ReviewConsistent age-dependent declines in human semen quality: A systematic review and meta-analysis
Introduction
Understanding how age affects fertility is becoming increasingly important as couples delay childbearing toward later stages of their lives (Sartorius and Nieschlag, 2010). The average age at which couples first reproduce has risen significantly in recent decades with mean age of first reproduction now around 30 years in many countries (Humm and Sakkas, 2013, Kühnert and Nieschlag, 2004, Sloter et al., 2006). While increasing maternal age is well established as a negative effector on fertility, reproductive success and offspring fitness (Belloc et al., 2008, Maheshwari et al., 2008), the influence of paternal age is poorly characterized. Nevertheless, increasing evidence suggests that advanced paternal age is associated with declines in fertility and offspring fitness, independent of maternal age (Aitken, 2014, Johnson and Gemmell, 2012, Kidd et al., 2001, Kong et al., 2012, Kühnert and Nieschlag, 2004, Sartorius and Nieschlag, 2010).
Quantitative and qualitative aspects of the ejaculate (Table 1), which hereafter are collectively referred to as semen traits, are considered a proxy of fertility and gamete fitness and are routinely used in fertility assessment (Cooper et al., 2010, WHO, 1999, WHO, 2010). As such, they have been a key focus of research with regard to changes in male fertility with age (Eskenazi et al., 2003, Kidd et al., 2001, Li et al., 2011, Plas et al., 2000, Sartorius and Nieschlag, 2010). Numerous studies have reported age-related declines in semen volume, sperm motility and the proportion of morphologically normal sperm (reviewed in Kidd et al., 2001, Kühnert and Nieschlag, 2004, Li et al., 2011). However, other studies have reported no associations or, more rarely, improvements in semen traits with age (reviewed in Kidd et al., 2001, Kühnert and Nieschlag, 2004). A review of the literature in 2001 showed that semen volume, sperm motility and normal sperm morphology are lower in men of 30 years than those aged 50 (Kidd et al., 2001), but that sperm concentration showed no such decline. One of the major criticisms of this earlier work is that most of the studies were conducted on men attending infertility clinics (Guryev et al., 2006, Kidd et al., 2001). More recent studies have been conducted on healthy, non-smoking populations and have reported similar declines in many semen traits (Eskenazi et al., 2003, Sloter et al., 2006), but again, the evidence is mixed for sperm concentration (Eskenazi et al., 2003). A growing number of studies have found increases in sperm DNA fragmentation with increasing male age (Rybar et al., 2011, Wyrobek et al., 2006, reviewed in Humm and Sakkas, 2013).
The mechanisms responsible for age-dependent patterns of decline in sperm fitness are not fully understood, but damage by oxidative stress is thought to be an important contributor (see Box 1). Males are also susceptible to accumulating deleterious germ-line mutations in an age-dependent manner (Crow, 2000, Kong et al., 2012). It is thus widely believed that older males are more likely to pass on genetic material of lower quality than their younger counterparts, likely affecting fertilization rates, pregnancy rates, the rate of pregnancy complication and ultimately offspring fitness (see Box 2). Hence, like increasing maternal age, increasing male age can have significant consequences on health care systems both in terms of ameliorative treatments for age related reductions in fertility and the potential health consequences that increasing paternal age may have on offspring.
While the general consensus is that increasing paternal age tends to be associated with a decline in semen quality (Kidd et al., 2001, Kühnert and Nieschlag, 2004, Sartorius and Nieschlag, 2010), this important topic has not previously been the subject of a comprehensive, formal meta-analysis. Such an analysis is warranted, as the ramifications of declining semen traits with increasing male age have largely been ignored owing to inconsistencies in the literature. Using data from 90 studies (93,839 subjects), we conducted a systematic review, performing meta-analysis to quantify the effect of paternal age on seven ejaculate traits: semen volume, sperm concentration, total sperm count, sperm morphology, total motility, progressive motility and sperm DNA fragmentation (see Table 1 for definitions). While methodologies have undoubtedly changed over time, this is not of major concern for meta-analysis because effect sizes are estimated from individual studies (i.e., a standardized effect size with dimensionless units (e.g., correlation coefficient) is estimated for each trait in each study population). Standardized effect sizes can thus be combined across different studies in order to investigate general trends and consistency in the literature (Borenstein et al., 2009, Nakagawa and Cuthill, 2007). We did, however, explore relative contributions of some different moderators or confounding factors (e.g., sample source, abstinence control, mean age, publication bias, etc.). Because a common criticism of studies investigating a decline in sperm concentration with age is that it is also declining globally over time (Carlsen et al., 1992), we investigated the decline in sperm concentration over time, by adding recent data to the previous published data (Carlsen et al., 1992). Our overall objective of this study was to quantitatively synthesize the current state of knowledge of this important topic and to present an overview of the empirical evidence. Importantly, further awareness of the potential consequences of advancing male age will inform clinicians and the general public of the risks associated with male aging.
Section snippets
Literature search
Our review has been registered with PROSPERO (CRD42013003668). We followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement (Moher et al., 2009) which uses a systematic approach to search the literature. On November 29, 2013, we conducted searches through PubMed, Web of Science, Scopus, and Embase by using the search string: “(age OR aging) AND (sperm OR semen) AND (men or male) AND (fertility OR fertile) AND (volume OR concentration OR morphology OR
Meta-analysis and heterogeneity analysis
The outcomes of our literature search are presented as a PRISMA diagram (Fig. 1). In summary, we arrived at 90 relevant studies (involving 93,839 subjects), which included suitable data for meta-analysis. The number of effect sizes for each semen parameter and the number of subjects are listed in Fig. 1 (see also Fig. 2 and Tables 2 and S1). A series of meta-analyses revealed that an increase in male age negatively and significantly affected all the semen properties except sperm concentration
Discussion
Through systematic review of the literature, meta-analysis and meta-regression, we have explored whether seven routinely examined ejaculate traits decline with increasing male age. Our meta-analysis included data on 93,839 male subjects, extracted from 90 studies. While the effect sizes were small to medium, the weight of the scientific evidence suggests that male age is associated with a decrease in semen volume, a decrease in total sperm count, a decrease in percent motility, a decrease in
Conflict of interest
The authors have no conflict of interest to declare.
Author's contribution
The authors have made the following declarations about their contributions: Conceived and designed the experiments: SLJ, NG, SN. Analyzed the data: SLJ, SN. Contributed reagents/materials/analysis tools: SLJ, NG, SN. Wrote the paper: SLJ, JD, NG, SN.
Acknowledgements
We thank M. Lagisz for advice on systematic review procedures and J. Peak and an anonymous reviewer for comments that improved the manuscript. SLJ is supported by a Royal Society of New Zealand Marsden Fund grant (UOO1111) and SN is supported by a Rutherford Discovery Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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