Sperm counts have been declining worldwide in recent decades, and infertility has become a serious health concern [1-4]. Male factor infertility has been identified in approximately 50% of infertile couples [5]. There has also been a parallel increase in chronic diseases and cancer. Studies have shown that men with poor semen quality are at risk for long-term morbidity and mortality [6-9]. Increased cancer and mortality rates related to lifestyle factors, obesity, and diabetes have been reported in men with impaired infertility [9,10], and there is growing evidence linking metabolic disturbances with male infertility. Obesity-related metabolic disorders, including metabolic syndrome, diabetes, hypogonadism, osteoporosis, and cardiovascular disease [11], may contribute to a potential decline in semen quality.

Metabolic syndrome, which is related to unhealthy dietary habits and a sedentary lifestyle, is also associated with poor general health and chronic systemic diseases. It is characterized by central obesity, dyslipidemia, insulin resistance, and hypertension [12]. In addition, both metabolic syndrome and male infertility have been associated with hypogonadism and high mortality risk [13,14]. Further studies have also shown that eugonadal men with a low sperm count had a higher risk for metabolic and cardiovascular diseases [13,14]. Body mass index (BMI), waist circumference (WC), and non-alcoholic fatty liver disease (the liver component of metabolic syndrome) have been associated with a decline in sperm output; however, the evidence regarding this point is still being debated and is far from conclusive [11].

Given the conflicting data and biological plausibility of this association, we conducted a screening study of healthy men. We investigated anthropometric and metabolic risk factors to identify predictive variables for seminal and sex steroidal hormone parameters.

Of the 304 cohort members invited to participate in the study, 121 (39.8%) men provided a semen sample and underwent all analyses including a physical examination, biochemistry assessment, and testicular ultrasound. All participants had college degrees and similar socio-economic status (data not shown). The mean age of the participants was 27.9 years (range, 22 to 32), none were married, and 69 (57%) and 19 (15.7%) were smokers and consumers of mild alcohol, respectively. No participants had cardiovascular, metabolic, congenital, or chronic diseases. Varicocele (grade 2+3) was detected by physical and ultrasound examinations in the left testicle of 23 men (19%), and subclinical varicocele was observed in 10 (8.2%) and six (4.9%) men in the left and right testicles, respectively. Semen analysis revealed normospermia in 101 (83.5%) participants. Azoospermia was not detected. Metabolic syndrome was observed in three participants (2.5%) based on the National Cholesterol Education Program-Adult Treatment Panel III definition (2001). The characteristics of the participants are presented in Table 1.

Changes in the seminal and hormonal parameters (dependent variables) explained by the metabolic or anthropometric parameters (independent variables) are shown in Table 2 and 3, respectively. The highest percentage of explanation performance for seminal parameters in the training data set was found for liquefaction time (SSE=35.04, RE=0.694), and in the testing data set for sperm count (SSE=3.831) and liquefaction time (RE=0.692) (Table 2). However, the highest explanatory performance for hormonal and testicular parameters was found for LH (SSE=30.12, RE=0.76), and right testis volume (SSE=5.61) and testosterone (RE=0.76) in the training and testing data sets, respectively (Table 3).

The associations observed in this study showed that WC may be a more useful measure for male infertility than BMI. Although BMI was associated with total sperm count, WC was additionally predictive of sperm concentration and morphology. However, basal metabolic rate (BMR) was observed as the only predictive anthropometric parameter for seminal pH, liquefaction time, and sperm motility. In terms of metabolic parameters, the measures of glucose metabolism were associated with a greater number of seminal parameters than cholesterol metabolism.

BMI has been identified as a risk factor for male infertility in several studies. However, conflicting results have been reported for numerous methodological reasons [16]. In addition, WC has been associated with a decline in semen volume [17-19], sperm concentration [19,20], total sperm count [17,18,21], sperm morphology [20], and sperm motility [14,18,19]. The studies were largely performed in infertile men whose testicular function was already impaired [17], and differences in the studies can be explained by variance in the study group proportions [17]. In addition to its associations with seminal parameters, WC was also a negative predictor of FSH, the most prominent hormone in spermatogenesis. In this study, BIA measurements were extensively studied for seminal and hormonal parameters. BIA is widely used for estimating body composition [22] and is a more accurate measure of adiposity than BMI. Adiposity is strongly associated with obesity-related health problems [23]. The BMR or daily minimum level of energy utilized by a body in a physical and psychological resting state [24], was found to be the only BIA measurement predictive of seminal pH, liquefaction time, and sperm motility. Although BMR may be an indirect indicator of energy expended during sperm motility, in this study a positive prediction was observed between testicular volume and testosterone. Androgen deficiency was associated with changes in whole-body metabolism including decreased rates of body protein turnover and decreased resting energy expenditure [25]. BMR decreases by 1% to 2% every 10 years, and testosterone levels fall at an average of 1.6% per year [26,27]. Like testosterone, BMR is related to the metabolic rate of tissues [25-27] and could be used as an indicator in the clinical evaluation of patients with hypogonadism. Further studies of this relationship are needed.

Cholesterol is the precursor of sex steroidal hormones; however, little is known about the relationship of cholesterol and lipid metabolism with seminal parameters. In this study, both cholesterol and glucose metabolism were found to explain the variance in seminal parameters. Preclinical models confirm our findings that a high-fat diet may result in decreased sperm motility, sperm count, and morphology, and in increased sperm cholesterol content [28,29]. In this study, WC, fat mass percentage and triglyceride level were negatively predictive of sex hormone binding globulin (SHBG). Lower levels of SHBG have been linked to obesity [30]. Obesity has been shown to affect the gonadotropin-releasing hormone-LH/FSH pulse, which may deteriorate testicular steroidogenesis and spermatogenesis [31]. Metformin, an oral insulin-sensitizing agent that improves insulin sensitivity, has been used in human and animal models and resulted in improvements in seminal parameters [32] and in obesity-induced poor spermatogenesis [33]. Insulin resistance and dyslipidemia are associated with oxidative stress [34], and increased levels of reactive oxygen species impair germ cell production and sperm motility and give rise to sperm DNA damage [35]. Apart from our findings on lipid and glucose metabolism, we found that serum levels of C-reactive protein negatively predicted sperm concentration and total sperm count. Chronic inflammation disrupts the hypothalamic–pituitary-testicular axis and may result in poor semen quality [36].

This study had limitations. Because the cohort included unmarried healthy young men without chronic and genetic diseases, selection bias was possible. Therefore, it is difficult to generalize the results to other male populations (e.g., men with infertility or advanced age). Although the cohort was recruited from a single academic outpatient clinic, the subjects participating in this study came from multiple parts of the country, and thus can be considered to represent the whole country. Only one semen sample was obtained per subject; nevertheless, it has been reported that one sample is adequate to evaluate semen quality in epidemiological studies [37]. Differences in the predictive variables between right and left testis volume may be due to volume differences, the fact that varicocele was more common on the left side, or by chance. Finally, the cross-sectional design does not permit inference of a causal relationship between metabolic and seminal parameters.

In conclusion, this study demonstrated that anthropometric and metabolic parameters have predictive relationships with seminal parameters and sex steroidal hormones. These findings add further insight into the underlying mechanisms of these relationships, which can be used to develop preventive and therapeutic interventions that improve semen quality in the management of infertile men.