What forms of male infertility are there left to cure?
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Epididymis↗
Biomedical subjects
S J Silber
Publications and source records attributed to S J Silber.
The use of epididymal and testicular spermatozoa for intracytoplasmic sperm injection: the genetic implications for male infertility.
The results and rationale of using testicular and epididymal spermatozoa with intracytoplasmic sperm injection (ICSI) for severe cases of male infertility are reviewed. A total of 72 consecutive microsurgical epididymal sperm aspiration (MESA) cases were performed for congenital absence of the vas (CAV) and for irreparable obstructive azoospermia. ICSI was used to obtain normal embryos for transfer and fertilization in 90% of the cases. The overall fertilization rate was 46% with a normal cleavage rate of 68%. The pregnancy and delivery rates per transfer were 58 and 37% respectively. The delivery rate per cycle was 33%. In many cases, no epididymal spermatozoa were available and so testicular sperm extraction (TESE) was used for sperm retrieval. The transfer rate was lower with TESE (84 versus 96%) and the spermatozoa could not be frozen and saved for use in future cycles. However, there was little difference in pregnancy rates using epidiymal or testicular spermatozoa. The results were not affected by whether the obstruction was caused by CAV or failed vasoepididymostomy. Both fresh and frozen spermatozoa gave similar results; the only significant factor appeared to be the age of the female. Because of the consistently good results obtained using epididymal sperm with ICSI when compared with conventional IVF, and the similarly good results with testicular tissue spermatozoa, ICSI is mandatory for all future MESA patients. All CAV patients and their partners should be offered genetic screening for cystic fibrosis; hence pre-implantation embryo diagnosis should be available in any full service MESA programme. It is now clear that even with non-obstructive azoospermia, e.g. Sertoli-cell only, or maturation arrest, there are usually some small foci of spermatogenesis which allow TESE with ICSI to be carried out. This means that even in men with azoospermia due to absence of spermatogenesis or to a block in meiosis, there are usually a few spermatozoa available in the testes that are adequate for successful ICSI. Finally, it is likely that some forms of severe male factor infertility are genetically transmitted and although ICSI offspring have been shown to be completely normal, it is possible that the sons of these infertile couples will also require ICSI when they grow up and wish to have a family.
Adult↗
Is congenital bilateral absence of vas deferens a primary form of cystic fibrosis? Analyses of the CFTR gene in 67 patients.
Congenital bilateral absence of the vas deferens (CBAVD) is an important cause of sterility in men. Although the genetic basis of this condition is still unclear, it has been shown recently that some of these patients carry mutations in their cystic fibrosis transmembrane conductance regulator (CFTR) genes. To extend this observation, we have analyzed the entire coding sequence of the CFTR gene in a cohort of 67 men with CBAVD, who are otherwise healthy. We have identified four novel missense mutations (A800G, G149R, R258G, and E193K). We have shown that 42% of subjects were carriers of one CFTR allele and that 24% are compound heterozygous for CFTR alleles. Thus, we have been unable to identify 76% of these patients as carrying two CFTR mutations. Furthermore, we have described the segregation of CFTR haplotypes in the family of one CBAVD male; in this family are two male siblings, with identical CFTR loci but displaying different phenotypes, one of them being fertile and the other sterile. The data presented in this family, indicating a discordance between the CBAVD phenotype and a marked carrier (delta F508) chromosome, support the involvement of another gene(s), in the etiology of CBAVD.
Alleles↗
Birth after preimplantation diagnosis of the cystic fibrosis delta F508 mutation by polymerase chain reaction in human embryos resulting from intracytoplasmic sperm injection with epididymal sperm.
Men with congenital bilateral absence of the vas deferens (CBAVD) have been regarded as presenting a mild form of cystic fibrosis (CF). In this article, we report a case of male-factor infertility, in which both partners are carriers of the delta F508 mutation and the male partner has CBAVD. Microsurgical epididymal sperm aspiration (MESA) was performed to obtain spermatozoa; intracytoplasmic sperm injection (ICSI) was carried out on the oocytes since the motility of the spermatozoa was severely impaired; and embryo biopsy and a polymerase chain reaction (PCR) were carried out for preimplantation diagnosis of the CF delta F508 mutation. Single-blastomere analysis was performed and indicated that two embryos were affected (homozygous delta F508) and three embryos were carriers. After transfer of the latter three embryos, a singleton pregnancy was established. At amniocentesis, the delta F508 carrier status of the fetus with a 46, XY karyotype was confirmed. A healthy boy was born and the presence of vasa deferentia, bilaterally, was confirmed. The CF sweat test was also normal. Successful fertilization can be obtained by combination of MESA and ICSI in patients with CBAVD. Preimplantation diagnosis of CF is indicated. Pregnancy and birth of normal children can ensue in such patients.
Adult↗
Correlation between epididymal length and fertilization rate in men with congenital absence of the vas deferens.
OBJECTIVE: To investigate whether the variable length of the epididymides in men with congenital absence of the vas deferens might have a correlation with IVF and pregnancy rate results. DESIGN: Microsurgical retrieval of epididymal sperm from men with congenital absence of the vas deferens and their use for IVF. SETTING: Center for Reproductive Health, University of California, Irvine, California. PATIENTS: One hundred eight men with confirmed diagnosis of congenital absence of the vas deferens enrolled in the microsurgical epididymal sperm aspiration and IVF program. INTERVENTIONS: Measurement in centimeters of the epididymal length at the time of the sperm aspiration procedure. MAIN OUTCOME MEASURE: Rates of fertilization and pregnancy according to the epididymal length. RESULTS: Three groups were identified: group I (n = 29), epididymal length between 0.5 and 1.9 cm; group II (n = 66), length between 2.0 and 4.0 cm; and group III (n = 13), length in excess of 4.0 cm. Although the aspiration site was the proximal caput for each case, patients of group III had the highest fertilization and pregnancy rate (24% and 43%, respectively). Patients with the shortest epididymis (group I) had the worst IVF outcome (fertilization rate 7% and pregnancy rate 7%) whereas in group II the fertilization rate was 13% and the pregnancy rate was 18%. CONCLUSION: This study demonstrates that epididymal sperm from men with congenital absence of the vas deferens having a longer epididymis have a better IVF rate. A long epididymis can allow [1] the arrival of more frequent waves of fresh sperm whereas in a short epididymis the system is completely congested and occupied by old and senescent sperm, [2] less obstructive damages, and [3] a back flow of biochemical factors produced in the more distal segments that could ultimately enhance the fertilization capacity of proximal epididymal sperm.
Epididymis↗
Normal fertilization of human oocytes after testicular sperm extraction and intracytoplasmic sperm injection.
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Adult↗
A modern view of male infertility.
It is archaic to view male factor infertility today separately from in vitro fertilization (IVF) and treatment of the female partner. Oligoasthenozoospermia may be an inherited condition (most likely on the Y chromosome), and is refractory to any treatment of the male including hormones and varicocelectomy. IVF technology is the only justifiable approach for achieving a pregnancy in these couples. The reasons for this view and the suggested modern approach to couples with oligoasthenozoospermia are outlined in this review. However, obstructive azoospermia is different as it can be successfully corrected with microsurgery in over 90% of men. When it cannot be corrected, as in congenital absence of vas, microsurgical sperm retrieval combined with IVF can still be highly effective in producing pregnancy with sperm from the husband. The most important arena for research into male infertility in the next decade will be to map out the deletions on the Y chromosome that might result in defective spermatogenesis, and which probably cause most cases of non-obstructive male factor infertility.
Female↗
Conventional in-vitro fertilization versus intracytoplasmic sperm injection for patients requiring microsurgical sperm aspiration.
Intracytoplasmic sperm injection (ICSI) has been successful in cases of extreme oligoasthenozoospermia in achieving pregnancies via in-vitro fertilization (IVF) with the lowest imaginable sperm counts. In azoospermia caused by congenital bilateral absence of the vas deferens (CBAVD), it has been shown that epididymal spermatozoa can be retrieved in large numbers, but fertilization rates using conventional IVF are low. Furthermore, no fertilization has ever been possible using testicular spermatozoa with conventional IVF. In the most extreme case of absence of the epididymis, spermatozoa can only be retrieved from macerated testicular biopsy specimens. In such cases, all that can be seen are free-floating Sertoli cells with many spermatids attached, and only occasional spermatozoa per high power field which have only the barest, occasional, slightly twitching motion. The objective of the present study was to determine whether ICSI could achieve better results than conventional IVF with microsurgical aspiration of spermatozoa (MESA). ICSI (using epididymal or testicular spermatozoa) from men with CBAVD or irreparable obstructive azoospermia, achieved good fertilization and normal embryos in 82% of cases, compared to 19% with conventional IVF. There was an overall fertilization rate of 45%, with 85% progressing to normally cleaving embryos using ICSI, compared to 6.9% using conventional IVF. The pregnancy rate with ICSI/MESA was 47% per stimulated cycle (normal delivery rate was 30%), compared to 4.5% with conventional IVF. These results were achieved in patients who had consistently failed to fertilize in previous cycles with MESA and conventional IVF.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Aetiology of congenital absence of vas deferens: genetic study of three generations.
Bilateral congenital absence of the vas deferens (CAVD) is a form of male sterility (found in otherwise normal men) of unknown aetiology. Because males with cystic fibrosis (CF) almost invariably have CAVD as well, we investigated the hypothesis that men with isolated CAVD might share a common genetic background with males with CF. Genetic testing for CF was carried out in three generations of subjects: 44 patients with CAVD and their wives, 24 of their parents, and 13 of their offspring generated by microsurgical epididymal sperm aspiration (MESA) and in-vitro fertilization (IVF). DNA extracted from peripheral lymphocytes was amplified by the polymerase chain reaction (PCR) and then analysed for 12 mutations in the cystic fibrosis transmembrane conductance regulatory (CFTR) gene. Among 44 patients tested with CAVD, 26 (59%) were positive for at least one CF mutation, while the carrier frequency for CF mutations in the general population is only 4%. Four patients were found to be compound heterozygotes, three with genotypes Delta F-508/R117H, one with R553X/R117H. Among 24 parents tested, 15 (seven fathers, eight mothers) had sons with CAVD who were positive for CF mutations. Of these, nine (four fathers and five mothers) were found to be carriers for CF mutations. These four fathers, although carriers of CF mutations, were obviously fertile. Of the 13 offspring tested, six (three boys and three girls) had CF positive fathers. Of these, three (two girls and one boy) were found to be carriers for CF mutations. These MESA/IVF children are the first offspring to whom men with CAVD have been able to transmit CF mutations.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Cystic fibrosis mutations impair the fertilization rate of epididymal sperm from men with congenital absence of the vas deferens.
One of the limiting factors for the successful treatment of male sterility due to congenital absence of the vas deferens (CAVD) is the low (< 20%) and extremely unpredictable rate of in-vitro fertilization of their epididymal spermatozoa. The recent demonstration that CAVD is a mild form of cystic fibrosis (CF) disease, almost exclusively involving the genital tract, has prompted us to investigate the hypothesis of whether there could be an association between particular CF genotype mutations and the in-vitro performance of epididymal sperm. In this study 63 patients with surgically confirmed diagnosis of CAVD undergoing microsurgical epididymal sperm aspiration (MESA) and in-vitro fertilization (IVF) were evaluated. The genetic screening was carried out on DNA extracted from peripheral lymphocytes and amplified by the polymerase chain reaction. A total of 12 mutations in the cystic fibrosis transmembrane regulator gene (CFTR), representing approximately 90% of the total known CF mutations, were tested. The presence or absence of mutations, as well as the type of mutation found, was correlated with the IVF and pregnancy rates. Of the 63 patients examined, 40 (64%) were positive to the CF screening and 23 were negative. In three cases no spermatozoa were found because of rete testis blockage. The difference in fertilization rates between patients testing positive and negative was highly significant (P = 0.000003), 13 versus 23%, respectively. In order to pinpoint which mutation could account for the most deleterious effect on the IVF results, we analysed these by keeping the patients separated by CF mutations.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Testicular origin of immunobead-reacting antigens in human sperm.
OBJECTIVE: To investigate, by means of immunobinding technique, the antigenic surface expression of human vasa efferentia sperm as compared with that of ejaculated sperm. DESIGN: Briefly, vasa efferentia sperm, retrieved microsurgically, and donors' ejaculated sperm (controls) were used. PATIENTS, PARTICIPANTS: Men with congenital absence of the vas deferens, undergoing sperm aspiration as part of their infertility treatment, and controls who were donors of our sperm bank were first assayed by direct immunobead test and, if found negative, were exposed to sera containing known high titers of antisperm antibodies and then retested by indirect immunobead test. RESULTS: The data showed no difference in binding titers and class of immunoglobulins between vasa efferentia and ejaculated sperm. CONCLUSIONS: These findings suggest that, in humans, sperm acquire those surface antigens commonly detected by immunobinding test within the testes before their transit through the epididymis.
Epididymis↗
The role of the laboratory in the handling of epididymal sperm for assisted reproductive technologies.
This report describes the historical experience of our laboratory in the handling and processing of epididymal sperm from men with congenital absence of the vas deferens. Three different methods of sperm preparation were used: swim-up or resuspension in the first group of patients treated, mini-Percoll in the second group, and mini-Percoll used in conjunction with pentoxifylline and 2' deoxyadenosine in the third group. Twenty-four percent of cases achieved fertilization in group I, whereas in groups II and III the rate was 59% and 57%, respectively. Fertilization rates in each group were 6.5% in group I, 16% in group II, and 35% in group III. Three pregnancies were obtained in group I, 13 in group II, and 2 in group III. Groups II (21%) and III (63%) were able to have excess embryos to cryopreserve.
Epididymis↗
Ultrastructure of human sperm in men with congenital absence of the vas deferens: clinical implications.
OBJECTIVE: To determine the ultrastructural features of epididymal and vasa efferentia sperm in men with congenital absence of the vas deferens. DESIGN: Prospective. SETTING: University of California Irvine Center for Reproductive Health. PATIENTS: Thirteen men with surgical diagnosis of congenital absence of the vas deferens undergoing epididymal and vasa efferentia aspiration for assisted reproductive technology procedures. RESULTS: The morphological quality and the integrity of the spermatozoa aspirated from the extratesticular segment of the rete testis, the vasa efferentia, and the caput epididymis were always markedly superior to those of sperm aspirated from the corpus and cauda epididymis, where the vast majority, if not all, were degenerating or frankly necrotic. The aspirates obtained from the distal segments of the epididymis also contained large numbers of sperm-laden macrophages; these were instead absent or exceptional in the fluids aspirated from the pre-epididymal portions of the excurrent pathways and from the caput of the epididymis. CONCLUSIONS: This study demonstrates that the ultrastructural morphology of spermatozoa obtained by aspiration from the rete testis, vasa efferentia, and caput epididymis of individuals with congenital absence of the vas deferens is indistinguishable from that of spermatozoa in the semen.
Congenital Abnormalities↗
Penetration of zona-free hamster oocytes using human sperm aspirated from the epididymis of men with congenital absence of the vas deferens: comparison with human in vitro fertilization.
OBJECTIVES: To assess the ability of sperm aspirated from the epididymis of men with congenital absence of the vas deferens to penetrate zona-free hamster oocytes. To directly compare the performance of human epididymal sperm in the zona-free hamster oocyte sperm penetration assay (SPA) with the results of human in vitro fertilization (IVF). DESIGN: Sperm penetration assay was carried out with epididymal sperm retrieved microsurgically, and with ejaculated sperm obtained from fertile donors (internal controls). For direct comparison, SPA was performed with the same epididymal sperm sample used for IVF. PATIENTS, PARTICIPANTS: Men with congenital absence of the vas deferens undergoing sperm aspiration as part of their infertility treatment and control donors who provided ejaculated sperm. RESULTS: Epididymal sperm penetrated SPA with a score of 0% to 30%. The SPA scores for internal controls using ejaculated sperm was 30% to 71%. Linear regression analysis of the association between penetration scores in SPA and fertilization rate in IVF indicated a positive correlation that was highly significative. CONCLUSIONS: These findings using SPA confirm previous reports on the fertilizing potential of human epididymal sperm and its ability to produce normal pregnancies. The good correlation between SPA and human IVF using epididymal sperm suggest that SPA is an excellent bioassay to test laboratory experimental conditions for improving fertilizing capacity of human epididymal sperm.
Adult↗
Relationship of epididymal sperm antibodies to their in vitro fertilization capacity in men with congenital absence of the vas deferens.
OBJECTIVES: To test, using the immunobead binding technique, for the presence of antisperm antibodies on epididymal sperm, in epididymal fluid, and in serum of men with congenital absence of the vas deferens. To evaluate the in vitro fertilization (IVF) capacity of human epididymal sperm in the presence of antisperm antibodies. DESIGN: Prospective. At the time of oocyte insemination, sperm from the proximal caput epididymis or vasa efferentia were tested by direct immunobinding technique. The epididymal fluid and serum were tested by indirect immunobinding technique. SETTING: Center for Reproductive Health, University of California-Irvine. PATIENTS: Forty-five patients with congenital absence of the vas deferens participating in the microsurgical epididymal sperm aspiration and IVF program. MAIN OUTCOME MEASURE: Incidence of antisperm antibodies to epididymal sperm and their relationship with IVF results. RESULTS: Sixteen men (35%) tested positively to the direct immunobead test on epididymal sperm; 7 (16%) were positive in epididymal fluid and 13 (29%) were positive in serum. Five pregnancies (31%) occurred in the positive group of which two were from patients who had sperm binding of 100% for immunoglobulin (Ig)G (all over sperm surface) and 90% (midpiece, tail) and 50% (tail, tiptail), respectively, for IgA. Five pregnancies (18%) were obtained in the negative group. No statistical difference was observed in the overall fertilization rate between the two groups. CONCLUSION: Human epididymal sperm and epididymal fluid retrieved from men with congenital absence of the vas deferens can react positively to immunobead test. However, the presence of antisperm antibodies do not seem to impair the IVF capacity of epididymal sperm.
Autoantibodies↗
Movement characteristics of human epididymal sperm used for fertilization of human oocytes in vitro.
STUDY OBJECTIVE: To develop mathematical models using kinematic parameters from Computer-Aided Sperm Analysis (CASA) that predict the fertilization rate of sperm recovered from the caput epididymidis and to test the hypothesis that fertilization was enhanced by the presence of specific sperm subpopulations in the inseminate. SETTING: In vitro fertilization (IVF) program. PATIENTS: Thirteen patients with congenital absence of the vas deferens provided epididymal sperm for IVF as well as for CASA. RESULTS: The mathematical model that was most predictive of fertilization rates included kinematic parameters of the epididymal aspirate (percent motility), the inseminate used for IVF (curvilinear velocity [VCL]), and the change in sperm movement after in vitro processing by the mini-Percoll technique (difference in amplitude of lateral head displacement [ALH]). Multivariate cluster analysis revealed that inseminates that resulted in higher fertilization rates had subpopulations of sperm that were characterized by high VCL and high mean angular displacement, as well as a greater change in ALH after processing. CONCLUSION: In vitro fertilization with epididymal sperm was more likely to succeed when the sperm population that was initially aspirated had a higher proportion of motile cells and when these sperm were capable of capacitation in vitro as indicated by the appearance of sperm subpopulations with motility that resembled hyperactivation.
Diagnosis, Computer-Assisted↗
When predictions don't predict.
One of the most widespread abuses of statistical methods involves the misinterpretation of statistical significance after the application of multiple comparisons. This paper highlights the problem by demonstrating 'significance' when clearly none exists.
Female↗