Though humans are considered to be non-seasonal mammals, we are undoubtedly sensitive to photoperiod [12], as exemplified by ‘seasonal affective disorder’ and by seasonal trends in the frequency of births and in the incidence of twins. Such effects are most obvious in Northern Europe where photoperiodic changes are most extreme [13]. Furthermore, both longitudinal and cross-sectional studies have demonstrated that sperm counts in men are consistently ~30% lower in summer than in spring and/or winter [14–16], though not all studies have reported such effects, and they may be less apparent or absent in tropical countries [17]. An alternative explanation is that exposure to the higher summer temperature is responsible for lowering sperm production (see below), though temperature changes do not account for all of the seasonal trends in births, especially in Northern Europe [12]. If the reported ‘seasonal’ changes in sperm counts/semen quality are an echo from our seasonally breeding ancestors, then this may be rather variable in its effect and, in most men, is unlikely to exert a major effect on their fertility. It is likely that any effects of season in humans/individuals will be driven by seasonal changes in the duration of melatonin secretion, as in seasonally breeding animals (below).

Studies in seasonally breeding animals have established the key pathways via which daylight length is able to regulate the reproductive axis, and melatonin secreted by the pineal gland plays a pivotal role [1, 2]. It is therefore curious that young men with hypogonadotropic hypogonadism (HH) show abnormal blood levels of melatonin, being increased in males with idiopathic HH and decreased in males with Kallmann syndrome, when compared with controls [18, 19]. However, as melatonin levels may be normalized by testosterone replacement therapy in HH men, it implies that the abnormal melatonin level may be a consequence rather than a cause of the HH [18], although this reasoning may not extend to men with hypergonadotropic hypogonadism [19]. More generally, the evidence for seasonal fluctuations in testosterone levels in men is equivocal [20] and is likely to be highly confounded by the influence of other factors such as obesity, activity levels and age.

Numerous published studies have retrospectively surveyed the occupations of men attending infertility clinics and/or compared occupations of fertile and infertile groups. There is some consensus in showing, for example, that farmers/agricultural workers or lorry drivers, painters or welders may be over-represented among infertile men, but overall the findings of such studies are inconsistent and have failed to identify common occupational causes of male infertility [21–24]. Occupation is only one of a range of factors that may cause male infertility, and therefore searching for such factors among patients at the infertility clinic may not be the most sensitive approach. Unfortunately, alternative approaches such as the direct investigation of particular working groups also have various problems [25]. Low participation rates are common and may be biased toward those who have experienced, or suspect, a fertility problem [26]. This makes interpretation of any findings difficult. Another common problem is the low numbers of workers who may eventually compose the ‘exposed’ or control groups, as many published studies involve 30–50 men or less per group [23, 25, 27]. As sperm counts and other semen parameters show great variation between subjects, detection of a workplace/occupational effect against such a background requires considerable numbers of subjects; otherwise, the study will lack sufficient power to detect anything other than a major change in semen parameters [25]. For example, ~80 control and ‘exposed’ men would be required to detect a 20% fall in sperm count. Moreover, because within-subject variation in semen parameters can also be substantial, a rigorous study should involve two or more semen samples per subject, adding considerably to study complexity and cost.

Finally, there are likely to be many confounding factors in any occupational study. These may include age, ejaculatory frequency/abstinence, smoking and alcohol consumption, recreational drug use, time spent seated (see below), recent infection or febrile period, past history of cryptorchidism and sexually transmitted disease [28]. Attempts can be made to control for some of these factors, but with the generally small numbers of subjects involved, this is inevitably less than satisfactory. Against this background, it is therefore unsurprising that relatively few occupations or workplace exposures have been shown consistently to impact significantly on male reproductive health (usually on sperm counts/fertility). However, there is reasonable evidence to suggest that exposure to some solvents [29], older glycol ethers [23, 30] and inorganic lead [31, 32] can impact one or more aspects of semen quality in exposed workers and in some instances affect fertility or miscarriage rates (though effects on the latter two parameters are small). Nevertheless, other studies that showed no significant effect of similar exposures can also be found in the literature [e.g., 33, 34]. This would support the view that such workplace exposures have relatively minor effects on semen quality and male fertility, though in some individuals, such as those with a low sperm count for other reasons, such effects might significantly impact fertility.

Information on occupational impacts on testosterone levels in men is even more equivocal, in part for reasons of study group sizes as just outlined for semen quality aspects. Moreover, any adverse effect on testosterone levels should automatically trigger a compensatory increase in LH secretion that will return testosterone levels toward normal, unless the factor(s) in question exerts its adverse effect via altering secretion of LH. While any such compensatory change should theoretically be detectable via LH measurement and calculation of the LH/testosterone ratio, the inter-individual variation in LH and its pulsatile secretion pattern as well as the circadian rhythm in testosterone levels can make differences difficult to detect unless changes are extreme, which would be unusual. Reasons such as these probably explain why the literature on this topic is small with highly equivocal, and usually very minor, findings. These will not be reviewed in any detail here, but an example is a Chinese study of 154 electrical power-plant workers, half of whom were exposed to electromagnetic fields, which was associated with a 3% average drop (p = 0.015) in total testosterone levels [35]; such a change is likely to be incidental. Where occupation has been associated with altered testosterone levels, it has been mainly in connection with pesticide/fungicide exposure, which is outlined below. A more convincing study involved Italian policemen exposed to traffic fumes [36], compared with police office workers. Those exposed to traffic fumes exhibited ~20% reduction in free testosterone levels, a difference that was even more marked (~29%) when those in the age range 30–40 years were compared [36]. Unfortunately, LH levels and the LH/testosterone ratio were not reported in that particular study, although a similar earlier study by the same authors (N = 166 traffic-exposed vs. 166 non-exposed) reported a mean 50% increase in LH levels (from 1.8 to 2.7 mIU/ml; p < 0.001), although no testosterone levels were reported in that study! [37] Thus, it appears that high exposure to traffic pollutants may induce compensated Leydig cell failure (i.e., decreased or normal testosterone in the face of elevated LH), but this requires direct confirmation in a properly designed study in which both LH and testosterone are measured in the same men. As to mechanism, there is some evidence that diesel exhaust might suppress expression of steroidogenic factor-1 in developmental animal studies [38].

The occupational exposure associated with the greatest change in sperm count and fertility was workplace exposure to the nematicide, dibromochloropropane (DBCP; Table 14.1). This toxin induced azoospermia or oligospermia in a high percentage of exposed workers, both those involved in its manufacture and those involved in its application on crops [39–41]. In a substantial proportion of DBCP-exposed workers who became azoospermic, no recovery of sperm counts occurred following removal from exposure [39, 40]. This lone example is frequently cited as reassuring evidence of the rarity of such workplace effects on sperm counts and male fertility. In reality this reassurance is a veil. The effects of DBCP were revealed, even though the affected workforces comprised fairly low numbers, because it had catastrophic effects on sperm counts/fertility. We can be reassured that similar catastrophes will also reveal themselves, but more modest effects of occupation on sperm counts/fertility will remain difficult or impossible to identify in all but very large, well-controlled studies. The latter are hugely expensive and laborious, both of which act as strong deterrents to their application.

The DBCP experience has had several important repercussions, the most scientifically important being the impetus that it gave to studies of wider pesticide exposure and male reproductive function, especially changes in semen quality and male fertility. Conversely, it has also helped trigger the default view that pesticide exposure results in lowered sperm counts/infertility, which has become more or less accepted as dogma in some circles. There have also been numerous studies of pesticide exposure and hormone levels in men, which is the primary focus of this chapter. However, as there is clear evidence that men with low sperm counts are at increased risk of having compensated Leydig cell failure [42, 43], it makes sense to consider the evidence for pesticide effects on both aspects of male reproductive function together.

There are numerous studies that show significant associations between exposure to various pesticides/fungicides and reduced semen quality (Table 14.1), but there are nearly as many studies showing no significant association. As this is not the primary focus of this chapter, only a brief overview is given here, and readers are referred to a 2008 review [44]. This paper reviewed all studies spanning a 15-year period and reported that only 13 of 20 studies showed a significant negative association between environmental or occupational pesticide exposure and semen quality with similar disparity for other parameters (e.g., sperm DNA damage). When considering individual pesticides or classes of pesticides, the results are in general equally inconsistent, for example, for persistent organochlorine pesticides such as DDT/DDE [45–48]. Recent studies that have focused on other pesticides such as organophosphates [47, 49, 50] or pyrethroids [51] have perhaps shown a more consistent association between exposure and reduced semen quality.

In terms of pesticide exposure and sex hormone levels in men, the perspective is quite similar to that for semen quality, although not as many studies have investigated hormone levels. Thus, reduced blood testosterone levels with or without altered (up/down) LH levels have been reported in men exposed to persistent organochlorine pesticides such as DDT/DDE [52], to organophosphates [53] or pyrethroids [51, 54]. However, for each of these classes of compounds there are comparable studies (mostly larger in size) showing no significant alteration of testosterone and/or LH levels in association with exposure to DDT/DDE or other persistent organochlorine pesticides [55–59], to organophosphates [60] or pyrethroids [61].

The inconsistencies in studies that have assessed the association between pesticide exposure and male reproductive function may be partly attributed to inter-study variation in a range of factors, such as methods, country of study, exposure assessments and outcomes [44]. Perhaps more important may be that many of the studies are based on either male partners of infertile couples or farmers/occupationally exposed men, neither of which is representative of the general male population. It is perhaps noteworthy that the majority of studies unaffected by such limitations have mostly found no association between pesticide exposure and male reproductive dysfunction [46, 48, 58, 61], although there are exceptions [53, 62], bearing in mind also that there will be significant under-reporting of negative data in the published literature. Arguably, the most informative study was the US LIFE study which was prospective and involved 501 male partners of couples who were just stopping contraceptive use, and in whom exposure to 36 PCBs, 9 organochlorine pesticides and 10 polybrominated diethyl ethers was measured [48]. Although a range of statistically significant associations was found between exposure to individual chemicals or classes of chemicals and semen quality, most of the associations were positive not negative. In this study, as well as in all of the others cited, it should be emphasized that where significant associations have been found between exposure(s) and semen quality or testosterone levels, the ‘effect’ sizes, whether negative or positive, have been generally small and could be incidental. The tentative conclusion, based on present data, is that for the general population at current levels of pesticide exposure, there is unlikely to be any biologically meaningful effect on adult male reproductive function although there may be some risk for those who are more highly exposed via their occupations, such as farmers.

Another situation in which occupational effects on male reproductive function might become apparent is if the ‘occupational effect’ applies to a large proportion of men; ‘scrotal heating’ may be one such example. Scrotal, and therefore testicular, temperature has to be maintained some 3–4 C lower than core body temperature if normal spermatogenesis is to occur, and this is achieved via a vascular heat exchanger system, the pampiniform plexus (Fig. 14.2). Interference with the normal scrotal cooling process can profoundly affect sperm production, quality and fertility [63–65], although there is no clear evidence for effects on testosterone levels. A straightforward example of this is the effects of repeated Finnish sauna exposure over 3 months, which lowered sperm counts and motility and induced adverse effects to sperm chromatin packaging but did not measurably alter testosterone levels; all of the adverse effects of the sauna were reversible within 6 months [66]. In theory, occupational or lifestyle factors that interfere with scrotal cooling/thermoregulation could be significant factors in lowering sperm counts [66, 67]. Examples of such potential factors are exposure to radiant heat, the wearing of tight trousers/underwear, time spent having hot baths and time spent seated (Fig. 14.2). Most of the older studies that sought to investigate such factors could rely only on establishing an association between such factors and poor semen quality, and perhaps not surprisingly the evidence proved equivocal or only marginally convincing in most cases [reviewed in ref. 25]. However, several epidemiological studies have shown that occupations involving prolonged sitting, and thus reduction in airflow around the scrotum [63, 66], are associated with significant reductions in sperm counts. An example is car or taxi driving [68, 69]. Away from occupational situations, the worst case might be paraplegic men who are confined to wheelchairs [70], although the poor semen quality in such men may have other contributory causes such as impaired accessory sex gland function, infection and increased proinflammatory cytokines [71].

More objective studies became possible once the technical problems relating to measurement of changes in scrotal temperature had been overcome, as this enabled quantification of scrotal heating. Scrotal temperature was measured continuously in normal young men or in men from couples planning their first pregnancy, and a significant relationship between average daily scrotal temperature and sperm counts was established [72]. Moreover, the same studies linked scrotal temperature to the amount of time spent seated, i.e., the more sedentary the lifestyle/occupation, the higher the average scrotal temperature, and this has been confirmed in more extensive recent studies [73]. Application of continuous scrotal temperature monitoring in reasonably large numbers of healthy men has demonstrated unequivocally that increase in average scrotal temperature is clearly linked to lower sperm counts as well as to associated changes in blood levels of FSH and inhibin-B [72–74]. Such findings raised the expectation that our increasingly sedentary lifestyles in the West might induce negative effects on semen quality in a high proportion of men [25], but this expectation is proving to be overly simplistic. For example, although time spent seated is an important determinant of scrotal temperature, the former has only a weak relationship with semen quality [74] and fertility [75], and other factors such as obesity [76], night-time scrotal temperature [73] and genetic determinants of scrotal temperature [77] may prove to be more important. There is reasonably strong evidence that physical activity is associated with better semen quality [75, 78] and marginally higher testosterone levels [78], when compared to men who have sedentary lifestyles. While this may be related to lower scrotal temperature, as physical activity is likely to improve scrotal cooling, there may be other effects of physical activity that also impact testis function.

From a clinical perspective, the number of men in whom infertility is induced partly or totally by elevated scrotal temperature is likely to be low. However, there are three other points to be kept in mind. First, even quite mild elevations in scrotal temperature in animal studies can increase DNA damage and miscarriage rates [64, 79], so its effects on sperm can be qualitative as well as quantitative. Second, ‘treatment’ to lower overall scrotal temperature in patients who have poor semen quality, though being a ‘shot in the dark,’ is relatively noninvasive and can be quite effective in some cases [80]—and there are no side effects! The discovery that there are genetic determinants of scrotal temperature [77] also reinforces the possibility that some individuals may be predisposed to adverse effects of prolonged seating or radiant heat on semen quality. While such individuals cannot yet be recognized, careful attention to lifestyle factors to minimize scrotal heating in all men with fertility problems is therapeutically benign and can have only beneficial effects. Third, the well-established, if inconsistent, effect of a varicocele on semen quality in men, may itself induce such effects by interfering with normal cooling of incoming arterial blood in the pampiniform plexus [76] (Fig. 14.2), and it is possible that such an effect might be exacerbated by the time spent seated or make such individuals more susceptible to effects of radiant heat than men without a varicocele.

The preceding section dealing with scrotal temperature obviously applies as much to sedentary lifestyles outside, as well as inside, of the workplace. Probably, the most important other factors are dietary habits, in particular obesity and alcohol intake, smoking, stress and recreational/sporting drug use.

Unlike the well-established relationship between calorific intake and maintenance of menstrual cycles in women, there is no such straightforward relationship in men regarding sperm counts. Underweight and overweight men both have a slightly increased risk of having low sperm counts, though there is considerable variation between studies, especially with regard to obesity [81, 82]. Moreover, there is only limited evidence that it is obesity per se that causes any semen quality changes (Fig. 14.3). Thus, although a 14-week residential weight loss program in 43 severely obese men was shown to increase semen volume and total sperm count [83], similar studies with small numbers of obese men undergoing bariatric surgery-induced weight loss have so far failed to find consistent benefits, and some studies even point to deleterious effects [84]. Nevertheless, the evidence that male obesity can negatively impact fertility is convincing. For example, obesity is over-represented among infertile men [80, 81], and in the setting of assisted reproduction, male obesity is associated with reduced embryo quality and pregnancy rate in the absence of any significant changes in semen quality [85]. Indeed, a recent meta-analysis of 30 studies (n = 115, 158 men) reported that male obesity was associated with a 66% increase in risk of infertility and a 35% reduction in live birth rate per cycle of assisted reproduction in the absence of significant differences in conventional semen parameters [86]. The underlying cause of obesity-related male infertility remains unclear and is likely to be multi-factorial [87]. However, there is compelling evidence emerging that points to changes in fatty acid composition of semen and sperm as being important [88, 89], and both human [90] and animal [91] studies provide evidence that the fat composition of our diets may be important in determining this and affecting semen quality (Fig. 14.3). Thus, it may be specific dietary factors in obese men that is important in relation to changes in semen quality and/or fertility, and that therefore not all obese men will be affected.

In contrast to the equivocal data on semen quality, the evidence that visceral obesity in men is associated with a fall in total testosterone levels in both young [92] and older [93] men is much more compelling (Fig. 14.3), and it is now widely accepted that visceral obesity and its associated metabolic changes invariably impact testosterone levels, encapsulated in the metabolic syndrome [94]; however, metabolic syndrome-associated changes in testosterone levels are dissociated from any change in semen parameters [95]. The primary mechanism via which obesity/the metabolic syndrome reduces testosterone levels is via suppression of pituitary LH secretion, but the mechanisms that underpin this are complex and incompletely known, but certainly involve changes in estradiol and sex hormone-binding globulin levels [96, 97] (Fig. 14.3). These interplay with the effects of adipokines, such as leptin and adiponectin, which may act both centrally [97, 98] or directly on the testis [99], although a recent systematic review suggests that direct testicular effects are probably of minor importance in comparison with central effects [99]. As other chapters in this book deal with these aspects, in particular the relationship of hypogonadism to the metabolic syndrome, they will not be discussed further here. However, there is one emerging aspect that has been hitherto overlooked, and which may turn out in the long term to be an important player, the gut microbiome.

There are various lines of evidence that the gut microbiome can affect male reproductive function, although the number of studies is presently too few to enable assessment of how important this might be [100]. However, its potential importance is highlighted by a series of intervention studies in mice, which have shown that feeding them from 8 weeks of age (young adulthood) with the probiotic species Lactobacillus reuteri was able to protect the mice against diet-induced, age-related obesity [101]. However, far more interesting was that this intervention completely prevented the age-related development of impaired spermatogenesis, reduced testis weight and hypogonadism [102], although until such studies are repeated, it is too early to conclude that similar effects could apply to man. The protective effects of the probiotic treatment were equally apparent in mice maintained on either a standard (control) diet or maintained on a ‘Western style diet.’ A series of studies by these authors have shown that the beneficial effects of the probiotic feeding regime appear to result from modulation of specific proinflammatory cytokines, such as interleukin-10 and interleukin-17A [102, 103]. As obesity/metabolic syndrome and hypogonadism are linked intrinsically to a more proinflammatory cytokine profile in blood in men [94, 104], it raises the interesting possibility that such health-relevant changes could be ameliorated either via probiotic supplementation or by dietary changes that alter the gut microbiome, an area richly deserving of further study.

Smoking by men sometimes emerges from epidemiology studies as a risk factor for low sperm counts or altered sperm morphology, but this is an inconsistent finding and ‘effect’ sizes are small [105]. Conversely, smoking is consistently associated with increased rather than decreased total and free testosterone levels, the mechanism for which is uncertain [106, 107]. As outlined below, smoking by mothers during pregnancy is associated with a consistent and substantial (20–40%) reduction in sperm counts in resulting male offspring in adulthood [25], whereas testosterone levels are unaffected [108]. In a large population-based cross-sectional study of >8000 young men, moderate alcohol intake was not associated with any change in semen quality, but was positively associated with free testosterone levels [109], whereas heavy alcohol intake is associated with lowered total testosterone levels [110].

Psychological stress arising for various reasons is usually associated with reduced semen quality with effects both on sperm count and motility, and testosterone levels are also usually lowered [111, 112]. The mechanisms behind such changes involve a complex interplay at various levels between the hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes; among these, direct inhibitory effects of adrenal cortisol on testicular testosterone production and indirect effects via cortisol-induced decrease in SHBG levels are probably important [111]. It should be noted, however, that much of the available data stem from experimental animal studies, as studies in men are much more difficult to control for confounding factors [111].

Though Western males are generally less physically active today than 30 or so years ago, for those who do participate in sports, it is far more competitive and this has led to usage of performance-enhancing drugs, the most common being anabolic androgenic steroids [113]. Outside of sports, there has been an explosion in use of the same drugs in pursuit of improving physique and body image [113]. Such use is now considered to be perhaps the single most important determinant of hypogonadism in young men [114], although this will be dependent on factors such as type of steroid, dose administered and perhaps duration of administration [115]. Although much of the anabolic steroid use is clandestine, clinicians faced with athletic young men with hypogonadism should always bear this possibility in mind [113, 115]. Similar awareness should be practiced for other non-steroidal drugs, as we live in an age when use of a range of ‘recreational’ drugs is widespread. For example, 25% of young American men report using marijuana within the last month [116], and 45% of Danish young men within the past 3 months [117]. In the latter study, which was a population-based study (N = 1215), regular weekly use of marijuana was associated with ~30% decrease in sperm count, and if marijuana use was combined with other recreational drugs, the decrease was >50% [117]. Considering the scale of marijuana/other recreational drug use, these statistics suggest that this may be a very important determinant of low sperm counts in young men. As has been found with tobacco smoking, marijuana use is associated with a significant increase in total (but not free) testosterone levels [117]. In contrast, use of opiate-based drugs by young men is associated with a uniform and quite substantial decrease in testosterone levels, based on a meta-analysis of 17 studies [118].

Finally, vigorous exercise such as long-distance running may result in temporary suppression of testosterone levels in men and minor decrements in semen quality, though the changes are by no means as pronounced as the anti-reproductive effects that can occur in female athletes [119, 120]. In contrast, less severe exercise generally has no effect on testosterone levels [120] (see Chap. 13).