Medicine by Alexandros G. Sfakianakis: Andrology

Enzalutamide: a new indication for nonmetastatic castration-resistant prostate cancer
Logan P Rhea, Brinda Gupta, Jeanny B Aragon-Ching

Asian Journal of Andrology 2019 21(2):107-108

Regulation of anti-Müllerian hormone (AMH) in males and the associations of serum AMH with the disorders of male fertility
Hui-Yu Xu, Hong-Xian Zhang, Zhen Xiao, Jie Qiao, Rong Li

Asian Journal of Andrology 2019 21(2):109-114

Anti-Müllerian hormone (AMH) is a functional marker of fetal Sertoli cells. The germ cell number in adults depends on the number of Sertoli cells produced during perinatal development. Recently, AMH has received increasing attention in research of disorders related to male fertility. This paper reviews and summarizes the articles on the regulation of AMH in males and the serum levels of AMH in male fertility-related disorders. We have determined that follicle-stimulating hormone (FSH) promotes AMH transcription in the absence of androgen signaling. Testosterone inhibits the transcriptional activation of AMH. The undetectable levels of serum AMH and testosterone levels indicate a lack of functional testicular tissue, for example, that in patients with anorchia or severe Klinefelter syndrome suffering from impaired spermatogenesis. The normal serum testosterone level and undetectable AMH are highly suggestive of persistent Müllerian duct syndrome (PMDS), combined with clinical manifestations. The levels of both AMH and testosterone are always subnormal in patients with mixed disorders of sex development (DSD). Mixed DSD is an early-onset complete type of disorder with fetal hypogonadism resulting from the dysfunction of both Leydig and Sertoli cells. Serum AMH levels are varying in patients with male fertility-related disorders, including pubertal delay, severe congenital hypogonadotropic hypogonadism, nonobstructive azoospermia, Klinefelter syndrome, varicocele, McCune-Albright syndrome, and male senescence.

The current status of hormone treatment for prostate cancer patients in Korean real-world practice: a multi-institutional observational study
Jung Kwon Kim, Jung Jun Kim, Taek Won Gang, Tae Kyun Kwon, Hong Sup Kim, Seung Chul Park, Jae-Shin Park, Jong-Yeon Park, Seok Joong Yoon, Youn-Soo Jeon, Jin Seon Cho, Kwan Joong Joo, Sung-Hoo Hong, Seok-Soo Byun, the Korean Urological Oncology Society

Asian Journal of Andrology 2019 21(2):115-120

We aimed to evaluate the current nationwide trend, efficacy, safety, and quality of life (QoL) profiles of hormone treatment in real-world practice settings for prostate cancer (PCa) patients in Korea. A total of 292 men with any biopsy-proven PCa (TanyNanyMany) from 12 institutions in Korea were included in this multi-institutional, observational study of prospectively collected data. All luteinizing hormone-releasing hormone (LHRH) agonists were allowed to be investigational drugs. Efficacy was defined as (1) the rate of castration (serum testosterone ≤50 ng dl−1) at 4-week visit and (2) breakthrough (serum testosterone >50 ng dl−1 after castration). Safety assessments included routine examinations for potential adverse events, laboratory tests, blood pressure, body weight, and bone mineral density (BMD, at baseline and at the last follow-up visit). QoL was assessed using the Expanded Prostate Cancer Index Composite-26 (EPIC-26). The most common initial therapeutic regimen was LHRH agonist with anti-androgen (78.0%), and the most commonly used LHRH agonist for combination and monotherapy was leuprolide (64.0% for combination and 58.0% for monotherapy). The castration and breakthrough rates were 78.4% and 6.6%, respectively. The laboratory results related to dyslipidemia worsened after 4 weeks of hormone treatment. In addition, the mean BMD T-score was significantly lower at the last follow-up (mean: −1.950) compared to baseline (mean: −0.195). The mean total EPIC-26 score decreased from 84.8 (standard deviation [s.d.]: 12.2) to 78.3 (s.d.: 8.1), with significant deterioration only in the urinary domain (mean: 23.5 at baseline and 21.9 at the 4-week visit). These findings demonstrate the nationwide trend of current practice settings in hormone treatment for PCa in Korea.

Proteomic analysis reveals dysregulated cell signaling in ejaculated spermatozoa from infertile men
Luna Samanta, Rakesh Sharma, Zhihong Cui, Ashok Agarwal

Asian Journal of Andrology 2019 21(2):121-130

Dysfunctional sperm maturation is the primary reason for the poor sperm motility and morphology in infertile men. Spermatozoa from infertile men were fractioned on three-layer density gradient (80%, 60%, and 40%). Fraction 1 (F1) refers to the least mature stage having the lowest density, whereas the fraction 4 (F4) includes the most dense and morphologically mature motile spermatozoa. Fraction 2 (F2) and fraction 3 (F3) represent the intermediate stages. Proteins were extracted and separated by 1-dimensional gel. Bands were digested with trypsin and analyzed on a LTQ-Orbitrap Elite hybrid mass spectrometer system. Functional annotations of proteins were obtained using bioinformatics tools and pathway databases. A total of 1585 proteins were detected in the four fractions of spermatozoa. A dysregulated protein turnover and protein folding may lead to accumulation of defective proteins or proteins that otherwise would have been eliminated during the process of maturation, resulting in the impairment of sperm function. Aberrant chaperone expression may be a major contributing factor to the defective sperm function. Androgen receptor was predicted as a transcription regulator in one of the networks and the affected pathways were chaperone-mediated stress response, proteosomal pathway, and sperm function. The downregulation of key pathways and proteins which compromises the fertilizing potential of spermatozoa may provide insight into the mechanisms that lead to male infertility.

Clinical activity of abiraterone plus prednisone in docetaxel-naοve and docetaxel-resistant Chinese patients with metastatic castration-resistant prostate cancer
Guo-Wen Lin, Gao-Xiang Li, Bo Dai, Ding-Wei Ye, Yun-Yi Kong, Yue Wang, Yi-Jun Shen

Asian Journal of Andrology 2019 21(2):131-136

This study investigated the clinical activity of abiraterone plus prednisone in docetaxel-naïve and docetaxel-resistant Chinese patients with metastatic castration-resistant prostate cancer (mCRPC). A total of 146 patients with docetaxel-naïve group (103 cases) and docetaxel-resistant group (43 cases) were enrolled from the Shanghai Cancer Center (Shanghai, China) in this retrospective cohort study. The efficacy endpoints were prostate-specific antigen response rate, prostate-specific antigen progression-free survival, clinical/radiographic progression-free survival, and overall survival in response to abiraterone plus prednisone. Significantly higher prostate-specific antigen response rate was found in docetaxel-naïve group (54.4%, 56/103) compared to docetaxel-resistant group (34.9%, 15/43) (P = 0.047). In addition, significantly higher median prostate-specific antigen progression-free survival (14.0 vs 7.7 months, P = 0.005), clinical or radiographic progression-free survival (17.0 vs 12.5 months, P = 0.003), and overall survival (27.0 vs 18.0 months, P = 0.016) were found in docetaxel-naïve group compared to docetaxel-resistant group, respectively. The univariate and multivariate analyses indicated that lower albumin and visceral metastases were independent significant predictors for shorter overall survival. To sum up, our data suggested that abiraterone plus prednisone was efficient in both docetaxel-naïve and docetaxel-resistant Chinese patients. Moreover, higher PSA response rate and longer overall survival were observed in the docetaxel-naïve group, which suggested that abiraterone was more effective for docetaxel- naïve patients than for docetaxel failures.

Predictive significance of serum inhibin B on testicular haploid gamete retrieval outcomes in nonobstructive azoospermic men
Zhi-Guo Zhu, Zhi-Gang Zhao, Qing-Yang Pang, Tong Chen, Jian-Min Zhang, Tai-Jian Zhang, Chao Xu, Hao-Bo Zhang, Wen Liu, Xu-Jun Xuan

Asian Journal of Andrology 2019 21(2):137-142

The purpose of this study was to determine the diagnostic accuracy of serum inhibin B (INHB) as a predictor of the retrieval outcome of testicular haploid gametes (spermatids and testicular spermatozoa) in nonobstructive azoospermic men. Serum hormone levels, testicular volume, and histological evaluation were performed in 403 Chinese nonobstructive azoospermic men. Testicular haploid gamete was successfully retrieved in 213 of 403 patients (52.85%). The haploid gamete group always had higher INHB levels than the non-haploid gamete group. According to the receiver operating characteristic (ROC) curve analysis, INHB was a good predictor of testicular haploid gamete retrieval outcome in all patients (sensitivity: 77.93% and specificity: 91.58%) and patients with normal follicle-stimulating hormone (FSH; sensitivity: 88.52% and specificity: 70.83%). The area under the ROC curve (AUC) of INHB was similar to that of FSH in all patients or patients with normal FSH. In patients with elevated FSH, INHB was superior to FSH in predicting the presence of haploid gamete (AUC: 0.73 vs 0.55, P < 0.05), with a sensitivity of 60.00% and a specificity of 80.28%. It concluded that serum INHB as an effective marker for spermatogenesis was a significant predictor of testicular haploid gamete retrieval outcomes in nonobstructive azoospermic men. Especially, INHB is superior to FSH in predicting the presence of haploid gamete in the patients with elevated FSH.

Novel noninvasive quantification of penile corpus cavernosum lesions in hyperlipidemia-induced erectile dysfunction in rabbits by two-dimensional shear-wave elastography
Jian-Lin Hu, Hui-Xing Chen, Hui-Rong Chen, Yu Wu, Xiao-Wen Sun, Zheng Li, Jin-Fang Xing

Asian Journal of Andrology 2019 21(2):143-149

Structural alterations in fibroelastic components of the penile corpus cavernousum (CC) may impair its compliance, resulting in venous leakage and erectile dysfunction (ED). Our study evaluated the effectiveness of noninvasive two-dimensional shear-wave elastography (2-D SWE) in quantifying penile CC lesions in rabbits with hyperlipidemia-induced ED. A total of 12 New Zealand white rabbits were randomly divided into two groups. Six were fed a high-cholesterol diet containing 2% cholesterol and 8.5% lard for 10 weeks and the other six were fed normal diet as controls. We measured the shear-wave elastic quantitative (SWQ) value of penile CC by 2-D SWE. Erectile function was investigated by intracavernous injection of papaverine, and immunohistochemical (IHC) staining and the western blot analysis to determine the penile CC lesions. After 10 weeks, the SWQ values obtained from penile CC were remarkably higher in the high-cholesterol-fed compared with the control group, and the ΔICP (ICP plateau minus ICP baseline)/MAP (ICP: intracavernous pressure, MAP: mean arterial pressure) was markedly decreased. The IHC staining and western blot revealed extracellular matrix (ECM) accumulation in penile cavernous tissues, and the smooth muscle cell (SMC) phenotypic transition was affected, as indicated by reduced alpha-smooth muscle actin and calponin-1 expression and increased phospho-myosin light chain20 (p-MLC20)/MLC20 and osteopontin expression. Hyperlipidemia resulted in ECM accumulation accompanied with SMC phenotypic transition in penile CC and impaired the erectile function eventually. These might, in turn, lead to variations in the SWQ values. It suggests that 2-D SWE may be a novel, noninvasive and effective approach that distinguishes penile CC lesions secondary to hyperlipidemia from normal.

Outcomes of men aged ≤50 years treated with radical prostatectomy: a retrospective analysis
Byeongdo Song, Hakmin Lee, Min Seung Lee, Sung Kyu Hong

Asian Journal of Andrology 2019 21(2):150-155

Previous studies investigating prostate cancer (PCa) features in younger men have reported conflicting findings. This study aimed to investigate pathologic outcomes and biochemical recurrence (BCR) status in younger men who underwent radical prostatectomy (RP) for PCa. Records of 2057 patients who underwent RP at Seoul National University Bundang Hospital (Seongnam, Korea) between 2006 and 2015 were reviewed; patients were divided according to age into the younger and older groups (men aged ≤50 and >50 years, respectively). Postoperative BCR status and functional outcomes and clinicopathologic features were compared between both groups. All analyses were repeated after propensity score matching. Younger men were more likely to have low-risk disease (P < 0.001), lower pathologic Gleason score (P < 0.001) and pathologic stages (P < 0.001) than older men. The pathologic Gleason score (P = 0.002) and rates of extracapsular extension (P = 0.004) were lower in younger men after propensity score matching. In multivariate analysis, age at RP was not an independent predictor of BCR-free survival after RP (P = 0.669). Moreover, at 1 year after RP, younger men with preoperative 5-item International Index of Erectile Function score ≥22 (n = 228) showed more favorable results for urinary continence (defined as nonuse of pads daily) (99.4% vs 95%, P = 0.009) and erections sufficient for vaginal intercourse (81.8% vs 55.5%, P = 0.001). Younger men had more favorable clinicopathologic features at RP than their older counterparts. Although age was not an independent predictor of BCR status outcome, younger men had better functional outcomes following RP.

Psychological burden prediction based on demographic variables among infertile men with sexual dysfunction
Hai-Ming Cao, Zi Wan, Yong Gao, Jun-Long Zhang, Yan Zhang, Hai-Peng Xiao, Xiang-An Tu, Xiang-Zhou Sun, Chun-Hua Deng

Asian Journal of Andrology 2019 21(2):156-162

There has been increasing interest in the psycho-socio-relational and sexual disorders of infertility, as the risk of psychological burden among infertile men with sexual dysfunctions is significant. The purpose of this study was to develop and to validate a predictive model to estimate individual psychological burden among infertile men with sexual dysfunction and study the association between them. Comprehensive data were collected for infertile men (n = 480) who sought treatment for infertility in a reproductive medicine center between June 2012 and December 2013. Using independent predictors of psychological burden from the least absolute shrinkage and selection operator, univariable and multivariable analyses were developed into two models. Predictive accuracy was compared between the models. We explored the association between sexual dysfunction and psychological burden. A total of 480 patients were analyzed using 10-fold cross-validation. Independent predictors of psychological burden were incorporated into a model to measure anxiety (corrected-area under curve (AUC): 77.3%) and a model to measure depression (corrected-AUC: 70.2%). Anxiety and depression were both associated with erectile dysfunction (P < 0.05), with anxiety demonstrating the strongest association. Only anxiety was associated with premature ejaculation (P < 0.05). Premature ejaculation was not found to be associated with depression (P > 0.05). Predictive models for psychological burden among infertile men with sexual dysfunction are presented, and we found that there is an association between psychological burden and sexual dysfunction. According to the models, proper counseling and treatment of sexual dysfunction in infertile men may reduce the psychological burden, help attain natural pregnancy, and improve the quality of life.

The preoperative serum cystatin-C as an independent prognostic factor for survival in upper tract urothelial carcinoma
Ping Tan, Ming Shi, Jie Chen, Hang Xu, Nan Xie, Huan Xu, Yong Jiang, Jian-Zhong Ai, Liang-Ren Liu, Lu Yang, Qiang Wei

Asian Journal of Andrology 2019 21(2):163-169

Cystatin-C (Cys-C) has been reported as a valuable prognostic biomarker in various malignancies. However, its effect on upper tract urothelial carcinoma (UTUC) patients has not been investigated before. Thus, to explore the impact of Cys-C on survival outcomes in patients undergoing radical nephroureterectomy (RNU), a total of 538 patients with UTUC who underwent RNU between 2005 and 2014 in our center (West China Hospital, Chengdu, China) were included in this study. Kaplan–Meier method and Cox regression analyses were performed to assess the relationship between Cys-C and survival outcomes using SPSS version 22.0. The cutoff value of Cys-C was set as 1.4 mg l−1 using the receiver operating characteristic (ROC) curves and Youden index. The mean age of patients included was 66.1 ± 11.1 years, and the median follow-up duration was 38 (interquartile range: 19–56) months. Overall, 162 (30.1%) patients had elevated Cys-C, and they were much older and had worse renal function than those with Cys-C <1.4 mg l−1 (both P < 0.001). Meanwhile, Kaplan–Meier analysis revealed that the group with elevated Cys-C had worse cancer-specific survival (CSS, P = 0.001), disease recurrence-free survival (RFS, P = 0.003), and overall survival (OS, P < 0.001). Multivariable Cox analysis suggested that the elevated Cys-C was identified as an independent prognostic predictor of CSS (hazard ratio [HR]: 1.997, 95% confidential interval [CI]: 1.331–2.996), RFS (HR: 1.429, 95% CI: 1.009–2.023), and OS (HR: 1.989, 95% CI: 1.366–2.896). In conclusion, our result revealed that the elevated preoperative serum Cys-C was significantly associated with worse outcomes in UTUC patients undergoing RNU.