Clinical management of nonobstructive azoospermia: An update.

Approximately 1% of the general male population has azoospermia, and nonobstructive azoospermia accounts for the majority of cases. The causes vary widely, including chromosomal and genetic abnormalities, varicocele, drug-induced causes, and gonadotropin deficiency; however, the cause is often unknown. In azoospermia caused by hypogonadotropic hypogonadism, gonadotropin replacement therapy can be expected to produce sperm in the ejaculate. In some cases, upfront varicocelectomy for nonobstructive azoospermia with varicocele may result in the appearance of ejaculated spermatozoa; however, the appropriate indication should be selected. Each guideline recommends microdissection testicular sperm extraction for nonobstructive azoospermia in terms of successful sperm retrieval and avoidance of complications. Sperm retrieval rates generally ranged from 20% to 70% but vary depending on the causative disease. Various attempts have been made to predict sperm retrieval and improve sperm retrieval rates; however, the evidence is insufficient. Further evidence accumulation is needed for salvage treatment in cases of failed sperm retrieval. In Japan, there is inadequate provision on the right to know the origin of children born from artificial insemination of donated sperm and the rights of sperm donors, as well as information on unrelated family members, and the development of these systems is challenging. In the future, it is hoped that the pathogenesis of nonobstructive azoospermia with an unknown cause will be elucidated and that technology for omics technologies, human spermatogenesis using pluripotent cells, and organ culture methods will be developed.

Sperm DNA fragmentation testing in clinical management of reproductive medicine.

Background: Approximately 8%-12% of couples worldwide face infertility, with infertility of individuals assigned male at birth (AMAB) contributing to at least 50% of cases. Conventional semen analysis commonly used to detect sperm abnormalities is insufficient, as 30% of AMAB patients experiencing infertility show normal results in this test. From a genetic perspective, the assessment of sperm DNA fragmentation (SDF) is important as a parameter of sperm quality. Methods: In this narrative study, we review and discuss pathophysiological causes, DNA repair mechanisms, and management of high SDF. We then summarize literature exploring the association between SDF and reproductive outcomes. Main Findings: Recent systematic reviews and meta-analyses have revealed a significant association between high SDF in AMAB individuals and adverse reproductive outcomes including embryo development, natural conception, intrauterine insemination, and in vitro fertilization. However, the association with live birth rates and pregnancy rates following intracytoplasmic injection remains inconclusive. The disparities among quantitative assays, inconsistent reference range values, absent high-quality prospective clinical trials, and clinical heterogeneity in AMAB patients with elevated SDF represent the main limitations affecting SDF testing. Conclusion: The evaluation and management of SDF plays an important role in a subset of AMAB infertility, but widespread integration into clinical guidelines will require future high-quality clinical trials and assay standardization.

Monozygotic adult twins with nonmosaic Klinefelter syndrome with different results of sperm retrieval.

Klinefelter syndrome and monozygotic twins are both rare. The reports of monozygotic twins with Klinefelter syndrome to have undergone fertility treatment are uncommon. This case report describes a case of 30-year-old monozygotic adult twin brothers diagnosed with nonmosaic Klinefelter syndrome following the complaint of infertility. The result of semen analysis showed cryptozoospermia (very low sperm count) and azoospermia (zero sperm count) with physical findings and lifestyles being very similar. They both underwent microtesticular sperm extraction. One had successful sperm retrieval and achieved pregnancy through intracytoplasmic sperm injection, whereas the other did not. Testicular pathological findings showed Sertoli cell-only syndrome. To the best of our knowledge, this is the first report on monozygotic adult twins both of whom underwent microtesticular sperm extraction and resulted in different outcomes.

Effect of keishibukuryogan combined with tocopherol nicotinate on sperm parameters in patients with a varicocele.

OBJECTIVE: To evaluate the efficacy of keishibukuryogan, a traditional Kampo formula known to be an anti-Oketsu (impaired microcirculation and non-physiological blood congestion) drug, in combination with an anti-oxidant for the treatment of varicoceles. METHODS: We retrospectively analyzed 119 patients with palpable and subclinical varicoceles who were treated with 7.5 g/day of keishibukuryogan and 600 mg/day of tocopherol nicotinate. Their motile sperm concentrations at the start of medication and after 3 months were compared. As a subgroup analysis, a comparison test was carried out between patients with a high-grade varicocele and those with a low-grade varicocele. RESULTS: The mean age of the study patients was 35.6 years. Among them, 17, 41, 44 and 17 had subclinical, grade 1, grade 2 and grade 3 varicoceles, respectively. Overall, the differences in motile sperm concentration (millions/mL) before and after treatment were not significant (median 0.58, 95% confidence interval -0.12 to 1.56; P = 0.115). The results of the subgroup analysis showed that the motile sperm concentration in patients with a low-grade varicocele significantly increased (median 1.21, 95% confidence interval 0.45-2.47; P = 0.024); however, no significant improvements were seen in patients with a high-grade varicocele. CONCLUSIONS: The results of the present study showed that the combination of keishibukuryogan and an anti-oxidant had a limited effect on varicoceles, but they suggest that it is effective for the treatment of low-grade varicoceles.

Fertility and sexual dysfunction in young male cancer survivors.

Background: Newly emerging serious post-treatment complications among young male cancer survivors involve fertility and sexual function, preventing them from pursuing a normal family life. Methods: We studied and summarized published studies that assess the relationship between cancer treatments and reduced spermatogenesis or sexual dysfunction. Main findings: Infertility often occurs because of anticancer therapies that impair spermatogenesis. While some patients postremission functionally recover fertility, others experience a decreased sperm count and azoospermia. Fertility-preserving modalities are currently being promoted worldwide to preserve spermatogenesis following cancer therapy. Patients who can ejaculate and have sperm in their semen should cryopreserve semen. However, for patients who have never ejaculated before puberty or in whom spermatogenesis has not been established, testis biopsy is performed to collect and preserve sperm or germ cells. Fertility preservation is gaining popularity and requires continuous information dissemination to oncologists and cancer treatment professionals. Furthermore, male sexual dysfunction predominantly involves erectile dysfunction and ejaculation disorder. Conclusion: Although preventive and therapeutic methods for these disorders have been established within urology, patients and medical professionals in other fields remain uninformed of these advances. Therefore, dissemination of information regarding fertility preservation techniques should be accelerated.

Effects of antioxidant co-supplementation therapy on spermatogenesis dysfunction in relation to the basal oxidation-reduction potential levels in spermatozoa: A pilot study.

Purpose: In this pilot study, the authors compared the effects of antioxidant co-supplementation therapy and methylcobalamin therapy in patients with impaired semen quality. Methods: Eighty-four subjects who visited male infertility clinics and showed abnormal semen test results were randomly subjected to one of the two therapies: antioxidant co-supplementation therapy with vitamin C, vitamin E, coenzyme Q10, and flaxseed oil or methylcobalamin therapy. The oxidation-reduction potential (ORP) and 8-hydroxy-2'-deoxyguanosine levels were used as indicators of oxidative stress levels in semen. Semen analysis was also performed. Results: The authors obtained results from 67 patients who had completed 3 months of treatment. Neither antioxidant co-supplementation therapy nor methylcobalamin therapy changed the semen parameters significantly (except for the sperm concentration, which was increased by the latter therapy). When the pre-treatment ORP value in semen was higher than the cutoff value, both therapies significantly increased the sperm concentration. The 8-hydroxy-2'-deoxyguanosine level did not yield any meaningful predictive value with regard to increased sperm concentrations. Conclusions: Both antioxidant co-supplementation therapy and methylcobalamin therapy increased the sperm concentration in patients with impaired semen quality when the basal ORP levels in their semen were elevated.

Oxidative stress and male infertility.

BACKGROUND: Between 30% and 80% of patients with male infertility produce excessive reactive oxygen species (ROS) in their ejaculate even though the cause of male infertility is unexplained in approximately half of cases. The strong connection between oxidative stress (OS) and male infertility has led recent investigators to propose the term "Male Oxidative Stress Infertility (MOSI)" to describe OS-associated male infertility. METHODS: We searched the PubMed database for original and review articles to survey the effects of OS on male infertility, and then verified the effects and treatments. MAIN FINDINGS: Seminal plasma contains many antioxidants that protect sperm from ROS, because low amounts of ROS are required in the physiological fertilization process. The production of excessive ROS causes OS which can lower fertility through lipid peroxidation, sperm DNA damage, and apoptosis. Several assays are available for evaluating OS, including the MiOXSYS® analyzer to measure oxidation-reduction potential. Several measures should be considered for minimizing OS and improving clinical outcomes. CONCLUSION: Accurately diagnosing patients with MOSI and identifying highly sensitive biomarkers through proteomics technology is vital for better clinical outcomes.

Genetic disorders and male infertility.

BACKGROUND: At present, one out of six couples is infertile, and in 50% of cases, infertility is attributed to male infertility factors. Genetic abnormalities are found in 10%-20% of patients showing severe spermatogenesis disorders, including non-obstructive azoospermia. METHODS: Literatures covering the relationship between male infertility and genetic disorders or chromosomal abnormalities were studied and summarized. MAIN FINDINGS RESULTS: Genetic disorders, including Klinefelter syndrome, balanced reciprocal translocation, Robertsonian translocation, structural abnormalities in Y chromosome, XX male, azoospermic factor (AZF) deletions, and congenital bilateral absence of vas deferens were summarized and discussed from a practical point of view. Among them, understanding on AZF deletions significantly changed owing to advanced elucidation of their pathogenesis. Due to its technical progress, AZF deletion test can reveal their delicate variations and predict the condition of spermatogenesis. Thirty-nine candidate genes possibly responsible for azoospermia have been identified in the last 10 years owing to the advances in genome sequencing technologies. CONCLUSION: Genetic testing for chromosomes and AZF deletions should be examined in cases of severe oligozoospermia and azoospermia. Genetic counseling should be offered before and after genetic testing.

[A Case of Polyorchidism Associated with Infertility].

A 30-year-old man present with infertility for 2 years. Magnetic resonance imaging (MRI) revealed two right testes in the scrotum and inguinal region, respectively. Semen analysis revealed cryptozoospermia. Polyorchidism was considered to have caused spermatogenic dysfunction and male infertility. We performed right high orchiectomy and simultaneous testicular sperm extraction on the same testis. To our knowledge, this is the first case of testicular sperm extraction performed for patients with polyorchidism.

Effect of Varicocele Repair in Patients with Nonobstructive Azoospermia.

OBJECTIVE: To evaluate the efficacy of varicocele repair in patients with nonobstructive azoospermia. STUDY DESIGN: Ten patients with nonobstructive azoospermia and clinical varicoceles who underwent varicocele repair were retrospectively investigated. According to the postoperative appearance of motile spermatozoa in the ejaculate, the patients were divided into 2 groups: Responder and Nonresponder. The outcomes of each group were investigated. RESULTS: There were 4 (40%) patients in the Responder group. Serum follicle-stimulating hormone levels were significantly higher in the Nonresponder group than in the Responder group (19.9±6.4 IU/mL vs. 10.8± 4.0 IU/mL, p<0.05). Mean sperm concentration was 5.4 million spermatozoa/mL in the Responder group. One patient achieved a spontaneous pregnancy, and another achieved an assisted pregnancy. In the Nonresponder group 5 patients underwent microdissection testicular sperm extraction (micro-TESE) postoperatively. In 1 patient, motile spermatozoa were successfully retrieved. Histopathological findings in the other 4 patients were Sertoli-cell-only. CONCLUSION: The present study suggested that varicocele repair could be considered in men with nonobstructive azoospermia who have clinical varicoceles. Moreover, varicocele repair seemed to improve sperm retrieval rate during micro-TESE for those in the Nonresponder group.

Reactive oxygen species measured in the unprocessed semen samples of 715 infertile patients.

Purpose: To determine whether reactive oxygen species (ROS) in semen samples could be measured with the Monolight™ 3010 Luminometer. Methods: Using the Monolight™ 3010 Luminometer, the ROS was measured in the unprocessed semen samples of infertile male patients, as well as the luminescence of 190 semen samples. The samples were classified as "luminescence-detectable" (n = 89) and "luminescence-undetectable" (n = 101). Thereafter, the luminescence of the semen samples that had been obtained from the 715 infertile patients was measured and compared by using Sperm Motility Analyzing System measurements. Moreover, in order to investigate the ROS measurement consistency, the chemiluminescence values of 84 samples were measured concurrently by using the Monolight™ 3010 Luminometer and the 1251 Luminometer™. Results: The semen volume, sperm motility, and progressive motility of the samples were significantly higher in the luminescence-undetectable samples. The sperm motility, straight-line velocity, curvilinear velocity, mean amplitude head displacement, beat cross frequency, and progressive motility showed an inverse correlation with the logarithmic-transformed luminescence level in the luminescence-detected samples. The integrated chemiluminescence levels in the 84 samples were correlated. Conclusion: The substance that was measured in the unprocessed semen with the Monolight™ 3010 Luminometer and stimulated chemiluminescence is ROS.

Developing a preoperative predictive model for ureteral length for ureteral stent insertion.

BACKGROUND: Ureteral stenting has been a fundamental part of various urological procedures. Selecting a ureteral stent of optimal length is important for decreasing the incidence of stent migration and complications. The aim of the present study was to develop and internally validate a model for predicting the ureteral length for ureteral stent insertion. METHODS: This study included a total of 127 patients whose ureters had previously been assessed by both intravenous urography (IVU) and CT scan. The actual ureteral length was determined by direct measurement using a 5-Fr ureteral catheter. Multiple linear regression analysis with backward selection was used to model the relationship between the factors analyzed and actual ureteral length. Bootstrapping was used to internally validate the predictive model. RESULTS: Patients all of whom had stone disease included 76 men (59.8%) and 51 women (40.2%), with the median and mean (± SD) ages of 60 and 58.7 (±14.2) years. In these patients, 53 (41.7%) right and 74 (58.3%) left ureters were analyzed. The median and mean (± SD) actual ureteral lengths were 24.0 and 23.3 (±2.0) cm, respectively. Using the bootstrap methods for internal validation, the correlation coefficient (R2) was 0.57 ± 0.07. CONCLUSION: We have developed a predictive model, for the first time, which predicts ureteral length using the following five preoperative characteristics: age, side, sex, IVU measurement, and CT calculation. This predictive model can be used to reliably predict ureteral length based on clinical and radiological factors and may thus be a useful tool to help determining the optimal length of ureteral stent.

Retrograde intrarenal surgery for urinary stone disease in patients with solitary kidney: A retrospective analysis of the efficacy and safety.

OBJECTIVES: To compare outcomes of retrograde intrarenal surgery for urolithiasis between patients with solitary kidneys and patients who have single-side urolithiasis with bilateral kidneys. METHODS: We retrospectively analyzed outcomes of retrograde intrarenal surgery in solitary kidney patients (group A) carried out during 2007-2014, and in patients with bilateral kidneys with comparable stone burdens (group B). Stone-free status was defined as no residual fragment on computed tomography 1 month later. RESULTS: There were 19 patients in group A (mean age 62.5 ± 18.4 years, range 14-76 years). The mean stone diameter and burden were 6.0 mm (range 3-24 mm) and 10.42 ± 6.92 mm, respectively. The stone-free rate was 94.7%, and no repeat procedure was required. The glomerular filtration rate tended to rise post-surgery (postoperative day 1: 48.67 ± 15.92 mL/min, 100.2%, P = 0.940; postoperative month 1: 51.32 ± 16.90 mL/min, 105.7%, P = 0.101) compared with preoperative rates. The stone-free rate and surgery time were not significantly different between the two groups, although post-surgical hospitalization time was longer for group A (4.05 vs 3.08 days, P = 0.037). The change in glomerular filtration rate was not significantly different between groups A and B (postoperative day 1: +0.101 vs +0.547 mL/min, respectively, P = 0.857; postoperative month 1: +2.749 vs 3.161 mL/min, respectively, P = 0.882). No significant difference was found in terms of complication rate. CONCLUSIONS: Retrograde intrarenal surgery in solitary kidney patients is as safe and effective as in bilateral kidney patients.

Risk factors of systemic inflammation response syndrome after endoscopic combined intrarenal surgery in the modified Valdivia position.

OBJECTIVE: To identify risk factors of developing systemic inflammation response syndrome after endoscopic combined intrarenal surgery in the modified Valdivia position for renal stone treatment. METHODS: We retrospectively analyzed 370 consecutive patients who underwent endoscopic combined intrarenal surgery procedures in the modified Valdivia position to treat renal stones. Antibiotic therapy based on preoperative urine cultures was administered to all patients from induction of anesthesia until at least postoperative day 3. Postoperative systemic inflammation response syndrome was diagnosed if the patient met two or more systemic inflammation response syndrome criteria. A multivariate logistic regression model with backward selection was used to evaluate the relationships between the incidence of systemic inflammation response syndrome after endoscopic combined intrarenal surgery and other clinical factors. RESULTS: Of the 370 patients, 61 patients (16.5%) were diagnosed with systemic inflammation response syndrome after endoscopic combined intrarenal surgery. Significant differences were found between the non-systemic inflammation response syndrome and systemic inflammation response syndrome groups with regard to female sex (29.8% vs 44.3%, P = 0.027), history of febrile urinary tract infection (16.5% vs 32.8%, P = 0.015) and number of involved calyces (2.68 vs 4.1, P < 0.001). Multivariate analysis found three independent predictors of postoperative systemic inflammation response syndrome: the number of involved calyces (P = 0.017), stone surface area (P = 0.021) and history of febrile urinary tract infection (P = 0.005). CONCLUSIONS: The number of involved calyces larger than four, stone surface area >500 mm(2) and a history of febrile urinary tract infection independently predicted the development of systemic inflammation response syndrome after endoscopic combined intrarenal surgery. This is the first study to identify the independent predictors of systemic inflammation response syndrome after endoscopic combined intrarenal surgery in the modified Valdivia position.

Development and internal validation of a nomogram for predicting stone-free status after flexible ureteroscopy for renal stones.

OBJECTIVE: To develop and internally validate a preoperative nomogram for predicting stone-free status (SF) after flexible ureteroscopy (fURS) for renal stones, as there is a need to predict the outcome of fURS for the treatment of renal stone disease. PATIENTS AND METHODS: We retrospectively analysed 310 fURS procedures for renal stone removal performed between December 2009 and April 2013. Final outcome of fURS was determined by computed tomography 3 months after the last fURS session. Assessed preoperative factors included stone volume and number, age, sex, presence of hydronephrosis and lower pole calculi, and ureteric stent placement. Multivariate logistic regression analysis with backward selection was used to model the relationship between preoperative factors and SF after fURS. Bootstrapping was used to internally validate the nomogram. RESULTS: Five independent predictors of SF after fURS were identified: stone volume (P < 0.001), presence of lower pole calculi (P = 0.001), operator with experience of >50 fURS (P = 0.026), stone number (P = 0.075), and presence of hydronephrosis (P = 0.047). We developed a nomogram to predict SF after fURS using these five preoperative characteristics. Total nomogram score (maximum 25) was derived from summing individual scores of each predictive variable; a high total score was predictive of successful fURS outcome, whereas a low total score was predictive of unsuccessful outcome. The area under the receiver operating characteristics for nomogram predictions was 0.87. CONCLUSION: The nomogram can be used to reliably predict SF based on patient characteristics after fURS treatment of renal stone disease.

Preoperative factors predicting spontaneous clearance of residual stone fragments after flexible ureteroscopy.

OBJECTIVE: To investigate factors predicting spontaneous clearance of residual renal fragments after flexible ureteroscopy. METHODS: Among 546 patients who underwent lithotripsy with flexible ureteroscopy, 81 had residual renal fragments, as determined by kidney-ureter-bladder films on postoperative day 1. The final outcome was determined at 3 months after the last flexible ureteroscopy session using non-contrast computed tomography. Patient characteristics and preoperative factors were analyzed using the unpaired t-test and χ(2)-test. Correlations between the possible predictive factors and the spontaneous clearance of residual renal fragments after flexible ureteroscopy were analyzed using a multivariate logistic regression model with backward selection. RESULTS: Non-contrast computed tomography at postoperative month 3 showed that 33 cases (40.7%) had spontaneous clearance of residual renal fragments, whereas 48 (59.3%) showed non-clearance. Significant differences were found between these cases in terms of stone number, stone location, presence of lower pole calculi and preoperative stent placement. Multivariate assessment showed that stone number (P = 0.004), presence of lower pole calculi (P = 0.021) and presence of hydronephrosis (P = 0.024) were independent predictors of the spontaneous clearance of residual renal fragments after flexible ureteroscopy. CONCLUSIONS: Stone number, presence of lower pole calculi and presence of hydronephrosis are independent predictive factors of the spontaneous clearance of residual renal fragments after flexible ureteroscopy.

[A Case of Kartagener's Syndrome in Infertile Male Patients].

The patient was a 33-year-old man attending the infertility clinic with primary infertility of 3 years duration. The semen examination showed oligozoospermia and suspected primary male infertility. He had a history of chronic sinusitis and respiratory disease. His chest X-ray showed dextrocardia. Abnormality of the ultrastructure of the cilia of the tract epithelium was found by electron microscopy, and further examination revealed bronchoectasis. We gave him a diagnosis of Kartagener syndrome from these findings. Kartagener syndrome consists of bronchiectasis, sinusitis and situs inversus and is considered a form of primary ciliary dyskinesia (PCD). PCD is also a cause of motor impairment of sperm flagella. This case had successful in-vitro fertilization pregnancy with spermatozoa from the patient.