Reproductive Outcomes of Testicular Versus Ejaculated Sperm for Intracytoplasmic Sperm Injection Among Men with High Levels of DNA Fragmentation in Semen: Systematic Review and Meta-Analysis

| Reproductive Health
*Sandro C. Esteves,1 Matheus Roque,2 Nicolás Garrido,3

The authors have declared no conflicts of interest.

EMJ Repro Health. ;3[1]:37-38. Abstract Review No. AR2.

Each article is made available under the terms of the .

Intracytoplasmic sperm injection (ICSI) has been widely used to overcome all forms of male factor infertility. Despite its overall acceptable success rates with the use of abnormal sperm, studies suggest that low sperm quality may adversely impact ICSI outcomes, likely due to altered sperm DNA content associated with impaired sperm characteristics.1-3 The negative impact of damaged paternal chromatin is usually manifested by impaired embryo development and early pregnancy loss, thus decreasing assisted reproductive therapy success.4

Sperm DNA fragmentation (SDF) assays measure the proportion of sperm with damaged chromatin in the neat ejaculate.4 Among couples undergoing ICSI, high SDF in the neat semen is found in ~30% of men.5 In recent studies, we found that the use of testicular sperm in preference over ejaculated sperm may offer better ICSI outcomes for men with high SDF in semen.6 The biological plausibility seems to be related to increased SDF in ejaculated, compared to testicular sperm, most probably due to elevated levels of reactive oxygen species in the epididymis that can cause post-testicular harm.7

At the European Society of Human Reproduction and Embryology (ESHRE) congress 2017, hosted in Geneva, Switzerland, these findings were presented concerning a PRISMA systematic review and meta-analysis of ICSI outcomes for testicular (Testi-ICSI) and ejaculated (Ejac-ICSI) sperm among non-azoospermic infertile men with confirmed post-testicular SDF. Our electronic search into major databases up to December 2016 identified seven studies, encompassing 507 ICSI cycles and 3,840 injected oocytes. Five studies provided paired data on SDF between ejaculated and testicular sperm, involving 143 patients who served as their own control. High SDF was defined according to the method and thresholds used in each study, most often terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) and 30%, respectively.

We found that SDF rates were lower in testicular rather than ejaculated sperm, with the mean difference by random-effect model (REM) being -24.58% (95% confidence interval [CI]: -32.53, -16.64; I2=92%; p<0.001). The pooled odds ratio (OR) for fertilisation rates using REM was 0.81 (95% CI: 0.58–1.15; I2=81%; p=0.24), with a trend to lower fertilisation rates in the Testi-ICSI group. Clinical pregnancy rates per fresh embryo transfer were higher with Testi-ICSI than Ejac-ICSI, with an OR using the fixed effects model (FEM) of 2.42 (95% CI: 1.57–3.73; I2=34%; p<0.001). As for miscarriage rates, we found that results favoured Testi-ICSI as compared to Ejac-ICSI, with an OR by FEM of 0.28 (95% CI: 0.11–0.68; p=0.005; I2=11%). Lastly, live birth rates per fresh embryo transfer were higher with Testi-ICSI as compared with Ejac-ICSI, with an OR by FEM of 2.58 (95% CI: 1.54–4.35; I2=0%; p<0.001).

To our knowledge, this is the first systematic review and meta-analysis summarising the evidence currently available concerning Testi-ICSI in men with high SDF in neat semen. Our findings offer novel insights on SDF-related infertility and offer a possible therapeutic approach with the use of Testi-ICSI. Given the overall moderate quality of studies included in our meta-analysis, and the risks associated with sperm retrieval, the use of testicular over ejaculated sperm should be considered only in ICSI candidates with confirmed post-testicular SDF. In particular, couples with previous failed treatment cycles, where efforts to reduce SDF in the ejaculate have also failed, then injected sperm should be used.

Strassburger D et al. Very low sperm count affects the result of intracytoplasmic sperm injection. J Assist Reprod Genet. 2000;17(8):431-6. Esteves SC, Agarwal A. Reproductive outcomes, including neonatal data, following sperm injection in men with obstructive and nonobstructive azoospermia: case series and systematic review. Clinics (Sao Paulo). 2013;68(Suppl 1):141-50. Esteves SC et al. Comparison of sperm retrieval and reproductive outcome in azoospermic men with testicular failure and obstructive azoospermia treated for infertility. Asian J Androl. 2014;16(4):602-6. Gosálvez J et al. Unpacking the mysteries of sperm DNA fragmentation: ten frequently asked questions. J Reprod Biotechnol Fertil. 2015;4:1-16. Bungum M et al. Sperm DNA integrity assessment in prediction of assisted reproduction technology outcome. Hum Reprod. 2007;22(1):174-9. Esteves SC et al. Comparison of reproductive outcome in oligozoospermic men with high sperm DNA fragmentation undergoing intracytoplasmic sperm injection with ejaculated and testicular sperm. Fertil Steril. 2015;104(6):1398-405. Esteves SC et al. Use of testicular sperm for intracytoplasmic sperm injection in men with high sperm DNA fragmentation: a SWOT analysis. Asian J Androl. 2017. [Epub ahead of print].