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Pure Hypertriglyceridemia Might be Associated with Erectile Dysfunction: A Pilot Study
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ORIGINAL RESEARCH—ERECTILE DYSFUNCTION Pure Hypertriglyceridemia Might be Associated with Erectile Dysfunction: A Pilot Study Rafi Heruti, MD,*†‡ Yaron Arbel, MD,‡§ Arie Steinvil, MD,§ Salman Zarka, MD,† Nili Saar, MD,§ Michael Kinori, MD,§ Galit Brenner, MD,† and Dan Justo, MD†‡§ *Sexual Rehabilitation Clinic, Reuth Medical Center, Tel-Aviv, Israel; †Israel Defense Force, Medical Corps, Israel; ‡ Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; §Department of Internal Medicine D, Sourasky Medical Center, Tel-Aviv, Israel DOI: 10.1111/j.1743-6109.2007.00766.x
ABSTRACT
Introduction. Unlike the association between erectile dysfunction (ED) and high levels of low-density lipoprotein (LDL) cholesterol, the association between ED and hypertriglyceridemia is still debatable. Aim. To study prevalence and severity of ED in young men with very high levels of triglycerides. Main Outcome Measures. Prevalence of ED, ED severity, total cholesterol levels, LDL cholesterol levels, and triglycerides levels. Methods. Men who were enrolled went through routine health checks including full lipid profiling and completion of the Sexual Health Inventory for Men (SHIM) questionnaire. Very high levels of triglycerides were defined as ⱖ500 mg/dL. Very high levels of LDL cholesterol were defined as ⱖ190 mg/dL. Men with diabetes, ischemic heart disease, high-density lipoprotein (HDL) cholesterol ⱖ60 mg/dL, and mixed hyperlipidemias were excluded. Results. Included were 88 men, aged 35.9 ⫾ 7.1 years (range: 25–51 years): 21 men with “pure” severe hypertriglyceridemia (triglyceride levels ⱖ500 mg/dL and non-HDL cholesterol ⱕ189 mg/dL), 34 men with “pure” severe hyperlipidemia (LDL cholesterol levels ⱖ190 mg/dL and triglycerides ⱕ199 mg/dL), and 33 men with normal cholesterol levels. No significant differences were found between these groups in terms of mean age and mean SHIM score. Prevalence of ED (i.e., SHIM score < 22) was higher among men with “pure” severe hypertriglyceridemia than among men with “pure” severe hyperlipidemia (42.9% vs. 29.4%) and men with normal cholesterol levels (42.9% vs. 24.2%), although these results were not statistically significant (P = 0.2 and 0.4, respectively). Conclusions. Conclusions. Prevalence of ED might be increased in young men with “pure” severe hypertriglyceridemia, though a larger cohort with a longitudinal follow-up is needed to prove that hypertriglyceridemia is an independent risk factor for ED. Heruti R, Arbel Y, Steinvil A, Zarka S, Saar N, Kinori M, Brenner G, and Justo D. Pure hypertriglyceridemia might be associated with erectile dysfunction: A pilot study. J Sex Med 2008;5:1230–1236. Key Words. Hypertriglyceridemia; Erectile Dysfunction; Hyperlipidemia
Introduction
E
rectile dysfunction (ED) precedes coronary heart disease (CHD) and both have common risk factors, such as diabetes mellitus, hypertension, and smoking [1]. Like CHD, ED is also associated with hyperlipidemia, namely high levels of low-density lipoprotein (LDL) cholesterol [2]. Unlike CHD, which is associated with hypertrig-
J Sex Med 2008;5:1230–1236
lyceridemia [3], and might precede hypertriglyceridemia in young men [4], the association between ED and hypertriglyceridemia is still debatable [5,6]. The prevalence of dyslipidemias is high among ED patients: 27.5–48% for hypercholesterolemia (total cholesterol ⱖ240 mg/dL) [5,7], 14.7–21% for hypertriglyceridemia (triglycerides ⱖ200 mg/ dL) [5,8], and 22.7–53% for hyperlipidemia (LDL © 2008 International Society for Sexual Medicine
Erectile Dysfunction and Pure Hypertriglyceridemia cholesterol ⱖ160 mg/dL) [5,7]. However, the association between ED severity and dyslipidemia severity is unclear. According to Smith et al., there is no association between ED severity and total cholesterol or triglyceride levels [6]. According to Paick et al., there is no association between ED severity and LDL cholesterol levels [9]. The association between hypertriglyceridemia and ED should be investigated in a group of young patients with as less as possible cardiovascular risk factors on one hand, and as high as possible triglycerides on the other hand. Hence, we investigated the prevalence and severity of ED in a unique cohort of young men with “pure” severe hypertriglyceridemia, i.e., with very high levels of triglycerides. Methods
Staff Periodic Examination Center All Israel Defense Forces (IDF) personnel aged 25 years and older are required to undergo medical screening examinations every 3–5 years at the Staff Periodic Examination Center (SPEC). Each patient completes a detailed questionnaire surveying his medical history and smoking habits. Current smoking is defined as smoking one or more cigarettes in the last 3 months [10]. The Sexual Health Inventory for Men (SHIM) questionnaire comprises part of the above-mentioned questionnaire, aiming to detect ED and assess its severity [11], though its completion is not mandatory. The SHIM questionnaire consists of five items, each rated on a 5-point scale. The final score, ranging from 1 to 25, is calculated by summing up individual question scores. Men who score below 22 on the SHIM questionnaire are considered as suffering from ED [12]. Blood samples for lipid profiling are drawn first thing in the morning following a 14-hour night fast. All lipid levels are directly measured by using a BM/Hitachi 917 automated analyzer (Boehringer, Mannheim, Germany), except for LDL cholesterol levels, which are calculated according to the Friedewald equation [13]. A complete physical exam, including height and weight measurements, is also performed. Study Design We conducted a retrospective case-controlled study. We used the SPEC database in this study. Three groups of men were compared in terms of the prevalence of ED and its severity: men
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with “pure” severe hypertriglyceridemia, men with “pure” severe hyperlipidemia, and men with normal cholesterol levels. All men gave their informed consent for participation in the study.
Included Men All men examined between March 2003 and December 2006 at the SPEC, who completed the SHIM questionnaire, and had “pure” severe hypertriglyceridemia (triglyceride levels ⱖ500 mg/dL and non-HDL cholesterol ⱕ189 mg/dL), or “pure” severe hyperlipidemia (LDL cholesterol levels ⱖ190 mg/dL and triglycerides ⱕ199 mg/ dL) were included in the study. Men with normal cholesterol levels namely total cholesterol levels ⱕ199 mg/dL, LDL cholesterol levels ⱕ129 mg/ dL, triglyceride levels ⱕ149 mg/dL, and highdensity lipoprotein (HDL) cholesterol levels between 41 and 59 mg/dL, were also included. These lipid levels were consistent with the definitions of the third report of the expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel [ATPIII]) [14]. Excluded Men Men with medical conditions that might affect ED severity or lipid levels were excluded from the study, including men taking lipid-lowering agents [15], men taking phosphodiesterase type-5 inhibitors [16], diabetic men, men with ischemic heart disease [1], and men with HDL cholesterol levels ⱖ60 mg/dL [2]. Men with “mixed” severe hyperlipidemia (LDL cholesterol levels ⱖ190 mg/dL and triglycerides ⱖ200 mg/dL) and men with “mixed” severe hypertriglyceridemia (triglyceride levels ⱖ500 mg/dL and non-HDL cholesterol ⱖ190 mg/dL) were also excluded [14]. Finally, men with missing data or lab errors were excluded from the study as well. Statistical Analysis Continuous variables were expressed as mean ⫾ SD. The student’s t-test was used to compare mean continuous variables of men who filled the SHIM questionnaire with those of men who did not fill the SHIM questionnaire. The chi-squared test was used to compare prevalence of cardiovascular risk factors of men who filled the SHIM questionnaire with that of men who did not fill the SHIM questionnaire. The Kruskal-Wallis test was used to compare mean age and mean SHIM scores for the three patient groups. The chi-squared test was used to compare prevalence of J Sex Med 2008;5:1230–1236
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Heruti et al. Total: 253 128 with LDL > 190 mg/dL 92 with TG > 500 mg/dL 33 with normal cholesterol levels
Excluded: 19 Missing data 13 DM 14 HDL > 60 mg/dL 1 IHD 1 Laboratory error
95 did not complete the SHIM
110 completed the SHIM
Excluded: 22 patients with “mixed” hyperlipidemias
33 normal cholesterol levels
21 “pure” severe hyperTG
34 “pure” severe hyperLDL
ED in each group. Spearman correlation coefficients were calculated to determine the association between SHIM scores, total cholesterol levels, LDL cholesterol levels, and triglyceride levels for men within each patient group. P values less than or equal to 0.05 were considered statistically significant throughout. The spss statistical package, version 14.0, was used to perform all statistical evaluation (SSPS Inc., Chicago, IL, USA). Results
More than 10,000 men participated in the SPEC medical screening exams between March 2003 and December 2006, 220 of whom had LDL cholesterol levels ⱖ190 mg/dL or triglyceride levels ⱖ500 mg/dL. The cohort included also 33 men with normal cholesterol levels. Overall, 48 men
Figure 1 The process of patient inclusion and exclusion. SHIM = Sexual Health Inventory for Men; IHD = ischemic heart disease; HDL = high-density lipoprotein; TG = triglycerides; LDL = low-density lipoprotein; DM = diabetes mellitus.
were excluded from the study because of high HDL cholesterol levels, diabetes mellitus, ischemic heart disease, missing data, or lab errors (Figure 1). Of the remaining 205 men, 110 (53.6%) completed the SHIM questionnaire. No significant differences were found between men who filled the SHIM questionnaire and men who did not fill the SHIM questionnaire in terms of mean age and prevalence of hypertension, obesity (body mass index ⱖ 30 kg/m2), and current smoking (Table 1). Finally, after excluding men with mixed hyperlipidemias, the study included 88 men, aged 35.9 ⫾ 7.1 years (range: 25–51 years), who completed the SHIM questionnaire and had “pure” severe hypertriglyceridemia (N = 21), or “pure” severe hyperlipidemia (N = 34), or normal cholesterol levels (N = 33). The mean SHIM score for all
Table 1 Characteristics of, and prevalence of cardiovascular risk factors among men who filled the SHIM questionnaire and men who did not fill the SHIM questionnaire
Age (years) Current smoking Obesity Hypertension
Mean ⫾ SD N (%) N (%) N (%)
Filled the SHIM questionnaire (N = 110)
Did not fill the SHIM questionnaire (N = 95)
P value
35.4 ⫾ 6.7 25 (22.7) 35 (31.8) 6 (5.5)
37.4 ⫾ 7.8 30 (31.6) 29 (30.5) 5 (5.3)
ns ns ns ns
SHIM = Sexual Health Inventory for Men; ns = non-significant (P < 0.05).
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Erectile Dysfunction and Pure Hypertriglyceridemia Table 2
Characteristics of, and prevalence of cardiovascular risk factors among the various patient groups
M ⫾ SD N (%) N (%) N (%)
Age (years) Current smoking Obesity Hypertension
“Pure” severe Hyper-LDL (N = 34)
“Pure” severe Hyper-TG (N = 21)
Normal cholesterol levels (N = 33)
P value
34.6 ⫾ 7.6 8 (23.5) 14 (41.2) 2 (5.9)
37.0 ⫾ 7.2 6 (28.6) 8 (38.1) 1 (4.8)
34.1 ⫾ 4.8 5 (15.2) 6 (18.2) 1 (3.0)
ns ns* ns* ns*
*Not including men with normal cholesterol levels. LDL = low-density lipoprotein; TG = triglycerides; ns = non-significant (P < 0.05).
patients was 21.9 ⫾ 3.7, and 30 (34.1%) patients suffered from ED. No significant differences were found between the three patient groups in terms of mean age. No significant differences were found between men with “pure” severe hyperlipidemia and men with “pure” severe hypertriglyceridemia in terms of prevalence of hypertension, obesity, and current smoking (Table 2). Prevalence of hypertension, obesity, and current smoking was lower in the normal cholesterol group. Nonetheless, no significant differences were found between the three patient groups in terms of mean SHIM scores (P = 0.68; Figure 2). Prevalence of ED was higher among men with “pure” severe hypertriglyceridemia compared with men with “pure” severe hyperlipidemia (42.9% vs. 29.4%) and men with normal cholesterol levels (42.9% vs. 24.2%), although these results were not statistically significant (P = 0.2 and 0.4, respec-
tively) (Figure 3). Finally, no associations were found between SHIM scores, total cholesterol levels, LDL cholesterol levels, and triglyceride levels within each patient group (Table 3). Discussion
The association between hyperlipidemia and ED was originally attributed to atherosclerosis of the pelvic arteries [17]. Later, Azadzoi et al. discovered that hyperlipidemia-induced endothelial dysfunction might impair cavernosal relaxation and cause ED [18]. Lipid-lowering agents may thus improve ED in men with hypercholesterolemia [19], by improving endothelial dysfunction. Though hypertriglyceridemia-induced ED is feasible in vitro [20], it has never been studied in humans. Erectile dysfunction and CHD share risk factors, such as hyperlipidemia. Though the con45.0
30.0
40.0 35.0
20.0
15.0
10.0
21.1
22.3
22.2
The prevalence of ED (%)
Mean SHIM scores
25.0
30.0 25.0 20.0
42.9
15.0
29.4 24.2
10.0 5.0
5.0 0.0
0.0 "pure" hyper-TG (n=21)
"pure" hyper-LDL Normal cholesterol (n=34) (n=33)
Figure 2 Mean SHIM score for each patient group. SHIM = Sexual Health Inventory for Men; TG = triglycerides; LDL = low-density lipoprotein.
"pure" hyper-TG (n=21)
"pure" hyper-LDL Normal cholesterol (n=34) (n=33)
Figure 3 Prevalence of erectile dysfunction (ED) within each patient group. TG = triglycerides; LDL = low-density lipoprotein.
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Heruti et al.
Table 3 Spearman correlation coefficients for SHIM scores, total cholesterol levels, low-density lipoprotein cholesterol levels, and triglyceride levels within each patient group
Total cholesterol levels and SHIM scores LDL cholesterol levels and SHIM scores Triglyceride levels and SHIM scores
“Pure” severe Hyper-LDL (N = 34)
“Pure” severe Hyper-TG (N = 21)
Normal cholesterol levels (N = 33)
r = 0.025 P = 0.888 r = 0.136 P = 0.444 r = -0.117 P = 0.509
r = -0.018 P = 0.939 *
r = -0.303 P = 0.086 r = -0.340 P = 0.053 r = -0.133 P = 0.462
r = -0.135 P = 0.560
*Not applicable since according to the Friedewald equation, low-density lipoprotein cholesterol levels cannot be calculated if triglycerides are higher than 400 mg/dL [12]. LDL = low-density lipoprotein; TG = triglycerides; SHIM = Sexual Health Inventory for Men.
tribution of high LDL cholesterol levels in predicting ED and CHD is clear [2,21], and though the contribution of high triglyceride levels in predicting CHD is becoming clear [3,22], the contribution of high triglyceride levels in predicting ED remains unclear; In a study conducted by Kim et al., the incidence of high LDL cholesterol levels was significantly higher in ED patients than in controls, but there was no significant difference in the incidence of high triglyceride levels between the two groups [23]; According to Ahn et al., the incidence of high triglyceride levels was significantly higher in ED patients than in controls [24]; In a study by Pinnock et al., high levels of triglycerides were independent predictors of poor sexual function, rather than ED, at older ages [25]. According to Fung et al., hypertriglyceridemia and hyperlipidemia can both help predict onset of ED years later [26]. However, the contributions of triglyceride levels and LDL cholesterol levels in predicting ED have never been studied in comparison with each other. According to the Fredrickson classification, hypertriglyceridemia is a feature of the following hyperlipidemias: type I hyperlipidemia (primary hyperlipoproteinemia), type IIb hyperlipidemia (combined hyperlipidemia), type III hyperlipidemia (Familial dysbetalipoproteinemia), type IV hyperlipidemia, and type V hyperlipidemia. Except for type IV hyperlipidemia, all of the above-mentioned hyperlipidemias also include high cholesterol levels [27]. Hence, it is very difficult to isolate patients with “pure” hypertriglyceridemia, let the more so, to study the sole effect of hypertriglyceridemia on erections in patients with no other risk factors for ED. In order to overcome these difficulties, we took the following measures in this study: (i) we excluded patients with diabetes mellitus and ischemic heart disease, which might be associated with ED [1]; (ii) we excluded patients with “mixed” hyperlipidemias; (iii) we studied J Sex Med 2008;5:1230–1236
young men in whom atherosclerosis was probably not advanced; and (iv) we used comparable groups of patients in terms of prevalence of current smoking and obesity. Although hypertension is probably not associated with ED in young men [28], we also used comparable groups of patients in terms of prevalence hypertension. Finally, we studied the prevalence of ED and its severity in a highly selective group of patients with very high levels of triglycerides, i.e., “pure” severe hypertriglyceridemia. Our findings suggest that the prevalence of ED might be increased in men with “pure” hypertriglyceridemia compared with men with high levels of LDL cholesterol and men with normal cholesterol levels; however, these findings were not statistically significant, probably because of the small cohort. Although a larger cohort with a longitudinal follow-up is needed to prove this hypothesis, the trend is there: the prevalence of ED was almost doubled in men with “pure” hypertriglyceridemia compared with men with high levels of LDL cholesterol and men with normal cholesterol levels. Hypertriglyceridemia is usually associated with diabetes mellitus, hypertension, high levels of LDL cholesterol, and the metabolic syndrome [29], all of which might be associated with ED [1,2,30]. Hypertriglyceridemia might be aggravated by obesity, alcohol consumption, and drugs such as thiazides and beta-blockers [29]. All of the above might also aggravate ED [30–32]. Corona et al. identified a significant association between hypertriglyceridemia and hypogonadism in men with sexual dysfunction [33]. On the other hand, exercise improves fasting and postprandial vascular function, as well as triglycerides concentrations [34] and ED [35]. Hence, it is difficult to prove that hypertriglyceridemia is an independent risk factor for ED, and that treating hypertriglyceridemia improves ED. We believe our findings
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Erectile Dysfunction and Pure Hypertriglyceridemia strengthen the role of hypertriglyceridemia as independent risk factor for ED. According to Kusterer et al., hypertriglyceridemia alone progressively impairs vascular endothelial response, with significant decrease in NO production [36]. According to Srilatha et al., hypertriglyceridemia impairs neuronal NOmediated cavernosal filling pressure [20]. Together with hypertriglyceridemia-induced increased blood viscosity [37], all of the above-mentioned mechanisms might induce ED in patients with hypertriglyceridemia.
Conflict of Interest: None declared. Statement of Authorship
Category 1 (a) Conception and Design Rafi J. Heruti; Dan Justo (b) Acquisition of Data Dan Justo; Galit Brenner G (c) Analysis and Interpretation of Data Dan Justo; Yaron Arbel
Category 2 Study Limitations
One might claim that the cohort was too young. However, only in young patients, we could isolate the hypertriglyceridemia factor from other risk factors for ED; in older men, other risk factors might have been more prevalent, and might have masked the effect of hypertriglyceridemia on the erections. Moreover, it might have been more difficult to find elderly men with very high levels of triglycerides, because triglycerides levels reach peak values between 40 and 50 years of age, and then decline slightly thereafter [38]. Clinical and Research Implication
Although less than 1% of adult population has very high triglycerides (ⱖ500 mg/dL), more than 16% of adult population has high triglycerides (ⱖ200 mg/dL) [14]. If high triglycerides are proved as an independent risk factor for ED by larger cohorts with a longitudinal follow-up, these patients will have to be treated accordingly. Since fibrates might aggravate ED [32], and since statins decrease triglycerides levels only mildly, weight loss and aerobic exercise will probably be the treatment of choice in these subjects [29], although this warren further investigation as well. Conclusions
Prevalence of ED might be increased in young men with “pure” severe hypertriglyceridemia, though a larger cohort with a longitudinal follow-up is needed to prove that milder hypertriglyceridemia is an independent risk factor for ED. Corresponding Author: Rafi Heruti, MD, Head— Sexual Rehabilitation Clinic, Reuth Medical Center, Hachayil 2 Blvd, Tel-Aviv, Israel 61092. Tel: +972-546791704; Fax: +972-3-6383680; E-mail: Heruti@post. tau.ac.il
(a) Drafting the Article Rafi J. Heruti; Dan Justo; Arie Steinvil; Salman Zarka; Nili Saar; Michael Kinori (b) Revising It for Intellectual Contant Rafi J. Heruti; Dan Justo; Arie Steinvil
Category 3 (a) Final Approval of the Completed Article Rafi J. Heruti; Dan Justo References
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ORIGINAL RESEARCH—ERECTILE DYSFUNCTION Pure Hypertriglyceridemia Might be Associated with Erectile Dysfunction: A Pilot Study Rafi Heruti, MD,*†‡ Yaron Arbel, MD,‡§ Arie Steinvil, MD,§ Salman Zarka, MD,† Nili Saar, MD,§ Michael Kinori, MD,§ Galit Brenner, MD,† and Dan Justo, MD†‡§ *Sexual Rehabilitation Clinic, Reuth Medical Center, Tel-Aviv, Israel; †Israel Defense Force, Medical Corps, Israel; ‡ Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; §Department of Internal Medicine D, Sourasky Medical Center, Tel-Aviv, Israel DOI: 10.1111/j.1743-6109.2007.00766.x
ABSTRACT
Introduction. Unlike the association between erectile dysfunction (ED) and high levels of low-density lipoprotein (LDL) cholesterol, the association between ED and hypertriglyceridemia is still debatable. Aim. To study prevalence and severity of ED in young men with very high levels of triglycerides. Main Outcome Measures. Prevalence of ED, ED severity, total cholesterol levels, LDL cholesterol levels, and triglycerides levels. Methods. Men who were enrolled went through routine health checks including full lipid profiling and completion of the Sexual Health Inventory for Men (SHIM) questionnaire. Very high levels of triglycerides were defined as ⱖ500 mg/dL. Very high levels of LDL cholesterol were defined as ⱖ190 mg/dL. Men with diabetes, ischemic heart disease, high-density lipoprotein (HDL) cholesterol ⱖ60 mg/dL, and mixed hyperlipidemias were excluded. Results. Included were 88 men, aged 35.9 ⫾ 7.1 years (range: 25–51 years): 21 men with “pure” severe hypertriglyceridemia (triglyceride levels ⱖ500 mg/dL and non-HDL cholesterol ⱕ189 mg/dL), 34 men with “pure” severe hyperlipidemia (LDL cholesterol levels ⱖ190 mg/dL and triglycerides ⱕ199 mg/dL), and 33 men with normal cholesterol levels. No significant differences were found between these groups in terms of mean age and mean SHIM score. Prevalence of ED (i.e., SHIM score < 22) was higher among men with “pure” severe hypertriglyceridemia than among men with “pure” severe hyperlipidemia (42.9% vs. 29.4%) and men with normal cholesterol levels (42.9% vs. 24.2%), although these results were not statistically significant (P = 0.2 and 0.4, respectively). Conclusions. Conclusions. Prevalence of ED might be increased in young men with “pure” severe hypertriglyceridemia, though a larger cohort with a longitudinal follow-up is needed to prove that hypertriglyceridemia is an independent risk factor for ED. Heruti R, Arbel Y, Steinvil A, Zarka S, Saar N, Kinori M, Brenner G, and Justo D. Pure hypertriglyceridemia might be associated with erectile dysfunction: A pilot study. J Sex Med 2008;5:1230–1236. Key Words. Hypertriglyceridemia; Erectile Dysfunction; Hyperlipidemia
Introduction
E
rectile dysfunction (ED) precedes coronary heart disease (CHD) and both have common risk factors, such as diabetes mellitus, hypertension, and smoking [1]. Like CHD, ED is also associated with hyperlipidemia, namely high levels of low-density lipoprotein (LDL) cholesterol [2]. Unlike CHD, which is associated with hypertrig-
J Sex Med 2008;5:1230–1236
lyceridemia [3], and might precede hypertriglyceridemia in young men [4], the association between ED and hypertriglyceridemia is still debatable [5,6]. The prevalence of dyslipidemias is high among ED patients: 27.5–48% for hypercholesterolemia (total cholesterol ⱖ240 mg/dL) [5,7], 14.7–21% for hypertriglyceridemia (triglycerides ⱖ200 mg/ dL) [5,8], and 22.7–53% for hyperlipidemia (LDL © 2008 International Society for Sexual Medicine
Erectile Dysfunction and Pure Hypertriglyceridemia cholesterol ⱖ160 mg/dL) [5,7]. However, the association between ED severity and dyslipidemia severity is unclear. According to Smith et al., there is no association between ED severity and total cholesterol or triglyceride levels [6]. According to Paick et al., there is no association between ED severity and LDL cholesterol levels [9]. The association between hypertriglyceridemia and ED should be investigated in a group of young patients with as less as possible cardiovascular risk factors on one hand, and as high as possible triglycerides on the other hand. Hence, we investigated the prevalence and severity of ED in a unique cohort of young men with “pure” severe hypertriglyceridemia, i.e., with very high levels of triglycerides. Methods
Staff Periodic Examination Center All Israel Defense Forces (IDF) personnel aged 25 years and older are required to undergo medical screening examinations every 3–5 years at the Staff Periodic Examination Center (SPEC). Each patient completes a detailed questionnaire surveying his medical history and smoking habits. Current smoking is defined as smoking one or more cigarettes in the last 3 months [10]. The Sexual Health Inventory for Men (SHIM) questionnaire comprises part of the above-mentioned questionnaire, aiming to detect ED and assess its severity [11], though its completion is not mandatory. The SHIM questionnaire consists of five items, each rated on a 5-point scale. The final score, ranging from 1 to 25, is calculated by summing up individual question scores. Men who score below 22 on the SHIM questionnaire are considered as suffering from ED [12]. Blood samples for lipid profiling are drawn first thing in the morning following a 14-hour night fast. All lipid levels are directly measured by using a BM/Hitachi 917 automated analyzer (Boehringer, Mannheim, Germany), except for LDL cholesterol levels, which are calculated according to the Friedewald equation [13]. A complete physical exam, including height and weight measurements, is also performed. Study Design We conducted a retrospective case-controlled study. We used the SPEC database in this study. Three groups of men were compared in terms of the prevalence of ED and its severity: men
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with “pure” severe hypertriglyceridemia, men with “pure” severe hyperlipidemia, and men with normal cholesterol levels. All men gave their informed consent for participation in the study.
Included Men All men examined between March 2003 and December 2006 at the SPEC, who completed the SHIM questionnaire, and had “pure” severe hypertriglyceridemia (triglyceride levels ⱖ500 mg/dL and non-HDL cholesterol ⱕ189 mg/dL), or “pure” severe hyperlipidemia (LDL cholesterol levels ⱖ190 mg/dL and triglycerides ⱕ199 mg/ dL) were included in the study. Men with normal cholesterol levels namely total cholesterol levels ⱕ199 mg/dL, LDL cholesterol levels ⱕ129 mg/ dL, triglyceride levels ⱕ149 mg/dL, and highdensity lipoprotein (HDL) cholesterol levels between 41 and 59 mg/dL, were also included. These lipid levels were consistent with the definitions of the third report of the expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel [ATPIII]) [14]. Excluded Men Men with medical conditions that might affect ED severity or lipid levels were excluded from the study, including men taking lipid-lowering agents [15], men taking phosphodiesterase type-5 inhibitors [16], diabetic men, men with ischemic heart disease [1], and men with HDL cholesterol levels ⱖ60 mg/dL [2]. Men with “mixed” severe hyperlipidemia (LDL cholesterol levels ⱖ190 mg/dL and triglycerides ⱖ200 mg/dL) and men with “mixed” severe hypertriglyceridemia (triglyceride levels ⱖ500 mg/dL and non-HDL cholesterol ⱖ190 mg/dL) were also excluded [14]. Finally, men with missing data or lab errors were excluded from the study as well. Statistical Analysis Continuous variables were expressed as mean ⫾ SD. The student’s t-test was used to compare mean continuous variables of men who filled the SHIM questionnaire with those of men who did not fill the SHIM questionnaire. The chi-squared test was used to compare prevalence of cardiovascular risk factors of men who filled the SHIM questionnaire with that of men who did not fill the SHIM questionnaire. The Kruskal-Wallis test was used to compare mean age and mean SHIM scores for the three patient groups. The chi-squared test was used to compare prevalence of J Sex Med 2008;5:1230–1236
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Heruti et al. Total: 253 128 with LDL > 190 mg/dL 92 with TG > 500 mg/dL 33 with normal cholesterol levels
Excluded: 19 Missing data 13 DM 14 HDL > 60 mg/dL 1 IHD 1 Laboratory error
95 did not complete the SHIM
110 completed the SHIM
Excluded: 22 patients with “mixed” hyperlipidemias
33 normal cholesterol levels
21 “pure” severe hyperTG
34 “pure” severe hyperLDL
ED in each group. Spearman correlation coefficients were calculated to determine the association between SHIM scores, total cholesterol levels, LDL cholesterol levels, and triglyceride levels for men within each patient group. P values less than or equal to 0.05 were considered statistically significant throughout. The spss statistical package, version 14.0, was used to perform all statistical evaluation (SSPS Inc., Chicago, IL, USA). Results
More than 10,000 men participated in the SPEC medical screening exams between March 2003 and December 2006, 220 of whom had LDL cholesterol levels ⱖ190 mg/dL or triglyceride levels ⱖ500 mg/dL. The cohort included also 33 men with normal cholesterol levels. Overall, 48 men
Figure 1 The process of patient inclusion and exclusion. SHIM = Sexual Health Inventory for Men; IHD = ischemic heart disease; HDL = high-density lipoprotein; TG = triglycerides; LDL = low-density lipoprotein; DM = diabetes mellitus.
were excluded from the study because of high HDL cholesterol levels, diabetes mellitus, ischemic heart disease, missing data, or lab errors (Figure 1). Of the remaining 205 men, 110 (53.6%) completed the SHIM questionnaire. No significant differences were found between men who filled the SHIM questionnaire and men who did not fill the SHIM questionnaire in terms of mean age and prevalence of hypertension, obesity (body mass index ⱖ 30 kg/m2), and current smoking (Table 1). Finally, after excluding men with mixed hyperlipidemias, the study included 88 men, aged 35.9 ⫾ 7.1 years (range: 25–51 years), who completed the SHIM questionnaire and had “pure” severe hypertriglyceridemia (N = 21), or “pure” severe hyperlipidemia (N = 34), or normal cholesterol levels (N = 33). The mean SHIM score for all
Table 1 Characteristics of, and prevalence of cardiovascular risk factors among men who filled the SHIM questionnaire and men who did not fill the SHIM questionnaire
Age (years) Current smoking Obesity Hypertension
Mean ⫾ SD N (%) N (%) N (%)
Filled the SHIM questionnaire (N = 110)
Did not fill the SHIM questionnaire (N = 95)
P value
35.4 ⫾ 6.7 25 (22.7) 35 (31.8) 6 (5.5)
37.4 ⫾ 7.8 30 (31.6) 29 (30.5) 5 (5.3)
ns ns ns ns
SHIM = Sexual Health Inventory for Men; ns = non-significant (P < 0.05).
J Sex Med 2008;5:1230–1236
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Erectile Dysfunction and Pure Hypertriglyceridemia Table 2
Characteristics of, and prevalence of cardiovascular risk factors among the various patient groups
M ⫾ SD N (%) N (%) N (%)
Age (years) Current smoking Obesity Hypertension
“Pure” severe Hyper-LDL (N = 34)
“Pure” severe Hyper-TG (N = 21)
Normal cholesterol levels (N = 33)
P value
34.6 ⫾ 7.6 8 (23.5) 14 (41.2) 2 (5.9)
37.0 ⫾ 7.2 6 (28.6) 8 (38.1) 1 (4.8)
34.1 ⫾ 4.8 5 (15.2) 6 (18.2) 1 (3.0)
ns ns* ns* ns*
*Not including men with normal cholesterol levels. LDL = low-density lipoprotein; TG = triglycerides; ns = non-significant (P < 0.05).
patients was 21.9 ⫾ 3.7, and 30 (34.1%) patients suffered from ED. No significant differences were found between the three patient groups in terms of mean age. No significant differences were found between men with “pure” severe hyperlipidemia and men with “pure” severe hypertriglyceridemia in terms of prevalence of hypertension, obesity, and current smoking (Table 2). Prevalence of hypertension, obesity, and current smoking was lower in the normal cholesterol group. Nonetheless, no significant differences were found between the three patient groups in terms of mean SHIM scores (P = 0.68; Figure 2). Prevalence of ED was higher among men with “pure” severe hypertriglyceridemia compared with men with “pure” severe hyperlipidemia (42.9% vs. 29.4%) and men with normal cholesterol levels (42.9% vs. 24.2%), although these results were not statistically significant (P = 0.2 and 0.4, respec-
tively) (Figure 3). Finally, no associations were found between SHIM scores, total cholesterol levels, LDL cholesterol levels, and triglyceride levels within each patient group (Table 3). Discussion
The association between hyperlipidemia and ED was originally attributed to atherosclerosis of the pelvic arteries [17]. Later, Azadzoi et al. discovered that hyperlipidemia-induced endothelial dysfunction might impair cavernosal relaxation and cause ED [18]. Lipid-lowering agents may thus improve ED in men with hypercholesterolemia [19], by improving endothelial dysfunction. Though hypertriglyceridemia-induced ED is feasible in vitro [20], it has never been studied in humans. Erectile dysfunction and CHD share risk factors, such as hyperlipidemia. Though the con45.0
30.0
40.0 35.0
20.0
15.0
10.0
21.1
22.3
22.2
The prevalence of ED (%)
Mean SHIM scores
25.0
30.0 25.0 20.0
42.9
15.0
29.4 24.2
10.0 5.0
5.0 0.0
0.0 "pure" hyper-TG (n=21)
"pure" hyper-LDL Normal cholesterol (n=34) (n=33)
Figure 2 Mean SHIM score for each patient group. SHIM = Sexual Health Inventory for Men; TG = triglycerides; LDL = low-density lipoprotein.
"pure" hyper-TG (n=21)
"pure" hyper-LDL Normal cholesterol (n=34) (n=33)
Figure 3 Prevalence of erectile dysfunction (ED) within each patient group. TG = triglycerides; LDL = low-density lipoprotein.
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Table 3 Spearman correlation coefficients for SHIM scores, total cholesterol levels, low-density lipoprotein cholesterol levels, and triglyceride levels within each patient group
Total cholesterol levels and SHIM scores LDL cholesterol levels and SHIM scores Triglyceride levels and SHIM scores
“Pure” severe Hyper-LDL (N = 34)
“Pure” severe Hyper-TG (N = 21)
Normal cholesterol levels (N = 33)
r = 0.025 P = 0.888 r = 0.136 P = 0.444 r = -0.117 P = 0.509
r = -0.018 P = 0.939 *
r = -0.303 P = 0.086 r = -0.340 P = 0.053 r = -0.133 P = 0.462
r = -0.135 P = 0.560
*Not applicable since according to the Friedewald equation, low-density lipoprotein cholesterol levels cannot be calculated if triglycerides are higher than 400 mg/dL [12]. LDL = low-density lipoprotein; TG = triglycerides; SHIM = Sexual Health Inventory for Men.
tribution of high LDL cholesterol levels in predicting ED and CHD is clear [2,21], and though the contribution of high triglyceride levels in predicting CHD is becoming clear [3,22], the contribution of high triglyceride levels in predicting ED remains unclear; In a study conducted by Kim et al., the incidence of high LDL cholesterol levels was significantly higher in ED patients than in controls, but there was no significant difference in the incidence of high triglyceride levels between the two groups [23]; According to Ahn et al., the incidence of high triglyceride levels was significantly higher in ED patients than in controls [24]; In a study by Pinnock et al., high levels of triglycerides were independent predictors of poor sexual function, rather than ED, at older ages [25]. According to Fung et al., hypertriglyceridemia and hyperlipidemia can both help predict onset of ED years later [26]. However, the contributions of triglyceride levels and LDL cholesterol levels in predicting ED have never been studied in comparison with each other. According to the Fredrickson classification, hypertriglyceridemia is a feature of the following hyperlipidemias: type I hyperlipidemia (primary hyperlipoproteinemia), type IIb hyperlipidemia (combined hyperlipidemia), type III hyperlipidemia (Familial dysbetalipoproteinemia), type IV hyperlipidemia, and type V hyperlipidemia. Except for type IV hyperlipidemia, all of the above-mentioned hyperlipidemias also include high cholesterol levels [27]. Hence, it is very difficult to isolate patients with “pure” hypertriglyceridemia, let the more so, to study the sole effect of hypertriglyceridemia on erections in patients with no other risk factors for ED. In order to overcome these difficulties, we took the following measures in this study: (i) we excluded patients with diabetes mellitus and ischemic heart disease, which might be associated with ED [1]; (ii) we excluded patients with “mixed” hyperlipidemias; (iii) we studied J Sex Med 2008;5:1230–1236
young men in whom atherosclerosis was probably not advanced; and (iv) we used comparable groups of patients in terms of prevalence of current smoking and obesity. Although hypertension is probably not associated with ED in young men [28], we also used comparable groups of patients in terms of prevalence hypertension. Finally, we studied the prevalence of ED and its severity in a highly selective group of patients with very high levels of triglycerides, i.e., “pure” severe hypertriglyceridemia. Our findings suggest that the prevalence of ED might be increased in men with “pure” hypertriglyceridemia compared with men with high levels of LDL cholesterol and men with normal cholesterol levels; however, these findings were not statistically significant, probably because of the small cohort. Although a larger cohort with a longitudinal follow-up is needed to prove this hypothesis, the trend is there: the prevalence of ED was almost doubled in men with “pure” hypertriglyceridemia compared with men with high levels of LDL cholesterol and men with normal cholesterol levels. Hypertriglyceridemia is usually associated with diabetes mellitus, hypertension, high levels of LDL cholesterol, and the metabolic syndrome [29], all of which might be associated with ED [1,2,30]. Hypertriglyceridemia might be aggravated by obesity, alcohol consumption, and drugs such as thiazides and beta-blockers [29]. All of the above might also aggravate ED [30–32]. Corona et al. identified a significant association between hypertriglyceridemia and hypogonadism in men with sexual dysfunction [33]. On the other hand, exercise improves fasting and postprandial vascular function, as well as triglycerides concentrations [34] and ED [35]. Hence, it is difficult to prove that hypertriglyceridemia is an independent risk factor for ED, and that treating hypertriglyceridemia improves ED. We believe our findings
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Erectile Dysfunction and Pure Hypertriglyceridemia strengthen the role of hypertriglyceridemia as independent risk factor for ED. According to Kusterer et al., hypertriglyceridemia alone progressively impairs vascular endothelial response, with significant decrease in NO production [36]. According to Srilatha et al., hypertriglyceridemia impairs neuronal NOmediated cavernosal filling pressure [20]. Together with hypertriglyceridemia-induced increased blood viscosity [37], all of the above-mentioned mechanisms might induce ED in patients with hypertriglyceridemia.
Conflict of Interest: None declared. Statement of Authorship
Category 1 (a) Conception and Design Rafi J. Heruti; Dan Justo (b) Acquisition of Data Dan Justo; Galit Brenner G (c) Analysis and Interpretation of Data Dan Justo; Yaron Arbel
Category 2 Study Limitations
One might claim that the cohort was too young. However, only in young patients, we could isolate the hypertriglyceridemia factor from other risk factors for ED; in older men, other risk factors might have been more prevalent, and might have masked the effect of hypertriglyceridemia on the erections. Moreover, it might have been more difficult to find elderly men with very high levels of triglycerides, because triglycerides levels reach peak values between 40 and 50 years of age, and then decline slightly thereafter [38]. Clinical and Research Implication
Although less than 1% of adult population has very high triglycerides (ⱖ500 mg/dL), more than 16% of adult population has high triglycerides (ⱖ200 mg/dL) [14]. If high triglycerides are proved as an independent risk factor for ED by larger cohorts with a longitudinal follow-up, these patients will have to be treated accordingly. Since fibrates might aggravate ED [32], and since statins decrease triglycerides levels only mildly, weight loss and aerobic exercise will probably be the treatment of choice in these subjects [29], although this warren further investigation as well. Conclusions
Prevalence of ED might be increased in young men with “pure” severe hypertriglyceridemia, though a larger cohort with a longitudinal follow-up is needed to prove that milder hypertriglyceridemia is an independent risk factor for ED. Corresponding Author: Rafi Heruti, MD, Head— Sexual Rehabilitation Clinic, Reuth Medical Center, Hachayil 2 Blvd, Tel-Aviv, Israel 61092. Tel: +972-546791704; Fax: +972-3-6383680; E-mail: Heruti@post. tau.ac.il
(a) Drafting the Article Rafi J. Heruti; Dan Justo; Arie Steinvil; Salman Zarka; Nili Saar; Michael Kinori (b) Revising It for Intellectual Contant Rafi J. Heruti; Dan Justo; Arie Steinvil
Category 3 (a) Final Approval of the Completed Article Rafi J. Heruti; Dan Justo References
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