Diet

Evidence suggests that male fertility (as well as female fertility) is decreased by men being either overweight or underweight (as defined by body mass index [BMI]>25 kg/m ² and BMI<20 kg/m ² , respectively). Healthy diet and regular exercise are therefore both recommended to maintain BMI between 20 and 25 kg/m ² .

Dietary fat has been shown to adversely affect semen quantity and quality. A recent study of 222 healthy men recorded diet, semen analysis (SA), physical examination, and BMI. Diets categorized as high in fish, fruit, vegetables, legumes, and whole grains were associated with significantly better sperm motility compared with diets categorized as high in red meat, processed meat, pizza, sugary drinks, and sweets. Other semen parameters were similar between groups. A similar small study of 30 infertile men who presented to a reproduction clinic found that these men had diets lower in fruits and vegetables, and higher in red meat and milk intake, compared with fertile controls.

To further define the relationship of fat intake with decreased SA parameters, Attaman and colleagues reported that men with high dietary saturated fat had decreased total sperm count and sperm density. However, omega-3 fats were shown to be positively correlated with healthy sperm morphology. More recent data have confirmed that omega-3, as well as omega-6, fatty acid intake is associated with improved total sperm count, semen motility, and morphology.

In addition to dietary fat causing adverse semen parameters, reactive oxygen species (ROS) have been reported to decrease sperm-oocyte fusion and loss of semen motility. A 2010 meta-analysis reviewed 17 randomized trials of oral antioxidant supplementation (vitamins C and E, zinc, selenium, folate, carnitine, and carotenoids) on pregnancy rate and semen parameters. Most of the included studies (82%) showed either or both of an increase in sperm quality or pregnancy rates after oral induction of antioxidant therapy. Specific effective antioxidants include carnitine, vitamin C, glutathione, selenium, and coenzyme Q10.

Studies on the effect of caffeine on fertility reach varied conclusions. A large Danish study of more than 2500 men correlated caffeine intake with semen quality and found that high caffeine intake (defined as >800 mg/d) was associated with decreased sperm concentration and total sperm count compared with non–caffeine drinkers.

Phytoestrogens or xenoestrogens are plant-derived nonsteroidal compounds that can mimic human estradiol (E2) and bind to estrogen receptors. Soy, legumes, and soy-based foods such as tofu, soya beans, oils, and seeds have been shown to adversely affect multiple SA parameters and spermatogenesis. In contrast, another study found that low or high intake of soy protein had no effects on semen parameters. The paucity of well-designed human studies on male infertility in relation to phytoestrogens makes drawing conclusions difficult.

Exercise

As noted earlier, maintaining a BMI between 20 and 25 kg/m ² is recommended to maintain optimal male fertility potential. Regular exercise is important, along with healthy diet, to prevent overweight or underweight body habitus. In addition to maintaining an optimal BMI, physical exertion has also been shown to have a relationship with testosterone (T) levels, thereby indirectly relating to fertility.

An observational study showed that moderately physically active men had significantly increased follicle-stimulating hormone (FSH), luteinizing hormone (LH), and T levels compared with sedentary controls. This finding is expected, given that high T levels have been widely associated with increased energy and muscle strength. However, some reports have found that moderate-intensity endurance training results in increased free and total T levels in young healthy men shortly after exertion. Other studies have found that there is no T level increase following exercise when corrected for exercise-induced increases in plasma levels. Studies are needed to determine whether exercise yields increases in T and FSH on a longer-term basis.

In contrast with the unclear impact of moderate exercise, data suggest that vigorous exercise results in decreased T levels. Steinacker and colleagues found that competitive rowers had unexpectedly low T levels. Another study of competitive athletes found that doubling the distance of cycling and running for 2 weeks resulted in a 17% decline in serum T concentration. High-intensity endurance runners (>160 km [100 miles] per week) had a 31% reduction in free and total serum T after 2 weeks of unusually vigorous training and, similarly, another study showed that athletes’ T levels significantly decreased after their training intensity was doubled over short periods of time. In addition, a randomized controlled study of long-term endurance treadmill use on the hypothalamus-pituitary-testis (HPT) axis randomized 286 men to either moderate or intensive exercise groups. There was a significant decrease in LH, FSH, and T concentrations in the high-intensity group as well as decreased semen motility, density, and morphology.

Obesity

The rate of obesity in reproductive-aged men has tripled in the past 30 years; during the same time period there has been a concomitant increase in male infertility. However, no definitive relationship between the two entities exists. Controlled studies have reported conflicting results concerning the relationship between obesity and fertility potential. Although one study of 2139 men observed no reduction in sperm count among obese men compared with normal-weight controls and another study of 2110 men failed to identify a relationship between BMI and any sperm quality parameters, a third study of 1558 young Danish men found that overweight men had a reduced sperm concentration and total sperm count (22% and 24%, respectively) compared with men of normal weight. However, there are conflicting studies regarding the impact of obesity on male infertility. A study by Qin and colleagues of 990 fertile men recruited from the Chinese general population found that being overweight may be a protective factor against low sperm concentration and low total sperm count.

Although studies of the association between BMI and semen parameters have yielded conflicting results, there seems to be a negative relationship between obesity and fertility outcomes. A review of the Danish National Birth Cohort identified a dose-response relationship between increasing male BMI and subfecundity (defined as a total time to pregnancy of more than 12 months), with an odds ratio of 1.2. These findings also apply to couples undergoing assisted reproduction. For example, among couples undergoing intracytoplasmic sperm injection, the odds of live birth in couples with obese male partners has been reported to be 84% lower than the odds in couples with men with normal BMI. More recently, Bakos and colleagues reported an association between increased paternal BMI and a decrease in blastocyst development, clinical pregnancy rates, and live birth outcomes. Keltz and colleagues reported that male BMI greater than 25.0 kg/m² was associated with a significantly lower clinical pregnancy rate (53.2% vs 33.6%), with the likelihood of clinical pregnancy following n vitro fertilization significantly reduced if the male partner was overweight (odds ratio, 0.2) on multivariate analysis.

In summary, the relationship between obesity and male fertility is complex and multifactorial, making it difficult to distinguish correlation from causation. However, the available data suggest that, although a consistent relationship between BMI and semen parameters has not been shown, high BMI does seem to be linked with a negative impact on fertility outcomes. Until prospective randomized trials provide a definitive answer, it is prudent to recommend weight loss for obese men with otherwise unexplained infertility.

Psychological Stress

Psychological stress has long been implicated as a cause of idiopathic male factor infertility and several studies have described a correlation between stress and impaired SA parameters. Men have been shown to have a significant decrease in sperm concentration and semen quality during stressful examination periods, times of war, periods of self-reported stress, following stressful situations at work, following the recent death of a close family member, and following 2 or more recent stressful life events. In a study that assessed various psychological traits of male partners of infertile couples attending an infertility clinic, Zorn and colleagues documented a significant relationship between the level of sperm concentration and the World Health Organization (WHO) Well-being Index score, with each successive score number correlating with a 7.3% increase in sperm concentration.

Infertility is itself a well-known psychological stressor, and it remains unclear to what extent stress is a cause, as opposed to a result, of impaired fertility potential. Although no studies have entirely attributed infertility to psychological stress, emotional and mental state is likely to be a relevant clinical issue for men with fertility problems. Identification and reduction of psychological stress has been associated by some studies with improvement of SA parameters but is also important as an aspect of overall patient care for many subfertile men.

Alcohol

Excessive alcohol consumption has been proposed as a risk factor for male infertility. Studies have linked ethanol to central action at the level of the hypothalamus, where it blocks secretion of gonadotrophin-releasing hormone (GnRH) and cleavage of GnRH precursor pre-pro-GnRH to a functionally active GnRH hormone. This process results in reduction of LH and FSH, with subsequent spermatogenic impairment. Ethanol has also been shown to exert a direct inhibitory effect on the pituitary by blocking LH production and secretion. These effects may explain the abnormal semen parameters observed in men who drink heavily. Animal studies have also elucidated the deleterious effects of ethanol at the level of the testis. Zhu and colleagues postulate that the Sertoli cells are the first testicular cells to be insulted by ethanol consumption. Transferrin protein and mRNA were increased in rats that imbibed ethanol. Martinez and colleagues exposed mice to 120 days of chronic oral ethanol consumption and noted significant reduction in testosterone and LH levels compared with controls. On histologic examination, the testes of mice in the alcohol arm were characterized by an abundance of lipid droplets, vacuoles, dilatation of the blood vessels, and a variation in seminal vesicle diameter. Other studies in mice have shown testicular atrophy, degeneration of sperm cells, decreased lumen of seminiferous tubules, and increased rates of apoptosis resulting from alcohol consumption.

In men, the relationship between ethanol consumption and infertility seems to be dose dependent. Consuming more than 8 drinks per week has been reported to decrease fecundity in men, with the most commonly reported semen parameter being teratospermia. Pajarinen and colleagues categorized alcohol intake on a spectrum as defined by daily intake of less than 40 g, 40 to 80 g, 80 to 160 g, and more than 160 g. Spermatogenic arrest and Sertoli cell–only syndrome showed a direct correlation with daily dose dependence, and daily imbibing of more than 40 g of ethanol per day showed an increase in spermatogenic disorders. A Dutch study showed that E2/T ratio increased and semen characteristics worsened after a 5-day alcohol binge in a cross-sectional study. Semen parameters were adversely affected by both chronic consumption of excessive alcohol doses and by excessive acute alcohol binges.

The threshold level of alcohol consumption required to adversely affect SA parameters remains unclear. Although the effect of ethanol on human spermatogenesis seems to be dose dependent, a European study of more than 10,000 couples found that high alcohol consumption (greater than 8 drinks/wk) was associated with reduced fecundity, but moderate intake was not. The best available evidence shows that alcohol intake and infertility are linked only with high levels of consumption (>8 drinks/wk or >40 g alcohol daily, depending on the study).

Cigarette Smoking

Despite mounting evidence concerning the multiple hazards to human health posed by cigarette smoking, the population of cigarette smokers globally is increasing and now approaches one-third of the worldwide population in individuals aged 15 years and older. Although the exact mechanism has not yet been established, cigarette smoking is a well-known cause of male subfertility. Proposed mechanisms for this effect include compromised delivery of oxygen to the testis and interference with the high metabolic requirements of spermatogenesis, as well as oxidative stress related to the large number of known mutagens and metabolites in cigarette smoke (including radioactive polonium, cadmium, benzopyrene, carbon monoxide, tar, naphthalene, and aromatic hydrocarbons).

Several studies have shown that cigarette smoking is associated with a decrease in sperm concentration, lower sperm motility, and a reduced percentage of morphologically normal sperm. In the largest meta-analysis to date, Li and colleagues pooled data from 57 studies and concluded that smoking is associated with deterioration of multiple SA parameters in both fertile and infertile men, including semen volume, sperm density, total sperm count, percentage of sperm progressive motility, and percentage of normal sperm morphology. These results were consistent with a prior meta-analysis that similarly linked reductions in sperm density and motility to cigarette smoking. However, these effects seem to be reversible, as shown by Santos and colleagues. In this report, smoking cessation for 3 months led to an increase in sperm count (29 million vs 72 million per ejaculate), motility (79% vs 33%), vitality (60% vs 20% necrotized), and the number of grade A spermatozoa recovered after swim-up (3 million vs 23 million per ejaculate).

The degradation of SA parameters related to cigarette use is further compounded by the detrimental effect of smoking on sperm vitality, seminal zinc (an important antioxidant) levels, sperm DNA integrity, and semen reactive oxygen species. In a review of 160 fertile men, Taha and colleagues found that fertile nonsmokers showed significantly higher progressive sperm motility, hypo-osmotic swelling (HOS) test percentage, and seminal zinc levels, as well as significantly lower sperm DNA fragmentation percentage and seminal ROS levels compared with fertile smokers. The number of cigarettes smoked per day and smoking duration were both positively correlated with seminal ROS and sperm DNA fragmentation percentage and negatively correlated with sperm count, motility, normal forms percentage, HOS test, and seminal Zn levels. Elsewhere it has been shown that the levels of bulky DNA adducts are almost 2-fold higher in current smokers than in never smokers, that the rate of sperm aerobic respiration is significantly lower in smokers, that smoking for more than 10 years or greater than 20 cigarettes/d negatively affects sperm DNA integrity and nuclear maturation, and that the zona-free hamster oocyte sperm penetration assay is markedly impaired in smokers compared with nonsmokers.

Although the pathophysiologic mechanisms are not yet fully elucidated, the available evidence overwhelmingly shows that cigarette smoking impairs male reproductive potential. In light of the numerous other untoward adverse health effects brought on by smoking, physicians should advise their patients to quit smoking as a critical component of preserving or restoring fertility potential.

Marijuana

Marijuana has the highest rate of use in the United States among all illicit drugs surveyed by the National Survey of Drug Use and Health, with 20%, 11%, and 5% of all men aged 26 to 34 years, 35 to 49 years, and 50 years and older, respectively, reporting use of marijuana in the past year. The frequency of marijuana abuse in these peak reproductive age groups is clinically significant given this drug’s negative effects on male reproductive physiology.

Marijuana contains the cannabinoid delta-9-tetrahydrocannabinol (THC), which blocks luteinizing hormone-releasing hormone (LHRH) release from the hypothalamus and LH production by the adenohypophysis. The central blockade of the hypothalamic-pituitary-gonadal (HPG) axis in men resulting from THC produces a dose-dependent reduction in plasma T levels that may take as long as 3 months to resolve after cessation. Clinical manifestations of chronic use can include gynecomastia, impaired libido, erectile dysfunction (ED), and ejaculatory dysfunction.

Within the testis, marijuana reduces T production and interferes with the spermatogenetic process. In animal models, chronic administration of THC impairs spermatogenesis at both mitotic and meiotic stages, with mature sperm showing severe morphologic defects. These findings are mirrored in humans, with more than one-third of chronic marijuana users having oligospermia. This effect is magnified by THC also activating endocannabinoid receptors on sperm, thereby inhibiting the capacitation-induced acrosomal reaction and reducing sperm motility in a dose-dependent manner. Although human studies are scarce, and those that do exist are limited by their observational nature, the available evidence supports the concept that marijuana use, whether illicit or prescribed, has a detrimental effect on male reproductive potential.

Anabolic Steroids

The lifetime prevalence of anabolic androgenic steroid (AAS) use in men is estimated to be between 3.0% to 4.2% and an estimated 56% of users have never revealed their AAS use to a physician. Most AAS abusers are young men in their reproductive years who may be unaware of the reproductive consequences of their actions. Exogenous hormonal steroids inhibit spermatogenesis by suppressing the HPG axis and decreasing the intratesticular testosterone levels. Anabolic steroids exert a negative feedback effect on the hypothalamus and pituitary, thus limiting the release of FSH and LH and in turn decreasing testicular T synthesis. Hypogonadism (HG) associated with AAS abuse is usually reversible within 3 to 6 months of discontinuation, but recovery has been reported to take as many as 3 years and occasionally may be irreversible.

On histopathology, AAS have also been shown primarily to produce Leydig cell alterations, accounting in part for the observed decrease in testicular T synthesis. However, specific end-stage spermatogenesis impairment with a lack of advanced forms of spermatids has also been reported. This manifests clinically as oligospermia/azoospermia, testicular atrophy, and an increased percentage of morphologically abnormal sperm. Following AAS discontinuation, Leydig cells proliferate but counts generally remain less than normal, accounting for delayed recovery of T levels and occasional irreversible effects of AAS.

Opiates

Nonmedical use of prescription narcotics such as hydrocodone and oxycodone have the second highest abuse rate among illicit drugs after marijuana, with 8.3%, 4.8%, and 2.4% of men aged 26 to 34 years, 35 to 49 years, and 50 years and older, respectively, reporting nonmedical use of prescription pain medication in the past year. These rates of opiate abuse among men of reproductive age are particularly significant because narcotics can interfere with spermatogenesis through 2 basic mechanisms. First, narcotics exert a negative feedback effect on the hypothalamus, thereby suppressing LH release from the anterior pituitary. Decreased LH levels result in decreased T levels, and the magnitude of HG is magnified by an opiate-induced increase in levels of sex hormone–binding globulin, which further restricts the pool of bioavailable T.

In a study by Abs and colleagues comparing 73 patients receiving intrathecal opiates for nonmalignant pain with 20 untreated control subjects, nearly all opiate-treated men reported symptoms of HG, such as decreased libido or ED, and had significantly lower T and LH levels. Oral use of narcotics has been shown to result in similar effects. A study by Daniell reviewed a cohort of 54 outpatient men who were treated with oral sustained-action opioids. When compared with controls, opioid consumers were shown to have much lower hormone levels in a dose-related pattern. Free T, total T, and E2 levels were subnormal in 56%, 74%, and 74%, respectively, of opioid users. Moreover, either total T or E2 level was subnormal in all men consuming the equivalent of 100 mg of methadone daily and in 73% of men consuming smaller opioid doses. In recognition of the hypogonadotropic hypogonadism that frequently results from opiate use, the 2010 Endocrine Society Clinical Practice Guideline Committee recommends that serum T levels be measured in all men receiving chronic opioids.

In a review of male heroin and/or methadone addicts, at least one semen analysis parameter from 100% and 45% of heroin and methadone users, respectively, were significantly impaired. All patients in this study had normal hormone levels, despite chronic opioid use, suggesting that heroin use may be directly toxic to spermatogenesis, as opposed to exerting this effect via HG.

Cell Phone Use

Widespread use of cellular phones has prompted concerns regarding the potentially harmful effects of radiofrequency electromagnetic radiation (RF-EMR). In particular, the increasing use of hands-free kits with belt-holstered phones has raised concern regarding the potential for RE-EMR exposure to the gonads. Several experiments in rat, mouse, and rabbit models have shown impairment of spermatogenesis with increasing exposure to cell phone RF-EMR, with Leydig cells, seminiferous tubules, and spermatozoa all being affected.

Several human observational studies have investigated the effects of RF-EMR directly on semen parameters and sperm function. In one observational study by Agarwal and colleagues, 361 men undergoing infertility evaluation were divided into 4 groups according to their reported cell phone use. Comparisons of semen parameters identified that mean sperm motility, viability, and normal morphology significantly differed between cell phone user groups, with an inverse relationship between the values of these parameters and the duration of daily exposure to cell phones. Fejes and colleagues correlated reported cell phone usage with semen analyses in 371 men, finding that the duration of phone possession and talk time correlated negatively with the proportion of rapid progressive motile sperm and positively with the proportion of slow progressive motile sperm. An additional observational study by Wdowiak and colleagues subdivided 304 men into 3 groups by cell phone usage. The investigators identified a link between the percentage of sperm cells with abnormal morphology and the duration of exposure to RF-EMR waves. Moreover, they confirmed that a decrease in the percentage of sperm with progressive motility was correlated with the frequency of using mobile phones. Gutschi and colleagues examined semen samples and measured hormone levels in more than 2100 men stratified by their reported cell phone use. The investigators observed a significant difference in sperm morphology between the two groups. In the patients reporting cell phone use, 68% of the spermatozoa featured a pathologic morphology compared with 58% in those subjects not reporting cell phone use. In addition, a retrospective observational study by Kilgallon and colleagues found that men who carried a mobile phone in their hip pockets or on their belts had lower sperm motility (49.3% ± 8.2%) than those who did not carry a mobile phone or carried one elsewhere on their body (55.4% ± 7.4%).

Several in vitro studies on human semen have also suggested that electromagnetic radiation exerts deleterious effects on sperm function. Agarwal and colleagues collected semen samples from 23 normal healthy donors and 9 infertile men and divided each sample into 2 aliquots: an experimental aliquot that was exposed to cellular phone radiation for 1 hour and an unexposed control sample. The investigators concluded that samples exposed to RF-EMR showed a significant decrease in sperm motility and viability, an increase in ROS level, and decrease in total antioxidant capacity score (the sum of enzymatic and nonenzymatic antioxidants). Erogul and colleagues obtained semen samples from 27 men, divided these equally into 2 aliquots, and exposed only 1 of these to RF-EMR emitted by an activated cellular phone. RF-EMR exposure was associated with a decrease in the rapid progressive and slow progressive sperm movements, as well as an increase in the no-motility category of sperm movement.

The literature suggests that cell phone use alters sperm parameters (particularly motility and morphology) and increases oxidative stress. Moreover, these abnormalities seem to be directly related to the duration of mobile phone use. However, these studies are all in vitro or clinically retrospective in nature, and prospective randomized studies are needed to definitively elucidate the possible mechanisms and magnitude of injury produced by RF-EMR on spermatozoa and testicular function.

Pollution

Exposure to both environmental and workplace air contaminants has also been hypothesized to negatively affect male reproductive potential. In a study of 225 men with occupational exposure to pesticides and chemical solvents, exposed men had significantly depressed SA parameters. Proposed mechanisms of action of pesticides on spermatogenesis include alteration of Leydig cell and/or Sertoli cell function and disruption of hormone synthesis, transport, release, or binding to receptors. Some compounds have been shown to be directly toxic to spermatogenesis, including dibromochloropropane and polychlorinated biphenyls.

Hammoud and colleagues correlated nearly 1700 SA reports with the local particulate matter (particle pollution) levels corrected by shifting backwards parameters for several months to account for the 72-day spermatogenesis cycle. High particle pollution levels were negatively correlated with sperm motility 2 and 3 months following these exposures. Other studies have shown that increased particulate matter is associated with decreased sperm motility, abnormal head shape, and increased DNA fragmentation. Sokol and colleagues analyzed air pollutant levels in California in relation to SA parameters from 5134 samples. They concluded that average sperm concentrations correlated negatively with increases in ozone levels ( P <.001).

The data suggest that various types of environmental pollution are toxic to spermatogenesis. However, the specific underlying causes of the varying pollutants are unknown. Further, the clinical relevance to reproduction is unclear because there are no published reports including pregnancy or live births as study end points. Challenges include identifying specific pollution risk factors for impaired spermatogenesis, defining the impact of genetic insult on sperm, and diagnosing environmentally induced infertility.

Heat Exposure

The testes are located outside the body cavity and are perfused by a countercurrent heat exchange system resulting in temperatures 2° to 4° cooler than body core temperature, which is thought to be critical in facilitating spermatogenesis and highlights the concept of increased testicular temperature as a potential risk factor for infertility.

In numerous animal studies, increases in scrotal temperature have been shown to cause reversible damage to the germinal epithelium, with the most significant consequence of heat stress on the testis being the loss of germ cells via apoptosis. Moreover, heat has been shown to affect sperm DNA integrity, to reduce the production of testicular androgen-binding protein, and to adversely affect Sertoli cell function. These changes brought on by heat stress have been shown collectively to lead to significant reductions in sperm motility, concentration, and the percentage of hypo-osmotic swelling water test–positive spermatozoa.

Human studies similarly show suppressed spermatogenesis in clinical conditions associated with increased testicular temperature, such as cryptorchidism, varicoceles, and acute febrile illness, although each of these may have other pathophysiologic mechanisms affecting spermatogenesis. Numerous reports have documented a negative influence of fever episodes on semen quality, with impaired sperm density and progressive motility presenting several weeks after the acute febrile illness and lasting for 1 to 3 months. Oligospermic men with varicoceles are theorized to have significantly higher scrotal temperatures than normospermic men as a result of pooling blood and inefficient countercurrent heat exchange. Varicocelectomy has been documented to reduce scrotal temperatures and is well established as method of improving semen parameters in subfertile men, although the mechanisms underlying the beneficial effects of varicocele surgery are unknown.

Several modifiable risk factors that cause scrotal hyperthermia have also been correlated with spermatogenic impairment, including sauna or steam room use, sleeping posture, and duration of sitting or driving. Although the minimum threshold of scrotal hyperthermia required to suppress spermatogenesis remains unclear, experimental studies using polyester-lined athletic supports to increase scrotal temperatures in healthy male volunteers suggest that this threshold is more than 1°C.

In normospermic subjects, sauna exposure has been reported to induce a significant but reversible impairment of spermatogenesis, including alteration of sperm parameters, mitochondrial function, and sperm DNA packaging. Improvements in total motile sperm count have been shown with discontinuation of hyperthermic sauna exposure. Another study showed that, although sauna sessions increase mean scrotal temperatures to a peak level of 41.6°, semen quality remains unaffected. Various studies have documented significant temperature changes in the scrotum while driving or while wearing restrictive clothing, using a laptop computer, using electric blankets, and with wearing tight-fitting underwear. None of these studies attempted to correlate SA parameters or fertility rates with their respective risk factors for scrotal hyperthermia.

Based on the available data, it is prudent to advise men with fertility concerns to limit their exposure to any factor capable of increasing scrotal temperature. However, the precise role of scrotal hyperthermia in fertility remains to be established, as does the concept of scrotal cooling.