Evolution of the WHO “Semen” processing manual from the first (1980) to the sixth edition (2021)
2022; Elsevier BV; Volume: 117; Issue: 2 Linguagem: Inglês
10.1016/j.fertnstert.2021.11.037
ISSN1556-5653
AutoresChristina Wang, Michael T. Mbizvo, Mario Festin, Lars Björndahl, Igor Toskin,
Tópico(s)Demographic Trends and Gender Preferences
ResumoAs stated clearly in all editions of the WHO Laboratory Manual for the Examination and Processing of Human Semen, the goal of the manual is to meet the growing needs for the standardization of semen analysis procedures. With constant advances in andrology and reproductive medicine and the advent of sophisticated assisted reproductive technologies for the treatment of infertility, the manual has been continuously updated to meet the need for new, evidence-based, validated tests to not only measure semen and sperm variables but also to provide a functional assessment of spermatozoa. The sixth edition of the WHO manual, launched in 2021, can be freely downloaded from the WHO website, with the hope of gaining wide acceptance and utilization as the essential source of the latest, evidence-based information for laboratory procedures required for the assessment of male reproductive function and health. As stated clearly in all editions of the WHO Laboratory Manual for the Examination and Processing of Human Semen, the goal of the manual is to meet the growing needs for the standardization of semen analysis procedures. With constant advances in andrology and reproductive medicine and the advent of sophisticated assisted reproductive technologies for the treatment of infertility, the manual has been continuously updated to meet the need for new, evidence-based, validated tests to not only measure semen and sperm variables but also to provide a functional assessment of spermatozoa. The sixth edition of the WHO manual, launched in 2021, can be freely downloaded from the WHO website, with the hope of gaining wide acceptance and utilization as the essential source of the latest, evidence-based information for laboratory procedures required for the assessment of male reproductive function and health. DIALOG: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/34279 DIALOG: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/34279 The World Health Organization (WHO) Laboratory Manual for the Examination and Processing of Human Semen was first published in 1980 to standardize the procedures for the examination of human semen. This WHO "semen" manual has undergone five revisions (Fig. 1) and has been translated into multiple languages in response to the growing global needs in andrology and reproductive medicine and to standardize procedures for the examination of human semen. The WHO manual provides standard laboratory methods for semen analysis that are used extensively by clinical and reference laboratories for the understanding of reproductive function in men, the diagnosis and planning of treatment for subfertile couples, assessment of male contraceptive methods, and large-scale population studies and research activities, such as the effects of viral, environmental, and other toxicants on male reproductive function. The development of each edition of the manual was coordinated by the United Nations Development Programme/United Nations Population Fund/United Nations Children's Fund/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP) within the WHO Department of Reproductive Health and Research, which worked with the respective Task Forces or later, Research Group for the Regulation of Male Fertility. The latter, including the editorial board, was drawn from global experts working in male reproductive function. HRP has played very vital roles in convening the development of the manual, including overall coordination, technical input, supporting evidence generation, document production, dissemination, and promotion, ensuring continuity across editions, and providing necessary financial support. Between 1976 and 1977, the WHO Task Force on Methods for the Regulation of Male Fertility (led by C.A. Paulsen, M.D., University of Washington, Seattle, and M.R.R. Prasad, Ph.D., Manager of the Task Force) recognized the importance of standardizing semen analysis to improve the quality of results allowing for the exchange and combination of data across laboratories. A series of consultations in Barcelona, Geneva, Berlin, and Hong Kong were held to develop a laboratory manual for semen analysis. These consultations/workgroups were conducted in collaboration with two other WHO Task Forces on the Diagnosis and Treatment of Male Infertility and Vaginal and Cervical Devices for Fertility Regulation within the HRP from the first to the current (sixth) edition. The support of the respective HRP directors and scientists has been critical in the development and publication of the manuals. The first edition, called the Laboratory Manual for the Examination of Human Semen and Semen-Cervical Mucus Interaction, was based on these consultations with 33 participants from Asia, Australia, Europe, North America, and South America. The focus of the manual was on semen analysis as the first laboratory test to study the physio-pathological testicular function in adults and establishing male fertility status in infertile couples, as well as monitoring spermatogenesis during and after male fertility regulation. The main objective of the first edition was to provide laboratory procedures for semen analysis that are standardized, precise, reproducible, sensitive, and validated. The manual consisted of only 43 pages with sections on the collection of the semen sample, initial examination, and assessment of sperm motility, concentration, morphology (including plates showing normal and abnormal spermatozoa), and viability. It included an Appendix with morphological classification and Papanicolaou staining for human spermatozoa with a standardized example for a semen analysis report form. It also included a section on sperm-cervical mucus interaction as a surrogate of sperm function, assessing sperm penetration of the cervical mucus using in vitro (capillary tube test) and in vivo (postcoital test) tests (1World Health OrganizationLaboratory manual for the examination of human semen and semen-cervical mucus interaction. Press Concern, Singapore1980Google Scholar) (Table 1).Table 1The major changes from the first to the sixth edition of the WHO Laboratory Manual for the Examination and Processing of Human SemenEditionYearPagesMajor changes1st198043Semen: sample collection, initial examination, sperm motility, sperm density, sperm morphology (plates and stains)Sperm-cervical mucus interaction: collection of mucus, in vitro test, postcoital test2nd198767Semen: Standard tests—includes all in the 1st edition + sperm antibody testsOptional tests—semen culture, seminal fluid biochemistry, zona-free hamster oocyte penetration test, sperm migration testCriteria of normality of semen samples3rd1992107Standard test—use "strict criteria for assessment of sperm morphology"Research tests—zona-free hamster oocyte penetration test, human zona pellucida binding test, acrosome reaction, computer-assisted sperm analysisSperm preparationQuality control of semen analysis4th1999128Optional tests—added hypoosmotic swelling test, multiple sperm defects indexResearch test—reactive oxygen speciesQuality control—statistical analyses of counting errors5th2010271Most extensive and comprehensive revision of the semen manualDetailed description of each procedureAdded total sperm output per ejaculate as a semen variableSperm motility combined rapid and slow into one grade of progressive motilitySperm preparations include spermatozoa from testis and epididymisUsing quality control to improve laboratory performanceAdded chapter on cryopreservation of spermatozoa6th2021276Step-by-step, easy-to-follow procedureBasic examination—standard tests, reintroduce slow progressive motilityExtended examination—optional tests included leucocyte, immature germ cells, added sperm aneuploidy, sperm genetics and DNA fragmentationAdvanced examination—research tests, added membrane ion channelsEmerging methods of semen analyses without a microscopeEliminated hamster zona-free penetration test, human zona binding test and section on sperm-cervical interaction Open table in a new tab The second, third, and fourth editions of the WHO semen manual were led by G.M.H. Waites, Ph.D., then as area Research Manager within HRP, in response to the developments in andrology, with increasing awareness of the importance of the objective assessment of the quality and functional characteristics of human spermatozoa (Table 1). More importantly, semen analysis was established as an important tool in assessing the male partner, with the rapid development of assisted reproductive techniques. A working group of experts in semen analysis, andrology, and reproductive medicine were constituted to revise the semen manual. The second edition was published in 1987 (2World Health OrganizationWHO Laboratory manual for the examination of human semen and semen-cervical mucus interaction.2nd ed. Cambridge University Press, Cambridge1987Google Scholar). Among the included changes from the first edition was the division of semen analysis into standard (all tests described in the 1980 manual plus antisperm antibody tests) and optional tests, including semen culture, seminal fluid biochemical tests, zona-free hamster oocyte penetration test, and sperm migration test ("swim-up"). The section on semen-cervical mucus interaction was not changed. Importantly, the second edition introduced the "normal" values for sperm variables based mainly on the early studies of Macleod and Gold in 1951 (3Macleod J. Gold R.Z. The male factor in fertility and infertility. II. Spermatozoon counts in 1000 men of known fertility and in 1000 cases of infertile marriage.J Urol. 1951; 66: 436-449Google Scholar, 4Macleod J. Gold R.Z. The male factor in fertility and infertility. III. An analysis of motile activity in the spermatozoa of 1000 fertile men and 1000 men in infertile marriage.Fertil Steril. 1951; 2: 187-204Google Scholar, 5MacLeod J. Gold R.Z. The male factor in fertility and infertility. IV. Sperm morphology in fertile and infertile marriage.Fertil Steril. 1951; 2: 394-414Google Scholar), which was updated in 1979 (6MacLeod J. Wang Y. Male fertility potential in terms of semen quality: a review of the past, a study of the present.Fertil Steril. 1979; 31: 103-116Google Scholar) with consensus-based modifications. The manual suggested that these values from such large-scale studies may be used by laboratories to guide the interpretation of semen analysis results. However, it was noted that although the data of Macleod et al. (3Macleod J. Gold R.Z. The male factor in fertility and infertility. II. Spermatozoon counts in 1000 men of known fertility and in 1000 cases of infertile marriage.J Urol. 1951; 66: 436-449Google Scholar, 4Macleod J. Gold R.Z. The male factor in fertility and infertility. III. An analysis of motile activity in the spermatozoa of 1000 fertile men and 1000 men in infertile marriage.Fertil Steril. 1951; 2: 187-204Google Scholar, 5MacLeod J. Gold R.Z. The male factor in fertility and infertility. IV. Sperm morphology in fertile and infertile marriage.Fertil Steril. 1951; 2: 394-414Google Scholar, 6MacLeod J. Wang Y. Male fertility potential in terms of semen quality: a review of the past, a study of the present.Fertil Steril. 1979; 31: 103-116Google Scholar) were obtained from large numbers of fertile and infertile men, the time taken to achieve a pregnancy in the female partner was not defined. The manual suggested that "normal values" should be evaluated from men who had achieved pregnancy with their partner within 12 months (Table 2). Appendices were expanded to provide technical details of some of the procedures. This 1987 version, translated into seven languages, was used in WHO Andrology Workshops that were held in Africa, Asia, and Eastern Europe with a hands-on demonstration of semen analysis techniques.Table 2Changes in Reference Values from the second to the sixth edition of the WHO Laboratory Manual for the Examination and Processing of Human SemenEditionNomenclatureSemen volume (ml)Sperm concentration (106/ml)/Total no. (106/ejaculate)Total /progressive sperm motility (%)Normal forms (%)Reference2ndNormal values≥2≥20/≥40≥50/≥25≥50Modified from (3Macleod J. Gold R.Z. The male factor in fertility and infertility. II. Spermatozoon counts in 1000 men of known fertility and in 1000 cases of infertile marriage.J Urol. 1951; 66: 436-449Google Scholar, 4Macleod J. Gold R.Z. The male factor in fertility and infertility. III. An analysis of motile activity in the spermatozoa of 1000 fertile men and 1000 men in infertile marriage.Fertil Steril. 1951; 2: 187-204Google Scholar, 5MacLeod J. Gold R.Z. The male factor in fertility and infertility. IV. Sperm morphology in fertile and infertile marriage.Fertil Steril. 1951; 2: 394-414Google Scholar), data from 1,000 men with known fertility (female partner currently pregnant) and 1,000 men in infertile marriage3rdNormal values≥2≥20/≥40≥50/≥25≥30Same as 2nd EditionEmpirical value used for normal sperm forms4thReference values≥2≥20/≥40≥50/≥25∗Same as 3rd Edition. ∗ Normal forms—population-based studies of normal forms in progress, data from assisted reproductive technology suggest <15 normal forms may be associated with decreased in vitro fertilization rate5thReference values of fertile men (5th centile lower reference limits)1.515/3940/324Population-based studies of approximately 1,900 fertile men (defined as men whose partner conceived within 12 months after stopping contraception) (23Cooper T.G. Noonan E. Von Eckardstein S. Auger J. Baker H.W. Behre H.M. et al.World Health Organization reference values for human semen characteristics.Hum Reprod Update. 2010; 16: 231-245Google Scholar).Morphology using "strict" criteria (8Kruger T.F. Acosta A.A. Simmons K.F. Swanson R.J. Matta J.F. Oehninger S. Predictive value of abnormal sperm morphology in in vitro fertilization.Fertil Steril. 1988; 49: 112-117Google Scholar, 11Menkveld R. Kruger T.F. Advantages of strict (Tygerberg) criteria for evaluation of sperm morphology.Int J Androl. 1995; 18: 36-42Google Scholar)6thDistribution of semen variables from fertile men (5th centile)1.416/3942/304Population-based studies of approximately 3,500 fertile men (defined as men whose partner had a natural conception with a confirmed time to pregnancy of ≤12 months) (41Campbell M.J. Lotti F. Baldi E. Schlatt S. Festin M.P.R. Björndahl L. et al.Distribution of semen examination results 2020 - a follow up of data collated for the WHO semen analysis manual 2010.Andrology. 2021; 9: 817-822Google Scholar).Morphology using "strict" criteria (8Kruger T.F. Acosta A.A. Simmons K.F. Swanson R.J. Matta J.F. Oehninger S. Predictive value of abnormal sperm morphology in in vitro fertilization.Fertil Steril. 1988; 49: 112-117Google Scholar, 11Menkveld R. Kruger T.F. Advantages of strict (Tygerberg) criteria for evaluation of sperm morphology.Int J Androl. 1995; 18: 36-42Google Scholar) Open table in a new tab Recognizing the rapid progress in assisted reproductive techniques used for the treatment of the infertile couple, the proliferation of many andrology laboratories in infertility treatment centers, the increasing concern about the putative effects or environmental pollutants on male reproductive function, and the need for new and better standard methods of semen analysis, the WHO laboratory manual was revised by a group of experts in 1992 (7World Health OrganizationWHO Laboratory manual for the examination of human semen and sperm-cervical mucus interaction.3rd ed. Cambridge University Press, Cambridge1992Google Scholar). The semen analysis section was divided into three sections standard procedures, optional tests, and research tests. The research tests included the zona-free hamster oocyte penetration test, human zona pellucida binding tests, acrosome reaction, and computer-assisted sperm analysis. The section on sperm-cervical mucus interaction was not significantly altered, but the title of this edition was changed to the WHO Laboratory Manual for the Examination of Human Semen and Sperm-Cervical Mucus Interaction. This edition contains two additional chapters relevant to the needs of laboratories, sperm preparation techniques and quality control of laboratory performance of semen analyses. In addition, in the appendices, this manual introduced basic safety guidelines and minimal equipment needed for any laboratory performing semen analysis. These additions were timely and responsive to the needs of many laboratories. In the few years preceding the revision of the third edition of the manual, the classification of sperm morphology was changed based on the morphology of spermatozoa able to reach the oocyte and bind to the zona pellucida. Emerging evidence related to outcomes in in vitro fertilization suggested that pregnancy rates in the female partner were more frequent when normal sperm morphology was above 14% (8Kruger T.F. Acosta A.A. Simmons K.F. Swanson R.J. Matta J.F. Oehninger S. Predictive value of abnormal sperm morphology in in vitro fertilization.Fertil Steril. 1988; 49: 112-117Google Scholar, 9Kruger 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: 1118-1123Google Scholar). In Appendix 1, the reference limits of semen variables were provided based on consensus limits in the first and second editions. It was noted that there were no population-based clinical studies on semen variables completed at that time, and an empirical reference value for sperm morphology in men was quoted as 30% without supportive data (7World Health OrganizationWHO Laboratory manual for the examination of human semen and sperm-cervical mucus interaction.3rd ed. Cambridge University Press, Cambridge1992Google Scholar) (Table 2). This empirical cut-point of 30% normal forms was reported not to be clinically useful as approximately half of fertile men had sperm morphology below this value (10Barratt C.L. Naeeni M. Clements S. Cooke I.D. Clinical value of sperm morphology for in-vivo fertility: comparison between World Health Organization criteria of 1987 and 1992.Hum Reprod. 1995; 10: 587-593Google Scholar). It is important to keep in mind that the criteria for characterizing human sperm morphology have changed substantially from those used by Macleod (5MacLeod J. Gold R.Z. The male factor in fertility and infertility. IV. Sperm morphology in fertile and infertile marriage.Fertil Steril. 1951; 2: 394-414Google Scholar) to the strict Tygerberg criteria (11Menkveld R. Kruger T.F. Advantages of strict (Tygerberg) criteria for evaluation of sperm morphology.Int J Androl. 1995; 18: 36-42Google Scholar). In 1999, the WHO/HRP fourth edition of the semen manual was published (12World Health OrganizationWHO Laboratory manual for the examination of human semen and sperm-cervical mucus interaction.4th ed. Cambridge University Press, Cambridge1999Google Scholar). This revision was in response to advances in the genetics of male infertility (Y chromosome microdeletions) (13Pryor J.L. Kent-First M. Muallem A. Van Bergen A.H. Nolten W.E. Meisner L. et al.Microdeletions in the Y chromosome of infertile men.N Engl J Med. 1997; 336: 534-540Google Scholar); the success of intracytoplasmic sperm injection (14Van Steirteghem A.C. Liu J. Joris H. Nagy Z. Janssenswillen C. Tournaye H. et al.Higher success rate by intracytoplasmic sperm injection than by subzonal insemination. Report of a second series of 300 consecutive treatment cycles.Hum Reprod. 1993; 8: 1055-1060Google Scholar); the demonstration of contraceptive efficacy of hormonally induced suppression of spermatogenesis (15World Health Organization Task Force on Methods for the Regulation of Male FertilityContraceptive efficacy of testosterone-induced azoospermia in normal men. World Health Organization Task Force on methods for the regulation of male fertility.Lancet. 1990; 336: 955-959Google Scholar, 16World Health Organization Task Force on the Regulation of Male FertilityContraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in normal men.Fertil Steril. 1996; 65: 821-829Google Scholar); and reports of declining sperm counts (17Carlsen E. Giwercman A. Keiding N. Skakkebaek N.E. Evidence for decreasing quality of semen during past 50 years.BMJ. 1992; 305: 609-613Google Scholar) and increasing incidence of testicular cancer (18Trabert B. Chen J. Devesa S.S. Bray F. McGlynn K.A. International patterns and trends in testicular cancer incidence, overall and by histologic subtype, 1973-2007.Andrology. 2015; 3: 4-12Google Scholar). These factors added urgency to the search for new methods to achieve better standardization and improved procedures for semen analysis. The WHO sought advice from experts throughout the world via letters, journals, and national andrology societies and formed a working group to revise the manual. The fourth edition of the WHO semen manual was a companion to the WHO Manual for the Standardized Investigation and Diagnosis of the Infertile Couple (19Rowe P.J. Comhaire F.H. Hargreave T.B. Mahmoud A.M.A. WHO Manual for the Standardized Investigation and Diagnosis of the Infertile Male. Cambridge University Press, Cambridge, United Kingdom2000Google Scholar). In this fourth edition, the multiple sperm defects index and the hypoosmotic swelling test were added to the optional tests, and measurement of reactive oxygen species was added to the research test. Importantly, the quality control section was expanded to include statistical consideration of counting errors. Again, in Appendix—"Reference Values for Semen Variables"—it was clearly stated that these reference values are not to be used as the minimum/lowest semen values compatible with fertility in vitro or in vivo. Taking into consideration the comments from the prior edition, this edition left the morphology variable blank with a note suggesting that a percent normal morphology <15% may be associated with a lower in vitro fertilization rate (Table 2). This fourth edition of the WHO Semen Manual was considered a significant improvement in the description and standardization of techniques, and the demand for the manual was high (20De Jonge C.J. Barratt C.L. WHO manual…who should care?.Hum Reprod. 1999; 14: 2431-2433Google Scholar, 21McLachlan R.I. Baker H.W. Clarke G.N. Harrison K.L. Matson P.L. Holden C.A. et al.Semen analysis: its place in modern reproductive medical practice.Pathology. 2003; 35: 25-33Google Scholar). After reviewing prior editions, WHO/HRP, in consultation with its Research Group for Male Fertility Regulation, the fifth edition of the laboratory manual's name was changed to WHO Laboratory Manual for the Examination and Processing of Human Semen, and the publisher changed from Cambridge University Press to the World Health Organization (22World Health OrganizationWHO laboratory manual for the examination and processing of human semen.5th ed. World Health Organization, Geneva, Swtizerland2010Google Scholar). The manual thus became free, available in print, and as an electronic version downloadable from the WHO website (https://apps.who.int/iris/handle/10665/44261), in an attempt to establish the manual as a global guidance that will set standards across various laboratory settings and resources. This increased the demand even further, with an external evaluation of HRP noting that the manual was among its global publications with the highest citations (4,271) and downloads (53,863 in the past 6 months). It also received further requests for translations. The fifth edition was the most extensive and comprehensive edition of the manual with 271 pages. Ten years after the fourth edition, the WHO considered revisions to the manual necessary because of advances in andrology technology and new tests that may be useful in the management of infertile couples with updated supporting evidence. After consultations with experts in the field and professional associations, the WHO/HRP, led then by Research Manager and later Director, M. Mbizvo, Ph.D., established an editorial committee with 20 members from Africa, Asia, Australia, Europe, and North America. The committee nominated T. G. Cooper, Ph.D. from the Institute of Reproductive Medicine at the University of Münster, Münster, Germany, a WHO-collaboration center, as editor-in-chief with support from the WHO Secretariat. After receiving comments from laboratory technicians and scientists, this edition improved on the prior editions and provided a detailed description with a rationale of alternate methods, examples, notes, and comments for each procedure. Dr. Cooper and the editorial committee decided to edit the fifth edition in accordance with the principles of "Evidence Based Medicine." This led the editors to collect and critically appraise original clinical studies in the field of spermatology and the definition of evidence-based thresholds and reference values. Semen analyses procedures remained the same, but the emphasis was placed on counting errors when an inadequate number of spermatozoa are assessed. Sperm preparation techniques extended beyond the ejaculate and included the collection of spermatozoa from the testis and epididymis. A chapter on cryopreservation of spermatozoa was added. The quality control chapter was rewritten with suggestions on how to improve laboratory performance. Most importantly, the fifth edition for the first time provided reference ranges based on in vivo data derived from studies in fertile men with partners who conceived within 12 months (23Cooper T.G. Noonan E. Von Eckardstein S. Auger J. Baker H.W. Behre H.M. et al.World Health Organization reference values for human semen characteristics.Hum Reprod Update. 2010; 16: 231-245Google Scholar). The lower fifth centile was used as the lower reference range with a clear statement indicating that this lower limit does not distinguish subfertile and fertile men and that clinical information must be used together with semen analyses data (Table 2). Although this edition of the WHO semen manual became one of the most frequently downloaded publications of the WHO/HRP, the reviews of the edition continued to be very favorable. Comments were received from all over the world on the usefulness of this edition in clinical and research settings (24Aitken R.J. Whither must spermatozoa wander? The future of laboratory seminology.Asian J Androl. 2010; 12: 99-103Google Scholar, 25Bailey J.L. Factors regulating sperm capacitation.Syst Biol Reprod Med. 2010; 56: 334-348Google Scholar, 26Ford W.C. Comments on the release of the 5th edition of the WHO Laboratory Manual for the Examination and Processing of Human Semen.Asian J Androl. 2010; 12: 59-63Google Scholar, 27Lamb D.J. Semen analysis in 21st century medicine: the need for sperm function testing.Asian J Androl. 2010; 12: 64-70Google Scholar, 28Lu W.H. Gu Y.Q. Insights into semen analysis: a Chinese perspective on the fifth edition of the WHO Laboratory Manual for the Examination and Processing of Human Semen.Asian J Androl. 2010; 12: 605-606Google Scholar, 29Jequier A.M. Semen analysis: a new manual and its application to the understanding of semen and its pathology.Asian J Androl. 2010; 12: 11-13Google Scholar, 30Joffe M. Semen quality analysis and the idea of normal fertility.Asian J Androl. 2010; 12: 79-82Google Scholar, 31Vasan S.S. Semen analysis and sperm function tests: How much to test?.Indian J Urol. 2011; 27: 41-48Google Scholar, 32De Jonge C. Semen analysis: looking for an upgrade in class.Fertil Steril. 2012; 97: 260-266Google Scholar, 33Menkveld R. Clinical significance of the low normal sperm morphology value as proposed in the fifth edition of the WHO Laboratory Manual for the Examination and Processing of Human Semen.Asian J Androl. 2010; 12: 47-58Google Scholar). Of note, some scientists commented that the wide use of assisted reproductive technology using intracytoplasmic sperm injection often bypassed in-depth evaluation of the male partner. In some men, understanding the qualitative and functional deficiency of spermatozoa including poor motility (e.g., primary ciliary dyskinesia), low viability (e.g., damage by reactive oxygen species), gross morphological abnormality (e.g., globozoospermia, macrozoospermia, different abnormalities of sperm flagella), allowed couples to consider further sperm functional assessment and genetic tests before making informed decisions on the optimal method of treatment (34Tournaye H. Krausz C. Oates R.D. Novel concepts in the aetiology of male reproductive impairment.Lancet Diabetes Endocrinol. 2017; 5: 544-553Google Scholar, 35Krausz C. Rosta V. Swerdloff R.S. Wang C. Genetics of male infertility.in: Pyertitz R. Korf B. Grody W. Emery and Rimoin's principles and practice of medical genetics and genomics. Vol. Perinatal and Reproductive Genetics. Elsevier, 2021Google Scholar). Importantly, traditional semen parameters in at least a single ejaculate are considered necessary for the appropriate investigation and treatment pathway for couples with male infertility (36Barratt 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 evidence to support the development of global WHO guidance-challenges and future research opportunities.Hum Reprod Update. 2017; 23: 660-680Google Scholar). Comments also suggested that this laboratory manual should follow the standardization in describing tests in clinical laboratories according to the International Federation of Clinical Chemistry and Laboratory Medicine and the Inte
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