The adenomyosis/endometriosis IVF patient - call for clinical focus.

Endometriosis and adenomyosis are distinct clinical conditions that carry the same pathophysiological features. In recent years the clinical focus on assisted reproductive technology patients with either condition (E/A) has increased, in the recognition that this subgroup of patients might need special attention to obtain reproductive success. Endometriosis and adenomyosis are characterized by a disruption of progesterone and oestrogen signalling pathways, resulting in local oestrogen dominance and progesterone resistance at the receptor level. Recent scientific evidence suggests that the endometrial progesterone receptor resistance encountered in E/A patients can be overcome by a freeze-all policy, followed by down-regulating circulating oestradiol concentrations prior to frozen embryo transfer (FET), in combination with an increase in exogenous luteal phase progesterone supplementation in hormonal replacement therapy (HRT) FET cycles. Specifically, for adenomyosis patients who do not respond to gonadotrophin-releasing hormone agonist down-regulation in terms of a decrease in circulating oestradiol concentrations, a small case series has suggested that the addition of an aromatase inhibitor for 21 days prior to HRT-FET is a valid option. Endometriosis and adenomyosis are hormonally active diseases, which need to be treated by controlling local hyperoestrogenism and progesterone resistance. Based on physiology and recent preliminary clinical data, the authors of this opinion paper wish to stimulate discussion and spark interest in research in E/A patients.

High-impact journal publishing: the devil is in the detail!

Research in medicine is an indispensable tool to advance knowledge and improve patient care. This may be particularly true in the field of human reproduction as it is a relatively new field and treatment options are rapidly evolving. This is of particular importance in an emerging field like 'human reproduction', where treatment options evolve fast.The cornerstone of evidence-based knowledge, leading to evidence-based treatment decisions, is randomized controlled trials as they explore the benefits of new treatment approaches. The study design and performance are crucial and, if they are carried out correctly, solid conclusions can be drawn and be implemented in daily clinical routines. The dissemination of new findings throughout the scientific community occurs in the form of publications in scientific journals, and the importance of the journal is reflected in part by the impact factor. The peer review process before publication is fundamental in preventing flaws in the study design. Thus, readers of journals with a high impact factor usually rely on a thorough peer review process and therefore might not question the published data. However, even papers published in high-impact journals might not be free of flaws, so the aim of this paper is to encourage readers to be aware of this fact and critically read scientific papers as 'the devil lies in the details'.

GnRH agonist trigger in poor prognosis patients undergoing a multicycle approach through DuoStim or consecutive stimulations: a SWOT analysis.

PURPOSE OF REVIEW: Identify the most recent and significant evidence regarding the ovulation trigger within the framework of a multicycle approach through DuoStim, providing valuable insights for improving treatment strategies in patients with a poor prognosis. RECENT FINDINGS: The trigger method plays a pivotal role in optimizing in-vitro fertilization (IVF) stimulation, influencing oocyte retrieval and maturation rates, as well as follicle recruitment in consecutive ovarian stimulations such as double stimulation. Decision-making involves multiple factors and, while guidelines exist for conventional stimulation, specific recommendations for the multicycle approach are not well established. SUMMARY: The different methods for inducing oocyte maturation underscore the need for personalization of IVF protocols. The GnRH agonist trigger induces rapid luteolysis and establishes favorable hormonal conditions that do not adversely affect the recruitment of consecutive follicular waves in the context of DuoStim. It serves as a valid alternative to hCG in freeze-all cycles. This strategy might enhance the safety and flexibility of ovarian stimulations with no impact on oocyte competence and IVF efficacy.

Oocyte Quality in Women with Endometriosis.

BACKGROUND: Endometriosis is a chronic gynecological condition that affects approximately 10% of women of reproductive age globally. It is associated with significant morbidity due to symptoms such as pelvic pain and infertility. Current knowledge suggests that endometriosis impacts oocyte quality, a critical factor for successful fertilization and pregnancy. Despite extensive research, the exact mechanisms remain unclear, and further updates are necessary to optimize treatment strategies. OBJECTIVES: This review aims to summarize current evidence regarding the impact of endometriosis on oocyte quality and its subsequent effects on fertility outcomes, particularly in the context of in vitro fertilization (IVF). METHODS: A comprehensive search was conducted in PubMed using the terms "endometriosis AND oocyte quality," "endometriosis AND infertility, and "endometriosis AND IVF." The review included studies published up to July 2024. OUTCOME: The review findings indicate that endometriosis may be associated with decreased oocyte quality, characterized by impaired morphological features and molecular abnormalities. These defects potentially lead to lower fertilization rates, impaired embryo development, and reduced pregnancy outcomes. However, some studies suggest that with controlled factors such as age and ovarian reserve, IVF outcomes may be comparable to those without endometriosis. CONCLUSIONS AND OUTLOOK: For clinicians and scientists working in medically assisted reproduction, understanding the impact of endometriosis on oocyte quality is crucial for improving fertility treatment outcomes. Advances in assisted reproductive technologies and personalized treatment approaches may mitigate these adverse effects. The potential for using artificial intelligence to assess oocyte quality presents a promising avenue for future research, as currently there is no direct and objective measure to assess this parameter.

Safety of assisted reproductive techniques in gynecological cancer patients.

PURPOSE OF REVIEW: Gynecological cancer is a very important cause of comorbidity and mortality in women. The current delay in motherhood is increasing the incidence of women under 40 years of age that have not yet achieved their maternity goals when they are diagnosed and standard treatment negatively impacts the reproductive potential of cancer survivors. In this review, we update the information available about the safety of fertility-sparing treatments in young gynecological cancer patients, as well as the safety and efficacy of assisted reproductive techniques (ART) in such group. We also evaluate the long-term gynecological cancer risk in women requiring ART. RECENT FINDINGS: Although eligibility criteria continue to be very strict, there are more and more reports of fertility-sparing approaches outside of what traditionally has been considered safe. Molecular assessment is starting to be used in the selection of appropriate candidates. Data increasingly shows the long term safety and the efficacy of ART and pregnancy in these patients. SUMMARY: Appropriate selection is key to safely preconize fertility-sparing alternatives. Because subfertility may be a result of these procedures, ART could be indicated in this setting. Neither ART nor pregnancy appear to increase recurrences or affect survival rates.

Preimplantation genetic testing for aneuploidy is not related to adverse obstetric and neonatal outcomes in singleton pregnancies.

STUDY QUESTION: What is the potential impact of preimplantation genetic testing for aneuploidy (PGT-A) on obstetric and neonatal outcomes? SUMMARY ANSWER: PGT-A is not associated with increased rates of adverse maternal and neonatal outcomes in singleton pregnancies following IVF/ICSI cycles. WHAT IS KNOWN ALREADY: PGT-A pregnancies may be associated with increased risks of lower birthweight, preterm delivery, and hypertensive disorders compared with natural pregnancies. In a recent meta-analysis, the overall obstetric and neonatal outcomes of PGT-A pregnancies were favorable compared with those of IVF/ICSI pregnancies, although PGT-A pregnancies were associated with a higher risk of hypertensive disorders. STUDY DESIGN, SIZE, DURATION: A multicenter retrospective cohort study was performed in University-affiliated infertility centers. Single live births following IVF/ICSI between October 2016 and January 2021 were included in the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 7146 live births after single embryo transfers with (n = 3296) or without (n = 3850) PGT-A were included. The primary outcome was pre-eclampsia and secondary outcomes included gestational diabetes, low birthweight and very low birthweight, cesarean section delivery, emergency cesarean section, as well as preterm birth, birthweight, congenital abnormalities, neonatal sex, Apgar score at 5 min, and neonatal intensive care unit admission. In a subgroup analysis, were included only blastocysts screened with next-generation sequencing (NGS). MAIN RESULTS AND THE ROLE OF CHANCE: Univariate analysis showed that pre-eclampsia, cesarean section incidence, and low Apgar score were higher in women undergoing PGT-A. However, after performing multivariate logistic and linear regression models accounting for many possible confounders, pregnancies that had been conceived after embryo biopsy showed no increase in adverse obstetric and neonatal outcomes. The subgroup analysis including patients with blastocysts screened by NGS showed a decreased risk of preterm birth in the group undergoing PGT-A. LIMITATIONS, REASONS FOR CAUTION: Caution should be used when interpreting the data because of its limitations, mainly related to its retrospective design. Although this is a large multicenter study, data acquisition included self-reporting questionnaires, and the deliveries occurred in different institutions with distinct protocols. WIDER IMPLICATIONS OF THE FINDINGS: The current study does not show any major adverse clinical outcomes after PGT-A. Efforts should be made to promote good quality research on embryo biopsy in terms of neonatal and obstetric outcomes, as well as its long-term consequences. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was obtained for this study. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

New insights into decidualization: immunological and genetic factors.

PURPOSE OF REVIEW: Nowadays, there are many efforts focused on improving embryo quality for assisted reproduction treatments. Nevertheless, there are important maternal aspects, such as decidualization, also essential for pregnancy, often forgotten. With this review, we intend to highlight the main events involved in this endometrial phenomenon, as well as the cells and molecules that have recently been related to it. RECENT FINDINGS: Decidualization entails a complete transformation of the endometrium, with recent research reaffirming progesterone as its main molecular trigger. Certain immune components and membrane molecules have also been found to play a role in it, notably the killer immunoglobulin-like receptors (KIR) of uterine natural killer (uNK) cells, as well as the human leukocyte antigen (HLA)-F. SUMMARY: Progesterone directs the cellular changes that take place during decidualization, as well as the recruitment and maturation of uNKs, along with the coordinated action of interleukin-15. Likewise, the role of KIR and HLA-F in this process and in the subsequent development of pregnancy is being highlighted in many studies, with effects on reproductive outcomes related to the different genotypes of these molecules.

COVID-19 mRNA vaccines have no effect on endometrial receptivity after euploid embryo transfer.

RESEARCH QUESTION: Does the COVID-19 vaccination affect endometrial receptivity after single euploid embryo transfer, measured by sustained implantation rate? DESIGN: A retrospective cohort study analysing two groups of single euploid embryo transfers using own oocytes: one historical cohort of 3272 transfers 1 year before the pandemic; and one comprising 890 transfers in women previously vaccinated with mRNA vaccines against severe acute respiratory syndrome coronavirus 2. The main outcomes were clinical pregnancy rate (CPR) and sustained implantation rate (SIR) per embryo transfer. These outcomes were compared between non-vaccinated and vaccinated women, and women who had received one and two doses. Lastly, vaccinated women were divided into quartiles according to the time from last dose to embryo transfer. RESULTS: Similar CPR and SIR were found between non-vaccinated and vaccinated women, and the odds ratio for both outcomes was not statistically significant after being controlled for potential confounders (OR 0.937, 95% CI 0.695 to 1.265 and OR 0.910, 95% CI 0.648 to 1.227 respectively). Within the vaccinated group, women who had received one or two doses also had similar outcomes. In addition, no differences were found according to the time interval from vaccination to embryo transfer. CONCLUSION: The administration of mRNA vaccines against COVID-19 had no effect on endometrial receptivity and embryo implantation, regardless of the number of doses and time interval from vaccination to embryo transfer. The potential negative effect of the vaccine on endometrial receptivity and reproductive outcomes is reassuring for patients in the process of undergoing assisted reproductive treatment.

Reproductive senescence impairs the energy metabolism of human luteinized granulosa cells.

RESEARCH QUESTION: Female age is the single greatest factor influencing reproductive performance and granulosa cells are considered as potential biomarkers of oocyte quality. Is there an age effect on the energy metabolism of human mural granulosa cells? DESIGN: Observational prospective cohort and experimental study including 127 women who had undergone IVF cycles. Women were allocated to two groups: a group of infertile patients aged over 38 years and a control group comprising oocyte donors aged less than 35 years. Individuals with pathologies that could impair fertility were excluded from both groups. Following oocyte retrieval, cumulus and granulosa cells were isolated and their bioenergetic properties (oxidative phosphorylation parameters, rate of aerobic glycolysis and adenine nucleotide concentrations) were analysed and compared. RESULTS: Human mural luteinized granulosa and cumulus cells present high rates of aerobic glycolysis that cannot be increased further when mitochondrial ATP synthesis is inhibited. Addition of follicular fluid to the experimental media is necessary to reach the full respiratory capacity of the cells. Granulosa cells from aged women present lower mitochondrial respiration (12.8 ± 1.6 versus 11.2 ± 1.6 pmol O2/min/mg; P = 0.046), although mitochondrial mass is not decreased, and lower aerobic glycolysis, than those from young donors (12.9 ± 1.3 versus 10.9 ± 0.5 mpH/min/mg; P = 0.009). The concurrent decrease in the two energy supply pathways leads to a decrease in the cellular energy charge (0.87 ± 0.01 versus 0.83 ± 0.02; P < 0.001). CONCLUSIONS: Human mural luteinized granulosa cells exhibit a reduction in their energy metabolism as women age that is likely to influence female reproductive potential.

The effect of late-follicular phase progesterone elevation on embryo ploidy and cumulative live birth rates.

RESEARCH QUESTION: Does late-follicular phase progesterone elevation have a deleterious effect on embryo euploidy, blastocyst formation rate and cumulative live birth rates (CLBR)? DESIGN: A multicentre retrospective cross-sectional study including infertile patients aged 18-40 years who underwent ovarian stimulation in a gonadotrophin-releasing hormone antagonist protocol and preimplantation genetic testing for aneuploidies (PGT-A) followed by a freeze-all strategy and euploid embryo transfer between August 2017 and December 2019. The sample was stratified according to the progesterone concentrations on the day of trigger: normal (≤1.50 ng/ml) and high (>1.50 ng/ml). Moreover, sensitivity analyses were performed to determine whether different conclusions would have been drawn if different cut-offs had been adopted. The primary outcome was the embryo euploidy rate. Secondary outcomes were the blastocyst formation rate, the number of euploid blastocysts and CLBR. RESULTS: Overall 1495 intracytoplasmic sperm injection PGT-A cycles were analysed. Late-follicular phase progesterone elevation was associated with significantly higher late-follicular oestradiol concentrations (2847.56 ± 1091.10 versus 2240.94 ± 996.37 pg/ml, P < 0.001) and significantly more oocytes retrieved (17.67 ± 8.86 versus 12.70 ± 7.00, P < 0.001). The number of euploid embryos was significantly higher in the progesterone elevation group (2.32 ± 1.74 versus 1.86 ± 1.42, P = 0.001), whereas the blastocyst formation rate (47.1% [43.7-50.5%] versus 51.0% [49.7-52.4%]), the embryo euploidy rate (48.3% [44.9-51.7%] versus 49.1% [47.7-50.6%], the live birth rate in the first frozen embryo transfer (34.1% versus 31.1%, P = 0.427) and CLBR (38.9% versus 37.0%, P = 0.637) were not significantly different between the two groups. CONCLUSIONS: Euploidy rate and CLBR do not significantly differ among PGT-A cycles with and without late-follicular progesterone elevation in a freeze-all approach.

Minimal ovarian stimulation is an alternative to conventional protocols for older women according to Poseidon's stratification: a retrospective multicenter cohort study.

OBJECTIVE: To investigate whether minimal ovarian stimulation (mOS) is as effective as conventional ovarian stimulation (cOS) for older women belonging to different groups according to the Poseidon criteria. MATERIAL AND METHODS: Observational retrospective multicentre cohort including women from Poseidon's groups 2 and 4 that underwent in vitro fertilization (IVF). We performed a mixed-effects logistic regression model, adding as a random effect the patients and the stimulation cycle considering the dependence of data. Survival curves were employed as a measure of the cumulative live birth rate (CLBR). The primary outcomes were live birth rate per embryo transfer and CLBR per consecutive embryo transfer and oocyte consumed until a live birth was achieved. RESULTS: A total of 2002 patients underwent 3056 embryo transfers (mOS = 497 and cOS = 2559). The live birth rates per embryo transfer in mOS and cOS showed no significant difference in both Poseidon's groups. Likewise, the logistic regression showed similar live birth rates between the two protocols in Poseidon's groups 2 (OR 1.165, 95% CI 0.77-1.77; p = 0.710) and 4 (OR 1.264 95% CI 0.59-2.70; p = 0.387). However, the survival curves showed higher CLBR per oocyte in women that received mOS (Poseidon group 2: p < 0.001 and Poseidon group 4: p = 0.039). CONCLUSIONS: Minimal ovarian stimulation is a good alternative to COS as a first-line treatment for patients belonging to Poseidon's groups 2 and 4. The number of oocytes needed to achieve a live birth seems inferior in mOS strategy than cOS.

Establishing the follitropin delta dose that provides a comparable ovarian response to 150 IU/day follitropin alfa.

RESEARCH QUESTION: The objective of this investigation was to determine the daily follitropin delta dose (µg) providing a similar ovarian response to 150 IU/day follitropin alfa. DESIGN: The study was a post-hoc analysis of ovarian response in 1591 IVF/intracytoplasmic sperm injection (ICSI) patients undergoing ovarian stimulation in a gonadotrophin-releasing hormone antagonist protocol in two recent randomized, assessor-blind, controlled trials in the development programme for follitropin delta: a phase II dose-response trial with a reference arm of a fixed daily dose of 150 IU follitropin alfa throughout stimulation, and a phase III efficacy trial with a comparator arm of 150 IU/day follitropin alfa as a starting dose. RESULTS: Daily follitropin delta doses of 10.0 µg (95% confidence interval [CI] 7.9-12.8) and 10.3 µg (95% CI 9.7-10.8) yielded the same number of oocytes as 150 IU/day follitropin alfa for all patients participating in the phase II and III trials, respectively. When analysing patients with either normal or high ovarian reserve (based on serum anti-Mullerian hormone ≥15 pmol/l) and no dose changes, the same number of oocytes was obtained with 150 IU/day follitropin alfa and daily doses of follitropin delta of 9.7 µg (95% CI 7.5-12.4) and 9.3 µg (95% CI 8.6-10.1) in the two trials. Daily follitropin delta doses in the range 9.5-10.4 µg were consistently estimated to correspond to 150 IU/day follitropin alfa for serum oestradiol concentration and number of follicles ≥12 mm at the end of stimulation across analysis populations in the phase III trial. CONCLUSIONS: A daily follitropin delta dose of 10 µg provides a similar ovarian response to 150 IU/day follitropin alfa in IVF/ICSI patients.

The performance of the Elecsys® anti-Müllerian hormone assay in predicting extremes of ovarian response to corifollitropin alfa.

RESEARCH QUESTION: What is the performance of anti-Müllerian hormone (AMH) as measured by the Elecsys® AMH assay in predicting ovarian response in women treated with 150 µg corifollitropin alfa (CFA)? DESIGN: Multicentre, prospective study conducted between December 2015 and April 2018. Women were aged 18-43 years, had regular menstrual bleeding, a body mass index of 17-35 kg/m2 and weighed 60 kg or over. EXCLUSION CRITERIA: previous oophorectomy, history of ovarian hyperstimulation syndrome, a previous IVF and intracytoplasmic sperm injection cycle producing over 30 follicles measuring 11 mm or wider, basal antral follicle count (AFC) over 20 or polycystic ovarian syndrome. All women were treated with 150 µg CFA followed by recombinant FSH (150-300 IU/day) in a fixed gonadotrophin releasing hormone antagonist protocol. RESULTS: Of the 219 patients enrolled, 22.8% had low ovarian response (three or fewer oocytes), 66.2% had normal response and 11% had high ovarian response (15 or more oocytes). The AMH and AFC presented an area under the curve of 0.883 (95% CI 0.830 to 0.936) and 0.879 (95% CI 0.826 to 0.930), respectively, for low ovarian response; and an AUC of 0.865 (95% CI 0.793 to 0.935) and 0.822 (95% CI 0.734 to 0.909) for high ovarian response. An AMH cut-off of 1.0 ng/ml provided a sensitivity of 92.0% and a specificity of 66.9% in the prediction of low ovarian response; a cut-off of 2.25 ng/ml predicted high ovarian response with a sensitivity of 54.2% and a specificity of 91.8%. CONCLUSIONS: The automated Elecsys® AMH assay predicts ovarian response in a CFA antagonist protocol. The best predictors of ovarian response in CFA-treated patients were AMH and AFC.

A 5-year multicentre randomized controlled trial comparing personalized, frozen and fresh blastocyst transfer in IVF.

RESEARCH QUESTION: Does clinical performance of personalized embryo transfer (PET) guided by endometrial receptivity analysis (ERA) differ from frozen embryo transfer (FET) or fresh embryo transfer in infertile patients undergoing IVF? DESIGN: Multicentre, open-label randomized controlled trial; 458 patients aged 37 years or younger undergoing IVF with blastocyst transfer at first appointment were randomized to PET guided by ERA, FET or fresh embryo transfer in 16 reproductive clinics. RESULTS: Clinical outcomes by intention-to-treat analysis were comparable, but cumulative pregnancy rate was significantly higher in the PET (93.6%) compared with FET (79.7%) (P = 0.0005) and fresh embryo transfer groups (80.7%) (P = 0.0013). Analysis per protocol demonstrates that live birth rates at first embryo transfer were 56.2% in PET versus 42.4% in FET (P = 0.09), and 45.7% in fresh embryo transfer groups (P = 0.17). Cumulative live birth rates after 12 months were 71.2% in PET versus 55.4% in FET (P = 0.04), and 48.9% in fresh embryo transfer (P = 0.003). Pregnancy rates at the first embryo transfer in PET, FET and fresh embryo transfer arms were 72.5% versus 54.3% (P = 0.01) and 58.5% (P = 0.05), respectively. Implantation rates at first embryo transfer were 57.3% versus 43.2% (P = 0.03), and 38.6% (P = 0.004), respectively. Obstetrical outcomes, type of delivery and neonatal outcomes were similar in all groups. CONCLUSIONS: Despite 50% of patients dropping out compared with 30% initially planned, per protocol analysis demonstrates statistically significant improvement in pregnancy, implantation and cumulative live birth rates in PET compared with FET and fresh embryo transfer arms, indicating the potential utility of PET guided by the ERA test at the first appointment.

Donor IUI is equally effective for heterosexual couples, single women and lesbians, but autologous IUI does worse.

STUDY QUESTION: Are there differences in the clinical outcomes of IUI among different populational groups (heterosexual couples, single women and lesbian couples)? SUMMARY ANSWER: The outcome of donor IUI (D-IUI) is similar in all populational groups and better than that seen with autologous insemination. WHAT IS KNOWN ALREADY: A vast body of literature on clinical outcome is available for counselling heterosexual couples regarding decisions related to ART. The reproductive potential of single women, lesbian couples and heterosexual couples who need donor semen is assumed to be better, but there is a scarcity of data on their ART performance to actually confirm it. STUDY DESIGN, SIZE, DURATION: In this retrospective multicentric cohort study, a total of 7228 IUI treatment cycles performed in 3807 patients between January 2013 and December 2016 in 13 private clinics belonging to the same reproductive medicine group in Spain were included. Patients with previous IUI attempts were excluded from the study. Only 1.9% of cycles were lost to follow-up. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 5318 D-IUI cycles were performed in three different populational groups: heterosexual couples (D-HC, 1167 cycles), single women (SW, 2839 cycles) and lesbian couples (LC, 1312), while a total of 1910 autologous IUI cycles were performed in heterosexual couples (A-HC). This last one was considered the control group and was composed of cycles performed in couples with a male partner with sperm parameters equivalent to those requested from donors. In order to identify factors with an impact on clinical outcome, a multivariate logistic regression analysis was performed. Regarding live birth rate (LBR), mixed effect models were employed to control for the fact that different patients were submitted to different numbers of treatments. MAIN RESULTS AND THE ROLE OF CHANCE: Parameters that were significant to the primary outcome (LBR) according to the multivariate analysis were the populational group (D-HC, SW, LC and A-HC) to which the patient belonged, female age and a diagnosis of low ovarian reserve. At the age range of good prognosis (≤37 years), LBR was similar in all groups that underwent D-IUI (18.8% for D-HC, 16.5% for SW and 17.6% for LC) but was significantly lower in the autologous IUI (A-HC) group (11%). For all these significant findings, the strength of the association was confirmed by P values <0.001. From 38 years of age on, no significant differences were observed among the populational groups studied, and for all of them, LBR was below 7% from 40 years of age on. LIMITATIONS, REASONS FOR CAUTION: To the best of our knowledge, a smoking habit was the only known factor with a potential effect on ART outcome that could not be controlled for, due to the unavailability of this information in a significant percentage of the clinical files studied. Our study was not capable of precisely quantifying the impact of a diagnosis of low ovarian reserve on the LBR of both IUI and D-IUI, due to the number of cycles performed in patients with such diagnosis (n = 231, 3.2% of the total). WIDER IMPLICATIONS OF THE FINDINGS: For the first time, a comparison among D-HC, SW, LC and A-HC was performed in a study with a robust sample size and controlling for potential sources of bias. There is now sound evidence that equivalent clinical outcome is seen in the three groups treated with donor semen (D-HC, SW and LC). Specifically, regarding the comparison between SW and LC, our findings rule out differences in LBR proposed by previous publications, with very similar clinical outcomes within the same age ranges. At age ranges of good prognosis (≤37 years), reproductive performance of D-IUI is significantly better than that seen in heterosexual couples undergoing autologous IUI, even when only cases of optimal sperm quality are considered in this last group. This finding is in agreement with the concept that, as a group, A-HC are more prone to have female factor infertility, even when their infertility assessment finds no contraindication to IUI. Age affects all these groups equally, with none of them reaching a 7% LBR after the age of 40 years. Our findings will be useful for the counselling of patients from the different populations studied here about ART strategies. STUDY FUNDING/COMPETING INTEREST(S): None.

Use of granulocyte colony-stimulating factor in ART treatment does not increase the risk of adverse perinatal outcomes.

RESEARCH QUESTION: Granulocyte colony-stimulating factor (G-CSF) acts on reproductive function at different stages, but its effects on the early stages of embryo development are unknown. The aim of this study was to assess the effect of G-CSF administration during treatment with assisted reproductive technologies (ART) and early pregnancy on newborns. DESIGN: Retrospective study in women undergoing egg donation, with a study group including 33 live-born children from a pregnancy in which G-CSF was administered, and a control group of 3798 children in which this medication was not ordered during pregnancy. The analysis was of perinatal outcomes resulting from G-CSF treatment administered off-label compared with a control group. RESULTS: No significant differences were found in maternal age (40.9 ± 0.1 versus 38.9 ± 1.8, P = 0.055), body mass index (23.2 ± 0.2 versus 22.6 ± 1.5, P = 0.503), infant birthweight (2952 ± 200 versus 3145 ± 270 g, P = 0.184), gestational age (38 ± 1 versus 37 ± 1 weeks, P = 0.926) or length (50.2 ± 1.5 versus 48.7 ± 2.7 cm, P = 0.678) (between the control group and women treated with G-CSF, respectively). The prematurity rates of births before week 36 (10.0% versus 9.5%, P = 0.783) or week 32 (2.2% versus 0.0%, P = 0.585) were similar in the control and study groups, respectively. The incidence of low birthweight (<2500 g; 19.6% versus 11.8%, P = 0.570) or very low birthweight (1500 g; 2.5% versus 0.0%, P = 0.454) was not significantly different between non-treated and G-CSF-treated women, respectively. CONCLUSIONS: Administration of G-CSF at embryo transfer and during early pregnancy in recurrent miscarriage patients with KIR-HLA-C mismatch undergoing egg donation ART treatment does not convey a higher risk of perinatal complications.

Serum and follicular fluid Stem Cell Factor assay in IVF poor responder and normal responder patients: a predictive biomarker of oocyte retrieval.

OBJECTIVE: The aim of the study is to investigate serum stem cell factor (SCF) concentrations as potential biomarker for oocyte retrieval efficiency in IVF patients with poor prognosis. METHODS: A pilot case-control study was performed on 30 poor and 30 normal responders that were stimulated with antagonist protocol. SCF concentrations were evaluated in samples of serum and follicular fluid obtained by all patients on the day of oocyte retrieval. At the time of oocyte retrieval, follicular fluid from at least two follicles ≥ 14 mm and two follicles < 14 mm was collected for SCF determination. RESULTS: We did not find any statistical difference when comparing serum and follicular fluid levels of SCF in both poor- and normal-responder patients, the same results were achieved when poor-responder patients were stratified according to the number of MII oocytes retrieved. Moreover, levels of SCF (OR 1.000, 0.994-1.006) or in follicular fluid from ovarian follicles ≥ 14 mm (OR 0.995, CI 0.989-1.001) or from ovarian follicles < 14 mm (OR 1.003, CI 0.999-1.0069), were not significantly associated with the chances of ongoing pregnancies in poor-responder patients. CONCLUSION: SCF was unable to predict oocyte retrieval efficiency or the chances of reaching embryo transfer.

Very low anti-müllerian hormone concentrations are not an independent predictor of embryo quality and pregnancy rate.

RESEARCH QUESTION: Is anti-Müllerian hormone (AMH) serum concentration a useful tool to predict the outcome of assisted reproductive treatment? DESIGN: Retrospective cohort study involving 2971 patients who underwent 5570 IVF cycles. Patients were classified into six groups according to their AMH levels and analysed for associations with reproductive outcome. Several parameters of ovarian response and clinical outcome were compared between groups. RESULTS: Cancellation rate and clinical pregnancy rate varied by AMH group, with highest cancellation rates (32.8%, P = 0.021) and lowest clinical pregnancy rates (9.8%, P < 0.001) in the group with lowest AMH. When these patients achieved embryo transfer, the implantation rate (30.5%) did not significantly differ from the other groups, and retained a low, but reasonable, clinical pregnancy rate per transfer (45.9%). When this group was classified into three female age groups, the clinical pregnancy rate was found to be significantly higher in the patients younger than 37 years (58.1%) compared with patients aged between 37 and 39 years (48.9%) and those aged over 39 years (27%, P < 0.001). CONCLUSIONS: Although significant differences in pregnancy rates were observed among the different AMH groups, even in the lowest AMH level group, the probability of achieving pregnancy was reasonable, especially if the patient's age is not very advanced.

The role of mitochondrial activity in female fertility and assisted reproductive technologies: overview and current insights.

Mitochondria have been implicated as key factors regulating female reproductive processes. Notable progress has been made in determining the role of mitochondria with respect to oocyte maturation, fertilization and early embryo development. In addition, mitochondrial function and dysfunction has been the subject of various studies in ovarian ageing and metabolic stress models. However, the overall mitochondrial impact on female fertility is yet to be uncovered. The mitochondrial DNA content of granulosa, cumulus and trophectoderm cells is being explored as a biomarker of oocyte quality and embryo viability. As growing evidence suggests that embryo potential could be related to the ability of oocyte mitochondria to generate energy, efforts have been made to investigate the possibility of improving mitochondrial capacity in women with poor outcomes after treatment with assistedreproductive technologies. Thus far, therapeutic attempts have focused mainly on using nutrients to restore mitochondrial function and transferring mitochondria from autologous germline precursor cells. Moreover, new perspectives on optimizing infertility treatments have arisen with modern mitochondrial replacement therapies, which are being applied in women with mitochondrial disease-causing mutations. This review explores aspects of the distinctive contribution of mitochondria to reproductive processes and discusses current and emerging clinical implications.