The metabolic syndrome (MetS) has become one of the major public health challenges worldwide. Emerging data have now clearly demonstrated its impact on male sexual function. The MetS appears to be strongly related to erectile dysfunction as well as hypogonadism. Few randomized studies exist to guide treatment of sexual dysfunction related to MetS; rather, most studies have been observational in nature. Medical therapy has formed the mainstay of treatment, with the advent of surgical intervention as a more recent phenomenon.
The global epidemic of obesity and diabetes has led to a striking increase in the number of people afflicted with the metabolic syndrome (MetS). The MetS, or Syndrome X, consists of a constellation of abnormalities, including central obesity, glucose intolerance, dyslipidemia, and hypertension (HTN). These comorbidities constitute major risk factors for atherosclerosis and subsequent cardiovascular disease. Although interest in the MetS initially arose because of its association with cardiovascular disease, subsequent data have emerged pointing to a clear relationship with male sexual dysfunction. This review attempts to synthesize the data linking MetS and its impact on male sexual function.
Definitions
Definitions for the MetS are heterogeneous, as multiple sets of diagnostic criteria were initially created to identify insulin-resistant subjects or to predict clinical events, such as cardiovascular disease. At present, 5 separate definitions for MetS exist ( Table 1 ): the World Health Organization (WHO) working definition (1999), the European Group for the Study of Insulin Resistance definition (1999), the American Association of Clinical Endocrinologists position statement (2003), the Adult Treatment Panel III (ATP III) guideline (2005), and the definition from the International Diabetes Federation Consensus Group (2005). Each of these definitions share certain common elements, such as criteria relating to obesity, hyperglycemia, dyslipidemia, and hypertension, but the laboratory value thresholds and the number of positive criteria required for diagnosis differ according to definition. The ATP III definition is the one most commonly used today as it incorporates key concepts of MetS, relies on frequently used laboratory studies, and is less restrictive than the other classifications. For the purposes of this review, the ATP III criteria have also been found to be the best predictors of arteriogenic erectile dysfunction (ED) and male hypogonadism.
| World Health Organization criteria (1999) | Presence of one of the following: diabetes mellitus, impaired glucose tolerance, impaired fasting glucose or insulin resistance, AND at least 2 of the following: |
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| European Group for the Study of Insulin Resistance (1999) | Insulin resistance defined as the top 25% of the fasting insulin values among nondiabetic individuals AND at least 2 of the following: |
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| American Association of Clinical Endocrinologists Position Statement (2003) |
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| US National Cholesterol Education Program Adult Treatment Panel III (2005) |
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| International Diabetes Federation (2005) | Central obesity AND at least 2 of the following: |
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Epidemiology
WHO global estimates for obesity in 2005 reported approximately 400 million obese adults, or 9.8% of the population. In the United States, this prevalence is expected to increase 40% for men by 2020, with the greatest increase in the superobese, that is, body mass index (BMI; calculated as the weight in kilograms divided by height in meters squared, ie, kg/m 2 ) of 50 or greater. Correspondingly, the prevalence of the MetS in the United States has risen to approximately 35% to 39% of the current adult population. The pediatric population has startlingly reflected this trend as well, with a doubling of overweight children in the past 30 years; this obesity is also associated with MetS features such as HTN, type 2 diabetes mellitus (DM2), and insulin resistance.
Epidemiology
WHO global estimates for obesity in 2005 reported approximately 400 million obese adults, or 9.8% of the population. In the United States, this prevalence is expected to increase 40% for men by 2020, with the greatest increase in the superobese, that is, body mass index (BMI; calculated as the weight in kilograms divided by height in meters squared, ie, kg/m 2 ) of 50 or greater. Correspondingly, the prevalence of the MetS in the United States has risen to approximately 35% to 39% of the current adult population. The pediatric population has startlingly reflected this trend as well, with a doubling of overweight children in the past 30 years; this obesity is also associated with MetS features such as HTN, type 2 diabetes mellitus (DM2), and insulin resistance.
Sexual dysfunction
A major limitation of the literature surrounding the impact of the MetS on sexual dysfunction revolves around the relative paucity of randomized trials. For example, no level 1 data exist regarding the impact of surgical treatment for the MetS on sexual function. Most data have therefore been drawn from cross-sectional or longitudinal studies, where association but not causation has been observed. In addition, the multiple definitions of the MetS have led to a lack of uniformity in how the MetS is diagnosed in relation to patients with sexual dysfunction.
This article addresses sexual dysfunction as related to the MetS by stratification into two main categories, ED versus male hypogonadism or androgen deficiency. Although data in the literature have yet to support a causal relationship, the elements underlying the MetS are closely related with those of male sexual dysfunction and, in fact, successful treatment of the latter may influence the natural history of the former. Pathophysiologic mechanisms are explored here, as well as potential therapeutic paradigms.
Erectile Dysfunction
Multiple cross-sectional studies have documented a concordance between the causes of ED and cardiovascular disease, that is, elements common to the MetS. This concordance was first reported by Gunduz and colleagues who reported a 100% prevalence of the MetS in all 38 study patients with ED. In a cross-sectional study of 2371 men, Heidler and colleagues noted that presence of the MetS, DM2, elevated waist-to-hip ratio, and HTN correlated with ED severity as defined by International Index of Erectile Function (IIEF) score, particularly in men older than 50 years. Bal and colleagues demonstrated in a group of 393 men that the risk of ED increased with the number of MetS components, specifically waist circumference (WC) (odds ratio [OR] = 1.94), increased WC plus abnormal high-density lipoprotein (HDL) or triglyceride (TG) level (OR = 2.97), and increased WC plus pathologic HDL and TG (OR = 3.38). Demir and colleagues demonstrated in a group of 89 patients with the MetS that ED as measured by IIEF–erectile function domain scores was correlated with the number of metabolic risk factors. Those with elevated fasting blood glucose, WC, or HTN had poorer erectile function compared with patients with other metabolic risk factors. It is interesting that Kupelian and colleagues, using data from the Massachusetts Male Aging Study, have also demonstrated that the presence of MetS is associated with increased ED risk (relative risk = 2.09) even in those with a BMI of less than 25.
Erectile Dysfunction: Mechanisms and Pathophysiology
The MetS may lead to ED through multiple mechanisms ( Table 2 ). Hypogonadism, which may be caused by the MetS, can lead to secondary ED through altered testosterone (T):estrogen levels. Corona and colleagues, for example, demonstrated that low T levels were associated with greater WC and prevalence of MetS in a series of 1647 men with sexual dysfunction; T levels were inversely related to the severity of ED and directly related to the magnitude of penile blood flow in the oldest quartile of patients. T may affect the ability to achieve erections by helping to stimulate the expression of nitric oxide (NO) synthase and thereby increase the availability of NO in cavernosal tissue. Atherosclerotic disease stemming from the same disease processes underlying the MetS may also lead to ED by affecting the vascular tissues of the penis. Indeed, ED could be seen as a marker for occult coronary artery disease in otherwise asymptomatic men. Blumentals and colleagues, for example, studied 12,285 men from the Integrated Healthcare Information Services National Managed Care Benchmark Database, demonstrating that men with ED had an almost twofold risk for acute myocardial infarction, even after adjustment for age at ED diagnosis, smoking, obesity, and use of angiotensin-converting enzyme inhibitors, β-blockers, and statins. Atherosclerosis can also lead to structural damage within the penile tissues. For example, Nehra and colleagues demonstrated induction of penile smooth muscle atrophy and fibrosis in rabbit models for hypercholesterolemia and atherosclerosis. Koca and colleagues reported on the relationship of the MetS on veno-occlusive dysfunction associated with ED in a group of 163 men. The MetS can also lead to endothelial dysfunction, which has been implicated in vascular disorders. Hyperglycemia, for example, induces a series of cellular events that increase the production of reactive oxygen species such as superoxide anion that (1) inactivates NO to form peroxynitrite and (2) increases oxygen-derived free radicals through activation of protein kinase C and other cellular elements. Endothelial dysfunction therefore leads to a decrease in vascular NO levels, with resulting impaired vasodilation; the increase in free radical concentration also leads to atherosclerotic damage. NO has been implicated in inhibiting platelet and leukocyte adhesion to vascular walls as well as decreasing smooth muscle proliferation. Hyperglycemia can also lead to glycation of penile cavernosal tissue, leading to an impairment of collagen turnover and, potentially, ED. Proinflammatory states, such as those found with DM2, can also lead to endothelial dysfunction through upregulation of E-selectin and altered tumor necrosis factor (TNF)-α:interleukin (IL)-10 ratio. On a clinical basis, Pohjantähti-Maaroos and colleagues reported on a group of 70 men with the MetS, where ED was shown to be correlated with decreased large arterial elasticity, independently of traditional cardiovascular risk factors. Long-standing diabetic neuropathy may also lead to urogenital sensory neuropathy, as reported in a series of 159 men by Bemelmans and colleagues. The use of β-blockers for hypertension can also contribute to ED.
| Mechanism | Comment |
|---|---|
| Hypogonadism | Altered testosterone:estrogen levels leads to hypogonadotropic hypogonadism; lowered testosterone leads to decrease in NO synthesis |
| Atherosclerosis | Damage to penile vasculature and cavernosal tissue leads to erectile dysfunction |
| Endothelial dysfunction | Decreased NO synthesis inhibits vasodilation; increased free radical production leads to atherosclerotic damage |
| Hyperglycemia | Glycation damage to penile tissues with resulting decrease in elasticity |
| Urogenital sensory neuropathy | Alteration in neural signaling to penis |
| Medications (eg, β-blockers) | Iatrogenically induced erectile dysfunction |
Male Hypogonadism/Androgen Deficiency
Male hypogonadism, or androgen deficiency, has been defined by some investigators as total T levels 2.5 standard deviations below the mean in young adults or less than 319 ng/dL (11 nmol/L), although clinical criteria are more ambiguous. Symptoms of hypogonadism include sexual dysfunction, fatigue, depression, irritability, hot flushes, decreased bone density, anemia, decreased lean body mass, and increased body fat. The MetS has been associated with low T levels, with a particular effect in aging males. Growing evidence now points to several potential mechanisms ( Table 3 ).
| Mechanism | Comment |
|---|---|
| Increased leptin levels | Decreased Leydig cell production of testosterone |
| Inflammation | Increased interleukin-1β, interleukin-6, and tumor necrosis factor α, leading to inhibition of testosterone production |
| Increased aromatase activity | Increased conversion of testosterone to estradiol leading to negative feedback on hypothalamus and hypogonadotropic hypogonadism |
The first mechanism through which MetS may influence male hypogonadism is via leptin, a protein synthesized by adipocytes that regulates energy intake and use through influence over the hypothalamus. Serum leptin levels have been shown to be directly correlated to BMI. In addition, Luukkaa and colleagues demonstrated in a cross-sectional study of 269 Turkish men that serum leptin levels varied inversely with T levels even after adjustment for BMI and insulin levels; administration of T to a cohort of 10 young men suppressed leptin levels until cessation of drug. Similar results were reported by Isidori and colleagues in a group of 28 obese men compared with age-matched controls. Increased levels of leptin released as a result of increased obesity associated with the MetS may therefore decrease T levels, likely through a functional leptin receptor isoform on Leydig cells. From a treatment perspective, T replacement or supplementation may decrease leptin levels and, therefore, obesity.
The MetS also causes a low-grade proinflammatory state, which may also lead to or exacerbate hypogonadism. The inflammatory state created by the MetS is associated with increased levels of cytokines, specifically IL-1β, IL-6, and TNF-α, which inhibit T production. TNF-α inhibits steroidogenesis at the nuclear receptor level, whereas IL-1 inhibits cholesterol side chain cleavage by cytochrome P450 in Leydig cells.
The MetS is also associated with increased central obesity, which results in an increase in aromatase activity, facilitating the conversion of T to estradiol (E 2 ). Patients with the MetS should therefore have lower T:E 2 levels compared with controls. This finding has been confirmed by groups such as Vermeulen and colleagues, who have demonstrated that obese men (BMI >35) have significantly lower T and higher plasma E 2 levels compared with controls. These obese men were also found to have a lower mean diurnal luteinizing hormone (LH) (LH level, LH pulse amplitude, and sum of LH pulse amplitudes); indeed, the decrease in LH pulse amplitudes was directly associated with lower T levels. This situation results in a functional state of isolated hypogonadotropic hypogonadism, likely stemming from the negative feedback of estrogen on the hypothalamus. From a therapeutic point of view, Zumoff and colleagues have studied the use of the aromatase antagonist testolactone in 6 obese men (BMI 38–73) with hypogonadotropic hypogonadism, demonstrating a decrease in E 2 levels (from 40 to 29 pg/mL) with a corresponding increase in both LH (from 14.4 to 19.3 mIU/mL) and mean T levels (from 290 to 403 ng/dL), supporting the suppressive role of estrogens in pituitary gonadotropin production in obese males. Overall, the altered T:E 2 levels in patients with MetS can also cause further excessive visceral adipose deposition, leading to additional elevated aromatase activity, creating a positive-feedback loop, termed the “hypogonadal-obesity cycle.” This process has been demonstrated in studies such as those by Kupelian and colleagues where hypogonadism was associated with a higher risk of developing MetS over time, particularly in nonoverweight, middle-aged men.
Treatment
Nonsurgical
Medical, or nonsurgical treatment, for sexual dysfunction associated with the MetS can target (1) the sexual symptoms resulting from the MetS as well as (2) different components of the MetS, for example, central obesity, hypertension, and insulin resistance.
At present, no direct pharmacologic treatment for the MetS exists; rather, lifestyle modifications in the form of diet change and physical exercise represent the foundation of therapy. Lifestyle modifications have been shown to improve endothelial function, decrease inflammatory marker levels, and prevent diabetes. Specifically, Esposito and colleagues studied 55 obese men with ED randomized to weight loss via reduction of caloric intake and increase in physical activity in comparison with a control group of 55 men. In addition to reduction in BMI, men in the treatment group showed improvement erectile function as measured by IIEF score. These men also showed reductions in IL-6 and C-reactive protein (CRP) levels, markers of inflammation. Changes in BMI, physical activity, and CRP levels in this study were independently associated with improvement in erectile function. Esposito and colleagues also showed in a randomized, single-blind trial of 180 patients that the use of the Mediterranean-style diet, which consists of foods containing higher levels of phytochemicals, antioxidants, α-linolenic acid, and fiber (ie, fruits, vegetables, nuts, whole grains, and olive oil), is effective in reducing the prevalence of the MetS and its associated cardiovascular risk. Follow-up studies further demonstrated that adherence to the diet resulted in improvements in erectile function after 2 years. Smoking cessation can also reduce oxidative damage from carbon monoxide and increases the ratio of HDL to low-density lipoprotein (LDL) cholesterol, reducing atherosclerotic disease. General principles to treat the different components of the MetS also include control of hypertension, hyperlipidemia, and insulin resistance. Antihypertensive therapy should reduce blood pressure as close as possible to 120/80 mm Hg or lower. Statins should be used to reduce cholesterol levels. Medications such as metformin and thiazolidinediones, which reduce insulin resistance, can help regulate glucose metabolism. Of interest, Kim and colleagues demonstrated that metformin activates adenosine monophosphate–activated protein kinase, thereby increasing the expression of neuronal and endothelial NO synthase, thus restoring NO synthase expression in penile tissue in mice and thus implying a potential benefit in humans.
Treatment of specific elements of sexual dysfunction include phosphodiesterase (PDE)-5 inhibitor and T replacement therapy (TRT) to address ED, and with the latter, hypogonadism as well. Sildenafil represents the prototypical PDE-5 inhibitor. The performance of sildenafil in specific patient groups was examined in a meta-analysis of 11 randomized, controlled trials by Carson and colleagues in 2002. Improvements in erectile function were found in 59% of patients with type 1 diabetes and 63% of patients with DM2, regardless of age, race, severity of ED, or the presence of various comorbidities. These response rates to sildenafil, however, were inferior to those in patients without diabetes (83%). The 2 other current PDE-5 inhibitors are tadalafil and vardenafil. Brock and colleagues demonstrated a similar response with tadalafil in patients with diabetes. In a study of 1112 men with mild to severe ED due to various causes, 58% of patients with diabetes achieved erections sufficient for intercourse, compared with 75% of men without diabetes. PDE-5 inhibitors are contraindicated in patients using nitrates, due to risk of orthostatic hypotension. Vardenafil is also not recommended in patients taking type 1A or type 3 antiarrhythmics.
TRT can alleviate hypogonadism and thereby also help treat ED, in addition to having ancillary side effects on aspects of the MetS. Kapoor and colleagues reported on 24 hypogonadal men with diabetes in a double-blind, placebo-controlled trial treated with intramuscular T versus placebo every 2 weeks for a total of 3 months. Treatment with T resulted in improvement in hemoglobin A 1c (HbA 1c ) (−0.37% ± 0.17%, P = .03), fasting blood glucose (−1.58 ± 0.68 mmol/L, P = .03), in addition to homeostasis model assessment (HOMA) index and cholesterol (−0.4 ± 0.17 mmol/L, P = .03) levels. Reductions in WC (−1.63 ± 0.71 cm, P = .03) and waist-to-hip ratio (−0.03 ± 0.01, P = .01) were also seen. Boyanov and colleagues reported on 48 men with DM2 and mild androgen deficiency in an open-label study where half of the patients were given T undecanoate and the other half placebo. Treatment with T resulted in statistically significant reductions in body weight (2.66%), waist-to-hip ratio (−3.96%), and body fat (−5.65%), in addition to improvement in HbA 1c from 10.4% to 8.6%. These results were echoed by Saad and colleagues, who found that administration of T undecanoate over a 12-month period improved WC, plasma cholesterol, LDL, and HDL, with no side effects. Similar results, namely, improvements in WC, percentage of body fat, and total as well as LDL cholesterol, were found by Permpongkosol and colleagues with similar medication in a group of 161 men with symptomatic late-onset hypogonadism. The impact of TRT was summarized in a meta-analysis of 5 randomized controlled trials by various groups who demonstrated significant improvements in fasting plasma glucose, HOMA index, triglycerides, HDL cholesterol, and WC, although not total cholesterol, blood pressure, or BMI. The use of T, however, has not been without its potential side effects. Basaria and colleagues, for example, reported on the use of T supplementation to increase muscle mass and strength in 209 hypogonadal men (total serum T 100–350 ng/dL or free serum T <50 pg/mL) aged 65 years and older with limitations in mobility. In a population with a relatively high prevalence of cardiovascular disease (47%–53%), diabetes (24%–27%), hyperlipidemia (50%–63%), and obesity (45%–49%), patients treated with transdermal T demonstrated an elevated risk for cardiovascular and dermatologic events (hazard ratio = 5.8) although greater increases in leg-press and chest-press strength and stair-climbing ability while carrying a load were seen. Because the trial was small in size and limited to a highly selected population, caution should be taken in administering T therapy. Overall, the small number of studies demonstrating the impact of TRT on insulin resistance or other elements of the metabolic syndrome in addition to the potential for deleterious effects in certain populations has led multiple organizations to not recommend such treatment in patients with MetS or DM2 in the absence of hypogonadism. An ancillary method of treating the hypogonadotropic hypogonadism seen with the MetS includes the use of the aromatase inhibitor letrozole. Loves and colleagues reported on an open-label 6-month uncontrolled trial in which 12 severely obese patients (BMI >35 kg/m 2 ) with hypogonadotropic hypogonadism were treated with 2.5 mg of letrozole weekly for 6 months. Use of letrozole produced a sustained normalization of serum total T, although free T levels rose to supraphysiologic levels in 7 of 12 (58%) men.
Surgical
Bariatric surgery represents an effective method to treat morbid obesity, albeit in highly selected patients. Patients must be motivated and able to participate in treatment and long-term follow-up, with clear and realistic expectations for how their lives may change after surgery. As per the American Society for Metabolic and Bariatric Surgery “Rationale for the Surgical Treatment of Morbid Obesity” statement, patients whose BMI exceeds 40 are potential candidates for surgery if they strongly desire substantial weight loss because their obesity severely impairs the quality of their lives. Bariatric surgery may be considered in less severely obese patients (BMI 35–40) with high-risk comorbidities such as life-threatening cardiopulmonary problems (eg, severe sleep apnea, Pickwickian syndrome, obesity related cardiomyopathy, or severe diabetes mellitus) or obesity-induced physical problems that are interfering with their lifestyle.
Several studies have demonstrated that surgically induced weight loss can benefit sexual function. Camps and colleagues reported on a group of 94 patients who had undergone bariatric surgery and who experienced improvements in body image, enjoyment of sexual intercourse, and quality of orgasm, echoing earlier reports by Hafner and colleagues and Gahtan and colleagues. More recently, Dallal and colleagues studied the use of gastric bypass surgery in 97 male patients with morbid obesity. Increasingly heavier patients reported greater sexual dysfunction as measured by the Brief Male Sexual Function Inventory (BMSFI), but the amount of weight loss after bariatric surgery was significantly correlated with the subsequent degree of improvement in sexual function. Patients experienced improvements in sexual drive, erectile function, ejaculatory function, problem assessment, and sexual satisfaction after surgery, with BMSFI scores approaching those of reference controls after an average 67% excess weight loss. The role of weight loss by bariatric surgery on sexuality, however, is also incompletely studied, and one study demonstrating a negative effect on sexual function has been reported. Di Frega and colleagues, for example, reported on secondary nonobstructive azoospermia with complete spermatogenic arrest in 6 previously fertile male patients who had undergone Roux-en-Y gastric bypass. Although gastric bypass provided sustained weight loss of 60 to 80 kg postoperatively, the nonobstructive azoospermia observed in these patients is concerning. The investigators hypothesized that this was likely secondary to nutritional deficiencies resulting from the bypass.
Surgery specific for ED can also be performed. The introduction of the intrapenile prosthesis (IPP) by Scott and colleagues formed the advent of prosthetic surgery for ED. The malleable penile prosthesis consists of a semirigid device with a central core allowing for the penis to be bent down for dressing and bent upward for coitus. The positionable penile prosthesis (Dura II; American Medical Systems Inc, Minnetonka, MN)) is a semirigid device with a series of articulating segments held together with a spring on each end. The two-piece inflatable penile prosthesis (Genesis; Coloplast Corporation, Minneapolis, MN, and Ambicor; American Medical Systems Inc.) consists of two cylinders connected to a small scrotal pump allowing for easier implantation, but with the disadvantage of increased mechanical failure. The 3-piece inflatable penile prosthesis (Titan; Coloplast Corporation, and AMS 700; American Medical Systems Inc) possesses paired corporeal cylinders, a scrotal pump, and an abdominal fluid reservoir to most closely replicate penile flaccidity and erection.
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