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OBJECTIVE: We aim to demonstrate a clinical difference in pregnancy outcomes in IVF cycles undergoing blastocyst-stage embryo biopsy and preimplantation genetic screening (PGS) in comparison to patients undergoing standard (non-PGS) IVF treatment. DESIGN: We conducted a retrospective cohort analysis of a private IVF clinic in Melbourne, Australia. MATERIALS AND METHODS: Details of patients undergoing PGS utilising blastocyst biopsy and next-generation sequencing from January 2015 to March 2018 were extracted from the clinic's database and compared to patients receiving standard IVF treatment and a blastocyst transfer from January 2010 to March 2018. Our analysis compared 719 PGS cases to 2920 non-PGS cases of single, frozen embryo transfer. Statistical analysis was conducted using Windows SPSS Version 25 and STATA 15. Demographic and stimulation cycle details were compared between groups using a combination of the Mann-Whitney-U test, Welch's t-test and student's ttest. Outcomes were analysed using logistic and linear regressions. RESULT(S): Statistically significant differences in some demographic factors, notably age and previous pregnancy/IVF history were apparent in PGS cycles. Our primary outcome was an ongoing and delivered pregnancy, with secondary outcomes of clinical pregnancy, twin delivery, gestation at delivery and birthweight. Adjustment regression models utilised almost all demographic and stimulation variables (except gravidity, parity and number of embryos biopsied). PGS had a statistically significant superior rate of ongoing and delivered pregnancies compared to non-PGS cases (OR 1.86, 95% CI 1.50-2.29, p=<0.001), with an associated superior clinical pregnancy rate (OR 1.66, 95% CI 1.36-2.04, p=<0.001). PGS produced superior ongoing and delivered pregnancy rates for women above 35 years (p=<0.001), but no difference under 35 years (p=0.92). Of note, there was no statistically significant difference between PGS and non-PGS groups related to twin del

OBJECTIVE: To evaluate whether GnRH-agonist (GnRHa) triggering improves embryo quality and live birth rates in 'freeze-all' cycles compared to human chorionic gonadotrophin (hCG). DESIGN: Retrospective cohort study. MATERIALS AND METHODS: This retrospective cohort study from January 2012 and December 2014 compared GnRHa and hCG-triggered 'freeze-all' cycles. Limiting for first cycle per patient, 396 GnRHa and 1,868 hCG-triggered cycles were included. Only cycles where embryos were available and thawed for transfer were included for live birth rates (LBR). 217 GnRHa and 509 hCG-triggered cycles were analysed for LBR. A multiple imputation approach was used to account for missing data. The primary outcome was LBR. Secondary outcomes included number of oocytes collected, embryo grade and quality, clinical pregnancy rates and the incidence of ovarian hyperstimulation syndrome (OHSS). Regression analysis was performed to adjust for confounders. P-values <0.05 were considered statistically significant. RESULT(S): The singleton LBR after one embryo transfer was higher in GnRHa triggered 'freeze-all' cycles compared to hCG (38.4% vs. 24.6%, p=0.001), as well as a non-significantly higher cumulative LBR (57.4% vs. 41.1%, p=0.18). There was no difference in the number of embryos thawed or transferred, and there was no difference in embryo grade or expansion. The incidence of OHSS was significantly lower in GnRHa triggered cycles (0.5% vs. 1.9%, p=0.008). CONCLUSION(S): GnRHa triggering resulted in a superior LBR compared to hCG in 'freeze-all' cycles, even after adjusting for confounders. GnRHa triggering did not compromise embryo quality and significantly reduced the risk of OHSS compared to hCG. Given these findings, GnRHa triggering appears to be the way of the future for 'freeze-all' cycles.

Importance Preimplantation genetic testing for aneuploidy (PGT-A) has undergone many technical developments over recent years, including changes in biopsy timings, methodology, and genetic analysis techniques. The evidence surrounding the efficaciousness of PGT-A is sporadic and inconsistent; as such, significant doubt and concern remain regarding its widespread implementation. Objective This review seeks to describe the historical development of PGT-A and to analyze and summarize the current published literature. Conclusions At times during its infancy, PGT-A failed to display conclusive improvements in results; with newer technologies, PGT-A appears to yield superior outcomes, including reductions in miscarriages and multiple gestations. Clinicians and patients should assess the use of PGT-A on a case-by-case basis, with laboratories encouraged to utilize blastocyst biopsy and next-generation sequencing when conducting PGT-A. Further studies providing cumulative live birth rates and time to live birth are required if PGT-A is to be proven as producing superior outcomes. Relevance PGT-A has the potential ability to impact in vitro fertilization success rates, and as it is increasingly adopted worldwide, it is crucial that clinicians are aware of the evidence for its continued use. Target Audience Obstetricians and gynecologists, family physicians. Learning Objectives After reading this review, physicians should be better able to summarize the history of PGT-A, including the development over time of biopsy and analytical techniques; explain the continued uncertainty regarding the efficacy of PGT-A and the associated safety concerns; and assess the impact mosaicism may have on the interpretation of PGT-A results and subsequent treatment recommendations.Copyright © Wolters Kluwer Health, Inc. All rights reserved.

Importance Preimplantation genetic testing for aneuploidy (PGT-A) has undergone many technical developments over recent years, including changes in biopsy timings, methodology, and genetic analysis techniques. The evidence surrounding the efficaciousness of PGT-A is sporadic and inconsistent; as such, significant doubt and concern remain regarding its widespread implementation. Objective This review seeks to describe the historical development of PGT-A and to analyze and summarize the current published literature. Conclusions At times during its infancy, PGT-A failed to display conclusive improvements in results; with newer technologies, PGT-A appears to yield superior outcomes, including reductions in miscarriages and multiple gestations. Clinicians and patients should assess the use of PGT-A on a case-by-case basis, with laboratories encouraged to utilize blastocyst biopsy and next-generation sequencing when conducting PGT-A. Further studies providing cumulative live birth rates and time to live birth are required if PGT-A is to be proven as producing superior outcomes. Relevance PGT-A has the potential ability to impact in vitro fertilization success rates, and as it is increasingly adopted worldwide, it is crucial that clinicians are aware of the evidence for its continued use. Target Audience Obstetricians and gynecologists, family physicians. Learning Objectives After reading this review, physicians should be better able to summarize the history of PGT-A, including the development over time of biopsy and analytical techniques; explain the continued uncertainty regarding the efficacy of PGT-A and the associated safety concerns; and assess the impact mosaicism may have on the interpretation of PGT-A results and subsequent treatment recommendations.Copyright © Wolters Kluwer Health, Inc. All rights reserved.

Objective: To evaluate oocyte maturation and fertilisation rates of intracytoplasmic sperm injection (ICSI) cycles triggered with intranasal and subcutaneous GnRH-agonists (GnRHa). Design(s): Retrospective cohort study. Material(s) and Method(s): This retrospective cohort study from May 2016 to August 2018 compared intranasal and subcutaneous GnRHa triggers in ICSI cycles. Data was extracted from 9588 ICSI cycles. A total of 781 cycles were included for analysis after excluding cycles triggered with hCG (n=8521), duplicate patient cycles (n=182), where a duel trigger was used (n=55) or where the trigger was not recorded (n=49). 214 cycles utilised the intranasal Nafarelin trigger (Synarel; Pfizer Pty Ltd) and 567 cycles used a subcutaneous formulation, either Triptorelin (Decapeptyl; Ferring Pharmaceuticals Pty Ltd) or Leuprorelin (Lucrin; AbbVie Pty Ltd). The primary outcome was oocyte maturation rate. Secondary outcomes included number of mature oocytes collected, number of fertilised oocytes, fertilisation rate and the incidence of ovarian hyperstimulation syndrome (OHSS). Categorical data was presented as a proportion (%) and p-values were obtained by performing a Mann-Whitney U test. Continuous and count data was presented as a mean with standard deviation and standard error of mean, and p-values were obtained by performing the student's T-test. Univariate and adjusted analyses were performed using negative binomial regression for count measures and linear regression for continuous measures. Statistical significance was defined as a p-value <0.05. Result(s): There was a trend towards higher oocyte maturation rates in patients receiving a subcutaneous GnRHa trigger compared to intranasal formulations (78.1% vs. 77.6%, p=0.059). There was a statistically significant difference in fertilisation rate in favour of the subcutaneous trigger (68.0% vs. 67.9%, p=0.016). There was no difference in the age or BMI of patients, nor was there a difference in the crude number

Objective: To evaluate whether GnRH-agonist (GnRHa) triggering improves embryo quality and live birth rates in 'freeze-all' cycles compared to human chorionic gonadotrophin (hCG). Design(s): Retrospective cohort study. Material(s) and Method(s): This retrospective cohort study from January 2012 and December 2014 compared GnRHa and hCG-triggered 'freeze-all' cycles. Limiting for first cycle per patient, 396 GnRHa and 1,868 hCG-triggered cycles were included. Only cycles where embryos were available and thawed for transfer were included for live birth rates (LBR). 217 GnRHa and 509 hCG-triggered cycles were analysed for LBR. A multiple imputation approach was used to account for missing data. The primary outcome was LBR. Secondary outcomes included number of oocytes collected, embryo grade and quality, clinical pregnancy rates and the incidence of ovarian hyperstimulation syndrome (OHSS). Regression analysis was performed to adjust for confounders. P-values <0.05 were considered statistically significant. Result(s): The singleton LBR after one embryo transfer was higher in GnRHa triggered 'freeze-all' cycles compared to hCG (38.4% vs. 24.6%, p=0.001), as well as a non-significantly higher cumulative LBR (57.4% vs. 41.1%, p=0.18). There was no difference in the number of embryos thawed or transferred, and there was no difference in embryo grade or expansion. The incidence of OHSS was significantly lower in GnRHa triggered cycles (0.5% vs. 1.9%, p=0.008). Conclusion(s): GnRHa triggering resulted in a superior LBR compared to hCG in 'freeze-all' cycles, even after adjusting for confounders. GnRHa triggering did not compromise embryo quality and significantly reduced the risk of OHSS compared to hCG. Given these findings, GnRHa triggering appears to be the way of the future for 'freeze-all' cycles. Reference: None.Copyright © 2019

Objective: To evaluate oocyte maturation and fertilisation rates of intracytoplasmic sperm injection (ICSI) cycles triggered with intranasal and subcutaneous GnRH-agonists (GnRHa). Design(s): Retrospective cohort study. Material(s) and Method(s): This retrospective cohort study from May 2016 to August 2018 compared intranasal and subcutaneous GnRHa triggers in ICSI cycles. Data was extracted from 9588 ICSI cycles. A total of 781 cycles were included for analysis after excluding cycles triggered with hCG (n=8521), duplicate patient cycles (n=182), where a duel trigger was used (n=55) or where the trigger was not recorded (n=49). 214 cycles utilised the intranasal Nafarelin trigger (Synarel; Pfizer Pty Ltd) and 567 cycles used a subcutaneous formulation, either Triptorelin (Decapeptyl; Ferring Pharmaceuticals Pty Ltd) or Leuprorelin (Lucrin; AbbVie Pty Ltd). The primary outcome was oocyte maturation rate. Secondary outcomes included number of mature oocytes collected, number of fertilised oocytes, fertilisation rate and the incidence of ovarian hyperstimulation syndrome (OHSS). Categorical data was presented as a proportion (%) and p-values were obtained by performing a Mann-Whitney U test. Continuous and count data was presented as a mean with standard deviation and standard error of mean, and p-values were obtained by performing the student's T-test. Univariate and adjusted analyses were performed using negative binomial regression for count measures and linear regression for continuous measures. Statistical significance was defined as a p-value <0.05. Result(s): There was a trend towards higher oocyte maturation rates in patients receiving a subcutaneous GnRHa trigger compared to intranasal formulations (78.1% vs. 77.6%, p=0.059). There was a statistically significant difference in fertilisation rate in favour of the subcutaneous trigger (68.0% vs. 67.9%, p=0.016). There was no difference in the age or BMI of patients, nor was there a difference in the crude number

Objective: To evaluate whether GnRH-agonist (GnRHa) triggering improves embryo quality and live birth rates in 'freeze-all' cycles compared to human chorionic gonadotrophin (hCG). Design(s): Retrospective cohort study. Material(s) and Method(s): This retrospective cohort study from January 2012 and December 2014 compared GnRHa and hCG-triggered 'freeze-all' cycles. Limiting for first cycle per patient, 396 GnRHa and 1,868 hCG-triggered cycles were included. Only cycles where embryos were available and thawed for transfer were included for live birth rates (LBR). 217 GnRHa and 509 hCG-triggered cycles were analysed for LBR. A multiple imputation approach was used to account for missing data. The primary outcome was LBR. Secondary outcomes included number of oocytes collected, embryo grade and quality, clinical pregnancy rates and the incidence of ovarian hyperstimulation syndrome (OHSS). Regression analysis was performed to adjust for confounders. P-values <0.05 were considered statistically significant. Result(s): The singleton LBR after one embryo transfer was higher in GnRHa triggered 'freeze-all' cycles compared to hCG (38.4% vs. 24.6%, p=0.001), as well as a non-significantly higher cumulative LBR (57.4% vs. 41.1%, p=0.18). There was no difference in the number of embryos thawed or transferred, and there was no difference in embryo grade or expansion. The incidence of OHSS was significantly lower in GnRHa triggered cycles (0.5% vs. 1.9%, p=0.008). Conclusion(s): GnRHa triggering resulted in a superior LBR compared to hCG in 'freeze-all' cycles, even after adjusting for confounders. GnRHa triggering did not compromise embryo quality and significantly reduced the risk of OHSS compared to hCG. Given these findings, GnRHa triggering appears to be the way of the future for 'freeze-all' cycles. Reference: None.Copyright © 2019

The endometrium lines a women's uterus becoming receptive, and allowing embryo implantation to occur, for just a few days during the post-ovulatory mid-secretory phase of each menstrual cycle. We investigated whether concentrations of proposed receptivity biomarkers (VEGF, IL8, FGF2, CSF3 sFlt-1, sGP130 and PlGF) secreted by the endometrium into the uterine cavity and forming the microenvironment for embryo implantation is altered among a population of age-matched women with unexplained (idiopathic) infertility compared to fertile women during the receptive mid-secretory phase (n = 16 fertile, 18 infertile) and the prior pre-receptive early secretory phase (n = 19 fertile, 18 infertile) of their cycle. In the mid-secretory cohort significantly elevated concentrations of five biomarkers; PlGF (p = 0.001), IL8 (p = 0.004), sGP130 (p = 0.009), sFlt-1 (p = 0.021), and CSF3 (p = 0.029) was present in uterine fluid of infertile women during the mid-secretory phase, but only CSF3 was significantly elevated in the pre-receptive early secretory phase (p = 0.006). In vitro studies of glycosylated and non-glycosylated forms of CSF3 at representative fertile (20 ng/mL) and infertile (70 ng/mL) effects on endometrium and embryo behaviour were performed. Non-glycosylated CSF3 at fertile concentrations significantly (p < 0.001) elevated endometrial epithelial cell proliferation however chronic treatment or elevated (infertile) concentrations of CSF3 in glycosylated form abrogated the positive effects. Both forms of CSF3 increased trophoblast cell invasion (p < 0.001) regardless of concentration. Mouse embryo outgrowth was significantly (p < 0.01) increased at fertile but not at infertile concentrations. The study confirmed potential utility of five biomarkers of endometrial receptivity for future application in the mid-secretory phase while highlighting CSF3 is elevated in the earlier pre-receptive phase. Our data provides evidence that CSF3 acts on both human endometrium and embr

The regenerative, proliferative phase of a woman's menstrual cycle is a critical period which lays the foundation for the subsequent, receptive secretory phase. Although endometrial glands and their secretions are essential for embryo implantation and survival, the proliferative phase, when these glands form, has been rarely examined. We hypothesized that alterations in the secreted proteome of the endometrium of idiopathic infertile women would reflect a disturbance in proliferative phase endometrial regeneration. Our aim was to compare the proteomic profile of proliferative phase uterine fluid from fertile (n = 9) and idiopathic infertile (n = 10) women. Proteins with >=2-fold change (P < 0.05) were considered significantly altered between fertile and infertile groups. Immunohistochemistry examined the endometrial localization of identified proteins. Western immunoblotting defined the forms of extracellular matrix protein 1 (ECM1) in uterine lavage fluid. Proteomic analysis identified four proteins significantly downregulated in infertile women compared to fertile women, including secreted frizzled-related protein 4 (SFRP4), CD44, and ECM1: two proteins were upregulated. Seven proteins were unique to the fertile group and six (including isoaspartyl peptidase/L-asparaginase [ASRGL1]) were unique to the infertile group. Identified proteins were classified into biological processes of tissue regeneration and regulatory processes. ASRGL1, SFRP4, and ECM1 localized to glandular epithelium and stroma, cluster of differentiation 44 (CD44) to stroma and immune cells. ECM1 was present in two main molecular weight forms in uterine fluid. Our results indicate a disturbance in endometrial development during the proliferative phase among infertile women, providing insights into human endometrial development and potential therapeutic targets for infertility.Copyright © The Author 2017. Published by Oxford University Press on behalf of Kazusa DNA Research Institute.

Purpose: The aim of this study was to explore the factors that influence the outcome of intrauterine human chorionic gonadotropin (hCG) infusion at the time of embryo transfer (ET), in particular, the effect of hCG infusions on fresh and frozen embryo transfers (FETs) and whether prior recurrent implantation failure (RIF) impacts upon outcomes. Method(s): This was a case-control study based on a standardized database from a multi-site in vitro fertilization clinic. The analysis contains 458 cases and 749 matched controls, with an intervention group of those given intrauterine hCG prior to ET and a control group of patients receiving no hCG infusion. Outcomes were defined as clinical pregnancy and live birth rates. Two analyses were performed. The first separated FETs (cases n = 224, controls n = 325) and fresh ETs (cases n = 234, controls n = 424), with outcomes calculated in each group. The second analysis divided patients into those with RIF (cases n = 149, controls n = 200) and those without (cases n = 309, controls n = 549). Result(s): Results in fresh ETs demonstrated a 5.8% reduction (adjusted odds ratio (AOR) = 0.60, p = 0.041) in clinical pregnancy rates with the use of intrauterine hCG. In those without defined RIF, clinical pregnancy rates were reduced by 8.1% (AOR = 0.61, p = 0.023) and live birth rates by 7.2% (AOR = 0.56, p = 0.32) with intrauterine hCG use. There were no significant differences in outcomes in FETs and in the RIF cohort. Conclusion(s): Intrauterine hCG at the time of ET not only seems to have no benefit, but rather a negative effect in fresh ETs and those without RIF.Copyright © 2017, Springer Science+Business Media, LLC.

The endometrium lines a women's uterus becoming receptive, and allowing embryo implantation to occur, for just a few days during the post-ovulatory mid-secretory phase of each menstrual cycle. We investigated whether concentrations of proposed receptivity biomarkers (VEGF, IL8, FGF2, CSF3 sFlt-1, sGP130 and PlGF) secreted by the endometrium into the uterine cavity and forming the microenvironment for embryo implantation is altered among a population of age-matched women with unexplained (idiopathic) infertility compared to fertile women during the receptive mid-secretory phase (n = 16 fertile, 18 infertile) and the prior pre-receptive early secretory phase (n = 19 fertile, 18 infertile) of their cycle. In the mid-secretory cohort significantly elevated concentrations of five biomarkers; PlGF (p = 0.001), IL8 (p = 0.004), sGP130 (p = 0.009), sFlt-1 (p = 0.021), and CSF3 (p = 0.029) was present in uterine fluid of infertile women during the mid-secretory phase, but only CSF3 was significantly elevated in the pre-receptive early secretory phase (p = 0.006). In vitro studies of glycosylated and non-glycosylated forms of CSF3 at representative fertile (20 ng/mL) and infertile (70 ng/mL) effects on endometrium and embryo behaviour were performed. Non-glycosylated CSF3 at fertile concentrations significantly (p < 0.001) elevated endometrial epithelial cell proliferation however chronic treatment or elevated (infertile) concentrations of CSF3 in glycosylated form abrogated the positive effects. Both forms of CSF3 increased trophoblast cell invasion (p < 0.001) regardless of concentration. Mouse embryo outgrowth was significantly (p < 0.01) increased at fertile but not at infertile concentrations. The study confirmed potential utility of five biomarkers of endometrial receptivity for future application in the mid-secretory phase while highlighting CSF3 is elevated in the earlier pre-receptive phase. Our data provides evidence that CSF3 acts on both human endometrium and embr

The regenerative, proliferative phase of a woman's menstrual cycle is a critical period which lays the foundation for the subsequent, receptive secretory phase. Although endometrial glands and their secretions are essential for embryo implantation and survival, the proliferative phase, when these glands form, has been rarely examined. We hypothesized that alterations in the secreted proteome of the endometrium of idiopathic infertile women would reflect a disturbance in proliferative phase endometrial regeneration. Our aim was to compare the proteomic profile of proliferative phase uterine fluid from fertile (n = 9) and idiopathic infertile (n = 10) women. Proteins with >=2-fold change (P < 0.05) were considered significantly altered between fertile and infertile groups. Immunohistochemistry examined the endometrial localization of identified proteins. Western immunoblotting defined the forms of extracellular matrix protein 1 (ECM1) in uterine lavage fluid. Proteomic analysis identified four proteins significantly downregulated in infertile women compared to fertile women, including secreted frizzled-related protein 4 (SFRP4), CD44, and ECM1: two proteins were upregulated. Seven proteins were unique to the fertile group and six (including isoaspartyl peptidase/L-asparaginase [ASRGL1]) were unique to the infertile group. Identified proteins were classified into biological processes of tissue regeneration and regulatory processes. ASRGL1, SFRP4, and ECM1 localized to glandular epithelium and stroma, cluster of differentiation 44 (CD44) to stroma and immune cells. ECM1 was present in two main molecular weight forms in uterine fluid. Our results indicate a disturbance in endometrial development during the proliferative phase among infertile women, providing insights into human endometrial development and potential therapeutic targets for infertility.Copyright © The Author 2017. Published by Oxford University Press on behalf of Kazusa DNA Research Institute.

Purpose: The aim of this study was to explore the factors that influence the outcome of intrauterine human chorionic gonadotropin (hCG) infusion at the time of embryo transfer (ET), in particular, the effect of hCG infusions on fresh and frozen embryo transfers (FETs) and whether prior recurrent implantation failure (RIF) impacts upon outcomes. Method(s): This was a case-control study based on a standardized database from a multi-site in vitro fertilization clinic. The analysis contains 458 cases and 749 matched controls, with an intervention group of those given intrauterine hCG prior to ET and a control group of patients receiving no hCG infusion. Outcomes were defined as clinical pregnancy and live birth rates. Two analyses were performed. The first separated FETs (cases n = 224, controls n = 325) and fresh ETs (cases n = 234, controls n = 424), with outcomes calculated in each group. The second analysis divided patients into those with RIF (cases n = 149, controls n = 200) and those without (cases n = 309, controls n = 549). Result(s): Results in fresh ETs demonstrated a 5.8% reduction (adjusted odds ratio (AOR) = 0.60, p = 0.041) in clinical pregnancy rates with the use of intrauterine hCG. In those without defined RIF, clinical pregnancy rates were reduced by 8.1% (AOR = 0.61, p = 0.023) and live birth rates by 7.2% (AOR = 0.56, p = 0.32) with intrauterine hCG use. There were no significant differences in outcomes in FETs and in the RIF cohort. Conclusion(s): Intrauterine hCG at the time of ET not only seems to have no benefit, but rather a negative effect in fresh ETs and those without RIF.Copyright © 2017, Springer Science+Business Media, LLC.

OBJECTIVE: To investigate the association between uterine adenomyosis diagnosed by ultrasound and the outcomes of in vitro fertilisation and embryo transfer (IVF/ET). DESIGN: Prospective cohort study. MATERIALS AND METHODS: All patients from our unit aged 18- 45 years undergoing a stimulated IVF cycle with embryo transfer between January 2016 and March 2017 were identified. Six-hundred and two of these patients had a standardised tertiary level pre-treatment ultrasound where signs of adenomyosis were actively investigated. Adenomyosis was identified in 113 (18.7%) of these patients and the IVF/ET coutcomes were compared with the remaining 489 patients. The data was not normally distributed and univariate analysis with Mann-Whitney testing was undertaken using SPSS. The primary outcome was clinical pregnancy rate per patient. Logistic regression was used to allow for potential confounders. This is an interim analysis. RESULT(S): A total of 602 patients were investigated. Patients with adenomyosis were older (37.9 years vs 36.9 years; p < 0.001), more likely to smoke (7.1% vs 1.6%; p = 0.001), have endometriosis (17.7% vs 9%; p = 0.007) and have poorer grade embryos (p = 0.001). Patients with adenomyosis had a significantly lower clinical pregnancy rate (23.9% vs 40.7%; p = 0.045) with an odds-ratio of 0.46 (0.28 - 0.75). This result remained significant even after logistic regression to control for confounders with an adjusted odds-ratio of 0.35 (0.14 - 0.88; p = 0.045). CONCLUSION(S): The presence of adenomyosis diagnosed by tertiary ultrasound is associated with lower clinical pregnancy rates in IVF/ET. The lower clinical pregnancy rate seen with adenomyosis is independent of the effects of poorer grade embryos, smoking, and advanced age. Further analysis of this trial once a larger population is collected will be done to verify these findings and assess effect on live births.

OBJECTIVE: Many in vitro fertilisation (IVF) clinics worldwide preferentially use elective embryo cryopreservation. This study compares GnRHa triggering in 'freeze-all' cycles with conventional human chorionic gonadotropin (hCG) triggering for live birth rates (LBR), neonatal outcomes and OHSS incidence. DESIGN: A multi-centre, retrospective cohort study was performed for matched autologous and donor cycles. MATERIALS AND METHODS: 467 autologous and 111 donor cycles utilised a GnRHa trigger and 'freeze-all' approach from January 2012 to July 2015. Cycles were matched at a 1:1 ratio with hCG triggered 'freezeall' cycles. Cycles were matched for age, body mass index, polycystic ovarian syndrome (PCOS), stimulation cycle number and starting gonadotropin dose. Cycles were sub-stratified for OHSS risk, according to the presence of PCOS and/or recruitment of >14 follicles at ovulation. LBR was recorded for the first blastocyst transfer, cumulative LBR included all subsequent transfers. Fisher's or Chi-squared tests were performed for categorical data. Continuous data was non-parametrically distributed and Mann-Whitney testing was performed. P-values <0.05 were considered statistically significant. RESULT(S): In high-risk autologous cycles, LBR was 41.3% vs 31.7% after GnRHa and hCG triggering (p=0.08). Cumulative LBR was 58.1% vs 50.7% (p=0.16), with no difference in the number of embryos transferred. A similar trend in LBR was observed in low-risk women (GnRHa 45.5% vs hCG 29.2%, p=0.19). The incidence of OHSS was significantly lower in highrisk women (GnRHa 1.2% vs hCG 10.6%; OR 0.10 (0.03-0.29); p<0.05). No cases of OHSS were reported in low-risk women. In high-risk donor cycles, LBR was 40.1% vs 41.4% after GnRHa and hCG triggering (p=0.97). Cumulative LBR was 61.2% vs 54.8% (p=0.53) in highrisk women, and 56.5% vs 42.3% (p=0.16) in low-risk women. The incidence ofOHSS was 1.8%vs 3.9%(p=0.61) afterGnRHa and hCGtriggering in highrisk women, and 0% vs 1.7% in low-risk w

OBJECTIVE: To investigate the association between uterine adenomyosis diagnosed by ultrasound and the outcomes of in vitro fertilisation and embryo transfer (IVF/ET). DESIGN: Prospective cohort study. MATERIALS AND METHODS: All patients from our unit aged 18- 45 years undergoing a stimulated IVF cycle with embryo transfer between January 2016 and March 2017 were identified. Six-hundred and two of these patients had a standardised tertiary level pre-treatment ultrasound where signs of adenomyosis were actively investigated. Adenomyosis was identified in 113 (18.7%) of these patients and the IVF/ET coutcomes were compared with the remaining 489 patients. The data was not normally distributed and univariate analysis with Mann-Whitney testing was undertaken using SPSS. The primary outcome was clinical pregnancy rate per patient. Logistic regression was used to allow for potential confounders. This is an interim analysis. RESULT(S): A total of 602 patients were investigated. Patients with adenomyosis were older (37.9 years vs 36.9 years; p < 0.001), more likely to smoke (7.1% vs 1.6%; p = 0.001), have endometriosis (17.7% vs 9%; p = 0.007) and have poorer grade embryos (p = 0.001). Patients with adenomyosis had a significantly lower clinical pregnancy rate (23.9% vs 40.7%; p = 0.045) with an odds-ratio of 0.46 (0.28 - 0.75). This result remained significant even after logistic regression to control for confounders with an adjusted odds-ratio of 0.35 (0.14 - 0.88; p = 0.045). CONCLUSION(S): The presence of adenomyosis diagnosed by tertiary ultrasound is associated with lower clinical pregnancy rates in IVF/ET. The lower clinical pregnancy rate seen with adenomyosis is independent of the effects of poorer grade embryos, smoking, and advanced age. Further analysis of this trial once a larger population is collected will be done to verify these findings and assess effect on live births.

OBJECTIVE: Many in vitro fertilisation (IVF) clinics worldwide preferentially use elective embryo cryopreservation. This study compares GnRHa triggering in 'freeze-all' cycles with conventional human chorionic gonadotropin (hCG) triggering for live birth rates (LBR), neonatal outcomes and OHSS incidence. DESIGN: A multi-centre, retrospective cohort study was performed for matched autologous and donor cycles. MATERIALS AND METHODS: 467 autologous and 111 donor cycles utilised a GnRHa trigger and 'freeze-all' approach from January 2012 to July 2015. Cycles were matched at a 1:1 ratio with hCG triggered 'freezeall' cycles. Cycles were matched for age, body mass index, polycystic ovarian syndrome (PCOS), stimulation cycle number and starting gonadotropin dose. Cycles were sub-stratified for OHSS risk, according to the presence of PCOS and/or recruitment of >14 follicles at ovulation. LBR was recorded for the first blastocyst transfer, cumulative LBR included all subsequent transfers. Fisher's or Chi-squared tests were performed for categorical data. Continuous data was non-parametrically distributed and Mann-Whitney testing was performed. P-values <0.05 were considered statistically significant. RESULT(S): In high-risk autologous cycles, LBR was 41.3% vs 31.7% after GnRHa and hCG triggering (p=0.08). Cumulative LBR was 58.1% vs 50.7% (p=0.16), with no difference in the number of embryos transferred. A similar trend in LBR was observed in low-risk women (GnRHa 45.5% vs hCG 29.2%, p=0.19). The incidence of OHSS was significantly lower in highrisk women (GnRHa 1.2% vs hCG 10.6%; OR 0.10 (0.03-0.29); p<0.05). No cases of OHSS were reported in low-risk women. In high-risk donor cycles, LBR was 40.1% vs 41.4% after GnRHa and hCG triggering (p=0.97). Cumulative LBR was 61.2% vs 54.8% (p=0.53) in highrisk women, and 56.5% vs 42.3% (p=0.16) in low-risk women. The incidence ofOHSS was 1.8%vs 3.9%(p=0.61) afterGnRHa and hCGtriggering in highrisk women, and 0% vs 1.7% in low-risk w

OBJECTIVE: Poor uterine receptivity may be one reason for implantation failure in IVF. Some evidence [1-3] suggests an immunological role for reduced uterine receptivity hence many interventions targeted at achieving an 'ideal' immune environment are being investigated. One such therapy, intralipid, has been shown to be effective at suppressing natural kill cell cytotoxicity [4-5] but it remains unclear as to the actual effect in improving pregnancy rates. Thus, the objective of our study was to evaluate the effect of intralipid on chemical pregnancy, clinical pregnancy, live births and clinical pregnancy loss. DESIGN: Retrospective cohort study. MATERIALS AND METHODS: The study evaluated all fresh and frozen embryo transfers (ETs) between 2011 and 2015 (N=29,852) from a multi-site IVF clinic. In patients who had one or more ETs with intralipid, all other ETs were excluded and a randomly selected single ET cycle was chosen for each patient, leaving 11,028 ETs for analysis. This included 545 ETs where intralipid was used and 10,483 control ETs. Intervention and control groups were matched for: year, cycle number, age, number of embryos transferred, number of previous ETs without a live birth, and use of adjuvant therapies. Univariate comparison of proportions was performed using the Chi square test, while Mann Whitney U testing was used for univariate comparison of continuous variables. Logistic regression was used to allow for potential confounding variables. Analysis was performed initially on the full cohort and then on matched cases and controls. RESULT(S): Analysis of the full cohort demonstrated reduced rates for the intralipid group of chemical pregnancy (crude OR 0.61 CI 0.50-0.70), clinical pregnancy (crude OR 0.58 CI 0.48-0.71) and live birth (crude OR 0.52 CI 0.42-0.65). Once confounding factors had been allowed for through logistic regression (adjusted ORs) no statistically significant differences were seen between ET cycles with or without intralipid.

OBJECTIVE: Poor uterine receptivity may be one reason for implantation failure in IVF. Some evidence [1-3] suggests an immunological role for reduced uterine receptivity hence many interventions targeted at achieving an 'ideal' immune environment are being investigated. One such therapy, intralipid, has been shown to be effective at suppressing natural kill cell cytotoxicity [4-5] but it remains unclear as to the actual effect in improving pregnancy rates. Thus, the objective of our study was to evaluate the effect of intralipid on chemical pregnancy, clinical pregnancy, live births and clinical pregnancy loss. DESIGN: Retrospective cohort study. MATERIALS AND METHODS: The study evaluated all fresh and frozen embryo transfers (ETs) between 2011 and 2015 (N=29,852) from a multi-site IVF clinic. In patients who had one or more ETs with intralipid, all other ETs were excluded and a randomly selected single ET cycle was chosen for each patient, leaving 11,028 ETs for analysis. This included 545 ETs where intralipid was used and 10,483 control ETs. Intervention and control groups were matched for: year, cycle number, age, number of embryos transferred, number of previous ETs without a live birth, and use of adjuvant therapies. Univariate comparison of proportions was performed using the Chi square test, while Mann Whitney U testing was used for univariate comparison of continuous variables. Logistic regression was used to allow for potential confounding variables. Analysis was performed initially on the full cohort and then on matched cases and controls. RESULT(S): Analysis of the full cohort demonstrated reduced rates for the intralipid group of chemical pregnancy (crude OR 0.61 CI 0.50-0.70), clinical pregnancy (crude OR 0.58 CI 0.48-0.71) and live birth (crude OR 0.52 CI 0.42-0.65). Once confounding factors had been allowed for through logistic regression (adjusted ORs) no statistically significant differences were seen between ET cycles with or without intralipid.

Background: Improvements in vitrification now make frozen embryo transfers (FETs) a viable alternative to fresh embryo transfer, with reports fromobservational studies and randomized controlled trials suggesting that: (i) the endometrium in stimulated cycles is not optimally prepared for implantation; (ii) pregnancy rates are increased following FET and (iii) perinatal outcomes are less affected after FET. methods: This review integrates and discusses the available clinical and scientific evidence supporting embryo transfer in a natural cycle. Result(s): Laboratory-based studies demonstrate morphological and molecular changes to the endometrium and reduced responsiveness of the endometriumtohCG, resulting fromcontrolledovarian stimulation.Theliteraturedemonstrates reducedendometrial receptivity incontrolledovarian stimulation cycles and supports the clinical observations that FET reduces the risk of ovarian hyperstimulation syndrome and improves outcomes for both the mother and baby. Conclusion(s): This review provides the basis for an evidence-based approach towards changes in routine IVF, which may ultimately result in higher delivery rates of healthier term babies.Copyright © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.

Background: Improvements in vitrification now make frozen embryo transfers (FETs) a viable alternative to fresh embryo transfer, with reports fromobservational studies and randomized controlled trials suggesting that: (i) the endometrium in stimulated cycles is not optimally prepared for implantation; (ii) pregnancy rates are increased following FET and (iii) perinatal outcomes are less affected after FET. methods: This review integrates and discusses the available clinical and scientific evidence supporting embryo transfer in a natural cycle. Result(s): Laboratory-based studies demonstrate morphological and molecular changes to the endometrium and reduced responsiveness of the endometriumtohCG, resulting fromcontrolledovarian stimulation.Theliteraturedemonstrates reducedendometrial receptivity incontrolledovarian stimulation cycles and supports the clinical observations that FET reduces the risk of ovarian hyperstimulation syndrome and improves outcomes for both the mother and baby. Conclusion(s): This review provides the basis for an evidence-based approach towards changes in routine IVF, which may ultimately result in higher delivery rates of healthier term babies.Copyright © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.

OBJECTIVE: Egg quality and therefore embryo quality is a limiting factor in IVF. Mitochondria supply ATP to cells, and higher levels are associated with better quality eggs. Excessive reactive oxygen species (ROS) are implicated in mitochondrial damage. Melatonin regulates reproductive physiology via gonadotropin release, but is also a powerful free radical scavenger and antioxidant. Our study examined the use of melatonin in IVF patients with multiple unsuccessful cycles. DESIGN: Retrospective case control study. MATERIALS AND METHODS: !?A3B2 tlsb=0.06pt?>From June 2012- April 2013, 13 women from Monash IVF Australia who had undergone at least two unsuccessful IVF cycles were given 4mg melatonin daily from the first day of follicle stimulating hormone. Two controls per case were matched for age, cycle number, stimulation type and dose; with consideration for BMI, infertility aetiology and andrology. Primary outcomes were oocyte quantity, oocyte maturity and utilization rates. Secondary outcomes included duration of FSH, peak oestrodial levels, number of follicles >11mm and clinical and biochemical pregnancies. T-tests were used to analyse continuous data and Fisher's exact test for categorical data; p<0.05 considered significant. RESULT(S): When the melatonin cases were compared to the matched controls, there were no statistically significant differences in any of the primary or secondary outcomes assessed. Interestingly, when melatonin cases were compared with their own previous cycle, oocyte number showed a trend towards increased value (5.1 vs 7.1, p=0.1744). Of clinical relevance, increase in mature oocyte numbers compared to previous cycles approached statistical significance (3.4 vs 4.9, p=0.0515). Duration of FSH, max E2, follicle number and utilization rate showed no significant changes. CONCLUSION(S): In patients with multiple unsuccessful IVF cycles, melatonin may improve oocyte quantity and increase development to mature oocytes. The trends in this small

Uterine fibroids are the most common benign tumour afflicting women of reproductive age. Despite the large healthcare burden caused by fibroids, there is only limited understanding of the molecular mechanisms that drive fibroid pathophysiology. Although a large number of genes are differentially expressed in fibroids compared with myometrium, it is likely that most of these differences are a consequence of the fibroid presence and are not causal. The aim of this study was to investigate the expression and regulation of NR2F2 and CTNNB1 based on their potential causal role in uterine fibroid pathophysiology. We used real-time quantitative RT-PCR, western blotting and immunohistochemistry to describe the expression of NR2F2 and CTNNB1 in matched human uterine fibroid and myometrial tissues. Primary myometrial and fibroid smooth muscle cell cultures were treated with progesterone and/or retinoic acid (RA) and sonic hedgehog (SHH) conditioned media to investigate regulatory pathways for these proteins. We showed that NR2F2 and CTNNB1 are aberrantly expressed in fibroid tissue compared with matched myometrium, with strong blood vessel-specific localisation. Although the SHH pathway was shown to be active in myometrial and fibroid primary cultures, it did not regulate NR2F2 or CTNNB1 mRNA expression. However, progesterone and RA combined regulated NR2F2 mRNA, but not CTNNB1, in myometrial but not fibroid primary cultures. In conclusion, we demonstrate aberrant expression and regulation of NR2F2 and CTNNB1 in uterine fibroids compared with normal myometrium, consistent with the hypothesis that these factors may play a causal role uterine fibroid development. © 2013 Society for Reproduction and Fertility.

OBJECTIVE: To investigate the association between uterine adenomyosis diagnosed by ultrasound on ovarian response and the outcomes of in vitro fertilisation and embryo transfer (IVF/ET). DESIGN: Retrospective case controlled study. MATERIALS AND METHODS: All patients from our unit aged <45 years and undergoing their first stimulated cycle with fresh embryo transfer between June 2002 and June 2012 were identified. Seventytwo cases were found to have adenomyosis on pre-treatment tertiary level ultrasound and were matched by year of treatment, age, gravidity, parity and BMI with 2438 controls without adenomyosis. The data were not normally distributed and univariate analysis with Mann-Whitney testing was undertaken using SPSS. The primary outcome was live birth rate per patient with secondary outcomes of ovarian response and miscarriage rate. RESULT(S): A total of 2510 patients were investigated. Patients with adenomyosis had a statistically significant lower follicle count (size>11mm) (7.21 vs 8.99; p = 0.001) and number of oocytes collected (7.75 vs 10.15; p < 0.001), inseminated (6.75 vs 8.8; p = 0.002) and fertilised (4.04 vs 5.61; p < 0.001). Whilst there was no difference in biochemical and clinical pregnancy rate, miscarriage rate was higher (13.9% vs 5.7%; p = 0.004) and live birth rate per patient significantly lower in patients with adenomyosis than controls (12.5% vs 24.12%; p = 0.023). These findings remained significant despite controlling individually or in combination for age, male factor infertility and the presence of endometriosis, endometriomas, fibroids or hydrosalpinx. CONCLUSION(S): The presence of adenomyosis diagnosed by tertiary ultrasound is associated with reduced ovarian response and live pregnancy birth rate in IVF/ET. The lower live birth rate seen with adenomyosis may occur as the result of poorer ovarian response and a higher miscarriage rate. Further prospective cohort studies are required to verify these findings.

OBJECTIVE: Egg quality and therefore embryo quality is a limiting factor in IVF. Mitochondria supply ATP to cells, and higher levels are associated with better quality eggs. Excessive reactive oxygen species (ROS) are implicated in mitochondrial damage. Melatonin regulates reproductive physiology via gonadotropin release, but is also a powerful free radical scavenger and antioxidant. Our study examined the use of melatonin in IVF patients with multiple unsuccessful cycles. DESIGN: Retrospective case control study. MATERIALS AND METHODS: !?A3B2 tlsb=0.06pt?>From June 2012- April 2013, 13 women from Monash IVF Australia who had undergone at least two unsuccessful IVF cycles were given 4mg melatonin daily from the first day of follicle stimulating hormone. Two controls per case were matched for age, cycle number, stimulation type and dose; with consideration for BMI, infertility aetiology and andrology. Primary outcomes were oocyte quantity, oocyte maturity and utilization rates. Secondary outcomes included duration of FSH, peak oestrodial levels, number of follicles >11mm and clinical and biochemical pregnancies. T-tests were used to analyse continuous data and Fisher's exact test for categorical data; p<0.05 considered significant. RESULT(S): When the melatonin cases were compared to the matched controls, there were no statistically significant differences in any of the primary or secondary outcomes assessed. Interestingly, when melatonin cases were compared with their own previous cycle, oocyte number showed a trend towards increased value (5.1 vs 7.1, p=0.1744). Of clinical relevance, increase in mature oocyte numbers compared to previous cycles approached statistical significance (3.4 vs 4.9, p=0.0515). Duration of FSH, max E2, follicle number and utilization rate showed no significant changes. CONCLUSION(S): In patients with multiple unsuccessful IVF cycles, melatonin may improve oocyte quantity and increase development to mature oocytes. The trends in this small

OBJECTIVE: To investigate the association between uterine adenomyosis diagnosed by ultrasound on ovarian response and the outcomes of in vitro fertilisation and embryo transfer (IVF/ET). DESIGN: Retrospective case controlled study. MATERIALS AND METHODS: All patients from our unit aged <45 years and undergoing their first stimulated cycle with fresh embryo transfer between June 2002 and June 2012 were identified. Seventytwo cases were found to have adenomyosis on pre-treatment tertiary level ultrasound and were matched by year of treatment, age, gravidity, parity and BMI with 2438 controls without adenomyosis. The data were not normally distributed and univariate analysis with Mann-Whitney testing was undertaken using SPSS. The primary outcome was live birth rate per patient with secondary outcomes of ovarian response and miscarriage rate. RESULT(S): A total of 2510 patients were investigated. Patients with adenomyosis had a statistically significant lower follicle count (size>11mm) (7.21 vs 8.99; p = 0.001) and number of oocytes collected (7.75 vs 10.15; p < 0.001), inseminated (6.75 vs 8.8; p = 0.002) and fertilised (4.04 vs 5.61; p < 0.001). Whilst there was no difference in biochemical and clinical pregnancy rate, miscarriage rate was higher (13.9% vs 5.7%; p = 0.004) and live birth rate per patient significantly lower in patients with adenomyosis than controls (12.5% vs 24.12%; p = 0.023). These findings remained significant despite controlling individually or in combination for age, male factor infertility and the presence of endometriosis, endometriomas, fibroids or hydrosalpinx. CONCLUSION(S): The presence of adenomyosis diagnosed by tertiary ultrasound is associated with reduced ovarian response and live pregnancy birth rate in IVF/ET. The lower live birth rate seen with adenomyosis may occur as the result of poorer ovarian response and a higher miscarriage rate. Further prospective cohort studies are required to verify these findings.

Uterine fibroids are the most common benign tumour afflicting women of reproductive age. Despite the large healthcare burden caused by fibroids, there is only limited understanding of the molecular mechanisms that drive fibroid pathophysiology. Although a large number of genes are differentially expressed in fibroids compared with myometrium, it is likely that most of these differences are a consequence of the fibroid presence and are not causal. The aim of this study was to investigate the expression and regulation of NR2F2 and CTNNB1 based on their potential causal role in uterine fibroid pathophysiology. We used real-time quantitative RT-PCR, western blotting and immunohistochemistry to describe the expression of NR2F2 and CTNNB1 in matched human uterine fibroid and myometrial tissues. Primary myometrial and fibroid smooth muscle cell cultures were treated with progesterone and/or retinoic acid (RA) and sonic hedgehog (SHH) conditioned media to investigate regulatory pathways for these proteins. We showed that NR2F2 and CTNNB1 are aberrantly expressed in fibroid tissue compared with matched myometrium, with strong blood vessel-specific localisation. Although the SHH pathway was shown to be active in myometrial and fibroid primary cultures, it did not regulate NR2F2 or CTNNB1 mRNA expression. However, progesterone and RA combined regulated NR2F2 mRNA, but not CTNNB1, in myometrial but not fibroid primary cultures. In conclusion, we demonstrate aberrant expression and regulation of NR2F2 and CTNNB1 in uterine fibroids compared with normal myometrium, consistent with the hypothesis that these factors may play a causal role uterine fibroid development. © 2013 Society for Reproduction and Fertility.

Buserelin acetate, a luteinizing hormone-releasing hormone agonist, is known to be effective in the shrinkage of uterine fibroids. A prospective trial was undertaken (1) to compare the efficacy of intranasal (IN) and subcutaneous (SC) administration of buserelin acetate and (2) to assess if tumor regression correlated with fibroid size and/or patient age. Forty patients were randomly allocated to receive 6 months of either IN buserelin acetate (n = 21) or SC buserelin acetate (n = 19). Four patients did not complete the study and were excluded from statistical analysis. Fibroid regression occurred in all 36 patients. Overall regression to 66% or less of the initial fibroid volume occurred in 70% of subjects. There was no significant difference in fibroid shrinkage between the two administration routes. A significant positive correlation was found between initial fibroid size and subsequent fibroid regression, with larger tumors being more likely to shrink than smaller fibroids. No correlation was found between the patient's age and the extent of fibroid regression.

Ovulation induction using clomiphene citrate, gonadotropins, and gonadotropin-releasing hormone is reviewed. The short- and long-term consequences of these therapies are discussed in detail.

Use of combined oral contraceptives (OC) is associated with a significant risk of thrombosis. The mechanisms of this effect are not clearly defined. Tissue factor pathway inhibitor (TFPI) is a circulating anti- coagulant that inhibits the earliest steps in activation of the extrinsic coagulation pathway. It plays a central role in control of coagulation but its contribution to the thrombotic risk associated with OC has not been assessed. Plasma TFPI antigen and activity, factor VIIa, prothrombin fragments 1 and 2, von Willebrand antigen, fibrinogen, and low density lipoprotein cholesterol were measured by standard assays in women taking OC (aged 16 to 45 years, n = 40) and age-matched women not taking OC (controls, n = 40). Plasma TFPI antigen did not vary significantly across the menstrual cycle in controls. Women on OC had a 25% reduction in plasma TFPI antigen (median 51.0 ng/ml; 95% confidence intervals [CI] 37.5 to 85.5; control 68.0 ng/ml, CI 61.0 to 95.0; P< 0.001) and a 29% reduction in TFPI activity (78.5 U/ml, CI 57.5 to 107.5; control 111.0 U/ml, CI 79.5 to 171.0; P < 0.001) compared to controls. Plasma factor VIIa activity and prothrombin fragments 1 and 2 were also significantly increased in women using OC (both P < 0.001), indicating activation of the extrinsic coagulation pathway. These results demonstrate that normal cyclic variations in estrogen and/or progesterone do not significantly alter plasma TFPI levels. However, estrogens and/or progestogens in OC result in activation of the extrinsic coagulation pathway and significantly reduce plasma TFPI, its major circulating inhibitor. Reduced plasma TFPI levels may underlie the thrombotic effects of OC.

Uterine fibroids are the most common tumours presenting in women. The pathophysiology of fibroids is poorly understood, but disordered angiogenesis and altered smooth muscle cell proliferation are believed to play a role. In this review, current knowledge of both of these processes will be summarized. Differences between 'normal' adjacent myometrium and fibroid tumours within the same uterus are outlined. Exploiting these differences represents one of the best opportunities for the development of medical treatments that target fibroid tissue selectively. © 2008 Elsevier Ltd. All rights reserved.

Fibroids are benign neoplasms of myometrial smooth muscle cells (SMC). Despite being the most common tumor in humans, their etiology is poorly understood. Recent microarray studies have demonstrated that multiple members of the retinoid pathway are differentially expressed between myometrium and fibroids. The aim of this present study was to investigate gene expression of members of the retinoid pathway in matched myometrium and fibroids. We have demonstrated differential gene expression of two binding proteins [cellular retinol-binding proteins (CRBP) 1 and 2], three enzymes [alcohol dehydrogenase 1 (ADH1), aldehyde dehydrogenase (ALDH1) and retinol dehydrogenase (RODH)] and two receptors [retinoid X receptors (RXR) alpha and gamma] involved in the retinoid pathway by real-time PCR. There were no differences in gene expression for retinoid receptors RARalpha, beta, gamma and RXRbeta, and for the metabolizing enzyme cytochrome P450, family 26 subfamily A. We confirmed results for ADH1, ALDH1, CRBP1 and CRABP2 at the protein level by western blot. Using immunohistochemistry these proteins were mostly localized to myometrial and fibroid SMC. An exception to this was ALDH1 protein, which displayed strong staining localized to cells of the connective tissue, presumably fibroblasts, with a striking differential expression pattern between myometrium and fibroids. These results demonstrate that the retinoid pathway is altered in fibroids when compared with normal myometrium and specifically identify ALDH1 in fibroid fibroblasts. These alterations can lead to aberrant retinoic acid (RA) production and signaling, and alter the expression of RA target genes, which may be an important step in fibroid development. © The Author 2007.

Fibroids (leiomyomata) are the most common tumors in women, but their etiology is unknown. The insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) may be important in the growth of these benign neoplasms. We have examined the presence of mRNA encoding both IGF-I and IGF-II and IGFBP-1, -2, and -3 in fibroids and corresponding myometrium from 20 women undergoing hysterectomy for symptomatic uterine fibroids. Northern blots of total cellular RNA were probed with oligonucleotides for IGF-I, IGF-II, IGFBP-2, and IGFBP-3 and a human IGFBP-1 cDNA. Western ligand blotting was also used to detect the presence of IGFBP proteins in both fibroid and myometrium. The data showed that in fibroids compared to myometrium, 1) the relative abundance of IGF-I mRNA was not different, but there was an increase in the relative abundance of IGF-II mRNA (P < 0.001); 2) IGFBP-1 mRNA was undetectable in fibroids and detectable in only 1 specimen of myometrium; 3) there was no difference in the relative abundance of IGFBP-2 mRNA, but there was an increase in the relative abundance of IGFBP-3 mRNA in myometrium (P < 0.05). By Western ligand blotting, both IGFBP-2 and -3 proteins were present. Our data show that the mRNAs encoding IGF-I, IGF-II, IGFBP-2, and IGFBP-3 are expressed in both fibroids and myometrium and that fibroids express more IGF- II and less IGFBP-3 mRNA than myometrium. We postulate that the net effect of the changes seen is to increase the bioavailability of free (bioactive) IGF, which may then play a major role in promoting fibroid tumor growth.

With the improved survival rate of childhood and young adult cancer patients, the long-term sequelae of the treatments used are increasingly important. In this review, current knowledge of the gonadotoxicity of commonly employed chemotherapeutic agents and radiotherapy regimens is examined. Differences between the effect of "high-risk" and "low-risk" agents are discussed. Tailoring treatment to suit the individual and counseling patients regarding reduced fertility have resulted in the best practice. TARGET AUDIENCE:: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES:: After completing this CME activity, physicians should be better able to evaluate and use appropriate methods to estimate ovarian reserve, assess the risk of infertility caused by commonly used cytotoxic chemotherapy regimens and radiation, and counsel patients regarding the gonadotoxic effects of cancer treatment. © 2011 by Lippincott Williams & Wilkins.

Objective: To explore whether the predictive value of antral follicle count (AFC) changes when measured at different times during the menstrual cycle. Antimullerian hormone (AMH) and AFC are considered to be equally predictive of poor ovarian response; however, AMH is considered to have an advantage over AFC, because AMH concentrations can be measured at any time during the menstrual cycle. Design(s): Retrospective cohort study. Setting(s): Private IVF clinic. Patient(s): A total of 3,117 patients with a transvaginal ultrasound within 3 months before their first IVF cycle. Intervention(s): None. Main Outcome Measure(s): Receiver operating curves (ROCs) were constructed for AFC as a screening test for poor ovarian response (fewer than four eggs collected). The areas under the curve (AUCs) were compared for ROCs from patients at different phases of the cycle. Result(s): When all patients except those with polycystic ovaries were included, the AUC was 0.79. Further subgroup ROC analyses revealed that the AUCs did not differ significantly when AFC was measured at different phases of the menstrual cycle. Conclusion(s): AFC can be measured regardless of the phase of the menstrual cycle without apparent effect on its predictive value for poor ovarian response. Copyright © 2011 American Society for Reproductive Medicine.

Objective: To determine whether women with polycystic ovary syndrome (PCOS) have masculinized finger length patterns compared to women without PCOS. Design(s): A case control study. Setting(s): University teaching hospital and in vitro fertilization unit. Patient(s): Seventy women aged between 18 and 40 years with PCOS were compared to 70 women without PCOS. Intervention(s): Measurement of the second to fourth finger length ratio on the ventral surface of the left and right hand from the basal crease of the digit to the tip was made using Vernier calipers. Main Outcome Measure(s): The second to fourth finger length ratio. Result(s): We found a significantly reduced ratio in the right hand of the women with PCOS compared to the controls. The geometric mean right finger length ratio in the PCOS group was 98.3% that of the controls (95% confidence interval, 99.3%-97.3%). Conclusion(s): Here we show a subtle difference in the finger length pattern of women with PCOS. This may constitute anatomical evidence of in utero androgen exposure in PCOS. ©2005 by American Society for Reproductive Medicine.

Ovulation induction using clomiphene citrate, gonadotropins, and gonadotropin-releasing hormone is reviewed. The short- and long-term consequences of these therapies are discussed in detail.

Buserelin acetate, a luteinizing hormone-releasing hormone agonist, is known to be effective in the shrinkage of uterine fibroids. A prospective trial was undertaken (1) to compare the efficacy of intranasal (IN) and subcutaneous (SC) administration of buserelin acetate and (2) to assess if tumor regression correlated with fibroid size and/or patient age. Forty patients were randomly allocated to receive 6 months of either IN buserelin acetate (n = 21) or SC buserelin acetate (n = 19). Four patients did not complete the study and were excluded from statistical analysis. Fibroid regression occurred in all 36 patients. Overall regression to 66% or less of the initial fibroid volume occurred in 70% of subjects. There was no significant difference in fibroid shrinkage between the two administration routes. A significant positive correlation was found between initial fibroid size and subsequent fibroid regression, with larger tumors being more likely to shrink than smaller fibroids. No correlation was found between the patient's age and the extent of fibroid regression.

Use of combined oral contraceptives (OC) is associated with a significant risk of thrombosis. The mechanisms of this effect are not clearly defined. Tissue factor pathway inhibitor (TFPI) is a circulating anti- coagulant that inhibits the earliest steps in activation of the extrinsic coagulation pathway. It plays a central role in control of coagulation but its contribution to the thrombotic risk associated with OC has not been assessed. Plasma TFPI antigen and activity, factor VIIa, prothrombin fragments 1 and 2, von Willebrand antigen, fibrinogen, and low density lipoprotein cholesterol were measured by standard assays in women taking OC (aged 16 to 45 years, n = 40) and age-matched women not taking OC (controls, n = 40). Plasma TFPI antigen did not vary significantly across the menstrual cycle in controls. Women on OC had a 25% reduction in plasma TFPI antigen (median 51.0 ng/ml; 95% confidence intervals [CI] 37.5 to 85.5; control 68.0 ng/ml, CI 61.0 to 95.0; P< 0.001) and a 29% reduction in TFPI activity (78.5 U/ml, CI 57.5 to 107.5; control 111.0 U/ml, CI 79.5 to 171.0; P < 0.001) compared to controls. Plasma factor VIIa activity and prothrombin fragments 1 and 2 were also significantly increased in women using OC (both P < 0.001), indicating activation of the extrinsic coagulation pathway. These results demonstrate that normal cyclic variations in estrogen and/or progesterone do not significantly alter plasma TFPI levels. However, estrogens and/or progestogens in OC result in activation of the extrinsic coagulation pathway and significantly reduce plasma TFPI, its major circulating inhibitor. Reduced plasma TFPI levels may underlie the thrombotic effects of OC.

Fibroids are benign neoplasms of myometrial smooth muscle cells (SMC). Despite being the most common tumor in humans, their etiology is poorly understood. Recent microarray studies have demonstrated that multiple members of the retinoid pathway are differentially expressed between myometrium and fibroids. The aim of this present study was to investigate gene expression of members of the retinoid pathway in matched myometrium and fibroids. We have demonstrated differential gene expression of two binding proteins [cellular retinol-binding proteins (CRBP) 1 and 2], three enzymes [alcohol dehydrogenase 1 (ADH1), aldehyde dehydrogenase (ALDH1) and retinol dehydrogenase (RODH)] and two receptors [retinoid X receptors (RXR) alpha and gamma] involved in the retinoid pathway by real-time PCR. There were no differences in gene expression for retinoid receptors RARalpha, beta, gamma and RXRbeta, and for the metabolizing enzyme cytochrome P450, family 26 subfamily A. We confirmed results for ADH1, ALDH1, CRBP1 and CRABP2 at the protein level by western blot. Using immunohistochemistry these proteins were mostly localized to myometrial and fibroid SMC. An exception to this was ALDH1 protein, which displayed strong staining localized to cells of the connective tissue, presumably fibroblasts, with a striking differential expression pattern between myometrium and fibroids. These results demonstrate that the retinoid pathway is altered in fibroids when compared with normal myometrium and specifically identify ALDH1 in fibroid fibroblasts. These alterations can lead to aberrant retinoic acid (RA) production and signaling, and alter the expression of RA target genes, which may be an important step in fibroid development. © The Author 2007.

Uterine fibroids are the most common tumours presenting in women. The pathophysiology of fibroids is poorly understood, but disordered angiogenesis and altered smooth muscle cell proliferation are believed to play a role. In this review, current knowledge of both of these processes will be summarized. Differences between 'normal' adjacent myometrium and fibroid tumours within the same uterus are outlined. Exploiting these differences represents one of the best opportunities for the development of medical treatments that target fibroid tissue selectively. © 2008 Elsevier Ltd. All rights reserved.

Fibroids (leiomyomata) are the most common tumors in women, but their etiology is unknown. The insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) may be important in the growth of these benign neoplasms. We have examined the presence of mRNA encoding both IGF-I and IGF-II and IGFBP-1, -2, and -3 in fibroids and corresponding myometrium from 20 women undergoing hysterectomy for symptomatic uterine fibroids. Northern blots of total cellular RNA were probed with oligonucleotides for IGF-I, IGF-II, IGFBP-2, and IGFBP-3 and a human IGFBP-1 cDNA. Western ligand blotting was also used to detect the presence of IGFBP proteins in both fibroid and myometrium. The data showed that in fibroids compared to myometrium, 1) the relative abundance of IGF-I mRNA was not different, but there was an increase in the relative abundance of IGF-II mRNA (P < 0.001); 2) IGFBP-1 mRNA was undetectable in fibroids and detectable in only 1 specimen of myometrium; 3) there was no difference in the relative abundance of IGFBP-2 mRNA, but there was an increase in the relative abundance of IGFBP-3 mRNA in myometrium (P < 0.05). By Western ligand blotting, both IGFBP-2 and -3 proteins were present. Our data show that the mRNAs encoding IGF-I, IGF-II, IGFBP-2, and IGFBP-3 are expressed in both fibroids and myometrium and that fibroids express more IGF- II and less IGFBP-3 mRNA than myometrium. We postulate that the net effect of the changes seen is to increase the bioavailability of free (bioactive) IGF, which may then play a major role in promoting fibroid tumor growth.

With the improved survival rate of childhood and young adult cancer patients, the long-term sequelae of the treatments used are increasingly important. In this review, current knowledge of the gonadotoxicity of commonly employed chemotherapeutic agents and radiotherapy regimens is examined. Differences between the effect of "high-risk" and "low-risk" agents are discussed. Tailoring treatment to suit the individual and counseling patients regarding reduced fertility have resulted in the best practice. TARGET AUDIENCE:: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES:: After completing this CME activity, physicians should be better able to evaluate and use appropriate methods to estimate ovarian reserve, assess the risk of infertility caused by commonly used cytotoxic chemotherapy regimens and radiation, and counsel patients regarding the gonadotoxic effects of cancer treatment. © 2011 by Lippincott Williams & Wilkins.

Objective: The hypothesis of this study was that oestrogen may play a role in fibroid growth and that a lack of oestrogen may be the reason for gonadotrophin-releasing hormone agonist (GnRHa) induced fibroid shrinkage. Therefore our aims were (1) to investigate oestrogen receptor (ER) and progesterone receptor (PR) binding in fibroids and myometrium from untreated women and in fibroids from GnRHa pretreated women, (2) to evaluate the mRNA expression of ER and PR in these tissues, and (3) to examine whether a correlation existed between receptor binding and mRNA expression for ER and PR. Design(s): Cytosolic ER and PR binding was assessed by the dextran-coated charcoal technique and ER and PR mRNA expression was assessed using Northern blots of total RNA. Patient(s): Fibroid and corresponding myometrial specimens were obtained from 20 women undergoing hysterectomy while fibroid specimens only were obtained from 10 women undergoing myomectomy after at least 3 months pretreatment with GnRHa. Result(s): We found that (1) ER binding was twice and PR binding was three times as great in fibroid as in myometrium and that there was no difference in binding for either receptor between fibroids from untreated and GnRHa pretreated women, (2) ER and PR mRNA abundances were similar in fibroids and myometrium from untreated women and In fibroids from untreated and GnRHa pretreated women, and (3) ER binding and ER mRNA abundance in both groups of fibroids and myometrium were independent of each other, but there was a positive correlation between PR binding and PR mRNA abundance in untreated fibroids and myometrium but not in GnRHa pretreated tumours. Conclusion(s): We conclude that (1) both oestrogen and progesterone may contribute to fibroid growth because of increased receptor binding in fibroids compared with myometrium and (2) in GnRHa treated women, fibroids may shrink because of a lowered circulating oestradiol level rather than because of a change in steroid receptor binding

Objective: To explore whether the predictive value of antral follicle count (AFC) changes when measured at different times during the menstrual cycle. Antimullerian hormone (AMH) and AFC are considered to be equally predictive of poor ovarian response; however, AMH is considered to have an advantage over AFC, because AMH concentrations can be measured at any time during the menstrual cycle. Design(s): Retrospective cohort study. Setting(s): Private IVF clinic. Patient(s): A total of 3,117 patients with a transvaginal ultrasound within 3 months before their first IVF cycle. Intervention(s): None. Main Outcome Measure(s): Receiver operating curves (ROCs) were constructed for AFC as a screening test for poor ovarian response (fewer than four eggs collected). The areas under the curve (AUCs) were compared for ROCs from patients at different phases of the cycle. Result(s): When all patients except those with polycystic ovaries were included, the AUC was 0.79. Further subgroup ROC analyses revealed that the AUCs did not differ significantly when AFC was measured at different phases of the menstrual cycle. Conclusion(s): AFC can be measured regardless of the phase of the menstrual cycle without apparent effect on its predictive value for poor ovarian response. Copyright © 2011 American Society for Reproductive Medicine.