Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2014) 1e9
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Metabolic syndrome and infertility in men Christopher D. Morrison, MD, Urology Resident 1, Robert E. Brannigan, MD, Professor * Department of Urology, Northwestern University, Feinberg School of Medicine, Galter Pavilion, Suite 20-150, 675 North Saint Clair Street, Chicago, IL 60611, USA
Keywords: metabolic syndrome obesity dyslipidemia insulin resistance inflammation hypogonadism
Metabolic syndrome is a compilation of symptoms including central obesity, insulin resistance, dyslipidemia, and hypertension. Initially used to predict cardiovascular disease, it is now clear that the molecular and physiologic abnormalities seen in metabolic syndrome extend well beyond the cardiovascular system. Growing evidence has linked metabolic syndrome and its individual symptoms to the increasing prevalence of male infertility. This manuscript reviews the recent evidence connecting metabolic syndrome to male infertility as well as the underlying pathophysiology. Currently, there are limited prospective studies examining the effects of treating metabolic syndrome on male reproduction and these relationships will need to be a focus of further investigation. © 2014 Elsevier Ltd. All rights reserved.
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 [1]. 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% [2,3]. Both male and/or female factors can contribute to infertility. Male factor infertility is estimated to be the causative or a contributing factor in 20e50% of couples [4]. Interestingly, there is some evidence that the prevalence of male factor
* Corresponding author. Tel.: þ1 312 695 6124; Fax: þ1 312 695 7030. E-mail addresses: [email protected] (C.D. Brannigan). 1 Tel.: þ1 312 695 6124; Fax: þ1 312 695 7030.
Morrison),
[email protected]
(R.E.
http://dx.doi.org/10.1016/j.bpobgyn.2014.10.006 1521-6934/© 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Morrison CD, Brannigan RE, Metabolic syndrome and infertility in men, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.10.006
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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 [5]. Furthermore, a review of 61 papers from 1938 to 1990 also documented declining sperm parameters over time [6]. 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 [7] (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) [8]. 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) [9]. 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 [10]. Female obesity has already been well established as a cause of female infertility [11]. 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 [12]. 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 normalweight 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 [13]. 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 [14]. 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 [15]. Given the conflicting data, further studies are needed to define the effects of obesity of fertilization rates in ART. Table 1 ATPIII criteria for metabolic syndrome (in men). Abdominal obesity (waist circumference >102cm) Triglycerides 150 mg/dL High-density lipoprotein cholesterol (HDL) < 40 mg/dL Blood pressure 130/86 mmHg Fasting glucose 110 mg/dL
Please cite this article in press as: Morrison CD, Brannigan RE, Metabolic syndrome and infertility in men, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.10.006
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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 hypothalamicepituitaryegonadal 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 [16]. Excess adipose tissue increases peripheral conversion of testosterone to estrogen. This increase in estrogen is thought to inhibit the hypothalamicepituitaryegonadal 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 [17]. 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 [18,19]. 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 (1987e89) and follow-up (1995e97). 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 [20]. 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 [21]. Other studies have demonstrated similar associations between obesity and decreased sperm quantity [22e24]. 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 [25]. 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 [17,26]. 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 [17]. 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 [27e29]. 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 [30]. 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 [31]. 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. Please cite this article in press as: Morrison CD, Brannigan RE, Metabolic syndrome and infertility in men, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.10.006
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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 [32]. 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. Insulin resistance, diabetes, and infertility The prevalence of diabetes was estimated at 347 million individuals worldwide in 2008 and is expected to continue to rise [33]. Insulin resistance and diabetes appear to negatively affect male infertility through similar pathophysiologic processes as obesity. Studies have demonstrated a relationship between hypogonadism and insulin resistance. The Massachusetts Male Aging Study followed 1156 men over 7e10 years. In this prospective study, the risk of developing diabetes was significantly increased in patients who had decreased free testosterone levels and low SHBG levels as the start of the study [34]. Similar cohort studies revealed similar results between hypogonadism and subsequent development of diabetes [35,36]. A retrospective study of 103 patients with type 2 diabetes mellitus (DM) demonstrated that 33% of these patients also had hypogonadotropic hypogonadism [37]. While cohort studies have demonstrated that hypogonadism is a risk factor for developing diabetes, it has yet to be elucidated whether hypogonadism directly leads to insulin resistance or whether there is a broader underlying pathophysiologic process leading to both hypogonadism and insulin resistance. In addition to its endocrine effects, insulin resistance and diabetes appear to negatively affect the sperm quantity and quality. Agbaje and colleagues compared semen samples from insulin-dependent diabetic patients and healthy controls. The authors reported significantly lower semen volumes and higher sperm DNA fragmentation rates (53% vs. 32%) in diabetic patients compared to controls [38]. A recent study examined the effects of treating 45 men with metabolic syndrome with metformin, a common first-line agent for insulin-resistant diabetes, and the subsequent effects on parameters of male infertility. In patients on metformin for a 6-month period, SHBG decreased significantly, testosterone and luteinizing hormone levels increased, and sperm concentration, motility, and morphology improved [39]. Although larger, randomized trials are required, this study demonstrated a promising improvement in endocrine function and sperm parameters with treatment of insulin resistance. The neurologic sequelae of diabetes can have an impact on male infertility. A study based on the Massachusetts Male Aging study revealed that the age-adjusted relative risk (1.83) of developing erectile dysfunction was significantly increased in men with diabetes compared to non-diabetic males [40]. Similarly, a questionnaire-based study of 2869 men using the International Index of Erectile Function-5 (IIEF-5) questionnaire demonstrated a significantly elevated odds ratio (3.0) of erectile dysfunction in diabetic patients [41]. In addition to erectile dysfunction, diabetes increases ejaculatory dysfunction. A recent prospective, blinded caseecontrol study consisting of 26 men with diabetes and 16 healthy matched controls found the rate of retrograde ejaculation in diabetic patients to be 35% versus 0% in controls [42]. For diabetic patients presenting to an infertility clinic with azoospermia or oligospermia, it is important to assess the patient for possible retrograde ejaculation. Similar to obesity, insulin resistance and diabetes affect male infertility through various mechanisms. Its disruption of the hypothalamicepituitaryegonadal axis can render patients with hypogonadism. Insulin resistance has been shown to alter normal sperm morphology and function. Finally, the neurologic effects of diabetes can diminish erectile and ejaculatory function. As the prevalence of diabetes is expected to continue to rise, it is important to diagnose and treat insulin resistance and diabetes when evaluating male patients with infertility. Dyslipidemia and infertility Dyslipidemia, defined by elevated triglycerides and/or low HDL, is another key component of metabolic syndrome. While the volume of research is less compared to that of obesity and diabetes, Please cite this article in press as: Morrison CD, Brannigan RE, Metabolic syndrome and infertility in men, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.10.006
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there are animal and human studies that correlate dyslipidemia with male infertility. In an animal study by Yamamoto and colleagues in 1999, 20 rabbits were given either a diet containing 3% cholesterol or a normal diet. The authors found that the sperm concentration and the percentage of motile spermatozoa were significantly decreased in the rabbits fed a high-cholesterol diet. The authors also noted that an increased incorporation of cholesterol in the plasma membranes in the sperm of the rabbits fed a high-cholesterol diet altered the sperm head morphology and inhibited the acrosomal reaction [43]. In a more recent animal study in 2010, rabbits were fed either a diet with 6.5% saturated fat and 0.05% cholesterol or a normal diet. The rabbits fed a high-cholesterol diet had significantly elevated cholesterol levels without a significant change in the BMI compared to the control group. It was noted that the rabbits in the experimental groups had decreased ejaculate volume, decreased sperm motility, and an increased number of morphological alterations in the sperm [44]. These studies illustrate that dyslipidemia likely disrupts molecular and metabolic pathways necessary for normal sperm development and function. In 2004, Shalaby and colleagues sought to investigate the effects of treating dyslipidemia with a cholesterol-lowering drug (Simvastatin) and/or an antioxidant (a-tocopherol) on male infertility in mice. At baseline, hypercholesteremic male mice had decreased fertility indices (defined as the percentage of matings that resulted in pregnancies), decreased sperm cell concentrations, viability, and motility compared to mice with normal cholesterol levels. When treated with simvastatin and/or atocopherol, the fertility index significantly improved [45]. These results suggest that hypercholesteremia and its resultant elevated levels of reactive oxygen species may alter normal sperm generation and function. Perhaps the most convincing clinical research that has been published to date examining the correlation between lipid concentrations and male infertility was from the LIFE study. As described in the obesity section, the LIFE study was a prospective cohort study examining environmental factors on fertility in couples from Michigan and Texas. The study subjects had non-fasting blood samples drawn for quantification of serum lipids. Elevated total cholesterol levels were associated with decreases in semen volume. The authors also found that increased free cholesterol and phospholipid levels were also associated with decreases in sperm head size and percentages of sperm with an intact acrosome [46]. In a separate publication, the lipid concentrations of both the male and female partners and the fecundity of the couples were examined. The study found that elevated cholesterol levels in either the male or female partners were associated with a longer time to pregnancy [47]. The results of these clinical studies correlate well with the previous animal studies. The pathophysiologic role of dyslipidemia in male infertility appears to occur at the molecular level by affecting normal sperm development and function as well as at the metabolic level by increasing levels of reactive oxygen species. Although animal studies suggest the role of cholesterol-lowering agents and antioxidants in improving male fertility, there have yet to be any prospective clinical trials validating their role.
Inflammation and infertility Although not a specific ATP III criteria for the diagnosis of metabolic syndrome, an association between inflammation and metabolic syndrome has been well established [8]. Adipose tissue in obese males has been shown to express higher levels of inflammatory molecules such as TNF-a, IL-6, and CRP [48]. A study in 2003 by Weisberg and colleagues analyzed perigonadal, perirenal, mesenteric, and subcutaneous fat from both obese and lean mice. The authors found that obese mice had higher percentages of macrophages per average adipocyte area compared to lean mice. Furthermore, the macrophages in obese mice had characteristics seen in chronic inflammation. The authors also examined adipose tissue in obese and lean humans and found that both BMI and average adipocyte cross-sectional area were associated with higher percentages of macrophages [48]. A study by Xu and authors found a similar increase in macrophages in adipose tissue of obese mice compared to lean mice. Furthermore, they found an upregulation of inflammatory genes prior to the development of insulin resistance. They hypothesized that the increase in macrophages in adipose tissues may contribute to the development of insulin resistance [49]. Please cite this article in press as: Morrison CD, Brannigan RE, Metabolic syndrome and infertility in men, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.10.006
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Inflammation of the reproductive tract, either from infectious or noninfectious causes, has been shown to be common in infertile male patients. The cytokines TNF-a and IL-1 have been implicated as the main mediators of the inflammatory process [50]. Inflammation increases levels of reactive oxygen species that can negatively impact normal reproductive pathways [51]. Specifically, studies have demonstrated that elevated oxidative stress leads to increased DNA damage of spermatozoa and is negatively correlated with normal sperm morphology [52e54]. Subsequently, Tunc and colleagues compared reactive oxygen levels in semen samples from both overweight/obese men and men of normal BMI. A weak but statistically significant positive correlation was seen between increasing BMI and reactive oxygen species levels [55]. Inflammation is implicated in both metabolic syndrome and male infertility, individually. However, inflammation may play a significant role in the pathophysiology that links metabolic syndrome to male infertility. For patients who present with dyslipidemia, there may be some benefit in fertility by treating with cholesterol-lowering agents and antioxidants.
Metabolic syndrome and infertility As detailed above, individual components of metabolic syndrome have been associated with male infertility. More recently, there has been an increase in studies examining metabolic syndrome as a whole and male infertility. In a 2005 cross-sectional study, Muller and colleagues found that decreasing levels of total testosterone, SHBG, and DHEA-S were associated with increasing risk factors for metabolic syndrome. The authors also found that low total testosterone and SHBG levels were associated with the individual components of metabolic syndrome [56]. These findings were corroborated by two recent publications. A study comprising 376 male patients who presented to an infertility clinic found that 7.7% of patients met International Diabetes Federation (IDF) and American Heart Association/ National Heart, Lung, and Blood Institute (AHA/NHLBI) criteria for metabolic syndrome. There was a significantly higher prevalence of secondary hypogonadism in subjects with metabolic syndrome compared to those who did not meet criteria for metabolic syndrome [57]. Choudhury and colleagues studied 40 male patients between the age of 20 and 40 who met IDF criteria for metabolic syndrome. When compared to 18 healthy age-matched controls, 20% of study subjects had testosterone levels
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Metabolic syndrome and infertility in men Christopher D. Morrison, MD, Urology Resident 1, Robert E. Brannigan, MD, Professor * Department of Urology, Northwestern University, Feinberg School of Medicine, Galter Pavilion, Suite 20-150, 675 North Saint Clair Street, Chicago, IL 60611, USA
Keywords: metabolic syndrome obesity dyslipidemia insulin resistance inflammation hypogonadism
Metabolic syndrome is a compilation of symptoms including central obesity, insulin resistance, dyslipidemia, and hypertension. Initially used to predict cardiovascular disease, it is now clear that the molecular and physiologic abnormalities seen in metabolic syndrome extend well beyond the cardiovascular system. Growing evidence has linked metabolic syndrome and its individual symptoms to the increasing prevalence of male infertility. This manuscript reviews the recent evidence connecting metabolic syndrome to male infertility as well as the underlying pathophysiology. Currently, there are limited prospective studies examining the effects of treating metabolic syndrome on male reproduction and these relationships will need to be a focus of further investigation. © 2014 Elsevier Ltd. All rights reserved.
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 [1]. 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% [2,3]. Both male and/or female factors can contribute to infertility. Male factor infertility is estimated to be the causative or a contributing factor in 20e50% of couples [4]. Interestingly, there is some evidence that the prevalence of male factor
* Corresponding author. Tel.: þ1 312 695 6124; Fax: þ1 312 695 7030. E-mail addresses: [email protected] (C.D. Brannigan). 1 Tel.: þ1 312 695 6124; Fax: þ1 312 695 7030.
Morrison),
[email protected]
(R.E.
http://dx.doi.org/10.1016/j.bpobgyn.2014.10.006 1521-6934/© 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Morrison CD, Brannigan RE, Metabolic syndrome and infertility in men, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.10.006
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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 [5]. Furthermore, a review of 61 papers from 1938 to 1990 also documented declining sperm parameters over time [6]. 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 [7] (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) [8]. 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) [9]. 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 [10]. Female obesity has already been well established as a cause of female infertility [11]. 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 [12]. 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 normalweight 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 [13]. 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 [14]. 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 [15]. Given the conflicting data, further studies are needed to define the effects of obesity of fertilization rates in ART. Table 1 ATPIII criteria for metabolic syndrome (in men). Abdominal obesity (waist circumference >102cm) Triglycerides 150 mg/dL High-density lipoprotein cholesterol (HDL) < 40 mg/dL Blood pressure 130/86 mmHg Fasting glucose 110 mg/dL
Please cite this article in press as: Morrison CD, Brannigan RE, Metabolic syndrome and infertility in men, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.10.006
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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 hypothalamicepituitaryegonadal 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 [16]. Excess adipose tissue increases peripheral conversion of testosterone to estrogen. This increase in estrogen is thought to inhibit the hypothalamicepituitaryegonadal 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 [17]. 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 [18,19]. 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 (1987e89) and follow-up (1995e97). 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 [20]. 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 [21]. Other studies have demonstrated similar associations between obesity and decreased sperm quantity [22e24]. 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 [25]. 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 [17,26]. 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 [17]. 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 [27e29]. 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 [30]. 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 [31]. 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. Please cite this article in press as: Morrison CD, Brannigan RE, Metabolic syndrome and infertility in men, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.10.006
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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 [32]. 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. Insulin resistance, diabetes, and infertility The prevalence of diabetes was estimated at 347 million individuals worldwide in 2008 and is expected to continue to rise [33]. Insulin resistance and diabetes appear to negatively affect male infertility through similar pathophysiologic processes as obesity. Studies have demonstrated a relationship between hypogonadism and insulin resistance. The Massachusetts Male Aging Study followed 1156 men over 7e10 years. In this prospective study, the risk of developing diabetes was significantly increased in patients who had decreased free testosterone levels and low SHBG levels as the start of the study [34]. Similar cohort studies revealed similar results between hypogonadism and subsequent development of diabetes [35,36]. A retrospective study of 103 patients with type 2 diabetes mellitus (DM) demonstrated that 33% of these patients also had hypogonadotropic hypogonadism [37]. While cohort studies have demonstrated that hypogonadism is a risk factor for developing diabetes, it has yet to be elucidated whether hypogonadism directly leads to insulin resistance or whether there is a broader underlying pathophysiologic process leading to both hypogonadism and insulin resistance. In addition to its endocrine effects, insulin resistance and diabetes appear to negatively affect the sperm quantity and quality. Agbaje and colleagues compared semen samples from insulin-dependent diabetic patients and healthy controls. The authors reported significantly lower semen volumes and higher sperm DNA fragmentation rates (53% vs. 32%) in diabetic patients compared to controls [38]. A recent study examined the effects of treating 45 men with metabolic syndrome with metformin, a common first-line agent for insulin-resistant diabetes, and the subsequent effects on parameters of male infertility. In patients on metformin for a 6-month period, SHBG decreased significantly, testosterone and luteinizing hormone levels increased, and sperm concentration, motility, and morphology improved [39]. Although larger, randomized trials are required, this study demonstrated a promising improvement in endocrine function and sperm parameters with treatment of insulin resistance. The neurologic sequelae of diabetes can have an impact on male infertility. A study based on the Massachusetts Male Aging study revealed that the age-adjusted relative risk (1.83) of developing erectile dysfunction was significantly increased in men with diabetes compared to non-diabetic males [40]. Similarly, a questionnaire-based study of 2869 men using the International Index of Erectile Function-5 (IIEF-5) questionnaire demonstrated a significantly elevated odds ratio (3.0) of erectile dysfunction in diabetic patients [41]. In addition to erectile dysfunction, diabetes increases ejaculatory dysfunction. A recent prospective, blinded caseecontrol study consisting of 26 men with diabetes and 16 healthy matched controls found the rate of retrograde ejaculation in diabetic patients to be 35% versus 0% in controls [42]. For diabetic patients presenting to an infertility clinic with azoospermia or oligospermia, it is important to assess the patient for possible retrograde ejaculation. Similar to obesity, insulin resistance and diabetes affect male infertility through various mechanisms. Its disruption of the hypothalamicepituitaryegonadal axis can render patients with hypogonadism. Insulin resistance has been shown to alter normal sperm morphology and function. Finally, the neurologic effects of diabetes can diminish erectile and ejaculatory function. As the prevalence of diabetes is expected to continue to rise, it is important to diagnose and treat insulin resistance and diabetes when evaluating male patients with infertility. Dyslipidemia and infertility Dyslipidemia, defined by elevated triglycerides and/or low HDL, is another key component of metabolic syndrome. While the volume of research is less compared to that of obesity and diabetes, Please cite this article in press as: Morrison CD, Brannigan RE, Metabolic syndrome and infertility in men, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.10.006
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there are animal and human studies that correlate dyslipidemia with male infertility. In an animal study by Yamamoto and colleagues in 1999, 20 rabbits were given either a diet containing 3% cholesterol or a normal diet. The authors found that the sperm concentration and the percentage of motile spermatozoa were significantly decreased in the rabbits fed a high-cholesterol diet. The authors also noted that an increased incorporation of cholesterol in the plasma membranes in the sperm of the rabbits fed a high-cholesterol diet altered the sperm head morphology and inhibited the acrosomal reaction [43]. In a more recent animal study in 2010, rabbits were fed either a diet with 6.5% saturated fat and 0.05% cholesterol or a normal diet. The rabbits fed a high-cholesterol diet had significantly elevated cholesterol levels without a significant change in the BMI compared to the control group. It was noted that the rabbits in the experimental groups had decreased ejaculate volume, decreased sperm motility, and an increased number of morphological alterations in the sperm [44]. These studies illustrate that dyslipidemia likely disrupts molecular and metabolic pathways necessary for normal sperm development and function. In 2004, Shalaby and colleagues sought to investigate the effects of treating dyslipidemia with a cholesterol-lowering drug (Simvastatin) and/or an antioxidant (a-tocopherol) on male infertility in mice. At baseline, hypercholesteremic male mice had decreased fertility indices (defined as the percentage of matings that resulted in pregnancies), decreased sperm cell concentrations, viability, and motility compared to mice with normal cholesterol levels. When treated with simvastatin and/or atocopherol, the fertility index significantly improved [45]. These results suggest that hypercholesteremia and its resultant elevated levels of reactive oxygen species may alter normal sperm generation and function. Perhaps the most convincing clinical research that has been published to date examining the correlation between lipid concentrations and male infertility was from the LIFE study. As described in the obesity section, the LIFE study was a prospective cohort study examining environmental factors on fertility in couples from Michigan and Texas. The study subjects had non-fasting blood samples drawn for quantification of serum lipids. Elevated total cholesterol levels were associated with decreases in semen volume. The authors also found that increased free cholesterol and phospholipid levels were also associated with decreases in sperm head size and percentages of sperm with an intact acrosome [46]. In a separate publication, the lipid concentrations of both the male and female partners and the fecundity of the couples were examined. The study found that elevated cholesterol levels in either the male or female partners were associated with a longer time to pregnancy [47]. The results of these clinical studies correlate well with the previous animal studies. The pathophysiologic role of dyslipidemia in male infertility appears to occur at the molecular level by affecting normal sperm development and function as well as at the metabolic level by increasing levels of reactive oxygen species. Although animal studies suggest the role of cholesterol-lowering agents and antioxidants in improving male fertility, there have yet to be any prospective clinical trials validating their role.
Inflammation and infertility Although not a specific ATP III criteria for the diagnosis of metabolic syndrome, an association between inflammation and metabolic syndrome has been well established [8]. Adipose tissue in obese males has been shown to express higher levels of inflammatory molecules such as TNF-a, IL-6, and CRP [48]. A study in 2003 by Weisberg and colleagues analyzed perigonadal, perirenal, mesenteric, and subcutaneous fat from both obese and lean mice. The authors found that obese mice had higher percentages of macrophages per average adipocyte area compared to lean mice. Furthermore, the macrophages in obese mice had characteristics seen in chronic inflammation. The authors also examined adipose tissue in obese and lean humans and found that both BMI and average adipocyte cross-sectional area were associated with higher percentages of macrophages [48]. A study by Xu and authors found a similar increase in macrophages in adipose tissue of obese mice compared to lean mice. Furthermore, they found an upregulation of inflammatory genes prior to the development of insulin resistance. They hypothesized that the increase in macrophages in adipose tissues may contribute to the development of insulin resistance [49]. Please cite this article in press as: Morrison CD, Brannigan RE, Metabolic syndrome and infertility in men, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.10.006
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Inflammation of the reproductive tract, either from infectious or noninfectious causes, has been shown to be common in infertile male patients. The cytokines TNF-a and IL-1 have been implicated as the main mediators of the inflammatory process [50]. Inflammation increases levels of reactive oxygen species that can negatively impact normal reproductive pathways [51]. Specifically, studies have demonstrated that elevated oxidative stress leads to increased DNA damage of spermatozoa and is negatively correlated with normal sperm morphology [52e54]. Subsequently, Tunc and colleagues compared reactive oxygen levels in semen samples from both overweight/obese men and men of normal BMI. A weak but statistically significant positive correlation was seen between increasing BMI and reactive oxygen species levels [55]. Inflammation is implicated in both metabolic syndrome and male infertility, individually. However, inflammation may play a significant role in the pathophysiology that links metabolic syndrome to male infertility. For patients who present with dyslipidemia, there may be some benefit in fertility by treating with cholesterol-lowering agents and antioxidants.
Metabolic syndrome and infertility As detailed above, individual components of metabolic syndrome have been associated with male infertility. More recently, there has been an increase in studies examining metabolic syndrome as a whole and male infertility. In a 2005 cross-sectional study, Muller and colleagues found that decreasing levels of total testosterone, SHBG, and DHEA-S were associated with increasing risk factors for metabolic syndrome. The authors also found that low total testosterone and SHBG levels were associated with the individual components of metabolic syndrome [56]. These findings were corroborated by two recent publications. A study comprising 376 male patients who presented to an infertility clinic found that 7.7% of patients met International Diabetes Federation (IDF) and American Heart Association/ National Heart, Lung, and Blood Institute (AHA/NHLBI) criteria for metabolic syndrome. There was a significantly higher prevalence of secondary hypogonadism in subjects with metabolic syndrome compared to those who did not meet criteria for metabolic syndrome [57]. Choudhury and colleagues studied 40 male patients between the age of 20 and 40 who met IDF criteria for metabolic syndrome. When compared to 18 healthy age-matched controls, 20% of study subjects had testosterone levels
