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.

[The influence of exogenous LH/hCG activity on serum progesterone levels on the day of hCG administration in in vitro fertilization]. / Influence de l'activité LH/hCG exogène sur le taux sérique de progestérone le jour de l'hCG en fécondation in vitro.

OBJECTIVES: Clarifying whether the addition of recombinant LH (rLH) to recombinant FSH (rFSH) leads to progesterone (P4) levels on dhCG comparable to those obtained with stimulation with FSH and hCG (HP-hMG) MATERIALS AND METHODS: Pituitary-desensitized patients, matched for age and follicle reserve, received rFSH+LH (n=729) or HP-hMG (n=729). In the rFSH+rLH group, rLH (75 UI/day) was started at day 6. To control for the influence of ovarian response on P4, we divided serum P4 levels by the number of growing follicles (13-22 mm; "per follicle" P4 levels) and performed a multivariate analysis. RESULTS: Serum P4 levels on dHCG were lower in the HP-hMG (median: 0.63 ng/mL, max-min: 0.10-2.97) than in the rFSH+rLH group (0.91 ng/mL; 0.10-4.65, P<0.0001), as well as "per-follicle" P4 levels (0.055 ng/mL/growing follicle, 0.006-0.284 vs 0.077 ng/mL/growing follicle, 0.003-0.336; P<0.0001). CONCLUSIONS: HP-hMG led to lower P4 levels on day hCG than rFSH+rLH irrespective of the intensity of the ovarian response and the adjunction of rLH (75 IU/day from day 6 onward).

[Cancer, fertility preservation and gonadotropins]. / Cancer, préservation de la fertilité et gonadotrophines.

The recent emergence of oncofertility raises the question of ovarian stimulation and its risks when performed for oocyte or/and embryo cryopreservation in a fertility preservation program. The relation between ovarian stimulation and cancer has been marked by the possible direct or indirect tumorigenic role for pituitary gonadotrophins in the tumorogenesis. Although the growth of many gonadal and extragonadal tumors is stimulated by gonadal sex hormones, whose production is regulated by gonadotrophins, there is still a lack of data to consider FSH and LH as tumor promoters. The purpose of this brief review is to present on one hand, the questions raised by the administration of exogenous gonadotrophins in cancer patients and on the other, to evaluate both experimental and clinical data about the possible relation between gonadotrophins and tumorogenesis.

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.

[Are mild ovarian stimulations for IVF-ET a significant progress in assisted reproductive technologies?]. / Les stimulations ovariennes modérées pour fécondation in vitro constituent-elles un réel progrès en assistance médicale à la procréation ?

Growing evidence indicates that mild ovarian stimulation for in vitro-fertilization-embryo transfer may be an interesting approach to reduce the incidence and severity of complications, the number of treatment days, cost, patient discomfort and number of patient drop-outs. However, the heterogeneity of FSH-sensitive follicles, presumably requires multiple follicular growth to improve oocyte-embryo selection. In addition, whether the acceptability probably is similar between standard ovarian stimulation and mild stimulation, per-treatment pregnancy rates with conventional stimulation is superior to mild stimulation in unselected populations. Hence, some specific indications tend to emerge such as alterations of the ovarian follicular reserve in women of less than 38 years, bad embryo qualities and implantation failure after conventional stimulation, patients with previous history of hyperstimulation syndrome or contraindications to hyperoestrogenia (estrogeno-related cancers and thromboembolic diseases). However, no randomized trials have ever been performed to compare the results of mild versus conventional stimulation in young patients and good responders. Therefore, there is insufficient scientific evidence to shift from standard stimulation to mild stimulation for all patients. Cultural standards have to be considered in the choice of the type of stimulation.

[Cancellation of IVF-ET cycles: poor prognosis, poor responder, or variability of the response to controlled ovarian hyperstimulation? An analysis of 142 cancellations]. / Annulations en fécondation in vitro : mauvais pronostic, mauvaises répondeuses, ou variabilité de la réponse à la stimulation ? Analyse de 142 annulations.

INTRODUCTION: This retrospective study aimed at analyzing IVF-ET management and outcome after cancellation of a first cycle for poor response. PATIENTS AND METHOD: One hundred and forty-two infertile patients were included in this observational study. After an overall analysis on the outcome of the second IVF-ET attempt, a sub-analysis was performed according to the presence or the absence of poor prognostic criteria defined as mentioned: patient age superior to 38 years old, antral follicle count (3-9 mm in diameter) inferior to 10 on cycle day 3 and day 3 serum AMH and FSH levels less than 1 ng/mL and more than 10 IU/mL, respectively. Main outcome measures were the cancellation rates, pregnancy and live birth rates. RESULTS: When a controlled ovarian stimulation was performed, patients with poor prognosis had higher cancellation rates (37.8% vs. 13.3%, P<0.004) and lower pregnancy and live birth rates (22.2% vs. 35.0%, P<0.05 and 11.1% vs. 26.1%, P<0.05, respectively) as compared to good prognosis women. CONCLUSION: The relatively high cancellation rate in patients with poor prognosis raises the question of the use of IVF modified natural cycle in this group.

[Preimplantation diagnosis with HLA typing: birth of the first double hope child in France]. / Diagnostic préimplantatoire avec typage HLA : naissance du premier enfant du double espoir en France.

Preimplantation genetic diagnosis (PGD) is authorized in France since 1999. After 10 years, technical results are encouraging. With the development of new technologies, our team is able to diagnosis the large majority of chromosome translocations and 75 monogenic diseases. However, PGD remains limited because of the growing augmentation of demands causing an increasing delay for the first procedure of more than 18 months. Since 2006, 19 couples asked for a PGD with HLA typing. In January 2011, 11 couples have already been included in our PGD program. The birth of the first child after PGD with HLA typing offers new perspectives of treatment for these couples.

[Fertility preservation in cancer women: a multidisciplinary approach]. / Préservation de la fertilité féminine en cas de cancer : intérêt d'une prise en charge pluridisciplinaire.

Over the past two decades, major advances in diagnostic modalities and treatment have markedly improved rates of cure for adult cancers. As a consequence, the number of long-term survivors is increasing, and fertility preservation has become a major issue for young patient about to start treatment for cancer. Whether fertility preservation is a promising option, most of the technologies currently used are far from being well established or are even still experimental. Patients should be aware that no method guarantees success. Psychological and ethical impacts of fertility preservation are major concerns and should be included in the multidisciplinary approach of the patients.

Is first-trimester crown-rump length associated with birthweight?

OBJECTIVE: To evaluate the relationship between first-trimester crown-rump length (CRL) and birthweight (BW) Z scores. DESIGN: Retrospective cohort study. SETTING: Two tertiary centres in France. POPULATION: Three hundred and seventeen pregnancies conceived through assisted reproductive techniques between April 2001 and December 2008. METHODS: We used CRL and worked forward to BW. Only pregnancies examined during the first trimester by an Fetal Medicine Foundation-certified operator were included. CRL was expressed as Z scores, and BW was transformed into Z scores by taking gestational age and gender into account. The influence of abnormal first-trimester CRL Z scores on BW was examined. MAIN OUTCOME MEASURES: Weight and gestational age at birth. RESULTS: Birth weight was significantly greater in babies with larger CRL: BW Z scores (± SD) were -0.36 (± 1.05), -0.27 (± 0.97), -0.10 (± 1.04) and 0.13 (± 0.96) in the first, second, third and fourth quartiles of CRL Z scores, respectively (P = 0.01). In contrast, there was no difference in gestational length according to the quartiles of the CRL Z scores. The CRL Z score was a significant predictor of the BW Z score (ß = 0.17, P = 0.001). After adjustment for maternal body mass index, a one-point increase in the first-trimester CRL Z score (i.e. 3.6 mm) was associated with a 39% decrease, 64% increase, 114% increase and 62% increase in the risk of having a BW below the 10th centile [odds ratio (OR), 0.61; 95% confidence intervals (95% CI), 0.39; 0.95; P=0.03], above the 90th centile (OR, 1.64; 95% CI, 1.03; 2.60; P = 0.02), above the 95th centile (OR, 2.14; 95% CI, 1.25; 3.68; P = 0.006) and above 4000 g (OR, 1.62; 95% CI, 1.04; 2.51; P = 0.04), respectively. CONCLUSIONS: Variations in BW may be partly explained by differences in growth trajectories that may express as early as the first trimester.

[Serum AMH level is not a predictive value for IVF in modified natural cycle: analysis of 342 cycles]. / L'AMH sérique n'a pas de valeur prédictive en fécondation in vitro en cycle naturel modifié : analyse de 342 cycles.

The objective is to compare the IVF procedures in modified natural cycle outcomes according to serum anti-Mullerian hormone (AMH) levels. We included in this retrospective study 342 patients undergoing their first IVF in modified natural cycle. Patients were regrouped in three groups according to their serum AMH level: group 1 was defined by patients with AMH level<0.97 ng/mL (<25th percentile), group 2, patients with AMH level between 0.97 ng/mL and 2.60 ng/mL (25-75th percentile), and group 3, patients with AMH level between 2.61 ng/mL and 6.99 ng/mL (>75th percentile). The main outcomes were cancellation rate, embryo transfer rate and clinical pregnancy rate, ongoing pregnancy rate and implantation rate. No difference has been observed on cancellation rate, embryo transfer rate, clinical pregnancy rate and implantation rate. The ongoing pregnancy rate per IVF cycle was respectively: 12.8±3.6% for AMH inferior to 0.97 ng/mL versus 12.5±2.5% for AMH between 0.97 to 2.60 ng/mL and 13.4±4.2% for AMH between 2.61 ng/mL and 6.99 ng/mL. In conclusion, IVF in modified natural cycles procedures should be considered as an option for patients with an altered ovarian reserve defined by a serum AMH inferior to 1 ng/mL. Serum AMH level seems a quantitative marker of the ovary but not a quality factor. Serum AMH level does not seem to be a prognostic factor for ongoing pregnancy rated in IVF modified cycles.

[In vitro maturation of oocytes: an option for fertility preservation in women]. / Préservation de la fertilité féminine: place de la maturation ovocytaire in vitro.

Although female cancer incidence may be on rise, antineoplastic regimens have become more successful. As a result, an increasing number of women with cancer survive to endure the long-term consequences of chemotherapy. One of the most important long-term consequences of cancers treatments in young female is premature ovarian failure and infertility. Because of the increasing survival rates, many of these young women are seeking methods to preserve their fertility. Currently, embryo/oocytes cryoporeservation obtained after ovarian stimulation appears to provide the best fertility preservation option. However, patients may not have sufficient time to undergo ovarian stimulation prior to chemotherapy and/or the hormones used in ovarian stimulation are contra-indicated for estrogen-dependant tumors. In vitro maturation of oocytes (IVM) has been suggested to avoid ovarian stimulation and time requirement in patients with cancer, and can be combined with ovarian tissue cryobanking. In this review, we will discuss the position of IVM in the strategy of fertility preservation in young women.

[Impact of elective single embryo transfer criteria on the twin pregnancy rate in a French population]. / L'impact des critères du élective single embryo transfer sur le taux de grossesses gémellaires dans la population française.

To reduce the twin pregnancy rate and their morbidity, several recommendations have been proposed to practice the "elective single embryo transfer" in a selected population. We decided to apply the criteria that were proposed in five articles from the literature to our population to evaluate the percentage of our population concerned and the impact on our twin pregnancy rate. The result is that these criteria only concern 2,4 to 10,8% of our population with a minor reduction of our twin pregnancy rate with a potential lake of chance concerning the pregnancy rate. We should study others possibilities than the population's criteria to reduce the number of embryo transferred.

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.

[Non-obstructive azoospermia: option of the testicular sperm extraction performed on the day of oocyte retrieval]. / Azoospermie non obstructive: intérêt du prélèvement testiculaire synchrone du recueil ovocytaire.

OBJECTIVE: Analyzing the results and validating the procedure of testicular sperm extraction (TESE) performed on the day of oocyte retrieval in non obstructive azoospermia (NOA) patients. PATIENTS AND METHODS: Sixty TESE were performed on the day of oocyte retrieval (dOR), in 52 NOA men. Patients were sorted into three groups according to the results of the surgical procedure: 1: sperm recovery with possible sperm freezing (n=20); 2: sperm recovery without freezing (n=27); 3: "negative" biopsy (n=13). ICSI outcomes in the two groups with sperm recovery were compared to those of ICSI performed with frozen-thawed sperm obtained from TESE performed (n=13). RESULTS: The rate of positive sperm retrieval was 78%. While the overall clinical pregnancy rate was 50%, no difference in the fertilization, implantation and clinical pregnancy rates was found in the two groups with positive sperm retrieval as compared to frozen-thawed sperm group. Twelve pregnancies were obtained in patients without further sperm cryopreservation. CONCLUSION: After TESE in NOA men, cryopreserved sperm produced comparable results with freshly obtained sperm. However, TESE performed on dOR can offer the opportunity, in patients with rare sperm that might not survive freeze-thaw, to have a possible fresh embryo transfer. Couples should be counselled regarding the possibility of oocyte retrieval without sperm for ICSI.

[Statement: cancer treatments and ovarian reserve]. / Mise au point: traitements anticancéreux et réserve ovarienne.

PURPOSE OF REVIEW: The purpose of this review is to update the reader on the impact of cancer treatment on fertility, the options of fertility preservation, and the new markers to assess ovarian function. ESSENTIAL POINTS: The impact of chemotherapy and radiotherapy on fertility depends on the drugs and the doses used. It often affects ovarian reserve significantly, and the presence of menstruation is not a reliable reflection of it. Fertility preservation techniques, such as ovarian protection, and preferably cryopreservation combined with assisted reproductive medicine, should be individually discussed and possibly proposed to the patients. The use of new markers for ovarian reserve assessment will help to evaluate infraclinic chemotherapy and/or radiotherapy-induced effects on ovarian reserve, prior to clinical effects.

[Anti-Müllerian hormone: player and marker of folliculogenesis]. / Hormone antimüllérienne: acteur et marqueur de la folliculogenèse.

All indicates that anti-Müllerian hormone (AMH), though initially studied for its importance on male development, plays an inhibiting role on the initial and cyclic processes of follicular recruitment. The aspects involved in its regulation are still poorly understood, but the oocyte, some steroids, and follicular development itself seem to be involved. In addition, AMH has become an important clinical marker of ovarian functioning for many reasons, including its exclusive production by granulosa follicles at many stages of development, its probable FSH independence, its low inter and intracycle variability and its reliable quantitative (qualitative?) relationship with ovarian follicles and their response to exogenous FSH. The growing interest in ovarian AMH incited us to review some important fundamental and clinical publications in this field.

[The role of ultrasound examination to evaluate ovarian reserve of infertile patients]. / Place de l'échographie pour le bilan de la réserve ovarienne dans le cadre d'une infertilité

The accurate assessment of ovarian reserve is an essential step before the treatment of infertile couples. Ovarian reserve could either be evaluated through clinical or biological parameters, but ultrasound plays a remarkable role, since it permits the direct visualization and count of ovarian antral follicles. Nevertheless, the available literature data are conflicting about the real sensibility and specificity of this method to predict the exact number of retrieved oocytes or the occurrence of pregnancy after a procedure for medical assisted reproduction. New technologies have been developed, as the 3D-ultrasound, who does not ameliorate ultrasound accuracy, but permits the reduction of the time necessary for patient's examination and virtually eliminates inter- and intra-observer bias. The place of the ovarian artery flow evaluation by Doppler remains unclear and need more studies.

[Is the stability of results in IVF possible?]. / La stabilité des résultats en fécondation in vitro est-elle possible ?

OBJECTIVES: To evaluate quality control impact, in assisted reproductive medecine, in view of the stability of results. MATERIALS AND METHODS: Prospective collection of all IVF cycles at the center of AMP at Antoine-Béclère hospital (Clamart), as well as pregnancy outcomes, from 2002 till 2006. RESULTS: 44.3% in the clinical pregnancy rate and 38.0% in the delivery rate per oocyte retrieval. These rates are stable during the five years studied. The rate of multiple pregnancy is of 30.7%, decreasing, with the decrease in number of transferred embryos. CONCLUSION: Results are stable over five years duration. Quality control seems to be necessary.

[Stimulation quality in IVF]. / Qualité de la stimulation en FIV.

Quality control in IVF stimulation requires first establishing the ovarian follicle status, then a hormone strategy, and finally monitoring follicle maturation. The ovary examination includes an ultrasound examination to evaluate the number of follicles and their size and hormone tests measuring FSH, E2, but most particularly AMH levels. The hormone strategy during COH mainly seeks to obtain a large number of antral follicles of a homogeneous size and quality, using either FSH suppression at the end of the luteal phase or the administration of a GnRH antagonist in the premenstrual phase. Follicle maturation during COH is usually monitored using ultrasound, with three-dimensional and/or software measurements to evaluate follicle volume.