Alessandra Sforza

Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis.

Introduction: Recent reports have significantly halted the enthusiasm regarding androgen-boosting; suggesting that testosterone supplementation (TS) increases cardiovascular (CV) events. Areas covered: In order to overcome some of the limitations of the current evidence, the authors performed an updated systematic review and meta-analysis of all placebo-controlled randomized clinical trials (RCTs) on the effect of TS on CV-related problems. Out of 2747 retrieved articles, 75 were analyzed, including 3016 and 2448 patients in TS and placebo groups, respectively, and a mean duration of 34 weeks. Our analyses, performed on the largest number of studies collected so far, indicate that TS is not related to any increase in CV risk, even when composite or single adverse events were considered. In RCTs performed in subjects with metabolic derangements a protective effect of TS on CV risk was observed. Expert opinion: The present systematic review and meta-analysis does not support a causal role between TS and adverse CV events. Our results are in agreement with a large body of literature from the last 20 years supporting TS of hypogonadal men as a valuable strategy in improving a patient’s metabolic profile, reducing body fat and increasing lean muscle mass, which would ultimately reduce the risk of heart disease.

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.

ORIGINAL RESEARCH—ERECTILE DYSFUNCTION: Penile Doppler Ultrasound in Patients with Erectile Dysfunction (ED): Role of Peak Systolic Velocity Measured in the Flaccid State in Predicting Arteriogenic ED and Silent Coronary Artery Disease

INTRODUCTION The use of the penile peak systolic velocity (PSV) measured in the flaccid state during penile color Doppler ultrasound (PCDU) examination has been questioned without substantial evidence. AIM To assess the validity of PSV measured in the flaccid state during PCDU, in patients consulting for erectile dysfunction (ED). METHODS A consecutive series of 1,346 (mean age 55.0 +/- 12.0 years) male patients was studied. MAIN OUTCOMES MEASURES All patients underwent PCDU performed both in the flaccid state and dynamic (after prostaglandin E1 stimulation) conditions. A subset of 20 subjects with uncomplicated type 2 diabetes underwent diagnostic testing for silent coronary heart disease by means of adenosine stress myocardial perfusion scintigraphy (SPECT). In these subjects penile arterial flow was simultaneously assessed by PCDU before and after systemic adenosine administration. RESULTS Flaccid PSV showed a significant (r = 0.513, P < 0.0001) correlation with dynamic PSV. Receiver operating characteristic (ROC) curve analysis demonstrated that when a threshold of 13 cm/seconds was chosen, flaccid PSV was predictive for dynamic PSV < 25 and <35 cm/seconds with an accuracy of 89% and 82%, respectively. Among the subset of patients who underwent SPECT, an impaired coronary flow reserve (ICFR) occurred in nine cases (45%). When the same threshold of <13 cm/seconds was chosen, PSV before SPECT was predictive of ICFR with an accuracy of 80% (area under the ROC curve = 0.798 +/- 0.10; P < 0.05). After adjustment for confounders, anxiety symptoms were related to dynamic PSV (Adj. r = -0.154, P < 0.05) but not to flaccid PSV. CONCLUSIONS Our results show that flow in the cavernosal arteries can be routinely evaluated by PCDU in the flaccid state. Performing PCDU only in the flaccid state allows identifying subjects with pathological dynamic PSV with accuracy higher than 80%. Furthermore, our preliminary data suggest that the same examination could identify diabetic subjects with ICFR with an accuracy of 80%.

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.

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.

Obesity and late-onset hypogonadism

Obesity and male hypogonadism (HG) are often associated, as demonstrated in all cross-sectional studies. Prospective studies have indicated that i) having HG at baseline increases the risk of visceral obesity (and metabolic syndrome) and that ii) obesity induces incident HG. Hence, there is a bidirectional relationship between the two conditions. This is the main topic of this review, along with some pathogenic considerations. Meta-analysis of intervention studies indicates that treating obesity is a very efficient treatment for obesity-induced HG. The mechanism by which obesity induces HG has not yet been completely understood, but dietary-induced hypothalamic inflammation, along with a decreased GnRH release, is plausible. Among patients seeking medical care for obesity, the proportion of HG is relatively high. The prevalence of obesity among patients referring for sexual dysfunction is also elevated. Hence, in symptomatic, obese, hypogonadal subjects, testosterone supplementation (TS) can be considered. Whereas long-term uncontrolled register studies suggest that TS could decrease weight, analysis of controlled studies only support a parallel increase in lean mass and decrease in fat mass, with a resulting null effect on weight. Considering that T induces an increase in muscle mass, it is conceivable that the amount of activity obese people can undertake after TS will increase, allowing a closer adherence to physical exercise programs. Some studies, here meta-analyzed, support this concept.

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.

SIEDY Scale 3, a New Instrument to Detect Psychological Component in Subjects with Erectile Dysfunction

INTRODUCTION We previously developed and validated a structured interview (SIEDY) dealing with the organic (Scale 1), relational (Scale 2), and psychological (Scale 3) components of erectile dysfunction (ED). AIM To identify a pathological threshold for SIEDY Scale 3 and to analyze Scale 3 score with biological and psychological correlates in subjects with sexual dysfunction. METHOD A pathological threshold of SIEDY Scale 3 score in predicting subjects with a medical history of psychopathology and using psychiatric drugs was identified through receiver operating characteristic (ROC) curve analysis in a sample of 484 patients (Sample A). MAIN OUTCOME MEASURE Sensitivity and specificity, along with possible interactions with biological and psychological (Middlesex Hospital Questionnaire, MHQ-score) correlates were verified in a further sample of 1,275 patients (Sample B). RESULTS In sample A, 39 (8%) and 60 (12.4%) subjects reported a positive medical history for psychiatric disturbances or for the use of psychotropic medication, respectively. The association with both conditions was present in 28 (5.8%) subjects. ROC curve showed that SIEDY Scale 3 score predicts psychopathology with an accuracy of 69.5 ± 5.9% (P<0.002), when a threshold of 3 was chosen. When the same threshold was applied in Sample B, it identified a higher ranking in MHQ-A (free-floating anxiety), MHQ-S (somatized anxiety) and MHQ-D (depressive symptoms) subscales, even after adjustment for age and Σ-MHQ (a broader index of general psychopathology). In the same sample, we also confirmed that pathological Scale 3 score was related to a higher risk of psychopathology at medical history or to the use of psychotropic drugs as well as with risky lifestyle behaviors, including smoking and alcohol abuse, and elevated BMI. CONCLUSIONS SIEDY represents an easy tool for the identification of patients with a relevant intra-psychic component who should be considered for psychological/psychiatric treatment.

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.