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Study question How a new specialized e-meeting for complex cases in oncofertility is used by fertility preservation specialists (FPS)? Summary answer The e-meeting for complex oncofertility cases is an innovative tool that fulfils the needs of FPS and could help them to improve their oncofertility practice. What is known already Little is known about the management of fertility preservation (FP) in rare cancer that could be challenging for FPS due to lack of experience and scientific data. To our knowledge, there is no specially dedicated meeting reported in published literature to provide highly specialized advices to FPS in these challenging situations of FP. Study design, size, duration We present three years of activity of a national French e-meeting dedicated to the management of challenging oncofertility cases. We conducted a retrospective analysis of all submitted cases. Second, a survey was conducted to evaluate the use of this e-meeting at participating FPS. Participants/materials, setting, methods The E-meeting for Complex Cases in Oncofertility was created in 2016 September in France, allowing for National oncofertility experts to share viewpoints about challenging cases for which they do not have experience and/or no sufficient data available in published literature. Demographic and clinical data, number of replies and proposal for each case were collected retrospectively. A survey to investigate the use and the interest of FPS for this tool was sent to its members. Main results and the role of chance: One hundred and four experts have joined the e-meeting since its set-up and 109 challenging cases have been submitted. Mean age of patients was 22.0 ± 8.9 years old and 87% were female. Most of cases were hematological cancers (n = 32/109; 29%), gynecologic cancers (n = 30/109; 27%) and neurological cancers (n = 12/109; 10.9%). Each submitted case received on average 2 ± 1 different strategy for FP and the opinion of 7 ± 2 experts. Among the FPS who submitted cases, seeking the opinions from others FPS allowed them to confirm their care plan (N = 49; 84%), to offer different options to their patient (N = 34; 58%) and to compare their practices with other specialists (N = 23; 39%). All respondents reported a self-perceived improvement in their practice of oncologic FP (n = 80; 100%). Limitations, reasons for caution Although this study showed a perceived improvement at FPS in the management of challenging oncofertility cases, we did not study in details their adherence to the e-meeting’s proposals. The value of this new tool has also not been assessed regarding patient’s quality of life and further fertility. Wider implications of the findings: Specific attention should be paid for challenging cases in oncofertility for which only experiences of individual exist. Enhancing communication between FPS through national and international networks, pooling experiences and collecting the most complex cases are required in order to improve the management of these patients. Trial registration number Not applicable

International audience; Objective: To present a case series of women with borderline ovarian tumours (BOTs) who underwent oocyte vitrification in addition to fertility-sparing surgery.Study design: Observational study of all women referred to a French fertility preservation unit between 2015 and 2019 for counselling regarding a fertility preservation (FP) strategy after BOT fertility-sparing surgery. All eligible women underwent one or more cycles of controlled ovarian stimulation (COS) using an antagonist protocol, followed by oocyte retrieval. Metaphase II (MII) oocytes were vitrified.Results: Twenty-five women with BOTs were referred during the study period. Among them, 11 women underwent at least one cycle of COS. One hundred and seven MII oocytes were vitrified. The mean number of vitrified MII oocytes per woman was 9.7 (standard deviation 5.2). Five live births were reported during follow-up of four women with vitrified oocytes: three spontaneous pregnancies, one in-vitro fertilization cycle with fresh embryo transfer, and one live birth after return of vitrified oocytes.Conclusion: Conservative surgery for BOTs offers a high spontaneous pregnancy rate but has a higher risk of relapse than radical treatment. Furthermore, women who undergo conservative BOT surgery have a higher risk of surgery-induced premature ovarian failure. Oocyte cryopreservation after COS appears to be an effective technique after the conservative management of BOTs in women of reproductive age. Although the available short-term data are reassuring, further long-term studies evaluating the safety and cost-effectiveness of this systematic FP strategy after BOT fertility-sparing surgery are required.

International audience; Despite rectal cancer being unusual before 40, fertility preservation (FP) remains a major concern for these reproductive-age women. Treatment usually involves pelvic radiotherapy, neoadjuvant chemotherapy, and surgery of rectum and mesorectum resection, at high risk of impairing fertility in women with risks of premature ovarian failure and radio-induced uterus damage. To date, there is no consensus on FP strategy for rectal cancer. We shared experiences between oncofertility experts from a French research network Groupe de Recherche et d'Etude en Cryoconservation Ovarienne et Testiculaire about a case of rectal cancer in a young woman. Indications, advantages and disadvantages of different FP strategies were discussed: ovarian transposition, cryopreservation of ovarian cortex and oocyte vitrification. This case was the starting point that led to the development of a French multidisciplinary e-meeting for sharing experiences and for suggesting the best strategy when faced with a complex oncofertility case.

International audience; Objective: To evaluate the percentage of parents in one French center for the study and preservation of eggs and sperm who disclose their use of donated spermatozoa to their children.Design: A questionnaire survey of couples who had a child using donated spermatozoa.Setting: University hospital laboratory.Patient(s): One hundred five couples.Intervention(s): Questionnaire sent by mail.Main Outcome Measure(s): The percentage of parents who disclose their use of donated spermatozoa to their child.Result(s): Among the 157 questionnaires sent, 105 couples answered, which corresponded to 138 children. There were 40 (38%) couples who had already disclosed the donor origin to their child and 65 (62%) who had not. Of the 40 couples who disclosed the donor origin, 37 (93%) had intended to do so before making use of assisted reproductive techniques (ART), but two (5%) had not wanted to do so before ART. Among the 65 couples who did not inform their child, 42 (65%) planned to inform their child soon, but 20 (31%) wanted to keep the sperm origin secret. Of the 20 couples who wanted to keep the origin secret, nine couples had told other persons about the gamete donation but had not informed their child and do not intend to inform their child in the future.Conclusion(s): This first report about disclosure attitude in a large cohort of parents of donor-conceived offspring in France showed that most parents had already disclosed their use of donated spermatozoa to their children or intended to disclose it soon and had an attitude after birth consistent with their intentions prior to ART.

International audience; A recent study of 17 men with decapitated spermatozoa found that 8 carried two rare SUN5 alleles, and concluded that loss of SUN5 function causes the acephalic spermatozoa syndrome. Consistent with this, the SUN5 protein localises to the head-tail junction in normal spermatozoa, and SUN proteins are known to form links between the cytoskeleton and the nucleus. However, six of the ten SUN5 variants reported were missense with an unknown effect on function, and only one man carried two high confidence loss-of-function (LOF) alleles: p.Ser284* homozygozity. One potential exonic splice mutation, homozygous variant p.Gly114Arg, was not tested experimentally. Thus, definitive proof that loss of SUN5 function causes the acephalic spermatozoa syndrome is still lacking. Based on these findings, we determined the sequence of the SUN5 gene in three related men of North African origin with decapitated spermatozoa. We found all three men to be homozygous for a deletion-insertion variant (GRCh38 - chr20:32995761_32990672delinsTGGT) that removes 5090 base pairs including exon 8 of SUN5, predicting the frameshift, p.(Leu143Serfs*30), and the inactivation of SUN5. We therefore present the second case where the acephalic spermatozoa syndrome is associated with two LOF alleles of SUN5. We also show that the p.Gly114Arg variant has a strong inhibitory effect on splicing in HeLa cells, evidence that homozygozity for p.Gly114Arg causes acephalic spermatozoa syndrome through loss of SUN5 function. Our results, together with those of the previous study, show that SUN5 is required for the formation of the sperm head-tail junction and male fertility.

International audience; Beside cytotoxic drugs, other drugs can impact men's fertility through various mechanisms. Via the modification of the hypothalamic-pituitary-gonadal axis hormones or by non-hormonal mechanisms, drugs may directly and indirectly induce sexual dysfunction and spermatogenesis impairment and alteration of epididymal maturation. This systematic literature review summarizes existing data about the negative impact and associations of pharmacological treatments on male fertility (excluding cytotoxic drugs), with a view to making these data more readily available for medical staff. In most cases, these effects on spermatogenesis/sperm maturation/sexual function are reversible after the discontinuation of the drug. When a reprotoxic treatment cannot be stopped and/or when the impact on semen parameters/sperm DNA is potentially irreversible (Sulfasalazine Azathioprine, Mycophenolate mofetil and Methotrexate), the cryopreservation of spermatozoa before treatment must be proposed. Deleterious impacts on fertility of drugs with very good or good level of evidence (Testosterone, Sulfasalazine, Anabolic steroids, Cyproterone acetate, Opioids, Tramadol, GhRH analogues and Sartan) are developed.

Sperm banking is an important procedure to preserve fertility before cancer therapy. The aim of this study was to comprehensively analyse cryopreservation activity retrospectively for 1080 patients referred to the sperm bank for sperm cryopreservation before cancer treatment. This study included 1007 patients diagnosed with testicular cancer (TC) (41.7%), lymphoma (26%), other haematological cancers (9.4%) or other types of cancer (22.8%); of these, 29 patients did not produce any semen sample and cryopreservation was impossible for 67 patients. Semen characteristics before treatment were within normal ranges, except moderate asthenospermia. Sperm concentration was significantly lower in TC than in non-TC. Straws from 57 patients (6.3%) were used in assisted reproductive technologies, which led to a 46.8% cumulative birth rate. Straws were destroyed for 170 patients (18.7%) and 140 patients performed semen analyses after cancer therapy. After an average delay of 22.5 months after the end of therapy, 43 patients (30.7%) exhibited azoospermia. This study of a large population of cancer patients revealed a high level of successful sperm storage. Utilization of cryopreserved spermatozoa led to good chances of fatherhood. Nevertheless, sperm banks should be aware of the low rates of straw use and straw destruction by cancer patients.

Resume But Une modification de la loi de bioethique francaise permettant aux enfants concus par don de gametes de connaitre l’identite des donneurs a ete proposee, alors qu’aucune etude ne permet d’evaluer la proportion de parents qui informent leur enfant sur son mode de conception en France. Le but de notre enquete a ete de savoir si les couples qui disaient vouloir informer leur enfant le faisaient reellement. Patients et methodes Nous avons adresse un questionnaire aux parents d’enfants issus de don de sperme, qui avaient manifeste l’intention d’informer leur futur enfant de son mode de conception, afin d’evaluer quantitativement le nombre de couples qui informent leur enfant, et qualitativement le ressenti du couple et de l’enfant face a la communication de cette information. Resultats Sur 38 questionnaires envoyes, 20 couples ont repondu. Quatorze declarent avoir informe leur enfant sur son mode de conception, la plupart ayant bien vecu ce moment. Quarante-sept pour cent des enfants ont reagi avec indifference. Alors que 19 couples ont informe leur entourage, six couples n’ont pas encore informe leur enfant, et deux d’entre eux ne souhaitent plus informer leur enfant. Conclusion Une reflexion approfondie en amont de la prise en charge et un accompagnement apres la naissance sont necessaires pour aider les couples a communiquer l’information a leur enfant. Sans cette communication, toute modification de la loi permettant de diffuser les donnees relatives au donneur nous semble inutile.

The aim of this study was to describe the association between various percentages of macronuclear spermatozoa (MNSs), sperm chromosomal abnormalities, and reproductive failure in 4 patients. One patient had a familial history of perinatal deaths. Patients were selected according to the coexistence of normal-sized spermatozoa and MNSs (19%, 22%, 29.5%, and 49.7%). Fluorescent in situ hybridization (FISH) on spermatozoa and semiautomated analysis of nuclear surface were assessed. All patients were characterized by an oligoasthenozoospermia. Three patients had a prevalence of irregular MNSs and prevalence of nondisjunction at the first meiotic division. One patient had a prevalence of regular MNSs and a prevalence of nondisjunction at the second meiotic division. FISH also showed a high rate of polyploidy and various rates of aneuploid sperm. The percentage of sperm with abnormal chromosome complements (25.6%, 43.6%, 51.4%, 71.7% with 3-color FISH) was higher than the percentage of MNSs. A population of apparently normal-sized spermatozoa that could be used for intracytoplasmic sperm injection (ICSI) was aneuploid. Sperm nuclear surface analysis revealed either a shift toward elevated values or distinguished 2 sperm subpopulations: normal and macronuclear. Patients underwent 7 ICSI cycles. The fertilization rate was low for 3 patients (50%, 40%, 50%) and normal for 1 patient (83.3%). Pregnancy rate per transfer was low (14.3%). The present study shows that the macronuclear phenotype can manifest a variety of clinical aspects. It is also shown that mild rates of MNSs impair fertility and constitute a risk of chromosomal abnormality for the embryos and a risk of perinatal death. We suggest conducting FISH on spermatozoa and genetic counseling for a couple when the percentage of MNSs reaches 20% in at least 1 spermiogram.

International audience; Purpose The aim of this study is to assess the feasibility of ă ovariectomy by single-port access laparoscopy for cryopreservation. ă Methods Observational prospective monocentric study including patients ă referred for an ovariectomy for ovarian tissue cryopreservation ă underwent ovariectomy by single-port access laparoscopy. Feasibility, ă intra-and post-operative complications, and quality of the ovarian ă tissue collected were reported. ă Results Height patients were included. No conversion to standard ă laparoscopy or laparotomy was performed and no intra-or post-operative ă complications were reported. Median duration of surgery was 35 min ă (30-60). The quality of all the ovarian tissue collected was correct, ă and cryopreservation was possible for all patients. ă Conclusions Ovariectomy for cryopreservation by laparoscopy with SPA ă seems feasible. The advantages of this technique are particularly ă interesting in these patients who require the least aggressive surgical ă technique possible and a rapid convalescence.

BACKGROUND: This study was aimed at evaluating the rate of pairing failure in pachytene spermatocytes of patients presenting either an obstructive (O) or a non-obstructive (NO) infertility. METHODS: Forty-one patients and 13 controls underwent testicular biopsy. Among the patients, 19 had an O infertility and 22 a NO infertility. Preparations of all patients and controls were Giemsa-stained, and synaptonemal complexes from nine of these patients and one control were immunostained. RESULTS: In all, 2931 pachytene nuclei were analysed. The mean rate of asynapsed nuclei from the NO group (25.4%) was significantly higher than that of the O group (9.8%). There was no significant difference between the O group and the controls (10.6%). Immunocytochemistry showed that the number of pachytene nuclei decreased from the early to late pachytene sub-stage in all patients. Two NO patients, one azoospermic and one oligozoospermic, had a high percentage of asynapsed nuclei (86 and 91.8% respectively); one of these patients also presented a precocious localized separation of sister chromatids. CONCLUSION: high levels of extended asynapsis could arise from a primary meiotic defect which may be responsible for 9% of the NO male infertilities at our centre. The prevalence of early pachytene substages suggests that the pachytene checkpoint is localized at the mid-pachytene stage in humans.

In spinal cord injured (SCI) patients, three main factors may cause infertility: erectile dysfunction, ejaculatory dysfunction and impaired semen quality. This letter aims to discuss how we can manage SCI patients’ fertility in accordance with patient-centred care. For such SCI patients aged 20 to 40, having children represents hope for the future. Furthermore, it is a way to rebuild a life after the spinal injury and must be seen as an important part of the rehabilitation program. We suggest that sperm cryopreservation may contribute to patient-centred care management of SCI patients’ fertility, although there is no scientific evidence that cryopreservation will improve fertility outcome after SCI. Indeed, sperm cryopreservation is an affordable and simple technique in specialised centres with trained staff. Here, a protocol to manage SCI patients’ fertility is discussed: we propose PVS for sperm banking to all SCI patients after the phase of spinal shock during the rehabilitation program. If live sperm are retrieved, they are frozen and stored; however, if no live sperm are retrieved, electroejaculation and/or surgical sperm extraction are proposed only for patients who desire biological fatherhood. Prospective studies on the evolution of semen parameters, ejaculatory dysfunction, post-infectious obstructions and spermatogenesis impairment in chronic SCI patients are urgently needed to provide robust data for the evidence-based management of SCI patients’ fertility. Even if use rates are expected to be low, sperm banking may be a simple and affordable preventative measure for selected male SCI patients.

Testicular cancer is the most common cancer in young men. Several studies have reported an alteration in semen quality in nonseminoma tumors, but this result has not been confirmed in all of the published data. We performed a retrospective study in a population of 1158 men with testicular cancer who banked sperm between 1999 and 2003 in 11 French Centre d'Etude et de Conservation des Oeufs et du Sperme humain laboratories. Our study evaluated prefreeze and postthaw sperm parameters according to patient medical history, tumor histological type, and disease stage. Pure seminomas were found in 48% of our population. Testicular cancer was generally diagnosed at stage I. In cases of a history of unilateral cryptorchidism, testicular cancer occurred preferentially in the maldescended testis. Semen samples were preferentially collected after orchiectomy. The sperm concentration and total sperm number were significantly lower before orchiectomy in seminomas compared with nonseminoma tumors (P < .001). After orchiectomy, these parameters decreased for nonseminoma tumors and did not vary for seminomas. Semen parameters were more severely impaired for stage III tumors, and when patients had a history of cryptorchidism or when they were less than 20 years of age. Azoospermia was more frequently observed before than after orchiectomy. In this study, we determined that sperm cryobanking should preferentially be performed before orchiectomy and that testicular sperm extraction concurrent with orchiectomy should be used in severe spermatogenesis impairment. Our study highlights that seminomas alter sperm production more significantly than nonseminoma tumors and seem to preferentially impair spermatogenesis in tumor-bearing testes.

AZFc deletions of the Y chromosome are the major known genetic cause of spermatogenetic failure. Meiotic studies have shown a prevalence of synaptonemal complex fragmentation and an excess of early-stage sperm cells, suggesting that the maturation block could involve apoptosis. We present a prospective and observational study of apoptotic markers in the sperm of four AZFc-deleted patients and two non-obstructive azoospermic controls without an AZFc deletion. Polycaspases assays and terminal deoxynucleotidyl transferase dUDP nick-end labelling (TUNEL) assays were combined to evaluate the incidence of apoptosis in pre-meiotic, meiotic and post-meiotic germs cells identified, respectively, using anti-melanoma-associated antigen A4 (MAGE-A4), anti-synaptonemal complex protein 3 (SCP3) and anti-sperm acrosome membrane-associated protein 1 (SPACA1) antibodies. We detected apoptosis at all stages of AZFc-deletion spermatogenesis. Using the caspase assay, the incidence of positive cells was found to be heterogeneous for pre-meiotic (from 4.8 to 84.5%) and meiotic stages (from 7.9 to 57.6%), while for post-meiotic cells, the mean incidence was 6% in AZFc-deleted patients compared with 26.5% in controls (P < 0.05). Using the TUNEL assay, the mean percentage with DNA fragmentation for meiotic cells was 54.0% in AZFc-deleted patients compared with 20.3% in controls (P < 0.05), while the percentage of TUNEL-positive post-meiotic cells ranged from 5.3 to 44.7%. Spermatocyte loss in AZFc-deleted patients occurs via the apoptotic pathway. In post-meiotic cells, the lower incidence of apoptosis in testis from three of the four AZFc-deleted patients, compared with controls, is consistent with AZFc deletions having little negative impact on sperm quality.

In couples presenting with retrograde ejaculation refractory to medical treatment, the first choice of fertility treatment should be Assisted Reproductive Techniques using rapidly purified spermatozoa retrieved from post-ejaculatory urine. The Hotchkiss technique and modified variants are simple and efficient for retrieving sperm from the bladder. We developed a new protocol, including a novel modified Hotchkiss technique involving sperm cryopreservation. The aim was to study the pregnancy rate and birth rate achieved by intra cytoplasmic sperm injection (ICSI) using frozen-thawed sperm retrieved from the bladder with this novel modified Hotchkiss technique in patients with refractory retrograde ejaculation.In this descriptive retrospective, single-center study, we analyzed the local database of all patients who banked sperm at the CECOS Laboratory Biology of Reproduction of La Conception University Hospital, Marseille, France, between 2004 and 2014. A total of 2171 patients banked sperm during this time, including 63 patients with retrograde ejaculation, of whom ten patients banked sperm that had been retrieved by the modified Hotchkiss technique. These ten couples underwent 26 ICSI cycles: nine clinical pregnancies were achieved in six couples, including eight after fresh embryo transfer and one after thawed embryo transfer, resulting in seven live births. The average live birth rate per transfer was 28 %.We report the largest series of births using frozen-thawed spermatozoa retrieved from post-ejaculatory urine by a modified Hotchkiss technique. This series of births demonstrates that this new modified Hotchkiss technique allows for successful association with sperm cryopreservation, leading to an efficient and easy management of couples with refractory retrograde ejaculation.Chez les couples dont l’homme présente une éjaculation rétrograde réfractaire au traitement médical, la première ligne de traitement de l’infertilité est le recours à l’aide médicale à la procréation (AMP) utilisant des spermatozoïdes purifiés des urines après éjaculation. La technique de Hotchkiss et les techniques de Hotchkiss modifiées sont simples et efficaces pour récupérer les spermatozoïdes de la vessie. Nous avons développé un nouveau protocole avec une nouvelle technique de Hotchkiss modifiée impliquant une cryoconservation des spermatozoïdes obtenus. L’objectif de cette étude était d’étudier les taux de grossesses et de naissances obtenues après injection intra cytoplasmique de spermatozoïdes (ICSI) provenant de paillettes congelées à partir des spermatozoïdes purifiés des urines avec la nouvelles méthode de Hotchkiss modifiée, chez les patients atteints d’éjaculation rétrograde réfractaire.Dans cette étude descriptive monocentrique rétrospective, nous avons analysé la base de données locale de tous les patients ayant conservé du sperme au CECOS du laboratoire de biologie de la reproduction de l’hôpital universitaire de la Conception à Marseille, France, entre 2004 et 2014. Un total de 2171 patients a conservé du sperme pendant cette période. Soixante trois présentaient une éjaculation rétrograde, parmi lesquels 10 ont conservé du sperme qui avait été purifié des urines selon la méthode de Hotchkiss modifiée. Ces 10 couples ont réalisé 26 tentatives d’ICSI. 9 grossesses cliniques ont été obtenues chez 6 couples; 8 après transfert d’embryon frais, et une après transfert d’embryon congelé, ayant conduit à 7 naissances. Le taux moyen de naissance par transfert était de 28 %.Nous rapportons ici la plus large série de naissances utilisant des paillettes de spermatozoïdes purifiés des urines après éjaculation rétrograde selon une méthode de Hotchkiss modifiée. Cette série de naissances démontre que cette nouvelle technique de Hotchkiss permet une association réussie avec la cryoconservation du sperme, permettant une prise en charge facile et efficace des couples avec éjaculation rétrograde réfractaire.

We report ICSI pregnancies in two couples with a history of long standing primary infertility in which the sperm of the male partner were either acephalic or had abnormal head-midpiece attachments. The two couples, in which the men are brothers, underwent ICSI. Sperm were analysed by transmission electron microscopy and immunocytochemistry with an anti-MPM2 monoclonal antibody. The first couple underwent two ICSI cycles, each consisting of the injection of two mature oocytes and the transfer of two embryos. A successful pregnancy occurred after the second transfer and led to the birth to a healthy girl. The second couple underwent three ICSI cycles, each consisting of the injection of 18 oocytes and the transfer of two embryos; the last of these led to a triple ongoing pregnancy which included two identical twins. Caesarean section led to the birth of three fetal-growth restricted children. This case report demonstrates that ongoing pregnancies can be achieved in cases of abnormal development of the head-neck attachment. The genetic origin of this syndrome is generally accepted, but the phenotypic heterogeneity observed by light and electron microscopy among published cases suggests that there are a variety of genetic causes of this syndrome.

The case of a couple with a history of long standing primary infertility is reported in which the man presented with a decapitated sperm defect. The woman had a normal history and presented with normal clinical characteristics. The couple underwent one unsuccessful conventional in-vitro fertilization (IVF). Subsequently, embryos were obtained and transferred after assisted fertilization attempts: in all, three subzonal inseminations and four intracytoplasmic sperm injections. A total of 49 mature oocytes was injected in both studies, 25 embryos obtained and 20 embryos transferred, three of them after freezing and thawing. Despite the good embryo morphology, implantation was unsuccessful and no pregnancy occurred. The failure of implantation may have resulted from an arrest in early embryonic development related to the sperm anomaly. One hypothesis is that transferred embryos may carry a chromosomal imbalance that prevents them from progressing to the blastocyst stage. Nevertheless, we cannot exclude the possibility that the woman is responsible for the implantation failure. Co-culture associated with a further attempt could provide information regarding the ability of embryos to progress to the blastocyst stage and implant.