Cecilia Melani

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.

DOSES OF INSULIN AND ITS ANALOGUES AND CANCER OCCURRENCE IN INSULIN-TREATED TYPE 2 DIABETIC PATIENTS

OBJECTIVE Recent epidemiological studies suggested that some insulin analogues could be associated with increased risk of cancer. The present study is aimed at assessing the long-term association of different insulin analogues with cancer incidence. RESEARCH DESIGN AND METHODS A nested case-control study dataset was generated from the cohort study dataset (n = 1,340 insulin-treated diabetic outpatients) by sampling control subjects from the risk sets. For each case subject, the control subjects (up to five) were chosen randomly from those members of the cohort who are at risk for the same follow-up time of the case subject. Five-year age classes, sex, and BMI classes (<18.5, 18.5–24.9, 25–29.9, and ≥30 kg/m2) were considered as additional categorical matching variables. RESULTS During a median follow-up of 75.9 months (interquartile range 27.4–133.7), 112 case subjects of incident cancer were compared with 370 matched control subjects. A significantly higher mean daily dose of glargine was observed in case subjects than in control subjects (0.24 IU/kg/day [0.10–0.39] versus 0.16 IU/kg/day [0.12–0.24], P = 0.036). Incident cancer was associated with a dose of glargine ≥0.3 IU/kg/day even after adjusting for Charlson comorbidity score, other types of insulin administration, and metformin exposure (odds ratio 5.43 [95% CI 2.18–13.53], P < 0.001). No association between incident cancer and insulin doses was found for human insulin or other analogues. CONCLUSIONS The possibility of association between cancer and higher glargine doses suggests that dosages should always be considered when assessing the possible association of insulin and its analogues with cancer.

METFORMIN AND CANCER OCCURRENCE IN INSULIN-TREATED TYPE 2 DIABETIC PATIENTS.

OBJECTIVE Metformin is associated with reduced cancer-related morbidity and mortality. The aim of this study was to assess the effect of metformin on cancer incidence in a consecutive series of insulin-treated patients. RESEARCH DESIGN AND METHODS A nested case-control study was performed in a cohort of 1,340 patients by sampling, for each case subject, age-, sex-, and BMI-matched control subjects from the same cohort. RESULTS During a median follow-up of 75.9 months, 112 case patients who developed incident cancer and were compared with 370 control subjects. A significantly lower proportion of case subjects were exposed to metformin and sulfonylureas. After adjustment for comorbidity, glargine, and total insulin doses, exposure to metformin, but not to sulfonylureas, was associated with reduced incidence of cancer (odds ratio 0.46 [95% CI 0.25–0.85], P = 0.014 and 0.75 [0.39–1.45], P = 0.40, respectively). CONCLUSIONS The reduction of cancer risk could be a further relevant reason for maintaining use of metformin in insulin-treated patients.

Prolactin levels independently predict major cardiovascular events in patients with erectile dysfunction

The physiological role of prolactin (PRL) in men is not completely clarified. We previously reported that in subjects consulting for sexual dysfunction, lower PRL plasma levels were associated with worse lipid and glycaemic profile, as well as with a higher prevalence of metabolic syndrome and arteriogenic erectile dysfunction (ED). The aim of this study was to assess possible associations between PRL levels and incident major cardiovascular events (MACE) in subjects with ED. When only subjects without pathological hyperprolactinaemia (PRL < 735 mU/L or 35 ng/mL) and pituitary diseases were considered, both unadjusted and adjusted analyses showed a significantly lower incidence of MACE in subjects with PRL levels in the highest PRL quintile (246-735 mU/L or 12-35 ng/mL) when compared with the rest of the sample. In particular, the risk of MACE was reduced by 5% (1-9%; p = 0.03) for each 10 ng/mL increment of PRL. Conversely, comparing patients with hyperprolactinaemia with matched controls, no significant difference was detected between cases and controls in MACE. In subjects at high risk for cardiovascular diseases, such as those with ED, a relatively high PRL plasma level is associated with an overall decreased chance of MACE, independently from other known risk factors.

Body Mass Index Regulates Hypogonadism-Associated CV Risk: Results from a Cohort of Subjects with Erectile Dysfunction

INTRODUCTION Obesity is an independent cardiovascular (CV) risk factor. Testosterone (T) is inversely related to body mass index (BMI) in males. There is substantial evidence suggesting that low T could play a role as a moderator of CV mortality in men. AIM This study is designed to assess the possible interaction between T and obesity in predicting major CV events (MACE) in a sample of subjects with erectile dysfunction. METHODS A consecutive series of 1,687 patients were studied. Different clinical, biochemical, and instrumental parameters were evaluated. According to BMI, subjects were divided into normal weight (BMI = 18.5-24.9 kg/m(2) ), overweight (BMI = 25.0-29.9 kg/m(2) ), and obese (BMI ≥ 30.0 kg/m(2) ). Hypogonadism was defined as total T below 10.4 nmol/L. Information on MACE was obtained through the City of Florence Registry Office. MAIN OUTCOME MEASURES Information on MACE was obtained through the City of Florence Registry Office. RESULTS Among the patients studied, 39.8% had normal weight, whereas 44.1% and 16.1% were overweight and obese, respectively. Unadjusted analysis in the whole sample showed that while hypogonadism and obesity were significantly associated with an increased risk of MACE, their interaction term was associated with a protective effect. In a Cox regression model, adjusting for confounders, hypogonadism showed a significant increased risk of MACE in normal weight subjects, whereas it was associated with a reduced risk in obese patients. CONCLUSIONS Hypogonadism-associated CV risk depends on the characteristics of subjects, being more evident in normal weight than in obese patients. Further studies are advisable to clarify if low T in obese patients is a (positive) consequence of a comorbid condition (i.e., to save energy) or if it represents a pathogenetic issue of the same illness. Hence, possible misuse/abuse of T treatment in obese subjects must be avoided.

Is Obesity a Further Cardiovascular Risk Factor in Patients with Erectile Dysfunction

INTRODUCTION Erectile dysfunction (ED) and, in particular, arteriogenic ED have been proposed as new markers of risk for incident major adverse cardiovascular events (MACE). Reduced penile blood flow is more common in obese people than in leaner ED subjects. AIM To explore the interaction of overweight/obesity and penile blood flow in the prediction of incident MACE. METHODS This is an observational prospective cohort study evaluating a consecutive series of 1,687 patients attending our andrological unit for ED. Different clinical, biochemical, and instrumental (penile flow at color Doppler ultrasound: PCDU) parameters were evaluated. MAIN OUTCOMES MEASURES According to body mass index (BMI), subjects were divided into three groups: normal weight (BMI = 18.5-24.9 kg/m(2)), overweight (BMI = 25.0-29.9 kg/m(2)), and obese (BMI >or= 30.0 kg/m(2)). Information on MACE was obtained through the City of Florence Registry Office. RESULTS Among patients studied, 39.8% were normal weight, while 44.1% and 16.1% showed BMI 25-29.9 and 30 kg/m(2) or higher, respectively. During a mean follow-up of 4.3 +/- 2.6 years, 139 MACE, 15 of which were fatal, were observed. Cox regression model, after adjusting for age and Chronic Diseases Score, showed that obesity classes along with the presence of arteriogenic ED (peak systolic velocity at PCDU <25 cm/second) were significantly and independently associated with incident MACE (hazard ratio = 1.47 [1.1-1.95], P < 0.05 and 2.58 [1.28-5.09], P < 0.001, respectively). When a separate analysis was performed for classes of obesity, reduced peak systolic velocity at PCDU (<25 cm/second) was significantly associated with incident MACE in obese (BMI >or= 30 kg/m(2)), but not in leaner, subjects. CONCLUSIONS In obese subjects, more than in leaner ED subjects, impaired penile blood flow is associated with an increased risk of incident cardiovascular disease. The interaction with concomitant risk factors, such as obesity, should be taken into account when assessing the predictive value of penile blood flow for cardiovascular diseases.

Severe Depressive Symptoms and Cardiovascular Risk in Subjects with Erectile Dysfunction

INTRODUCTION Erectile dysfunction (ED) and mood depression are often associated and both are correlated with an increased risk of cardiovascular morbidity and mortality. AIM The aim of the present study is to explore biological and clinical correlates of depressive symptomatology in a sample of men consulting for sexual dysfunction and to verify possible associations between depressive symptoms and incidence of major cardiovascular events (MACE). METHODS A consecutive series of 2,303 male patients attending the Outpatient Clinic for sexual dysfunction was retrospectively studied. A subset of the previous sample (N= 1,687) was enrolled in a longitudinal study. All patients were investigated using a Structured Interview on Erectile Dysfunction (SIEDY), composed of 3 scales which explore organic, relational and intra-psychic components of ED. MHQ-D scoring from Middlesex Hospital Questionnaire (MHQ) was used as a putative marker of depressive symptoms. MAIN OUTCOME MEASURES Information on MACE was obtained through the City of Florence Registry Office. RESULTS We found a positive relationship between MHQ-D score and a progressive impairment in obtaining an erection hard enough for penetration, even after adjusting for confounding factors. Moreover, we observed positive relationships between MHQ-D score and the three pathogenetic domains underlying ED. When the longitudinal subset was evaluated, during a mean follow-up of 4.3±2.6 years, 139 MACE, 15 of which were fatal, were observed. Unadjusted incidence of MACE was significantly associated with baseline depressive symptoms. When the presence of severe depressive symptoms were introduced in a Cox regression model, along with the arteriogenic ED and partners hypoactive sexual desire, after adjusting for age, Chronic Diseases Score, and ΣMHQ (a broader index of psychopathology), severe depressive symptomatology was independently associated with a higher incidence of MACE. CONCLUSION Depressive symptomatology constitutes an independent risk factor for cardiac morbidity and mortality in men with ED.

Poor Response to Alprostadil ICI Test is Associated with Arteriogenic Erectile Dysfunction and Higher Risk of Major Adverse Cardiovascular Events

INTRODUCTION Intracavernous alprostadil injection (ICI) test has been considered useless in assessing the vascular status of subjects with erectile dysfunction (ED). AIM To analyze the clinical correlates of ICI test in patients with ED and to verify the value of this test in predicting major adverse cardiovascular events (MACE). METHODS A consecutive series of 2,396 men (mean age 55.9 ± 11.9 years) attending our outpatient clinic for sexual dysfunction was retrospectively studied. A subset of this sample (N = 1,687) was enrolled in a longitudinal study. MAIN OUTCOME MEASURES Several clinical, biochemical, and instrumental (penile color Doppler ultrasound; PCDU) factors were evaluated. All patients underwent an ICI test, and responses were recorded on a four-point scale ranging from 1 = no response to 4 = full erection. RESULTS Among the patients studied, 16.4%, 41.2%, 40.2% and 2.2% showed grade 4, 3, 2, and 1 ICI test response, respectively. After adjusting for confounders, subjects with grade 1 ICI test response showed reduced perceived sleep-related, masturbation-related, and sexual-related erections when compared with the rest of the sample. In addition, a worse response to ICI test was associated with a higher prevalence of hypogonadism-related symptoms and signs along with lower testosterone levels. The prevalence of both diabetes mellitus and metabolic syndrome was inversely related to ICI test response. Accordingly, dynamic and basal peak systolic velocity (PSV), as well as acceleration at PCDU, decreased as a function of ICI test response. In the longitudinal study, after adjusting for confounders, grade 1 response was independently associated with a higher incidence of MACE (hazard ratio = 2.745 [1.200-6.277]; P < 0.05). These data were confirmed even when only subjects with normal PSV (>25 cm/s) were considered. CONCLUSIONS Our results demonstrate that poor ICI test response is associated with several metabolic disturbances and higher incidence of MACE. We strongly recommend performing ICI test with alprostadil in all ED subjects.

Pulse Pressure Independently Predicts Major Cardiovascular Events in Younger But Not in Older Subjects with Erectile Dysfunction

INTRODUCTION Pulse pressure (PP; i.e., the arithmetic difference between systolic and diastolic blood pressure) has been suggested to be an independent cardiovascular risk (CV) factor in the general population. We previously also reported a negative association between PP and arteriogenic erectile dysfunction (ED). This finding has recently been questioned. AIM To verify the association of PP with ED severity and to evaluate its role in predicting forthcoming CV events. METHODS This is an observational prospective cohort study evaluating a consecutive series of 1,687 patients attending our Andrological Unit for ED. MAIN OUTCOME MEASURES Several hormonal and biochemical parameters were studied, along with SIEDY structured interviews and penile Doppler ultrasound. RESULTS Subjects with PP in the lowest quartile (I: 20-45; II: 46-55; III: 56-62; IV: 63-115 mm Hg) had a significant reduction in the risk of severe ED (RR = 0.60[0.47-0.76]; P < 0.0001). When the same analysis was repeated as a function of age quartile (I = 17-44, II = 45-55, III = 56-62, and IV = 63-88 years old), after adjusting for testosterone levels, mean blood pressure, Chronic Disease Score, and body mass index, PP was inversely related to ED only in the youngest age group. During a mean follow up of 4.4 ± 2.6 years, 147 major cardiovascular events (MACE) were observed. In a Cox regression model, after adjusting for possible confounding factors, a lower PP was associated with a lower risk of MACE in the whole sample and in younger subjects, but not in the older ones. CONCLUSIONS Checking for blood pressure in ED subjects and calculating PP should become a routine practice in sexual medicine. In younger individuals, low PP reflects not only sexual health (better erection) but also cardiovascular health (less prevalence of MACE).