Category Archives: Δημοσιευμένες εργασίες


Metabolic responsiveness to training depends on insulin sensitivity and protein content of exosomes in insulin-resistant males

C E L L  B I O L O G Y

Maria Apostolopoulou, Lucia Mastrototaro, Sonja Hartwig, Dominik Pesta, Klaus Straßburger, Elisabetta de Filippo, Tomas Jelenik, Yanislava Karusheva,
Sofiya Gancheva, Daniel Markgraf, Christian Herder, K. Sreekumaran Nair,
Andreas S. Reichert , Stefan Lehr, Karsten Müssig, Hadi Al-Hasani,
Julia Szendroedi , Michael Roden

High-intensity interval training (HIIT) improves cardiorespiratory fitness (VO2max), but its impact on metabolism remains unclear. We hypothesized that 12-week HIIT increases insulin sensitivity in males with or without type 2 diabetes [T2D and NDM (nondiabetic humans)]. However, despite identically higher VO2max, mainly insulin-resistant (IR) persons (T2D and IR NDM) showed distinct alterations of circulating small extracellular vesicles (SEVs) along with lower inhibitory metabolic (protein kinase Cε activity) or inflammatory (nuclear factor κB) signaling in muscle of T2D or IR NDM, respectively. This is related to the specific alterations in SEV proteome reflecting down-regulation of the phospholipase C pathway (T2D) and up-regulated antioxidant capacity (IR NDM). Thus, SEV cargo may con-tribute to modulating the individual metabolic responsiveness to exercise training in humans.

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Bisphenol A correlates with fewer retrieved oocytes in women with tubal factor infertility

Hormones (Athens) 2022 May 6. doi: 10.1007/s42000-022-00370-1. Online ahead of print.

Areti Mina, Georgios Boutzios, Ioannis Papoutsis, George Kaparos, Panagiotis Christopoulos, Eleni Kousta, Minas Mastrominas, Sotirios Athanaselis, George Mastorakos
PMID: 35524040, DOI: 10.1007/s42000-022-00370-1

Abstract: Purpose | Serum and urinary bisphenol A (BPA) concentrations have been associated negatively with the number of retrieved oocytes after in vitro fertilization (IVF). The impact of BPA upon women with polycystic ovary syndrome (PCOS) and women with tubal factor infertility (TFI), following IVF, was investigated. To this purpose, associations among serum and urinary and follicular fluid (FF) BPA concentrations and the number of retrieved and fertilized oocytes and comparisons between pregnancy rates were evaluated. Methods | This was a cross-sectional study conducted at a university-affiliated assisted conception unit between January and November 2019, including 93 women of reproductive age (PCOS: 45; TFI: 48) following IVF. Unconjugated FF and serum BPA concentrations and total urinary BPA concentration were measured using a novel gas chromatography-mass spectrometry method. The number of retrieved and fertilized oocytes and pregnancy rate were documented and evaluated. Results | The number of oocytes retrieved from PCOS women was greater than that of 21 TFI women, independently of BMI. Lower FF BPA concentrations were found in all PCOS women and in overweight/obese PCOS compared to TFI women (0.50, 0.38, and 1.13 ng/mL, respectively). In TFI women, FF BPA concentrations correlated negatively with the number of retrieved oocytes. Serum and FF and urinary BPA concentrations did not significantly affect the number of fertilized oocytes and pregnancy rate in both groups. Conclusion | FF BPA concentrations were lower in all PCOS women and in overweight/obese PCOS than in TFI women. In TFI women, FF BPA concentrations correlated negatively with retrieved oocytes. Confirmation of these findings might lead to moderation of use of BPA-containing products by women undergoing IVF.


Uterine sparing management in patients with endometrial cancer: a narrative literature review

Journal of Obstetrics and Gynaecology

Maria Zisi, Dimitrios Zygouris, Orestis Tsonis, Sofia Papadimitriou, Mastorakos George, Sophia Kalantaridou& Minas Paschopoulos

Abstract: Endometrial cancer is the most common malignancy of the female genital tract. Approximately 25% of cases occur in premenopausal women, and up to 5% of cases occur in women who are younger than 40 years old. The survival rate in these cases is 99%; therefore, uterine-sparing management could be considered under strict criteria selection and the strong desire of the woman to preserve uterus and fertility. Diagnosis should be performed after a hysteroscopic biopsy instead of dilatation and curettage. The highest remission rate was achieved after combining a hysteroscopic resection with hormonal therapy compared to single hormonal treatment. The most common regiments are the following progestins: megestrol acetate (MA) and medroxyprogesterone acetate (MPA) taken orally with a daily dosage of 160 mg–320 mg for MA and 250 mg–600 mg for MP. Evaluations at three and six months could be performed by office endometrial biopsy and/or hysteroscopic directed biopsy especially in the presence of levonorgestrel intrauterine system, and in cases of remission, either a pregnancy attempt or maintenance therapy should be considered. After childbearing, hysterectomy with bilateral salpingo–oophorectomy is recommended, whereas ovarian preservation could be considered depending on the patient’s age and whether they fulfil the strict criteria selection.

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Major histocompatibility complex(mhc) molecules identification in vaginal cells during menstrual cycle


Socrates Megoulas, Savvidi Amalia, Stelios Fiorentzis and Mihail Tziolas

Abstract: Causes of subfertility in women are under investigation, with the vaginal canal being the first barrier before the fertilization and implantation process. Although the mechanisms of protection of the allogeneic fetus from the maternal immune response seem to have a main role through the preimplantation period, they are not yet described in detail. There appears to be an important relation between them and the polymorphism of major histocompatibility complex (MHC) proteins. However, it is unknown which are expressed in the vaginal canal cells and how they behave during the menstrual cycle. This clinical research aimed to prove the existence of these unusual MHC proteins in vaginal cells, especially during ovulation. We selected women of reproductive age in different menstrual cycle phases and collected vaginal samples. The samples then were processed with immunofluorescence protocol or ELISA protocol techniques. The protein molecules that were calculated are MHCI, MHCII, TCRa b, TCRg d. During ovulation, MHCII and TCRg d were expressed in higher numbers over MHCI and TCRa b (p=0.0461, p=0.0104), using immunofluorescence. Whereas using ELISA showed statistical significance only in the expression of TCRg d over TCRa b (p=0.0012). Managing to identify the existence of polymorphic molecules of the immune system in the vagina proves the immunological reaction starts taking place in the vagina, and there is possibly a relation between the immunosuppression mechanisms surrounding trophoblast implantation and early pregnancy success. As the research progresses, it is possible to trace those mechanisms back to subfertility cases.

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The role of gut microbiome in prevention, diagnosis and treatment of gestational diabetes mellitus

J Obstet Gynaecol, 2021 Oct 25;1-7. doi: 10.1080/01443615.2021.1959534. Online ahead of print.

Ermioni Tsarna, Panagiotis Christopoulos

Abstract: Gestational diabetes mellitus (GDM) is a common metabolic disease associated with maternal and foetal complications; gut microbiome might participate in GDM pathogenesis. Possible biological links include short chain fatty acids, incretin hormones, bile acids homeostasis and peroxisome proliferator-activated receptor gamma deficiency. Gut microbiome differs in patients with GDM even in early pregnancy, but no differences are observed five years postpartum. Patients have enriched Verrucomicrobia phylum, Christensenellaceae and Lachnospiraceae families, Haemophilus, Prevotella, Actinomyces, Collinsella and Ruminococcus genera during pregnancy. Clostridiales order, Alistipes, Faecalibacterium, Blautia, Eubacterium and Roseburia genera are depleted. However, there is great heterogeneity in the reviewed studies and scientific data on the use of gut microbiome characteristics and related biomarkers in GDM risk stratification and diagnosis are scarce. Probiotics and synbiotics have been tested for prevention and treatment for GDM with limited efficacy. Future studies should explore the effect of probiotics administration at first trimester of pregnancy and their value as adjuvant therapy.

Keywords: GDM; Gestational diabetes; gut microbiome; probiotics; synbiotics.


Placental CRH as a Signal of Pregnancy Adversity and Impact on Fetal Neurodevelopment

Front. Endocrinol., 02 August 2021 |

Ifigeneia Kassotaki, Georgios Valsamakis, George Mastorakos, Dimitris K. Grammatopoulos

Abstract: Early life is a period of considerable plasticity and vulnerability and insults during that period can disrupt the homeostatic equilibrium of the developing organism, resulting in adverse developmental programming and enhanced susceptibility to disease. Fetal exposure to prenatal stress can impede optimum brain development and deranged mother’s hypothalamic–pituitary–adrenal axis (HPA axis) stress responses can alter the neurodevelopmental trajectories of the offspring. Corticotropin-releasing hormone (CRH) and glucocorticoids, regulate fetal neurogenesis and while CRH exerts neuroprotective actions, increased levels of stress hormones have been associated with fetal brain structural alterations such as reduced cortical volume, impoverishment of neuronal density in the limbic brain areas and alterations in neuronal circuitry, synaptic plasticity, neurotransmission and G-protein coupled receptor (GPCR) signalling. Emerging evidence highlight the role of epigenetic changes in fetal brain programming, as stress-induced methylation of genes encoding molecules that are implicated in HPA axis and major neurodevelopmental processes. These serve as molecular memories and have been associated with long term modifications of the offspring’s stress regulatory system and increased susceptibility to psychosomatic disorders later in life. This review summarises our current understanding on the roles of CRH and other mediators of stress responses on fetal neurodevelopment.

Keywords: Assisted reproductive techniques; Diabetes mellitus; Neonatal complications; Pregnancy outcome.


Assisted reproduction technology outcomes in women with infertility and preexisting diabetes mellitus: a systematic review

Hormones (Athens), 2021 Oct 20, doi: 10.1007/s42000-021-00329-8. Online ahead of print.

Christos F Zymperdikas, Vasileios F Zymperdikas, George Mastorakos, Grigorios Grimbizis, Dimitrios G Goulis


Objective: To assess maternal and neonatal outcomes in women with or without preexisting diabetes mellitus (DM) undergoing assisted reproduction technology (ART) treatment.
Methods: Prospective or retrospective controlled trials reporting on women with or without preexisting DM undergoing ART treatment were considered eligible. Twelve electronic databases were systematically searched up to December 2020. The risk of bias was assessed by the Cochrane Risk OF Bias In Non-randomized Studies of Interventions (ROBINS-I) tool. Each primary outcome was extracted and pooled as maternal- or neonatal-related.
Results: Two studies were included in the systematic review, reporting on both maternal- and neonatal-related parameters after ART treatment. Due to the limited data, no meta-analysis was conducted. Preterm birth, placenta previa, and excessive bleeding during pregnancy were observed more often in pregnancies complicated by preexisting DM conceived by ART compared with pregnancies without DM. There was no difference in the risk for placental abruption between the groups. Regarding the neonatal outcomes, large-for-gestational-age (LGA) embryos and neonatal intensive care unit (NICU) admission were more commonly reported for women with preexisting DM. In one study, preexisting DM was marginally associated with infant mortality.
Conclusions: Despite the scarce data, preexisting DM in pregnancies conceived by ART is associated with increased risk for maternal and neonatal complications.

Keywords: Assisted reproductive techniques; Diabetes mellitus; Neonatal complications; Pregnancy outcome.


Clinical practices of neuroprotective care for premature neonates

D. Metallinou, K. Tzounara, P. Nikolaidis, C. Nanou, A. Lykeridou

Abstract: Disruption of smooth intrauterine brain development is a significant consequence of premature birth that can lead to adverse neurological outcomes. Although noteworthy progress has been made in the management of preterm neonates, rates of neonatal morbidity and neurodevelopmental disorders remain high in this population, underlining the need to find and institute care practices that protect, in particular, the central nervous system (CNS). A promising model of care for premature neonates is “neuroprotective care”, which reduces the sensory and environmental stimuli of the neonatal intensive care unit (NICU), supporting, in this way, the neuroplasticity of the developing neonatal brain. The clinical practices of this model aim to prevent or minimize the presentation of neurodevelopmental disorders. They can be applied by a specialized interdisciplinary team in the NICU, and close cooperation with the family of the neonate in the care plan is crucial.

Key words: Clinical practices, Neuroprotective care, Premature neonate

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Postpartum human breast milk levels of neutrophil gelatinase-associated lipocalin (NGAL) and matrix metalloproteinase-9 (MMP-9)/NGAL complex in normal and pregnancies complicated with insulin-dependent gestational diabetes mellitus. A prospective pilot case-control study

J Obstet Gynaecol. 2020 May;40(4):461-467. doi: 10.1080/01443615.2019.1628191. Epub 2019 Jul 29.

Dimitra Metallinou, Katerina Lykeridou, Grigorios Karampas, Georgios Theodoros Liosis, Chrysanthi Skevaki, Myrto Rizou, Ioannis Papassotiriou, Demetrios Rizos

Abstract: Neutrophil gelatinase-associated lipocalin (NGAL) and its complex with matrix metalloproteinase-9 (MMP-9) are present in a variety of human tissues and extracellular fluids. The aim of this pilot prospective case-control study was to detect NGAL and MMP-9/NGAL complex in human breast milk postpartum in women with normal and pregnancies that developed insulin-depended gestational diabetes mellitus (iGDM). We detected both biomarkers in human breast milk and concentrations were determined at the first day of colostrum secretion and two days after, in 22 normal pregnancies and 13 pregnancies with iGDM. Mean NGAL concentration decreased significantly from the first to the second sample, in both groups. Mean MMP-9/NGAL complex concentration decreased also significantly from the first to the second sample in normal pregnancies. Mean complex concentration was significantly higher in diabetic pregnancies compared to normal ones in the second sample.IMPACT STATEMENT What is already known on this subject? There is limited information on the presence of Neutrophil gelatinase-associated lipocalin (NGAL) in human milk and its physiological role. What the results of this study add? It is the first time that MMP-9/NGAL complex is detected in human milk in both normal and pregnancies complicated with insulin-depended gestational diabetes mellitus (iGDM). We confirm the presence of NGAL in colostrum of normal pregnancies and for the first time we detected NGAL in milk of pregnancies with iGDM. Concentrations of NGAL and MMP-9/NGAL complex tend to lessen postpartum in both groups. Pregnancies with iGDM compared to normal ones showed significantly higher concentration of MMP-9/NGAL complex two days after the beginning of lactation.What the implications are of these findings for clinical practice and/or further research? Further studies are necessary to determine the levels of NGAL and MMP-9/NGAL complex in human milk postpartum in normal and pathological pregnancies. Taking into consideration the well-established NGAL’s ability to act as a bacteriostatic agent and its mucosal healing activity in gastrointestinal track, early breastfeeding of neonates is a logical recommendation. Finally, new studies on the actual physiological role of milk NGAL in neonates are necessary.

Keywords: MMP-9/NGAL complex; Milk; NGAL; diabetic pregnancy; lipocalin-2.



Hypothalamic Inflammation as a Potential Pathophysiologic Basis for the Heterogeneity of Clinical, Hormonal, and Metabolic Presentation in PCOS

Danai Barlampa, Maria Sotiria Bompoula, Alexandra Bargiota, Sophia Kalantaridou ,  George Mastorakos, Georgios Valsamakis


Abstract: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age. It is a heterogeneous condition characterized by reproductive, endocrine, metabolic, and psychiatric abnormalities. More than one pathogenic mechanism is involved in its development. On the other hand, the hypothalamus plays a crucial role in many important functions of the body, including weight balance, food intake, and reproduction. A high-fat diet with a large amount of long-chain saturated fatty acids can induce inflammation in the hypothalamus. Hypothalamic neurons can sense extracellular glucose concentrations and participate, with a feedback mechanism, in the regulation of whole-body glucose homeostasis. When consumed nutrients are rich in fat and sugar, and these regulatory mechanisms can trigger inflammatory pathways resulting in hypothalamic inflammation. The latter has been correlated with metabolic diseases, obesity, and depression. In this review, we explore whether the pattern and the expansion of hypothalamic inflammation, as a result of a high-fat and -sugar diet, may contribute to the heterogeneity of the clinical, hormonal, and metabolic presentation in PCOS via pathophysiologic mechanisms affecting specific areas of the hypothalamus. These mechanisms could be potential targets for the development of effective therapies for the treatment of PCOS.

Keywords: high-fat diet; nutrients overconsumption; polycystic ovary syndrome; PCOS; hypothalamic inflammation; hypothalamus

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