Introduction

Infertility, defined by the World Health Organization as the inability to achieve a clinical pregnancy despite 12 months of unprotected intercourse, is estimated to affect 48.5 million couples worldwide . Based on data collected through the National Survey of Family Growth, the prevalence of infertility in the United States is estimated between 12% and 15% . Both male and/or female factors can contribute to infertility. Male factor infertility is estimated to be the causative or a contributing factor in 20–50% of couples . Interestingly, there is some evidence that the prevalence of male factor infertility may be increasing. A New England Journal of Medicine publication in 1995 reported the decline in semen quality received by a single sperm bank in Paris, France, between 1973 and 1992. While the semen volume remained unchanged overtime, the mean concentration of sperm and the percentage of motile sperm decreased over the course of 20 years . Furthermore, a review of 61 papers from 1938 to 1990 also documented declining sperm parameters over time . What could explain this decline in semen quality?

With the increasing prevalence of obesity and diabetes, metabolic syndrome has been postulated to be a potential contributing factor for the decline in semen quality and a contributing factor to male infertility. Metabolic syndrome is a cluster of physiologic abnormalities associated with an increased risk for cardiovascular disease. As defined by the Adult Treatment Panel III (ATPIII), metabolic syndrome is the presence of three or more of the following risk factors: abdominal obesity, elevated fasting glucose, elevated triglycerides, low high-density lipoprotein (HDL) cholesterol, and elevated blood pressure ( Table 1 ). Although not strictly included in the diagnosis, patients with metabolic syndrome frequently have a pro-inflammatory state, often with elevated cytokines and acute phase reactants, such as C-reactive protein (CRP) . In a study of more than 3000 adults aged 20 and over between 2003 and 2006, 34% of subjects met the criteria for metabolic syndrome. Furthermore, the likelihood of meeting criteria for metabolic syndrome increased with age and body mass index (BMI) . This paper reviews the recent literature linking obesity, insulin resistance, dyslipidemia, inflammation, and metabolic syndrome as a whole to male infertility. While hypertension is one of the criteria for the diagnosis of metabolic syndrome, to our knowledge, there is little, if any, evidence directly linking hypertension to male infertility and thus will not be addressed in this chapter.

Abdominal obesity and infertility

Obesity is a cardinal feature of metabolic syndrome and has been increasing in prevalence . Female obesity has already been well established as a cause of female infertility . More recently, however, there has been considerable research examining the links between obesity and male factor infertility. In a 2007 study from Norway examining over 26,000 planned pregnancies and the length of time required to achieve pregnancy, after adjusting for female BMI and smoking habits, it was determined that overweight and obese men had an odds ratio of infertility of 1.19 and 1.36, respectively . A similar study comprising nearly 48,000 couples between 1996 and 2002 examined the effects of both male and female obesity on infertility. In this study, overweight and obese men coupled with normal-weight females had an odds ratio for reduced fertility of 1.18 and 1.53, respectively. In couples where both parents were overweight or obese, the odds ratios for reduced fertility were 1.41 and 2.74, respectively .

The effects of male obesity and fertility rates have not been limited to couples attempting unassisted pregnancies. Obesity has also been studied in patients undergoing assisted reproductive therapy (ART). In 2012, Colaci and colleagues examined 114 couples who underwent a total of 172 ART cycles. In this study, BMI was not related to overall fertilization rates (via intra-cytoplasmic sperm infection (ICSI) or in vitro fertilization (IVF)), poor quality embryos, pregnancy rates (either biochemical or clinical), or live-birth rates . Conversely, a 2011 study consisting of 305 couples undergoing ART demonstrated that sperm concentration was significantly lower in overweight, obese, and morbidly obese groups. The fertilization rate was consistent across all groups; however, pregnancy rates decreased with an increase in paternal BMI. Of note, maternal BMI did not differ between groups with the exception of the morbidly obese male group with had females with a higher BMI . Given the conflicting data, further studies are needed to define the effects of obesity of fertilization rates in ART.

While the exact pathophysiology for how obesity affects male infertility has yet to be clearly defined, it is hypothesized to occur through several different mechanisms. First, it is hypothesized that obesity and increased peripheral adipose tissue lead to perturbations in the hypothalamic–pituitary–gonadal axis. Second, obesity may lead to increased oxidative stress and production of reactive oxygen species that may affect sperm quantity and quality. Finally, an increase in suprapubic and scrotal fat may create an environment too warm for normal spermatogenesis .

Excess adipose tissue increases peripheral conversion of testosterone to estrogen. This increase in estrogen is thought to inhibit the hypothalamic–pituitary–gonadal axis and lead to secondary hypogonadism. A 2010 animal study examined the effects of a high-fat diet on testosterone levels. Mice that were initially fed a high-fat diet were found to have lower serum testosterone levels compared to mice fed a control diet. Mice that were subsequently switched to a control diet had restoration of normal serum testosterone levels . Several human studies have demonstrated the effects of male obesity and a significant decrease in total testosterone, free testosterone, and sex hormone-binding globulin (SHBG) levels . More recently, Derby and colleagues published the results of a longitudinal study examining the effects of obesity on male sex hormones in patients enrolled in the Massachusetts Male Ageing Study. In this study, the sex hormone levels of 942 patients were analyzed at baseline (1987–89) and follow-up (1995–97). Levels of total testosterone, free testosterone, and SHBG were all inversely correlated with waist circumference and BMI at baseline. Furthermore, at follow-up, patients who were obese were more likely to have a greater decline in hormone levels compared to nonobese patients . These studies illustrate the association between obesity and disruption of the central endocrinologic regulation of male infertility.

The effects of obesity on semen parameters have been a developing focus in male infertility research. The recently published data from the Longitudinal Investigation of Fertility and the Environment (LIFE) study sought to determine the relationship between male BMI and waist circumference and semen quantity. In this study, a cohort of 501 couples from two different geographical areas was followed up between 2005 and 2009. The authors found a linear association between increasing BMI and the incidence of oligospermia. Six percent of men with a normal BMI were oligospermic compared to 17% of obese men. Waist circumference was also correlated with low sperm concentration and low total sperm count . Other studies have demonstrated similar associations between obesity and decreased sperm quantity . A 2013 systematic review of 21 studies with a total of more than 13,000 men found that, relative to normal weight males, the odds ratio for azoospermia or oligospermia for overweight, obese, and morbidly obese men were 1.11, 1.28, and 2.04, respectively .

In addition to decreased sperm concentration, obesity has been negatively associated with sperm parameters, specifically sperm motility, morphology, and DNA fragmentation. Animal studies have demonstrated that mice fed a high-fat diet had a decrease in sperm motility compared to lean mice . Furthermore, in one of these studies, diet and exercise were shown to increase sperm motility, decrease abnormal sperm tail morphology, and decrease DNA damage in sperm . The decrease in sperm quality seen in obese males is postulated to be secondary to an increase in oxidative stress. The effects of oxidative stress and infertility will be discussed in greater detail later in the “Inflammation and Infertility” section.

Obese patients are also at higher risk for mechanical factors hypothesized to negatively impact fertility. An increase in fat, specifically around the testicle, within the spermatic cord, adjacent to the spermatic cord, in the suprapubic region, and in the medial thighs, may raise intratesticular temperatures above what are required for normal spermatogenesis. A number of animal studies have demonstrated that increased scrotal temperature can cause sperm DNA damage, decrease sperm viability, and can affect subsequent embryo quality . In 1981, Shafik and Olaf performed autopsies on a series of fertile and infertile male cadavers. The authors documented the presence of scrotal lipomatosis in 86% of idiopathic infertile males . The authors followed up this work by performing scrotal lipectomy on 102 infertile men with scrotal lipomatosis; 22 of these same men also underwent suprapubic lipectomy for removal of redundant suprapubic fat. The authors reported that 64.7% of the men had improvement in semen quality, and 19.6% achieved a pregnancy after the procedure . To our knowledge, there has been no further investigation into scrotal lipectomy for the treatment of male infertility and it is not a commonly performed procedure for infertility.

Obesity likely affects male factor infertility through multiple disruptions in normal physiology. The effects of weight loss on improving or restoring male infertility have yet to be studied in depth. A recently published case series followed six men who lost abdominal fat over a several-month period. All subjects in the series lost abdominal fat with a subsequent decrease in sperm DNA fragmentation rate and increase in testosterone-to-estradiol ratios . Given the small size of these and other trials, further prospective studies are necessary to determine whether weight loss will positively affect male infertility. However, for overweight and obese male patients who present to an infertility clinic, weight loss may aid in improving their fertility.

Abdominal obesity and infertility

Obesity is a cardinal feature of metabolic syndrome and has been increasing in prevalence . Female obesity has already been well established as a cause of female infertility . More recently, however, there has been considerable research examining the links between obesity and male factor infertility. In a 2007 study from Norway examining over 26,000 planned pregnancies and the length of time required to achieve pregnancy, after adjusting for female BMI and smoking habits, it was determined that overweight and obese men had an odds ratio of infertility of 1.19 and 1.36, respectively . A similar study comprising nearly 48,000 couples between 1996 and 2002 examined the effects of both male and female obesity on infertility. In this study, overweight and obese men coupled with normal-weight females had an odds ratio for reduced fertility of 1.18 and 1.53, respectively. In couples where both parents were overweight or obese, the odds ratios for reduced fertility were 1.41 and 2.74, respectively .

The effects of male obesity and fertility rates have not been limited to couples attempting unassisted pregnancies. Obesity has also been studied in patients undergoing assisted reproductive therapy (ART). In 2012, Colaci and colleagues examined 114 couples who underwent a total of 172 ART cycles. In this study, BMI was not related to overall fertilization rates (via intra-cytoplasmic sperm infection (ICSI) or in vitro fertilization (IVF)), poor quality embryos, pregnancy rates (either biochemical or clinical), or live-birth rates . Conversely, a 2011 study consisting of 305 couples undergoing ART demonstrated that sperm concentration was significantly lower in overweight, obese, and morbidly obese groups. The fertilization rate was consistent across all groups; however, pregnancy rates decreased with an increase in paternal BMI. Of note, maternal BMI did not differ between groups with the exception of the morbidly obese male group with had females with a higher BMI . Given the conflicting data, further studies are needed to define the effects of obesity of fertilization rates in ART.

While the exact pathophysiology for how obesity affects male infertility has yet to be clearly defined, it is hypothesized to occur through several different mechanisms. First, it is hypothesized that obesity and increased peripheral adipose tissue lead to perturbations in the hypothalamic–pituitary–gonadal axis. Second, obesity may lead to increased oxidative stress and production of reactive oxygen species that may affect sperm quantity and quality. Finally, an increase in suprapubic and scrotal fat may create an environment too warm for normal spermatogenesis .

Excess adipose tissue increases peripheral conversion of testosterone to estrogen. This increase in estrogen is thought to inhibit the hypothalamic–pituitary–gonadal axis and lead to secondary hypogonadism. A 2010 animal study examined the effects of a high-fat diet on testosterone levels. Mice that were initially fed a high-fat diet were found to have lower serum testosterone levels compared to mice fed a control diet. Mice that were subsequently switched to a control diet had restoration of normal serum testosterone levels . Several human studies have demonstrated the effects of male obesity and a significant decrease in total testosterone, free testosterone, and sex hormone-binding globulin (SHBG) levels . More recently, Derby and colleagues published the results of a longitudinal study examining the effects of obesity on male sex hormones in patients enrolled in the Massachusetts Male Ageing Study. In this study, the sex hormone levels of 942 patients were analyzed at baseline (1987–89) and follow-up (1995–97). Levels of total testosterone, free testosterone, and SHBG were all inversely correlated with waist circumference and BMI at baseline. Furthermore, at follow-up, patients who were obese were more likely to have a greater decline in hormone levels compared to nonobese patients . These studies illustrate the association between obesity and disruption of the central endocrinologic regulation of male infertility.

The effects of obesity on semen parameters have been a developing focus in male infertility research. The recently published data from the Longitudinal Investigation of Fertility and the Environment (LIFE) study sought to determine the relationship between male BMI and waist circumference and semen quantity. In this study, a cohort of 501 couples from two different geographical areas was followed up between 2005 and 2009. The authors found a linear association between increasing BMI and the incidence of oligospermia. Six percent of men with a normal BMI were oligospermic compared to 17% of obese men. Waist circumference was also correlated with low sperm concentration and low total sperm count . Other studies have demonstrated similar associations between obesity and decreased sperm quantity . A 2013 systematic review of 21 studies with a total of more than 13,000 men found that, relative to normal weight males, the odds ratio for azoospermia or oligospermia for overweight, obese, and morbidly obese men were 1.11, 1.28, and 2.04, respectively .

In addition to decreased sperm concentration, obesity has been negatively associated with sperm parameters, specifically sperm motility, morphology, and DNA fragmentation. Animal studies have demonstrated that mice fed a high-fat diet had a decrease in sperm motility compared to lean mice . Furthermore, in one of these studies, diet and exercise were shown to increase sperm motility, decrease abnormal sperm tail morphology, and decrease DNA damage in sperm . The decrease in sperm quality seen in obese males is postulated to be secondary to an increase in oxidative stress. The effects of oxidative stress and infertility will be discussed in greater detail later in the “Inflammation and Infertility” section.

Obese patients are also at higher risk for mechanical factors hypothesized to negatively impact fertility. An increase in fat, specifically around the testicle, within the spermatic cord, adjacent to the spermatic cord, in the suprapubic region, and in the medial thighs, may raise intratesticular temperatures above what are required for normal spermatogenesis. A number of animal studies have demonstrated that increased scrotal temperature can cause sperm DNA damage, decrease sperm viability, and can affect subsequent embryo quality . In 1981, Shafik and Olaf performed autopsies on a series of fertile and infertile male cadavers. The authors documented the presence of scrotal lipomatosis in 86% of idiopathic infertile males . The authors followed up this work by performing scrotal lipectomy on 102 infertile men with scrotal lipomatosis; 22 of these same men also underwent suprapubic lipectomy for removal of redundant suprapubic fat. The authors reported that 64.7% of the men had improvement in semen quality, and 19.6% achieved a pregnancy after the procedure . To our knowledge, there has been no further investigation into scrotal lipectomy for the treatment of male infertility and it is not a commonly performed procedure for infertility.

Obesity likely affects male factor infertility through multiple disruptions in normal physiology. The effects of weight loss on improving or restoring male infertility have yet to be studied in depth. A recently published case series followed six men who lost abdominal fat over a several-month period. All subjects in the series lost abdominal fat with a subsequent decrease in sperm DNA fragmentation rate and increase in testosterone-to-estradiol ratios . Given the small size of these and other trials, further prospective studies are necessary to determine whether weight loss will positively affect male infertility. However, for overweight and obese male patients who present to an infertility clinic, weight loss may aid in improving their fertility.