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Although hundreds of knockout mice show infertility as a major phenotype, the causative genic mutations of male infertility in humans remain rather limited. Here, we report the identification of a missense mutation (D136G) in the X-linked TAF7L gene as a potential cause of oligozoospermia in men. The human aspartate (D136) is evolutionally conserved across species, and its change to glycine (G) is predicted to be detrimental. Genetic complementation experiments in budding yeast demonstrate that the conserved aspartate or its analogous asparagine (N) residue in yeast TAF7 is essential for cell viability and thus its mutation to G is lethal. Although the corresponding D144G substitution in the mouse Taf7l gene does not affect male fertility, RNA-seq analyses reveal alterations in transcriptomic profiles in the Taf7l (D144G) mutant testes. These results support TAF7L mutation as a risk factor for oligozoospermia in humans., (© The Author(s) 2022. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Non-obstructive azoospermia accounts for 10-15% of male infertility, resulting in 60% of all cases of azoospermia and affecting about 1% of the male population. About 30% of these cases are due to Y chromosome microdeletions, chromosome abnormalities, or hormonal disorders. Pathogenic variants in genes on the sex chromosomes have key roles in spermatogenic failure. The co-occurrence of azoospermia and congenital cataracts ranges between 1 in 165,000 and 1 in 500,000. Our 28-year-old patient with normal intelligence and abnormally shaped teeth presented with both disorders. A microarray revealed a microdeletion at Xp23.13 with a whole NHS gene deletion as well as a contiguous deletion of two other genes [SCML1 and RAI2]. This observation represents the first report of non-obstructive azoospermia with congenital cataracts and a contiguous deletion of the SCML1 gene, a transcript of which is exclusively expressed in the testis. SCML1 is the putative culprit gene, which requires functional study or animal experiments. Our analysis of 60 known spermatogenesis failure-related genes by whole-exome sequencing revealed no other candidate. The Nance-Horan syndrome due to pathogenic variants in the NHS gene at Xp23.13 including whole gene deletion does not have azoospermia as a feature. Our report adds to the completeness of genetic counseling for an individual with azoospermia and congenital cataracts.

This monograph, written by the pioneers of IVF and reproductive medicine, celebrates the history, achievements, and medical advancements made over the last 40 years in this rapidly growing field., (Copyright © 2018 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Herein, we describe the consensus guideline methodology, summarize the evidence-based recommendations we provided to the World Health Organization (WHO) for their consideration in the development of global guidance and present a narrative review of the diagnosis of male infertility as related to the eight prioritized (problem or population (P), intervention (I), comparison (C) and outcome(s) (O) (PICO)) questions. Additionally, we discuss the challenges and research gaps identified during the synthesis of this evidence., Objective and Rationale: The aim of this paper is to present an evidence-based approach for the diagnosis of male infertility as related to the eight prioritized PICO questions., Search Methods: Collating the evidence to support providing recommendations involved a collaborative process as developed by WHO, namely: identification of priority questions and critical outcomes; retrieval of up-to-date evidence and existing guidelines; assessment and synthesis of the evidence; and the formulation of draft recommendations to be used for reaching consensus with a wide range of global stakeholders. For each draft recommendation the quality of the supporting evidence was then graded and assessed for consideration during a WHO consensus., Outcomes: Evidence was synthesized and recommendations were drafted to address the diagnosis of male infertility specifically encompassing the following: What is the prevalence of male infertility and what proportion of infertility is attributable to the male? Is it necessary for all infertile men to undergo a thorough evaluation? What is the clinical (ART/non ART) value of traditional semen parameters? What key male lifestyle factors impact on fertility (focusing on obesity, heat and tobacco smoking)? Do supplementary oral antioxidants or herbal therapies significantly influence fertility outcomes for infertile men? What are the evidence-based criteria for genetic screening of infertile men? How does a history of neoplasia and related treatments in the male impact on (his and his partner's) reproductive health and fertility options? And lastly, what is the impact of varicocele on male fertility and does correction of varicocele improve semen parameters and/or fertility?, Wider Implications: This evidence synthesis analysis has been conducted in a manner to be considered for global applicability for the diagnosis of male infertility., (© The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.)

Infertility is a widespread problem and a male contribution is involved in 20-70% of affected couples. As a man's fertility relies on the quantity and quality of his sperm, semen analysis is generally used as the proxy to estimate fertility or gain insight into the underlying reasons for infertility. Male reproductive impairment might result from factors that affect sperm production, quality, function, or transport. Although in most men the origin of infertility remains unexplained, genetic causes are increasingly being discovered. In this first of two papers in The Lancet Diabetes and Endocrinology Series on male reproductive impairment, we propose a novel, clinically based aetiological construct with a genetic focus, and consider how this might serve as a helpful way to conceptualise a diagnostic algorithm., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

An accurate medical history and directed physical examination are essential in diagnosis of male infertility. We review the hormonal assessments and specific genetic analyses that are useful additional tests, and detail other evidence-based examinations that are available to help guide therapeutic strategies. By contrast with female infertility treatments-especially hormonal manipulations to stimulate or enhance oocyte production-spermatogenesis and sperm quality abnormalities are much more difficult to affect positively. In general, a healthy lifestyle can improve sperm quality. A few men have conditions in which evidence-based therapies can increase their chances for natural conception. In this second of two papers in The Lancet Diabetes and Endocrinology Series on male reproductive impairment, we examine the agreements and controversies that surround several of these conditions. When we are not able to cure, correct, or mitigate the cause of conditions such as severe oligozoospermia, non-remedial ductal obstruction, and absence of sperm fertilising ability, assisted reproductive technologies, such as in-vitro fertilisation (IVF) with intracytoplasmic sperm injection (ICSI), can be used as an adjunctive measure to allow for biological paternity. Not considered possible just two decades ago, azoospermia due to testicular failure, including 47,XXY (Klinefelter syndrome), is now treatable in approximately 50% of cases when combining surgical harvesting of testicular sperm and ICSI. Although genetic fatherhood is now possible for many men previously considered sterile, it is crucial to discover and abrogate causes as best possible, provide reliable and evidenced-based therapy, consider seriously the health and wellness of any offspring conceived, and always view infertility as a possible symptom of a more general or constitutional disease., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

As men age, medical and surgical diseases involving the genitourinary tract become more common. The conditions themselves, if not their treatments, can negatively impact the fertility potential of an affected man. Many older men maintain the desire to father children, so it is critical to understand the disturbed anatomy and physiology involved to properly counsel that individual. Should this or that treatment regimen be employed? Should sperm banking be undertaken before institution of a permanently ablative/suppressive therapy? What are the long-term consequences of one therapy over another vis-à-vis sperm production, sperm quality, and/or sperm transport? In this context, some of the more common genitourinary afflictions of the older male and the treatment options that are available will be discussed., (Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Genome-wide recombination is essential for genome stability, evolution, and speciation. Mouse Tex11, an X-linked meiosis-specific gene, promotes meiotic recombination and chromosomal synapsis. Here, we report that TEX11 is mutated in infertile men with non-obstructive azoospermia and that an analogous mutation in the mouse impairs meiosis. Genetic screening of a large cohort of idiopathic infertile men reveals that TEX11 mutations, including frameshift and splicing acceptor site mutations, cause infertility in 1% of azoospermic men. Functional evaluation of three analogous human TEX11 missense mutations in transgenic mouse models identified one mutation (V748A) as a potential infertility allele and found two mutations non-causative. In the mouse model, an intronless autosomal Tex11 transgene functionally substitutes for the X-linked Tex11 gene, providing genetic evidence for the X-to-autosomal retrotransposition evolution phenomenon. Furthermore, we find that TEX11 protein levels modulate genome-wide recombination rates in both sexes. These studies indicate that TEX11 alleles affecting expression level or substituting single amino acids may contribute to variations in recombination rates between sexes and among individuals in humans., (© 2015 The Authors. Published under the terms of the CC BY 4.0 license.)

Introduction: Sexual dysfunction and infertility are prevalent in the spina bifida (SB) population; however, the mechanism of how they affect a person with spina bifida is poorly understood. Additionally, the management of children with spina bifida becomes more difficult as they exit from pediatric institutes., Objective: The present study sought to evaluate sexual health (using validated questionnaires) and fertility in adults with spina bifida and to correlate spinal cord level and ambulatory status with degree of sexual function., Study Design: After institutional board review approval, 199 adult patients with SB, aged 18 and older and who were followed in one pediatric institution, were identified. Patients who were non-English speaking, cognitively and/or developmentally delayed, or unable to be contacted were excluded. Surveys regarding demographics, sexual health and infertility were mailed to the patients and administered in the clinic with the option to opt-out of the survey. Survey questions regarding sexual health were constructed using validated questionnaires: Female Sexual Function Index (FSFI) for females, and International Index of Erectile Function (IIEF) and Sexual Health Inventory for Men (SHIM) for males. Sexual dysfunction scores were correlated to the patients' spinal level and ambulatory status., Results: Of the 121 eligible patients, 45 replied, with a response rate of 39%. For females, using a cut-off value of 26.5 for FSFI scoring, 25 out of 28 (89%) had sexual dysfunction. No association was seen between spinal level or ambulatory status and overall FSFI, satisfaction, or desire scores. For males, 10 out of 17 (59%) had severe erectile dysfunction (ED), and one out of 17 (6%) had no ED. No association was seen between ambulatory status and sexual function scores for the males. However, SHIM, satisfaction, and ED scores were higher in males with lower spinal lesions. People with spina bifida of both genders tended to have more severe dysfunction compared to those with sexual dysfunction of other etiologies, except with similar sexual desire scores. Regarding questions on fertility, no participant attempted to have children; thus, there was no infertility reported., Discussion: Few studies have been conducted on sexual health and fertility in adults with SB. Three studies have utilized validated questionnaires and found varying degrees of sexual dysfunction in this subset of patients; however, only one study found sexual activity to be more likely in patients with more caudal levels of neurologic impairment. The present study also showed that SHIM, satisfaction, and ED scores were higher in males with lower spinal lesions. Limitations to this study primarily included the small sample size and low survey response rate., Conclusion: Limited information is known about adults with SB, and sexual function and fertility. While expressing sexual desire, adults with SB appear to experience high rates of sexual dysfunction. Fertility rates were inadequately assessed; this was possibly due to the high rate of sexual dysfunction. Sexual health in the SB population is an important component of the myriad of urologic care issues for these people. Due to the disparity in their care after reaching adulthood, it is prudent to follow these patients and understand their pathophysiology as they continue to mature through life., (Copyright © 2015 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Ejaculatory dysfunction may occur after many different disorders ranging from traumatic spinal cord injury to diabetes mellitus. With an understanding of the many facets and nuances of the ejaculatory apparatus, both anatomic and neurologic, the well-versed clinician can proceed along a safe, efficient, and appropriate treatment algorithm to help affected men and their partners achieve parenthood., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Deletions involving the Y chromosome's AZFc region are the most common known genetic cause of severe spermatogenic failure (SSF). Six recurrent interstitial deletions affecting the region have been reported, but their population genetics are largely unexplored. We assessed the deletions' prevalence in 20,884 men in five populations and found four of the six deletions (presented here in descending order of prevalence): gr/gr, b2/b3, b1/b3, and b2/b4. One of every 27 men carried one of these four deletions. The 1.6 Mb gr/gr deletion, found in one of every 41 men, almost doubles the risk of SSF and accounts for ∼2% of SSF, although <2% of men with the deletion are affected. The 1.8 Mb b2/b3 deletion, found in one of every 90 men, does not appear to be a risk factor for SSF. The 1.6 Mb b1/b3 deletion, found in one of every 994 men, appears to increase the risk of SSF by a factor of 2.5, although <2% of men with the deletion are affected, and it accounts for only 0.15% of SSF. The 3.5 Mb b2/b4 deletion, found in one of every 2,320 men, increases the risk of SSF 145 times and accounts for ∼6% of SSF; the observed prevalence should approximate the rate at which the deletion arises anew in each generation. We conclude that a single rare variant of major effect (the b2/b4 deletion) and a single common variant of modest effect (the gr/gr deletion) are largely responsible for the AZFc region's contribution to SSF in the population., (Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Once thought to be a chromosomal aberration associated with absolute sterility, Klinefelter syndrome may now be potentially treatable by testicular sperm retrieval coupled with intracytoplasmic sperm injection. With these therapeutic advances, azoospermic 47,XXY men now may have an opportunity for biological paternity. However, our knowledge of the basic mechanisms underlying germ cell loss and Leydig cell compromise is lagging, and is just now beginning to evolve and provide answers to some of the field's most vexing questions: how to maximize and preserve fertility in Klinefelter males many years or even decades before they wish to actively pursue fatherhood. This article reviews the development of the androgenic and spermatogenic compartments of the Klinefelter testis through puberty, and recommends that it is only with a clear understanding of the basic facts that a rational, considered approach to fertility optimization and preservation can be determined., (Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Severe male factor infertility may have a presently identifiable genetic basis. Y chromosomal microdeletions (e.g., an AZFc microdeletion), karyotypic anomalies (e.g., Klinefelter Syndrome), and mutations in both alleles of the cystic fibrosis transmembrane conductance regulator (CFTR) gene may be found, depending upon the etiology of the reproductive compromise. Which patients should be tested, what are the tests that can be performed, when should those tests be ordered, and what might a positive outcome mean, are all critically valuable clinical questions for the couple that help guide evaluation and management. It is imperative that they be asked and results discussed prior to any intervention such as testis tissue extraction, microsurgical epididymal sperm aspiration, or intracytoplasmic sperm injection so that the couple can incorporate them in their decisions moving forward vis-à-vis their reproductive choices and options. The role of reproductive medicine clinicians should not be limited to just helping couples establish a pregnancy, but instead be expanded to educating them about the reasons and causes of their reproductive failure that affect not only them as individuals but also may have implications for their offspring.

Massive palindromes in the human Y chromosome harbor mirror-image gene pairs essential for spermatogenesis. During evolution, these gene pairs have been maintained by intrapalindrome, arm-to-arm recombination. The mechanism of intrapalindrome recombination and risk of harmful effects are unknown. We report 51 patients with isodicentric Y (idicY) chromosomes formed by homologous crossing over between opposing arms of palindromes on sister chromatids. These ectopic recombination events occur at nearly all Y-linked palindromes. Based on our findings, we propose that intrapalindrome sequence identity is maintained via noncrossover pathways of homologous recombination. DNA double-strand breaks that initiate these pathways can be alternatively resolved by crossing over between sister chromatids to form idicY chromosomes, with clinical consequences ranging from spermatogenic failure to sex reversal and Turner syndrome. Our observations imply that crossover and noncrossover pathways are active in nearly all Y-linked palindromes, exposing an Achilles' heel in the mechanism that preserves palindrome-borne genes.

Purpose of Review: Therapies for the treatment of severe male factor infertility have advanced well beyond our knowledge of the conditions we are treating. An intact Y chromosome is necessary for optimal spermatogenesis. It is imperative for the clinician to understand the molecular basis and clinical implications of anomalies that might afflict the Y chromosome., Recent Findings: The molecular geography of the Y chromosome has recently been described, allowing correlations to be made to various clinical states of severe spermatogenic compromise. Microdeletions of parts of the Y chromosome are found in a small number of men with spermatogenic failure involving, predominantly, three regions termed AZFa, AZFb, and AZFc., Summary: It is necessary that a Y chromosomal microdeletion assay be carried out prior to any intervention using ejaculated sperm or prior to any surgical procedure to try to find spermatozoa in an azoospermic man.

Evolving therapies have allowed the use of sperm from men with spermatogenic compromise, obstructive azoospermia, and sperm functional deficiency, enabling these men to procreate when unable to do so naturally. The genetic basis of only a portion of these conditions is known and research must be pursued into the genetic underpinnings of those that have not yet been delineated. Education and provision of information to patients is the responsibility of all involved in the care of men with reproductive failure. The author concentrates on some of the known causes of nonobstructive azoospermia and obstructive azoospermia with a well-established genetic cause such as congenital bilateral absence of the vas deferens.

Purpose: To investigate the impact of an adjuvant Web-based teaching program on medical students' learning during clinical rotations., Method: From April 2003 to May 2004, 351 students completing clinical rotations in surgery-urology at four U.S. medical schools were invited to volunteer for the study. Web-based teaching cases were developed covering four core urologic topics. Students were block randomized to receive Web-based teaching on two of the four topics. Before and after a designated duration at each institution (ranging one to three weeks), students completed a validated 28-item Web-based test (Cronbach's alpha = .76) covering all four topics. The test was also administered to a subset of students at one school at the conclusion of their third-year to measure long-term learning., Results: Eighty-one percent of all eligible students (286/351) volunteered to participate in the study, 73% of whom (210/286) completed the Web-based program. Compared to controls, Web-based teaching significantly increased test scores in the four topics at each medical school (p < .001, mixed analysis of variance), corresponding to a Cohen's d effect size of 1.52 (95% confidence interval [CI], 1.23-1.80). Learning efficiency was increased three-fold by Web-based teaching (Cohen's d effect size 1.16; 95% CI 1.13-1.19). Students who were tested a median of 4.8 months later demonstrated significantly higher scores for Web-based teaching compared to non-Web-based teaching (p = .007, paired t-test). Limited learning was noted in the absence of Web-based teaching., Conclusions: This randomized controlled trial provides Class I evidence that Web-based teaching as an adjunct to clinical experiences can significantly and durably improve medical students' learning.

The human Y chromosome is replete with amplicons-very large, nearly identical repeats-which render it susceptible to interstitial deletions that often cause spermatogenic failure. Here we describe a recurrent, 1.8-Mb deletion that removes half of the azoospermia factor c (AZFc) region, including 12 members of eight testis-specific gene families. We show that this "b2/b3" deletion arose at least four times in human history-likely on inverted variants of the AZFc region that we find exist as common polymorphisms. We observed the b2/b3 deletion primarily in one family of closely related Y chromosomes-branch N in the Y-chromosome genealogy-in which all chromosomes carried the deletion. This branch is known to be widely distributed in northern Eurasia, accounts for the majority of Y chromosomes in some populations, and appears to be several thousand years old. The population-genetic success of the b2/b3 deletion is surprising, (i) because it removes half of AZFc and (ii) because the gr/gr deletion, which removes a similar set of testis-specific genes, predisposes to spermatogenic failure. Our present findings suggest either that the b2/b3 deletion has at most a modest effect on fitness or that, within branch N, its effect has been counterbalanced by another genetic, possibly Y-linked, factor.

Many human Y-chromosomal deletions are thought to severely impair reproductive fitness, which precludes their transmission to the next generation and thus ensures their rarity in the population. Here we report a 1.6-Mb deletion that persists over generations and is sufficiently common to be considered a polymorphism. We hypothesized that this deletion might affect spermatogenesis because it removes almost half of the Y chromosome's AZFc region, a gene-rich segment that is critical for sperm production. An association study established that this deletion, called gr/gr, is a significant risk factor for spermatogenic failure. The gr/gr deletion has far lower penetrance with respect to spermatogenic failure than previously characterized Y-chromosomal deletions; it is often transmitted from father to son. By studying the distribution of gr/gr-deleted chromosomes across the branches of the Y chromosome's genealogical tree, we determined that this deletion arose independently at least 14 times in human history. We suggest that the existence of this deletion as a polymorphism reflects a balance between haploid selection, which culls gr/gr-deleted Y chromosomes from the population, and homologous recombination, which continues to generate new gr/gr deletions.

Background: Severe spermatogenic compromise may be the result of a Y-chromosomal deletion of the AZFc region. Prior studies are limited to relatively small numbers of AZFc-deleted men. In this study, we have fully characterized 42 infertile men with a Y chromosome microdeletion strictly confined to the AZFc region, and we report on 18 children conceived through the use of ICSI., Methods: A total of 42 oligospermic or azoospermic men had AZFc deletions. History, physical examination, karyotype, FSH, LH, testosterone, testis histology and results of ICSI using ejaculated or testis sperm were retrospectively accumulated in two academic clinical practices., Results: All men were somatically healthy. Karyotypes were 46,XY in all but two men. FSH, LH, testosterone and testis histology could not differentiate those with oligospermia or azoospermia, nor could they predict whether sperm could be found in harvested testis tissue. Paternal age was not increased. Sperm production appeared stable over time. The results of ICSI were not affected by the AZFc deletion. All but one of the offspring were healthy. The sons inherited the AZFc deletion with no increase in length., Conclusions: AZFc-deleted men are somatically healthy, will most likely have useable sperm, will have stable sperm production over time and will have a good chance to experience biological paternity, but their sons will also be AZFc-deleted.

It is widely believed that at least three nonoverlapping regions of the human Y chromosome-AZFa, AZFb, and AZFc ("azoospermia factors" a, b, and c)-are essential for normal spermatogenesis. These intervals are defined by interstitial Y-chromosome deletions that impair or extinguish spermatogenesis. Deletion breakpoints, mechanisms, and lengths, as well as inventories of affected genes, have been elucidated for deletions of AZFa and of AZFc but not for deletions of AZFb or of AZFb plus AZFc. We studied three deletions of AZFb and eight deletions of AZFb plus AZFc, as assayed by the STSs defining these intervals. Guided by Y-chromosome sequence, we localized breakpoints precisely and were able to sequence nine of the deletion junctions. Homologous recombination can explain seven of these deletions but not the remaining two. This fact and our discovery of breakpoint hotspots suggest that factors in addition to homology underlie these deletions. The deletions previously thought to define AZFb were found to extend from palindrome P5 to the proximal arm of palindrome P1, 1.5 Mb within AZFc. Thus, they do not define a genomic region separate from AZFc. We also found that the deletions of AZFb plus AZFc, as assayed by standard STSs heretofore available, in fact extend from P5 to the distal arm of P1 and spare distal AZFc. Both classes of deletions are massive: P5/proximal-P1 deletions encompass up to 6.2 Mb and remove 32 genes and transcripts; P5/distal-P1 deletions encompass up to 7.7 Mb and remove 42 genes and transcripts. To our knowledge, these are the largest of all human interstitial deletions for which deletion junctions and complete intervening sequence are available. The restriction of the associated phenotype to spermatogenic failure indicates the remarkable functional specialization of the affected regions of the Y chromosome.

Purpose: To define the success of testis sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI) in azoospermic men with a history of chemotherapy., Patients and Methods: In a retrospective study, 23 men with ejaculatory azoospermia and a history of chemotherapy underwent TESE in a search for usable spermatozoa. In six patients cryopreserved tissue and in nine patients fresh tissue provided sperm for an ICSI cycle. Histologic analysis of the testis was performed in all patients. The presence or absence of sperm, fertilization rates with ICSI, and final outcomes of pregnancy were recorded., Results: Spermatozoa were found on TESE in 15 (65.2%) of 23 men. On histopathology, the predominant pattern observed was Sertoli cell only (47.8%), followed by hypospermatogenesis (30.4%), mixed (17.4%), and late maturation arrest (4.3%). The fertilization rate was 65.2%, and ongoing/delivered pregnancies occurred in 30.8% of cycles. Six healthy boys and four healthy girls have been born to date., Conclusion: Men who are azoospermic and have had prior cytotoxic therapy make up a small subgroup of males with nonobstructive azoospermia. It is important to define and characterize this subgroup and better define their true fertility potential. Approximately two thirds of these men have retrievable testis sperm, which may be used with ICSI to have healthy offspring. This exciting avenue for paternity has heretofore not been available to such patients.

Objective: To describe a case involving the cryopreservation of testis tissue retrieved from a 15-year-old male teenager with Klinefelter's syndrome., Design: Case report., Setting: An academic medical center., Patient(s): A 15-year-old boy with Klinefelter's syndrome., Intervention(s): Microsurgical testis sperm extraction with cryopreservation of harvested tissue., Main Outcome Measure(s): Spermatozoa within testis tissue., Result(s): Successful extraction and cryopreservation of three vials of sperm-containing testis tissue. No effect on subsequent testosterone levels., Conclusion(s): Testis tissue extraction in the adequately virilized but azoospermic young male with 47, XXY Klinefelter's syndrome may be a strategy to preserve future biological paternity.

Background: Men with cystic fibrosis (CF) have bilateral absence of the vas deferens causing an obstructive azoospermia that is not amenable to surgical correction. Advances in the field of reproductive medicine allow for the procurement of viable sperm and facilitate fertilization and pregnancy in couples where the man has CF., Objectives: To describe patient anatomy and semen characteristics and to determine the pregnancy rates of couples in whom the male partner has CF and who have undergone microsurgical epididymal sperm aspiration coupled with in vitro technology, specifically intracytoplasmic sperm injection (ICSI)., Design: Retrospective analysis., Setting: Clinical department of urology and two reproductive medicine units., Patients: Thirteen married men with CF who were referred for infertility., Interventions: History, physical examination, semen analysis, transrectal and renal ultrasonography, CF mutation analysis, and microsurgical sperm aspiration coupled with ICSI., Results: All 13 men had low-volume azoospermia, absent vasa, and aplasia/hypoplasia of the seminal vesicles. CF mutation analysis was carried out in 11 of 13 men, and 9 of 11 were DeltaF508 homozygous. Eight men underwent microsurgical sperm aspiration, and their partners underwent one or more cycles of ICSI. Five couples (62.5%) achieved a pregnancy, with four couples delivering (three sets of twins and one singleton)., Conclusions: CF in men is accompanied by bilateral vasal aplasia. The resultant obstructive azoospermia can be treated quite successfully with a combination of sperm aspiration and ICSI. It is important for physicians involved in the care of men with CF to convey the message that prospects for fatherhood are excellent with current technology.

Objectives: Epididymovasostomy is commonly performed at the most distal site of the epididymis where whole sperm are present within the lumen, regardless of their motility status. Although more fresh and motile sperm can be found more proximally within the epididymis, it is believed that the outcome of epididymovasostomy is better more distally. Because the current results of epididymovasostomy are far from perfect, it would be ideal to be able to harvest motile sperm for cryopreservation at the time of surgery in case the patient remains azoospermic postoperatively. The objective of this study was to determine the effect of the level of epididymal anastomosis and quality of sperm on the outcome of surgery., Methods: An end-to-side epididymovasostomy was performed on 131 azoospermic men with a mean age of 39 years and a mean obstructive interval of 18 years. The etiology of obstruction was vasectomy in 48%, infectious in 19%, congenital in 20%, and unknown in 13%. The average duration of follow-up was 32 months. The overall patency rate was 67% and pregnancy rate was 27%. Subgroups of patients with an anastomosis to the same level of the epididymis on all functional sides were identified as follows: caput (56), corpus (28), and cauda (13). These groups were compared in regard to the presence of motile sperm within the epididymal lumen at the time of surgery, patency rates, postoperative semen quality, and pregnancy rates., Results: Motile sperm were present more often in both the caput (54%) and corpus (61%) than in the cauda epididymis (25%) (P < 0.05). The patency rates for the three subgroups were not significantly different. The postoperative total motile sperm count and pregnancy rate for the corpus epididymis (13 x 10(6) and 45%) was significantly (P < 0.05) better than for the caput (4.4 x 10(6) and 22%) but no different than that of the cauda (10 x 10(6) and 23%). The patency and pregnancy rates for anastomoses performed at levels demonstrating motile sperm were not significantly better than at sites with nonmotile sperm, but the postoperative total motile sperm count was better (P < 0.05)., Conclusions: The results of this study suggest that the outcomes of epididymovasostomy to the corpus and cauda epididymis are roughly equivalent and superior to the caput. Therefore, it may be reasonable to move more proximally from the cauda to corpus in the search for motile sperm for cryopreservation during an end-to-side epididymovasostomy. In contrast, moving from the corpus to the caput epididymis has a significant adverse effect upon outcome; it is, therefore, not worthwhile to search for viable sperm for cryopreservation in this clinical setting.

Testicular tissue extraction (TESE) to obtain spermatozoa for use with intracytoplasmic sperm injection (ICSI) has recently been employed in patients with non-obstructive azoospermia. Standard protocol is to retrieve a new sample of testis tissue on the day of oocyte recovery. Unfortunately, approximately 30% of men will possess no spermatozoa in their tissue, making ICSI an impossibility. We investigated whether testicular tissue that was intentionally obtained well before any planned ICSI cycle and cryopreserved could then serve as an efficacious sperm source in a subsequent ICSI cycle. This study reports on 10 men with non-obstructive azoospermia who did have spermatozoa found within their testis tissue at the time of TESE and who chose to use their frozen samples as the source of spermatozoa for a later cycle of ICSI. In 19 cycles the overall fertilization rate was 48%. Embryo transfer occurred in 89% of cycles. Two couples have achieved pregnancy (one ongoing, one delivered). All patients except one had multiple vials of frozen tissue remaining following their first cycle. This approach is offered as an alternative to repeated testicular tissue sampling, as the availability of spermatozoa is assured prior to the initiation of ovulation induction. This tissue can be harvested at the same time as diagnostic biopsy, thereby minimizing the number of surgical procedures.

Some men with non-obstructive azoospermia harbour fully formed spermatozoa within their testicular tissue that can be used to achieve pregnancy via intracytoplasmic sperm injection (ICSI). Recently, Reijo et al. (1995) provided compelling evidence that the DAZ gene cluster is a strong candidate for one of the elusive azoospermia factors (AZF) located on the long arm of the Y chromosome. The DAZ gene cluster is deleted in 13% of azoospermic men and a small percentage of severely oligozoospermic men. Vertical transmission from father to son of AZF region deletions has also been described. Presumably these fathers were oligozoospermic. This led us to ask whether the azoospermic male with deletions of the AZF/DAZ region can also complete minimal spermatogenesis and whether any spermatozoa found could participate in fertilization, embryo development and pregnancy. Three out of six (50%) of the azoospermic men with AZF/DAZ deletions had spermatozoa identified within their harvested testicular tissue. When these spermatozoa were used for ICSI, fertilization occurred in 36% of injected oocytes. This compared favourably with testicular spermatozoa retrieved from non-obstructive azoospermic men without AZF/DAZ gene deletions. In one case, a twin conception resulted, which represents the first term pregnancy reported using spermatozoa from an AZF/DAZ deleted azoospermic male. Therefore it is necessary to take the possibility of transmission of infertility or sterility to our patients' offspring seriously when utilizing today's reproductive technologies, as spermatogenesis in men with AZF/DAZ deletions is by no means an exceptional occurrence.

Objectives: Hitherto, patients with testicular dysfunction and azoospermia had to resort to adoption, donor sperm insemination, or child-free living. The realization that a proportion of such men harbor spermatozoa in their testicular parenchyma, combined with the ability of intracytoplasmic sperm injection (ICSI) to effect pregnancy with single sperm, has prompted male infertility clinicians to explore testicular sperm extraction (TESE) in this patient population. We sought to investigate the likelihood of finding spermatozoa during TESE from men presenting with nonobstructive azoospermia and to define if any factors existed that were predictive of eventual sperm presence or absence., Methods: Thirty patients with nonobstructive azoospermia underwent TESE and simultaneous formal testis biopsy, cytologic analysis, and wet preparation analysis. Tissue obtained from TESE was analyzed according to a rigorous protocol, followed by exhaustive searching by trained embryologists., Results: Twenty-one patients (70%) had spermatozoa found on testicular tissue analysis. Neither patient age nor follicle-stimulating hormone (FSH) level was predictive of the ability to find sperm. With regard to histologic pattern, 50% of men with Sertoli cell-only, 75% of patients with maturation arrest, and 100% of patients with spermatids seen on histologic analysis had sperm retrieved from their testicular tissue during TESE. Absence of sperm on cytologic smear and wet preparation analysis failed to predict the presence of sperm on formal testicular tissue analysis in 40% of patients., Conclusions: Men with nonobstructive azoospermia may have mature spermatozoa present within their testicular parenchyma. Relying on these data, patients should not be excluded from TESE based on serum FSH level, age, prior histopathologic pattern, or cytology/wet preparation results. These figures will allow clinicians to counsel patients with nonobstructive azoospermia informatively regarding TESE and their chances of having testicular sperm retrieved.

Congenital bilateral absence of the vas deferens (CBAVD) was once thought to be a distinct clinical entity, but genetic similarities in men with cystic fibrosis (CF) and CBAVD are described increasingly. We evaluated the clinical status, growth and nutritional state, and respiratory function of 18 men with CBAVD to determine whether these men with different CF transmembrane regulator (CFTR) genotypes may have clinical evidence of mild CF. Following a thorough history and examination, pulmonary function tests, sweat test, and renal ultrasound were performed. Genetic evaluation for 50 known CF mutations, screening for private mutations (single-strand conformational polymorphism and direct sequencing), and assay of the length of the polypyrimidine tract in the splice site acceptor of intron 8 was performed. A history of pulmonary disease was present in three, and an additional man had some features suggestive of malabsorption. Results of general physical examination and anthropomorphic measurements were unremarkable in all patients, with a mean (SD) body mass index of 26 (3). Pulmonary function tests of large and small airway function as well as lung volumes were normal in all except one whose results were consistent with moderate asthma. Five men were compound heterozygotes for CFTR mutations, four of whom had positive sweat tests (sweat chloride > 60 mEq/L). Twelve men were heterozygotes for CFTR mutations while no mutations were identified in one man. Although putative etiologic factors may suggest that men with CBAVD and CFTR mutations could be considered within the spectrum of clinical CF, the authors suggest that in men with CBAVD without any other clinical features of CF, the diagnosis of CF may not be made.

Purpose: The conception rate of patients with spinal cord injuries following penile vibratory stimulation and rectal probe electroejaculation in conjunction with self-insemination, intrauterine insemination or assisted reproductive technique is poorly documented. We reviewed our success rates with penile vibratory stimulation and rectal probe electroejaculation, and the pregnancy rates achieved with self-insemination, intrauterine insemination and assisted reproductive techniques., Materials and Methods: A total of 78 consecutive patients with spinal cord injuries had a complete neurological examination and was treated initially with penile vibratory stimulation. If unsuccessful, rectal probe electroejaculation was performed to obtain an ejaculate. The ejaculate was then used with self-insemination, intrauterine insemination or assisted reproductive techniques and pregnancies were monitored., Results: Vibratory stimulation was successful in 20 of 37 patients (54%) with a cervical lesion, 14 of 26 (54%) with a lesion at or above T10 and none of 15 when the lesion was below T10. All patients except 2 who elected followup rectal probe electroejaculation had antegrade or retrograde ejaculate. Six patients (7.7%) with extremely poor semen quality were not candidates for assisted fertilization. Of 27 couples who attempted conception 17 were successful (5 self-insemination, 5 intrauterine insemination and 7 assisted reproductive techniques)., Conclusions: Penile vibratory stimulation should be used as first line therapy in patients with lesions above T10 while rectal probe electroejaculation should be considered as a second option. Motivated patients can achieve success with self-insemination, intrauterine insemination and assisted reproductive techniques.

Microsurgical epididymal sperm aspiration was a great advance in the therapy of patients with non-reconstructable, obstructive azoospermia, most notably congenital bilateral absence of the vas deferens. Using conventional in-vitro fertilization, pregnancies were rarely achieved because the rate of oocyte fertilization was extremely poor. However, the use of retrieved spermatozoa in conjunction with intracytoplasmic sperm injection (ICSI) has dramatically increased the likelihood of embryo formation. Typically, sperm and oocyte harvesting are performed simultaneously. We have investigated whether frozen-thawed spermatozoa work as well as fresh spermatozoa. When we had concluded from our own population of patients (groups I and II) that they did, we adopted a policy of aspirating spermatozoa, primarily cryopreserving them and using them for ICSI at a later date. We found the fertilization rates of this latter cohort of patients (group III) to be excellent (37% per oocyte), and the ongoing pregnancy rate is quite satisfactory (40% per couple, 29% per cycle). We offer this approach as an alternative to the traditional scheme because it markedly eases the burden of partner scheduling on both the couple and the clinicians involved. In addition, assurance of the availability of male partner spermatozoa can be attained prior to beginning ovulation induction.

Objective: To evaluate the success of electroejaculation with assisted reproductive technologies (ART) in anejaculate men after retroperitoneal lymph node dissection (RPLND) for testicular cancer., Design: Retrospective clinical study., Setting: Tertiary care, university-affiliated IVF program., Patients: Anejaculate men after RPLND, spouses., Interventions: Electroejaculation, microsurgical sperm aspiration, various assisted reproductive technologies., Main Outcome Measures: Sperm density and motility, fertilization rate, pregnancy rate (PR)., Results: Compared with patients not receiving chemotherapy, patients who received chemotherapy had diminished average sperm densities and motilities (63 x 10(6) and 20% versus 101 x 10(6) 32%, respectively); decreased fertilization rates per cycle for IVF and intracytoplasmic sperm injection (ICSI) (11% versus 26%, respectively); lower PRs per cycle of hMG-IUI and IVF (14% versus 60% and 8% versus 50%, respectively). No pregnancies were achieved with natural cycle-IUI, clomiphene citrate-IUI, or GIFT. Two couples progressed to intracytoplasmic sperm injection with one achieving the successful delivery of healthy twins. The overall PR per cycle was 22%., Conclusions: Patients receiving chemotherapy had decreased sperm densities, motilities, fertilization, and PRs for each modality used. Rectal probe electroejaculation with ART can help anejaculate men after RPLND achieve biologic paternity. An early move to the more aggressive therapies (hMG-IUI, IVF, ICSI) is supported.

A total of 21 infertile men with congenital unilateral absence of the vas deferens (CUAVD) were studied to determine if this disorder involves mutations in the cystic fibrosis (CF) gene. This hypothesis derives from previous work which has established the genetic commonality of CF and congenital bilateral absence of the vas deferens (CBAVD). Both CF and CBAVD may result from compound heterozygosity for CF mutations. In our patients with unilateral vasal aplasia, 12 had anatomically complete and patent vasa deferentia on the contralateral side, i.e. side of the scrotally palpable vas. No CF mutations were detected in this subgroup. The remaining nine patients had a non-iatrogenic occlusion of the contralateral vas at either the inguinal or pelvic level. In this subgroup, eight out of nine (89%) had a mutation detected in one of their two CF genes. This is the first study to define accurately the clinically and anatomically heterogeneous nature of CUAVD and to begin to clarify the genetic basis of unilateral absence of the vas deferens.

The frequency and timing of the delayed appearance of sperm following an end-to-side vasoepididymostomy were determined in 89 patients. The surgical patency rate, defined as greater than 1 million sperm in the ejaculate, was 56% (50 of 89 consecutive patients). None of the 7 patients without sperm in the epididymal fluid at the anastomosis had sperm in the ejaculate postoperatively. Of the remaining 82 patients 31 had sperm on initial semen analysis within 3 months postoperatively. Seven of the 51 patients whose initial postoperative semen sample revealed azoospermia were lost to followup. Among the remaining 44 patients 18 (41%) had delayed appearance of sperm in the ejaculate (mean delay 6 months, range 3 to 15). The ultimate mean sperm count and motility in the patients with initially positive postoperative semen samples were not significantly different from those in patients with delayed appearance of sperm. In addition, the delayed anastomotic obstruction for both groups was the same (10% and 11%, respectively). Our results demonstrate that delayed appearance of sperm after end-to-side vasoepididymostomy is common and that the prognosis for patients with delayed appearance of sperm is not significantly worse than that for patients with sperm on the initial semen analysis.

Adequate male development and spermatogenesis involve a complex array of events, all prescribed by numerous gene products in an orderly temporal and spatial sequence. A single defect in any portion of these myriad steps may lead to total failure of testicular development or simply subtle spermatogenic deficiency. As emphasis continues to be placed upon elucidation of the molecular and genetic basis underlying clinical and phenotypic human failings, knowledge will slowly accumulate to explain these failings and, it is hoped, to suggest treatment strategies for some.

Ten patients who presented for infertility had unilateral absence of the scrotal vas deferens and a contralateral mesonephric duct anomaly, including contralateral ejaculatory duct or epididymal/vasal obstruction. The details of the physical examination, semen analysis and transrectal ultrasound led to an accurate preoperative diagnosis in each case. Therapeutic manipulations appropriate in this group included transurethral resection of the ejaculatory duct, microscopic vasoepididymostomy and microsurgical sperm aspiration coupled with in vitro fertilization. Only 3 patients had ipsilateral renal agenesis or ectopia (30%), which is well below the stated percentage for patients with unilateral vasal agenesis (90%). An aberration in the proper sequence of mesonephric embryological development may partly explain this bilateral constellation of abnormalities.

These three cases exemplify, in increasing order of complexity, how the common sense application of already successful techniques might be applied to augment the chance of pregnancy in this group of patients. We believe this to be the first report specifically outlining measures that may assist this group in their goal of pregnancy achievement. To our knowledge, vasal sperm aspiration has never been used for this indication.

CF and CBAVD are really just ends of a clinical spectrum. The type and nature of the mutations in the CF gene probably determine the phenotypic expression of the patient. Perhaps all patients homozygous for delta F508, for example, will have severe pulmonary and pancreatic disease as well as absent vasa, whereas those with other combinations, such as delta F508/D1270N, will be unaffected in terms of pulmonary and pancreatic function but will have absent vasa. Besides contributing to a better understanding of the nature of CBAVD, this linkage of CF and CBAVD most importantly mandates genetic screening and counseling for appropriate family members and even the patient's spouse. In addition, a broader understanding of CF is now at hand, as this brings a whole new cohort of patients under the CF umbrella. Many of these will have at least one, if not two, rare or novel CF gene mutations. Once all of these mutations have been detected and defined, our knowledge of the CF gene, its mutations, and their implications will be dramatically expanded.

Ultrasound (US) has become crucial in the assessment of infertility of couples, in 50% of whom the male partner is responsible. Male infertility is caused by many diverse conditions, from reparable obstructive disorders to noncorrectable intrinsic testicular failure. During the past 4 years, a select group of 70 young infertile men with azoospermia or oligospermia and low ejaculate volume were examined with transrectal US. Twenty-six patients had congenital bilateral absence of the vas deferens, 11 had congenital unilateral absence of the vas deferens and contralateral obstructive pathology, 15 had additional abnormalities thought to be directly related to semen deficiencies, and 18 patients with other causes for semen deficiency and infertility had findings that were either normal or showed minor abnormalities. The delineation of congenital and obstructive abnormalities of the distal urogenital tract with transrectal US enables an accurate diagnosis of certain cases of male infertility and helps guide appropriate clinical and surgical management.