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2017| November-December | Volume 19 | Issue 6
Online since October 24, 2017
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AMP-activated kinase in human spermatozoa: identification, intracellular localization, and key function in the regulation of sperm motility
Violeta Calle-Guisado, Ana Hurtado de Llera, David Martin-Hidalgo, Jose Mijares, Maria C Gil, Ignacio S Alvarez, Maria J Bragado, Luis J Garcia-Marin
November-December 2017, 19(6):707-714
DOI:10.4103/1008-682X.185848 PMID:27678462
AMP-activated kinase (AMPK), a protein that regulates energy balance and metabolism, has recently been identified in boar spermatozoa where regulates key functional sperm processes essential for fertilization. This work's aims are AMPK identification, intracellular localization, and their role in human spermatozoa function. Semen was obtained from healthy human donors. Sperm AMPK and phospho-Thr172-AMPK were analyzed by Western blotting and indirect immunofluorescence. High- and low-quality sperm populations were separated by a 40%-80% density gradient. Human spermatozoa motility was evaluated by an Integrated Semen Analysis System (ISAS) in the presence or absence of the AMPK inhibitor compound C (CC). AMPK is localized along the human spermatozoa, at the entire acrosome, midpiece and tail with variable intensity, whereas its active form, phospho-Thr172-AMPK, shows a prominent staining at the acrosome and sperm tail with a weaker staining in the midpiece and the postacrosomal region. Interestingly, spermatozoa bearing an excess residual cytoplasm show strong AMPK staining in this subcellular compartment. Both AMPK and phospho-Thr172-AMPK human spermatozoa contents exhibit important individual variations. Moreover, active AMPK is predominant in the high motility sperm population, where shows a stronger intensity compared with the low motility sperm population. Inhibition of AMPK activity in human spermatozoa by CC treatment leads to a significant reduction in any sperm motility parameter analyzed: percent of motile sperm, sperm velocities, progressivity, and other motility coefficients. This work identifies and points out AMPK as a new molecular mechanism involved in human spermatozoa motility. Further AMPK implications in the clinical efficiency of assisted reproduction and in other reproductive areas need to be studied.
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A successful pregnancy by intracytoplasmic sperm injection using ejaculate sperm from an infertile man with 46, XX/46, XY true hermaphrodite
Yan-Wei Sha, Yan-Kun Sha, Lu Ding, Shao-Bin Lin, Zhi-Yong Ji, Xu Wang, Yue-Qiang Song, Ping Li
Impact of antioxidants on seminal vesicles function and fertilizing potential in diabetic rats
Panagiota Tsounapi, Masashi Honda, Fotios Dimitriadis, Bunya Kawamoto, Katsuya Hikita, Kuniyasu Muraoka, Motoaki Saito, Nikolaos Sofikitis, Atsushi Takenaka
Diabetes mellitus significantly affects the male reproduction and sexual function. In the present study, we investigated the diabetes-induced dysfunction of seminal vesicles (SVs) in the diabetes-rat model and the role of antioxidants. Streptozotocin-induced diabetes after 4 weeks caused smaller size of the organs, hypercontractility, histological abnormalities, increased concentrations of malondialdehyde in the serum and tissue, overexpression of oxidative stress markers, and cleaved caspase-3 as identified by immunohistochemistry in the SVs. In addition, diabetes resulted in deceased levels of serum testosterone and no newborns after the mating studies. Antioxidants significantly normalized all the above parameters, except for the severely decreased serum testosterone levels and the negative outcome of the mating studies. The present study gives evidence for the important role of diabetes-induced oxidative stress in the function and structure of these androgen-dependent organs. Antioxidants may be a promising supplementary therapy for diabetic male patients to alleviate ejaculatory disorders but alone is not efficient treatment for the mitigation of infertility.
Sertraline-induced reproductive toxicity in male rats: evaluation of possible underlying mechanisms
Ozlem Atli, Merve Baysal, Gozde Aydogan-Kilic, Volkan Kilic, Seyda Ucarcan, Burak Karaduman, Sinem Ilgin
This study was conducted to clarify the toxic effects of sertraline (SRT) on the reproductive system of male rats and to elucidate the underlying mechanisms. Rats were treated orally with SRT at doses of 5, 10, and 20 mg kg−1 for 28 consecutive days. At the end of the treatment period, sperm concentration, sperm motility, and sperm morphology were investigated by computer-assisted sperm analysis system whereas sperm DNA damage was detected by comet assay. The oxidative status of the testes was investigated, and a histopathological examination was conducted. Serum testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels were measured to determine the effects of SRT on the spermatogenesis process. One-way ANOVA, post-hoc Dunnett's T3 test for the sperm comet assay, and post-hoc Tukey's test for the others were performed for statistical analysis. The results showed that SRT caused an increase in sperm DNA damage and induced histopathological lesions in all groups treated with SRT. There was abnormal sperm morphology and increased malondialdehyde (MDA) in the 10 mg kg−1 treatment group. More dramatic changes were observed in the 20 mg kg−1 treatment group. Decreased sperm count was accompanied by a significant increase in abnormal sperm morphology, DNA damage, and degeneration in cellular-tubular structures. Serum LH and testosterone levels were elevated in the 20 mg kg−1 treatment group. Decreased glutathione (GSH) and increased MDA were signs of enhanced oxidative stress (OS). In conclusion, SRT induced testicular toxicity in a dose-dependent manner and OS is suggested as a crucial mechanism.
Pulsatile gonadotropin-releasing hormone therapy is associated with earlier spermatogenesis compared to combined gonadotropin therapy in patients with congenital hypogonadotropic hypogonadism
Jiang-Feng Mao, Zhao-Xiang Liu, Min Nie, Xi Wang, Hong-Li Xu, Bing-Kun Huang, Jun-Jie Zheng, Le Min, Ursula Brigitte Kaiser, Xue-Yan Wu
Both pulsatile gonadotropin-releasing hormone (GnRH) infusion and combined gonadotropin therapy (human chorionic gonadotropin and human menopausal gonadotropin [HCG/HMG]) are effective to induce spermatogenesis in male patients with congenital hypogonadotropic hypogonadism (CHH). However, evidence is lacking as to which treatment strategy is better. This retrospective cohort study included 202 patients with CHH: twenty had received pulsatile GnRH and 182 had received HCG/HMG. Patients had received therapy for at least 12 months. The total follow-up time was 15.6 ± 5.0 months (range: 12-27 months) for the GnRH group and 28.7 ± 13.0 months (range: 12-66 months) for the HCG/HMG group. The median time to first sperm appearance was 6 months (95% confidence interval [CI]: 1.6-10.4) in the GnRH group versus 18 months (95% CI: 16.4-20.0) in the HCG/HMG group (P < 0.001). The median time to achieve sperm concentrations ≥5 × 10 6 ml−1 was 14 months (95% CI: 5.8-22.2) in the GnRH group versus 27 months (95% CI: 18.9-35.1) in the HCG/HMG group (P < 0.001), and the median time to concentrations ≥10 × 10 6 ml−1 was 18 months (95% CI: 10.0-26.0) in the GnRH group versus 39 months (95% CI unknown) in the HCG/HMG group. Compared to the GnRH group, the HCG/HMG group required longer treatment periods to achieve testicular sizes of ≥4 ml, ≥8 ml, ≥12 ml, and ≥16 ml. Sperm motility (a + b + c percentage) evaluated in semen samples with concentrations >1 × 10 6 ml−1 was 43.7% ± 20.4% (16 samples) in the GnRH group versus 43.2% ± 18.1% (153 samples) in the HCG/HMG group (P = 0.921). Notably, during follow-up, the GnRH group had lower serum testosterone levels than the HCG/HMG group (8.3 ± 4.6 vs 16.2 ± 8.2 nmol l−1 , P < 0.001). Our study found that pulsatile GnRH therapy was associated with earlier spermatogenesis and larger testicular size compared to combined gonadotropin therapy. Additional prospective randomized studies would be required to confirm these findings.
Sex determination and maintenance: the role of DMRT1 and FOXL2
Shengsong Huang, Leping Ye, Haolin Chen
In many species, including mammals, sex determination is genetically based. The sex chromosomes that individuals carry determine sex identity. Although the genetic base of phenotypic sex is determined at the moment of fertilization, the development of testes or ovaries in the bipotential early gonads takes place during embryogenesis. During development, sex determination depends upon very few critical genes. When one of these key genes functions inappropriately, sex reversal may happen. Consequently, an individual's sex phenotype may not necessarily be consistent with the sex chromosomes that are present. For some time, it has been assumed that once the fetal choice is made between male and female in mammals, the gonadal sex identity of an individual remains stable. However, recent studies in mice have provided evidence that it is possible for the gonadal sex phenotype to be switched even in adulthood. These studies have shown that two key genes, doublesex and mad-3 related transcription factor 1 (Dmrt1) and forkhead box L2 (Foxl2), function in a Yin and Yang relationship to maintain the fates of testes or ovaries in adult mammals, and that mutations in either gene might have a dramatic effect on gonadal phenotype. Thus, adult gonad maintenance in addition to fetal sex determination may both be important for the fertility.
Melatonin ameliorates the adverse effects of leptin on sperm
Fayez A Almabhouh, Khairul Osman, Siti Fatimah Ibrahim, Sergey Gupalo, Justin Gnanou, Effendi Ibrahim, Harbindar Jeet Singh
This study examined the effects of melatonin on leptin-induced changes in sperm parameters in adult rats. Five groups of Sprague-Dawley rats were treated with either leptin or leptin and melatonin or melatonin for 6 weeks. Leptin was given daily via the intraperitoneal route (60 μg kg−1 body weight) and melatonin was given in drinking water (10 mg kg−1 or 20 mg kg−1 body weight per day). Upon completion, sperm count, sperm morphology, 8-hydroxy-2-deoxyguanosine, Comet assay, TUNEL assay, gene expression profiles of antioxidant enzymes, respiratory chain reaction enzymes, DNA damage, and apoptosis genes were estimated. Data were analyzed using ANOVA. Sperm count was significantly lower whereas the fraction of sperm with abnormal morphology, the level of 8-hydroxy-2-deoxyguanosine, and sperm DNA fragmentation were significantly higher in rats treated with leptin only. Microarray analysis revealed significant upregulation of apoptosis-inducing factor, histone acetyl transferase, respiratory chain reaction enzyme, cell necrosis and DNA repair genes, and downregulation of antioxidant enzyme genes in leptin-treated rats. Real-time polymerase chain reaction showed significant decreases in glutathione peroxidase 1 expression with increases in the expression of apoptosis-inducing factor and histone acetyl transferase in leptin-treated rats. There was no change in the gene expression of caspase-3 (CASP-3). In conclusion, the adverse effects of leptin on sperm can be prevented by concurrent melatonin administration.
Effect of statins type on incident prostate cancer risk: a meta-analysis and systematic review
Ping Tan, Chen Zhang, Shi-You Wei, Zhuang Tang, Liang Gao, Lu Yang, Qiang Wei
The aim of this study is to investigate the effect of statins type or even when grouping statins by hydrophilic or hydrophobic nature on prostate cancer risk. A literature search was performed without language restrictions using the databases of PubMed (1984.1-2015.3), MEDLINE (1984.1-2015.3), and EMBASE (1990.1-2015.3). Two independent reviewers appraised eligible studies and extracted data. Weighted averages were reported as relative risk (RR) with 95% confidence intervals (CI). Statistic heterogeneity scores were assessed with the standard Cochran's Q-test and I2 statistic. Publication bias was detected using the Begg's and Egger's tests. All statistical analyses were conducted by STATA version 10. Finally, fourteen studies were included in the meta-analysis. Both hydrophilic and hydrophobic statins showed no association with incidence of prostate cancer (RR = 1.00, 95% CI: 0.82-1.17; RR = 0.90, 95% CI: 0.73-1.08, respectively). Meanwhile, the risk of prostate cancer was not reduced in simvastatin (RR = 0.89, 95% CI: 0.72-1.05), pravastatin (RR = 1.02, 95% CI: 0.94-1.11), atorvastatin (RR = 0.89, 95% CI: 0.76-1.02), fluvastatin (RR = 0.99, 95% CI: 0.97-1.01), or lovastatin users (RR = 0.94, 95% CI: 0.79-1.08). The funnel plot showed that there was no publication bias. The results showed that statins had a neutral effect on prostate cancer risk; hydrophilic and hydrophobic statins as well as any subtype of statins did not affect the risk of prostate cancer.
Is age at puberty associated with semen quality and reproductive hormones in young adult life?
Lea LB Lauridsen, Linn H Arendt, Henrik Støvring, Jørn Olsen, Cecilia H Ramlau-Hansen
The evidence is scarce on the association between age at puberty and semen quality. A cohort of 320 Danish men aged 18-21 years enrolled in the "Healthy Habits for Two" birth cohort provided self-reported data on pubertal indicators and delivered semen and blood samples. The results indicated an association between older age at pubertal development and lower semen quality and altered reproductive hormones concentrations as measured in young adult life. Men who had their first nocturnal emission, start of pubic hair growth and first voice break episode when older than 15 years had 37.0%, 45.0% and 32.7% lower sperm concentration; 37.8%, 44.2% and 29.1% lower total sperm count; 7.4%, 13.4% and 15.3% lower testosterone concentration; and 21.3%, 1.5% and 3.7% lower inhibin B concentration, respectively, compared with the men who were younger than 13 years at their first pubertal indicators. Only few of the results were statistically significant, but similar tendencies were seen in several of the reproductive parameters suggesting an association between the timing of pubertal development and reproductive health later in life.
The impact of autophagy in spermiogenesis
Nihan Ozturk, Klaus Steger, Undraga Schagdarsurengin
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Characterization of MAGEG2 with testis-specific expression in mice
Juri Jeong, Sora Jin, Heejin Choi, Jun Tae Kwon, Jihye Kim, Jaehwan Kim, Zee Yong Park, Chunghee Cho
Male germ cell development is a well-defined process occurring in numerous seminiferous tubules of the testis. Uncovering testicular novel genes related to intrinsic regulation of spermatogenesis is essential for the understanding of spermatogenesis. In the present study, we investigated mouse Mageg2, which belongs to a group of melanoma-associated antigens (MAGEs). Mageg2 is transcribed in the testis specifically, and its expression level is increased at the pachytene spermatocyte stage, indicating that Mageg2 is expressed predominantly in germ cells. We generated an antibody against mouse MAGEG2 for further characterization at the protein level. Immunoblot analysis suggested that MAGEG2 has specific testicular expression and the expression primarily occurred in pachytene spermatocytes. Proteomic analyses demonstrated that mouse MAGEG2 binded to testicular germ cell-specific serine/threonine-protein kinase 31 (STK31) and heat shock protein 9 (HSPA9). Direct binding with both interaction partners was confirmed by co-immunoprecipitation. We found that STK31 and HSPA9 bind MAGEG2 directly but not with each other. Interestingly, MAGEG2 reduced the kinase activity of STK31. Our study suggests that mouse MAGEG2 has at least two functions, including chaperone activity related to HSPA9 and regulation of pachytene spermatocyte-specific kinase, STK31. Altogether, our results provide the first information about MAGEG2 at the transcript and protein levels and suggest its potential molecular functions.
Serum lipid profiles are associated with semen quality
Chin-Yu Liu, Yu-Ching Chou, Shyh-Hsiang Lin, Sheng-Tang Wu, Tai-Lung Cha, Hong-I Chen, Chih-Wei Tsao
We aimed to explore the associations between different lipid profiles and semen quality in a large-scale general male population. Sperm concentration, total sperm motility, progressive motility, and normal sperm morphology of total 7601 participants were recorded. The association of these semen parameters with the triglyceride, total cholesterol, high-density lipoprotein, low-density lipoprotein, and very low-density lipoprotein of serum lipid profiles was analyzed. Sperm concentration was statistically positively correlated with triglyceride and very low-density lipoprotein (adjusted P = 0.001 and P = 0.005, respectively). Total sperm motility and progressive motility were statistically increased with increasing low-density lipoprotein and cholesterol levels (both adjusted P = 0.008 and P < 0.001, respectively). The similar J-shaped associations (high-low-low-high) were noted between individual lipid profile and normal sperm morphology, especially low-density lipoprotein and cholesterol with statistical significance (adjusted P = 0.017 and P = 0.021, respectively). The prevalence of abnormal total sperm motility and progressive motility was decreased in participants with high levels of cholesterol (P = 0.008 and P = 0.019, respectively), and the reverse J-shaped associations (low-high-high-low) were noted between high-density lipoprotein, triglyceride, very low-density lipoprotein, and the prevalence of abnormal normal sperm morphology (P = 0.010, P = 0.037, and P = 0.025, respectively). A high cholesterol level was associated with better sperm motility. Similar J-shaped associations were noted between all lipid profiles and normal sperm morphology; meanwhile, the reverse J-shaped trends were identified between them and abnormal normal sperm morphology prevalence.
Simultaneous expression analysis of deleted in azoospermia-family genes and CDC25A: their potential as a predictor for successful testicular sperm extraction
Candela Rocío González, Cristian Alvarez Sedó, Florencia Nodar, Sergio Papier, Alfredo Daniel Vitullo
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Minimally invasive simple prostatectomy for a case of giant benign prostatic hyperplasia
Qin-Song Zeng, Yong-Bin Zhao, Bang-Qi Wang, Min Ying, Wei-Lie Hu
Association between serotonin transporter 5-HTTLPR and STin2 VNTR polymorphisms and anejaculation: a preliminary report
Yuan-Yuan Huang, Xian-Sheng Zhang, Jing-Jing Gao, Pan Gao, Chao-Zhao Liang
Can the lower urinary tract storage symptoms be completely resolved after plasmakinetic enucleation of the prostate?
Bing-Kun Li, Bin-Shen Chen, Yu-Hong Xin, Chun-Xiao Liu, Shao-Bo Zheng, Ya-Wen Xu, Hu-Lin Li, Yong Zou, Li-Ping Li
The aim of this study was to determine whether the lower urinary tract storage symptoms of benign prostatic obstruction (BPO) could be completely resolved after plasmakinetic enucleation of the prostate (PKEP) and the possible predictors of persistent symptoms. Two hundred and sixty-seven cases of BPO performed PKEP from July 2008 to June 2009 were retrospectively analyzed. Five-year postoperative data were collected and compared with the preoperative data. According to the urodynamic results, the patients were divided into involuntary detrusor contraction (IDC) group (n = 95) and no IDC group (n = 172) preoperatively; the patients with IDC were divided into IDC-persistent group (n = 33) and IDC-resolved group (n = 62) after PKEP. The predictors of persistent IDC were analyzed. Compared with the preoperative data, the 5-year postoperative data showed that the IDC rate was lower (P = 0.000), Overactive Bladder Symptom Score (OABSS) was lower (P = 0.000), maximum cystometric capacity (MCC) was larger (P = 0.000), Prostate volume (PV) was smaller (P = 0.000), and prostate-specific antigen (PSA) was lower (P = 0.000). Compared with the no IDC group, the IDC group showed that the age was older (P = 0.016), MCC was smaller (P = 0.004), PSA was higher (P = 0.016), and Chronic Inflammation rate was higher (P = 0.004). Compared with IDC-resolved group after PKEP, IDC-persistent group showed that the age was older (P = 0.019), MCC was smaller (P = 0.000), PSA was higher (P = 0.013), and Chronic Inflammation rate was higher (P = 0.032). The present study shows that the storage symptoms are still needed to be focused on after PKEP. The advanced patient age, MCC, PSA, and chronic inflammation may be the important clinical predictors of persistent IDC.
Potential therapeutic effect of epigenetic therapy on treatment-induced neuroendocrine prostate cancer
Xiang Xu, Yu-Hua Huang, Yan-Jing Li, Alexa Cohen, Zhen Li, Jill Squires, Wei Zhang, Xu-Feng Chen, Min Zhang, Jiao-Ti Huang
Although adenocarcinomas of the prostate are relatively indolent, some patients with advanced adenocarcinomas show recurrence of treatment-induced neuroendocrine prostate cancer, which is highly aggressive and lethal. Detailed biological features of treatment-induced neuroendocrine prostate cancer have not been characterized owing to limited biopsies/resections and the lack of a cellular model. In this study, we used a unique cellular model (LNCaP/NE1.8) to investigate the potential role of cancer stem cells in treatment-induced neuroendocrine prostate cancer with acquired resistance to hormonal therapy and chemotherapy. We also studied the role of cancer stem cells in enhancing invasion in treatment-induced neuroendocrine prostate cancer cells that recurred after long-term androgen-ablation treatment. Using an in vitro system mimicking clinical androgen-ablation, our results showed that the neuroendocrine-like subclone NE1.8 cells were enriched with cancer stem cells. Compared to parental prostate adenocarcinoma LNCaP cells, NE1.8 cells are more resistant to androgen deprivation therapy and chemotherapeutic agents and show increased cancer cell invasiveness. Results from this study also suggest a potential epigenetic therapeutic strategy using suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, as a chemotherapeutic agent for therapy-resistant treatment-induced neuroendocrine prostate cancer cells to minimize the risk of prostate cancer recurrence and metastasis.
Microsurgical tunica albuginea transplantation in an animal model
Salvatore Sansalone, Carla Loreto, Rosario Leonardi, Giuseppe Vespasiani, Giuseppe Musumeci, Claudia Lombardo, Sergio Castorina, Venera Cardile, Rosario Caltabiano
Several andrological diseases require surgical repair or reconstruction of tunica albuginea, which envelops the corpora cavernosa penis. Despite intense research efforts involving a variety of biological materials, such as skin, muscle aponeurosis, human dura mater, tunica vaginalis, and pericardium, engineered tunica albuginea suitable for graft use is yet to be obtained. The study investigates microsurgical tunica albuginea allotransplantation in an animal model with the purpose of creation of an organ-specific tissue bank to store penile tissue, from cadaveric donors and male-to-female trans-sexual surgery, for allogeneic transplantation. Materials were tunica albuginea tissue explanted from 15 donor rats, cryopreserved at −80°C, gamma-irradiated, and implanted in 15 recipient rats, of which three rats were used as controls. Penile grafts were explanted at different time intervals; after macroscopic evaluation of the organ, the grafts were processed to morphological, histochemical, and immunohistochemical examinations by light microscopy. Detection of pro-inflammatory cytokines was also performed. Examination of the tunica albuginea allografts collected 1, 3, or 6 months after surgery and of control tunica albuginea fragments showed that tunica albuginea implants achieved biointegration with adjacent tissue at all-time points. The integration of cryopreserved rat tunica albuginea allografts, documented by our study, encourages the exploration of tunica albuginea allotransplantation in humans. In conclusion, the effectiveness and reliability of the tunica albuginea conditioning protocol described here suggest the feasibility of setting up a tunica albuginea bank as a further tissue bank.
Risk stratification for disease progression in pT3 prostate cancer after robot-assisted radical prostatectomy
Jeong Hee Hong, Young Suk Kwon, Isaac Yi Kim
The aim of this study is to identify optimal patients for adjuvant radiation therapy (ART) in pT3 prostate cancer. The role of ART for patients with adverse pathologic features after radical prostatectomy (RP) has been demonstrated, but over- or under-treatment remains a significant concern. Two-hundred and five patients with pT3N0M0 who underwent robot-assisted RP without ART were analyzed. Multivariate Cox proportional regression analyses were used to identify predictors of biochemical recurrence (BCR) and clinical progression (CP). The estimated 5-year BCR-free survival (BCRFS) and CP-free survival (CPFS) were 52.8% and 85.6%, respectively. Preoperative prostate-specifc antigen (PSA) ≥10 ng ml−1 (hazard ratio [HR]: 3.288-6.027; P = 0.003), pathologic Gleason score (pGS) ≥8 (HR: 4.146; P = 0.014), and lymphovascular invasion (LVI) (HR: 2.167; P = 0.026) were associated with BCR. Based on these factors, a risk stratification tool was developed. Patients with no risk factors (PSA <10 ng ml−1 , pGS 6, and absent LVI) showed excellent BCRFS and CPFS at 5 years (91.9% and 100.0%, respectively), but those with two or more risk factors (PSA ≥10 ng ml−1 , pGS ≥8, or present LVI) had poor BCRFS and CPFS (12.1% and 54.6%, respectively). In addition, the multivariate analysis revealed that pathologic stage pT3b (HR: 5.393; P = 0.025) was the only predictor of CP. Our study demonstrated the heterogeneity of oncologic outcomes in patients with pT3 prostate cancer. The proposed risk stratification can be used to identify patients who are at risk for disease progression and may aid in identifying the best patients for ART.