Extended indications for sperm retrieval: summary of current literature

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Esteves" }, { "@type": "Person", "name": "Matheus Roque" } ], "publisher": { "@type": "Organization", "name": "F1000Research", "logo": { "@type": "ImageObject", "url": "https://f1000research.com/img/AMP/F1000Research_image.png", "height": 480, "width": 60 } }, "image": { "@type": "ImageObject", "url": "https://f1000research.com/img/AMP/F1000Research_image.png", "height": 1200, "width": 150 }, "description": "Sperm retrieval combined with intracytoplasmic sperm injection (ICSI) is the treatment of choice for couples with untreatable azoospermia-related infertility. However, an increasing body of evidence has been mounting, suggesting that ICSI with testicular sperm instead of ejaculated sperm (when both are available) increases pregnancy outcomes in some specific scenarios. This has led to the exploration of extended indications for sperm retrieval. This review summarizes the current literature concerning sperm retrieval and ICSI for non-azoospermic men with elevated sperm DNA fragmentation, oligozoospermia, and cryptozoospermia." } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/8-2054", "name": "Extended indications for sperm retrieval: summary of current literature" } } ] } Home Browse Extended indications for sperm retrieval: summary of current literature ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Esteves SC and Roque M. Extended indications for sperm retrieval: summary of current literature [version 1; peer review: 2 approved] . F1000Research 2019, 8 (F1000 Faculty Rev):2054 ( https://doi.org/10.12688/f1000research.20564.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Review Extended indications for sperm retrieval: summary of current literature [version 1; peer review: 2 approved] Sandro C. Esteves https://orcid.org/0000-0002-1313-9680 1-3 , Matheus Roque 4 Sandro C. Esteves https://orcid.org/0000-0002-1313-9680 1-3 , Matheus Roque 4 PUBLISHED 04 Dec 2019 Author details Author details 1 ANDROFERT, Andrology and Human Reproduction Clinic, Campinas, SP, Brazil 2 Department of Surgery (Division of Urology), State University of Campinas, Campinas, SP, Brazil 3 Faculty of Health, Aarhus University, Aarhus, Denmark 4 MATER PRIME Clinic, São Paulo, SP, Brazil Sandro C. Esteves Roles: Conceptualization, Project Administration, Writing – Original Draft Preparation Matheus Roque Roles: Formal Analysis, Resources, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS Abstract Sperm retrieval combined with intracytoplasmic sperm injection (ICSI) is the treatment of choice for couples with untreatable azoospermia-related infertility. However, an increasing body of evidence has been mounting, suggesting that ICSI with testicular sperm instead of ejaculated sperm (when both are available) increases pregnancy outcomes in some specific scenarios. This has led to the exploration of extended indications for sperm retrieval. This review summarizes the current literature concerning sperm retrieval and ICSI for non-azoospermic men with elevated sperm DNA fragmentation, oligozoospermia, and cryptozoospermia. READ ALL READ LESS Keywords sperm DNA fragmentation, sperm chromatin damage, sperm retrieval, testicular sperm, ejaculated sperm, assisted reproductive technology, in vitro fertilization, intracytoplasmic sperm injection, oligozoospermia, cryptozoospermia, pregnancy, offspring health, male infertility Corresponding Author(s) Sandro C. Esteves ( [email protected] ) Close Corresponding author: Sandro C. Esteves Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2019 Esteves SC and Roque M. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Esteves SC and Roque M. Extended indications for sperm retrieval: summary of current literature [version 1; peer review: 2 approved] . F1000Research 2019, 8 (F1000 Faculty Rev):2054 ( https://doi.org/10.12688/f1000research.20564.1 ) First published: 04 Dec 2019, 8 (F1000 Faculty Rev):2054 ( https://doi.org/10.12688/f1000research.20564.1 ) Latest published: 04 Dec 2019, 8 (F1000 Faculty Rev):2054 ( https://doi.org/10.12688/f1000research.20564.1 ) Introduction Intracytoplasmic sperm injection (ICSI) was an extraordinary achievement in the field of assisted reproduction technology (ART). Introduced in 1992 as a modification of conventional in vitro fertilization (IVF), ICSI enables men with low sperm quantity and quality to father a child 1 , 2 . Nowadays, ICSI has become not only the most commonly used method of fertilization in ART but also the method of choice for overcoming untreatable severe male factor infertility 3 . ICSI is typically carried out with ejaculated sperm, which are generally regarded as having the highest fertilization potential since they have completed their transit through the male reproductive tract. By contrast, sperm retrieval methods—developed a few years after the introduction of ICSI—have been used to harvest sperm from the epididymides and testes of men with azoospermia-related infertility 4 , 5 . After retrieval of epididymal or testicular sperm, ICSI is mandatory as the retrieved gametes are unable to fertilize the oocytes by conventional IVF. However, as experience accumulated, reports of an association between semen quality and ICSI outcomes increased steadily 6 – 8 . Concerns of a possible role of the paternal gamete on ICSI outcomes led Greco et al. , in 2005, to investigate the utility of sperm retrieval in a group of 18 non-azoospermic patients with elevated sperm DNA fragmentation (SDF) on neat semen 9 . On the day of oocyte retrieval, the male partners underwent sperm retrieval using percutaneous or open methods to harvest sperm from the seminiferous tubules. In this series, ICSI with testicular sperm (Testi-ICSI) resulted in eight clinical pregnancies (44.5%) whereas only one pregnancy (5.6%) that ended in miscarriage had been obtained in previous ICSI cycles with the use of ejaculated sperm. Given this information, the utility of sperm retrieval in indications other than azoospermia has been investigated. Here, the current support for these indications, including elevated SDF, severe oligozoospermia, and cryptozoospermia—denoted by very few spermatozoa (or none) in the fresh ejaculate but observed after microscopic examination of centrifuged pellet—will be summarized. Extended sperm retrieval indications: biological plausibility It is well established that sperm chromatin integrity is vital for the birth of healthy infants 10 . Fertilization of oocytes by sperm with DNA fragmentation might increase the risk of fertilization failure, embryo development arrest, implantation failure, miscarriage, congenital malformations, and perinatal and postnatal morbidity 11 – 13 . Notably, infertile men often have elevated SDF rates in neat semen 14 , 15 . Varicocele, systemic diseases, male accessory gland infections, advanced paternal age, obesity, lifestyle and environmental factors, radiation, and heat exposure are some of the conditions associated with SDF 16 , 17 . These stressors have in common the trait of oxidative stress, which represents a significant cause of SDF 18 . The mechanisms involve reactive oxygen species (ROS) attack on sperm membranes and nuclear and mitochondrial DNA, mostly during sperm transit through the male reproductive tract 19 – 21 . Interestingly, data from human studies assessing paired testicular and ejaculated specimens of non-azoospermic men indicate that SDF is two to three times lower in testicular sperm than in ejaculated sperm 9 , 22 – 25 . A 2017 systematic review—followed by a meta-analysis—compiled the results of five studies including 143 patients and showed that the mean difference (MD) in SDF rates was −24.6% (95% confidence interval [CI] −32.5 to −16.6%, I 2 = 92%, P <0.001) in favor of testicular sperm 26 . In that report, SDF was measured by using the terminal deoxyribonucleotide transferase–mediated dUTP nick-end labeling (TUNEL) assay (four studies, pooled MD: −19.8%, 95% CI −22.3 to −17.2%, I 2 = 15%, P <0.001) or the sperm chromatin dispersion (SCD) assay (one study, MD: −32.4%, 95% CI −34.85 to −29.95%, P <0.001). Elevated sperm DNA fragmentation After the report by Greco et al. 9 , several authors investigated the utility of sperm retrieval in non-azoospermic men with elevated SDF in neat semen ( Table 1 ) 19 , 24 , 25 , 27 – 32 . In a 2017 systematic review, we aggregated the evidence of five studies including 507 ICSI cycles 26 . In total, 3,840 oocytes were injected with either ejaculated sperm or testicular sperm. Using meta-analysis, we showed higher clinical pregnancy rates (odds ratio [OR] 2.42, 95% CI 1.57 to 3.73, I 2 = 34%, P <0.0001) and live birth rates (OR 2.58, 95% CI 1.54 to 4.35, I 2 = 0%, P = 0.0003), and lower miscarriage rates (OR 0.28, 95% CI 0.11 to 0.68, I 2 = 11%, P = 0.005) when comparing Testi-ICSI with ejaculated ICSI. Table 1. Studies reporting ICSI outcomes with testicular versus ejaculated sperm in non-azoospermic men with high sperm DNA fragmentation in the neat semen. Study characteristics Indication Sperm retrieval method Outcomes Author (year) Design Subjects and cohort size (N) Test used for sperm chromatin damage assessment and cutoff values (%) Paired SDF results in testicular and ejaculated sperm (%) Sperm retrieval method Sperm retrieval success and complication rates (%) Fertilization rate (%) Clinical pregnancy rate (%) Ongoing pregnancy rate or live birth rate a (%) Greco et al . 9 (2005) Case series Predominantly normozoospermic infertile men (18); couples with history of ICSI failure performed with ejaculated sperm TUNEL (15) 23.6 ± 5.1 (E) and 4.8 ± 3.6 (T) ( P <0.001) TESE and TESA 100.0 and NR 74.9 b 44.4 c NR Sakkas and Alvarez 19 (2010) Case series Couples with history of IVF/ICSI failure (68) with ejaculated sperm TUNEL (20) NR TESA NR 58.0; range: 20.0–100.0 40.0 NR Esteves et al . 24 (2015) Prospective cohort Oligozoospermic (sperm concentration 5–15 million/mL) infertile men (172); couples with no history of ICSI failure (Testi-ICSI, n = 81 and Ejac-ICSI, n = 91) SCD (30) 40.9 ± 10.2 (E) and 8.3 ± 5.3 (T) ( P <0.001) TESE and TESA 100.0 and 6.2 69.4 (E) vs. 56.1 (T) ( P = 0.0001) 40.2 (E) vs. 51.9 (T) (NS) LBR: 26.4 (E) vs. 46.7 (T) ( P = 0.007) Mehta et al . 25 (2015) Case series Oligozoospermic (sperm concentration <5 million/mL) infertile men (24); couples with one or more failed IVF or ICSI cycles using ejaculated sperm TUNEL (7) 24.0 (95% CI 19–34) (E) and 5.0 (95% CI 3–7) (T) ( P = 0.001) Micro-TESE 100.0 and NR 54.0 50.0 50.0 Bradley et al . 27 (2016) Retrospective cohort Predominantly oligozoospermic infertile men; Testi-ICSI (n = 148) d , Ejac-ICSI (n = 80) d SCIT (29) NR TESE and TESA NR 66.0 (E) vs. 57.0 (T) ( P <0.001) 27.5 (E) vs. 49.5 (T) ( P <0.01) LBR: 24.2 (E) vs. 49.8 (T) ( P <0.05) Pabuccu et al . 28 (2016) Retrospective cohort Normozoospermic infertile men (71); couples with history of ICSI failure using ejaculated sperm (Testi-ICSI, n = 31; Ejac-ICSI, n = 40) TUNEL (30) 41.7 ± 8.2 (E) TESA 100.0 and NR 74.1 ± 20.7 (T) vs. 71.1 ± 26.9 (E) (NS) 41.9 (T) vs. 20.0 (E) ( P = 0.04) OPR: 38.7 (T) vs. 15.0 (E) ( P = 0.02) Arafa et al . 29 (2018) Prospective cohort; interventions applied in the same patients Oligozoospermic and normozoospermic infertile men (36); couples with history of ICSI failure performed with ejaculated sperm SCD (30) 56.3 ± 15.3 (E) TESA 100.0 and NR 46.4 (T) vs. 47.8 (E) (NS) 38.9 (T) vs. 13.8 (E) ( P <0.0001) LBR: 38.9 (T) vs. 8.0 (E) ( P <0.0001) Zhang et al . 30 (2018) Prospective cohort e Oligozoospermic and normozoospermic infertile men (102); couples with no history of ICSI failure (Testi-ICSI, n = 61; Ejac-ICSI, n = 41) SCSA (30) NR TESA 100.0 and NR 70.4 (T) vs. 75.0 (E) (NS) 36.0 (T) vs. 14.6 (E) ( P = 0.01) LBR: 36.0 (T) vs. 9.8 (E) ( P = 0.001) Herrero et al . 31 (2019) Retrospective cohort Couples with no previous live births and a history of at least two previous failed ICSI cycles with ejaculated sperm (Testi-ICSI, n = 77; Ejac-ICSI, n = 68) SCSA (25); TUNEL (36%) NR TESE NR SCSA: 66.3 (T); 62.9 (E) (NS) TUNEL: 61.2 (T); 57.6 (E) (NS) SCSA: 18.2 (T); 9.1% (E) ( P <0.02) TUNEL: 23.1 (T); 0.0 (E) ( P <0.02) f SCSA: 21.7 (T); 9.1 (E) ( P <0.01) TUNEL: 20.0 (T); 0.0 (E) ( P <0.02) Alharbi et al . 32 (2019) Retrospective cohort Couples with one or more failed ICSI cycles with ejaculated sperm Testi- ICSI, n = 52; Ejac-ICSI, n = 48) SCSA (15); subgroup analysis using SCSA thresholds of 30% NR TESA 100.0 and NR 58.0 ± 27.0 (T) vs. 70.0 ± 23.0 ( P = 0.03) DFI >15%: 48.6 (T) vs. 38.7 (E); DFI >30%: 48.0% vs. 25.0% ( P = 0.25) g DFI >15%: 36.4 (T) vs. 30.0 (E); DFI >30%: 29.2 vs. 25.0 (NS) a Herrero et al . 31 reported cumulative live birth rates. b 2PN fertilization rate with use of testicular sperm; data from previous cycles with use of ejaculated sperm not provided. c The authors reported only one pregnancy with ejaculated sperm which miscarried. d Number of intracytoplasmic sperm injection (ICSI) cycles. e Inferred from the study’s reported data. f Cumulative live birth rates. g Alharbi et al . 32 reported pregnancy rates per embryo transfer; live birth data were incomplete as a number of patients achieving clinical pregnancy were lost in follow-up. E, ejaculated sperm group; Ejac-ICSI, ICSI with ejaculated sperm; LBR, live birth rate; micro-TESE, microdissection testicular sperm extraction; NR, not reported; NS, not significantly different; OPR, ongoing pregnancy rate; SCD, sperm chromatin dispersion; SCIT, sperm chromatin integrity test, a variation of sperm chromatin structure assay (SCSA); SDF, sperm DNA fragmentation; T, testicular sperm group; TESA, testicular sperm aspiration; TESE, Testicular sperm extraction, Testi-ICSI, ICSI with testicular sperm; TUNEL, terminal deoxyribonucleotide transferase–mediated dUTP nick-end labeling assay. Recent studies providing live birth data corroborate the effectiveness of testicular sperm for ICSI in men with high SDF 29 – 31 . Thus, despite the limited evidence and lack of randomized controlled trials, data from seven retrospective studies and three prospective studies, including a total of 830 patients and 902 ICSI cycles, suggest that Testi-ICSI is superior to ICSI with ejaculated sperm to overcome infertility among non-azoospermic men with elevated SDF in semen. Testi-ICSI has been postulated to bypass post-testicular sperm chromatin damage caused by oxidative stress during sperm transit through the epididymis 33 . As a result, the chances of oocyte fertilization by genomically intact spermatozoa and formation of a normal embryonic genome are increased, thus positively impacting the likelihood of achieving a live birth. Notably, a single study 32 including 110 couples with sperm DNA damage data failed to corroborate the latter findings; however, in that study, SDF thresholds of 15% (by sperm chromatin structure assay, or SCSA) were used to select couples eligible for Testi-ICSI; those thresholds are not fully consistent with the 30% SCSA thresholds reported to be associated with adverse pregnancy outcomes in ART 34 . Thus, the inclusion of ~30% of men with SDF values between 15% and 30% in the above study might have diluted the positive effect of Testi-ICSI. Severe oligozoospermia and cryptozoospermia Weissman et al ., in 2008, reported the first series of Testi-ICSI in patients with severe oligozoospermia (<5 million sperm/mL) 35 . The authors performed testicular sperm injections in four couples with a history of multiple failed IVF/ICSI cycles after the use of poor-quality ejaculated sperm. The male partners had sperm counts ranging from 0.2 million/mL to 2.0 million/mL. On the day of oocyte retrieval, sperm retrieval was performed, and in all cases, motile spermatozoa were retrieved from the testis. All couples achieved embryo implantation and delivery of healthy offspring after embryo transfers. Given the success reported by Weissman et al. 35 , many authors sought to investigate the utility of sperm retrieval for ICSI in non-azoospermic patients with severe oligozoospermia or cryptozoospermia ( Table 2 ) 36 – 39 . These studies report an overall better pregnancy outcome with the use of testicular than ejaculated sperm. But surprisingly, in 2016, a systematic review and meta-analysis aggregating the data of the above studies concluded that sperm retrieval should not be recommended in men with severe oligozoospermia or cryptozoospermia 40 . In that report, the relative risk (RR) of achieving pregnancy (272 cycles, RR = 0.53, 95% CI 0.19 to 1.42) with the use of testicular or ejaculated sperm for ICSI was not different. However, we performed a careful examination of the authors’ data and discovered that they inadvertently inverted the number of pregnancies reported in the study by Bendikson et al. 36 concerning the group of patients undergoing ICSI with testicular and ejaculated sperm. This critical mistake inflated the total number of pregnancies in the ejaculate sperm group, thus leading to an erroneous RR calculation. We reassessed the pregnancy results of the meta-analysis by Abhyankar et al. 40 —after correcting the incongruency mentioned above—and found a significantly higher pregnancy rate with the use of testicular sperm than with ejaculated sperm in men with cryptozoospermia and severe oligozoospermia (272 cycles, RR = 3.21, 95% CI 1.70 to 6.05, I 2 = 42%, P = 0.0003) ( Figure 1 ; unpublished data). Table 2. Characteristics and main outcome measures of studies reporting ICSI outcomes with testicular versus ejaculated sperm in non-azoospermic men with severe oligozoospermia/cryptozoospermia. Study characteristics Indication Sperm retrieval method Outcomes Author (year) Design Subjects and cohort size (N) SDF assessment Sperm retrieval method Sperm retrieval success and complication rates (%) Fertilization rate (%) Clinical pregnancy rate (%) Live birth rate (%) Weissman et al . 35 (2008) Case series Severe oligozoospermic (<5 million/mL) infertile men (4) undergoing Testi-ICSI; couples with a history of multiple failed ICSI cycles with ejaculated sperm; in total, five TESA-ICSI cycles were carried out in the cohort of four patients No TESA 100.0 and NR 67.6 75.0 75.0 Bendikson et al . 36 (2008) Case series Cryptozoospermic infertile men (16); couples with history of IVF/ICSI failure (16) with ejaculated sperm; in total, 21 TESA-ICSI cycles were carried out in the cohort of 16 patients No Micro-TESE 100.0 and NR 51.7 (T) vs. 59.9 (E) (NS) 20.8 (E) vs. 47.4 (T) (NS) 20.8 (E) vs. 42.1 (T) (NS) Hauser et al . 37 (2011) Prospective cohort Cryptozoospermic infertile men (13); in total, 93 ICSI cycles (ICSI with ejaculated sperm, n = 34; ICSI with fresh testicular sperm, n = 9; ICSI with frozen-thawed testicular sperm, n = 50) were carried out in the cohort of 13 patients No TESE 100.0 and NR 38.2 (E) vs. 50.0 (T, fresh) vs. 46.7 (T, frozen-thawed) a ( P <0.05, pairwise comparisons between T and E sperm) 14.3 (E) vs. 42.9 (T, fresh) vs. 12.8 (T, frozen- thawed) (NS) 14.3 (E) vs. 42.9 (T, fresh) vs. 12.8 (T, frozen-thawed) (NS) Ben-Ami et al . 39 (2013) Case series Cryptozoospermic (17) infertile men; couples with multiple failed ICSI cycles using ejaculated sperm; in total, 116 ICSI cycles (Testi-ICSI, n = 48; Ejac-ICSI, n = 68) were carried out in the cohort of 16 patients No TESE 100.0 and NR 38.0 (E) vs. 46.7 (T) (NS) 15.1 (E) vs. 42.5 (T) ( P = 0.004) 9.4 (E) vs. 27.5 (T) ( P = 0.028) Ketabchi 41 (2016) Prospective cohort Cryptozoospermic (<10 3 sperm/mL) infertile men (73) undergoing ICSI with sperm retrieved from the epididymis or testis (18) No PESA and TESE 100.0 and NR 55.3 (E) vs. 85.7. (T+E) ( P <0.001) 31.6 (E) vs. 57.1 (T) ( P <0.001) NR Cui et al . 42 (2017) Retrospective cohort Cryptozoospermic infertile men undergoing Testi-ICSI; couples (285) undergoing ICSI with ejaculated sperm (214) or testicular sperm (71) No TESA and TESE 97.9 and NR 59.6 (E) vs. 60.6 (T) (NS) 33.3 (E) vs. 53.6 (T) ( P <0.01) 27.1 (E) vs. 44.0 (T) ( P = 0.03) Yu et al. 45 (2019) Retrospective cohort Cryptozoospermic infertile men (35) undergoing Testi-ICSI; in total, 19 cycles (18 patients) were performed with ejaculated sperm and 19 cycles (17 patients) with testicular sperm No TESA and micro-TESE 100.0 and NR 74.7 (E) and 62.4 (T) in men <35 years old ( P = 0.01); 60.9 (E) and 56.6 (T) in men ≥35 years old (NS) 74.7 (E) and 62.4 (T) in men <35 years old ( P = 0.01); 60.9 (E) and 56.6 (T) in men ≥35 years old (NS) 44.4 (E) and 52.9 (T) in men <35 years old (NS); 0.0 (E) and 42.9 (T) in men ≥35 years old a 2PN fertilization using motile sperm. E, ejaculated sperm group; Ejac-ICSI, intracytoplasmic sperm injection with ejaculated sperm; LBR, live birth rate; micro-TESE, microdissection testicular sperm extraction; NR, not reported; NS, not significantly different; OPR, ongoing pregnancy rate; SDF, sperm DNA fragmentation; T, testicular sperm group; TESA, testicular sperm aspiration; TESE, Testicular sperm extraction, Testi-ICSI, intracytoplasmic sperm injection with testicular sperm. Figure 1. Pregnancy rates according to sperm source in non-azoospermic men with cryptozoospermia or severe oligozoospermia. Forest plot showing odds ratio for pregnancy with use of ejaculated sperm or testicular sperm for intracytoplasmic sperm injection in men with cryptozoospermia/severe oligozoospermia. CI, confidence interval; M-H, Mantel–Haenszel analysis. Recently, additional reports and systematic reviews on the matter concerned were published 41 – 45 . In a 2018 systematic review and meta-analysis, Kang et al . pooled the data of six studies including a total of 578 patients and 761 ICSI cycles 43 . The authors showed that sperm retrieval and Testi-ICSI improved the likelihood of achieving good-quality embryos (RR = 1.17, 95% CI 1.05 to 1.30, P = 0.005), implantation (RR = 1.52, 95% CI 1.02 to 2.26, P = 0.04), and pregnancy (RR = 1.74, 95% CI 1.20 to 2.52, P = 0.004). These results were corroborated by Ku et al ., who pooled the evidence of studies that provided miscarriage and live birth data 44 . The authors included a total of 331 patients and 479 ICSI cycles. In that report, miscarriage rates were not affected by the use of testicular or ejaculated sperm for ICSI (RR = 1.06, 95% CI 0.48 to 2.35), but live birth rates per initiated cycle were increased among couples that had undergone Testi-ICSI (RR = 1.77, 95% CI 1.28 to 2.44, P = 0.0005). Collectively, evidence from seven retrospective studies and one prospective study, including a total of 613 patients and 799 ICSI cycles, suggests that Testi-ICSI is superior to ICSI with ejaculated sperm to overcome infertility among non-azoospermic men with severe oligozoospermia or cryptozoospermia ( Table 2 ). Likewise, Testi-ICSI has been postulated to bypass post-testicular sperm damage during sperm transit through the genital tract. However, no randomized controlled study has been published yet to support the routine use of sperm retrieval and testicular sperm for ICSI to non-azoospermic men with low sperm count undergoing ICSI. Confounding factors The relatively low testicular sperm positivity for DNA damage might explain the better reproductive outcomes with the use of testicular sperm rather than ejaculated sperm for ICSI. Nevertheless, it is important to acknowledge that the evidence concerning the superiority of Testi-ICSI relies overwhelmingly on cohort studies with few patients, in which confounding factors, such as maternal and paternal age, etiology of male factor infertility, use of medication with possible gonadotoxic effect, and lifestyle factors, to cite a few, were not properly controlled. For instance, it has been suggested that the adverse effect of sperm DNA damage on reproductive outcomes is modulated by female age because of the intrinsic (albeit limited) capacity of oocytes from young women to repair the DNA damage 46 – 48 . On the other hand, women of advanced reproductive age have significantly fewer euploid embryos available for transfer, which will reduce ART success irrespective of the type of sperm used 49 . Since not all sperm DNA damage is repairable, it seems sound to suggest that surgically retrieved sperm should not be used as a last resort after years of treatment with ejaculated sperm because the oocyte apparatus to repair sperm DNA damage is less efficient as both ovarian reserve and maternal age increase 48 . These observations highlight the importance of controlling for confounders in future studies evaluating the clinical utility of testicular sperm in non-azoospermic men. Technical aspects Both percutaneous and open sperm retrieval procedures can be used to harvest sperm from the seminiferous tubules in non-azoospermic men ( Figure 2 ) 50 – 52 . The testicle rather than the epididymis is the target organ because of the reported lower SDF rates in the former 53 – 55 . In such patients, the reported sperm retrieval success rates are close to 100% with the use of testicular sperm aspiration (TESA), testicular sperm extraction (TESE), or microdissection TESE (micro-TESE) ( Table 1 and Table 2 ). Our choices are TESA for men with elevated SDF and TESE or micro-TESE for cryptozoospermic patients 24 , 56 . In our hands, these methods are carried out on an outpatient basis on the same day of oocyte retrieval 50 – 52 , 56 – 58 . The reason relates to the fact that prolonged sperm incubation—in particular, at 37°C—and sperm freezing might negatively affect sperm chromatin integrity 21 , 59 , 60 . Figure 2. Sperm retrieval methods ( A ) Testicular sperm aspiration. The illustration depicts a 13G needle—connected to a 20-mL syringe and fitted to the Cameco holder—being percutaneously inserted into the testis. Negative pressure is created, and the tip of the needle is moved within the testis to disrupt the seminiferous tubules and sample different areas. ( B ) Testicular sperm extraction (TESE). Single or multiple incisions are made on the tunica albuginea, and one or several testicular biopsies are taken. ( C ) Microsurgical TESE (micro-TESE). With aid of an operating microscope, the dilated seminiferous tubules are identified and removed with microforceps. The illustration in the middle of the figure depicts histopathology cross-sections of dilated seminiferous tubules with active spermatogenesis* and a thin tubules with germ cell aplasia ‡ . Adapted by permission from Macmillan Publishers Ltd 3 . In the context of non-azoospermic men, sperm retrieval is associated with few complications (less than 5%) as minimal tissue extraction yields sufficient numbers of sperm for ICSI 26 , 33 , 51 , 52 . Nevertheless, given the potential risk for complications and adverse effects on testicular function, sperm retrieval should be performed by well-trained urologists. Offspring health The use of sperm retrieval in non-azoospermic men has raised concerns about the health of resulting offspring because of the reports of increased sperm aneuploidy rates in testicular sperm (versus ejaculated sperm) 23 , 61 – 64 . On the one hand, ICSI has been associated with possible increased risks of congenital malformations, epigenetic disorders, chromosomal abnormalities, infertility, cancer, delayed psychological and neurological development, and impaired cardiometabolic profile compared with naturally conceived children and this is probably due to the influence of parental subfertility 3 . On the other hand, data concerning risks and sequelae to offspring health with the use of surgically retrieved gametes from azoospermic men are overall reassuring albeit limited 3 , 65 – 70 . However, no study has yet examined whether ICSI with testicular instead of ejaculated sperm (when both are available) affects the risk of malformations and long-term health of offspring. Nevertheless, new data generated by whole-exome sequencing molecular karyotype suggest that sperm aneuploidy in testicular specimens is not a major concern 71 . In this series, paired assessments in ejaculated and surgically retrieved testicular samples of non-azoospermic patients with elevated SDF in semen showed that the rates of aneuploidy (1.3% versus 8.4%, respectively, P = 0.02) were lower in testicular sperm than in ejaculated sperm. Along these lines, Weng et al . showed that the origin of sperm used for ICSI had no marked influence on embryo aneuploidy rates 72 . Moreover, a 2019 ICSI study from our group—using 24-chromosome genetic testing—revealed that euploid blastocyst rate per metaphase II oocyte was not differently affected whether ejaculated or testicular sperm retrieved from men with elevated SDF was used for ICSI (18.7% versus 18.2%, respectively) 73 . These observations corroborate the safe utilization of sperm retrieval in non-azoospermic men, but owing to limited data concerning the health of resulting offspring, continuous monitoring is warranted. Conclusions A growing body of evidence supports sperm retrieval for ICSI in non-azoospermic men with elevated SDF, severe oligozoospermia, and cryptozoospermia. In these scenarios, Testi-ICSI instead of ICSI with ejaculated sperm seems to be associated with improvements in pregnancy outcomes. Percutaneous aspiration and open TESE (with and without the aid of microsurgery) are the methods that have been applied, with high success rates and few complications, to harvest sperm from the seminiferous tubules of non-azoospermic men. However, it is essential to acknowledge the limitations of existing evidence. First, most of the data summarized derive from small observational studies in which confounder factors were not properly controlled. Thus, level 1 evidence in support of Testi-ICSI is still lacking. Second, sperm retrieval is an invasive procedure with potential complications. Thus, identification and treatment of the male factor associated with high SDF, oligozoospermia, and cryptozoospermia are essential to potentially avoid the use of surgical retrieval. We recommend a holistic approach to improve paternal health—whenever there is an opportunity—to patients embarking on any type of ART treatment. Lastly, there are limited data concerning the health of resulting offspring with the use of sperm retrieval and ICSI in cases where both ejaculated and testicular sperm are available. Keeping these limitations in mind, by summarizing the current literature, this article might guide health-care providers in presenting available evidence to patients to help them make informed decisions. Author contributions SCE contributed to conceptualization, project administration, and writing (original draft preparation). 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Meijerink AM, Ramos L, Janssen AJ: Behavioral, cognitive, and motor performance and physical development of five-year-old children who were born after intracytoplasmic sperm injection with the use of testicular sperm. Fertil Steril. 2016; 106 (7): 1673–1682.e5. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 68. Tsai CC, Huang FJ, Wang LJ, et al. : Clinical outcomes and development of children born after intracytoplasmic sperm injection (ICSI) using extracted testicular sperm or ejaculated extreme severe oligo-astheno-teratozoospermia sperm: A comparative study. Fertil Steril. 2011; 96 (3): 567–71. PubMed Abstract | Publisher Full Text 69. 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. PubMed Abstract | Publisher Full Text | Free Full Text 70. Esteves SC, Prudencio C, Seol B, 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. PubMed Abstract | Publisher Full Text | Free Full Text 71. Cheung S, Schlegel PN, Rosenwaks Z, et al. : Revisiting aneuploidy profile of surgically retrieved spermatozoa by whole exome sequencing molecular karyotype. PLoS One. 2019; 14 (1): e0210079. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 72. Weng SP, Surrey MW, Danzer HC, et al. : Chromosome abnormalities in embryos derived from microsurgical epididymal sperm aspiration and testicular sperm extraction. Taiwan J Obstet Gynecol. 2014; 53 (2): 202–5. PubMed Abstract | Publisher Full Text 73. Figueira R, Carvalho JF, Bento FC, et al. : ICSI using surgically retrieved testicular sperm of non-azoospermic men with high sperm DNA fragmentation index and blastocyst ploidy: a safe approach. Abstracts of the 35th Annual Meeting of the European Society of Human Reproduction and Embryology. Hum Reprod. 2019; 34 (Supp 1): i1–i543. Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 04 Dec 2019 ADD YOUR COMMENT Comment Author details Author details 1 ANDROFERT, Andrology and Human Reproduction Clinic, Campinas, SP, Brazil 2 Department of Surgery (Division of Urology), State University of Campinas, Campinas, SP, Brazil 3 Faculty of Health, Aarhus University, Aarhus, Denmark 4 MATER PRIME Clinic, São Paulo, SP, Brazil Sandro C. Esteves Roles: Conceptualization, Project Administration, Writing – Original Draft Preparation Matheus Roque Roles: Formal Analysis, Resources, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (1) version 1 Published: 04 Dec 2019, 8:2054 https://doi.org/10.12688/f1000research.20564.1 Copyright © 2019 Esteves SC and Roque M. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Esteves SC and Roque M. Extended indications for sperm retrieval: summary of current literature [version 1; peer review: 2 approved] . F1000Research 2019, 8 (F1000 Faculty Rev):2054 ( https://doi.org/10.12688/f1000research.20564.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Editorial Note on the Review Process Faculty Reviews are review articles written by the prestigious Members of Faculty Opinions . The articles are commissioned and peer reviewed before publication to ensure that the final, published version is comprehensive and accessible. The reviewers who approved the final version are listed with their names and affiliations. Reviewers who approved this article Ricardo P. Bertolla , Department of Surgery, Division of Urology, Universidade Federal de São Paulo, Brazil; Hospital São Paulo, Brazil Competing interests: No competing interests were declared. (for version 1) Sheena Lewis , Examen Ltd, UK; Queen's University, UK Competing interests: No competing interests were declared. (for version 1) Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 04 Dec 2019 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 Version 1 04 Dec 19 Faculty Reviews are review articles written by the prestigious Members of Faculty Opinions . The articles are commissioned and peer reviewed before publication to ensure that the final, published version is comprehensive and accessible. The reviewers who approved the final version are listed with their names and affiliations. Ricardo P. Bertolla , Department of Surgery, Division of Urology, Universidade Federal de São Paulo, Brazil; Hospital São Paulo, Brazil Competing interests: No competing interests were declared. View more View less Sheena Lewis , Examen Ltd, UK; Queen's University, UK Competing interests: No competing interests were declared. View more View less Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. 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