Lycopene is a carotenoid found in high concentrations in tomatoes, tomato products and other red-pigmented foods which has received considerable interest in recent years as a potential therapeutic agent for a variety of health conditions [27]. However, the bioavailability of lycopene from fresh tomatoes is low, but this is enhanced by processing, heating and co-delivery of tomatoes with oil [28]. As such, this study used the nutritional supplement lactolycopene, the main ingredient of which is lycopene embedded in a whey protein matrix for enhanced intestinal absorption. The 14 mg/d of lactolycopene supplied to the men in this study is equivalent to consuming 2 kg of cooked tomatoes or 2 tablespoons of concentrated tomato puree each day, and so represented a sizable increase in the lycopene intake of the study participants.

For this study, we chose to enrol as our study participants young healthy volunteers with no known fertility issues. However, this was done with the knowledge that a sizeable proportion of them would have poor sperm quality at the outset [29] but since they were less likely to have tested their fertility and they were not actively trying to conceive, they would be blind to their own semen quality (unlike fertility patients attending a clinic) and, therefore, unlikely to make other adjustments to their lifestyle to enhance fertility. It is noteworthy that at the outset of the study, 31 of the 56 men (see Table 3) did not have normal semen parameters (normozoospermia), suggesting that our original assumption was correct.

For the primary outcome measure, we chose to use the concentration of motile sperm since this has been shown to be the variable obtained from semen analysis most likely to be associated with the probability of conception [30]. However, whilst this was not statistically improved after lycopene supplementation (p = 0.058) two other measures of sperm quality were significantly altered: (i) the proportion of fast-progressive sperm (p = 0.006) and (ii) the proportion of sperm with normal morphology (p < 0.001). The direction of both these changes is positive, but it is impossible to say how they might impact chances of natural pregnancy or the choice of assisted reproduction treatment (ART) had our participants been attending an infertility clinic. In theory, both are clinical improvements in sperm quality and would presumably be welcomed by infertile men. Whilst many measures of sperm motility [31, 32] and morphology [33] are difficult to make, we used computer-assisted sperm analysis for both measures, which provides a level of objectivity; furthermore, the sperm quality measures were performed blind to the allocation of each participant. In comparison to the changes observed in the men randomized to lycopene supplementation, the only statistically significant change observed in the placebo group was a reduction in the percent of non-progressive sperm (p = 0.002). We are unable to explain this observation but conclude that it is unlikely to be clinically significant since it was only accompanied by a non-significant increase in the percent non-motile sperm, and sperm with these motility characteristics are unlikely to participate in natural conception [2]. Interestingly, we saw no change in sperm DNA damage, but given the ongoing controversy about its measurement and interpretation [34] this is perhaps not surprising.

The 12-week duration of the study was chosen to increase plasma lycopene levels across the full (~ 70 day) window required to make (and ejaculate) new sperm [35] because we did not want to make any assumptions about when lycopene supplementation might be most beneficial. Therefore, it is not possible to conclude whether there is an optimum duration of lycopene supplementation that would give the same results as those reported here without undertaking further study.

Similarly, the choice of lactolycopene dose was a pragmatic one based on the availability of the supplement from the supplier, and the use of similar lycopene dosages and durations in clinical trials of cardiovascular disease [36]. So, again, we are unable to comment whether different doses of the supplement to the ones used here may lead to the same results. However, it is noteworthy that the results we describe are similar to those previously reported in an open-label study showing improvements in sperm morphology and motility using 4 mg of daily lycopene supplementation for 3 months [18]. The daily dose of 14 mg lycopene was certainly able to significantly increase the plasma lycopene level in our study participants (see Table 3) compared to those randomized to placebo. However, whether this is the optimum level to maximize any effects on sperm quality measures remains to be established.

The underlying biological mechanism of action whereby lycopene exerts an effect on the sperm is currently unknown. The antioxidant properties of lycopene have been the primary focus of mechanistic investigation of the action of lycopene on idiopathic male infertility to date [17]. Oxidative stress is believed to play a role in the pathogenesis of idiopathic male infertility and although reactive oxygen species play an important role in normal sperm function, disequilibrium of reactive oxygen species and antioxidant defence appears to be detrimental [37]. While it is well known that sperm are very vulnerable to damage by free radicals [38], we cannot assume that the beneficial effects of lycopene we observed are because of its antioxidant properties as we did not make any relevant measurements of oxidative stress in biological fluids such as seminal plasma. However, an antioxidant role for lycopene is a plausible hypothesis.

The study reported here had a modest sample size and is not without its limitations. First, to increase the rates of compliance by the study participants, we allowed them to produce their samples at home rather than in a clinic and this would have inevitably led to a delay in undertaking some of the measurements we have reported here. However, the World Health Organisation Laboratory Manual for the examination and processing of human semen [3] recommends that all measurements be performed within 1 h of sample production and others [39] have argued that specimen collection at home is not detrimental as long as samples are delivered in a timely manner and motility measurements are done at the correct temperature. In this study, the median delay in processing the samples was 58.5 min (range 35–115 min) and was not different between those men randomized to lycopene vs placebo. Furthermore, all motility measurements were undertaken at 37 °C as per WHO (2010) recommendations. Second, it is known that BMI is related to aspects of semen quality [10] and although the majority of the study participants had a normal BMI, a high proportion (45%) fell in the overweight or obese category. This may reflect a high muscle mass rather than a high fat mass since a proportion of the men were recruited via University Sports clubs. Interestingly, the BMI of men randomized to lycopene was significantly higher (p = 0.049) compared to those randomized to placebo (Table 1) which suggests that the observed improvement in semen quality in these men could be more remarkable than in men with a lower BMI. However, the difference in BMI is small and probably biologically insignificant, although in future studies it could be useful to consider undertaking an analysis of body composition using bioelectrical impendence [40] for a more accurate assessment of percentage body fat.

In conclusion, we report a modest but statistically significant improvement in the semen quality of healthy young men randomized to receive 14 mg lactolycopene per day for 12 weeks. Whilst the study demonstrates improvements in some measures of sperm quality in response to lycopene supplementation, the clinical impact on fertility and the chances of pregnancy, and live birth are unknown. Future studies should focus on men from infertile partnerships to determine not only the optimum dose and timing of lycopene both to improve sperm quality but also whether this enhances pregnancy outcome for these couples.