Valentina Boddi

Low Testosterone is Associated with an Increased Risk of MACE Lethality in Subjects with Erectile Dysfunction

INTRODUCTION Although testosterone (T) has been suggested to play a protective role against the development of atherosclerosis, studies demonstrating an association between low T and incident major adverse cardiovascular events (MACE) are scanty in the general population and absent in subjects with erectile dysfunction (ED). AIM To investigate whether low T in subjects with ED predict incident fatal or nonfatal MACE. METHODS This is an observational prospective cohort study evaluating a consecutive series of 1687 patients attending our andrological unit for ED. Patients were interviewed using the structured interview on erectile dysfunction (SIEDY) and ANDROTEST structured interviews measuring components relative to ED and hypogonadal-related symptoms, respectively. MAIN OUTCOME MEASURES Total T was evaluated at baseline. Information on MACE was obtained through the City of Florence Registry Office. RESULTS Among the patients studied, 5.2, 13.8, and 22.4% were hypogonadal according to different thresholds (T < 8, 10.4 and 12 nmol/L or 230, 300 and 350 ng/dL, respectively). During a mean follow-up of 4.3 + or - 2.6 years, 139 MACE, 15 of which were fatal, were observed. Unadjusted incidence of MACE was not associated with T levels. Conversely, the proportion of lethal events among MACE was significantly higher in hypogonadal patients, using either 10.4 nmol/L (300 ng/dL) or 8 nmol/L (230 ng/dL) thresholds. However, after adjustment for age and Chronic Diseases Score in a Cox regression model, only the association between incident fatal MACE and T < 8 nmol/L (230 ng/dL) was confirmed (HR = 7.1 [1.8-28.6]; P < 0.001). Interestingly, measuring hypogonadal-related symptoms and signs through ANDROTEST, only fatal MACE were also associated with a higher score (HR = 1.2 [1.0-1.5] for each ANDROTEST score increment; P = 0.05 after adjustment for age and Chronic Diseases Score). CONCLUSIONS T levels are associated with a higher mortality of MACE. The identification of low T levels should alert the clinician thus identifying subjects with an increased cardiovascular risk.

Male Sexuality and Cardiovascular Risk. A Cohort Study in Patients with Erectile Dysfunction

INTRODUCTION Although penile blood flow (PBF) has been recommended as an additional diagnostic test in identifying erectile dysfunction (ED) patients at risk for latent cardiovascular disease, no study has ever assessed the possible association of PBF and the relational component of sexual function with incident major cardiovascular events (MACE). AIM The aim of this study is to investigate whether severity of ED, PBF, and other factors related to a couples relationship predict incident MACE. METHODS A consecutive series of 1,687 patients was studied. Different clinical, biochemical, and instrumental (penile flow at color Doppler ultrasound) parameters were evaluated. MAIN OUTCOME MEASURES Information on MACE was obtained through the City of Florence Registry Office. RESULTS During a mean follow-up of 4.3 +/- 2.6 years, 139 MACE, 15 of which were fatal, were observed. Cox regression analysis, after adjustment for age and Chronic Disease Score, showed that severe ED predicted MACE (hazard ratio [HR] 1.75; 95% confidence interval 1.10-2.78; P < 0.05). In addition, lower PBF, evaluated both in flaccid (before) and dynamic (after prostaglandin-E1 stimulation) conditions, was associated with an increased risk of MACE (HR = 2.67 [1.42-5.04] and 1.57 [1.01-2.47], respectively, for flaccid [<13 cm/second] and dynamic [<25 cm/second] peak systolic velocity; both P < 0.05). Reported high sexual interest in the partner and low sexual interest in the patient proved to have a protective effect against MACE. CONCLUSIONS The investigation of male sexuality, and in particular PBF, and sexual desire, could provide insights not only into present cardiovascular status but also into prospective risk.

ORIGINAL RESEARCH–EPIDEMIOLOGY: Selective Serotonin Reuptake Inhibitor-Induced Sexual Dysfunction

INTRODUCTION Sexual dysfunctions are often present in subjects with mood disturbances; however. antidepressants can induce per se sexual dysfunctions. AIM To explore the relationship between the use of selective serotonin reuptake inhibitors (SSRIs), non-SSRIs antidepressants and benzodiazepines (BDZ), hormonal parameters, and reported sexual dysfunction (as assessed by the Structured Interview on Erectile Dysfunction [SIEDY]) in male subjects with comparable psychopathological symptoms (as assessed by the Middlesex Hospital Questionnaire [MHQ] a self-reported test for the screening of mental disorders in a non-psychiatric setting). METHODS A consecutive series of 2,040 (mean age 51 +/- 13 years) male patients with sexual dysfunction was studied. MAIN OUTCOME MEASURES Several hormonal and biochemical parameters were investigated, along with SIEDY and the MHQ. RESULTS Higher prolactin was observed only in patients using SSRIs, whereas no other hormonal difference was found after adjustment for confounders. Use of SSRIs was associated with a twofold risk for patient hypoactive sexual desire and with a higher impairment of reported erectile function. However, no difference in penile blood flow was observed. A very high risk (sevenfold) for delayed ejaculation (DE) was observed in SSRI users. Interestingly, the association with the mild, but not severe, form of DE was observed also in subjects using non-SSRI antidepressants (3.35 [1.48-7.59]; P < 0.005). Different life stressors and relational parameters were also associated with SSRI use. SSRI users reported less enjoyment with masturbation and decreased partner desire and climax. Conversely, a lack of significant association was observed among BDZ or non-SSRI antidepressant users and all the aforementioned life-stressors and relational parameters. CONCLUSIONS SSRIs can negatively affect all the steps of the male sexual response cycle (desire-arousal-excitement-orgasm). SSRI-associated sexual dysfunction has a deleterious effect on both auto- and couple-erotic performances. Conversely, other antidepressants and BDZ are less often associated with sexual impairment.

The age-related decline of testosterone is associated with different specific symptoms and signs in patients with sexual dysfunction.

In males, testosterone (T) levels decline with ageing. Several symptoms characteristic of the ageing process are similar to those related to hypogonadism. The aim of the present study was to evaluate the specific association among hypogonadism-related symptoms and signs and the ageing process. A consecutive series of 1647 (mean age 52.4 +/- 13.1 years) male patients with sexual dysfunction were investigated. Several hormonal and biochemical, instrumental and psychological parameters were studied. The parameters significantly associated with total levels in the entire cohort, after adjustment for confounders, were studied as a function of age and T quartiles. In all age quartiles, low T was associated with higher waist circumference and triglyceride levels and with an increased prevalence of metabolic syndrome. The prevalence of hypoactive sexual desire decreased as a function of T only in the youngest (17- to 42-year old) age quartile as well as the reported reduction in nocturnal erections. In the oldest age quartile, we found an inverse relationship between T levels and the prevalence of severe erectile dysfunction and a positive relationship with intercourse frequency. Accordingly, in the oldest age quartile, subjects with higher T levels showed better penile flow at penile colour doppler ultrasound as well as a better lipid profile. Finally, an inverse association between somatized anxiety and T levels was observed only in the oldest age quartile. In conclusion, our study shows for the first time that in subjects with sexual dysfunction, some hypogonadism-related symptoms can be age-specific. In particular, low T is associated with sexual dysfunction more often in the oldest subjects.

Premature and delayed ejaculation: two ends of a single continuum influenced by hormonal milieu.

Although it is well established that all the aspects of male reproduction are hormonally regulated, the endocrine control of the ejaculatory reflex is still not completely clarified. Sex steroids, thyroid and pituitary hormones (oxytocin and prolactin) have been proposed to control the ejaculatory process at various levels; however, only a few reports are currently available. The aim of this study was to evaluate the contribution of testosterone, thyrotropin (TSH) and prolactin (PRL) in the pathogenesis of ejaculatory dysfunction in a large series of subjects consulting for sexual dysfunction. Among the 2652 patients studied, 674 (25.2%) and 194 (7.3%) reported premature and delayed ejaculation (PE and DE), respectively. Categorizing ejaculatory difficulties on an eight-point scale starting from severe PE and ending with anejaculation (0 = severe PE, 1 = moderate PE, 2 = mild PE, 3 = no difficulties, 4 = mild DE, 5 = moderate DE, 6 = severe DE and 7 = anejaculation), PRL as well as TSH levels progressively increased from patients with severe PE towards those with anejaculation. Conversely, the opposite was observed for testosterone levels. All of these associations were confirmed after adjustment for age (adjusted r = 0.050, 0.053 and -0.038 for PRL, TSH and testosterone, respectively; all p < 0.05). When all hormonal parameters were introduced in the same regression model, adjusting for age, ΣMHQ (an index of general psychopathology) and use of selective serotonin reuptake inhibitor antidepressants, they were independently associated with ejaculatory problems (adjusted r = 0.056, 0.047 and -0.059 for PRL, TSH and testosterone, respectively; all p < 0.05). This study indicates endocrine system is involved in the control of ejaculatory function and that PRL, TSH and testosterone play an independent role.

ORIGINAL RESEARCH–ENDOCRINOLOGY: Hypoprolactinemia: A New Clinical Syndrome in Patients with Sexual Dysfunction

INTRODUCTION The physiological role of prolactin (PRL) in male sexual behavior is poorly understood. Conversely, the association between PRL pathological elevation in both reproductive and sexual behavior is well defined. AIM The aim of the present study is to assess the correlates of normal PRL (PRL < 735 mU/L or 35 ng/mL), in male subjects consulting for sexual dysfunction. METHODS A consecutive series of 2,531 (mean age 52.0 +/- 12.9 years) subjects was investigated. Patients were interviewed using the structured interview on erectile dysfunction (SIEDY), a 13-item tool for the assessment of erectile dysfunction (ED)-related morbidities. Middlesex Hospital Questionnaire was used for the evaluation of psychological symptoms. MAIN OUTCOME MEASURES Several hormonal (testosterone, thyroid stimulation hormone, and PRL) and biochemical parameters (glycemia and lipid profile) were studied, along with penile Doppler ultrasound (PDU) and SIEDY items. RESULTS After adjustment for confounders anxiety symptoms decreased across PRL quartiles (I: <113 mU/L or 5 ng/mL; II: 113-156 mU/L or 5.1-7 ng/mL; III: 157-229 mU/L or 7.1-11 ng/mL; IV: 229-734 mU/L or 11.1-34.9 ng/mL). Patients in the lowest PRL quartile showed a higher risk of metabolic syndrome (MetS; odds ratio [OR] = 1.74 [1.01-2.99], P < 0.05), arteriogenic ED (peak systolic velocity at PDU < 35 cm/sec; OR = 1.43 [1.01-2.03], P < 0.05), and premature ejaculation (PE; OR = 1.38 [1.02-1.85]; P < 0.05). Conversely, comparing subjects with PRL-secreting pituitary adenomas (N = 13) with matched controls, no significant difference was observed, except for a higher prevalence of hypoactive sexual desire in hyperprolactinemia. CONCLUSIONS Our findings demonstrate that, in subjects consulting for sexual dysfunction, PRL in the lowest quartile levels are associated with MetS and arteriogenic ED, as well as with PE and anxiety symptoms. Further studies are advisable in order to confirm our preliminary results in different populations.

ORIGINAL RESEARCHORIGINAL RESEARCH–EPIDEMIOLOGY: Selective Serotonin Reuptake Inhibitor-Induced Sexual Dysfunction

INTRODUCTION Sexual dysfunctions are often present in subjects with mood disturbances; however. antidepressants can induce per se sexual dysfunctions. AIM To explore the relationship between the use of selective serotonin reuptake inhibitors (SSRIs), non-SSRIs antidepressants and benzodiazepines (BDZ), hormonal parameters, and reported sexual dysfunction (as assessed by the Structured Interview on Erectile Dysfunction [SIEDY]) in male subjects with comparable psychopathological symptoms (as assessed by the Middlesex Hospital Questionnaire [MHQ] a self-reported test for the screening of mental disorders in a non-psychiatric setting). METHODS A consecutive series of 2,040 (mean age 51 +/- 13 years) male patients with sexual dysfunction was studied. MAIN OUTCOME MEASURES Several hormonal and biochemical parameters were investigated, along with SIEDY and the MHQ. RESULTS Higher prolactin was observed only in patients using SSRIs, whereas no other hormonal difference was found after adjustment for confounders. Use of SSRIs was associated with a twofold risk for patient hypoactive sexual desire and with a higher impairment of reported erectile function. However, no difference in penile blood flow was observed. A very high risk (sevenfold) for delayed ejaculation (DE) was observed in SSRI users. Interestingly, the association with the mild, but not severe, form of DE was observed also in subjects using non-SSRI antidepressants (3.35 [1.48-7.59]; P < 0.005). Different life stressors and relational parameters were also associated with SSRI use. SSRI users reported less enjoyment with masturbation and decreased partner desire and climax. Conversely, a lack of significant association was observed among BDZ or non-SSRI antidepressant users and all the aforementioned life-stressors and relational parameters. CONCLUSIONS SSRIs can negatively affect all the steps of the male sexual response cycle (desire-arousal-excitement-orgasm). SSRI-associated sexual dysfunction has a deleterious effect on both auto- and couple-erotic performances. Conversely, other antidepressants and BDZ are less often associated with sexual impairment.

ORIGINAL RESEARCHORIGINAL RESEARCH–ENDOCRINOLOGY: Hypoprolactinemia: A New Clinical Syndrome in Patients with Sexual Dysfunction

INTRODUCTION The physiological role of prolactin (PRL) in male sexual behavior is poorly understood. Conversely, the association between PRL pathological elevation in both reproductive and sexual behavior is well defined. AIM The aim of the present study is to assess the correlates of normal PRL (PRL < 735 mU/L or 35 ng/mL), in male subjects consulting for sexual dysfunction. METHODS A consecutive series of 2,531 (mean age 52.0 +/- 12.9 years) subjects was investigated. Patients were interviewed using the structured interview on erectile dysfunction (SIEDY), a 13-item tool for the assessment of erectile dysfunction (ED)-related morbidities. Middlesex Hospital Questionnaire was used for the evaluation of psychological symptoms. MAIN OUTCOME MEASURES Several hormonal (testosterone, thyroid stimulation hormone, and PRL) and biochemical parameters (glycemia and lipid profile) were studied, along with penile Doppler ultrasound (PDU) and SIEDY items. RESULTS After adjustment for confounders anxiety symptoms decreased across PRL quartiles (I: <113 mU/L or 5 ng/mL; II: 113-156 mU/L or 5.1-7 ng/mL; III: 157-229 mU/L or 7.1-11 ng/mL; IV: 229-734 mU/L or 11.1-34.9 ng/mL). Patients in the lowest PRL quartile showed a higher risk of metabolic syndrome (MetS; odds ratio [OR] = 1.74 [1.01-2.99], P < 0.05), arteriogenic ED (peak systolic velocity at PDU < 35 cm/sec; OR = 1.43 [1.01-2.03], P < 0.05), and premature ejaculation (PE; OR = 1.38 [1.02-1.85]; P < 0.05). Conversely, comparing subjects with PRL-secreting pituitary adenomas (N = 13) with matched controls, no significant difference was observed, except for a higher prevalence of hypoactive sexual desire in hyperprolactinemia. CONCLUSIONS Our findings demonstrate that, in subjects consulting for sexual dysfunction, PRL in the lowest quartile levels are associated with MetS and arteriogenic ED, as well as with PE and anxiety symptoms. Further studies are advisable in order to confirm our preliminary results in different populations.

The Effect of Statin Therapy on Testosterone Levels in Subjects Consulting for Erectile Dysfunction

INTRODUCTION Previous clinical studies on effect of statins treatment on testosterone (T) levels have produced mixed results. AIM The aim of the present study is to evaluate the association between statin therapy and hormonal parameters in a large series of subjects seeking medical care at our unit for erectile dysfunction (ED). METHODS A consecutive series of 3,484 (mean age 51.6 + or - 13.1 years) patients with ED was studied. MAIN OUTCOME MEASURES Several hormonal and biochemical parameters were investigated, along with ANDROTEST structured interview measuring hypogonadism-related symptoms. RESULTS Among the patients studied, 244 (7%) patients were being treated with statins. After adjustment for confounding factors (including body mass index and Progetto Cuore cardiovascular (CV) risk engine score), both total and calculated free testosterone levels were significantly lower in subjects taking statins, when compared to the rest of the sample (hazard ratio [HR] = 0.93 [0.90; 0.96] and 0.26 [0.01; 0.18] for each decrement of total T and calculated free T, respectively; both P < 0.0001). The use of statins was also associated with a reduced testis volume and a higher prevalence of hypogonadism-related symptoms and signs, as assessed by higher ANDROTEST score (HR = 1.12 [1.03; 1.21]; P < 0.01 after adjustment for confounders). Follicle-stimulating hormone levels were significantly higher in subjects treated with statins when compared to the rest of the sample, while there was a trend toward higher luteinizing hormone levels, but this did not reach statistical significance. The lower levels of total and calculated free T observed in subjects treated with statins were also confirmed comparing them with age-waist circumference and CV risk score matched controls. Finally, subjects being treated with statins showed lower prolactin levels when compared to the rest of the sample. CONCLUSIONS Our data demonstrated that statin therapy might induce an overt primary hypogonadism and should be considered as a possible confounding factor for the evaluation of testosterone levels in patients with ED.

Impairment of Couple Relationship in Male Patients with Sexual Dysfunction is Associated with Overt Hypogonadism

INTRODUCTION Couple sexual dysfunction is a common, but not often studied, problem. AIM We have previously reported that disturbance in the relational domain, as measured by SIEDY Scale 2 (exploring, as reported by the patient, menopausal symptoms, partners medical illness interfering with sexual activity, and reduced partner desire and climax), is associated with different sexual dysfunctions, such as hypoactive sexual desire, erectile dysfunction (ED), delayed ejaculation, and psychological disturbances. As all of these symptoms could be associated with hypogonadism, we have investigated the possible relationship between androgen levels and an unhappy couple relationship. METHODS A consecutive series of 2,302 (mean age 53.2 +/- 12.5 years) male patients with ED was studied. MAIN OUTCOME MEASURES Several hormonal parameters were investigated, along with penile Doppler ultrasound (PDU) and the Structured Interview on Erectile Dysfunction (SIEDY) and ANDROTEST. Higher ANDROTEST score identifies a higher prevalence of hypogonadism-related symptoms and signs. RESULTS SIEDY Scale 2 score was associated with decreased intercourse frequency, severe ED, lower dynamic peak systolic velocity at PDU, and clinical (ANDROTEST score) and biochemical (low total and free testosterone) hypogonadism, even after adjusting for cofounders, such as patients and partners age, waist circumference, and smoking habit. Alternative models were explored using these different factors as dependent variables in order to evaluate the specific relationship among the parameters studied. Multiple logistic regression analysis indicated that low penile blood flow and decreased intercourse frequency are bi-directionally coupled to poor relational domain, while the association with hypogonadism was mediated through sexual hypoactivity or inertia. CONCLUSIONS Our data suggest that, in subjects consulting for sexual dysfunction, a deterioration of the couples relationship is associated with impairment in sexual activities, which, in turn, can lead to a mild hypogonadism. Any speculation on pathogenetic relationships should be confirmed through prospective studies or intervention trials.