Treatment with MG132 prevents spontaneous activation of rat oocyte in culture and promotes embryonic development after intracytoplasmic sperm injection.

Intracytoplasmic sperm injection (ICSI) is an effective reproductive technique for obtaining rat offspring using preserved sperm with low or no motility. However, rat oocytes undergo spontaneous activation immediately after retrieval from the oviduct and poorly develop after ICSI unless it is performed quickly. Here, we evaluated whether treatment with MG132, the proteasome inhibitor, suppresses the spontaneous activation of oocytes before and during ICSI. After retrieval from the oviducts, the rate of development into morula and blastocyst from the oocytes cultured in vitro for 1 h prior to ICSI significantly decreased compared with that from the control oocytes subject to ICSI without culture (7% versus 36%). However, a higher proportion of oocytes treated with MG132 for 0, 1, and 3 h before and during ICSI developed into morulae and blastocysts (70%, 60%, and 52%, respectively). Offspring were obtained from oocytes treated with MG132 for 0 and 1 h before and during ICSI (percentage: 31%). Altogether, MG132 could suppress the spontaneous activation of rat oocytes and increase embryonic development after ICSI.

Population PK-PD-PD Modeling of Recombinant Follicle Stimulating Hormone in In Vitro Fertilization/Intracytoplasmic Sperm Injection: Implications on Dosing and Timing of Gonadotrophin Therapy.

This study aimed to characterize an interactive and clinically applicable population pharmacokinetic-pharmacodynamic-pharmacodynamic (PK-PD-PD) model describing follicle-stimulating hormone (FSH)-inhibin B-oocyte relationship in women undergoing assisted reproduction with in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). The study was a prospective analysis of 25 healthy women undergoing IVF/ICSI using gonadotropin-releasing hormone (GnRH) antagonist protocol. The developed model used the FSH PK profiles to predict both inhibin B (first PD end point) and oocyte retrieval (second PD end point). The modeling framework involved 2 stages. First, the FSH-inhibin B model was developed by the simultaneous approach and applied to estimate the individual area under the inhibin B-time curve (AUCInhb ) at the end of stimulation cycles that varied in length in each woman. In the second stage, the estimated AUCInhb was introduced as a link covariate to predict oocyte retrieval and response category. The population FSH-inhibin B model was described as 3 submodels; PK (exogenous), endogenous, and inhibin B PD models. Weight was the main determinant of both endogenous and exogenous FSH exposures. GnRH antagonist therapy was a significant time-varying covariate when tested against the endogenous FSH production rate (P < .001). AUCInhb could be predicted with women's age and weight. Log-transformed AUCInhb was a significant covariate when tested against oocyte retrieval (P < .001). Simulations concluded a target AUCInhb of 144-303 ng·h/mL for optimal ovarian response. The GnRH antagonist was better started on day 7 of the cycle. Covariate-based dosing suggests lower recombinant follicle-stimulating hormone requirements in a thin and/or young population. An interactive web application "GonadGuide" was developed to facilitate the application in clinical practice.

Follicle stimulating hormone versus clomiphene citrate in intrauterine insemination for unexplained subfertility: a randomized controlled trial.

STUDY QUESTION: Is FSH or clomiphene citrate (CC) the most effective stimulation regimen in terms of ongoing pregnancies in couples with unexplained subfertility undergoing IUI with adherence to strict cancellation criteria as a measure to reduce the number of multiple pregnancies? SUMMARY ANSWER: In IUI with adherence to strict cancellation criteria, ovarian stimulation with FSH is not superior to CC in terms of the cumulative ongoing pregnancy rate, and yields a similar, low multiple pregnancy rate. WHAT IS ALREADY KNOWN: FSH has been shown to result in higher pregnancy rates compared to CC, but at the cost of high multiple pregnancy rates. To reduce the risk of multiple pregnancy, new ovarian stimulation regimens have been suggested, these include strict cancellation criteria to limit the number of dominant follicles per cycle i.e. withholding insemination when more than three dominant follicles develop. With such a strategy, it is unclear whether the ovarian stimulation should be done with FSH or with CC. STUDY DESIGN, SIZE, DURATION: We performed an open-label multicenter randomized superiority controlled trial in the Netherlands (NTR 4057). PARTICIPANTS/MATERIALS, SETTING, METHODS: We randomized couples diagnosed with unexplained subfertility and scheduled for a maximum of four cycles of IUI with ovarian stimulation with 75 IU FSH or 100 mg CC. Cycles were cancelled when more then three dominant follicles developed. The primary outcome was cumulative ongoing pregnancy rate. Multiple pregnancy was a secondary outcome. We analysed the data on intention to treat basis. We calculated relative risks and absolute risk difference with 95% CI. MAIN RESULTS AND THE ROLE OF CHANCE: Between July 2013 and March 2016, we allocated 369 women to ovarian stimulation with FSH and 369 women to ovarian stimulation with CC. A total of 113 women (31%) had an ongoing pregnancy following ovarian stimulation with FSH and 97 women (26%) had an ongoing pregnancy following ovarian stimulation with CC (RR = 1.16, 95% CI: 0.93-1.47, ARD = 0.04, 95% CI: -0.02 to 0.11). Five women (1.4%) had a multiple pregnancy following ovarian stimulation with FSH and eight women (2.2%) had a multiple pregnancy following ovarian stimulation with CC (RR = 0.63, 95% CI: 0.21-1.89, ARD = -0.01, 95% CI: -0.03 to 0.01). LIMITATIONS, REASONS FOR CAUTION: We were not able to blind this study due to the nature of the interventions. We consider it unlikely that this has introduced performance bias, since pregnancy outcomes are objective outcome measures. WIDER IMPLICATIONS OF THE FINDINGS: We revealed that adherence to strict cancellation criteria is a successful solution to reduce the number of multiple pregnancies in IUI. To decide whether ovarian stimulation with FSH or with CC should be the regimen of choice, costs and patients' preferences should be taken into account. STUDY FUNDING/COMPETING INTEREST(S): This trial received funding from the Dutch Organization for Health Research and Development (ZonMw). Prof. Dr B.W.J. Mol is supported by a NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for Merck, ObsEva and Guerbet. The other authors declare that they have no competing interests. TRIAL REGISTRATION NUMBER: Nederlands Trial Register NTR4057. TRIAL REGISTRATION DATE: 1 July 2013. DATE OF FIRST PATIENT'S ENROLMENT: The first patient was randomized at 27 August 2013.

Is there an association between artificial sweetener consumption and assisted reproduction outcomes?

Previous studies have suggested an association between high intake of sweetened beverages and a number of adverse health outcomes. In this cross-sectional study, we investigated the association between daily consumption of sweetened soft drinks or coffee and the outcome of intracytoplasmic sperm injection (ICSI) treatment. Patients (n = 524) were interviewed by a nutritionist before ICSI treatment, using a food frequency questionnaire. Regression analysis showed that consumption of ≥3 servings of regular soft drinks or any amount of diet soft drinks was associated with oocyte dysmorphism, diminished embryo quality on days 2 and 3 of culture, and a mild effect on blastocyst formation, implantation and pregnancy rate. Consumption of artificially sweetened coffee was negatively associated with embryo quality on days 2 and 3. However, consumption of coffee or soft drinks was not associated with the odds of live birth. Even so, patients should be advised about the potential negative effects of sugar and artificial sweeteners before attempting infertility treatment. This study is limited by the use of a non-validated food frequency questionnaire, lack of information on quantity of sweeteners consumed, and lack of data on glucose levels in blood serum or follicular fluid. Further investigation is warranted.

A prospective randomized study comparing two commercially available types of human embryo culture media: G1-PLUS™/G2-PLUS™ sequential medium (Vitrolife) and the GL BLAST™ sole medium (Ingamed).

OBJECTIVE: To check the efficacy of two types of commercially available embryo culture medium: G1-PLUS™/G2-PLUS™ sequential (Vitrolife, Gothenburg, Sweden) and GV BLAST™ sole (Ingamed, Maringá, Brazil) with regards to fertilization, cleavage, blastocyst and pregnancy rates. METHODS: Prospective and randomized study conducted from March to July 2015, using the medical records of 60 patients submitted to Intracytoplasmic Sperm Injection techniques (ICSI). Data regarding the age of patients, together with fertilization, cleavage, blastocyst and pregnancy rates, were collected and compared in relation to the: G1-PLUS™/G2-PLUS™ sequential and GV BLAST™ sole mediums. The data were tabulated and compared using the Pearson's Chi-Square test (95% CI). RESULTS: There was no significant difference when comparing patients divided into higher and lower fertility age. No significant statistical difference was noted between the fertilization rates (P=0.59), cleavage (P=0.91), evolution to blastocyst (P=0.33) and total pregnancy (P=0.83) when comparing the embryos cultured in the different media analysed. CONCLUSION: We conclude that the G1-PLUS™/G2-PLUS™ sequential and GV BLAST™ sole mediums are equally effective with regards to fertilization, cleavage, blastocyst development and total pregnancy rates.

Melatonin promotes development of haploid germ cells from early developing spermatogenic cells of Suffolk sheep under in vitro condition.

Promotion of spermatogonial stem cell (SSC) differentiation into functional sperms under in vitro conditions is a great challenge for reproductive physiologists. In this study, we observed that melatonin (10(-7) M) supplementation significantly enhanced the cultured SSCs differentiation into haploid germ cells. This was confirmed by the expression of sperm special protein, acrosin. The rate of SSCs differentiation into sperm with melatonin supplementation was 11.85 ± 0.93% which was twofold higher than that in the control. The level of testosterone, the transcriptions of luteinizing hormone receptor (LHR), and the steroidogenic acute regulatory protein (StAR) were upregulated with melatonin treatment. At the early stage of SSCs culture, melatonin suppressed the level of cAMP, while at the later stage, it promoted cAMP production. The similar pattern was observed in testosterone content. Expressions for marker genes of meiosis anaphase, Dnmt3a, and Bcl-2 were upregulated by melatonin. In contrast, Bax expression was downregulated. Importantly, the in vitro-generated sperms were functional and they were capable to fertilize oocytes. These fertilized oocytes have successfully developed to the blastula stage.

Is the GnRH Antagonist Protocol Effective at Preventing OHSS for Potentially High Responders Undergoing IVF/ICSI?

OBJECTIVE: To determine if the GnRH antagonist protocol is effective in preventing ovarian hyperstimulation syndrome (OHSS) in potentially high responders. METHODS: A total of 660 IVF-ET/ICSI cycles were retrospectively identified. The inclusion criterion was age ≤ 30 years. Cycles were divided into two groups: a GnRHa group and a GnRHant group. In the GnRHa group, the patients received one single injection of 1.0mg-1.3mg Triptorelin in previous mid-luteal phase. In the GnRHant group, a daily dose of 0.25 mg Cetrotide was initiated when a lead follicle obtained a mean diameter of 14 mm, continued up until the day of hCG administration. The duration of stimulation, total dose of Gn, implantation rate, pregnancy rate, and OHSS rate were compared. RESULTS: The duration of stimulation, E2 level on hCG day, numbers of oocytes retrieved, MII oocytes, and high-quality embryos in the GnRHa group were all significantly more than those in the GnRHant group. In the GnRHa group, 83.53% of cancelled fresh-transferred cycles were cancelled because of high risk of OHSS, which was significantly higher than that in the GnRHant group (43.55%, P<0.05). The incidence of OHSS in the GnRHa group was slightly higher than that in the GnRHant group. The implantation and clinical pregnancy rates in the GnRHa group were significantly higher than those in the GnRHant group (37.36% VS 19.25%, 62.78% VS 31.06%; P<0.05). CONCLUSIONS: Our study demonstrated that for potentially high responders, the GnRHant protocol can, to some extent, lower the cancellation and incidence rates of OHSS. The GnRHa protocol was superior to the GnRHant protocol in terms of implantation and clinical pregnancy rates.

In vitro fertilization outcomes in treated hypothyroidism.

BACKGROUND: Levothyroxine has been shown to enhance pregnancy outcomes in women with hypothyroidism requiring in vitro fertilization (IVF). However, the precise magnitude of these benefits remains to be determined. In particular, it has yet to be clarified whether levothyroxine may fully overcome the detrimental effects of hypothyroidism or, conversely, whether affected women remain at reduced prognosis for pregnancy outcomes. METHODS: Patients who underwent IVF-intracytoplasmic sperm injection (ICSI) over a 3-year period were reviewed. Cases were deemed eligible if they were diagnosed with clinical or subclinical hypothyroidism and were receiving levothyroxine. Controls were two subsequently age-matched euthyroid women for every case. Both cases and controls were selected only if serum thyrotropin was ≤2.5 mIU/L. RESULTS: In total, 137 women with treated hypothyroidism and 274 controls were included. Baseline characteristics of the two study groups were similar with the exception of body mass index, which was slightly higher among the cases (22.9±3.9 vs. 21.9±3.3 kg/m2, p=0.013). Most IVF-ICSI cycle outcome variables were also similar, with the exception of a higher rate of cancellation for poor response (3.6% vs. 0.7%, p=0.04), a longer duration of stimulation (10.9±2.2 vs. 10.1±2.0 days, p=0.001), a higher proportion of women failing to obtain viable embryos (17% vs. 7%, p=0.006), and a lower fertilization rate (75% vs. 86%, p=0.017) among cases. Conversely, the clinical pregnancy rate per started cycle, the implantation rate, and the live birth rate per started cycle did not differ; they were 36% and 34% (p=0.93), 28% and 22% (p=0.11), and 30% and 27% (p=0.50) in cases and controls, respectively. Subgroup analyses comparing women with (n=79) and without (n=58) thyroid autoimmunity and comparing women who were diagnosed with overt hypothyroidism (n=70) or subclinical hypothyroidism (n=67) failed to identify relevant differences. CONCLUSIONS: In our population, IVF-ICSI outcome was not significantly hampered in women with adequately treated hypothyroidism. The magnitude of the detected differences in cycle outcome was mild, and we failed to document any differences for the most relevant outcomes, i.e., pregnancy rate, implantation rate, and delivery rate. In conclusion, adequate levothyroxine treatment maintaining thyrotropin serum levels below 2.5 mIU/L may overcome the detrimental effects of hypothyroidism.

Utility of animal models for human embryo culture: nonhuman primates.

Nonhuman primates are the closest relatives to humans and therefore our most evolutionary close cousins. While marvelous insights are gleaned from studying rodents and other systems, it is impossible to envision how those mechanistic findings can be responsibly translated to the clinic without the appropriate use of nonhuman primates. Thankfully, noninvasive technologies now permit nonhuman primate studies without endangering the model itself. Work with primates is predicted to continue to lead the fields of reproductive and regenerative medicine for the rest of the twenty-first century.

Peri-implantation glucocorticoid administration for assisted reproductive technology cycles.

BACKGROUND: In order to improve embryo implantation for in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) cycles the use of glucocorticoids has been advocated. It has been proposed that glucocorticoids may improve the intrauterine environment by acting as immunomodulators to reduce the uterine natural killer (NK) cell count and normalise the cytokine expression profile in the endometrium and by suppression of endometrial inflammation. OBJECTIVES: To investigate whether the administration of glucocorticoids around the time of implantation improved clinical outcomes in subfertile women undergoing IVF or ICSI when compared to no glucocorticoid administration. SEARCH METHODS: The Cochrane Menstrual Disorders and Subfertility Group Trials Register (September 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (September 2011), MEDLINE (1966 to September 2011), EMBASE (1976 to September 2011), CINAHL (1982 to September 2011) and Science Direct (1966 to September 2011) were searched. Reference lists of relevant articles and relevant conference proceedings were handsearched. SELECTION CRITERIA: All randomised controlled trials (RCTs) addressing the research question were included. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility and quality of trials and extracted relevant data. MAIN RESULTS: Fourteen studies (involving 1879 couples) were included. Three studies reported live birth rate and these did not identify a significant difference after pooling the (preliminary) results (OR 1.21, 95% CI 0.67 to 2.19). With regard to pregnancy rates, there was also no evidence that glucocorticoids improved clinical outcome (13 RCTs; OR 1.16, 95% CI 0.94 to 1.44). However, a subgroup analysis of 650 women undergoing IVF (6 RCTs) revealed a significantly higher pregnancy rate for women using glucocorticoids (OR 1.50, 95% CI 1.05 to 2.13). There were no significant differences in adverse events, but these were poorly and inconsistently reported. AUTHORS' CONCLUSIONS: Overall, there was no clear evidence that administration of peri-implantation glucocorticoids in ART cycles significantly improved the clinical outcome. The use of glucocorticoids in a subgroup of women undergoing IVF (rather than ICSI) was associated with an improvement in pregnancy rates of borderline statistical significance and should be interpreted with care. These findings were limited to the routine use of glucocorticoids and cannot be extrapolated to women with autoantibodies, unexplained infertility or recurrent implantation failure. Further well designed randomised studies are required to elucidate the possible role of this therapy in well defined patient groups.

Poor ovarian response in patients younger than 35 years: is it also a qualitative decline in ovarian function?

OBJECTIVE: To investigate whether poor response to controlled ovarian stimulation (COS) is due to a qualitative decline in ovarian function. METHODS: This retrospective cohort study included 436 patients younger than 35-years old, undergoing COS for intracytoplasmic sperm injection (ICSI). Patients with four or fewer MII oocytes after COS (poor-responder group, PR, n = 52) were age-matched with normoresponder patients (NR, n = 364). RESULTS: Although similar duration of stimulation (10.5 +/- 0.4 and 9.3 +/- 0.8 days; p = 0.1358), increased doses of gonadotrophins (2510 +/- 865 and 2253 +/- 572 IU; p = 0.0061) were used in the PR. The results show a increased chance of cycle ending of PR (PR: 26.9% and NR: 3.1%; p < 0.0001). Although the lower total number of oocytes retrieved (2.4 +/- 1.4 and 16.2 +/- 9.3; p < 0.0001), equal rate of fertilization (70.2% and 72.0%, p = 0.1190) and high quality embryos were obtained (50.0% and 45.2%; p = 0.4895), resulting in similar implantation (14.5% and 19.7%; p = 0.2246) and abortion (10.0% and 15.4%; p = 1.00) rates, respectively. A trend towards increased pregnancy rate per embryo transfer in NR group was noted (PR: 26.3% and NR: 42.2%; p = 0.0818). CONCLUSIONS: Low ovarian response could be associated mainly with a quantitative rather than a qualitative decline in ovarian function. Therefore, even if the ovarian response to stimulation is low, patients aged < or =35 years should process to oocyte retrieval.

Successful pregnancy and childbirth after intracytoplasmic sperm injection with calcium ionophore oocyte activation in a globozoospermic patient.

OBJECTIVE: To check the effectiveness of intracytoplasmic sperm injection (ICSI) combined with assisted oocyte activation (AOA) in a globozoospermic patient. DESIGN: Case report. SETTING: Instituto Valenciano de Infertilidad, Valencia, Spain. PATIENT(S): A patient with globozoospermia. INTERVENTION(S): ICSI was administered in 14 oocytes. ICSI combined with AOA, in which a small amount of calcium was injected followed by calcium ionophore exposure, was done in 9 oocytes. MAIN OUTCOME MEASURE(S): Fertilization rate and embryo quality was assessed in both groups. RESULT(S): Chemical activation increased fertilization rate (55.6% vs. 35.7%) and the number of embryos with less multinucleation on day 2 (0 vs. 60%). Two embryos generated from AOA were transferred into the uterus (on day 3), resulting in a pregnancy and a healthy newborn. CONCLUSION(S): The AOA with calcium ionophore treatment improved fertilization rate and quality of the embryos, and was found to be an effective method for AOA in this patient with a low fertilization rate after previous ICSI treatment.

Oral contraceptive pretreatment does not improve outcome in microdose gonadotrophin-releasing hormone agonist protocol among poor responder intracytoplasmic sperm injection patients.

PURPOSE: To compare oral contraceptive (OC) pretreatment plus microdose GnRH-a in flare-up protocol and non-OC microdose GnRH-a in flare-up protocol among poor responder ICSI patients. METHODS: A retrospective analysis of poor responder ICSI patients. Patients were divided into two groups according to used microdose protocol. Precycle treatment with OC followed by follicular phase administration of 40 microg s.c. leuprolide acetate (LA) every 12 h beginning on after 2 day pill-free period and rFSH administration was begun on the third day of LA administration (OC-Group, n=26). Alternatively on day 2 after menses, patients were administered similar stimulation regime (non-OC Group, n=27). RESULTS: There were no significant differences between groups in the number of oocytes, peak estradiol levels, endometrial thickness, fertilization rates and embryo quality. Implantations and pregnancy rates per embryo transfer were similar. CONCLUSION: OC pretreatment plus microdose GnRHa in flare-up protocol does not offer advantages over non-OC microdose GnRHa in flare-up protocol among poor responder ICSI patients.

Prospective randomized study comparing luteal phase support for ICSI patients up to the first ultrasound compared with an additional three weeks.

BACKGROUND: There is a consensus that administration of progesterone to women after IVF for luteal phase support (LPS) is associated with a higher ongoing pregnancy rate. However there are few studies, including only one randomized study, which have examined the optimal duration of LPS. METHODS: A questionnaire concerning details of LPS was returned from 21 leading IVF centres. We then randomized 257 women, who were pregnant after ICSI on day of first ultrasound, into two groups: to continue LPS for three more weeks or to stop on the day of ultrasound. RESULTS: The duration of LPS in the questionnaire varied from the day of positive pregnancy test up to 12 weeks of pregnancy in different centres. In the randomized study, 132 patients in Group A continued LPS for 3 weeks after first ultrasound, whereas 125 patients in Group B stopped LPS on day of first ultrasound. After confirming pulsations, the miscarriage rate up to 20 weeks of gestation was 4.6% (6/132) in group A and 4.8% (6/125) in group B [odds ratios (OR) = 0.94; 95% confidence intervals (CI) = 0.3-3.1]. Bleeding episodes were 15.9% in Group A compared with 20.8% in group B (OR = 0.72; 95% CI = 0.38-1.36). CONCLUSIONS: There is no international consensus about the duration of LPS; our single-centre randomized trial did not support extending the LPS beyond the day of first ultrasound demonstrating echoes and pulsations. Trials registry number-ISRCTN: 88722916.

In vitro equine oocyte maturation in pure follicular fluid plus interleukin-1 and fertilization following ICSI.

The interleukin-1 (IL-1) system is thought to be involved in periovulatory events in the mare. Previous in vivo studies have demonstrated that IL-1beta induces oocyte maturation, but depresses the pregnancy rate 14 days after ovulation. To better understand the role of IL-1 in oocyte maturation and fertilization, the effects of IL-1 on the in vitro maturation rate of equine oocytes in pure follicular fluid were evaluated and fertilization rate assessed following intracytoplasmic sperm injection (ICSI). Oocytes collected from slaughterhouse ovaries were cultured in four different media for 30 h prior to fertilization. Two experiments were performed, each using three maturation media as the experimental treatments. Medium 1 was pure follicular fluid from subordinate follicles. Medium 2 was medium 1 plus 50 ng/ml recombinant human IL-1beta. Medium 3 was pure follicular fluid collected from mares administered crude equine gonadotropin (CEG). Medium 4 was medium 2 plus 50 ng/ml of recombinant human IL-1 receptor antagonist. Media 1, 2 and 3 were compared in experiment 1. In experiment 2, media 1, 2 and 4 were compared. After maturation, metaphase II oocytes were submitted to microinjection and assessed for signs of fertilization. In experiment 1, 101 oocytes were evaluated. The rate of polar body extrusion was 66, 51 and 68% and the proportions of normally fertilized oocytes after ICSI were 40, 18 and 38% for media 1, 2 and 3, respectively. In experiment 2, 122 oocytes were evaluated. The rate of polar body extrusion was 55, 48 and 42% and the proportions showing normal fertilization after ICSI were 14, 25 and 29% for media 1, 2 and 4, respectively. There was no positive effect of IL-1beta on maturation in both experiments, but the fertilization rate and percentage of embryos reaching four-cell were low in the presence of IL-1beta, indicating that this cytokine may interfere with fertilization and early embryo development.

Evidence of absence or absence of evidence? A reanalysis of the effects of low-dose aspirin in in vitro fertilization.

OBJECTIVE: To assess the conflicting evidence whether low-dose aspirin is beneficial in IVF and to evaluate the meta-analysis performed by Gelbaya et al. and reported in March 2007 in Human Reproduction Update, in which they found no effects of low-dose aspirin and recommended discontinuing its use in IVF. We present a reanalysis of the effects of low-dose aspirin in IVF and raise methodological questions regarding the analysis by Gelbaya et al. DESIGN: A meta-analysis of prospective randomized trials evaluating the effects of low-dose aspirin in IVF. PATIENT(S): Women undergoing IVF/intracytoplasmic sperm injection. INTERVENTION(S): Low-dose acetylsalicylic acid (aspirin). MAIN OUTCOME MEASURE(S): Pregnancy rates, implantation rates, miscarriage rates. RESULT(S): Ten randomized clinical trials were included in the analysis. Clinical pregnancy rate per ET was significant when low-dose aspirin was compared with no treatment (risk ratio 1.15, 95% confidence interval 1.03-1.27). Nonsignificant estimates comparing low-dose aspirin with no treatment were found for implantation and miscarriage rates. CONCLUSION(S): Our results suggest that aspirin may increase clinical pregnancy rates and that more data are needed to resolve the issue. At this point, there is no reason to change clinical management and discontinue the use of aspirin.

Extension of GnRH agonist through the luteal phase to improve the outcome of intracytoplasmic sperm injection.

OBJECTIVE: To investigate the effect of continuous administration of gonadotropin-releasing hormone agonist (GnRHa) during the luteal phase in an intracytoplasmic sperm injection program. STUDY DESIGN: One hundred eighty-one women underwent a down-regulation protocol of GnRHa administered from the 21st day of the preceding cycle. Patients were randomized at initiation of stimulation by a computer-generated list. Group 1 patients (n = 90) were continuously administered GnRHa for 12 days after embryo transfer, while in group 2 patients GnRHa was stopped on the day of human chorionic gonadotropin administration. RESULTS: Demographic parameters, infertility etiologies, number of gonadotropin ampules used, number of mature oocytes recovered, rates of testicular sperm usage, number of embryos transferred, and cycle and transfer cancellation rates were similar in both groups. Clinical pregnancy rates, implantation rates and live birth rates did not show a significant difference. CONCLUSION: Extending GnRHa treatment through the luteal phase appeared not to have a significant impact on pregnancy or implantation rates in intracytoplasmic sperm injection cycles.

Growth hormone deficiency and supplementation at in-vitro fertilisation.

INTRODUCTION: This study aims to evaluate the differences in oocyte stimulation, endometrial thickness, fertilisation rate and embryo quality at in-vitro fertilisation (IVF) in patients with documented growth hormone (GH) deficiency, after GH supplementation. METHODS: This was a retrospective analysis of 20 cases of patients who were pregnant and had GH supplementation during IVF at the Singapore General Hospital between 1993 and 2003. All these patients had previously failed IVF due to poor stimulation, poor egg quality, poor fertilisation at intracytoplasmic sperm injection (ICSI) or failed implantation, and they had documented GH deficiency. These initial cycles were compared with their subsequent IVF cycles with GH supplementation. A non-parametric test was used for statistical analysis. RESULTS: Embryo quality, determined by scoring the embryos on Day two using morphology, improved significantly after supplementation of GH (p-value is less than 0.001, median embryo score increased from 10.7 to 16). There was also a statistically significant increase in the fertilisation rate for those patients who had ICSI. There was no statistical difference in the number of oocytes retrieved or in the mean endometrial thickness with GH. CONCLUSION: This study implies that GH supplementation may improve embryo quality in selected patients with GH deficiency. Its role in improving fertilisation rate at ICSI merits further research and evaluation.

A randomised control trial examining the effect of an antioxidant (Menevit) on pregnancy outcome during IVF-ICSI treatment.

BACKGROUND: Evidence has accumulated supporting the role of reactive oxygen species (ROS) in the pathogenesis of sperm dysfunction among men with infertility. Damage to sperm DNA by ROS can lead to failure of conception, miscarriage or potentially even childhood cancer. The objective of this study was to examine the effect of male antioxidant treatment on embryo quality and pregnancy outcome during in vitro fertilisation-intracytoplasmic sperm injection (IVF-ICSI) treatment. METHODS: Sixty couples with severe male factor infertility were enrolled in a prospective randomised double-blind placebo-controlled trial. Male participants were randomly assigned to take either one capsule per day of the Menevit antioxidant or an identical in appearance placebo for three months prior to their partner's IVF cycle. The primary outcome was cleavage stage embryo quality and the secondary outcomes were oocyte fertilisation rate, pregnancy rates and treatment side-effects. Approval by the local Human Research Ethics Committee was obtained prior to the commencement of this study. RESULTS: The antioxidant group recorded a statistically significant improvement in viable pregnancy rate (38.5% of transferred embryos resulting in a viable fetus at 13 weeks gestation) compared to the control group (16% viable pregnancy). No significant changes in oocyte fertilisation rate or embryo quality were detected between the antioxidant and the placebo groups. Side-effects on the Menevit antioxidant were rare (8%) and mild in nature. CONCLUSIONS: The Menevit antioxidant appears to be a useful ancillary treatment that significantly improves pregnancy rates in couples undergoing IVF-ICSI treatment for severe male factor infertility.