Long-term tadalafil once daily in Chinese men with erectile dysfunction:a 2-year final analysis of a post-marketing,multicenter,randomized,open-label trial

The long-term safety and effectiveness of once-daily tadalafil is crucial,but limited data are available in Chinese patients witherectile dysfunction(ED).In this post-marketing,multicenter,randomized,open-label trial with 2-year follow-up,635 ED caseswere randomized to receive daily oral tadalafil 2.5 mg or 5 mg for 3 months,of whom 580 continued once-daily tadalafil 5 mg for21 months.Treatment-emergent adverse events in the 12-month and 24-month period were similar,with the most common beingviral upper respiratory tract infection,upper respiratory tract infection,and headache.Significant improvement from baseline inthe International Index of Erectile Function-Erectile Function(IIEF-EF)score was detected at month 12(least squares mean[LSM]change:7.9,95%confidence interval[CI]:7.5–8.4,P<0.001)and was maintained to month 24(LSM change:8.6,95%CI:8.1–9.0,P<0.001).The proportions of patients regaining normal erectile function(IIEF-EF score≥26)were 43.7%and 48.0%at months 12 and 24,respectively.Global Assessment Questionnaire results showed improved erection function in 97.5%ofpatients and improved ability to engage in sexual activity in 95.9%of patients at month 12;these values were 96.1%and 95.0%at month 24,respectively.The quality of sexual life score based on the Sexual Life Quality Questionnaire(SLQQ)was increased by52.2%at month 12 and by 55.3%at month 24(both P<0.001).The treatment satisfaction score determined by SLQQ(mean±standard deviation)was 62.4±21.0 at month 12 versus 65.9±20.2 at month 24.Two-year daily application of tadalafil 5mg in Chinese men with ED showed a favorable safety profile and durable improvement in sexual performance and satisfaction.

Development of a predictive model for increasing sperm retrieval sucpess by microdissection testicular sperm extraction in patients with nonobstructive azoospermia

Microdissection testicular sperm extraction(micro-TESE)is widely used to treat nonobstructive azoospermia.However,a good prediction model is required to anticipate a successful sperm retrieval rate before performing micro-TESE.This retrospective study analyzed the clinical records of 200 nonobstructive azoospermia patients between January 2021 and December 2021.The backward method was used to perform binary logistic regression analysis and identify factors that predicted a successful micro-TESE sperm retrieval.The prediction model was constructed using acquired regression coefficients,and its predictive performance was assessed using the receiver operating characteristic curve.In all,67 patients(sperm retrieval rate:33.5%)underwent successful micro-TESE.Follicle-stimulating hormone,anti-Miillerian hormone,and inhibin B levels varied significantly between patients who underwent successful and unsuccessful micro-TESE.Binary logistic regression analysis yielded the following six predictors:anti-Mullerian hormone(odds ratio[OR]=0.902,95%confidence interval[Cl]:0.821-0.990),inhibin B(OR=1.012,95%Cl:1.001-1.024),Klinefelter’s syndrome(OR=0.022,95%Cl:0.002-0.243),Y chromosome microdeletion(OR=0.050,95%Cl:0.005-0.504),cryptorchidism with orchiopexy(OR=0.085,95%Cl:0.008-0.929),and idiopathic nonobstructive azoospermia(OR=0.031,95%Cl:0.003-0.277).The prediction model had an area under the curve of 0.720(95%Cl:0.645-0.794),sensitivity of 65.7%,specificity of 72.2%,Youden index of 0.379,and cut-off value of 0.305 overall,indicating good predictive value and accuracy.This model can assist clinicians and nonobstructive azoospermia patients in decision-making and avoiding negative micro-TESE results.

Factors influencing the sperm retrieval rate of microdissection testicular sperm extraction in patients with nonmosaic Klinefelter syndrome

To investigate the factors affecting the sperm retrieval rate of microdissection testicular sperm extraction(micro-TESE)in patients with nonmosaic Klinefelter syndrome(KS),64 patients with nonmosaic KS who underwent micro-TESE in the Center for Reproductive Medicine of Peking University Third Hospital(Beijing,China)between January 2016 and December 2017 were included in the study.Data on medical history,physical examination and laboratory examination results,and micro-TESE outcomes were collected.Patients were divided into two groups according to micro-TESE outcomes.The following factors were compared between the two groups by the Mann‒Whitney U test or Student’s t-test based on the distribution(nonnormal or normal)of the factors:age,testicular size,follicle-stimulating hormone level,luteinizing hormone level,testosterone level,and anti-Müllerian hormone level.The overall success rate of sperm retrieval was 50.0%.Correlation analysis showed that testicular volume was positively correlated with testosterone level.Using a logistic regression model,age and anti-Müllerian hormone levels were found to be better predictors for the sperm retrieval rate than the other parameters.

Evaluation of the long-term safety and effectiveness of tadalafil once daily in Chinese men with erectile dysfunction： interim results of a multicenter, randomized, open-label trial

Once-daily tadalafil administration has been well established; however, studies about tadalafil once-daily treatment in the Chinese population are lacking. In this phase 4, postmarketing study, we ascertained the long-term safety and effectiveness of tadalafil 2.5 mg and 5.0 mg once daily in Chinese men with erectile dysfunction （n = 635）. The primary endpoint of the study was safety at 12 months as assessed by the proportion of patients experiencing at least one treatment-emergent adverse event （serious or nonserious）. The secondary endpoints included safety and effectiveness, measured by the International Index of Erectile Function-Erectile Function （IIEF-EF） domain scores. Similar adverse events to the known safety profile of tadalafil, such as nasopharyngitis, upper respiratory tract infection, headache, and dizziness, were detected. No new cardiovascular safety concerns were observed. After 3 months of treatment, significant increases in IIEF-EF domain scores were detected for both 2.5-mg （least squares [LS] mean change： 6.3; 95% confidence interval [CI]： 5.4-7.1; P 〈 0.001） and 5.0-mg （LS mean change： 7.4; 95% CI： 6.8-7.9; P 〈 0.001） tadalafil doses, and significance was maintained up to 12 months. In addition, approximately 40% of patients regained normal erectile function （IIEF-EF 〉26） following 1 year of tadalafil once-daily treatment. The findings in this study provide evidence for the extended effectiveness and tolerability of tadalafil, demonstrating no new safety concerns, in a Chinese population and make once-daily tadalafil administration a viable option for improving sexual performance and satisfaction in Chinese men with erectile dysfunction.

Multiple factors affecting surgical outcomes and patency rates in use of single-armed two-suture microsurgical vasoepididymostomy： a single surgeon＇s experience with 81 patients

Vasoepididymostomy （VE）, as the most challenging procedure in microsurgeries, is often carried out with a double-armed two-suture technique. In this study, we evaluated the efficacy and safety of the single-armed two-suture VEs on humans and studied the factors that could possibly affect the patency rates. From July 2012 to July 2013, we reviewed 81 patients with consecutive primary epididymal obstruction who underwent single-armed two-suture longitudinal intussusception microsurgical VEs by a single surgeon, Kai Hong （KH）. At the same time, we analyzed seven factors that possibly related to the patency rates. With the single-armed technique, a total of 81 men underwent the microsurgical VEs. Data on 62 patients were completely recorded. 19 patients were lost to follow-up. Mean age was 31 years old. Mean follow-up time was 8.8 （2-17） months. The patency rate was 66.1% （41/62）. Natural pregnancy rate was 34.1% （14/41）. Overall pregnancy rate was 22.6% （14/62）. No severe surgical complications were noted. With logistic regression test analysis, there were two factors related to a higher patency rate： anastomosis sites （P = 0.035） and motile sperm found in the epididymal fluid （P = 0.006）. Motile sperm found in the epididymal fluid were associated with a higher patency rate （OR = 11.80, 95% CI = 1.79, 77.65）. The single-armed two-suture longitudinal VE technique is feasible for microsurgical practice. The patency and pregnancy rates are comparable to the doubled-armed technique. Anastomosis sites and motile sperm found in the epididymal fluid were the most two important factors related to higher patency.

Sperm retrieval rates and clinical outcomes for patients with different causes of azoospermia who undergo microdissection testicular sperm extraction-intracytoplasmic sperm injection

The aim of our study was to compare the sperm retrieval rates(SRRs)and clinical outcomes of patients with different causes of azoospermia who underwent microdissection testicular sperm extraction-intracytoplasmic sperm injection(micro-TESE-ICSI).We conducted a retrospective study at the Reproductive Medicine Center of Peking University Third Hospital in Beijing,China,from January 2014 to December 2017.This study examined 769 patients with nonobstructive azoospermia who underwent 347 cycles of micro-TESE-ICSI.Patients with azoospermia were classified into Group A(Klinefelter syndrome,n=284,125 cycles),Group B(azoospermia Y chromosome factor c[AZFc]microdeletion,n=91,64 cycles),Group C(cryptorchidism,n=52,39 cycles),Group D(previous mumps and bilateral orchitis,n=23,23 cycles),and Group E(idiopathic azoospermia,n=319,96 cycles).Clinical characteristics,SRR,embryonic development,and pregnancy outcomes of the patients were compared between all groups.Patients in Group D had the highest and most successful SRR.The average SRR for all patients was 46.0%.The rates of clinical pregnancy,implantation,and live birth in Group D were 78.3%,65.0%,and 74.0%,respectively,which were higher than those in all other groups(P<0.05).Group B patients had the lowest clinical pregnancy,implantation,and live birth rates of all groups(P<0.05).No differences were found in the miscarriage rate or birth defects among the groups(P>0.05).Patients with orchitis had the highest SRR and best clinical outcomes.Although AZFc microdeletion patients had a higher SRR,their clinical outcomes were worse.

Nanotechnology-assisted adipose-derived stem cell （ADSC） therapy for erectile dysfunction of cavernous nerve injury： In vivo cell tracking, optimized injection dosage, and functional evaluation

Stem cell therapy is a potentially promising option for erectile dysfunction; however, its risk of tumorigenicity is a clinical hurdle and the risk is positively related to the number of injected cells. Our previous study showed that nanotechnology improved adipose-derived stem cell （ADSC） therapy for erectile dysfunction of cavernous nerve injury （CNI） by attracting cells in the corpus cavernosum. These results indicated the possibility of using a reduced dosage of ADSCs for intracavernous injection. In this exploratory study, we used lower dosage （2 × 105 cells） of ADSCs for intracavernous injection （ICI） and the nanotechnology approach. Intracavernous pressure and mean arterial pressure were measured at day 28 to assess erectile function. The low-dose ADSC therapy group showed favorable treatment effects, and nanotechnology further improved these effects. In vivo imaging of ICI cells revealed that the fluorescein signals of NanoShuttle-bound ADSCs （NanoADSCs） were much stronger than those of ADSCs at days 0, 1, and 3. Both immunofluorescence and Western blot analysis showed a significant increase in smooth muscle, endothelium, and nerve tissue in the ADSC group compared to that in the CNI group; further improvement was achieved with assisted nanotechnology. These findings demonstrate that nanotechnology can be used to further improve the effect of small dosage of ADSCs to improve erectile function. Abundant NanoADSCs remain in the corpus cavernosum in vivo for at least 3 days. The mechanism of erectile function improvement may be related to the regeneration of the smooth muscle, endothelium, and nerve tissues.

Clinical outcomes of microdissection testicular sperm extraction-intracytoplasmic sperm injection with fresh or cryopreserved sperm in patients with nonobstructive azoospermia

We performed this study to evaluate the clinical outcomes of microdissection testicular sperm extraction-intracytoplasmic sperm injection(micro-TESE-ICSI)treatment that used fresh or cryopreserved sperm in patients with nonobstructive azoospermia(NOA).A total of 338 NOA patients with 344 consecutive cycles received treatment in the reproductive medicine center of Peking University Third Hospital in Beijing,China,from January 2014 to December 2017.Fresh oocytes and fresh sperm were used in 222 patients with 234 cycles(Group A).Fresh oocytes and cryopreserved sperm were used in 116 patients with 110 cycles(Group B).We compared patient characteristics,embryonic development,and pregnancy outcomes between Groups A and B.There was no statistical difference in the patient characteristics,and no differences were observed with fertilization or quality embryo rates between Groups A and B.The rates of clinical pregnancy and live birth were both higher for Group A than those for Group B(both P<0.05).In conclusion,fresh testicular sperm appears to produce better ICSI outcomes than cryopreserved testicular sperm in patients with NOA.

RNAs in the testicular tissue of patients with non-obstructive azoospermia

Circular RNAs(circRNAs)are highly conserved and ubiquitously expressed noncoding RNAs that participate in multiple reproductionrelated diseases.However,the expression pattern and potential functions of circRNAs in the testes of patients with non-obstructive azoospermia(NOA)remain elusive.In this study,according to a circRNA array,a total of 37881 circRNAs were identified that were differentially expressed in the testes of NOA patients compared with normal controls,including 19874 upregulated circRNAs and 18007 downregulated circRNAs.Using quantitative real-time polymerase chain reaction(qRT-PCR)analysis,we confirmed that the change tendency of some specific circRNAs,including hsa_circ_0137890,hsa_circ_0136298,and hsa_circ_0007273,was consistent with the microarray data in another larger sample.The structures and characteristics of these circRNAs were confirmed by Sanger sequencing,and fluorescence in situ hybridization revealed that these circRNAs were primarily expressed in the cytoplasm.Bioinformatics analysis was used to construct the competing endogenous RNA(ceRNA)network,and numerous miRNAs that could be paired with circRNAs validated in this study were reported to be vital for spermatogenesis regulation.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses indicated that genes involved in axoneme assembly,microtubule-based processes,and cell proliferation were significantly enriched.Our data suggest that there are aberrantly expressed circRNA profiles in patients with NOA and that these circRNAs may help identify key diagnostic and therapeutic molecular biomarkers forNoA patients.

Fertility achieved through in vitro fertilization in a male patient with 48,XXYY syndrome

The 48,XXYY syndrome is a rare sex chromosome aneuploidy with an incidence of 1：18 000-1：40 000 male births and is associated with hypergonadotropic hypogonadism as an endocrine disorder. Most men with this syndrome are never diagnosed in China. Due to sex chromosome aneuploidies and limited effective communication, these patients suffer from infertility.