Y chromosome polymorphisms contribute to an increased risk of non-obstructive azoospermia: a retrospective study of 32,055 Chinese men.

PURPOSE: To investigate the prevalence of Y chromosome polymorphisms in Chinese men and analyze their associations with male infertility and female adverse pregnancy outcomes. METHODS: The clinical data of 32,055 Chinese men who underwent karyotype analysis from October 2014 to September 2019 were collected. Fisher's exact test, chi-square test, or Kruskal-Wallis test was used to analyze the effects of Y chromosome polymorphism on semen parameters, azoospermia factor (AZF) microdeletions, and female adverse pregnancy outcomes. RESULTS: The incidence of Y chromosome polymorphic variants was 1.19% (381/32,055) in Chinese men. The incidence of non-obstructive azoospermia (NOA) was significantly higher in men with the Yqh- variant than that in men with normal karyotype and other Y chromosome polymorphic variants (p < 0.050). The incidence of AZF microdeletions was significantly different among the normal karyotype and different Y chromosome polymorphic variant groups (p < 0.001). The detection rate of AZF microdeletions was 28.92% (24/83) in the Yqh- group and 2.50% (3/120) in the Y ≤ 21 group. The AZFb + c region was the most common AZF microdeletion (78.57%, 22/28), followed by AZFc microdeletion (7.14%,2/28) in NOA patients with Yqh- variants. There was no significant difference in the distribution of female adverse pregnancy outcomes among the normal karyotype and different Y chromosome polymorphic variant groups (p = 0.528). CONCLUSIONS: Patients with 46,XYqh- variant have a higher incidence of NOA and AZF microdeletions than patients with normal karyotype and other Y chromosome polymorphic variants. Y chromosome polymorphic variants do not affect female adverse pregnancy outcomes.

Development and validation predictive models of sperm retrieval for azoospermic men undergoing testicular sperm aspiration: a multicentre, retrospective, cohort study.

PURPOSE: Testicular sperm aspiration (TESA) is widely used to retrieve sperm from testis. Diagnostic testicular biopsy should not be routinely performed for azoospermia. Therefore, a good predictive model is needed before TESA. METHODS: A total of 1972 azoospermia patients constituted the modelling set, and 260 azoospermia patients from two other centres constituted the validation set. An integrated predictive model was built using logistic regression. Receiver operating characteristic (ROC), calibration and decision curve analyses were performed to evaluate the performance of follicle-stimulating hormone (FSH), semen volume, testicular volume and the integrated model. RESULTS: The FSH level was the best univariate predictor for successful sperm retrieval (SSR) and was better than semen volume and testicular volume alone (p<0.001, threshold 6.17 IU/L, modelling set area under receiver operating characteristic curve (AUC) 0.80, accuracy 0.79; validation set AUC 0.87, accuracy 0.78). The integrated predictive model had excellent accuracy for predicting SSR (modelling set: AUC 0.93, accuracy 0.89; validation set: AUC 0.96, accuracy: 0.89). Calibration curve analysis indicated that the integrated model calibration was good and better than that of FSH, semen volume and testicular volume alone. Decision curve analysis indicated with a threshold probability between 0.05 and 0.98, the integrated model added more benefit than treating either all or no patients. CONCLUSIONS: The integrated model has excellent discrimination and good calibration. It can help azoospermic men make better decisions before TESA. It should be noted that TESA is not the first-line treatment for non-obstructive azoospermia because of a low sperm retrieval rate.

Seminal plasma neutral alpha-glucosidase activity as an early predictor of patency and natural pregnancy after microsurgical vasoepididymostomy.

Microsurgical vasoepididymostomy (MVE) is recommended as a first-line option for treatment of epididymal obstructive azoospermia (EOA). However, early indicators for predicting patency and natural pregnancy are unclear. Our aim was to explore the early predictive value of seminal plasma neutral alpha-glucosidase (NAG) activity for patency and natural pregnancy after MVE. Eighty-four patients with EOA who underwent MVE were enrolled in this study. The post-operative patency and natural pregnancy rates were 60.71% and 33.33% respectively. The presence of motile epididymal spermatozoa at the anastomosis site and NAG activity measured at the first month after MVE were early and independent predictors of patency and natural pregnancy. The areas under the receiver operating characteristic curves (AUCs) of NAG activity for prediction of patency and natural pregnancy were 0.78 (95% confidence interval [CI]: 0.68-0.88) and 0.82 (95% CI: 0.73-0.92). The best cut-off values of NAG activity for predicting patency and pregnancy were 15.9 and 17.0 m IU/ejaculate respectively. In conclusion， NAG activity measured at the first month after MVE is an early and independent predictor of patency and natural pregnancy.

[Microsurgical treatment of obstructive azoospermia: a report of 76 cases].

OBJECTIVE: To investigate the clinical effect of microsurgical vasoepididymostomy and/or vasovasostomy in the treatment of obstructive azoospermia. METHODS: This study included 76 patients with obstructive azoospermia, 53 treated by bilateral vasoepididymostomy (8 involving the epididymal head, 18 involving the epididymal body, 5 involving the epididymal tail, and 22 involving the epididymal head, body and tail), 14 by unilateral vasoepididymostomy, and the other 9 by unilateral vasoepididymostomy + unilateral vasovasostomy (including cross anastomosis). We followed up the patients for 2 to 16 months for the patency rate, routine semen parameters, and pregnancy outcomes. RESULTS: The success rate of bilateral vasoepididymostomy, unilateral vasoepididymostomy, and unilateral vasoepididymostomy + unilateral vasovasostomy (including cross anastomosis) were 62.26% (33/53), 35.71% (5/14), and 77.78% (7/9), respectively. The average sperm concentrations in the three groups of patients were (27.9 +/- 5.74), (11.8 +/- 8.33), and (19.9 +/- 7.53) x 10(6)/ml, the average total sperm counts were (65.6 +/- 13.71), (28.0 +/- 15.86), and (69.2 +/- 28.59) x 10(6), and the mean rates of progressively motile sperm were (22.3 +/- 3.18), (11.0 +/- 9.77), and (15.8 +/- 5.05)%, respectively. The success rates of bilateral vasoepididymostomy that involved the epididymal head, body, tail, and all the three parts were 62.5, 72.22, 60, and 54.55%, respectively. Natural pregnancy was achieved in 8 (10.53%) of the total number of cases. CONCLUSION: Microsurgery is effective for the treatment obstructive azoospermia. Unilateral vasoepididymostomy + unilateral vasovasostomy is superior to the other procedures, followed by bilateral vasoepididymostomy. Bilateral vasoepididymostomy involving the epididymal body may achieve a slightly better effect than that involving the other epididymal parts.

Re-assessment of the close relationship between serum FSH levels and semen quality: a retrospective cohort study of 11,929 Chinese men.

PURPOSE: To establish a medically valuable normal reference interval of follicle-stimulating hormone (FSH) levels in males with normal semen and to assess the predictive value of FSH in males exhibiting semen abnormalities. METHODS: The study involved male patients who underwent their initial serum sex hormone test and semen test between October 2013 and June 2023. The reference interval was identified as the 95% confidence interval (CI) of FSH values in the patients with normal semen parameters. Then, in the total study population, receiver operating characteristic (ROC) curves were performed to evaluate the discriminatory ability of FSH for oligozoospermia and non-obstructive azoospermia (NOA). Besides, multivariable logistic regression was performed to investigate the association of FSH with oligozoospermia and NOA adjusted by age. RESULTS: A total of 11,929 patients were finally enrolled in the study. The normal reference interval of FSH ranged from 1.70 IU/L to 7.60 IU/L (median: 3.98 IU/L) based on 4595 patients with normal semen routine parameters. In the total patients, ROC curves showed FSH to have a "fair" discriminatory ability for oligozoospermia (area under receiver operating characteristic curve (AUC) 0.747, threshold 7.32 IU/L, accuracy 0.734, positive predictive value (PPV) 0.754, negative predictive value (NPV) 0.726), while ROC curves showed FSH to have a "excellent" discriminatory ability for NOA (AUC: 0.921, threshold 10.18 IU/L, accuracy 0.903, PPV 0.593, NPV 0.972). Besides, multivariable logistic regression showed that FSH ≥ 7.32 IU/L was associated with a 8.51-fold increase in the risk of oligozoospermia adjusted by age, while FSH ≥ 10.18 IU/L was associated with a 38.93-fold increase in the risk of NOA. CONCLUSIONS: Our findings indicated that the reference interval for FSH in males with normal semen was 1.70-7.60 IU/L and found that FSH was capable of effectively discerning oligospermia and NOA.

Activation of Follicle-Stimulating Hormone Receptor in Adrenal Zona Fasciculata Cells Promotes Cortisol Secretion: Implications for the Development of Menopause-Associated Diseases.

OBJECTIVE: Changes in postmenopausal hormone levels are associated with a variety of disorders. This study elucidated the mechanism by which follicle-stimulating hormone (FSH) increases cortisol production involved in development of menopause-related diseases. METHODS: The expression of FSH receptors (FSHRs) in murine adrenal zona fasciculata (AZF) cells and ATC7 cells was verified by immunofluorescence, western blotting and RT-PCR. The function of FSHR in promoting cortisol production was analyzed by cell culture and molecular biological methods. FSHR signaling pathways in ATC7 cells were analyzed by ELISA, qRT-PCR, and western blotting. Further, a mouse model was established by ovariectomy. Ovariectomized mice were treated with GnRHa. Ovariectomized mice initially received physiological doses of estrogen and were then injected with recombinant FSH. Then serum FSH, luteinizing hormone (LH), estradiol, and cortisol, and bone mineral density (BMD), blood pressure (BP) and heart rate (HR) were determined. RESULTS: FSHRs were expressed in murine AZF cells and ATC7 cells. FSH accelerated cortisol production through activated protein kinase A (PKA), cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB), protein kinase B (PKB/AKT) and 5' AMP-activated protein kinase (MAPK) signaling pathways by Gsα-coupled FSHRs in ATC7 cells. Serum FSH levels (P<0.001) were elevated in ovariectomized mice with concurrent increases in cortisol (P<0.01), areal BMD (aBMD) (P<0.05), volumetric BMD (vBMD) (P<0.05), systolic BP (SBP) (P<0.05), diastolic BP (DBP) (P<0.05), and HR (P<0.05). However, the administration of GnRHa suppressed the increase in FSH levels and the elevation of cortisol, aBMD, vBMD, SBP, DBP, and HR induced by ovariectomy, even in the presence of normal serum estradiol levels. CONCLUSION: The study findings indicate that elevated FSH levels stimulate cortisol secretion, through a mechanism related to FSHRs expression in AZF cells.

Effects of major depression and bipolar disorder on erectile dysfunction: a two-sample mendelian randomization study.

BACKGROUND AND AIMS: There are currently no clear conclusions about whether major depression (MD) and bipolar disorder (BD) increase the risk of erectile dysfunction (ED). In our study, we used a Mendelian randomization (MR) analysis to discover the causal associations between MD, BD and ED. METHODS: We got single-nucleotide polymorphisms (SNPs) related to MD, BD and ED from the MRC IEU Open genome-wide association study (GWAS) datasets. After a series of selection, SNPs left were selected as instrumental variables (IVs) of MD and BD for the following MR test to evaluate the relationship of genetically predicted MD or BD with the incidence of ED. Among them, we used the random-effects inverse-variance weighted (IVW) method as the main analysis. Finally, sensitivity analyses were further performed using Cochran's Q test, funnel plots, MR-Egger regression, Leave-one-out method and MR- pleiotropy residual sum and outlier (PRESSO). RESULTS: Genetically-predicted MD was causally related to the incidence of ED in the IVW methods (odds ratio (OR), 1.53; 95% confidence interval (CI), 1.19-1.96; p = 0.001), while no causal impact of BD on the risk of ED (OR = 0.95, 95% CI 0.87-1.04; p = 0.306). The results of sensitivity analyses supported our conclusion, and no directional pleiotropy were found. CONCLUSION: The findings of this research found evidence of a causal relationship between MD and ED. However, we did not find a causal relationship between BD and ED in European populations.

Identification of a differentiation-related prognostic nomogram based on single-cell RNA sequencing in clear cell renal cell carcinoma.

Renal cell carcinoma (RCC) is a kidney cancer that is originated from the lined proximal convoluted tubule, and its major histological subtype is clear cell RCC (ccRCC). This study aimed to retrospectively analyze single-cell RNA sequencing (scRNA-seq) data from the Gene Expression Omnibus (GEO) database, to explore the correlation among the evolution of tumor microenvironment (TME), clinical outcomes, and potential immunotherapeutic responses in combination with bulk RNA-seq data from The Cancer Genome Atlas (TCGA) database, and to construct a differentiation-related genes (DRG)-based prognostic risk signature (PRS) and a nomogram to predict the prognosis of ccRCC patients. First, scRNA-seq data of ccRCC samples were systematically analyzed, and three subsets with distinct differentiation trajectories were identified. Then, ccRCC samples from TCGA database were divided into four DRG-based molecular subtypes, and it was revealed that the molecular subtypes were significantly correlated with prognosis, clinicopathological features, TME, and the expression levels of immune checkpoint genes (ICGs). A DRG-based PRS was constructed, and it was an independent prognostic factor, which could well predict the prognosis of ccRCC patients. Finally, we constructed a prognostic nomogram based on the PRS and clinicopathological characteristics, which exhibited a high accuracy and a robust predictive performance. This study highlighted the significance of trajectory differentiation of ccRCC cells and TME evolution in predicting clinical outcomes and potential immunotherapeutic responses of ccRCC patients, and the nomogram provided an intuitive and accurate method for predicting the prognosis of such patients.

Clinical application of cross microsurgical vasovasostomy in scrotum for atypical obstructive azoospermia.

Seminal duct obstruction may result in obstructive azoospermia (OA) and severe oligoasthenoteratozoospermia (OAT) (<0.5 million/mL) (Nordhoff et al., 2015). Cases of partial OA and OAT can be treated effectively by microsurgical anastomosis (Goldstein and Kim, 2013) to obtain successful surgical reversal. However, microsurgical vasovasostomy (VV) (Dickey et al., 2015) and vasoepididymostomy (VE) (Peng et al., 2017) are not suitable for patients with atypical OA and poor epididymis conditions or unpredictable obstruction of the distal vas deferens. For those patients, cross anastomosis may be applied instead of routine VE or VV. A single-center, retrospective, comparison study was conducted, which assessed the usefulness of the cross VV (CVV) in the scrotum for indication and efficacy. A total of 77 cases with OA or OAT were included, and 20 cases implemented cross anastomosis, including unilateral CVV (UCVV) in 4 cases, unilateral VE plus CVV (UVE+CVV) in 11 cases, and unilateral VV-based CVV (UVV+CVV) in 5 cases. The other 57 cases received no cross-matching anastomosis. The patency and natural pregnancy rates in one year were 75.0% and 50.0%, respectively, in the UCVV group; 54.5% and 27.3%, respectively, in the UVE+CVV group; and 60.0% and 40.0%, respectively, in the UVV+CVV group. The CVV in the scrotum in the selected patients with OA and severe OAT could yield good results. We regard the CVV in the scrotum as an efficacious operation with a lower risk of injury in cases of atypical OA.