Risk factors for poor oocyte yield and oocyte immaturity after GnRH agonist triggering.

STUDY QUESTION: What are the potential risk factors for poor oocyte recuperation rate (ORR) and oocyte immaturity after GnRH agonist (GnRHa) ovulation triggering? SUMMARY ANSWER: Lower ovarian reserve and LH levels after GnRHa triggering are risk factors of poor ORR. Higher BMI and anti-Müllerian hormone (AMH) levels are risk factors of poor oocyte maturation rate (OMR). WHAT IS KNOWN ALREADY: The use of GnRHa to trigger ovulation is increasing. However, some patients may have a suboptimal response after GnRHa triggering. This suboptimal response can refer to any negative endpoint, such as suboptimal oocyte recovery, oocyte immaturity, or empty follicle syndrome. For some authors, a suboptimal response to GnRHa triggering refers to a suboptimal LH and/or progesterone level following triggering. Several studies have investigated a combination of demographic, clinical, and endocrine characteristics at different stages of the treatment process that may affect the efficacy of the GnRHa trigger and thus be involved in a poor endocrine response or efficiency but no consensus exists. STUDY DESIGN, SIZE, DURATION: Bicentric retrospective cohort study between 2015 and 2021 (N = 1747). PARTICIPANTS/MATERIALS, SETTING, METHODS: All patients aged 18-43 years who underwent controlled ovarian hyperstimulation and ovulation triggering by GnRHa alone (triptorelin 0.2 mg) for ICSI or oocyte cryopreservation were included. The ORR was defined as the ratio of the total number of retrieved oocytes to the number of follicles >12 mm on the day of triggering. The OMR was defined as the ratio of the number of mature oocytes to the number of retrieved oocytes. A logistic regression model with a backward selection method was used for the analysis of risk factors. Odds ratios (OR) are displayed with their two-sided 95% confidence interval. MAIN RESULTS AND THE ROLE OF CHANCE: In the multivariate analysis, initial antral follicular count and LH level 12-h post-triggering were negatively associated with poor ORR (i.e. below the 10th percentile) (OR: 0.61 [95% CI: 0.42-0.88]; P = 0.008 and OR: 0.86 [95% CI: 0.76-0.97]; P = 0.02, respectively). A nonlinear relationship was found between LH level 12-h post-triggering and poor ORR, but no LH threshold was found. A total of 25.3% of patients suffered from oocyte immaturity (i.e. OMR < 75%). In the multivariate analysis, BMI and AMH levels were negatively associated with an OMR < 75% (OR: 4.34 [95% CI: 1.96-9.6]; P < 0.001 and OR: 1.22 [95% CI: 1.03-1.12]; P = 0.015, respectively). Antigonadotrophic pretreatment decreased the risk of OMR < 75% compared to no pretreatment (OR: 0.72 [95% CI: 0.57-0.91]; P = 0.02). LIMITATIONS, REASONS FOR CAUTION: Our study is limited by its retrospective design and by the exclusion of patients who had hCG retriggers. However, this occurred in only six cycles. We were also not able to collect information on the duration of pretreatment and the duration of wash out period. WIDER IMPLICATIONS OF THE FINDINGS: In clinical practice, to avoid poor ORR, GnRHa trigger alone should not be considered in patients with higher BMI and/or low ovarian reserve, balanced by the risk of ovarian hyperstimulation syndrome. In the case of a low 12-h post-triggering LH level, practicians must be aware of the risk of poor ORR, and hCG retriggering could be considered. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: N/A.

The follicular output rate in normo-ovulating women undergoing ovarian stimulation is increased after unilateral oophorectomy.

STUDY QUESTION: Does unilateral oophorectomy modify the antral follicular responsiveness to exogenous FSH, assessed by the Follicular Output RaTe (FORT) in normo-ovulating women? SUMMARY ANSWER: Antral follicle responsiveness to exogenous FSH, as assessed by the FORT index, is significantly higher in women with a single ovary in comparison with the ipsilateral ovary of age-matched controls. WHAT IS KNOWN ALREADY: Growing evidence indicates that the innovative FORT may be a remarkable tool to evaluate the follicle responsiveness to exogenous FSH, independently of the size of the pretreatment cohort of small antral follicles. It is conceivable that in the unclear compensating mechanisms at play in women having undergone unilateral oophorectomy, an increase in the sensitivity of antral follicles to FSH may be involved. To clarify this issue, we decided to investigate whether the responsiveness of follicles to exogenous FSH, as assessed by the FORT, is altered in unilaterally oophorectomized patients. STUDY DESIGN, SIZE, DURATION: The study included 344 non-polycystic ovary syndrome, non-endometriotic women, aged 22-43 years old. There were 86 women who had a single ovary as a result of unilateral oophorectomy or adnexectomy (Single Ovary group; average time since surgery: 52 (8-156) months), and each of them was retrospectively matched with three patients having two intact ovaries, according to age (±1 year), year of ovarian stimulation, and FSH starting dose (±50 IU) (Control group, n = 258). PARTICIPANTS/MATERIALS, SETTING, METHODS: Serum anti-Mullerian hormone (AMH) levels and total antral follicle count (AFC) (3-12 mm) were assessed on cycle day 3 in both groups. In all patients, follicles were counted before exogenous FSH administration (baseline) and on the day of oocyte trigger (OT) (dOT; preovulatory follicles; 16-22 mm). Antral follicle responsiveness to FSH was estimated in both groups by the FORT, determined by the ratio of the preovulatory follicle count on dOT × 100 to the small AFC at baseline. FORT in the Single Ovary group was compared to the overall FORT considering both ovaries or the index calculated on the ipsilateral ovary of matched controls. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, serum AMH levels and total AFC (1.0 (0.5-2.1) vs 1.8 (1.0-3.3), P < 0.005) and (9.0 (6.0-17.0) vs 13.0 (8.0-21.0), P < 0.001, respectively) were lower in the Single Ovary group compared to the Control group. When considering the FORT calculated on the basis of the overall ovarian response in women with two ovaries, the results were similar when compared to those obtained in patients unilaterally oophorectomized (30.4% (15.6-50.0) vs 32.5% (14.0-50.0), respectively). Interestingly, the comparison of FORT between women with a single ovary and the ipsilateral ovary of age-matched controls, revealed, after adjustment for AMH and AFC, a significantly higher ratio after unilateral oophorectomy (32.5% (14.8-50.0) vs 25.0% (10.0-50.0), P < 0.002, respectively). LIMITATIONS, REASONS FOR CAUTION: This study was based on retrospective data in a limited population. In addition, the FORT index has inherent limitations due to its indirect assessment of follicular responsiveness to FSH. WIDER IMPLICATIONS OF THE FINDINGS: The present investigation provides evidence that the responsiveness of antral follicles to exogenous FSH is increased in women having undergone unilateral oophorectomy when compared to the ipsilateral ovary of age-matched controls. This is consistent with the implication of a compensating phenomenon that drives the follicular changes in unilaterally oophorectomized patients. Further studies directly assessing the granulosa cell function and the density of FSH receptors in small antral follicles are required to confirm our findings. STUDY FUNDING/COMPETING INTEREST(S): The authors have no funding or competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.

The HERA (Hyper-response Risk Assessment) Delphi consensus for the management of hyper-responders in in vitro fertilization.

PURPOSE: To provide agreed-upon guidelines on the management of a hyper-responsive patient undergoing ovarian stimulation (OS) METHODS: A literature search was performed regarding the management of hyper-response to OS for assisted reproductive technology. A scientific committee consisting of 4 experts discussed, amended, and selected the final statements. A priori, it was decided that consensus would be reached when ≥66% of the participants agreed, and ≤3 rounds would be used to obtain this consensus. A total of 28/31 experts responded (selected for global coverage), anonymous to each other. RESULTS: A total of 26/28 statements reached consensus. The most relevant are summarized here. The target number of oocytes to be collected in a stimulation cycle for IVF in an anticipated hyper-responder is 15-19 (89.3% consensus). For a potential hyper-responder, it is preferable to achieve a hyper-response and freeze all than aim for a fresh transfer (71.4% consensus). GnRH agonists should be avoided for pituitary suppression in anticipated hyper-responders performing IVF (96.4% consensus). The preferred starting dose in the first IVF stimulation cycle of an anticipated hyper-responder of average weight is 150 IU/day (82.1% consensus). ICoasting in order to decrease the risk of OHSS should not be used (89.7% consensus). Metformin should be added before/during ovarian stimulation to anticipated hyper-responders only if the patient has PCOS and is insulin resistant (82.1% consensus). In the case of a hyper-response, a dopaminergic agent should be used only if hCG will be used as a trigger (including dual/double trigger) with or without a fresh transfer (67.9% consensus). After using a GnRH agonist trigger due to a perceived risk of OHSS, luteal phase rescue with hCG and an attempt of a fresh transfer is discouraged regardless of the number of oocytes collected (72.4% consensus). The choice of the FET protocol is not influenced by the fact that the patient is a hyper-responder (82.8% consensus). In the cases of freeze all due to OHSS risk, a FET cycle can be performed in the immediate first menstrual cycle (92.9% consensus). CONCLUSION: These guidelines for the management of hyper-response can be useful for tailoring patient care and for harmonizing future research.

Oncologic results of fertility sparing surgery of cervical cancer: An updated systematic review.

BACKGROUND: Several techniques can be proposed as fertility sparing surgery in young patients treated for cervical cancer but uncertaincies remain concerning their outcomes. Analysis of oncological issues is then the first aim of this review in order to evaluate the best strategy. RESULTS: Data were identified from searches of MEDLINE, Current Contents, PubMed and from references in relevant articles from January 1987 to 15th of September 2021. We carry out an updated systematic review involving 5862 patients initially selected for fertility-sparing surgery in 275 series. FINDINGS: In patients having a stage IB1 disease, recurrence rate/RR in patients undergoing simple conisation/trachelectomy, radical trachelectomy/RT by laparoscopico-vaginal approach, laparotomic or laparoscopic approaches are respectively: 4.1%, 4.7%, 2.4% and 5.2%. In patients having a stage IB2 disease, RR after neoadjuvant chemotherapy or RT by laparotomy are respectively 13.2% and 4.8% (p = .0035). After neoadjuvant treatment a simple cone/trachelectomy was carried out in 91 (30%) patients and a radical one in 210 (70%) cases. But the lowest pregnancy rate is observed in patients undergoing RT by laparotomy (36%). CONCLUSIONS: The choice between these treatments should be based above all, on objective oncological data that strike a balance for each procedure between the best chances for cure and the fertility results. In patients having a stage IB1 disease, oncological results are quite similar according to the procedure used. In patients having a stage IB2 disease, RT by open approach has the lowest RR. Anyway the lowest pregnancy rate is observed in patients undergoing RT by laparotomy.

Could hormonal and follicular rearrangements explain timely menopause in unilaterally oophorectomized women?

STUDY QUESTION: Does unilateral oophorectomy modify the relationship between serum anti-Müllerian hormone (AMH) levels and antral follicle count (AFC)? SUMMARY ANSWER: No altered 'per-ovary' and 'per-follicle' AMH production and antral follicle distribution was evident in unilaterally oophorectomized women compared to matched controls. WHAT IS KNOWN ALREADY: The age of menopause onset is relatively unchanged in patients having undergone unilateral oophorectomy. Mechanisms that occur to preserve and maintain ovarian function in this context remain to be elucidated. STUDY DESIGN, SIZE, DURATION: Forty-one infertile women, with no polycystic ovary syndrome (PCOS) and no endometriosis, aged 19-42 years old, having undergone unilateral oophorectomy (One Ovary group; average time since surgery: 23.8 ± 2.2 months) were retrospectively age-matched (±1 year) with 205 infertile women having two intact ovaries and similar clinical features (Control group). PARTICIPANTS/MATERIALS, SETTING, METHODS: Serum AMH levels, 3-4 mm AFC, 5-12 mm AFC, and total AFC (3-12 mm) were assessed on cycle Day 3 in both groups. Hormonal and ultrasonographic measurements obtained from patients in the Control group (i.e. having two ovaries) were divided by two to be compared with measurements obtained from patients of the One Ovary group (i.e. having one single remaining ovary). To estimate per-follicle AMH production, we calculated the ratio between serum AMH levels over 3-4 mm AFC, 5-12 mm AFC, and total AFC (3-12 mm), and the strength of the correlation between serum AMH levels and total AFC. The main outcome measure was to assess Day 3 AMH/Day 3 AFC ratio and hormonal-follicular correlation. MAIN RESULTS AND THE ROLE OF CHANCE: As expected, before correction, mean serum AMH levels (1.46 ± 0.2 vs 2.77 ± 0.1 ng/ml, P < 0.001) and total AFC (7.3 ± 0.6 vs 15.1 ± 0.4 follicles, P < 0.0001) were lower in the One Ovary group compared to the Control group, respectively. Yet, after correction, per-ovary AMH levels (1.46 ± 0.2 vs 1.39 ± 0.1 ng/ml) and total AFC (7.3 ± 0.6 vs 7.5 ± 0.2 follicles) values were comparable between the two groups. Consistently, per-follicle AMH levels (3-4 mm, 5-12 mm, and total) were not significantly different between the two groups (0.39 ± 0.05 vs 0.37 ± 0.02 ng/ml/follicle; 0.69 ± 0.12 vs 0.59 ± 0.05 ng/ml/follicle, and 0.23 ± 0.03 vs 0.19 ± 0.01 ng/ml/follicle; respectively). In addition, the prevalence of 3-4 mm follicles was comparable between the two groups (66.7% for One Ovary group vs 58.8% for Control group, respectively). Finally, the correlation between serum AMH levels and total AFC was similar for patients in the One Ovary group (r = 0.70; P < 0.0001) compared to those in the Control group (r = 0.68; P < 0.0001). LIMITATIONS/REASONS FOR CAUTION: The retrospective character of the analysis might lead to potential bias. WIDER IMPLICATIONS OF THE FINDINGS: The present investigation did not provide evidence of altered 'per-ovary' and 'per-follicle' AMH production and antral follicle distribution in unilaterally oophorectomized women compared to matched controls. Further studies are warranted to support the hypothesis that follicle-sparing mechanisms are clearly at stake in remaining ovaries after unilateral oophorectomy to explain their long-lasting function and timely menopausal onset. STUDY FUNDING/COMPETING INTEREST(S): The authors have no funding or competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.

What is the threshold of mature oocytes to obtain at least one healthy transferable cleavage-stage embryo after preimplantation genetic testing for fragile X syndrome?

STUDY QUESTION: What are the chances of obtaining a healthy transferable cleavage-stage embryo according to the number of mature oocytes in fragile X mental retardation 1 (FMR1)-mutated or premutated females undergoing preimplantation genetic testing (PGT)? SUMMARY ANSWER: In our population, a cycle with seven or more mature oocytes has an 83% chance of obtaining one or more healthy embryos. WHAT IS KNOWN ALREADY: PGT may be an option to achieve a pregnancy with a healthy baby for FMR1 mutation carriers. In addition, FMR1 premutation is associated with a higher risk of diminished ovarian reserve and premature ovarian failure. The number of metaphase II (MII) oocytes needed to allow the transfer of a healthy embryo following PGT has never been investigated. STUDY DESIGN, SIZE, DURATION: The study is a monocentric retrospective observational study carried out from January 2006 to January 2020 that is associated with a case-control study and that analyzes 38 FMR1 mutation female carriers who are candidates for PGT; 16 carried the FMR1 premutation and 22 had the full FMR1 mutation. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 95 controlled ovarian stimulation (COS) cycles for PGT for fragile X syndrome were analyzed, 49 in premutated patients and 46 in fully mutated women. Only patients aged ≤38 years with anti-Müllerian hormone (AMH) >1 ng/ml and antral follicle count (AFC) >10 follicles were eligible for the PGT procedure. Each COS cycle of the FMR1-PGT group was matched with the COS cycles of partners of males carrying any type of translocation (ratio 1:3). Conditional logistic regression was performed to compare the COS outcomes. We then estimated the number of mature oocytes needed to obtain at least one healthy embryo after PGT using receiver operating characteristic curve analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, in the FMR1-PGT group, the median number of retrieved and mature oocytes per cycle was 11 (interquartile range 7-15) and 9 (6-12), respectively. The COS outcomes of FMR1 premutation or full mutation female carriers were not altered compared with the matched COS cycles in partners of males carrying a balanced translocation in their karyotype. Among the 6 (4-10) Day 3 embryos obtained in the FMR1-PGT group, a median number of 3 (1-6) embryos were morphologically eligible for biopsy, leading to 1 (1-3) healthy embryo. A cutoff value of seven MII oocytes yielded a sensitivity of 82% and a specificity of 61% of having at least one healthy embryo, whereas a cutoff value of 10 MII oocytes led to a specificity of 85% and improved positive predictive value. LIMITATIONS, REASONS FOR CAUTION: This study is retrospective, analyzing a limited number of cycles. Moreover, the patients who were included in a fresh PGT cycle were selected on ovarian reserve parameters and show high values in ovarian reserve tests. This information could influence our conclusion. WIDER IMPLICATIONS OF THE FINDINGS: The results relate only to the target population of this study, with a correct ovarian reserve of AMH >1 and AFC >10. However, the information provided herein extends knowledge about the current state of COS for FMR1 mutation carriers in order to provide patients with proper counseling regarding the optimal number of oocytes needed to have a chance of transferring an unaffected embryo following PGT. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: N/A.

What threshold values of antral follicle count and serum AMH levels should be considered for oocyte cryopreservation after in vitro maturation?

STUDY QUESTION: What threshold values of ultrasonographic antral follicle count (AFC) and serum anti-Müllerian hormone (AMH) levels should be considered for ensuring the cryopreservation of sufficient number of in vitro matured (IVM) oocytes, in cancer patients seeking fertility preservation (FP)? SUMMARY ANSWER: AFC and serum AMH values >20 follicles and 3.7 ng/ml, respectively, are required for obtaining at least 10 IVM oocytes for cryopreservation. WHAT IS KNOWN ALREADY: IVM of cumulus oocyte complexes (COCs) followed by oocyte cryopreservation has emerged recently as an option for urgent FP. Recent data have reported that, in healthy patients, 8-20 cryopreserved oocytes after ovarian stimulation would maximize the chance of obtaining a live birth. Although both AFC and AMH have been reported as predictive factors of IVM success in infertile patients with polycystic ovary syndrome (PCOS), there is a dramatic lack of data regarding the values of these parameters in oncological patients as candidates for FP. STUDY DESIGN, SIZE, DURATION: From January 2009 to April 2015, we prospectively studied 340 cancer patients, aged 18-41 years, as candidates for oocyte cryopreservation following IVM. PARTICIPANTS/MATERIALS, SETTING, METHODS: All patients had AFC and AMH measurements, 48-72 h before oocyte retrieval, regardless of the phase of the cycle. COCs were recovered under ultrasound guidance 36 h after hCG priming. Logistic regression allowed the determination of threshold values of AFC and AMH, for obtaining at least 8, 10 or 15 matures oocytes frozen after the IVM procedure. Similar analyses were performed for a final number of mature oocytes ≤2. MAIN RESULTS AND THE ROLE OF CHANCE: Among the 340 cancer patients included, 300 were diagnosed with breast cancers, 14 had hematological malignancies and 26 underwent the procedure for others indications. Overall, the mean age of the population was 31.8 ± 4.5 years. Mean AFC and serum AMH levels were 21.7 ± 13.3 follicles and 4.4 ± 3.8 ng/ml, respectively. IVM was performed in equal proportions during the follicular or luteal phase of the cycle (49 and 51%, respectively). Statistical analysis showed that AFC and AMH values above 28 follicles and 3.9 ng/ml, 20 follicles and 3.7 ng/ml and 19 follicles and 3.5 ng/ml are required, respectively, for obtaining at least 15, 10 or 8 frozen IVM oocytes with a sensitivity ranging from 0.82 to 0.90. On the contrary, ≤2 IVM oocytes were cryopreserved when AFC and AMH were <19 follicles and 3.0 ng/ml, respectively. LIMITATIONS, REASONS FOR CAUTION: Although the potential of cryopreserved IVM oocytes from cancer patients remains unknown, data obtained from infertile PCOS women have shown a dramatically reduced competence of these oocytes when compared with that of oocytes recovered after ovarian stimulation. As a consequence, the optimal number of IVM oocytes frozen in candidates for FP is currently unpredictable. WIDER IMPLICATIONS OF THE FINDINGS: Cryopreservation of oocytes after IVM should be considered in the FP strategy when ovarian stimulation is unfeasible, in particular when markers of the follicular ovarian status are at a relatively high range. Further investigation is needed to objectively assess the real potential of these IVM oocytes after cryopreservation. Therefore, even when a good COCs yield is expected, we should systematically encourage IVM in combination with ovarian tissue cryopreservation. STUDY FUNDING/COMPETING INTERESTS: No external funding was obtained for the present study. The authors have no conflict of interest to declare. TRIAL REGISTRATION NUMBER: Not applicable.

Similar in vitro maturation rates of oocytes retrieved during the follicular or luteal phase offer flexible options for urgent fertility preservation in breast cancer patients.

STUDY QUESTION: Are in vitro maturation (IVM) rates of cumulus-oocyte complexes (COCs), retrieved from breast cancer patients seeking urgent fertility preservation (FP) before neoadjuvant chemotherapy, different between those recovered in the follicular or in the luteal phase of the cycle? SUMMARY ANSWER: The present investigation reveals no major difference in the number of COCs recovered or their IVM rates whatever the phase of the cycle at which egg retrieval is performed, suggesting that IVM is a promising tool for breast cancer patients seeking urgent oocyte cryopreservation. WHAT IS KNOWN ALREADY: FP now represents a standard of care for young cancer patients having to undergo gonadotoxic treatment. Mature oocyte cryopreservation after IVM of COCs has been proposed for urgent FP, especially in women, who have no time to undergo ovarian stimulation, or when it is contraindicated. STUDY DESIGN, SIZE, DURATION: From January 2011 to December 2014, we prospectively studied 248 breast cancer patients awaiting neoadjuvant chemotherapy, aged 18-40 years, candidates for oocyte vitrification following IVM, either at the follicular or the luteal phase of the cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS: Serum anti-Müllerian hormone and progesterone levels and antral follicle count (AFC) were measured prior to oocyte retrieval. Patients were sorted into two groups according to the phase of the cycle during which eggs were harvested (Follicular phase group, n = 127 and Luteal phase group, n = 121). Number of COCs recovered, maturation rates after 48 h of culture and total number of oocytes cryopreserved were assessed. Moreover, the oocyte retrieval rate (ORR) was calculated by the number of COCs recovered ×100/AFC. MAIN RESULTS AND THE ROLE OF CHANCE: In the Follicular and the Luteal phase groups, women were comparable in terms of age, BMI and markers of follicular ovarian status. There was no significant difference in the number of COCs recovered (mean ± SEM), 9.3 ± 0.7 versus 11.1 ± 0.8, and ORR (median (range)) 43.1 (1-100) versus 47.8 (7.7-100)%. Moreover, maturation rates after 48 h of culture (median (range)) were comparable in the follicular and luteal phase groups, 66.7 (20-100) versus 64.5 (0-100)%. Finally, the total number of oocytes cryopreserved (mean ± SEM) was similar in both groups (6.2 ± 0.4 versus 6.8 ± 0.5). LIMITATIONS, REASONS FOR CAUTION: Despite the intact meiotic competence of immature oocytes recovered during the follicular or the luteal phase, there is a dramatic lack of data regarding the outcome of IVM oocytes cryopreserved in cancer patients. WIDER IMPLICATIONS OF THE FINDINGS: IVM of oocytes may be an interesting method of FP in urgent situations. Improving the culture conditions will be needed to increase the maturation rates and the overall potential of in vitro matured oocytes. STUDY FUNDING/COMPETING INTERESTS: None. TRIAL REGISTRATION NUMBER: N/A.

Is controlled ovarian stimulation safe in patients with hormone receptor-positive breast cancer receiving neoadjuvant chemotherapy?

INTRODUCTION: Controlled ovarian stimulation (COS) for oocyte/embryo cryopreservation is the method of choice for fertility preservation (FP) in young patients diagnosed with early-stage breast cancer (eBC). Nevertheless, some challenges still question its role, particularly in the neoadjuvant setting, where concerns arise about potential delay in the onset of anticancer treatment, and in hormone receptor-positive (HR+) disease, as cancer cells may proliferate under the estrogenic peak associated with stimulation. Therefore, this review aims to examine the available evidence on the safety of COS in eBC patients eligible for neoadjuvant treatment (NAT), particularly in HR+ disease. METHODS: A comprehensive literature search was conducted to identify studies evaluating the feasibility and safety of COS in eBC and including patients referred to NAT and/or with HR+ disease. Time to NAT and survival outcomes were assessed. RESULTS: Of the three matched cohort studies assessing the impact of COS on time to start NAT, only one reported a significant small delay in the cohort undergoing COS compared with the control group, whereas the other studies found no difference. Regarding survival outcomes, overall, no increased risk of recurrence or death was found, either in patients undergoing COS in the neoadjuvant setting regardless of HR expression or in HR+ disease regardless of the timing of COS relative to surgery. However, there are no data on the safety of COS in the specific combined scenario of HR+ disease undergoing NAT. CONCLUSION: Neither the indication to NAT nor the HR positivity constitutes per se an a priori contraindication to COS. Shared decision making between clinicians and patients is essential to carefully weigh the risks and benefits in each individual case. Prospective studies designed to specifically investigate this issue are warranted.

First-line surgery vs first-line ART to manage infertility in women with deep endometriosis without bowel involvement: A multi-centric propensity-score matching comparison.

OBJECTIVE: To compare first-line surgery with first-line assisted reproductive techniques (ART) in infertile women with deep infiltrating endometriosis (DIE) without colorectal involvement. STUDY DESIGN: A retrospective comparative cohort study with a propensity-score matching analysis, in four tertiary-care referral centers. The population was infertile women with DIE without colorectal involvement. The patients were managed either by first-line surgery followed by spontaneous conception attempts and/or ART, or by first-line ART. 284 patients were extracted from the databases. After matching, 92 patients were compared in each group. Clinical pregnancy rates (PR) and live-birth rates (LBR) were the primary outcomes, and cumulative pregnancy rate (CPR) and cumulative live birth rate (CLBR) were the secondary outcomes. RESULTS: The mean number of IVF-ICSI cycles per patient was 1.4, with a significant difference between the groups: 1.6 in the first-line ART group and 1.2 in the first-line surgery group (p = 0.006). The PR was significantly higher in the first-line surgery group (72 % vs 35 %; p < 0.001). In the first-line surgery group, non-ART pregnancies occurred in 18 % (17/92) while no non-ART pregnancies was noted in the first-line ART group. The LBR was significantly higher in the first-line surgery group (61 % vs 24 %; p < 0.001). After ART, the CPR were 72 % (47/67) in the first-line surgery group, and 35 % (32/92) in the first-line ART group (p < 0.001). CONCLUSION: After matching, our results support that first-line surgery offer higher pregnancy and live-birth rates than first-line ART in patients with DIE without colorectal involvement.

Comparative effectiveness of gonadotropins used for ovarian stimulation during assisted reproductive technologies (ART) in France: A real-world observational study from the French nationwide claims database (SNDS).

This comparative non-interventional study using data from the French National Health Database (Système National des Données de Santé) investigated real-world (cumulative) live birth outcomes following ovarian stimulation, leading to oocyte pickup with either originator recombinant human follicle-stimulating hormone (r-hFSH) products (alfa or beta), r-hFSH alfa biosimilars, or urinaries including mainly HP-hMG (menotropins), and marginally u-hFSH-HP (urofollitropin). Using data from 245,534 stimulations (153,600 women), biosimilars resulted in a 19% lower live birth (adjusted odds ratio (OR) 0.81, 95% confidence interval (CI) 0.76-0.86) and a 14% lower cumulative live birth (adjusted hazard ratio (HR) 0.86, 95% CI 0.82-0.89); and urinaries resulted in a 7% lower live birth (adjusted OR 0.93, 95% CI 0.90-0.96) and an 11% lower cumulative live birth (adjusted HR 0.89, 95% CI 0.87-0.91) versus originator r-hFSH alfa. Results were consistent across strata (age and ART strategy), sensitivity analysis using propensity score matching, and with r-hFSH alfa and beta as the reference group.

ESGO/ESHRE/ESGE Guidelines for the fertility-sparing treatment of patients with endometrial carcinoma.

Background: The standard surgical treatment of endometrial carcinoma (EC) consisting of total hysterectomy with bilateral salpingo-oophorectomy drastically affects the quality of life of patients and creates a challenge for clinicians. Recent evidence-based guidelines of the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy & Oncology (ESTRO) and the European Society of Pathology (ESP) provide comprehensive guidelines on all relevant issues of diagnosis and treatment in EC in a multidisciplinary setting. While also addressing work-up for fertility preservation treatments and the management and follow-up for fertility preservation, it was considered relevant to further extend the guidance on fertility sparing treatment. Objectives: To define recommendations for fertility-sparing treatment of patients with endometrial carcinoma. Materials and Methods: ESGO/ESHRE/ESGE nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of EC (11 experts across Europe). To ensure that the guidelines are evidence-based, the literature published since 2016, identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 95 independent international practitioners in cancer care delivery and patient representatives. Results: The multidisciplinary development group formulated 48 recommendations for fertility-sparing treatment of patients with endometrial carcinoma in four sections: patient selection, tumour clinicopathological characteristics, treatment and special issues. Conclusions: These recommendations provide guidance to professionals caring for women with endometrial carcinoma, including but not limited to professionals in the field of gynaecological oncology, onco-fertility, reproductive surgery, endoscopy, conservative surgery, and histopathology, and will help towards a holistic and multidisciplinary approach for this challenging clinical scenario. What is new? A collaboration was set up between the ESGO, ESHRE and ESGE, aiming to develop clinically relevant and evidence-based guidelines focusing on key aspects of fertility-sparing treatment in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide.

ESGO/ESHRE/ESGE Guidelines for the fertility-sparing treatment of patients with endometrial carcinoma.

Background: The standard surgical treatment of endometrial carcinoma (EC) consisting of total hysterectomy with bilateral salpingo-oophorectomy drastically affects the quality of life of patients and creates a challenge for clinicians. Recent evidence-based guidelines of the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy & Oncology (ESTRO) and the European Society of Pathology (ESP) provide comprehensive guidelines on all relevant issues of diagnosis and treatment in EC in a multidisciplinary setting. While also addressing work-up for fertility preservation treatments and the management and follow-up for fertility preservation, it was considered relevant to further extend the guidance on fertility sparing treatment. Objectives: To define recommendations for fertility-sparing treatment of patients with endometrial carcinoma. Materials and Methods: ESGO/ESHRE/ESGE nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of EC (11 experts across Europe). To ensure that the guidelines are evidence-based, the literature published since 2016, identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 95 independent international practitioners in cancer care delivery and patient representatives. Results: The multidisciplinary development group formulated 48 recommendations for fertility-sparing treatment of patients with endometrial carcinoma in four sections: patient selection, tumour clinicopathological characteristics, treatment and special issues. Conclusions: These recommendations provide guidance to professionals caring for women with endometrial carcinoma, including but not limited to professionals in the field of gynaecological oncology, onco-fertility, reproductive surgery, endoscopy, conservative surgery, and histopathology, and will help towards a holistic and multidisciplinary approach for this challenging clinical scenario. What is new?: A collaboration was set up between the ESGO, ESHRE and ESGE, aiming to develop clinically relevant and evidence-based guidelines focusing on key aspects of fertility-sparing treatment in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide.

Antral follicle responsiveness to follicle-stimulating hormone administration assessed by the Follicular Output RaTe (FORT) may predict in vitro fertilization-embryo transfer outcome.

BACKGROUND: Looking for a qualitative marker of ovarian function, we aimed to verify whether responsiveness of antral follicles to FSH administration, as reflected by the Follicular Output RaTe (FORT), is related to their reproductive competence. METHODS: We studied 322 IVF-ET candidates aged 25-43 years who underwent controlled ovarian hyperstimulation with similar initial FSH doses. Antral follicle (3-8 mm) count (AFC) and pre-ovulatory follicle (16-22 mm) count (PFC) were performed, respectively, at the achievement of pituitary suppression (before FSH treatment) and on the day of hCG administration. The FORT was calculated by PFC × 100/AFC. FORT groups were set according to tercile values: low (<42%; n= 102), average (42-58%; n= 123) and high (>58%; n= 97). RESULTS: The average FORT was 50.6% (range, 16.7-100.0%). Clinical pregnancy rates per oocyte retrieval increased progressively from the low to the high FORT groups (33.3, 51.2 and 55.7%, respectively, P< 0.003) and such a relationship assessed by logistic regression was independent of the confounding covariates, women's ages, AFC and PFC. CONCLUSIONS: The observed relationship between IVF-ET outcome and the percentage of antral follicles that effectively respond to FSH administration reaching pre-ovulatory maturation suggests that FORT may be a qualitative reflector of ovarian follicular competence. Further studies with broader inclusion criteria and more personalized protocols are needed to validate these results.

Serum anti-Müllerian hormone levels are negatively related to Follicular Output RaTe (FORT) in normo-cycling women undergoing controlled ovarian hyperstimulation.

BACKGROUND: Since in rodents anti-Müllerian hormone (AMH) has been shown to inhibit antral follicle responsiveness to FSH, we aimed at verifying whether a relationship exists between serum AMH levels and antral follicle responsiveness to exogenous FSH in normo-cycling women. METHODS: Serum AMH, estradiol (E(2)) and FSH levels were prospectively measured on cycle day 3 in patients undergoing controlled ovarian hyperstimulation (COH) with a time-release GnRH agonist and standardized FSH doses. In 162 patients, follicles were counted after pituitary suppression and before FSH administration (baseline; small antral follicles; 3-8 mm), and on the day of hCG (dhCG; pre-ovulatory follicles; 16-22 mm). Antral follicle responsiveness to FSH was estimated by the Follicular Output RaTe (FORT), determined by the ratio pre-ovulatory follicle count on dhCG × 100/small antral follicle count at baseline. RESULTS: Serum AMH levels were positively correlated with the number of small antral follicles at baseline (r = 0.59; P < 0.0001) and pre-ovulatory follicles on dhCG (r = 0.17; P < 0.04). Overall, FORT was 47.5 ± 1.4% and failed to be influenced by the woman's age, BMI or basal E(2) and FSH level. Conversely, multiple regression analysis showed that FORT was negatively correlated with AMH levels (r = -0.30; P < 0.001), irrespective of duration of COH and total FSH dose. CONCLUSIONS: The percentage of follicles that effectively respond to FSH by reaching pre-ovulatory maturation is negatively and independently related to serum AMH levels. Although the mechanisms underlying this finding remain unclear, it is in keeping with the hypothesis that AMH inhibits follicle sensitivity to FSH.

Impact of oxygen tension according to embryo stage of development: a prospective randomized study.

Human embryo culture under 2-8% O2 is recommended by ESHRE revised guidelines for good practices in IVF labs. Nevertheless, notably due to the higher costs of embryo culture under hypoxia, some laboratories perform embryo culture under atmospheric O2 tension (around 20%). Furthermore, recent meta-analyses concluded with low evidence to a superiority of hypoxia on IVF/ICSI outcomes. Interestingly, a study on mice embryos suggested that oxidative stress (OS) might only have an adverse impact on embryos at cleavage stage. Hence, we aimed to demonstrate for the first time in human embryos that OS has a negative impact only at cleavage stage and that sequential culture conditions (5% O2 from Day 0 to Day 2/3, then «conventional¼ conditions at 20% O2 until blastocyst stage) might be a valuable option for human embryo culture. 773 IVF/ICSI cycles were included in this randomized clinical trial from January 2016 to April 2018. At Day 0 (D0), patients were randomized using a 1:2 allocation ratio between group A (20% O2; n = 265) and group B (5% O2; n = 508). Extended culture (EC) was performed when ≥ 5 Day 2-good-quality-embryos were available (n = 88 in group A (20% O2)). In subgroup B, 195 EC cycles were randomized again at Day 2 (using 1:1 ratio) into groups B' (5% O2 until Day 6 (n = 101)) or C (switch to 20% O2 from Day 2 to Day 6 (n = 94). Fertilization rate, cleavage-stage quality Day 2-top-quality-embryo (D2-TQE), blastocyst quality (Day 5-top-quality-blastocyst (D5-TQB) and implantation rate (IR) were compared between groups A and B (= cleavage-stage analysis), or A(20% O2), B'(5% O2) and C(5%-to-20% O2). Overall, characteristics were similar between groups A and B. Significantly higher rates of early-cleaved embryos, top-quality and good-quality embryos on Day 2 were obtained in group B compared to group A (P < 0.05). This association between oxygen tension and embryo quality at D2 was confirmed using an adjusted model (P < 0.05). Regarding blastocyst quality, culture under 20% O2 from Day 0 to Day 6 (group A) resulted in significantly lower Day 5-TQB number and rates (P < 0.05) compared to both groups B' and C. Furthermore, blastocyst quality was statistically equivalent between groups B' and C (P = 0.45). At Day 6, TQB numbers and rates were also significantly higher in groups B' and C compared to group A (P < 0.05). These results were confirmed analyzing adjusted mean differences for number of Day 5 and Day 6 top quality embryos obtained in group A when compared to those respectively in groups B' and C (P < 0.05). No difference in clinical outcomes following blastocyst transfers was observed. These results would encourage to systematically culture embryos under hypoxia at least during early development stages, since OS might be detrimental exclusively before embryonic genome activation.

Borderline ovarian tumors: Guidelines from the French national college of obstetricians and gynecologists (CNGOF).

It is recommended to classify Borderline Ovarian Tumors (BOTs) according to the WHO classification. Transvaginal and suprapubic ultrasonography are recommended for the analysis of an ovarian mass (Grade A). In case of an undetermined ovarian lesion on ultrasonography, it is recommended to perform a pelvic MRI (Grade A) with a score for malignancy (ADNEX MR/O-RADS) (Grade C) included in the report and to formulate a histological hypothesis (Grade C). Pelvic MRI is recommended to characterize a tumor suspected of being BOT (Grade C). It is recommended to evaluate serum levels of HE4 and CA125 and to use the ROMA score for the diagnosis of indeterminate ovarian mass on imaging (grade A). If there is a suspicion of a mucinous BOT on imaging, serum levels of CA 19-9 may be proposed (Grade C). For Early Stages (ES) of BOT, if surgery without risk of tumor rupture is possible, laparoscopy with protected extraction is recommended over laparotomy (Grade C). For treatment of a bilateral serous ES BOT with a strategy to preserve fertility and/or endocrine function, bilateral cystectomy is recommended where possible (Grade B). For mucinous BOTs with a treatment strategy of fertility and/or endocrine function preservation, unilateral salpingo-oophorectomy is recommended (grade C). For mucinous BOTs treated by initial cystectomy, unilateral salpingo-oophorectomy is recommended (grade C). For serous or mucinous ES BOTs, routine hysterectomy is not recommended (Grade C). For ES BOTs, lymphadenectomy is not recommended (Grade C). For ES BOTs, appendectomy is recommended only in case of a macroscopically pathological appendix (Grade C). Restaging surgery is recommended in cases of serous BOTs with micropapillary architecture and an incomplete abdominal cavity inspection during initial surgery (Grade C). Restaging surgery is recommended for mucinous BOTs after initial cystectomy or in cases where the appendix was not examined (Grade C). If restaging surgery is decided for ES BOTs, the following procedures should be performed: peritoneal washing (grade C), omentectomy (grade B), complete exploration of the abdominal cavity with peritoneal biopsies (grade C), visualization of the appendix and appendectomy in case of a pathological macroscopic appearance (grade C) as well as unilateral salpingo-oophorectomy in case of a mucinous BOT initially treated by cystectomy (grade C). In advanced stages (AS) of BOT, it is not recommended to perform a lymphadenectomy as a routine procedure (Grade C). For AS BOT in a patient with a desire to fall pregnant, conservative treatment involving preservation of the uterus and all or part of the ovary may be proposed (Grade C). Restaging surgery aimed at removing all lesions, not performed initially, is recommended for AS BOTs (Grade C). After treatment, follow-up for a duration greater than 5 years is recommended due to the median recurrence time of BOTs (Grade B). It is recommended that a systematic clinical examination be carried out during follow-up of a treated BOT (Grade B). If the determination of tumor markers is normal preoperatively, the routine dosage of tumor markers in BOT follow-up is not recommended (Grade C). In case of an initial elevation in serum CA 125 levels, it is recommended to monitor CA 125 during follow up (Grade B). In case of conservative treatment, it is recommended to use transvaginal and transabdominal ultrasound during follow up of a treated BOT (Grade B). In the event of a BOT recurrence in a woman of childbearing age, a second conservative treatment may be proposed (Grade C). A consultation with a physician specialized in Assisted Reproductive Technique (ART) should be offered in the case of BOTs in women of childbearing age (Grade C). When possible, a conservative surgical strategy is recommended to preserve fertility in women of childbearing age (Grade C). In the case of optimally treated BOT, there is no evidence to contraindicate the use of ART. The use of hormonal contraception after serous or mucinous BOT is not contraindicated (Grade C). After management of mucinous BOT, for women under 45 years, given the benefit of Hormonal Replacement Therapy (HRT) on cardiovascular and bone risks, and the lack of hormone sensitivity of mucinous BOTs, it is recommended to offer HRT (Grade C). Over 45 years of age, HRT can be prescribed in case of a climacteric syndrome after individual benefit to risk assessment (Grade C).

[Borderline Ovarian Tumours: CNGOF Guidelines for Clinical Practice - Fertility]. / Tumeurs frontières de l'ovaire. Recommandations pour la pratique clinique du CNGOF ­ Fertilité.

OBJECTIVES: Borderline ovarian tumours (BOT) represent around 15% of all ovarian neoplasms and are more likely to be diagnosed in women of reproductive age. Overall, given the epidemiological profile of BOT and their favourable prognosis, ovarian function and fertility preservation should be systematically considered in patients presenting these lesions. METHODS: The research strategy was based on the following terms: borderline ovarian tumour, fertility, fertility preservation, infertility, fertility-sparing surgery, in vitro fertilization, ovarian stimulation, oocyte cryopreservation, using PubMed, in English and French. RESULTS AND CONCLUSIONS: Fertility counselling should become an integral part of the clinical management of women with BOT. Patients with BOT should be informed that surgical management of BOT may cause damage ovarian reserve and/or peritoneal adhesions. Nomogram to predict recurrence, ovarian reserve markers and fertility explorations should be used to provide a clear and relevant information about the risk of infertility in patients with BOT. Fertility-sparing surgery should be considered for young women who wish preserving their fertility when possible. There is insufficient evidence to claim a causal relation between controlled ovarian stimulation (COS) and BOT. However, in case of poor prognosis factors, the use of COS should be considered cautiously through a multidisciplinary approach. In case of infertility after surgery for BOT, COS can be performed without delay, once histopathological diagnosis of BOT is confirmed. There is insufficient consistent evidence that fertility drugs and COS increase the risk of recurrence of BOT after conservative management. The conservative surgical treatment can be associated to oocyte cryopreservation considering the high risk of recurrence of the disease. In women with BOT recurrence in a single ovary and in women with bilateral ovarian involvement when the conservative management is not possible, other fertility preservation strategies are available, but still experimental.