It is doubtful that diffusion can deliver sufficient ATP from the mitochondria to sustain activity at the distal end of the sperm flagellum. Glycolytic enzymes bound to the fibrous sheath could provide energy along the flagellum at the point it is required. An obligatory role for glycolysis is supported by the lack of progressive motility in sperm from mice where the gene for sperm-specific glyceraldehyde-3-phosphate dehydrogenase (GAPDHs) had been 'knocked out'. Here, I review some evidence against this idea. First, pure diffusion from the mitochondrion is likely to be adequate in species with smaller sperm, and it is possible that rapid ATP delivery required in larger sperm could be achieved by an adenylate kinase shuttle. Second, experience with alpha-chlorohydrin demonstrates that sperm can remain motile with normal ATP concentrations despite inhibition of GAPDHs; adverse effects only occur if glucose is added and high levels of glycolytic intermediates accumulate. These observations undermine the GAPDHs knockout mouse as evidence for an essential role of local glycolysis. Third, sperm from many species can remain motile for long periods in sugar-free media and excepting dog sperm, evidence that gluconeogenesis is a possible explanation, is weak. In most species, it is unlikely that local glycolysis is the only way that ATP can be supplied to the distal flagellum.

Sperm capacitation can be increased by the addition of reactive oxygen species (ROS) and decreased by antioxidants. Broadly consistent results have been achieved with a wide variety of methods and across different species. Exposure to ROS increases protein tyrosine phosphorylation consequent on an increase in cAMP and activation of tyrosine kinase and inhibition of tyrosine phosphatase. The measurement of ROS production by sperm is complicated by contamination of suspensions by leukocytes, laying many studies open to doubt. In human sperm the observation that extracellular NADPH could support superoxide production detected with the chemiluminescent probe lucigenin and had physiological effects similar to hydrogen peroxide led to the suggestion that they contained NADPH oxidase activity to generate ROS to support capacitation. However, the realization that lucigenin can signal superoxide artefactually, combined with failure to detect superoxide production using spin trapping techniques or to detect NADPH oxidase components in mature sperm, and confirmation of old reports that NADPH solution contains substantial amounts of hydrogen peroxide due to autoxidation, have undermined this hypothesis. Although the presence of significant NADPH oxidase activity in mature human sperm now seems less likely, other observations continue to suggest that they can make ROS in some way. There is stronger evidence that animal sperm can make ROS although these may be mainly of mitochondrial origin.

The impact of male age on fecundity remains controversial. Here, a large population study was used to investigate the effect of paternal age on time to conception. All couples in the Avon Health district expecting a baby between 1 April 1991 and 31 December 1992 were eligible. Questionnaires completed by both the man and the woman at 18 weeks gestation covered specific fertility factors, e.g. parity, paternity, cohabitation and oral contraception; and non-specific factors, e.g. educational achievement, housing, cigarette smoking, alcohol consumption, obesity. Logistic regression was used to identify factors independently related to conception in < or =6 or < or =12 months. Of 8515 planned pregnancies, 74% were conceived in < or =6 months, 14% in the second 6 months and 12% after more than a year. Nine variables, including the age of the woman, were independently related to time to conception. After adjustment for these, the likelihood of conception within 6 or 12 months was lower in older men. Compared to men <25 years old, the adjusted odds ratios (95% confidence interval) for conception in < or =12 months were 0.62 (0.40, 0.98), 0.50 (0.31, 0.81) and 0.51 (0.31, 0.86) in men aged 30-34, 35-39 and > or =40 years respectively.

Nitric oxide (NO) enhances human sperm motility and capacitation associated with increased protein phosphorylation. NO activates soluble guanylyl cyclase, but can also modify protein function covalently via S-nitrosylation of cysteine. Remarkably, this mechanism remains unexplored in sperm although they depend on post-translational protein modification to achieve changes in function required for fertilisation. Our objective was to identify targets for Snitrosylation in human sperm. Spermatozoa were incubated with NO donors and S-nitrosylated proteins were identified using the biotin switch assay and a proteomic approach using tandem mass spectrometry. 240 S-nitrosylated proteins were detected in sperm incubated with Snitrosoglutathione. Minimal levels were observed in glutathione or untreated samples. Proteins identified consistently based on multiple peptides included established targets for S-nitrosylation in other cells e.g. tubulin,, glutathione-S-transferase and heat shock proteins but also novel targets including A-kinase anchoring protein (AKAP) types 3 and 4, voltage-dependent anion-selective channel protein 3 and semenogelin 1 and 2. In situ localisation revealed S-nitrosylated targets on the post-acrosomal region of the head and throughout the flagellum. Potential targets for Snitrosylation in human sperm include physiologically significant proteins not previously reported in other cells. Their identification will provide novel insight into the mechanism of action of NO in spermatozoa.

The authors of the World Health Organization Semen Analysis Manual are to be congratulated on producing a new edition; it is an essential tool to disseminate good practice in andrology. However, the tests described have poor prognostic power to predict a man's fertility and show little about the underlying causes of sub-fertility. This commentary urges a revival of research into the diagnosis of male fertility. It suggests that fertility should be regarded as a continuum and that the artificial binary division between fertile and infertile should be abandoned. Models to predict a sub-fertile couple's chance of conception in a year should be developed on the basis of prospective data. These models would allow for sophisticated decision making about management. The future lies in the identification of tests to detect underlying pathologies open to specific treatment. Leads such as oxidative stress, defects in the intracellular regulation and the developing field of proteomics should be explored.

CATs are of predictive value in the detection of tubal damage and are quantitatively related to the severity of damage. For practical clinical purposes, Chlamydia serology is useful mainly as a screening test for the likelihood of tubal damage in infertile women and may facilitate decisions on which women should proceed with further investigations without delay.

Although sperm dysfunction is the single most common cause of infertility, we have poor methods of diagnosis and surprisingly no effective treatment (excluding assisted reproductive technology). In this review, we challenge the usefulness of a basic semen analysis and argue that a new paradigm is required immediately. We discuss the use of at-home screening to potentially improve the diagnosis of the male and to streamline the management of the sub-fertile couple. Additionally, we outline the recent progress in the field, for example, in proteomics, which will allow the development of new biomarkers of sperm function. This new knowledge will transform our understanding of the spermatozoon as a machine and is likely to lead to non-ART treatments for men with sperm dysfunction. Reproduction (2007) 133 675-684

This study aims to determine the relative contribution of oocyte and/or sperm dysfunction to the reduction of fertilization rates in vitro in cases of minor endometriosis and prolonged unexplained infertility. The results of in-vitro fertilization (IVF) treatment with ovarian stimulation have been compared between couples with the above conditions and women with tubal infertility (as control for oocyte function) and the use of donor spermatozoa (as control for sperm function). Fertilization and cleavage rates using husband's spermatozoa were significantly reduced in endometriosis couples (56%, n = 194, P < 0.001) and further significantly reduced in couples with unexplained infertility (52%, n = 327, P < 0.001) compared with tubal infertility (60%, n = 509). Using donor spermatozoa the rates were the same as using husband's spermatozoa in tubal infertility (61%, n = 27) or endometriosis (55%, n = 21) but significantly though only partly improved with unexplained infertility (57%, n = 60, P < 0.02). In unexplained infertility, a significantly increased proportion of couples experienced complete failure of fertilization and cleavage in a cycle (5-6% versus 2-3%). However, complete failure was not usually repetitive, and the affected couples did not account for the overall reduction in fertilization and cleavage rates, which remained significantly lower in the rest of the unexplained and endometriosis groups. Implantation and pregnancy rates appeared similar in all groups. The benefit of IVF treatment in cases of minor endometriosis and prolonged unexplained infertility is due to superabundance of oocytes obtained by stimulation. The reduction in natural fertility associated with endometriosis appears to be at least partly due to a reduced fertilizing ability of the oocyte. In unexplained infertility, there is distinct impairment due to otherwise unsuspected sperm dysfunction but probably also oocyte dysfunction.