Comparison of reproductive outcome in oligozoospermic men with high sperm DNA fragmentation undergoing intracytoplasmic sperm injection with ejaculated and testicular sperm

Capsule:
The sperm DNA fragmentation index is w5-fold lower in testicular compared with in ejaculated sperm. The use of testicular sperm was associated with improved intracytoplasmic sperm injection outcomes in men with oligozoospermia and persistent high sperm DNA fragmentation.

Authors:
Sandro C. Esteves, M.D., Ph.D., Fernando Sánchez-Martín, M.D., Pascual Sánchez-Martín, M.D., Danielle T. Schneider, M.Sc., Jaime Gosálvez, Ph.D.

Volume 104, Issue 6, Pages 1398-1405

Abstract:

Objective:
To investigate the effectiveness of intracytoplasmic sperm injection (ICSI) using testicular sperm as a strategy to overcome infertility in men with high sperm DNA fragmentation (SDF).

Design:
Prospective, observational, cohort study.

Setting:
Private IVF centers.

Patient(s):
A total of 147 couples undergoing IVF-ICSI and day 3 fresh ETs whose male partner has oligozoospermia and high SDF.

Intervention(s):
Sperm injections were carried out with ejaculated sperm (EJA-ICSI) or testicular sperm (TESTI-ICSI) retrieved by either testicular sperm extraction (TESE) or testicular sperm aspiration (TESA). SDF levels were reassessed on the day of oocyte retrieval in both ejaculated and testicular specimens.

Main Outcome Measure(s):
Percentage of testicular and ejaculated spermatozoa containing fragmented DNA (%DFI) and clinical pregnancy, miscarriage, and live-birth rates.

Result(s):
The %DFI in testicular sperm was 8.3%, compared with 40.7% in ejaculated sperm. For the TESTI-ICSI group versus the EJA-ICSI group, respectively, the clinical pregnancy rate was 51.9% and 40.2%, the miscarriage rate was 10.0% and 34.3%, and the live-birth rate was 46.7% and 26.4%.

Conclusion(s):
ICSI outcomes were significantly better in the group of men who had testicular sperm used for ICSI compared with those with ejaculated sperm. SDF was significantly lower in testicular specimens compared with ejaculated counterparts. Our results suggest that TESTI-ICSI is an effective option to overcome infertility when applied to selected men with oligozoospermia and high ejaculated SDF levels.

  • Sperm DFI is a valuable test that has suffered from vague indications and different methodologies used to assay. The use of sperm DFI testing in the setting of failed IVF cycle with ejaculated sperm and using testicular sperm for the second cycle is reasonable given that couples are heartened by the fact that the doctors are attempting something different for the second time around. The increased success in the repeat cycle can be contributed to several other factors other than use of testicular sperm but certainly something to be studied in the future as suggested by the previous discussants

    • Sandro Esteves

      Measurement of SDF in the semen is suggested after a failed IVF attempt. The reason relies on the reported lower pregnancy outcome after ICSI in cases of elevated SDF. Obviously many other factors can contribute to a failed IVF cycle, but in the face of elevated SDF an option to be discussed with the couple would be the use of testicular sperm.

      However, it is worth mentioning some key aspects of our methods: 1. Our population comprised infertile couples in their first IVF attempt; 2. All male partners had persistent high SDF even after antioxidant therapy for at least 3 months; 3. Patients were re-tested for SDF at the day of egg collection, and again SDF were above normal thresholds. Additionally, SDF was measured in testicular specimens – as well as in the semen – in the group subjected to TESTI-ICSI. SDF rates in testicular sperm were 5-fold lower than ejaculated sperm. Our results were reassuring to suggest an association between the use of sperm with low SDF and better live birth rates after ICSI. Based on these results, we now advocate SDF testing to IVF candidates prior to their first attempt. In the face of abnormal results, we discuss with our patients options to decrease SDF. These include antioxidant therapy and life style changes, repair of clinical varicoceles, treatment of subclinical infection, serial ejaculation, and use of testicular sperm for ICSI. If high SDF persists, we offer TESTI-ICSI as a first line therapy to overcome the cases of poor IVF outcome due to damaged sperm chromatin.

  • Jason M. Franasiak

    Thank you Dr. Esteves for your follow-up comment. It might also be of interest to employ a paired embryo transfer study in which the best embryo from each of the split M2 cohorts is picked and DNA fingerprinting is utilized to identify singleton outcomes from each group. Thank you again for your thoughts and fascinating work.

  • Jason M. Franasiak

    Another interesting study investigating surgical sperm as a possible intervention for high sperm DNA fragmentation. It may be on interest in the future to do a paired study to compare fertilization rates and embryologic parameters in the same individual: randomize M2 oocytes to ICSI with ejaculated sperm and microsurgical sperm to evaluate impact on a single couples outcomes. May limit any confounders seen when comparing couples and would also provide additional evidence that this intervention may improve outcomes in an individual, rather than between groups.

    • Sandro Esteves

      Dear Jason,
      Thank you for pointing this out. Actually, we have unpublished data on ejaculated versus testicular sperm in split M2 oocytes. What we have seen is a variable response in terms of embryonic outcomes, including cases in which no difference was observed as well as some favoring ejaculated sperm. It seems that abnormally elevated DFI will have a more pronounced negative effect at the time of implantation or later (late paternal effect). But following your insights, two aspects that might be interesting to consider in future studies would be to analyze blastocyst quality and embryo development by Time-lapse culture, and embryo biopsy of resulting embryos.

  • Esteves et al present similar data to the Cornell group in a previous article in this month’s journal. There is mounting evidence for much lower DFI in testicular sperm compared to ejaculated sperm. The pregnancy/delivery outcomes are significantly higher with testicular sperm. DFI testing may become a very important part of the ISCI evaluation for the male partner especially when there is oligospermia and elevated DFI levels. Although there is a small risk associated with having a procedure to extract testicular sperm compared to using ejaculated sperm, the outcomes using testicular sperm are better.

    • Sandro Esteves

      Dear Ed,
      Thanks for your comment. As I pointed out in the reply to Mike, I consider important to test for SDF after 2 days abstinence only. As it has been shown that the longer the abstinence period the higher the DFI, we’ve utilized a fixed period of 2 days abstinence lately. Following this strategy, you could avoid performing TESA/TESE in men with mild DFI elevation who turn out to be within normal DFI range with short abstinence. We have also applied TESTI-ICSI in men with unexplained male infertility and elevated DFI and results have been consistent with our reported observations in oligozoospermic men.

  • interesting articles on treating elevated sDFI using testicular sperm retrieval. in my practice, I only screen men with history of miscarriage or failed ART and have also observed improved outcome using testicular sperm retrieval. since this study focused on all men with oligospermia regardless of prior history, do the authors recommend sDFI screening before all IVF ICSI cycles?

    • Sandro Esteves

      Dear Mike,
      Thank you for your comment.
      We currently screen all ART candidates for SDF, except those cases in which testing is not feasible due to methodological reasons.
      For testing, we now ask patients to abstain from ejaculation for 2 days rather than allowing patients to collect as per the WHO recommendation of 2-7 days. This allows increasing test specificity and thus deselecting some cases that would test abnormal as a result of longer abstinence from TESTI-ICSI.

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