Single-nucleotide polymorphisms in HORMAD1 may be a risk factor for azoospermia caused by meiotic arrest in Japanese patients

Genetic mechanisms are implicated as a cause of some male infertility, yet are poorly understood. Meiosis is unique to germ cells and essential for reproduction. The synaptonemal complex is a critical component for chromosome pairing, segregation and recombination. Hormadl is essential for mammalian gametogenesis as knockout male mice are infertile. Hormadl-deficient testes exhibit meiotic arrest in the early pachytene stage and synaptonema! complexes cannot be visualized. To analyze the hypothesis that the human HORMAD1 gene defects are associated with human azoospermia caused by meiotic arrest, mutational analysis was performed in all coding regions by direct sequence analysis of 30 Japanese men diagnosed with azoospermia resulting from meiotic arrest. By the sequence analysis, three polymorphism sites, Single Nucleotide Polymorphism 1 （c. 163A〉G）, SNP2 （c. 501T〉G） and SNP3 （c. 918C〉T）, were found in exons 3, 8 and 10. The 30 patients with azoospermia and 80 normal pregnancy-proven, fertile men were analyzed for HORMAD1 polymorphisms. Both SNP1 and SNP2 were associated with human azoospermia caused by complete early meiotic arrest （P〈0.0S）. We suggest that the HORMAD1 has an essential meiotic function in human spermatogenesis.

Androgen-independent growth in LNCaP cell lines and steroid uridine diphosphate-glucuronosyltransferase expression

<abstract>Aim: To investigate the mechanism of androgen-independent growth of prostate cancer after androgen ablation in LNCaP cells and the effect of glucuronidation activity. Methods: To establish androgen-independent growth in prostate cancer LNCaP-SF, continuous passage was performed in androgen-stripped medium and the cells were evaluated for glucuronidation activity. The expression vector of antisense uridine diphosphate glucuronosyltransferase (UGT) 2B15 cDNA was also constructed and evaluated. Results: LNCaP-SF lead to a higher expression in UGT2B15 and their glucuronidation activity is 2.5 times higher than that of LNCaP cells. Significantly fewer LNCaP and LNCaP-SF than control were transfected with the antisense UGT2B15 cDNA, suggesting that UGT2B15 plays an important part in the glucuronidation activity of androgens in both cells. Conclusion: The alteration of UGT2B15 expression in LNCaP-SF cells is proposed as a biological characteristic involved in the growth of hormonerefractory prostate cancer.

荷尔蒙疗法治疗前列腺癌的疗效及副作用：来自日本的经验和观点

目前，随着对前列腺癌去势抵抗机制的诠释，各种新型抗雄激素及雄激素生物合成抑制剂相继被开发出来了。相信这些新药物会改善激素疗法。另一方面，越来越多的人却对激素疗法提出质疑，如可能诱发心血管疾病等不良反应等。鉴于激素疗法对白种人和亚洲人的疗效及不良反应存在种族差异，本文综述了日本激素疗法治疗前列腺癌的经验。首先，本研究发现基础的激素疗法能长期控制某些局部前列腺癌患者的病情，还发现接受激素疗法的患者生活质量比之前预想的要好。激素疗法作为一种新辅助治疗和辅助治疗方法，对患有高危前列腺癌、局部晚期前列腺癌并接受前列腺根治术及放疗的患者十分有效。激素疗法作为辅助疗法的疗效还有待进一步临床试验证实。本研究还发现，日本心血管疾病死亡人数中，接受过激素疗法的患者并不比普通人群多。不过，即便是在日本，由于患者生活方式的改变可能会增加对激素疗法不良反应的易感性，因此还应努力减少副作用，这对糖尿病等内分泌和代谢性疾病的管理必不可少。预计未来将开发靶向治疗列腺癌的新型激素药物，如选择性激素受体调节剂。

Understanding prostate-specific antigen dynamics in monitoring metastatic castration-resistant prostate cancer： implications for clinical practice

Availability of novel hormonal therapies as well as docetaxel and cabazitaxel treatment for metastatic castration-resistant prostate cancer （CRPC） has changed the outlook for this group of patients with improvements in progression-free survival and overall survival. Physicians often diagnose the progression of prostate cancer using serum prostate-specific antigen （PSA）. However, serum PSA is not always correlated with the clinical status in CRPC. To evaluate the PSA dynamics with greater precision, understanding of the control of PSA and of the mechanisms of development of CRPC is needed. Moreover, it is necessary to use new hormonal therapies with an appropriate timing to optimally improve the prognosis and the QOL of the patients. In the present review, we ascertain the PSA dynamics and the mechanisms of the development of CRPC to assist in optimal utilization of the new treatments for mCRPC.

Effects of long-term androgen replacement therapy on the physical and mental statuses of aging males with late-onset hypogonadism： a multicenter, randomized controlled trial in Japan （EARTH Study）

Androgen replacement therapy （ART） efficacy on late-onset hypogonadism （LOH） has been widely investigated in Western countries; however, it remains controversial whether ART can improve health and prolong active lifestyles. We prospectively assessed long-term ART effects on the physical and mental statuses of aging men with LOH in Japan. The primary endpoint was health-related quality of life assessed by questionnaires. Secondary endpoints included glycemic control, lipid parameters, blood pressure, waist circumference, body composition, muscular strength, International Prostate Symptom Scores （IPSS）, International Index of Erectile Function-5 （IIEF-5） scores, and serum prostate-specific antigen levels. Of the 1637 eligible volunteers, 334 patients 〉 40 years with LOH were randomly assigned to either the ART （n = 169） or control groups （n = 165）. Fifty-two weeks after the initial treatment, ART significantly affected the role physical subdomain of the short form-36 health survey （SF-36） scale （P= 0.0318）. ART was also associated with significant decreases in waist circumstance （P = 0.002） and serum triglyceride （TG） （P = 0.013） and with significant increases in whole-body and leg muscle mass volumes （P= 0.071 and 0.0108, respectively）, serum hemoglobin （P 〈 0.001）, IPSS voiding subscore （P = 0.0418）, and the second question on I IEF-5 （P = 0.0049）. There was no significant difference between the groups in terms of severe adverse events. In conclusion, in patients with LOH, long-term ART exerted beneficial effects on Role Physical subdomain of the SF-36 scale, serum TG, waist circumstance, muscle mass volume, voiding subscore of IPSS, and the second question of IIEF-5. We hope our study will contribute to the future development of this area.