Martin Miner

The Princeton III Consensus Recommendations for the Management of Erectile Dysfunction and Cardiovascular Disease

The Princeton Consensus (Expert Panel) Conference is a multispecialty collaborative tradition dedicated to optimizing sexual function and preserving cardiovascular health. The third Princeton Consensus met November 8 to 10, 2010, and had 2 primary objectives. The first objective focused on the evaluation and management of cardiovascular risk in men with erectile dysfunction (ED) and no known cardiovascular disease (CVD), with particular emphasis on identification of men with ED who may require additional cardiologic work-up. The second objective focused on reevaluation and modification of previous recommendations for evaluation of cardiac risk associated with sexual activity in men with known CVD. The Panels recommendations build on those developed during the first and second Princeton Consensus Conferences, first emphasizing the use of exercise ability and stress testing to ensure that each mans cardiovascular health is consistent with the physical demands of sexual activity before prescribing treatment for ED, and second highlighting the link between ED and CVD, which may be asymptomatic and may benefit from cardiovascular risk reduction.

Erectile dysfunction and coronary artery disease prediction: Evidence-based guidance and consensus

•  A significant proportion of men with erectile dysfunction (ED) exhibit early signs of coronary artery disease (CAD), and this group may develop more severe CAD than men without ED (Level 1, Grade A). •  The time interval among the onset of ED symptoms and the occurrence of CAD symptoms and cardiovascular events is estimated at 2–3 years and 3–5 years respectively; this interval allows for risk factor reduction (Level 2, Grade B). •  ED is associated with increased all‐cause mortality primarily due to increased cardiovascular mortality (Level 1, Grade A). •  All men with ED should undergo a thorough medical assessment, including testosterone, fasting lipids, fasting glucose and blood pressure measurement. Following assessment, patients should be stratified according to the risk of future cardiovascular events. Those at high risk of cardiovascular disease should be evaluated by stress testing with selective use of computed tomography (CT) or coronary angiography (Level 1, Grade A). •  Improvement in cardiovascular risk factors such as weight loss and increased physical activity has been reported to improve erectile function (Level 1, Grade A). •  In men with ED, hypertension, diabetes and hyperlipidaemia should be treated aggressively, bearing in mind the potential side effects (Level 1, Grade A). •  Management of ED is secondary to stabilising cardiovascular function, and controlling cardiovascular symptoms and exercise tolerance should be established prior to initiation of ED therapy (Level 1, Grade A). •  Clinical evidence supports the use of phosphodiesterase 5 (PDE5) inhibitors as first‐line therapy in men with CAD and comorbid ED and those with diabetes and ED (Level 1, Grade A). •  Total testosterone and selectively free testosterone levels should be measured in all men with ED in accordance with contemporary guidelines and particularly in those who fail to respond to PDE5 inhibitors or have a chronic illness associated with low testosterone (Level 1, Grade A). •  Testosterone replacement therapy may lead to symptomatic improvement (improved wellbeing) and enhance the effectiveness of PDE5 inhibitors (Level 1, Grade A). •  Review of cardiovascular status and response to ED therapy should be performed at regular intervals (Level 1, Grade A).

Cardiovascular Aspects of Sexual Medicine

INTRODUCTION Erectile dysfunction (ED) is common and considered to be predominantly of vascular origin. AIM To evaluate the link between ED and coronary artery disease (CAD) and provide a consensus report regarding evaluation and management. METHODS A committee of eight experts from six countries was convened to review the worldwide literature concerning ED and CAD and provide a guideline for management. MAIN OUTCOME MEASURE Expert opinion was based on grading the evidence-based medical literature, widespread internal committee discussion, public presentation, and debate. RESULTS ED and CAD frequently coexist. Between 50-70% of men with CAD have ED. ED can arise before CAD is symptomatic with a time window of 3-5 years. ED and CAD share the same risk factors, and endothelial dysfunction is the common denominator. Treating ED in cardiac patients is safe, provided that their risks are properly evaluated. CONCLUSION ED is a marker for silent CAD that needs to be excluded. Men with CAD frequently have ED that can be treated safely following guidelines.

Association of Sexual Dysfunction With Lower Urinary Tract Symptoms of BPH and BPH Medical Therapies: Results From the BPH Registry

OBJECTIVES The severity of lower urinary tract symptoms (LUTS) has correlated with erectile dysfunction (ED) and ejaculatory dysfunction (EjD) in large-scale epidemiologic studies. ED and EjD are also side effects of some medical therapies for LUTS suggestive of benign prostatic hyperplasia (LUTS/BPH). These relationships were examined in a physician office-based population of men enrolled in the BPH Registry. METHODS Enrolled men with LUTS/BPH who completed the International Prostate Symptom Score (IPSS), IPSS bother question, 5-item International Index of Erectile Function, and the 3 ejaculatory function items of the Male Sexual Health Questionnaire-EjD short form at baseline were eligible. The relationship between sexual dysfunction and LUTS/BPH and BPH medical therapies were examined using multivariate analyses. RESULTS Of 6924 men enrolled, 5042 (mean age 65 years) completed all 4 baseline assessments. Of 3084 sexually active men, age, total IPSS, IPSS bother score, hypertension, diabetes, and black race/ethnicity were independent predictors of both ED and EjD (all P < .05). For the subset of 1362 men receiving BPH medical therapy, a significant association (P < .0001) was demonstrated for ED and EjD with specific BPH medical therapies. The alpha(1A)-subtype nonsuperselective quinazoline alpha(1)-blockers alfuzosin, doxazosin, and terazosin appeared to be associated with better ejaculatory function than were the alpha(1A)-subtype superselective sulfonamide alpha(1)-blocker tamsulosin, 5alpha-reductase inhibitors, and alpha(1)-blocker plus 5alpha-reductase inhibitor combination therapy. CONCLUSIONS These results have provided additional evidence of the link between LUTS/BPH and sexual dysfunction in aging men and support clinical trial results indicating different rates of sexual side effects for BPH medical therapies.

Peyronie’s Disease: AUA Guideline

PURPOSE The purpose of this guideline is to provide a clinical framework for the diagnosis and treatment of Peyronies disease. MATERIALS AND METHODS A systematic review of the literature using the PubMed®, EMBASE® and Cochrane databases (search dates 1/1/1965 to 1/26/15) was conducted to identify peer-reviewed publications relevant to the diagnosis and treatment of PD. The review yielded an evidence base of 303 articles after application of inclusion/exclusion criteria. RESULTS The systematic review was used to create guideline statements regarding treatment of PD. When sufficient evidence existed, the body of evidence for a particular treatment was assigned a strength rating of A (high quality evidence; high certainty), B (moderate quality evidence; moderate certainty), or C (low quality evidence; low certainty). Evidence-based statements of Strong, Moderate, or Conditional Recommendation were developed based on benefits and risks/burdens to patients. Additional consensus statements related to the diagnosis of PD are provided as Clinical Principles and Expert Opinions due to insufficient published evidence. CONCLUSIONS There is a continually expanding literature on PD; the Panel notes that this document constitutes a clinical strategy and is not intended to be interpreted rigidly. The most effective approach for a particular patient is best determined by the individual clinician and patient in the context of that patients history, values, and goals for treatment. As the science relevant to PD evolves and improves, the strategies presented here will be amended to remain consistent with the highest standards of clinical care.

Cardiometabolic Risk and Female Sexual Health: The Princeton III Summary (CME)

INTRODUCTION Female sexual function is dependent, in part, upon normal endothelial function within the genital arterial (hypogastric-cavernosal) vascular bed. The first two Princeton Consensus Conferences were focused on relationships between male sexual function and cardiovascular health, and development of contemporary clinical guidelines for dysfunction management. AIM The third Princeton Consensus Conference updated recommendations and assessed, for the first time, the association between female sexual dysfunction (FSD) and presence of systemic vascular endothelial dysfunction and its consequences in women. This report focuses on the association between cardiometabolic risk factors and female sexual health. METHODS A panel of experts reviewed multinational data concerning associations between several cardiometabolic risks in women (hypertension, dyslipidemia and/or hyperlipemia, cigarette smoking, diabetes mellitus, and metabolic syndrome/obesity) and sexual health. Literature was reviewed concerning associations between FSD and presence or absence of cardiovascular disease, predictive association of FSD with cardiovascular events, and the possibility of vascular risk factor treatment modifying FSD. MAIN OUTCOME MEASURE Main outcome measures used were cardiometabolic risk factors and female sexual health, specifically genital arousal. RESULTS Women treated for hypertension have more FSD than normotensives. Women with hyperlipidemia but without cardiovascular disease have more FSD than women without hyperlipidemia. Women with metabolic syndrome/obesity have more FSD than those without. Cardiometabolic risk factors, diabetes, and coronary heart disease are associated with more FSD. Data support that treatment of metabolic syndrome/obesity is associated with less FSD. Currently, there are no data to support that FSD is a predictor of future cardiovascular events. CONCLUSION Female sexual health is complex: there is relative independence between subjective and objective aspects of arousal and desire, with numerous contributing factors (hormonal, psychological, interpersonal, and social). Based on limited current data, there appears to be an association between female sexual health and vascular risk factors (hypertension, hyperlipidemia, metabolic syndrome/obesity, diabetes, and coronary heart disease). More research is needed.

Prognostic utility of erectile dysfunction for cardiovascular disease in younger men and those with diabetes.

Multiple published studies have established erectile dysfunction (ED) as an independent risk marker for cardiovascular disease (CVD). In fact, incident ED has a similar or greater predictive value for cardiovascular events than traditional risk factors including smoking, hyperlipidemia, and family history of myocardial infarction. Here, we review evidence that supports ED as a particularly significant harbinger of CVD in 2 populations: men <60 years of age and those with diabetes. Although addition of ED to the Framingham Risk Score only modestly improved the 10-year predictive capacity of the Framingham Risk Score for myocardial infarction or coronary death data in men enrolled in the Massachusetts Male Aging Study, other epidemiologic studies suggest that the predictive value of ED is quite strong in younger men. Indeed, in the Olmstead County Study, men 40 to 49 years of age with ED had a 50-fold higher incidence of new-incident coronary artery disease than those without ED. However, ED had less predictive value (5-fold increased risk) for coronary artery disease in men 70 years and older. Several studies, including a large analysis of more than 6300 men enrolled in the ADVANCE study, suggest that ED is a particularly powerful predictor of CVD in diabetic men as well. Based on the literature reviewed here, we encourage physicians to inquire about ED symptoms in all men more than 30 years of age with cardiovascular risk factors. Identification of ED, particularly in men <60 years old and those with diabetes, represents an important first step toward CVD risk detection and reduction.

Correlation of age and heart weight with tortuosity and caliber of normal human coronary arteries.

Summary Whether or not the size of the epicardial coronary arteries can increase to keep pace with cardiac mass in abnormally enlarged hearts, and what the mathematical relationship is between the enlarging heart and its vascular tree, has been uncertain. Relationships were sought between patients age, heart weight, coronary artery caliber, and tortuosity of epicardial coronary arteries in 145 cases with normal coronary arteries as judged by postmortem arteriography. The hearts were normal (33 cases) or had left ventricular hypertrophy (25 cases), right ventricular hypertrophy (30 cases), or myocardiopathy (57 cases) as a predominant pathological finding. Multivariable regression analysis for prediction of coronary artery caliber showed a direct linear relationship between heart weight and arterial diameter raised to the third power for normal hearts and those with left ventricular hypertrophy. Although coronary caliber was principally related to heart size, tortuosity which may be considered as length relative to distance traveled, also contributed to its prediction in the whole group. Tortuosity itself was predicted by an equation combining age positively and heart weight negatively to about equal importance and, to a lesser extent, arterial caliber positively. Tortuosity increases with age and with cardiac shrinkage; it increases in parallel with increase in coronary arterial caliber but decreases with cardiac enlargement. The results show that normal coronary arteries enlarge their caliber by at least the cube of the diameter proportionate to increase in heart size. It appears that this increase in caliber should be sufficient to maintain adequate blood flow to the myocardium and even very large hearts would not outstrip their blood supply.

All Men with Vasculogenic Erectile Dysfunction Require a Cardiovascular Workup

An association between erectile dysfunction and cardiovascular disease has long been recognized, and studies suggest that erectile dysfunction is an independent marker of cardiovascular disease risk. Therefore, assessment and management of erectile dysfunction may help identify and reduce the risk of future cardiovascular events, particularly in younger men. The initial erectile dysfunction evaluation should distinguish between predominantly vasculogenic erectile dysfunction and erectile dysfunction of other etiologies. For men believed to have predominantly vasculogenic erectile dysfunction, we recommend that initial cardiovascular risk stratification be based on the Framingham Risk Score. Management of men with erectile dysfunction who are at low risk for cardiovascular disease should focus on risk-factor control; men at high risk, including those with cardiovascular symptoms, should be referred to a cardiologist. Intermediate-risk men should undergo noninvasive evaluation for subclinical atherosclerosis. A growing body of evidence supports the use of emerging prognostic markers to further understand cardiovascular risk in men with erectile dysfunction, but few markers have been prospectively evaluated in this population. In conclusion, we support cardiovascular risk stratification and risk-factor management in all men with vasculogenic erectile dysfunction.

Improved Sexual Function with Testosterone Replacement Therapy in Hypogonadal Men: Real-World Data from the Testim Registry in the United States (TRiUS)

INTRODUCTION Up to 30% of erectile dysfunction (ED) patients treated with phosphodiesterase type 5 (PDE5) inhibitors do not show improved sexual function, which may be due in part to low serum testosterone. Hypogonadal patients already receiving testosterone replacement therapy (TRT) likewise can still suffer from symptoms of sexual dysfunction. In these patient populations, augmenting with, or switching, TRT treatment may improve sexual function. AIM To determine if 12-month treatment with a testosterone gel improves sexual function in hypogonadal men, as measured by the Brief Male Sexual Function Inventory (BMSFI), and in subgroups defined by low testosterone, PDE5 inhibitor use, and prior TRT. METHODS The Testim Registry in the United States (TRiUS) was a large (N = 849) multicenter registry of hypogonadal men treated with Testim (testosterone 1%) topical gel and followed for 12 months. MAIN OUTCOME MEASURES Data collected at suggested visits (baseline; 1, 3, 6, and 12 months) included total testosterone (TT), free testosterone (FT), BMSFI scores, physical exam, and body measurements. RESULTS TRiUS had 271 patients with baseline testosterone and BMSFI measurements. At 12 months of TRT, TT and FT levels significantly increased from baseline (P < 0.001), with mean ± standard deviation final TT = 17.37 ± 8.61 nmol/L (500.6 ± 248.2 ng/dL) and FT = 240.1 ± 296.0 pmol/L (69.2 ± 85.3 pg/mL). The mean total BMSFI score significantly increased from baseline at 12 months (27.4 ± 10.3 to 33.8 ± 9.8, P < 0.001) and at each visit in all domains (sex drive/libido, erectile function, ejaculatory function, level of bother), overall and for all subgroups. Regression analysis indicated that increased total BMSFI score was significantly associated with increased TT levels at 6 months. CONCLUSIONS In hypogonadal patients, 12-month administration of topical testosterone gel resulted in increased TT and FT levels and significantly improved sexual function. All subgroups studied, including men taking PDE5 inhibitors for ED and those previously on TRT, demonstrated significant improvement in sexual function from baseline scores.