Basel
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| 2. |
- Rodanaki, Maria, 1987-, et al.
(author)
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Adding a protease inhibitor to sampling tubes increases the acylated ghrelin and decreases the desacylated ghrelin levels in girls
- 2021
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In: Hormone Research in Paediatrics. - : S. Karger. - 1663-2818 .- 1663-2826. ; 94:Suppl. 1, s. 111-112
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Journal article (other academic/artistic)abstract
- Introduction: Ghrelin is a growth hormone-releasing acylated peptide stimulating the appetite, mainly produced in the stomach, and with an important role in pubertal development (1). Two ghrelin forms have been described, acylated (AG) and desacylated (DAG), but it is debated whether DAG is an active hormone or a degradation product of AG (2). Our aim was to evaluate the effects of adding the protease inhibitor 4-(2-aminoethyl) benzenesufonyl fluoride hydrochloride (AEBSF) to sampling tubes and acidification of plasma on levels of AG and DAG in girls with suspected central precocious puberty (CPP).Methods: 13 girls aged 6.6 to 10.1 years with suspected CPP undergoing a gonadotropin-releasing hormone stimulation test during 2015-2017 at the Departments of Paediatrics, at Örebro or Uppsala University Hospital were included. Blood samples were collected at 0 min in precooled EDTA tubes with or without AEBSF at a final concentration of 2mg/ml. After cold centrifugation, HCl at a final concentration of 50 μmol/l, was added to 50% of the plasma tubes containing AEBSF. The AG and DAG concentrations were measured by ELISA kits. Comparison was performed using one-way ANOVA for repeated measurements.Results: The mean plasma AG levels were significantly higher after the addition of AEBSF only (650.9 +/- 257.1 pg/ml) or AEBSF+HCl (681.2 +/- 299 pg/ml) compared to the concentrations without additives (247.6 +/- 123.4 pg/ml, p<0.01 for both comparisons). There was no significant difference between the AG levels after AEBSF and AEBSF+HCl addition. The plasma levels of DAG were significantly lower after the addition of AEBSF+HCl (69.3 +/- 30.6 pg/ml) and even further lowered after the addition of AEBSF only (56.3+/- 30.9 pg/ml) compared to the concentrations of DAG in tubes without any additives (149.9 +/- 73.7 pg/ml, p < 0.01 for both comparisons).Discussion: Due to the unstable nature of AG, special procedures are required for accurate measurement of its plasma levels in children, including the use of a protease inhibitor like AEBSF. However, DAG was still measurable indicating that it may not only be a degradation product of AG. 1. Kojima M, Kangawa K. Ghrelin: structure and function. Physiol Rev. 2005;85(2):495-522.2. Blatnik M, Soderstrom CI, Dysinger M, Fraser SA. Prandial ghrelin attenuation provides evidence that des-acyl ghrelin may be an artifact of sample handling in human plasma. Bio-analysis. 2012;4(20):2447-55.
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| 3. |
- Rodanaki, Maria, 1987-, et al.
(author)
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Delayed puberty in boys in central Sweden : an observational study on diagnosing and management in clinical practice
- 2022
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In: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 12:2
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Journal article (peer-reviewed)abstract
- OBJECTIVES: To compare the usefulness of the classical definition of delayed puberty (DP) in boys with puberty nomograms and to describe the management of DP in boys in a hospital-based setting.STUDY DESIGN: Observational retrospective multicentre study with a short-term follow-up.SETTING AND PARTICIPANTS: Boys diagnosed with DP during 2013-2015 at paediatric departments in four counties in central Sweden. The medical records of 165 boys were reviewed.PRIMARY AND SECONDARY OUTCOME MEASURES: Number of boys with DP after re-evaluation of the diagnosis according to the classical definition in comparison with puberty nomograms. Description of investigations performed and treatment provided to boys with DP.RESULTS: In total, 45 and 58 boys were found to have DP according to the classical definition and the nomograms, respectively. Biochemical and/or radiological testing was performed in 91% of the 58 boys, but an underlying disease was only found in 9% of them. Approximately 79% of the boys received testosterone treatment, either as injections of testosterone enanthate or as testosterone undecanoate.CONCLUSIONS: Puberty nomograms may be helpful instruments when diagnosing pubertal disorders in boys as they are not limited to an age close to 14 years and also identify boys with pubertal arrest. The majority of boys with DP undergo biochemical or radiological examinations, but underlying diseases are unusual emphasising the need for structural clinical practice guidelines for this patient group.
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| 4. |
- Rodanaki, Maria, 1987-, et al.
(author)
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The effect of a GnRH analogue injection on the circulating levels of kisspeptin-1 in girls with suspected central precocious puberty
- 2022
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In: Hormone Research in Paediatrics. - : S. Karger. - 1663-2818 .- 1663-2826. ; 95:Suppl. 2, s. 341-341
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Journal article (other academic/artistic)abstract
- Introduction: Kisspeptin stimulates the gonadotropin releasing hormone (GnRH) neurons in hypothalamus initiating puberty. However, it is not known whether GnRH inhibits kisspeptin secretion by negative feedback and whether there are any associations between circulating levels of kisspeptin and other hormones, like ghrelin, important for the onset of puberty.Methods: Thirteen girls with suspected central precocious puberty performed an adjusted GnRH stimulation test twice, placebo-controlled in a randomized order, at Örebro or Uppsala University Hospital, Sweden. Blood was sampled 0, 30, 60, 90, 120 and 150 min after the iv injection of either Relefact LHRH® or saline. The protease inhibitor 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF) was added to the sampling tubes to a final concentration of 2 mg/ml. An ELISA kit from LifeSpan BioSciences, Inc. (No LS-F8231) was used for the analyses of Kisspeptin-1 levels. The levels of acylated ghrelin were analyzed with Millipore® Human Ghrelin (Active) ELISA kit (#EZGRA-88K). Serum ultrasensitive estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), insulin and glucose levels were analyzed using the usual clinical methods.Results: The median Kisspeptin-1 level at baseline was 39 pg/ml (min–max: 0.1–221.3 pg/ml). The area-under-the curve for Kisspeptin-1 levels was not significantly lower after the GnRH injection as compared to the placebo injection. We did not find any significant correlations between the levels of kisspeptin-1 and acylated ghrelin, estradiol, LH, FSH, or insulin. However, we could see a positive correlation between kisspeptin-1 and glucose levels at baseline (Spearman’s rank test, rho = 0.63, p=0.021).Discussion: We did not find evidence of a negative feedback mechanism between GnRH and kisspeptin in girls with suspected central precocious puberty since the circulating levels of kisspeptin-1 were unaffected by an intravenous injection of a GnRH analogue. However, paracrine actions in the hypothalamus cannot be ruled out by this study. The positive correlation found between kisspeptin-1 and glucose levels is in accordance with previous findings in both adults and children, suggesting a possible role for kisspeptin signaling in glucose metabolism.
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| 5. |
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| 6. |
- Allbrand, Marianne, 1958-
(author)
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Gene expression of inflammatory markers and growth factors in placenta in relation to maternal obesity and foetal and postnatal growth
- 2020
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Doctoral thesis (other academic/artistic)abstract
- Maternal obesity is a growing health problem, that contributes to obstetrical complications in pregnancy, as well as neonatal morbidity and mortality. The placenta serves for gas and nutrient exchange between the mother and the foetus, and obesity may influence and modify placental growth and function. The aims of this thesis were to investigate associations between maternal obesity without associated morbidity and gene expression of inflammatory markers and growth factors in the placenta, as well as offspring birth weight and postnatal growth. Study I and III were designed as matched case-control studies including 32 obese women with an early pregnancy body mass index (BMI) ≥ 35.0 kg/m2, study II was an experimental study examining twelve placentas of normal weight women, and study IV was a cohort study including 109 obese women with a BMI ≥ 34.5 kg/m2. In studies I-IV analyses of gene expression were performed and in study III additionally cord blood concentrations were determined. No difference was found in the occurrence of placental gene expression of inflammatory markers or growth factors between obese and normal weight women, nor did the sampling site in placentas of normal weight women influence gene expression of these markers, except for leptin gene (LEP) and insulin receptor gene (INSR) expression. Ghrelin gene (GHRL) and LEP expression, as well as cord blood ghrelin and adiponectin levels, was not altered in maternal obesity, and a negatively U-shaped relationship between LEP expression and infant birth weight (BW) z-scores was observed in the placentas of obese women.In conclusion, no statistically significant difference in gene expressions of inflammatory markers and growth factors in the placenta between severely obese and normal weight women was found. These results are in contrast with earlier studies and could be due to the fact that we examined mainly healthy obese women. The correlations we found between gene expression of leptin in the placenta and the birth weight of the infants warrants further studies.
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| 7. |
- Allbrand, Marianne, 1958-, et al.
(author)
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Gene expression of leptin, leptin receptor isoforms and inflammatory cytokines in placentas of obese women : Associations to birth weight and fetal sex
- 2022
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In: Placenta. - : Elsevier. - 0143-4004 .- 1532-3102. ; 117, s. 64-71
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Journal article (peer-reviewed)abstract
- INTRODUCTION: Leptin signaling in placentas of obese women may influence fetal growth and may be dependent on fetal sex. The aim of this study was to investigate placental gene expression of leptin, its receptor and inflammatory cytokines in obese mothers in relation to offspring birth weight and sex.METHODS: In total, 109 placental tissue samples from severely obese women (body mass index in first trimester ≥35 kg/m2) giving birth vaginally at term to a healthy child were included. Quantitative real-time PCR was used for the analysis of leptin (LEP), its receptor LEPR with two splice variants, interleukin (IL)1B, chemokine (C-X-C motif) ligand 8 (CXCL8), tumour necrosis factor (TNF), IL6, IL10, hypoxia-inducible factor 1-alpha (HIF1A) and insulin receptor (INSR). The subjects were divided into three groups based on LEP expression percentiles (<25th percentile; 25-75th percentile and >75th percentile).RESULTS: A reverse U-shaped association between LEP expression and birth weight z-scores was found (R2 = 0.075, p = 0.005). Placental LEPRb expression was downregulated (p = 0.034) in those with highest LEP expression. Female infants had higher birth weight z-scores than males (0.58 (-1.49-2.88) vs 0.21 (-1.50-2.93), p = 0.020) and their placental LEPRb expression was upregulated (p = 0.047). The associations between expression of different genes differed by sex.DISCUSSION: A reverse U-shaped relationship between placental LEP expression and offspring birth weight z-scores was found together with sexual dimorphism in LEPRb expression indicating a complex regulation of fetal growth by placental leptin signaling in maternal obesity.
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| 8. |
- Bakoyan, Zaki, et al.
(author)
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Childhood atopic disorders in relation to placental changes-A systematic review and meta-analysis
- 2024
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In: Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. - : Munksgaard Forlag. - 0905-6157 .- 1399-3038. ; 35:5, s. 1-17
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Research review (peer-reviewed)abstract
- Fetal programming may arise from prenatal exposure and increase the risk of diseases later in life, potentially mediated by the placenta. The objective of this systematic review was to summarize and critically evaluate publications describing associations between human placental changes and risk of atopic disorders during childhood. The review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. The inclusion criteria were original research articles or case reports written in English describing a human placental change in relation to disease occurring in offspring during childhood. The MEDLINE and EMBASE databases were searched for eligible studies. Risk of bias (RoB) was assessed using the ROBINS-I tool. The results were pooled both in a narrative way and by a meta-analysis. Nineteen studies were included (n = 12,997 participants). All studies had an overall serious RoB, and publication bias could not be completely ruled out. However, five studies showed that histological chorioamnionitis in preterm-born children was associated with asthma-related problems (pooled odds ratio = 3.25 (95% confidence interval = 2.22-4.75)). In term-born children, a large placenta (≥750 g) increased the risk of being prescribed anti-asthma medications during the first year of life. Placental histone acetylation, DNA methylation, and gene expression differences were found to be associated with different atopic disorders in term-born children. There is some evidence supporting the idea that the placenta can mediate an increased risk of atopic disorders in children. However, further studies are needed to validate the findings, properly control for confounders, and examine potential mechanisms.
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| 9. |
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| 10. |
- Chelslín, Felix, 1991-, et al.
(author)
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Smoking during pregnancy is associated with the placental proteome
- 2023
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In: Reproductive Toxicology. - : Elsevier. - 0890-6238 .- 1873-1708. ; 119
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Journal article (peer-reviewed)abstract
- Maternal smoking during pregnancy (MSDP) is a significant risk factor for the development of foetal, neonatal, and childhood morbidities. We hypothesized that infants exposed to MSDP have a distinct proteomic expression in their term placentas compared to infants without such an exposure. A total of 39 infants exposed (cord blood cotinine levels of >1ng/ml) and 44 infants not exposed to MSDP were included in the study. Women with chronic disease, body mass index of >30, or a history of uterine surgery were excluded. Total proteome abundance was analysed with quantitative mass spectrometry. For univariate analysis of differences in placental protein levels between groups, ANOVA with multiple testing corrections by the Benjamini-Hochberg method was used. For multivariate analysis, we used principal component analysis, partial least squares, lasso, random forest, and neural networks. The univariate analyses showed four differentially abundant proteins (PXDN, CYP1A1, GPR183, and KRT81) when heavy and moderate smoking groups were compared to non-smokers. With the help of machine learning, we found that an additional six proteins (SEPTIN3, CRAT, NAAA, CD248, CADM3, and ZNF648) were discriminants of MSDP. The placental abundance of these ten proteins together explained 74.1% of the variation in cord blood cotinine levels (p = 0.002). Infants exposed to MSDP showed differential abundance of proteins in term placentas. We report differential placental abundance of several proteins for the first time in the setting of MSDP. We believe that these findings supplement the current understanding of how MSDP affects the placental proteome.
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