Obesity and Male Genitourinary Disorders

by Mostafa Elmissiry, MD; Ayman Mahdy, MD; Gamal Ghoniem, MD, FACS

All authors are from Cleveland Clinic Florida.

Introduction
In the United States, most of the 10 leading causes of death are associated with obesity. Cardiovascular diseases, cancer, stroke, respiratory failure, and diabetes mellitus are all linked to obesity, making it, in aggregate, the leading preventable cause of death in the US, exceeding smoking, according to recent statistics.1 Obese patients have numerous other associated diseases or comorbidities, such as hypertension, thromboembolism, low back pain, osteoarthritis, and depression, all of which contribute substantially to overall healthcare expenditures.1

In this article, we will address specific male health problems that are closely related to obesity and greatly modifiable with treatment of obesity. These health problems include the following: lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH), sexual dysfunction, fertility problems, and genitourinary malignancy.

Obesity and LUTS/BPH
Obese men usually develop metabolic syndrome. This syndrome is characterized by overweight, visceral abdominal fat distribution, dyslipidemia, hypertension, impaired glucose metabolism, autonomic sympathetic hyperactivity, and increased c-reactive proteins. Recently, increasing evidence has pointed toward a relationship between LUTS/BPH and the presence of metabolic syndrome. This relationship has been supported by recent epidemiologic findings.2

Haidinger and colleagues examined risk factors for LUTS in elderly men using the International Prostate Symptom Score. The data of 1,557 men demonstrated an association of age, obesity, smoking, hypertension, and alcohol consumption with LUTS.3

Soygur and colleagues examined the association between obesity and prostatic enlargement, in addition to serum levels of estradiol and testosterone. They reported an increase in the larger adenomas with increasing obesity, but no increase in symptom score. In addition, they found significantly elevated estradiol levels, thought to be caused by the aromatization of testosterone to estrogen in adipose tissue.4

An association between abdominal obesity and increasing serum insulin levels was reported by Dahle and colleagues with its impact on benign prostatic hyperplastic tissue (BPH).5 Hammarsten and colleagues also confirmed the association between BPH and obesity.6

Rohrman and colleagues studied the association of components of the metabolic syndrome with lower urinary tract symptoms (LUTS), which often result from prostate enlargement and heightened tone of prostate and bladder smooth muscle. They did a third National Health and Examination Survey (NHANES III), from which LUTS cases and controls were selected. A total of 2,372 men ages 60 and over were included. They found a strong correlation between LUTS/BPH and diabetes (Odds Ratio [OR]=1.67), hypertension (OR=1.76), and increased body mass index (OR=1.65). The odds of LUTS increased with increasing glycosylated hemoglobin (P-trend=0.005). They also found that men classified as having three or more components of the metabolic syndrome had an increased odds of LUTS/BPH (OR=1.80).7

Multiple pathophysiologic mechanisms (table1.jpg) have been postulated to explain the relationship between metabolic syndrome and LUTS/BPH. These include low grade inflammation, hormonal disturbance, sympathetic hyperactivity, direct effect of hyperinsulinemia, and osmotic diuresis from glucosuria.2

Central obesity usually leads to increased level of C-reactive protein, Interlukin-6, and leucocytes. These factors can produce insulin resistance with subsequent hyperinsulinemia. Hyperinsulinemia has a direct effect on tissue growth factors (TGF), increasing their levels in prostatic tissue leading to prostatic enlargement and LUTS.2

Another possible mechanism is autonomic sympathetic overactivity, which results from central obesity, hyperinsulinemia, and decreased physical activity. Animal studies support a link between autonomic nervous system (ANS) overactivity and the development of urinary symptoms, low bladder compliance, and compensatory prostatic hyperplasia. ANS overactivity plays a key role in increasing the severity of LUTS in each BPH patient.8

Obesity and Sexual Dysfunction
In general, aging, diabetes mellitus, and atherosclerosis all play a role in the development of sexual dysfunction. In obese men, a number of different sexual difficulties are more frequently encountered than in non-obese men. These include erectile dysfunction (ED), difficulties in penetration with lack of orgasm, decreased intercourse frequency, reduced sexual desire, premature ejaculation, and lack of perceived sexual satisfaction.9

Many studies are done to detect the relationship between obesity and sexual dysfunction in men. Bacon and colleagues did the largest and most comprehensive study, which included 31,742 men from the Health Professionals Follow-up Study in US, 53 to 90 years of age (all without ED at baseline). The study showed an OR of 1.4 of developing ED with obesity (defined as BMI>28.7kg/m2).10

Gunduz and colleagues examined 79 patients (ages 31–74 years) with coronary artery disease and lipid metabolism disorders. Twenty-three were obese and all but one (95.6%) had ED (P>0.001). Additionally, among overweight (n=33), 70 percent had ED, whereas the fraction of the normal weight patients (n=23) with ED was 60 percent. Chung and colleagues12 evaluated 325 patients with ED and stratified them according to body weight. They found a statistically significant decrease in the quality of erectile function in patients with obesity.11

Mechanisms Relating ED with Obesity (table2.jpg)
A number of biological mechanisms may link obesity to sexual dysfunction. Potential mechanisms include endothelial dysfunction, metabolic syndrome and diabetes, altered endocrine function, dyslipidemia and related drugs, social and psychological problems, and ordinary physical disabilities.

Endothelial dysfunction. A few have examined the relation between obesity, endothelial dysfunction, and ED. Esposito, et al., suggested that, in obese men, endothelial dysfunction might contribute to ED because of a reduced blood flow and an abnormal platelet aggregation response. Furthermore, they suggested that the explanation of the relation between ED, obesity, and endothelial dysfunction could depend on a decreased ability to relax the vascular smooth muscle cells, possibly because of alterations in the nitric oxide activity.13

Diabetes mellitus and metabolic syndrome. Several studies have suggested an increased risk of ED as a complication of diabetes mellitus. The risk of ED is further related to age, duration of the diabetes mellitus, poor metabolic control, and the presence of diabetic complications. Additionally, some studies suggest that also men with type 1 diabetes mellitus and a high BMI are at increased risk of ED.14

Altered endocrine function. Obesity has been found to be associated with increased androgen production among women, whereas studies in men show a low androgen production.15
Dyslipidemia and related drugs. Obesity is often accompanied by hyperlipidemia, and ED has been linked to serum lipid levels. Many investigators described hyperlipidemia as a common condition in ED patients.16

However, conflicting results on associations between the use of hypolipidemic drugs and ED exist. Although some old studies argued that ED may be a side effect of the lipid-lowering drugs, recent studies suggest that statin therapy improves endothelial function, especially among patients with preexisting endothelium dysfunction, and therefore found a potential positive effect from these compounds.17-19

Psychological problems. ED is also influenced by psychologic factors. Obesity can make normally sized penises appear smaller or shorter than they actually are, a phenomenon known as hidden penis. Surgical correction of this problem may involve resection of lower abdominal skin, suprapubic lipectomy, and tacking of subdermis of penoscrotal junction to tunica albuginea.20

Physical inactivity. Both ED and obesity may be related to physical inactivity. It is hypothesized that physical activity may increase blood flow and improve lipid profile, thereby affecting penile vasculature. In agreement, one study examined the effect of nine months of exercise on sexuality among 78 healthy, sedentary men, and showed that sedentary behaviors were associated with ED risk.21

Interventional Studies on Weight Reduction and ED
Different studies examined the effects of weight loss and sexual difficulties. Kolotkin, et al., examined the effect of weight loss on quality of life including six questions about sexual life among 37 men and women. Among men, the post-treatment scores of sexual life differed significantly from pre-scores, indicating that the weight loss program seemed to have been beneficial. However, among women there was no association between weight changes and changes in sexual life.22

Kaukua, et al., studied the association between weight loss, sex hormones, and sexual functioning among 38 obese men (BMI>35kg/m2) and showed that testosterone increased, but the sexual function scores were unaffected after weight loss.23

Rand, et al., compared sexual functioning among 32 morbidly obese women and 56 morbidly obese men (more than 45kg overweight), median age 36 (8 years) before and after surgery. One year after surgery, 61 percent of the included men (n=88) reported a better sex life compared to the presurgery condition, whereas 27 percent reported no change. Fourteen (34%) reported an increased interest in sex, and 56 percent reported that the partner had attained more interest in sex.24

Obesity and Fertility Problems
Male fertility requires that the testicles have a lower temperature than the core body. Increased scrotal temperature caused by tight-fitting clothes or obesity may decrease spermatogenesis. This effect is reversible, however. Varicoceles are prevalent in obese men and may be a cause of infertility.25

The high incidence of impotence in obese men, which is multifactorial, plays another important role in subfertility in this kind of population.26

Obesity and Genitourinary Malignancy
Obesity may play a role in cancer development and progression through many mechanisms: Diet and obesity play a role by increasing the amount of free radicals that may affect the cell’s DNA, causing mutations.27

Other agents that seem to play a role in neoplasia are polypeptide growth factors found in adipose tissues in varying amounts. One of the earliest to be identified was basic fibroblast growth factor (FGF-2), which is a potent mitogen for mesodermal- and ectodermal-derived cells and a potent angiogenic factor, stimulating endothelial cell proliferation.28, 29

Adipose tissue also may have a central role in immunosurveillance, which indirectly affects carcinogenesis. Adipose tissue stores lipids, which may alter immune competence by interfering with macrophage function, and may be a source for mutagenic, peroxidized lipids and gonadal steroid precursors, which have been implicated in several types of tumors.30,31
In addition, mitochondria in cells from obese patients are less efficient at metabolizing lipids, and are thus more likely to accumulate oxidative-damaging agents. Examples of such damaging free radicals are superoxide, hydroxy radical, hydrogen peroxide, and peroxynitrite (the result of nitric oxide interacting with superoxide).31,32

Adipose tissue is also a large repository of cholesterol and triglycerides. Metabolites of cholesterol, such as testosterone and androstenedione, may stimulate prostate epithelial and stromal cell growth by regulating androgen receptors.30,31

Recently, the ob protein (leptin) was discovered, which is a hormone produced by fat cells. In rodents, leptin was found to have angiogenic activity, which may affect prostate tumor biology.33,34

Obesity and Prostate Cancer
Andersson and colleagues reported that total caloric intake was a risk factor for prostate cancer in a population-based, case-control study in Sweden. Giovannucci and colleagues reported that animal fat causes increased incidence of prostate cancer, rather than other fats, such as vegetable or fish oils.35,36

Although many studies have demonstrated that a high-fat diet is a risk factor for prostate cancer, the effect of obesity alone, independent of dietary fat intake, on prostate cancer has been debatable.

Saglam and colleagues reported that leptin, a peptide that helps regulate body fat, is associated with prostate cancer. In prostate cancer patients, serum leptin correlates with prostate-specific antigen (PSA) levels and Gleason score through testosterone and other factors related to obesity.33,37

In another study, Hammarsten and colleagues found that men with faster growing BPH had a greater risk for developing prostate cancer.38 In a study of 194 patients, Irani and colleagues reported that obese men had 2.5 times the risk for having prostate cancer.39

In a study of patients who underwent radical prostatectomies, Mydlo and colleagues demonstrated an increase in stage and positive-margin status in patients with increasing BMIs. Histologically, specimens from patients with a higher BMI had a greater microvessel density.40

Another warning finding by Amling and colleagues in 860 patients with prostate cancer is that prostate cancer appears at a younger age in obese patients. Moreover, it usually presents with higher-grade and more advanced cancers. They also found that Black men had higher-grade cancers and significantly higher BMIs.41

These studies suggest that the adipose tissue may stimulate prostate cancer growth, either by way of reservoir stores of angiogenic growth factors, testosterone precursors, impaired immune surveillance, or other mechanisms.

Obesity and Bladder Cancer
Not much has been published regarding the association of obesity and bladder cancer. A report by Calatayud and colleagues, however, demonstrated an association between smoking, obesity, and bladder cancer in an epidemiologic study of 514 patients with bladder cancer.42

In an experimental canine study, Glickman and colleagues demonstrated a risk for bladder cancer with insecticides and overweight or obese dogs. Although some studies revealed an association between dietary fat intake and bladder cancer, others did not.43-45

Obesity and Testicular Cancer
In a study by Kolonel and colleagues examining testicular cancer in the Pacific basin, obesity showed an increased risk. One hypothesis is that obesity caused a hormonal imbalance, particularly an excess of estrogen, in addition to failure of normal thermal regulation of the testis associated with obesity.46

Technical Factors Influencing Outcome
Many surgeons are reluctant to operate on morbidly obese patients for many reasons, including technical difficulties, high infection rate, and poor wound healing. With the increase of obesity in the population, however, more reports are comparing outcomes between patients with obesity versus those of normal weight.

From the anesthesiologist’s point of view, treatment of patients with obesity raises certain questions about safe ventilatory pressures, the best way to monitor fluid management, how to prevent rhabdomyolysis in patients who undergo surgery for many hours, and the effectiveness of the defibrillator.47

Several observations have been made with the advent of laparoscopic surgery. El-Feel and colleagues analyzed several risk factors for laparoscopic prostatectomy and demonstrated that although prior abdominal surgery did not affect the overall operating time, grade 1 obesity did. In open radical prostatectomies, obesity may hinder the vesicourethral anastomosis.48

Other technical factors may influence tumor recurrence and progression. Several studies have shown the presence of thousands of circulating tumor cells in the peripheral vasculature after surgery for organ-confined disease, especially in channel transurethral resection of the prostate and radical prostatectomies.49,50

It is reasonable that such “shedding” of tumor cells may have greater impact in patients with a compromised immune system, but this has not been studied yet. Other factors that may contribute to the shedding of tumor cells include tumor size, compromise in technique because of obesity, and proximity to blood vessels. This shedding may account for the differences seen in tumor recurrences in patients with similar grades and stages of particular tumors, like prostate cancer, and may be one explanation for poorer outcomes in obese men.

Protective Factors
Numerous animal experiments have demonstrated that caloric restriction prolongs survival. Studies have shown that caloric restriction is more important in reducing the risk for mammary tumors in rodents than restricting fat or linoleic acid intake.51

Low-fat Diets and Dietary Factors
Low-fat diets are protective against cancer, as has been demonstrated for prostate cancer in the laboratory. Wang and colleagues reported less growth of prostate cancer cells implanted in nude mice fed low-fat diets.52 A recent clinical report found that dietary modification of fat intake could lower PSA levels without affecting overall testosterone levels, although it is not clear whether this influenced the prognosis.53

Giovannucci and colleagues reported a reduced risk for prostate cancer associated with increased overall intake of fruits and vegetables, and lycopene, an ingredient in tomato-based foods, was associated with a lower risk of prostate cancer in an epidemiologic study.36

Isoflavonoid extracts from soybean foods, such as genistein, inhibit prostate cancer cells in vitro.54 This agrees with the observation of a lower incidence of prostate cancer in Asians who have high-soy diets.51 No studies, however, have shown that soybean supplementation decreases the incidence of prostate cancer in humans.

Antioxidants
Selenium has been suggested to reduce prostate cancer progression. Clark and colleagues reported a 63-percent decrease in prostate cancer incidence using selenium supplements in the diet. Beta carotene and vitamin E also were evaluated for their cancer-inhibiting potential, but only vitamin E was associated with a decrease in the incidence of prostate cancer.55, 56

Vitamin D
Vitamin D has not been proven to be beneficial in patients with prostate cancer, but there are some interesting laboratory findings. First, vitamin D receptors are present on the cells of the prostate cancer cell line LNCaP, and physiologic doses of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] inhibited these prostate cancer cells in culture.57

Corder and colleagues found low serum levels of 1,25(OH)2D in men above 57 years of age with palpable tumors, but not in younger men with tumors diagnosed incidentally. The northern US has a greater incidence of prostate cancer than the south. Because sunlight is known to activate vitamin D, the reduced sunlight in the north may play a role in the absence of vitamin D activation.58

Exercise
Prospective studies have shown that overweight patients who exercise have less morbidity and mortality than those who are sedentary. Although no well controlled studies have compared cancer incidence in sedentary and active overweight persons, exercise seems to be protective against prostate cancer.59-61

Weight Loss
Some reports have found no change in the risk for cancer in patients with obesity who have lost weight, whereas other studies found that the risk ratio for cancer mortality did not alter if patients lost weight, gained weight, or showed no change in body weight. Although weight loss provides many benefits, it also may have undesirable consequences, such as gallstones and nutrient deficiencies.62, 63

Summary
Obesity is a risk factor for many men’s health problems, including BPH/LUTS, sexual dysfunction, fertility problems, and genitourinary malignancy. Numerous publications have demonstrated that a high dietary intake of fat increases prostate cancer risk, although the mechanisms are not clear.

Thus, dietary modification and other public health measures directed at reducing weight may reduce the incidence of these health problems. More studies are necessary to determine the therapeutic effects of weight loss and dietary modification on the incidence and progression of urologic tumors.

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Category: Past Articles, Review