Armand Zini

Sperm DNA damage is associated with an increased risk of pregnancy loss after IVF and ICSI: systematic review and meta-analysis

BACKGROUNDnSperm DNA damage is common amongst infertile men and may adversely impact natural reproduction, IUI-assisted reproduction and to a lesser degree IVF pregnancy. The aim of this study was to examine the influence of sperm DNA damage on the risk of spontaneous pregnancy loss after IVF and ICSI.nnnMETHODSnWe conducted a systematic review and meta-analysis of studies on sperm DNA damage and pregnancy loss after an IVF and/or ICSI pregnancy.nnnRESULTSnTwo by two tables were constructed and odds ratios (ORs) were derived from 11 estimates of pregnancy loss (five IVF and six ICSI studies from seven reports). These 11 studies involved 1549 cycles of treatment (808 IVF and 741 ICSI cycles) with 640 pregnancies (345 IVF and 295 ICSI) and 122 pregnancy losses. The combined OR of 2.48 (95% CI 1.52, 4.04, P < 0.0001) indicates that sperm DNA damage is predictive of pregnancy loss after IVF and ICSI.nnnCONCLUSIONSnIn conclusion, sperm DNA damage is associated with a significantly increased risk of pregnancy loss after IVF and ICSI. These data provide a clinical indication for the evaluation of sperm DNA damage prior to IVF or ICSI and a rationale for further investigating the association between sperm DNA damage and pregnancy loss.

Sperm DNA: organization, protection and vulnerability: from basic science to clinical applications—a position report

This article reports the results of the most recent in a series of EHSRE workshops designed to synthesize the current state of the field in Andrology and provide recommendations for future work (for details see Appendix). Its focus is on methods for detecting sperm DNA damage and potential application of new knowledge about sperm chromatin organization, vulnerability and repair to improve the diagnosis and treatment of clinical infertility associated with that damage. Equally important is the use and reliability of these tests to identify the extent to which environmental contaminants or pharmaceutical agents may contribute to the incidence of sperm DNA damage and male fertility problems. A working group (for workshop details, see Appendix) under the auspices of ESHRE met in May 2009 to assess the current knowledgebase and suggest future basic and clinical research directions. This document presents a synthesis of the working groups understanding of the recent literature and collective discussions on the current state of knowledge of sperm chromatin structure and function during fertilization. It highlights the biological, assay and clinical uncertainties that require further research and ends with a series of 5 key recommendations.

Semen Analysis and Sperm Function Assays: What Do They Mean?

Appropriate laboratory testing is an integral component of the proper evaluation of the male presenting with infertility. This article reviews the semen analysis and sperm function assays. Sperm function testing is used to determine if the sperm have the biologic capacity to perform the tasks necessary to reach and fertilize ova and ultimately result in live births. For a sperm to be fertile in vivo, it must be able to traverse the cervical mucus and reach the ova. The sperm must undergo capacitation and the acrosome reaction, fuse with the oolemma, and incorporate into the ooplasm. Proper embryo development requires that functional DNA be delivered to the ooplasm. Defects in any of these steps may result in infertility. A variety of tests are available to evaluate different aspects of these functions. To accurately use these functional assays, the clinician must understand what the tests measure, what the indications are for the assays, and how to interpret the results to direct further testing or patient management.

How to overcome male infertility after 40: Influence of paternal age on fertility

The recent trend toward delayed parenthood raises major safety concerns because of the adverse effects of aging on couple fertility. Studies have demonstrated that aging clearly affects female fertility, but can also affect male fertility. Although several theories have been proposed, the exact mechanisms responsible for the observed age-related decline in male fertility remain to be elucidated. It has been shown that advanced paternal age (PA) is associated with reduced semen volume as well as, reduced sperm count, motility and morphology. Recent studies have also reported that paternal aging is associated with a significant increase in the prevalence of both genomic and epigenomic sperm defects. In the context of natural and intrauterine insemination (IUI) conception, advanced paternal age has been associated with lower pregnancy rates and increased rates of spontaneous abortion (independent of maternal age). In IVF and oocyte donation programs, a significant decrease in late blastocyst development has been seen in those cycles using spermatozoa of men older than 55. However, no significant relationship between paternal age and IVF or ICSI pregnancy rates has been observed. Although there are no treatments that can fully restore the age-related decline in male fertility, various measures have been shown to optimize male fertility potential. Specific therapies (e.g. varicocelectomy) and lifestyle changes (e.g. dietary antioxidant supplements) may help minimize some of the age-related deleterious effects on spermatogenesis, such as, oxidative stress and endocrine abnormalities.

CUA Guideline: The workup of azoospermic males.

A committee was established at the request of the CUA to determine guidelines for the investigation and management of azoospermia. Members of the committee, all of whom have special expertise in the investigation and management of male infertility, were chosen from different communities across Canada. The members represent different practices in different communities.

Varicocele: Red Flag or Red Herring?

The debate concerning the relationship between varicocele and male infertility has been ongoing for several decades, and correction of varicocele for the treatment of male infertility remains controversial. Proponents of varicocele repair believe that there is an association between the two conditions and point to the many studies showing improvements in semen parameters and other markers of fertility after surgery as evidence of such a relationship. Opponents argue that the mere presence of dilated testicular veins does not necessarily imply that these lesions are the cause of a mans subfertility and that incontrovertible pregnancy outcome data after varicocele repair remains to be shown. To shed some light on this topic, we have reviewed the most current data concerning the impact of varicocele on male fertility and have analyzed the literature on the value of varicocele repair in the setting of male infertility. We have determined that whereas there is a definite association between varicocele and male infertility, a cause and effect relationship between varicocele and infertility has not been established conclusively. A critical review of the available pregnancy outcome data does support varicocelectomy as a viable option for infertile couples with a clinical varicocele.

Influence of microsurgical varicocelectomy on human sperm mitochondrial DNA copy number: a pilot study

BackgroundThere is good evidence to show that varicocele repair can improve conventional sperm parameters, as well as, sperm DNA integrity, in infertile men with a clinical varicocele.ObjectiveTo examine the effect of varicocelectomy on sperm quality, specifically, sperm nuclear chromatin integrity and sperm mitochondrial DNA (mtDNA) copy number.Design, Setting, and ParticipantsA prospective study done between March 2007 and January 2008. We evaluated a consecutive series of infertile men (nu2009=u200914) presenting to Ovo clinic with one year or more history of infertility, a clinically palpable varicocele and poor motility (<25xa0% rapid progressive and <50xa0% progressive).Surgical ProcedureMicrosurgical sub-inguinal varicocelectomy.Outcome Measurements and Statistical AnalysisConventional sperm parameters, sperm mtDNA copy number (by real time PCR) and sperm chromatin structure assay (SCSA) parameters (%DFI,% HDS) before and 4xa0months after microsurgical varicocelectomy.Results and LimitationsSperm concentration and SCSA parameters (%DFI and %HDS) improved significantly after surgery (Pu2009<u20090.05). Sperm mitochondrial DNA copy number decreased significantly after surgery (27u2009±u200930 to 9u2009±u20096 copies per sperm, respectively, Pu2009=u20090.032). There was a significant negative correlation between mitochondrial DNA copy number and sperm motility (ru2009=u2009− 0.71, Pu2009=u20090.002).ConclusionThese findings support the concept that correction of a varicocele can improve spermatogenesis and sperm function, as mitochondrial DNA copy number has been suggested to reflect the efficiency of spermatogenesis and has been inversely related to sperm motility.

Surgically retrieved spermatozoa versus ejaculated spermatozoa in modified natural IVF-ICSI cycles

A retrospective cohort study was performed to evaluate the outcome of modified natural IVF-intracytoplasmic sperm injection (mnIVF-ICSI) cycles to compare 81 mnIVF-ICSI first cycles using ejaculated spermatozoa with 44 mnIVF-ICSI first cycles using surgically retrieved spermatozoa. There were no differences between the two groups in terms of number of oocytes retrieved, oocyte maturity or female age. However, male age was significantly higher in the surgically retrieved compared with the ejaculated group (41.5 versus 36.5 years, P=0.001). There were no significant differences in fertilization rate or cleavage rate between the ejaculated and the surgically retrieved groups; however the prevalence of embryo transfer was higher in the surgically retrieved group (65.9% versus 45.7%, P=0.03). Only single-embryo transfer was performed. Biochemical (34.5% versus 37.8%) and clinical (31.0% versus 35.1%) pregnancy rates per embryo transfer were similar between the ejaculated and the surgically retrieved groups. The data suggest that mnIVF-ICSI is an alternative treatment option in couples with severe male factor infertility where surgical sperm retrieval is required. The aim of the present study was to evaluate and compare the outcomes of modified natural IVF-intracytoplasmic sperm injection (mnIVF-ICSI) with surgically retrieved spermatozoa (in male partners with obstructive azoospermia) and ejaculated spermatozoa (in couples with mild-to-moderate male factor). Eighty-one mnIVF-ICSI first cycles using ejaculated spermatozoa were compared with forty-four mnIVF-ICSI first cycles using surgically retrieved spermatozoa. There were no differences between the two groups in terms of number of oocytes retrieved, oocyte maturity or female age. However, male age was significantly higher in the surgically retrieved compared with the ejaculated group. There were no significant differences in fertilization rate, or cleavage rate between the two groups; however, there were more patients having embryo transfers in the surgically retrieved group. Only single-embryo transfer was performed. Biochemical and clinical pregnancy rates per embryo transfer were similar between both groups. The data suggest that mnIVF-ICSI is an alternative treatment option in couples with severe male factor infertility where surgical sperm retrieval is required.

Antioxidants and Sperm DNA Damage

Infertile men have higher levels of sperm DNA damage than do fertile men, and this damage may reduce male fertility potential and may impact on reproductive capacity. This is particularly important in the context of assisted reproductive technologies, as there is a mounting concern regarding the safety of utilizing DNA-damaged spermatozoa in this setting. A better understanding of the etiology of sperm DNA damage may help identify strategies to reduce sperm DNA damage. In this chapter, we xaddiscuss the rationale for antioxidant therapy, examine the relationship between oxidative stress and sperm DNA damage, and evaluate the studies on dietary and in vitro antioxidants on sperm DNA damage. The review focuses primarily on clinical (human) studies with some examples taken from experimental (animal) data.

Clinical Utility of Sperm DNA Integrity Tests

Tests of sperm DNA integrity are being used increasingly in the evaluation of infertile men with the premise that these tests may better diagnose the infertility and predict reproductive outcomes. Indeed, a systematic review of the literature allows us to conclude that sperm DNA damage is associated with lower natural, IUI, and IVF pregnancy rates. By contrast, studies to date have not shown a clear association between sperm DNA and chromatin defects and pregnancy outcomes after ICSI. In couples undergoing IVF or ICSI, there is also evidence to show that sperm DNA damage is associated with an increased risk of pregnancy loss. A limitation of the systematic reviews and meta-analyses is that they do not address an important feature of the clinical studies on sperm DNA damage, the often marked heterogeneity of the individual study characteristics. Although the clinical utility of tests of sperm DNA damage remains to be established, the data suggest that there is clinical value in testing couples prior to assisted reproductive technologies – ARTs (IUI, IVF, and ICSI) and in those couples with recurrent abortions. Large, well-designed prospective studies are needed before testing becomes a routine part of patient care.