Andrology最新文献

Objective: To examine the association between semen parameters, assessed according to World Health Organization (WHO)-2021 criteria, and paternal body mass index (BMI) and age, with embryological and clinical outcomes in ICSI cycles involving preimplantation genetic testing for aneuploidy (PGT-A).

Design: Retrospective study at a private in vitro fertilization (IVF) clinic.

Subjects: 3101 couples undergoing 4013 intracytoplasmic sperm injection (ICSI) + PGT-A cycles with own-oocytes (years 2013-2021).

Intervention: We performed trophectoderm biopsy, and comprehensive chromosome testing to report uniform aneuploidies and vitrified-warmed euploid single-blastocyst-transfers. Regression analyses adjusted for relevant confounders were conducted to outline putative associations of semen analysis and characteristics and paternal BMI and age with all embryological/clinical outcomes.

Results: Maternal age was the only significant confounding variable affecting euploidy blastocyst rate (EBR) (primary embryological outcome). When categorized, motility < 5^th-percentile (-2.5%, 95%CI -4.9 to -0.2%, p = 0.03), concentration plus morphology < 5^th-percentile (-2.7%,95%CI -4.8 to -0.6%, p = 0.01), concentration plus morphology plus motility < 5^th-percentile (-4.0%,95%CI -5.5 to -2.6%, p < 0.01), obstructive-azoospermia [OA] (-5.5%,95%CI -9 to -2%, p = 0.02) and non-obstructive azoospermia (NOA) (-5.8%,95%CI -10.9 to -0.6%, p = 0.03) showed significantly lower results compared to all parameters > 5^th-percentile. Furthermore, after adjusting for maternal age and the number of metaphase-II-oocytes inseminated, the only significant confounding variable affecting the chance of obtaining ≥ 1 live birth among completed cycles (primary clinical outcome) was basal and post sperm processing motility. When categorized, concentration plus morphology plus motility < 5^th-percentile (multivariable-OR: 0.73, 95%CI 0.58-0.93, p = 0.01) and OA (multivariable-OR: 0.47, 95%CI 0.24-0.92, p = 0.03) showed significantly lower chances compared to all parameters > 5^th-percentile. Advanced paternal age (defined as > 44 years) was associated only with lower day 5-blastocyst and Gardner's AA-grade (i.e., top quality) blastocyst rates.

Conclusions: This comprehensive analysis provides IVF professionals with useful figures to counsel infertile couples about their chances of success, taking into account the impact of semen characteristics and paternal BMI and age. These estimates are valuable for personalized decision-making about the most effective reproductive strategies to adopt, especially not underestimating male factor, by improving sperm concentration and motility whenever possible before assisted reproductive technologies.

Background: Among erectile dysfunction (ED) caused by metabolic abnormalities, diabetes mellitus-induced ED (DMED) progresses rapidly, manifests with severe symptoms, and shows reduced responsiveness to conventional medications. Hyperglycemia in the corpus cavernosum has been linked to the induction of both ferroptosis and oxidative stress, which are mediated by nuclear factor E2 related factor 2 (Nrf2). Hesperidin (Hes), a flavonoid compound, has been revealed to activate Nrf2 in certain diabetic complications, yet the efficacy of Hes on DMED and the specific mechanism remain unclear.

Objectives: To elucidate the potential mechanism and efficacy of Hes in regulating Nrf2-mediated ferroptosis and oxidative stress in DMED.

Materials and methods: DMED rats were constructed through the intraperitoneal injection of streptozotocin (STZ), partially supplemented with Hes. In parallel, in vitro research utilized human umbilical vein endothelial cells (HUVECs), with glucose addition to simulating a high glucose (HG) environment, and induced with Hes or ML385 (an Nrf2 inhibitor). Penile tissues and HUVECs were harvested for subsequent analyses.

Results: The results of this study indicate that Hes partially reversed the impaired erectile function. The expression of Nrf2, glutathione peroxidase 4 (GPX4), and heme oxygenase-1 (HO-1) in the corpus cavernosum elevated after supplementing with Hes, resulted in an inhibition in ferroptosis and oxidative stress. Moreover, the quantity and function of erectile effector cells were restored, and cavernous fibrosis was ameliorated. In HG-induced HUVECs, Hes ameliorated Nrf2-mediated ferroptosis and oxidative stress, effects which ML385 partially reversed.

Conclusions: Hes exerts a therapeutic effect on DMED rats and a regulatory mechanism on the Nrf2-HO-1/GPX4 axis, concurrently revitalizing endothelial and smooth muscle cells, and diminishing fibrosis. Our study provides robust preclinical evidence for employing Hes in treating DMED.

Background: Poor sperm motility leading to male infertility has become a profound crisis to be addressed in this contemporary era. In many cases, the origin of poor sperm motility remains unexplained. Few studies reported the indispensable role of sperm-specific glyceraldehyde 3-phosphate dehydrogenase (GAPDHS) in sperm motility, however, studies on GAPDHS are severely confined.

Objectives: The present study aimed to assess the localization patterns, expression levels, and enzyme activity of GAPDHS in normal and asthenozoospermic bulls and to examine their association with sperm functional parameters.

Materials and methods: The bull semen samples were classified into high-motile and low-motile groups (n = 7 per each group) based on the ejaculate rejection rate. Sperm kinetic parameters were assessed using computer-assisted sperm analysis (CASA). Sperm viability, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and intracellular calcium levels were measured through flow cytometry. Subsequently, GAPDHS localization was observed via immunocytochemistry. The expression levels and enzyme activity of GAPDHS were estimated using western blotting and a GAPDHS activity assay kit.

Results and discussion: Sperm viability, MMP, ROS, and live sperm intracellular calcium levels did not differ significantly between high and low motile groups. A significant positive correlation was found between MMP and sperm viability, whereas no significant association was found between MMP and sperm progressive motility. The GAPDHS was localized in the principal piece, head-midpiece junction, and at the acrosome region of bull sperm. GAPDHS localization intensity, expression levels, and enzyme activity were found significantly (p < 0.05) higher in the high motile group than in low motile group. Furthermore, we noticed a significant positive correlation between GAPDHS activity and sperm kinetic parameters.

Conclusions: The analysis of GAPDHS localization patterns, expression levels, and enzyme activity indicated its potential role in sperm motility, suggesting that GAPDHS could serve as a candidate biomarker for sperm motility and male fertility.

Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disorder characterized by dysfunction of motile cilia in various organ systems, including the respiratory and reproductive tracts. A key manifestation in males is infertility, primarily attributed to impaired sperm motility. Although sperm vitality may be preserved, immotility or abnormal flagellar function significantly impairs natural conception. While a minority of men with PCD achieve fatherhood without medical intervention, most require assisted reproductive techniques (ART). The genetic etiology of PCD-related male infertility is rooted in mutations affecting dynein arms and other axonemal components essential for ciliary movement. Diagnostic evaluation relies on semen analysis, ultrastructural ciliary assessment, and genetic testing. Sperm vitality testing is critical when motility is severely compromised, providing crucial insight into fertilization potential. Management of male infertility in PCD predominantly involves ART. Intracytoplasmic sperm injection (ICSI) is particularly effective, as it circumvents the requirement for sperm motility. In cases where spermatozoa retrieval from ejaculate is not feasible, testicular sperm extraction (TESE) offers a viable alternative. Advances in diagnostic techniques and personalized therapeutic approaches have significantly improved fertility outcomes for PCD patients. Ongoing research into genetic therapies and targeted treatments holds promise for further enhancing reproductive success in this population. This review offers a comprehensive examination of the current knowledge surrounding PCD and its impact on male fertility, elucidating the genetic mechanisms, diagnostic challenges, and evolving therapeutic strategies in the management of PCD-associated male infertility.

Background: Erectile dysfunction (ED) is the most common type of sexual dysfunction, which seriously affects male reproductive health. Recently, stem cell therapy and low-intensity pulsed ultrasound (LIPUS) have been applied in the treatment of ED, but the specific mechanism is still unclear.

Objectives: The study aims to investigate the effect and underlying mechanism of further LIPUS treatment on the basis of bone marrow mesenchymal stem cells (BMSCs) transplantation in the treatment of ED rats.

Materials and methods: We established a cavernosa injury-induced ED rat model and injected BMSCs into the penile corpus cavernosum with or without LIPUS treatment every other day for three times. The survival rate of BMSCs, value of ICP/MAP, blood flow, the endothelial content, and expression of CD31 and ɑ-SMA in the rat penis were investigated. Transcriptome analyses and in vitro assays of cell proliferation, migration, and tube formation were also performed.

Results: The results showed that LIPUS treatment significantly promoted the survival rate of BMSCs in the rat penis after 1, 7, and 14 days of final treatment. The values of ICP/MAP and blood flow in rats treated with BMSCs were significantly increased compared to the control group, and the values were further enhanced in rats treated with BMSCs plus LIPUS. The endothelial content and CD31 and ɑ-SMA mRNA and protein expression in the BMSCs plus LIPUS group were remarkably higher than in other groups, indicating improved endothelial vascular function. Transcriptome analyses found that insulin-like growth factor binding protein-3 (IGFBP3) was remarkably downregulated in the BMSCs plus LIPUS group compared to the other two groups. In in vitro assays, LIPUS intervention significantly increased BMSCs proliferation and HUVECs migration, and HUVECs angiogenesis was improved after IGFBP3 siRNA transfection.

Conclusions: BMSCs transplantation combined with LIPUS treatment could improve erectile function in ED rats via downregulation of IGFBP3, which might be a proposed optimized strategy for the ED treatment.

Background: It is well-established that spermatogenesis, semen quality, and reproductive hormones are interlinked. It is, however, less well-described how various specific testicular histopathologies are linked to reproductive hormones and semen quality.

Objectives: To describe the detailed relationship between specific testicular histopathologies and the serum concentrations of reproductive hormones and semen quality.

Materials and methods: Descriptive histological patterns on testicular biopsies from 4245 patients referred for andrological workup in our clinic between 1990 and 2022 were grouped according to a published histological coding system: (1) complete spermatogenesis (completeSPG, n = 3171), (2) reduced spermatogenesis (reducedSPG, n = 657), (3) heterogeneous (hetArrest, n = 226), and (4) homogeneous (homArrest, n = 191) spermatogenic arrest at the spermatocyte or spermatid stage. As a proxy for the number of spermatogonia, spermatocytes, and spermatids, immunohistochemical staining for MAGE-A4, PIWIL1, and TNP1 were quantified on a representative set of biopsies (n = 100). Serum concentrations of FSH, LH, T, SHBG, and inhibin B (n = 1813) and semen parameters (n = 833) were available.

Results: Compared with the completeSPG group, the number of spermatogonia was only reduced in the hetArrest group, while the number of spermatocytes and spermatids were lower in all groups. All groups had significantly higher FSH and LH and lower T, free T, and inhibin B concentrations when compared with the completeSPG group, except for the homArrest group, where inhibin B was unaffected. The hetArrest group had the lowest number of germ cells, the most pronounced change in reproductive hormones, and the lowest sperm counts. We found a strong correlation between the number of germ cells present and the corresponding serum concentrations of FSH, LH, T, and inhibin B.

Discussion and conclusions: A histopathological pattern of heterogeneous spermatogenic arrest is associated with a more severe phenotype than a pattern of homogeneous arrest, and the group with reduced spermatogenesis showed the mildest phenotype.

Background: Inhibition of sperm maturation in the epididymis is a promising post-testicular strategy for short-acting male contraceptives. It has been shown that ROS1, a receptor tyrosine kinase expressed in the epididymis, is essential for epididymal differentiation, sperm maturation, and male fertility in mice. However, it is unknown if inhibition of ROS1 suppresses male fertility reversibly.

Objectives: Our study aimed to investigate the effects of ROS1 inhibitor administration in male mice on sperm function and fertility.

Materials and methods: We used lorlatinib, an anti-cancer drug that inhibits ROS1. We treated 10-week-old sexually mature male mice with lorlatinib for 3 weeks and performed fertility tests, histological staining, in vitro fertilization, sperm motility analyses, and immunoblot analyses. We also performed the same analyses 3 weeks after discontinuing the lorlatinib treatment.

Results: Inhibition of ROS1 for 3 weeks suppressed male fertility. Lorlatinib-treated mice showed no overt abnormalities in testicular sections, but epithelium maintenance of the epididymal initial segment was impaired. Accordingly, the levels of OVCH2, RNASE10, and ADAM28, which are expressed in the epididymis, decreased. Spermatozoa from the lorlatinib-treated mice lost their ability to bind to the zona pellucida, and ADAM3 processing was abnormal. Sperm motility was also impaired in the lorlatinib-treated mice. These impairments were recovered 3 weeks after discontinuing the drug treatment.

Discussion and conclusion: Inhibition of ROS1 with lorlatinib suppressed sperm maturation and male fertility reversibly. Future exploration of molecules that specifically target ROS1 and the ROS1 pathway in the epididymis may lead to the development of safe and reversible male contraceptives.

Background: Retinoic acid (RA) is essential for spermatogenesis. Genetic deletion of the retinoic acid synthesizing enzymes, Aldh1a1/1a2, in the testes causes infertility in mice. An inhibitor of the ALDH1A1/1A2 enzymes, WIN 18,446 reversibly inhibit spermatogenesis and is a promising approach to male contraception. Previously we reported that a 4-week treatment of WIN 18,446 inhibits spermatogenesis and 9-week recovery from treatment normalized fertility of treated mice. However, the precise kinetics of this process has not been studied.

Objectives: To extend our knowledge of kinetics of ALDH1A inhibition, we studied the changes in the seminiferous epithelium and retinoic acid synthesis capacity of the testes during 4 weeks of WIN 18,446 treatment and during 9 weeks of recovery.

Materials and methods: Male mice were fed a diet containing WIN 18,446 for 4 weeks followed by a normal diet for up to 8 weeks. Frequently, during the treatment and recovery period, five mice were euthanized, and testes were analyzed for testicular histology and retinoic acid synthesis capacity and compared with controls.

Results: Testes weights progressively decreased, and the seminiferous epithelium deteriorated over the time with WIN 18,446 treatment and returned to normal after 8 weeks. Retinoic acid synthesis capacity was significantly inhibited 3 days after the WIN 18,446 treatment and recovered after 7 days of no treatment. After 4 weeks of treatment, complete blockage of spermatogenesis with only spermatogonia and Sertoli cells was observed. The RA biosynthetic capacity of the testes was significantly reduced before the disruption of spermatogenesis was observed and recovered prior to the reinitiation of spermatogonial differentiation.

Conclusions: Effects of ALDH1A inhibition on spermatogenesis are reversible. Our observation that strong inhibition of ALDH1A disrupts the seminiferous epithelium prior to the completion of a full cycle of spermatogenesis suggests that episodic inhibition of ALDH1A may function as a male contraceptive.

Background: Hypospadias with lichen sclerosus (LS) poses surgical challenges due to lack of materials for urethral reconstruction and coverage and the limited number of reports on this clinical condition.

Objectives: To report surgical strategies and outcomes for primary and redo hypospadias patients with LS.

Materials and methods: We conducted a retrospective observational descriptive study with 31 patients with primary/redo hypospadias and LS between 2013 and 2023. Of these patients, 9 had primary hypospadias with 7 distal types and 2 proximal types, and 22 were redo patients. Nineteen of the 31 patients underwent various surgical techniques, and 12 underwent the oral mucosa onlay procedure (OMOP). Postoperative uroflowmetry, hypospadias objective scoring evaluation (HOSE), and complications were evaluated.

Results: For primary distal hypospadias with LS-affected skin, five patients underwent circumcision; these patients had normal postoperative urinary flow, and only one patient had an inconspicuous penis after surgery. For the patients with primary proximal hypospadias with an LS-affected urethra, one patient required perineal urethrostomy following a modified Koyanagi procedure for recurrent stricture; the other patient underwent two-stage transverse preputial island flap urethroplasty with no postoperative lower urinary tract symptoms (LUTS) and satisfactory aesthetic scores. In two remaining cases of primary distal hypospadias with meatus/urethral LS, no LUTS or postoperative complications occurred following meatoplasty/circumcision and penile basal fixation. During reoperations, compared with those of patients who underwent other redo procedures, twelve patients who underwent OMOP had better Qmax and uroflowmetry (p = 0.002) and higher HOSE scores (p = 0.01).

Conclusions: For primary hypospadias patients with LS, enhanced exposure of the penile shaft and glans may benefit distal hypospadias, whereas staged surgery may be suitable for proximal hypospadias. The oral mucosa is favored for urethral augmentation in patients with redo hypospadias complicated with LS, and the OMOP can address neourethra coverage effectively.