Pretreatment with luteal estradiol for programming antagonist cycles compared to no pretreatment in advanced age women stimulated with corifollitropin alfa: a non-inferiority randomized controlled trial.

STUDY QUESTION: Does luteal estradiol (E2) pretreatment give a similar number of retrieved oocytes compared to no-pretreatment in advanced-aged women stimulated with corifollitropin alfa in an antagonist protocol? SUMMARY ANSWER: Programming antagonist cycles with luteal E2 gave similar number of retrieved oocytes compared to no-pretreatment in women aged 38-42 years. WHAT IS KNOWN ALREADY: Programming antagonist cycles with luteal E2 pretreatment is a valuable tool to organize the IVF procedure better and is safe without any known impact on cycle outcome. However, variable effects were observed on the number of retrieved oocytes depending on the treated population. In advanced-age women, recruitable follicles tend to decrease in number and to be more heterogeneous in size but it remains unclear if estradiol pretreatment could change the oocyte yield through its negative feed-back effect on FSH intercycle rise. STUDY DESIGN, SIZE, DURATION: This non-blinded randomized controlled non-inferiority trial was conducted between 2016 and 2022 with centrally computerized randomization and concealed allocation. Participants were 324 women aged 38-42 years undergoing IVF treatment. The primary endpoint was the total number of retrieved oocytes. Statistical analysis was performed with one-sided alpha risk of 2.5% and 95% confidence interval (CI) with the non-inferiority of E2 pretreatment proved by a P value <0.025 and a lower delta margin of the CI within two oocytes compared to no pretreatment. Secondary endpoints were duration and total dosage of recombinant FSH, cancellation rate, percentage of oocyte pick-up (OPU) on working days, total number of metaphase II oocytes and obtained embryos, fresh transfer live birth rate, and cumulative live birth rate. PARTICIPANTS/MATERIALS, SETTING, METHODS: This multicentric study enrolled women with regular cycles, weight >50 kg and body mass index <32, IVF cycle 1-2. According to randomization, micronized estradiol 2 mg twice a day was started on days 20-24 and continued until Wednesday beyond the onset of menses followed by administration of corifollitropin alfa on Friday, i.e. stimulation (S)1 or from D1-3 of a natural cycle in unpretreated patients. GnRH antagonist was started at S6 and additional FSH at S8. MAIN RESULTS AND THE ROLE OF CHANCE: Basal characteristics were similar in patients randomized in E2 pretreated (n = 164) and non-pretreated (n = 160) groups (intended to treat (ITT) population). A total of 291 patients started treatment (per protocol (PP) population), 147 in E2 pretreated group with a mean number [SD] of pre-treatment days 9.8 [2.6] and 144 in the non-pretreated group. Despite advanced age, oocyte yields ranged from 0 to 29 in both groups with a median number of 6 retrieved oocytes in accordance with a mean anti-Müllerian hormone (AMH) level above 1.2 ng/ml. We demonstrated the non-inferiority of E2 pretreatment with a mean difference of -0.1 oocyte 95% CI [-1.5; 1.3] P = 0.004 in the PP population and a mean difference of -0.44 oocyte [-1.84; 0.97] P = 0.014 in the ITT population. Oocyte retrieval was more often on working days in E2 pretreated patients (91.9 versus 74.2%, P < 0.001). In patients reaching OPU, the duration of stimulation was statistically significantly longer (11.7 [1.7] versus 10.8 [1.8] days, P < 0.001) and the extra FSH dosage in addition to corifollitropin alfa was statistically significantly higher (1040 [548] versus 778 [504] IU, P < 0.001) in E2 pretreated than non-pretreated patients. We did not observe any significant differences in the number of retrieved oocytes (8.4 [6.1] versus 9.1 [6.0]), in the number of Metaphase 2 oocytes (7 [5.5] versus 7.3 [5.2]) nor in the number of obtained embryos (5 [4.6] versus 5.2 [4.2]) in E2 pretreated patients compared to non-pretreated patients. The live birth rate after fresh transfer (16.2% versus 18.5%, respectively), and the cumulative live birth rate per patient (17.7% versus 22.9%, respectively) were similar in both groups. Among the PP population, 31.6% of patients fulfilled the criteria for group 4 of Poseïdon classification (AMH <1.2 ng/ml and/or antral follicle count <5). In this sub-group of patients, we observed in contrast a statistically higher number of retrieved oocytes in E2 pretreated patients compared to non-pretreated (5.1 [3.8] versus 3.4 [2.7], respectively, the mean difference of +1.7 oocyte [0.2; 3.2] P = 0.022) but without significant difference in the cumulative live birth rate per patient (15.7% versus 7.3%, respectively). LIMITATIONS, REASONS FOR CAUTION: Our stimulated women older than 38 years obtained a wide range of collected oocytes suggesting very different stages of ovarian aging in both groups. E2 pretreatment is more likely to increase oocyte yield at the stage of ovarian aging characterized by asynchrony of a reduced follicular cohort. Another limitation is the sample size in sub-group analysis of patients with AMH <1.2 ng/ml. Finally, the absence of placebo for pretreatment could also introduce possible bias. WIDER IMPLICATIONS OF THE FINDINGS: Programming antagonist cycles with luteal E2 pretreatment seems a useful tool in advanced age women to better schedule oocyte retrievals on working days. However, the potential benefit of the number of collected oocytes remains to be demonstrated in a larger population displaying the characteristics of decreased ovarian reserve encountered in Poseïdon classification. STUDY FUNDING/COMPETING INTEREST(S): Research grant from (MSD) Organon, France. I.C., S.D., B.B., X.M., S.G., and C.J. have no conflict of interest with this study. I.C.D. declares fees as speaker from Merck KGaA, Gedeon Richter, MSD (Organon, France), Ferring, Theramex, and IBSA and participation on advisory board from Merck KGaA. I.C.D. also declares consulting fees, and travel and meeting support from Merck KGaA. N.M. declares grants paid to their institution from MSD (Organon, France); consulting fees from MSD (Organon, France), Ferring, and Merck KGaA; honoraria from Merck KGaA, General Electrics, Genevrier (IBSA Pharma), and Theramex; support for travel and meetings from Theramex, Merck KGaG, and Gedeon Richter; and equipment paid to their institution from Goodlife Pharma. N.C. declares grants from IBSA Pharma, Merck KGaA, Ferring, and Gedeon Richter; support for travel and meetings from IBSA Pharma, Merck KGaG, MSD (Organon, France), Gedeon Richter, and Theramex; and participation on advisory board from Merck KGaA. A.G.L. declares fees as speaker from Merck KGaA, Gedeon Richter, MSD (Organon, France), Ferring, Theramex, and IBSA. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT02884245. TRIAL REGISTRATION DATE: 29 August 2016. DATE OF FIRST PATIENT'S ENROLMENT: 4 November 2016.

Genetic landscape of a large cohort of Primary Ovarian Insufficiency: New genes and pathways and implications for personalized medicine.

BACKGROUND: Primary Ovarian Insufficiency (POI), a public health problem, affects 1-3.7% of women under 40 yielding infertility and a shorter lifespan. Most causes are unknown. Recently, genetic causes were identified, mostly in single families. We studied an unprecedented large cohort of POI to unravel its molecular pathophysiology. METHODS: 375 patients with 70 families were studied using targeted (88 genes) or whole exome sequencing with pathogenic/likely-pathogenic variant selection. Mitomycin-induced chromosome breakages were studied in patients' lymphocytes if necessary. FINDINGS: A high-yield of 29.3% supports a clinical genetic diagnosis of POI. In addition, we found strong evidence of pathogenicity for nine genes not previously related to a Mendelian phenotype or POI: ELAVL2, NLRP11, CENPE, SPATA33, CCDC150, CCDC185, including DNA repair genes: C17orf53(HROB), HELQ, SWI5 yielding high chromosomal fragility. We confirmed the causal role of BRCA2, FANCM, BNC1, ERCC6, MSH4, BMPR1A, BMPR1B, BMPR2, ESR2, CAV1, SPIDR, RCBTB1 and ATG7 previously reported in isolated patients/families. In 8.5% of cases, POI is the only symptom of a multi-organ genetic disease. New pathways were identified: NF-kB, post-translational regulation, and mitophagy (mitochondrial autophagy), providing future therapeutic targets. Three new genes have been shown to affect the age of natural menopause supporting a genetic link. INTERPRETATION: We have developed high-performance genetic diagnostic of POI, dissecting the molecular pathogenesis of POI and enabling personalized medicine to i) prevent/cure comorbidities for tumour/cancer susceptibility genes that could affect life-expectancy (37.4% of cases), or for genetically-revealed syndromic POI (8.5% of cases), ii) predict residual ovarian reserve (60.5% of cases). Genetic diagnosis could help to identify patients who may benefit from the promising in vitro activation-IVA technique in the near future, greatly improving its success in treating infertility. FUNDING: Université Paris Saclay, Agence Nationale de Biomédecine.

Low Luteal Serum Progesterone Levels Are Associated With Lower Ongoing Pregnancy and Live Birth Rates in ART: Systematic Review and Meta-Analyses.

Progesterone plays a key role in implantation. Several studies reported that lower luteal progesterone levels might be related to decreased chances of pregnancy. This systematic review was conducted using appropriate key words, on MEDLINE, EMBASE, and the Cochrane Library, from 1990 up to March 2021 to assess if luteal serum progesterone levels are associated with ongoing pregnancy (OP) and live birth (LB) rates (primary outcomes) and miscarriage rate (secondary outcome), according to the number of corpora lutea (CLs). Overall 2,632 non-duplicate records were identified, of which 32 relevant studies were available for quantitative analysis. In artificial cycles with no CL, OP and LB rates were significantly decreased when the luteal progesterone level falls below a certain threshold (risk ratio [RR] 0.72; 95% confidence interval [CI] 0.62-0.84 and 0.73; 95% CI 0.59-0.90, respectively), while the miscarriage rate was increased (RR 1.48; 95% CI 1.17-1.86). In stimulated cycles with several CLs, the mean luteal progesterone level in the no OP and no LB groups was significantly lower than in the OP and LB groups [difference in means 68.8 (95% CI 45.6-92.0) and 272.4 (95% CI 10.8-533.9), ng/ml, respectively]. Monitoring luteal serum progesterone levels could help in individualizing progesterone administration to enhance OP and LB rates, especially in cycles without corpus luteum. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=139019, identifier 139019.

Is letrozole during ovarian stimulation useful in breast cancer patients undergoing fertility preservation to reduce early luteal progesterone levels following GnRH-agonist trigger?

BACKGROUND: In absence of contraindication, breast cancer patients of reproductive age can undergo fertility preservation with controlled ovarian stimulation for oocyte/embryo cryopreservation before the administration of potentially gonadotoxic treatments. High hormonal levels induced by ovarian stimulation might have an adverse impact on hormone-positive breast cancer. Whether letrozole supplementation during ovarian stimulation (COSTLES) reduces serum progesterone levels after GnRHa trigger remains unknown. We aimed to determine whether COSTLES might be useful for breast cancer patients undergoing fertility preservation to reduce early luteal progesterone levels following GnRH-agonist (GnRHa)trigger. METHODS: All women who underwent COS with GnRH antagonist protocol with GnRHa trigger were included. Serum progesterone level measured 12 h after GnRHa trigger was compared between patients undergoing COS with letrozole supplementation (COSTLES group) and patients undergoing COS without letrozole (Control group) for fertility preservation purposes. RESULTS: A total of 246 patients were included, of which 84 patients (34.1%) in the COSTLES group and 162 patients (65.6%) in the Control group. All patients in the COSTLES group were BC patients (n = 84, 100%), while the Control group included 77 BC patients (47.5%). Patients in the two groups were comparable. The mean number of oocytes recovered and vitrified at metaphase 2 stage did not significantly differ between the two groups. Serum progesterone levels on the day after GnRHa trigger were significantly lower in the COSTLES group (8.6 ± 0.7 vs. 10.5 ± 0.5 ng/mL, respectively, p < 0.03), as well as serum E2 levels (650.3 ± 57.7 vs. 2451.4.0 ± 144.0 pg/mL, respectively, p < 0.01). However, the GnRHa-induced LH surge was significantly higher in in the COSTLES group (71.9 ± 4.6 vs. 51.2 ± 2.6 UI/L, respectively, p < 0.01). CONCLUSIONS: Our results show that COSTLES for fertility preservation in breast cancer patients using GnRHa trigger reduces serum progesterone levels compared to ovarian stimulation without letrozole. These findings encourage the use of COSTLES in this context to decrease the potential deleterious effect of elevated hormonal levels on hormone-positive breast cancer.

Influence of breast cancer prognostic factors on oocyte in vitro maturation outcomes performed for urgent fertility preservation.

STUDY QUESTION: Do breast cancer (BC) characteristics influence IVM of oocytes outcomes in patients undergoing fertility preservation (FP)? SUMMARY ANSWER: Scarff-Bloom-Richardson (SBR) III grade, triple-negative BC and HER2 overexpression are independent predictors of fewer oocytes or poor IVM outcomes in young women seeking FP. WHAT IS KNOWN ALREADY: SBR grade, triple-negative status and overexpression of HER2, as well as a high Ki67 proliferation index are all established prognostic factors for BC, influencing patients' therapeutic management. Yet there are also concerns about the potential impact of cancer status on ovarian reserve and function. Previous studies analysing the results of ovarian stimulation in BC patients have shown conflicting findings. Nevertheless, there is no data on the potential impact of BC status and prognostic factors on IVM outcome in women undergoing urgent FP. STUDY DESIGN, SIZE, DURATION: We studied 321 BC patients, 18 to 41 years of age, who were also candidates for oocyte cryopreservation following IVM. The number of oocytes recovered, maturation rate and total number of cryopreserved oocytes were assessed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Ovarian reserve markers (antral follicle count [AFC] and serum anti-Müllerian hormone [AMH] levels) and IVM outcomes were compared according to BC characteristics (Ki67 proliferation index >20%, progesterone and/or oestrogen receptors expression, HER2 status and SBR grade). Logistic regression analysis was then performed to determine the variables that could be independently associated with poor IVM outcomes, such as oocyte retrieval rate <50%, oocyte maturation rate <60% and total number of frozen oocytes <5. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, the mean age of the population was 32.3 ± 4.1 years. Mean AFC and serum AMH levels were 22.8 ± 13.9 follicles and 3.8 ± 3.1 ng/ml, respectively. AMH levels were significantly lower in case of triple-negative BC when compared with ER/PR/HER2 status positive cancer (3.1 ± 2.6 ng/ml vs 4.0 ± 3.3 ng/ml, P = 0.02). The mean number of recovered oocytes was 10.2 ± 9.1. After a mean maturation rate of 58.0 ± 26.1%, 5.8 ± 5.3 mature oocytes were cryopreserved per cycle. The number of retrieved and cryopreserved oocytes after IVM were significantly lower in patients presenting with an SBR III tumour when compared with an SBR I or II tumour (9.6 ± 8.7 vs 11.7 ± 9.8, P = 0.02 and 5.4 ± 5.4 vs 6.6 ± 5.8, P = 0.02, respectively). Multivariate statistical analysis showed that HER2 positive status was associated with a mean maturation rate <60% (odds ratio: 0.54; 95% CI (0.30-0.97)). Ki67 and hormonal status were not correlated with poor IVM outcomes. LIMITATIONS, REASONS FOR CAUTION: A weakness is the retrospective nature of the study. Moreover, as with many studies focusing on FP in oncology patients, the lack of data after reutilization of IVM oocytes prevents drawing reliable conclusions on the fate of these frozen gametes. WIDER IMPLICATIONS OF THE FINDINGS: BC prognostic factors might influence IVM outcomes. Moreover, HER2 is likely to be involved in the ovarian function and oocyte maturation process. Further investigations are needed to better understand the mechanisms at play and their possible impact on the competence of IVM oocytes. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was used and there are no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Economic evaluation of Medically Assisted Reproduction: An educational overview of methods and applications for healthcare professionals.

Economic evaluations of the value-for-money of Medically Assisted Reproduction (MAR) interventions are increasingly important due to growing pressure on healthcare budgets. Although such evaluations are commonplace in the published literature, the number/methodological complexity of different evaluations available, and the challenges specific to MAR interventions, can complicate the interpretation of such analyses for fertility treatments. This article aims to serve as an educational resource and provide context on the design/interpretation of economic analyses for MAR interventions. Several areas are relevant for first-line providers and decision makers: scope of analysis, comparator used, perspective/time horizon considered, outcomes used to measure success, and how results from cost-effectiveness studies can be summarised and used in clinical practice. We aim to help clinicians better understand the strengths/weaknesses of economic analyses, to enable the best use of the evidence in practice, so resources available for MAR interventions can provide maximum value to patients and society.

Women utilizing oocyte donation have a decreased live birth rate if they displayed a low progesterone level in a previous hormonal replacement mock cycle.

PURPOSE: Is serum progesterone(P) level on day 2 of vaginal P administration in a hormonally substituted mock cycle predictive of live birth in oocyte donation(OD)? METHODS: Retrospective analysis of 110 mock cycles from 2008 to 2016 of OD recipients having at least one subsequent embryo transfer (ET). Endometrial preparation consisted of sequential administration of vaginal estradiol, followed by transdermal estradiol and 600 mg/day vaginal micronized P. In mock cycles, serum P was measured 2 days after vaginal P introduction. OD was performed 1 to 3 years later, without P measurement. RESULTS: In mock cycles, mean serum P level on day 2 was 12.8 ± 4.5 ng/mL (range: 4-28 ng/mL). A total of 32% patients had P < 10 ng/mL. At the time of first OD, age of recipients and donors, number of retrieved and attributed oocytes, and number of transferred embryos were comparable between patients with P < 10 ng/mL in their mock cycles compared with P ≥ 10 ng/mL. Pregnancy and live birth rate after first ET were significantly lower for patients with P < 10ng/mL (9% vs. 35 %; P = 0.002 and 9% vs. 32%; P = 0.008, respectively). Considering both fresh and subsequent frozen-thawed ET, cumulative live birth rate per-patient and per-transfer were significantly lower in patients with P < 10 ng/mL in their mock cycle (14% vs. 35%; P = 0.02 and 11% vs. 27%; P = 0.03). CONCLUSION: A low P level in hormonally substituted cycles several years before ET performed with the same endometrial preparation is associated with a significantly lower chance of live birth. This suggests that altered vaginal P absorption is a permanent phenomenon. Monitoring serum P in hormonally substituted cycles appears mandatory to adjust luteal P substitution.

Cryopreservation of small numbers of human spermatozoa in a Stripper tip: Report of the first live-birth worldwide.

PURPOSE: The aim is to report the first live-birth following ICSI using spermatozoa previously vitrified in a Stripper Tip. PRINCIPAL RESULTS: A 34-year-old cryptozoospermic man was enrolled in a sperm vitrification program. After failure of conventional freezing technique, spermatozoa were vitrified using two carriers: a commercially-available, Cell Sleeper, and a "home-made" one, Stripper Tip. This man and his 30-year-old wife underwent an ICSI attempt using vitrified-warmed spermatozoa from these devices. All frozen-warmed spermatozoa were quickly recovered. Among the oocytes retrieved, six were injected with sperm from the Cell Sleeper, and seven with sperm from the Stripper tip, leading to 4 embryos in each case. Two embryos, arising from sperm frozen in the Stripper tip, were transferred, resulting in a healthy live-birth. CONCLUSIONS: This is the first successful delivery following the use of spermatozoa frozen in an original device, the Stripper Tip, giving a promising prospect for managing severe male infertilities.

Priming Before In Vitro Maturation Cycles in Cancer Patients Undergoing Urgent Fertility Preservation: a Randomized Controlled Study.

In vitro maturation (IVM) of oocytes retrieved at germinal vesicle stage, followed by vitrification of mature oocytes, has emerged as a fertility preservation (FP) option. This technique was first developed for patients with polycystic ovarian syndrome. In this population, providing LH activity prior to oocyte collection has been associated with better IVM outcomes. However, the benefit of this treatment in normo-ovulatory breast cancer (BC) patients undergoing IVM for FP purpose has never been investigated. To assess if the absence of therapeutic intervention prior to oocyte retrieval for IVM modifies IVM outcomes in BC patients undergoing urgent FP, we performed a non-inferiority, randomized controlled trial. The main outcome was the total number of mature oocytes obtained and cryopreserved after IVM. A total of 172 normo-ovulatory women, suffering from BC, 18 to 39 years of age received no injection or a subcutaneous injection of hCG or GnRH agonist (GnRHa) 36 h before oocytes retrieval according to randomized allocation. The total number of cryopreserved oocytes were 5.1 ± 3.8, 5.4 ± 3.8, and 6.0 ± 4.2 oocytes, respectively in the without, hCG and GnRHa groups. Mean differences were not significant between the three groups (- 0.5; CI 97.5% [- 2.03:1.02] and - 0.22; CI 97.5% [- 1.75:1.32], respectively). Intention to treat analyses failed to show non-inferiority in the "without injection group" in comparison with hCG or GnRHa groups. Our results are not conclusive enough to modify our practices and to stop administering hCG or GnRHa before IVM cycles for FP. The study was retrospectively registered to clinical trial (ID NCT03954197) in May 2019.

Effectiveness of a therapeutic multiple-lifestyle intervention taking into account the periconceptional environment in the management of infertile couples: study design of a randomized controlled trial - the PEPCI study.

BACKGROUND: Infertility is defined as the inability to conceive after 12 months of unprotected intercourse. It affects approximately one in six couples seeking pregnancy in France or western countries. Many lifestyle factors of the couples' pre and peri-conceptional environment (weight, diet, alcohol, tobacco, coffee, drugs, physical activity, stress, sleep…) have been identified as risk factors for infertility in both males and females. The high prevalence rates of unhealthy diets and lifestyles in the reproductive population of industrialized countries are worrisome. Nevertheless, adoption of a healthy lifestyle may improve fertility but lifestyle changes are difficult to achieve and to maintain due notably to behavioral factors. METHODS: Consequently, we decided to propose an interventional study aimed at improving the quality of life of infertile couples before the start of assisted reproductive technology treatment. It is a randomized controlled multicentre trial. Both members of the couples are involved in an integrated global care program (PEPCI for "Parcours Environnement PériConceptionnel en Infertilité") vs. usual care. This global intervention not only considers diet and/or physical activity but follows a holistic approach, including a multidisciplinary assessment to address complete physical, psychological and social well-being. According to patient needs, this includes interventions on weight, exercise, diet, alcohol and drugs, mental and social health. DISCUSSION: The main objective of trial is to demonstrate that periconceptional multidisciplinary care has a positive impact on reproductive functions. We will also focus on feasibility, acceptance, compliance and conditions of success of a multifaceted lifestyle intervention. TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov, Identifier: NCT02961907 on November 11, 2016.

Serum progesterone concentration and live birth rate in frozen-thawed embryo transfers with hormonally prepared endometrium.

RESEARCH QUESTION: Is serum progesterone measurement on the day of embryo transfer associated with outcome of frozen-thawed embryo transfer (FET) in cycles using hormonal replacement therapy (HRT) for endometrium preparation? DESIGN: This single-centre retrospective study assessed the relationship between serum progesterone on embryo transfer day and live birth rates in 227 FET cycles. Endometrial preparation was performed by sequential administration of vaginal oestradiol until endometrial thickness was >7 mm, followed by transdermal oestradiol combined with 600 mg vaginal micronized progesterone. RESULTS: Mean serum embryo transfer day progesterone was 11.4 ng/ml. Serum progesterone <10 ng/ml was observed in 37% of cycles and was associated with significantly lower pregnancy (34% versus 48%, P= 0.04) and live birth rates (17% versus 31%, P= 0.01). Multivariate logistic regression analysis identified serum embryo transfer day progesterone as a significant prognostic factor for live birth rate (odds ratio [OR]: 2.75, 95% confidence interval [CI]: 1.40-5.43]). Receiver operator curve analysis for live birth rates by serum progesterone levels on embryo transfer day gave an area under the curve of 0.62 (95% CI: 0.53-0.72). CONCLUSIONS: The data show that serum progesterone concentration is associated with live birth rate. This outlines the importance of measuring serum progesterone in FET with HRT although progesterone monitoring is not usually performed in routine practice. However, the optimal timing for measurement and further adaptive management in the presence of low values remain to be determined.

Anti Müllerian Hormone: More than a biomarker of female reproductive function.

Anti-Müllerian hormone (AMH), known for its role during sexual differentiation, is a dimeric glycoprotein that belongs to the transforming growth factor-ß (TGF-ß) family. AMH has recently been identified as a reliable marker of ovarian reserve that can help predict early ovarian follicle loss and menopause onset. AMH levels also reflect the effects of damaging gynecologic surgeries or gonadotoxic treatments such as chemotherapy on ovarian reserve. Furthermore, AMH participates in the diagnosis of certain diseases such as granulosa cell tumors or Polycystic Ovary Syndrome (PCOS). Currently used to establish patient profiles and predict ovarian response to stimulation, its role in ART techniques is crucial. Nevertheless, AMH appears to be a weak independent predictor of qualitative outcomes such as implantation, pregnancy, and live birth. As the reliability and reproducibility of AMH dosage have raised many doubts due to different existing standards and thresholds, an international consensus is still expected to improve AMH measurement and interpretation.

Impact of post-warming culture duration on clinical outcomes of vitrified good-quality blastocyst transfers: a prospective randomized study.

OBJECTIVE: To determine whether post-warming culture duration (1 hour vs. 18 hours) influences implantation rates (IRs) of good-quality blastocysts (GQB) in a good-prognosis population. DESIGN: Prospective interventional randomized study. SETTING: University hospital. PATIENT(S): One hundred sixty-two GQB transfers. INTERVENTION(S): Patients' vitrified blastocysts were randomly allocated to group A, warming on the day before transfer (n = 81), or B, warming on the day of transfer (n = 81). MAIN OUTCOME MEASURE(S): IR, live birth rate, reexpansion degree, and quality after warming and immediately before transfer. RESULT(S): Quality of the warmed and transferred blastocysts was similar (respectively, 39.1% and 32.7% top quality [≥B4AA/AB/BA] in group A vs. 41.7 and 42.2% in group B). In group A, 14 of 102 blastocysts (12.2%) appeared to be unsuitable for transfer, versus only 1 of 103 (0.9%) in group B, thus leading to an additional warming. As expected, reexpansion degree just before transfer was higher in group A (0.90 vs. 0.70). Likewise, the proportion of hatched blastocysts before transfer was higher after a longer culture period (38.6% in group A vs. 12.7% in group B). IRs were similar (38.0% in group A vs. 36% in group B), as were live birth rates (35.8% in group A vs. 34.6% in group B). CONCLUSION(S): IRs were not different, whatever the duration of post-warming culture of GQB. Both warming strategies could be applied to good-prognosis patients to optimize the laboratory workflow without any detrimental effect.

PATL2 is a key actor of oocyte maturation whose invalidation causes infertility in women and mice.

The genetic causes of oocyte meiotic deficiency (OMD), a form of primary infertility characterised by the production of immature oocytes, remain largely unexplored. Using whole exome sequencing, we found that 26% of a cohort of 23 subjects with OMD harboured the same homozygous nonsense pathogenic mutation in PATL2, a gene encoding a putative RNA-binding protein. Using Patl2 knockout mice, we confirmed that PATL2 deficiency disturbs oocyte maturation, since oocytes and zygotes exhibit morphological and developmental defects, respectively. PATL2's amphibian orthologue is involved in the regulation of oocyte mRNA as a partner of CPEB However, Patl2's expression profile throughout oocyte development in mice, alongside colocalisation experiments with Cpeb1, Msy2 and Ddx6 (three oocyte RNA regulators) suggest an original role for Patl2 in mammals. Accordingly, transcriptomic analysis of oocytes from WT and Patl2-/- animals demonstrated that in the absence of Patl2, expression levels of a select number of highly relevant genes involved in oocyte maturation and early embryonic development are deregulated. In conclusion, PATL2 is a novel actor of mammalian oocyte maturation whose invalidation causes OMD in humans.

Fertility preservation in BRCA-mutated women: when and how?

BRCA 1 and 2 genes play a critical role in the safeguarding of DNA integrity. It is now well established that BRCA1 and BRCA2-mutated women are at increased risk of breast and ovarian cancers. However, several lines of evidence indicate that this genetic status may also be associated with ovarian dysfunction, in particular a reduced ovarian reserve. Considering the gonadal toxicity of cancer treatments and the recommendation of prophylactic bilateral salpingo-oophorectomy around 40 years, young BRCA mutation carriers are confronted with difficult family planning decisions. Recent development in fertility preservation offers new possibilities for these women, not only before a potential cancer treatment, but also in healthy carriers. If the pregnancy seems to be safe in this population, oocyte vitrification following ovarian stimulation might help BRCA-mutated patients to conceive after cancer treatment or to undergo prenatal genetic diagnosis in order to avoid the risk of transmitting the genetic abnormality to their offspring. The present article aims to extensively discuss the fertility issues related to BRCA gene mutations and the questions raised by the possibility of fertility in this population.

The impact of ovulation induction and ovarian stimulation on the risk of pregnancy-induced hypertension and on neonatal outcomes: A case/control study.

OBJECTIVES: To study the role of ovarian stimulation procedures on the risk of pregnancy-induced hypertension, gestational diabetes mellitus and neonatal outcomes according to women's characteristics and the causes of infertility. DESIGN: Retrospective, observational, case/control study. PATIENTS: Spontaneous pregnancies (group A, n=8107), pregnancies achieved after mild ovarian ovulation induction without other Assisted Reproductive Technology (ART) procedures (group B, n=44), pregnancies after mild ovarian stimulation and ART procedures (group C, n=53) or pregnancies after multi (>2) follicular stimulation with gonadotrophin therapy and ART procedures (group D, n=133); all of the groups had identical protocols for prenatal care. MAIN OUTCOME MEASUREMENTS: Pregnancy-induced hypertension (PIH), fetal macrosomia (estimated fetal weight >90th percentile), gestational diabetes mellitus, caesarean section, and neonatal outcomes. RESULTS: The incidence rates of PIH (2.7, 11.6, 4.2, and 2.5%) in groups A, B, C and D, respectively, (p=0.004), fetal macrosomia (4.7, 7.0, 20.8, and 7.6%, respectively, p<0.001), caesarean section (21.8, 37.2, 21.7, and 17.6%, respectively, p=0.048), differed among the groups. The high incidence of PIH in pregnancies following ovulation induction was driven by polycystic ovarian syndrome (PCOS) per se. CONCLUSION: PCOS per se was associated with more PIH, and ART procedures after mild mono/bi follicular ovarian stimulation were associated with more fetal macrosomia.

Should we consider day-2 and day-3 embryo morphology before day-5 transfer when blastocysts reach a similar good quality?

Clinical outcomes of 291 day-5 blastocyst transfers carried out between January 2012 and March 2016 were retrospectively compared according to their quality at day 2 and 3. Inclusion criteria were female age younger than 37 years; first or second IVF and intracytoplasmic sperm injection cycle; quality of the transferred blastocyst: blastocoele B3 or higher; inner-cell-mass A/B; trophectoderm A/B; and known implantation outcome for each transferred blastocyst. Blastocysts were classified into good-quality and poor-quality embryo groups at day 2 and 3. Implantation (38.7% versus 41.4), clinical pregnancy (40.3% versus 45.9%), miscarriage (22.2% versus 26.7%;) and live birth rates (37.4% versus 38.8%) were comparable in day 2 good and poor-quality embryo groups. No signficiant differences in morphology of transferred blastocysts at day 3 were found. Multivariable analysis highlighted that poor or good embryo quality at day 2 and day 3 were not predictive of the implantation of good-quality blastocysts (at day 2: adjusted odds ratio = 0.82 CI 95% 0.49 to 1.38; at day 3: adjusted odds ratio = 1.39; CI 95% 0.77 to 2.52). Good-quality blastocyst transfer should, therefore, be carried out irrespective of embryo quality at cleavage stage, as it may not compromise success rates in a good-prognosis population.

Should metaphase 1 and 2 stages oocytes be vitrified in the same time for fertility preservation?

AIMS: Could metaphase 1 (M1) and 2 (M2) stages oocytes from in vitro maturation (IVM) cycles and controlled-ovarian hyperstimulation (COH) cycles be frozen at the same time without any adverse effect of vitrification on further survival (SR) and maturation rates (MR)? MATERIALS & METHODS: M1 from cancer patients were prospectively included in IVM/COH groups, and in study or control subgroups if they were vitrified or not. In each study subgroup, SR were compared with that of M2 oocytes vitrified/warmed from egg donors. MR were compared with those of fresh-M1 oocytes from control IVM/COH subgroups. RESULTS: SR were not different between groups. MR compared respectively between survived- and fresh-M1 oocytes were similar when resulting from COH (85.2 vs 81.1%) but significantly lower after IVM (39.1 vs 73.3%). CONCLUSION: Simultaneous freezing of M1/M2 oocytes could be applied to COH but not to IVM during the course of fertility preservation.

History of ABVD alters the number of oocytes vitrified after in vitro maturation in fertility preservation candidates.

AIM: This retrospective case-control study aimed at analyzing the results of in vitro maturation (IVM) of oocytes, used for fertility preservation (FP), in patients with history of ABVD (adriamycin, bleomycin, vinblastine and dacarbazine) for classical Hodgkin lymphoma. PATIENTS & METHODS: A total of 22 candidates for FP, having received ABVD at least 2 years before IVM for FP were studied. IVM results were compared with those of 44 breast cancer patients, without history of chemotherapy, matched for ovarian reserve parameters. RESULTS: The number of cumulo-oocyte complexes recovered and the total number of matured oocytes vitrified was lower in patients having received AVBD (5.5 ± 4.8 vs 8.5 ± 4.4 oocytes; p = 0.03 and 3.5 ± 3.7 vs 6 ± 3.0 oocytes; p < 0.04, respectively). CONCLUSION: In light of these results, FP should be discussed before ABVD.

Hypertensive pathologies and egg donation pregnancies: Results of a large comparative cohort study.

OBJECTIVE: To determine whether egg donation (ED) pregnancies are at higher risk of pregnancy-induced hypertension (PIH) than those achieved by autologous assisted reproductive technology (ART; controls). DESIGN: Anonymous comparative observational matched cohort study. SETTING: Assisted reproductive technology centers. PATIENT(S): Two hundred seventeen ED and 363 control singleton pregnancies matched at 7-8 weeks (pregnancy date, parity, cycle type [fresh/frozen] and women's age). According to French practice, all women were under 45. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Percentage of PIH for ED versus controls. RESULT(S): The groups were comparable (mean age, 34.5). PIH was more frequent during ED pregnancies (17.8% vs. 5.3%), as was preeclampsia (11.2% vs. 2.8%) and eclampsia (1.8% vs. 0.0%). In multivariate analyses, PIH risk increased with ED (odds ratio [OR], 3.92; 95% confidence interval [CI], 1.93-7.97) and women's age (OR, 1.08; 95% CI, 1.00-1.16). No significant effect of previous pregnancies or cycle rank/type was observed. CONCLUSION(S): This study had sufficient power to detect doubling of the PIH rate. It was demonstrated that the risk of PIH was tripled for ED versus controls. Even in young women, ED is a risk factor for PIH. An immunological explanation seems most likely, that is, the fetus is fully allogeneic to its mother. This risk must be acknowledged to inform couples and provide careful pregnancy monitoring.