|Year : 2015 | Volume
| Issue : 4 | Page : 107-116
Association of Male Infertility to Metabolic Syndrome and Other Related Disorders
Sanjay Kumar1, Divya Agrawal2, Kunal Sharma1, Trupti Rekha Swain3
1 Department of Pharmacology, IMS and SUM Hospital, Bhubaneswar, Odisha, India
2 Department of Anatomy, IMS and SUM Hospital, Bhubaneswar, Odisha, India
3 Department of Pharmacology, S C B Medical College, Cuttack, Odisha, India
|Date of Web Publication||28-Oct-2015|
Department of Pharmacology, RKDF Medical College Hospital and Research Centre, SRK University, Bhopal - 462 026, Madhya Pradesh
Source of Support: None, Conflict of Interest: None
Metabolic syndrome is a common global problem. This condition is also multifaceted and potential precursor to significant disturbance of numerous physiologic processes. The interconnected complexities of this disorder may varies from, life threatening risk of cardiovascular atherosclerotic diseases, type 2 diabetes, and hypertension to many of other metabolic diseases like male or female infertility. This review article cogitate the literature regarding metabolic syndrome and male reproductive health. The association between abdominal obesity, insulin resistance, systemic hypertension, and dyslipidemia are each examined with regard to their interconnected deleterious effects on male fertility. At the conclusion of this manuscript, we propose a new metabolic syndrome with male infertility paradigm. Supplementary acquisition particularly addressing the components of metabolic syndrome and their impact on male reproduction will enhance our understanding of the underlying pathophysiology. These studies may also help elucidate the role for therapeutic intervention.
Keywords: Diabetes, hypogonadism, male infertility, metabolic syndrome
|How to cite this article:|
Kumar S, Agrawal D, Sharma K, Swain TR. Association of Male Infertility to Metabolic Syndrome and Other Related Disorders. J Integr Nephrol Androl 2015;2:107-16
|How to cite this URL:|
Kumar S, Agrawal D, Sharma K, Swain TR. Association of Male Infertility to Metabolic Syndrome and Other Related Disorders. J Integr Nephrol Androl [serial online] 2015 [cited 2022 Dec 8];2:107-16. Available from: http://www.journal-ina.com/text.asp?2015/2/4/107/168524
| Introduction|| |
Metabolic syndrome is known by various names such as insulin resistance syndrome, plurimetabolic syndrome, deadly quartlet,  civilization syndrome,  and syndrome X.  Metabolic syndrome is the most commonly used term,  hence it will be used in this review article. It is a cluster of endocrine irregularities such as obesity, insulin resistance, systemic hypertension, and dyslipidemia.  In 2003, the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) definition includes high level of fasting blood sugar, increased waist circumference, high systemic blood pressure, high level of triglyceride, and low high-density lipoprotein cholesterol.  Recently, the International Diabetes Federation and the American Heart Association/National Heart, Lung, and Blood Institute supported that waist measurement depending upon race and gender would be taken as a useful preliminary screening tool rather than central obesity. Three out of five findings would be considered for the diagnosis of metabolic syndrome.  The advantage of this new definition is its ease of application. Metabolic syndrome is characterized by both male and female infertility. It is estimated that 15% of couples attempting to conceive are not able to do so within 1-year.  Male factor of infertility is present in 20-50% of couples either independently or in conjunction with female factor infertility issues.  Polycystic ovarian syndrome characterized by chronic anovulation, amenorrhoea or oligomenorrhoea, hyperandrogenism, polycystic ovary morphology in pelvic ultrasound, hyperinsulinemia, and insulin resistance is seen is 5-8% of obese premenopausal women with this syndrome.  In the setting of an increasing prevalence and understanding of metabolic syndrome, researchers are actively studying the potential relationship between metabolic syndrome and male factor infertility. The knowledge acquired from this innovative work may provide wide therapeutic options for male partners in affected infertile couples. This review will evaluate metabolic syndrome with its each component in order to establish a concept of male factor infertility.
| Obesity and Infertility|| |
The effect of obesity on male infertility with metabolic syndrome is postulated to occur by many mechanisms. There are two types of adipose tissue found in mammals, white adipose tissue and another one is brown adipose tissue. White adipose tissue comprises 20% of the body weight in males. It is an important mediator of inflammation and metabolism.  The white adipose tissue acts as an endocrine organ as a number of adipose derived hormones are secreted from it, the important one being leptin the others are angiotensinogen, resistin, adipsin, acylation stimulating protein, adiponectin, tumor necrosis factor, retinol binding protein, and many more. , Excess fat accumulation causes dysregulation of these proteins. The leptin which is a 16 kDa adipokine encoded by ob gene plays a key role.  In the fed state, leptin is released by the white adipose tissue and stimulates the satiety center, also regulates energy expenditure, glucose metabolism, puberty and reproduction,  hematopoesis, and angiogenesis.  Leptin level is raised in obese individuals than nonobese. , The effect of mutated ob gene resulting in elevated leptin levels and obesity is controversial, but definitely there is a functional leptin resistance in obese individuals.  Leptin receptors are found on the plasma membrane of sperm and leptin has been found in semen, hence a positive correlation between leptin levels and the male reproductive system can be linked.  Increased leptin levels have a deleterious effect on spermatogenesis and androgen production which is supported by an animal study where mice deficient in leptin showed impaired spermatogenesis, germ cell apoptosis, and increased expression of proapoptotic genes within the testis.  By decreasing elevated leptin levels in obese individuals, it might be possible to reverse some of the potential suppressive effects of excess leptin on the hypothalamic-pituitary gonadal axis and restore normal spermatogenesis and sperm function.
Many studies have demonstrated the condition of imbalance in the hypothalamic- and pituitary-gonadal axis in obese male with the outcome of significant depression in total testosterone and sex hormone binding globulin. ,,,,, Few researchers observed that the decreased sex hormone binding globulin allows for normalization of free testosterone in the setting of low total testosterone,  others have watched a decrease in all three (total testosterone, free testosterone, and sex hormone binding globulin). ,,, Later one of the researchers reported a negative correlation between body mass index (BMI) and free testosterone.  The insulin is known to inhibit sex hormone binding globulin synthesis and is important for the obese males with metabolic syndrome. , Several other researchers were also demonstrated the inverse correlation between metabolic syndrome with both sex hormone-binding globulin and testosterone. ,,,, So, the persons with metabolic syndrome have a low level of total testosterone, free testosterone, and sex hormone-binding globulins. 
In the previously mentioned studies, the normal or low levels of follicle stimulating hormone and luteinizing hormone were found in obese male individuals. ,, The peripheral conversion of testosterone to estrogen in adipose tissue may lead to secondary hypogonadism by suppression of the hypothalamic-pituitary gonadal axis. ,, Therefore the resulted decrease in testosterone levels in obese males are likely due to several factors, including inhibition of sex hormone binding globulin synthesis, and decreased gonadotropin secretion.  As an outcome, the obese population may be at an increased risk for infertility.
A study between obese and nonobese individuals was done in 1993 and reported that men who were both infertile and obese had significantly lower testosterone levels and testosterone-estradiol ratios than nonobese fertile, obese fertile, and nonobese infertile counterparts.  The interesting finding was infertile- obese males had significantly low level of sex hormone binding globulin with appreciable high levels of bio-available testosterone and estradiol. The researchers of this study were argued that all these changes are ultimately results in the establishment of a lower total testosterone set point in the hypothalamic- pituitary-gonadal axis. Inhibin B, growth like a factor, is produced by Sertoli cells More Details in the testis, and normally acts to inhibit both follicular stimulating hormone production and stimulation of testosterone production by Leydig cells in the testis. Surprisingly, the expected compensatory increase in follicular stimulating hormone levels in response to low levels of inhibin B is not observed in obese men. A low level of inhibin B might result from the suppressive effects of elevated estrogen levels. Even though this hypothesis differs from the other earlier mentioned observers and the study reveals aberrations in male endocrine reproductive homeostasis that may lead to decreased fertility but This study further highlighted the need for additional evidence correlating hormonal dysregulation in obese males to infertility.
Till date, many studies have tested the relationship between components of obesity (weight, BMI, waist-to-hip ratio, etc.) and semen quality. In 2005, another group of researchers  examined lifestyle and ecological factors, which have been hypothesized to adversely affect semen quality. Among the three groups (male factor subfertility, female factor subfertility, and idiopathic subfertility), they found a three times higher incidence of obesity (BMI > 30) in individuals with male factor subfertility compared with the other two groups. After combining the idiopathic subfertility and female factor subfertility groups, they found that BMI was negatively correlated with sperm concentration and sperm count, and there was no such correlations existed within the male factor subfertility group. They also found that the men with a sedentary level of work activity had low normal sperm density than the individuals had intermediate or active levels of work activities. These results were concluded as the elevated scrotal temperatures associated with sedentary activity rather than with obesity itself may be the main culprit to cause of low sperm count.
In the same year, another study  was conducted over infertile male of reproductive age group (37 ± 5.4 years). In this study the other determinant of infertility like chronic diseases, reproductive organ heterotaxy, reproductive pathology, seminal infection, and social factors were excluded. Associations between anthropometric data and WHO semen analysis parameters and reproductive hormonal levels were assessed. In this study, they observed a negative correlation between serum volume with waist circumference and waist-hip ratio; total sperm count and total motile sperm with weight, hip circumference, and waist circumference. There was a negative correlation between total rapid progressive motile sperm with hip circumference and waist circumference. In addition, weight, BMI, hip circumference, waist circumference, and waist to hip ratio all significantly negatively linked with sex hormone binding globulin, testosterone, and testosterone/17b-estradiol, but not follicle stimulating hormone, luteinizing hormone, or 17b-estradiol levels. These data suggest a significant relationship between infertility, hypogonadism, and obesity as indicated by semen analysis.
Similar type of study was done in 2006 by another group  of scientist, they analyzed the association between BMI and traditional semen parameters (volume, sperm concentration, sperm motility percentage, and normal sperm morphology percentage) and sperm chromatin integrity in larger number male partners (n = 520) in infertile couples of reproductive age group (range 26-45 years). The researchers also assessed semen quality by normal motile spermatozoa, defined as volume × concentration × percent motility × percent normal morphology (with morphology defined by Tygerberg criteria). The Sperm chromatin integrity was examined by DNA fragmentation index. The individuals were arranged by BMI, with the range of normal (20-24), overweight (25-30), and obese (>30), and the groups then were compared with the above measures of semen quality. They found a significant negative correlation between BMI and normal motile spermatozoa, with significant differences among all BMI groups: Normal, 18.6 × 106 normal motile spermatozoa; overweight, 3.6 × 106 normal motile spermatozoa; and obese, 0.7 × 106 normal motile spermatozoa. Additionally, a significant direct correlation was found between BMI and DNA fragmentation index, indicating increased DNA fragmentation with increased BMI. No statistically appreciable differences were found between the overweight and obese groups.
In brief, the above three studies suggested a pattern in which obesity is negatively correlated with normal motile spermatozoa and positively correlated with sperm DNA damage. In proper order, it suggests decreased reproductive potential in obese males. However, a biological correlation is needed to simultaneously account for both declines in normal motile spermatozoa and increase in DNA damage. Therefore, oxidative stress is considered as the possible cause of the obesity with infertility.
Oxidative stress is a common pathophysiological process in many diseases like autoimmune, cardiovascular, and infectious processes.  It originates when excess concentrations of reactive oxidative species, molecules nourishing an unpaired electron and are present in a particular physiological microenvironment. These molecules are highly reactive and unstable, and have potency to induce a significant cellular damage throughout the body. In relation to male reproductive health, various studies have revealed that oxidative stress results in sperm membrane lipid peroxidation, causing damage in sperm motility, and sperm-oocyte interaction. Some studies showed both in vivo and in vitro that, the DNA of spermatozoa from infertile males had greater oxidative harm when compared to controls. , In short, oxidative stress may cause decreased spermatogenesis and results in lipid peroxidation of the sperm membrane. The membrane lipid peroxidation of sperm leads to decreased motility and membrane dysfunction; excessive oxidative stress may also results in the damage of sperm DNA, with impaired genetic viability of the affected sperm. Numerous researchers have noted that, the components of metabolic syndrome are associated with systemic proinflammatory states and increased oxidative stress with lipid peroxidation. , In the obese groups, the elevated DNA fragmentation index may in fact reflect an abnormally increased oxidative state in the testicular microenvironment  and excurrent ductal system which ultimately explaining the increased DNA damage in obese males.
In obesity, the molecular and hormonal alteration along with gross mechanical causes may play a vital role in impairing male reproductive health. Suprapubic and thigh fat have been theorized by some researchers to cause elevated scrotal temperatures and resulting infertility.  A study also noted specific patterns of scrotal lipomatosis (abnormally distributed scrotal fat present along the spermatic cord and testes) in obese infertile males which not seen in nonobese infertile patients ,, and scrotal lipectomy resulted in substantial recovery in semen quality as, morphology sperm count, and motility of sperm, in 65% of patients. Additionally, 20% of the patients achieved conceptions after lipectomy.  Till date, no other groups has investigated scrotal lipectomy as a claimed therapeutic modality for infertility due to obesity. The above study researchers also reported in their sequence that all the cases of scrotal lipomatosis demonstrated varicosity of the cremasteric veins, and few cases demonstrated varicosities of the pampiniform plexus; although, the varicosities were not clinically palpable. The researchers suggested that the increased incidence of varices they noticed with scrotal lipomatosis may lead to infertility, particularly in obese males.
However, later studies were not accepting this assertion. In a study  of 398 males with varices, reported negative correlation between varicocele formation and BMI and suggested that adipose tissue may protect against the "nutcracker effect." Some researchers have found decreasing prevalence of varicocele with increasing BMI in a study of about thirty two hundreds of infertile male.  A study reported varicoceles were more prevalent in tall young boys with a lower BMI, who had progressed through puberty quickly.  Finally, few researchers voiced, whether the decreased prevalence of varicoceles in obese males were true anatomically or an issue of decreased detection due to body physique. As described by earlier researchers,  scrotal lipomatosis in obese males may signify a distinct pathological manifestation of obesity involving the scrotum hindering varicocele detection. While the literatures are thus not entirely clear regarding the true prevalence of varicoceles in obese males. Although, many evidences supporting that, varicoceles are associated with a big number of harmful changes, including increased germ cell apoptosis, testicular atrophy, and reduced sperm motility, which may compound the several potential hormonal and molecular aberrations in obese men with infertility. , The another study has focused on genital heat stress as a potential cause of impaired semen quality in cases of sedentary occupations, the occurrence of frequent fever, and varicocele. 
| Diabetes and Infertility|| |
In general, insulin resistance is considered as the pivotal defect in metabolic syndrome. The studies on type 2 diabetic individuals would provide important insight into a metabolic syndrome -infertility pattern. Almost 80% of type 2 diabetes are obese and having a strong interrelationship between obesity, hyperinsulinemia, and defective spermatogenesis.  In the diabetic group males, the magnitude of nuclear and mitochondrial DNA damage in the sperm was significantly higher than control group but the other parameters of semen (concentration, motility, and morphology) did not vary from counter group.  Resistin (adipose tissue specific factor) is considered to induce insulin resistance.  The hyperinsulinemia has an inhibitory effect on normal spermatogenesis and can be linked to decreased male fertility. 
Lot of existing literatures had discussed the association between hypogonadism and type 2 diabetes. Some of the observer analyzed data from the multiple risk factor intervention trial for the prevention of coronary heart disease cohort and demonstrating a significant risk of developing type 2 diabetes among the participants who had low sex hormone binding globulins.  Some of the researchers found that low levels of sex hormone binding globulins and also low free testosterone values were predictive of developing type 2 diabetes mellitus in male aging study. , Although, all of the mentioned studies suggested that hypogonadism as a predictive factor of subsequent development of type 2 diabetes but the exact underlying pathophysiology has not been fully established till date. Insulin also alters the level of sex hormone binding globulin, by inhibiting its synthesis in the liver. This decrease in sex hormone binding globulin will cause more biologically active estrogen and less of bound estrogen in addition to the conversion of testosterone to estrogen.  However, a separate relationship between testosterone and insulin levels exists.  Insulin resistance might be a common causative factor for both hypogonadism and onset of type 2 diabetes mellitus. Although, in a study reported, type 2 diabetic male showed more of nuclear and mitochondrial DNA damage in sperm. 
Many studies were conducted in the patients with type 2 diabetes and reported higher rates of hypogonadism in males. In 1990, a group of researchers had studied over the serum testosterone and sex hormone binding globulin. They reported a significant lower level of these hormones in males with type 2 diabetes. This research was followed by another group of scientists and also found comparable results as previous one, these authors also investigated free testosterone and reported no difference in free testosterone, leuteinizing hormone, and follicle stimulating hormone levels in patients with type 2 diabetes. ,, The incidence of hypogonadism in 33% of type 2 diabetic males was recorded a decade back and also noted significant decrease in the level of follicle stimulating hormone and leuteinizing hormone in participants of hypogonadal group as compared with the eugonadal group.  Ultimately, all the above research was suggesting a substantial rate of hypogonadotropic hypogonadism among men with type 2 diabetes. Later on, increasing insulin resistance was found associated with decreased testosterone secretion at the by the Leydig cell and was not due to any changes in hypothalamic or pituitary function.  Although, these all studies are collectively demonstrate an association between type 2 diabetes and hypogonadism but, the specific propinquity between type 2 diabetes and hypogonadism is still not fully explicated and should be addressed in future studies.
Therapeutic metabolic effects of testosterone have been already demonstrated in males with type 2 dibetes and hypogonadism. An open-label, randomized controlled trial conducted in middle-aged obese males with type 2 diabetes and symptoms of androgen deficiency showed significant improvement in all of the parameters, when treated with testosterone undecanoate every day for the period of 3 months.  Specifically, patients experienced control in blood glucose levels and HbA1c values with improved symptoms of androgen deficiency. In a similar type of study, males with type 2 diabetes was given intramuscular testosterone 200 mg for every 2 weeks for 3 months, which demonstrated beneficial effects on blood sugar control, insulin resistance, total cholesterol, and visceral adiposity.  These studies exhibited a possible therapeutic role for testosterone in a male with type 2 diabetes and hypogonadism, with fine improvement in numerous metabolic deficiencies in concomitant individuals. Thereby, future studies evaluating the influence of such agents as the leuteinizing hormone agonist -human chorionic gonadotropin and the selective estrogen receptor modulator clomiphene citrate are requisite in order to assess efficacy in optimizing serum testosterone levels in such hypogonadal males with type 2 diabetes, as exogenous testosterone replacement therapy suppresses spermatogenesis, therefore, it is contraindicated in hypogonadal males struggling to achieve pregnancy. A higher sperm concentration and lower sperm motility was reported more in the cases of diabetic neuropathy as compare to the patients of type 2 diabetes without neuropathy was reported in a study.  Though it is limited but, the data suggested sperm dysfunction in some males with type 2 diabetes. The factors leading to contradictory increased sperm concentration in males with type 2 diabetes and neuropathy in this study were unclear, but the researcher observed a decreased semen volume in such groups, may indicate decreased seminal secretion and an overall concentration of the ejaculated sperm.
The erectile dysfunction, retrograde ejaculation, and failure of seminal emission are known complications of type 2 diabetes which have a major impact on male reproductive potential. Erectile dysfunction in the individuals with type 2 diabetes stems in part from autonomic neuropathy and vascular disease. Several studies have demonstrated an increased risk for erectile dysfunction in males with type 2 diabetes and increased its severity with worsening diabetes. ,,, About 32% of males with type 2 diabetes, affected by varying degree of autonomic neuropathy, which results in ejaculatory dysfunction such as, failure of emission and retrograde ejaculation.  The ejaculatory dysfunction may represent the most common cause of infertility in diabetic males.  Per se, clinicians evaluating diabetic patients with metabolic syndrome should obtain postejaculatory urinalysis to rule out retrograde ejaculation, if the clinical findings necessitate, like as a low ejaculatory volume. In this situation, certain tricyclic antidepressants (imipramine) and oral sympathomimetics (pseudoephedrine), sperm isolation from urine, assisted reproductive techniques, and electroejaculation may facilitate reproductive efforts in these types of patients.
Dyslipidemia is another guarding feature of metabolic syndrome which may have an impact on semen quality and fertility. Studies from 106 male partners of infertile couples have shown dyslipidemia in 65% (either hypercholesterolemia/triglyceridemia/both).  The incidence of overweight (30.2%), obesity (18%), systemic hypertension (26%), glucose intolerance (15%), and type 2 diabetes (4.7%) were also reported, although there was no correlation with sperm abnormalities was observed. Numerous authors have noted that increased oxidative stress are associated with obesity and its causative factors like insulin resistance and dyslipidemia. , This association is most likely the result of the higher than usual metabolic rates required to maintain normal biological processes and an increased level of stress in the local testicular microenvironment, both of which naturally produce reactive oxygen species (ROS). ROS is considered as an independent marker of male factor infertility, which can lead to damaged plasma membrane integrity, DNA damage, and deformity in sperm. Sperm mitochondrial genomes can also be damaged by ROS and results into alterations in normal sperm function and motility. Thereby, disturbing mitochondrial function and decreasing energy production and oxidative stress is involved in the pathophysiological mechanism of erectile dysfunction and might explain a higher incidence of this condition in obese type 2 diabetic individuals.  Even though, these studies suggested the association between lipid abnormalities and infertility but no clear mechanism was postulated till date. Withal oxidative stress is an attractive candidate as described earlier.
An animal study has supported the above hypothesis, in which the researchers have examined the effects of a high-cholesterol diet and anti-cholesterol therapy on male rat fertility. The findings of male rats fed with a high-cholesterol diet (1% by composition) had significant decline in fertility, sperm characteristics, and testicular weight as compared with the male rats with a cholesterol-free diet.  In addition, the researchers treated subgrouped male rats on a high-cholesterol diet with no-intervention, anti-oxidant group, hypolipidemic agent group, or both therapeutic agent group. The outcome of anti-oxidant group (a-tocopherol), hypolipidemic agent group (simvastatin), and its combination which significantly improved the fertility index (mating success rate) from 42.5% to 71.5%, 61.25%, and 79.5%, respectively. Improved fertility seen with combination therapy was significantly higher to simvastatin alone, but not with a-tocopherol alone. Moreover, all three treatment groups have demonstrated significant improvement in testicular weight, sperm viability, sperm motility, sperm count, and significantly decreased sperm idiosyncrasy. In this facet of the study, the combination therapy was superior to both individual therapies, which were not markedly different from one another. The researchers not only demonstrated decreased fertility with a high-cholesterol diet, but they also indicated therapeutic advantage in fertility with anti-oxidant and hypolipidemic agents. These outcomes support a probable role for dyslipidemia-induced oxidative stress in the testes and/ or excurrent ductal system, leading to deterioration in fertility.
| Hypertension and Infertility|| |
Hypertension is major risk factor for cardiovascular disease. Systemic blood pressure more than 130/ 85 is considered as hypertension according to ATP III criteria. Although, hypertension is a well-established risk factor for erectile dysfunction and have direct effect on male fertility. End organ damage is a well-documented eidolon of hypertension, but till date, testicular end-organ injury caused by hypertension has not been clearly outlined. Many studies have demonstrated a significant contrary relationship between systemic blood pressure and total serum testosterone, which could be linked with impaired reproductive potential, ,,, free testosterone, ,, and sex hormone binding globulin. ,, This observed relationship between increased blood pressure and decreased androgens is not straightforward, although some researchers suggested that, androgen deficiency may be the root cause of hypertension by inducing increased arterial stiffness.  Another studies demonstrated that male patients treated with androgen suppression have increased aortic and arterial stiffness as compared with age matched controls. , The studies examining the effects of anti-hypertensive agents on testosterone levels found treatment either decreases or has no influence on testosterone levels depending on the agent inutiles. ,,,, Till date, there is no such compelling data specifically linking hypertension with impairment of male reproductive potential, but this issue has not been properly investigated.
| Sleep Apnea and Infertility|| |
Sleep apnea is characterized by a fragmented sleep course owing to repeated episodes of upper airway obstructions and hypoxia, and is often diagnosed in obese and diabetic males. Patients with sleep apnea have a disrupted nightly rise in testosterone levels and, therefore, lower mean levels of testosterone and luteinizing hormone compared with controls. In a study into sleep apnea in obese, control and lean males, the researcher  concluded that the condition is associated with hypothalamic pituitary gonadal dysfunction and that the accompanying decline in testosterone concentrations is the result of obesity, and to a lesser degree, sleep fragmentation and hypoxia. This disturbance has been associated with abnormal spermatogenesis and male reproductive potential.
Metabolic syndrome and infertility: Based on evidence
In 2005, a study pointed that low levels of testosterone and sex hormone binding globulin were significantly correlated with metabolic syndrome and its integral components (BMI, waist-height ratio, and waist circumference).  A group of researchers in 2003 demonstrated that males with metabolic syndrome (as per WHO criteria) had 19% lower total testosterone, 11% lower calculated free testosterone, and 18% lower sex hormone binding protein than controls  and also found considerable association between metabolic syndrome and C-reactive protein (inflammatory marker), is implicated as another pathogenic correlate of this syndrome. , After the standardization of age and BMI the inverse correlation were found between free testosterone, total testosterone and sex hormone binding protein with insulin, glucose, and triglycerides levels. While as, total testosterone, free testosterone, and sex hormone binding proteins were also found to be directly correlated with high density lipoprotein levels. In addition, males with 1/3 low hormone levels from the normal were more prone to develop metabolic syndrome even in strictest modeling.
These results were strengthened by a recent study done in 2005,  they showed that bioavailable testosterone, total testosterone and sex hormone-binding globulin were inversely associated with several of the risk factors of metabolic syndrome as defined by the NCEP. The linear regression models demonstrated that bioavailable testosterone, total testosterone, and sex hormone-binding globulin were positively correlated with higher insulin sensitivity. In 2006, the another group of researchers found that total testosterone were negatively correlated with insulin level, insulin resistance, and BMI in male individuals with metabolic syndrome.  These observations are important when considering insulin resistance as the potential underlying disturbance in metabolic syndrome.
The baseline total serum testosterone in male participants was studied with two different lipid treatment.  The study group was divided according to presence or absence of metabolic syndrome. The observation made by using Pearson correlation coefficients and found an inverse correlation between BMI and serum testosterone in males with and without metabolic syndrome. In addition, multiple linear regression analysis among the 5 ATP III diagnostic criteria revealed significant negative relations between total serum testosterone level and triglyceride status (150 mg/dL vs. 150 mg/dL), BMI (30 kg/m 2 vs. 30 kg/m 2 ), and presence of diabetes.  In view of the obesity, type 2 diabetes, hypogonadism paradigm, it follows that hypogonadism is prevalent in few individuals with metabolic syndrome.
A final statement should be made regarding the increase in literature on the association of metabolic syndrome with erectile dysfunction, as it can damnify reproductive potentiality.  The worsening of erectile dysfunction with the severity of metabolic syndrome has been already demonstrated by many studies, , and erectile dysfunction may also be predictive of metabolic syndrome in many times.  The development of diabetes and erectile dysfunction are considered as same pathophysiology process with an supplementary role for hypogonadism in individuals with metabolic syndrome. , As recited earlier, the increased oxidative stress has potential pathophysiological role in causing erectile dysfunction in males with metabolic syndrome. The association of oxidative stress and erectile dysfunction is reviewed elsewhere.
| Conclusion|| |
Metabolic syndrome is an important global medical entity, as its harmful effects on patients are firmly established. The infertility in male population may represent another physiological abnormalities observed in some patients with metabolic syndrome. Currently, there is sufficient evidence to suggest a male infertility paradigm versus metabolic syndrome [Figure 1]. Obesity or overweight may result in elevated scrotal temperatures, impaired spermatogenesis, decreased sperm concentration and motility, increased sperm DNA damage, and hypogonadism. In a similar way, insulin resistance or type 2 diabetes may conduce to and compound this situation. Dyslipidemia with increased oxidative stress in the testicular microenvironment and excurrent ductal system may lead to further decrease in fertility capability. Additional studies are required to completely elucidate the pathophysiologic link between the components of metabolic syndrome and male infertility pattern.
|Figure 1: Male infertility pattern. Source: Reproduced from Kasturi et al. 2008|
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I want to acknowledge the idea and guidance given by my guide, Dr. Shantilata Patnaik and my seniors, Dr. Suhasini Dehury and Dr. Priti Das in finalizing this review manuscript.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Kaplan NM. The deadly quartet. Upper-body obesity, glucose intolerance, hypertriglyceridemia, and hypertension. Arch Intern Med 1989;149:1514-20.
Björntorp P. Visceral obesity: A "civilization syndrome". Obes Res 1993;1:206-22.
Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988;37:1595-607.
Björntorp P. Abdominal obesity and the metabolic syndrome. Ann Med 1992;24:465-8.
De Fronzo RA, Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidaemia, and artherosclerotic cardiovascular diseases. Diabetes Care 1991;14:173-94.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of The National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001;285:2486-97.
Sharma K, Behera R, Agrawal D, Kumar S. Metabolic syndrome: Evolution, etiopathogenesis and recent trends in its management. Res J Pharm Biol Chem Sci 2015;6:378-410.
Kasturi SS, Tannir J, Brannigan RE. The metabolic syndrome and male infertility. J Androl 2008;29:251-9.
Sharlip ID, Jarow JP, Belker AM, Lipshultz LI, Sigman M, Thomas AJ, et al.
Best practice policies for male infertility. Fertil Steril 2002;77:873-82.
Franks S. Polycystic ovary syndrome. N Engl J Med 1995;333: 853-61.
Wozniak SE, Gee LL, Wachtel MS, Frezza EE. Adipose tissue: The new endocrine organ? A review article. Dig Dis Sci 2009;54: 1847-56.
Wang P, Mariman E, Renes J, Keijer J. The secretory function of adipocytes in the physiology of white adipose tissue. J Cell Physiol 2008;216:3-13.
Trayhurn P, Beattie JH. Physiological role of adipose tissue: White adipose tissue as an endocrine and secretory organ. Proc Nutr Soc 2001;60:329-39.
Hofny ER, Ali ME, Abdel-Hafez HZ, Kamal Eel-D, Mohamed EE, Abd El-Azeem HG, et al.
Semen parameters and hormonal profile in obese fertile and infertile males. Fertil Steril 2010;94:581-4.
Jope T, Lammert A, Kratzsch J, Paasch U, Glander HJ. Leptin and leptin receptor in human seminal plasma and in human spermatozoa. Int J Androl 2003;26:335-41.
Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, et al.
Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 1996;334:292-5.
Isidori AM, Caprio M, Strollo F, Moretti C, Frajese G, Isidori A, et al.
Leptin and androgens in male obesity: Evidence for leptin contribution to reduced androgen levels. J Clin Endocrinol Metab 1999;84:3673-80.
Bhat GK, Sea TL, Olatinwo MO, Simorangkir D, Ford GD, Ford BD, et al.
Influence of a leptin deficiency on testicular morphology, germ cell apoptosis, and expression levels of apoptosis-related genes in the mouse. J Androl 2006;27:302-10.
Glass AR, Swerdloff RS, Bray GA, Dahms WT, Atkinson RL. Low serum testosterone and sex-hormone-binding-globulin in massively obese men. J Clin Endocrinol Metab 1977;45:1211-9.
Zumoff B, Strain GW, Miller LK, Rosner W, Senie R, Seres DS, et al.
Plasma free and non-sex-hormone-binding-globulin-bound testosterone are decreased in obese men in proportion to their degree of obesity. J Clin Endocrinol Metab 1990;71:929-31.
Amatruda JM, Harman SM, Pourmotabbed G, Lockwood DH. Depressed plasma testosterone and fractional binding of testosterone in obese males. J Clin Endocrinol Metab 1978;47:268-71.
Schneider G, Kirschner MA, Berkowitz R, Ertel NH. Increased estrogen production in obese men. J Clin Endocrinol Metab 1979;48:633-8.
Strain GW, Zumoff B, Kream J, Strain JJ, Deucher R, Rosenfeld RS, et al.
Mild Hypogonadotropic hypogonadism in obese men. Metabolism 1982;31:871-5.
Kley HK, Deselaers T, Peerenboom H, Krüskemper HL. Enhanced conversion of androstenedione to estrogens in obese males. J Clin Endocrinol Metab 1980;51:1128-32.
Pasquali R, Casimirri F, De Iasio R, Mesini P, Boschi S, Chierici R, et al.
Insulin regulates testosterone and sex hormone-binding globulin concentrations in adult normal weight and obese men. J Clin Endocrinol Metab 1995;80:654-8.
Plymate SR, Matej LA, Jones RE, Friedl KE. Inhibition of sex hormone-binding globulin production in the human hepatoma (Hep G2) cell line by insulin and prolactin. J Clin Endocrinol Metab 1988;67:460-4.
Seidell JC, Björntorp P, Sjöström L, Kvist H, Sannerstedt R. Visceral fat accumulation in men is positively associated with insulin, glucose, and C-peptide levels, but negatively with testosterone levels. Metabolism 1990;39:897-901.
Phillips GB. Relationship between serum sex hormones and the glucose-insulin-lipid defect in men with obesity. Metabolism 1993;42:116-20.
Vermeulen A, Kaufman JM, Giagulli VA. Influence of some biological indexes on sex hormone-binding globulin and androgen levels in aging or obese males. J Clin Endocrinol Metab 1996;81:1821-6.
Tsai EC, Matsumoto AM, Fujimoto WY, Boyko EJ. Association of bioavailable, free, and total testosterone with insulin resistance: Influence of sex hormone-binding globulin and body fat. Diabetes Care 2004;27:861-8.
Osuna JA, Gómez-Pérez R, Arata-Bellabarba G, Villaroel V. Relationship between BMI, total testosterone, sex hormone-binding-globulin, leptin, insulin and insulin resistance in obese men. Arch Androl 2006;52:355-61.
Jarow JP, Kirkland J, Koritnik DR, Cefalu WT. Effect of obesity and fertility status on sex steroid levels in men. Urology 1993;42:171-4.
Magnusdottir EV, Thorsteinsson T, Thorsteinsdottir S, Heimisdottir M, Olafsdottir K. Persistent organochlorines, sedentary occupation, obesity and human male subfertility. Hum Reprod 2005;20:208-15.
Fejes I, Koloszár S, Szöllosi J, Závaczki Z, Pál A. Is semen quality affected by male body fat distribution? Andrologia 2005;37: 155-9.
Kort HI, Massey JB, Elsner CW, Mitchell-Leef D, Shapiro DB, Witt MA, et al.
Impact of body mass index values on sperm quantity and quality. J Androl 2006;27:450-2.
Oliva A, Spira A, Multigner L. Contribution of environmental factors to the risk of male infertility. Hum Reprod 2001;16:1768-76.
Kodama H, Yamaguchi R, Fukuda J, Kasai H, Tanaka T. Increased oxidative deoxyribonucleic acid damage in the spermatozoa of infertile male patients. Fertil Steril 1997;68:519-24.
Twigg J, Fulton N, Gomez E, Irvine DS, Aitken RJ. Analysis of the impact of intracellular reactive oxygen species generation on the structural and functional integrity of human spermatozoa: Lipid peroxidation, DNA fragmentation and effectiveness of antioxidants. Hum Reprod 1998;13:1429-36.
Dandona P, Aljada A, Chaudhuri A, Mohanty P, Garg R. Metabolic syndrome: A comprehensive perspective based on interactions between obesity, diabetes, and inflammation. Circulation 2005; 111:1448-54.
Davì G, Falco A. Oxidant stress, inflammation and atherogenesis. Lupus 2005;14:760-4.
Hjollund NH, Bonde JP, Jensen TK, Olsen J. Diurnal scrotal skin temperature and semen quality. The Danish First Pregnancy Planner Study Team. Int J Androl 2000;23:309-18.
Shafik A, Olfat S. Scrotal lipomatosis. Br J Urol 1981;53:50-4.
Hammoud AO, Wilde N, Gibson M, Parks A, Carrell DT, Meikle AW. Male obesity and alteration in sperm parameters. Fertil Steril 2008;90:2222-5.
Shafik A, Olfat S. Lipectomy in the treatment of scrotal lipomatosis. Br J Urol 1981;53:55-61.
Nielsen ME, Zderic S, Freedland SJ, Jarow JP. Insight on pathogenesis of varicoceles: Relationship of varicocele and body mass index. Urology 2006;68:392-6.
Handel LN, Shetty R, Sigman M. The relationship between varicoceles and obesity. J Urol 2006;176:2138-40.
Prabakaran S, Kumanov P, Tomova A, Hubaveshki S, Agarwal A. Adolescent varicocele: Association with somatometric parameters. Urol Int 2006;77:114-7.
Schlesinger MH, Wilets IF, Nagler HM. Treatment outcome after varicocelectomy. A critical analysis. Urol Clin North Am 1994;21:517-29.
Barqawi A, Caruso A, Meacham RB. Experimental varicocele induces testicular germ cell apoptosis in the rat. J Urol 2004;171: 501-3.
Jung A, Schuppe HC. Influence of genital heat stress on semen quality in humans. Andrologia 2007;39:203-15.
Bener A, Al-Ansari AA, Zirie M, Al-Hamaq AO. Is male fertility associated with type 2 diabetes mellitus? Int Urol Nephrol 2009;41:777-84.
Agbaje IM, Rogers DA, McVicar CM, McClure N, Atkinson AB, Mallidis C, et al.
Insulin dependant diabetes mellitus: Implications for male reproductive function. Hum Reprod 2007; 22:1871-7.
Haffner SM, Shaten J, Stern MP, Smith GD, Kuller L. Low levels of sex hormone-binding globulin and testosterone predict the development of non-insulin-dependent diabetes mellitus in men. MRFIT Research Group. Multiple Risk Factor Intervention Trial. Am J Epidemiol 1996;143:889-97.
Stellato RK, Feldman HA, Hamdy O, Horton ES, McKinlay JB. Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: Prospective results from the Massachusetts male aging study. Diabetes Care 2000;23: 490-4.
Oh JY, Barrett-Connor E, Wedick NM, Wingard DL; Rancho Bernardo Study. Endogenous sex hormones and the development of type 2 diabetes in older men and women: The Rancho Bernardo study. Diabetes Care 2002;25:55-60.
Lima N, Cavaliere H, Knobel M, Halpern A, Medeiros-Neto G. Decreased androgen levels in massively obese men may be associated with impaired function of the gonadostat. Int J Obes Relat Metab Disord 2000;24:1433-7.
Barrett-Connor E, Khaw KT, Yen SS. Endogenous sex hormone levels in older adult men with diabetes mellitus. Am J Epidemiol 1990;132:895-901.
Andersson B, Mårin P, Lissner L, Vermeulen A, Björntorp P. Testosterone concentrations in women and men with NIDDM. Diabetes Care 1994;17:405-11.
Chang TC, Tung CC, Hsiao YL. Hormonal changes in elderly men with non-insulin-dependent diabetes mellitus and the hormonal relationships to abdominal adiposity. Gerontology 1994;40:260-7.
Dhindsa S, Prabhakar S, Sethi M, Bandyopadhyay A, Chaudhuri A, Dandona P. Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. J Clin Endocrinol Metab 2004;89:5462-8.
Pitteloud N, Hardin M, Dwyer AA, Valassi E, Yialamas M, Elahi D, et al.
Increasing insulin resistance is associated with a decrease in Leydig cell testosterone secretion in men. J Clin Endocrinol Metab 2005;90:2636-41.
Boyanov MA, Boneva Z, Christov VG. Testosterone supplementation in men with type 2 diabetes, visceral obesity and partial androgen deficiency. Aging Male 2003;6:1-7.
Kapoor D, Goodwin E, Channer KS, Jones TH. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol 2006;154:899-906.
Ali ST, Shaikh RN, Siddiqi NA, Siddiqi PQ. Semen analysis in insulin-dependent/non-insulin-dependent diabetic men with/without neuropathy. Arch Androl 1993;30:47-54.
Braun M, Wassmer G, Klotz T, Reifenrath B, Mathers M, Engelmann U. Epidemiology of erectile dysfunction: Results of the 'Cologne Male Survey'. Int J Impot Res 2000;12:305-11.
Johannes CB, Araujo AB, Feldman HA, Derby CA, Kleinman KP, McKinlay JB. Incidence of erectile dysfunction in men 40 to 69 years old: Longitudinal results from the Massachusetts male aging study. J Urol 2000;163:460-3.
Nicolosi A, Moreira ED Jr, Shirai M, Bin Mohd Tambi MI, Glasser DB. Epidemiology of erectile dysfunction in four countries: Cross-national study of the prevalence and correlates of erectile dysfunction. Urology 2003;61:201-6.
De Berardis G, Pellegrini F, Franciosi M, Belfiglio M, Di Nardo B, Greenfield S, et al.
Identifying patients with type 2 diabetes with a higher likelihood of erectile dysfunction: The role of the interaction between clinical and psychological factors. J Urol 2003;169: 1422-8.
Shaban S, Seaman E, Lipschultz LI. Treatment of abnormalities of ejaculation. In: Lipschultz LI, Howards SS, editors. Infertility in the Male. 3 rd
ed. St. Louis: Mosby Year Book; 1991. p. 423-38.
Sexton WJ, Jarow JP. Effect of diabetes mellitus upon male reproductive function. Urology 1997;49:508-13.
Ramírez-Torres MA, Carrera A, Zambrana M. High incidence of hyperestrogenemia and dyslipidemia in a group of infertile men. Ginecol Obstet Mex 2000;68:224-9.
Agarwal A, Nandipati KC, Sharma RK, Zippe CD, Raina R. Role of oxidative stress in the pathophysiological mechanism of erectile dysfunction. J Androl 2006;27:335-47.
Shalaby MA, el-Zorba HY, Kamel GM. Effect of alpha-tocopherol and simvastatin on male fertility in hypercholesterolemic rats. Pharmacol Res 2004;50:137-42.
Khaw KT, Barrett-Connor E. Blood pressure and endogenous testosterone in men: An inverse relationship. J Hypertens 1988; 6:329-32.
Fogari R, Preti P, Derosa G, Marasi G, Zoppi A, Rinaldi A, et al.
Effect of antihypertensive treatment with valsartan or atenolol on sexual activity and plasma testosterone in hypertensive men. Eur J Clin Pharmacol 2002;58:177-80.
Fogari R, Zoppi A, Preti P, Rinaldi A, Marasi G, Vanasia A, et al.
Sexual activity and plasma testosterone levels in hypertensive males. Am J Hypertens 2002;15:217-21.
Hughes GS, Mathur RS, Margolius HS. Sex steroid hormones are altered in essential hypertension. J Hypertens 1989;7:181-7.
Svartberg J, von Mühlen D, Schirmer H, Barrett-Connor E, Sundfjord J, Jorde R. Association of endogenous testosterone with blood pressure and left ventricular mass in men. The Tromsø Study. Eur J Endocrinol 2004;150:65-71.
Li C, Ford ES, Li B, Giles WH, Liu S. Association of testosterone and sex hormone-binding globulin with metabolic syndrome and insulin resistance in men. Diabetes Care 2010; 33:1618-24.
Le TN, Nestler JE, Strauss JF 3 rd
, Wickham EP 3 rd
. Sex hormone-binding globulin and type 2 diabetes mellitus. Trends Endocrinol Metab 2012;23:32-40.
Dockery F, Bulpitt CJ, Donaldson M, Fernandez S, Rajkumar C. The relationship between androgens and arterial stiffness in older men. J Am Geriatr Soc 2003;51:1627-32.
Dockery F, Bulpitt CJ, Agarwal S, Rajkumar C. Testosterone suppression in men with prostate cancer is associated with increased arterial stiffness. Aging Male 2002;5:216-22.
Dockery F, Rajkumar C, Agarwal S, Waxman J, Bulpitt CJ. Androgen deprivation in males is associated with decreased central arterial compliance and reduced central systolic blood pressure. J Hum Hypertens 2000;14:395-7.
Andersen P, Seljeflot I, Herzog A, Arnesen H, Hjermann I, Holme I. Effects of doxazosin and atenolol on atherothrombogenic risk profile in hypertensive middle-aged men. J Cardiovasc Pharmacol 1998;31:677-83.
Suzuki H, Tominaga T, Kumagai H, Saruta T. Effects of first-line antihypertensive agents on sexual function and sex hormones. J Hypertens Suppl 1988;6:S649-51.
Koshida H, Takeda R, Miyamori I. Lisinopril decreases plasma free testosterone in male hypertensive patients and increases sex hormone binding globulin in female hypertensive patients. Hypertens Res 1998;21:279-82.
Luboshitzky R, Lavie L, Shen-Orr Z, Herer P. Altered luteinizing hormone and testosterone secretion in middle-aged obese men with obstructive sleep apnea. Obes Res 2005;13:780-6.
Makhsida N, Shah J, Yan G, Fisch H, Shabsigh R. Hypogonadism and metabolic syndrome: Implications for testosterone therapy. J Urol 2005;174:827-34.
Laaksonen DE, Niskanen L, Punnonen K, Nyyssönen K, Tuomainen TP, Salonen R, et al.
Sex hormones, inflammation and the metabolic syndrome: A population-based study. Eur J Endocrinol 2003;149:601-8.
Malik S, Wong ND, Franklin S, Pio J, Fairchild C, Chen R. Cardiovascular disease in U.S. patients with metabolic syndrome, diabetes, and elevated C-reactive protein. Diabetes Care 2005;28: 690-3.
Haffner SM. The metabolic syndrome: Inflammation, diabetes mellitus, and cardiovascular disease. Am J Cardiol 2006;97: 3A-11A.
Muller M, Grobbee DE, den Tonkelaar I, Lamberts SW, van der Schouw YT. Endogenous sex hormones and metabolic syndrome in aging men. J Clin Endocrinol Metab 2005;90:2618-23.
Robeva R, Kirilov G, Tomova A, Kumanov P. Low testosterone levels and unimpaired melatonin secretion in young males with metabolic syndrome. Andrologia 2006;38:216-20.
Kaplan SA, Meehan AG, Shah A. The age related decrease in testosterone is significantly exacerbated in obese men with the metabolic syndrome. What are the implications for the relatively high incidence of erectile dysfunction observed in these men? J Urol 2006;176 (4 Pt 1):1524-7.
Esposito K, Giugliano F, Martedì E, Feola G, Marfella R, D'Armiento M, et al.
High proportions of erectile dysfunction in men with the metabolic syndrome. Diabetes Care 2005;28:1201-3.
Demir T, Demir O, Kefi A, Comlekci A, Yesil S, Esen A. Prevalence of erectile dysfunction in patients with metabolic syndrome. Int J Urol 2006;13:385-8.
Corona G, Mannucci E, Schulman C, Petrone L, Mansani R, Cilotti A, et al.
Psychobiologic correlates of the metabolic syndrome and associated sexual dysfunction. Eur Urol 2006;50: 595-604.
Kupelian V, Shabsigh R, Araujo AB, O'Donnell AB, McKinlay JB. Erectile dysfunction as a predictor of the metabolic syndrome in aging men: Results from the Massachusetts Male Aging Study. J Urol 2006;176:222-6.
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