http://informahealthcare.com/tam ISSN: 1368-5538 (print), 1473-0790 (electronic) Aging Male, 2015; 18(3): 186–194 ! 2015 Informa UK Ltd. DOI: 10.3109/13685538.2015.1046044

ORIGINAL ARTICLE

Erectile dysfunction is a prognostic indicator of comorbidities in men with late onset hypogonadism Yousef Almehmadi1, Dany-Jan Yassin2, and Aksam A. Yassin1,3 1

Institute of Urology/Andrology, Norderstedt, Hamburg, Germany, 2Department of Urology, Klinikum Braunschweig, Braunschweig, Germany, and Dresden International University, Dresden, Germany

3

Abstract

Keywords

Introduction: The role of testosterone deficiency in erectile dysfunction (ED) is increasingly recognized; however, there is a need to clarify the nature of the relationship between ED and late onset hypogonadism (LOH). Aim: In this study, we sought to determine the correlators of ED severity amongst men with LOH. Methods: 130 patients diagnosed with LOH fulfilling the criteria of total testosterone 3.5 ng/ml (512 nmol/l) and with an erectile function domain score 521 on the International Index of Erectile Function questionnaire (IIEF questions 1–5) were enrolled for a subsequent trial of Testosterone Undecanoate. Demographic data were recorded at baseline. Main outcome measures: Subjects completed three standardised questionnaires to assess sexual health including International Prostate Symptom Score (IPSS), Aging Males Symptoms (AMS) and IIEF Sexual Health Inventory for Men (SHIM). Patients were stratified by ED severity with SHIM scores of 1–7 considered severe ED, 8–11 moderate ED and 12–16 mild to moderate. Serum testosterone, sex hormone binding globulin (SHBG) and lipids (total cholesterol, triglycerides, high-density lipoprotein and low-density lipoprotein) were assessed along with plasma fasting glucose and HbA1c. Weight, BMI and waist circumference were also recorded. Results: A significant association was observed between severity of ED and mean weight (p ¼ 0.000), waist circumference (p ¼ 0.000), triglycerides (p ¼ 0.009), total cholesterol (p ¼ 0.027), HbA1c (p ¼ 0.000), fasting glucose (p ¼ 0.003) and AMS scores (p ¼ 0.043). No significant differences were seen in testosterone fractions and SHBG levels between ED subgroups. A positive correlation existed between the prevalence of diabetes mellitus (type 1 and type 2) and ED severity in this cohort (p ¼ 0.018). Conclusions: The descriptive data of our cohort show that increased severity of ED within LOH patients correlated with an increased waist circumference, hyperglycemia, hypertriglyceridemia, hyperlipidemia and a history of diabetes mellitus. Severe ED functions as a prognostic indicator of co-morbidities in men with LOH.

Erectile dysfunction, hypogonadism, testosterone, metabolic syndrome

Introduction Longitudinal data from the Massachusetts Male Aging Study show that total testosterone concentrations gradually decline with age at a rate of 1.6% per year from approximately the third decade of life [1]. Recent evidence indicates that falling testosterone concentrations may be more directly related to body weight and composition than age per se [2–4]. However, it is this decline with age that is considered the central feature of late onset hypogonadism (LOH), ‘‘a biochemical syndrome in men with advancing age characterized by

Address for correspondence: Aksam A. Yassin, Rathausallee 94 a, 22846 Norderstedt, Hamburg, Germany. Tel: +40-40-5262157. Fax: +49-405262820. E-mail: [email protected]

History Received 16 December 2014 Revised 22 April 2015 Accepted 25 April 2015 Published online 1 June 2015

hypogonadal symptoms and either deficiency in total serum testosterone (TT) levels or low calculated free testosterone levels (below the young healthy adult male reference range)’’ [5]. LOH is a recognized diagnostic entity and is not simply a result of reduced sexual activity in elderly men. Diagnosis of LOH, however, is complicated by the syndrome’s nonspecific symptoms. Low-endogenous testosterone concentrations in the aging male population are of clinical concern, primarily due to the multitude of comorbidities that co-exist with testosterone deficiency in prevalence studies. Indeed, the majority of epidemiological studies have demonstrated that there is a high prevalence of testosterone deficiency in men with proven coronary artery disease (CAD), type 2 diabetes (T2D) and/or the metabolic syndrome (MetS) [6–9], and increasing allcause mortality risk [10–12]. Androgen deprivation therapy

ED predicts comorbidities in men with LOH

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for the treatment of prostate cancer also increases the risk of coronary heart disease (CHD), T2D and cardiovascular death [13]. Moreover, the inverse relationship between testosterone and comorbidities was shown to be true as patients with MetS were found to have an increased odds-ratio of developing hypogonadism during an 11-year follow-up period [14]. The role of low testosterone as a cause or marker of these comorbidities remains unclear, yet awareness of the associations between them is clinically relevant for screening high-risk patients. Hypogonadism includes sexual symptoms such as loss of libido, erectile dysfunction (ED), difficulty achieving orgasm and reduced sexual penile sensation [15]. Accordingly, hypogonadism is associated with a reduced number and quality of erections [16] with low-androgen levels reported in between 23 and 36% of the patients presenting with ED [17]. As such, a sub-physiological testosterone concentration is considered a predisposing factor for ED [18–20]. The prevalence of ED increases with age [21–23] and is associated with CAD risk factors such as hypertension [22,24], obesity [23,25] and smoking [26]. ED is more severe in men with diabetes and correlates with the level of glycaemic control and the duration of the disease [27–31]. Moreover, there is a strong relationship between ED and silent coronary artery disease amongst men with apparently uncomplicated type 2 diabetes [32]. The association between ED and comorbidities that are risk factors for CAD suggests that the presence and development of ED may be a warning signal for the occurrence of correlated disease. Indeed, the incidence of MetS increased with the severity of ED, as assessed by the sexual health inventory for men (SHIM), as did the presence of insulin resistance in 154 men with ED [33]. Shabsigh and colleagues also found that hypertension, high cholesterol and vascular conditions including angina, diabetes and incidence of heart attack, increased with ED severity in a cross-national survey of 28 691 men [34]. The authors suggest that ED may be a prognostic marker of overall health and an important marker of future morbidity. ED was found to be predictive of the MetS in the Massachusetts Male Aging Study (MMAS), supporting the idea that ED may be a warning sign and provide an opportunity for early intervention in men otherwise considered at lower risk of concomitant CAD [35]. Shabsigh et al. [36,37] developed the men’s health calculator which utilizes ED to raise awareness about CAD and diabetes risk. Erectile dysfunction and testosterone deficiency are both independently associated with an increased risk of CAD [38]. Testosterone deficiency is also known to be associated with a reduced health-related quality of life (HRQoL), especially with regard to sexual function [39]. Testosterone deficiency is associated with increased severity of ED [31], therefore it can be seen that LOH, ED and a reduced HRQoL are all closely interlinked [40]. Kapoor et al. [31] demonstrated that between 55 and 58% of their study population (diabetic men with ED) had low testosterone levels with approximately 40% presenting with either primary or secondary hypogonadism [31]. Zhody et al. [41] found a significant association between increasing body mass index (BMI) and frequency of ED and hypogonadism. In the cross-national survey on men’s

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health issues, higher prevalence of vascular conditions was associated with increased ED, and ED occurrence increased with age consistent with the known androgen age-related decline [34]. Additionally, in two animal models of chemically induced diabetes, testosterone was found to restore diabetes-induced ED and responsiveness to the phosphodiesterase-5 inhibitor (PDE-5i), sildenafil [42]. The role of testosterone and ED as indicators of co-morbidities, however, remains unclear, and the nature of the relationship between hypogonadism, MetS, diabetes, CAD and ED is complex. The aim of this study was to define important correlators with the severity of ED in men diagnosed with LOH and determine whether the epidemiological association between hypogonadism and ED may predict clinical co-morbidities, such as MetS and T2D, increasing CAD risk in these patients.

Methods Subjects 130 men were diagnosed with LOH, fulfilling the criteria of total serum testosterone concentration 3.5 ng/ml on two blood samples and presenting with ED (International Index of Erectile Function (IIEF) score 521 and analysis of patient history) for at least 6 months were recruited onto the study (mean age 65.2 ± 6.8 years, range 47–80 years). Following physical exam, patients were excluded if they had severe diabetes mellitus, IPSS 418, prostatitis, hyperprolactinaemia (420 ng/ml), CAD events within the last 6 months or the presence of known clinically significant diseases that would prejudice the completion of the study. All subjects consented to be included in the study, demonstrated adequate understanding of their treatment protocol and gave written informed consent in accordance with the Declaration of Helsinki and following ethical guidelines as formulated by the German ¨ rztekammer (the German Medical Association) for obserA vational studies in patients receiving standard treatment. Assessment Assessments were routinely made between 8 and 10 am to avoid diurnal fluctuations in hormonal measurements. Patients’ height and weight were recorded, and body mass index (BMI) was calculated [BMI ¼ weight (kg)/height2 (m2)]. Waist circumference was measured midway between the iliac crest and the costal margin. Laboratory tests included haematological parameters, prostate specific antigen (PSA), blood sugar, HbA1c, lipid profile, C-reactive protein, antistreptolysin, rheumatoid factor (RF) and the following hormonal parameters: total testosterone, SHBG, DHT, free androgen index, LH, FSH, prolactin (Table 1). Following the withdrawal of 20 ml of venous blood, serum samples were obtained by allowing samples to clot and centrifuged (for 10 min at 1458 g) and were immediately stored at minus 20  C until further analysis. Total testosterone and SHGB were measured by enzyme-linked immunosorbent assay (Axym System, Abbott Germany. Threshold: 10–73 nmol/l). Testosterone concentration  3.5 ng/ml (12 nmol/l) on two blood samples was considered to be low. Bioavailable and free testosterone were calculated from total testosterone and SHBG using Vermeulen’s formula, calculated as

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Table 1. Demographics of the study parameters, with population divided into three subgroups based upon IIEF-5 SHIM Scores for severity of ED. Severe

Age Weight BMI Waist circumference Total cholesterol Triglycerides LDL HDL HbA1c Glucose Haemoglobin Haematocrit Total testosterone SHBG Free testosterone Bioavailable testosterone IPSS AMS SHBG

Moderate

Mild-moderate

Cohort

Mean

SD

Mean

SD

Mean

SD

Mean

SD

p Value (one-way ANOVA)

65.7 110.4 34.1 110.9 277.4 278 166.6 40.4 7.2 119.5 14.4 41.8 2.16 29.9 0.044 1.029 12 55.01 29.9

7.3 13.1 4.1 9.4 45 75.7 26.6 16.4 1.4 37.1 1.2 4.8 0.51 21.3 0.178 0.417 4.7 6.6 21.3

65.1 101.4 33.9 104 260.5 249.6 164.5 38.5 6.4 105 14.7 42.4 2.15 35.3 0.0431 1.006 11.1 53.9 35.3

6.5 10.5 3.6 6.6 40.8 52.9 21.6 12.8 1 24.6 1.1 3.1 0.5 24.2 0.0212 0.51 4.1 7.6 24.2

62.2 101 34.2 102.2 249.5 226.8 162.8 35.4 5.8 89.5 14.7 41.9 2.28 37.2 0.0431 0.941 11.2 50.8 37.2

3.5 11.2 4 8.2 26.5 20.2 7.7 3.8 0.4 22.6 0.7 2 0.4 17.1 0.0117 0.274 4.2 6.1 17.1

65.2 106.3 34 107.6 268.6 262.8 165.5 39.2 6.7 111.4 14.5 42 2.17 32.8 0.0431 1.009 11.6 54.6 32.8

6.8 12.8 4 9.2 43 66.7 23.5 14.4 1.3 33.3 1.1 4.7 0.49 21.9 0.0186 0.436 4.4 7.2 21.9

0.227 0.000 0.962 0.000 0.027 0.009 0.813 0.482 0.000 0.003 0.506 0.801 0.685 0.414 0.830 0.824 0.536 0.043 0.414

Differences are significant when p50.05. Total cohort, N ¼ 130; severe subgroup, n ¼ 71; moderate subgroup, n ¼ 46; mild-moderate subgroup, n ¼ 13.

recommended by the International Society for the Study of the Aging Male (ISSAM). HbA1c levels were determined by high-performance liquid chromatography (HPLC). Serum glucose was measured by the hexokinase method (interassay coefficient of variation ¼ 1.5%). Serum levels of total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides were also analysed. Efficacy measures included the 5-item version of the International Index of Erectile Function (IIEF-5 [maximum score of 25] or the Sexual Health Inventory for Men (SHIM) questionnaire, see Table 1). IIEF is a validated, multidimensional, self-administrated questionnaire commonly employed to assess ED and therapeutic efficacy thereof [43]. Severity of ED was then stratified into three categories, as patients with a SHIM score of 1–7 were considered to have severe ED (S), 8–11 moderate ED (M) and 12–16 mild to moderate (MM). Patients were also asked to fill in two further standardized questionnaires Aging Males’ Symptoms questionnaire (AMS), and the IPSS to assess symptoms of aging (independent from those which are disease-related) and benign prostatic hyperplasia (BPH) respectively. Demographic data including past medical history, smoking and alcohol use were also recorded and analysed as binary or ordinal variables. Statistical analysis Statistical analyses were performed with Minitab statistical program version 15 (Minitab Inc., State College, PA). Student’s t test analysis was used to compare means of continuous variables between the ED severity groups, and comparisons between categorical variables were performed using 2 test. Confirmatory univariate and multivariate linear analysis was performed to examine the relationship between ED and associated factors. All results are expressed as means ± SD. A p value of 50.05 was considered significant.

Results Population demographics A total of 130 hypogonadal (mean serum total testosterone 2.2 ± 0.5 ng/ml) patients with a mean age 65.2 ± 6.8 years were enrolled in this study. Study participants were diagnosed with LOH by fulfilling the criteria of having total testosterone 3.5 ng/ml and presenting with ED, having an IIEF-5 score of 521. 10% of the patient population was classified as having MM ED, 35.4% had M ED and the remaining 54.6% were classified as having S ED when stratified by SHIM scores. 53.8% of the patients were smokers or ex-smokers. Baseline mean testosterone fractions of the whole study population were bioavailable testosterone 1.009 ± 0.436 nmol/l and free testosterone 0.0431 ± 0.0185 nmol/l. Diabetes was present in 33.8% of the patients with 6.2% of the total population type 1 and 27.8% type 2. Mean HbA1c levels were 6.7 ± 1.3% with a fasting glucose of 111.4 ± 33.3 mg/dl. MetS was identified in 19.2% of the population, while 4.6% were considered to have cardiovascular co-morbidity. The study population was considered obese with a mean BMI of 34.0 ± 4.0 and a waist circumference of 107.6 ± 9.2 cm. 16.9% of the study population were hypertensive and 46.2% had dyslipidemia, with total population mean lipid concentrations in the high range for total cholesterol (268.6 ± 43.0 mg/dl), LDL (165.5 ± 23.5 mg/dl), high triglyceride (262.8 ± 66.7 mg/dl) and low HDL (39.2 ± 14.4). Benign prostatic hyperplasia (BPH) was apparent in 76.2% of patients. Demographics of the study population are shown in Table 1. Associations between continuous variables and ED severity Based on IIEF-5 SHIM scores, 54.6% of the hypogonadal population was classified as having severe ED, compared to 35.4% with moderate ED and 10% with mild-moderate ED. Following stratification of ED severity, significant differences

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Figure 1. Weight and waist circumference (mean ± SD) stratified by subgroups of men with varying severity of ED [SHIM 1–7, severe ED (S), 8–11 moderate ED (M) and 12–16 mild to moderate (MM)]. *Oneway ANOVA sig. p50.05.

Figure 2. Total cholesterol and triglyceride levels (mean ± SD) between subgroups of men with varying severity of ED [SHIM 1–7, severe ED (S), 8–11 moderate ED (M) and 12–16 mild to moderate (MM)]. *Oneway ANOVA sig. p50.05.

were observed between these subgroups. Weight was significantly augmented as ED severity increased (MM, 101.0 ± 11.2 kg; M, 101.4 ± 10.5 kg; S, 110.4 ± 12.1 kg; p ¼ 0.000), as was waist circumference (MM 102.2 ± 8.2 cm; M, 104.0 ± 6.6 cm; S, 110.9 ± 9.4 cm; p ¼ 0.000) (Figure 1). However, no significant differences in BMI were observed between the three subgroups (S, 34.1 ± 4.1; M, 33.9 ± 3.6; MM 34.2 ± 4.0; p ¼ 0.962). An increased severity of ED within LOH patients correlated with hyperlipidemia. Total cholesterol levels were significantly higher amongst men with severe ED (MM, 249.5 ± 26.5 mmol/dl; M, 260.5 ± 40.8 mmol/dl; S, 277.4 ± 45 mmol/dl; p ¼ 0.027) (Figure 2). A similar association was also observed for triglyceride levels (MM,

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Figure 3. Glycosylated haemoglobin (HbA1c) levels (mean ± SD) between subgroups of men with varying severity of ED [SHIM 1–7, severe ED (S), 8–11 moderate ED (M) and 12–16 mild to moderate (MM)]. *One-way ANOVA sig. p50.05.

Figure 4. Serum fasting glucose levels (mean ± SD) between subgroups of men with varying severity of ED [(SHIM 1-7, severe ED (S), 8-11 moderate ED (M), and 12-16 mild to moderate (MM)]. *One way ANOVA Sig. p50.05.

226.8 ± 20.2; M, 249.6 ± 52.9; S, 278 ± 75.7; p ¼ 0.009) (Figure 2). Cholesterol fractions, however, were not significantly different between ED subgroups, with neither LDL levels nor HDL levels being statistically different between all groups (p ¼ 0.813, p ¼ 0.482, respectively; Table 1). Parameters of glucose control were directly proportional to the severity of ED. HbA1c levels were significantly lower amongst men with the least severe ED (MM, 5.8 ± 0.4%; M, 6.4 ± 1.0%; S, 7.2 ± 1.4%; p ¼ 0.000) (Figure 3). Poor erectile function was also associated with raised fasting glucose levels in a stepwise manner (S, 119.5 ± 37.1; M, 105.0 ± 24.6; MM, 89.5 ± 22.6; p ¼ 0.003) (Figure 4). In the three erectile function subgroups, mean AMS scores significantly increased

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with the severity of ED (mild-moderate, 50.8; moderate, 53.9; severe subgroup, 55.01; p ¼ 0.043) (Figure 5). Serum hormonal components were not associated with ED as total testosterone (p ¼ 0.685), bioavailable testosterone (p ¼ 0.824), free testosterone (p ¼ 0.830) and SHBG (p ¼ 0.414) failed to show a statistical correlation between

subgroups of differing erectile function within this hypogonadal population (Table 1). Associations between ED severity and comorbidities An increasing severity of ED was associated with a higher prevalence of type 1 and type 2 diabetes mellitus (p ¼ 0.018; Table 2; Figure 6). Also, rates of CAD were significantly increased with severity of ED (p ¼ 0.023; Table 2). No significant differences were identified between erectile function subgroups with regard to prevalence of hypertension (p ¼ 0.373), benign prostatic hyperplasia (BPH, p ¼ 0.670), hyperlipidaemia (p ¼ 0.202), MetS (p ¼ 0.505), smoking (p ¼ 0.492) or alcohol consumption (p ¼ 0.796) Table 2.

Discussion Key symptoms in the criteria for identifying LOH include the presence of ED combined with a low total or free testosterone concentration [44]. Indeed, low testosterone is implicated in the aetiology of ED and has also been shown to be associated with poor health in men, particularly with regard to CAD comorbidities [6–9,18–20]. Vascular disease is considered the most common cause of ED [45]; thereby suggesting that these ailments of elderly men are inter-linked and are not simply separate entities. ED is therefore implicated as a useful predictor of CAD co-morbidities in some patient populations [34,35]. The present study demonstrated that a high percentage of the hypogonadal population had poor erectile function, with patients classified as having the most severe ED being more likely to have correlated disease. The progression of ED

Figure 5. Total AMS Scores (mean ± SD) between subgroups of men with varying severity of ED [SHIM 1–7, severe ED (S), 8–11 moderate ED (M) and 12–16 mild to moderate (MM)]. *One-way ANOVA sig. p50.05.

Table 2. Frequencies of categorical variables stratified by severity of ED. Severe Variable Cardiovascular No Yes Diabetes No Type 1 Type 2 Hypertension No Yes BPH No Yes Hyperlipidemia No Yes Metabolic syndrome No Yes Smoking No Yes Alcohol No Rarely Occasionally Weekly Daily

Frequency 65 6

Moderate

Percentage 52 100

Mild-moderate

Frequency

Percentage

Frequency

Percentage

2 Sig.

46 0

35.4 0

13 0

10.5 0

0.023

39 6 26

45.3 75 72.2

34 2 10

39.5 25 27.8

13 0 0

15.1 0 0

0.018

60 11

55.6 50

39 7

36.1 31.8

9 4

8.3 18.2

0.373

19 52

61.3 52.5

9 37

29 37.4

3 10

9.7 10.1

0.67

43 28

61.4 46.7

22 24

31.4 40

5 8

7.2 13.3

0.202

59 12

56.2 48

37 9

35.2 36

9 4

8.6 16

0.505

40 31

57.1 51.7

25 21

35.7 35

5 8

7.2 13.3

0.492

1 19 7 3 13

50 59.4 35 33.4 48.1

1 8 8 4 11

50 25 40 44.4 40.7

0 5 5 2 3

0 15.6 25 22.2 11.2

0.796

The right hand column displays p values representing Chi squared tests between subgroups.

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Figure 6. Percentage of patients with type 2 diabetes mellitus (T2D) amongst subgroups of men with varying severity of ED [SHIM 1–7, severe ED (S), 8–11 moderate ED (M) and 12–16 mild to moderate (MM)]. *Pearson chi-square test (2) sig. p50.05.

severity in our patient cohort was associated with an increased presence of T2D. This supports the previous suggestion that men with T2D have a particularly high prevalence of hypogonadism and ED [46]. Indeed, our data and others suggest that the glycaemic control, as assessed by HbA1c, was associated with severity of ED [27–30]. We found that fasting glucose was also directly proportional to severity of ED. A relationship between low testosterone, ED and diabetes is therefore apparent. In a previous study, levels of both bioavailable and free testosterone concentrations were shown to be significantly lower in diabetic men with ED than those without, although this association did not extend to total testosterone concentrations [7]. A direct correlation between plasma testosterone levels and insulin sensitivity has been demonstrated in cross-sectional epidemiological studies, and low testosterone levels are associated with an increased risk of T2D in men [47–50]. Moreover, previous research found that 33% of diabetic men were considered testosterone deficient [51]. Klinefelter’s syndrome, the most common cause of primary hypogonadism, is additionally associated with insulin resistance and diabetes [52]. At the same time, it is well established that ED is common in diabetic men, with prevalence reported between 30 and 90% versus 26% in general population [7,53]. Mechanistically, metabolic derangements induced by hyperglycaemia may disable homeostatic penile response to erectile stimuli thus impairing the modulation of vascular contractile tone, which is crucial for normal erectile functionality [54]. Indeed, testosterone is known to influence penile vascular tone directly by facilitating the effect of endogenous vasoconstrictors and vasorelaxing agents, and maintaining the structure and function of different micro-anatomical components in the penis [55–57], but may also act indirectly by improving glycaemic control, insulin sensitivity and consequently vascular compliance [58–60]. Therefore, given the common occurrence of hypogonadism, ED and T2D and their interlinked pathologies, it is

ED predicts comorbidities in men with LOH

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suggested that diagnosis of one of these conditions should elicit inquiry into the other two conditions [46]. Obesity is a major CAD risk factor and a common co-morbidity with ED. Increased body fat is a well-known clinical feature of hypogonadism, and obese men are at an increased risk of developing hypogonadism based on an 11-year follow-up [14]. In the current study, hypogonadal men with ED had a collective BMI in the high range. Following ED stratification, a significant difference in BMI was not observed in our study. However, this may be indicative of known limitations associated with the use of BMI as a prognostic indicator of obesity [61]. Central, or visceral, obesity may be more reflective of underlying CAD risk [62]. Indeed, weight and waist circumference were both significantly higher amongst individuals with the most severe ED in this study cohort, potentially implying an underlying association between visceral obesity and erectile function in LOH. Total cholesterol and triglyceride levels were also significantly higher amongst men in the subgroup with the most severe ED. Despite this, cholesterol fractions, namely HDL and LDL levels, were comparable between the three subgroups with differing erectile function, and an association between ED severity and hyperlipidemia was not apparent. Similarly, prevalence of hyperlipidaemia in the present study was comparable between ED subgroups potentially due to these HDL and LDL findings. Dysfunctional lipid homeostasis, in some cases, is known to lead to incorrect adipose tissue storage creating a lipid ‘‘spillover’’ effect into non-adipose tissue [63]. Of interest, adipocyte accumulation in the corpus cavernosum of penile tissue has been proposed as one of the underlying reasons for veno-occlusive dysfunction in hypogonadal animals [64]. The link between testosterone and obesity is complicated by uncertainty regarding causality, with obesity-induced androgen deficiency and hypogonadism-induced obesity apparent. However, as testosterone levels are directly related to erectile function [31], the diagnosis of obesity and ED should prompt assessment of testosterone levels and subsequently correlated CAD comorbidities. The correction of testosterone levels through replacement therapy in hypogonadal men has been shown to produce sustained weight loss (indicated by BMI, body weight and WC) over 5 years suggesting that testosterone influences obesity and has potential therapeutic benefits [65]. Strong epidemiological evidence links the subsequent risk of ED to the presence of well-recognized risk factors for coronary heart disease, such as increased body weight, hypertension and dyslipidemia [66,67]. Although ED severity was associated with CAD risk factors (HbA1c, fasting glucose, total cholesterol, triglycerides and history of diabetes) in men with LOH in our study, only a trend towards a difference in history of CAD was identified between ED groups. This could perhaps be explained by the existence of a latent period between the presentation of ED and the development of symptomatic CAD of 5–10 years [68]. These data suggest that ED may be a prognostic indicator for the development of cardiovascular morbidity, and there is a consensus that ED in the otherwise asymptomatic man may be a marker for underlying coronary artery disease (CAD) [69]. Indeed, hypogonadism and ED have emerged as predictors of CAD [46]. Gazzaruso et al. evaluated the

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prevalence of ED in 133 uncomplicated diabetic men with silent CAD and 127 diabetic men without myocardial ischemia [32]. One third of patients with CAD displayed ED, assessed by IIEF-5, in contrast to only 5% of patients without silent myocardial ischemia demonstrating an 8-fold higher prevalence. The authors suggest that in uncomplicated T2DM patients at relatively low risk for CAD, ED should be regarded as a potential predictor of silent CAD [32]. Due to the increased risk of CAD amongst men with LOH [70], findings from the present study similarly support a role for routinely assessing the severity of ED to identify individuals at increased risk of CAD. Therefore, the IIEF-5 questionnaire or SHIM scores may be regarded not only as tools to screen ED, but also as potential tools to assess the global CAD risk profile of men with LOH. AMS scores in our patient cohort showed a linear relationship with the severity of ED, with AMS questionnaires being scored more positively amongst men with the worst severity of ED. This supports the use of the AMS questionnaire in individuals with LOH as it is sensitive to the severity of patients’ sexual function and indicates patient’s perceived quality of life (QoL). Furthermore, improvement of BMI correlated with both improvements of IIEF and AMS in 184 men suffering from both the MetS and hypogonadism treated with testosterone undecanoate, thus further showing the link between obesity, sexual function and QoL [71]. In contrast to previous findings [31], levels of total testosterone and testosterone fractions were not associated with the severity of ED in this patient cohort. Statistical analysis did not show significant differences between the subgroups, despite total testosterone levels appearing to be higher amongst men with the least severe ED. This observation was, however, contradicted by the free and bioavailable testosterone fractions which were slightly reduced amongst men with the least severe ED, although not statistically significant. As patients enrolled in this study were hypogonadal with a testosterone level of 3.5 ng/ml as inclusion criteria, further differences within the ED stratified groups may not be detectable within these low levels. These results highlight the need for further studies to quantify any relationship between testosterone levels and erectile function in hypogonadal males. A limitation of this study is that correlations and regression analyses were used to analyse data retrospectively. This prevents us from drawing conclusions about the direction of identified relationships between any two factors. Therefore, it is difficult to draw conclusions about causal relationships, despite the strength of evidence presented. The complexities of defining a cause and effect relationship between low testosterone and vascular disease are noted in the literature. Indeed, Araujo et al. suggest that CAD in hypogonadal patients is driven by underlying health status and that low testosterone is simply a marker of poor general health [72]. Similarly, rather than a disease in itself, ED is sometimes considered a manifestation of pathologies of the biological systems involved in erectile function and including the vasculature, particularly in elderly men with normal sexual function earlier in life [34]. One study has even suggested a correlation between ED and CAD severity [73]. It is likely that a bidirectional effect between hypogonadism and disease

Aging Male, 2015; 18(3): 186–194

pathology exists as concomitant CAD risk factors (including obesity and insulin resistance) are known to reduce testosterone levels and that testosterone confers beneficial effects on these CAD risk factors [74]. More interventional studies utilizing testosterone replacement are needed to determine a causal relationship between testosterone and CAD morbidity in the context of ED. Indeed, a recent study investigating long-term testosterone treatment in elderly hypogonadal men with ED demonstrated improved cardiovascular risk factors including parameters of metabolic syndrome, obesity (BMI, body weight, WC), HbA1c, glucose, LDL, HDL, triglycerides, blood pressure and self-assessed quality of life [75].

Conclusions These data indicate that in some LOH patients severity of ED is associated with an increased waist circumference, hyperglycemia, hypertriglyceridemia, hyperlipidemia and a history of diabetes mellitus. A close relationship therefore exists between hypogonadism and CAD risk factors, and an integral diagnostic approach may be of clinical relevance. Severe ED may function as a prognostic indicator of poor health and CAD co-morbidities in men with LOH. Worsening of ED scores in LOH patients should draw the attention of physicians towards the presence of concomitant disease and risk factors such as new onset diabetes, visceral obesity and dyslipidaemia, or more likely the worsening of common co-morbidities. Early indication may allow for not only therapeutic improvement of symptoms but also potentially reduction of concurrent disease and subsequent CAD events.

Acknowledgements We would like to thank the editorial support for the manuscript provided by Astra-Health, www.astrahealth.co.uk.

Declaration of interest Aksam Yassin has occasionally received honoraria for lectures from Bayer Pharma, Germany; Ferring Pharmaceuticals, Germany; and Glaxo-Smith-Kline, Germany. Dany-Jan Yassin and Yousef Almehmadi have nothing to disclose.

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