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Zhang G, Ye F, Yang Y, Xiong D, Zhi W, Wu Y, Sun Y, Zeng J, Liu W. Identification of a novel mutation in chibby family member 2 in a non-obstructive azoospermic patient. Reprod Biol 2024; 24:100891. [PMID: 38733656 DOI: 10.1016/j.repbio.2024.100891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 04/25/2024] [Accepted: 04/27/2024] [Indexed: 05/13/2024]
Abstract
Azoospermia constitutes a significant factor in male infertility, defined by the absence of spermatozoa in the ejaculate, afflicting 15% of infertile men. However, a subset of azoospermic cases remains unattributed to known genetic variants. Prior investigations have identified the chibby family member 2 (CBY2) as prominently and specifically expressed in the testes of both humans and mice, implicating its potential involvement in spermatogenesis. In this study, we conducted whole exome sequencing (WES) on an infertile family to uncover novel genetic factors contributing to azoospermia. Our analysis revealed a homozygous c .355 C>A variant of CBY2 in a non-obstructive azoospermic patient. This deleterious variant significantly diminished the protein expression of CBY2 both in vivo and in vitro, leading to a pronounced disruption of spermatogenesis at the early round spermatid stage post-meiosis. This disruption was characterized by a nearly complete loss of elongating and elongated spermatids. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) and co-immunoprecipitation assays demonstrated the interaction between CBY2 and Piwi-like protein 1 (PIWIL1). Immunofluorescence staining further confirmed the co-localization of CBY2 and PIWIL1 in the testes during the spermatogenic process in both humans and mice. Additionally, diminished PIWIL1 expression was observed in the testicular tissue from the affected patient. Our findings suggest that the homozygous c .355 C>A variant of CBY2 compromises CBY2 function, contributing to defective spermatogenesis at the round spermiogenic stage and implicating its role in the pathogenesis of azoospermia.
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Affiliation(s)
- Guohui Zhang
- Key Laboratory of Reproductive Medicine, Sichuan Provincial Maternity and Child Health Care Hospital, Chengdu 610045, China; Reproductive Medicine Center, Sichuan Provincial Maternity and Child Health Care Hospital, Chengdu 610045, China
| | - Fei Ye
- Reproductive Medicine Center, Sichuan Provincial Maternity and Child Health Care Hospital, Chengdu 610045, China
| | - Yihong Yang
- Reproduction Medical Center of West China Second University Hospital, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu 610041, China
| | - Dongsheng Xiong
- Reproductive Medicine Center, Sichuan Provincial Maternity and Child Health Care Hospital, Chengdu 610045, China
| | - Weiwei Zhi
- Reproductive Medicine Center, Sichuan Provincial Maternity and Child Health Care Hospital, Chengdu 610045, China
| | - Yang Wu
- Reproductive Medicine Center, Sichuan Provincial Maternity and Child Health Care Hospital, Chengdu 610045, China
| | - Yongkang Sun
- Department of Obstetrics/Gynecology, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Jiuzhi Zeng
- Reproductive Medicine Center, Sichuan Provincial Maternity and Child Health Care Hospital, Chengdu 610045, China.
| | - Weixin Liu
- Key Laboratory of Reproductive Medicine, Sichuan Provincial Maternity and Child Health Care Hospital, Chengdu 610045, China.
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Zhang G, Xiong D, Ye F, Zhao Y, Du X, Zhi W, Liu F, Zeng J, Xu W, Liu W, Shi Y. A Key regulatory protein QRICH2 governing sperm function with profound antioxidant properties, enhancing sperm viability. Reprod Biol 2024; 24:100881. [PMID: 38772286 DOI: 10.1016/j.repbio.2024.100881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 03/25/2024] [Accepted: 04/01/2024] [Indexed: 05/23/2024]
Abstract
Infertility poses a global health and social challenge, affecting approximately 15% of couples at childbearing age, with half of the cases attributed to male factors, wherein genetic factors exert a substantial role. In our prior investigation, we identified loss-of-function variants within the gene encoding glutamine-rich protein 2 (QRICH2) in two consanguineous families, leading to various morphological abnormalities in sperm flagella and male infertility. Moreover, our observations in Qrich2 knockout mice revealed a pronounced reduction in spermatozoa count. However, the underlying mechanism remains elusive, prompting further investigation in the current study. By conducting experiments such as Hematoxylin-eosin (HE) staining, immunofluorescence staining, flow cytometry, and single sperm metabolism analysis on the testes and spermatozoa of Qrich2 knockout mice, we found a strong antioxidant capacity mediated by QRICH2 both in vivo and in vitro. Qrich2 knockout led to elevated levels of ROS, consequently inducing DNA damage in spermatids, which in turn triggered increased autophagy and apoptosis, ultimately causing a significant decrease in spermatozoa count. Incubation with the N-terminal purified protein of QRICH2 exhibited potent strong antioxidant activity at the cell and spermatozoa levels in vitro, thereby enhancing spermatozoa viability and motility. Therefore, QRICH2 plays a crucial role in safeguarding spermatids from excessive ROS-induced damage by augmenting antioxidant capacity, thereby promoting spermatozoa survival and improving motility. Furthermore, the N-terminal purified protein of QRICH2 shows promise as an additive for protecting spermatozoa during preservation and cryopreservation.
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Affiliation(s)
- Guohui Zhang
- Sichuan Provincial Key Laboratory for Human Disease Gene Study and the Center for Medical Genetics, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology, Chengdu 610072, China; Key Laboratory of Reproductive Medicine, Center of Reproductive Medicine, Sichuan Provincial Maternity and Child Health Care Hospital, Chengdu 610045, China
| | - Dongsheng Xiong
- Key Laboratory of Reproductive Medicine, Center of Reproductive Medicine, Sichuan Provincial Maternity and Child Health Care Hospital, Chengdu 610045, China
| | - Fei Ye
- Key Laboratory of Reproductive Medicine, Center of Reproductive Medicine, Sichuan Provincial Maternity and Child Health Care Hospital, Chengdu 610045, China
| | - Yuhong Zhao
- School of Laboratory Medicine, Chengdu Medical College, Chengdu 610500, China
| | - Xinrong Du
- Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Weiwei Zhi
- Key Laboratory of Reproductive Medicine, Center of Reproductive Medicine, Sichuan Provincial Maternity and Child Health Care Hospital, Chengdu 610045, China
| | - Fulin Liu
- Sichuan Provincial Key Laboratory for Human Disease Gene Study and the Center for Medical Genetics, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology, Chengdu 610072, China; Research Unit for Blindness Prevention, Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu 610072, China
| | - Jiuzhi Zeng
- Key Laboratory of Reproductive Medicine, Center of Reproductive Medicine, Sichuan Provincial Maternity and Child Health Care Hospital, Chengdu 610045, China
| | - Wenming Xu
- Department of Obstetrics and Gynecology, Joint Laboratory of Reproductive Medicine (SCU-CUHK), Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, China.
| | - Weixin Liu
- Key Laboratory of Reproductive Medicine, Center of Reproductive Medicine, Sichuan Provincial Maternity and Child Health Care Hospital, Chengdu 610045, China.
| | - Yi Shi
- Sichuan Provincial Key Laboratory for Human Disease Gene Study and the Center for Medical Genetics, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology, Chengdu 610072, China; Research Unit for Blindness Prevention, Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu 610072, China.
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Svanholm S, Brouard V, Roza M, Marini D, Karlsson O, Berg C. Impaired spermatogenesis and associated endocrine effects of azole fungicides in peripubertal Xenopus tropicalis. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 270:115876. [PMID: 38154155 DOI: 10.1016/j.ecoenv.2023.115876] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 12/11/2023] [Accepted: 12/19/2023] [Indexed: 12/30/2023]
Abstract
Early life exposure to endocrine disrupting chemicals (EDCs) has been suggested to adversely affect reproductive health in humans and wildlife. Here, we characterize endocrine and adverse effects on the reproductive system after juvenile exposure to propiconazole (PROP) or imazalil (IMZ), two common azole fungicides with complex endocrine modes of action. Using the frog Xenopus tropicalis, two short-term (2-weeks) studies were conducted. I: Juveniles (2 weeks post metamorphosis (PM)) were exposed to 0, 17 or 178 µg PROP/L. II: Juveniles (6 weeks PM) were exposed to 0, 1, 12 or 154 µg IMZ/L. Histological analysis of the gonads revealed an increase in the number of dark spermatogonial stem cells (SSCs)/testis area, and in the ratio secondary spermatogonia: dark SSCs were increased in all IMZ groups compared to control. Key genes in gametogenesis, retinoic acid and sex steroid pathways were also analysed in the gonads. Testicular levels of 3β-hsd, ddx4 were increased and cyp19 and id4 levels were decreased in the IMZ groups. In PROP exposed males, increased testicular aldh1a2 levels were detected, but no histological effects observed. Although no effects on ovarian histology were detected, ovarian levels of esr1, rsbn1 were increased in PROP groups, and esr1 levels were decreased in IMZ groups. In conclusion, juvenile azole exposure disrupted testicular expression of key genes in retinoic acid (PROP) and sex steroid pathways and in gametogenesis (IMZ). Our results further show that exposure to environmental concentrations of IMZ disrupted spermatogenesis in the juvenile testis, which is a cause for concern as it may lead to impaired fertility. Testicular levels of id4, ddx4 and the id4:ddx4 ratio were associated with the number of dark SSCs and secondary spermatogonia suggesting that they may serve as a molecular markers for disrupted spermatogenesis.
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Affiliation(s)
- Sofie Svanholm
- Department of Environmental Toxicology, Uppsala University, SE-754 36 Uppsala, Sweden.
| | - Vanessa Brouard
- Department of Environmental Toxicology, Uppsala University, SE-754 36 Uppsala, Sweden
| | - Mauricio Roza
- Science for Life Laboratory, Department of Environmental Science, Stockholm University, Stockholm 114 18, Sweden
| | - Daniele Marini
- Department of Environmental Toxicology, Uppsala University, SE-754 36 Uppsala, Sweden; Department of Veterinary Medicine, University of Perugia, 06126 Perugia, Italy
| | - Oskar Karlsson
- Science for Life Laboratory, Department of Environmental Science, Stockholm University, Stockholm 114 18, Sweden
| | - Cecilia Berg
- Department of Environmental Toxicology, Uppsala University, SE-754 36 Uppsala, Sweden
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Leng X, Xie S, Tao D, Wang Z, Shi J, Yi M, Tan X, Zhang X, Liu Y, Yang Y. Mouse Tspyl5 promotes spermatogonia proliferation through enhancing Pcna-mediated DNA replication. Reprod Fertil Dev 2024; 36:RD23042. [PMID: 38185096 DOI: 10.1071/rd23042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 12/07/2023] [Indexed: 01/09/2024] Open
Abstract
CONTEXT The human TSPY1 (testis-specific protein, Y-linked 1) gene is critical for spermatogenesis and male fertility. However, there have been difficulties with studying the mechanism underlying its function, partly due to the presence of the Tspy1 pseudogene in mice. AIMS TSPYL5 (TSPY-like 5), an autosomal homologous gene of TSPY1 showing a similar expression pattern in both human and mouse testes, is also speculated to play a role in male spermatogenesis. It is beneficial to understand the role of TSPY1 in spermatogenesis by investigating Tspyl5 functions. METHODS Tspyl5 -knockout mice were generated to investigate the effect of TSPYL5 knockout on spermatogenesis. KEY RESULTS Tspyl5 deficiency caused a decline in fertility and decreased the numbers of spermatogonia and spermatozoa in aged male mice. Trancriptomic detection of spermatogonia derived from aged Tspyl5 -knockout mice revealed that the Pcna -mediated DNA replication pathway was downregulated. Furthermore, Tspyl5 was proven to facilitate spermatogonia proliferation and upregulate Pcna expression by promoting the ubiquitination-degradation of the TRP53 protein. CONCLUSIONS Our findings suggest that Tspyl5 is a positive regulator for the maintenance of the spermatogonia pool by enhancing Pcna -mediated DNA replication. IMPLICATIONS This observation provides an important clue for further investigation of the spermatogenesis-related function of TSPY1 .
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Affiliation(s)
- Xiangyou Leng
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Shengyu Xie
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Dachang Tao
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Zhaokun Wang
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Jiaying Shi
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Ming Yi
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Xiaolan Tan
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Xinyue Zhang
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Yunqiang Liu
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Yuan Yang
- Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
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Kuntsal E, Kadıoğlu A, Şirvancı S. Testicular Apoptosis and Proliferation in Relation to Body Mass Index and m-TESE Success in Nonobstructive Azoospermic Men. Andrologia 2023; 2023:1-10. [DOI: 10.1155/2023/4720387] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2025] Open
Abstract
Male infertility occurs due to the disruption of the balance of proliferation and apoptosis in the testicular tissue. It is important to show the effect of increased body mass index, which is one of the factors that disrupts this balance of apoptosis and proliferation, not only at the blood hormone level but also at the tissue level. For this reason, the present study is aimed at demonstrating the relation between body mass index and cell turnover in the testis using immunohistochemical methods. In the present study, patients were grouped as normal, overweight and obese, and as m-TESE positive and negative. The sperm retrieval rate with microsurgical testicular sperm extraction (m-TESE) was 41.67%. Histological diagnosis of testicular tissues was made with hematoxylin and eosin and Masson’s trichrome staining. Apoptosis and proliferation in the testicular tissue were demonstrated by TUNEL and PCNA immunohistochemical methods, respectively. It was concluded that BMI had no significant effect on reproductive hormone profile (FSH, LH, and testosterone), m-TESE success, apoptosis, and proliferation in testicular tissue in nonobstructive azoospermic men. In addition TUNEL positivity and proliferative index was found to be significantly correlated with testicular histology and m-TESE outcome.
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Affiliation(s)
- Ekin Kuntsal
- Department of Histology and Embryology, School of Medicine, Marmara University, Istanbul, Turkey
| | - Ateş Kadıoğlu
- Department of Urology, School of Medicine, Istanbul University, Istanbul, Turkey
| | - Serap Şirvancı
- Department of Histology and Embryology, School of Medicine, Marmara University, Istanbul, Turkey
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Haimbaugh A, Akemann C, Meyer D, Gurdziel K, Baker TR. Insight into 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced disruption of zebrafish spermatogenesis via single cell RNA-seq. PNAS NEXUS 2022; 1:pgac060. [PMID: 35799832 PMCID: PMC9252172 DOI: 10.1093/pnasnexus/pgac060] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 06/17/2022] [Indexed: 02/05/2023]
Abstract
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent and environmentally persistent endocrine disrupting chemical. Our previous work demonstrated the latent reproductive maladies of early-life TCDD exposure in zebrafish. Zebrafish acutely exposed to low, environmentally relevant levels of TCDD (50 pg/mL) during two windows of sexual differentiation in development (1 hour of exposure at 3 and 7 weeks postfertilization) were later infertile, showed a reduction in sperm, and exhibited gene expression consistent with an altered microenvironment, even months after exposure. Due to the highly heterogeneous cell- type and -stage landscape of the testes, we hypothesized various cell types contribute markedly different profiles toward the pathology of TCDD exposure. To investigate the contributions of the diverse cell types in the adult zebrafish testes to TCDD-induced pathology, we utilized single-cell RNA-seq and the 10x Genomics platform. The method successfully captured every stage of testicular germ cell development. Testes of adult fish exposed during sexual differentiation to TCDD contained sharply decreased populations of late spermatocytes, spermatids, and spermatozoa. Spermatogonia and early spermatocyte populations were, in contrast, enriched following exposure. Pathway analysis of differentially expressed genes supported previous findings that TCDD exposure resulted in male infertility, and suggested this outcome is due to apoptosis of spermatids and spermatozoa, even years after exposure cessation. Increased germ cell apoptosis was confirmed histologically. These results provide support for an environmental exposure explanation of idiopathic male infertility.
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Affiliation(s)
- Alex Haimbaugh
- Department of Pharmacology, School of Medicine, Wayne State University, Detroit, MI 48207, USA
| | - Camille Akemann
- Department of Pharmacology, School of Medicine, Wayne State University, Detroit, MI 48207, USA
| | - Danielle Meyer
- Department of Pharmacology, School of Medicine, Wayne State University, Detroit, MI 48207, USA
| | - Katherine Gurdziel
- Applied Genome Technology Center, School of Medicine, Wayne State University, Detroit, MI 48207, USA
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Hu JY, Huang WL, Gao Y, Yang Z, Ding L, Xie Y, Xie XY, Hu HT, Wang Z. Preliminary investigation of the diagnostic value of shear wave elastography in evaluating the testicular spermatogenic function in patients with azoospermia. Andrologia 2021; 53:e14039. [PMID: 33682169 DOI: 10.1111/and.14039] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Revised: 01/30/2021] [Accepted: 02/17/2021] [Indexed: 12/15/2022] Open
Abstract
To assess the diagnostic value of shear wave elastography (SWE) for evaluating the histological spermatogenic function of azoospermic males, 91 patients with azoospermia who underwent standardised greyscale ultrasound and SWE examinations followed by testicular biopsy were retrospectively recruited. Spermatogenic function was classified by biopsy as normal testicular spermatogenesis (n = 61), hypospermatogenesis (n = 18), spermatogenesis arrest (n = 6) and Sertoli cell-only syndrome (n = 6). Significant differences in testicular size and SWE values were observed between these 4 groups (p < .01). The mean SWE value had good discrimination power (AUC = 0.79) with a cut-off value of 1.55 KPa, a sensitivity of 0.58, specificity of 0.85, positive predictive value (PPV) of 0.36 and negative predictive value (NPV) of 0.93. Testicular volume had an AUC of 0.75. With a cut-off value of 8.41 ml, the testicular volume had a sensitivity of 0.58, specificity of 0.92, PPV of 0.54 and NPV of 0.93. The mean SWE value and testicular volume efficiently discriminated patients with normal spermatogenesis and hypospermatogenesis from patients with Sertoli cell-only syndrome and spermatogenesis arrest.
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Affiliation(s)
- Jia-Ying Hu
- Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Wan-Ling Huang
- Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yong Gao
- Reproductive Medicine Centre, The Key Laboratory for Reproductive Medicine of Guangdong Province, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zheng Yang
- Department of Pathology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Li Ding
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yun Xie
- Department of Andrology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiao-Yan Xie
- Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Hang-Tong Hu
- Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zhu Wang
- Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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Caroppo E, Colpi GM. Hormonal Treatment of Men with Nonobstructive Azoospermia: What Does the Evidence Suggest? J Clin Med 2021; 10:jcm10030387. [PMID: 33498414 PMCID: PMC7864204 DOI: 10.3390/jcm10030387] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 12/26/2020] [Accepted: 01/18/2021] [Indexed: 12/25/2022] Open
Abstract
Hormonal stimulation of spermatogenesis prior to surgery has been tested by some authors to maximize the sperm retrieval yield in patients with nonobstructive azoospermia. Although the rationale of such an approach is theoretically sound, studies have provided conflicting results, and there are unmet questions that need to be addressed. In the present narrative review, we reviewed the current knowledge about the hormonal control of spermatogenesis, the relationship between presurgical serum hormones levels and sperm retrieval rates, and the results of studies investigating the effect of hormonal treatments prior to microdissection testicular sperm extraction. We pooled the available data about sperm retrieval rate in patients with low vs. normal testosterone levels, and found that patients with normal testosterone levels had a significantly higher chance of successful sperm retrieval compared to those with subnormal T levels (OR 1.63, 95% CI 1.08–2.45, p = 0.02). These data suggest that hormonal treatment may be justified in patients with hypogonadism; on the other hand, the available evidence is insufficient to recommend hormonal therapy as standard clinical practice to improve the sperm retrieval rate in patients with nonobstructive azoospermia.
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Affiliation(s)
- Ettore Caroppo
- Asl Bari, PTA “F Jaia”, Andrology Outpatients Clinic, 70014 Conversano (BA), Italy
- Correspondence:
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Tatour Y, Bar-Joseph H, Shalgi R, Ben-Yosef T. Male sterility and reduced female fertility in SCAPER-deficient mice. Hum Mol Genet 2020; 29:2240-2249. [PMID: 32510560 DOI: 10.1093/hmg/ddaa113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 05/31/2020] [Accepted: 06/01/2020] [Indexed: 11/12/2022] Open
Abstract
Mutations in S-phase cyclin A-associated protein in the endoplasmic reticulum (SCAPER) cause a recessively inherited multisystemic disorder whose main features are retinal degeneration and intellectual disability. SCAPER, originally identified as a cell cycle regulator, was also suggested to be a ciliary protein. Because Scaper mutant males are sterile, we set up to characterize their phenotype. The testes of Scaper mutant mice are significantly smaller than those of WT mice. Histology revealed no signs of spermatogenesis, and seminiferous tubules contained mainly Sertoli cells with a few spermatogonia/spermatogonial stem cells (SSCs). In WT testes, SCAPER is expressed by SSCs and in the various stages of spermatogenesis, as well as in Sertoli cells. In WT spermatozoa SCAPER is not expressed in the flagellum but rather in the head compartment, where it is found both in the nucleus and in the perinuclear region. Scaper mutant females present reduced fertility, manifested by a significantly smaller litter size compared to WT females. Mutant ovaries are similar in size but comprised of significantly less primordial and antral follicles, compared to WT ovaries, while the number of atretic follicles is significantly higher. In WT ovarian follicles SCAPER is expressed in the somatic granulosa cells as well as in the oocyte. In conclusion, our data demonstrate that SCAPER is a crucial component in both male and female reproductive systems. We hypothesize that the reproductive phenotype observed in Scaper mutant mice is rooted in SCAPER's interaction with cyclin A/Cdk2, which play an important role, however different, in male and female gonads.
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Affiliation(s)
- Yasmin Tatour
- Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel
| | - Hadas Bar-Joseph
- The TMCR unit, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Ruth Shalgi
- Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Tamar Ben-Yosef
- Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel
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Sun J, Niu L, Gao S, Yi X, Chen J. miR-509-5p Downregulation Is Associated With Male Infertility And Acts As A Suppressor In Testicular Germ Cell Tumor Cells Through Targeting MDM2. Onco Targets Ther 2019; 12:10515-10522. [PMID: 31819532 PMCID: PMC6897070 DOI: 10.2147/ott.s215998] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 09/13/2019] [Indexed: 11/23/2022] Open
Abstract
Background The dysregulation of microRNAs (miRNAs) has been linked with male infertility. miR-509-5p is highly expressed in testis and exerts suppressive effects on multiple types of human cancers. Objectives Yet, whether miR-509-5p is connected with male infertility and plays a role in testicular germ cell tumor (TGCT) have not been explored. Materials and methods This study detected miR-509-5p expression in germ cells from MA patients, and further characterize its functional roles in the proliferation and apoptosis of TGCT cells in vitro. Results We report that miR-509-5p is downregulated in germ cells from infertile men with maturation arrest (MA), which implies an inverse association between miR-509-5p level and male infertility. In addition, miR-509-5p suppresses proliferation and induces apoptosis of TGCT cells in vitro, suggesting that it exhibits tumor-suppressive effects on TGCT. Mechanistically, miR-509-5p targets the mouse double minute 2 (MDM2), an oncogenic factor in TGCT, and moreover, restored expression of MDM2 rescues miR-509-5p suppressive effects on TGCT cells, demonstrating that miR-509-5p suppresses TGCT cells through targeting MDM2. Conclusion Collectively, these results implicate that miR-509-5p may participate in the pathogenesis of male infertility and TGCT through regulating proliferation and apoptosis, two critical cellular activities for spermatogenesis and TGCT tumorigenesis.
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Affiliation(s)
- Jinxia Sun
- Department of Reproductive Medicine, Linyi Central Hospital, Linyi City, Shandong Province 276400, People's Republic of China
| | - Lei Niu
- Department of Respiratory Medicine, Linyi Central Hospital, Linyi City, Shandong Province 276400, People's Republic of China
| | - Shanxia Gao
- Department of Reproductive Medicine, Linyi Central Hospital, Linyi City, Shandong Province 276400, People's Republic of China
| | - Xijuan Yi
- Department of Reproductive Medicine, Linyi Central Hospital, Linyi City, Shandong Province 276400, People's Republic of China
| | - Jianxia Chen
- Department of Reproductive Medicine, Linyi Central Hospital, Linyi City, Shandong Province 276400, People's Republic of China
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11
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Ferreiro ME, Amarilla MS, Glienke L, Méndez CS, González C, Jacobo PV, Sobarzo CM, De Laurentiis A, Ferraris MJ, Theas MS. The inflammatory mediators TNFα and nitric oxide arrest spermatogonia GC-1 cell cycle. Reprod Biol 2019; 19:329-339. [PMID: 31757605 DOI: 10.1016/j.repbio.2019.11.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 10/08/2019] [Accepted: 11/02/2019] [Indexed: 01/01/2023]
Abstract
During an inflammatory process of the testis, the network of somatic, immune, and germ cell interactions is altered leading to organ dysfunction. In testicular biopsies of infertile men, spermatogenesis impairment is associated with reduced spermatogonia proliferation, increased number of immune cells, and content of pro-inflammatory cytokines. TNFα-TNFR and nitric oxide (NO)-NO synthase systems are up-regulated in models of testicular damage and in human testis with maturation arrest. The purpose of this study was to test the hypothesis that TNFα-TNFR system and NO alter the function of spermatogonia in the inflamed testis. We studied the effect of TNFα and NO on GC-1 spermatogonia cell cycle progression and death by flow cytometry. GC-1 cells expressed TNFR1 and TNFR2 (immunofluorescence). TNFα (10 and 50 ng/ml) and DETA-Nonoate (0.5 and 2 mM), a NO releaser, increased the percentage of cells in S-phase of the cell cycle and reduced the percentage in G1, inducing also cell apoptosis. TNFα effect was not mediated by oxidative stress unlike NO, since the presence of N-acetyl-l-cysteine (2.5 and 5.0 mM) prevented NO induced cell cycle arrest and death. GC-1 spermatogonia overpass NO induced cell cycle arrest but no TNFα, since after removal of NO, spermatogonia progressed through the cell cycle. We propose TNFα and NO might contribute to impairment of spermatogenesis by preventing adequate functioning of the spermatogonia population. Our results showed that TNFα and NO impaired spermatogonia cell cycle, inducing GC-1 arrest in the S phase.
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Affiliation(s)
- María Eugenia Ferreiro
- Universidad de Buenos Aires, Facultad de Medicina, Departamento de Biología Celular, Cátedra II de Histología, Buenos Aires, Argentina, CONICET-Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina
| | - María Sofía Amarilla
- Universidad de Buenos Aires, Facultad de Medicina, Departamento de Biología Celular, Cátedra II de Histología, Buenos Aires, Argentina, CONICET-Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina
| | - Leilane Glienke
- Universidad de Buenos Aires, Facultad de Medicina, Departamento de Biología Celular, Cátedra II de Histología, Buenos Aires, Argentina, CONICET-Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina
| | - Cinthia Soledad Méndez
- Universidad de Buenos Aires, Facultad de Medicina, Departamento de Biología Celular, Cátedra II de Histología, Buenos Aires, Argentina, CONICET-Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina
| | - Candela González
- Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y Diagnósticos (CEBBAD), Universidad Maimónides, Buenos Aires, Argentina
| | - Patricia Verónica Jacobo
- Universidad de Buenos Aires, Facultad de Medicina, Departamento de Biología Celular, Cátedra II de Histología, Buenos Aires, Argentina, CONICET-Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina
| | - Cristian Marcelo Sobarzo
- Universidad de Buenos Aires, Facultad de Medicina, Departamento de Biología Celular, Cátedra II de Histología, Buenos Aires, Argentina, CONICET-Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina
| | - Andrea De Laurentiis
- Centro de Estudios Farmacológicos y Botánicos (CEFYBO) CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina
| | - María Jimena Ferraris
- Universidad de Buenos Aires, Facultad de Medicina, Departamento de Biología Celular, Cátedra II de Histología, Buenos Aires, Argentina, CONICET-Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina
| | - María Susana Theas
- Universidad de Buenos Aires, Facultad de Medicina, Departamento de Biología Celular, Cátedra II de Histología, Buenos Aires, Argentina, CONICET-Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina.
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12
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Khawar MB, Mehmood R, Roohi N. MicroRNAs: Recent insights towards their role in male infertility and reproductive cancers. Bosn J Basic Med Sci 2019; 19:31-42. [PMID: 30599090 DOI: 10.17305/bjbms.2018.3477] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 05/20/2018] [Indexed: 12/13/2022] Open
Abstract
Spermatogenesis is a tightly controlled, multi-step process in which mature spermatozoa are produced. Disruption of regulatory mechanisms in spermatogenesis can lead to male infertility, various diseases of male reproductive system, or even cancer. The spermatogenic impairment in infertile men can be associated with different etiologies, and the exact molecular mechanisms are yet to be determined. MicroRNAs (miRNAs) are a type of non-protein coding RNAs, about 22 nucleotides long, with an essential role in post-transcriptional regulation. miRNAs have been recognized as important regulators of various biological processes, including spermatogenesis. The aim of this review is to summarize the recent literature on the role of miRNAs in spermatogenesis, male infertility and reproductive cancers, and to evaluate their potential in diagnosis, prognosis and therapy of disease. Experimental evidence shows that aberrant expression of miRNAs affects spermatogenesis at multiple stages and in different cell types, most often resulting in infertility. In more severe cases, dysregulation of miRNAs leads to cancer. miRNAs have enormous potential to be used as diagnostic and prognostic markers as well as therapeutic targets in male infertility and reproductive system diseases. However, to exploit this potential fully, we need a better understanding of miRNA-mediated regulation of spermatogenesis, including the characterization of yet unidentified miRNAs and related regulatory mechanisms.
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Affiliation(s)
- Muhammad Babar Khawar
- Molecular Physiology/Endocrinology Laboratory, Department of Zoology, University of the Punjab, Lahore, Pakistan State Key Laboratory of Stem Cells and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China University of Chinese Academy of Sciences, Beijing, China.
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13
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Spermatogenesis Abnormalities following Hormonal Therapy in Transwomen. BIOMED RESEARCH INTERNATIONAL 2018; 2018:7919481. [PMID: 29808166 PMCID: PMC5902106 DOI: 10.1155/2018/7919481] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Revised: 01/03/2018] [Accepted: 03/01/2018] [Indexed: 11/17/2022]
Abstract
Objective To measure spermatogenesis abnormalities in transwomen at the time of sex reassignment surgery (SRS) and to analyze the association between hormonal therapy duration and infertility severity. Design Retrospective study. Setting University hospital. Patients One-hundred seventy-three transwomen who underwent SRS from January 2000 to December 2015. Interventions All orchidectomy specimens were retrospectively reviewed and classified. History of hormonal therapy duration was retrieved from medical records. Main Outcome Measures Histological examinations of orchidectomy specimens were performed to assess spermatogenesis. Results One-hundred seventy-three orchidectomy specimens were evaluated. Histological examinations showed maturation arrest in 36.4%, hypospermatogenesis in 26%, Sertoli cell-only syndrome in 20.2%, normal spermatogenesis in 11%, and seminiferous tubule hyalinization in 6.4% of the specimens. Spermatogenesis abnormality severity was not associated with the total therapy duration (P = 0.81) or patient age at the time of surgery (P = 0.88). Testicular volumes and sizes were associated with spermatogenesis abnormality severity (P = 0.001 and P = 0.026, right testicle and left testicle, resp.). Conclusions Feminizing hormonal treatment leads to reductions in testicular germ cell levels. All transwomen should be warned about this consequence, and gamete preservation should be offered before starting hormonal treatment.
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14
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Abdel-Hamid AAM, Atef H, Zalata KR, Abdel-Latif A. Correlation between testicular mast cell count and spermatogenic epithelium in non-obstructive azoospermia. Int J Exp Pathol 2018; 99:22-28. [PMID: 29479754 DOI: 10.1111/iep.12261] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Accepted: 12/11/2017] [Indexed: 12/20/2022] Open
Abstract
Although there is emerging evidence that mast cells are involved in infertility, their exact role has not been elucidated clearly. Here we carried out a retrospective case-control study to find out whether there is a correlation between mast cell (MC) count and proliferation (Ki67 index) of the spermatogenic epithelium as well as of the Sertoli cells (vimentin-positive) in non-obstructive azoospermia (NOA). We assessed MCs, Ki67 and vimentin expression in Sertoli cells in testicular biopsies of germ cell aplasia (GCA, n = 14) and maturation arrest (MA, n = 14) vs. normal spermatogenesis (n = 14) cases. There was a significant decrease in the spermatogonial Ki67 index (1.25 ± 0.91, 4.21 ± 1.81 vs. 39.57 ± 3.92) and Johnsen score (2.48 ± 0.65, 4.89 ± 1.05 vs. 9.75 ± 0.30) as well as a significant increase (P < 0.001) in MC count (29.00 ± 4.11, 7.57 ± 1.95 vs. 3.00 ± 1.30) in seminiferous tubules of infertile cases with GCA and MA vs. controls. On the other hand, the percentage of vimentin-expressing Sertoli cells was significantly decreased (P < 0.001) in biopsies of cases with MA (35.50 ± 15.62) compared to those of cases with GCA and controls (72.64 ± 10.67 and 98.57 ± 1.45 respectively). Additionally, a significant negative correlation was detected between MC count and Ki67 index as well as Johnsen score in the MA group which became more significant in the GCA group. The significant increase in MC count in the GCA group and to a lesser extent in the MA group indicates their possible role in NOA particularly at the spermatogonial proliferation level and this is supported by the significant negative correlation with the Ki67 index.
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Affiliation(s)
- Ahmed A M Abdel-Hamid
- Department of Histology and Cell Biology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Hoda Atef
- Department of Histology and Cell Biology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Khaled R Zalata
- Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Atef Abdel-Latif
- Department of General Surgery, Mansoura University Hospitals, Faculty of Medicine, Mansoura University, Mansoura, Egypt
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15
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Stukenborg JB, Jahnukainen K, Hutka M, Mitchell RT. Cancer treatment in childhood and testicular function: the importance of the somatic environment. Endocr Connect 2018; 7:R69-R87. [PMID: 29351905 PMCID: PMC5817964 DOI: 10.1530/ec-17-0382] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Accepted: 01/19/2018] [Indexed: 02/06/2023]
Abstract
Testicular function and future fertility may be affected by cancer treatment during childhood. Whilst survival of the germ (stem) cells is critical for ensuring the potential for fertility in these patients, the somatic cell populations also play a crucial role in providing a suitable environment to support germ cell maintenance and subsequent development. Regulation of the spermatogonial germ-stem cell niche involves many signalling pathways with hormonal influence from the hypothalamo-pituitary-gonadal axis. In this review, we describe the somatic cell populations that comprise the testicular germ-stem cell niche in humans and how they may be affected by cancer treatment during childhood. We also discuss the experimental models that may be utilized to manipulate the somatic environment and report the results of studies that investigate the potential role of somatic cells in the protection of the germ cells in the testis from cancer treatment.
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Affiliation(s)
- Jan-Bernd Stukenborg
- NORDFERTIL Research Lab StockholmPediatric Endocrinology Unit, Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm, Sweden
| | - Kirsi Jahnukainen
- NORDFERTIL Research Lab StockholmPediatric Endocrinology Unit, Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm, Sweden
- Division of Haematology-Oncology and Stem Cell TransplantationChildren's Hospital, University of Helsinki, Helsinki University Central Hospital, Helsinki, Finland
| | - Marsida Hutka
- MRC Centre for Reproductive HealthThe Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK
| | - Rod T Mitchell
- MRC Centre for Reproductive HealthThe Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK
- Edinburgh Royal Hospital for Sick ChildrenEdinburgh, UK
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16
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Nihi F, Gomes M, Carvalho F, Reis A, Martello R, Melo R, Almeida F, Chiarini-Garcia H. Revisiting the human seminiferous epithelium cycle. Hum Reprod 2017; 32:1170-1182. [DOI: 10.1093/humrep/dex064] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 03/16/2017] [Indexed: 11/13/2022] Open
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17
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Halder A, Kumar P, Jain M, Iyer VK. Copy number variations in testicular maturation arrest. Andrology 2017; 5:460-472. [DOI: 10.1111/andr.12330] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Revised: 12/13/2016] [Accepted: 12/28/2016] [Indexed: 01/01/2023]
Affiliation(s)
- A. Halder
- Department of Reproductive Biology; All India Institute of Medical Sciences; New Delhi India
| | - P. Kumar
- Department of Reproductive Biology; All India Institute of Medical Sciences; New Delhi India
| | - M. Jain
- Department of Reproductive Biology; All India Institute of Medical Sciences; New Delhi India
| | - V. K. Iyer
- Department of Pathology; All India Institute of Medical Sciences; New Delhi India
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18
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Shiraishi K, Oka S, Matsuyama H. Predictive Factors for Sperm Recovery after Varicocelectomy in Men with Nonobstructive Azoospermia. J Urol 2017; 197:485-490. [DOI: 10.1016/j.juro.2016.08.085] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/10/2016] [Indexed: 01/17/2023]
Affiliation(s)
- Koji Shiraishi
- Department of Urology, Yamaguchi University School of Medicine, Yamaguchi, Japan
| | - Shintaro Oka
- Department of Urology, Yamaguchi University School of Medicine, Yamaguchi, Japan
| | - Hideyasu Matsuyama
- Department of Urology, Yamaguchi University School of Medicine, Yamaguchi, Japan
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19
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Levi M, Hasky N, Stemmer SM, Shalgi R, Ben-Aharon I. Anti-Müllerian Hormone Is a Marker for Chemotherapy-Induced Testicular Toxicity. Endocrinology 2015; 156:3818-27. [PMID: 26252060 DOI: 10.1210/en.2015-1310] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Due to increased numbers of young cancer patients and improved survival, the impact of anticancer treatments on fertility has become a major health concern. Despite mounting research on ovarian toxicity, there is paucity of data regarding reliable biomarkers of testicular toxicity. Our aim was to evaluate anti-Müllerian hormone (AMH) as a marker for chemotherapy-induced testicular toxicity. Serum AMH and a panel of gonadal hormones were measured in male cancer patients at baseline and after chemotherapy. In the preclinical setting, mice were injected with diverse chemotherapies and were killed 1 week or 1, 3, or 6 months later. We evaluated spermatogenesis by AMH as well as qualitative and quantitative sperm parameters. Nineteen patients were enrolled, the median age was 38 years (21-44 y). Serum AMH was correlated with increased FSH and T and decreased inhibin-B in gonadotoxic protocols (cisplatin or busulfan) and remained unchanged in nongonadotoxic protocols (capecitabine). AMH expression had the same pattern in mice serum and testes; it was negatively correlated with testicular/epididymal weight and sperm motility. The increase in testicular AMH expression was also correlated with elevated apoptosis (terminal transferase-mediated deoxyuridine 5-triphosphate nick-end labeling) and reduced proliferation (Ki67, proliferating cell nuclear antigen; all seminiferous tubules cells were analyzed). Severely damaged mice testes demonstrated a marked costaining of AMH and GATA-4, a Sertoli cell marker; staining that resembled the pattern of the Sertoli cell-only condition. Our study indicates that the pattern of serum AMH expression, in combination with other hormones, can delineate testicular damage, as determined in both experimental settings. Future large-scale clinical studies are warranted to further define the role of AMH as a biomarker for testicular toxicity.
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Affiliation(s)
- Mattan Levi
- Department of Cell and Developmental Biology (M.L., N.H., R.S.), Sackler Faculty of Medicine, Tel Aviv University, Israel and Institute of Oncology (S.M.S., I.B-A.), Davidoff Center, Rabin Medical Center, Beilinson Campus, Petah-Tiqva 49100, and Sackler Faculty of Medicine, Tel-Aviv University, Israel
| | - Noa Hasky
- Department of Cell and Developmental Biology (M.L., N.H., R.S.), Sackler Faculty of Medicine, Tel Aviv University, Israel and Institute of Oncology (S.M.S., I.B-A.), Davidoff Center, Rabin Medical Center, Beilinson Campus, Petah-Tiqva 49100, and Sackler Faculty of Medicine, Tel-Aviv University, Israel
| | - Salomon M Stemmer
- Department of Cell and Developmental Biology (M.L., N.H., R.S.), Sackler Faculty of Medicine, Tel Aviv University, Israel and Institute of Oncology (S.M.S., I.B-A.), Davidoff Center, Rabin Medical Center, Beilinson Campus, Petah-Tiqva 49100, and Sackler Faculty of Medicine, Tel-Aviv University, Israel
| | - Ruth Shalgi
- Department of Cell and Developmental Biology (M.L., N.H., R.S.), Sackler Faculty of Medicine, Tel Aviv University, Israel and Institute of Oncology (S.M.S., I.B-A.), Davidoff Center, Rabin Medical Center, Beilinson Campus, Petah-Tiqva 49100, and Sackler Faculty of Medicine, Tel-Aviv University, Israel
| | - Irit Ben-Aharon
- Department of Cell and Developmental Biology (M.L., N.H., R.S.), Sackler Faculty of Medicine, Tel Aviv University, Israel and Institute of Oncology (S.M.S., I.B-A.), Davidoff Center, Rabin Medical Center, Beilinson Campus, Petah-Tiqva 49100, and Sackler Faculty of Medicine, Tel-Aviv University, Israel
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20
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Levi M, Tzabari M, Savion N, Stemmer SM, Shalgi R, Ben-Aharon I. Dexrazoxane exacerbates doxorubicin-induced testicular toxicity. Reproduction 2015; 150:357-66. [DOI: 10.1530/rep-15-0129] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Infertility induced by anti-cancer treatments pose a major concern for cancer survivors. Doxorubicin (DXR) has been previously shown to exert toxic effects on the testicular germinal epithelium. Based upon the cardioprotective traits of dexrazoxane (DEX), we studied its potential effect in reducing DXR-induced testicular toxicity. Male mice were injected with 5 mg/kg DXR, 100 mg/kg DEX, combination of both or saline (control) and sacrificed either 1, 3 or 6 months later. Testes were excised and further processed. Glutathione and apoptosis assays were performed to determine oxidative stress. Immunohistochemistry and confocal microscopy were used to study the effects of the drugs on testicular histology and on spermatogonial reserve. DXR and the combined treatment induced a striking decline in testicular weight. DEX prevented DXR-induced oxidative stress, but enhanced DXR-induced apoptosis within the testes. Furthermore, the combined treatment depleted the spermatogonial reserve after 1 month, with impaired recovery at 3 and 6 months post-treatment. This resulted in compromised sperm parameters, testicular and epididymal weights as well as significantly reduced sperm motility, all of which were more severe than those observed in DXR-treated mice. The activity of DEX in the testis may differ from its activity in cardiomyocytes. Adding DEX to DXR exacerbates DXR-induced testicular toxicity.
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21
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Ceylan GG, Ceylan C. Genetics and male infertility. World J Clin Urol 2015; 4:38-47. [DOI: 10.5410/wjcu.v4.i1.38] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2014] [Revised: 09/05/2014] [Accepted: 01/12/2015] [Indexed: 02/06/2023] Open
Abstract
The goal of this review is to explain the requirement for understanding the genetic structure of infertility arising from male factor and to discuss the essentials of these genetic elements (2). The majority of the population is affected by this disorder caused by male factor infertility (1); but the etiologies are still unknown. After the primary genetic structure in infertile phenotypes is searched, an evaluation can be made. Thus the reasons causing infertility can be discovered and patients can benefit from effective therapies (1). Publications about male infertility within the recent 10 years in the Pubmed database were discussed (1). There are some approachments for describing the function of specific genes, but no adequate study is present to be useful for diagnosing and treating male infertility (1). Male fertility and fertility in offspring of males are considerably affected by the exact transition of epigenetic information (1). When the genetic factors playing a role in male infertility were analysed, significant steps will be taken for treating patients and determining the reasons of idiopathic infertility (1). Developments in technology associated with the impact of genetics may enable to specify the etiology of male infertility by determining specific infertile phenotype marks (1).
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22
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ZHANG LIYUAN, DING XIANPING, NIE SHUANGSHUANG, LI-LING JESSE, ZHANG YUPING, ZHANG HUI, CHEN LIN, LI LINGXIAO, DING MIN. Association of hsa-miR-145 overexpression in human testicular cells with male infertility. Mol Med Rep 2015; 11:4365-72. [DOI: 10.3892/mmr.2015.3273] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2014] [Accepted: 01/02/2015] [Indexed: 11/05/2022] Open
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23
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Shiraishi K. Hormonal therapy for non-obstructive azoospermia: basic and clinical perspectives. Reprod Med Biol 2014; 14:65-72. [PMID: 29259404 DOI: 10.1007/s12522-014-0193-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Accepted: 09/02/2014] [Indexed: 11/29/2022] Open
Abstract
Microdissection testicular sperm extraction (micro-TESE) combined with intracytoplasmic sperm injection is a standard therapeutic option for patients with non-obstructive azoospermia (NOA). Hormonal treatment has been believed to be ineffective for NOA because of high gonadotropin levels; however, several studies have stimulated spermatogenesis before or after micro-TESE by using anti-estrogens, aromatase inhibitors, and gonadotropins. These results remain controversial; however, it is obvious that some of the patients showed a distinct improvement in sperm retrieval by micro-TESE, and sperm was observed in the ejaculates of a small number of NOA patients. One potential way to improve spermatogenesis is by optimizing the intratesticular testosterone (ITT) levels. ITT has been shown to be increased after hCG-based hormonal therapy. The androgen receptor that is located on Sertoli cells plays a major role in spermatogenesis, and other hormonal and non-hormonal factors may also be involved. Before establishing a new hormonal treatment protocol to stimulate spermatogenesis in NOA patients, further basic investigations regarding the pathophysiology of spermatogenic impairment are needed. Gaining a better understanding of this issue will allow us to tailor a specific treatment for each patient.
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Affiliation(s)
- Koji Shiraishi
- Department of Urology Yamaguchi University School of Medicine 755-8505 Ube Yamaguchi Japan
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24
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Borgers M, Wolter M, Hentrich A, Bergmann M, Stammler A, Konrad L. Role of compensatory meiosis mechanisms in human spermatogenesis. Reproduction 2014; 148:315-20. [PMID: 24987152 DOI: 10.1530/rep-14-0279] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Disturbances of checkpoints in distinct stages of spermatogenesis (mitosis, meiosis, and spermiogenesis) contribute to impaired spermatogenesis; however, the efficiency of meiotic entry has not been investigated in more detail. In this study, we analyzed azoospermic patients with defined spermatogenic defects by the use of octamer-binding protein 2 for type A spermatogonia, sarcoma antigen 1 for mitosis-meiosis transition and SMAD3 for pachytene spermatocytes. Especially patients with maturation arrest (MA) at the level of primary spermatocytes showed significantly reduced numbers of spermatogonia compared with patients with histologically intact spermatogenesis or patients with hypospermatogenesis (Hyp). For a detailed individual classification of the patients, we distinguished between 'high efficiency of meiotic entry' (high numbers of pachytene spermatocytes) and 'low efficiency of meiotic entry' (low numbers of pachytene spermatocytes). Only patients with histologically normal spermatogenesis (Nsp) and patients with Hyp showed normal numbers of spermatogonia and a high efficiency of meiotic entry. Of note, only patients with histologically Nsp or patients with Hyp could compensate low numbers of spermatogonia with a high efficiency of meiotic entry. In contrast, patients with MA always showed a low efficiency of meiotic entry. This is the first report on patients with impaired spermatogenesis, showing that half of the patients with Hyp but all patients with MA cannot compensate reduced numbers in spermatogonia with a highly efficient meiosis. Thus, we suggest that compensatory meiosis mechanisms in human spermatogenesis exist.
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Affiliation(s)
- Mareike Borgers
- Department of Obstetrics and GynecologyMedical Faculty, Feulgenstraße 12, D-35392 Giessen, GermanyInstitute of Veterinary-Anatomy-Histology and -Embryology, Frankfurter Straße 98, D-35392 Giessen, Germany
| | - Martin Wolter
- Department of Obstetrics and GynecologyMedical Faculty, Feulgenstraße 12, D-35392 Giessen, GermanyInstitute of Veterinary-Anatomy-Histology and -Embryology, Frankfurter Straße 98, D-35392 Giessen, Germany
| | - Anna Hentrich
- Department of Obstetrics and GynecologyMedical Faculty, Feulgenstraße 12, D-35392 Giessen, GermanyInstitute of Veterinary-Anatomy-Histology and -Embryology, Frankfurter Straße 98, D-35392 Giessen, Germany
| | - Martin Bergmann
- Department of Obstetrics and GynecologyMedical Faculty, Feulgenstraße 12, D-35392 Giessen, GermanyInstitute of Veterinary-Anatomy-Histology and -Embryology, Frankfurter Straße 98, D-35392 Giessen, Germany
| | - Angelika Stammler
- Department of Obstetrics and GynecologyMedical Faculty, Feulgenstraße 12, D-35392 Giessen, GermanyInstitute of Veterinary-Anatomy-Histology and -Embryology, Frankfurter Straße 98, D-35392 Giessen, Germany
| | - Lutz Konrad
- Department of Obstetrics and GynecologyMedical Faculty, Feulgenstraße 12, D-35392 Giessen, GermanyInstitute of Veterinary-Anatomy-Histology and -Embryology, Frankfurter Straße 98, D-35392 Giessen, Germany
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25
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Rondanino C, Ouchchane L, Chauffour C, Marceau G, Déchelotte P, Sion B, Pons-Rejraji H, Janny L, Volle DH, Lobaccaro JMA, Brugnon F. Levels of liver X receptors in testicular biopsies of patients with azoospermia. Fertil Steril 2014; 102:361-371.e5. [PMID: 24842676 DOI: 10.1016/j.fertnstert.2014.04.033] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2014] [Revised: 04/12/2014] [Accepted: 04/18/2014] [Indexed: 11/28/2022]
Abstract
OBJECTIVE To determine whether the transcription factors liver X receptors (LXRs) and their downstream genes, which are involved in the regulation of several testicular functions in mouse models, are differentially expressed in testes of men with nonobstructive azoospermia (NOA) or obstructive azoospermia (OA). DESIGN Prospective study. SETTING University hospital. PATIENT(S) Patients with various types of NOA (n=22) and with OA (n=5). INTERVENTION(S) Human testicular biopsies. MAIN OUTCOME MEASURE(S) Transcript levels were measured in testicular biopsies with the use of quantitative polymerase chain reaction. Correlations of LXR mRNA levels with the number of germ cells, the expression of proliferation and apoptosis markers, and the amount of intratesticular lipids and testosterone were evaluated. The localization of LXRα was analyzed by immunofluorescence. RESULT(S) LXR mRNA levels were decreased by 49%-98% in NOA specimens and positively correlated with germ cell number. Accumulations of IDOL and SREBP1c (LXR targets involved in lipid homeostasis) were 1.8-2.1 times lower in NOA samples and mRNA levels of the SREBP1c target gene ELOVL6 were increased 1.9-2.4-fold. Interestingly, the amount of triglycerides and free fatty acids were higher in NOA testes (3.4-12.2-fold). LXRα was present in Leydig cells. Accumulations of LXR downstream genes encoding the steroidogenic proteins StAR and 3βHSD2 were higher in NOA testes (5.9-12.8-fold). CONCLUSION(S) Knowledge of changes in the transcript levels of LXRs and some of their downstream genes during altered spermatogenesis may help us to better understand the physiopathology of testicular failure in azoospermic patients.
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Affiliation(s)
- Christine Rondanino
- Génétique Reproduction et Développement, Clermont Université, Clermont-Ferrand, France; CNRS, UMR 6293, GReD, Aubière, France; INSERM, UMR 1103, GReD, Aubière, France; Centre de Recherche en Nutrition Humaine d'Auvergne, Clermont-Ferrand, France; AMP-CECOS, CHU Clermont-Ferrand, CHU Estaing, Clermont-Ferrand, France
| | - Lemlih Ouchchane
- Laboratoire ISIT, UMR 6284 Université d'Auvergne-CNRS, Clermont-Ferrand, France; Service de Biostatistiques, Clermont-Ferrand, France
| | - Candice Chauffour
- Génétique Reproduction et Développement, Clermont Université, Clermont-Ferrand, France; CNRS, UMR 6293, GReD, Aubière, France; INSERM, UMR 1103, GReD, Aubière, France; Centre de Recherche en Nutrition Humaine d'Auvergne, Clermont-Ferrand, France; AMP-CECOS, CHU Clermont-Ferrand, CHU Estaing, Clermont-Ferrand, France
| | - Geoffroy Marceau
- Laboratoire de Biochimie, CHU Clermont-Ferrand, Clermont-Ferrand, France
| | - Pierre Déchelotte
- Service d'Anatomie Pathologique, CHU Clermont-Ferrand, CHU Estaing, Clermont-Ferrand, France
| | - Benoît Sion
- Laboratoire NEURO-DOL, INSERM U 1107, Clermont-Ferrand, France; Laboratoire de Pharmacologie Fondamentale et Clinique de la Douleur, Université d'Auvergne, Clermont-Ferrand, France
| | - Hanae Pons-Rejraji
- Génétique Reproduction et Développement, Clermont Université, Clermont-Ferrand, France; CNRS, UMR 6293, GReD, Aubière, France; INSERM, UMR 1103, GReD, Aubière, France; AMP-CECOS, CHU Clermont-Ferrand, CHU Estaing, Clermont-Ferrand, France
| | - Laurent Janny
- Génétique Reproduction et Développement, Clermont Université, Clermont-Ferrand, France; CNRS, UMR 6293, GReD, Aubière, France; INSERM, UMR 1103, GReD, Aubière, France; AMP-CECOS, CHU Clermont-Ferrand, CHU Estaing, Clermont-Ferrand, France
| | - David H Volle
- Génétique Reproduction et Développement, Clermont Université, Clermont-Ferrand, France; CNRS, UMR 6293, GReD, Aubière, France; INSERM, UMR 1103, GReD, Aubière, France; Centre de Recherche en Nutrition Humaine d'Auvergne, Clermont-Ferrand, France
| | - Jean-Marc A Lobaccaro
- Génétique Reproduction et Développement, Clermont Université, Clermont-Ferrand, France; CNRS, UMR 6293, GReD, Aubière, France; INSERM, UMR 1103, GReD, Aubière, France; Centre de Recherche en Nutrition Humaine d'Auvergne, Clermont-Ferrand, France
| | - Florence Brugnon
- Génétique Reproduction et Développement, Clermont Université, Clermont-Ferrand, France; CNRS, UMR 6293, GReD, Aubière, France; INSERM, UMR 1103, GReD, Aubière, France; AMP-CECOS, CHU Clermont-Ferrand, CHU Estaing, Clermont-Ferrand, France.
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Shinjo E, Shiraishi K, Matsuyama H. The effect of human chorionic gonadotropin-based hormonal therapy on intratesticular testosterone levels and spermatogonial DNA synthesis in men with non-obstructive azoospermia. Andrology 2013; 1:929-35. [DOI: 10.1111/j.2047-2927.2013.00141.x] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2013] [Revised: 08/17/2013] [Accepted: 09/09/2013] [Indexed: 11/30/2022]
Affiliation(s)
- E. Shinjo
- Department of Urology; Yamaguchi University; School of Medicine; Ube Japan
| | - K. Shiraishi
- Department of Urology; Yamaguchi University; School of Medicine; Ube Japan
| | - H. Matsuyama
- Department of Urology; Yamaguchi University; School of Medicine; Ube Japan
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27
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Vija L, Meduri G, Comperat E, Vasiliu V, Izard V, Ferlicot S, Boukari K, Camparo P, Viengchareun S, Constancis E, Dumitrache C, Lombès M, Young J. Expression and characterization of androgen receptor coregulators, SRC-2 and HBO1, during human testis ontogenesis and in androgen signaling deficient patients. Mol Cell Endocrinol 2013; 375:140-8. [PMID: 23707616 DOI: 10.1016/j.mce.2013.05.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2013] [Revised: 04/11/2013] [Accepted: 05/06/2013] [Indexed: 11/17/2022]
Abstract
Androgen receptor (AR) is essential for testicular physiology and spermatogenesis. SRC-2 and HBO1 are two AR coregulators yet their expression and roles in human testis are unknown. For the first time, we studied by immunohistochemistry and RT-PCR, the expression and distribution of these two coregulators during human testicular ontogenesis, in patients with altered AR signaling (Androgen insensitivity syndrome, AIS) and evaluated the functional impact of SRC-2 and HBO1 on AR signaling in a Sertoli cell context. SRC-2 was present in Sertoli cells at all developmental stages. HBO1 was barely or focally detected in the fetal testis yet its expression, in Sertoli and germ cells, drastically increased postnatally from early infancy to adulthood. In transient co-transfection studies we showed that SRC-2 induced, while HBO1 inhibited AR-mediated transactivation of reporter constructs in murine Sertoli SMAT1 cells. HBO1, but not SRC-2, expression was reduced in testes of patients with AIS compared to normal testes.
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Affiliation(s)
- Lavinia Vija
- Univ Paris-Sud, Faculté de Médecine Paris-Sud, UMR-S693, Le Kremlin-Bicêtre F-94276, France
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28
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Sun P, Zheng J, She G, Wei X, Zhang X, Shi H, Zhou X. Expression pattern of asialoglycoprotein receptor in human testis. Cell Tissue Res 2013; 352:761-8. [PMID: 23604802 DOI: 10.1007/s00441-013-1616-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2012] [Accepted: 03/11/2013] [Indexed: 02/05/2023]
Abstract
During acute or chronic hepatitis B virus (HBV) infection, the virus can invade the male reproductive system, pass through the blood-testis barrier and integrate into the germ line, resulting in abnormal spermatozoa. However, the pathway remains unclear. The asialoglycoprotein receptor (ASGR), a potential receptor for HBV, is mainly distributed in hepatocytes. We have examined the distribution of ASGR in human testis and found it in the seminiferous tubules and interstitial region but its enrichment in human testis is much lower than that in liver. By multiple immunoenzyme histochemistry staining, ASGR was precisely co-localized with vimentin (Sertoli cell marker) but not proliferating cell nuclear antigen (spermatogonial cell marker) in testis tissue. ASGR was expressed in human Leydig cells, stromal cells in the seminiferous tubules and Sertoli cells but seldom in spermatogonial cells. Therefore, ASGR could provide HBV with access to the luminal compartment of human testis. The mechanism by which HBV invades germ cells remains unknown.
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Affiliation(s)
- Pingnan Sun
- Department of Pathology, Shantou University Medical College, Shantou, People's Republic of China
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29
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Hentrich A, Wolter M, Szardening-Kirchner C, Lüers GH, Bergmann M, Kliesch S, Konrad L. Reduced numbers of Sertoli, germ, and spermatogonial stem cells in impaired spermatogenesis. Mod Pathol 2011; 24:1380-9. [PMID: 21685910 DOI: 10.1038/modpathol.2011.97] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
A key step in the investigation of male infertility is the appropriate classification of impaired spermatogenesis. In this study, we precisely identified Sertoli and distinct germ-cell types in the rat, the mouse, and in the human testis. As a proof of principle, we studied testis biopsy samples from azoospermic patients with defined spermatogenic defects. Remarkably, we found that already the numbers of Sertoli cells, spermatogonia and a subset of spermatogonia including stem cells are significantly reduced in patients with maturation arrest at the level of primary spermatocytes (n=33) compared with patients with histologically normal spermatogenesis (n=33). In patients with hypospermatogenesis (n=44) a significant reduction of spermatogonial cell numbers was observed. The numbers of primary and diplotene spermatocytes were reduced by 84%. However, the strongest reduction (96%) was revealed in the numbers of spermatids in patients with maturation arrest. In contrast, patients with hypospermatogenesis showed only modestly reduced numbers of spermatocytes and spermatids compared with normal spermatogenesis. No correlation was found with age or obstruction. For a detailed analysis of the patients, we distinguished between 'pool of founder cells'-related deficiencies (reduced numbers of Sertoli cells, spermatogonia, and spermatogonial stem cells) and 'meiotic' deficiencies (reduced numbers of spermatocytes, meiotic divisions, and spermatids). Interestingly, patients with maturation arrest showed meiotic deficiencies (36%), while the majority additionally demonstrated deficiencies in the founder pool (58%). In contrast, patients with normal spermatogenesis most often had no deficiencies at all (45%) or founder pool-related deficiencies (33%) but an apparently normal meiosis. This is the first report showing that many infertile patients face besides meiotic defects the problem of reduced numbers of Sertoli cells, spermatogonia, and spermatogonial stem cells.
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Affiliation(s)
- Anna Hentrich
- Department of Obstetrics and Gynecology, Medical Faculty, Giessen, Germany
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30
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Sertoli cells proliferate in adult rats with prenatal exposure to 3,3′,4,4′,5-pentachlorobiphenyl. Arch Toxicol 2011; 86:159-62. [DOI: 10.1007/s00204-011-0736-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2011] [Accepted: 07/05/2011] [Indexed: 11/27/2022]
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31
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Downregulation of microRNA-383 is associated with male infertility and promotes testicular embryonal carcinoma cell proliferation by targeting IRF1. Cell Death Dis 2010; 1:e94. [PMID: 21368870 PMCID: PMC3032325 DOI: 10.1038/cddis.2010.70] [Citation(s) in RCA: 121] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Our previous studies have shown that microRNA-383 (miR-383) expression is downregulated in the testes of infertile men with maturation arrest (MA). However, the underlying mechanisms of miR-383 involved in the pathogenesis of MA remain unknown. In this study, we showed that downregulation of miR-383 was associated with hyperactive proliferation of germ cells in patients with mixed patterns of MA. Overexpression of miR-383 in NT2 (testicular embryonal carcinoma) cells resulted in suppression of proliferation, G1-phase arrest and induction of apoptosis, whereas silencing of miR-383 reversed these effects. The effects of miR-383 were mediated through targeting a tumor suppressor, interferon regulatory factor-1 (IRF1), and miR-383 was negatively correlated with IRF1 protein expression in vivo. miR-383 inhibited IRF1 by affecting its mRNA stability, which subsequently reduced the levels of the targets of IRF1, namely cyclin D1, CDK2 and p21. Downregulation of IRF1 or cyclin D1, but not that of CDK2, enhanced miR-383-mediated effects, whereas silencing of p21 partially inhibited the effects of miR-383. Moreover, miR-383 downregulated CDK4 by increasing proteasome-dependent degradation of CDK4, which in turn resulted in an inhibition of phosphorylated retinoblastoma protein (pRb) phosphorylation. These results suggest that miR-383 functions as a negative regulator of proliferation by targeting IRF1, in part, through inactivation of the pRb pathway. Abnormal testicular miR-383 expression may potentiate the connections between male infertility and testicular germ cell tumor.
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32
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Cerilli LA, Kuang W, Rogers D. A practical approach to testicular biopsy interpretation for male infertility. Arch Pathol Lab Med 2010; 134:1197-204. [PMID: 20670143 DOI: 10.5858/2009-0379-ra.1] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT The combination of testicular biopsy and clinical evaluation for male infertility is becoming progressively more important because new technologies allow men previously considered infertile to father children. Although most general pathologists are experienced with normal, neoplastic, and cryptorchid testicular specimens, the testicular biopsy for infertility requires understanding of a different set of diagnostic categories not otherwise commonly encountered. OBJECTIVE To highlight a standardized nomenclature for germ cell abnormalities allowing for effective communication with the urologist and maximal clinical benefit from the biopsy. DATA SOURCES Previously published consensus statements, review articles, peer-reviewed research publications, and abstracts. CONCLUSIONS A practical approach to evaluating testicular biopsies for fertility and the clinical implications for each abnormality are herein outlined.
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Affiliation(s)
- Lisa A Cerilli
- Department of Pathology, University of New Mexico, Albuquerque, NM 87131, USA.
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Shiraishi K, Naito K. Effects of 4-Hydroxy-2-Nonenal, a Marker of Oxidative Stress, on Spermatogenesis and Expression of p53 Protein in Male Infertility. J Urol 2007; 178:1012-7; discussion 1017. [PMID: 17632137 DOI: 10.1016/j.juro.2007.05.027] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2007] [Indexed: 11/18/2022]
Abstract
PURPOSE Oxidative stress is involved in male infertility. However, little is known about how it impairs spermatogenesis. We investigated the presence of oxidative stress in human testes by studying the generation of 4-hydroxy-2-nonenal modified proteins and expressions of proliferating cell nuclear antigen and p53. MATERIALS AND METHODS A total of 47 testicular biopsies from patients with varicocele, obstructive azoospermia and idiopathic infertility were included. Localization and generation of 4-hydroxy-2-nonenal modified proteins were determined by immunohistochemistry and Western blotting. The expressions of proliferating cell nuclear antigen and p53 were assessed by Western blotting. The interaction between 4-hydroxy-2-nonenal modified proteins and p53 was examined by immunoprecipitation. Data were compared to clinicopathological parameters. RESULTS 4-Hydroxy-2-nonenal modified proteins were strongly positive in spermatogonia, primary spermatocytes and Sertoli's cells, and generation was inversely correlated with expression of proliferating cell nuclear antigen. The expression of p53 was increased in testes with varicocele (p <0.01) and obstructive azoospermia (p <0.05), and there was a positive or inverse correlation with 4-hydroxy-2-nonenal modified proteins and proliferating cell nuclear antigen. Immunoprecipitated p53 was detected by anti-4-hydroxy-2-nonenal modified protein antibody. CONCLUSIONS 4-Hydroxy-2-nonenal impairs the proliferation of germ cells through the up-regulation of p53 protein, especially in testes with varicocele. Modification by 4-hydroxy-2-nonenal might alter normal function and stabilization of p53 protein.
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Affiliation(s)
- Koji Shiraishi
- Department of Urology, Yamaguchi University School of Medicine, Yamaguchi, Japan.
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Brehm R, Rey R, Kliesch S, Steger K, Marks A, Bergmann M. Mitotic activity of Sertoli cells in adult human testis: an immunohistochemical study to characterize Sertoli cells in testicular cords from patients showing testicular dysgenesis syndrome. ACTA ACUST UNITED AC 2006; 211:223-36. [PMID: 16429274 DOI: 10.1007/s00429-005-0075-8] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/12/2005] [Indexed: 12/31/2022]
Abstract
During puberty, normal somatic Sertoli cells undergo dramatic morphological changes due to the differentiation of immature pre-Sertoli cells in functionally active adult Sertoli cells. Sertoli cell maturation is accompanied with loss of their mitotic activity before onset of spermatogenesis and loss of pre-pubertal and occurrence of adult immunohistochemical Sertoli cell differentiation markers. Testes of infertile adult patients often exhibit numerous histological signs of testicular dysgenesis syndrome (TDS) such as microliths, Sertoli cell only (SCO) tubules, tubules containing carcinoma in situ and immature seminiferous tubules (Sertoli cell nodules). Sertoli cell tumours, however, are very rare neoplasms possibly due to the fact that the mechanism and temporal origin of neoplastic Sertoli cells underlying Sertoli cell tumourigenesis still remain unknown. To clarify the state of Sertoli cell differentiation in both immature seminiferous tubules of adult patients with TDS and Sertoli cell tumour, we compared the expression of the Sertoli cell differentiation markers vimentin, inhibin-alpha, anti-Muellerian-hormone, cytokeratin 18, M2A-antigen, androgen receptor and connexin43 with that of SCO tubules with hyperplasia. In addition, we demonstrated for the first time the existence of proliferating Sertoli cells by Ki67- and PCNA-immunostaining in Sertoli cell nodules of the adult human testis. Our data indicate that mitotically active Sertoli cells in Sertoli cell nodules will be arrested prior to puberty and, contrary to dogma, do not represent foetal or neonatal cells. Since all markers in Sertoli cell nodules revealed a staining pattern identical to that in neoplastic Sertoli cells, but different to that in Sertoli cells of SCO tubules with hyperplasia, it may be speculated that Sertoli cell tumours in adult men may originate from Sertoli cell nodules.
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Affiliation(s)
- Ralph Brehm
- Institute of Veterinary Anatomy, Histology and Embryology, University of Giessen, Giessen, Germany.
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