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Patients with the Mayer–Rokitansky–Küster–Hauser syndrome (MRKH) have a congenital utero–vaginal cervical aplasia, but normal or hypoplastic adnexa and develop with normal female phenotype. Some reports mostly demonstrated regular steroid hormone levels in small MRKH cohorts including single MRKH patients with hyperandrogenemia and a clinical presentationof hirsutism and acne has also been shown. Genetically a correlation ofWNT4mutations with singular MRKH patients and hyperandrogenemia was noted. This study analyzed the hormone status of 215 MRKH patients by determining the levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, 17-OH progesterone, testosterone, dehydroepiandrosterone sulfate (DHEAS), sex hormone–binding globulin (SHBG) and prolactin to determine the incidence of hyperandrogenemia and hyperprolactinemia in MRKH patients. Additional calculations and a ratio of free androgen index and biologically active testosterone revealed a hyperandrogenemia rate of 48.3%, hyperprolactinemia of 9.8% and combined hyperandrogenemia and hyperprolactinemia of 4.2% in MRKH patients. The rates of hirsutism, acne and especially polycystic ovary syndrome (PCOS) were in the normal range of the population and showed no correlation with hyperandrogenemia. A weekly hormone assessment over 30 days comparing 5 controls and 7 MRKH patients revealed high androgen and prolactin, but lower LH/FSH and SHBG levels with MRKH patients. The sequencing ofWNT4,WNT5A,WNT7AandWNT9Bdemonstrated no significant mutations correlating with hyperandrogenemia. Taken together, this study shows that over 52% of MRKH patients have hyperandrogenemia without clinical presentation and 14% hyperprolactinemia, which appeals for general hormone assessment and adjustments of MRKH patients.

Zielsetzung: Die bakterielle CRISPR-associated protein 9 Nuklease (Cas9) aus Streptococcus pyogenes ist eine Caspase, welche zielgerichtet genomische DNA-Strange schneiden kann. Sie wird eingesetzt, um DNA-Abschnitte zu modifizieren. Die Nuklease wird durch die Expression einer guidedRNA (gRNA) zur Ziel-DNA Sequenz gefuhrt und induziert dort Einzel- oder Doppelstrangbruche. Ziel dieses Projektes war ein Knockout des humanen endogenen Retrovirus Erv3 mittels CRISPR-Cas9 induzierter Deletion in der Chorionkarzinomzelllinie Jeg-3. Materialien und Methoden: Fur die Klonierung der CRISPR-Cas9 Vektoren wurde die entsprechende gRNA unter Verwendung des CRISPR Design Tools entworfen. Die gRNA wurde in den pSpCas9(BB)-2A-GFP Vektor kloniert. Nach der Transfektion des Konstrukts in die Chorionkarzinomzelllinie Jeg-3 wurden anschliesend Einzelzellklone uber Fluoreszenz-activated-Cellsorting isoliert. Induzierte Mutationen im Erv3 Gen wurden mittels Sequenzierung detektiert. Western Blot Analysen wurden zum Protein-Nachweis genutzt. Ergebnisse: Mittels CRISPR-Cas9 induzierter Mutation konnten in insgesamt sieben Jeg-3 Klonen unterschiedliche Mutationen im Erv3 Genom erzeugt werden. Wir konnten Deletionen von 1 – 186 Nukleotiden, sowie eine heterozygote Punktmutation induzieren. In zwei Klonen wurde durch die Deletion ein Frameshift erzeugt, welcher zum Verlust des Erv3 Proteins fuhrte. Zusammenfassung: CRISPR-Cas9 ist eine Methode, welche eine zielgerichtete Mutation der DNA ermoglicht. Wir konnten in diesem Projekt mittels induzierter Deletion erfolgreich die Expression des humanen endogenen Retrovirus Erv3 ausschalten.

The placenta is a major barrier that prevents potentially infectious agents from causing fetal diseases or related complications during pregnancy. Therefore, we postulated that the placenta might express a broad repertoire of antimicrobial proteins as well as inflammatory chemokines and cytokines to combat invading microorganisms. Here we demonstrate that placental cells indeed express a wide range of AMPs (antimicrobial peptides and proteins) including bactericidal/permeability-increasing protein (BPI), secretory leukocyte protease inhibitor (SLPI), human β-defensin 2 (hBD2), acyloxyacyl hydrolase (AOAH), and cathelicidin (CAP18). In addition, these cells also secrete pro-inflammatory cytokines and chemokines upon stimulation with bacterial ligands. Notably, we show that BPI expression by placental cells could be completely attributed to granulocytes while highly purified placental trophoblasts expressed only a subset of the AMPs like SLPI. Unexpectedly, trophoblast AMPs did not exhibit inducible secretion in response to various TLR ligands and further investigations showed that the unresponsiveness of trophoblasts to lipopolysaccharide (LPS) was due to a lack of TLR4 expression. In summary, we have shown that the expression of different AMPs can be allocated to various cells in the placenta and the repertoire of the AMPs expressed by placental cells is a result of a cooperation of leukocytes as well as cells from embryonic origin.

Dysmenorrhoea is the major symptom in women with endometriosis. Recently, pain modulation through Neurokinin-1-receptor (NK1R) pathways have been investigated in neuropathic pain patients. Aim of this study was, therefore, to examine the effect of a single nucleotide polymorphism (SNP) of the NK1R gene on the susceptibility for endometriosis and the disease free survival (DFS) after surgery for endometriosis.A case-control study was conducted and germline DNA was isolated. Patients were followed up for a recurrence of the disease up to 4 years. Case-control analyses were performed for parameters of the medical history and the genotype of the NK1R-SNP rs881. Furthermore, DFS probabilities were calculated.Concerning the DFS preoperative pain levels and the NK1R genotype were independent predictors for a recurrence with hazard ratios of 2.55 (95% CI: 1.32-4.95) for patients with a high preoperative pain level and 0.44 for patients with a heterozygous or homozygous variant genotype in rs881 (95% CI: 0.21-0.88).The polymorphism rs811 seems to be associated with a lower recurrence risk in endometriosis patients. Thus, there might be a clinical relevant role of the NK1 pathway in the pain perception of endometriosis patients.

None of the existing theories provides a satisfactory explanation of the development of endometriosis. One hypothesis that may lead to further clarification is that the expression of specific proteins of human endogenous retroviruses (HERVs) might influence the development of endometriosis lesions. Such endogenous retroviral proteins include syncytin, coded by HERV-W, which is associated with the physiological development of the placenta during pregnancy. This study investigated the influence of HERV-W gene expression in endometriosis foci (EM) quantitatively at the RNA level.Specific RNA expression of syncytin (HERV-W) was investigated in various endometrial tissues from 42 patients (with normal endometrium, postmenopausal endometrium, EM, and endometrial carcinoma). RNA was isolated from the tissue samples and transcribed into DNA using reverse transcriptase polymerase chain reaction. The resulting DNA fragments were analyzed using agarose gel electrophoresis and assessed quantitatively.Normalized syncytin expression was low in EM. In Histologically normal endometrium from endometriosis patients, the expression of normalized syncytin was seven times higher in comparison with the histologically normal endometrium in the control group.HERV-W syncytin expression apparently does not play a role in EM. However, it may possibly influence the development of endometriosis because of increased expression in normal endometrium in endometriosis patients.

BACKGROUND: Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome is a malformation of the female genital tract (vaginal aplasia, rudimentary uterus, normal fallopian tubes and high ovaries). The incidence is one in 4000 female newborns. The aim of the present study was to record genital and associated malformations among siblings and relatives of MRKH patients in order to draw possible conclusions regarding the etiology of the syndrome: her- edity (dominant versus recessive) or spontaneous malformation. METHODS: Using a standardized questionnaire, affected MRKH patients were asked about other cases of MRKH and/or associated malformations among siblings and relatives. RESULTS: No other cases of MRKH syndrome had occurred among the siblings or relatives of 73 MRKH patients; however, 13 associated malformations were recorded among a total of 103 siblings. Musculoskeletal malformations were markedly increased (3.27 times higher) in comparison with the prevalence of congenital malfor- mations among newborns in the normal population. CONCLUSIONS. This study shows that dominant inheritance cannot play a role in the etiology of MRKH syndrome, as no further cases of MRKH syndrome occurred among any of the siblings. The study provides support for the view that the syndrome has a multifactorial pathogenesis. Sib- lings/relatives of MRKH patients should be examined for associated musculoskeletal/urogenital malformations.

Objective With an incidence of up to 5% in the general population, genital malformations are a frequent clinical occurrence. The aim of this study was to assess whether a connection could be demonstrated between various degrees of severity of genital malformations and associated abnormalities. Design All patients were classified using the Vagina, Cervix, Uterus, Adnex, and Associated Malformation (VCUAM) classification. Setting University hospital. Patient(s) Two hundred eleven premenopausal patients with female genital malformations. Intervention(s) The patients underwent diagnostic workup for genital malformations using laparoscopy as well as hysteroscopy. Associated malformations were detected by either magnetic resonance imaging (MRI) or ultrasound. Main Outcome Measure(s) Demonstration of a connection between various degrees of severity of genital malformations and associated abnormalities. Result(s) In 72 cases (36%) out of 202 patients with uterine malformations (VCUAM U1–4) we found associated abnormalities. The predominant findings were alterations in the renal system. When vaginal abnormality (VCUAM V1–5) alone was taken into consideration, an associated developmental disturbance in the renal tract was found in 30% of cases (n = 32 from 107). Conclusion(s) A close connection was demonstrated between genital malformations and associated abnormalities. For this reason, the diagnostic workup in patients with malformations should always include the renal system. Depending on the severity of the clinical picture, examinations may need to be extended further.

Endometriosis is a chronic inflammatory disease, which is especially found in women with subfertility problems with an incidence of up to 30%. The disease is considered an estrogen-dependent disorder, where DNA polymorphisms of the estrogen receptor α (ERα) in connection with endometriosis are controversially discussed. From a German population of women, clinical data associated with the disease, including the American Fertility Society (AFS) I–IV classification, and non-clinical parameters were evaluated statistically in endometriosis patients (n= 98) and in control women (n= 98) without endometriosis. Using a multivariate statistical analysis, significant associations of endometriosis with dysmenorrhea (P< 0.001) and allergies against medicaments (P= 0.042) were found. A positive trend between first grade family history of endometriosis and allergies against medicaments was also observed, suggesting a genetic relationship. From both collectives, DNA from peripheral blood was analyzed for the frequency of the ERα DNA polymorphisms Xba1 (A/G) and PvuII (T/C) in intron 1 and the ERα exonic DNA polymorphism (G229A) with an amino acid exchange (Gly77Ser) in the transactivation domain. DNA samples from endometriosis lesions and control tissues from the same collectives were also analyzed for the exonic G229A polymorphism. Only homozygote wild-type alleles for the polymorphism G229A were found, making it a rare polymorphism in mid-European individuals. Allele types for the PvuII and Xba1 polymorphisms were analyzed with the observed statistically significant clinical parameters and showed no significant association with endometriosis; however a trend with AFS IV was noted, which could contribute to lesion severity. In conclusion, the analyzed polymorphisms in the ERα do not have a functional role concerning specific clinical parameters associated with endometriosis.

Objective With an incidence of up to 5% in the general population, genital malformations are a frequent clinical occurrence. However, using the existing published classifications of malformations, difficulties arise in classifying genital malformations appropriately. The aim of the present study was to produce a simple, systematic, and reproducible classification system. Design A systematic arrangement of genital and associated malformaltions, using a structure similar to that in the TNM classification of oncological tumors, was developed and validated. Setting Patients with genital malformations in a university hospital. Patient(s) Ninty-nine premenopausal patients with genital malformations. Intervention(s) Patients were diagnosed for genital malformation using laparoscopy or magnetic resonance imaging. Main Outcome Measure(s) A new classification (VCUAM) is presented to evaluate patients with different genital malformations. Result(s) The external and internal female genital organs were divided into the following subgroups in accordance with the anatomy: vagina (V), cervix (C), uterus (U), and adnexa (A). Associated malformations were assigned to a subgroup (M) relative to each specific organ. The classification was validated in a group of 99 patients with genital malformations. Conclusion(s) The VCUAM classification for the first time makes it possible to reflect even complex malformations in a precise and individual fashion, taking associated malformations into account. The classification makes it easier to provide appropriate clinical care for the affected patients.

Ein klinischer Aspekt der Praeklampsie/Eklampsie ist die periphere Vasokonstriktion, deren Ursache in einer Storung der Endothelfunktion liegt. Die Praeklampsie ist eine komplexe, multifaktorielle, nahezu alle Organsysteme betreffende Erkrankung, die nur in der Schwangerschaft auftritt. Bei manifester Praeklampsie stellt die Substitution von Magnesium und Kalzium eine therapeutische Option besonders zur Pravention der Eklampsie dar. Das Ziel dieser Studie war eine qualitative und quantitative Analyse von Magnesium und Kalzium in humanen Zellen wahrend des Zellzyklus sowie die Folgen einer Depletion dieser Kationen fur die Zelle. Humane Lymphozyten und Fibroblasten in verschiedenen Zellzyklusstadien wurden auf reinen Silicium-Chips kultiviert und im Sandwichverfahren aufgebrochen. Ein „Scanning“-Ionenmikroskop mit sekundarem Ionenmassenspektrometer analysierte dann gebundene und ungebundene Kationen, wie Magnesium und Kalzium, in den Zellen. Diese Studie zeigte eine spezifische zellzyklusabhangige Verteilung der beiden bivalenten Kationen Magnesium und Kalzium in humanen Zellen. Beide Kationen wurden hauptsachlich im Zytoplasma wahrend der Interphase und chromosomenassoziiert wahrend der Mitose vorgefunden. Eine Depletion dieser Kationen resultierte in einen Zellzyklusstopp, in dekondensierten und destabilisierten Chromosomen und Zelltod. Magnesium und Kalzium sind fur die Zell- und Chromosomenfunktion und -struktur essenziell. Ein Mangel dieser Kationen kann zu zellzyklusarretierten, hydrophischen und/oder apoptotischen Zellen mit konsekutiver Storung der Endothelzellfunktion, wie sie bei der schweren Praeklampsie gefunden wird, fuhren. Die ausreichende Kationensubstitution, vor allem von Magnesium, restauriert die Zellfunktion und -struktur und konnte so die positive therapeutische Wirkung bei der schweren Praeklampsie/Eklampsie erklaren. Preeclampsia is a complex and multifactorial disease during pregnancy, which can target almost all organ systems. One clinical finding of preeclampsia/eclampsia is peripheral vasoconstriction, where dysfunctional endothelial cells have been implicated. One treatment for severe preeclampsia/eclampsia is the intravenous substitution of magnesium and calcium. The purpose of this study was to perform a qualitative and quantitative analysis of magnesium and calcium in normal human cells during the cell cycle as well as determining the impact of cation depletion in the cell. Human lymphocytes and fibroblasts from different cell cycle stages were cultivated on pure silicon chips and cryofractured. Bound and unbound magnesium and calcium in cells were analysed using a scanning ion microprobe with secondary ion mass spectrometry at 50 nm resolution. Our study showed that the two main cellular divalent cations, magnesium and calcium, show a specific cell cycle distribution, which is mainly cytosolic during interphase but which becomes chromosomal bound during mitosis. A depletion of magnesium or calcium resulted in cell cycle arrest, decondensed and destabilized chromosomes leading to cell death. Magnesium and calcium are pivotal for normal cell growth and chromosome structure and function. Disturbed or failed endothelial cell function during preeclampsia, resulting in e.g. vasoconstriction due to arrested or dying cells can be associated with a depletion of cations. Cation substitution of magnesium in particular restores the endothelial cell function and structure and could explain the positive preventive effect and therapy during preeclampsia.

Sequenzierungen des humanen und murinen Genoms haben ergeben, dass 50 Protein-kodierende Sequenzen von retroviralen gag-Genen abstammen. Die Familie der Mammalian retrotransposon-derived (MART)-Gene umfasst 9 dieser Gene, welche intakte ORFs besitzen und somit neue Funktionen als sogenannte Neogene erlangt haben. Die Literatur zeigt, dass einige dieser Gene eine Rolle in der humanen Karzinogenese spielen. Knockout Modelle fur murine Mart-Gene zeigten eine essentielle Rolle wahrend der Plazentogenese. Fragestellung: Es sollte geklart werden, ob die humanen MART eine funktionelle Rolle in der humanen Plazentogenese haben. Des Weiteren sollte ein Vergleich zwischen Kontroll- und pathologischen Plazenten gezogen werden. Methodik: Zur quantitativen Analyse der Expression der MART-Gene wurde die Methode der SYBR-green basierenden real time PCR fur Kontroll- (n = 24) und pathologische Plazenten (PE: n = 12; IUGR: n = 13; HELLP: n = 8) des dritten Trimesters durchgefuhrt. Um die Lokalisation der Gene zu untersuchen, wurden In-situ Hybridisierungen und immunhistochemische Farbungen mit MART-spezifischen Antikorpern verwendet. Western Blot-Analysen gaben Aufschluss auf die Grose der Proteine in den Plazenten. Ergebnis: Die Ergebnisse zeigen, dass MART1, MART2, MART7 und MART8 am hochsten in der humanen Kontroll-Plazenta exprimiert werden. Im Vergleich zu Kontrollen wurde vor allem MART1 in den PE, IUGR und HELLP Plazenten signifikant herunterreguliert. Die Lokalisation der MART Gene zeigte sich hauptsachlich in den verschiedenen Trophoblasten-Subtypen, aber auch in den Endothelzellen der Blutgefase. Schlussfolgerung: Die Gene der MART-Familie werden in Kontroll- und pathologischen Plazenten unterschiedlich exprimiert. Dies und der Nachweis der Proteine lassen eine funktionelle Rolle wahrend der Plazentogenese vermuten.

Die RNA der einzelnen Kompartimente (SCT, innnerer Villi und GC) konnte in guter Quantitat und Qualitat isoliert und analysiert werden. Die unterschiedliche Expression, der mit IHC gezeigten Markerproteine, konnte mit den Chip Daten bestatigt werden. Auserdem gab es viele andere hochsignifikante Unterschiede in der Genexpression zwischen den drei Zellkompartimenten. In der Abbildung unten sind die Anzahl der unterschiedlich exprimierten Gene im Vergleich zueinander dargestellt (mind. 2-fach hohere Expr.). 2. Laser micro-dissection Mikroskopie und Microarray Plazentares Gewebe von drei Patientinnen wurde direkt nach Sectio caesarea in Stickstoff gefroren und anschliesend in 12μm dicke Schnitte auf Rnase-free membrane-covered slides (Zeiss) gezogen. Diese wurden in 70% Ethanol fixiert und die Kerne mit 0,1% Cresyl Violet gefarbt. Mit einem PALM laser micro-dissection and catapulting system (Zeiss) wurden die einzelnen Kopartimente ausgeschnitten und in einem collection tube (Zeiss) mit Lysepuffer (Agilent) gesammelt. Die Abbildung zeigt Beispiele der mit der PALM Robo software (Zeiss) markierten Regionen vor und nach dem Ausschneiden und Katapultieren.

We identified differentially expressed genes comparing peritoneal endometriosis lesions (n = 18), eutopic endometrium (n = 17), and peritoneum (n = 22) from the same patients with complete menstrual cycles using microarrays (54 675 probe sets) and immunohistochemistry. Peritoneal lesions and peritoneum demonstrated 3901 and 4973 significantly differentially expressed genes compared to eutopic endometrium, respectively. Peritoneal lesions significantly revealed no correlation with a specific menstrual cycle phase by gene expression and histopathology, exhibited low expressed proliferation genes, and constant levels of steroid hormone receptor genes. Tissue remodeling genes in cytoskeleton, smooth muscle contraction, cellular adhesion, tight junctions, and O-glycan biosynthesis were the most significant to lesions, including desmin and smooth muscle myosin heavy chain 11. Protein expression and location of desmin, alpha-actin, and h-caldesmon in peritoneal lesions discriminated between smooth muscle hyperplasia and metaplasia. Peritoneal lesions demonstrate no menstrual cycle phasing but constant steroid hormone receptor expression where a slow but steady growth is linked with tissue remodeling. Our study contributes to the molecular pathology of peritoneal endometriosis and will help to identify clinical targets for treatment and management.

Terminal differentiation of villous cytotrophoblasts (CT) ends in formation of the multinucleated syncytiotrophoblast representing the fetal-maternal interface. Aberrations during this cell-fusion process are associated with Intrauterine Growth Restriction (IUGR), Preeclampsia (PE) and High Elevated Liver and Low Platelets (HELLP) Syndrome. Syncytin-1, the envelope gene of the human Endogenous Retrovirus ERVW-1, is one of the most important genes involved in cell-fusion and showed decreased gene expression during these pathological pregnancies. The aim of this study was to determine the methylation pattern of the entire promoter of ERVW-1 and to correlate these findings with the expression profile of Syncytin-1 in the placental syndromes. 14 isolated villous cytotrophoblasts from control (n = 3), IUGR (n = 3), PE (n = 3), PE/IUGR (n = 3) and HELLP/IUGR (n = 2) placentae were used to determine the mean methylation level (ML) for the ERVW-1 promoter region. ML rose significantly from 29% in control CTs to 49% in IUGR, 53% in PE, 47% in PE/IUGR and 64% in HELLP/IUGR indicating an epigenetic down-regulation of Syncytin-1 by promoter hypermethylation. DNA demethylation of the trophoblast like cell lines BeWo, JEG-3 and JAR with 5-AZA-2'desoxycytidine (AZA) showed an increased Syncytin-1 expression and fusion ability in all cell lines. Promoter activity of the 5'LTR could be inhibited by hypermethylation 42-fold using a luciferase based reporter-gene assay. Finally overexpression of the methyltransferases DNMT3a and LSH could be responsible for a decreased Syncytin-1 expression by promoter hypermethylation of ERVW-1. Our study linked decreased Syncytin-1 expression to an epigenetic hypermethylation of the entire promoter of ERVW-1. Based on our findings we are predicting a broad aberrant epigenetic DNA-methylation pattern in pathological placentae affecting placentogenesis, but also the development of the fetus and the mother during pregnancy.

The F-box protein Fbxw8 is a cofactor of Cullin 7 (Cul7), which regulates protein transfer to the proteasome and cell growth. Cul7 or Fbxw8 deficiency is associated with intrauterine growth restriction (IUGR) due to abnormal placental development leading to poor oxygen supply to the fetus. We studied the role of hypoxia for Fbxw8 and Cul7 expression in trophoblastic cells.Immunomagnetic bead-separated extravillous trophoblast (EVT) and villous trophoblast (VT) and trophoblast cell lines were incubated with 1 or 8% O(2). Fbxw8 and Cul7 expression was determined in IUGR versus matched control placentas.Fbxw8 was expressed uniformly in trophoblasts, whereas Cul7 expression was most prominent in trophoblast cell lines. Hypoxia reduced expression of Cul7 and Fbxw8 in all trophoblastic cells, except for villous trophoblasts. In vivo, Cul7 and Fbxw8 were detected in syncytiotrophoblast cells, VT, and EVT cells. Although no significant changes in expression levels of Fbxw8 or Cul7 were noted in IUGR compared with control placentas, Fbxw8 expression correlated negatively with gestational age in the control, but not in the IUGR group.Fbxw8 and Cul7 expression reveals a complex regulation in trophoblastic cells. Our findings suggest that dysregulation of Cul7 and Fbxw8 expression might affect trophoblast turnover in IUGR.

Objective: The etiology of endometriosis is still a research field in which few consistent data are available. Large case–control studies or even cohort studies are rare, and most of the published data are conflicting. The aim of the present study was therefore to examine common epidemiological and endometriosis-specific risk factors in a German case–control study. Design: From 2001 to 2010, a pool of 595 laparoscopically confirmed cases and 475 controls were recruited in a hospital-based setting. After matching for age, 298 cases and 300 controls remained in the pool. Age at menarche, menstrual cycle length, duration of menstrual bleeding, number of pregnancies, live births, miscarriages, use of contraceptive pills, body mass index (BMI), and smoking status were analyzed with logistic regression models predicting endometriosis case–control status. Results: Menstrual cycle length, duration of menstrual bleeding, number of pregnancies, number of miscarriages, and smoking status, as relevant predictors for endometriosis case–control status, were identified as risk factors for endometriosis. Other factors such as age at menarche, number of live births, ever having used contraceptive pills, and BMI were not predictive. Conclusions: This hospital-based case–control study reproduced most of the familiar risk factors. Comparison of this study with others reveals a wide variety of effect sizes and directions of association with risk factors and may increase the information available about the characteristics of the patient population being treated in the relevant hospital setting.

To assess the association between pregnancy-associated symptoms and common single nucleotide polymorphisms (SNPs) in genes known to be involved in the pathogenesis of nausea and vomiting.In a standardized, questionnaire-based interview, women selected from a control cohort for association studies were asked retrospectively about nausea and vomiting during their first pregnancy.A total of 593 women who had completed at least one pregnancy and for whom germline DNA was available were selected.Eight SNPs in the serotonin receptor genes HTR3A, HTR3B, HTR3C, HTR3D, HTR3E, and NK1R (TACR1) were tested using polymerase chain reaction. The occurrence of nausea and vomiting was correlated with the patients' genotyping results and medical history parameters.Both young age at first pregnancy and positive smoking status were significantly associated with vomiting and nausea during pregnancy. After adjustment for these two parameters, the two SNPs rs6806362 (odds ratio (OR) 1.38 per allele; 95% confidence interval (CI) 1.06-1.79; p = 0.017) and rs6807670 (OR 1.37; 95% CI 1.05-1.79 per allele; p = 0.023) were marginally associated with pregnancy-related nausea. None of the other polymorphisms showed any association.Polymorphisms in the subunit gene HTR3C of the serotonin receptor may be involved in the pathogenesis of pregnancy-associated nausea.

Pain symptoms in endometriosis patients do not necessarily correlate with the extent of the disease, and there is little evidence regarding the recurrence risk. Aim of this study was to assess the risk factors for the recurrence of endometriosis, with regard to preoperative and postoperative pain.Retrospective observational study.Single institution study.A total of 150 patients were followed up for recurrence after surgical treatment for endometriosis.The patients were interviewed retrospectively to obtain information about pain levels during the course of the disease.Disease free survival.High preoperative pain levels were associated with a higher risk of recurrence after 4 years of follow-up. The hazards ratio was 2.30 (95% CI, 1.22-4.31; p = 0.009). None of the other parameters assessed for medical history, reproductive history, or lifestyle was associated with the recurrence risk.The risk for recurrence after surgery for endometriosis may be substantially influenced by the patients' perception of pain. Risk classifications for the recurrence risk in endometriosis are nonexistent. Developing these is imperatively needed soon to improve further treatment and/or prophylaxis for patients after surgery. A classification might be improved by adding sensory testing before surgery.

This study investigated genetic variations in the estrogen pathway and their association with miscarriages.A total of 483 patients were recruited from a comprehensive control group for case-control studies. Three variants of the CYP19A1 gene (rs10046, rs4646 and rs700519) and one variant each of the estrogen (ESR1) and progesterone (PGR) receptor genes (rs3020314 and rs1042838) were investigated using polymorphism genotyping. The chi-squared test and one-way analysis of variation (ANOVA) were used for statistical analysis.For rs10046 (CYP19A1), the C/C genotype was associated with a greater frequency of miscarriages (P = 0.017). The other genotypes were not found to be associated with recurrent miscarriage.This is the first study that has identified a single-nucleotide polymorphism in the aromatase gene that suggests a significant association between genotypes and miscarriage. As aromatase is an essential enzyme in the estrogen pathway, it may be speculated that variations in the aromatase gene in some way give rise to different conditions in the endocrine environment that can lead to impaired fertility.

Objective To investigate whether sexually transmitted viruses or prokaryotes, like human papilloma viruses (HPV), herpes viruses, and Chlamydia trachomatis , are associated with endometriosis lesions. Design Sixty-six endometriosis lesions from 56 patients, including 49 peritoneum, 16 ovarian, and one endometrium, were analyzed using polymerase chain reaction–based ELISA and Invader technology. Thirty control tissues including endometrium and peritoneum from patient-matched (n = 13) and patients without endometriosis (n = 13) and one cervical carcinoma were tested for HPV DNA. Setting University hospital. Patient(s) Seventy individual patients with and without endometriosis. Intervention(s) Laparoscopy or laparotomy was performed, and endometriotic lesions were isolated. Result(s) Herpes viruses and Chlamydia trachomatis were not detected in endometriosis lesions. High-risk and medium-risk HPV were detected in 11.3% of lesions, corresponding to 13.2% of patients. In addition, 27.5% of control tissues were positive for HPV high and medium risk. One HPV18-positive ovarian endometriosis also associated with an ovarian carcinoma. Associating clinical history with HPV-positive endometriosis and control tissues, all patients had a prior HPV cervical infection. Conclusion(s) HPV infection in endometriosis lesions including control tissues supports spreading of the virus or HPV-infected endometrial cells via retrograde menstruation. Owing to an association of HPV in carcinomas, we propose that persistent HPV infection of endometriosis lesions could contribute to malignant progression.