Testosterone levels in men with erectile dysfunction

Original Article TESTOSTERONE LEVELS IN MEN WITH ED MARTÍNEZ-JABALOYAS et al. Testosterone levels in men with erectile dysfunction JOSÉ M. MARTÍNEZ-JABALOYAS, ALFONSO QUEIPO-ZARAGOZÁ*, FRANCISCO PASTOR-HERNÁNDEZ, MANUEL GIL-SALOM and PASCUAL CHUAN-NUEZ Servicio de Urología and *Laboratorio de Bioquímica Clínica, Hospital Clínico Universitario de Valencia, Spain Accepted for publication 20 January 2006 OBJECTIVE To investigate the frequency of hypogonadism in men with erectile dysfunction (ED) and to assess which factors are related with low testosterone levels. PATIENTS AND METHODS In all, 165 men with ED were assessed; the evaluation included: hormonal profiles, serum total and free testosterone (using Vermeulen s formula) levels, and self-reported questionnaires on erectile function and desire domains of the International Index of Erectile Function. The frequency of hypogonadism was established using total and free testosterone levels as diagnostic criteria. The factors that might influence testosterone levels were evaluated by univariate and multivariate statistical analysis, and a logistic regression was used to determine which factors can predict free testosterone levels below normal limits (biochemical hypogonadism). RESULTS Using the total testosterone levels, 4.8% of the men were hypogonadal, whereas when using the free testosterone levels, 17.6% were hypogonadal. In the univariate analyses, not smoking and hypertension were associated with lower total and free testosterone levels. Ageing, absence of nocturnal erections and a lower erectile function score were only associated with lower free testosterone serum levels. There was no association between total and free testosterone levels and desire. In the multivariate analysis, only total testosterone levels were related to hypertension, while free testosterone levels were related to age and nocturnal erections. For biochemical hypogonadism, simple logistic regression analysis selected age, erectile function score and aetiological diagnosis of ED as predictors. In the multivariate analysis only the erectile function score had significant independent prognostic value. CONCLUSIONS The frequency of hypogonadism is higher when free testosterone levels are used for diagnosis. The total and free testosterone levels were not related to the level of sexual desire in men with ED. The free testosterone levels could be related to the quality and frequency of nocturnal erections, and when ED is more severe, it is more probable that free testosterone levels are below the normal limit. KEYWORDS testosterone, erectile dysfunction, hypogonadism, andropause. INTRODUCTION Ageing is associated with a progressive decline in serum testosterone levels, which mainly affects free testosterone [1], and there is a direct relationship between the occurrence and severity of erectile dysfunction (ED) and ageing [2]. Although these events coincide, they might not be directly related, and there is considerable controversy about the importance of androgens in the initiation and maintenance of erection. However, several data support the theory that free testosterone is associated with sexual function [3]. There is wide interest in testosterone deficiency in men with ED. Some authors favour determining testosterone levels only when there is a decrease in libido or bilateral testicular atrophy [4]. However, hypogonadism in adults (except in the most severe cases) is difficult to diagnose without biochemical studies [5]. It was recently shown that testosterone plays a permissive role in erectile function. The expression of nitric oxide synthase depends on adequate androgen levels, and androgen deprivation might affect the expression of the phosphodiesterase type-5 (PDE-5) gene [6]. It was also reported that some men with hypogonadism and ED who do not respond to PDE-5 inhibitors might respond to an androgenic supplement [7]. Therefore, although many points need to be clarified, it seems clear that testosterone is important in the erection mechanism. In the present study we analysed the total and free testosterone levels in a group of men with ED, and assessed the relationship of these levels with their clinical background and sexual function. PATIENTS AND METHODS A prospective study was carried out on 165 men referred to our urology clinic for ED, which was the sole inclusion criterion. Exclusion criteria were: a previous history of radical pelvic surgery, the use of concomitant treatments that could modify hormone levels, clinical antecedents of known hypogonadism and/or hyperprolactinaemia, and severe penile deformity. The men were included sequentially, and were evaluated by a history, physical exploration, standard blood test, including glycaemia, lipid and hormonal profiles, and any complementary examinations considered necessary for an approximate aetiological diagnosis (intracavernosal injection with prostaglandin E 1, Doppler ultrasonography, somatosensory evoked potentials by pudendal nerve stimulation). Nocturnal erections were classed as absent, occasional penile tumescence, and frequent rigid erections according to each patient s account. All of the men answered the erectile function and sexual desire domains of the International Index of Erectile Function (IIEF). Men with a clinical background consistent with vascular or neurological disorders were also evaluated 1278 JOURNAL COMPILATION 2006 BJU INTERNATIONAL 97, 1278 1283 doi:10.1111/j.1464-410x.2006.06154.x

TESTOSTERONE LEVELS IN MEN WITH ED by dynamic Doppler ultrasonography or somatosensory evoked potential by pudendal nerve stimulation, when indicated. Men with abnormal results were classified as organic ED, even when additional psychological components were present. Men were classified as psychogenic ED if no risk factors or clinical data of organic diseases were detected, or when diagnostic test results were normal. Blood samples were collected between 08.00 and 10.00 hours, and hormonal tests included total testosterone (Chemiluminescent Microparticle Immunoassay, Abbott Laboratories, Abbott Parks, IL, USA), sexhormone binding globulin (SHBG; DELFIA SHBG kit, fluoroimmunoassay, WALLAC Oy, Turku, Finland), free testosterone, FSH, LH and prolactin. Free testosterone was determined using the second-degree equation developed by Vermeulen et al. [8]: ([T] (N [FT]))/(K t {SHBG [T] + N[FT]}) Eq 1 where: N = K a C a + 1; K a is the association constant of SHBG for free testosterone; K a is the association constant of albumin for testosterone; C a is the albumin concentration; FT is free testosterone; and T is total testosterone. Before this study, we established normal limits for free testosterone using 129 healthy men aged 18 45 years as, according to the recommendations of the International Society for the Study of the Aging Male, free testosterone levels in ageing men should be compared with the normal range in young men [9]. The relationship between total and free testosterone levels (dependent variable) and age, medical histories, aetiology of the ED, and the IIEF results (erectile function and sexual desire domains), was analysed. The means of independent qualitative variables were compared (Student s t-test and ANOVA for results with a normal distribution, and Mann Whitney U-test and Kruskal Wallis for non-normal distributions). For independent quantitative variables, a simple linear regression analysis was used. The multivariate study consisted of a multiple linear regression analysis. The frequency of hypogonadism was described according to total and free testosterone levels. The variables were analysed using a simple and multiple logistic regression analysis to determine which could predict free testosterone levels below the normal limit. Variables giving significance levels of P < 0.3 in the univariate analyses were included in the multivariate analysis. RESULTS The mean (SD) age of the men was 55 (10) years. Their clinical backgrounds are outlined in Table 1: 37% were smokers and 24.2% ex-smokers; 26.7% drank 7 21 units of alcohol (56 168 g ethanol) per week and 6.7% drank >21 units (>168 g ethanol); 24.8% had a history of hypertension, 23.6% diabetes mellitus, 19.4% dyslipidaemia, and 7.9% ischaemic cardiopathy. The mean (SD) time for the development of ED was 29 (27) months. The mean IIEF score for the ED domain was 12 (6); ED was classified as severe in 70 men (42.4%), moderate in 48 (29.1%) and mild in 47 (28.5%). The mean score for the sexual desire domain was 5.98 (2.14);. 36% of the men reported no nocturnal erections, and in 54.5% of the cases ED was classified as organic and in 45.5% as psychogenic (Table 1). The mean (SD) total testosterone level was 19.66 (7.08) nmol/l, the free testosterone level was 0.336 (0.101) nmol/l, and the SHBG level was 47.7 (24.1) nmol/l. There was no significant difference in SHBG levels between men grouped according to clinical background (Table 1). The lower limit of normal free testosterone in our reference population was 0.228 nmol/l, and the normal limits for total testosterone were from 9.720 to 27.760 nmol/l (2.8 8 ng/ ml). Using total testosterone levels as the diagnostic criterion for hypogonadism, only eight men (4.8%) were below the normal limit, but using free testosterone levels, 29 (17.6%) were hypogonadal. The results of the univariate analyses are shown in Tables 1 and 2. There was a significant decline in free testosterone with age, but although total testosterone also declined with age, this relationship was not statistically significant (Table 2). Smokers and normotensive men had significantly higher total and free testosterone levels than nonsmokers and hypertensive men, respectively. Men with frequent, rigid nocturnal erections also had significantly higher free testosterone levels than men without nocturnal erections or with only occasional tumescence (Table 1). Diabetic men had lower free testosterone levels, but this was not statistically significant. Free testosterone levels were significantly lower when the IIEF score for the ED domain was lower, but this was not the case for total testosterone levels. There was no relationship between total and free testosterone levels and desire (Table 2). In the multivariate analysis, total testosterone levels were related only to hypertension, while free testosterone was related both to age and nocturnal erections (Table 3). In the simple logistic regression analysis for the presence of hypogonadism according to free testosterone levels (Table 4), age, the IIEF score for erectile function, and aetiological diagnosis for the ED were selected as significant predictors. However, in the multivariate analysis, only the IIEF score had significant independent prognostic value. Therefore, the higher the erectile function score, the higher the probability that free testosterone levels were below the normal range. DISCUSSION Sexual behaviour is influenced by several factors, and the role of testosterone is not clear. Total testosterone levels decline by 1% per year from 50 years of age onwards [10], but there are large differences between individuals, and so it is hard to show a statistically significant relationship with age [11]. Serum levels of free testosterone also differ between individuals, but show a more pronounced and consistent fall as age increases [10,12]. In the present study, only 5% of the men had subnormal levels of total testosterone, but 18% had subnormal levels of free testosterone. As the active form is free testosterone, many cases of hypogonadism would not be diagnosed if only total testosterone were measured. Therefore, the present study confirms that it is better to measure free testosterone rather than total testosterone [13]. Some authors who do not favour the routine determination of testosterone use total testosterone levels as a diagnostic test for hypogonadism [14] because this is the simplest and most economical way to assess androgenic function. However, if total JOURNAL COMPILATION 2006 BJU INTERNATIONAL 1279

MARTÍNEZ-JABALOYAS ET AL. TABLE 1 The total testosterone, free testosterone and SHBG levels (all nmol/l) according to clinical background (qualitative variables) Total testosterone Free testosterone SHBG Variable N (%) Mean (SD) P Mean (SD) P P Mean (SD) Smoking Never 64 (38.8) 19.25 (7.26) 0.319 (0.097) 49.0 (25.1) Current 61 (37.0) 21.13 (6.58) 0.047* 0.364 (0.109) 0.044* 48.5 (21.8) n.s* Former 40 (24.2) 18.10 (7.26) 0.322 (0.089) 44.8 (22.2) Alcohol intake, units/week <7 110 (66.7) 19.70 (7.02) 0.332 (0.099) 49.0 (23.9) 7 21 44 (26.7) 19.24 (6.95) n.s* 0.349 (0.111) n.s* 43.0 (18.0) n.s* >21 11 (6.7) 21.12 (8.69) 0.327 (0.090) 57.1 (33.1) Hypertension No 124 (75.2) 20.41 (7.17) 0.021 0.347 (0.105) 0.03 48.7 (24.1) n.s Yes 41 (24.8) 17.46 (6.39) 0.307 (0.083) 45.6 (20.7) Diabetes mellitus No 126 (76.4) 19.60 (6.69) n.s 0.344 (0.104) n.s 46.0 (19.5) n.s Yes 39 (23.6) 19.86 (8.26) 0.314 (0.092) 54.4 (32.3) Dyslipidaemia No 133 (80.6) 19.55 (6.88) n.s 0.335 (0.098) n.s 47.5 (22.6) n.s Yes 32 (19.4) 19.29 (6.51) 0.327 (0.087) 49.3 (25.6) Ischaemic cardiopathy No 152 (92.1) 19.55 (7.04) n.s 0.334 (0.097) n.s 47.6 (23.4) n.s Yes 13 (7.9) 21.01 (7.73) 0.327 (0.077) 51.1 (20.7) Nocturnal erections Absent 60 (36.3) 19.23 (6.92) 0.310 (0.093) 50.6 (28.9) Occasional tumescence 53 (32.2) 18.62 (5.50) n.s 0.318 (0.083) 0.002 47.8 (21.0) n.s* Frequent erections 52 (31.5) 21.37 (6.48) 0.377 (0.113) 44.5 (16.7) Aetiological diagnosis Psychogenic 75 (45.5) 19.83 (6.40) n.s 0.354 (0.108) n.s 45.0 (19.0) n.s Organic 90 (54.5) 19.53 (7.60) 0.322 (0.094) 50.2 (26.0) n.s, no significant differences; *Kruskal Wallis; Student s t-test; Mann Whitney U-test; ANOVA; 7 units of alcohol &EQUALS; 56 g ethanol and 21 units of alcohol = 168 g ethanol. testosterone levels are used for endocrine screening in ED, only 6.6% of the cases of hypogonadism are detected [15]. A rise in SHBG with age was reported, which implies an increase in total testosterone [10] with no increase in the biologically active fraction (free and albumin-bound testosterone). Thus, the diagnosis of hypogonadism in men aged 60 years rises from 7% when total testosterone level is used, to 35% when free testosterone is used [16]. Similarly, when bioavailable testosterone levels are determined, 42% of men are wrongly classified, with 26% false-negatives and 16% false-positives [17]. For these reasons, bioavailable testosterone and free testosterone are the indicators of choice for biochemical hypogonadism [9]. The methods for measuring free testosterone are also controversial, and its calculation using Vermeulen s formula [8] is the method of choice [9]. TABLE 2 Simple linear regression for total and free testosterone levels (dependent variables) and age, time of development of ED, IIEF desire domain score, IIEF erectile function domain score (independent quantitative variables) Total testosterone Free testosterone Variable r B P r B P Age 0.144 0.098 n.s 0.332 0.003 <0.001 Time of ED evolution 0.038 0.010 n.s 0.019 0.0006 n.s Desire 0.057 0.189 n.s 0.078 0.004 n.s Erectile function 0.043 0.047 n.s 0.154 0.002 0.045 r, Pearson correlation coefficient; B, regression coefficient (coefficient of linear regression equation); n.s, no significant difference. In the present study, we analysed the relationship between total testosterone levels and patients characteristics, but only found a significant association between low total testosterone levels and arterial hypertension. This relationship was also reported in previous studies [18,19], and it was proposed that low testosterone levels could cause hypertension via compensatory hyperinsulinaemia [19]. Free testosterone levels are independently related to nocturnal erections. Spontaneous 1280 JOURNAL COMPILATION 2006 BJU INTERNATIONAL

TESTOSTERONE LEVELS IN MEN WITH ED Variable B β P r Total testosterone Hypertension 2.952 0.204 0.016 0.204 Free testosterone Age 0.003 0.288 0.001 0.370 Nocturnal erections 0.019 0.168 0.045 B, coefficient of linear regression equation; β, standardized regression coefficient (dimensionless coefficient, an indicator of the relative importance of variables); r, Pearson correlation coefficient. TABLE 3 Multiple regression linear analysis for total and free testosterone (dependent variables) and age, clinical backgrounds, aetiological diagnosis ED, nocturnal erections, and erectile function domain score (independent variables) TABLE 4 Logistic regression analysis for hypogonadal values of free testosterone and the different variables studied Univariate Multivariate Variable OR (95% CI) P OR (95% CI) P Age 1.05 (1.01 1.10) 0.024 0.063 Smoking 0.566 Never 1.00* Former 0.99 (0.37 2.67) 0.988 Current 0.62 (0.23 1.61) 0.324 Alcohol intake, units/week 0.511 <7 1.00* 7 21 0.63 (0.23 1.67) 0.351 >21 0.43 (0.05 3.58) 0.434 Hypertension 0.098 0.208 Yes 2.06 (0.88 4.83) Dyslipidaemia 0.395 Yes 0.61 (0.20 1.90) Ischaemic cardiopathy 0.376 Yes 0.39 (0.05 3.14) Diabetes mellitus 0.165 0.253 Yes 1.85 (0.78 4.41) Time ED evolution, months 1.01 (0.99 1.02) 0.343 Nocturnal erections 0.151 Absence 1.00* Occasional tumescence 0.61 (0.23 1.65) 0.336 Frequent erections 0.31 (0.09 1.03) 0.056 Erectile function domain IIEF 0.90 (0.84 0.96) 0.002 0.90 (0.84 0.96) 0.002 Sexual desire domain IIEF 1.05 (0.87 1.27) 0.624 Aetiological diagnosis 0.022 0.100 Psychogenic 1.00* Organic 2.91 (1.16 7.28) *reference category; 7 units of alcohol = 56 g ethanol, and 21 units of alcohol = 168 g ethanol. reports, while Foresta et al. used nocturnal penile tumescence and rigidity monitoring), it must be taken into account that the men studied by Foresta et al. had no pathological history. It is possible that when diverse risk factors are implicated in irregularity of the vascular endothelium, low testosterone levels have more influence on the erection mechanism. Nevertheless, in the present study we found no independent relationship between nocturnal erections and whether testosterone levels were in the normal range or subnormal, as the testosterone threshold at which sexual behaviour is affected is not constant, and inter-individual differences are apparent [20,23]. Hypogonadism is more likely when the IIEF score is higher; i.e., when ED is more severe, it is more likely that free testosterone levels are subnormal. Ahn et al. [24] found a relationship between free testosterone levels (but not total testosterone levels) and the erectile function domain, but no association between desire and either the total or free testosterone level [24]. Rhoden et al. [25] found no relationship between total testosterone and ED, even in men with severe ED and attending for an assessment of the prostate. The cause of the independent relationship between free testosterone levels and the severity of ED is hard to establish. The role of androgens in modulating the synthesis and action of neurotransmitters [6], in addition to the apoptosis of cavernosal cells induced after androgenic decline [26], would allow an increase in cavernosal diastolic flow and a decrease in systolic flow, as shown in studies using Doppler ultrasonography to evaluate men with severe hypogonadism [27]. Therefore, hypoandrogenism associated with other factors might cause a greater deterioration of erectile function in ageing men. The loss of sexual activity because of ED causes a reduction in total and free testosterone levels, which reverses when sexual activity is reinitiated after the ED is resolved [28]. Severe ED would therefore cause a loss of sexual activity, causing testosterone levels to fall further, causing a further deterioration of erectile function. nocturnal erections seem to be androgendependent, and are worse in hypogonadal men (in terms of rigidity and tumescence) than in eugonadal men [20,21]. By contrast, Foresta et al. [22] found no relationship between biochemical hypogonadism in healthy men aged >50 years and nocturnal penile tumescence recorded by the Rigi-Scan system. In addition to methodological differences (we used individual patient s Testosterone is directly related to sexual desire, and it was suggested that testosterone should only be measured when there is a complete loss of sexual desire [4]. However, the relationship between sexual desire and testosterone levels is less clear in older men. As in the present study, Ahn et al. [24] found JOURNAL COMPILATION 2006 BJU INTERNATIONAL 1281

MARTÍNEZ-JABALOYAS ET AL. no relationship between testosterone levels and sexual desire. Predicting low testosterone levels from a decrease in sexual desire has low specificity, sensitivity and efficiency [15]. Sexual desire involves complex biological and psychological mechanisms on which testosterone has a significant impact during puberty [29], but the influence of testosterone is less clear when the decrease in sexual desire is not obvious, as in late-onset age-related hypogonadism. Androgens are necessary (but not sufficient) for normal sexual desire, and the required hormone levels are not established clearly [30]. Finally, there is a lack of uniformity regarding the use of total, free or bioavailable testosterone in studies of the relationship between testosterone and ED. As the two biologically active fractions are free and bioavailable testosterone, criteria for their use should be unified. These are the hormones that should be used for comparing results and for establishing the critical hormone levels in these men, as well as for evaluating their relationship with the different variables analysed. In conclusion, when free testosterone levels are evaluated, some men can be diagnosed as hypogonadal who cannot be diagnosed from total testosterone levels. An effort should be made to determine free or bioavailable testosterone, with the aim of using uniform criteria that make it easier to compare results. The serum levels of total and free testosterone are not related to the level of sexual desire in men with ED. Free testosterone levels might be related to the quality and frequency of nocturnal erections, and when ED is more severe, it is more likely that free testosterone levels are subnormal. CONFLICT OF INTEREST None declared. REFERENCES 1 Tenover JS. Declining testicular function in aging men. 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TESTOSTERONE LEVELS IN MEN WITH ED Garolla A, Ferlin A. Role of androgens in erectile function. J Urol 2004; 171: 2358 62 28 Jannini EA, Screponi E, Carosa E et al. Lack of sexual activity from erectile dysfunction is associated with a reversible reduction in serum testosterone. Int J Androl 1999; 22: 385 92 29 Meuleman EJ, van Lankveld JJ. Hypoactive sexual desire disorder: an underestimated condition in men. BJU Int 2005; 95: 291 6 30 Rochira V, Zirilli L, Madeo B, Balestrieri A, Granata AR, Carani C. Sex steroids and sexual desire mechanism. J Endocrinol Invest 2003; 26 (Suppl. 3): 29 36 Correspondence: José M. Martínez-Jabaloyas, Servicio de Urología. Hospital Clínico Universitario, Avda. Blasco Ibáñez 17, 46.010. Valencia, Spain. e-mail: jaba@pulso.com Abbreviations: ED, erectile dysfunction; PDE, phosphodiesterase; IIEF, International Index of Erectile Function; SHBG, sex-hormone binding globulin. JOURNAL COMPILATION 2006 BJU INTERNATIONAL 1283