The development of intracytoplasmic sperm injection (ICSI), first described just over 25 years ago1, marked a major milestone in the treatment of infertile couples using in vitro fertilization. In addition to being immensely successful when used for couples with a history of complete and unexplained fertilization failure, ICSI became the ultimate tool to treat patients with male factor infertility2. Since its inception, ICSI has gained worldwide popularity3, and its use for nonmale factor indications has grown considerably, leading us to wonder: are we now abusing ICSI?
From 1993 to 2018, nearly 37,976 ICSI cycles were performed at our center. While the large majority was with ejaculated spermatozoa, 9.8% of ICSI treatments utilized either fresh or frozen surgically retrieved spermatozoa. The proportion of ICSI use in comparison to standard in vitro insemination has risen dramatically over this period, and in 2018 it accounted for over 90% of all insemination cycles done at Weill Cornell Medicine. This increase mirrors the rising trend seen worldwide4, which includes the increased use of ICSI in the fertilization of thawed and donor oocytes, as well as in preimplantation genetic testing5. Moreover, at our center, ICSI is used when there is questionable maturity of the female gamete and low oocyte yield at retrieval. It also remains the best treatment option for couples experiencing all types of male factor infertility.
Ejaculated spermatozoa have been utilized in 33,856 cycles performed at our center, with 28,171 (83.3%) treatments utilizing spermatozoa with compromised characteristics and 5685 (16.8%) using semen samples with normal parameters as defined by 2010 WHO criteria6. Among the population treated by ICSI using ejaculated spermatozoa with abnormal semen parameters are patients who suffer from severe oligozoospermia (≤1 million/mL) and cryptozoospermia (no sperm seen during the initial analysis of the sample). Severe oligozoospermia was a factor in 2260 ICSI cycles that resulted in a 62.6% fertilization rate and a clinical pregnancy rate (CPR) of 46.1%. Cryptozoospermia accounted for 354 ICSI cycles, which yielded a fertilization rate of 54.9% and a CPR of 45.2%. The success seen with these patients underscores the important role of ICSI insemination in cases of severe male factor infertility.
A total of 3075 ICSI treatments have been performed on couples in which the male partner has either obstructive azoospermia (OA) or nonobstructive azoospermia (NOA). Retrieving spermatozoa from patients with OA involves microsurgical epididymal sperm aspiration (MESA), in which gametes displaying adequate concentration and motility are aspirated directly from the epididymis. In rare cases in which the epididymal approach is not feasible, sperm cells are retrieved directly from the seminiferous tubule. At our center, there have been 592 cycles performed with MESA samples for congenital causes and 609 cycles performed with MESA samples for acquired causes of OA. Patients with congenital OA have had a better fertilization rate (72.1% vs. 70.2%; P=0.01) and CPR (53.2% vs 43.2%; P<0.001). This includes both fresh and frozen epididymal sperm. Fertilization rates using fresh and frozen epididymal samples are nearly identical, but there is a significantly greater CPR when cycles utilize fresh epididymal sperm followed by cryopreserved sperm in this chronological series (60.1% vs. 44.5%; P<0.00001).
Patients with NOA undergo testicular sperm extraction (TESE), which yields spermatozoa in 61.7% of procedures performed at our center. Sperm taken directly from the testicle has been used in 1877 cycles. Despite having low concentration and motility, as well as atypical morphology, TESE sperm has been used successfully in these cases. However, testicular spermatozoa perform better in cases of OA (cases that cannot benefit from MESA) than NOA in terms of the fertilization rate (65.9% vs. 48.5%; P=0.0001) and CPR (42.8% vs. 36.1%; P=0.05). TESE cycles utilizing fresh spermatozoa outperform their frozen counterparts in terms of generating a pregnancy (P<0.05). Using next-generation sequencing and fluorescent in situ hybridization, our team has even revisited the safety of TESE and found that testicular spermatozoa have less aneuploidy than ejaculated specimens and are just as safe to use7.
Assays such as the sperm chromatin structure assay and terminal deoxynucleotidyl dUTP transferase nick end labeling (TUNEL), which measure the sperm chromatin fragmentation (SCF) of the male gamete, are now commonly used to thoroughly evaluate a man’s fertility and ability to father a child. Men with elevated ejaculate SCF have poor clinical outcomes as compared with men without compromised sperm chromatin integrity. It has been proposed that men with high SCF in their ejaculate undergo surgical retrieval of spermatozoa directly from the seminiferous tubule8,9 reporting enhanced implantation rate and CPRs (P<0.05).
In a new and more conservative approach, we have processed ejaculated samples using a microfluidic device that drastically reduces SCF of the final sample (P<0.0001), which is used for ICSI insemination. Our initial findings are encouraging, demonstrating an increase in the generation of euploid embryos and pregnancies (P<0.0001) as compared with ICSI cycles using conventional sperm selection methods.
We are constantly testing the potential and limits of this versatile and sophisticated technique. ICSI has evolved from a tool used for couples struggling with male infertility and unexpected and complete fertilization failure into a treatment utilized for the majority of our assisted reproductive technology population. The quest to select the best spermatozoon will always be vital, particularly as we gain more insight into male fertility through the study of its genome and epigenome.
While the reliability of this technique is undeniable, its use should be applied judiciously while monitoring its safety to allow ICSI to remain a fundamental pillar in the treatment of infertility.
Conflict of interest statement
The authors declare that they have no financial conflict of interest with regard to the content of this report.
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