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Dear Editor In their recent article, Hansen et al [1][1] reported no benefit for transmuscular quadratus lumborum (QL) block in patients undergoing total laparoscopic hysterectomy (LH). The authors indicated that there is no evidence to explain the lack of efficacy of QL block in this group of

Obesity is having an increasingly significant impact on health care services across the developed world. Although initially laparoscopic surgery was thought to be contraindicated in cases of obesity, surgeons, including gynaecologists, are now routinely performing laparoscopic surgery on obese patients. Limited research has been conducted into the effect of obesity on outcomes of major laparoscopic pelvic surgery. Some authors report worsening outcomes in obese women having laparoscopic hysterectomies; others suggest that complication rates do not increase, but operating times are longer. Here, we report our experience from 250 total laparoscopic hysterectomies performed for benign, malignant and pre-malignant conditions, and we compare outcomes among normal, overweight, obese and morbidly obese patients. We used a composite score index calculated on the basis of operating and theatre times, estimated blood loss, length of stay and number and severity of complications for our comparisons. Our conclusions suggest that meticulous, consistent surgical technique may produce similar outcomes in normal and obese patients having total laparoscopic hysterectomy, with longer operating/theatre times noted only at BMI levels >40.

Background Optimal postoperative pain therapy for patients undergoing minimally invasive surgery remains controversial. The aim of this meta-analysis was to compare the efficacy and safety of the novel laparoscopic-guided transversus abdominis plane block (L-TAP) with other analgesic alternatives in adults undergoing minimally invasive surgery. Study design A systematic literature search of several databases was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines through March 9, 2020, to identify randomized controlled trials (RCTs) reporting on L-TAP. Primary outcomes were pain scores at rest and movement at 24 hours postoperatively. Secondary outcomes included postoperative pain scores at 0 to 4 and 48 hours, opioid consumption, hospital stay, functional recovery, patient satisfaction, and adverse events. Results Nineteen RCTs with 1,983 patients were included. All trials compared L-TAP with ultrasound-guided transversus abdominis plane block (US-TAP), local infiltration analgesia (LIA), or inactive control; none controlled for epidural analgesia. Methodologic quality of these RCTs ranged from moderate to high. L-TAP provided comparable pain control compared with US-TAP, and better early pain control compared with LIA. Recovery parameters, 24-hour opioid consumption, and postoperative nausea and vomiting (PONV) were comparable between L-TAP and US-TAP. Meanwhile, 24-hour opioid consumption, PONV incidence, hospital stay, and patient satisfaction favored L-TAP compared with LIA. None of the studies reported adverse events related to the L-TAP procedure. Conclusions L-TAP is safe, and superior to LIA with respect to early pain control, opioid consumption, and patient satisfaction in adults undergoing minimally invasive surgery. Given its equivalence to US-TAP, L-TAP can be used as a safer and pragmatic alternative to epidural analgesia in this patient population.

OBJECTIVE To compare the efficiency of laparoscopically guided transversus abdominis plane block (LTAP) versus port-site local anaesthetic infiltration (LAI) in reducing postoperative pain following laparoscopic excision of endometriosis. DESIGN A prospective, double-blind randomised controlled trial. SETTING A tertiary referral centre for endometriosis and minimally invasive gynaecological surgery. POPULATION Women undergoing laparoscopic excision of endometriosis from December 2015 through July 2016. METHODS Participants were randomised to receive: port-site infiltration with bupivacaine and placebo LTAP (LAI group, n = 21); placebo port-site infiltration and LTAP with bupivacaine (LTAP group, n = 24); placebo port-site infiltration and placebo LTAP (placebo group, n = 25). MAIN OUTCOME MEASURES Post-operative pain at 2-4, 6-8, 10-12 and 24 hours, analgesic requirements, TAP block-related complications and opioid-related adverse effects. RESULTS There were no differences in patient characteristics between the groups. In comparison with placebo, both LTAP and LAI groups had significantly less pain at 2-4, 6-8, and 10-12 hours (median 3, 3, 3.5 versus 3, 6, 4 versus 8, 8, 7 for LTAP, LAI, and placebo, respectively, P

The management of women with abnormally invasive placenta remains one of the most challenging aspects of obstetric care. Various surgical and interventional radiological techniques have been developed to limit the risk of massive haemorrhage at caesarean section. Here we describe our experience with three such cases that required caesarean hysterectomy and were managed with prophylactic balloon catheterisation of the common iliac arteries. The details of three cases that received prophylactic balloon catheterisation of the common iliac arteries for the surgical management of placenta accreta/percreta are presented. Observational conclusions from these cases as well as a review of the relevant literature are discussed. Our three cases required caesarean hysterectomy for suspected placenta accreta/percreta. The mean estimated blood loss was 3,333 ml. In one of the cases, we observed notable reduction in blood loss during occlusion of the common iliac arteries, as the balloons were deflated every 5 min to avoid lower limb ischemia. The cases presented here, and also our literature review, suggest that occlusion of the common iliac arteries appears to be more effective than, and as safe as the occlusion of the internal iliac arteries. Clinicians need to be aware of the potential risks and employ measures to prevent them. Further research is required to investigate the optimum length of occlusion and balance between reducing blood loss and risking ischemia of the limbs when occluding the common iliac arteries.

Pregnancy in a uterine rudimentary horn carries a high risk of uterine rupture with severe and potentially lethal intra-abdominal haemorrhage. There is now growing evidence that this condition can be safely managed by minimally invasive surgery. We report a case of an unruptured 11-week rudimentary horn pregnancy that was diagnosed and treated laparoscopically. We have performed a literature review using PubMed, Embase and Cochrane Database of Systematic Reviews to identify relevant cases and draw conclusions with regards to their management. We have collated 20 published cases of rudimentary horn pregnancies that were managed by laparoscopy. The surgical technique appears consistent among these cases with few variations. In advanced gestations, feticide may need to be performed. Morcellation has been shown to be possible without compromising patient safety from trophoblast spill. The possibility of uncommon presentations such as duplicated or absent ureter should be taken into account. Extracorporeal Roeder knot can be used safely to secure unusually dilated vascular pedicles. Overall, laparoscopy appears to be as safe as and potentially superior to laparotomy for the management of rudimentary horn pregnancies.

Surgical site infection can result in increased morbidity for the patient, prolonged hospital stay and hospital readmission. Preoperative antibiotics reduce the incidence of such infections, particularly in open surgery. Universal use of antibiotic prophylaxis, however, is not recommended due to the risks of adverse reactions, generation of resistant bacteria and additional cost. Endoscopic procedures carry low risk of wound contamination and infection. Limited data suggest wide variability in antibiotic prophylaxis in gynaecological surgery and potential overuse of antibiotics in gynaecological endoscopic surgery. Bringing together the existing evidence allows for a consensus proposal for the use of preoperative antibiotics in gynaecological endoscopy.

Complete surgical eradication is considered the mainstay of treatment for endometriosis. The aim of the present study was to investigate patients' own assessment of whether their laparoscopic treatment made a difference to their quality of life, as well as to assess local recurrence rates. We performed a retrospective analysis of 49 women who had laparoscopic treatment for endometriosis at our unit between 1 January 2008 and 1 January 2010. Patients were sent the Short Form EHP-5 questionnaire and asked to score their quality of life in relation to endometriosis symptoms, prior to the surgery and up to 48 months afterwards. Subgroup analysis of stage I/II and stage III/IV disease was performed as well as stratification of the period post-operation into 12-24, 25-36 and 37-48 months for follow-up analysis. Overall, the patients reported improvement in quality of life scores with a significant drop in mean scores from 46.9 pre- to 27.5 post-surgery, signifying benefits from the surgical intervention. All subgroups reported improvement in quality of life scores. The overall symptom recurrence rate was 18.3%. We conclude that patients, post-laparoscopic treatment of endometriosis, experience significant improvement in their quality of life, regardless of stage and this can be quantified and qualified.

Key content Injury of the urinary tract is the most common major complication of gynaecological laparoscopic surgery. Injury to either bladder or ureter results in significant morbidity for the patient and may lead to litigation. Knowledge of pelvic anatomy, training and meticulous technique are of paramount importance in reducing the incidence of urinary tract injury. Ideally an injury should be identified and repaired during the primary operation, but vigilance in the immediate postoperative period may result in early recognition and intervention. Learning objectives To understand the common risk factors of urinary tract injury at laparoscopy. To learn strategies to prevent injury where possible. To learn strategies for intraoperative and postoperative recognition and repair of such injuries. To understand the significance of multi-disciplinary management of such injuries. Ethical issues Limited evidence shows that laparoscopic hysterectomy may carry a higher risk of urinary tract injury compared with abdominal hysterectomy. Should patients be counselled accordingly?

We report a case of a woman with chronic right-sided pelvic pain with an unusual combination of broad ligament defects and associated terminal ileum and caecum herniation. Reduction of the hernia and closure of the defects at laparoscopy resulted in resolution of the patient’s painful symptoms. Review of the literature suggests that, although rare, such defects should be considered in the differential diagnosis of persistent pelvic pain. Where found incidentally, broad ligament defects should be repaired in order to prevent sinister complications such as bowel obstruction and strangulation.

Corticotropin-releasing hormone (CRH) and its receptors are expressed in human placenta. Recently, the impaired function of this system has been associated with a number of complications of pregnancy, including pre-eclampsia. The aim of the study was to test the hypothesis that CRH participates in the pathophysiology of pre-eclampsia through the induction of macrophage-mediated apoptosis of extravillous trophoblasts (EVTs). We found that the expression of CRH was increased in the EVT of the placental bed biopsy specimens from pre-eclamptic pregnancies (1.8-fold increase; P < 0.05). In addition, significantly larger numbers of apoptotic EVT were detected in pre-eclamptic placentas compared with normal ones (P < 0.05), and only in pre-eclamptic placentas, decidual macrophages were found to be Fas ligand (FasL)-positive. In vitro studies on the effect of CRH on human macrophages suggested that CRH induced the expression of the FasL protein in human macrophages and potentiated their ability to induce the apoptosis of a Fas-expressing EVT-based hybridoma cell line in co-cultures. These findings demonstrate a possible mechanism by which the aberrant expression of CRH in pre-eclampsia may activate the FasL-positive decidual macrophages, impair the physiological turnover of EVT and eventually disturb placentation.

Lewis antigens belong to the blood group of antigens and mediate cellular adhesion through interaction with selectins. Invasive trophoblasts use an array of adhesion molecules to facilitate cell-cell and cell-extracellular matrix interactions. Here, we examined immunohistochemically the expression of Sialyl Lewis a (sLe(a)), Sialyl Lewis x (sLe(x)) and Lewis y (Le(y)) in term placentas obtained from cases of normal, intrauterine growth retardation (IUGR), preeclamptic (PE) and hemolysis, elevated liver enzymes and low platelets syndrome (HELLP) pregnancies. We report the expression of sLe(x) in third trimester extravillous trophoblasts (EVT). sLe(x) was significantly decreased in IUGR and moderately decreased in PE compared to normal placentas. sLe(x) was additionally found in syncytiotrophoblast, without however any significant differences in staining intensity between normal and pathological cases. sLe(a) was restricted to amnion epithelium. Finally, Le(y) was expressed in cytotrophoblasts and villous endothelial cells. Le(y) expression was significantly upregulated in IUGR and HELLP, whereas there was a trend toward increase in PE compared to normal placentas. The present study suggests that downregulation of sLe(x) in EVT might be associated with IUGR and PE. Furthermore, Le(y), which was recently described as a potent angiogenic factor, is upregulated in placental villi in conditions associated with placental malperfusion.

Corticotropin-releasing factor (CRF), also termed corticotropin-releasing hormone (CRH) or corticoliberin, is the major regulator of the adaptive response to internal or external stresses. An essential component of the adaptation mechanism is the adrenal gland. CRF regulates adrenal function indirectly through the central nervous system (CNS) via the hypothalamic-pituitary-adrenal (HPA) axis and via the autonomic nervous system by way of locus coeruleus (LC) in the brain stem. Accumulating evidence suggests that CRF and its related peptides also affect the adrenals directly, i.e. not through the CNS but from within the adrenal gland where they form paracrine regulatory loops. Indeed, CRF and its related peptides, the urocortins (UCNs: UCN1, UCN2 and UCN3), their receptors CRF type 1 (CRF(1)) and 2 (CRF(2)) as well as the endogenous pseudo-receptor CRF-binding protein (CRF-BP) are all expressed in adrenal cortical, medullary chromaffin and resident immune cells. The intra-adrenal CRF-based regulatory system is complex and depends on the balance between the local concentration of CRF ligands and the availability of their receptors.

Corticotropin-releasing factor (CRF) affects catecholamine production both centrally and peripherally. The aim of the present work was to examine the presence of CRF, its related peptides, and their receptors in the medulla of human and rat adrenals and their direct effect on catecholamine synthesis and secretion. CRF, urocortin I (UCN1), urocortin II (UCN2), and CRF receptor type 1 (CRF1) and 2 (CRF2) were present in human and rat adrenal medulla as well as the PC12 pheochromocytoma cells by immunocytochemistry, immunofluorescence, and RT-PCR. Exposure of dispersed human and rat adrenal chromaffin cells to CRF1 receptor agonists induced catecholamine secretion in a dose-dependent manner, an effect peaking at 30 min, whereas CRF2 receptor agonists suppressed catecholamine secretion. The respective effects were blocked by CRF1 and CRF2 antagonists. CRF peptides affected catecholamine secretion via changes of subplasmaliminal actin filament polymerization. CRF peptides also affected catecholamine synthesis. In rat chromaffin and PC12 cells, CRF1 and CRF2 agonists induced catecholamine synthesis via tyrosine hydroxylase. However, in human chromaffin cells, activation of CRF1 receptors induced tyrosine hydroxylase, whereas activation of CRF2 suppressed it. In conclusion, it appears that a complex intraadrenal CRF-UCN/CRF-receptor system exists in both human and rat adrenals controlling catecholamine secretion and synthesis.

To investigate whether corticotropin-releasing hormone (CRH) and corticotropin (ACTH) plasma concentrations in women diagnosed with preterm labor are of potential clinical value in the assessment of the risk of preterm birth.Plasma samples of 79 women diagnosed with preterm labor were used in this study. Samples were divided into three groups based on the week of gestation (24th-28th, 29th-32nd, 33rd-37th). CRH and ACTH values were determined by ELISA.Mean maternal peripheral plasma values of CRH and ACTH were significantly higher (p0.001) in women who were initially diagnosed with preterm labor and finally delivered a preterm birth, compared to women with the same diagnosis but with term birth.CRH and ACTH serum levels in women diagnosed with preterm labor could be used as predictors for the timing of parturition.

CRF, CRF-related peptides and CRF receptors constitute a complex physiological system which has a key role in facilitating the adaptation of the organism to the stressful stimuli of the environment. The behavioral, endocrine, autonomic and immune branches of stress response are considered to be under the coordinating effects of CRF and its related peptides. The effects of these peptides are mediated through two distinct receptors, types 1 and 2 CRF receptors (CRF(1) and CRF(2)). The two receptors are encoded by separate genes and belong to the G-coupled receptor superfamily. The wide influence of the CRF system on physiological processes in both brain and periphery, suggests the implication of the respective peptides in the pathophysiology of numerous disorders which involve dysregulated stress responses. The potential use of CRF antagonists in such disorders is currently under intense investigation. Furthermore, such compounds have been invaluable in elucidating the physiology of the CRF system. This review will focus on existing data on the structural and pharmacological characteristics as well as the experimental and potential clinical uses of non-peptide, small molecule CRF antagonists.

Implantation of the blastocyst into the endometrium is a delicately controlled process and a prerequisite for the furtherance of the mammalian species. A complex network of molecules is involved in preparing both the endometrium and blastocyst for a successful interaction. However, the exact molecular steps are poorly understood. Studies so far have shown that disruption of certain pathways results in fertility defects. Impaired implantation is currently considered to be the most important limiting factor for the establishment of viable pregnancies in assisted reproduction. It is expected that elucidating the molecular background of the process will enable accurate diagnosis and effective treatment of infertility. Trends Endocrinol Metab

Adiponectin exerts anti-inflammatory effects via macrophages, suppressing the production of pro-inflammatory cytokines in response to bacterial lipopolysaccharide (LPS). Here, we provide experimental evidence that the "anti-inflammatory" effect of adiponectin may be due to an induction of macrophage tolerance: globular adiponectin (gAd) is a powerful inducer of TNF-alpha and IL-6 secretion in primary human peripheral macrophages, in the THP-1 human macrophage cell line, and in primary mouse peritoneal macrophages. Pre-exposure of macrophages to 10 microg/ml gAd rendered them tolerant to further gAd exposure or to other pro-inflammatory stimuli such as TLR3 ligand polyI:C and TLR4 ligand LPS, while pre-exposure to 1 microg/ml of and re-exposure to 10 microg/ml gAd unmasked its pro-inflammatory properties. GAd induced NF-kappaB activation and tolerance to further gAd or LPS exposure. Our data suggest that adiponectin constant presence in the circulation in high levels (in lean subjects) renders macrophages resistant to pro-inflammatory stimuli, including its own.

Ο εκλυτικός παράγοντας της κορτικοτροπίνης (CRF) και τα ομόλογά του πεπτίδια ουροκορτίνες (UCNI, UCNII, UCNIII) αποτελούν τους κύριους ρυθμιστές και συντονιστές των συμπεριφορικών, ενδοκρινικών και ανοσολογικών αποκρίσεων του ανθρώπινου οργανισμού απέναντι στο στρες. Οι δράσεις τους διαμεσολαβούνται μέσω δύο κύριων τύπων υποδοχέων των CRFR1 και CRFR2. Τα πεπτίδια και οι υποδοχείς τους εντοπίζονται στο κεντρικό νευρικό σύστημα αλλά και σε πλήθος ιστών της περιφέρειας, συμπεριλαμβανομένου σχεδόν του συνόλου των ιστών της αναπαραγωγικής οδού. Ο βιολογικός ρόλος του «αναπαραγωγικού» συστήματος των CRF πεπτιδίων μελετάται και προσδιορίζεται τα τελευταία χρόνια. Μέχρι στιγμής έχει διαπιστωθεί η συμμετοχή των πεπτιδίων, ως παρακρινείς και αυτοκρινείς ρυθμιστές, σε σημαντικές λειτουργίες του αναπαραγωγικού συστήματος όπως η ωορρηξία, η ωχρινοποίηση, η εμφύτευση της βλαστοκύστης, η φθαρτοποίηση του στρώματος του ενδομητρίου, η λειτουργία της εμβρυο-πλακουντιακής κυκλοφορίας και η έναρξη του τοκετού. Επίσης προτείνεται ότι τοπική δυσλειτουργία του συστήματος των CRF πεπτιδίων μπορεί να οδηγήσει σε διαταραχές των ανωτέρω διαδικασιών. Στην παρούσα διδακτορική διατριβή μελετήθηκε ο ρόλος των πεπτιδίων CRF και CEACAM1 στη φυσιολογία της τροφοβλαστικής διείσδυσης καθώς και ο ρόλος των πεπτιδίων CRF, Ucn και των προ-αποπτωτικών Fas/FasL, στην διαταραχή της εμφύτευσης της ανθρώπινης βλαστοκύστης, όπως αυτή εκδηλώνεται κλινικά με τις αυτόματες αποβολές. Η μελέτη επεκτάθηκε στη διερεύνηση της αλληλεπίδρασης εξωλαχνωτής τροφοβλάστης (ΕΛΤ) και φθαρτικών λεμφοκυττάρων ως πιθανό στοιχείο των κυτταρικών και μοριακών μηχανισμών που συνθέτουν την παθοφυσιολογία αυτής της κλινικής οντότητας. Διαπιστώθηκε ότι ο CRF ελαττώνει τη διεισδυτική ικανότητα απομονωμένων κυττάρων ΕΛΤ. Η δράση αυτή ήταν ειδική μέσω του CRFR1 υποδοχέα και οφειλόταν σε ελάττωση της έκφρασης του διασυνδετικού μορίου CEACAM1 στην επιφάνεια των κυττάρων. Αποκλεισμός της λειτουργίας του CEACAM1 στα ίδια κύτταρα είχε σαν αποτέλεσμα σημαντική μείωση της διεισδυτικότητάς τους. Επίσης χρησιμοποιήθηκε μια κυτταρική σειρά εξωλαχνωτνών τροφοβλαστών που δεν εκφράζει το CEACAM1 μόριο. Διαμόλυνση των κυττάρων αυτών με το CEACAM1 γονίδιο, οδήγησε σε σημαντική αύξηση της διεισδυτικής τους ικανότητας. Η UCN εκφράζεται στη θέση εμφύτευσης του ανθρώπινου εμβρύου και συγκεκριμένα στην ΕΛΤ σε φυσιολογικούς πλακούντες πρώτου τριμήνου. Οι αυτόματες αποβολές στον άνθρωπο σχετίζονται με αυξημένη έκφραση CRF και UCN στη θέση εμφύτευσης, αυξημένη έκφραση FasL στα λευκοκύτταρα του φθαρτού και αυξημένη έκφραση Fas στην ΕΛΤ. Τα ανωτέρω μόρια μελετήθηκαν σε επίπεδο πεπτιδίου και mRNA. Επιπρόσθετα, οι αυτόματες αποβολές σχετίζονται με αυξημένη απόπτωση της διάμεσης ΕΛΤ. Τέλος, τα πεπτίδια CRF και UCN ενισχύουν την ικανότητα των φθαρτικών λεμφοκυττάρων να προκαλούν Fas-επαγώμενη απόπτωση στην κυτταρική σειρά εξωλαχνωτής τροφοβλάστης. Συμπερασματικά, η παρούσα διατριβή παρουσιάζει νέα δεδομένα στο ρόλο των CRF και UCN στην εμφύτευση της ανθρώπινης βλαστοκύστης και την ακόλουθη πλακουντιοποίηση, καθώς και στην διαταραχή των διαδικασιών αυτών.

OBJECTIVES Pregnancy following endometrial ablation is a rare event that carries significant risks to the mother. The majority of women elect to terminate such pregnancies. This brings into question which of the available methods should best be employed and what kinds of problems to anticipate. CASE We present a case of a pregnancy following radiofrequency endometrial ablation that was terminated surgically and review the relevant English literature. CONCLUSIONS Medical or surgical abortion can be considered as primary methods of terminating a first trimester intrauterine pregnancy following endometrial ablation. The choice will depend on patient preference but also on the available expertise. Cervical stenosis and/or intrauterine adhesions may limit the effectiveness of these methods. In such cases methotrexate is an alternative option, whereas hysterotomy or hysterectomy should be considered as final options. Counselling patients at the time of endometrial ablation regarding the need for contraception, even after prolonged periods of amenorrhoea is of paramount importance. Laparoscopic or hysteroscopic sterilisation can be offered together with endometrial ablation.

The authors present a case history of a woman with vaginal bleeding who was found to have a ruptured ectopic pregnancy, initially misdiagnosed as an incomplete miscarriage. Doctors need to have a high suspicion of ectopic pregnancy in early diagnosis and interventions. Copyright © 2009 Wiley Interface Ltd

We report the case of a 37-year-old woman who developed idiopathic brachial plexus neuritis, also referred to as Parsonage-Turner syndrome, after laparoscopic excision of endometriosis. The differential diagnosis between this non-position-related neuritis and brachial plexus injury is discussed. The aim of this report was to raise awareness on this distressing postoperative complication.

A 30-year-old para 1 woman presented to labour ward with pre-labour spontaneous rupture of membranes at 41 weeks' gestation. Labour was augmented with the use of oxytocics. Fetal cardiotocography s...

DHEA analogues with modifications at positions C3 or C17 were synthesized and evaluated for neuroprotective activity against the neural-crest-derived PC12 cell model of serum deprivation-induced apoptosis. The most potent compounds were the spiro-epoxy derivatives 17beta-spiro[5-androstene-17,2'-oxiran]-3beta-ol (20), (20S)-3beta,21-dihydroxy-17beta,20-epoxy-5-pregnene (23), and (20R)-3beta,21-dihydroxy-17alpha,20-epoxy-5-pregnene (27) with IC(50) values of 0.19 +/- 0.01, 99.0 +/- 4.6, and 6.4 +/- 0.3 nM, respectively. Analogues 20, 23, and 27, up to the micromolar range of concentrations, were unable to activate estrogen receptor alpha and beta (ERalpha and ERbeta) or to interfere with ER-dependent gene expression significantly. In addition, they were unable to stimulate the growth of Ishikawa, MCF-7, and LNCaP cells. Our results suggest that the spiro-epoxyneurosteroid derivatives 20, 23, and 27 may prove to be lead molecules for the synthesis of novel neuroprotective agents. J Med Chem

Human reproduction is remarkably inefficient, with more than half of spontaneous conceptions failing to complete the first trimester. However, little is known on the molecular events that take place at the implantation site during abortion. Here, we examined the hypothesis that the expression of the proapoptotic Fas/FasL system at the implantation site is impaired in abortions. We found that, in contrast to normal pregnancy, abortive deciduas contain leukocytes that are positive for FasL and extravillous trophoblasts (EVTs), which show increased expression of Fas and increased rates of apoptosis. In addition, the neuropeptides, corticotropin-releasing hormone and urocortin, were elevated in placental material obtained from abortions. In vitro, these peptides induced the expression of FasL in decidual lymphocytes (DL) obtained from elective termination of pregnancy placentas and thus potentiated the cells' ability to induce Fas-mediated apoptosis in an EVT-based hybridoma cell line. Finally, DL from abortion sites effectively induced apoptosis of EVT without prior treatment. It is possible that these events may impede successful early placentation and thus contribute to the pathophysiology of human abortion. Mol Hum Reprod

The neuroactive steroids dehydroepiandrosterone (DHEA), its sulfate ester DHEAS, and allopregnanolone (Allo) are produced in the adrenals and the brain. Their production rate and levels in serum, brain, and adrenals decrease gradually with advancing age. The decline of their levels was associated with age-related neuronal dysfunction and degeneration, most probably because these steroids protect central nervous system (CNS) neurons against noxious agents. Indeed, DHEA(S) protects rat hippocampal neurons against NMDA-induced excitotoxicity, whereas Allo ameliorates NMDA-induced excitotoxicity in human neurons. These steroids exert also a protective role on the sympathetic nervous system. Indeed, DHEA, DHEAS, and Allo protect chromaffin cells and the sympathoadrenal PC12 cells (an established model for the study of neuronal cell apoptosis and survival) against serum deprivation-induced apoptosis. Their effects are time- and dose-dependent with EC(50) 1.8, 1.1, and 1.5 nM, respectively. The prosurvival effect of DHEA(S) appears to be NMDA-, GABA(A)- sigma1-, or estrogen receptor-independent, and is mediated by G-protein-coupled-specific membrane binding sites. It involves the antiapoptotic Bcl-2 proteins, and the activation of prosurvival transcription factors CREB and NF-kappaB, upstream effectors of the antiapoptotic Bcl-2 protein expression, as well as prosurvival kinase PKCalpha/beta, a posttranslational activator of Bcl-2. Furthermore, they directly stimulate biosynthesis and release of neuroprotective catecholamines, exerting a direct transcriptional effect on tyrosine hydroxylase, and regulating actin depolymerization and submembrane actin filament disassembly, a fast-response cellular system regulating trafficking of catecholamine vesicles. These findings suggest that neurosteroids may act as endogenous neuroprotective factors. The decline of neurosteroid levels during aging may leave the brain unprotected against neurotoxic challenges.

Several recently published reports, including ours, suggest that adiponectin is a strong proinflammatory agent. Indeed, exposure of human placenta and adipose tissue to adiponectin induces the production of interleukin-1beta (IL-1beta), IL-6, tumor necrosis factor alpha (TNF-alpha), and prostaglandin E2 (PGE2). We have previously shown that adiponectin is a powerful inducer of proinflammatory cytokines production by macrophages. The reported anti-inflammatory effect of adiponectin may be due to the induction of macrophage tolerance to further adiponectin exposure or to other proinflammatory stimuli including the Toll-like receptor (TLR) 3 ligand polyI:C and the TLR4 ligand lipopolysaccharide (LPS). We now present additional data supporting the hypothesis that adiponectin is a strong proinflammatory adipokine. More specifically, we demonstrate that adiponectin induces IL-1beta and IL-8 from THP-1 macrophage cell line. The effect of adiponectin is not restricted to differentiated THP-1 macrophages but it is evident at lower levels in undifferentiated THP-1 monocytes promoting TNF-alpha, IL-6, and IL-8 production. Thus, its high levels in the circulation of lean subjects render their macrophages resistant to several proinflammatory stimuli including its own thus acting in effect as an anti-inflammatory agent. Lowering of its high levels, as a consequence of increased body mass index (BMI), renders macrophages sensitive to any proinflammatory insult.

Successful embryo implantation in mammals requires the co-ordinated development of a blastocyst competent to implant and an adhesive endometrium. Given the indispensable role of implantation for the furtherance of the species, a number of molecular mechanisms have evolved to regulate the process. A variety of molecules, produced by embryo as well as maternal tissue participates in the cross-talk between the implanting blastocyst and the endometrium. The interplay between the various molecules and the routes in which they are involved is beginning to be elucidated. Because impaired implantation represents the most important limiting factor in the establishment of pregnancy, it is believed that research in the field will allow clinicians to improve the respective rates. This paper reviews certain groups of molecules that are considered to have key roles in the mechanisms of implantation.

The stress neuropeptides, corticotropin-releasing hormone (CRH) and urocortin (UCN), modulate the inflammatory response via the hypothalamus-pituitary-adrenal axis and locally, in a paracrine manner, act on mast and macrophage cells. Kupffer cells (KCs) are the resident macrophages of the liver. They represent the bulk of tissue macrophages in the body and they are the first to face invading noxious agents reaching the body via the portal circulation. The aim of the present report was to study the expression of the CRH system in rat KC and test its functionality. Our findings are as follows: (1) In highly purified KCs the transcripts of UCN, of its receptors CRHR1, CRHR2 and that of the pseudoreceptor CRH-binding protein (CRHBP) were present while that of CRH was not detectable. (2) Similarly, immunoreactive UCN, CRHR1, CRHR2 and CRHBP were easily detectable by immunohistochemistry and immunofluorescence in sections of whole rat liver (localized in KC) as well as in purified KC while CRH was again not detectable. (3) Exposure of purified KC to CRH or UCN suppressed lipopolysaccharide-induced tumor necrosis factor alpha production, an effect completely prevented by the CRHR1 and CRHR2 receptor antagonist astressin. Our data demonstrate the presence of UCN and its receptors in rat KC, the absence of CRH, and the functionality of these receptors. We propose that a UCN-based system may affect local inflammatory phenomena in the liver acting in a paracrine manner.

Abnormalities in the process of trophoblast invasion may result in abnormal placentation. Both the embryonic trophoblast and maternal decidua produce corticotropin-releasing hormone (CRH), which promotes implantation. Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), which is expressed in extravillous trophoblasts (EVTs) of normal human placenta, may also function in tro-phoblast/endometrial interactions. We investigated whether locally produced CRH plays a role in trophoblast invasion, primarily by regulating CEACAM1 expression. We examined cultures of freshly isolated human EVTs, which express CEACAM1, and an EVT-based hybridoma cell line, which is devoid of endogenous CEACAM1. CRH inhibited EVT invasion in Matrigel invasion assays, and this effect was blocked by the CRH receptor type 1 (CRHR1)-specific antagonist antalarmin. Additionally, CRH decreased CEACAM1 expression in EVTs in a dose-dependent manner. After transfection of the hybridoma cell line with a CEACAM1 expression vector, the invasiveness of these cells was strongly enhanced. This effect was inhibited by addition of blocking monoclonal antibody against CEACAM1. Furthermore, blocking of endogenous CEACAM1 in EVTs inhibited the invasive potential of these cells. Taken together these findings suggest that CRH inhibits trophoblast invasion by decreasing the expression of CEACAM1 through CRHR1, an effect that might be involved in the pathophysiology of clinical conditions, such as preeclampsia and placenta accreta. Am J Pathol

Urocortin (UCN) is a 40 amino acid peptide which is closely related to corticotropin-releasing hormone and binds with high affinity to both CRH type 1 and type 2 receptors. UCN is expressed in human reproductive tissues including endometrium, ovary, and placenta. This study was designed to investigate the cellular localization of UCN at the implantation site of the human blastocyst, as well as the regulation of the UCN promoter by two major intracellular signaling pathways, the cAMP/PKA and diacylglycerol/PKC pathways, in cells of placental origin. For this reason, immunohistochemistry was performed on tissue sections from paraffin-embedded human first trimester placentas and freshly isolated human invasive extravillous trophoblast cells (EVT) were analyzed for UCN expression using RT-PCR and immunofluorescence. Finally, UCN promoter activity was analyzed in the JEG3 human choriocarcinoma cell line. Immunohistochemistry revealed expression of UCN in the cytotrophoblast, the EVT and decidual cells. Both UCN mRNA and peptide were detectable in freshly isolated EVT. Finally, a human UCN promoter luciferase reporter construct transfected into JEG3 cells was significantly inducible by phorbol ester plus ionomycin, but not by phorbol ester alone or by forskolin. Collectively, the present study reports the expression of UCN in EVT and the activation of the UCN gene promoter by the diacylglycerol/PKC pathway. The functional significance of urocortin for the physiology of EVT requires further investigation.

Establishment of early pregnancy is promoted by a complex network of signalling molecules that mediate cell-to-cell and cell-to-extracellular matrix communications, in order to manifest controlled invasion of the trophectoderm and successful implantation. During the period known as the 'window of implantation', the endometrium expresses specialized proteins, many of which exhibit potential use as markers of endometrial receptivity. Trophoblast differentiation to the invasive phenotype also depends on the up-regulation of certain peptides and the down-regulation of others. Disruption of each pathway is theoretically possible, and studies in animal models suggest that implantation defects result when the function of these proteins is blocked. Indeed, the implantation process is currently considered the most important limiting factor for the establishment of viable pregnancy. The present overview of the literature reports critical families of molecules located at the embryo-maternal interface and describes the mechanisms of interplay and control. Since these factors are crucial to the process of implantation, targeting them might be a valuable contraceptive tool. Conversely, induction of specific peptides may prove to be beneficial in certain infertility cases.

Prolactin was first identified as an anterior pituitary lobe hormone, responsible for the regulation of mammary gland growth and development. Prolactin receptors have been localized in a number of peripheral tissues, including tissues involved in reproduction. Studies with knockout animals have shown that prolactin receptor deficient mice present reproductive defects, whereas prolactin promotes the developmental potential of preimplantation mouse and rat embryos in vitro. To better understand the role of prolactin in the process of reproduction and early embryo development in mice, the expression of the four transcript variants of prolactin receptor was examined in the first stages of mouse embryo development. Prolactin long receptor mRNA was expressed in all stages examined, that is in cumulus cells, oocytes, zygotes, 2-cell embryos, 4-cell embryos, morulae and blastocysts. Prolactin receptor type S1 mRNA was observed only in cumulus cells, while S2 mRNA was present in cumulus cells, oocytes, zygotes and 2-cell embryos. S3 mRNA was expressed only in cumulus cells and oocytes. These results indicate that different isoforms of prolactin receptors may be present in the various stages of mouse preimplantation embryo and may play an important role in the control of its growth and development.

Purpose: To examine the frequency distribution of the Ser680Asn polymorphism of the follicle-stimulating hormone receptor (FSHR) gene in ovarian dysfunction (OD) infertile women, “poor responders” (PR) and “good responders” (GR). Methods: The hormonal profiles and treatment of all patients were analyzed and FSHR polymorphism was examined by PCR and RFLP. Women from all groups were classified as Asn/Asn, Asn/Ser, and Ser/Ser genotypes. Results: The frequency distribution of Ser/Ser, Asn/Ser and Asn/Asn variants in OD patients was 45.5, 22.7, and 31.8%, respectively. Day 3 FSH levels in OD and GR patients were higher in Ser/Ser and Asn/Asn subgroups. Asn/Ser carriers from OD and GR groups provided more follicles and oocytes compared to other allelic variants. Conclusions: GR patients carry more often the Asn/Ser genotype. The latter is correlated with more follicles and oocytes in both OD and GR patients. The Ser/Ser variant might be related to higher serum FSH levels, while the Asn/Ser with lower.

delivery. Manual rotation is part of the art of obstetrics. It achieves delivery of occipito-transverse (OT) or occipitoposterior (OP) positions, after rotation to the occipitoanterior (OA) position and application of either ventuse or forceps. Two techniques are described for manual rotation. In the first one, the entire hand is placed in the woman’s vagina with the palm facing upwards. The foetal head is flexed and the occiput is rotated anteriorly. Alternatively, the operator may use his fingers to apply pressure along the lambdoid sutures in a dialling rotational motion [1]. The manoeuvre is thought to be safe and effective in reducing the Caesarean section rate, provided that certain criteria are met, including the correct assessment of the position and station of the foetal head by a competent obstetrician, and the application of the chosen instrument during the phase of uterine relaxation [2, 3]. A common problem encountered with manual rotation is the occasional tendency of the foetal head to rotate towards its original position at the end of the manoeuvre. We