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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?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.Overall, 1248 patients were enrolled. The AMH concentration had a strong positive correlation with oocyte yield (Spearman's rho = 0.74, P0.001). 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% (ROvarian 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.

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.Retrospective cohort study, December 1, 2018, to May 30, 2019.Private medical center.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 of9.2 ng/mL and received iLPS. Additionally, a historical group of 426 patients with serum P levels of9.2 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.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).Live birth rate.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 of9.2 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 of9.2 ng/mL without iLPS and patients with serum P levels of ≥9.2 ng/mL when using either own or donated oocytes.Individualized LPS for patients with low serum P levels produces LBRs similar to those of patients with adequate serum P levels.

Our aim was to determine prospectively whether increased body mass index (BMI) affects endometrial receptivity through displacement of the window of implantation (dWOI) using the endometrial receptivity analysis (ERA), and whether this effect is BMI-dependent. We recruited a population of 170 infertile women with a normal uterus and no clinical history of recurrent miscarriage or implantation failure. These women were divided into four groups according to BMI: normal weight (18.5-24.9 kg/m2; n = 44), overweight (25-29.9 kg/m2; n = 29), class I obese (30.0-34.9 kg/m2; n = 54), and class II and III obese (> 35 kg/m2; n = 43). We also assigned the patients to one of two larger BMI cohorts: non-obese (normal weight and overweight; n = 73) and obese (class I, II, and III obese; n = 97). We compared analytical and clinical data and dWOI in these categories, finding significant metabolic differences in glycemia, TSH, insulin, HDL cholesterol, LDL cholesterol, triglycerides, and systolic and diastolic blood pressure among the different BMI groups. One-day dWOI increased significantly with BMI, and significant differences were observed in the non-obese versus obese categories (9.7% vs 25.3 %, respectively (p = 0.02)). dWOI was most pronounced in patients with class II-III obesity. In addition, displacement was longer as BMI increased since ERA revealed a higher proportion of displacements of 1 day than of 12 h and showed they were predominantly pre-receptive. In conclusion, obesity has a negative effect on endometrial receptivity through delaying of the WOI, which increases in function of BMI as well as the metabolic disturbances of the patient.

PURPOSE: Some women undergoing stimulated cycles have elevated serum progesterone (P) on the day of ovulation trigger, but its effect on embryo quality is unclear. We analyze embryo quality among patients with high and low serum P undergoing preimplantation genetic testing for aneuploidy (PGT-A). METHODS: This retrospective study included 1597 patients divided into two groups by serum P values: < 1.5 ng/mL or ≥ 1.5 ng/mL. A gonadotrophin-releasing hormone (GnRH) antagonist protocol was established for each patient. Serum P levels were measured on the day of triggering. Propensity score matching and Poisson regression were done. Age, body mass index, and ovarian sensitivity index were also compared. RESULTS: Elevated serum P was not significantly associated with euploid embryo rate or other embryo-quality variables evaluated in our study. Age was the only variable associated with euploidy rate (per MII oocyte, P < 0.001; per biopsied embryo, P = 0.008), embryo biopsy rate (P < 0.001), absolute number of euploid embryos (P = 0.008), and top-quality embryo rate (P = 0.008). Categorical variables decreased in value for every year of increased age in patients with high serum P. CONCLUSIONS: Elevated serum P did not affect the number of euploid and good-quality embryos for transfer in GnRH antagonist intracytoplasmic sperm injection (ICSI) cycles. Contrary to the clear influence of premature P elevation on endometrial receptivity based on literature, our results may help to tip the balance towards the absence of a negative effect of P elevation on embryo competence. More studies are needed to fully understand the effect of P elevation on reproductive outcomes.

Purpose of review Management of the luteal phase (LP) in assisted reproductive cycles has aroused interest in recent years. The reason is that it seems that the individualization of LP support may be necessary, since the concept of 'one size fits all' does not apply to this treatment. Recent findings Studies carried out in hormone replacement therapy cycles (also called artificial cycles) have shown that serum levels of progesterone (P) are related to pregnancy outcomes. This represents a milestone in the management of artificial cycles (AC), because until a few years ago it was believed that serum levels did not really reflect the effectiveness of P, which is why they were neglected. However, it is not as straightforward as it seems, because the interpretation of serum progesterone values will depend on the type of progesterone used and its route of administration. Likewise, the findings observed in AC are not applicable to what occurs in a fresh transfer cycle after ovarian stimulation or an embryo transfer in the context of a natural cycle. Summary In this manuscript, we will summarize the current situation in LP management.

STUDY QUESTION Is there a serum progesterone (P) threshold on the day of embryo transfer (ET) in artificial endometrium preparation cycles below which the chances of ongoing pregnancy are reduced? SUMMARY ANSWER Serum P levels WHAT IS KNOWN ALREADY We previously found that serum P levels STUDY DESIGN, SIZE, DURATION This prospective cohort study was performed between September 2017 and November 2018 and enrolled 1205 patients scheduled for ET after an artificial endometrial preparation cycle with estradiol valerate and micronized vaginal P (MVP, 400 mg twice daily). PARTICIPANTS/MATERIALS, SETTING, METHODS Patients ≤50 years old with a triple-layer endometrium ≥6.5 mm underwent transfer of one or two blastocysts. A total of 1150 patients treated with own oocytes without preimplantation genetic testing for aneuploidies (PGT-A) (n = 184), own oocytes with PGT-A (n = 308) or donated oocytes (n = 658) were analyzed. The primary endpoint was the OPR beyond pregnancy week 12 based on serum P levels measured immediately before ET. MAIN RESULTS AND THE ROLE OF CHANCE Women with serum P levels LIMITATIONS, REASONS FOR CAUTION Only women with MVP were included. Extrapolation to other P administration forms needs to be validated. WIDER IMPLICATIONS OF THE FINDINGS This study identified the threshold of serum P as 8.8 ng/ml on the day of ET for artificial endometrial preparation cycles necessary to optimize outcomes, in cycles with own or donated oocytes. One-third of patients receiving MVP show inadequate levels of serum P that, in turn, impact the success of the ART cycle. Monitoring P levels in the mid-luteal phase is recommended when using MVP to adjust the doses according to the needs of the patient. STUDY FUNDING/COMPETING INTEREST(S) None. TRIAL REGISTRATION NUMBER NCT03272412.

Progesterone is the main hormone in the luteal phase. It plays a key role in preparing the uterus for a possible pregnancy, and in maintaining it after it has occurred. In assisted reproduction treatments, there is usually a luteal phase deficiency, so it is necessary to supplement this critical phase to obtain the best results, not only of implantation but also of ongoing pregnancy. Among all the available options, exogenously administered progestogens are the most used, as they have proven their efficacy and safety. This review will address the most relevant aspects of luteal phase support with progesterone in the different scenarios an embryo transfer can be performed, such as the stimulated cycle, the artificial cycle, or the natural cycle. Although there is no evidence of the perfect protocol for all patients, recent studies point to the need of individualizing luteal phase support according to the needs of each patient.

Does serum progesterone concentration vary on the day of embryo transfer according to female body mass index (BMI)?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/mMean 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 (P0.001). A trend was observed towards impaired reproductive results in obese patients with suboptimal progesterone concentrations, absent when concentrations were optimal.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.

Ovarian aging leads to a decrease in the quantity and quality of oocytes. Aged oocytes have significantly reduced amounts of mitochondria, the energy factories of cells, leading to lower fertilization rates and poor embryonic development. Various techniques have tried to use heterologous or autologous sources of mitochondria to reestablish oocyte health by providing more energy. However, heterologous sources are no longer used owing to the known risk of heteroplasmy. Although autologous methods have recently been tested in humans, they have not shown a clear improvement in embryo quality. In this review, we describe the techniques that have been tested in recent years to provide a state of the art on oocyte rejuvenation through extra injection of mitochondria.

At the end of December 2017, some colleagues and I reported results from a prospective cohort study (N=211) into the relationship between serum progesterone (P) and endometrial volume on the day of embryo transfer (ET) and ongoing pregnancy rates (OPR) in artificial endometrium preparation cycles.1

Research Question Is measurement of hyperglycosylated human chorionic gonadotropic (hhCG) superior to beta-HCG (HCG+β) for early pregnancy detection after in vitro fertilization (IVF)-embryo transfer (ET)? Design Blood samples for the purpose of this study were collected on Day 4 (+1), 7 (+1) and 11 (+2) after ET from women aged 18–45 years undergoing first/second fresh/frozen IVF-ET 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; Quest Diagnostics) and HCG+β (Elecsys® HCG+β assay, Roche Diagnostics) levels were measured. Performance of hhCG and HCG+β for predicting pregnancy was evaluated and cut-offs selected. Results In total, 155 women were enrolled and received IVF-ET. Area under the curve (AUC) (95% confidence interval) at Day 4 was not significantly different for hhCG (0.88; 0.83–0.94) and HCG+β (0.90; 0.84–0.95), as was predictive performance on Day 7 and 11, with higher AUC estimates versus Day 4. Applying cut-offs derived according to Youden's index at Day 4 (hhCG, 100 pg/ml; HCG+β, 1.30 mIU/ml), both biomarkers demonstrated high negative predictive values for ruling out pregnancy (hhCG, 83.8%; HCG+β, 82.8%) and high positive predictive values for ruling in pregnancy (hhCG, 89.0%; HCG+β, 84.9%) at Day 21. Diagnostic performance improved from Day 4 through 11. Conclusions Predictive performance for early pregnancy post-IVF-ET of Day 5 blastocysts was not significantly different for hhCG and HCG+β; hhCG superiority over HCG+β was not shown.

STUDY QUESTION Is there a relationship between serum and endometrial progesterone (P4) levels, including P4 and metabolites (oestrone, oestradiol and 17α-hydroxyprogesterone), and endometrial receptivity? SUMMARY ANSWER Serum P4 levels were not correlated with endometrial P4, nor associated with endometrial receptivity as determined by the ERA® test; however, endometrial P4 and 17α-hydroxyprogesterone levels were positively correlated and related to endometrial receptivity by ERA. WHAT IS KNOWN ALREADY Acquisition of endometrial receptivity is governed by P4, which induces secretory transformation. A close relationship between serum P4 and pregnancy outcome is reported for hormone replacement therapy (HRT) cycles. However, the relationship between serum and uterine P4 levels has not been described, and it is unknown whether uterine receptivity depends more on serum or uterine P4 levels. STUDY DESIGN, SIZE, DURATION A prospective cohort study was performed during March 2018–2019 in 85 IVF patients undergoing an evaluation-only HRT cycle with oestradiol valerate (6 mg/day) and micronised vaginal progesterone (400 mg/12 h). PARTICIPANTS/MATERIALS, SETTING, METHODS Patients were under 50 years of age, had undergone at least one failed IVF cycle, had no uterine pathology, and had adequate endometrial thickness (> 6.5 mm). The study was conducted at IVI Valencia and IVI Foundation. An endometrial biopsy and a blood sample were collected after 5 days of P4 vaginal treatment. Measures included serum P4 levels, ERA®-based evaluation of endometrial receptivity, and endometrial P4 levels along with metabolites (oestrone, oestradiol and 17α-hydroxyprogesterone) measured by ultra-performance liquid chromatography–tandem mass spectrometry. MAIN RESULTS AND THE ROLE OF CHANCE Seventy-nine women were included (mean age: 39.9 ± 4.6, BMI: 24.2 ± 3.9 kg/m2, endometrial thickness: 8.2 ± 1.4 mm). The percentage of endometria indicated as receptive by ERA® was 40.5%. When comparing receptive versus non-receptive groups, no differences were observed in baseline characteristics nor in steroid hormones levels in serum or endometrium. No association between serum P4 and endometrial steroid levels or ERA result was found (P LIMITATIONS, REASONS FOR CAUTION This study did not analyse pregnancy outcomes. Further, the findings can only be extrapolated to HRT cycles with micronised vaginal progesterone for luteal phase support. WIDER IMPLICATIONS OF THE FINDINGS Our findings suggest that the combined benefits of different routes of progesterone administration for luteal phase support could be leveraged to ensure an adequate concentration of progesterone both in the uterus and in the bloodstream. Further studies will confirm whether this method can optimise both endometrial receptivity and live birth rate. Additionally, targeted treatment to increase P4 endometrial levels may normalise the timing of the window of implantation without needing to modify the progesterone administration day. STUDY FUNDING/COMPETING INTEREST(S) This research was supported by the IVI-RMA Valencia (1706-VLC-051-EL) and Consellería d’Educació, Investigació, Cultura, i esport Generalitat Valenciana (Valencian Government, Spain, GV/2018//151). Almudena Devesa-Peiro (FPU/15/01398) and Cristina Rodriguez-Varela (FPU18/01657) were supported by the FPU program fellowship from the Ministry of Science, Innovation and Universities (Spanish Government). P.D.-G. is co-inventor on the ERA patent, with non-economic benefits. The other authors have no competing interests. TRIAL REGISTRATION NUMBER NCT03456375.

To investigate the association between luteal serum progesterone levels and frozen embryo transfer (FET) outcomes.Systematic review and meta-analysis.Not applicable.Women undergoing FET.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.Ongoing pregnancy or live birth rate, clinical pregnancy rate, and miscarriage rate.Among the studies analyzing serum progesterone level thresholds10 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.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.CRD42019157071.

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.

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.

Our aim was to determine prospectively whether increased body mass index (BMI) affects endometrial receptivity through displacement of the window of implantation (dWOI) using the endometrial receptivity analysis (ERA), and whether this effect is BMI-dependent. We recruited a population of 170 infertile women with a normal uterus and no clinical history of recurrent miscarriage or implantation failure. These women were divided into four groups according to BMI: normal weight (18.5-24.9 kg/m

El soporte de fase lútea en tratamientos de reproduccion asistida ha incitado un interés creciente en los últimos años, puesto que se ha observado que existe una correlación entre los niveles de P en sangre y las tasas de éxito de embarazo, y ello ofrece la posibilidad de realizar un ajuste en la dosis, la ruta o el tipo de progesterona administrada con el fin de optimizar los resultados. El objetivo es ofrecer un soporte adecuado que permita favorecer la implantacion embrionaria y, una vez acontecida esta, prevenir posibles pérdidas gestacionales y partos prematuros. En este capítulo se hará una revisión de la evidencia existente hasta la fecha sobre el impacto de la progesterona sérica en las tasas de embarazo, qué perfil de pacientes tiene mayor predisposición a presentar una progesterona baja el día de la transferencia y cómo llevar a cabo un tratamiento para asegurar un correcto soporte de fase lútea.

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.

Objective To assess the mitochondrial DNA (mtDNA) load and variation in human oocytes and during preimplantation embryo development using specimens donated for research. Design Prospective cohort study. Setting Not applicable. Patients A total of 50 in vitro fertilization patients and 11 oocyte donors whose specimens were obtained between July 2017 and July 2018. Interventions None. Main Outcome Measures All specimens were separately collected. Quantitative polymerase chain reaction was performed with SurePlex DNA Amplification System (Illumina). Primers for the adenosine triphosphate 8 mitochondrial gene and the β-actin were used. Data were statistically analyzed by analysis of variance with the Scheffe multiple pairwise comparison for categorical variables and by linear regression for numerical variables. Results Human metaphase II (MII) oocytes had significantly more total mtDNA copy number than day 3 embryos, and day 3 embryos had more total and per-cell mtDNA copy number than aneuploid blastocysts. There was a significant decrease in mtDNA content associated with failed-fertilized oocytes compared to noninseminated metaphase II oocytes. Conclusions During preimplantation development, before implantation, human embryos undergo a significant decrease in total mtDNA content and no increase in mtDNA content at the blastocyst stage. Oocytes need to carry a correct threshold of mitochondrial load in the oocyte in order to successfully fertilize. An active degradation of mtDNA before implantation occurs after fertilization takes place. These findings could be used to improve knowledge about the best embryo culture conditions and would serve as a basis for further studies addressing again the use of mtDNA content as an embryo viability marker.

Since the first in vitro fertilization (IVF) birth in 1978, assisted reproductive techniques (ART) have evolved, and the use of natural cycles was very soon replaced by ovarian stimulation protocols to optimize the results of the technique. The main goal of controlled ovarian stimulation (COS) is to obtain a large number of mature oocytes that can be fertilized resulting in a cohort of embryos. This strategy has substantially increased pregnancy rates in patients because more oocytes are obtained per cycle and, presumably, a greater embryo selection for transfer becomes possible [1].

Progesterone elevation during the late follicular phase of ovarian stimulation for in vitro fertilization negatively impacts the assisted reproductive technology-outcome. The evidence available supports an advanced endometrial maturation and a direct negative effect on its receptivity. On the other hand, some retrospective analysis suggests an impairment of oocyte and embryo quality. Recent publications confirm that enhanced follicle-stimulating hormone-stimulation towards the end of the follicular phase of ovarian stimulation is the main course of progesterone elevation. A key element in preventing this event is the individualization of ovarian stimulation according to the patient's ovarian reserve and the adaption of the stimulation dosage during late follicular phase according to the patient's response. Additional measures as corticosteroid administration, avoidance of prolonged stimulation and cycle segmentation with freeze-all-policy can be discussed.

Introduction This study sought to compare the ovarian response and follicular dynamics after stimulation with HP-hMG vs. rFSH + rLH in ovulation induction treatment. We hypothesized that the administration of 75 IU of HP-hMG should be similar to 75 IU of rFSH + 75 IU of rLH in terms of ovarian response. Material and method Prospective, randomized, open-label study was conducted in the Instituto Valenciano de Infertilidad (IVI). It included 75 patients 2 ) of 75 pg/mL between days 1 and 6 of stimulation. Results No differences were observed in terms of serum E 2 increase, follicles recruited on day 6, serum E 2 the day of hCG administration and days of stimulation. Rates of cancellation, pregnancy, pregnancy loss and clinical pregnancy between the two groups were similar. Although no statistically significant differences in the distribution of mature, medium-sized and small follicles were observed on the day of hCG administration, the number of medium-sized follicles tended to be lower in the group receiving HP-hMG. Discussion Stimulation with rFSH + rLH or HP-hMG offers similar results in terms of ovarian response, demonstrating that bioactivity is comparable between the two treatments when administered in the same ratio. The additional advantage of HP-hMG is the lower proportion of medium-sized follicles, which could be responsible for an increased risk of OHSS and multiple gestations. Administration of HP-hMG can be a valid and safe option for the induction of ovulation in IUI.

Without any doubt the regimen used to mature multiple capable oocytes for IVF impacts IVF outcomes. Studies have indicated that the inclusion of LH activity, adjuvant agents such as growth hormone (GH), and regimens providing for simultaneous action of both LH and FSH during final oocyte maturation may have beneficial effects on IVF outcomes. Because of the difficulty in improving IVF outcomes in poor responders, the studies on GH are of particular interest. As pointed out in this review, the apparent beneficial effects of GH on oocyte competence may also apply to older women or to normal responders with reduced embryo quality. A much more difficult question is whether and how much ovarian stimulation impacts on oocyte competence. Paradoxically it seems that there are not demonstrated differences between the stimulated and the natural unstimulated cycle, whereas studies in laboratory animals and IVF patients have shown deleterious effects of higher compared with lower doses of gonadotropins. Recent studies suggest that the use of high doses of gonadotropins as an independent factor correlates negatively with the probability of live birth, whereas a high ovarian response per se is associated with better cumulative pregnancy rates, owing to the availability of more euploid and good-quality embryos. Although adjunctive use of androgens has not been discussed here, it is briefly covered in the first review of this series.

Introduction Kisspeptin hormone has been recently suggested as a new candidate drug to indirectly stimulate secretion of gonadotropins providing a more physiological approach to the ovarian function, due to concerns about the use of gonadotropins such as the risk of ovarian hyperstimulation syndrome (OHSS). This review describes and compares the results of those clinical trials carried out hitherto with exogenous administration of kisspeptin on humans, with special interest on those focused on healthy women. In addition, the potential use of this hormone on programming and inducing ovulation as an alternative for choriogonadotropin (CG) and GnRH agonists in controlled ovarian stimulation (COS) is also addressed. Material and methods MEDLINE/Pubmed (US National Library of Medicine) database was searched for articles published between 2000 and 2014. All searches included the terms ‘kisspeptin’, ‘ovarian stimulation’ and ‘infertility’. Special interest was given to clinical trials. Results Administration of kisspeptin seems effective in activating the LH surge in women. All trials reported high increases of LH above baseline levels in the preovulatory phase of the cycle. Recent results indicate that a single subcutaneous injection of kisspeptin-54 is enough to induce egg maturation. This strategy might offer the advantage of avoiding OHSS and without the necessity of following a freeze-all strategy as pregnancy rates are maintained after its use. Furthermore, clinical trials show that administration of this hormone is not harmful for women and does not affect their reproductive physiology. Discussion If kisspeptin is able to offer an acceptable ratio of metaphase II oocytes per follicle aspirated with no risk of OHSS and without affecting pregnancy rates in fresh cycles it would be definitely a good option for triggering. Before implementing its routine use, well-designed studies should be carried out in the human model in order to compare IVF results between the different types of triggering proposed to date.

Objective To study if autologous mitochondrial transfer (AUGMENT) improves outcome in patients with previously failed in vitro fertilization (IVF). Design Randomized, controlled, triple-blind, experimental study. Setting Private infertility center, Valencian Institute of Infertility (IVI-RMA), Valencia, Spain. Patient(s) Infertile women ≤42 years of age, body mass index 5 million/mL motile sperm, at least one previous IVF with at least five metaphase oocytes (MIIs) collected, and low embryo quality. Interventions(s) An ovarian cortex biopsy was performed to isolate egg precursor cells to obtain their mitochondria. Sibling MIIs were randomly allocated to AUGMENT (experimental) or intracytoplasmic sperm injection (Control). In AUGMENT, mitochondrial suspension was injected along with the sperm. Viable blastocysts from both groups were biopsied for preimplantation genetic testing for aneuploidy. Main Outcome Measure(s) Pregnancy, embryo quality. Result(s) An interim analysis was conducted. The patients’ mean age was 36.3 ± 3.6 years, and they had an average of 2.5 ± 1.5 previous IVF cycles. Two of the 59 enrolled patients spontaneously conceived (one miscarried). Fifty-seven patients had ovarian biopsies and underwent stimulation. Oocyte retrieval was performed in 56 patients (premature ovulation; n = 1). A total of 253 MIIs were inseminated in AUGMENT and 250 in Control; fertilization rates were 62.7 ± 30.0% and 68.7 ± 29.1%, respectively. Statistical differences were observed in day 5 blastocyst formation rates (23.3 ± 32.0% vs. 41.1 ± 36.9%). Neither the euploid rate per biopsied blastocyst (43.8 ± 41.7% vs. 63.8 ± 44.1%) nor the euploid rate per MII (9.8 ± 20.5% vs. 11.9 ± 16.1%) between AUGMENT and Control achieved statistical significance. Moreover, no differences were seen regarding mitochondrial DNA content and relevant morphokinetic variables. Thirty patients were able to undergo embryo transfer. Cumulative live birth rates per transferred embryo were 41.6% in AUGMENT and 41.2% in Control. Conclusion(s) AUGMENT does not seem to improve prognosis in this population. Therefore, the study has been discontinued. Clinical Trial Registration Number: NCT02586298 .

Research question Is minimal ovarian stimulation (MOS) as effective as conventional ovarian stimulation (COS) in ovarian response and embryo quality in the same 46 poor-responder patients according to the Bologna criteria? Design An intra-patient comparison of patients undergoing both protocols. Ovaries were stimulated with either a gonadotrophin-releasing hormone antagonist protocol and a combination of recombinant FSH and highly purified human menotrophin (HP-HMG) daily (COS), or with the use of clomiphene citrate 50 mg daily and 150 IU of HP-HMG or recombinant FSH every other day from simulation day 4 (MOS). Results After MOS, significantly more good-quality embryos (1.0 ± 1.2 versus 0.3 ± 0.6) (P = 0.002), oocytes (3.2 ± 1.9 versus 2.0 ± 1.8) (P = 0.002), and mature (metaphase II) oocytes (2.6 ± 1.7 versus 1.6 ± 1.7) (P = 0.001) were obtained. In COS cycles, a significantly higher total gonadotrophin dose was needed per good-quality embryo (+2194 IU; 95% CI 618 to 3170). Conclusions In poor responder patients, MOS is a good alternative when COS has failed, or even as a first-line treatment. It offered a significantly greater number of good-quality embryos as well as a higher number of oocytes, using significantly lower doses of gonadotrophins per oocyte and embryo obtained.

Is there a relationship between serum progesterone (P) and endometrial volume on the day of embryo transfer (ET) with ongoing pregnancy rate (OPR) in artificial endometrium preparation cycles?Patients with serum P9.2 ng/ml on the day of ET had a significantly lower OPR but endometrial volume was not related with OPR.A window of optimal serum P levels during the embryo implantation period has been described in artificial endometrium preparation cycles. A very low endometrial volume is related to poor reproductive outcome.Prospective cohort study with 244 patients who underwent ET in an oocyte donation cycle after an artificial endometrial preparation cycle with estradiol valerate and vaginal micronized progesterone (400 mg/12 h). The study period went from 22 February 2016 to 25 October 2016 (8 months). Sample size was calculated to detect a 20% difference in OPR (35-55%) between two groups according to serum P levels in a two-sided test (80% statistical power, 95% confidence interval (CI)).Patients undergoing their first/second oocyte donation cycle, aged50, BMI30 kg/m2, triple layer endometrium6.5 mm and 1-2 good quality transferred blastocysts. A private infertility centre. Serum P determination and 3D ultrasound of uterine cavity were performed on the day of ET. Endometrial volume measurements were taken using a virtual organ computer-aided analysis (VOCAL™) system. The primary endpoint was OPR beyond pregnancy week 12.About 211 of the 244 recruited patients fulfilled all the inclusion/exclusion criteria. Mean serum P on the day of embryo transfer was 12.7 ± 5.4 ng/ml (Centiles 25, 9.2; 50, 11.8; 75,15.8). OPRs according to serum P quartiles were: Q1: 32.7%; Q2: 49.1%; Q3: 58.5%; Q4: 50.9%. The OPR of Q1 was significantly lower than Q2-Q4: 32.7% versus 52.8%; P = 0.016; RR (95% CI): 0.62 (0.41-0.94). The mean endometrial volume was 3.4 ± 1.9 ml. Serum P on the day of ET did not correlate with endometrial volume. A logistic regression analysis, adjusted for all the potential confounders, showed that OPR significantly lowered between women with serum P9.2 ng/ml versus ≥9.2 ng/ml (OR: 0.297; 95%CI: 0.113-0.779); P = 0.013. The ROC curve showed a significant predictive value of serum P levels on the day of ET for OPR, with an AUC (95%CI) = 0.59 (0.51-0.67).Only the women with normal uterine cavity, appropriate endometrial thickness and good quality blastocysts transfer were included. Extrapolation to an unselected population or to other routes and/or doses of administering P needs to be validated. The role of endometrial volume could not be fully defined as very few patients presented a very low volume.The present study suggests a minimum threshold of serum P values on the day of ET that needs to be reached in artificial endometrial preparation cycles to optimize outcome. No upper threshold could be defined.None.NCT02696694.