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Re: Y Chromosome Microdeletions, Sperm DNA Fragmentation and Sperm Oxidative Stress as Causes of Recurrent Spontaneous Abortion of Unknown Etiology
1404
MALE INFERTILITY
convert them into strand breaks. Results: In IVF, FR and ECS decreased as DF increased in both semen and DGC sperm, and couples who failed to achieve a CP had higher DF than successful couples (⫹12.2% semen, p ⫽ 0.004; ⫹9.9% DGC sperm, p ⫽ 0.010). When MB were added to existing strand breaks, total DF was markedly higher (⫹17.1% semen, p ⫽ 0.009 and ⫹13.8% DGC sperm, p ⫽ 0.045). DF was not associated with FR, ECS or CP in either semen or DGC sperm following ISCI. In contrast, by including MB, there was significantly more DNA damage (⫹16.8% semen, p ⫽ 0.008 and ⫹15.5% DGC sperm, p ⫽ 0.024) in the group who did not achieve CP. Conclusions: DF can predict ART outcome for IVF. Converting MB into further DNA strand breaks increased the test sensitivity, giving negative correlations between DF and CP for ICSI as well as IVF. Editorial Comment: Whether assessed by TUNEL, single cell gel electrophoresis (comet) or flow cytometric methods such as sperm chromatin structure assay, the role of measuring sperm DNA integrity remains an open question. Part of the problem is how one defines DNA integrity, as measurement of the whole structure and sequence of a single sperm DNA is not yet technologically possible. These authors describe assessing 8-OHdG, a modified base of the purine guanosine, in addition to overall sperm DNA structure with the comet assay, and report increased accuracy for predicting clinical pregnancy. As we have available more ways to measure DNA integrity, we may see its role expand in clinical use. Craig Niederberger, M.D.
Re: Y Chromosome Microdeletions, Sperm DNA Fragmentation and Sperm Oxidative Stress as Causes of Recurrent Spontaneous Abortion of Unknown Etiology J. Bellver, M. Meseguer, L. Muriel, S. Garcia-Herrero, M. A. Barreto, A. L. Garda, J. Remohi, A. Pellicer and N. Garrido Instituto Valenciano de Infertilidad, University of Valencia, Valencia, Spain Hum Reprod 2010; 25: 1713–1721.
Background: The aim of the present study was to evaluate the implication of male factor, in terms of sperm DNA oxidation and fragmentation, and Y chromosome microdeletions in recurrent spontaneous abortion (RSA) of unknown origin in a strictly selected cohort. Methods: A prospective cohort study was carried out in a private university-affiliated setting. Three groups, each comprised of 30 males, were compared. The first was formed by healthy and fertile sperm donors (SD) with normal sperm parameters (control group), the second by men presenting severe oligozoospermia (SO) without RSA history, and the third by men from couples who had experienced idiopathic RSA. Frequency of Y chromosome microdeletions and mean sperm DNA fragmentation and oxidation were determined. Results: Y chromosome microdeletions were not detected in any of the males enrolled in the study. Moreover, sperm DNA oxidation measurements were not demonstrated to be relevant to RSA. Interestingly, sperm DNA fragmentation was higher in the SO group than in the RSA and the SD groups, and also higher in the RSA group compared with the SD group, but lacked an adequate predictive power to be employed as a discriminative test of RSA condition. Conclusions: Sperm DNA features and Y chromosome microdeletions do not seem to be related to RSA of unknown origin. Other molecular features of sperm should be studied to determine their possible influence on RSA. Editorial Comment: Sperm are often assumed to be the culprits in recurrent pregnancy loss, and sperm DNA quality is a factor that may thwart developmental events beyond fertilization. These authors sought to relate sperm DNA oxidation and fragmentation and Y chromosomal microdeletions to recurrent spontaneous abortion, and could not find a relationship in 3 groups of 30 men. DNA fragmentation, for example, in receiver operator characteristic curve analysis did no better in predicting outcomes than chance. However, 30 men per group is a small number when considering microstructural events such as Y chromosomal microdeletions, and the most apt appraisal of this study is that if sperm DNA
MALE INFERTILITY
1405
is responsible for recurrent pregnancy loss, specific genetic events either individually or in combination that are not yet assessed in clinical practice are most likely at fault. Craig Niederberger, M.D.
Sperm DNA Integrity in Cancer Patients Before and After Cytotoxic Treatment M. Smit, N. J. van Casteren, M. F. Wildhagen, J. C. Romijn and G. R. Dohle Andrology Unit, Department of Urology, Erasmus MC, Rotterdam, The Netherlands Hum Reprod 2010; 25: 1877–1883.
Background: We assessed sperm DNA fragmentation index (DFI) in cancer patients before and after treatment to evaluate if sperm DNA integrity is compromised by cancer itself or its treatment. Methods: In a prospective study, DFI was assessed in 127 patients diagnosed with testicular germ cell tumours (TGCT), Hodgkin’s lymphoma (HL), non-Hodgkin’s lymphoma (NHL) and various malignancies. The severity of cancer and tumour markers at diagnosis was recorded. Follow-up DFI after treatment was available in 52 patients who were mostly less severely affected. Results: In patients diagnosed with TGCT, HL and various malignancies, pretreatment DFI levels were not significantly different from that of proven fertile controls, but in patients with NHL an increased DFI was found. An overall significant decrease in post-treatment DFI (13.2% range 5.0 –70.5) compared with pretreatment values (17.1% range 5.1– 66.6) was found (p ⫽ 0.040). In TGCT patients, post-treatment DFI was significantly higher in patients who were treated with radiotherapy (16.9% range 11.5–39.9) compared with that in patients treated with chemotherapy (CT) alone (10.9% range 5.5–39.9) (p ⫽ 0.037). In HL patients, the type of treatment or number of CT cycles was not associated with DFI. Overall, post-treatment DFI in cancer patients was not significantly different from that of proven fertile controls. Conclusions: In this study, the presence of cancer does not seem to negatively affect the sperm DNA integrity in TGCT and HL patients; only NHL patients showed increased DFI at the time of diagnosis compared with healthy controls. Our results confirm previous reports that DFI decreases significantly following various anti-cancer treatments. In contrast, radiotherapy in TGCT patients is associated with an increase in DFI compared with CT treatment alone. Editorial Comment: An all too common clinical scenario is that of a patient undergoing cytotoxic cancer chemotherapy who wants to know when he can safely rely on ejaculated sperm to achieve conception. Typical answers range from 6 months to 2 years based on scant human trials and projections from in vitro data. These authors used the sperm chromatin structure assay (SCSA) as a measure of DNA integrity before and after chemotherapy. Also, as cancer itself is known to cause spermatogenic dysfunction and potential sperm DNA damage, they compared the outcomes to SCSA results from known fertile men. Interestingly they observed a pretreatment high DFI only in men with NHL, and it decreased with chemotherapy. Although the SCSA does not tell the whole story with DNA changes such as single point mutations, we are probably erring on the side of caution when we instruct men to wait a year or 2 after cytotoxic cancer chemotherapy to father children. Craig Niederberger, M.D.
MALE INFERTILITY
convert them into strand breaks. Results: In IVF, FR and ECS decreased as DF increased in both semen and DGC sperm, and couples who failed to achieve a CP had higher DF than successful couples (⫹12.2% semen, p ⫽ 0.004; ⫹9.9% DGC sperm, p ⫽ 0.010). When MB were added to existing strand breaks, total DF was markedly higher (⫹17.1% semen, p ⫽ 0.009 and ⫹13.8% DGC sperm, p ⫽ 0.045). DF was not associated with FR, ECS or CP in either semen or DGC sperm following ISCI. In contrast, by including MB, there was significantly more DNA damage (⫹16.8% semen, p ⫽ 0.008 and ⫹15.5% DGC sperm, p ⫽ 0.024) in the group who did not achieve CP. Conclusions: DF can predict ART outcome for IVF. Converting MB into further DNA strand breaks increased the test sensitivity, giving negative correlations between DF and CP for ICSI as well as IVF. Editorial Comment: Whether assessed by TUNEL, single cell gel electrophoresis (comet) or flow cytometric methods such as sperm chromatin structure assay, the role of measuring sperm DNA integrity remains an open question. Part of the problem is how one defines DNA integrity, as measurement of the whole structure and sequence of a single sperm DNA is not yet technologically possible. These authors describe assessing 8-OHdG, a modified base of the purine guanosine, in addition to overall sperm DNA structure with the comet assay, and report increased accuracy for predicting clinical pregnancy. As we have available more ways to measure DNA integrity, we may see its role expand in clinical use. Craig Niederberger, M.D.
Re: Y Chromosome Microdeletions, Sperm DNA Fragmentation and Sperm Oxidative Stress as Causes of Recurrent Spontaneous Abortion of Unknown Etiology J. Bellver, M. Meseguer, L. Muriel, S. Garcia-Herrero, M. A. Barreto, A. L. Garda, J. Remohi, A. Pellicer and N. Garrido Instituto Valenciano de Infertilidad, University of Valencia, Valencia, Spain Hum Reprod 2010; 25: 1713–1721.
Background: The aim of the present study was to evaluate the implication of male factor, in terms of sperm DNA oxidation and fragmentation, and Y chromosome microdeletions in recurrent spontaneous abortion (RSA) of unknown origin in a strictly selected cohort. Methods: A prospective cohort study was carried out in a private university-affiliated setting. Three groups, each comprised of 30 males, were compared. The first was formed by healthy and fertile sperm donors (SD) with normal sperm parameters (control group), the second by men presenting severe oligozoospermia (SO) without RSA history, and the third by men from couples who had experienced idiopathic RSA. Frequency of Y chromosome microdeletions and mean sperm DNA fragmentation and oxidation were determined. Results: Y chromosome microdeletions were not detected in any of the males enrolled in the study. Moreover, sperm DNA oxidation measurements were not demonstrated to be relevant to RSA. Interestingly, sperm DNA fragmentation was higher in the SO group than in the RSA and the SD groups, and also higher in the RSA group compared with the SD group, but lacked an adequate predictive power to be employed as a discriminative test of RSA condition. Conclusions: Sperm DNA features and Y chromosome microdeletions do not seem to be related to RSA of unknown origin. Other molecular features of sperm should be studied to determine their possible influence on RSA. Editorial Comment: Sperm are often assumed to be the culprits in recurrent pregnancy loss, and sperm DNA quality is a factor that may thwart developmental events beyond fertilization. These authors sought to relate sperm DNA oxidation and fragmentation and Y chromosomal microdeletions to recurrent spontaneous abortion, and could not find a relationship in 3 groups of 30 men. DNA fragmentation, for example, in receiver operator characteristic curve analysis did no better in predicting outcomes than chance. However, 30 men per group is a small number when considering microstructural events such as Y chromosomal microdeletions, and the most apt appraisal of this study is that if sperm DNA
MALE INFERTILITY
1405
is responsible for recurrent pregnancy loss, specific genetic events either individually or in combination that are not yet assessed in clinical practice are most likely at fault. Craig Niederberger, M.D.
Sperm DNA Integrity in Cancer Patients Before and After Cytotoxic Treatment M. Smit, N. J. van Casteren, M. F. Wildhagen, J. C. Romijn and G. R. Dohle Andrology Unit, Department of Urology, Erasmus MC, Rotterdam, The Netherlands Hum Reprod 2010; 25: 1877–1883.
Background: We assessed sperm DNA fragmentation index (DFI) in cancer patients before and after treatment to evaluate if sperm DNA integrity is compromised by cancer itself or its treatment. Methods: In a prospective study, DFI was assessed in 127 patients diagnosed with testicular germ cell tumours (TGCT), Hodgkin’s lymphoma (HL), non-Hodgkin’s lymphoma (NHL) and various malignancies. The severity of cancer and tumour markers at diagnosis was recorded. Follow-up DFI after treatment was available in 52 patients who were mostly less severely affected. Results: In patients diagnosed with TGCT, HL and various malignancies, pretreatment DFI levels were not significantly different from that of proven fertile controls, but in patients with NHL an increased DFI was found. An overall significant decrease in post-treatment DFI (13.2% range 5.0 –70.5) compared with pretreatment values (17.1% range 5.1– 66.6) was found (p ⫽ 0.040). In TGCT patients, post-treatment DFI was significantly higher in patients who were treated with radiotherapy (16.9% range 11.5–39.9) compared with that in patients treated with chemotherapy (CT) alone (10.9% range 5.5–39.9) (p ⫽ 0.037). In HL patients, the type of treatment or number of CT cycles was not associated with DFI. Overall, post-treatment DFI in cancer patients was not significantly different from that of proven fertile controls. Conclusions: In this study, the presence of cancer does not seem to negatively affect the sperm DNA integrity in TGCT and HL patients; only NHL patients showed increased DFI at the time of diagnosis compared with healthy controls. Our results confirm previous reports that DFI decreases significantly following various anti-cancer treatments. In contrast, radiotherapy in TGCT patients is associated with an increase in DFI compared with CT treatment alone. Editorial Comment: An all too common clinical scenario is that of a patient undergoing cytotoxic cancer chemotherapy who wants to know when he can safely rely on ejaculated sperm to achieve conception. Typical answers range from 6 months to 2 years based on scant human trials and projections from in vitro data. These authors used the sperm chromatin structure assay (SCSA) as a measure of DNA integrity before and after chemotherapy. Also, as cancer itself is known to cause spermatogenic dysfunction and potential sperm DNA damage, they compared the outcomes to SCSA results from known fertile men. Interestingly they observed a pretreatment high DFI only in men with NHL, and it decreased with chemotherapy. Although the SCSA does not tell the whole story with DNA changes such as single point mutations, we are probably erring on the side of caution when we instruct men to wait a year or 2 after cytotoxic cancer chemotherapy to father children. Craig Niederberger, M.D.