Assessment of male factor




The assessment of male infertility is largely based around the examination of a freshly produced ejaculate by a trained technician according to laboratory methods agreed by the World Health Organization. Although many suggestions have been made to improve this approach, the basic techniques of semen analysis established in the 1950s are still being used. Although several putative tests of sperm function have been developed (e.g. the measurement of sperm hyperactivation, sperm acrosomal status, or sperm penetration through mucus or binding to zona pellucida), none have made it into routine clinical practice. Recently, several ‘new’ tests of sperm function and sperm selection have been developed. These include the use of microfluidic chambers, electrophoresis, the binding of sperm to hyaluronic acid, and high magnification sperm selection. Randomised-controlled trials are needed to evaluate these as a replacement or addition to routine semen analysis or current sperm preparation methods.


Background to male infertility


The incidence of infertility in men is difficult to establish reliably, but current evidence suggests that up to 20–25% of young men have poor semen quality and, in 30–50% of couples undergoing in-vitro fertilisation (IVF), a male factor contributes to infertility. Unlike the situation in some cases of female infertility (e.g. amenorrhea), possible male infertility is not outwardly obvious because, macroscopically, the ejaculates of fertile and infertile men appear the same. It is only when couples fail to achieve conception, that male infertility may be suspected and laboratory tests (e.g. semen analysis) are clearly required to establish this reliably.


In recent years, whether or not the incidence of male infertility has increased has been furiously debated. This has largely been based on the hypothesis that, as yet, unknown factors in the environment are affecting the testicular development of an increasing number of male babies before birth. It is proposed that after puberty such affected individuals are more likely to produce ejaculates with reduced sperm count and consequently are less fertile. Direct evidence to support this hypothesis, however, is lacking; moreover, more recent prospective data have suggested that semen quality in young men is not declining in the way that was originally proposed from an analysis of retrospective studies. Although increasing rates of urogenital defects and incidence of testicular cancer have been demonstrated, lending some support to the original theory, the cause of such urogenital conditions is clearly more complex than was first proposed.


As well as pre-natal exposures, the spermatogenesis of post-pubertal males can also be influenced by a number of medical and lifestyle factors. For example, the ejaculates of men who have been treated with chemotherapy or radiotherapy typically have lower sperm concentrations than men not treated with these agents. Similarly, men exposed to glycol ether in the workplace, or men who have been infected with the sexually transmitted infection Chlamydia trachomatis have lower sperm concentrations. Direct and independent effects on sperm motility, sperm morphology, or both, are less well described but equally important in their effect on male fertility.




Background to semen analysis


Antonie van Leeuwenhoek first described human spermatozoa in 1678, although it wasn’t until the 1950s when the first clinical descriptions of the relationship between semen quality and conception were made. In 1980, the World Health Organization (WHO) then published an internationally agreed ‘reference range’ designed to help clinicians make decisions using data on semen quality ; over the next 30 years, four further updates were produced as shown in Table 1 .



Table 1

World Health Organization reference ranges from 1980 to 2010 for the minimum semen quality thought to be compatible with unassisted conception.










































































1980 1987 1992 1999 2010
Semen volume (ml) ≥2.0 ≥2.0 ≥2.0 ≥1.5
pH 7.2–7.8 7.2–7.8 7.2
Sperm concentration (×10 6 /ml) ≥20 ≥20 ≥20 ≥20 ≥15
Total sperm number (×10 6 ) ≥40 ≥40 ≥40 ≥39
Progressive Motility (%) ≥60 ≥50 ≥50 ≥50 ≥32
Normal morphology (%) ≥80 ≥50 ≥30 ≥4
Vitality (% alive) ≥50 ≥75 ≥75 ≥58
White blood cells ≤5.0 ≤1.0 ≤1.0 ≤1.0 ≤1.0
Antibody coated sperm (%) ≤10 ≤20 ≤50 ≤50


As these ‘ranges’ became widely used in clinical practice, two issues became apparent. The first was how the variation in the technique used in different laboratories could affect the semen analysis results being reported significantly. This was illustrated in a series of studies in the UK and the USA, leading to the establishment of training programmes and external quality-assurance programmes in andrology. The second was that, even when semen analysis was carried out robustly, and with appropriate quality-control measures in place, a significant uncertainty could remain about the relationship between semen profile and the probability of conception. As a consequence, commentators argued the need to further revise the WHO ‘reference ranges’. To some extent, the publication of the 5th edition of the WHO manual in 2011 has addressed this problem in basing the reference ranges for the first time on ‘real world’ data. This also introduced the importance of ‘confidence intervals’, allowing the user to understand the individual semen analysis values obtained in the context of measurement error ( Table 2 ).



Table 2

The current World Health Organization reference ranges for minimum semen quality (fifth centile of a fertile population) showing the associated 95% confidence interval for each variable.




























Variable Fifth centile (95% confidence interval)
Semen volume (ml) 1.5 (1.4–1.7)
Sperm concentration (×10 6 /ml) 15 (12–16)
Total sperm number (×10 6 ) 39 (33–46)
Progressive motility (%) 32 (31–34)
Total motility (%) 40 (38–42)
Vitality (% alive) 58 (55–63)
Normal morphology (%) 4 (3–4)


It has long been recognised that semen analysis only goes so far in providing a physical description of the ejaculate. Therefore, in an attempt to improve on this, many investigators have now turned their attention to the potential value of assessing aspects of sperm DNA either as a routine part of semen analysis or as a replacement to it. This concept is underpinned by the logic that, although sperm may appear motile and have normal morphology, if their DNA is damaged or inappropriately packaged, fertilisation, embryo development, or both, may fail because the oocyte only has a limited capacity to repair the damage. Sperm DNA may be damaged by a variety of environmental and lifestyle factors, and substantial data have reported the relationship between sperm DNA packaging and fragmentation and live birth rate and pregnancy loss in IVF and intracytoplasmic sperm injection (ICSI). The problem is that significant debate about which tests may be clinically useful remains. Interestingly, both the American Society for Reproductive Medicine (ASRM) and the European Society for Human Reproduction and Embryology (ESHRE) have both published recent position statements indicating that they do not yet support the use of sperm DNA testing on a routine basis.




Background to semen analysis


Antonie van Leeuwenhoek first described human spermatozoa in 1678, although it wasn’t until the 1950s when the first clinical descriptions of the relationship between semen quality and conception were made. In 1980, the World Health Organization (WHO) then published an internationally agreed ‘reference range’ designed to help clinicians make decisions using data on semen quality ; over the next 30 years, four further updates were produced as shown in Table 1 .



Table 1

World Health Organization reference ranges from 1980 to 2010 for the minimum semen quality thought to be compatible with unassisted conception.










































































1980 1987 1992 1999 2010
Semen volume (ml) ≥2.0 ≥2.0 ≥2.0 ≥1.5
pH 7.2–7.8 7.2–7.8 7.2
Sperm concentration (×10 6 /ml) ≥20 ≥20 ≥20 ≥20 ≥15
Total sperm number (×10 6 ) ≥40 ≥40 ≥40 ≥39
Progressive Motility (%) ≥60 ≥50 ≥50 ≥50 ≥32
Normal morphology (%) ≥80 ≥50 ≥30 ≥4
Vitality (% alive) ≥50 ≥75 ≥75 ≥58
White blood cells ≤5.0 ≤1.0 ≤1.0 ≤1.0 ≤1.0
Antibody coated sperm (%) ≤10 ≤20 ≤50 ≤50


As these ‘ranges’ became widely used in clinical practice, two issues became apparent. The first was how the variation in the technique used in different laboratories could affect the semen analysis results being reported significantly. This was illustrated in a series of studies in the UK and the USA, leading to the establishment of training programmes and external quality-assurance programmes in andrology. The second was that, even when semen analysis was carried out robustly, and with appropriate quality-control measures in place, a significant uncertainty could remain about the relationship between semen profile and the probability of conception. As a consequence, commentators argued the need to further revise the WHO ‘reference ranges’. To some extent, the publication of the 5th edition of the WHO manual in 2011 has addressed this problem in basing the reference ranges for the first time on ‘real world’ data. This also introduced the importance of ‘confidence intervals’, allowing the user to understand the individual semen analysis values obtained in the context of measurement error ( Table 2 ).



Table 2

The current World Health Organization reference ranges for minimum semen quality (fifth centile of a fertile population) showing the associated 95% confidence interval for each variable.




























Variable Fifth centile (95% confidence interval)
Semen volume (ml) 1.5 (1.4–1.7)
Sperm concentration (×10 6 /ml) 15 (12–16)
Total sperm number (×10 6 ) 39 (33–46)
Progressive motility (%) 32 (31–34)
Total motility (%) 40 (38–42)
Vitality (% alive) 58 (55–63)
Normal morphology (%) 4 (3–4)


It has long been recognised that semen analysis only goes so far in providing a physical description of the ejaculate. Therefore, in an attempt to improve on this, many investigators have now turned their attention to the potential value of assessing aspects of sperm DNA either as a routine part of semen analysis or as a replacement to it. This concept is underpinned by the logic that, although sperm may appear motile and have normal morphology, if their DNA is damaged or inappropriately packaged, fertilisation, embryo development, or both, may fail because the oocyte only has a limited capacity to repair the damage. Sperm DNA may be damaged by a variety of environmental and lifestyle factors, and substantial data have reported the relationship between sperm DNA packaging and fragmentation and live birth rate and pregnancy loss in IVF and intracytoplasmic sperm injection (ICSI). The problem is that significant debate about which tests may be clinically useful remains. Interestingly, both the American Society for Reproductive Medicine (ASRM) and the European Society for Human Reproduction and Embryology (ESHRE) have both published recent position statements indicating that they do not yet support the use of sperm DNA testing on a routine basis.




Background to sperm function tests


Sperm function tests differ from the measurements undertaken at semen analysis, as they set out to try and examine aspects of sperm biology that have physiological relevance as sperm ascend through the female reproductive tract or are used in the various techniques of assisted conception. Clearly, during natural (unassisted) conception, sperm need to undertake a greater range of functional steps (e.g. passage through cervical mucus or the ability to migrate through the utero-tubal junction) than sperm that are used in assisted conception (e.g. ICSI) as shown in Table 3 . Some of the main sperm function tests developed over the past few years are presented in Table 4 , and the advantages and disadvantages of each are highlighted. Although it can be seen that many putative tests of sperm function have been developed, however, none have yet been universally accepted and incorporated into routine clinical practice. Therefore, it is clear that a need remains for new sperm function tests to be developed. The following sections outline some of the promising avenues.


Nov 9, 2017 | Posted by in OBSTETRICS | Comments Off on Assessment of male factor

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