Cumulus cell (CC) gene expression is suggested as a non-invasive analysis method to predict oocyte competence. There are, however, important between-patient differences in CC gene expression. These can be compensated when expression results are combined with patient and cycle characteristics using a multiple regression analysis model.
METHODS
From ICSI patients stimulated with GnRH antagonist and recombinant FSH (n= 25) or GnRH agonist and highly purified menotrophin (n= 20), CC were collected and oocytes were individually fertilized and cultured. CC were analyzed for the expression of Syndecan 4 (SDC4), Prostaglandin-endoperoxide synthase 2 (PTGS2), Versican (VCAN), Activated leukocyte cell adhesion molecule, Gremlin 1, transient receptor potential cation channel, subfamily M, member 7 (TRPM7), Calmodulin 2 and Inositol 1,4,5-trisphosphate 3-kinase A (ITPKA) using quantitative PCR. Results were analyzed in relation to the stimulation protocol. Within-patient variation in gene expression was related to oocyte maturity and developmental potential. Models predictive for normal embryo or blastocyst development and pregnancy in single embryo transfer cycles were developed.
RESULTS
Mature oocytes have higher PTGS2 and lower VCAN expression in their cumulus. All genes except VCAN had a positive correlation with good embryo or blastocyst morphology and were used to develop predictive models for embryo or blastocyst development (P< 0.01). Specific models were obtained for the two stimulation protocols. In both groups, better cleavage-stage embryo prediction relied on TRPM7 and ITPKA expression and pregnancy prediction relied on SDC4 and VCAN expression. In the current data set, the use of CC expression for pregnancy prediction resulted in a sensitivity of >70% and a specificity of >90%.
CONCLUSIONS
Multivariable models based on CC gene expression can be used to predict embryo development and pregnancy.
Severe pre-eclampsia (sPE) causes significant maternal morbidity and intrauterine growth restriction as a result of severe placental dysfunction. Defects in the formation of both extra-villous and villous trophoblast are characteristic of this disease. The outer syncytiotrophoblast layer covering the placental villi develops syncytial knots and focal necrosis while reduced invasion of the extra-villous trophoblast results in a reduced maternal blood supply and ischemia of the placental villi. The transcription factor glial cell missing-1 (GCM1) regulates formation of both types of trophoblast. GCM1 expression is reduced in placental villi of women with sPE but the functional downstream consequences of reduced GCM1 expression are unknown.
METHODS AND RESULTS
In floating first trimester villous explants we demonstrated increased mRNA (2.5-fold, n = 12) and protein level (9.8-fold) of tissue inhibitor of metalloproteinase-4 (TIMP4) following repression of GCM1 (70 ± 7%) by small interfering-RNA, using RT–PCR and western blot, respectively. Similar increases in TIMP4 mRNA (4.2-fold, n = 7, P< 0.001 versus control) and protein levels were found following gene silencing of GCM1 in BeWo cells (<90% knock down of protein). TIMP4 protein was increased in placenta from women with sPE (3.5 ± 0.4 pg/µg, n = 8), compared with preterm (1.7 ± 0.17 pg/µg, n = 9) and term controls (1.6 ± 0.16 pg/µg, n = 9; P< 0.01; quantified by enzyme-linked immunosorbent assay and visualized using immunohistochemistry) with reduced GCM1 expression, mostly in the pathologic syncytial knots.
CONCLUSIONS
TIMP4 is a downstream target of GCM1 that may link the consequences of reduced GCM-1-directed trophoblast differentiation to histologic and functional components of disordered placentation in sPE.
Endometriosis is a common, multifactorial disease in which angiogenesis may be involved in the growth of endometrium outside the uterus. microRNAs (miRNAs) are 21–22 nucleotide non-coding RNAs that regulate gene expression and play fundamental roles in biological processes. The objective of this study was to analyze several miRNAs related to angiogenesis and the angiogenic factors, vascular endothelial growth factor-A (VEGF-A) and thrombospondin-1 (TSP-1), in endometriotic lesions (ovarian endometrioma, peritoneal lesion and rectovaginal nodule) and eutopic endometrium from women with endometriosis.
METHODS
TaqMan real-time PCR was used to assess the expression of the miRNAs (miR-15b, -16, -17-5p, -20a, -21, -125a, -221 and -222), while VEGF-A and TSP-1 mRNA were assessed by real-time PCR, with SYBR Green I and VEGF-A and TSP-1 protein levels were quantified by ELISA. Included in the study were 58 women with endometriosis and 38 control women.
RESULTS
In paired samples, ovarian endometrioma showed significantly lower VEGF-A mRNA (P =0.02) and protein (P=0.002) expression than eutopic endometrium and higher expression of miR-125a (P=0.003) and miR-222 (P <0.001). However, ovarian endometrioma had significantly higher expression of the angiogenic inhibitor TSP-1 and lower expression of miR-17-5p than eutopic endometrium (P<0.001). Moreover, a significant inverse correlations between miR-222 and VEGF-A protein levels (–0.267, P=0.018) and between miR-17-5p and TSP-1 protein levels (–0.260, P=0.022) were observed. Peritoneal lesions showed a significant increase in VEGF-A in comparison with ovarian endometrioma (P<0.01).
CONCLUSIONS
Expression levels of miRNAs related to angiogenesis were different in eutopic endometrium from that observed in ovarian endometrioma. This could influence the expression of angiogenic factors and play a role in the pathogenesis of endometriosis.
Our objective was to evaluate the impact of intraperitoneal pressure (IPP) and duration of a CO2 pneumoperitoneum on the peritoneal fibrinolytic system during laparoscopic surgery.
METHODS
Human study: Patients undergoing laparoscopic surgery were divided into two groups: low (8 mmHg, n= 32) or standard (12 mmHg, n= 36) IPP. Normal peritoneum was collected from the parietal wall at the beginning of surgery and every 60 min thereafter. Mouse study: Mice were divided into three groups: low (2 mmHg) or high (8 mmHg) IPP or laparotomy. Peritoneal tissue was collected at 0, 4, 8, 24, 48 and 72 h, and 5 and 7 days after surgery. Real-time RT–PCR was performed in humans and mice to measure the levels of tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) mRNA in peritoneal tissues.
RESULTS
Human study: The tPA/PAI-1 mRNA ratio was significantly decreased in the 12 mmHg group at 1 h [P< 0.0001 versus matched initial peritoneal biopsies (MI)]. The tPA/PAI-1 mRNA ratio decreased in both groups at 2 h (P< .0.01 versus MI). Mouse study: The tPA/PAI-1 ratio was decreased at 0 h, and the difference was significant at 4 h in both the laparotomy (P< 0.001 versus controls, 0 h, 5 and 7 days) and high-IPP (P< 0.0001 versus 0, 48 and 72 h, 5 and 7 days) groups. No changes in tPA/PAI-1 ratio were observed in the low-IPP group.
CONCLUSIONS
A low IPP and shorter duration of surgery appear to minimally impact the fibrinolytic system during a CO2 pneumoperitoneum.
An alginate-based matrix supports the three-dimensional (3D) architecture of non-human primate follicles and, in the presence of FSH, permits the in vitro development of pre-antral follicles to the small antral stage, including the production of ovarian steroids and paracrine factors. The current study investigated the ability of gonadotrophins, fetuin and oxygen (O2) to improve primate follicle growth and oocyte maturation in vitro.
METHODS
Macaque secondary follicles were isolated from the early follicular phase ovaries, encapsulated in a sodium alginate matrix and cultured individually for 40 days in supplemented medium. The effects of recombinant human (rh) FSH (15, 3 and 0.3 ng/ml for high, medium and low FSH, respectively), bovine fetuin (1 or 0 mg/ml) and O2 (5 or 20% v/v) were examined. Half of the follicles in each culture condition received rhLH on Day 30–40. Follicles that reached antral stage were treated with rh chorionic gonadotrophin for 34 h to initiate oocyte meiotic maturation. Media were analyzed for ovarian steroids and anti-müllerian hormone (AMH).
RESULTS
Improved culture conditions supported non-human primate, secondary follicle growth to the antral stage and, for the first time, promoted oocyte maturation to the MII stage. In the presence of fetuin at 5% O2, follicles had the highest survival rate if cultured with high or medium FSH, whereas follicles grew to larger diameters at Week 5 in low FSH. Oocyte health and maturation were promoted under 5% O2. High FSHstimulated steroid production by growing follicles, and steroidogenesis by follicles cultured with low FSH was promoted by LH. AMH biosynthesis was elevated with high compared with low FSH and for longer under 5% O2 than under 20% O2.
CONCLUSIONS
This encapsulated 3D culture model permits further studies on the endocrine and local factors that influence primate follicle growth and oocyte maturation, with relevance to enhancing fertility preservation options in women.
This multicenter, double-blinded RCT investigated the efficacy of GnRH antagonists in cycles with mild ovarian hyperstimulation (MOH) followed by IUI in subfertile women.
METHODS
Couples diagnosed with unexplained, male factor subfertility or associated with the presence of minimal or mild endometriosis were randomized with a computer-generated list of numbers by a third party in a double-blinded setting to receive either a GnRH antagonists or a placebo in 12 institutional or academic hospitals. All women were treated with recombinant FSH in a low-dose step-up regimen starting on Day 2–4 of the cycle. A GnRH antagonist was added when one or more follicles of 14 mm diameter or more were visualized. When at least one follicle reached a size of ≥18 mm, ovulation was induced by hCG injection. A single IUI was performed 38–40 h later. Couples were offered a maximum of three consecutive cycles. The primary outcome of the trial was live births. Secondary outcomes were pregnancy rates, multiple pregnancy rates, miscarriages and ovarian hyperstimulation syndrome rate.
RESULTS
A total of 233 couples were included from January 2006 to February 2009, starting 572 treatment cycles. Live birth rates were not significantly different between the group treated with GnRH antagonist (8.4%; 23/275) and the placebo group (12%; 36/297) (P = 0.30). Three twin pregnancies occurred in the GnRH antagonist group and two twin pregnancies in the placebo group.
CONCLUSIONS
Adding a GnRH antagonist in cycles with MOH in an IUI program does not increase live birth rates.
The evidence underpinning the timing of an oocyte collection in IVF or ICSI is limited. The aim of this study was to assess the effect of the follicle diameter size of the dominant follicle on ongoing pregnancy rates.
METHODS
We conducted a randomized controlled trial, including women aged between 18 and 43 years who were scheduled for GnRH agonist down-regulated IVF/ICSI treatment in four assisted conception units. Women were randomized between timing oocyte collection when the leading follicle had a diameter of 22 mm or when the leading follicle had a diameter of 18 mm. The primary end-point was ongoing pregnancy, defined as a viable pregnancy at 12 weeks of gestation.
RESULTS
The trial had major problems with recruiting patients and after the planned 2 years of recruiting only half of the aimed 400 inclusions were obtained. We allocated 97 women to the 22-mm group and 93 women to the 18-mm group. In the 22-mm group more women reached an ongoing pregnancy (37 of 97 women, 38%) compared with the 18-mm group (22 of 93 women, 24%) resulting in a relative risk of 1.6 [95% confidence interval (CI): 1.03–2.5]. In a logistic regression analysis, the timing of oocyte collection, adjusted for female age, IVF/ICSI and centre, was still associated with ongoing pregnancy, although the association was no longer statistically significant (OR: 2.0; 95% CI: 0.96–4.2)
CONCLUSIONS
This study suggests that delaying the timing of oocyte collection in IVF or ICSI results in better ongoing pregnancy rates, however, larger studies have to be performed to prove or refute these findings.
Conventional meta-analysis has estimated the sensitivity and specificity of hysterosalpingography (HSG) to be 65% and 83%. The impact of patient characteristics on the accuracy of HSG is unknown. The aim of this study was to assess by individual patient data meta-analysis whether the accuracy of HSG is associated with different patient characteristics.
METHODS
We approached authors of primary studies reporting on the accuracy of HSG using findings at laparoscopy as the reference. We assessed whether patient characteristics such as female age, duration of subfertility and a clinical history without risk factors for tubal pathology were associated with the accuracy of HSG, using a random intercept logistic regression model.
RESULTS
We acquired data of seven primary studies containing data of 4521 women. Pooled sensitivity and specificity of HSG were 53% and 87% for any tubal pathology and 46% and 95% for bilateral tubal pathology. In women without risk factors, the sensitivity of HSG was 38% for any tubal pathology, compared with 61% in women with risk factors (P = 0.005). For bilateral tubal pathology, these rates were 13% versus 47% (P = 0.01). For bilateral tubal pathology, the sensitivity of HSG decreased with age [factor 0.93 per year (P = 0.05)]. The specificity of HSG was very stable across all subgroups.
CONCLUSIONS
The accuracy of HSG in detecting tubal pathology was similar in all subgroups, except for women without risk factors in whom sensitivity was lower, possibly due to false-positive results at laparoscopy. HSG is a useful tubal patency screening test for all infertile couples.
Patient-centredness is one of the core dimensions of quality of care. It can be monitored with surveys measuring patients’ experiences with care. The objective of the present study was to determine to what extent gynaecologists, physicians specializing in infertility and nurses can estimate the level of patient-centredness of their clinic.
METHODS
A random sample of 1189 couples with fertility problems and 194 physicians and nurses from 29 Dutch fertility clinics participated in this cross-sectional study. Differences between patients’ experiences with fertility care and professionals’ perceptions of these experiences as measured with the patient-centredness questionnaire-infertility (PCQ-infertility) were calculated. The questionnaire's structure, comprising one total scale (level 1), seven subscales (level 2) and 46 single items (level 3), was used as a framework.
RESULTS
Response rates were 75% (n = 888) in the patient sample and 83% (n = 160) in the professional sample. Independent sample t-tests, corrected for multiple comparisons with the Bonferroni correction method (P < 0.05), showed no significant differences in mean scores on the total scale of patient-centredness for either professionals or patients. At level 2, professionals underestimated most subscales, namely, ‘Accessibility’, ‘Communication’, ‘Patient involvement' and ‘Competence’, whereas ‘Continuity of care’ was overestimated. Professionals significantly and clinically relevantly misjudged 29 care aspects.
CONCLUSIONS
Professionals within fertility care cannot adequately evaluate their performance regarding patient-centredness, and specifically the care aspects to which their own patients attribute the greatest improvement potential. Providing detailed feedback might start improvement of patient-centredness and quality of care.
This study examined the relationship between emotional distress as measured by the Hospital Anxiety and Depression Scale (HADS) and the Fertility Quality of Life (FertiQoL) questionnaire.
METHODS
The FertiQoL and HADS were distributed to a random sample of 785 patients attending 29 Dutch clinics for medically assisted reproduction. FertiQoL was psychometrically tested for reliability. Pearson's correlations were calculated between subscales of FertiQoL and HADS. Using an independent t-test, differences between patient subgroups were computed for both instruments. The threshold for clinically meaningful depression/anxiety on the HADS subscales was used to ascertain the critical threshold for high distress on the FertiQoL scales.
RESULTS
FertiQoL and HADS were completed by 583 patients (response 74%). Reliability of FertiQoL scales was high (reliability coefficient between 0.72 and 0.91). Significant negative correlations were found between FertiQoL subscales and HADS scores for anxiety and depression, ranging from –0.29 to –0.71. Means on FertiQoL scales and HADS scales of couples undergoing an assisted reproductive technology (ART) treatment and a non-ART treatment did not differ significantly. Patients scoring above the HADS threshold for pathology on anxiety had an average FertiQoL score of 58.8, whereas patients exceeding the HADS depression threshold had a FertiQoL total score of 51.9 (range 0–100).
CONCLUSIONS
Our study confirms the expected negative relation between quality of life as measured by FertiQoL and anxiety and depression. The data support that FertiQoL reliably measures QoL in women facing infertility. FertiQoL enables clinicians to tailor care more specifically to the patient in a comprehensive way.
Many clinicians and patients believe that endometriosis-associated pain is due to the lesions. Yet causality remains an enigma, because pain symptoms attributed to endometriosis occur in women without endometriosis and because pain symptoms and severity correlate poorly with lesion characteristics. Most research and reviews focus on the lesions, not the pain. This review starts with the recognition that the experience of pain is determined by the central nervous system (CNS) and focuses on the pain symptoms.
METHODS
Comprehensive searches of Pubmed, Medline and Embase were conducted for current basic and clinical research on chronic pelvic pain and endometriosis. The information was mutually interpreted by a basic scientist and a clinical researcher, both in the field of endometriosis. The goal was to develop new ways to conceptualize how endometriosis contributes to pain symptoms in the context of current treatments and the reproductive tract.
RESULTS
Endometriotic lesions can develop their own nerve supply, thereby creating a direct and two-way interaction between lesions and the CNS. This engagement provides a mechanism by which the dynamic and hormonally responsive nervous system is brought directly into play to produce a variety of individual differences in pain that can, in some women, become independent of the disease itself.
CONCLUSIONS
Major advances in improving understanding and alleviating pain in endometriosis will likely occur if the focus changes from lesions to pain. In turn, how endometriosis affects the CNS would be best examined in the context of mechanisms underlying other chronic pain conditions.
Treatment of colorectal endometriosis is difficult and challenging. We reviewed the clinical outcome of surgical treatment of deeply infiltrating endometriosis (DIE) with colorectal involvement.
METHODS
Review was based upon a literature search using following search terms: (1) ‘surgery’ and ‘colorectal endometriosis’, (2) ‘bowel’ and ‘endometriosis’ and ‘surgery’. Inclusion criteria: clear explanation of surgical technique and follow-up data on at least one of the following items: complications, pain, quality of life (QOL), fertility and recurrence.
RESULTS
Most of the 49 studies included complications (94%) and pain (67%); few studies reported recurrence (41%), fertility (37%) and QOL (10%); only 29% reported (loss of) follow-up. Out of 3894 patients, 71% received bowel resection anastomosis, 10% received full-thickness disc excision and 17% were treated with superficial surgery. Comparison of clinical outcome between different surgical techniques was not possible. Post-operative complications were present in 0–3% of the patients. Although pain improvement was reported in most studies, pain evaluation was patient-based in <50% (Visual Analogue Scale in only 18%). While QOL was improved in most studies, prospective data were only available for 149 patients. Pregnancy rates were 23–57% with a cumulative pregnancy rate of 58–70% within 4 years. The overall endometriosis recurrence rate in studies (>2 years follow-up) was 5–25% with most of the studies reporting 10%. Owing to highly variable study design and data collection, a CONSORT-inspired checklist was developed for future studies.
CONCLUSIONS
Prospective studies reporting standardized and well-defined clinical outcome after surgical treatment of DIE with colorectal involvement with long-term follow-up are needed.
The Chlamydia IgG antibody test (CAT) shows considerable variations in reported estimates of test accuracy, partly because of the use of different assays and cut-off values. The aim of this study was to reassess the accuracy of CAT in diagnosing tubal pathology by individual patient data (IPD) meta-analysis for three different CAT assays.
METHODS
We approached authors of primary studies that used micro-immunofluorescence tests (MIF), immunofluorescence tests (IF) or enzyme-linked immunosorbent assay tests (ELISA). Using the obtained IPD, we performed pooled receiver operator characteristics analysis and logistic regression analysis with a random effects model to compare the three assays. Tubal pathology was defined as either any tubal obstruction or bilateral tubal obstruction.
RESULTS
We acquired data of 14 primary studies containing data of 6191 women, of which data of 3453 women were available for analysis. The areas under the curve for ELISA, IF and MIF were 0.64, 0.65 and 0.75, respectively (P-value < 0.001) for any tubal pathology and 0.66, 0.66 and 0.77, respectively (P-value = 0.01) for bilateral tubal pathology.
CONCLUSIONS
In Chlamydia antibody testing, MIF is superior in the assessment of tubal pathology. In the initial screen for tubal pathology MIF should therefore be the test of first choice.
Cell-free fetal DNA (cff DNA) and RNA can be detected in maternal plasma and used for non-invasive prenatal diagnostics. Recent technical advances have led to a drastic change in the clinical applicability and potential uses of free fetal DNA and RNA. This review summarizes the latest clinical developments in non-invasive prenatal diagnosis in the context of the latest technical developments.
METHODS
We searched PubMed with the search terms ‘prenatal’, ‘non-invasive’, ‘fetal DNA’, ‘mRNA’ and cross-referenced them with ‘diagnostics’, ‘microRNA’, ‘aneuploidy’, ‘trisomy’ and ‘placenta’. We also searched the reference list of the articles identified by this search strategy.
RESULTS
Genome-wide methods have been, or can be, successfully applied on total DNA (DNA-seq), methylated DNA immunoprecipitation (with tiling array), microRNA (Megaplex) and total RNA (RNA-seq). Chromosome- or gene-specific assays have been successively applied on placenta RNA (allele ratio) or DNA multiplex ligation-dependent probe amplification (MLPA). These methods are reviewed for their merits and pitfalls with consideration of the placental biology. For the purpose of clarity, the technical and clinical characteristics are limited to non-invasive prenatal detection of chromosomal aneuploidies, with emphasis on trisomy 21.
CONCLUSIONS
The technical advances for non-invasive aneuploidy tests based on cff DNA and placental mRNA in maternal plasma have been enormous. Multimarker assays including genome-wide approaches with the option of qualitative information on variation (polymorphism or mutation) besides quantitative information are the preferred methods of choice. The time for population-based, double blind, large-scale clinical cohort trials has come.
Research into cell-free fetal (cff) nucleic acids has primarily focused on maternal plasma; however, cff DNA and RNA are also detectable in other body fluids such as amniotic fluid (AF). In AF, cff DNA is present in much greater concentrations than in maternal plasma and represents a pure fetal sample uncontaminated by maternal- and trophoblast-derived nucleic acids. The aim of this review was to summarize the current knowledge on cff nucleic acids in AF and to outline future research directions.
METHODS
MEDLINE and PREMEDLINE were searched up to August 2010 for original investigations of cell-free RNA or DNA in AF. Sixteen studies were included in the review.
RESULTS
AF cff DNA represents a physiologically separate pool from cff DNA in maternal plasma. The placenta is not a major source of nucleic acids in AF. It is feasible to isolate cff nucleic acids from small volumes of discarded AF supernatant in sufficient quality and quantity to perform microarray studies and downstream applications such as pathway analysis. This ‘discovery-driven approach’ has resulted in new information on the pathogenesis of Down syndrome and polyhydramnios. There is otherwise a paucity of information relating to the basic biology and clinical applications of cff nucleic acids in AF.
CONCLUSIONS
AF supernatant is a valuable and widely available but under-utilized biological resource. Further studies of cff nucleic acids in AF may lead to new insights into human fetal development and ultimately new approaches to antenatal treatment of human disease.
Marijuana, the most used recreational drug, has been shown to have adverse effects on human reproduction. Endogenous cannabinoids (also called endocannabinoids) bind to the same receptors as those of 9-tetrahydrocannabinol (THC), the psychoactive component of Cannabis sativa. The most extensively studied endocannabinoids are anandamide (N-arachidonoylethanolamine, AEA) and 2-arachidonoylglycerol. The endocannabinoids, their congeners and the cannabinoid receptors, together with the metabolic enzymes and putative transporters form the endocannabinoid system (ECS). In this review, we summarize current knowledge about the relationships of ECS, sex steroid hormones and cytokines in female fertility, and underline the importance of this endocannabinoid–hormone–cytokine network.
METHODS
Pubmed and the Web of Science databases were searched for studies published since 1985, looking into the ECS, sex hormones, type-1/2 T-helper (Th1/Th2) cytokines, leukaemia inhibitory factor, leptin and reproduction.
RESULTS
The ECS plays a pivotal role in human reproduction. The enzymes involved in the synthesis and degradation of endocannabinoids normalize levels of AEA for successful implantation. The AEA degrading enzyme (fatty acid amide hydrolase) activity as well as AEA content in blood may potentially be used for the monitoring of early pregnancies. Progesterone and oestrogen are involved in the maintenance of endocannabinoid levels. The ECS plays an important role in the immune regulation of human fertility.
CONCLUSIONS
The available studies suggest that tight control of the endocannabinoid–hormone–cytokine network is required for successful implantation and early pregnancy maintenance. This hormone–cytokine network is a key element at the maternal–foetal interface, and any defect in such a network may result in foetal loss.
There is significant evidence that continuous and prolonged exposure to several endocrine disrupting chemicals (EDC) is a risk factor for reduced fertility and fecundity in women. There is also evidence that ED exposure has trans-generational effects. In this systematic review, we evaluate the evidence for an association between EDC exposure and women's reproductive health.
METHODS
Studies were found by searching the PubMed database for articles published up to 2010. Associations between ED exposure and women's reproductive health reported in the PubMed database are summarized and classified as fertility and fecundity, pregnancy outcomes, transgenerational exposure and effects.
RESULTS
Epidemiological studies on EDCs are not always consistent, in part due to limitations imposed by practical constraints. In order to make progress in this field, we recommend taking advantage of biomonitoring and biobanks, including the development of appropriate biomarkers, and taking into greater consideration modulating factors such as genetic polymorphisms and dietary habits. Further human studies are warranted with particular focus on impaired fertility/fecundity associated with currently widespread ED (e.g. bisphenol A, phthalates and polybrominated flame retardants).
CONCLUSIONS
A detailed appraisal of compounds specifically related to adverse reproductive outcomes is very important for prevention and risk-communication strategies. Besides research needs, the current evidence is sufficient to prompt precautionary actions to protect women's reproductive health.
The placenta is of utmost importance for intrauterine fetal development and growth. Deregulation of placentation can lead to adverse outcomes for both mother and fetus, e.g. gestational trophoblastic disease (GTD), pre-eclampsia and fetal growth retardation. A significant factor in placental development and function is epigenetic regulation.
METHODS
This review summarizes the current knowledge in the field of epigenetics in relation to placental development and function. Relevant studies were identified by searching PubMed, Medline and reference sections of all relevant studies and reviews.
RESULTS
Epigenetic regulation of the placenta evolves during preimplantation development and further gestation. Epigenetic marks, like DNA methylation, histone modifications and non-coding RNAs, affect gene expression patterns. These expression patterns, including the important parent-of-origin-dependent gene expression resulting from genomic imprinting, play a pivotal role in proper fetal and placental development. Disturbed placental epigenetics has been demonstrated in cases of intrauterine growth retardation and small for gestational age, and also appears to be involved in the pathogenesis of pre-eclampsia and GTD. Several environmental effects have been investigated so far, e.g. ethanol, oxygen tension as well as the effect of several aspects of assisted reproduction technologies on placental epigenetics.
CONCLUSIONS
Studies in both animals and humans have made it increasingly clear that proper epigenetic regulation of both imprinted and non-imprinted genes is important in placental development. Its disturbance, which can be caused by various environmental factors, can lead to abnormal placental development and function with possible consequences for maternal morbidity, fetal development and disease susceptibility in later life.
Mast cells (MCs) are the classical mediators of allergy, however, their importance in the development of innate and adaptive immune responses is increasingly being recognized. Herein, the present MC literature is summarized, with particular focus on studies of MCs in the endometrium and myometrium, and their involvement in fertility, implantation, pregnancy and labour.
METHODS
Recent developments in MC biology were identified by systematic searches of PubMed, Medline and Google Scholar from 2000 to November 2009. To specifically examine the role of MCs in fertility and pregnancy, we then performed a systematic review of English literature cited in the PubMed, Medline and Google Scholar databases, but extended the search period, from 1980 to January 2010
RESULTS
MCs can respond to immunoglobulin E-independent innate immune stimuli and are present within the endometrium, with activation and release of mediators occurring prior to menstruation and in association with endometriosis. With respect to pregnancy, MCs are redundant during blastocyst implantation and although their mediators can induce myometrial contractility, there is no epidemiological link of preterm birth with allergy, suggesting a non-essential role or robust regulation. In males, MCs are present in the testes and are increased in oligo- and azoospermia, with MC mediators directly suppressing sperm motility in a potentially reversible manner.
CONCLUSIONS
MCs are prevalent in the female and male reproductive tract. However, whether MCs are absolutely required for a successful pregnancy or are fundamental to reproductive pathology, and thereby a therapeutic target, remains to be determined.
Vascular endothelial growth factor (VEGF) and its kinase insert domain receptor (KDR) play an important role in angiogenesis, and their gene expression patterns also suggest a close relationship with early pregnancy. However, limited information is available regarding the role of the VEGF system, especially its KDR receptor, in recurrent pregnancy loss (RPL). This study was conducted to investigate a genetic association between VEGF and its receptor gene (KDR) with idiopathic RPL.
METHODS
In this case–control study, 115 women who had experienced at least two consecutive spontaneous miscarriages (n= 62 women with two miscarriages, n= 53 with three or more) and 170 controls were included. A total of 14 tag single-nucleotide polymorphisms (SNPs) of VEGF and KDR were selected from the HapMap Web site and three functional SNPs [rs1570360 (–1154G/A) of VEGF; rs2305948 (V297I) and rs1870377 (Q472H) of the KDR gene] were genotyped using primer extension analysis. We further used multifactor dimensionality reduction analysis to evaluate gene–gene interactions.
RESULTS
One tag SNP (rs6838752) and the functional SNP (Q472H) of the KDR gene were in complete linkage and showed significant differences between patients and controls (P< 0.05). The frequencies of haplotypes of VEGF (A-T-G haplotype) and KDR (A-C-A-T-G haplotype) showed significant differences in patients versus controls (P< 0.05). All comparisons with controls remained significant when the subgroup of women with three or more miscarriages was analyzed.
CONCLUSIONS
VEGF and its receptor gene (KDR) are associated with idiopathic RPL. The VEGF/KDR system jointly contributes to recurrent miscarriage in Taiwanese Han women.
