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Re: X-Linked TEX11 Mutations, Meiotic Arrest, and Azoospermia in Infertile Men
MALE INFERTILITY
444
Re: Prospective Evaluation of Postoperative Penile Rehabilitation: Penile Length/Girth Maintenance 1 Year following Coloplast Titan Inflatable Penile Prosthesis G. D. Henry, R. Carrion, C. Jennermann and R. Wang Regional Urology, Shreveport, Louisiana, Department of Urology, Morsani College of Medicine, University of South Florida, Tampa, Florida, and Division of Urology, UT-Houston Medical School, Houston, Texas J Sex Med 2015; 12: 1298e1304. doi: 10.1111/jsm.12833
Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25872574 Editorial Comment: The authors of this study prospectively measured penile length in a series of 40 patients with an inflatable penile prosthesis who were sized aggressively and instructed to pump the device regularly. One year later an average of 1 cm length expansion was noted, with 61% of patients having greater satisfaction compared to immediately preoperatively. An increasing number of pumps was noted during the 12-month period. The question here is whether inflatable penile prosthesis cylinders act as tissue expanders and, moreover, whether a device that does not expand in length, such as the TitanÒ, can, in fact, lengthen the penis. While a 1 cm length increase may not seem like much, it underscores our observation that reimplant cases almost always require a longer cylinder the second time around. At least we have more data that debunk the widespread teaching that the penis is somehow shorter as a result of the device. Allen F. Morey, MD
Male Infertility Re: X-Linked TEX11 Mutations, Meiotic Arrest, and Azoospermia in Infertile Men € pke, A. J. Berman, T. Jaffe, M. Olszewska, A. N. Yatsenko, A. P. Georgiadis, A. Ro € er, J. Sanfilippo, M. Kurpisz, A. Rajkovic, S. A. Yatsenko, S. Kliesch, B. Westernstro € ttelmann S. Schlatt and F. Tu Departments of Obstetrics, Gynecology and Reproductive Sciences, and Urology, University of Pittsburgh School of Medicine, and Department of Biological Sciences, Kenneth P. Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, Institute of Human Genetics, and Center of Reproductive Medicine and Andrology, University of Mu¨nster, Mu¨nster, Germany, and Department of Reproductive Biology and Stem , Poland Cells, Institute of Human Genetics, Polish Academy of Sciences, Poznan N Engl J Med 2015; 372: 2097e2107. doi: 10.1056/NEJMoa1406192.
Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25970010 Editorial Comment: This is a nice story. Deletion of the testis expressed 11 (TEX11) gene results in meiotic arrest at the pachytene stage of spermatogenesis in mice, and it is consequently a promising genetic target to study in patients with azoospermia due to spermatogenic dysfunction. These investigators identified TEX11 mutations in 7 of 289 patients (2.4%) with azoospermia due to spermatogenic dysfunction, the majority of whom had pathology consistent with maturation arrest in meiosis. No TEX11 mutations were observed in men with Sertoli cell-only histology or in 384 controls with normal sperm concentrations. However, from a diagnostic viewpoint a genetic cause of spermatogenic dysfunction remains elusive, suggesting 2 possibilities. In the first scenario many different genes cause infertility in a diverse array of individual men. In the second scenario mechanisms external to the genome, such as epigenetic phenomena, are responsible for the majority of reproductive difficulties in males. Only time will tell which, if either, is accurate. Craig Niederberger, MD
MALE INFERTILITY
445
Re: Fluorescence In Situ Hybridization Detects Increased Sperm Aneuploidy in Men with Recurrent Pregnancy Loss R. Ramasamy, J. M. Scovell, J. R. Kovac, P. J. Cook, D. J. Lamb and L. I. Lipshultz Department of Urology, Center for Reproductive Medicine, and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas Fertil Steril 2015; 103: 906e909.e1. doi: 10.1016/j.fertnstert.2015.01.029.
Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25707335 Editorial Comment: Sperm are a varied lot, and predicting pregnancy outcomes based on the DNA contents of the male gamete is challenging. These investigators studied women with recurrent pregnancy loss and the amount of chromosomal aneuploidy as measured by fluorescence in situ hybridization (FISH) in the sperm of their male partners. They observed that although combined sex chromosome and chromosome 18 and 13/21 aneuploidy is common in men, it is more common in those who have abnormal bulk seminal parameters and whose partners have recurrent pregnancy loss. Sperm DNA fragmentation, as measured by TUNEL assay, could not be used as a surrogate for FISH. Recurrent pregnancy loss is then a reasonable target for assessment of sperm aneuploidy with FISH, although the question remains, how can that information best be clinically used? Craig Niederberger, MD
Re: DNA Methylation Differences between In Vitro- and In Vivo-Conceived Children are Associated with ART Procedures Rather than Infertility S. Song, J. Ghosh, M. Mainigi, N. Turan, R. Weinerman, M. Truongcao, C. Coutifaris and C. Sapienza Fels Institute for Cancer Research and Molecular Biology, and Department of Pathology and Laboratory Medicine, Temple University School of Medicine, and Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Clin Epigenetics 2015; 7: 41. doi: 10.1186/s13148-015-0071-7.
Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25901188 Editorial Comment: DNA methylation is a central regulatory mechanism in gene expression, and past studies suggest differences in DNA methylation between children conceived with vs without in vitro fertilization. This finding is obviously concerning for its possible consequences for unborn children and their future lives. However, a possible explanation is that the underlying pathological condition leading to infertility in the parent may be responsible. In an elegant series of experiments these investigators are anything but reassuring, as they provide evidence that the technique of in vitro fertilization itself is likely at least partly responsible for the differences observed in DNA methylation in offspring. This clearly is an area that begs for further scrutiny, as the powerful and wonderful opportunities that in vitro fertilization provides should be made as safe as possible for couples who would otherwise be unable to have children. Craig Niederberger, MD
Re: DNA Double Strand Breaks in Human Spermatozoa can be Predictive for Assisted Reproductive Outcome A. Garolla, I. Cosci, A. Bertoldo, B. Sartini, E. Boudjema and C. Foresta Department of Medicine, Section of Clinical Pathology and Unit for Human Reproduction Pathology, University of Padova, Padova, Italy Reprod Biomed Online 2015; 31: 100e107. doi: 10.1016/j.rbmo.2015.03.009.
Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25985994 Editorial Comment: DNA is tightly packaged in the sperm head, and researchers have sought to discover disturbances of DNA structure that lead to reproductive dysfunction. Unfortunately,
MALE INFERTILITY
446
discriminating ability that is clinically useful still eludes most tests of sperm DNA integrity. These investigators studied sperm DNA of 100 consecutive men with some bulk seminal abnormality who were candidates for intracytoplasmic sperm injection. Assays included a variety of well studied methods of directly and indirectly detecting DNA strand breaks and internal structure, and a more novel assessment quantifying a phosphorylated form of the histone H2AX (gH2AX) present to varying degrees in mature spermatozoa and postulated to be related to induced DNA damage. Each test was correlated to in vitro fertilization with intracytoplasmic sperm injection outcomes. As observed in many reports, the more traditional methods did not predict in vitro fertilization outcomes well. However, sperm gH2AX metrics were significantly different comparing nonpregnant and pregnant couples. Of course, many of the more traditional assays of DNA integrity were promising when first reported, and this newer assay must stand the test of time. However, at a minimum it offers an additional way of interrogating sperm DNA. Craig Niederberger, MD
Re: Aged Men Share the Sperm Protein PATE1 Defect with Young Asthenozoospermia Patients F. J. Liu, X. Liu, J. L. Han, Y. W. Wang, S. H. Jin, X. X. Liu, J. Liu, W. T. Wang and W. J. Wang Central Laboratory, Clinical Laboratory and Reproduction Medical Center, Yantai Yu Huang Ding Hospital/Qingdao University, Yantai, Shandong and Clinical Laboratory, Taizhou People’s Hospital, Taizhou, Jiangsu, P. R. China Hum Reprod 2015; 30: 861e869. doi: 10.1093/humrep/dev003.
Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25637620 Editorial Comment: With an eye on male age these investigators analyzed sperm proteins by comparative sperm proteomic analysis from young adults and older men, identifying prostate and testis expressed 1 (PATE1) as a promising candidate. In a validation of the concept that reproductive aging and infertility at a younger age may share common pathology the results revealed that expression and localization of sperm were similar for older men and young ones with asthenozoospermia. Further experimentation suggested roles for PATE1 in ova penetration by sperm and motility. By studying similarities between the changes in reproductive biology in aging men and in younger ones suffering from inability to impregnate their partners, the authors demonstrate a clever way in which we may discover the underlying mechanisms of male reproductive dysfunction. Craig Niederberger, MD
Re: Interferometric Phase Microscopy for Label-Free Morphological Evaluation of Sperm Cells M. Haifler, P. Girshovitz, G. Band, G. Dardikman, I. Madjar and N. T. Shaked Department of Biomedical Engineering, Faculty of Engineering, Tel-Aviv University, Ramat Aviv, and Department of Urology and Male Fertility Clinic, Chaim Sheba Medical Center, Ramat Gan, Israel Fertil Steril 2015; 104: 43e47.e2. doi: 10.1016/j.fertnstert.2015.04.013
Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26003272 Editorial Comment: Nondestructive selection of single sperm cells for use in intracytoplasmic sperm injection is one of the holy grails of male reproductive medicine. At this point no such technique reliably identifies sperm with better reproductive potential. One avenue of study has been morphology, attempting to better define what constitutes normal sperm by their shape. Typically applying a fixative to sperm improves identification of subtle optical features but the stain renders the sperm unusable for intracytoplasmic sperm injection. These investigators compared interferometric phase microscopy, a type of holographic microscopic imaging, to traditional bright field microscopy in demonstrating morphological features revealed by fixing and staining sperm, and they observed that the technique performs well. However, as the relationship between sperm
444
Re: Prospective Evaluation of Postoperative Penile Rehabilitation: Penile Length/Girth Maintenance 1 Year following Coloplast Titan Inflatable Penile Prosthesis G. D. Henry, R. Carrion, C. Jennermann and R. Wang Regional Urology, Shreveport, Louisiana, Department of Urology, Morsani College of Medicine, University of South Florida, Tampa, Florida, and Division of Urology, UT-Houston Medical School, Houston, Texas J Sex Med 2015; 12: 1298e1304. doi: 10.1111/jsm.12833
Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25872574 Editorial Comment: The authors of this study prospectively measured penile length in a series of 40 patients with an inflatable penile prosthesis who were sized aggressively and instructed to pump the device regularly. One year later an average of 1 cm length expansion was noted, with 61% of patients having greater satisfaction compared to immediately preoperatively. An increasing number of pumps was noted during the 12-month period. The question here is whether inflatable penile prosthesis cylinders act as tissue expanders and, moreover, whether a device that does not expand in length, such as the TitanÒ, can, in fact, lengthen the penis. While a 1 cm length increase may not seem like much, it underscores our observation that reimplant cases almost always require a longer cylinder the second time around. At least we have more data that debunk the widespread teaching that the penis is somehow shorter as a result of the device. Allen F. Morey, MD
Male Infertility Re: X-Linked TEX11 Mutations, Meiotic Arrest, and Azoospermia in Infertile Men € pke, A. J. Berman, T. Jaffe, M. Olszewska, A. N. Yatsenko, A. P. Georgiadis, A. Ro € er, J. Sanfilippo, M. Kurpisz, A. Rajkovic, S. A. Yatsenko, S. Kliesch, B. Westernstro € ttelmann S. Schlatt and F. Tu Departments of Obstetrics, Gynecology and Reproductive Sciences, and Urology, University of Pittsburgh School of Medicine, and Department of Biological Sciences, Kenneth P. Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, Institute of Human Genetics, and Center of Reproductive Medicine and Andrology, University of Mu¨nster, Mu¨nster, Germany, and Department of Reproductive Biology and Stem , Poland Cells, Institute of Human Genetics, Polish Academy of Sciences, Poznan N Engl J Med 2015; 372: 2097e2107. doi: 10.1056/NEJMoa1406192.
Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25970010 Editorial Comment: This is a nice story. Deletion of the testis expressed 11 (TEX11) gene results in meiotic arrest at the pachytene stage of spermatogenesis in mice, and it is consequently a promising genetic target to study in patients with azoospermia due to spermatogenic dysfunction. These investigators identified TEX11 mutations in 7 of 289 patients (2.4%) with azoospermia due to spermatogenic dysfunction, the majority of whom had pathology consistent with maturation arrest in meiosis. No TEX11 mutations were observed in men with Sertoli cell-only histology or in 384 controls with normal sperm concentrations. However, from a diagnostic viewpoint a genetic cause of spermatogenic dysfunction remains elusive, suggesting 2 possibilities. In the first scenario many different genes cause infertility in a diverse array of individual men. In the second scenario mechanisms external to the genome, such as epigenetic phenomena, are responsible for the majority of reproductive difficulties in males. Only time will tell which, if either, is accurate. Craig Niederberger, MD
MALE INFERTILITY
445
Re: Fluorescence In Situ Hybridization Detects Increased Sperm Aneuploidy in Men with Recurrent Pregnancy Loss R. Ramasamy, J. M. Scovell, J. R. Kovac, P. J. Cook, D. J. Lamb and L. I. Lipshultz Department of Urology, Center for Reproductive Medicine, and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas Fertil Steril 2015; 103: 906e909.e1. doi: 10.1016/j.fertnstert.2015.01.029.
Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25707335 Editorial Comment: Sperm are a varied lot, and predicting pregnancy outcomes based on the DNA contents of the male gamete is challenging. These investigators studied women with recurrent pregnancy loss and the amount of chromosomal aneuploidy as measured by fluorescence in situ hybridization (FISH) in the sperm of their male partners. They observed that although combined sex chromosome and chromosome 18 and 13/21 aneuploidy is common in men, it is more common in those who have abnormal bulk seminal parameters and whose partners have recurrent pregnancy loss. Sperm DNA fragmentation, as measured by TUNEL assay, could not be used as a surrogate for FISH. Recurrent pregnancy loss is then a reasonable target for assessment of sperm aneuploidy with FISH, although the question remains, how can that information best be clinically used? Craig Niederberger, MD
Re: DNA Methylation Differences between In Vitro- and In Vivo-Conceived Children are Associated with ART Procedures Rather than Infertility S. Song, J. Ghosh, M. Mainigi, N. Turan, R. Weinerman, M. Truongcao, C. Coutifaris and C. Sapienza Fels Institute for Cancer Research and Molecular Biology, and Department of Pathology and Laboratory Medicine, Temple University School of Medicine, and Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Clin Epigenetics 2015; 7: 41. doi: 10.1186/s13148-015-0071-7.
Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25901188 Editorial Comment: DNA methylation is a central regulatory mechanism in gene expression, and past studies suggest differences in DNA methylation between children conceived with vs without in vitro fertilization. This finding is obviously concerning for its possible consequences for unborn children and their future lives. However, a possible explanation is that the underlying pathological condition leading to infertility in the parent may be responsible. In an elegant series of experiments these investigators are anything but reassuring, as they provide evidence that the technique of in vitro fertilization itself is likely at least partly responsible for the differences observed in DNA methylation in offspring. This clearly is an area that begs for further scrutiny, as the powerful and wonderful opportunities that in vitro fertilization provides should be made as safe as possible for couples who would otherwise be unable to have children. Craig Niederberger, MD
Re: DNA Double Strand Breaks in Human Spermatozoa can be Predictive for Assisted Reproductive Outcome A. Garolla, I. Cosci, A. Bertoldo, B. Sartini, E. Boudjema and C. Foresta Department of Medicine, Section of Clinical Pathology and Unit for Human Reproduction Pathology, University of Padova, Padova, Italy Reprod Biomed Online 2015; 31: 100e107. doi: 10.1016/j.rbmo.2015.03.009.
Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25985994 Editorial Comment: DNA is tightly packaged in the sperm head, and researchers have sought to discover disturbances of DNA structure that lead to reproductive dysfunction. Unfortunately,
MALE INFERTILITY
446
discriminating ability that is clinically useful still eludes most tests of sperm DNA integrity. These investigators studied sperm DNA of 100 consecutive men with some bulk seminal abnormality who were candidates for intracytoplasmic sperm injection. Assays included a variety of well studied methods of directly and indirectly detecting DNA strand breaks and internal structure, and a more novel assessment quantifying a phosphorylated form of the histone H2AX (gH2AX) present to varying degrees in mature spermatozoa and postulated to be related to induced DNA damage. Each test was correlated to in vitro fertilization with intracytoplasmic sperm injection outcomes. As observed in many reports, the more traditional methods did not predict in vitro fertilization outcomes well. However, sperm gH2AX metrics were significantly different comparing nonpregnant and pregnant couples. Of course, many of the more traditional assays of DNA integrity were promising when first reported, and this newer assay must stand the test of time. However, at a minimum it offers an additional way of interrogating sperm DNA. Craig Niederberger, MD
Re: Aged Men Share the Sperm Protein PATE1 Defect with Young Asthenozoospermia Patients F. J. Liu, X. Liu, J. L. Han, Y. W. Wang, S. H. Jin, X. X. Liu, J. Liu, W. T. Wang and W. J. Wang Central Laboratory, Clinical Laboratory and Reproduction Medical Center, Yantai Yu Huang Ding Hospital/Qingdao University, Yantai, Shandong and Clinical Laboratory, Taizhou People’s Hospital, Taizhou, Jiangsu, P. R. China Hum Reprod 2015; 30: 861e869. doi: 10.1093/humrep/dev003.
Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25637620 Editorial Comment: With an eye on male age these investigators analyzed sperm proteins by comparative sperm proteomic analysis from young adults and older men, identifying prostate and testis expressed 1 (PATE1) as a promising candidate. In a validation of the concept that reproductive aging and infertility at a younger age may share common pathology the results revealed that expression and localization of sperm were similar for older men and young ones with asthenozoospermia. Further experimentation suggested roles for PATE1 in ova penetration by sperm and motility. By studying similarities between the changes in reproductive biology in aging men and in younger ones suffering from inability to impregnate their partners, the authors demonstrate a clever way in which we may discover the underlying mechanisms of male reproductive dysfunction. Craig Niederberger, MD
Re: Interferometric Phase Microscopy for Label-Free Morphological Evaluation of Sperm Cells M. Haifler, P. Girshovitz, G. Band, G. Dardikman, I. Madjar and N. T. Shaked Department of Biomedical Engineering, Faculty of Engineering, Tel-Aviv University, Ramat Aviv, and Department of Urology and Male Fertility Clinic, Chaim Sheba Medical Center, Ramat Gan, Israel Fertil Steril 2015; 104: 43e47.e2. doi: 10.1016/j.fertnstert.2015.04.013
Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26003272 Editorial Comment: Nondestructive selection of single sperm cells for use in intracytoplasmic sperm injection is one of the holy grails of male reproductive medicine. At this point no such technique reliably identifies sperm with better reproductive potential. One avenue of study has been morphology, attempting to better define what constitutes normal sperm by their shape. Typically applying a fixative to sperm improves identification of subtle optical features but the stain renders the sperm unusable for intracytoplasmic sperm injection. These investigators compared interferometric phase microscopy, a type of holographic microscopic imaging, to traditional bright field microscopy in demonstrating morphological features revealed by fixing and staining sperm, and they observed that the technique performs well. However, as the relationship between sperm