Androgens (dehydroepiandrosterone or testosterone) for women undergoing assisted reproduction.

BACKGROUND: Practitioners in the field of assisted reproductive technology (ART) continually seek alternative or adjunct treatments to improve ART outcomes. This Cochrane review investigates the adjunct use of synthetic versions of two naturally produced hormones, dehydroepiandrosterone (DHEA) and testosterone (T), in assisted reproduction. Steroid hormones are proposed to increase conception rates by positively affecting follicular response to gonadotrophin stimulation. This may lead to a greater oocyte yield and, subsequently, an increased chance of pregnancy. OBJECTIVES: To assess the effectiveness and safety of DHEA and T as pre- or co-treatments in infertile women undergoing assisted reproduction. SEARCH METHODS: We searched the following electronic databases up to 8 January 2024: the Gynaecology and Fertility Group (CGF) Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, and trial registries for ongoing trials. We also searched citation indexes, Web of Science, PubMed, and OpenGrey. We searched the reference lists of relevant studies and contacted experts in the field for any additional trials. There were no language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing DHEA or T as an adjunct treatment to any other active intervention, placebo, or no treatment in women undergoing assisted reproduction. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, extracted relevant data, and assessed risk of bias. We pooled data from studies using fixed-effect models. We calculated odds ratios (ORs) for each dichotomous outcome. Analyses were stratified by type of treatment. We assessed the certainty of evidence for the main findings using GRADE methods. MAIN RESULTS: We included 29 RCTs. There were 1599 women in the intervention group and 1469 in the control group. Apart from three trials, the trial participants were women identified as 'poor responders' to standard in vitro fertilisation (IVF) protocols. The included trials compared either T or DHEA treatment with placebo or no treatment. Pre-treatment with DHEA versus placebo/no treatment: DHEA likely results in little to no difference in live birth/ongoing pregnancy rates (OR 1.30, 95% confidence interval (CI) 0.95 to 1.76; I² = 16%, 9 RCTs, N = 1433, moderate certainty evidence). This suggests that in women with a 12% chance of live birth/ongoing pregnancy with placebo or no treatment, the live birth/ongoing pregnancy rate in women using DHEA will be between 12% and 20%. DHEA likely does not decrease miscarriage rates (OR 0.85, 95% CI 0.53 to 1.37; I² = 0%, 10 RCTs, N =1601, moderate certainty evidence). DHEA likely results in little to no difference in clinical pregnancy rates (OR 1.18, 95% CI 0.93 to 1.49; I² = 0%, 13 RCTs, N = 1886, moderate certainty evidence). This suggests that in women with a 17% chance of clinical pregnancy with placebo or no treatment, the clinical pregnancy rate in women using DHEA will be between 16% and 24%. We are very uncertain about the effect of DHEA on multiple pregnancy (OR 3.05, 95% CI 0.47 to 19.66; 7 RCTs, N = 463, very low certainty evidence). Pre-treatment with T versus placebo/no treatment: T likely improves live birth rates (OR 2.53, 95% CI 1.61 to 3.99; I² = 0%, 8 RCTs, N = 716, moderate certainty evidence). This suggests that in women with a 10% chance of live birth with placebo or no treatment, the live birth rate in women using T will be between 15% and 30%. T likely does not decrease miscarriage rates (OR 1.63, 95% CI 0.76 to 3.51; I² = 0%, 9 RCTs, N = 755, moderate certainty evidence). T likely increases clinical pregnancy rates (OR 2.17, 95% CI 1.54 to 3.06; I² = 0%, 13 RCTs, N = 1152, moderate certainty evidence). This suggests that in women with a 12% chance of clinical pregnancy with placebo or no treatment, the clinical pregnancy rate in women using T will be between 17% and 29%. We are very uncertain about the effect of T on multiple pregnancy (OR 2.56, 95% CI 0.59 to 11.20; 5 RCTs, N = 449, very low certainty evidence). We are uncertain about the effect of T versus oestradiol or T versus oestradiol + oral contraceptive pills. The certainty of the evidence was moderate to very low, the main limitations being lack of blinding in the included trials, inadequate reporting of study methods, and low event and sample sizes in the trials. Data on adverse events were sparse; any reported events were minor. AUTHORS' CONCLUSIONS: Pre-treatment with T likely improves, and pre-treatment with DHEA likely results in little to no difference, in live birth and clinical pregnancy rates in women undergoing IVF who have been identified as poor responders. DHEA and T probably do not decrease miscarriage rates in women under IVF treatment. The effects of DHEA and T on multiple pregnancy are uncertain. Data regarding adverse events were very limited; any reported events were minor. Research is needed to identify the optimal duration of treatment with T. Future studies should include data collection on adverse events and multiple pregnancy.

Autologous platelet-rich plasma for assisted reproduction.

BACKGROUND: Autologous platelet-rich plasma (PRP) consists of plasma and a concentrate of platelets extracted from fresh whole blood of the person being treated. Research has suggested that intrauterine or intraovarian infusion/injection of PRP before embryo transfer may improve endometrial receptivity and response to ovarian stimulation in women undergoing assisted reproduction. We compared these interventions to standard treatment, placebo, or other interventions (mechanical or pharmacological). OBJECTIVES: To assess the effectiveness and safety of intrauterine and intraovarian infusion/injection of platelet-rich plasma in infertile women undergoing assisted reproductive technology cycles. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group's Specialised Register, CENTRAL, MEDLINE, Embase, and the Epistemonikos database in January 2023. We also searched the reference lists of relevant articles and contacted the trial authors and experts in the field for any additional trials. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that evaluated the application of PRP in the uterine cavity, ovaries, or both versus no intervention, placebo, or any other intervention (either mechanical or pharmacological) in women undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycles. DATA COLLECTION AND ANALYSIS: We followed standard methodological procedures recommended by Cochrane, including use of the updated risk of bias tool (RoB 2). The primary outcomes were live birth (or ongoing pregnancy) and miscarriage. The secondary outcomes were clinical pregnancy, complications of the procedure, multiple pregnancy, ectopic pregnancy, fetal growth restriction, preterm delivery, and fetal abnormality. We estimated the average effect of the interventions by fitting a Der Simonian-Laird's random-effects meta-analysis model. We reported pooled odds ratios (ORs) with 95% confidence intervals (CIs). We restricted the primary analyses to trials at low risk of bias for the outcomes and performed sensitivity analyses that included all studies. MAIN RESULTS: We included 12 parallel-group RCTs that recruited a total of 1069 women. We identified three different comparison groups. Using GRADE, we assessed the certainty of evidence as very low for almost all outcomes. Intrauterine injection/infusion of platelet-rich plasma versus no intervention or placebo Nine studies evaluated intrauterine PRP versus no intervention or placebo. Eight included women with at least two or three previous implantation failures. Only one was assessed at low risk of bias for each outcome. This study provided very low-certainty evidence about the effect of intrauterine PRP injection versus no intervention on live birth (OR 1.10, 95% CI 0.38 to 3.14; 94 women) and miscarriage (OR 0.96, 95% CI 0.13 to 7.09; 94 women). If the likelihood of live birth following no intervention is assumed to be 17%, then the likelihood following intrauterine PRP would be 7% to 40%; and if the risk of miscarriage following no intervention is 4%, then the risk following intrauterine PRP would be 1% to 24%. When we analyzed all studies (regardless of risk of bias), we found very low-certainty evidence about the effect of intrauterine PRP compared with placebo or no intervention on live birth or ongoing pregnancy (OR 2.38, 95% CI 1.16 to 4.86; I² = 54%; 6 studies, 564 women) and miscarriage (OR 1.54, 95% CI 0.59 to 4.01; I² = 0%; 5 studies, 504 women). The study at low risk of bias provided very low-certainty evidence about the effect of intrauterine PRP compared with no intervention on clinical pregnancy (OR 1.55, 95% CI 0.64 to 3.76; 94 women) and ectopic pregnancy (OR 2.94, 95% CI 0.12 to 73.95; 94 women). The synthesis of all studies provided very low-certainty evidence about the effect of intrauterine PRP compared with placebo or no intervention on clinical pregnancy (OR 2.22, 95% CI 1.50 to 3.27; I² = 24%; 9 studies, 824 women), multiple pregnancy (OR 2.68, 95% CI 0.81 to 8.88; I² = 0%; 2 studies, 240 women), and ectopic pregnancy (OR 2.94, 95% CI 0.12 to 73.95; 1 study, 94 women; very low-certainty evidence). Intrauterine infusion of PRP may increase the risk of preterm delivery compared with no intervention (OR 8.02, 95% CI 1.72 to 37.33; 1 study, 120 women; low-certainty evidence). No studies reported pain, infection, allergic reaction, fetal growth restriction, or fetal abnormality. Intrauterine infusion of platelet-rich plasma versus intrauterine infusion of granulocyte colony-stimulating factor Two RCTs evaluated intrauterine PRP versus intrauterine granulocyte colony-stimulating factor (G-CSF); both included women with thin endometrium, and neither was judged at low risk of bias for any outcome. We are uncertain about the effect of intrauterine PRP compared with intrauterine G-CSF on live birth (OR 0.88, 95% CI 0.43 to 1.81; 1 study, 132 women; very low-certainty evidence), miscarriage (OR 1.94, 95% CI 0.63 to 5.96; 1 study, 132 women; very low-certainty evidence), and clinical pregnancy (OR 1.24, 95% CI 0.66 to 2.35; 2 studies, 172 women; very low-certainty evidence). Neither study reported adverse outcomes other than miscarriage. Intraovarian injection of platelet-rich plasma versus no intervention One RCT evaluated PRP injection into both ovaries versus no intervention; it was judged at high risk of bias for the two outcomes it reported. We are uncertain about the effect of intraovarian PRP injection compared with no intervention on ongoing pregnancy (OR 1.09, 95% CI 0.33 to 3.63; 73 women; very low-certainty evidence) and clinical pregnancy (OR 0.90, 95% CI 0.31 to 2.60; 73 women; very low-certainty evidence). The study examined no safety outcomes. AUTHORS' CONCLUSIONS: We are uncertain about the effect of intrauterine or intraovarian administration of PRP on outcomes of assisted reproduction technology in infertile women. The pooled results should be interpreted with caution. Only one of the 12 included studies was judged at low risk of bias. Other limitations of the included trials were failure to report live birth, poor reporting of methods, lack of prospective protocol registration, low precision due to the small number of enrolled participants, indirectness due to the specific subpopulations and settings studied, and insufficient or absent safety data.

Endometrial injection of embryo culture supernatant for subfertile women in assisted reproduction.

BACKGROUND: Despite substantial improvements in the success of assisted reproduction techniques (ART), live birth rates may remain consistently low, and practitioners may look for innovative treatments to improve the outcomes. The injection of embryo culture supernatant in the endometrial cavity can be undertaken at various time intervals before embryo transfer. It provides an altered endometrial environment through the secretion of factors considered to facilitate implantation. It is proposed that injection of the supernatant into the endometrial cavity prior to embryo transfer will stimulate the endometrium and provide better conditions for implantation to take place. An increased implantation rate would subsequently increase rates of clinical pregnancy and live birth, but current robust evidence on the efficacy of injected embryo culture supernatant is lacking. OBJECTIVES: To evaluate the effectiveness and safety of endometrial injection of embryo culture supernatant before embryo transfer in women undergoing ART. SEARCH METHODS: Our search strategies were designed with the help of the Cochrane Gynaecology and Fertility Group Information Specialist. We sought to identify all published and unpublished randomised controlled trials (RCTs) meeting inclusion criteria. Searches were performed on 2 December 2019. We searched the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, CENTRAL, MEDLINE, Embase, CINAHL, trials registries and grey literature. We made further searches in the UK National Institute for Health and Care Excellence (NICE) fertility assessment and treatment guidelines. We handsearched reference lists of relevant systematic reviews and RCTs, together with searches of PubMed and Google for any recent trials that have not yet been indexed in the major databases. We had no language or location restrictions. SELECTION CRITERIA: We included RCTs testing the use of endometrial injection of embryo culture supernatant before embryo transfer during an ART cycle, compared with the non-use of this intervention, the use of placebo or the use of any other similar drug. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias, extracted data from studies and attempted to contact the authors where data were missing. We pooled studies using a fixed-effect model. Our primary outcomes were live birth/ongoing pregnancy and miscarriage. We performed statistical analysis using Review Manager 5. We assessed evidence quality using GRADE methods. MAIN RESULTS: We found five RCTs suitable for inclusion in the review (526 women analysed). We made two comparisons: embryo culture supernatant use versus standard care or no intervention; and embryo culture supernatant use versus culture medium. All studies were published as full-text articles. Data derived from the reports or through direct communication with investigators were available for the final meta-analysis performed. The GRADE evidence quality of studies ranged from very low-quality to moderate-quality. Factors reducing evidence quality included high risk of bias due to lack of blinding, unclear risk of publication bias and selective outcome reporting, serious inconsistency among study outcomes, and serious imprecision due to wide confidence intervals (CIs) and low numbers of events. Comparison 1. Endometrial injection of embryo culture supernatant before embryo transfer versus standard care or no intervention: One study reported live birth only and two reported the composite outcome live birth and ongoing pregnancy. We are uncertain whether endometrial injection of embryo culture supernatant before embryo transfer during an ART cycle improves live birth/ongoing pregnancy rates compared to no intervention (odds ratio (OR) 1.11, 95% CI 0.73 to 1.70; 3 RCTs; n = 340, I2 = 84%; very low-quality evidence). Results suggest that if the chance of live birth/ongoing pregnancy following placebo or no treatment is assumed to be 42%, the chance following the endometrial injection of embryo culture supernatant before embryo transfer would vary between 22% and 81%. We are also uncertain whether the endometrial injection of embryo culture supernatant could decrease miscarriage rates, compared to no intervention (OR 0.89, 95% CI 0.44 to 1.78, 4 RCTs, n = 430, I2 = 58%, very low-quality evidence). Results suggest that if the chance of miscarriage following placebo or no treatment is assumed to be 9%, the chance following injection of embryo culture supernatant would vary between 3% and 30%. Concerning the secondary outcomes, we are uncertain whether the injection of embryo culture supernatant prior to embryo transfer could increase clinical pregnancy rates (OR 1.13, 95% CI 0.80 to 1.61; 5 RCTs; n = 526, I2 = 0%; very low-quality evidence), decrease ectopic pregnancy rates (OR 0.32, 95% CI 0.01 to 8.24; n = 250; 2 RCTs; I2 = 41%; very low-quality evidence), decrease multiple pregnancy rates (OR 0.70, 95% CI 0.26 to 1.83; 2 RCTs; n = 150; I2 = 63%; very low-quality evidence), or decrease preterm delivery rates (OR 0.63, 95% CI 0.17 to 2.42; 1 RCT; n = 90; I2 = 0%; very low-quality evidence), compared to no intervention. Finally, there may have been little or no difference in foetal abnormality rates between the two groups (OR 3.10, 95% CI 0.12 to 79.23; 1 RCT; n = 60; I2 = 0%; low-quality evidence). Comparison 2. Endometrial injection of embryo culture supernatant versus endometrial injection of culture medium before embryo transfer We are uncertain whether the use of embryo culture supernatant improves clinical pregnancy rates, compared to the use of culture medium (OR 1.09, 95% CI 0.48 to 2.46; n = 96; 1 RCT; very low-quality evidence). No study reported live birth/ongoing pregnancy, miscarriage, ectopic or multiple pregnancy, preterm delivery or foetal abnormalities. AUTHORS' CONCLUSIONS: We are uncertain whether the addition of endometrial injection of embryo culture supernatant before embryo transfer as a routine method for the treatment of women undergoing ART can improve pregnancy outcomes. This conclusion is based on current available data from five RCTs, with evidence quality ranging from very low to moderate across studies. Further large well-designed RCTs reporting on live births and adverse clinical outcomes are still required to clarify the exact role of endometrial injection of embryo culture supernatant before embryo transfer.

Association of modulation of pro-inflammatory responses by dectin-2 with preterm delivery: An experimental model.

PROBLEM: Pro-inflammatory responses of pathogen recognition receptors (PRR) are implicated in preterm delivery (PTD). Dectin-2 is one PRR recognizing unselective carbohydrate structures; its participation in PTD has never been studied before. METHOD OF STUDY: In an experimental model, PTD was induced in female pregnant wild-type (WT) mice and mice with homologous deficiency for dectin-2 by the intraperitoneal injection of bacterial lipopolysaccharide (LPS) on day 14 of pregnancy. Time to delivery and fetal mortality were recorded. Challenged mice were killed for tissue collection and splenocyte isolation 6 hours later. Concentrations of tumour necrosis factor-alpha (TNFα), interleukin (IL)-1α, and IL-1ß were measured. RESULTS: Delivery was induced significantly earlier in WT than dectin-2-/- mice; however, fetal mortality was higher among dectin-2-/- mice. Candida albicans challenge could not lead to these changes. Sacrifice experiments showed that LPS challenge led to significant increase of TNFα, IL-1α, and IL-1ß in maternal tissues of WT; this was further enhanced for TNFα and IL-1ß in dectin-2-/- mice. Pre-treatment with the prostaglandin inhibitor diclofenac delayed time to delivery of WT mice, but not of dectin2-/- mice. TNFα stimulation of splenocytes of dectin2-/- mice was enhanced with the addition of anti-TLR4 and decreased in the presence of lipid A. CONCLUSIONS: Dectin-2 delays LPS-induced PTD by enhancing the production of pro-inflammatory cytokines.

Nonsteroidal anti-inflammatory drugs for assisted reproductive technology.

BACKGROUND: Despite substantial improvements in the success of treatments through assisted reproduction technologies (ART), live birth rates remain constantly low, and practitioners are seeking aetiologic treatments to improve the outcomes.Local inflammatory response is believed to contribute to implantation failure, where prostaglandins may increase uterine contractions and decrease uterine receptivity, decreasing the possibility of an IVF cycle leading to successful embryo transfer. In this context, nonsteroidal anti-inflammatory drugs (NSAIDs) have been employed to inhibit the negative prostaglandin effect. They are often offered in clinical practice to improve ART outcomes, but current robust evidence on their efficacy is lacking. OBJECTIVES: To evaluate the effectiveness and safety of nonsteroidal anti-inflammatory drugs as co-treatments in infertile women undergoing assisted reproduction, in terms of improving live birth and miscarriage rates. SEARCH METHODS: We designed the search using standard Cochrane methods and performed it on databases from their inception to 20 February 2019.We searched the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, CENTRAL via the Cochrane Central Register of Studies Online, MEDLINE, Embase, CINAHL, and the trial registers for ongoing and registered trials, grey literature and treatment guidelines. We handsearched reference lists of relevant systematic reviews and RCTs, and PubMed and Google for any recent trials. There were no restrictions by language or country of origin. SELECTION CRITERIA: All RCTs on the use of NSAIDs as co-treatment during an ART cycle compared with no use or the use of placebo or any other similar drug, along with the comparison of any NSAID to another. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. Our primary outcomes were live birth/ongoing pregnancy and miscarriage. We performed statistical analysis using Review Manager 5. We assessed evidence quality using GRADE methods. MAIN RESULTS: We found 11 RCTs (1884 women) suitable for inclusion in the review. Most studies were at unclear or high risk of bias. The main limitations in the overall quality of the evidence were high risk of bias, unexplained heterogeneity and serious imprecision and indirectness.There were no data on our primary outcome - live birth per woman randomised - in any review comparisons.NSAIDs vs. placebo/no treatmentWe are uncertain of an effect on ongoing pregnancy when NSAIDs were compared to placebo/no treatment (risk ratio (RR) 1.06, 95% confidence interval (CI) 0.71 to 1.59; 4 studies, 1159 participants; I² = 53%; very low quality evidence). Results suggest that if the chance of ongoing pregnancy following placebo or no treatment is assumed to be 15%, the chance following the use of NSAIDs is estimated to be between 12% and 24%. Subgroup analysis according to the type of NSAID yielded similar results.We are also uncertain of an effect on miscarriage rates when NSAIDs were compared to placebo/no treatment (RR 0.62, 95% CI 0.33 to 1.16; 4 studies, 525 participants; I² = 43%; very low quality evidence). Results suggest that if the chance of miscarriage following placebo or no treatment is assumed to be 21%, the chance following the use of NSAIDs is estimated to be between 7% and 27%. The results were similar when two studies were excluded due to high risk of bias.Concerning the secondary outcomes, we are uncertain of an effect on clinical pregnancy rates (RR 1.23, 95% CI 1.00 to 1.52; 6 studies, 1570 participants; I² = 49%; low-quality evidence); on ectopic pregnancy (RR 0.56, 95% CI 0.05 to 5.89; 1 study, 72 participants); on multiple pregnancy (RR 2.00, 95% CI 0.18 to 21.67; 1 study, 180 participants); and on side effects (RR 1.39, 95% CI 0.02 to 119.35; 3 studies, 418 participants; I² = 79%). The evidence suggests that if the chance of clinical pregnancy following placebo or no treatment is assumed to be 30%, the chance following the use of NSAIDs is estimated to be between 31% and 45%. If the chance of ectopic pregnancy following placebo or no treatment is assumed to be 5%, the chance following the use of NSAIDs is estimated to be between 0.3% and 31%. If the chance of multiple pregnancy following placebo or no treatment is assumed to be 1%, the chance following the use of NSAIDs is estimated to be between 0.2 % and 24%.There were no cases of congenital anomalies during antenatal ultrasound screening of the women in one study.NSAID vs. another NSAIDOnly one study compared piroxicam with indomethacin: we are uncertain of an effect on ongoing pregnancy (RR 1.12, 95% CI 0.63 to 2.00; 1 study, 170 participants; very low quality evidence); and on miscarriage (RR 1.00, 95% CI 0.44 to 2.28; 1 study, 170 participants; very low quality evidence). The evidence suggests that if the chance of ongoing pregnancy following indomethacin is assumed to be 20%, the chance following the use of piroxicam is estimated to be between 13% and 40%; while for miscarriage, the evidence suggests that if the chance following indomethacin is assumed to be 12%, the chance following the use of piroxicam is estimated to be between 5% and 27%.Similar results were reported for clinical pregnancy (RR 1.07, 95% CI 0.71 to 1.63; 1 study, 170 participants; very low quality evidence).There were no data for the other outcomes specified in this review.NSAID vs. aspirinNo study reported this comparison. AUTHORS' CONCLUSIONS: Currently we are uncertain of an effect of the routine use of NSAIDs as co-treatments in infertile women undergoing assisted reproduction in order to improve ongoing pregnancy and miscarriage rates. This is based on available data from RCTs, where very low quality evidence showed that there is no single outcome measure demonstrating a benefit with their use. Further large, well-designed randomised placebo-controlled trials reporting on live births are required to clarify the exact role of NSAIDs.

In vitro maturation in subfertile women with polycystic ovarian syndrome undergoing assisted reproduction.

BACKGROUND: Polycystic ovarian syndrome (PCOS) occurs in 4% to 7% of all women of reproductive age and 50% of women presenting with subfertility. Subfertility affects 15% to 20% of couples trying to conceive. A significant proportion of these women ultimately need assisted reproductive technology (ART). In vitro fertilisation (IVF) is one of the assisted reproduction techniques employed to raise the chances of achieving a pregnancy. For the standard IVF technique, stimulating follicle development and growth before oocyte retrieval is essential, for which a large number of different methods combining gonadotrophins with a gonadotrophin-releasing hormone (GnRH) agonist or antagonist are used. In women with PCOS, the supra-physiological doses of gonadotrophins used for controlled ovarian hyperstimulation (COH) often result in an exaggerated ovarian response, characterised by the development of a large cohort of follicles of uneven quality, retrieval of immature oocytes, and increased risk of ovarian hyperstimulation syndrome (OHSS). A potentially effective intervention for women with PCOS-related subfertility involves earlier retrieval of immature oocytes at the germinal-vesicle stage followed by in vitro maturation (IVM). So far, the only data available have derived from observational studies and non-randomised clinical trials. OBJECTIVES: To assess the effectiveness and safety of IVM followed by IVF or ICSI versus conventional IVF or ICSI among women with PCOS undergoing assisted reproduction. SEARCH METHODS: This is the second update of this review. We performed the search on 17 April 2018.The search was designed with the help of the Cochrane Gynaecology and Fertility Group Information Specialist, for all published and unpublished randomised controlled trials (RCTs).We searched the the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, CENTRAL via the Cochrane Central Register of Studies Online, MEDLINE, Embase, CINAHL, and the trial registers for ongoing and registered trials and the Open Grey database for grey literature from Europe. We made further searches in the National Institute for Health and Care Excellence (NICE) fertility assessment and treatment guidelines. We handsearched reference lists of relevant systematic reviews and RCTs, together with PubMed and Google for any recent trials that have not yet been indexed in the major databases. SELECTION CRITERIA: All RCTs on the intention to perform IVM before IVF or ICSI compared with conventional IVF or ICSI for subfertile women with PCOS, irrespective of language and country of origin. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias, extracted data from studies, and attempted to contact the authors of studies for which data were missing. Our primary outcomes were live birth per woman randomised and miscarriage. We performed statistical analysis using Review Manager 5. We assessed evidence quality using GRADE methods. MAIN RESULTS: We found two RCTs suitable for inclusion in the review and six ongoing trials that have not yet reported results. Both included studies were published as abstracts in international conferences.Both studies were at unclear or high risk of bias for most of the seven domains assessed. Common problems were unclear reporting of study methods and lack of blinding. The main limitations in the overall quality of the evidence were high risk of bias and serious imprecision.There were no data on the primary outcomes of this review, namely live birth per woman randomised and miscarriage.Both studies reported clinical pregnancy rate: there was evidence of an effect between IVM and IVF, favouring the former (odds ratio 3.10, 95% confidence interval 1.06 to 9.00; 71 participants; 2 studies; I2 = 0%; very low-quality evidence). The incidence of OHSS was zero in both studies in both groups.There were no data for the other outcomes specified in this review. AUTHORS' CONCLUSIONS: Though promising data on the in vitro maturation (IVM) technique have been published, unfortunately there is still no evidence from properly conducted randomised controlled trials upon which to base any practice recommendations regarding IVM before in vitro fertilisation (IVF) or intracytoplasmic sperm injection for women with polycystic ovarian syndrome. Regarding our secondary outcomes, very low-quality evidence showed that clinical pregnancy was higher with IVM when compared to IVF, whereas the incidence of ovarian hyperstimulation syndrome was zero in both studies in both groups. We are awaiting the results of six ongoing trials and eagerly anticipate further evidence from good-quality trials in the field.

Metabolomics for improving pregnancy outcomes in women undergoing assisted reproductive technologies.

BACKGROUND: In order to overcome the low effectiveness of assisted reproductive technologies (ART) and the high incidence of multiple births, metabolomics is proposed as a non-invasive method to assess oocyte quality, embryo viability, and endometrial receptivity, and facilitate a targeted subfertility treatment. OBJECTIVES: To evaluate the effectiveness and safety of metabolomic assessment of oocyte quality, embryo viability, and endometrial receptivity for improving live birth or ongoing pregnancy rates in women undergoing ART, compared to conventional methods of assessment. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Trials Register, CENTRAL, MEDLINE, Embase, CINAHL and two trial registers (Feburary 2018). We also examined the reference lists of primary studies and review articles, citation lists of relevant publications, and abstracts of major scientific meetings. SELECTION CRITERIA: Randomised controlled trials (RCTs) on metabolomic assessment of oocyte quality, embryo viability, and endometrial receptivity in women undergoing ART. DATA COLLECTION AND ANALYSIS: Pairs of review authors independently assessed trial eligibility and risk of bias, and extracted the data. The primary outcomes were rates of live birth or ongoing pregnancy (composite outcome) and miscarriage. Secondary outcomes were clinical pregnancy, multiple and ectopic pregnancy, cycle cancellation, and foetal abnormalities. We combined data to calculate odds ratios (ORs) for dichotomous data and 95% confidence intervals (CIs). Statistical heterogeneity was assessed using the I² statistic. We assessed the overall quality of the evidence for the main comparisons using GRADE methods. MAIN RESULTS: We included four trials with a total of 924 women, with a mean age of 33 years. All assessed the role of metabolomic investigation of embryo viability. We found no RCTs that addressed the metabolomic assessment of oocyte quality or endometrial receptivity.We found low-quality evidence of little or no difference between metabolomic and non-metabolomic assessment of embryos for rates of live birth or ongoing pregnancy (OR 1.02, 95% CI 0.77 to 1.35, I² = 0%; four RCTs; N = 924), live birth alone (OR 0.99, 95% CI 0.69 to 1.44, I² = 0%; three RCTs; N = 597), or miscarriage (OR 1.18, 95% CI 0.77 to 1.82; I² = 0%; three RCTs; N = 869). A sensitivity analysis excluding studies at high risk of bias did not change the interpretation of the results for live birth or ongoing pregnancy (OR 0.90, 95% CI 0.66 to 1.25, I² = 0%; two RCTs; N = 744). Our findings suggested that if the rate of live birth or ongoing pregnancy was 36% in the non-metabolomic group, it would be between 32% and 45% with the use of metabolomics.We found low-quality evidence of little or no difference between groups in rates of clinical pregnancy (OR 1.11, 95% CI 0.85 to 1.45; I²= 44%; four trials; N = 924) or multiple pregnancy (OR 1.50, 95% CI 0.70 to 3.19; I² = 0%; two RCTs, N = 180). Rates of cycle cancellation were higher in the metabolomics group (OR 1.78, 95% CI 1.18 to 2.69; I² = 51%; two RCTs; N = 744, low quality evidence). There was very low-quality evidence of little or no difference between groups in rates of ectopic pregnancy rates (OR 3.00, 95% CI 0.12 to 74.07; one RCT; N = 417), and foetal abnormality (no events; one RCT; N = 125). Data were lacking on other adverse effects. A sensitivity analysis excluding studies at high risk of bias did not change the interpretation of the results for clinical pregnancy (OR 1.03, 95% CI 0.76 to 1.38; I² = 40%; two RCTs; N = 744).The overall quality of the evidence ranged from very low to low. Limitations included serious risk of bias (associated with poor reporting of methods, attrition bias, selective reporting, and other biases), imprecision, and inconsistency across trials. AUTHORS' CONCLUSIONS: According to current trials in women undergoing ART, there is no evidence to show that metabolomic assessment of embryos before implantation has any meaningful effect on rates of live birth, ongoing pregnancy, miscarriage, multiple pregnancy, ectopic pregnancy or foetal abnormalities. The existing evidence varied from very low to low-quality. Data on other adverse events were sparse, so we could not reach conclusions on these. At the moment, there is no evidence to support or refute the use of this technique for subfertile women undergoing ART. Robust evidence is needed from further RCTs, which study the effects on live birth and miscarriage rates for the metabolomic assessment of embryo viability. Well designed and executed trials are also needed to study the effects on oocyte quality and endometrial receptivity, since none are currently available.

Metabolomics for improving pregnancy outcomes in women undergoing assisted reproductive technologies.

BACKGROUND: In order to overcome the low effectiveness of assisted reproductive technologies (ART) and the high incidence of multiple births, metabolomics is proposed as a non-invasive method to assess oocyte quality, embryo viability, and endometrial receptivity, and facilitate a targeted subfertility treatment. OBJECTIVES: To evaluate the effectiveness and safety of metabolomic assessment of oocyte quality, embryo viability, and endometrial receptivity for improving live birth or ongoing pregnancy rates in women undergoing ART, compared to conventional methods of assessment. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Trials Register, CENTRAL, MEDLINE, Embase, CINAHL and two trial registers (November 2016). We also examined the reference lists of primary studies and review articles, citation lists of relevant publications, and abstracts of major scientific meetings. SELECTION CRITERIA: Randomised controlled trials (RCTs) on metabolomic assessment of oocyte quality, embryo viability, and endometrial receptivity in women undergoing ART. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and risk of bias, and extracted the data. The primary outcomes were rates of live birth or ongoing pregnancy (composite outcome) and miscarriage. Secondary outcomes were clinical pregnancy, multiple and ectopic pregnancy, cycle cancellation, and foetal abnormalities. We combined data to calculate odds ratios (ORs) for dichotomous data and 95% confidence intervals (CIs). Statistical heterogeneity was assessed using the I² statistic. We assessed the overall quality of the evidence for the main comparisons using GRADE methods. MAIN RESULTS: We included four trials with a total of 802 women, with a mean age of 33 years. All assessed the role of metabolomic investigation of embryo viability. We found no RCTs that addressed the metabolomic assessment of oocyte quality or endometrial receptivity.We found low-quality evidence of little or no difference between metabolomic and non-metabolomic assessment of embryos for rates of live birth or ongoing pregnancy (OR 1.11, 95% CI 0.83 to 1.48; I² = 0%; four RCTs; N = 802), or miscarriage (OR 0.96, 95% CI 0.52 to 1.78; I² = 0%; two RCTs; N = 434). A sensitivity analysis excluding studies at high risk of bias did not change the interpretation of the results for live birth or ongoing pregnancy (OR 0.99, 95% CI 0.71 to 1.38; I² = 0%; two RCTs; N = 621). Our findings suggested that if the rate of live birth or ongoing pregnancy was 36% in the non-metabolomic group, it would be between 32% and 45% with the use of metabolomics.We found low-quality evidence of little or no difference between groups in rates of clinical pregnancy (OR 1.22, 95% CI 0.92 to 1.62; I²= 26%; four trials; N = 802), or multiple pregnancy (OR 1.52, 95% CI 0.71 to 3.23; I² = 0%; two RCTs, N = 181). There was very low-quality evidence of little or no difference between groups in ectopic pregnancy rates (OR 3.37, 95% CI 0.14 to 83.40; one RCT; N = 309), and foetal abnormalities (no events; one RCT; N = 125), and very low-quality evidence of higher rates of cycle cancellation in the metabolomics group (OR 1.78, 95% CI 1.18 to 2.69; I² = 51%; two RCTs; N = 744). Data were lacking on other adverse effects. A sensitivity analysis excluding studies at high risk of bias did not change the interpretation of the results for clinical pregnancy (OR 1.14, 95% CI 0.83 to 1.57; I² = 0%; two RCTs; N = 621).The overall quality of the evidence ranged from very low to low. Limitations included serious risk of bias (associated with poor reporting of methods, attrition bias, selective reporting, and other biases), imprecision, and inconsistency across trials. AUTHORS' CONCLUSIONS: According to current trials in women undergoing ART, there is insufficient evidence to show that metabolomic assessment of embryos before implantation has any meaningful effect on rates of live birth, ongoing pregnancy, or miscarriage rates. The existing evidence varied from very low to low-quality. Data on adverse events were sparse, so we could not reach conclusions on these. At the moment, there is no evidence to support or refute the use of this technique for subfertile women undergoing ART. Robust evidence is needed from further RCTs, which study the effects on live birth and miscarriage rates for the metabolomic assessment of embryo viability. Well designed and executed trials are also needed to study the effects on oocyte quality and endometrial receptivity, since none are currently available.

Risk of endometrial cancer in women treated with ovary-stimulating drugs for subfertility.

BACKGROUND: Medical treatment for subfertility principally involves the use of ovary-stimulating agents, including selective oestrogen receptor modulators (SERMs), such as clomiphene citrate, gonadotropins, gonadotropin-releasing hormone (GnRH) agonists and antagonists, as well as human chorionic gonadotropin. Ovary-stimulating drugs may act directly or indirectly upon the endometrium (lining of the womb). Nulliparity and some causes of subfertility are recognized as risk factors for endometrial cancer. OBJECTIVES: To evaluate the association between the use of ovary-stimulating drugs for the treatment of subfertility and the risk of endometrial cancer. SEARCH METHODS: A search was performed in CENTRAL, MEDLINE (Ovid) and Embase (Ovid) databases up to July 2016, using a predefined search algorithm. A search in OpenGrey, ProQuest, ClinicalTrials.gov, ZETOC and reports of major conferences was also performed. We did not impose language and publication status restrictions. SELECTION CRITERIA: Cohort and case-control studies reporting on the association between endometrial cancer and exposure to ovary-stimulating drugs for subfertility in adult women were deemed eligible. DATA COLLECTION AND ANALYSIS: Study characteristics and findings were extracted by review authors independently working in pairs. Inconsistency between studies was quantified by estimating I2. Random-effects (RE) models were used to calculate pooled effect estimates. Separate analyses were performed, comparing treated subfertile women versus general population and/or unexposed subfertile women, to address the superimposition of subfertility as an independent risk factor for endometrial cancer. MAIN RESULTS: Nineteen studies were eligible for inclusion (1,937,880 participants). Overall, the quality of evidence was very low, due to serious risk of bias and indirectness (non-randomised studies (NRS), which was reflected on the GRADE assessment.Six eligible studies, including subfertile women, without a general population control group, found that exposure to any ovary-stimulating drug was not associated with an increased risk of endometrial cancer (RR 0.96, 95% CI 0.67 to 1.37; 156,774 participants; very low quality evidence). Fifteen eligible studies, using a general population as the control group, found an increased risk after exposure to any ovary-stimulating drug (RR 1.75, 95% CI 1.18 to 2.61; 1,762,829 participants; very low quality evidence).Five eligible studies, confined to subfertile women (92,849 participants), reported on exposure to clomiphene citrate; the pooled studies indicated a positive association ( RR 1.32; 95% CI 1.01 to 1.71; 88,618 participants; very low quality evidence), although only at high dosage (RR 1.69, 95% CI 1.07 to 2.68; two studies; 12,073 participants) and at a high number of cycles (RR 1.69, 95% CI 1.16 to 2.47; three studies; 13,757 participants). Four studies found an increased risk of endometrial cancer in subfertile women who required clomiphene citrate compared to a general population control group (RR 1.87, 95% CI 1.00 to 3.48; four studies, 19,614 participants; very low quality evidence). These data do not tell us whether the association is due to the underlying conditions requiring clomiphene or the treatment itself.Using unexposed subfertile women as controls, exposure to gonadotropins was associated with an increased risk of endometrial cancer (RR 1.55, 95% CI 1.03 to 2.34; four studies; 17,769 participants; very low quality evidence). The respective analysis of two studies (1595 participants) versus the general population found no difference in risk (RR 2.12, 95% CI 0.79 to 5.64: very low quality evidence).Exposure to a combination of clomiphene citrate and gonadotropins, compared to unexposed subfertile women, produced no difference in risk of endometrial cancer (RR 1.18, 95% CI 0.57 to 2.44; two studies; 6345 participants; very low quality evidence). However, when compared to the general population, an increased risk was found , suggesting that the key factor might be subfertility, rather than treatment (RR 2.99, 95% CI 1.53 to 5.86; three studies; 7789 participants; very low quality evidence). AUTHORS' CONCLUSIONS: The synthesis of the currently available evidence does not allow us to draw robust conclusions, due to the very low quality of evidence. It seems that exposure to clomiphene citrate as an ovary-stimulating drug in subfertile women is associated with increased risk of endometrial cancer, especially at doses greater than 2000 mg and high (more than 7) number of cycles. This may largely be due to underlying risk factors in women who need treatment with clomiphene citrate, such as polycystic ovary syndrome, rather than exposure to the drug itself. The evidence regarding exposure to gonadotropins was inconclusive.

Aspirin for in vitro fertilisation.

BACKGROUND: Aspirin is used with the aim of optimising the chance of live birth in women undergoing assisted reproductive technology (ART), despite inconsistent evidence of its efficacy and safety (in terms of intraoperative bleeding during oocyte retrieval and risk of miscarriage). The most appropriate time to commence aspirin therapy and the length of treatment required are also still to be determined. This is the second update of the review first published in 2007. OBJECTIVES: To evaluate the effectiveness and safety of aspirin in women undergoing ART. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 4) in the Cochrane Library (searched 9 May 2016); the databases MEDLINE (1946 to 9 May 2016) and Embase (1974 to 9 May 2016); and trial registers (ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform search portal). We also examined the reference lists of all known primary studies and review articles, citation lists of relevant publications and abstracts of major scientific meetings, combined with the Cochrane Gynaecology and Fertility Group's search strategy. SELECTION CRITERIA: Randomised controlled trials on aspirin for women undergoing ART. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and risk of bias and extracted the data. The primary review outcome was live birth. Secondary outcomes included clinical pregnancy, ongoing pregnancy, multiple pregnancy, miscarriage, and other complications associated with IVF/ICSI or with pregnancy and birth. We combined data to calculate risk ratios (RRs) (for dichotomous data) and mean differences (MDs) (for continuous data) and 95% confidence intervals (CIs). Statistical heterogeneity was assessed using the I² statistic. We assessed the overall quality of the evidence for the main comparisons using GRADE methods. MAIN RESULTS: The search identified 13 trials as eligible for inclusion in the review, including a total of 2653 participants with a mean age of 35 years. Ten studies used a dose of 100 mg and three used 80 mg of aspirin per day. In most of them, aspirin was commenced immediately at the start of down-regulation, while the duration of treatment varied widely. Eight studies provided a placebo for the control group.There was no evidence of a difference between the aspirin group and the group receiving no treatment or placebo in rates of live birth (RR 0.91, 95% CI 0.72 to 1.15, 3 RCTs, n = 1053, I² = 15%, moderate-quality evidence). In addition, clinical pregnancy rates were also similar for the two groups (RR 1.03, 95% CI 0.91 to 1.17, 10 RCTs, n = 2142, I² = 27%, moderate-quality evidence); sensitivity analysis, excluding studies at high risk of bias, did not change the effect estimate. There was no evidence of a difference between groups in terms of multiple pregnancy as confirmed by ultrasound (RR 0.67, 95% CI 0.37 to 1.25, 2 RCTs, n = 656, I² = 0%, low-quality evidence), miscarriage (RR 1.10, 95% CI 0.68 to 1.77, 5 RCTs, n = 1497, I² = 0%, low-quality evidence), ectopic pregnancy (RR 1.86, 95% CI 0.75 to 4.63, 3 RCTs, n = 1135, I² = 0%, very low quality evidence) or vaginal bleeding (RR 1.01, 95% CI 0.14 to 7.13, 1 RCT, n = 487, very low quality evidence). Data were lacking on other adverse effects.The overall quality of the evidence ranged from very low to moderate; limitations were poor reporting of study methods and suspected publication bias. AUTHORS' CONCLUSIONS: Currently there is no evidence in favour of routine use of aspirin in order to improve pregnancy rates for a general IVF population. This is based on available data from randomised controlled trials, where there is currently no evidence of an effect of aspirin on women undergoing ART, as there is no single outcome measure demonstrating a benefit with its use. Furthermore, current evidence does not exclude the possibility of adverse effects.

Gonadotrophin-releasing hormone agonist protocols for pituitary suppression in assisted reproduction.

BACKGROUND: Gonadotrophin-releasing hormone agonists (GnRHa) are commonly used in assisted reproduction technology (ART) cycles to prevent a luteinising hormone surge during controlled ovarian hyperstimulation (COH) prior to planned oocyte retrieval, thus optimising the chances of live birth. OBJECTIVES: To evaluate the effectiveness of the different GnRHa protocols as adjuncts to COH in women undergoing ART cycles. SEARCH METHODS: We searched the following databases from inception to April 2015: the Cochrane Menstrual Disorders and Subfertility Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (2015, Issue 3), MEDLINE, EMBASE, CINAHL, PsycINFO, and registries of ongoing trials. Reference lists of relevant articles were also searched. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing any two protocols of GnRHa used in in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) cycles in subfertile women. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed trial eligibility and risk of bias, and extracted the data. The primary outcome measure was number of live births or ongoing pregnancies per woman/couple randomised. Secondary outcome measures were number of clinical pregnancies, number of oocytes retrieved, dose of gonadotrophins used, adverse effects (pregnancy losses, ovarian hyperstimulation, cycle cancellation, and premature luteinising hormone (LH) surges), and cost and acceptability of the regimens. We combined data to calculate odds ratios (OR) for dichotomous variables and mean differences (MD) for continuous variables, with 95% confidence intervals (CIs). We assessed statistical heterogeneity using the I² statistic. We assessed the overall quality of the evidence for the main comparisons using 'Grading of Recommendations Assessment, Development and Evaluation' (GRADE) methods. MAIN RESULTS: We included 37 RCTs (3872 women), one ongoing trial, and one trial awaiting classification. These trials made nine different comparisons between protocols. Twenty of the RCTs compared long protocols and short protocols. Only 19/37 RCTs reported live birth or ongoing pregnancy.There was no conclusive evidence of a difference between a long protocol and a short protocol in live birth and ongoing pregnancy rates (OR 1.30, 95% CI 0.94 to 1.81; 12 RCTs, n = 976 women, I² = 15%, low quality evidence). Our findings suggest that in a population in which 14% of women achieve live birth or ongoing pregnancy using a short protocol, between 13% and 23% will achieve live birth or ongoing pregnancy using a long protocol. There was evidence of an increase in clinical pregnancy rates (OR 1.50, 95% CI 1.18 to 1.92; 20 RCTs, n = 1643 women, I² = 27%, moderate quality evidence) associated with the use of a long protocol.There was no evidence of a difference between the groups in terms of live birth and ongoing pregnancy rates when the following GnRHa protocols were compared: long versus ultrashort protocol (OR 1.78, 95% CI 0.72 to 4.36; one RCT, n = 150 women, low quality evidence), long luteal versus long follicular phase protocol (OR 1.89, 95% CI 0.87 to 4.10; one RCT, n = 223 women, low quality evidence), when GnRHa was stopped versus when it was continued (OR 0.75, 95% CI 0.42 to 1.33; three RCTs, n = 290 women, I² = 0%, low quality evidence), when the dose of GnRHa was reduced versus when the same dose was continued (OR 1.02, 95% CI 0.68 to 1.52; four RCTs, n = 407 women, I² = 0%, low quality evidence), when GnRHa was discontinued versus continued after human chorionic gonadotrophin (HCG) administration in the long protocol (OR 0.89, 95% CI 0.49 to 1.64; one RCT, n = 181 women, low quality evidence), and when administration of GnRHa lasted for two versus three weeks before stimulation (OR 1.14, 95% CI 0.49 to 2.68; one RCT, n = 85 women, low quality evidence). Our primary outcomes were not reported for any other comparisons.Regarding adverse events, there were insufficient data to enable us to reach any conclusions except about the cycle cancellation rate. There was no conclusive evidence of a difference in cycle cancellation rate (OR 0.95, 95% CI 0.59 to 1.55; 11 RCTs, n = 1026 women, I² = 42%, low quality evidence) when a long protocol was compared with a short protocol. This suggests that in a population in which 9% of women would have their cycles cancelled using a short protocol, between 5.5% and 14% will have cancelled cycles when using a long protocol.The quality of the evidence ranged from moderate to low. The main limitations in the evidence were failure to report live birth or ongoing pregnancy, poor reporting of methods in the primary studies, and imprecise findings due to lack of data. Only 10 of the 37 included studies were conducted within the last 10 years. AUTHORS' CONCLUSIONS: When long GnRHa protocols and short GnRHa protocols were compared, we found no conclusive evidence of a difference in live birth and ongoing pregnancy rates, but there was moderate quality evidence of higher clinical pregnancy rates in the long protocol group. None of the other analyses showed any evidence of a difference in birth or pregnancy outcomes between the protocols compared. There was insufficient evidence to make any conclusions regarding adverse effects.

Androgens (dehydroepiandrosterone or testosterone) for women undergoing assisted reproduction.

BACKGROUND: Infertility is a condition affecting 10% to 15% of couples of reproductive age. It is generally defined as "the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse". The treatment of infertility may involve manipulation of gametes or of the embryos themselves. These techniques are together known as assisted reproductive technology (ART). Practitioners are constantly seeking alternative or adjunct treatments, or both, in the hope that they may improve the outcome of assisted reproductive techniques. This Cochrane review focusses on the adjunct use of synthetic versions of two naturally-produced hormones, dehydroepiandrosterone (DHEA) and testosterone (T), in assisted reproduction.DHEA and its derivative testosterone are steroid hormones proposed to increase conception rates by positively affecting follicular response to gonadotrophin stimulation, leading to greater oocyte yields and, in turn, increased chance of pregnancy. OBJECTIVES: To assess the effectiveness and safety of DHEA and testosterone as pre- or co-treatments in subfertile women undergoing assisted reproduction. SEARCH METHODS: We searched the following electronic databases, trial registers and websites up to 12 March 2015: the Cochrane Central Register of Controlled Trials (CENTRAL), the Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, MEDLINE, EMBASE, PsycINFO, CINAHL, electronic trial registers for ongoing and registered trials, citation indexes, conference abstracts in the Web of Science, PubMed and OpenSIGLE. We also carried out handsearches. There were no language restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing DHEA or testosterone as an adjunct treatment to any other active intervention, placebo, or no treatment in women undergoing assisted reproduction. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, extracted relevant data and assessed them for risk of bias. We pooled studies using fixed-effect models. We calculated odds ratios (ORs) for each dichotomous outcome. Analyses were stratified by type of treatment. There were no data for the intended groupings by dose, mode of delivery or after one/more than one cycle.We assessed the overall quality of the evidence for the main findings using the GRADE working group methods. MAIN RESULTS: We included 17 RCTs with a total of 1496 participants. Apart from two trials, the trial participants were women identified as 'poor responders' to standard IVF protocols. The included trials compared either testosterone or DHEA treatment with placebo or no treatment.When DHEA was compared with placebo or no treatment, pre-treatment with DHEA was associated with higher rates of live birth or ongoing pregnancy (OR 1.88, 95% CI 1.30 to 2.71; eight RCTs, N = 878, I² statistic = 27%, moderate quality evidence). This suggests that in women with a 12% chance of live birth/ongoing pregnancy with placebo or no treatment, the live birth/ongoing pregnancy rate in women using DHEA will be between 15% and 26%. However, in a sensitivity analysis removing trials at high risk of performance bias, the effect size was reduced and no longer reached significance (OR 1.50, 95% CI 0.88 to 2.56; five RCTs, N = 306, I² statistic = 43%). There was no evidence of a difference in miscarriage rates (OR 0.58, 95% CI 0.29 to 1.17; eight RCTs, N = 950, I² statistic = 0%, moderate quality evidence). Multiple pregnancy data were available for five trials, with one multiple pregnancy in the DHEA group of one trial (OR 3.23, 95% CI 0.13 to 81.01; five RCTs, N = 267, very low quality evidence).When testosterone was compared with placebo or no treatment we found that pre-treatment with testosterone was associated with higher live birth rates (OR 2.60, 95% CI 1.30 to 5.20; four RCTs, N = 345, I² statistic = 0%, moderate evidence). This suggests that in women with an 8% chance of live birth with placebo or no treatment, the live birth rate in women using testosterone will be between 10% and 32%. On removal of studies at high risk of performance bias in a sensitivity analysis, the remaining study showed no evidence of a difference between the groups (OR 2.00, 95% CI 0.17 to 23.49; one RCT, N = 53). There was no evidence of a difference in miscarriage rates (OR 2.04, 95% CI 0.58 to 7.13; four RCTs, N = 345, I² = 0%, low quality evidence). Multiple pregnancy data were available for three trials, with four events in the testosterone group and one in the placebo/no treatment group (OR 3.09, 95% CI 0.48 to 19.98; three RCTs, N = 292, very low quality evidence).One study compared testosterone with estradiol and reported no evidence of a difference in live birth rates (OR 2.06, 95% CI 0.43 to 9.87; one RCT, N = 46, very low quality evidence) or miscarriage rates (OR 0.70, 95% CI 0.11 to 4.64; one RCT, N = 46, very low quality evidence).The quality of the evidence was moderate, the main limitations being lack of blinding in the included trials, inadequate reporting of study methods, and low event and sample sizes in some trials. AUTHORS' CONCLUSIONS: In women identified as poor responders undergoing ART, pre-treatment with DHEA or testosterone may be associated with improved live birth rates. The overall quality of the evidence is moderate. There is insufficient evidence to draw any conclusions about the safety of either androgen. Definitive conclusions regarding the clinical role of either androgen awaits evidence from further well-designed studies.

The immunomodulatory and anti-apoptotic effect of dexamethasone in imminent preterm labor: an experimental study.

The study was designed to investigate the effect of dexamethasone (DEX) on the latency period to delivery in a murine model of preterm labor. To this purpose, pregnant mice were randomly assigned in groups: the control group received water for injection (n=20), the preterm labor group was injected with lipopolysaccharide (LPS) (n=22), while the glucocorticoids group was administered DEX either 1h before (n=17) or after (n=7) lipopolysaccharide. In a first set of experiments animals were monitored to record perinatal outcomes. In another set of experiments, the remaining animals were sacrificed eight h after interventions. Fetuses were homogenized to measure tumor necrosis alpha in supernatants. Maternal splenocytes were isolated and stimulated for cytokine production. Serum of mice was incubated with donor cells from healthy pregnant and non-pregnant animals to induce apoptosis. LPS induced preterm labor but treatment or pretreatment with DEX delayed parturition exerting a favorable impact on survival of delivered fetuses. DEX inverted the increase of fetoplacental tumor necrosis alpha levels. Serum of LPS-stimulated mice induced apoptosis of splenocytes of either pregnant or non-pregnant healthy mice; this was reversed after incubation of splenocytes with serum coming from DEX pre-treated mice. The presented findings suggest that DEX administered either as pre-treatment or treatment prolonged gestation and promoted neonatal survival in a sterile murine model of preterm labor. These favorable outcomes were closely linked to alterations in both immune and apoptotic responses of animals.

Angiopoietin-2 primes infection-induced preterm delivery.

Current knowledge on the participation of angiopoietin-2 (Ang-2) in the inflammatory process and on the importance of bacterial endotoxins (LPS) in the induction of preterm delivery (PTD) led us to investigate the role of Ang-2/LPS interplay in the pathogenesis of PTD. At a first stage, Ang-2 was measured at the end of the first trimester of pregnancy in the serum of 50 women who delivered prematurely; of 88 women well-matched for age and parity who delivered full-term; and of 20 non-pregnant healthy women. Ang-2 was greater in pregnant than in non-pregnant women. The time until delivery was shorter among those with Ang-2 greater than 4 ng/ml (odds ratio for delivery until week 34; p: 0.040). To further investigate the role of Ang-2 for PTD, an experimental model of PTD induced by the intraperitoneal injection of LPS in mice was used. Ang-2 was administered intraperitoneally before LPS on day 14 of pregnancy. When Ang-2 was administered before the LPS diluent, all mice delivered full-term. However, administration of Ang-2 prior LPS accelerated further the time until delivery. Sacrifice experiments showed that the effect of Ang-2 was accompanied by decrease of the penetration of Evans Blue in the embryos and by increase of its penetration in maternal tissues. In parallel, the concentration of tumour necrosis factor-alpha in the maternal circulation, in fetal tissues and in the placentas was significantly decreased. Results indicate that Ang-2 accelerated the phenomena of PTD induced by LPS. This is related with deprivation of fetal perfusion.

In vitro maturation in subfertile women with polycystic ovarian syndrome undergoing assisted reproduction.

BACKGROUND: Polycystic ovarian syndrome (PCOS) occurs in 4% to 7% of all women of reproductive age and 50% of women presenting with subfertility. Subfertility affects 15% to 20% of couples trying to conceive. A significant proportion of these women ultimately need assisted reproductive technology (ART). In vitro fertilisation (IVF) is one of the assisted reproduction techniques employed to raise the chances of achieving a pregnancy. For the standard IVF technique, stimulating follicle development and growth before oocyte retrieval is essential, for which a large number of different methods combining gonadotrophins with a gonadotrophin-releasing hormone (GnRH) agonist or antagonist are used. In women with PCOS, the supra-physiological doses of gonadotrophins used for controlled ovarian hyperstimulation (COH) often result in an exaggerated ovarian response, characterised by the development of a large cohort of follicles of uneven quality, retrieval of immature oocytes, and increased risk of ovarian hyperstimulation syndrome. A potentially effective intervention for women with PCOS-related subfertility involves earlier retrieval of immature oocytes at the germinal-vesicle stage followed by in vitro maturation (IVM). So far, the only data available have derived from observational studies and non-randomised clinical trials. OBJECTIVES: To compare outcomes associated with in vitro maturation (IVM) followed by vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) versus conventional IVF or ICSI, among women with polycystic ovarian syndrome (PCOS) undergoing assisted reproductive technologies (ART). SEARCH METHODS: We searched the Menstrual Disorders and Subfertility Group (MDSG) Specialised Register of controlled trials to May 2013 for any relevant trials identified from the title, abstract, or keyword sections. This was followed by a search of the electronic database MEDLINE, EMBASE, LILACS and CINAHL, without language restriction. We also performed a manual search of the references of all retrieved articles; sought unpublished papers and abstracts submitted to international conferences, searched the clinicaltrials.gov and WHO portal registries for submitted protocols of clinical trials, and contacted experts. In addition, we examined the National Institute of Clinical Excellence (NICE) fertility assessment and treatment guidelines and handsearched reference lists of relevant articles (from 1970 to May 2013). SELECTION CRITERIA: All randomised trials (RCTs) on the intention to perform IVM before IVF or ICSI compared with conventional IVF or ICSI for subfertile women with PCOS. DATA COLLECTION AND ANALYSIS: Three review authors (CS, MK and NV) independently assessed eligibility and quality of trials. Primary outcome measure was live birth rate per randomised woman. MAIN RESULTS: There were no RCTs suitable for inclusion in the review, although there are currently three ongoing trials that have not yet reported results. AUTHORS' CONCLUSIONS: Though promising data on the IVM technique have been published, unfortunately there is still no evidence from RCTs upon which to base any practice recommendations regarding IVM before IVF or ICSI for women with PCOS. Meanwhile, the results of the above-mentioned ongoing trials are awaited and, of course, further evidence from good quality trials in the field is eagerly anticipated.

Artificial neural networks in gynaecological diseases: current and potential future applications.

Current (and probably future) practice of medicine is mostly associated with prediction and accurate diagnosis. Especially in clinical practice, there is an increasing interest in constructing and using valid models of diagnosis and prediction. Artificial neural networks (ANNs) are mathematical systems being used as a prospective tool for reliable, flexible and quick assessment. They demonstrate high power in evaluating multifactorial data, assimilating information from multiple sources and detecting subtle and complex patterns. Their capability and difference from other statistical techniques lies in performing nonlinear statistical modelling. They represent a new alternative to logistic regression, which is the most commonly used method for developing predictive models for outcomes resulting from partitioning in medicine. In combination with the other non-algorithmic artificial intelligence techniques, they provide useful software engineering tools for the development of systems in quantitative medicine. Our paper first presents a brief introduction to ANNs, then, using what we consider the best available evidence through paradigms, we evaluate the ability of these networks to serve as first-line detection and prediction techniques in some of the most crucial fields in gynaecology. Finally, through the analysis of their current application, we explore their dynamics for future use.

What have the 'omics done for endometriosis?

A review of the current literature was attempted in order to determine to what degree new technological features, such as the use of proteomics, genomics, and gene microarrays, have contributed to the elucidation of the specific pathways to the formation of endometriosis as well as to the discovery of potential biomarkers and new treatment strategies. Endometriosis is well described as a condition in which multiple genetic components and still foggy environmental risk factors are important determinants of the disease's origin, maintenance, persistence, and clinical outcome. The concept is that because of the special features and complexity of the disease, endometriosis is ideally suited as a target for genome- and proteome-wide scanning. Reviewing the current literature we found that, apart from the better understanding of the pathophysiology and the metabolic pathways which lead to potential biomarkers for endometriosis, there are still issues to be clarified and applications to be achieved. The evolving genomic and proteomic technologies remain poised to revolutionize the diagnosis and treatment of endometriosis but have not yet lead to a single new therapy or tested biomarker. The reasons have mainly to do with the complex and multifactorial character of the disease itself.