High-resolution sonography of the normal extrapelvic vas deferens.

OBJECTIVE: The purpose of this study was to determine the reliability of sonographic visualization of the normal extrapelvic vas deferens and to analyze its appearance and dimensions. METHODS: Scans of the scrotum and spermatic cords were obtained in 25 fertile volunteers. Identification of the vas deferens was attempted bilaterally in the scrotal, suprascrotal, and prepubic segments in all volunteers. When possible, the total thickness and the diameter of the lumen were measured. Visualization and dimensions were correlated with the body mass index (BMI) and abstinence interval. RESULTS: All segments of the vas deferens were identified bilaterally in all volunteers. In all cases, it appeared as an anechoic or very hypoechoic tubular structure that was noncompressible and contained no detectable blood flow. It was convoluted inferiorly and became straight as it progressed from the scrotum to the suprascrotal and prepubic segments. The lumen was seen in the suprascrotal segment in all of the volunteers except the one with the highest BMI. The total thickness of the vas ranged from 1.5 to 2.7 mm (mean, 1.89 mm). The lumen of the vas ranged from 0.2 to 0.7 mm (mean, 0.43 mm). There was no correlation between the luminal diameter and the abstinence interval. CONCLUSIONS: The extrapelvic portion of the vas deferens is reliably visualized sonographically. Its appearance is characteristic and reproducible. The lumen can be measured in almost all cases.

Prevalence and predictors of sexual problems, relationship stress, and depression in female partners of infertile couples.

INTRODUCTION: Infertility has been associated with anxiety, stress, and sexual problems in both men and women. AIM: To assess quality of life, sexual health, and depression in the female partner of infertile couples. METHODS: Couples presenting for the evaluation of infertility at two tertiary care medical centers were invited to participate in a survey study. MAIN OUTCOME MEASURES: Female partners completed the Female Sexual Function Index (FSFI) and a modified Self-Esteem and Relationship (SEAR) Questionnaire. Male partners completed the SEAR and the International Index of Erectile Function (IIEF). Both partners completed the Center for Epidemiological Studies Depression Scale (CES-D) for depression and the Short Form-36 (SF-36) for general quality of life. Demographic, fertility, and comorbidity information was recorded. RESULTS: One hundred and twenty-one couples constitute the study population. Mean female and male age was 32 +/- 5 and 35 +/- 7 years, respectively. Most (92%) couples were married. Mean duration of relationship and marriage were 6.4 +/- 3.9 and 3.8 +/- 3.2 years, respectively. Mean duration of attempted conception was 24 +/- 24 months. On CES-D, 19% of women had moderate and 13% had severe depression. Women reported significantly worse SF-36 Mental Health subscale scores (mean = 47.8, P < 0.05) compared with normative values. The mean total FSFI score was 28 +/- 7 (maximum score of 36), with 26% of the women scoring below 26.55, an established cut-off for high risk of female sexual dysfunction. FSFI scores had a modest positive correlation with male IIEF scores (r = 0.37, P < 0.01), and there was a trend toward a negative correlation with female CES-D scores (r = -0.16, P < 0.06). These relationships were maintained on multivariate analysis. CONCLUSIONS: Depression and sexual dysfunction are prevalent in female partners of infertile couples. Female sexual function is positively correlated with male partner sexual function in this population.

Sexual function and quality of life in the male partner of infertile couples: prevalence and correlates of dysfunction.

PURPOSE: We prospectively collected data on mental and physical health related quality of life as well as sexual and relationship function in couples presenting for the treatment of infertility. MATERIALS AND METHODS: Infertile couples were invited to complete a demographic survey, the Short Form 36 and the Center for Epidemiological Studies Depression Inventory. Male partners completed the International Index of Erectile Function and the Self-Esteem and Relationship Quality scale. Female partners completed the Female Sexual Function Index and a version of the Self-Esteem and Relationship Quality Scale modified for women. Multiple regression analysis was conducted to assess for associations between partner responses. RESULTS: A total of 121 couples were enrolled at 2 sites. Male partners reported significantly lower standardized scores on the Mental Health subscale of the Short Form 36 (mean 47.6, p <0.05) compared to normative values. Of the men surveyed 11% and 12% reported moderate or severe depression, respectively. There were 18% who had mild erectile dysfunction and 4% had moderate erectile dysfunction. The mean transformed score for the Self-Esteem and Relationship Quality Scale in our subjects was 29.44 (range 0 to 100). In multivariate analysis white race and partner Female Sexual Function Index score were significant predictors of International Index of Erectile Function Erectile Function Domain scores (p <0.01). Relationship duration and partner Self-Esteem and Relationship Quality Scale scores were significantly associated with male Self-Esteem and Relationship Quality Scale score on multivariate analysis. CONCLUSIONS: Depression, erectile dysfunction and sexual relationship problems are prevalent among male partners of infertile couples. Partner sexual function is a significant predictor of male partner sexual function. Relationship duration and female partner assessment of relationship health are predictive of men's assessment of their relationship status.

Premature ejaculation in infertile couples: prevalence and correlates.

INTRODUCTION: The incidence of premature ejaculation (PE) and other sexual problems in infertile couples is unknown. AIMS: We attempted to determine the prevalence of PE in infertile couples. METHODS: Infertile couples presenting for evaluation at our institutions were invited to participate in our study. Multiple regression analysis was conducted to assess for associations between partner responses. MAIN OUTCOME MEASURE: Respondents completed a demographic survey, the Short Form-36 (SF-36), and the Center for Epidemiological Studies Depression (CES-D) scale. Both partners also completed a gender-specific survey instrument to detect PE and distress related to the condition. Male partners completed the International Index of Erectile Function (IIEF) and the Self-Esteem and Relationship Quality (SEAR) scale. Female partners completed the Female Sexual Function Index (FSFI) and a modified version of the SEAR. RESULTS: Fifty percent of men reported that they ejaculated more rapidly than they wished. When men reported PE, their partners agreed with the diagnosis in 47% of cases. Female partners of men who did not report PE reported PE in 11% of cases. Partner frustration related to PE was reported by 30% of men. Partners agreed that they were frustrated in 43% of these cases. Among the 70% of men who did not report partner frustration from PE, 93% of the partners agreed that they were not frustrated. There was a statistically significant negative association between male and female report of PE and SEAR scores. There were no other statistically significant associations between PE responses and demographic variables, IIEF, FSFI, CES-D, and SF-36 scores. CONCLUSIONS: PE is prevalent among infertile couples although the perceived incidence of the condition among men is higher than partner perceived incidence. Additionally, many men may overestimate the level of partner frustration related to PE. PE is associated with lower relationship satisfaction in both men and women. Further research is required.

Does the number and size of veins ligated at left-sided microsurgical subinguinal varicocelectomy affect semen analysis outcomes?

OBJECTIVES: To determine whether the preoperative and intraoperative findings at unilateral microsurgical subinguinal varicocelectomy are predictive of semen analysis changes postoperatively. METHODS: We identified 42 men who had undergone left-sided microsurgical subinguinal varicocelectomy at our institution and had at least one semen analysis before and after surgery. The preoperative varicocele grade and number and size of spermatic cord veins ligated were recorded. The veins were defined as small (less than 1.0 mm), medium (1.0 to 3.9 mm), and large (4.0 mm or larger). The generalized estimating equation approach was used to assess whether patient age, varicocele grade, number of small, medium, or large veins ligated, total number of veins ligated, and net diameter of all veins ligated were predictive of repeated measurements of semen analysis outcomes. RESULTS: Increasing patient age was associated with a slight decline in sperm concentration (P = 0.046). The number of veins ligated correlated positively with an increase in total motility (P = 0.017). The repair of grade II varicoceles was associated with a significantly greater increase in normal morphology than did the repair of grade I or III varicoceles (P = 0.004). None of the other variables examined were predictive of semen analysis outcome (P >0.05). CONCLUSIONS: The relationship between the preoperative/intraoperative findings and semen analysis outcomes after microsurgical subinguinal varicocelectomy remains unclear.

Tslc1 (nectin-like molecule-2) is essential for spermatozoa motility and male fertility.

The nectin-like molecule-2 (TSLC1) is a cell-cell adhesion molecule expressed in testicular germ cells. To directly examine the role of Tslc1 in male fertility, we generated Tslc1+/- mice that have greater than 90% reduction in Tslc1 expression. Tslc1+/- males exhibited reduced fertility and rarely transmitted the Tslc1 mutant allele, whereas Tslc1+/- females were consistently able to transmit the mutant allele. Histologic and electron microscopic analyses of the testes in Tslc1+/- mice demonstrated disruption of the junctional scaffold between germ cells and Sertoli cells. Reduced Tslc1 expression had no effect on germ cell proliferation or apoptosis. While evidence of normal spermatozoal maturation was supported by Fluorescence Activated Cell Sorting (FACS) analysis, spermatozoa from Tslc1+/- mice demonstrated markedly reduced motility without compromised viability. Collectively, these results establish an essential role for Tslc1 in spermatozoal maturation and motility, distinct from other members of the nectin family.

Glial cell-line derived neurotrophic factor-mediated RET signaling regulates spermatogonial stem cell fate.

Normal spermatogenesis is essential for reproduction and depends on proper spermatogonial stem cell (SSC) function. Genes and signaling pathways that regulate SSC function have not been well defined. We report that glial cell-line-derived neurotrophic factor (GDNF) signaling through the RET tyrosine kinase/GFRA1 receptor complex is required for spermatogonial self-renewal in mice. GFRA1 and RET expression was identified in a subset of gonocytes at birth, was restricted to SSCs during normal spermatogenesis, and RET expressing cells were abundant in a cryptorchid model of SSC self-renewal. We used the whole-testis transplantation technique to overcome the limitation of neonatal lethality of Gdnf-, Gfra1-, and Ret-deficient mice and found that each of these genes is required for postnatal spermatogenesis and not for embryological testes development. Each mutant testis shows severe SSC depletion by Postnatal Day 7 during the first wave of spermatogenesis. These defects were due to lack of SSC proliferation and an inability of SSCs to maintain an undifferentiated state. Our results demonstrate that GDNF-mediated RET signaling is critical for the fate of undifferentiated spermatogonia and that abnormalities in this pathway may contribute to male infertility and testicular germ cell tumors.

Status of women in urology: based on a report to the Society of University Urologists.

PURPOSE: Written responses from American trained women in urological surgery were obtained to evaluate practice patterns, career choices and workplace satisfaction. MATERIALS AND METHODS: A 3-page unblinded questionnaire was mailed in March 2003 to American trained women in urological surgery available through the databases of the Society of Women in Urology with subsequent statistical analysis. RESULTS: The response rate was 60% but inclusive of all women in current academic practice in the United States. A total of 61% reported working 51 or more hours a week whereas 2% have left practice due to retirement or medical infirmity. There were 41% who had completed fellowships including 87% reporting active practice within their subspecialty, whereas 62% of fellowship trained surgeons remained in an academic practice. Among United States women in academic urological practice, academic progression has occurred in a third of this cohort. CONCLUSIONS: Threats to successful practice, consistent with other workplace surveys of physicians and professional women including gender based role limitation and inadequate mentoring, were commonly reported. These correctable workplace deficiencies represent an opportunity for American urology to enhance the professional workplace for all urologists regardless of gender.

Increased seminal reactive oxygen species levels in patients with varicoceles correlate with varicocele grade but not with testis size.

Increased levels of reactive oxygen species (ROS) are associated with clinical varicoceles; however, its correlation with varicocele grade and testis size is unknown. In our study, seminal ROS levels showed significant correlation with left varicocele grade and significantly elevated seminal ROS levels were seen in men with left varicocele grade 2 and 3 compared to grade 1.

Mice expressing a dominant-negative Ret mutation phenocopy human Hirschsprung disease and delineate a direct role of Ret in spermatogenesis.

The Ret receptor tyrosine kinase mediates physiological signals of glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) and is essential for postnatal survival in mice. It is implicated in a number of human diseases and developmental abnormalities. Here, we describe our analyses of mice expressing a Ret mutant (RetDN) with diminished kinase activity that inhibits wild-type Ret activity, including its activation of AKT. All RetDN/+ mice died by 1 month of age and had distal intestinal aganglionosis reminiscent of Hirschsprung disease (HSCR) in humans. The RetDN/+ proximal small intestine also had severe hypoganglionosis and reduction in nerve fiber density, suggesting a potential mechanism for the continued gastric dysmotility in postsurgical HSCR patients. Unlike Ret-null mice, which have abnormalities in the parasympathetic and sympathetic nervous systems, the RetDN/+ mice only had defects in the parasympathetic nervous system. A small proportion of RetDN/+ mice had renal agenesis, and the remainder had hypoplastic kidneys and developed tubulocystic abnormalities postnatally. Postnatal analyses of the testes revealed a decreased number of germ cells, degenerating seminiferous tubules, maturation arrest and apoptosis, indicating a crucial role for Ret in early spermatogenesis.

Does varicocele grade predict vein number and size at microsurgical subinguinal repair?

OBJECTIVES: To correlate the varicocele grade on physical examination with the number and size of the veins present and ligated during surgery. Varicoceles are correctable causes of male factor infertility. No prior anatomic studies have correlated the preoperative clinical grade of a varicocele with the number of veins discovered and ligated during microsurgical subinguinal repair. METHODS: A total of 65 consecutive men (mean age 33.8 years) diagnosed during office evaluation with either unilateral left varicocele or bilateral varicoceles underwent microsurgical subinguinal varicocelectomy by one urologist. At surgery, the number and size (small, less than 1.0 mm; medium, 1.0 mm or greater to less than 4.0 mm; large, 4.0 mm or greater) of the spermatic cord veins present and ligated were recorded. These findings were correlated with the size of the preoperative varicocele grade. RESULTS: Of the 71 varicocele units, 65 qualified for analysis. Of the patients with a grade 1 varicocele, a mean (+/-SD) of 2.4 (+/-2.5) small veins, 4.7 (+/-2.1) medium veins, 0.3 (+/-0.58) large veins, and 7.5 (+/-3.0) total veins were ligated. Of patients with a grade 2 varicocele, a mean of 2.6 (+/-2.3) small veins, 5.3 (+/-3.1) medium veins, 0.47 (+/-0.78) large veins, and 8.3 (+/-3.2) total veins were ligated. Of patients with grade 3 varicoceles, a mean of 1.8 (+/-1.8) small veins, 4.6 (+/-2.3) medium veins, 1.0 (+/-0.75) large veins, and 6.9 (+/-2.6) total veins were ligated. Using analysis of variance, the grade 3 varicoceles had significantly more large veins than did grade 1 varicoceles (P <0.05). CONCLUSIONS: Grade 3 varicoceles have a greater number of large veins compared with grade 1 varicoceles.

The use of URYX for reversible vasectomy in a rabbit model.

URYX is a biocompatible polymer of ethylene vinyl alcohol dissolved in a dimethyl sulfoxide (DMSO) carrier to allow injection of a very low-viscosity fluid into tissue. Once the material comes into contact with body tissue or fluid, the DMSO rapidly dissipates from the polymer, which results in a precipitate of a coherent solid mass. The purpose of the present study was to determine whether URYX can effectively occlude the vas deferens and whether patency can be restored by redissolving the URYX in vivo using the solvent DMSO. Eight male New Zealand White rabbits (age range, 25-41 weeks; mean age, 33.9 +/- 7.5 weeks; mean weight, 4.0 +/- 0.2 kg) were used in 2 experiments (E1 and E2). In E1, 3 rabbits underwent unilateral vasectomy, and the contralateral vas was injected with either 0.05 or 0.10 mL of URYX, to determine the amount of URYX required to cause obstruction. Two animals underwent bilateral vasectomy, to serve as controls. In E2, 3 animals underwent bilateral URYX injection and were compared with the bilateral vasectomy control rabbits used in E1. After 1 month of initial bilateral URYX treatment, all animals in E2 underwent attempted unilateral reversal with 1.5 mL of DMSO injected into 1 occluded vas deferens. Two end points were evaluated-a clinical end point assessed by semen analyses and a pathological end point assessed by histological analysis of treated tissues, to assess for safety. A 1.5-cm infrapubic incision was made to expose both vasa in anesthetized rabbits. The vasal injection of URYX was performed with a 30-gauge needle. Vasectomy was performed by excision of a 1-cm segment of the vas deferens and subsequent ligation with a 6-0 prolene suture. Semen was collected using an artificial vagina 2-3 times/wk before and 1 month later, after injection treatments and vasectomy. Manual sperm counts were performed. All animals were sacrificed, and tissues (distal vas, injection site, proximal vas, cauda epididymis, caput epididymis, and testis) were harvested and examined for the presence of URYX. The inflammatory response of the wall and adventitia of the vas deferens was given a score (0-15) based on the sum of grades (0 = none, 1 = mild, 2 = moderate, and 3 = severe) for the following categories: foreign body giant cell reaction, granulation tissue, lymphocytes, eosinophils, and scarring, as evaluated by a single pathologist (J.M.). Vasal injection with 0.05 mL of URYX was not sufficient to cause occlusion. Both animals injected with 0.1 mL of URYX were effectively occluded. The injection of occluded vasa with DMSO did not dissolve the URYX plug in the vas lumen. There was no significant difference in vasal inflammatory response scores between vasal units treated with URYX only and vasal units in the vasectomy model. Vasal units subjected to URYX followed by DMSO demonstrated greater inflammatory response scores than vasal units treated with URYX followed by normal saline, URYX alone, or vasectomy. Epididymal and testicular histology remained unaffected in all vasal units in E1. The vasal units in E2 subjected to URYX followed by normal saline showed no histological abnormalities of the epididymis and testis. However, those vasal units subjected to URYX followed by DMSO in E2 showed evidence of adhesions, necrosis, and degenerating cells in the epididymis and a focal foreign body giant cell reaction in the testis. The bilateral vasal injection of URYX can result in azoospermia in the rabbit model. Reversal with subsequent DMSO injection was not achieved. A minimal inflammatory response of the vas deferens was observed with URYX injection alone; however, DMSO following URYX injection resulted in increased vasal inflammation, in addition to epididymal and testicular changes.

Development of an inexpensive artificial vagina for semen collection from rabbits.

The rabbit is well suited for infertility research because of the animal's size, relatively low cost, and accessibility of the genitalia. There are several studies reporting sperm count and motility in rabbits; however, no easily reproducible or inexpensive device for semen collection has been reported. Herein, we report the construction of an inexpensive, effective artificial vagina assembled from easily obtainable products that may be used to collect rabbit ejaculates. This device was used to perform 243 ejaculation trials on 17 rabbits. Eighty-six percent (209/243) of the trials resulted in rabbit mounts. Overall, 91% (191/209) of mounts resulted in successful semen collection. After 60 mounts, a 98% successful ejaculate collection rate was achieved. The cost of the reusable device is 2.64 US dollars, plus silicone condoms at 7.50 each US dollars. This practical artificial vagina for semen collection is an inexpensive and effective means of obtaining semen from rabbits for andrologic study.

Optimizing laboratory use of human vas deferens specimens for microsurgical practice.

OBJECTIVES: To determine whether freezing harvested human vas deferens would preserve the tissue for later microsurgical practice. Learning and maintaining microsurgical skills requires laboratory practice. The proper preservation of the human vas deferens is important if harvested specimens are to be used for laboratory vasovasostomy. METHODS: Segments of human vas deferens harvested at the time of radical retropubic prostatectomy were preserved at -20 degrees C without media, in normal saline and in glycerol. At 2 weeks, the specimens were thawed and graded for freshness of appearance, mucosal preservation, mucosal suturing quality, muscularis preservation, and muscularis suturing quality at laboratory vasovasostomy (grade 1, poor; 2, fair; and 3, good). Mucosa and muscularis scores were calculated as the sum of the respective preservation and suturing quality grades. The preserved samples were compared with fresh human vas deferens specimens. RESULTS: Freezing human vas deferens segments in normal saline or glycerol improved the mucosa and muscularis scores at 2 weeks compared with freezing tissues without media. However, a decrease in the freshness of appearance grade was noted. None of the freezing methods resulted in tissue quality as good as fresh vas deferens. CONCLUSIONS: Human vas deferens can be preserved for later microsurgical vasovasostomy practice at -20 degrees C. Freezing in normal saline and glycerol improved the mucosa and muscularis scores compared with freezing without media, although a decrease in the freshness of appearance grade was noted. All three methods of freezing provided sufficient preservation for laboratory microsurgical vasovasostomy compared with fresh tissue.

Conditional loss of Nkx3.1 in adult mice induces prostatic intraepithelial neoplasia.

The homeodomain-containing transcription factor NKX3.1 is a putative prostate tumor suppressor that is expressed in a largely prostate-specific and androgen-regulated manner. Loss of NKX3.1 protein expression is common in human prostate carcinomas and prostatic intraepithelial neoplasia (PIN) lesions and correlates with tumor progression. Disruption of the murine Nkx3.1 gene results in defects in prostate branching morphogenesis, secretions, and growth. To more closely mimic the pattern of NKX3.1 loss that occurs in human prostate tumors, we have used Cre- and loxP-mediated recombination to delete the Nkx3.1 gene in the prostates of adult transgenic mice. Conditional deletion of one or both alleles of Nkx3.1 leads to the development of preinvasive lesions that resemble PIN. The pattern of expression of several biomarkers (Ki-67, E-cadherin, and high-molecular-weight cytokeratins) in these PIN lesions resembled that observed in human cases of PIN. Furthermore, PIN foci in mice with conditional deletion of a single Nkx3.1 allele lose expression of the wild-type allele. Our results support the role of NKX3.1 as a prostate tumor suppressor and indicate a role for this gene in tumor initiation.