The ubiquitin-conjugating yeast enzyme RAD6 and its human homologs hHR6A and hHR6B are implicated in postreplication repair and damage-induced mutagenesis. The yeast protein is also required for sporulation and may modulate chromatin structure via histone ubiquitination. We report the phenotype of the first animal mutant in the ubiquitin pathway: inactivation of the hHR6B-homologous gene in mice causes male infertility. Derailment of spermatogenesis becomes overt during the postmeiotic condensation of chromatin in spermatids. These findings provide a parallel between yeast sporulation and mammalian spermatogenesis and strongly implicate hHR6-dependent ubiquitination in chromatin remodeling. Since heterozygous male mice and even knockout female mice are completely normal and fertile and thus able to transmit the defect, similar hHR6B mutations may cause male infertility in man.

During mammalian spermatogenesis, the chromatin of the spermatogenic cells is profoundly reorganized. Somatic histones are partly replaced by testis-specific histones. These histones are then replaced by transition proteins and finally by protamines. This series of nucleoprotein rearrangements results in a highly condensed sperm cell nucleus. In contrast to spermatozoa from other species, human spermatozoa still contain a significant amount of histones, including testis-specific histone 2B (TH2B). In the present study it is shown that an antibody targeting tyrosine hydroxylase, which has been found previously to cross-react with rat TH2B, also specifically immunoreacts with human TH2B on Western blots, in immunohistochemistry of human testis tissue, and in immunocytochemistry of decondensed human spermatozoa. In human testis tissue, TH2B immunostaining first apparent in spermatogonia, shows marked variation, especially at the pachytene spermatocyte stage, and then reaches an intense signal in round spermatids. Shortly before spermatid elongation, a portion of the spermatid nucleus, corresponding to the acrosomal region, loses its immunoreactivity. During condensation of the spermatid nucleus, the immunodetectability of TH2B disappears gradually, from the anterior region of the nucleus onwards. At the final stages of spermiogenesis, the immunostaining is completely absent. Immunocytochemical staining of spermatozoa revealed no TH2B immunosignal, but immunostaining was observed when spermatozoa obtained from semen were decondensed to make nuclear proteins accessible to the antibody. There was, however, a striking intercellular variability in the intensity of staining of spermatozoa within an ejaculate. In a population of 35 men attending our Andrology Clinic, we observed interindividual differences in total sperm TH2B content, which showed a significant, although not very pronounced, negative correlation with normal morphology (P = 0.05).

Our results indicate that long-term graft survival is not affected by a surgically treated urological complication.

The debate regarding the efficacy of varicocele ligation for improvement of semen parameters and pregnancy rates is ongoing. In addition, no consensus exists as to the benefit of treatment of subclinical varicoceles. The aim of this study was to investigate, retrospectively, the effect of high ligation of both subclinical and clinical varicoceles on sperm count and motility. The value of several factors from history-taking and physical examination for the prediction of successful varicocelectomy was analysed. A total of 139 patients, operated on for a unilateral varicocele on the left side, were studied. Varicoceles were subclinical in 73 patients, based on colour Doppler ultrasonography, and 66 varicoceles were clinical, based on palpation in addition to ultrasonography. Comparison of semen parameters before and after surgery revealed a significant improvement. The median sperm count increased from 10.0 to 14.7, and from 18.2 to 28.6 million/ejaculate, in patients with subclinical and clinical varicoceles, respectively (p < 0.001). The percentage improvement in median sperm count in subclinical varicoceles was not statistically different from the improvement in clinical varicoceles. Mean progressive motility improved significantly after ligation (p < 0.001). The improvement in motility in subclinical varicoceles, from 16 to 23%, was significantly larger than the 24 to 27% improvement in clinical varicoceles. The increase in sperm count was related positively to testicular volume before surgery (p < 0.05). The increase in sperm motility was significantly lower in patients with a history of cryptorchidism (n = 22, p < 0.05). The present data show that ligation of varicoceles detected using Doppler ultrasonography, whether palpable or not, results in an increase in sperm concentration and motility.

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