BACKGROUND

Uterine adenomyosis was initially thought to be found only in parous women, and final diagnosis was made at histology after hysterectomy. With better imaging techniques and with women attending clinics at older ages, adenomyosis is diagnosed with increasing frequency in women attending infertility clinics. A dozen conservative interventions have been advocated, with variable reports of their impact on fertility. This presents a dilemma for clinicians managing such patients. Hence, this systematic review of adenomyosis was performed to determine (i) the prevalence in a subfertile population, (ii) the accuracy of diagnostic tests, (iii) the efficacy of fertility sparing treatment options and (iv) the reproductive and obstetric/perinatal outcomes in women with adenomyosis.

METHODS

Systematic searches of various databases were performed independently by two reviewers, and data were extracted according to predefined criteria by two reviewers.

RESULTS

There is little data on the epidemiology of adenomyosis associated with subfertility. Both magnetic resonance imaging and ultrasound are non-invasive tests with equivalent accuracy in diagnosing adenomyosis (area under curve 0.91 and 0.88, respectively). Most studies on treatments have been uncontrolled and outcomes are usually reported in the form of case series. Hence, the true impact of various treatments on fertility is not known. There are variable reports of the impact of adenomyosis on the success of IVF. Increased incidence of preterm labour and premature rupture of membranes has been reported in women with adenomyosis.

CONCLUSIONS

Further studies are needed to determine the natural history of adenomyosis and implications for fertility and reproductive outcomes, with and without treatment. Currently, there is no evidence that we should find and treat adenomyosis in patients who wish to conceive.

Source:
http://humupd.oxfordjournals.org/rss/current.xml

BACKGROUND

Increasing age and post-menopausal status are associated with decreasing androgen concentrations in females. Women with premature loss of ovarian function, such as primary ovarian insufficiency (POI) or iatrogenic menopause may be at increased risk for diminished testosterone levels at a relatively young age. Differentiation between a hypoandrogenic or normoandrogenic state in women with premature loss of ovarian function is problematic due to trueness and precision problems using various testosterone assays. The current meta-analysis was conducted to evaluate current literature reporting serum total testosterone concentrations under these conditions, including stratification for various testosterone assays.

METHODS

A systematic review and meta-analysis of controlled observational studies were performed. The electronic databases of Pubmed, Embase and the Cochrane Library were systematically searched until October 2011 for comparative studies on total testosterone concentrations in women with spontaneous POI or iatrogenic menopause compared with controls. The literature search, data extraction and critical appraisal, using the Newcastle–Ottawa Scale, were performed by two independent investigators. The effect measure was the weighted mean difference (WMD) with 95% confidence interval (95% CI) in a random effects model.

RESULTS

A total of 206 articles for spontaneous POI and 1358 for iatrogenic menopause were reviewed, of which 9 and 17 papers, respectively, were selected for final analysis. Both groups demonstrated significantly lower total testosterone concentrations compared with controls [WMD (95% CI) –0.38 (–0.55 to –0.22) nmol/l, and –0.29 (–0.39 to –0.18) nmol/l, respectively], but with substantial between-study heterogeneity. Subgroup analysis for assay type was statistically significant for spontaneous POI only. Sensitivity analyses of high-quality studies did not change the results, and resulted in a substantial decrease in heterogeneity in spontaneous POI studies.

CONCLUSIONS

The current meta-analysis demonstrates that total testosterone concentrations are decreased in women with spontaneous POI or iatrogenic menopause. The potential implications of hypoandrogenism in these women remain to be elucidated.

Source:
http://humupd.oxfordjournals.org/rss/current.xml

BACKGROUND

Spermatogenesis culminates in production of one of the most highly differentiated cells in biology, the spermatozoon. The gametes that emerge from the testes are, however, functionally immature and only acquire full functionality once they have completed a process of post-testicular maturation in the epididymis and female reproductive tract. Remarkably, this acquisition of sperm function occurs while these cells are transcriptionally and translationally silent and is therefore highly dependent on post-translational modifications to their existing protein complement. In this review, we consider the emerging roles of several prominent molecular chaperone families in orchestrating both the morphological differentiation of male germ cells during spermatogenesis and their functional transformation during sperm maturation.

METHODS

Journal databases were searched using key words, including chaperone, heat shock protein, testes, spermatogenesis, spermatozoa, epididymal maturation, capacitation and fertilization.

RESULTS

In the past two decades, molecular chaperones have been acknowledged to play key roles in controlling both the morphological transformation of germ cells during spermatogenesis and the post-testicular maturation of these cells as they transit the male and female reproductive tracts. Furthermore, there is mounting evidence that aberrant chaperone expression may be a major contributing factor to the defective sperm function seen in many cases of male infertility.

CONCLUSIONS

Molecular chaperones are critically involved in all phases of sperm development. Targeted disruption of these proteins has the ability to arrest spermatogenesis, compromise sperm maturation and inhibit fertilization. These proteins therefore hold considerable promise as targets for novel contraceptive strategies and as diagnostic biomarkers for male infertility.

Source:
http://humupd.oxfordjournals.org/rss/current.xml

BACKGROUND

During pregnancy, maternal uterine spiral arteries (SAs) are remodelled from minimal-flow, high-resistance vessels into larger diameter vessels with low resistance and high flow. Fetal extravillous trophoblasts (EVT) have important roles in this process. Decidual natural killer cells (dNK cells) are the major maternal immune component of the decidua and accumulate around SAs before trophoblast invasion. A role for dNK cells in vessel remodelling is beginning to be elucidated. This review examines the overlapping and dissimilar mechanisms used by EVT and dNK cells in this process and how this may mirror another example of tissue remodelling, namely cancer development.

METHODS

The published literature was searched using Pubmed focusing on EVT, dNK cells and SA remodelling. Additional papers discussing cancer development are also included.

RESULTS

Similarities exist between actions carried out by dNK cells and EVT. Both interact with vascular cells lining the SA, as well as with each other, to promote transformation of the SA. EVT differentiation has previously been likened to the epithelial–mesenchymal transition in cancer cells, and we discuss how dNK–EVT interactions at the maternal–fetal interface can also be compared with the roles of immune cells in cancer.

CONCLUSIONS

The combined role that dNK cells and EVT play in SA remodelling suggests that these interactions could be described as a partnership. The investigation of pregnancy as a multicellular system involving both fetal and maternal components, as well as comparisons to similar examples of tissue remodelling, will further identify the key mechanisms in SA remodelling that are required for a successful pregnancy.

Source:
http://humupd.oxfordjournals.org/rss/current.xml

BACKGROUND

Pre-eclampsia, small-for-gestational-age infants, preterm birth and recurrent miscarriage complicate a significant number of pregnancies. The vascular endothelial growth factor (VEGF) family of angiogenic growth factors is implicated in the pathophysiology of these complications. We aimed to elucidate the role of these angiogenic factors in placentation and to evaluate the predictive value of their protein concentrations and genetic variations in pregnancy complications.

METHODS

We performed a systematic search of PubMed, and retrieved original articles. The search included a combination of terms such as VEGF-A, placental growth factor (PlGF), kinase insert domain receptor, fms-like-tyrosine-kinase receptor 1, soluble fms-like-tyrosine-kinase receptor 1, pre-eclampsia, small-for-gestational-age infants, preterm birth, recurrent miscarriage, placenta, prediction and polymorphisms.

RESULTS

This review summarizes the current knowledge of the roles of the VEGF family in early placentation and of the abnormalities in maternal plasma and placental expression of angiogenic proteins in adverse pregnancy outcomes compared with normal pregnancy. PlGF and sFLT-1 in combination with other clinical and biochemical markers in late first or second trimester appear to predict early-onset pre-eclampsia with a high sensitivity and specificity. However, VEGF family proteins do not have sufficient power to accurately predict late-onset pre-eclampsia, small-for-gestational age pregnancies or preterm birth. Functional polymorphisms in these angiogenic genes are implicated in pregnancy complications, but their contribution appears to be minor.

CONCLUSIONS

Although the VEGF family has important roles in normal and complicated pregnancy, the current predictive value of the VEGF family as biomarkers appears to be limited to early-onset pre-eclampsia.

Source:
http://humupd.oxfordjournals.org/rss/current.xml

Unexplained recurrent miscarriage (RM) can be a challenging and frustrating condition for both patients and clinicians. For the former, there is no diagnosis available for consolation, while for the latter there is little evidence-based treatment to offer. However, the majority of these patients have an excellent prognosis without the need for any treatment. Epidemiological associations suggest that the reason for this is that the majority of women with unexplained RM are in fact healthy individuals, with no underlying pathology, who have suffered three miscarriages purely by chance. Nevertheless, a certain proportion of women with unexplained RM will continue to miscarry, and preliminary studies suggest the presence of pathology in some women of this group. As a result, two types of unexplained RM can be described: Type I unexplained RM, which occurs by chance in women who have no underlying pathology and has a good prognosis; and Type II unexplained RM, which occurs due to an underlying pathology that is currently not yet identified by routine clinical investigations and has a poorer prognosis. Distinguishing between Types I and II unexplained RM can be achieved by considering several factors: the age of the woman, the definition used for RM (i.e. whether biochemical pregnancy losses are considered as miscarriages), the number of previous miscarriages suffered and the karyotype of the products of conception, where available. A better understanding of the two types of unexplained RM could lead to more targeted referrals, investigations and treatments, which would improve cost-effectiveness and overall clinical care.

Source:
http://humrep.oxfordjournals.org/rss/current.xml

BACKGROUND

Acrosome biogenesis is a key event in sperm differentiation that depends on the proper interaction between the Golgi complex and the nuclear envelope of early spermatids. We studied the development, structure and biochemical characteristics of human acrosomes in germ cells and spermatozoa from testicular biopsies and semen samples of fertile men and patients with acrosomeless spermatozoa (globozoospermia). A set of proteins collectively known as the perinuclear theca (PT), which has been related to acrosomal development in many mammalian species, were also investigated.

METHODS

We evaluated spermatozoa from five males with globozoospermia and six fertile men, and immature germ cells from testicular biopsies of one globozoospermic patient and three men with obstructive azoospermia. Samples were assessed by transmission electron microscopy, immunofluorescence microscopy, ultrastructural immunocytochemistry and proteomic analysis by western blot.

RESULTS

In normal spermiogenesis, the development of the acrosome depends on the correct formation of Golgi-derived proacrosomal vesicles and simultaneous modifications in the nuclear envelope. PT proteins are consistently found in proacrosomic vesicles, localize underneath the acrosome and expand over the nuclear surface along acrosome biogenesis. In fertile men, the PT is composed of six proteins, similar to those previously described for other mammals (16, 22, 29, 34, 50 and 68 kDa). In globozoospermia, abnormal proacrosomal vesicles and paranuclear multivesicular and multilamellar structures were observed that resulted in acrosomes insufficiently developed or detached from the nuclear envelope. PT proteins, dissociated from the acrosomes, were ectopically localized in the cytoplasm. Proteomic analysis showed a significant decrease in all six PT proteins.

CONCLUSIONS

The alterations observed during early acrosome biogenesis in globozoospermia are due to anomalous development of Golgi-derived proacrosomic vesicles, failure of PT proteins to properly associate with the nuclear surface and significant deficiencies in specific PT components that are necessary for proper acrosome formation, implantation and expansion over the spermatid nucleus.

Source:
http://humrep.oxfordjournals.org/rss/current.xml

BACKGROUND

The aneuploidy rate is higher in poor-quality sperm samples, which also have higher DNA fragmentation index values. The aim of this study was to assess the relationship between sperm DNA fragmentation in samples from infertile men belonging to couples with recurrent miscarriage or implantation failure and the aneuploidy rate in spermatozoa as well as in embryos from patients.

METHODS

This prospective study evaluated DNA damage and the aneuploidy rate in fresh and processed (density gradient centrifugation) ejaculated sperm as well as the aneuploidy rate in biopsied embryos from fertility cycles. Fluorescence in situ hybridization was used for the aneuploidy analysis. Results were compared using linear regression and analysis of variance.

RESULTS

A total of 154 embryos were evaluated from 38 patients undergoing PGD cycles; 35.2% of the embryos were chromosomally normal. Analysis of the same sperm samples showed an increased DNA fragmentation after sperm preparation in 76% of the patients. There was no correlation between DNA fragmentation and the aneuploidy rate in embryos or in fresh or processed sperm samples.

CONCLUSIONS

Sperm DNA fragmentation is not related to chromosomal anomalies in embryos from patients with recurrent miscarriage or implantation failure. However, we cannot rule out the possibility that a relationship between DNA fragmentation and aneuploidy exists for other causes of infertility. Furthermore, the different methods used to evaluate DNA fragmentation may produce different results.

Source:
http://humrep.oxfordjournals.org/rss/current.xml

AZFc deletions of the Y chromosome are the major known genetic cause of spermatogenetic failure. Meiotic studies have shown a prevalence of synaptonemal complex fragmentation and an excess of early-stage sperm cells, suggesting that the maturation block could involve apoptosis. We present a prospective and observational study of apoptotic markers in the sperm of four AZFc-deleted patients and two non-obstructive azoospermic controls without an AZFc deletion. Polycaspases assays and terminal deoxynucleotidyl transferase dUDP nick-end labelling (TUNEL) assays were combined to evaluate the incidence of apoptosis in pre-meiotic, meiotic and post-meiotic germs cells identified, respectively, using anti-melanoma-associated antigen A4 (MAGE-A4), anti-synaptonemal complex protein 3 (SCP3) and anti-sperm acrosome membrane-associated protein 1 (SPACA1) antibodies. We detected apoptosis at all stages of AZFc-deletion spermatogenesis. Using the caspase assay, the incidence of positive cells was found to be heterogeneous for pre-meiotic (from 4.8 to 84.5%) and meiotic stages (from 7.9 to 57.6%), while for post-meiotic cells, the mean incidence was 6% in AZFc-deleted patients compared with 26.5% in controls (P < 0.05). Using the TUNEL assay, the mean percentage with DNA fragmentation for meiotic cells was 54.0% in AZFc-deleted patients compared with 20.3% in controls (P < 0.05), while the percentage of TUNEL-positive post-meiotic cells ranged from 5.3 to 44.7%. Spermatocyte loss in AZFc-deleted patients occurs via the apoptotic pathway. In post-meiotic cells, the lower incidence of apoptosis in testis from three of the four AZFc-deleted patients, compared with controls, is consistent with AZFc deletions having little negative impact on sperm quality.

Source:
http://humrep.oxfordjournals.org/rss/current.xml

BACKGROUND

Human sperm nuclear decondensation in vivo involves protamine disulfide bond reduction by glutathione (GSH) and protamine/histone exchange, presumably with heparan sulfate (HS) as the protamine acceptor. The aim of the present study was to test the hypothesis that these two events occur simultaneously rather than sequentially, as has been hitherto accepted, and to test for the presence of HS in the human oocyte.

METHODS

Spermatozoa and isolated sperm nuclei obtained from normal volunteers were exposed in vitro to heparin, the functional analogue of HS and either GSH or dithiothreitol (DTT) as the disulfide reducing agent. Decondensing reagents were added either simultaneously or sequentially. Percentage sperm nuclear decondensation was assayed by phase contrast microscopy. Thiol reduced status of isolated sperm nuclei was evaluated both indirectly [acridine orange (AO) staining of acid-denatured DNA] and directly [monobromobimane (mBBr) staining of protamine-free thiols]. The presence of HS in mature metaphase II (MII) human oocytes was analyzed by immunocytochemistry.

RESULTS

Sequential addition of reagents always resulted in significantly lower decondensation if GSH was used as the disulfide bond reducer (P < 0.05 for sperm and P < 0.001 for nuclei), but only when heparin was used first, when DTT was the disulfide reducing agent (P < 0.05 for sperm and P < 0.01 for nuclei). Both AO staining of DNA and mBBr staining of protamines revealed that the addition of heparin to GSH but not to DTT significantly increased the thiol reduced status of sperm chromatin. HS was detected in the ooplasm of zona-free MII human oocytes.

CONCLUSIONS

The results presented in this paper clearly show that heparin enhances the sperm chromatin thiol reducing activity of GSH in vitro, suggesting that in vivo thiol reduction and protamine/histone exchange could occur as simultaneous, rather than sequential, events. We also demonstrate for the first time the presence of HS in the human oocyte.

Source:
http://humrep.oxfordjournals.org/rss/current.xml

BACKGROUND

Several studies have suggested that endometrial interleukin 15 (IL-15) and the leukaemia inhibitory factor (LIF) may be important in embryo implantation. IL-15 is postulated to play a role in the control of uterine natural killer (uNK) cell proliferation and function, and uNK cells are also known to play a role in implantation. The aims of this study was to (1) compare endometrial levels of IL-15 and the LIF in women with recurrent implantation failure (RIF) after IVF with those in fertile women (controls) and (2) examine the relation of IL-15 and LIF levels to the uNK cell number.

METHODS

We investigated IL-15 and LIF in precisely timed endometrial biopsies (days LH + 7-LH + 9, where the day of the LH surge is LH + 0) obtained from control women (n = 15) and women with RIF (n = 45) by immunohistochemistry. A semi-quantitative analysis was performed by the H-score analysis of staining intensity in the stroma, glandular epithelium and luminal epithelium, separately. We also correlated expression of LIF and IL15 with uNK cell numbers (obtained in an earlier study of the same samples).

RESULTS

The quantity of the LIF protein in endometrial glandular epithelium in women with RIF [median and range; 179 (70–365)] was lower (P = 0.01) than in control women [median and range; 247 (120–287)]. In contrast, the level of the IL-15 protein in the stroma in women with RIF [median and range; 90 (0–175)] was higher (P = 0.009) than in control women [median and range; 60 (15–150)]. There was a significant correlation between the uNK cell number and stromal expression of IL-15 (r = 0.427, P = 0.001). No correlation between the LIF expression in any compartment and the uNK cell number was seen.

CONCLUSIONS

The results show an altered expression of LIF and IL-15 in the endometrium of women with RIF. Despite the limitation of not identifying uNK cells by phenotypic markers, the correlation between the uNK cell number and the stromal cell IL-15 suggests that IL-15 may play a role in the control of endometrial uNK cell function or proliferation.

Source:
http://humrep.oxfordjournals.org/rss/current.xml

BACKGROUND

We have previously shown that the medium used for culturing IVF embryos affects the birthweight of the resulting newborns. This observation with potentially far-reaching clinical consequences during later life, was made in singletons conceived during the first IVF treatment cycle after the transfer of fresh embryos. In the present study, we hypothesize that in vitro culture of embryos during the first few days of preimplantation development affects perinatal outcome, not only in singletons conceived in all rank order cycles but also in twins and in children born after transfer of frozen embryos. Furthermore, we investigated the effect of culture medium on gestational age (GA) at birth.

METHODS

Oocytes and embryos from consecutive treatment cycles were alternately assigned to culture in either medium from Vitrolife or from Cook. Data on a cohort of 294 live born singletons conceived after fresh transfer during any of a patient's IVF treatment cycles, as well as data of 67 singletons conceived after frozen embryo transfer (FET) and of 88 children of 44 twin pregnancies after fresh transfer were analysed by means of multiple linear regression.

RESULTS

In vitro culture in medium from Cook resulted in singletons after fresh transfer with a lower mean birthweight (adjusted mean difference, 112 g, P= 0.03), and in more singletons with low birthweight (LBW) <2500 g (P= 0.006) and LBW for GA ≥37 weeks (P= 0.015), when compared with singletons born after culture in medium from Vitrolife AB. GA at birth was not related to the medium used (adjusted difference, 0.05 weeks, P = 0.83). Among twins in the Cook group, higher inter-twin mean birthweight disparity and birthweight discordance were found. Z-scores after FET were –0.04 (±0.14) in the Cook group compared with 0.18 (±0.21) in the Vitrolife group (P> 0.05).

CONCLUSIONS

Our findings support our hypothesis that culture medium influences perinatal outcome of IVF singletons and twins. A similar trend is seen in case of singletons born after FET. GA was not affected by culture medium. These results indicate that in vitro culture might be an important factor explaining the poorer perinatal outcome after assisted reproduction technology (ART). Further research is needed to confirm this culture medium-induced effect in humans and to provide more insight into whether it is caused by epigenetic disturbance of imprinted genes in fetal or placental tissues. Moreover, embryo culture media and their effects need to be investigated thoroughly to select the best embryo culture medium in order to minimize or prevent short-term risks and maybe even long-term disease susceptibility.

Source:
http://humrep.oxfordjournals.org/rss/current.xml

BACKGROUND

Our previous studies have demonstrated that cyclosporin A (CsA) can increase the cell number in and invasion by human first-trimester trophoblasts and induce maternal–fetal tolerance. C-X-C chemokine receptor type 4 (CXCR4) and C-X-C chemokine ligand 12 (CXCL12) are important mediators at the maternal–fetal interface during early pregnancy. In this study, we further investigate the molecular mechanisms underlying modulation by CsA of the crosstalk between human cytotrophoblast and decidual stromal cell (DSC).

METHODS

Human first-trimester cytotropoblast and DSC were treated with CsA in the absence or presence of U0126 pretreatment, and then the mRNA and protein levels of CXCL12 and CXCR4 were measured by RT–PCR, qPCR, in-cell western blots and enzyme-linked immunosorbent assay (ELISA), respectively. 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide and Matrigel invasion assays were used to determine the invasiveness of cytotrophoblast, respectively. The activity of matrix metalloproteinase (MMP)-9 and MMP-2 was detected by gelatin zymography. A co-culture with direct contact between cytotrophoblast and DSC was established and used to investigate the interaction between these two cells.

RESULTS

CsA up-regulated CXCL12 and CXCR4 expression in human first-trimester cytotrophoblast cells, but not in DSCs. Blocking the mitogen-activated proteinkinase/extracellular signal-regulated kinase (MAPK/ERK1/2) signaling by U0126 abrogated the CsA-induced increase in CXCL12 and CXCR4 expression and neutralizing antibodies to CXCL12 or CXCR4 completely inhibited the CsA-induced increase in cell number, invasion and MMP-9 and MMP-2 activity of cytotrophoblast. CsA also significantly promoted the activity of MMP-9 and MMP-2 in DSCs, but this was unaffected by CXCL12 or CXCR4 neutralizing antibody. Furthermore, the CsA-induced MMP-9 and MMP-2 activity and the invasiveness of cytotrophoblast in the cytotrophoblast and DSC co-culture were significantly increased compared with CsA-treated trophoblast cultured alone, and CXCR4 blocking antibody effectively abolished the increased MMP activity and invasion of cytotrophoblasts in the cytotrophoblast-DSC co-culture stimulated by CsA.

CONCLUSIONS

CsA can promote the crosstalk between cytotrophoblast and DSC through up-regulating CXCL12/CXCR4 interaction via MAPK signaling, resulting in the increased numbers of and invasion by human cytotrophoblast cells.

Source:
http://humrep.oxfordjournals.org/rss/current.xml

BACKGROUND

Despite the success of ICSI, total fertilization failure (TFF) still occurs in 1–3% of all ICSI cycles. ICSI followed by assisted oocyte activation (ICSI-AOA) can restore fertilization, most efficiently in cases of sperm-related fertilization deficiency. The indication for ICSI-AOA is less obvious when the capacity of the sperm to activate oocytes is considered normal, as proved by a heterologous ICSI model, such as the mouse oocyte activation test (MOAT). In this study, we verified whether ICSI-AOA is beneficial for patients in whom an oocyte-related activation deficiency is suspected.

METHODS

A prospective study was conducted including patients presenting with a history of TFF or low fertilization (LF) following conventional ICSI in our centre (in-house cases, n= 2) or elsewhere (out-house cases, n= 12). In all cases a sperm deficiency was refuted by the MOAT. In a next treatment cycle, ICSI-AOA was performed on half of the sibling metaphase II oocytes and conventional ICSI on the rest (‘split ICSI-AOA cycle’). The main outcome parameters were fertilization, pregnancy and live birth rates.

RESULTS

Overall, ICSI-AOA was able to improve fertilization rates in couples with a suspected oocyte-related fertilization problem, with a mean fertilization rate of 74.2% following ICSI-AOA compared with 43.5% following conventional ICSI (P< 0.001). Cumulative pregnancy rate and live birth rate per cycle were 35.7 and 14.3%, respectively. Considering the out-house patients only, fertilization rates with ICSI-AOA were higher in couples with previous TFF than with conventional ICSI (P< 0.001). Interestingly, for out-house patients who had experienced low, but not zero, fertilization elsewhere, ICSI-AOA could not enhance the fertilization rate. For the two in-house patients, both suffering from previous LF following conventional ICSI, the ICSI-AOA procedure enhanced the mean fertilization rate (25 versus 75%, respectively).

CONCLUSIONS

For patients with a suspected oocyte-related activation deficiency, as diagnosed by a heterologuous ICSI model, the indication for ICSI-AOA still remains debatable. Our data show that ICSI-AOA is very efficient in patients with a suspected oocyte-related activation deficiency and previous TFF after conventional ICSI. In contrast, when there was a history of LF in another centre, one should be careful and test the efficiency of ICSI-AOA on half of the sibling oocytes, because ICSI-AOA is not always beneficial for patients with previous LF and a suspected oocyte-related activation deficiency. For these patients, a split ICSI-AOA cycle using sibling oocytes can help to distinguish between a molecular oocyte-related activation deficiency and a previous technical or other biological failure. Moreover, this split ICSI-AOA strategy enables us to set the appropriate strategy for future treatment cycles. Further research with larger groups of patients is now required.

Source:
http://humrep.oxfordjournals.org/rss/current.xml

BACKGROUND

The role of the plasminogen-plasmin (PLG-PLA) system in fertilization is unknown, although its dysfunction has been associated with subfertility in humans. We have recently detected and quantified plasminogen in the oviductal fluid of two mammals and showed a reduction in sperm penetration during IVF when plasminogen is present. The objective of this study was to describe the mechanism by which PLG-PLA system regulates sperm entry into the oocyte.

METHODS AND RESULTS

By combining biochemical, functional, electron microscopic, immunocytochemical and live cell imaging methods, we show here that (i) plasminogen is activated into the protease plasmin, by gamete interaction; (ii) urokinase-type and tissue-type plasminogen activators are present in oocytes, but they are not of cortical granule origin; (iii) sperm binding to oocytes triggers the releasing of plasminogen activators and (iv) the generated plasmin causes sperm detachment from the zona pellucida.

CONCLUSIONS

Our results describe a novel mechanism for the success or failure of fertilization in mammals, by which molecules present in the oviductal environment are activated by molecules originating within the gametes. We anticipate that therapeutic up- or down-regulation of this physiological mechanism may be used to help in conception or as a contraceptive tool. Since components of the PLG-PLA system are already available as drugs for heart attacks or cancer therapies, basic research on this novel function would be rapidly transferable for clinical application.

Source:
http://humrep.oxfordjournals.org/rss/current.xml

BACKGROUND

Intrauterine devices (IUDs) have been studied for use for emergency contraception for at least 35 years. IUDs are safe and highly effective for emergency contraception and regular contraception, and are extremely cost-effective as an ongoing method. The objective of this study was to evaluate the existing data to estimate the efficacy of IUDs for emergency contraception.

METHODS

The reference list for this study was generated from hand searching the reference lists of relevant articles and our own article archives, and electronic searches of several databases: Medline, Global Health, Clinicaltrials.gov, Popline, Wanfang Data (Chinese) and Weipu Data (Chinese). We included studies published in English or Chinese, with a defined population of women who presented for emergency contraception and were provided with an IUD, and in which the number of pregnancies was ascertained and loss to follow-up was clearly defined. Data from each article were abstracted independently by two reviewers.

RESULTS

The 42 studies (of 274 retrieved) that met our inclusion criteria were conducted in six countries between 1979 and 2011 and included eight different types of IUD and 7034 women. The maximum timeframe from intercourse to insertion of the IUD ranged from 2 days to 10 or more days; the majority of insertions (74% of studies) occurred within 5 days of intercourse. The pregnancy rate (excluding one outlier study) was 0.09%.

CONCLUSIONS

IUDs are a highly effective method of contraception after unprotected intercourse. Because they are safe for the majority of women, highly effective and cost-effective when left in place as ongoing contraception, whenever clinically feasible IUDs should be included in the range of emergency contraception options offered to patients presenting after unprotected intercourse. This review is limited by the fact that the original studies did not provide sufficient data on the delay between intercourse and insertion of the IUD, parity, cycle day of intercourse or IUD type to allow analysis by any of these variables.

Source:
http://humrep.oxfordjournals.org/rss/current.xml

BACKGROUND

Interleukin 33 (IL-33) is a cytokine involved in fibrotic disorders. We have analyzed IL-33 levels in the sera and peritoneal fluids of women with various forms of endometriosis and investigated the correlation with disease activity.

METHODS

We conducted a prospective laboratory study in a tertiary-care university hospital between January 2005 and December 2010. Five hundred and ten women with histologically proven endometriosis and 132 endometriosis-free controls were enrolled in this study. Complete surgical exploration of the abdominopelvic cavity was performed in each patient. Blood samples and peritoneal fluids were obtained before and during surgical procedures, respectively. IL-33 was measured by an enzyme-linked immunosorbent assay in sera and peritoneal fluids, and the concentrations correlated with the extent and the severity of endometriotic lesions.

RESULTS

IL-33 was detectable in 23.1% of serum samples from all 642 women studied and 75.0% of peritoneal fluid samples studied (44 women with endometriosis and 36 controls). Serum IL-33 was higher in deeply infiltrating endometriosis (DIE) (median, 104.9 pg/ml; range, 8.0–104.9) than in endometriosis-free women (median, 61.3 pg/ml; range, 7.5–526.0; P = 0.022) or in women affected by superficial endometriosis (median, 36.8 pg/ml; range, 7.5–179.0; P < 0.001). Peritoneal IL-33 was higher in DIE than in endometriosis-free women (median, 642.0 pg/ml; range, 25.9–3350.6 versus median, 194.2 pg/ml; range, 12.7–1818.2, respectively; P = 0.003). We found positive correlations between serum IL-33 concentration and intensity of dysmenorrhea (r = 0.174; P = 0.028) and gastrointestinal symptoms (r = 0.199; P = 0.027), total number of DIE lesions (r = 0.224; P = 0.016) and the worst DIE lesion (r = 0.299; P < 0.001).

CONCLUSIONS

In spite of the number of samples with undetectable levels, serum IL-33 is abnormally elevated in women with endometriosis and principally in DIE. Elevated serum IL-33 is correlated with the intensity of preoperative painful symptoms, and with the extent and severity of the DIE. IL-33 may be considered as a novel cytokine involved in the pathogenesis of DIE.

Source:
http://humrep.oxfordjournals.org/rss/current.xml

BACKGROUND

An early semi-invasive diagnosis of endometriosis has the potential to allow early treatment and minimize disease progression but no such test is available at present. Our aim was to perform a combined mRNA microarray and proteomic analysis on the same eutopic endometrium sample obtained from patients with and without endometriosis.

METHODS

mRNA and protein fractions were extracted from 49 endometrial biopsies obtained from women with laparoscopically proven presence (n= 31) or absence (n= 18) of endometriosis during the early luteal (n= 27) or menstrual phase (n= 22) and analyzed using microarray and proteomic surface enhanced laser desorption ionization-time of flight mass spectrometry, respectively. Proteomic data were analyzed using a least squares-support vector machines (LS-SVM) model built on 70% (training set) and 30% of the samples (test set).

RESULTS

mRNA analysis of eutopic endometrium did not show any differentially expressed genes in women with endometriosis when compared with controls, regardless of endometriosis stage or cycle phase. mRNA was differentially expressed (P< 0.05) in women with (925 genes) and without endometriosis (1087 genes) during the menstrual phase when compared with the early luteal phase. Proteomic analysis based on five peptide peaks [2072 mass/charge (m/z); 2973 m/z; 3623 m/z; 3680 m/z and 21133 m/z] using an LS-SVM model applied on the luteal phase endometrium training set allowed the diagnosis of endometriosis (sensitivity, 91; 95% confidence interval (CI): 74–98; specificity, 80; 95% CI: 66–97 and positive predictive value, 87.9%; negative predictive value, 84.8%) in the test set.

CONCLUSION

mRNA expression of eutopic endometrium was comparable in women with and without endometriosis but different in menstrual endometrium when compared with luteal endometrium in women with endometriosis. Proteomic analysis of luteal phase endometrium allowed the diagnosis of endometriosis with high sensitivity and specificity in training and test sets. A potential limitation of our study is the fact that our control group included women with a normal pelvis as well as women with concurrent pelvic disease (e.g. fibroids, benign ovarian cysts, hydrosalpinges), which may have contributed to the comparable mRNA expression profile in the eutopic endometrium of women with endometriosis and controls.

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BACKGROUND

Endometriosis, which is characterized by the growth of endometrial tissue at ectopic locations as well as vascular development and inflammation, is still an unmet clinical need since an optimal drug that allows for both pain and infertility management does not exist. Since both the eutopic and the ectopic endometrium express the vitamin D receptor (VDR), and VDR agonists are endowed with anti-proliferative and anti-inflammatory properties, we evaluated the effect of elocalcitol, a VDR agonist with low calcaemic liability, in a mouse model of experimentally induced endometriosis.

METHODS AND RESULTS

Endometriosis was induced by injection of syngeneic endometrial tissue fragments into adult Balb/c female mice. After having confirmed by immunohistochemistry that endometriotic lesions developing in mice expressed VDR, the mice were administered with elocalcitol (100 μg/kg) or vehicle orally, once a day, for various durations of time. In this model, elocalcitol was able to reduce total lesion weight up to 70% upon treatment for 1 week before and 2 weeks after disease induction. Interestingly, a therapeutic effect was also observed on already established lesions. Elocalcitol was shown to reduce the capacity of mouse endometrial cells to adhere to collagen. In addition in treated mice, a decreased state of peritoneal inflammation was demonstrated by the inhibition of macrophage recruitment and inflammatory cytokine secretion.

CONCLUSIONS

The VDR agonist elocalcitol inhibits lesion development in a validated mouse model of endometriosis, and exerts a protective effect on both the implantation and organization of transferred endometrial tissue. These preliminary data in mice provide a sound rationale for further testing in primate models and eventually in humans.

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BACKGROUND

Live birth per cycle and live birth per embryo transfer are commonly used outcome measures for IVF treatment. In contrast, the assessment of the reproductive efficiency of human oocytes fertilized in vitro is seldom performed on an egg-to-egg basis. This approach may however gain importance owing to the increasingly widespread use of oocyte cryopreservation, as the technique is becoming more established. The aim of the current study is to quantify the reproductive efficiency of the oocyte according to ovarian ageing and ovarian response.

METHODS

We performed a retrospective analysis of the outcome of all consecutive patients attending for treatment between 1992 and 2009. The outcome in terms of live birth after fresh and cryopreserved embryo transfer per mature oocyte was calculated for 207 267 oocytes retrieved in 23 354 ovarian stimulation cycles. The oocyte utilization rate (number of live births per mature oocyte) was further analysed in relation to the ovarian response.

RESULTS

The oocyte utilization rate in women in the age of ≤37 years remains constant with a mean of 4.47% live birth per mature oocyte [95% confidence interval (CI): 4.32–4.61]. From the age of 38 years onwards, a significantly lower oocyte utilization rate was noted, declining from 3.80% at the age of 38 years to 0.78% at 43 years (P < 0.001). In this 38–43 years age group, oocyte utilization rate was no longer dependent on ovarian response (P = 0.87).

CONCLUSIONS

The major strength of the study, which is also its weakness, is the fact that we included a large number of cycles performed over a long period of time. According to our results, the oocyte utilization rate between 23 and 37 years of age depends largely on ovarian response and to a much lesser extent on age. From the age of 38 years onwards, the utilization rate depends largely on age and to a much lesser extent on ovarian response. Considering the increased use of oocyte freezing for fertility preservation, these data are extremely valuable as they provide an estimate of the number of oocytes needed to achieve a live birth.

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http://humrep.oxfordjournals.org/rss/current.xml