Publications by authors named "Stavros Sifakis"

92 Publications

Phthalate metabolites concentrations in amniotic fluid and maternal urine: Cumulative exposure and risk assessment.

Toxicol Rep 2020 19;7:529-538. Epub 2020 Apr 19.

Laboratory of Toxicology Science and Research, Medical School, University of Crete, 71003, Heraklion, Crete, Greece.

Phthalates are used in industry as plasticizers or additives in everyday products and they have been considered as endocrine disrupting chemicals. Maternal exposure during pregnancy has been associated with neonatal exposure, preterm birth and impacts in the reproductive and respiratory systems. The aim of this study is to determine six phthalate metabolites (mono isobutyl phthalate, miBP, mono n-butyl phthalate, mnBP, mono benzyl phthalate, mBzP, mono ethylhexyl phthalate, mEHP, mono 2-ethyl-5-hydroxyhexyl phthalate, mEHHP, mono 2-ethyl-5-oxohexyl-phthalate, mEOHP) in amniotic fluid and urine from 100 pregnant women. Participants answered questionnaires for the use of plastics and cosmetics, dietary habits, health effects, pregnancy problems, health and infant development. Positive amniotic fluid samples ranged from 1% to 21% and urine from 27% to 54%. The median levels for amniotic fluid were 2.3 μg/L - 10.7 μg/L and for urine 4.9 μg/L - 46.7 μg/L. The major results include significant correlations between urinary phthalates indicating their common sources of exposure, the frequent use of deodorant was significantly associated with higher urinary miBP (p = 0.050) and mnBP (p = 0.028) and a weak inverse association was found for the use of make-up products with mBzP (p = 0.053). The frequent use of plastic food containers was significantly associated with urinary mEHP (p = 0.026), and a positive trend was noticed for mEHP in amniotic fluid (p = 0.093). An association although weak was found between urinary mEHP and lower birth length (rs = 0.396, p = 0.062). No other associations were found for infant health problems or development. The daily intake of the total phthalates was calculated 5.4 μg/kg body weight/day which corresponds to hazard index 0.10 and exposure follows the declining trend that has been observed the last decades.
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http://dx.doi.org/10.1016/j.toxrep.2020.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186561PMC
April 2020

Biomonitoring of bisphenols A and S and phthalate metabolites in hair from pregnant women in Crete.

Sci Total Environ 2020 Apr 20;712:135651. Epub 2019 Nov 20.

Laboratory of Toxicology Science and Research, Medical School, University of Crete, 71003 Heraklion, Crete, Greece. Electronic address:

Phthalates, bisphenols A and S (BPA, BPS) are used as plasticizers and many of them are documented or suspected of being endocrine disruptors. Several studies indicate that exposure during pregnancy may affect the newborn's health and development. The aim of this cross-sectional study is the biomonitoring of seven phthalate metabolites, BPA and BPS in hair from 100 pregnant women in Crete. The most frequently detected compounds were monoethylhexyl phthalate (mEHP) (68%), mono isobutyl phthalate (miBP) (40%), BPA (37%), BPS (34%) and mono-n-butyl phthalate (mnBP) (28%). Phthalate metabolites were detected at medians from 19.5 to 44.4 pg/mg, BPA at 69.9 pg/mg and BPS at 3.5 pg/mg. Significant positive correlations between phthalate metabolites were found which indicated their common sources of exposure. The frequent use of plastics for food storage was strongly associated with mEHP (p = .013) and a weaker association was found for miBP (p = .063). The frequent use of cosmetics during or before pregnancy was associated with levels of phthalate metabolites in hair. More specifically, the use of hair spray before pregnancy was significantly correlated with monobenzyl phthalate (mBzP) (p = .041) and a trend was found for miBP (p = .066). The use of makeup products during pregnancy was strongly associated with miBP (p = .015) and the use of deodorant during pregnancy was inversely associated with mEHP (p = .021). Strong associations came up between mEHP and lower birth weight (Spearman correlation coefficient, r = -0.302, p = .021) and exposure to BPS was associated with increased body mass index of the participants (p = .036). Although data in literature on biomonitoring of the compounds in hair are limited, the findings of this study are promising and in agreement with existing data in hair or urine.
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http://dx.doi.org/10.1016/j.scitotenv.2019.135651DOI Listing
April 2020

Organochlorine pollutants' levels in hair, amniotic fluid and serum samples of pregnant women in Greece. A cohort study.

Environ Toxicol Pharmacol 2020 Jan 16;73:103279. Epub 2019 Oct 16.

Laboratory of Toxicology Science and Research, Medical School, University of Crete, Heraklion, Greece. Electronic address:

Persistent organic pollutants are synthetic chemicals highly resistant to degradation with strong tendency to bioaccumulation. Assessment of human exposure to these compounds is crucial for public health protection, especially during vulnerable periods. The aim of the present cohort study was to evaluate the level of contamination to PCBs, o,p'- and p,p'-DDE, o,p' and p,p'-DDD, o,p' and p,p'-DDT and HCB in pregnant women. Hair, amniotic fluid and serum samples were collected and analyzed by HS-SPME-GCMS. The most detected analytes in amniotic fluids were p,p'-DDE, p,p'-DDD, o,p'-DDE and PCB101, in serum p,p'-DDE, HCB and PCB101 and in hair p,p'-DDE, HCB and PCB101. The levels of HCB and PCB101 in amniotic fluids were positively correlated with those in hair. Higher levels of DDDs and DDTs in hair samples and PCB28 in amniotic fluids were observed in smoker pregnant women. Gestation age was inversely proportional with the detected levels of PCB101 in all tested samples.
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http://dx.doi.org/10.1016/j.etap.2019.103279DOI Listing
January 2020

Investigating exposure to endocrine disruptors via hair analysis of pregnant women.

Environ Res 2019 11 26;178:108692. Epub 2019 Aug 26.

Laboratory of Toxicology Science and Research, Medicine School, University of Crete, Heraklion, Crete, GR, 70013, Greece. Electronic address:

The aim of this study was the monitoring of the levels of parabens (PBs) and triclosan (TCS) in head hair samples of women collected during the first months of their pregnancy. Personal details concerning somatometric and demographic characteristics, dietary habits, use of personal care products and the medical and obstetrical history of the pregnant women as well as infants' somatometric characteristics and health condition were recorded through relevant questionnaires. Ninety five hair samples were collected, extracted by solid-liquid extraction and analysed using a liquid chromatography-mass spectrometry system (LC-MS). Analysis revealed high percentage of positive samples for all tested compounds (90-100% except from BePB (15.8%)). The mean concentration levels were 4501.2 pg/mg (17.6-27,437.0 pg/mg) for MePB; 510.1 pg/mg (11.0-4224.5 pg/mg) for EtPB; 22.9 pg/mg (2.1-66.6 pg/mg) for BePB; 237.1 pg/mg (1.8-2513.7 pg/mg) for BuPB and 245.0 pg/mg (8.8-8070.2 pg/mg) for TCS. Statistical analysis of both analytical results and questionnaires' data showed that the frequent use of personal care and hygiene products, such as makeup, hairspray and sunscreens, is correlated with higher levels of PBs in hair of the pregnant women. Additionally, positive correlation was observed between the BePB levels in hair and the infants' height. Finally, no other correlation was observed between endocrine disruptors' levels in maternal hair and infants' somatometric characteristics or health condition. Our study is the first one that determined PBs and TCS levels in hair samples, simultaneously. At the same time, correlation of the detected levels with the use of personal care products was accomplished, leading to significant association of BePB levels in hair of pregnant women with infants' height.
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http://dx.doi.org/10.1016/j.envres.2019.108692DOI Listing
November 2019

Management of Endocrinopathies in Pregnancy: A Review of Current Evidence.

Int J Environ Res Public Health 2019 03 4;16(5). Epub 2019 Mar 4.

Department of Obstetrics and Gynecology, Medical School, University of Crete, 71110 Heraklion, Crete, Greece.

Pregnancy in women with associated endocrine conditions is a therapeutic challenge for clinicians. These disorders may be common, such us thyroid disorders and diabetes, or rare, including adrenal and parathyroid disease and pituitary dysfunction. With the development of assisted reproductive techniques, the number of pregnancies with these conditions has increased. It is necessary to recognize symptoms and correct diagnosis for a proper pharmacotherapeutic management in order to avoid adverse side effects both in mother and fetus. This review summarizes the pharmacotherapy of these clinical situations in order to reduce maternal and fetal morbidity.
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http://dx.doi.org/10.3390/ijerph16050781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6427139PMC
March 2019

Biomonitoring of bisphenol A, triclosan and perfluorooctanoic acid in hair samples of children and adults.

J Appl Toxicol 2018 08 3;38(8):1144-1152. Epub 2018 May 3.

Laboratory of Toxicology Science and Research, Medical School, University of Crete, Heraklion, Greece.

Bisphenol A (BPA), triclosan (TCS) and perfluorooctanoic acid (PFOA) are endocrine disruptors linked with negative health effects such as developmental, reproductive and cardiovascular toxicity. The aim of this study was to determine simultaneously the concentration of BPA, TCS and PFOA in hair from children and adults and examine possible associations between biomonitoring data and age, gender, dietary habits and body mass index. Methanolic extraction was applied and the compounds were determined by liquid chromatography-mass spectrometry. Low levels of exposure to PFOA were detected for children and adults at concentrations below limit of quantification. The mean concentration of BPA in children and adults was 20.6 and 16.6 pg mg , while for TCS 275.2 and 687.0 pg mg , respectively. Children were highly exposed to BPA relative to adults (P = .011) although adults had greater exposure to TCS (P = .003). Hair from girls had a greater burden of BPA (P = .06) compared to boys. Moreover, higher TCS levels were depicted for females in both examined groups (children P = .200 and adults P = .213) compared to males, but no statistical differences were observed. Significant differences were also observed between age groups (P = .0007) for TCS. No correlations were found between BPA or TCS levels and body mass index or dietary habits for both children and adults. Children have a greater exposure to BPA compared to adults, whereas exposure of adults to TCS seems to be higher than that in children and elderly people. Exposure to BPA occurs mainly via ingestion whereas exposure to TCS mainly via dermal absorption.
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http://dx.doi.org/10.1002/jat.3627DOI Listing
August 2018

Placental expression of PAPPA, PAPPA-2 and PLAC-1 in pregnacies is associated with FGR.

Mol Med Rep 2018 May 9;17(5):6435-6440. Epub 2018 Mar 9.

Department of Obstetrics and Gynecology, Attikon University Hospital, University of Athens, 12462 Athens, Greece.

Fetal growth restriction (FGR) is a gynecological disorder of varying etiology. In the present study, an expression analysis of pregnancy-associated plasma protein A (PAPPA), pregnancy-associated plasma protein A2 (PAPPA2) and placenta-specific-1 (PLAC-1) was conducted in pregnancies with FGR and control pregnancies. Placental tissues were collected from pregnancies with FGR (n=16) and control pregnancies (n=16) and the expression of the genes of interest was examined by qPCR. The mean expression levels of PAPPA and PAPPA2 were significantly lower (P<0.001) in placental tissues from FGR pregnancies compared with tissues from healthy subjects, whereas the opposite pattern was observed for PLAC-1 (P<0.001). PAPPA and PLAC-1 expression in FGR and control subjects correlated with birth weight (P<0.001). The findings suggest a possible pathophysiological link between the development of FGR and the expression of PAPPA, PAPPA2 and PLAC-1.
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http://dx.doi.org/10.3892/mmr.2018.8721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5928614PMC
May 2018

Endocrine Disruptors Leading to Obesity and Related Diseases.

Int J Environ Res Public Health 2017 10 24;14(10). Epub 2017 Oct 24.

Department of Forensic Sciences and Toxicology, Faculty of Medicine, University of Crete, 71003 Heraklion, Crete, Greece.

The review aims to comprehensively present the impact of exposure to endocrine disruptors (EDs) in relation to the clinical manifestation of obesity and related diseases, including diabetes mellitus, metabolic syndrome, cardiovascular diseases, carcinogenesis and infertility. EDs are strong participants in the obesity epidemic scenery by interfering with cellular morphological and biochemical processes; by inducing inflammatory responses; and by presenting transcriptional and oncogenic activity. Obesity and lipotoxicity enhancement occur through reprogramming and/or remodeling of germline epigenome by exposure to EDs. Specific population groups are vulnerable to ED exposure due to current dietary and environmental conditions. Obesity, morbidity and carcinogenicity induced by ED exposure are an evolving reality. Therefore, a new collective strategic approach is deemed essential, for the reappraisal of current global conditions pertaining to energy management.
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http://dx.doi.org/10.3390/ijerph14101282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664782PMC
October 2017

Partial monosomy 8p and trisomy 16q in two children with developmental delay detected by array comparative genomic hybridization.

Mol Med Rep 2017 Dec 10;16(6):8808-8818. Epub 2017 Oct 10.

Access To Genome, Laboratory of Genetics, Athens 11528‑Thessaloniki 55134, Greece.

Two cases of liveborn unrelated children with developmental delay and overlapping unbalanced translocations der(8)t(8;16)(p23.2;q23.3) and der (8)t(8;16)(p23.1;q23.1), leading to partial monosomy 8p and partial trisomy 16q, are reported in the present study. The first patient was a 10‑year‑old boy with mild developmental delay and minor congenital anomalies (borderline microcephaly, clinodactyly, hypertelorism, epicanthus, mild systolic murmur and kidney reflux). The second patient was a 3 year‑old girl with developmental delay, gross motor milestone delay and dysmorphic features. Array‑comparative genomic hybridization analysis revealed that partial chromosome 8p monosomy extended from 8p23.2 to 8pter (4.8 Mb) in Patient 1 and from 8p23.1 to 8pter (9.5 Mb) in Patient 2, and partial chromosome 16 trisomy extended from 16q23.3 to 16qter (5.6 Mb) in Patient 1 and from 16q23.1 to 16qter (11.7 Mb) in Patient 2. The mechanism of appearance of the rearrangement in association with the genes involved and the architecture of the region is discussed.
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http://dx.doi.org/10.3892/mmr.2017.7760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5779959PMC
December 2017

Human placental growth hormone in normal and abnormal fetal growth.

Biomed Rep 2017 Aug 21;7(2):115-122. Epub 2017 Jun 21.

Department of Obstetrics and Gynecology, University Hospital of Heraklion, Heraklion 71201, Greece.

Human placental growth hormone (PGH), encoded by the growth hormone (GH) variant gene on chromosome 17, is expressed in the syncytiotrophoblast and extravillous cytotrophoblast layers of the human placenta. Its maternal serum levels increase throughout pregnancy, and gradually replaces the pulsatile secreted pituitary GH. PGH is also detectable in cord blood and in the amniotic fluid. This placental-origin hormone stimulates glyconeogenesis, lipolysis and anabolism in maternal organs, and influences fetal growth, placental development and maternal adaptation to pregnancy. The majority of these actions are performed indirectly by regulating maternal insulin-like growth factor-I levels, while the extravillous trophoblast involvement indicates a direct effect on placental development, as it stimulates trophoblast invasiveness and function via a potential combination of autocrine and paracrine mechanisms. The current review focuses on the role of PGH in fetal growth. In addition, the association of PGH alterations in maternal circulation and placental expression in pregnancy complications associated with abnormal fetal growth is briefly reviewed.
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http://dx.doi.org/10.3892/br.2017.930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5526045PMC
August 2017

Human exposure to endocrine disrupting chemicals: effects on the male and female reproductive systems.

Environ Toxicol Pharmacol 2017 Apr 6;51:56-70. Epub 2017 Mar 6.

Department of Clinical Virology, University of Crete, Medical School, Heraklion, GR 71003, Greece.

Endocrine disrupting chemicals (EDCs) comprise a group of chemical compounds that have been examined extensively due to the potential harmful effects in the health of human populations. During the past decades, particular focus has been given to the harmful effects of EDCs to the reproductive system. The estimation of human exposure to EDCs can be broadly categorized into occupational and environmental exposure, and has been a major challenge due to the structural diversity of the chemicals that are derived by many different sources at doses below the limit of detection used by conventional methodologies. Animal and in vitro studies have supported the conclusion that endocrine disrupting chemicals affect the hormone dependent pathways responsible for male and female gonadal development, either through direct interaction with hormone receptors or via epigenetic and cell-cycle regulatory modes of action. In human populations, the majority of the studies point towards an association between exposure to EDCs and male and/or female reproduction system disorders, such as infertility, endometriosis, breast cancer, testicular cancer, poor sperm quality and/or function. Despite promising discoveries, a causal relationship between the reproductive disorders and exposure to specific toxicants is yet to be established, due to the complexity of the clinical protocols used, the degree of occupational or environmental exposure, the determination of the variables measured and the sample size of the subjects examined. Future studies should focus on a uniform system of examining human populations with regard to the exposure to specific EDCs and the direct effect on the reproductive system.
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http://dx.doi.org/10.1016/j.etap.2017.02.024DOI Listing
April 2017

Plasma biomarkers for the identification of women at risk for early-onset preeclampsia.

Expert Rev Proteomics 2017 03 20;14(3):269-276. Epub 2017 Feb 20.

a 3rd Department of Obstetrics Gynecology , Athens University school of Medicine , Athens , Greece.

Background: To identify potential biomarkers in the 1st trimester of pregnancy for the identification of women destined to develop early onset preeclampsia (EOPE).

Methods: Blood samples were obtained from pregnant women at 11-13 weeks of gestation. Women were followed up until delivery. Five samples from EOPE complicated pregnancies and 5 from unaffected ones were analysed using 2-DE and MALDI-TOF-TOF MS/MS. The altered expression of selected proteins was verified by ELISA in an extended sample cohort.

Results: Twelve proteins were differentially expressed in the plasma of women who subsequently developed EOPE as compared to controls. Alpha-1-antitrypsin (A1AT), CD5 antigen-like molecule (CD5L) Keratin, type I cytoskeletal 9 (K1C9), Myeloid cell nuclear differentiation antigen (MNDA), Transferrin (TRFE) and Vitamin D-binding protein (VTDB) were up-regulated with fold changes 3.14, 2.18, 1.53, 1.53, 4.26 3.38 respectively, whereas Alpha-2-HS-glycoprotein (FETUA), Beta-2-glycoprotein 1 (APOH), Complement factor B (CFAB), Haptoglobin (HPT), Vitronectin (VTNC) and Zinc-alpha-2-glycoprotein (ZA2G) were down-regulated with fold changes -0.38, -0.76, -0.24, -0.47, -0.23, and -0.50 respectively. The down-regulation of APOH, VTNC and HPT was verified using ELISA.

Conclusions: The differentially expressed proteins represent potential biomarkers for the early screening for EOPE. Follow-up experiments however are necessary for evaluation.
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http://dx.doi.org/10.1080/14789450.2017.1291345DOI Listing
March 2017

A global assessment of phthalates burden and related links to health effects.

Environ Int 2016 Dec 24;97:212-236. Epub 2016 Sep 24.

Department of Chemistry, University of Crete, and Foundation for Research and Technology-Hellas, FORTH-IESL, GR-71003 Heraklion, Crete, Greece.

Phthalates are ubiquitous environmental contaminants which are used in industry as plasticizers and additives in cosmetics. They are classified as Endocrine Disrupting Chemicals (EDCs) which impair the human endocrine system inducing fertility problems, respiratory diseases, childhood obesity and neuropsychological disorders. The aim of this review is to summarize the current state of knowledge on the toxicity that phthalates pose in humans based on human biomonitoring studies conducted over the last decade. Except for conventional biological matrices (such as urine and serum), amniotic fluid, human milk, semen, saliva, sweat, meconium and human hair are also employed for the estimation of exposure and distribution of pollutants in the human body, although data are not enough yet. Children are highly exposed to phthalates relative to adults and in most studies children's daily intake surpasses the maximum reference dose (RfD) set from US Environmental Protection Agency (US EPA). However, the global trend is that human exposure to phthalates is decreasing annually as a result of the strict regulations applied to phthalates.
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http://dx.doi.org/10.1016/j.envint.2016.09.013DOI Listing
December 2016

DNA methylation in endometriosis (Review).

Mol Med Rep 2016 Apr 22;13(4):2939-48. Epub 2016 Feb 22.

Laboratory of Clinical Virology, University of Crete Medical School, Heraklion 71409, Greece.

Endometriosis is defined by the presence and growth of functional endometrial tissue, outside the uterine cavity, primarily in the ovaries, pelvic peritoneum and rectovaginal septum. Although it is a benign disease, it presents with malignant characteristics, such as invasion to surrounding tissues, metastasis to distant locations and recurrence following treatment. Accumulating evidence suggests that various epigenetic aberrations may play an essential role in the pathogenesis of endometriosis. Aberrant DNA methylation represents a possible mechanism repsonsible for this disease, linking gene expression alterations observed in endometriosis with hormonal and environmental factors. Several lines of evidence indicate that endometriosis may partially be due to selective epigenetic deregulations influenced by extrinsic factors. Previous studies have shed light into the epigenetic component of endometriosis, reporting variations in the epigenetic patterns of genes known to be involved in the aberrant hormonal, immunologic and inflammatory status of endometriosis. Although recent studies, utilizing advanced molecular techniques, have allowed us to further elucidate the possible association of DNA methylation with altered gene expression, whether these molecular changes represent the cause or merely the consequence of the disease is a question which remains to be answered. This review provides an overview of the current literature on the role of DNA methylation in the pathophysiology and malignant evolution of endometriosis. We also provide insight into the mechanisms through which DNA methylation-modifying agents may be the next step in the research of the pharmaceutical treatment of endometriosis.
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http://dx.doi.org/10.3892/mmr.2016.4925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4805102PMC
April 2016

Interstitial deletion at 11q14.2-11q22.1 may cause severe learning difficulties, mental retardation and mild heart defects in 13-year old male.

Mol Cytogenet 2015 17;8:71. Epub 2015 Sep 17.

Access to genome P.C., Clinical Laboratory Genetics, 33A Ethn. Antistaseos str, 55134 Thessaloniki, Greece ; Department of Medical Genetics, University of Cagliari, Binaghi Hospital, Cagliari, Italy.

Interstitial deletions of the long arm of chromosome 11 are rare, and they could be assumed as non-recurrent chromosomal rearrangements due to high variability of the size and the breakpoints of the deleted region. The exact region of the deletion was difficult to be determined before the use of molecular cytogenetic techniques such as array comparative genomic hybridization (aCGH). Here, a 13-year old boy with severe learning difficulties, mental retardation and mild heart defects is described. Conventional G-band karyotyping was performed and it is found that the patient is a carrier of a de novo interstitial deletion on the long arm of chromosome 11, involving 11q14 and 11q22 breakpoints. Further investigation, using aCGH, specified the deleted region to 11q14.2-11q22.1. There was a difficulty in correlating the genotype with the phenotype of the patient due to lack of similar cases in literature. More studies should be done in order to understand the genetic background that underlies the phenotypic differences observed in similar cases.
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http://dx.doi.org/10.1186/s13039-015-0175-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574176PMC
September 2015

Diabetes mellitus and gynecologic cancer: molecular mechanisms, epidemiological, clinical and prognostic perspectives.

Arch Gynecol Obstet 2016 Feb 4;293(2):239-46. Epub 2015 Sep 4.

2nd Department of Obstetrics and Gynecology, Aretaieio Hospital, University of Athens Medical School, Athens, Greece.

Introduction: Diabetes mellitus, the prevalence of which has increased dramatically worldwide, may put patients at a higher risk of cancer. The aim of our study is the clarification of the possible mechanisms linking diabetes mellitus and gynecological cancer and their epidemiological relationship.

Materials And Methods: This is a narrative review of the current literature, following a search on MEDLINE and the Cochrane Library, from their inception until January 2012. Articles investigating gynecologic cancer (endometrial, ovarian, and breast) incidence in diabetic patients were extracted.

Results: The strong evidence for a positive association between diabetes mellitus and the risk for cancer indicates that energy intake in excess to energy expenditure, or the sequelae thereof, is involved in gynecological carcinogenesis. This risk may be further heightened by glucose which can directly promote the production of tumor cells by functioning as a source of energy. Insulin resistance accompanied by secondary hyperinsulinemia is hypothezised to have a mitogenic effect. Steroid hormones are in addition potent regulators of the balance between cellular differentiation, proliferation, and apoptosis. Inflammatory pathways may also be implicated, as a correlation seems to exist between diabetes mellitus and breast or endometrial carcinoma pathogenesis, although an analogous correlation with ovarian carcinoma is still under investigation. Antidiabetic agents have been correlated with elevated cancer risk, while metformin seems to lower the risk.

Conclusion: Diabetes mellitus is associated with an elevation in gynecologic cancer risk. Moreover, there are many studies exploring the prognosis of patients with diabetes and gynecological cancer, the outcome and the overall survival in well-regulated patients.
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http://dx.doi.org/10.1007/s00404-015-3858-zDOI Listing
February 2016

Downregulation of notch signaling pathway in late preterm and term placentas from pregnancies complicated by preeclampsia.

PLoS One 2015 11;10(5):e0126163. Epub 2015 May 11.

Laboratory of Clinical Virology, Medical School, University of Crete, Heraklion, Crete, Greece.

Preeclampsia (PE) is a major cause of maternal mortality and morbidity, affecting 3-5% of all pregnancies. The Notch signaling pathway plays an important role during placental development, activating several target genes. Defects in the Notch pathway have adverse effect on placentation. The aim of this study was to investigate the expression of receptors NOTCH1,-2,-3,-4, ligands DLL1,-3,-4, JAG1,-2 and target genes HEY1,-2 in placental tissue samples from 20 late preterm or term pregnancies complicated by PE versus 20 normal pregnancies. mRNA levels of the studied molecules were measured by quantitative Real-Time PCR (qRT-PCR), while the protein expression of the intracellular domain of NOTCH2 (NICD2) and NOTCH3 (NICD3) was measured by Western Blot (WB). qRT-PCR analysis revealed that NOTCH1, NOTCH4 and DLL1 were not expressed in the placenta. On the contrary, NOTCH2, NOTCH3, DLL3, DLL4, JAG1, JAG2, HEY1 and HEY2 mRNA levels were downregulated in PE samples vs. controls (p<0.01). WB confirmed that NICD2 (p = 0.014) and NICD3 (p<0.001) protein levels were also lower in PE specimens. Statistical analysis revealed several significant associations: of NOTCH3 mRNA expression with smoking during pregnancy (p = 0.029), of NICD3 protein levels (p = 0.028) and DLL3 mRNA levels (p = 0.041) with birth weight centile, and of HEY2 transcript levels with parity (p = 0.034) and mode of delivery (p = 0.028). Our results suggest that Notch pathway downregulation is associated with PE. Further studies are required in order to determine the role of these molecules in PE pathogenesis and to evaluate their potential use for the early detection and treatment of PE.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0126163PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4427301PMC
February 2016

Awareness of prenatal screening for fetal aneuploidy among pregnant women in Greece.

In Vivo 2015 Jan-Feb;29(1):155-60

Department of Medical Genetics, Medical School, Athens University, Athens, Greece.

Aim: To estimate the level of awareness of prenatal screening (PS) and explore the underlying demographic, lifestyle and medical history parameters of Greek and non-Greek pregnant women undergoing prenatal diagnosis.

Patients And Methods: A structured questionnaire was answered by 354 women at the time of receiving the results of invasive prenatal testing. Summary statistics and multiple logistic regression analyses were performed.

Results: Adequate knowledge of the effectiveness of PS tests was reported by 50.8% of women. Popular press reading was associated with more than 2-fold higher level of awareness [odds ratio (OR)=0.51, p=0.0004]. Inadequate awareness was recorded among pregnant women of non-Greek nationality (OR=2.07, p=0.04), as well as among those also unaware of the effects of smoking during pregnancy (OR=2.39, p=0.004).

Conclusion: Pre-gestational prenatal counseling is essential in order to improve knowledge and attitudes of women towards PS and reduce the health gap between different cultural and social groups.
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September 2015

Cell-free fetal DNA and pregnancy-related complications (review).

Mol Med Rep 2015 Apr 19;11(4):2367-72. Epub 2014 Dec 19.

Department of Clinical Virology, School of Medicine, University of Crete, Heraklion, Crete, Greece.

Cell‑free fetal DNA (cff‑DNA) is a novel promising biomarker that has been applied in various aspects of obstetrical research, notably in prenatal diagnosis and complicated pregnancies. It is easily detected by semi‑quantitative PCR for the SRY target gene. It is well recognized that the levels of circulating cff‑DNA play a role in various complications of pregnancy. In this review, we explore the implications of the detection of cff‑DNA in a range of pregnancy-related complications, such as preeclampsia, intrauterine growth restriction (IUGR), preterm labor, placenta previa and hyperemesis gravidarum. cff‑DNA is released due to apoptotic mechanisms occurring on trophoblastic cells, although recent in vivo studies support the existence of additional mechanisms. The increase in the levels of cff‑DNA can be used to predict pregnancy-related complications and has great value in the field of prenatal diagnosis and in common pregnancy-related complications, as it precedes the clinical symptoms of the disease. Gestational age is a factor that determines the elevation in cff‑DNA levels in response to pathological conditions. In conclusion, the detection of cff‑DNA levels has a number of valuable applications in prenatal screening; however, the detection of cff‑DNA levels has not yet been applied in clinical practice for the diagnosis of pregnancy-related disorders. Thus, studies are focusing on unraveling the etiology of alterations in its levels under pathological conditions during pregnancy, in order to determine the potential predictive and diagnostic applications of this biomarker.
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http://dx.doi.org/10.3892/mmr.2014.3118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4337476PMC
April 2015

Expression profile of CYP1A1 and CYP1B1 enzymes in endometrial tumors.

Tumour Biol 2014 Oct 24;35(10):9549-56. Epub 2014 Jun 24.

First Department of Surgery, Laiko Hospital, Medical School, University of Athens, Athens, 11527, Greece.

The cytochrome P450 CYP1A1 and CYP1B1 enzymes are phase I extrahepatic enzymes involved in the activation of pro-carcinogenic compounds to carcinogenic metabolites. Although differential overexpression of CYP1A1 and CYP1B1 has been documented at the messenger RNA (mRNA) and protein level, studies that have examined CYP1 expression by enzyme activity assays are limited. In the current study, the expression of CYP1A1 and CYP1B1 was investigated in a panel of human tumors of endometrial origin by quantitative reverse transcriptase PCR (qRT-PCR), Western blotting, and enzyme activity assays. The data revealed that approximately 36 % (5/14) and 43 % (6/14) of the endometrial tumors overexpressed CYP1A1 and CYP1B1 mRNA, whereas in 57 % of the endometrial tumors, CYP1 mRNA levels were downregulated. The mean mRNA levels of CYP1B1 and CYP1A1 in endometrial tumors did not show a significant difference compared to normal tissues (p > 0.05). Western blotting confirmed the qRT-PCR results and CYP1A1 and CYP1B1 proteins were shown to be downregulated in 7/14 (50 %) of the tumors and overexpressed in 4/14 (29 %) of the tumors. As regards to enzyme activity, 21 % (3/14) of the endometrial samples revealed elevated CYP1 activity levels across the tumor counterparts. Overall, the data suggest a putative downregulation of CYP1A1 and CYP1B1 expression in endometrial tumors, whereas overexpression of active CYP1 enzymes in 21 % of the tumors highlights the potential use of the latter enzymes as chemotherapeutic targets in endometrial cancer.
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http://dx.doi.org/10.1007/s13277-014-2240-2DOI Listing
October 2014

Insulin-like growth factors in embryonic and fetal growth and skeletal development (Review).

Mol Med Rep 2014 Aug 21;10(2):579-84. Epub 2014 May 21.

1st Department of Pathology, School of Medicine, University of Athens, Athens, Greece.

The insulin-like growth factors (IGF)-I and -II have a predominant role in fetal growth and development. IGFs are involved in the proliferation, differentiation and apoptosis of fetal cells in vitro and the IGF serum concentration has been shown to be closely correlated with fetal growth and length. IGF transcripts and peptides have been detected in almost every fetal tissue from as early in development as pre‑implantation to the final maturation stage. Furthermore, IGFs have been demonstrated to be involved in limb morphogenesis. However, although ablation of Igf genes in mice resulted in growth retardation and delay in skeletal maturation, no impact on outgrowth and patterning of embryonic limbs was observed. Additionally, various molecular defects in the Igf1 and Igf1r genes in humans have been associated with severe intrauterine growth retardation and impaired skeletal maturation, but not with truncated limbs or severe skeletal dysplasia. The conflicting data between in vitro and in vivo observations with regard to bone morphogenesis suggests that IGFs may not be the sole trophic factors involved in fetal skeletal growth and that redundant mechanisms may exist in chondro- and osteogenesis. Further investigation is required in order to elucidate the functions of IGFs in skeletal development.
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http://dx.doi.org/10.3892/mmr.2014.2258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4094767PMC
August 2014

DNA methylation profiles in ovarian cancer: implication in diagnosis and therapy (Review).

Mol Med Rep 2014 Jul 8;10(1):3-9. Epub 2014 May 8.

Department of Obstetrics and Gynecology, University Hospital of Heraklion, Heraklion, Crete, Greece.

Genetic alterations alone cannot account for the complexity of ovarian cancer. The potential reversibility of epigenetic mechanisms makes them attractive candidates for the prevention and/or treatment of ovarian carcinoma. Detection of the epigenetic signature of each cancer cell may be useful in the identification of candidate biomarkers for disease detection, classification and monitoring and may also facilitate personalized cancer treatment. In ovarian cancer, in addition to other non‑gynaecological cancers, two opposite epigenetic phenomena occur. The first involves an overall global decrease in DNA methylation of heterochromatin leading to demethylation of several oncogenes, while the second involves specific CpG island hypermethylation associated with the promoters of tumor suppressor genes. Early studies focused on the methylation patterns of single genes associated with tumorigenesis. However, newer genome-wide methods have identified a group of genes whose regulation is altered by DNA methylation during ovarian cancer progression.
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http://dx.doi.org/10.3892/mmr.2014.2221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4068729PMC
July 2014

Prenatal diagnosis of proximal partial trisomy 1q confirmed by comparative genomic hybridization array: molecular cytogenetic analysis, fetal pathology and review of the literature.

Birth Defects Res A Clin Mol Teratol 2014 Apr 12;100(4):284-93. Epub 2014 Feb 12.

Department of Obstetrics and Gynecology, University Hospital of Heraklion, Heraklion, Crete, Greece.

Background: Partial trisomy of the long arm of chromosome 1 (1q) is an exceptionally rare chromosomal abnormality and most of the prenatally diagnosed cases are associated with either complete (q11-qter) or large (q21-qter) duplications with pre- or perinatal demise of all reported cases. The most common sonographic findings associated with this karyotype abnormality include ventriculomegaly, increased nuchal translucency or nuchal fold, renal and cardiac abnormalities, craniofacial dysmorphism, and limb deformities. However, there is a wide spectrum of clinical manifestations due to the great variability in the extent of the duplication size and the possible contribution of additional genetic rearrangements in the final phenotype.

Case Report: We report on a female fetus with sole partial trisomy 1q presenting with multiple structural malformations in the second trimester scan. Standard karyotyping demonstrated a large duplication on the proximal end of chromosome 1 [46,XX,dup(1)(pter→q31::q31→q12::q31→qter)] and further application of comparative genomic hybridization array confirmed the diagnosis and offered a precise characterization of the genetic defect.

Conclusion: A fetus with nonmosaic partial trisomy 1q that was prenatally diagnosed upon multiple abnormal ultrasound findings is presented. A detailed review of the currently available literature on the prenatal diagnostic approach of partial trisomy 1q in terms of fetal sonographic assessment and molecular cytogenetic investigation is also provided. The use of novel molecular techniques such comparative genomic hybridization array could shed further light on the correlation between the genes identified in the chromosomal region of interest and the resultant phenotype.
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http://dx.doi.org/10.1002/bdra.23213DOI Listing
April 2014

Reduced ANXA5 mRNA and protein expression in pregnancies complicated by preeclampsia.

Thromb Res 2014 Mar 22;133(3):495-500. Epub 2013 Dec 22.

Department of Obstetrics and Gynaecology, University Hospital of Heraklion, Crete, Greece. Electronic address:

Introduction: The placental anticoagulant protein Annexin A5 (ANXA5) is a multifunctional protein that is highly expressed on the apical surfaces of syncytiotrophoblasts, and plays an important role in haemostatic regulations, maintaining blood fluidity of the placenta. The aim of this study was to investigate the expression of ANXA5 in pregnancies complicated by preeclampsia (PE).

Materials And Methods: Placental tissue samples were collected from 23 pregnancies with PE and 34 normal pregnancies. ANXA5 mRNA levels were measured by quantitative Real-Time PCR (qPCR), while ANXA5 protein expression was measured by Western Blot (WB) and immunohistochemistry.

Results: ANXA5 mRNA expression in PE samples was lower than 1% of its expression in normal samples (mean ± SD: 0.002 ± 0.004 vs. 0.55 ± 0.38, p < 0.001), while ANXA5 protein levels in PE samples were approximately at 65% of the average normal expression (mean ± SD: 0.53 ± 0.30 vs. 0.81 ± 0.25, p=0.001). Immunohistochemical analysis also verified the above results, since PE placentas tended to have low labelling indexes (LIs), in contrast to controls which demonstrated high LIs (p=0.020). Statistical analysis of the WB data revealed that ANXA5 protein expression was increased in PE smokers vs. PE non-smokers (mean ± SD: 0.64 ± 0.23 vs. 0.41 ± 0.33, p=0.027).

Conclusions: These results suggest that ANXA5 downregulation could be part of the pathophysiology of PE and the possible impairment in coagulation processes, which are seen in pregnancies that demonstrate PE. Further studies may investigate whether ANXA5 could be used as a biomarker for the early detection of PE and for the prediction of its severity.
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http://dx.doi.org/10.1016/j.thromres.2013.12.027DOI Listing
March 2014

Acute lung injury in preterm fetuses and neonates: mechanisms and molecular pathways.

J Matern Fetal Neonatal Med 2013 Nov 20;26(17):1696-704. Epub 2013 May 20.

2nd Department of Obstetrics and Gynecology, University of Athens Medical School, Aretaieio Hospital , Athens , Greece .

Acute lung injury (ALI) results in high morbidity and mortality among preterm neonates and efforts have therefore been devoted to both antenatal and postnatal prevention of the disease. ALI is the result of an inflammatory response which is triggered by a variety of different mechanisms. It mostly affects the fetal lung and, in particular, causes damage to the integrity of the lung's alveolar-capillary unit while weakening its cellular linings. Chemotactic activity and inflammatory products, such as proinflammatory cytokines TNF-α, IL-1, IL-6, IL-11, VEGF,TGF-α and TGF-β, provoke serious damage to the capillary endothelium and the alveolar epithelium, resulting in hyaline membrane formation and leakage of protein-rich edema fluid into the alveoli. Chorioamnionitis plays a major part in triggering fetal lung inflammation, while mechanical ventilation, the application of which is frequently necessary in preterm neonates, also causes ALI by inducing proinflammatory cytokines. Many different ventilation-strategies have been developed in order to reduce potential lung injury. Furthermore, tissue injury may occur as a result of injurious oxygen by-products (Reactive Oxygen Species, ROS), secondary to hyperoxia. Knowledge of the inflammatory pathways that connect intra-amniotic inflammation and ALI can lead to the formulation of novel interventional procedures. Future research should concentrate on the pathophysiology of ALI in preterm neonates and οn possible pharmaceutical interventions targeting prevention and/or resolution of ALI.
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http://dx.doi.org/10.3109/14767058.2013.798284DOI Listing
November 2013

Endocrine, paracrine, and autocrine placental mediators in labor.

Hormones (Athens) 2012 Oct-Dec;11(4):397-409

2nd Department of Obstetrics and Gynecology, University of Athens Medical School, Aretaieio Hospital, Athens, Greece.

Considering that preterm birth accounts for about 6-10% of all births in Western countries and of more than 65% of all perinatal deaths, elucidation of the particularly complicated mechanisms of labor is essential for determination of appropriate and effective therapeutic interventions. Labor in humans results from a complex interplay of fetal and maternal factors, which act upon the uterus to trigger pathways leading gradually to a coordinated cervical ripening and myometrial contractility. Although the exact mechanism of labor still remains uncertain, several components have been identified and described in detail. Based on the major role played by the human placenta in pregnancy and the cascade of labor processes activated via placental mediators exerting endocrine, paracrine, and autocrine actions, this review article has aimed at presenting the role of these mediators in term and preterm labor and the molecular pathways of their actions. Some of the aforementioned mediators are involved in myometrial activation and preparation and others in myometrial stimulation leading to delivery. In the early stages of pregnancy, myometrial molecules, like progesterone, nitric oxide, and relaxin, contribute to the retention of pregnancy. At late stages of gestation, fetal hypothalamus maturation signals act on the placenta causing the production of hormones, including CRH, in an endocrine manner; the signals then enhance paracrinically the production of more hormones, such as estrogens and neuropeptides, that contribute to cervical ripening and uterine contractility. These molecules act directly on the myometrium through specific receptors, while cytokines and multiple growth factors are also produced, additionally contributing to labor. In situations leading to preterm labor, as in maternal stress and fetal infection, cytokines trigger placental signaling sooner, thus leading to preterm birth.
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http://dx.doi.org/10.14310/horm.2002.1371DOI Listing
September 2013

Placental growth factor (PlGF): a key to optimizing fetal growth.

J Matern Fetal Neonatal Med 2013 Jul 14;26(10):995-1002. Epub 2013 Feb 14.

2nd Department of Obstetrics and Gynecology, University of Athens Medical School, Athens, Greece.

The needs of the uterus and the fetus for the provision of nutrients and oxygen, supplied by the blood flow, are understandably extremely high, with the circulatory system playing the most important role in this action. Abnormal vascular growth and transformation that create a high vessel resistance network have been associated with various pregnancy pathologies, including miscarriage, small for gestational age (SGA) fetuses with or without preeclampsia and intrauterine growth restriction (IUGR). Placental growth factor (PlGF) has a major role in vasculogenesis and angiogenesis in human placenta. Low concentrations of PlGF and high concentrations of its inhibitor-soluble Fms-like tyrosine kinase-1 (sFlt-1) are linked with impaired angiogenesis and placental development, leading to the above pregnancy complications. The activity of vascular endothelial growth factor (VEGF), which is the most potent of all angiogenic mediators, is partly modulated by PlGF. Although the mechanisms via which PlGF exerts its various effects are still under investigation, we herein discuss the known actions exerted by this major mediator together with its results on fetal growth.
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http://dx.doi.org/10.3109/14767058.2013.766694DOI Listing
July 2013

Prognostic value of tgfb1 protein in endometrioid adenocarcinoma.

Eur J Clin Invest 2013 Jan 26;43(1):79-90. Epub 2012 Nov 26.

Department of Virology, Medical School, University of Crete, Heraklion, Crete, Greece.

Background: Angiogenesis is a prerequisite for tumour development, progression and metastasis; however, its underlying molecular mechanisms in endometrial carcinoma are poorly understood.

Design: In this study, the mRNA and protein expression profiles of two key regulators of angiogenesis, vascular endothelial growth factor (VEGF) and transforming growth factor beta-1 (TGFB1), were evaluated by real-time PCR and western blot analysis in 23 endometrial cancer tissue-paired specimens (malignant vs. adjacent normal tissues). We aimed to investigate whether VEGF and TGFB1 serve as markers of the malignant transformation of the endometrium and whether VEGF or TGFB1 expression can constitute a useful prognostic marker of survival in patients with endometrial carcinoma.

Results: Tissue-pair analysis revealed VEGF transcriptional up-regulation and TGFB1 mRNA down-regulation as the most frequent transcriptional features. VEGF and TGFB1 mRNA were positively correlated (P < 0·001). VEGF protein levels were higher in endometrioid-type tissue pairs (P = 0·047). TGFB1 protein and mRNA levels were negatively correlated (P = 0·042). TGFB1 protein expression was related to survival only in patients with endometrioid adenocarcinoma (P = 0·045).

Conclusions: Tissue-pair mRNA and protein analysis reveals VEGF transcriptional up-regulation and TGFB1 down-regulation that are correlated with the malignant transformation of the endometrium, while post-transcriptional mechanisms control VEGF and TGFB1 protein. TGFB1 protein demonstrated a prognostic value only in endometrioid adenocarcinoma.
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http://dx.doi.org/10.1111/eci.12017DOI Listing
January 2013

Therapeutic management of fetal anemia: review of standard practice and alternative treatment options.

J Perinat Med 2013 Jan;41(1):71-82

First Department of Obstetrics and Gynecology, Alexandra Hospital, University of Athens, Athens, Greece.

Fetal anemia, mainly due to red cell alloimmunization, is still a significant cause of fetal and neonatal mortality and morbidity. The focus of current clinical research has shifted from an invasive approach to non-invasive management and treatment of affected pregnancies, and the progress in this field is associated with a major improvement in perinatal outcome. During the last 50 years, intrauterine red cells transfusion (IUT), fi rst via the intraperitoneal route and later directly to fetal circulation, is the standard practice in most centers, with survival rates that exceed 90 % , particularly if anemia is diagnosed early and treated in a timely manner. In addition, plasmapheresis and intravenous administration of highdose immunoglobulin have been implicated in the treatment of pregnancies complicated with early-onset severe red cell alloimmunization, alone or in combination with IUTs before the 20(th) week of pregnancy, but there are still issues to be clarified further. This review article aims to provide an overview of the current standard therapeutic management and alternative treatment modalities in pregnancies complicated by fetal anemia.
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http://dx.doi.org/10.1515/jpm-2012-0093DOI Listing
January 2013

Review: Impact of mediators present in amniotic fluid on preterm labour.

In Vivo 2012 Sep-Oct;26(5):799-812

Second Department of Obstetrics and Gynaecology, University of Athens Medical School, Aretaieio Hospital, 124B Vasilisis Sofias Ave., 11526, Athens, Greece.

Preterm birth continues to be one of the most important issues in current obstetric medicine, being the single largest cause of perinatal morbidity and mortality. The signals that initiate preterm and term labour remain a mystery. Intrauterine inflammation with the secretion of cytokines is one of the accepted explanations for the mechanism of initiation of preterm labour. This review discusses the current understanding of the molecular mechanisms for the initiation of preterm labour, focusing chiefly on the role of intra-amniotic fluid mediators, whether endogenous or infection-induced, in the regulation of inflammatory response pathways associated with spontaneous preterm labour. Prostaglandins (PGs) are considered to be one of the key mediators of preterm labour, with the concentration of biologically active PGs in the amniotic fluid, particularly PGE(2) and PGF(2α), being significantly higher in women with preterm labour. Cytokines, such as interleukins and tumour necrosis factor alpha, additionally play a dominant role in preterm labour, particularly in association with infection. Elevated amniotic fluid concentrations of extracellular matrix mediators, including metalloproteases, are also implicated in the process of foetal membrane rupture in preterm labour. Allelic variations in the main amniotic fluid mediators may be the key to understanding the disparity in the rates of preterm birth between different ethnic populations. We also discuss the role of other potential mediators such as cell-adhesion molecules, nitric oxide and novel biomarkers found in the amniotic fluid.
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January 2013