Limits of current male fertility testing
2019; Elsevier BV; Volume: 111; Issue: 5 Linguagem: Inglês
10.1016/j.fertnstert.2019.03.005
ISSN1556-5653
AutoresSergio Oehninger, Willem Ombelet,
Tópico(s)Reproductive Health and Technologies
ResumoIn the current approach to male fertility testing, basic semen analysis has limitations as a predictor of fertility status, and the technology is fraught with variability. Nonetheless, it remains the cornerstone of the evaluation of the male infertility, and we recommend adherence to most recent World Health Organization guidelines. Although the current sperm function tests (bioassays) have important drawbacks, they are still valuable as research tools. Sperm quality assays with analysis of sperm DNA fragmentation need further investigation before they can be recommended for routine clinical use. The answer to the many current challenging questions relies on identifying spermatogenesis pathologies and the resulting sperm dysfunctions at the cellular and molecular levels. New discoveries may bring answers or new avenues to explore. In the current approach to male fertility testing, basic semen analysis has limitations as a predictor of fertility status, and the technology is fraught with variability. Nonetheless, it remains the cornerstone of the evaluation of the male infertility, and we recommend adherence to most recent World Health Organization guidelines. Although the current sperm function tests (bioassays) have important drawbacks, they are still valuable as research tools. Sperm quality assays with analysis of sperm DNA fragmentation need further investigation before they can be recommended for routine clinical use. The answer to the many current challenging questions relies on identifying spermatogenesis pathologies and the resulting sperm dysfunctions at the cellular and molecular levels. New discoveries may bring answers or new avenues to explore. Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/44802-27709 Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/44802-27709 The World Health Organization (WHO) has made valuable contributions toward interpreting and standardizing the results of semen analysis. In the most recent edition of the WHO guidelines (1World Health Organization Laboratory manual for the examination and processing of human semen.5th ed. WHO, Geneva2010Google Scholar), updated methods were described and lower reference limits (5th centiles and their 95% confidence intervals) were provided for semen characteristics. These new values were obtained by direct, retrospective selection of fertile men, defined as men with partners who conceived within 12 months of stopping contraception (natural conceptions of recent fathers). These guidelines were introduced to improve the quality of semen analysis and to allow comparison of results investigating “male fertility status,” and they have been useful for monitoring spermatogenesis during and after research protocols (both promoting and constraining fertility). Undoubtedly, semen analysis in individuals needs to be interpreted in conjunction with clinical information after a thorough history and physical examination. The WHO guidelines were not intended to provide a definite means of diagnosing “natural” male fertility potential or conversely infertility status. Men whose semen characteristics fall below the lower limits are not necessarily infertile, and “normal” values do not guarantee fertility. Nor were the guidelines developed to predict the success or failure of intrauterine insemination (IUI) therapy or advanced assisted reproduction technology (ART) such as in vitro fertilization and intracytoplasmic sperm injection (IVF-ICSI), although they have been used for this purpose. Semen analysis, which remains the cornerstone of male fertility evaluation, provides hints as to whether a problem is present in the male partner and can to some extent estimate its severity. A complete “basic” semen analysis should provide additional information about semen volume, liquefaction, chemistry features (pH), and biochemical makeup, which can point to etiologies such as infection or genital tract obstructions. But there is a large overlap between fertile and infertile populations for the three main sperm parameters—concentration, motility, and morphology— so the test can only be used as a guide. Although each of the main sperm measurements can help to distinguish between fertile and infertile men, none has enough power to be diagnostic for infertility (2Guzick D.S. Overstreet J.W. Factor-Ltvak P. Brazil C. Nakajima T. Coutifaris C. et al.Sperm morphology, motility and concentration in fertile and infertile men.N Engl J Med. 2001; 345: 1388-1393Crossref PubMed Scopus (935) Google Scholar, 3Ombelet W. Bosmans E. Janssen M. Cox A. Vlasselaer J. Gyselaers W. et al.Semen parameters in a fertile versus subfertile population: a need for change in the interpretation of semen testing.Hum Reprod. 1997; 12: 987-993Crossref PubMed Scopus (189) Google Scholar). Furthermore, the unconditional recommendation of the “Tygerberg strict criteria” (4Kruger T.F. Menkveld R. Stander F.S. Lombard C.J. van der Merwe J.P. van Zyl J.A. et al.Sperm morphologic features as a prognostic factor in in vitro fertilization.Fertil Steril. 1986; 46: 1118-1123Abstract Full Text PDF PubMed Scopus (1071) Google Scholar) for morphologic evaluation has been challenged (5Eliasson R. Semen analysis with regard to sperm number, sperm morphology and functional aspects.Asian J Androl. 2010; 12: 26-32Crossref PubMed Scopus (54) Google Scholar), and the limitations of semen analysis as related to different male populations have been raised (6Sigman M. Normal ranges: normal for whom?.Fertil Steril. 2017; 108: 392Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar). Fertility is multifactorial and relies on thresholds of sperm features, on coital frequency and sexual function, and on coexisting female factors. To discern the cause of the underlying abnormality requires further testing, which includes assessing the general health of the male partner (smoking, use of other toxics and medications, obesity, hypogonadism, chronic diseases), performing genetic testing, and excluding male tract obstructions. Pretesticular and posttesticular origins may be amenable to specific therapies (such as lifestyle changes, or medical or urological interventions). Testicular causes and other frequently found conditions defined as “unexplained”—such as cases of moderate to severe oligoasthenoteratozoospermia (OAT)—are usually directed to ART. However, these common and often severely abnormal results rarely identify the cause of the infertility. Slow but steady progress is being made toward identifying the origin(s) of teratozoospermia. There are rare single structural defects that involve the totality of ejaculated sperm. These monomorphic forms of infertility are of genetic origin and are generally transmitted as an autosomal recessive trait (7Coutton C. Escoffier J. Martinez G. Arnoult C. Ray P.F. Teratozoospermia: spotlight on the main genetic actors in the human.Hum Reprod Update. 2015; 21: 455-485Crossref PubMed Scopus (191) Google Scholar, 8Francavilla S. Cordeschi G. Pelliccione F. Bocchio M. Francavilla F. Isolated teratozoospermia: a cause of male sterility in the era of ICSI?.Front Biosci. 2007; 12: 69-88Crossref PubMed Scopus (17) Google Scholar). Acrosome agenesis or globozoospermia results from the perturbed expression of nuclear proteins or from an altered Golgi-nuclear recognition during spermiogenesis. The production of the casein IIa subunit appears to be faulty. Failed ICSI fertilization of acrosomeless sperm is consistent with an inability of sperm to activate oocytes. Complete globozoospermia is associated with phospholipase Cζ deficiency, and in vitro treatment with calcium ionophore and ICSI can result in pregnancy (9Taylor S.L. Yoon S.Y. Morshedi M.S. Lacey D.R. Jellerette T. Fissore R.A. et al.Complete globozoospermia associated with PLCζ deficiency treated with calcium ionophore and ICSI results in pregnancy.Reprod Biomed Online. 2010; 20: 559-564Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar, 10Elinati E. Kuentz P. Redin C. Jaber S. Vanden Meerschaut F. Makarian J. et al.Globozoospermia is mainly due to DPY19L2 deletion via non-allelic homologous recombination involving two recombination hotspots.Hum Mol Genet. 2012; 21: 3695-3702Crossref PubMed Scopus (81) Google Scholar). Homozygous mutations of aurora kinase C (AURKC) have been described for cases of macrozoospermia. Other abnormalities also may be of genetic origin but with unknown molecular mechanisms, such as acephalic spermatozoa, which results from a head-neck defect due to a failure of migration of the tail anlagen and related centriole to the caudal pole of spermatids. An abnormal sperm centrosome function may explain defective embryo cleavage after ICSI with sperm carrying a fragile head-neck junction. Primary cilia dyskinesia (PCD) and dysplasia of the fibrous sheath (DFS) are isolated defects associated with absent or greatly reduced sperm motility due to an abnormal ciliary structure and function (PCD) or to a disorganized fibrous sheath (DFS) (7Coutton C. Escoffier J. Martinez G. Arnoult C. Ray P.F. Teratozoospermia: spotlight on the main genetic actors in the human.Hum Reprod Update. 2015; 21: 455-485Crossref PubMed Scopus (191) Google Scholar, 8Francavilla S. Cordeschi G. Pelliccione F. Bocchio M. Francavilla F. Isolated teratozoospermia: a cause of male sterility in the era of ICSI?.Front Biosci. 2007; 12: 69-88Crossref PubMed Scopus (17) Google Scholar). But in clinical scenarios, isolated teratozoospermia more typically presents as various phenotypic patterns of slightly or severely amorphous spermatozoa, usually in combination with other abnormalities such as tapered heads, small-large heads, or various neck and tail defects. These forms of teratozoospermia occur with a normal motile count (isolated teratozoospermia), or they can be associated with moderate or severe OAT, are likely polymorphic in origin, and are due to various degrees of testicular insufficiency. The postulated causes include genetic defects (protein 4.1 defects have been described in amorphous spermatozoa) (11Rousseaux-Prévost R. Lesur P. Collier F. Rigot J.M. Dalla Venezia N. Pol P.S. et al.Abnormal expression of protein 4.1 in spermatozoa of infertile men with teratospermia.Lancet. 1994; 343: 764-765Abstract PubMed Scopus (19) Google Scholar), Sertoli cell dysfunction, defective spermiogenesis, or epididymal, drug/toxin, or environmental influences (12Chemes H.E. Phenotypic varieties of sperm pathology: genetic abnormalities or environmental influences can result in different patterns of abnormal spermatozoa.Anim Reprod Sci. 2018; 194: 41-56Crossref PubMed Scopus (21) Google Scholar, 13Ray P.F. Toure A. Metzler-Guillemain C. Mitchell M.J. Arnoult C. Coutton C. Genetic abnormalities leading to qualitative defects of sperm morphology or function.Clin Genet. 2017; 91: 217-232Crossref PubMed Scopus (101) Google Scholar, 14Oumaima A. Tesnim A. Zohra H. Amira S. Ines Z. Sana C. et al.Investigation on the origin of sperm morphological defects: oxidative attacks, chromatin immaturity, and DNA fragmentation.Environ Sci Pollut Res Int. 2018; 25: 13775-13786Crossref PubMed Scopus (29) Google Scholar). Polymorphic isolated teratozoospermia may be due to sperm differentiation defects (at spermiogenesis, including disorders of chromatin/DNA packing), but in OAT these abnormalities may be accompanied by other, earlier spermatogenesis molecular alterations, leading to reduced sperm output, dyskinesia, and other dysfunctions (15Song S.H. Chiba K. Ramasamy R. Lamb D.J. Recent advances in the genetics of testicular failure.Asian J Androl. 2016; 18: 350-355Crossref PubMed Scopus (4) Google Scholar). These frequent clinical presentations require further investigation into their origins, which could lead to physiopathologically oriented therapies rather than empirically directing couples to ICSI. The assessment of sperm morphology in the clinical laboratory, even when using strict criteria, is not without problems. High intra- and inter-laboratory variabilities continue to be a problem, despite major efforts designed to overcome these disparities through intensive training programs (16Franken D.R. Menkveld R. Kruger T.F. Sekadde-Kigondu C. Lombard C. Monitoring technologist reading skills in a sperm morphology quality control program.Fertil Steril. 2003; 79: 1637-1643Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 17Franken D.R. Aneck-Hahn N. Kruger T.F. Lombaard C. Semenology training programs: 8 years' experience.Fertil Steril. 2010; 94: 2615-2619Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 18Franken D.R. Oehninger S. Semen analysis and sperm function testing.Asian J Androl. 2012; 14: 6-13Crossref PubMed Scopus (60) Google Scholar). There is also a known sampling error related to the limited number of spermatozoa assessed per sample (19Auger J. Jouannet P. Eustache F. Another look at human sperm morphology.Hum Reprod. 2016; 31: 10-23Crossref PubMed Scopus (96) Google Scholar). Notwithstanding these limitations, a recent epidemiologic study showed that normal sperm morphology is associated with the time to pregnancy in natural conception (20Buck Louis G.M. Sundaram R. Schisterman E.F. Sweeney A. Lynch C.D. Kim S. et al.Semen quality and time to pregnancy: the Longitudinal Investigation of Fertility and the Environment Study.Fertil Steril. 2014; 101: 453-462Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar). Moreover, sperm morphology proved to be highly predictive of IVF rates of fertilization and even pregnancy in IUI in several studies (21Kruger T.F. Coetzee K. The role of sperm morphology in assisted reproduction.Hum Reprod Update. 1999; 5: 172-178Crossref PubMed Scopus (71) Google Scholar, 22Van Waart J. Kruger T.F. Lombard C.J. Ombelet W. Predictive value of normal sperm morphology in intrauterine insemination (IUI): a structured literature review.Hum Reprod Update. 2001; 7: 495-500Crossref PubMed Scopus (172) Google Scholar), although contradictory results for the value of sperm morphology assessments in IUI programs have been recently described (23Lemmens L. Kos S. Beijer C. Brinkman J.W. van der Horst F.A. van den Hoven L. et al.Semen Section of the Dutch Foundation for Quality Assessment in Medical Laboratories. Predictive value of sperm morphology and progressively motile sperm count for pregnancy outcomes in intrauterine insemination.Fertil Steril. 2016; 105: 1462-1468Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 24Thijssen A. Creemers A. Van der Elst W. Creemers E. Vandormael E. Dhont N. et al.Predictive value of different covariates influencing pregnancy rate following intrauterine insemination with homologous semen: a prospective cohort study.Reprod Biomed Online. 2017; 34: 463-472Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar). Within the IVF setting it has been established that frequently observed morphological abnormalities of the male gamete could be used as a biomarker of gamete dysfunctions (25Oehninger S. Clinical management of male infertility in assisted reproduction: ICSI and beyond.Int J Androl. 2011; 34: e319-e329Crossref PubMed Scopus (18) Google Scholar). These dysfunctions were proven to be multiple, and they could be assessed in a sequential diagnosis. They included motility/dyskinetic disorders, a deficient capacity to undergo a physiologically induced acrosome reaction (by solubilized human zona pellucida), a diminished competence to bind to and penetrate the homologous zona pellucida, and an impaired efficiency to fuse with and penetrate zona-free hamster eggs. Additionally, dysmorphic spermatozoa frequently display multiple defects at a cellular level, such as abnormal basal and stimulated intracellular calcium concentration, abnormal creatine kinase content, and enhanced capacity to generate detrimental reactive oxygen species. When produced in excessive amounts, these metabolites can lead to DNA fragmentation and a loss of sperm function associated with peroxidative damage to the sperm plasma membrane. Further research led to the concept of sperm “immaturity.” It was demonstrated that dysmorphic and defective spermatozoa from infertile men display markers of cellular dysmaturity, including the retention of excess residual cytoplasm (and thus abnormal morphology), persistent nuclear histones, poor capacity to bind to the zona pellucida, and disrupted chaperone content (26Huszar G. Vigue L. Incomplete development of human spermatozoa is associated with increased creatine phosphokinase concentration and abnormal head morphology.Mol Reprod Dev. 1993; 34: 292-298Crossref PubMed Scopus (117) Google Scholar, 27Aitken R.J. The Amoroso Lecture. The human spermatozoon—a cell in crisis?.J Reprod Fertil. 1999; 115: 1-7Crossref PubMed Scopus (371) Google Scholar, 28Cayli S. Sakkas D. Vigue L. Demir R. Huszar G. Cellular maturity and apoptosis in human sperm: creatine kinase, caspase-3 and Bcl-XL levels in mature and diminished maturity sperm.Mol Hum Reprod. 2004; 10: 365-372Crossref PubMed Scopus (141) Google Scholar, 29Oehninger S. Pathophysiology of oligoasthenoteratozoospermia: are we improving in the diagnosis?.Reprod Biomed Online. 2003; 7: 433-439Abstract Full Text PDF PubMed Scopus (10) Google Scholar). As the clinical focus shifted to sperm/oocyte manipulation, ICSI quickly became the selected technique for cases of male factor infertility and for couples with previously failed fertilization with conventional IVF (25Oehninger S. Clinical management of male infertility in assisted reproduction: ICSI and beyond.Int J Androl. 2011; 34: e319-e329Crossref PubMed Scopus (18) Google Scholar, 29Oehninger S. Pathophysiology of oligoasthenoteratozoospermia: are we improving in the diagnosis?.Reprod Biomed Online. 2003; 7: 433-439Abstract Full Text PDF PubMed Scopus (10) Google Scholar, 30Barroso G. Valdespin C. Vega E. Kershenovich R. Avila R. Avendaño C. et al.Developmental sperm contributions: fertilization and beyond.Fertil Steril. 2009; 92: 835-848Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar). It was demonstrated that the basic semen parameters of the unprocessed ejaculate or even after separation of the fraction with highest motility had no impact on the outcome of ICSI as determined by fertilization, clinical and ongoing pregnancy rates (31Nagy Z.P. Liu J. Joris H. Verheyen G. Tournaye H. Camus M. Derde M.C. Devroey P. Van Steirteghem A.C. The result of intracytoplasmic sperm injection is not related to any of the three basic sperm parameters.Hum Reprod. 1995; 10: 1123-1129Crossref PubMed Scopus (428) Google Scholar, 32Oehninger S. Veeck L. Lanzendorf S. Maloney M. Toner J. Muasher S. Intracytoplasmic sperm injection: achievement of high pregnancy rates in couples with severe male factor infertility is dependent primarily upon female and not male factors.Fertil Steril. 1995; 64: 977-981Abstract Full Text PDF PubMed Scopus (139) Google Scholar). Intracytoplasmic sperm injection resulted in high levels of fertilization in the presence of multiple morphological and dysfunctional sperm defects as well as after the use of ejaculated, testicular, or epididymal sperm, cryopreserved-thawed sperm, and in cases of obstructive and nonobstructive azoospermia after sperm extraction from the testis or epididymis (33Devroey P. Van Steirteghem A. A review of ten years' experience of ICSI.Hum Reprod Update. 2004; 10: 19-28Crossref PubMed Scopus (217) Google Scholar). Sperm morphology assessed by strict criteria has little prognostic value in ICSI cycle outcomes, and the standard microscopic selection of sperm with “normal” morphology during the ICSI procedure allows excellent outcomes even in samples with severe teratozoospermia (34French D.B. Sabanegh Jr., E.S. Goldfarb J. Desai N. Does severe teratozoospermia affect blastocyst formation, live birth rate, and other clinical outcome parameters in ICSI cycles?.Fertil Steril. 2010; 93: 1097-1103Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). Although there are positive correlations between the degrees and types of teratozoospermia and sperm chromosomal anomalies/DNA damage, sperm morphology per se is not a strong predictor of aneuploidies or DNA fragmentation (35Celik-Ozenci C. Jakab A. Kovacs T. Catalanotti J. Demir R. Bray-Ward P. et al.Sperm selection for ICSI: shape properties do not predict the absence or presence of numerical chromosomal aberrations.Hum Reprod. 2004; 19: 2052-2059Crossref PubMed Scopus (113) Google Scholar). The fact that morphology does not predict ICSI does not negate the value of assessment. The percentage of sperm with normal morphologic features has the greatest discriminatory power for natural fertility (2Guzick D.S. Overstreet J.W. Factor-Ltvak P. Brazil C. Nakajima T. Coutifaris C. et al.Sperm morphology, motility and concentration in fertile and infertile men.N Engl J Med. 2001; 345: 1388-1393Crossref PubMed Scopus (935) Google Scholar). The presence of teratozoospermia indicates different degrees of dysfunctional sperm. Clinical experience has shown that isolated forms of mild–moderate teratozoospermia may not have a negative impact on pregnancy in natural conception and in IUI. In fact, pregnancies can be initiated in IUI if there is an adequate total motile count of spermatozoa after wash, despite the presence of severe teratozoospermia (36Ombelet W. Vandeput H. Van de Putte G. Cox A. Janssen M. Jacobs P. et al.Intrauterine insemination after ovarian stimulation with clomiphene citrate: predictive potential of inseminating motile count and sperm morphology.Hum Reprod. 1997; 12: 1458-1463Crossref PubMed Scopus (126) Google Scholar). Therefore, this parameter must be used in the clinical setting, understanding its limitations, as it provides evidence of an underlying defect and can help guide management. The limited predictive value of basic semen analysis for pregnancy in couples trying to achieve natural conception or undergoing ART highlights the need for more extended sperm functional testing (37Oehninger S. Franken D.R. Ombelet W. Sperm functional tests.Fertil Steril. 2014; 102: 1528-1533Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 38Barratt C.L.R. Björndahl L. De Jonge C.J. Lamb D.J. Osorio Martini F. McLachlan R. et al.The diagnosis of male infertility: an analysis of the evidenceto support the development of global WHO guidance—challenges and future research opportunities.Hum Reprod Update. 2017; 23: 660-680Crossref PubMed Scopus (235) Google Scholar). Work derived from the early IVF days demonstrated that defective acrosome reaction and/or an abnormal sperm–zona pellucida interaction were frequently observed with the ejaculated sperm of infertile men (39Liu D.Y. Liu M.L. Garrett C. Baker H.W. Comparison of the frequency of defective sperm–zona pellucida (ZP) binding and the ZP-induced acrosome reaction between subfertile men with normal and abnormal semen.Hum Reprod. 2007; 22: 1878-1884Crossref PubMed Scopus (34) Google Scholar). Such findings were observed in the presence of normal or abnormal “basic” sperm parameters. Both types of dysfunctions were associated with either failure or low fertilization rates. Consequently, acrosome reaction tests and sperm–zona pellucida binding assays were developed to meet a real need for assessing sperm functional competence as part of an “extended” evaluation in the infertility work-up before conventional IVF was performed. In the current ICSI era, the results of such functional assays can still provide valuable information to the clinician, who might instead recommend low-complexity alternatives such as IUI therapy or direct couples to ICSI (25Oehninger S. Clinical management of male infertility in assisted reproduction: ICSI and beyond.Int J Androl. 2011; 34: e319-e329Crossref PubMed Scopus (18) Google Scholar, 29Oehninger S. Pathophysiology of oligoasthenoteratozoospermia: are we improving in the diagnosis?.Reprod Biomed Online. 2003; 7: 433-439Abstract Full Text PDF PubMed Scopus (10) Google Scholar, 30Barroso G. Valdespin C. Vega E. Kershenovich R. Avila R. Avendaño C. et al.Developmental sperm contributions: fertilization and beyond.Fertil Steril. 2009; 92: 835-848Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar). Sperm functional assays are qualified as research tests by WHO (1World Health Organization Laboratory manual for the examination and processing of human semen.5th ed. WHO, Geneva2010Google Scholar). These tests were originally conceived as aids for predicting the fertilization potential of male gametes in vitro. For these bioassays, spermatozoa must be prepared under capacitating conditions that mimic the female tract environment. The first bioassay developed was the heterologous hamster egg–human sperm penetration assay (SPA) (40Rogers B.J. Van Campen H. Ueno M. Lambert H. Bronson R. Hale R. Analysis of human spermatozoal fertilizing ability using zona-free ova.Fertil Steril. 1979; 32: 664-670Abstract Full Text PDF PubMed Scopus (241) Google Scholar), which was widely used in the pre-ICSI days. The SPA measures the spermatozoa's ability to undergo capacitation, acrosome reaction, fusion and penetration through the oolemma, and decondensation within the cytoplasm of hamster oocytes. The test results can be difficult to interpret because of the absence of a zona pellucida, which differs from the physiological situation. False-negative results (i.e., men whose spermatozoa fail the SPA but successfully fertilize human oocytes in vitro or in vivo) have frequently been recorded. This limitation, added to the need for hamster eggs and other technical difficulties, led to the general discontinuance of this test. The two most commonly used sperm–zona pellucida binding tests are the hemizona assay (41Burkman L.J. Coddington C.C. Franken D.R. Krugen T.F. Rosenwaks Z. Hogen G.D. The hemizona assay (HZA): development of a diagnostic test for the binding of human spermatozoa to the human hemizona pellucida to predict fertilization potential.Fertil Steril. 1988; 49: 688-697Abstract Full Text PDF PubMed Google Scholar) and the competitive intact-zona sperm binding test (42Liu D.Y. Lopata A. Johnston W.I. Baker H.W. A human sperm–zona pellucida binding test using oocytes that failed to fertilize in vitro.Fertil Steril. 1988; 50: 782-788Abstract Full Text PDF PubMed Scopus (134) Google Scholar). Although they are different in their methodologies, both use assessment of tight binding of sperm to the zona pellucida as the primary end point in an independent comparison in an internally controlled assay. Both have a demonstrated high predictive value for the outcome of fertilization in vitro (18Franken D.R. Oehninger S. Semen analysis and sperm function testing.Asian J Androl. 2012; 14: 6-13Crossref PubMed Scopus (60) Google Scholar, 37Oehninger S. Franken D.R. Ombelet W. Sperm functional tests.Fertil Steril. 2014; 102: 1528-1533Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 39Liu D.Y. Liu M.L. Garrett C. Baker H.W. Comparison of the frequency of defective sperm–zona pellucida (ZP) binding and the ZP-induced acrosome reaction between subfertile men with normal and abnormal semen.Hum Reprod. 2007; 22: 1878-1884Crossref PubMed Scopus (34) Google Scholar). Although the results of these assays correlate with fertilization in vitro with high statistical significance, they have definite drawbacks, including the need for human material (i.e., zonae pellucidae to be solubilized, and/or intact eggs). Both are technically demanding and time consuming, making them awkward for the routine clinical laboratory (37Oehninger S. Franken D.R. Ombelet W. Sperm functional tests.Fertil Steril. 2014; 102: 1528-1533Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 43ESHRE Andrology Special Interest GroupConsensus Workshop on Advanced Diagnostic Andrology Techniques.Hum Reprod. 1996; 11: 1463-1479Crossref PubMed Scopus (128) Google Scholar). Nowadays, sperm function testing is not frequently performed for couples with moderate-to-severe nonobstructive OAT because these cases are typically referred to IVF augmented with ICSI. Intracytoplasmic sperm injection bypasses multiple steps of the natural fertilization process by introducing an apparently intact spermatozoon into the ooplasm. Questions have arisen about the potential impact of the male gamete in postfertilization events (i.e., untoward effects). The terms “early” and “late” paternal effects have been proposed to represent the impact of sperm contributions to pathological conditions seen in IVF-ICSI. The diagnosis of an early paternal effect is based upon poor zygote or early embryo morphology and low cleavage speed, and it is not associated with sperm DNA fragmentation. The late paternal effect, on the other hand, is manifested by poor developmental competence leading to failure of implantation and is associated with an increased incidence of sperm DNA fragmentation in the absence of zygote and early cleavage-stage morphological abnormalities (44Tesarik J. Mendoza C. Greco E. Paternal effects acting during the first cell cycle of human preimplantation development after ICSI.Hum Reprod. 2002; 17: 184-189Crossref PubMed Scopus (167) Google Scholar, 45Tesarik J. Greco E. Mendoza C. Late, but not early, paternal effect on human embryo development is related to sperm DNA fragmentation.Hum Reprod. 2004; 19: 611-615Crossref PubMed Scopus (337) Google Scholar). This issue is of critical importance: it is related to establishing the immediate and long-term safety of ART, including embryonic anomalies resulting in developmental arrest and/or chromosomal, ge
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