Minimum number of mature oocytes needed to obtain at least one euploid blastocyst according to female age in in vitro fertilization treatment cycles.

OBJECTIVE: To find a useful tool for estimating the minimum number of metaphase II (MII) oocytes needed to obtain at least one euploid blastocyst according to female age. DESIGN: Retrospective analysis of in vitro fertilization (IVF) treatment cycles with preimplantational genetic testing for aneuploidies (PGT-A) performed over 5 years in IVIRMA Valencia (Spain), January 2017-March 2022. Approval from the Institutional Review Board of IVI Valencia (2204-VLC-040-CR). SETTING: Private infertility clinic in Spain. PATIENTS: Eligible patients were undergoing their first IVF-PGT-A treatment cycle, in which at least one MII oocyte was obtained, regardless of oocyte and semen origin. Oocyte donation cycles were included in the donor group (≤34 years old). Treatment cycles from women with their own oocytes were selected only when the oocytes were aged ≥35 years (patient group). Only trophoectoderm biopsies performed on days 5 or 6 of development and analyzed using next-generation sequencing were included. Preimplantational genetic testing for aneuploidy cycles because of a known abnormal karyotype were excluded. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Number of MII oocytes needed to obtain one euploid blastocyst according to female age. RESULTS: A total of 2,660 IVF-PGT-A treatment cycles were performed in the study period in the eligible population (patients group = 2,462; donors group =198). The mean number of MII oocytes needed to obtain one euploid blastocyst increased with age, as did the number of treatment cycles that did not get at least one euploid blastocyst. An adjusted multivariate binary regression model was designed using 80% of the patient group sample (n = 2,462; training set). A calculator for the probability of obtaining at least one euploid blastocyst was created using this model. The validation of this model in the remaining 20% of the patient group sample (n = 493; validation set) showed that it could estimate the event of having at least one euploid blastocyst with an accuracy of 72.0%. CONCLUSIONS: Our results show a preliminary model capable of predicting the number of MII oocytes needed to obtain at least one euploid blastocyst according to female age, calculated with the largest database of IVF-PGT-A treatment cycles ever used for this purpose, including only treatment cycles using next-generation sequencing on trophoectoderm biopsies. Once this model has been properly validated, it could help with decision-making for both clinicians and patients coming to an infertility clinic.

Do Popular Diets Impact Fertility?

Infertility affects 15% of the population in developed countries, and its prevalence is increasing. Fertility can be influenced by different factors. Although key factors like maternal age cannot be changed, there is growing evidence that other modifiable factors, such as diet, can have an impact on fertility. Diet has become increasingly important in recent years for a number of reasons: the new trend toward a healthy lifestyle, the higher prevalence of certain digestive disorders, a lack of time that leads people to consume more prepared and processed food, and personal choice to not eat meat, among others. To meet these needs, several diets have recently become popular, such as the Mediterranean diet, known as the gold standard of health; the DASH diet, known for preventing hypertension; the Western diet, characterized by processed food; the ketogenic diet, characterized by low carbohydrate intake; and the vegetarian diet, which is the choice for people who do not eat meat or animal by-products. Diets present a unique composition characterized by the presence or absence of specific nutrients, which have also been associated with male and female fertility individually. This review assesses the impact of these diets and of macro- and micronutrients on both female and male fertility.

Luteal phase support using micronized vaginal progesterone as pessaries or capsules in artificial cycles: is there any difference?

RESEARCH QUESTION: Is there a difference between the proportion of patients with serum progesterone <8.8 ng/ml on the day of embryo transfer when micronized vaginal progesterone (MVP) for luteal phase support (LPS) is given as pessaries versus capsules? DESIGN: This retrospective, matched-cohort, single-centre study compared pessaries (Cyclogest) versus capsules (Utrogestan, Progeffik) for LPS in hormone replacement treatment-embryo transfer (HRT-ET) cycles. Patients under 50 years old with a triple-layer endometrial thickness of ≥6.5 mm underwent transfer of one or two blastocysts. Serum progesterone concentrations were measured on the day of transfer; patients with concentrations <8.8 ng/ml received a single 'rescue' dose of additional progesterone by subcutaneous injection. RESULTS: In total 2665 HRT-ET cycles were analysed; 663 (24.9%) used pessaries for LPS and 2002 (75.1%) used capsules. Mean serum progesterone concentrations with standard deviations on the day of embryo transfer were significantly higher in the group using MVP pessaries compared with those using capsules (14.5 ± 5.1 versus 13.0 ± 4.8 ng/ml; P = 0.000). The percentage of participants with suboptimal serum progesterone concentrations on the day of embryo transfer (<8.8 ng/ml) was significantly lower in the pessary group than the capsule group (10.3%, 95% confidence interval [CI] 7.9-12.6% versus 17.9%, 95% CI 16.2-19.6%; adjusted odds ratio 0.426, 95% CI 0.290-0.625; P = 0.000). No differences in pregnancy outcome were observed between the groups. CONCLUSIONS: Using MVP pessaries rather than capsules for LPS resulted in significantly fewer patients having suboptimal serum progesterone concentrations on the day of embryo transfer. Consequently, almost 50% fewer patients in the pessary group needed rescue treatment.

Detecting partial premature ovulation during follicular aspiration compromises the quantity, but not the quality, of the oocytes retrieved in stimulated in vitro fertilization (IVF) cycles.

OBJECTIVE: To analyze if partial premature ovulation (PPO) detection during oocyte pick-up (OPU) impairs the quality of the retrieved oocyte cohort. METHODS: The PPO concept refers to the situation when premature ovulation happens only in some of the follicles and it is detected during OPU. This study constitutes a retrospective analysis performed in an infertility clinic (Spain) during 2016-2021 with patients undergoing OPU after controlled ovarian hyperstimulation for an in vitro fertilization (IVF) treatment. Study code: 2110-VLC-091- VG, registered on December 9 2021. Data from women with PPO (n=111) were compared to a matched control sample of cycles without PPO (n=333) at a proportion of 1:3. RESULTS: Cycles were matched for age, body mass index (BMI), treatment year, embryo genetic analysis and stimulation protocol type. The mean numbers of oocytes (6.1 vs. 11.2), mature oocytes (4.7 vs. 8.8), correctly fertilized oocytes (3.6 vs. 6.6) and top-quality blastocysts (0.9 vs. 1.8) were significantly lower in the PPO group than the nonPPO group (p<0.05). However, maturation, fertilization, top-quality blastocyst and pregnancy rates were statistically comparable among groups (p>0.05). CONCLUSIONS: Cycles with PPO have fewer available oocytes and, thus, fewer available embryos for transfer, al though their quality is intact, and still offer chances of pregnancy in these cases. Hence cycle cancellation may not be worth associated money, time and morale losses once PPO is detected.

Serum progesterone is lower in ovarian stimulation with highly purified HMG compared to recombinant FSH owing to a different regulation of follicular steroidogenesis: a randomized controlled trial.

STUDY QUESTION: Does ovarian stimulation with highly purified (hp)-HMG protect from elevated progesterone in the follicular phase compared to recombinant FSH (r-FSH) cycles through a different regulation of follicular steroidogenesis? SUMMARY ANSWER: hp-HMG enhanced the Δ4 pathway from pregnenolone to androstenodione leading to lower serum progesterone at the end of the cycle, while r-FSH promoted the conversion of pregnenolone to progesterone causing higher follicular phase progesterone levels. WHAT IS KNOWN ALREADY: Elevated progesterone in the follicular phase has been related to lower clinical outcome in fresh IVF cycles. Progesterone levels are positively correlated to ovarian response, and some studies have shown that when r-FSH alone is used for ovarian stimulation serum progesterone levels on the day of triggering are higher than when hp-HMG is given. Whether this is caused by a lower ovarian response in hp-HMG cycles or to a difference in follicular steroidogenesis in the two ovarian stimulation regimens has not been well characterized. STUDY DESIGN, SIZE, DURATION: A randomized controlled trial including 112 oocyte donors undergoing ovarian stimulation with GnRH antagonists and 225 IU/day of r-FSH (n = 56) or hp-HMG (n = 56) was carried out in a university-affiliated private infertility clinic. Subjects were recruited between October 2016 and June 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: The women were aged 18-35 years with a regular menstrual cycle (25-35 days) and normal ovarian reserve (serum anti-Müllerian hormone (AMH) = 10-30 pMol/l) undergoing ovarian stimulation for oocyte donation. FSH, LH, estradiol (E2), estrone, progesterone, pregnenolone, 17-OH-progesterone, androstenodione, dehidroepiandrostenodione, and testosterone were determined on stimulation Days 1, 4, 6, and 8 and on day of triggering in serum and in follicular fluid. Samples were frozen at -20°C until assay. Total exposures across the follicular phase were compared by polynomic extrapolation. MAIN RESULTS AND THE ROLE OF CHANCE: Subjects in both groups were comparable in terms of age, BMI, and AMH levels. Ovarian response was also similar: 17.5 ± 7.9 (mean ± SD) versus 16.5 ± 7.5 oocytes with r-FSH and hp-HMG, respectively (P = 0.49). Serum progesterone (ng/ml) on day of trigger was 0.46 ± 0.27 in the hp-HMG group versus 0.68 ± 0.50 in the r-FSH group (P = 0.010). Differences for progesterone were also significant on stimulation days 6 and 8. The pregnenolone: progesterone ratio was significantly increased in the r-FSH group from stimulation day 8 to the day of trigger (P = 0.019). Serum androstenodione (ng/ml) on day of trigger was 3.0 ± 1.4 in the hp-HMG group versus 2.4 ± 1.1 in the r-FSH group (P = 0.015). Differences in adrostenodione were also significant on stimulation Day 8. The pregnenolone:androstenodione ratio was significantly higher in the hp-HMG group (P = 0.012) on Days 6 and 8 and trigger. There were no other significant differences between groups. Follicular fluid E2, FSH, LH, dehidroepioandrostenodione, androstenodione, and testosterone were significantly higher in the hp-HMG than r-FSH group. No differences were observed for progesterone, estrone, 17-OH-progesterone, and pregnenolone in follicular fluid. LIMITATIONS, REASONS FOR CAUTION: All women included in the study were young, not infertile, and had a normal BMI and a good ovarian reserve. The findings might be different in other patient subpopulations. Hormone analyses with immunoassays are subject to intra-assay variations that may influence the results. WIDER IMPLICATIONS OF THE FINDINGS: Stimulation with hp-HMG may prevent progesterone elevation at the end of the follicular phase because of a different follicular steroidogenesis pathway, regardless of ovarian response. This should be considered, particularly in patients at risk of having high progesterone levels at the end of the follicular phase when a fresh embryo transfer is planned. STUDY FUNDING/COMPETING INTEREST(S): Roche Diagnostics provided unrestricted funding for all serum and follicular fluid hormone determinations. J.L.R., M.M., and A.P. have nothing to declare. E.B. has received consulting fees from Ferring, Merck, Gedeon Richter, and Roche and has participated in a research cooperation with Gedeon-Richter. In addition, the author has participated in speakers' bureau and received fees from Ferring, Gedeon Richter, Merck, and Roche. P.A. has received consulting fees from MSD and has participated in speakers' bureau and received fees from Ferring. P.A. also declares travel/meeting support from MSD. E.L. has received consulting fees from Ferring and MSD. In addition, the author has participated in a research cooperation with Gedeon-Richter. Also, the author has participated in speakers' bureau and received fees from Ferring and IBSA, as well as travel/meeting support from IBSA and Gedeon Richter. E.B., P.A., and E.L. also own stocks in IVIRMA Valencia. TRIAL REGISTRATION NUMBER: NCT: NCT02738580. TRIAL REGISTER DATE: 19 February 2016. DATE OF FIRST PATIENT'S ENROLMENT: 03 October 2016.

Duration of oestrogen exposure does not affect reproductive outcome in artificial cycles: a retrospective analysis of more than 7000 hormonal replacement therapy cycles for an embryo transfer.

Introduction: Optimal duration of oestrogen exposure before an embryo transfer in artificial cycles has not been defined yet, as its correlation with reproductive outcome remains controversial. The length of oestrogen treatment before starting luteal phase support varies significantly among patients. Materials and methods: In this study, we conducted a retrospective analysis of a huge database of our own clinical results in artificial cycles in the past five years. The aim of this study was to assess the effect of the length of estrogen exposure on reproductive outcome and to evaluate if there is any optimal duration of estrogen exposure in order to maximize success rates. Results: Differences in pregnancy rates according to oestrogen length, if present, were not clinically relevant. Discussion: Our results suggest that the length of oestrogen exposure (in days) before exogenous progesterone administration do not affect clinical outcomes.

Extracellular vesicles secreted by adenomyosis endometrial organoids contain miRNAs involved in embryo implantation and pregnancy.

RESEARCH QUESTION: Do extracellular vesicles secreted by the endometrium of women with adenomyosis contain miRNAs involved in adenomyosis-related infertility? DESIGN: A descriptive study using organoids from eutopic endometrium of women with adenomyosis (n = 4) generated and differentiated to secretory and gestational phases, in which miRNA cargo from extracellular vesicles secreted by these differentiated organoids in each phase was analysed by next-generation sequencing. miRNAs in secretory-extracellular vesicles and gestational-extracellular vesicles were selected based on the counts per million. miRNAs target genes in each phase were obtained from miRNet and gene ontology was used for enrichment analysis. RESULTS: miRNA sequencing identified 80 miRNAs in secretory-phase extracellular vesicles, including hsa-miR-21-5p, hsa-miR-24-3p, hsa-miR-26a-5p, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-miR-200c-3p and hsa-miR-423a-5p, related to adenomyosis pathogenesis and implantation failure. Further, 60 miRNAs were identified in gestational-phase extracellular vesicles, including hsa-miR-21-5p, hsa-miR-26a-5p, hsa-miR-30a-5p, hsa-miR-30c-5p, hsa-miR-222-3p and hsa-miR-423a-5p were associated with preeclampsia and miscarriage. Among the target genes of these miRNAs, PTEN, MDM4, PLAGL2 and CELF1, whose downregulation (P = 0.0003, P < 0.0001, P = 0.0002 and P = 0.0003, respectively) contributes to adenomyosis pathogenesis, and impaired early embryo development, leading to implantation failure and miscarriage, are highlihghted. Further, functional enrichment analyses of the target genes revealed their involvement in cell differentiation, proliferation, apoptosis, cell cycle regulation and response to extracellular stimuli. CONCLUSIONS: Eutopic endometrium in secretory and gestational phase from women with adenomyosis releases extracellular vesicles containing miRNAs involved in adenomyosis progression, impaired embryo implantation and pregnancy complications.

Prediction of ovarian response using the automated Elecsys anti-Müllerian hormone assay in gonadotrophin-releasing hormone antagonist cycles.

RESEARCH QUESTION: What is the capability of serum anti-Müllerian hormone (AMH) measured using the automated Elecsys® AMH immunoassay to (Roche Diagnostics International Ltd) determine ovarian response after fertility treatment? DESIGN: Single-centre, retrospective, observational, cohort study including women undergoing ovarian stimulation. Serum AMH concentrations were determined using the Elecsys AMH immunoassay based on one blood sample drawn 6 months or less before treatment. Stimulation was conducted in accordance with a gonadotrophin-releasing hormone (GnRH) antagonist protocol. Patients were divided into four ovarian response categories based on their oocyte yield: low (0-3), suboptimal (4-9), optimal (10-15) and high (>15). Areas under the curve were calculated for each ovarian response group. RESULTS: Overall, 1248 patients were enrolled. The AMH concentration had a strong positive correlation with oocyte yield (Spearman's rho = 0.74, P < 0.001). Areas under the curve (95% CI) for AMH predicting ovarian response were 0.85 (0.83 to 0.88) for low and 0.89 (0.87 to 0.91) for high response. Optimal serum AMH cut-offs for predicting a low and high response using the Elecsys AMH immunoassay were 6.4 pmol/l (0.89 ng/ml) and 14.2 pmol/l (1.99 ng/ml), respectively. Multivariable regression analysis showed that 47% (R2 = 0.470) of variation in ovarian response could be attributed to AMH alone, increasing to 50.9% (R2 = 0.509) with the addition of age, body weight, and total dose of gonadotrophin. CONCLUSION: Ovarian response and oocyte yield after stimulation in a GnRH antagonist cycle can be predicted with high accuracy using a single determination of serum AMH before ovarian stimulation.

Serum progesterone concentrations are reduced in obese women on the day of embryo transfer.

RESEARCH QUESTION: Does serum progesterone concentration vary on the day of embryo transfer according to female body mass index (BMI)? DESIGN: Retrospective analysis including 3210 infertile patients undergoing an embryo transfer in the context of an artificial endometrial preparation cycle with sequential administration of oestrogens and micronized vaginal progesterone (MVP) (400 mg/12 h). Serum progesterone was measured on the day of embryo transfer, 6 ± 2 h after last MVP administration. Serum progesterone concentrations were subdivided into optimal (≥9.2 ng/ml) or suboptimal (<9.2 ng/ml) concentrations, and the cut-off point was defined according to our previous results. The primary objective was the correlation between progesterone concentrations on the day of embryo transfer and patient BMI, as a continuous variable and according to four ranges (underweight: <18.5 kg/m2; normal weight: 18.5-24.9 kg/m2; overweight: 25-29.9 kg/m2; and obesity: ≥30 kg/m2), according to the World Health Organization classification. Secondary objectives included the evaluation of reproductive outcome according to patient BMI and progesterone concentrations on the day of embryo transfer. RESULTS: Mean serum progesterone concentrations and the ratio of patients with progesterone concentrations above the cut-off point of 9.2 ng/ml fell progressively as BMI increased. Overweight and obese patients had lower mean serum progesterone concentrations than underweight and normal weight women (P < 0.001). A trend was observed towards impaired reproductive results in obese patients with suboptimal progesterone concentrations, absent when concentrations were optimal. CONCLUSIONS: Serum progesterone concentrations on the day of embryo transfer in artificial cycles with MPV decrease as BMI increases. It is highly recommended that serum progesterone concentrations are moitored to ensure optimal concentrations and reproductive outcomes.

Role of Mitochondria Transfer in Infertility: A Commentary.

Mitochondria transfer techniques were first designed to prevent the transmission of diseases due to mutations in mtDNA, as these organelles are exclusively transmitted to the offspring by the oocyte. Despite this, given the crucial role of mitochondria in oocyte maturation, fertilization and subsequent embryo development, these approaches have been proposed as new potential strategies to overcome poor oocyte quality in infertile patients. This condition is a very common cause of infertility in patients of advanced maternal age, and patients with previous in vitro fertilization (IVF) attempt failures of oocyte origin. In this context, the enrichment or the replacement of the whole set of the oocyte mitochondria may improve its quality and increase these patients' chances of success after an IVF treatment. In this short review, we will provide a brief overview of the main human studies using heterologous and autologous mitochondria transfer techniques in the reproductive field, focusing on the etiology of the treated patients and the final outcome. Although there is no current clearly superior mitochondria transfer technique, efforts must be made in order to optimize them and bring them into regular clinical practice, giving these patients a chance to achieve a pregnancy with their own oocytes.

Individualized luteal phase support normalizes live birth rate in women with low progesterone levels on the day of embryo transfer in artificial endometrial preparation cycles.

OBJECTIVE: To analyze the impact on live birth rates (LBRs) of the individualized luteal phase support (termed iLPS) in patients with low serum progesterone (P) levels compared with patients without iLPS. DESIGN: Retrospective cohort study, December 1, 2018, to May 30, 2019. SETTING: Private medical center. PATIENT(S): A total of 2,275 patients checked for serum P on the day of blastocyst transfer were analyzed. During the study period, 1,299 patients showed serum P levels of ≥9.2 ng/mL, whereas 550 showed serum P levels of <9.2 ng/mL and received iLPS. Additionally, a historical group of 426 patients with serum P levels of <9.2 ng/mL but no iLPS were used for comparison. Eligible patients were aged ≤50 years with adequate endometrium morphology after receiving estrogens. Luteal phase support was provided with micronized vaginal P (MVP) to all women. Patients with personalized initiation of exogenous P according to the endometrial receptivity assay test, polyps, fibroids distorting the cavity, or hydrosalpinx were not included in the analysis. INTERVENTION(S): As routine practice since December 2018, patients with low serum P levels received an iLPS with a daily injection of 25 mg of subcutaneous P from the day of embryo transfer (ET) in addition to standard LPS (400 mg of MVP twice a day). MAIN OUTCOME MEASURE(S): Live birth rate. RESULT(S): The LBR was 44.9% in the iLPS cases vs. 45.0% in patients with normal serum P levels (crude odds ratio [OR], 1.0; 95% confidence interval [CI], 0.82-1.22). By regression analysis, low serum P levels did not affect the LBR after adjusting for possible confounders (age, oocyte origin, fresh vs. frozen, day of ET, embryo quality, number of embryos transferred) (adjusted OR, 0.99; 95% CI, 0.79-1.25). Similarly, no differences were observed in other pregnancy outcomes between groups. The LBR was significantly higher in the group of patients who received additional subcutaneous P (iLPS) compared with the historical group with low serum P levels and no iLPS (44.9% vs. 37.3%; OR, 1.37; 95% CI, 1.06-1.78). In the overall population, patients showing P levels of <9.2 ng/mL on the day of ET were slightly younger and had higher body mass index and lower estradiol and P levels during the proliferative phase compared with patients with P levels of ≥9.2 ng/mL. No differences were observed with regard to the time in between the last dose of MVP and the serum P determination. After a multivariable logistic regression analysis, only body mass index and estradiol levels in the proliferative phase reminded statistically significant. Significant differences in the LBR were observed between patients with serum P levels of <9.2 ng/mL without iLPS and patients with serum P levels of ≥9.2 ng/mL when using either own or donated oocytes. CONCLUSION(S): Individualized LPS for patients with low serum P levels produces LBRs similar to those of patients with adequate serum P levels.

Early detection of pregnancy after IVF and embryo transfer with hyperglycosylated HCG versus Elecsys HCG+ß assay.

RESEARCH QUESTION: Is measurement of hyperglycosylated HCG (hHCG) superior to beta-HCG (HCG+ß) for early pregnancy detection after IVF and embryo transfer? DESIGN: Blood samples were collected on day 4 (+1), 7 (+1) and 11 (+2) after embryo transfer from women aged 18-45 years undergoing first or second fresh or frozen IVF embryo transfer cycles. Biochemical pregnancy was assessed on-site by HCG determination on day 11; clinical pregnancy was assessed by ultrasound on day 21 (+4/-3). Serum hHCG (immunochemiluminometric assay) and HCG+ß (Elecsys® HCG+ß assay) concentrations were measured. Performance of hHCG and HCG+ß for predicting pregnancy was evaluated and cut-offs selected. RESULTS: In total, 155 women were enrolled and underwent IVF and embryo transfer. Area under the curve (AUC) (95% CI) on day 4 was not significantly different for hHCG (AUC 0.88; 95% CI 0.83 to 0.94) and HCG+ß (AUC 0.90; 95% CI 0.84 to 0.95), as was predictive performance on day 7 and 11, with higher AUC estimates compared with day 4. Applying cut-offs derived according to Youden's index on day 4 (hHCG, 100 pg/ml; HCG+ß, 1.30 mIU/ml), both biomarkers demonstrated high negative predictive values for ruling out pregnancy (hHCG, 83.8%; HCG+ß, 82.8%) and high positive predictive values for ruling in pregnancy (hHCG, 89.0%; HCG+ß, 84.9%) on day 21. Diagnostic performance improved from day 4 to day 11. CONCLUSIONS: Predictive performance for early pregnancy post-IVF embryo transfer of day-5 blastocysts was not significantly different for hHCG and HCG+ß; hHCG superiority over HCG+ß was not shown.

What Do We Know about Classical and Non-Classical Progesterone Receptors in the Human Female Reproductive Tract? A Review.

The progesterone hormone regulates the human menstrual cycle, pregnancy, and parturition by its action via the different progesterone receptors and signaling pathways in the female reproductive tract. Progesterone actions can be exerted through classical and non-classical receptors, or even a combination of both. The former are nuclear receptors whose activation leads to transcriptional activity regulation and thus in turn leads to slower but long-lasting responses. The latter are composed of progesterone receptors membrane components (PGRMC) and membrane progestin receptors (mPRs). These receptors rapidly activate the appropriate intracellular signal transduction pathways, and they can subsequently initiate specific cell responses or even modulate genomic cell responses. This review covers our current knowledge on the mechanisms of action and the relevance of classical and non-classical progesterone receptors in female reproductive tissues ranging from the ovary and uterus to the cervix, and it exposes their crucial role in female infertility.

Does Coenzyme Q10 Supplementation Improve Human Oocyte Quality?

Acquiring oocyte competence requires optimal mitochondrial function and adequate ATP levels. In this context, CoQ10 supplementation may improve human oocyte quality and subsequent reproductive performance given its role in ATP synthesis and mitochondrial protection from ROS oxidative damage. In infertility treatments, CoQ10 therapy can be orally supplied to promote a more favorable environment for oocyte development in vivo or by its addition to culture media in an attempt to improve its quality in vitro. Human clinical studies evaluating the impact of CoQ10 on reproductive performance are summarized in this review, although the available data do not clearly prove its ability to improve human oocyte quality. The main objective is to provide readers with a complete overview of this topic's current status as well as the keys for potential future research lines that may help to take this therapy to clinical practice. Indeed, further clinical trials are needed to confirm these results along with molecular studies to evaluate the impact of CoQ10 supplementation on oxidative stress status and mitochondrial function in human gametes.

Serum luteal phase progesterone in women undergoing frozen embryo transfer in assisted conception: a systematic review and meta-analysis.

OBJECTIVE: To investigate the association between luteal serum progesterone levels and frozen embryo transfer (FET) outcomes. DESIGN: Systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): Women undergoing FET. INTERVENTION(S): We conducted electronic searches of MEDLINE, PubMed, CINAHL, EMBASE, the Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov, and grey literature (not widely available) from inception to March 2021 to identify cohort studies in which the serum luteal progesterone level was measured around the time of FET. MAIN OUTCOME MEASURE(S): Ongoing pregnancy or live birth rate, clinical pregnancy rate, and miscarriage rate. RESULT(S): Among the studies analyzing serum progesterone level thresholds <10 ng/mL, a higher serum progesterone level was associated with increased rates of ongoing pregnancy or live birth (relative risk [RR] 1.47, 95% confidence interval [CI] 1.28 to 1.70), higher chance of clinical pregnancy (RR 1.31, 95% CI 1.16 to 1.49), and lower risk of miscarriage (RR 0.62, 95% CI 0.50 to 0.77) in cycles using exclusively vaginal progesterone and blastocyst embryos. There was uncertainty about whether progesterone thresholds ≥10 ng/mL were associated with FET outcomes in sensitivity analyses including all studies, owing to high interstudy heterogeneity and wide CIs. CONCLUSION(S): Our findings indicate that there may be a minimum clinically important luteal serum concentration of progesterone required to ensure an optimal endocrine milieu during embryo implantation and early pregnancy after FET treatment. Future clinical trials are required to assess whether administering higher-dose luteal phase support improves outcomes in women with a low serum progesterone level at the time of FET. PROSPERO NUMBER: CRD42019157071.

Mitochondrial enrichment in infertile patients: a review of different mitochondrial replacement therapies.

Poor ovarian responders exhibit a quantitative reduction in their follicular pool, and most cases are also associated with poor oocyte quality due to patient's age, which leads to impaired in vitro fertilisation outcomes. In particular, poor oocyte quality has been related to mitochondrial dysfunction and/or low mitochondrial count as these organelles are crucial in many essential oocyte processes. Therefore, mitochondrial enrichment has been proposed as a potential therapy option in infertile patients to improve oocyte quality and subsequent in vitro fertilisation outcomes. Nowadays, different options are available for mitochondrial enrichment treatments that are encompassed in two main approaches: heterologous and autologous. In the heterologous approach, mitochondria come from an external source, which is an oocyte donor. These techniques include transferring either a portion of the donor's oocyte cytoplasm to the recipient oocyte or nuclear material from the patient to the donor's oocyte. In any case, this approach entails many ethical and safety concerns that mainly arise from the uncertain degree of mitochondrial heteroplasmy deriving from it. Thus the autologous approach is considered a suitable potential tool to improve oocyte quality by overcoming the heteroplasmy issue. Autologous mitochondrial transfer, however, has not yielded as many beneficial outcomes as initially expected. Proposed mitochondrial autologous sources include immature oocytes, granulosa cells, germline stem cells, and adipose-derived stem cells. Presently, it would seem that these autologous techniques do not improve clinical outcomes in human infertile patients. However, further trials still need to be performed to confirm these results. Besides these two main categories, new strategies have arisen for oocyte rejuvenation by improving patient's own mitochondrial function and avoiding the unknown consequences of third-party genetic material. This is the case of antioxidants, which may enhance mitochondrial activity by counteracting and/or preventing oxidative stress damage. Among others, coenzyme-Q10 and melatonin have shown promising results in low-prognosis infertile patients, although further randomised clinical trials are still necessary.

Serum Progesterone Profile Across the Mid and Late Luteal Phase in Artificial Cycles Is Associated With Pregnancy Outcome.

Introduction: Recent studies have shown that low serum progesterone levels on the day of embryo transfer (ET) are associated with poorer pregnancy outcome in hormonal replacement therapy cycles. It is of interest to know if serum progesterone levels during late luteal phase (following days after ET) are also related with the chances of ongoing pregnancy. Objective: To evaluate the luteal phase endocrine profile through measurements of serum progesterone and estradiol on days ET+4, ET+7 and ET+11, to test their predictive value in relation to pregnancy outcome. Setting: Private infertility center, Valencia, Spain. Materials and Methods: Prospective cohort study performed between June 2017 and August 2018. Eligible patients were aged between 18-42 years, with a normal uterus, and being transferred 1-2 good quality blastocysts in a frozen ET cycle after an artificial endometrial preparation with estradiol valerate and vaginal micronized progesterone (400 mg/12 hours). Results: A total of 127 patients were included. Mean age = 38.0 ± 3.9 years; BMI = 23.6 ± 3.6 kg/m2; endometrial thickness = 9.1 ± 1.6mm. Overall ongoing pregnancy rate = 47.2% (95%CI:38.3-56.3). Significantly higher levels of serum progesterone were observed on ET+4 (13.6 ± 6.0 vs. 11.1 ± 4.6ng/ml, p = 0.03) and ET+11 (15.7 ± 1.2 vs. 10.3 ± 0.6ng/ml, respectively; p = 0.000) in ongoing pregnancies versus negative ß-hCG (ß-human chorionic gonadotrophin) cases. On ET+7, ongoing pregnancies also had higher serum progesterone levels (14.2 ± 0.9 vs. 11.7 ± 0.8ng/ml, but did not reach statistical significance (p = 0.07). Serum estradiol levels were not related with pregnancy outcome at any moment of the luteal phase (p > 0.05). On days ET+4, +7 and +11, the ROC analysis showed that serum progesterone levels were predictive of ongoing pregnancy, and Pearson's coefficient showed a significant association (p<0.05) of serum ß-hCG levels with serum progesterone. Conclusions: In hormonal replacement therapy cycles, serum progesterone levels across luteal phase days are associated with pregnancy outcome. Ongoing pregnancies were associated with a higher exposure to progesterone in comparison with pregnancy losses or negative ß-hCG. Therefore, serum progesterone might be playing an important role not only during implantation, but also in pregnancy maintenance. It remains unknown if the variability in serum progesterone levels among patients, after receiving the exact same progesterone dose for luteal phase support, is the cause or just a consequence of pregnancy results.

The impact of the female genital tract microbiome in women health and reproduction: a review.

PURPOSE: The aim of this review is to gather the available research focusing on female genital tract (FGT) microbiome. Research question focuses in decipher which is the role of FGT microbiota in eubiosis, assisted reproduction techniques (ARTs), and gynaecological disorders, and how microbiome could be utilised to improve reproduction outcomes and to treat fertility issues. METHODS: PubMed was searched for articles in English from January 2004 to April 2021 for "genital tract microbiota and reproduction", "endometrial microbiome", "microbiome and reproduction" and "microbiota and infertility". Manual search of the references within the resulting articles was performed. RESULTS: Current knowledge confirms predominance of Lactobacillus species, both in vagina and endometrium, whereas higher variability of species is both found in fallopian tubes and ovaries. Microbial signature linked to different disorders such endometriosis, bacterial vaginosis, and gynaecological cancers are described. Broadly, low variability of species and Lactobacillus abundance within the FGT is associated with better reproductive and ART outcomes. CONCLUSION: Further research regarding FGT microbiome configuration needs to be done in order to establish a more precise link between microbiota and eubiosis or dysbiosis. Detection of bacterial species related with poor reproductive outcomes, infertility or gynaecological diseases could shape new tools for their diagnosis and treatment, as well as resources to assess the pregnancy prognosis based on endometrial microbiota. Data available suggest future research protocols should be standardised, and it needs to include the interplay among microbiome, virome and mycobiome, and the effect of antibiotics or probiotics on the microbiome shifts.