What is the optimal means of preparing the endometrium in frozen-thawed embryo transfer cycles? A systematic review and meta-analysis

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BACKGROUND

Frozen–thawed embryo transfer (FET) enables surplus embryos derived from IVF or IVF-ICSI treatment to be stored and transferred at a later date. In recent years the number of FET cycles performed has increased due to transferring fewer embryos per transfer and improved laboratory techniques. Currently, there is little consensus on the most effective method of endometrium preparation prior to FET.

METHODS

Using both MEDLINE and EMBASE database a systematic review and meta-analysis of literature was performed. Case-series, case–control studies and articles in languages other than English, Dutch or Spanish were excluded. Those studies comparing clinical and ongoing pregnancy rates as well as live birth rates in (i) true natural cycle FET (NC-FET) versus modified NC-FET, (ii) NC-FET versus artificial cycle FET (AC-FET), (iii) AC-FET versus artificial with GnRH agonist cycle FET and (iv) NC-FET versus artificial with GnRH agonist cycle FET were included. Forest plots were constructed and relative risks or odds ratios were calculated.

RESULTS

A total of 43 publications were selected for critical appraisal and 20 articles were included in the final review. For all comparisons, no differences in the clinical pregnancy rate, ongoing pregnancy rate or live birth rate could be found. Based on information provided in the articles no conclusions could be drawn with regard to cancellation rates.

CONCLUSIONS

Based on the current literature it is not possible to identify one method of endometrium preparation in FET as being more effective than another. Therefore, all of the current methods of endometrial preparation appear to be equally successful in terms of ongoing pregnancy rate. However, in some comparisons predominantly retrospective studies were included leaving these comparisons subject to selection and publication bias. Also patients' preferences as well as cost-efficiency were not addressed in any of the included studies. Therefore, prospective randomized studies addressing these issues are needed.

Source:
http://humupd.oxfordjournals.org/cgi/content/short/19/5/458?rss=1

Progesterone elevation and probability of pregnancy after IVF: a systematic review and meta-analysis of over 60 000 cycles

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BACKGROUND

The aim of this meta-analysis was to evaluate the association of progesterone elevation (PE) on the day of hCG administration with the probability of pregnancy in fresh, frozen–thawed and donor/recipient IVF cycles.

METHODS

A literature search in MEDLINE, SCOPUS, COCHRANE CENTRAL and ISI Web of Science was performed aiming to identify studies comparing the probability of pregnancy in patients with or without PE after ovarian stimulation with gonadotrophins and GnRH analogues. Standard meta-analytic methodology was used for the synthesis of results and meta-regression for exploration of heterogeneity.

RESULTS

Sixty-three eligible studies were identified evaluating 55 199 fresh IVF cycles, nine studies evaluating 7229 frozen–thawed cycles and eight studies evaluating 1330 donor/recipient cycles. In fresh IVF cycles, a decreased probability of pregnancy achievement was present in women with PE (when PE was defined using a threshold ≥0.8 ng/ml) when compared with those without PE. The pooled effect sizes were 0.8–1.1 ng/ml: odds ratio (OR) = 0.79; 1.2–1.4 ng/ml: OR = 0.67; 1.5–1.75 ng/ml: OR = 0.64; 1.9–3.0 ng/ml: OR: 0.68 (P < 0.05 in all cases). No adverse effect of PE on achieving pregnancy was observed in the frozen–thawed and the donor/recipient cycles.

CONCLUSIONS

Based on the analysis of more than 60 000 cycles, it can be supported that PE on the day of hCG administration is associated with a decreased probability of pregnancy achievement in fresh IVF cycles in women undergoing ovarian stimulation using GnRH analogues and gonadotrophins. On the other hand, an adverse effect of PE does not seem to be present in frozen–thawed and donor/recipient cycles.

Source:
http://humupd.oxfordjournals.org/cgi/content/short/19/5/433?rss=1

The spinal control of ejaculation revisited: a systematic review and meta-analysis of anejaculation in spinal cord injured patients

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BACKGROUND

After spinal cord injury (SCI), most men cannot ejaculate without medical assistance. A major advance in the knowledge of the spinal control of ejaculation has been achieved with the discovery of a spinal generator of ejaculation (SGE) in the rat. The aim of this report was to review studies about ejaculation after SCI in order to revisit the spinal control of ejaculation and especially to assess the existence of an SGE in man.

METHODS

Studies were identified from Embase, PubMed, EBSCOhost and Cochrane Library. Studies were eligible when they specify the occurrence of antegrade ejaculation as a function of the neurological characterization of SCI. Studies were excluded when ejaculation was elicited by rectal electrical stimulation or when ejaculation could not be discriminated from climax. Meta-analyses were performed to assess the reference ejaculation rates for each procedure used to elicit ejaculation, i.e. masturbation or coïtus, penile vibratory stimulation (PVS) or acetylcholine esterase (AchE) inhibitors prior to masturbation. Subgroup analyses were performed according to the procedure used to elicit ejaculation on (i) the completeness of the SCI and (ii) the upper and lower limits of the SCI. To assess the existence of an SGE, the effect of concurrent lesions of different spinal segments was assessed by means of a stratified bivariate analysis.

RESULTS

From 523 studies, 45 were selected (n = 3851). Ejaculation occurred in response to masturbation or coïtus, PVS or AchE inhibitors followed by masturbation in, respectively, 11.8% (n = 1161), 47.4% (n = 597) and 54.7% (n = 309) of patients with complete SCI and in, respectively, 33.2% (n = 343), 52.8% (n = 305) and 78.1% (n = 32) of patients with incomplete SCI. Ejaculation, in the case of complete lesion of the sympathetic centres (T12 to L2), of the parasympathetic and somatic centres (S2–S4) or of all spinal ejaculation centres (T12 to S5) occurred in response to PVS in none of the patients (respectively, n = 5, n = 4 and n = 21) and in response to AchE inhibitors followed by masturbation in 4.9% (n = 61), 30.8% (n = 26) and 0% (n = 16) of the patients, respectively. Ejaculation in response to PVS or AchE inhibitors prior to masturbation was rhythmic forceful in 97.9% (n = 48) of the patients with complete lesion strictly above Onuf's nucleus (segments S2–S4). Complete lesion of the S2–S4 segments precluded the occurrence of rhythmic forceful ejaculation (n = 5). Controlling for the number of the injured segments between T12 and L2, the ejaculation rate sharply decreased when the lesion extended to the L3 segment and below.

CONCLUSIONS

The results reinforce the crucial roles of the spinal sympathetic and parasympathetic centres for emission and the somatic centre for expulsion. The spinal segments between L2 and S2 is more than a pathway to connect the ejaculation centres and likely harbours an SGE in man located in the L3, L4 and L5 segments.

Source:
http://humupd.oxfordjournals.org/cgi/content/short/19/5/507?rss=1

Autotransplantation of cryopreserved ovarian tissue in cancer survivors and the risk of reintroducing malignancy: a systematic review

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BACKGROUND

The risk of recurrent oncological disease due to the reintroduction of cancer cells via autotransplantation of cryopreserved ovarian tissue is unknown.

METHODS

A systematic review of literature derived from MEDLINE, EMBASE and the Cochrane Library was conducted. Studies on follow-up after autotransplantation; detection of cancer cells in ovarian tissue from oncological patients by histology, polymerase chain reaction or xenotransplantation; and epidemiological data on ovarian metastases were included.

RESULTS

A total of 289 studies were included. Metastases were repeatedly detected in ovarian tissue obtained for cryopreservation purposes from patients with leukaemia, as well as in one patient with Ewing sarcoma. No metastases were detected in ovarian tissue from lymphoma and breast cancer patients who had their ovarian tissue cryopreserved. Clinical studies indicated that one should be concerned about autotransplantation safety in patients with colorectal, gastric and endometrial cancer. For patients with low-stage cervical carcinoma, clinical data were relatively reassuring, but studies focused on the detection of metastases were scarce. Oncological recurrence has been described in one survivor of cervical cancer and one survivor of breast cancer who had their ovarian tissue autotransplanted, although these recurrences may not be related to the transplantation.

CONCLUSIONS

It is advisable to refrain from ovarian tissue autotransplantation in survivors of leukaemia. With survivors of all other malignancies, current knowledge regarding the safety of autotransplantation should be discussed. The most reassuring data regarding autotransplantation safety were found for lymphoma patients.

Source:
http://humupd.oxfordjournals.org/cgi/content/short/19/5/483?rss=1

Venous thromboembolism in women: a specific reproductive health risk

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BACKGROUND

Venous thromboembolism (VTE) is a specific reproductive health risk for women.

METHODS

Searches were performed in Medline and other databases. The selection criteria were high-quality studies and studies relevant to clinical reproductive medicine. Summaries were presented and discussed by the European Society of Human Reproduction and Embryology Workshop Group.

RESULTS

VTE is a multifactorial disease with a baseline annual incidence around 50 per 100 000 at 25 years and 120 per 100 000 at age 50. Its major complication is pulmonary embolism, causing death in 1–2% of patients. Higher VTE risk is associated with an inherited thrombophilia in men and women. Changes in the coagulation system and in the risk of clinical VTE in women also occur during pregnancy, with the use of reproductive hormones and as a consequence of ovarian stimulation when hyperstimulation syndrome and conception occur together. In pregnancy, the risk of VTE is increased ~5-fold, while the use of combined hormonal contraception (CHC) doubles the risk and this relative risk is higher with the more recent pills containing desogestrel, gestodene and drospirenone when compared with those with levonorgestrel. Similarly, hormone replacement therapy (HRT) increases the VTE risk 2- to 4-fold. There is a synergistic effect between thrombophilia and the various reproductive risks. Prevention of VTE during pregnancy should be offered to women with specific risk factors. In women who are at high risk, CHC and HRT should be avoided.

CONCLUSIONS

Clinicians managing pregnancy or treating women for infertility or prescribing CHC and HRT should be aware of the increased risks of VTE and the need to take a careful medical history to identify additional co-existing risks, and should be able to diagnose VTE and know how to approach its prevention.

Source:
http://humupd.oxfordjournals.org/cgi/content/short/19/5/471?rss=1

The role of the peritoneum in the pathogenesis of endometriosis

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BACKGROUND

Endometriosis affects 6–10% of women of reproductive age and is associated with chronic pelvic pain, dysmenorrhoea, dyspareunia and infertility. Endometriosis is defined by the presence of endometrial tissue outside the uterus, most commonly attached to the pelvic peritoneum. The endometrium in women with endometriosis is reported to be altered and there is increasing evidence that the phenotype of the pelvic peritoneum may also play a role in the establishment and maintenance of the disease. The aim of this review is to discuss the putative role of the pelvic peritoneum in the pathophysiology of peritoneal endometriosis.

METHODS

A review was undertaken of the published literature on (i) the anatomy and physiology of the peritoneum and (ii) the potential roles played by peritoneal cells in the establishment and maintenance of peritoneal endometriosis. The current understanding of the biology of peritoneal endometriosis is summarized and the potential interaction of the peritoneum with ectopic endometrial cells in endometriosis is highlighted.

RESULTS

Several studies indicate that differential expression of peritoneal mesothelial adhesion factors occurs in women with endometriosis, providing potential ectopic endometrial cell attachment sites for the establishment of endometriosis lesions. Changes in the peritoneal mesothelial cell phenotype, including loss of tight junctions, may allow ectopic cells to bind to, or early lesions to invade into, the extracellular matrix. Epithelial-to-mesenchymal transition of peritoneal mesothelial cells may also lead to an increase in lesion invasion and formation of fibrotic tissue in and around the lesion. There is evidence that the peritoneal mesothelium may also play a role in the invasion potential of ectopic cells by production of MMPs increasing local tissue remodelling. Peritoneal immune scavenging function may be lowered in women with endometriosis; for example there is a notable increase in macrophage-derived secretion products in women with endometriosis associated with increases in cell proliferation, cell adhesion and neovascularization.

CONCLUSIONS

The pelvic peritoneum appears to play a key role in the development and maintenance of endometriosis.

Source:
http://humupd.oxfordjournals.org/cgi/content/short/19/5/558?rss=1

The motile and invasive capacity of human endometrial stromal cells: implications for normal and impaired reproductive function

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BACKGROUND

Mechanisms underlying early reproductive loss in the human are beginning to be elucidated. The migratory and invasive capacity of human endometrial stromal cells (ESCs) is increasingly recognized to contribute to the intense tissue remodelling associated with embryo implantation, trophoblast invasion and endometrial regeneration. In this review, we examine the signals and mechanisms that control ESC migration and invasion and assess how deregulation of these cell functions contributes to common reproductive disorders.

METHODS

The PubMed database was searched for publications on motility and invasiveness of human ESCs in normal endometrial function and in reproductive disorders including implantation failure, recurrent pregnancy loss (RPL), endometriosis and adenomyosis, covering the period 2000–2012.

RESULTS

Increasing evidence suggests that implantation failure and RPL involve abnormal migratory responses of decidualizing ESCs to embryo and trophoblast signals. Numerous reports indicate that endometriosis, as well as adenomyosis, is associated with increased basal and stimulated invasiveness of ESCs and their progenitor cells, suggesting a link between a heightened menstrual repair response and the formation of ectopic implants. Migration and invasiveness of ESCs are controlled by a complex array of hormones, growth factors, chemokines and inflammatory mediators, and involve signalling through Rho GTPases, phosphatidylinositol-3-kinase and mitogen-activated protein kinase pathways.

CONCLUSIONS

Novel concepts are extending our understanding of the key functions of ESCs in effecting tissue repair imposed by cyclic menstruation and parturition. Migration of decidualizing ESCs also serves to support blastocyst implantation and embryo selection through discriminate motile responses directed by embryo quality. Targeting regulatory molecules holds promise for developing new strategies for the treatment of reproductive disorders such as endometriosis and recurrent miscarriage; and harnessing the migratory capacity of progenitor mesenchymal stem cells in the endometrium may offer new opportunities in regenerative medicine.

Source:
http://humupd.oxfordjournals.org/cgi/content/short/19/5/542?rss=1

Motile sperm organelle morphology examination (MSOME) and sperm head vacuoles: state of the art in 2013

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BACKGROUND

Approximately 10 years after the first publication introducing the motile sperm organelle morphology examination (MSOME), many questions remained about sperm vacuoles: frequency, size, localization, mode of occurrence, biological significance and impact on male fertility potential. Many studies have tried to characterize sperm vacuoles, to determine the sperm abnormalities possibly associated with vacuoles, to test the diagnostic value of MSOME for male infertility or to question the benefits of intracytoplasmic morphologically selected sperm injection (IMSI).

METHODS

We searched PubMed for articles in the English language published in 2001–2012 regarding human sperm head vacuoles, MSOME and IMSI.

RESULTS

A bibliographic analysis revealed consensus for the following findings: (i) sperm vacuoles appeared frequently, often multiple and preferentially anterior; (ii) sperm vacuoles and sperm chromatin immaturity have been associated, particularly in the case of large vacuoles; (iii) teratozoospermia was a preferred indication of MSOME and IMSI.

CONCLUSION

The high-magnification system appears to be a powerful method to improve our understanding of human spermatozoa. However, its clinical use remains unclear in the fields of male infertility diagnosis and assisted reproduction techniques (ARTs).

Source:
http://humupd.oxfordjournals.org/cgi/content/short/19/5/527?rss=1

Structural and functional plasticity of the luteinizing hormone/choriogonadotrophin receptor

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BACKGROUND

In recent years it became evident that several types of the luteinizing hormone/choriogonadotrophin receptor (LHCGR) exist. In addition to the classical receptor type known in rodents, an LHCGR type containing an additional exon is present in primates and humans. This specific exon 6A introduces a hitherto unknown regulatory pathway of the LHCGR at the transcriptional level which can lead to the expression of an alternative protein covering the extracellular part only. Furthermore, an LHCGR type lacking exon 10 at the mRNA and protein levels has been described in the New World primate lineage, giving rise to an additional receptor type in which amino acids of the extracellular hinge region connecting the leucine-rich repeat domain and transmembrane domain are missing.

METHODS

Topic-related information was retrieved by systematic searches using Medline/PubMed. Structural homology models were retrieved from a glycoprotein hormone receptors web application and from recent publications.

RESULTS

In a novel approach, we combine functional aspects with three-dimensional properties of the LHCGR and the different receptor types to deduce causative relationships between these two parameters. On this basis, the physiological impact and patho-physiological consequences of the different LHCGR types are inferred.

CONCLUSIONS

The complex system of different LHCGR types and two corresponding hormones (LH and CG) represents a major challenge for future studies on selective hormone binding, signal transduction and receptor regulation. The presence of these naturally occurring LHCGR types requires re-examining of our present view on receptor function, experimental set-ups and data interpretation, but also offers new clinical approaches to interfere with LH/CG action in humans.

Source:
http://humupd.oxfordjournals.org/cgi/content/short/19/5/583?rss=1

Prevalence of endometriosis diagnosed by laparoscopy in adolescents with dysmenorrhea or chronic pelvic pain: a systematic review

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BACKGROUND

Endometriosis associated with pain symptoms in adolescents has been extensively reported, but the exact prevalence is unclear because pain symptoms may be atypical and endometriosis can only be diagnosed by laparoscopy. The aim of this paper is to provide a systematic review of the prevalence of endometriosis diagnosed by laparoscopy in adolescents.

METHODS

A systematic literature search was carried out for relevant articles published between 1980 and 2011 in the databases PUBMED and EMBASE, based on the keywords ‘endometriosis’, ‘laparoscopy’, ‘adolescents’ and ‘chronic pelvic pain (CPP)’. In addition, the reference lists of the selected articles were examined.

RESULTS

Based on 15 selected studies, the overall prevalence of visually confirmed endometriosis was 62% (543/880; range 25–100%) in all adolescent girls undergoing laparoscopic investigation, 75% (237/314) in girls with CPP resistant to treatment, 70% (102/146) in girls with dysmenorrhea and 49% (204/420) in girls with CPP that is not necessarily resistant to treatment. Among the adolescent girls with endometriosis, the overall prevalence of American Society of Reproductive Medicine classified moderate–severe endometriosis was 32% (82/259) in all girls, 16% (17/108) in girls with CPP resistant to treatment, 29% (21/74) in girls with dysmenorrhea and 57% (44/77) in girls with CPP that is not necessarily resistant to treatment. Due to the quality of the included papers an overestimation of the prevalence and/or severity of endometriosis is possible.

CONCLUSIONS

About two-thirds of adolescent girls with CPP or dysmenorrhea have laparoscopic evidence of endometriosis. About one-third of these adolescents with endometriosis have moderate–severe disease. The value of early detection of endometriosis in symptomatic adolescents and the indications for laparoscopic investigation in adolescents require more research.

Source:
http://humupd.oxfordjournals.org/cgi/content/short/19/5/570?rss=1

Density gradient centrifugation prior to cryopreservation and hypotaurine supplementation improve post-thaw quality of sperm from infertile men with oligoasthenoteratozoospermia

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STUDY QUESTION

Can selection of spermatozoa by density gradient centrifugation prior to cryopreservation and/or hypotaurine supplementation improve the post-thaw quality of sperm from infertile men with oligoasthenoteratozoospermia?

SUMMARY ANSWER

Sperm selection by density gradient centrifugation before freezing and supplementation of the media by hypotaurine is beneficial for the cryopreservation of semen samples of patients with oligoasthenoteratozoospermia.

WHAT IS KNOWN ALREADY

Sperm from men with oligoasthenoteratozoospermia are more susceptible than normal to cryoinjury. Density gradient centrifugation before sperm freezing may allow the selection of a subpopulation of spermatozoa more resistant to cryopreservation. Hypotaurine is an antioxidant with a protective effect on sperm functions.

STUDY DESIGN, SIZE, DURATION

The experiment was carried out according to a factorial design involving two binary factors resulting in four treatment combinations which were randomly allocated in oligoasthenoteratozoospermia sperm samples from 64 patients recruited between January 2009 and June 2010.

PARTICIPANTS/MATERIALS, SETTING, METHODS

Semen was provided by 64 men undergoing evaluation for infertility at the Centre for Reproductive Medicine of the University Hospital in Clermont-Ferrand, France, between January 2009 and June 2010. Four treatment combinations were tested: sperm freezing before selection without (F-S/H–; n = 16) and with hypotaurine supplementation (F-S/H+; n = 16); sperm selection before freezing without (S-F/H–; n = 16) and with hypotaurine supplementation (S-F/H+; n = 16). Measurements of sperm recovery rates and markers of apoptosis (externalization of phosphatidylserine (PS), mitochondrial membrane potential and DNA fragmentation) were compared in recovered spermatozoa after each procedure.

MAIN RESULTS AND THE ROLE OF CHANCE

Higher recovery rates of progressive and total motile spermatozoa were observed when sperm selection was performed before freezing (P < 0.05). The protective effect of hypotaurine was only observed on the percentage of live spermatozoa with PS externalization among total live spermatozoa (AN+ PI–/((AN+ PI–) + (AN– PI–)) when the sperm selection by density gradient centrifugation was performed before freezing (S-F/H+ versus S-F/H–: 6.8 ± 1.09 versus 11.8 ± 2.03%, P = 0.04). The percentage of mitochondrial membrane potential (DiOC6(3) high) spermatozoa was higher (P = 0.001) when sperm selection was done before freezing compared with procedures in which sperm selection was done after sperm freezing with (S-F/H+ versus F-S/H+: 58.1 ± 3.50 versus 46.7 ± 5.48%) or without (S-F/H– versus F-S/H–: 57.0 ± 5.18 versus 35.4 ± 4.99%) hypotaurine supplementation. The percentages of TUNEL+ spermatozoa were significantly lower (P = 0.001) when sperm selection was done before sperm freezing compared with procedures in which sperm selection was done after sperm freezing with (S-F/H+ versus F-S/H+: 38.6 ± 9.59 versus 55.7 ± 5.88%) or without hypotaurine supplementation (S-F/H– versus F-S/H–: 37.2 ± 7.91 versus 71.0 ± 5.66%).

LIMITATIONS, REASONS FOR CAUTION

The ICSI outcomes were not assessed and the fertility of the spermatozoa remains unknown.

WIDER IMPLICATIONS OF THE FINDINGS

Sperm selection by density gradient centrifugation before freezing and hypotaurine supplementation could improve the cryopreservation of sperm from oligoasthenoteratozoospermic men and make a larger number of functional spermatozoa available for ICSI.

STUDY FUNDING/COMPETING INTERETS(S)

This work was supported by a hospital grant (Projet Hospitalier Recherche Clinique, CHU Clermont Ferrand, France). None of the authors has any conflict of interest to declare.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/8/2045?rss=1

The ESHRE/ESGE consensus on the classification of female genital tract congenital anomalies

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STUDY QUESTION

What classification system is more suitable for the accurate, clear, simple and related to the clinical management categorization of female genital anomalies?

SUMMARY ANSWER

The new ESHRE/ESGE classification system of female genital anomalies is presented.

WHAT IS KNOWN ALREADY

Congenital malformations of the female genital tract are common miscellaneous deviations from normal anatomy with health and reproductive consequences. Until now, three systems have been proposed for their categorization but all of them are associated with serious limitations.

STUDY DESIGN, SIZE AND DURATION

The European Society of Human Reproduction and Embryology (ESHRE) and the European Society for Gynaecological Endoscopy (ESGE) have established a common Working Group, under the name CONUTA (CONgenital UTerine Anomalies), with the goal of developing a new updated classification system. A scientific committee (SC) has been appointed to run the project, looking also for consensus within the scientists working in the field.

PARTICIPANTS/MATERIALS, SETTING, METHODS

The new system is designed and developed based on (i) scientific research through critical review of current proposals and preparation of an initial proposal for discussion between the experts, (ii) consensus measurement among the experts through the use of the DELPHI procedure and (iii) consensus development by the SC, taking into account the results of the DELPHI procedure and the comments of the experts. Almost 90 participants took part in the process of development of the ESHRE/ESGE classification system, contributing with their structured answers and comments.

MAIN RESULTS AND THE ROLE OF CHANCE

The ESHRE/ESGE classification system is based on anatomy. Anomalies are classified into the following main classes, expressing uterine anatomical deviations deriving from the same embryological origin: U0, normal uterus; U1, dysmorphic uterus; U2, septate uterus; U3, bicorporeal uterus; U4, hemi-uterus; U5, aplastic uterus; U6, for still unclassified cases. Main classes have been divided into sub-classes expressing anatomical varieties with clinical significance. Cervical and vaginal anomalies are classified independently into sub-classes having clinical significance.

LIMITATIONS, REASONS FOR CAUTION

The ESHRE/ESGE classification of female genital anomalies seems to fulfill the expectations and the needs of the experts in the field, but its clinical value needs to be proved in everyday practice.

WIDER IMPLICATIONS OF THE FINDINGS

The ESHRE/ESGE classification system of female genital anomalies could be used as a starting point for the development of guidelines for their diagnosis and treatment.

STUDY FUNDING/COMPETING INTEREST(S)

None.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/8/2032?rss=1

Altered expression of interleukin-6, interleukin-8 and their receptors in decidua of women with sporadic miscarriage

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STUDY QUESTION

Are alterations in decidual expression of interleukin (IL)-6 and IL-8 associated with sporadic miscarriage?

SUMMARY ANSWER

IL-6 and IL-8 secretion from decidual uterine natural killer (uNK) cells and macrophages isolated from women with spontaneous miscarriage was reduced compared with normal controls.

WHAT IS KNOWN ALREADY

Miscarriage is a common gynaecological problem with huge financial and personal implications. Eleven to twenty per cent of all clinically recognized pregnancies are lost before the 20th week of gestation, with miscarriages often being divided into early (≤12 completed weeks from last menstrual period) and late (≥13 weeks). Spiral artery remodelling is a key feature of early pregnancy; failure of this process has been implicated in sporadic miscarriage. The molecular triggers that initiate spiral artery remodelling are not clear, although cytokines such as IL-6 and IL-8 may play a role.

STUDY DESIGN, SIZE, DURATION

This was a laboratory-based study using decidual and placental bed biopsy samples from women with sporadic miscarriage (n = 30) and termination of pregnancy controls (n = 30).

PARTICIPANTS/MATERIALS, SETTING, METHODS

Total adherent decidual cells, CD10+ stromal cells, CD14+ macrophages and CD56+ uNK cells were isolated from decidua from apparently normal pregnancies that were terminated at either 8–10 or 12–14 weeks' gestation. In addition, CD14+ macrophages and CD56+ uNK cells were isolated from decidua from sporadic miscarriage at 8–10 weeks' gestation. Secreted IL-8 was measured in all isolated cell populations, while IL-6 was measured in CD14+ macrophages and CD56+ uNK cells from both sporadic miscarriage and normal controls. Placental bed biopsies were taken from women after sporadic miscarriage or termination of pregnancy at ≤12 completed weeks' or >13 weeks' gestational age, formalin-fixed, paraffin-embedded and immunostained for IL-6, IL-6Rα, GP130, IL-8, CXCR1, CXCR2 and CD13 (aminopeptidase N). Staining intensity for each factor was assessed in extravillous trophoblast cell populations, myometrial and decidual stroma, myometrial and decidual spiral arteries and decidual glandular epithelium. A CPA model was used to assess the potential role of IL-6 and IL-8 in spiral artery remodelling.

MAIN RESULTS AND THE ROLE OF CHANCE

IL-8 was secreted by total adherent decidual cells, CD10+ stromal cells and CD14+ macrophages at both 8–10 and 12–14 weeks' gestation, with CD14+ cells secreting the highest levels. Both CD14+ and CD56+ cells isolated from decidua of early sporadic miscarriage produced lower IL-6 (P = 0.04, P = 0.01, respectively) and IL-8 levels (P = 0.0007, P = 0.002, respectively) compared with normal cases. In addition, altered expression of IL-6, IL-8 and their receptors was observed in various cell types in placental bed (myometrial stroma, glandular epithelium, interstitial extravillous trophoblast cells, vascular smooth muscle cells and endothelial cells) in sporadic miscarriage, particularly from later gestational ages. IL-6 and IL-8 disrupted vascular smooth muscle morphology and organization in an in vitro model of spiral artery remodelling.

LIMITATIONS, REASONS FOR CAUTION

By the nature of sampling at the time of miscarriage, it was not possible to ascertain the cause or effect in the observed alterations of levels of IL-6 and IL-8 in sporadic miscarriage.

WIDER IMPLICATIONS OF THE FINDINGS

Alterations in the expression of IL-6, IL-8 and their receptors may be associated with the aetiology of sporadic miscarriage, especially given the potential role of these cytokines in the regulation of trophoblast invasion and spiral artery remodelling.

STUDY FUNDING/COMPETING INTEREST(S)

This project was supported by funding from Wellbeing of Women (RG1000). The authors have no competing interests to declare.

TRIAL REGISTRATION NUMBER

Not applicable.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/8/2075?rss=1