[EUGIC (Extension of the Use of Gametes in Intra-Conjugal): New uses of gametes within the couple]. / EUGIC (Extension de l'Utilisation de Gamètes en IntraConjugal) : les nouveaux usages des gamètes au sein du couple.

OBJECTIVE: New possibilities for using gametes within a couple were created by the French law of August 2, 2021 related to bioethics by opening Assisted Reproductive Technics (ART) to all women. It concerns previously self-preserved gametes, thus avoiding the need for gamete donation. The objective of our study is to evaluate the perception of these new uses by ART practitioners. METHOD: A questionnaire of twelve short questions was sent to professionals concerned with gamete donation. RESULTS: One hundred and ten professionals answered the questionnaire. The majority of them approve of the Reception of Oocytes from the Partner (ROPA), notably if there is a medical indication. Requests are rarer for the care of trans* people, and raise more questions. Although less favorable to the use of eggs from trans* men, more of them support the practice when it is an alternative to oocyte donation. CONCLUSION: The acronym EUGIC (Extension of the Use of Gametes in Intra-Conjugal) makes it possible to group together these new situations generated by the change in the French law.

Motivations and personality characteristics of candidate sperm and oocyte donors according to parenthood status: a national study from the French CECOS network.

STUDY QUESTION: In a non-commercial national gamete donation programme, do the motivations and personality characteristics of candidate sperm and oocyte donors differ according to their parenthood status? SUMMARY ANSWER: Moderate differences exist between non-parent and parent candidate donors in motivations for gamete donation and representations as well as in personality characteristics. WHAT IS KNOWN ALREADY: Several studies have analysed the motivations and experiences of oocyte or sperm donors, but mainly in countries where gamete donation is a commercial transaction, and very few studies have reported results of personality traits using personality inventory tests. No study has specifically investigated the motivations and personality characteristics of candidate gamete donors according to parenthood status. STUDY DESIGN SIZE DURATION: A prospective study was carried out including 1021 candidate donors from 21 centres (in university hospitals) of the national sperm and egg banking network in France between November 2016 and December 2018. PARTICIPANTS/MATERIALS SETTING METHODS: In total, 1021 candidate gamete donors were included in the study. During their first visit, male (n = 488) and female candidate donors (n = 533) completed a questionnaire on sociodemographic characteristics, their motivations for donation and their representations of donation, infertility and family. Secondly, a NEO Personality Inventory (NEO-PI-R) exploring the Big Five personality traits was completed online. Results were compared between parent and non-parent candidate donors. MAIN RESULTS AND THE ROLE OF CHANCE: Altruistic values were the principal motive for donation irrespective of parenthood status. Reassurance about their fertility or preservation of sperm for future use was more often reported in non-parent than in parent candidate donors. With regard to representation of gamete donation or of the family, independently of their parenthood status, candidate donors more frequently selected social rather than biological representations. Mean personality characteristics were in the normal range. Non-parent candidate donors had higher scores on openness and depression than parents, while parent candidate donors appeared more social than non-parents. LIMITATIONS REASONS FOR CAUTION: The personality characteristics inventory was not completed by all candidate donors included in the study. However, family status did not differ between the two groups (NEO-PI-R completed (n = 525) or not), while the group who completed the NEO-PI-R had a higher educational level. This national study was performed in a country where gamete donation is subject to strict legislation. WIDER IMPLICATIONS OF THE FINDINGS: In a global context where reproductive medicine is commercialized and gamete donor resources are limited, this study found that altruism and social representations of gamete donation and family are the main motivations for gamete donation in a country which prohibits financial incentive. These findings are relevant for health policy and for gamete donation information campaigns. STUDY FUNDING/COMPETING INTERESTS: Grant from the Agence de la Biomédecine, France. The authors have nothing to disclose related to this study. TRIAL REGISTRATION NUMBER: N/A.

Fertility preservation after fertility-sparing surgery in women with borderline ovarian tumours.

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.

The impact of drugs on male fertility: a review.

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.

Genetic abnormalities leading to qualitative defects of sperm morphology or function.

Infertility, defined by the inability of conceiving a child after 1 year is estimated to concern approximately 50 million couples worldwide. As the male gamete is readily accessible and can be studied by a simple spermogram it is easier to subcategorize male than female infertility. Subjects with a specific sperm phenotype are more likely to have a common origin thus facilitating the search for causal factors. Male infertility is believed to be often multifactorial and caused by both genetic and extrinsic factors, but severe cases of male infertility are likely to have a predominant genetic etiology. Patients presenting with a monomorphic teratozoospermia such as globozoospermia or macrospermia with more than 85% of the spermatozoa presenting this specific abnormality have been analyzed permitting to identify several key genes for spermatogenesis such as AURKC and DPY19L2. The study of patients with other specific sperm anomalies such as severe alteration of sperm motility, in particular multiple morphological anomalies of the sperm flagella (MMAF) or sperm unability to fertilize the oocyte (oocyte activation failure syndrome) has also enable the identification of new infertility genes. Here we review the recent works describing the identification and characterization of gene defects having a direct qualitative effect on sperm morphology or function.

Single gene defects leading to sperm quantitative anomalies.

Azoospermia, defined by the absence of sperm in the ejaculate, is estimated to affect up to 1% of men in the general population. Assisted reproductive technologies have revolutionized the treatment of infertility, and some azoospermic men, those with a post-meiotic defect, can conceive following the use of viable spermatoza recovered from testicular or epididymal biopsies. Although male infertility is a multifactorial disease, it is believed that genetic factors are predominant in the etiology of azoospermia and severe oligozoospermia. Despite that assumption, substantiated by the high number of infertile knockout (KO) mice and the even higher number of genes expressed essentially in the testis, little is known about the pathophysiology of reduced sperm production, its primary causes or the genetic and epigenetic consequences for the gamete and the future conceptus. The identification of genetic abnormalities is therefore paramount to understand spermatogenesis, to adopt the best course of action for the patient and to provide adequate genetic counseling. We provide here a review of the recent literature on the genetics of azoospermia and oligozoospermia, focusing on defects directly altering sperm production. New sequencing technologies are contributing to the rapid evolution of the recent field of infertility genetics.

Sperm cryopreservation before cancer treatment: a 15-year monocentric experience.

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.

[Female fertility preservation: feasibility of emergency IVF for embryo freezing]. / Faisabilité de la congélation embryonnaire dans la préservation de la fertilité féminine.

With the improvement of the anticancerous treatments, the preservation of the feminine fertility before gonadotoxic treatment tends at present to stand out as a legal obligation, with a duty of information to patients. When emergency IVF can be performed, the cryopreservation of embryos is the best mastered method which offers most chances to patients to obtain a pregnancy after cancer remission thanks to the transfer of frozen embryos. This article proposes an overview about the indications, the feasibility and the ethical and practical limitations of IVF emergency for embryo freezing before gonadotoxic anticancerous treatment.

[Do couples who procreate through sperm donation inform their children?]. / Les couples qui procréent par don de sperme en informent-ils leurs enfants ?

OBJECTIVES: An amendment to the French bioethics law allowing children conceived by gamete donation to know the identity of donors is proposed, while no study can assess the proportion of parents in France that disclose the nature of conception to their donor conceived offspring. The aim of our study was to know whether couples who wish to inform their offspring actually did it. PATIENTS AND METHODS: We sent a questionnaire to parents who had expressed an intention to disclose the nature of conception to their future offspring conceived by sperm donation. This allowed us to evaluate the number of couples who inform their offspring, and the couple and offspring feelings when information was given. RESULTS: Among 38 questionnaires sent, 20 couples answered. Fourteen informed their offspring about the nature of conception, most having lived serenely this moment. 47% of offspring have reacted with indifference. While 19 couples informed their friends or family, six couples did not inform their offspring, and two of them no longer want to disclose anymore. CONCLUSION: Careful thought before the beginning of assisted reproductive technology and support after birth are needed to help couples communicate information to their offspring. Without this communication, any policy of openness to know donor related data seems vain.

[Sex chromosomes and meiosis]. / Chromosomes sexuels et méiose.

Sex chromosome behaviour fundamentally differs between male and female meiosis. In oocyte, X chromosomes synapse giving a XX bivalent which is not recognizable in their morphology and behaviour from autosomal bivalents. In human male, X and Y chromosomes differ from one another in their morphology and their genetic content, leading to a limited pairing and preventing genetic recombination, excepted in homologous region PAR1. During pachytene stage of the first meiotic prophase, X and Y chromosomes undergo a progressive condensation and form a transcriptionally silenced peripheral XY body. The condensation of the XY bivalent during pachytene stage led us to describe four pachytene substages and to localize the pachytene checkpoint between substages 2 and 3. We also defined the pachytene index (PI=P1+P2/P1+P2+P3+P4) which is always less than 0.50 in normal meiosis. XY body undergoes decondensation at diplotene stage, but transcriptional inactivation of the two sex chromosomes or Meiotic Sex Chromosome Inactivation (MSCI) persists through to the end of spermatogenesis. Sex chromosome inactivation involves several proteins, some of them were now identified. Two isoforms of the HP1 protein, HP1beta and HP1gamma, are involved in the facultative heterochromatinization of the XY body, but the initiation of this process involves the phosphorylation of the protein H2AX by the kinase ATR whose recruitment depends on BRCA1. Extensive researches on the inactivation of the sex chromosomes during male meiosis will allow to a better understanding of some male infertilities.

[Genetic aspects of the teratozoospermia]. / Aspects génétiques de la tératozoospermie.

Recent mutation identification in well-known sperm defects gives proof that there are genetic causes of infertility. Familial forms and some features of the spermograms lead toward the genetic origin of these syndromes. For each syndrome, several clinical aspects and partial forms were described. In these latter, apparently normal spermatozoa coexist with those showing the phenotype of interest. Transmission electron microscopy is the better tool to characterize the specific details of each syndrome. The frequency of genetic teratozoospermia is weak, the most studied syndromes are the globozoospermia, the macrocephaly, the syndrome of decapitated spermatozoa and the dyplasia of the fibrous sheat. A mutation was identified for two from these syndromes, but the two mutations does not account for all the cases from each syndrome. The various clinical aspects observed for each syndrome suggest that either other mutations or other genes are probably involved in these spermatogenic failures. The use of spermatozoa from patients for intra cytoplasmic sperm injection (ICSI) may pose two problems: fertilization problems and genetic risk for the progeny, including chromosomic and genic risk. Except for total macrocephaly which is excluded from ICSI because of sperm chromosomal abnormalities, these syndromes are consistent with assisted fertilization, but with uncertain rates of fertilization and pregnancy.

[The hand: embryology and main malformative mechanisms]. / La main: embryologie et principaux mécanismes malformatifs.

Upper limb bud appears in the cervical region of the embryo during the fifth week of development. It is made of epithelia and underlying mesenchyme. Diffusible growth factors, expressed by the apical ectodermal ridge, direct the proximal-distal growth. Other factors are expressed by zone of polarizing activity and ectoderm. They induce together anterior-posterior growth and dorsal-ventral polarity of the limb bud. The development of axial skeleton pattern is controlled by transcription factors from the HOX family, which are expressed in a stripe along the proximal and distal edges of the limb bud. Embryologic mechanisms of the main hand malformations are described, as well as their known genetic or mechanical aetiologies.

Meiotic abnormalities in patients bearing complete AZFc deletion of Y chromosome.

BACKGROUND: We studied meiosis in three infertile patients presenting complete AZFc microdeletion and three controls. METHODS: Primary spermatocytes were immunolabeled with SCP3, BRCA1 and gammaH2AX. We quantified the leptotene, zygotene and pachytene stages, and pachytene abnormalities: asynapsis and fragmented and dotted synaptonemal complexes (SCs). RESULTS: SCP3 level was significantly higher in leptotene and zygotene (bouquet) stages in patients, suggesting AZFc may have a direct effect on early prophase. SCs were abnormal in 77.3% of pachytene nuclei of patients versus 30.8% of controls. The two groups differed significantly (P < 0.001) in asynapsed nuclei, fragmented SC and dotted SCs. In patients, asynapsis were short and limited to a few bivalents. Staging of pachytene nuclei based on the morphology of the XY pair with BRCA1 revealed a prevalence of early pachytene substages (70.7%) in patients. H2AX was normally phosphorylated. CONCLUSIONS: In the absence of the AZFc region, the transient zygotene stage is extended, and chromosome condensation is reduced. The low level of limited asynapsis, the normal H2AX staining and the incomplete loss of germ cells at the pachytene checkpoint indicate that the AZFc region is not critical for meiotic recombination. We suggest that the pachytene phenotype develops secondarily to a primary defect that influences meiosis.

Meiotic anomalies in infertile men with severe spermatogenic defects.

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.

Sequence family variant loss from the AZFc interval of the human Y chromosome, but not gene copy loss, is strongly associated with male infertility.

BACKGROUND: Complete deletion of the complete AZFc interval of the Y chromosome is the most common known genetic cause of human male infertility. Two partial AZFc deletions (gr/gr and b1/b3) that remove some copies of all AZFc genes have recently been identified in infertile and fertile populations, and an association study indicates that the resulting gene dose reduction represents a risk factor for spermatogenic failure. METHODS: To determine the incidence of various partial AZFc deletions and their effect on fertility, we combined quantitative and qualitative analyses of the AZFc interval at the DAZ and CDY1 loci in 300 infertile men and 399 control men. RESULTS: We detected 34 partial AZFc deletions (32 gr/gr deletions), arising from at least 19 independent deletion events, and found gr/gr deletion in 6% of infertile and 3.5% of control men (p>0.05). Our data provide evidence for two large AZFc inversion polymorphisms, and for relative hot and cold spots of unequal crossing over within the blocks of homology that mediate gr/gr deletion. Using SFVs (sequence family variants), we discriminate DAZ1/2, DAZ3/4, CDY1a (proximal), and CDY1b (distal) and define four types of DAZ-CDY1 gr/gr deletion. CONCLUSIONS: The only deletion type to show an association with infertility was DAZ3/4-CDY1a (p = 0.042), suggesting that most gr/gr deletions are neutral variants. We see a stronger association, however, between loss of the CDY1a SFV and infertility (p = 0.002). Thus, loss of this SFV through deletion or gene conversion could be a major risk factor for male infertility.

HP1beta and HP1gamma, but not HP1alpha, decorate the entire XY body during human male meiosis.

During meiosis in male mammals, the X and Y chromosomes become heterochromatic and transcriptionally silent, and form the XY body. Although the HP1 proteins are known to be involved in the packaging of chromosomal DNA into repressive heterochromatin domains, their involvement in facultative heterochromatinization has not been precisely determined. Here, we analyse, for the first time in humans, the subcellular distribution of the heterochromatin protein HP1alpha, HP1beta and HP1gamma isoforms, in male pachytene spermatocytes, and the XY body facultative heterochromatin in particular. Our results demonstrate that HP1beta and HP1gamma, but not the HP1alpha isoforms, decorate the entire XY body in half the pachytene nuclei observed. In some nuclei, the XY body appears to be only partially labelled. In these cases, the HP1beta and HP1gamma signals are adjacent to the Yq12 constitutive heterochromatin and signal appears to originate in this region before spreading over the entire XY body. This distribution suggests that HP1beta and HP1gamma proteins, which are components of the constitutive heterochromatin, may also be involved in the facultative heterochromatinization of the XY body. Nevertheless, their absence from the early pachytene substage, even though the XY body is already condensed, suggests that these proteins are not involved in the initiation of this process.