Category Archives: Δημοσιευμένες εργασίες


Identification of the Rare Ala871Glu Mutation in the Androgen Receptor Gene Leading to Complete Androgen Insensitivity Syndrome in an Adolescent Girl with Primary Amenorrhea

Aikaterini Kapama, Dimitrios T. Papadimitriou, George Mastorakos, Nikolaos F. Vlahos and Maria Papagianni

Abstract: Complete Androgen Insensitivity Syndrome (CAIS) is a rare genetic condition by mutations in the androgen receptor (AR) gene resulting in target issue resistance to androgens and a female phenotype in genetically male individuals. A 16-year-old phenotypically female individual presented to our clinic with primary amenorrhea. Her clinical evaluation showed normal female external genitalia, Tanner III breast development and sparse pubic and axillary hair (Tanner stage II). Hormonal assessment revealed increased concentrations of Luteinizing Hormone (LH), Testosterone and Antimüllerian Hormone (AMH). Image studies detected no uterus or gonads, but a blind vagina and the karyotype was 46, XY. These findings suggested the diagnosis of CAIS, and genetic testing of the AR gene revealed a rare pathogenic mutation of cytosine to adenine (c.2612C>A) replacing alanine with glutamic acid at position 871 (p.Ala871Glu) in the AR, previously described once in two adult sisters. The patient underwent gonadectomy and received hormonal replacement therapy. This study expands the AR mutation database and shows the complexity and the importance of prompt diagnosis, proper management, and follow-up for CAIS patients, underlining the need for standardized protocols.

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The addition of clomiphene citrate to ovarian stimulation protocols for poor responders

Olga Triantafyllidou, Giorgos Sigalos, Laertis Gkoles, Stavroula Kastora, Panagiotis Vakas, Eugenia Batsiou, Nikos Vlahos

Poor ovarian response (POR) is one of the most challenging problems in assisted reproduction. Several strategies have been used to improve pregnancy rates. The use of Clomiphene Citrate (CC) has been shown to improve ovarian stimulation outcomes and decrease gonadotropin requirements in women of advanced reproductive age. However, the combination of CC and gonadotropins to improve pregnancy rates after in IVF in poor responders is still unexplored due to the small number of trials with few participants.
This is a prospective cohort trial involving 12 patients diagnosed with poor ovarian response who underwent ovarian stimulation during the period between June 2015 and September of 2017. All patients were treated with the maximum dose of gonadotropins (hMG, 300 IU/day, hMG group) according to a short gonadotropin/GnRH antagonist protocol. In a subsequent cycle those patients underwent the same stimulation protocol with the addition of 100 mg of CC from day 3 to day 7 (CC-hMG group).
Supplementation with 100 mg of CC resulted in a statistically significant increase in estradiol levels, number of follicles and number of oocytes retrieved, as well as an increase in the number of total embryos available for transfer. Furthermore, a significant reduction was observed in cancellation rates in the CChMG group. Two clinical pregnancies, which resulted in two live births and 3 biochemical pregnancies were achieved in the CC/hMG group. Furthermore, by employing open-source, biological data we identified a common gene (Estrogen Receptor 1, ESR1) between genetic targets of clomiphene treatment and POR which could explain the benefits of clomiphene in this group of patients.
In conclusion, the addition of CC 100 mg to the stimulation regimen in women diagnosed with POR and previous failed IVF cycles could improve stimulation results, but this study could not demonstrate any benefit in terms of clinical pregnancies and live births. The effectiveness of this treatment requires further investigation.

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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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