Anastasia-Konstantina Sakali, Alexandra Bargiota, Maria Papagianni, Aleksandra Rasic-Markovic & George Mastorakos

Rosario Pivonello, Evanthia Diamanti-Kandarakis (eds)

Abstract

Over the recent years, female fertility problems and number of pregnancies resulting into negative outcomes have been on the rise becoming a matter of particular concern among women of childbearing age. The rise in the above adverse reproductive health outcomes could be partly attributed to the exposure to hazardous factors ubiquitously found in the environment. To investigate this hypothesis, in this chapter, we summarize the current evidence on the impact of environmental factors and endocrine disruptors (EDs) on female fertility (either nonassisted or assisted) and on pregnancy outcomes (ectopic pregnancy, pregnancy losses, gestational diabetes, hypertensive disorders of pregnancy, preterm birth, intrauterine growth restriction, small and large for gestational age, and birth defects). Because it has been established that environmental factors and EDs are capable to induce epigenetic alterations, special care has been given to the exploration of their transgenerational effects on female fertility and pregnancy outcomes.

Agni Kakouri, Georgia Kanti, Efthymios Kapantais, Alexandros Kokkinos, Leonidas Lanaras, Paul Farajian, Christos Galanakis, Georgios Georgantopoulos, Nikos F. Vlahos, George Mastorakos, Alexandra Bargiota and Georgios Valsamakis

Abstract: The worldwide upward trend in obesity in adults and the increased incidence of overweight children suggests that the future risk of obesity-related illnesses will be increased. The existing anti-obesity drugs act either in the central nervous system (CNS) or in the peripheral tissues, controlling the appetite and metabolism. However, weight regain is a common homeostatic response; current anti-obesity medications show limited effectiveness in achieving long-term weight loss maintenance; in addition to being linked to various side effects. Combined anti-obesity medications (per os or injectable) target more than one of the molecular pathways involved in weight regulation, as well as structures in the CNS. In this systematic review, we conducted a search of PubMed and The ClinicalTrials.gov up to February 2021. We summarized the Food and Drug Administration (FDA)- approved medications, and we focused on the combined pharmacological treatments, related to the incretin hormones, currently in a clinical trial phase. We also assessed the mechanism of action and therapeutic utility of these novel hybrid peptides and potential interactions with other regulatory hormones that may have beneficial effects on obesity. As we improve our understanding of the pathophysiology of obesity, we hope to identify more novel treatment strategies.

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Περισσότερες πληροφορίες στο σύνδεσμο «Προϋποθέσεις Εισαγωγής» του ιστοχώρου και στη γραμματεία του Δ.Π.Μ.Σ. (Μαρία Ρήγα, 210-7286298, e-mail: mrriga@med.uoa.gr).

Eirini Papadimitriou, Georgios Boutzios, Alexander G. Mathioudakis, Nikos F. Vlahos, Panayiotis Vlachoyiannopoulos, George Mastorakos

Abstract
Purpose: A systematic review and meta-analysis was conducted comparing the presence of antiphospholipid (anti-PL) antibodies between women of reproductive age, without diagnosis of antiphospholipid syndrome, who experienced at least two implantation failures following in vitro fertilization and embryo transfer (IVF-ET), and either women who had a successful implantation after IVF-ET or women with at least one successful spontaneous pregnancy or unselected healthy fertile women with no history of IVF-ET.

Methods: Systematic search of the literature and meta-analysis of the relevant studies studying presence of antiphospholipid antibodies in women experiencing at least two implantation failures in IVF-ET as compared to either women who had a successful implantation after IVF-ET or/and women with at least one successful spontaneous pregnancy or unselected healthy fertile women with no history of IVF-ET. Six hundred ninety-four published reports were retrieved; 17 of them fulfilled the inclusion criteria set.

Results: Presence of either any type of anti-phospholipid or anticardiolipin antibodies or lupus-anticoagulant in women experiencing at least two implantation failures in IVF-ET was associated with increased implantation failure compared to women who had a successful implantation after IVF-ET (relative risk, RR: 3.06, 5.06 and 5.81, respectively). Presence of either anticardiolipin or lupus-anticoagulant or anti-beta2 glycoprotein-I or anti-phosphatidylserine antibodies in women experiencing at least two implantation failures in IVF-EΤ was associated with increased implantation failure compared to unselected healthy fertile women with no history of IVF-ET (RR:13.92, 6.37, 15.04 and 164.58, respectively).

Conclusion: The prevalence of antiphospholipid antibodies, particularly that of anti-beta2 glycoprotein-I and anti-phosphatidylserine antibodies, in women experiencing at least two implantation failures in IVF-ET without diagnosis of antiphospholipid syndrome is significantly greater than either in women who had a successful implantation after IVF-ET or women with at least one successful spontaneous pregnancy or unselected healthy fertile women with no history of IVF-ET.

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Eleftheria Kakargia, Eleftherios Mamalakis, Maximos Frountzas, Evangelos  Anagnostou, Charalampos Siristatidis

Abstract
Purpose This systematic review is designed to summarize the evidence concerning the impact of maternal physical activity on the reproductive outcomes following assisted reproduction techniques (ART), namely in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI).
Methods We searched for eligible studies on PubMed, EMBASE databases and the Cochrane Library from their inception until September 2021. Our primary outcomes were live birth rate and miscarriage, while secondary ones included clinical pregnancy and implantation rates. The quality of the evidence was evaluated using a study-specific adaptation of the Robins I tool.
Results Quantitative data from 10 cohort studies (CS) and 2 randomized control trials (RCT), involving 3431 women undergoing ART treatments, were included in the analyses. The pooled results exhibited uncertainty regarding the effect of physical activity on live birth rate per woman (OR 1.15, 95% CI 0.92–1.43, p = 0.23, I2 = 61%, 9 studies) and miscarriage rates (OR 0.79, 95% CI 0.44–1.43, p = 0.43, I2 = 44%, 6 studies). However, physical activity was associated with significantly improved clinical pregnancy rate after ART (OR 1.39, 95% CI 1.08–1.79, p = 0.0009, I2 = 68%, 10 studies), whereas implantation rate after ART almost reached statistical significance (OR = 1.95, 95% CI 0.99–3.82, p = 0.05, I2 = 77%).
Conclusion The current evidence is still insufficient to firmly conclude on the effect of maternal physical activity on live birth, miscarriage and implantation rates. Although clinical pregnancy rates favored physical activity in this group of patients, these results must be undertaken with caution due to the low quality and the high heterogeneity of the studies included.

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C. Ampatzis, S. Zervoudis, G. Iatrakis, G. Mastorakos

Abstract
Contraceptives are widely used in our times and a lot of research has been conducted to clarify their impact on Bone Mineral Density. Combined Oral Contraceptives (COCs) may be detrimental to the BMD of adolescents. However, low-dose are more protective than ultra-low-dose COCs. When it comes to premenopause and perimenopause, COCs have no impact on BMD in women with good ovarian function and no estrogen deficiency. In women with impaired ovarian function, it seems that COCs have a positive influence on BMD. Progestin onlypills may not affect BMD, but further research is needed. Depot medroxyprogesterone acetate injection (DMPA) has a negative impact, especially in adolescents, which is duration related but evidence shows that BMD recovers after discontinuation. Levonorgestrel-releasing intrauterine system (LNG-IUS) has no impact on BMD.

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Kyriaki Mitta, Gesthimani Mintziori, George Mastorakos, Eleftheria Taousani, Maria Tzitiridou and Dimitrios G. Goulis

Background: Pregnancy is a period of physiological and hormonal alterations that can decrease the quality of life (QoL). Women’s subjective perception of QoL is clinically relevant for assessing the effectiveness of interventions and identifying susceptibility to depression.Objective: This review aims to identify, present, and critically appraise the assessment tools of QoL during pregnancy.Methods: A narrative review of the English-language literature was conducted through the PubMed, CENTRAL, Scopus, and Google Scholar electronic databases.Conclusion: Several generic instruments have been proposed, such as pregnancy-specific and disease- specific questionnaires concerning common diseases during pregnancy. Plasma, salivary and hair cortisol, inflammatory, genetic and epigenetic biomarkers and gut microbiome have also been investigated as potential indicators of maternal anxiety. Their use can quantify the association between pregnancy-specific anxiety and QoL. Application of validated assessment tools of QoL during pregnancy could improve QoL, maternal health interventions, and early identification of susceptibility to maternal depression.

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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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Theodoros Kalampokas, Anna Rapani, Maria Papageorgiou, Sokratis Grigoriadis, Evangelos Maziotis, George Anifandis, Olga Triantafyllidou, Despoina Tzanakaki, Spyridoula Neofytou, Panagiotis Bakas, Mara Simopoulou and Nikolaos Vlahos

Abstract: Despite the volume of publications dedicated to unraveling the biological characteristics and clinical manifestations of SARS-CoV-2, available data on pregnant patients are limited. In the current review of literature, we present an overview on the developmental course, complications, and adverse effects of COVID-19 on pregnancy. A comprehensive review of the literature was performed in PubMed/Medline, Embase, and Cochrane Central databases up to June 2021. This article collectively presents what has been so far reported on the identified critical aspects, namely complications during pregnancy, delivery challenges, neonatal health care, potential routes of viral transmission, including vertical transmission or breastfeeding, along with the risks involved in the vaccination strategy during pregnancy. Despite the fact that we are still largely navigating uncharted territory, the observed publication explosion in the field is unprecedented. The overwhelming need for data is undoubtable, and this serves as the driver for the plethora of publications witnessed. Nonetheless, the quality of data sourced is variable. In the midst of the frenzy for reporting on SARSCoV-2 data, monitoring this informational overload is where we should head to next, considering that poor quality research may in fact hamper our attempts to prevail against this unparalleled pandemic outbreak.

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Varvara Ermioni Triantafyllidi, Despoina Mavrogianni, Andreas Kalampalikis, Michael Litos, Stella Roidi and Lina Michala

Abstract: Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a congenital condition characterizing females with absence of the uterus and part of the vagina. Several genetic defects have beencorrelated with the presence of MRKH; however, the exact etiology is still unknown due to the complexity of the genetic pathways implicated during the embryogenetic development of the Müllerian ducts. A systematic review (SR) of the literature was conducted to investigate the genetic causes associated with MRKH syndrome and Congenital Uterine Anomalies (CUAs). This study aimed to identify the most affected chromosomal areas and genes along with their associated clinical features in order to aid clinicians in distinguishing and identifying the possible genetic cause in each patient offering better genetic counseling. We identified 76 studies describing multiple genetic defects potentially contributing to the pathogenetic mechanism of MRKH syndrome. The most reported chromosomal regions and the possible genes implicated were: 1q21.1 (RBM8A gene), 1p31-1p35 (WNT4 gene), 7p15.3 (HOXA gene), 16p11 (TBX6 gene), 17q12 (LHX1 and HNF1B genes), 22q11.21, and Xp22. Although the etiology of MRKH syndrome is complex, associated clinical features can aid in the identification of a specific genetic defect.

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