COVID-19 and andrology: Recommendations of the French-speaking society of andrology (Société d'Andrologie de langue Française SALF).

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) metamorphosed our medical practice. In early June 2020, more than 6,400,000 COVID-19 (coronavirus-19 disease) cases were diagnosed across the world and more than 380,000 deaths were linked to COVID-19. Many medical symptoms of COVID-19 were reported. We will focus, here, on potential impacts of COVID-19 on men's andrological health. Our society (French-speaking society of andrology, SALF) also emitted some recommendations in the andrological management of men infected by SARS-CoV-2. First, considering the fever and the potential presence of SARS-CoV2 in semen, SALF recommends waiting for 3 months (duration of one spermatogenesis cycle and epididymal transit) before re-starting ART in the case of men diagnosed COVID-19 positive. Whatever the nature of testosterone and COVID-19 relationships, we recommend an andrological examination, sperm parameters, and hormonal evaluation at the time of the COVID-19 is diagnosed, and several months later. Furthermore, we are concerned by the potential morbid-mortality of the COVID-19, which mainly affects men. This "andrological bias", if proven, must be reduced by specific andrological diagnosis, therapeutic and prophylactic measures. Research in this direction must be substantiated and financially supported over the next few months (years).

Le SRAS-CoV-2 (nouveau coronavirus ou coronavirus numéro 2 responsable du syndrome respiratoire aigu sévère) a métamorphosé notre pratique médicale. Début juin 2020, plus de 6,400,000 cas de COVID-19 (maladie à coronavirus 2019) ont été diagnostiqués dans le monde et plus de 380,000 décès ont été reliés à cette maladie. De nombreux symptômes médicaux de cette infection virale ont été signalés. Nous nous concentrerons, ici, sur les impacts potentiels de COVID-19 sur la santé andrologique des hommes. Notre société (Société d'andrologie de langue Française, SALF) émet ici quelques recommandations dans la prise en charge andrologique des hommes infectés par le SRAS-CoV-2. Tout d'abord, compte tenu de la fièvre et de la présence potentielle du SRAS-CoV2 dans le sperme, la SALF recommande d'attendre 3 mois (durée d'un cycle de spermatogenèse et transit épididymaire) avant de recommencer les techniques d'assistance médicale à la procréation pour les hommes diagnostiqués COVID-19 positifs. Quelle que soit la nature des relations entre la testostérone et l'infection à SARS-CoV-2, nous recommandons un examen andrologique, un examen des paramètres du sperme et une évaluation hormonale au moment du diagnostic de l'infection, ainsi qu'à distance (3­6 mois plus tard). De plus, nous sommes préoccupés par la morbidité et la mortalité potentielles de l'infection COVID-19, qui touche principalement les hommes. Ce "biais andrologique", s'il est. prouvé, doit être réduit par un diagnostic andrologique spécifique et des mesures thérapeutiques et prophylactiques. La recherche dans ce sens doit être étayée et soutenue financièrement au cours des prochains mois (années).

Disparities in reproductive outcomes according to the endometrial preparation protocol in frozen embryo transfer : The risk of early pregnancy loss in frozen embryo transfer cycles.

PURPOSE: The purpose of this study was to determine the effect of stimulated and artificial endometrial preparation protocols on reproductive outcomes in frozen embryo transfer (FET) cycles. METHODS: We performed a retrospective study of 1926 FET cycles over a 3.5-year period in the Fertility Unit at a University Hospital. Stimulated and artificial protocols were used for endometrial preparation. The embryos for FET were obtained from either in vitro fertilization or intracytoplasmic sperm injection cycles. Live birth rate and early pregnancy loss rates were retrospectively compared. In artificial protocols, oral or vaginal administration of oestradiol 2 mg two or three times a day was followed by vaginal supplementation with progesterone 200 mg two or three times a day. In stimulated protocols, recombinant follicle-stimulating hormone was administered from day 4 onward. Vaginal ultrasound was used for endometrial and ovarian monitoring. A pregnancy test was performed 14 days after FET. If it was positive, oestradiol and progesterone were administered up until the 12th week of gestation in artificial cycles. We defined early pregnancy losses as biochemical pregnancies (preclinical losses) and miscarriages. RESULTS: Data on 865 artificial cycles (45% of the total) and 1061 stimulated cycles (55%) were collected. Early pregnancy loss rate was significantly lower for stimulated cycles (34.2%) than for artificial cycles (56.9%), and the live birth rate was significantly higher for stimulated cycles (59.7%) than for artificial cycles (29.1%). CONCLUSION: In frozen embryo transfer, artificial cycles were associated with more early pregnancy loss and lower live birth rate than stimulated cycles.

[Environment and lifestyle: Impacts on male fertility?] / Toxiques, mode de vie, environnement : quels impacts sur la fertilité masculine ?

In this last century, an increase of men infertility has been registered. It has been suggested that environmental factors could a negative impact over sperm quality. Among these factors, impact of environmental toxicant has been spread by media. In this review of scientific literature, we identify several environmental factors that could impact men fertility in a negative way. These factors are tobacco, marijuana, weight, body mass index, heat, nutritional state, electromagnetic waves and altitude. For each of these factors, the impact over men fertility, their mechanism, as well their influence over the use of Assisted Reproductive Technics are reported.

[Necrozoospermia: From etiologic diagnosis to therapeutic management]. / La necrozoospermie : du diagnostic étiologique à la prise en charge thérapeutique.

This review describes necrospermia, its diagnosis, causes and management. Sperm vitality is commonly assessed in the laboratory of reproductive biology, with the eosin test or with the hypo-osmotic swelling test. Necrospermia is defined by a percentage of living spermatozoa inferior to 58%, and can be related to male infertility. Several pathological mechanisms may be involved and can be classified either in testicular causes (hyperthyroidism, local hyperthermia, varicocele), or post-testicular causes (epididymal necrospermia, dysregulation of seminal plasma, adult polycystic kidney disease, vasectomy reversal, anti-sperm antibodies) or both (infection, toxic, age, spinal cord injury). The first treatment is to correct the underlying cause, if possible. Repetitive ejaculation has demonstrated to be effective as well. Many drugs would also improve the sperm vitality (antioxidants, non-and-steroidal anti-inflammatory drugs) but there is currently no guideline to recommend their use. With necrospermia, fertilization rates are lower but in vitro fertilization (IVF) with Intracytoplasmic sperm injection (ICSI) improves the chances of conception.

Extreme spermatogenesis failure: andrological phenotype and intracytoplasmic sperm injection outcomes.

Patients with very low sperm count through direct sperm examination can exhibit extreme oligozoospermia or cryptozoospermia (after centrifugation). The management of these patients is a real challenge for both clinicians and biologists. In this retrospective and comparative cohort study, we compared the andrological phenotype of patients with extreme alterations of spermatogenesis and assessed whether the origin of spermatozoa (testicular or ejaculate) had any influence on intracytoplasmic sperm injection (ICSI) outcomes. A total of 161 ICSI cycles were performed using ejaculated spermatozoa from 75 patients with extreme oligozoospermia (EOS) or cryptozoospermia (CS) and 150 ICSI cycles using extracted testicular spermatozoa from 74 patients with non-obstructive azoospermia (NOA). Physical, hormonal, ultrasound assessments, and ICSI outcomes were performed in each group. Cryptorchidism was significantly more frequent in the NOA group (60.8% vs. 22.6%, p = 0.001). FSH levels were significantly higher [18.9 IU/L (5.9-27.0) vs. 15.3 IU/L (9.0-46.5), p = 0.001] and the majority of inhibin B levels measured were found mostly undetectable in the NOA group as compared to EOS/CS group (31.1% vs. 10.7%, p = 0.0004). Moreover, we found no significant differences in the respect to the fertilization rates (48.9% and 43.3%, p = 0.43), implantation rates (17.4% and 15.9%, p = 0.77), and percentage of top quality embryo (22.4% and 20.4%, p = 0.73) between the two groups. The clinical pregnancy rates per embryo transferred were comparable in both groups (28.3% and 27.4%, p = 0.89). In this study, we showed for the first time a different andrological phenotype between EOS/CS and NOA groups. Indeed, cryptorchidism was significantly more frequent with more severe endocrine parameters found in the NOA group. These results reflect a more profound alteration in spermatogenesis in NOA patients. However, there was no difference in ICSI outcomes between NOA and EOS/CS groups.

[Effects of father's age on fertility, results of ART and health of children]. / Conséquences de l'âge du père sur la fertilité, les résultats de l'AMP et la santé des enfants.

Many studies exist on the impact of female age on fertility, success of assisted reproductive technologies and on obstetric, fetal and neonatal adverse outcomes. Late paternity seems commonplace especially in the media… But there are reliable scientific data which confirm decline of fertility related to male age but also an increased risk of genetic diseases for the offspring. The objective of this article is to make a synthesis of the literature on this subject.

[Male age in assisted reproductive technologies: Is there a limit?] / Âge du père en assistance médicale à la procréation : faut-il une limite ?

In France, there does exist any age limit for infertile men management neither in the law nor for the coverage by the "French Assurance Maladie". French law specifies only that both partners of the couple have to be "of childbearing age", but there is no definition for men of childbearing age. Does legislation have to determine a limit on man management in function of his age? Could ART practitioners decide (themselves) whether they take care of infertile men or not? Should male age be a criteria to decide this management? Would ART practitioners "need" a legislation to help them to decide? In 2016, the "French Assurance Maladie" covers all costs for infertile couple if woman is less than 43 years old, whatever male age. If an age-threshold should be establish for the coverage of infertile men management by the "French Assurance Maladie", then what should be this threshold? In order to try to answer these questions, we asked them to French ART practitioners (gynecologists and embryologists) and gynecologists. The first questionnaire included 13 questions and was filled by 244 ART specialists; the second was filled by 138 gynecologists. Most of them agree to limit the male management and the coverage by the "French Assurance Maladie" at 60 for men in ART. Gynecologists who does not practice ART wish a limit for insurance (80% of them but are only 57% to wish a legal limit).

To be or not to be [fertile], that is the question.

BACKGROUND: According to our literature analysis, there are no data focused on spermatozoa emotional representations in childless men and data on the emotional repercussions of a diagnosis of infertility on men are still scarce. Thus, in this work, we investigated what the presence or absence of spermatozoa in the semen symbolize for men. MATERIAL AND METHODS: To answer this question, 441 childless heterosexual men participated in an anonymous, prospective, Internet-based survey. RESULTS: In response to the question "What would having a high or normal sperm count symbolize for you?" the most frequent answer was "ability to father a child". Men living with a partner were significantly more likely than single men to answer "ability to father a child" (p < 0.05) and less likely to answer "virility" and/or "ability to have an erection/ejaculation" (p = 0.001). In response to the question "If you found out that you had a low sperm count or no spermatozoa at all, how would you feel?", most of the men stated that they would be disappointed. Men living with a partner were more likely to state that they would feel ashamed (p < 0.05) or guilty with regard to their partner (p < 0.0001). CONCLUSIONS: These preliminary results should help us to improve (i) the way that male infertility is announced (it is easier to find the right words if one understands the possible importance of having a high sperm count) and (ii) the psychological, marital and sexual counselling provided to men with a diagnosis of infertility.

CONTEXTE: Dans la littérature, peu d'articles traitent du ressenti des hommes vis à vis de leurs spermatozoïdes. Que signifie pour un homme "avoir ou non des spermatozoïdes"? Voilà la question que nous nous sommes posée. MATERIEL ET METHODES: Pour y répondre nous avons élaboré un questionnaire qui a été rempli en ligne par 441 hommes hétérosexuels âgés de 18 à 45 ans et sans enfants. RESULTATS: A la question, "que signifie pour vous avoir des spermatozoïdes?", la majorité d'entre eux a répondu "être père". Les hommes en couple ont statistiquement répondu plus fréquemment "être père" (p < 0.05) et significativement moins fréquemment "être un (vrai) homme", "être viril", "être capable d'avoir une érection/éjaculation" comparativement aux hommes célibataires (p = 0.001). A la question, "qu' éprouveriez vous si on vous annonçait que vous n'aviez pas de spermatozoïdes ou moins que la normale?" la majorité d'entre eux à répondu "je serais déçu". Les hommes en couples ont répondu significativement plus fréquemment qu'ils se sentiraient honteux (p < 0.05) ou coupables vis à vis de leur partenaire (p < 0.0001). CONCLUSIONS: Ces résultats préliminaires doivent nous aider à mieux comprendre le ressenti des hommes vis à vis de leurs spermatozoïdes et nous aider, nous spécialistes de l'infertilité, à mieux annoncer des infertilités par azoospermie ou oligospermie en adoptant une démarche de conseil psychologique, sexuel et conjugal dans l'annonce de cette infertilité masculine. En effet "ne pas avoir un nombre élevé de spermatozoïdes et a fortiori ne pas en avoir du tout" peut avoir un impact négatif sur l'homme en termes d'humeur, de culpabilité et d'estime de soi.

[Squirting and female ejaculation in 2015?]. / Que sait-on des femmes fontaines et de l'éjaculation féminine en 2015?

Since Antiquity, women who expulse a large quantity of liquid during sexual stimulation have remained a mystery. This phenomena is usually called "squirting". Many physicians have proposed different explications, however, there are very few scientific publications and their conclusions are discordant. Today, squirting is fashionable in the media, and some recent studies have brought new information. Through medical publications, we present the conclusions concerning the origin and the nature of squirting, the psychological experience of these squirting women and the feelings of their partners.

A human morphologically normal spermatozoon may have noncondensed chromatin.

According to numerous assisted reproductive medicine practitioners, semen with normal characteristics might not require further investigation. However, on the scale of the individual spermatozoon, it is well known that normal morphology does not guarantee optimal nuclear quality. Here, for 20 patients with normal sperm characteristics and a high proportion of spermatozoa with noncondensed chromatin, we subsequently assessed chromatin condensation status (aniline blue staining) and morphology (Papanicolaou staining) of the same 3749 spermatozoa. Although the overall proportion of morphologically normal spermatozoa was not correlated with the overall proportion of spermatozoa with noncondensed chromatin, an individual spermatozoon's morphology appeared to be closely related to its chromatin condensation status. Morphologically normal spermatozoa with noncondensed chromatin were seen in all patients; the proportion averaged 23.3% [min 10.9%-max 44.4%]. Morphologically abnormal spermatozoa were more likely to have noncondensed chromatin than morphologically normal ones (P < 0.0001). Small-, large- or multiple-headed spermatozoa presented the highest degree of noncondensation (>80% for each type), and more than half the vacuolated spermatozoa also presented noncondensed chromatin. However, a morphologically normal spermatozoon may also have a noncondensed chromatin.

[How can we nowadays select the best embryo to transfer?]. / Comment sélectionner aujourd'hui le meilleur embryon à transférer ?

Multiple pregnancies stand as the most common adverse outcome of assisted reproduction technologies (ART) and the dangers associated with those pregnancies have been reduced by doing elective single embryo transfers (e-SET). Many studies have shown that e-SET is compatible with a continuously high pregnancy rate per embryo transfer. Yet, it still becomes necessary to improve the selection process in order to define the quality of individual embryos - so that the ones we choose for transfer are more likely to implant. First, analysis of embryo morphology has greatly helped in this identification and remains the most relevant criterion for choosing the embryo. The introduction of time-lapse imaging provides new criteria predictive of implantation potential, but the real contribution of this system - including the benefit/cost ratio - seems to be not yet properly established. In this context, extended culture until blastocyst stage is an essential practice but it appears wise to keep it for a population showing a good prognosis. Then, the failure of aneuploid embryos to implant properly led to achieve preimplantation genetic screening (PGS) in order to increase pregnancy and delivery rates after ART. However, PGS by fluorescence in situ hybridization (FISH) at day 3 is a useless process - and may even be harmful. Another solution involves using comparative genomic hybridisation (CGH) and moving to blastocyst biopsy. Finally, it is envisaged that morphology will also be significantly aided by non-invasive analysis of biomarkers in the culture media that give a better reflection of whole-embryo physiology and function.

Sperm FISH analysis of a 44,X,der(Y),t(Y;15)(q12;q10)pat,rob(13;14)(q10;q10)mat complex chromosome rearrangement.

Complex chromosome rearrangements (CCR) with two independent chromosome rearrangements are rare. Although CCRs lead to high unbalanced gamete rates, data on meiotic segregation in this context are scarce. A male patient was referred to our clinic as part of a family screening programme prompted by the observation of a 44,X,der(Y),t(Y;15)(q12;q10)pat,rob(13;14)(q10;q10)mat karyotype in his brother. Karyotyping identified the same CCR. Sperm FISH (with locus-specific probes for the segments involved in the translocations and nine chromosomes not involved in both rearrangements) was used to investigate the rearrangements meiotic segregation products and establish whether or not an inter-chromosomal effect was present. Sperm nuclear DNA fragmentation was also evaluated. For rob(13;14) and der(Y), the proportions of unbalanced products were, respectively, 26.4% and 60.6%. Overall, 70.3% of the meiotic segregation products were unbalanced. No evidence of an inter-chromosomal effect was found, and the sperm nuclear DNA fragmentation rate was similar to our laboratory's normal cut-off value. In view of previously published sperm FISH analyses of Robertsonian translocations (and even though the mechanism is still unknown), we hypothesise that cosegregation of der(Y) and rob(13;14) could modify rob(13;14) meiotic segregation.

High-magnification selection of spermatozoa prior to oocyte injection: confirmed and potential indications.

Intracytoplasmic morphologically selected sperm injection (IMSI) involves the use of differential interference contrast microscopy at high magnification (at least ·6300) to improve the observation of live human spermatozoa (particularly by showing sperm head vacuoles that are not necessarily seen at lower magnifications) prior to intracytoplasmic sperm injection (ICSI) into the oocyte. However, a decade after IMSI's introduction, the technique's indications and ability to increase pregnancy and/or birth rates (relative to conventional ICSI) are subject to debate. In an attempt to clarify this debate, this work performed a systematic literature review according to the PRISMA guidelines. The PubMed database was searched from 2001 onwards with the terms 'IMSI', 'MSOME' and 'high-magnification, sperm'. Out of 168 search results, 22 relevant studies reporting IMSI outcomes in terms of blastocyst, pregnancy, delivery and/or birth rates were selected and reviewed. The studies' methodologies and results are described and discussed herein. In view of the scarcity of head-to-head IMSI versus ICSI studies, the only confirmed indication for IMSI is recurrent implantation failure following ICSI. All other potential indications of IMSI require further investigation.

[Varicocele and infertility: where do we stand in 2013?]. / Varicocèle et infertilité: où en sommes-nous en 2013?

While the incidence of clinical varicocele is common in infertile men (about 40%), the reasons why varicocele may affect sperm parameters is still unclear. In addition, the improvement of fertility after treatment of varicocele is also a subject of debate. The purpose of this review is to get new insight into the physiopathology of varicocele, its impact on sperm parameters and the effectiveness of varicocele treatment on fertility. Treatment is likely to be effective in infertile men with clinical varicocele and impaired spermatogenesis. Even if it does not systematically lead to an improvement in sperm parameters, it may prevent further sperm degradation. In case of non-obstructive azoospermia, few studies reported a slight improvement in the process of spermatogenesis. The critical role of an adequate methodology in order to establish clinical guidelines needs to be stressed. Indeed, the huge intra-individual variability in sperm production makes the usual analysis of sperm parameters inadequate to measure treatment effectiveness. Regarding the assessment of conception, it requires not only well designed and properly sized studies but also a multivariate analysis for weighing predictive factors of success. Thus, an active scientific research is needed to better identify pathogenic agents and appropriately assess the impact of varicocele treatment.

A genome-wide DNA methylation study in azoospermia.

The objective of this study was to assess genome-wide DNA methylation in testicular tissue from azoospermic patients. A total of 94 azoospermic patients were recruited and classified into three groups: 29 patients presented obstructive azoospermia (OA), 26 displayed non-obstructive azoospermia (NOA) and successful retrieval of spermatozoa by testicular sperm extraction (TESE+) and 39 displayed NOA and failure to retrieve spermatozoa by TESE (TESE-). An Illumina Infinium Human Methylation27 BeadChip DNA methylation array was used to establish a testicular DNA methylation pattern for each type of azoospermic patient. The OA and NOA groups were compared in terms of the relative M-value (the log2 ratio between methylated and non-methylated probe intensities) for each CpG site. We observed significantly different DNA methylation profiles for the NOA and OA groups, with differences at over 9000 of the 27 578 CpG sites; 212 CpG sites had a relative M-value >3. The results highlighted 14 testis-specific genes. Patient clustering with respect to these 212 CpG sites corresponded closely to the clinical classification. The DNA methylation patterns showed that in the NOA group, 78 of the 212 CpG sites were hypomethylated and 134 were hypermethylated (relative to the OA group). On the basis of these DNA methylation profiles, azoospermic patients could be classified as OA or NOA by considering the 212 CpG sites with the greatest methylation differences. Furthermore, we identified genes that may provide insight into the mechanism of idiopathic NOA.

Small human sperm vacuoles observed under high magnification are pocket-like nuclear concavities linked to chromatin condensation failure.

Since an embryo's ability to grow to the blastocyst stage and implant can be improved by selection of a normal spermatozoon with a vacuole-free head, this study set out to determine the nature of small sperm vacuoles observed under high magnification (>×6300). For 15 infertile men with various sperm profiles, high-magnification microscopy was used to select motile, morphometrically normal spermatozoa with no vacuoles (n=450) or more than two small vacuoles (each of which occupied less than 4% of the head's area; n=450). Spermatozoa acrosome reaction status and degree of chromatin condensation were analysed. Three-dimensional deconvolution microscopy was used to accurately image the nucleus and acrosome at all depths in all spermatozoa. In all 450 spermatozoa with small vacuoles, the latter were seen to be abnormal, DNA-free nuclear concavities. Spermatozoa with small vacuoles were significantly more likely than vacuole-free spermatozoa to have noncondensed chromatin (39.8% versus 9.3%, respectively; P<0.0001). There was no significant difference between the two groups of spermatozoa in terms of acrosome reaction status. No association between chromatin condensation and acrosome reaction status was observed. Small human sperm vacuoles observed under high magnification are pocket-like nuclear concavities related to failure of chromatin condensation.