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In Situ End-Labeling of Human Testicular Tissue Demonstrates Increased Apoptosis in Conditions of Abnormal Spermatogenesis
1940
MALE INFERTILITY
Recombinant Human Follicle Stimulating Hormone for Treatment of Male Idiopathic Infertility: A Randomized, Double-Blind, Placebo-Controlled, Clinical Trial A. WISCHKE,H. M. BEHRE, M. BERGMA”,M. SIMONI, T. S C H ~AND E RE. NIESCHLAG, Institute of Reproductive Medicine of University, Miinster and Institute for Anatomy and Cell Biology of University, Halle, Germany Hum. Reprod., 1 3 596-603, 1998 Permission to Publish Abstract Not Granted
Treatment of the Male With Follicle-Stimulating Hormone in Intrauterine Insemination With Husband’s Spermatozoa: A Randomized Study R. MATORRAS, C. P ~ R E Z B., CORC~STEGUI, J. I. PIJOAN,0. RAMON, P. DELGADO AND F.J. RODR~GUEZ-ESCUDERO, Department of Obstetrics and Gynecology, and Clinical Epidemiology Unit, Hospital from Cruces, Universidad del Pais Vasco, Baracaldo, Spain Hum. Reprod., 12: 24-28, 1997 Permission to Publish Abstract Not Granted
Editorial Comment: The authors emphasize the importance of controlled studies of therapies for idiopathic infertility. Recombinant follicle-stimulating hormone (FSH) was thought to enhance the fertility of men with idiopathic infertility based on a prior uncontrolled study.’ However, these 2 controlled studies document the lack of efficacy of FSH therapy in the male patient as a solitary intervention or when combined with intrauterine insemination for the treatment of idiopathic oligoasthenospermia. Although FSH has an important role in sperm production, increasing serum FSH levels in men with normal basal FSH does not provide any significant beneficial effect. Jonathan P. Jarow, M.D. 1. Acosta, A. A, Khalifa, E. and Oehninger, S.: Pure human follicle stimulating hormone has a role in the treatment of severe male infertility by assisted reproduction:Norfolk’s total experience. Hum. Reprod., 7: 1067,1992.
In Situ End-Labeling of Human Testicular Tissue Demonstrates Increased Apoptosis in Conditions of Abnormal Spermatogenesis W. W. LIN,D. J. LAMB, T. M. WHEELER, L. I. LIPSHULTZ AND E. D. KIM,Baylor College of Medicine, Houston, Texas Fertil. Steril., 6 8 1065-1069, 1997 Objective: To determine, using an in situ end-labeling technique, whether the frequency of apoptosis is increased in testis biopsy specimens that demonstrate abnormal spermatogenesis. Design: Immunohistochemical analysis was performed on archived paraffin-embedded testis biopsy specimens. Apoptotic indices, defined as the number of apoptotic bodies per the total number of cells or the number of Sertoli cells, were calculated after counting all the intratubular spermatogenic cells and Sertoli cells in 20 tubules. Setting: Major academic male factor infertility clinic. Patient(s): Forty-eight testis biopsy specimens were obtained for routine clinical purposes from 38 men with azoospermia or severe oligozoospermia. Interventiods): In situ end-labeling was performed on archived paraffin-embedded testis biopsy specimens using terminal deoxynucleotidyl transferase. Main Outcome Measure(s): Apoptotic indices. Result(s1: Significantly increased apoptotic indices were observed in patients with spermatocyte arrest, spermatid arrest, and hypospermatogenesis compared with patients with normal spermatogenesis and the Sertoli cell-only pattern. Conclusion(s): In situ end-labeling of testis biopsy specimens from infertile men demonstrates increased apoptosis in maturation arrest and hypospermatogenesis states compared with normal spermatogenesis and the Sertoli cell-only pattern. This unique observation implicates a prominent role for this form of programmed cell death in the pathophysiology of maturation arrest and hypospermatogenesis states. Editorial Comment: Four spermatozoa should be produced from each spermatogonia committed to meiosis. Yet, cell kinetic studies in rodent models of spermatogenesis reveal production rates approximately half that expected. Current thinking is that apoptosis (programmed cell death) is responsible for cytoreduction of the germ cell line during normal spermatogenesis. The strongest evidence of this process is the observation of overcrowding of the seminiferous tubules with germ cells when the genes responsible for apoptosis are knocked out in transgenic
MALE INFERTILITY
mice. Thus, the sperm count on semen analysis is a reflection of a balance between cell proliferation and cell death during the course of normal spermatogenesis. This study using the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling assay to detect apoptosis demonstrates a 10-fold increase in the Sertoli cell corrected germ cell apoptosis rate in human testes with abnormal spermatogenesischaracterized by the histological patterns of maturation arrest and hypospermatogenesis. This study provides the most credible evidence to date to support the theory that clinical male infertility may be due, at least in part, to an increase in cell death rather than a reduction in cell proliferation. Jonathan P. Jarow, M.D.
Chromosome Abnormalities in 447 Couples Undergoing Intracytoplasmic Sperm InjectionPrevalence, Types, Sex Distribution and Reproductive Relevance D. MESCHEDE, B. LEMCKE, J. R. EXELER, CH.DE GEYTER, H. M. BEHRE,E. NIESCHLAG AND J. HORST,Znstitute of Human Genetics, WonenS Hospital, and Znstitute of Reproductive Medicine of University, Munster, Germany Hum. Reprod., 13: 576-582, 1998 Permission to Publish Abstract Not Granted
Cytogenetic Survey of 1,007 Infertile Males A. YOSHIDA, K. MIURA AND M. SHIRAI, First Department of Urology, Toho University School ofMedicine, Tokyo, Japan Urol. Int., 5 8 166-176, 1997 Permission to Publish Abstract Not Granted
Incidence of Sex ChromosomeAbnormalities in Spermatozoa From Patients Entering an IVF or ICSI Protocol R. T. STORENG, M. PLACHOT, D. THEOPHILE, J. MANDELBAUM, J. BEWSCH-ALLART AND M. VEKEMANS, Laboratoire de F N e t Biologie de la Reproduction and Service de cytogenetique, H6pital Necker and H6pital de Sevres, Sevres, France Acta Obst. Gynec. Scand., 77: 191-197,1998 Objective. The objective of this study was the determination of sex chromosome aneuploidy frequency in spermatozoa from patients included in an in vitro fertilization (IVF)or intra cytoplasmic sperm injection (ICSI) protocol. Methods. Spermatozoa from nineteen patients, including patients with normal seminal parameters according to World Health Organization (WHO) criteria and patients exhibiting abnormal seminal parameters, were analyzed by dual color fluorescence in situ hybridization (FISH) for aneuploidies of the X and Y chromosomes. Our technique, using only probes for sex chromosomes and not for autosomes, does not discriminate between hyperhaploid and diploid sperm nuclei. The results were analyzed in two different ways: in relation to the semen status, denoted normal or abnormal and with regard t o the ability of the sperm to fertilize oocytes when IVF or ICSI was performed. Results. Abnormal semen showed a significant increase in the overall rate of sperm nuclei with XY, XX and W sex chromosome complements, 1.59% compared to normal semen, 0.78% (p < 0.02). Semen shown to be able to fertilize oocytes only by ICSI showed a higher incidence of XY-bearing spermatozoa, 1.26%, compared to semen able to fertilize oocytes by conventional IVF, 0.37% (p < 0.001). The incidence of XX- or W-bearing sperm nuclei was also significantly elevated in the ICSI group (0.25% XX, 0.50% W)(p < 0.02) as compared to the IVF group (0.06% XX, 0.16% W). Conclusions. We concluded that infertile men requiring ICSI treatment showed a higher incidence of sex chromosome aneuploidy, due t o meiosis I and I1 nondisjunction, in their spermatozoa as compared to men requiring IVF for reasons of predominantly female infertility. Editorial Comment: The advent of intracytoplasmic sperm injection allows men who were previously considered sterile to father children. Transmission of inheritable disorders is a major Concern regarding this technology. These 3 studies document a statistically significant but small prevalence of chromosomal abnormalities among infertile men. Meschede et al reviewed 447 couples who underwent intracytoplasmic sperm iqjection for male factor infertility
1941
MALE INFERTILITY
Recombinant Human Follicle Stimulating Hormone for Treatment of Male Idiopathic Infertility: A Randomized, Double-Blind, Placebo-Controlled, Clinical Trial A. WISCHKE,H. M. BEHRE, M. BERGMA”,M. SIMONI, T. S C H ~AND E RE. NIESCHLAG, Institute of Reproductive Medicine of University, Miinster and Institute for Anatomy and Cell Biology of University, Halle, Germany Hum. Reprod., 1 3 596-603, 1998 Permission to Publish Abstract Not Granted
Treatment of the Male With Follicle-Stimulating Hormone in Intrauterine Insemination With Husband’s Spermatozoa: A Randomized Study R. MATORRAS, C. P ~ R E Z B., CORC~STEGUI, J. I. PIJOAN,0. RAMON, P. DELGADO AND F.J. RODR~GUEZ-ESCUDERO, Department of Obstetrics and Gynecology, and Clinical Epidemiology Unit, Hospital from Cruces, Universidad del Pais Vasco, Baracaldo, Spain Hum. Reprod., 12: 24-28, 1997 Permission to Publish Abstract Not Granted
Editorial Comment: The authors emphasize the importance of controlled studies of therapies for idiopathic infertility. Recombinant follicle-stimulating hormone (FSH) was thought to enhance the fertility of men with idiopathic infertility based on a prior uncontrolled study.’ However, these 2 controlled studies document the lack of efficacy of FSH therapy in the male patient as a solitary intervention or when combined with intrauterine insemination for the treatment of idiopathic oligoasthenospermia. Although FSH has an important role in sperm production, increasing serum FSH levels in men with normal basal FSH does not provide any significant beneficial effect. Jonathan P. Jarow, M.D. 1. Acosta, A. A, Khalifa, E. and Oehninger, S.: Pure human follicle stimulating hormone has a role in the treatment of severe male infertility by assisted reproduction:Norfolk’s total experience. Hum. Reprod., 7: 1067,1992.
In Situ End-Labeling of Human Testicular Tissue Demonstrates Increased Apoptosis in Conditions of Abnormal Spermatogenesis W. W. LIN,D. J. LAMB, T. M. WHEELER, L. I. LIPSHULTZ AND E. D. KIM,Baylor College of Medicine, Houston, Texas Fertil. Steril., 6 8 1065-1069, 1997 Objective: To determine, using an in situ end-labeling technique, whether the frequency of apoptosis is increased in testis biopsy specimens that demonstrate abnormal spermatogenesis. Design: Immunohistochemical analysis was performed on archived paraffin-embedded testis biopsy specimens. Apoptotic indices, defined as the number of apoptotic bodies per the total number of cells or the number of Sertoli cells, were calculated after counting all the intratubular spermatogenic cells and Sertoli cells in 20 tubules. Setting: Major academic male factor infertility clinic. Patient(s): Forty-eight testis biopsy specimens were obtained for routine clinical purposes from 38 men with azoospermia or severe oligozoospermia. Interventiods): In situ end-labeling was performed on archived paraffin-embedded testis biopsy specimens using terminal deoxynucleotidyl transferase. Main Outcome Measure(s): Apoptotic indices. Result(s1: Significantly increased apoptotic indices were observed in patients with spermatocyte arrest, spermatid arrest, and hypospermatogenesis compared with patients with normal spermatogenesis and the Sertoli cell-only pattern. Conclusion(s): In situ end-labeling of testis biopsy specimens from infertile men demonstrates increased apoptosis in maturation arrest and hypospermatogenesis states compared with normal spermatogenesis and the Sertoli cell-only pattern. This unique observation implicates a prominent role for this form of programmed cell death in the pathophysiology of maturation arrest and hypospermatogenesis states. Editorial Comment: Four spermatozoa should be produced from each spermatogonia committed to meiosis. Yet, cell kinetic studies in rodent models of spermatogenesis reveal production rates approximately half that expected. Current thinking is that apoptosis (programmed cell death) is responsible for cytoreduction of the germ cell line during normal spermatogenesis. The strongest evidence of this process is the observation of overcrowding of the seminiferous tubules with germ cells when the genes responsible for apoptosis are knocked out in transgenic
MALE INFERTILITY
mice. Thus, the sperm count on semen analysis is a reflection of a balance between cell proliferation and cell death during the course of normal spermatogenesis. This study using the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling assay to detect apoptosis demonstrates a 10-fold increase in the Sertoli cell corrected germ cell apoptosis rate in human testes with abnormal spermatogenesischaracterized by the histological patterns of maturation arrest and hypospermatogenesis. This study provides the most credible evidence to date to support the theory that clinical male infertility may be due, at least in part, to an increase in cell death rather than a reduction in cell proliferation. Jonathan P. Jarow, M.D.
Chromosome Abnormalities in 447 Couples Undergoing Intracytoplasmic Sperm InjectionPrevalence, Types, Sex Distribution and Reproductive Relevance D. MESCHEDE, B. LEMCKE, J. R. EXELER, CH.DE GEYTER, H. M. BEHRE,E. NIESCHLAG AND J. HORST,Znstitute of Human Genetics, WonenS Hospital, and Znstitute of Reproductive Medicine of University, Munster, Germany Hum. Reprod., 13: 576-582, 1998 Permission to Publish Abstract Not Granted
Cytogenetic Survey of 1,007 Infertile Males A. YOSHIDA, K. MIURA AND M. SHIRAI, First Department of Urology, Toho University School ofMedicine, Tokyo, Japan Urol. Int., 5 8 166-176, 1997 Permission to Publish Abstract Not Granted
Incidence of Sex ChromosomeAbnormalities in Spermatozoa From Patients Entering an IVF or ICSI Protocol R. T. STORENG, M. PLACHOT, D. THEOPHILE, J. MANDELBAUM, J. BEWSCH-ALLART AND M. VEKEMANS, Laboratoire de F N e t Biologie de la Reproduction and Service de cytogenetique, H6pital Necker and H6pital de Sevres, Sevres, France Acta Obst. Gynec. Scand., 77: 191-197,1998 Objective. The objective of this study was the determination of sex chromosome aneuploidy frequency in spermatozoa from patients included in an in vitro fertilization (IVF)or intra cytoplasmic sperm injection (ICSI) protocol. Methods. Spermatozoa from nineteen patients, including patients with normal seminal parameters according to World Health Organization (WHO) criteria and patients exhibiting abnormal seminal parameters, were analyzed by dual color fluorescence in situ hybridization (FISH) for aneuploidies of the X and Y chromosomes. Our technique, using only probes for sex chromosomes and not for autosomes, does not discriminate between hyperhaploid and diploid sperm nuclei. The results were analyzed in two different ways: in relation to the semen status, denoted normal or abnormal and with regard t o the ability of the sperm to fertilize oocytes when IVF or ICSI was performed. Results. Abnormal semen showed a significant increase in the overall rate of sperm nuclei with XY, XX and W sex chromosome complements, 1.59% compared to normal semen, 0.78% (p < 0.02). Semen shown to be able to fertilize oocytes only by ICSI showed a higher incidence of XY-bearing spermatozoa, 1.26%, compared to semen able to fertilize oocytes by conventional IVF, 0.37% (p < 0.001). The incidence of XX- or W-bearing sperm nuclei was also significantly elevated in the ICSI group (0.25% XX, 0.50% W)(p < 0.02) as compared to the IVF group (0.06% XX, 0.16% W). Conclusions. We concluded that infertile men requiring ICSI treatment showed a higher incidence of sex chromosome aneuploidy, due t o meiosis I and I1 nondisjunction, in their spermatozoa as compared to men requiring IVF for reasons of predominantly female infertility. Editorial Comment: The advent of intracytoplasmic sperm injection allows men who were previously considered sterile to father children. Transmission of inheritable disorders is a major Concern regarding this technology. These 3 studies document a statistically significant but small prevalence of chromosomal abnormalities among infertile men. Meschede et al reviewed 447 couples who underwent intracytoplasmic sperm iqjection for male factor infertility
1941