The assessment of vascular risk in men with erectile dysfunction: the role of the cardiologist and general physician.

Erectile dysfunction (ED) and cardiovascular disease (CVD) share risk factors and frequently coexist, with endothelial dysfunction believed to be the pathophysiologic link. ED is common, affecting more than 70% of men with known CVD. In addition, clinical studies have demonstrated that ED in men with no known CVD often precedes a CVD event by 2-5 years. ED severity has been correlated with increasing plaque burden in patients with coronary artery disease. ED is an independent marker of increased CVD risk including all-cause and especially CVD mortality, particularly in men aged 30-60 years. Thus, ED identifies a window of opportunity for CVD risk mitigation. We recommend that a thorough history, physical exam (including visceral adiposity), assessment of ED severity and duration and evaluation including fasting plasma glucose, lipids, resting electrocardiogram, family history, lifestyle factors, serum creatinine (estimated glomerular filtration rate) and albumin:creatinine ratio, and determination of the presence or absence of the metabolic syndrome be performed to characterise cardiovascular risk in all men with ED. Assessment of testosterone levels should also be considered and biomarkers may help to further quantify risk, even though their roles in development of CVD have not been firmly established. Finally, we recommend that a question about ED be included in assessment of CVD risk in all men and be added to CVD risk assessment guidelines.

Global experiences with vardenafil in men with erectile dysfunction and underlying conditions.

OBJECTIVE: Vardenafil has demonstrated efficacy for the pharmacological management of erectile dysfunction (ED). Accumulating evidence suggests that ED is frequently associated with underlying cardiovascular and metabolic conditions which are thought to be involved in the aetiology of ED. The present review aims to summarise and discuss the available evidence for the efficacy, safety and tolerability of vardenafil in patients with underlying conditions including diabetes, hypertension and dyslipidaemia. METHODS: Relevant articles were identified through a PubMed search of clinical trials and postmarketing surveillance studies of vardenafil in patients with ED including those with diabetes, hypertension and dyslipidaemia. RESULTS: Across all trials, vardenafil showed good efficacy for the treatment of ED in patients with diabetes, hypertension and dyslipidaemia. Vardenafil also showed a favourable safety and tolerability profile. The concomitant use of medication to treat hypertension or dyslipidaemia was not associated with an increase in adverse events following vardenafil treatment. CONCLUSIONS: The prevalence of both diagnosed and undiagnosed underlying conditions is high among men with ED. The evidence presented in this review suggests that vardenafil is efficacious and well tolerated in patients with ED and diabetes, hypertension and/or dyslipidaemia and can be recommended as first-line treatment for ED in patients with these conditions.

Clomiphene increases free testosterone levels in men with both secondary hypogonadism and erectile dysfunction: who does and does not benefit?

Secondary hypogonadism is more common than primary gonadal failure and is seen in chronic and acute illnesses. Although testosterone has a role in erections, its importance in erectile dysfunction (ED) has been controversial. Hypogonadism produced by functional suppression of pituitary gonadotropins has been shown to correct with clomiphene citrate, but with a modest effect on sexual function. We wondered if longer treatment would produce improved results. A total of 178 men with secondary hypogonadism and ED received clomiphene citrate for 4 months. Sexual function improved in 75%, with no change in 25%, while significant increases in luteinizing hormone (P<0.001) and free testosterone (P<0.001) occurred in all patients. Multivariable analysis showed that responses decreased significantly with aging (P<0.05). Decreased responses also occurred in men with diabetes, hypertension, coronary artery disease, and multiple medication use. Since these conditions are more prevalent with aging, chronic disease may be a more important determinant of sexual dysfunction. Men with anxiety-related disorders responded better to normalization of testosterone. Assessment of androgen status should be accomplished in all men with ED. For those with lower than normal age-matched levels of testosterone treatment directed at normalizing testosterone with clomiphene citrate is a viable alternative to giving androgen supplements.

Yohimbine treatment of organic erectile dysfunction in a dose-escalation trial.

Yohimbine has had questionable effects in men with organic erectile dysfunction. We conducted this study to better define the population of men responsive to yohimbine, because tobacco was thought to affect a regimen of yohimbine more than other risk factors. We measured nocturnal penile tumescence with the RigiScan monitor, hormone profiles, answers to the Florida Sexual Health Questionnaire, and clinical responses at baseline and after two different doses of yohimbine in 18 nonsmoking men with erectile dysfunction. Of the 18 men, nine (50%) were successful in completing intercourse in more than 75% of attempts. The yohimbine responders were men with less severe erectile dysfunction as manifested by improved increased rigidity on RigiScan testing, higher Florida Sexual Health Questionnaire scores, and slightly higher levels of serum testosterone. Yohimbine is an effective therapy to treat organic erectile dysfunction in some men with erectile dysfunction.

Decreased free testosterone and dehydroepiandrosterone-sulfate (DHEA-S) levels in women with decreased libido.

A prior study has shown that premenopausal women could have decreased testosterone levels and still have regular menstrual cycles (Guay, 2001). Since ovarian function in such women was normal, the question of a possible adrenal dysfunction causing androgen deficiency was considered. If this was true, the question then arose as to whether the same defect could be seen in postmenopausal women. We studied 105 women who presented during a 6-month period of time with the chief complaint of decreased sexual desire. On subsequent testing, 74 of the women (70%) were found to have decreased total testosterone, free testosterone, and dehydroepiandrosterone sulfate (DHEA-S). Thirty-six of these women were premenopausal (ages range 24-50 years), and 38 were postmenopausal (ages range 47-78 years). All androgen levels for the women were lower than age-matched control groups found in the literature. The decreased DHEA-S levels suggest a a defect in adrenal steroidogenesis, which was seen in both premenopausal and postmenopausal women. Possible defects in regulatory mechanisms of adrenal steroidogenesis are discussed.

Efficacy and safety of sildenafil citrate for treatment of erectile dysfunction in a population with associated organic risk factors.

The objective of this study was to determine the efficacy and safety of sildenafil in patients with erectile dysfunction (ED) and associated organic risk factors in a multispecialty clinic. Patients (n = 521) were diagnosed with ED based on self-assessment. Associated risk factors were managed by medication or life-style modifications, or both, before treatment with sildenafil for ED. Patients received a 50-mg dose of sildenafil that could be adjusted to 100 mg or 25 mg based on tolerability and efficacy. Patients recorded the number of successful intercourse encounters for 6 to 8 weeks, and the number of adverse events. Overall, there was an 82% successful intercourse rate with sildenafil treatment. The predominant associated risk factors for ED were hypertension (39%), hypogonadism (37%), and multiple medications (34%). Common adverse events due to sildenafil treatment were mild to moderate in nature and resulted in <2% patient discontinuation. Clinicians should be particularly careful to evaluate patients presenting with ED because the condition can be accompanied by a wide spectrum of risk factors requiring monitoring and treatment. However, with adequate treatment and control of these risk factors, the use of sildenafil in a representative population of men with ED in a multispecialty clinic can achieve a higher efficacy rate than previous studies have indicated.

Decreased testosterone in regularly menstruating women with decreased libido: a clinical observation.

Much more information is available concerning decreased libido in postmenopausal than in premenopausal women. Even less is known about androgen deficiency in younger women. We measured total and free testosterone levels in 12 consecutive premenopausal women complaining of decreased libido. Of the 12 women, 8 had low or immeasurable levels of testosterone despite having regular menstrual periods. Androgen precursor hormones, DHEA-S and Androstenedione, were low-normal to high-normal. Treatment with oral DHEA, 50 to 100 mg per day, restored sexual desire in 6 of the 8 women, gave partial improvement in one, and failed in another. Possible significance and etiological mechanism are discussed.

Assessment of the efficacy and safety of Viagra (sildenafil citrate) in men with erectile dysfunction during long-term treatment.

Long-term efficacy and safety of sildenafil was assessed in 1008 patients with erectile dysfunction (ED) enrolled in four flexible-dose (25 - 100 mg), open-label, 36- or 52-week extension studies. After 36 and 52 weeks, 92% and 89% of patients felt that treatment with sildenafil had improved their erections. Responses to a Sexual Function Questionnaire indicated that 52 weeks of sildenafil treatment resulted in clinically significant improvements in the duration and firmness of erections, overall satisfaction with sex life, and the frequency of stimulated erections. Commonly reported adverse events (AEs) were headache, flushing, dyspepsia, and rhinitis, which were generally mild to moderate. Reports of abnormal vision were consistent with previous clinical trials. The occurrence of treatment-related cardiovascular AEs, such as hypertension, tachycardia, and palpitation, was <1%. Discontinuations due to treatment-related AEs were low (2%). Long-term therapy does not diminish the efficacy of sildenafil in patients with ED and remains well tolerated.

Sexual dysfunction in the diabetic patient.

The incidence of diabetes mellitus is increasing at an alarming rate, and diabetic men already make up a quarter of the men in our own specific medically-oriented population of erectile dysfunction. The incidence of sexual dysfunction in men with diabetes approaches 50%, and this is only slightly lower in diabetic women. Hypertension is a frequent risk co-factor, being seen between 40% and 60% of diabetics in the literature. Obesity and hyperlipidemia are other frequent co-factors. Interestingly, these risk factors are the same as those for coronary artery disease. The final common pathway for most of these factors is endothelial cell dysfunction.

Clinical experience with intraurethral alprostadil (MUSE) in the treatment of men with erectile dysfunction. A retrospective study. Medicated urethral system for erection.

OBJECTIVE: The Food and Drug Administration (USA) approved the transurethral administration of prostaglandin (alprostadil in January 1997), which had an efficacy of approximately 50% in clinical trials. We studied its effectiveness in clinical practice. METHODS: Patient and partner education was followed by an initial office trial of a medicated urethral system for erection (MUSE) after other medical risk factors were corrected during a 2- to 4-month period. The initial titration dose of alprostadil was usually 125 or 250 microg. Further titration, if needed, was instituted by the patient at home. Success was determined as the satisfactory completion of sexual intercourse in more than 66% of attempts, with a minimum of two being required. RESULTS: Two hundred and seventy patients entered the trials, and follow-up information was available in 229 (85%). The overall success rate was 56%. The dose required was 500 microg in 49.2% and 1,000 microg in 42.2%. Of the 44% in whom treatment failed, 61.4% did so because of lack of efficacy and 38.6% because of side effects (genital pain or urethral bleeding). Minor urogenital symptoms, which did not interfere with treatment, occurred in an additional 40% of patients. CONCLUSIONS: The efficacy of transurethral administration of alprostadil (56%) is higher than the initial published clinical trial data and higher than recent reported clinical experiences, although higher doses were required in our study. Men over 50 years of age, having an organic cause for erectile dysfunction, had better responses. Patient and partner education is important for successful treatment, and the in-office initial titration is an integral part of this success. Prior correction of medical risk factors may enhance the success rate.

Testosterone treatment in hypogonadal men: prostate-specific antigen level and risk of prostate cancer.

OBJECTIVE: To assess prostate-specific antigen (PSA) levels in hypogonadal men after testosterone replacement by three different methods and attempt to determine any possible relationship between hypogonadism and prostate cancer in this study population. METHODS: A total of 90 consecutive men who had erectile dysfunction and were found to have hypogonadism were monitored with digital rectal examination (DRE) and measurement of PSA levels before and after testosterone replacement therapy. The patients were treated with one of three options: (1) testosterone enanthate by intramuscular injections, 200 or 300 mg every 2 or 3 weeks (N = 25); (2) testosterone nonscrotal patches, 5 mg daily (N = 16); or (3) clomiphene citrate, 50 mg orally three times a week, in patients with functional secondary hypogonadism (N = 49). Treatment was continued for 2 to 3 months, after which PSA levels were reassessed. Patients with suspicious results on DRE and increased PSA levels before or after treatment with testosterone underwent prostate biopsy. For statistical analysis, patients were categorized into two age-groups--40 to 60 years old and 61 to 80 years old. RESULTS: With all methods of testosterone replacement, PSA levels increased in both age-groups. Endogenous testosterone elevation from clomiphene stimulation raised PSA levels the highest, and testosterone patches yielded the least PSA response. Ten men underwent biopsy of the prostate. In one patient, a nodule was found on DRE; the other nine men underwent biopsy because of suspicious PSA levels. Of these patients, two were found to have adenocarcinoma, and a third man who underwent rebiopsy was also found to have cancer. Therefore, 3 of the 90 patients (3.3%) had prostate cancer. CONCLUSIONS: PSA levels increased in response to all types of testosterone replacement, regardless of whether the testosterone level was raised endogenously or exogenously. PSA levels are inappropriately low in hypogonadal men and may mask an underlying cancer. Determining PSA levels before and after testosterone treatment is recommended. Elevated PSA levels before or after testosterone therapy should prompt performance of a urologic evaluation for possible prostate biopsy.

Characterization of patients in a medical endocrine-based center for male sexual dysfunction.

OBJECTIVE: To characterize the patient population in a multidisciplinary sexual dysfunction clinic whose focal person is an endocrinologist and to summarize the initial manifestations, the demographics of the study group, and their associated medical conditions. METHODS: We undertook a retrospective analysis of the medical records of all new consultations in a center for sexual function during a recent 2-year period. RESULTS: During the period from July 1995 to July 1997, 1,050 men were seen in new consultations for sexual dysfunction at our medical facility, and complete medical records could be retrieved for 990 of them. Of the overall study group of 990 men, most (93.2%) had erectile dysfunction (versus libido or ejaculatory problems), but combinations of problems were common. Most men had organic causes of their sexual dysfunction that correlated with increasing age; however, their dysfunction was more often the result of chronic medical conditions than of advancing age itself. Most men were married (72.1%) and in long-term relationships (mean duration, more than 20 years). Hypogonadism was the most common medical condition (36.3%), a finding that reflected an endocrine referral bias. Testosterone treatment alone corrected the complaints in a minority of patients. Hypertension was a more common diagnosis than diabetes (35.8% versus 23.1%), and pituitary tumors were rare. Successful outcomes were achieved in about two-thirds of men having a strong organic cause of sexual dysfunction, but treatments were less successful when pronounced psychologic factors were present. The patient dropout rate was substantial and was similar in each of the four 6-month quarters--an indication that even as newer therapies became available, dissatisfaction was still evident. CONCLUSION: Many patients have more than one manifestation of sexual dysfunction, which may have to be addressed separately. In a sexual dysfunction clinic managed by an endocrinologist, referral bias may direct more patients with hypogonadism and fewer patients who have had transurethral retropubic prostatectomy or a radical prostatectomy. Treatment of hypogonadism corrects sexual dysfunction in only a few men, and only when other medical problems are not present. Although the percentage of men with diabetes would be expected to be high in this study, the number of patients with hypertension was higher. A considerable dropout rate during evaluation and treatment persisted throughout this study.

Asymptomatic 'big' hyperprolactinemia in two men with pituitary adenomas.

'Big' and 'big-big' hyperprolactinemia, the presence of increased serum concentrations of high molecular weight (50-60 and 150 kDa respectively) prolactin forms, has mostly been reported in women with idiopathic hyperprolactinemia and normal hypothalamic-pituitary ovarian axis function. It has been suggested that both 'big' and 'big-big' prolactin species are biologically less active than the 22 kDa form predominating in normal individuals. We report the cases of two men with pituitary adenomas who were secreting significant amounts of 'big' (50-60 kDa) prolactin documented by Sephadex G-100 column chromatography. Both patients reported normal sexual function despite high prolactin levels. Results of nocturnal rigidity and tumescence testing were normal, confirming that significant hyperprolactinemia was not interfering with either patient's sexual function. 'Big' hyperprolactinemia should thus be suspected even in male patients with prolactin-secreting pituitary adenomas who maintain adequate sexual function in the presence of high prolactin levels.

Cessation of smoking rapidly decreases erectile dysfunction.

OBJECTIVE: To assess the relationship between cessation of smoking and rapid improvement in erectile capacity as well as the effect of nicotine patches on nocturnal penile tumescence and rigidity. METHODS: Nocturnal penile erections were studied in 10 smokers with use of the RigiScan portable home monitor. Two nights were monitored: for the first night, the patients had not stopped smoking; for the second night, the patients had stopped smoking for 24 hours. In addition, four men were monitored after cessation of smoking and wearing nicotine patches for 1 month. RESULTS: Multiple variables studied showed a statistically significant improvement in nocturnal penile tumescence and rigidity in the men who had stopped smoking for 24 hours. Continued improvement was noted in the four men who were monitored while not smoking and wearing nicotine patches for 1 month. CONCLUSION: Stopping cigarette smoking is a factor that rapidly improves penile tumescence and rigidity. Because the improvement continues while the patient is receiving nicotine from transdermal patches, some factor or factors other than the nicotine are responsible for the erectile dysfunction.

The endocrinologist as the focus in a multidisciplinary approach to management of erectile dysfunction.

OBJECTIVE: To present an approach to the complete but cost-effective office evaluation and treatment of erectile dysfunction. METHODS: The numerous medical, hormonal, and psychologic causes of erectile dysfunction are reviewed, and the various treatment strategies are outlined. RESULTS: Erectile dysfunction, which might also include libido and ejaculatory disturbances, is the most frequently encountered type of sexual dysfunction seen in office practice. Before 1960, the assessment of this disorder was dominated by psychiatrists; later, urologists assumed a role. More recently, physicians in internal medicine have become involved in the management of this problem. Diabetes mellitus, hypertension, and tobacco abuse are the three most common causes of erectile dysfunction in men older than 50 years of age. In addition to optimizing the management of diabetes, the endocrinologist can treat other endocrine problems associated with erectile dysfunction. CONCLUSION: A multidisciplinary approach to the evaluation and treatment of erectile dysfunction is logical, and the endocrinologist--because of an extensive background in internal medicine and expertise in hormonal diagnosis and treatment--should be the focal point of this diagnostic and therapeutic team.

Comparison of results of nocturnal penile tumescence and rigidity in a sleep laboratory versus a portable home monitor.

OBJECTIVES: To validate the results of the home penile tumescence monitor versus the sleep laboratory studies of erectile function. METHODS: We used both methods to study 18 episodes of rigidity and 19 episodes of tumescence in 10 subjects with erectile dysfunction before and after the use of an experimental vasodilating medication. RESULTS: The tumescence measurement in the sleep laboratory compared favorably with the changes in tumescence with the RigiScan portable home monitor: at the base (r = 0.70; P < 0.001), and at the tip (r = 0.84; P < 0.001). In measuring rigidity, the buckling pressure in the sleep laboratory compared favorably with the RigiScan measurements of percent average rigidity at the base (r = 0.56; P = 0.017), at the tip (r = 0.62; P = 0.006), and mean rigidity of the base and tip (r = 0.64; P = 0.004). In a comparison of the buckling pressure with the new RigiScan Plus quantitative program, there was good correlation with the rigidity activity units at the base (r = 0.70; P = 0.001) and at the tip (r = 0.72; P < 0.001). A clinical estimate of penetrable rigidity correlates with the RigiScan base rigidity of 55% to 60% and tip rigidity of about 50%. CONCLUSIONS: The portable home monitor is a viable and cost-effective clinical tool to measure nocturnal penile activity.

Delayed diagnosis of psychological erectile dysfunction because of the presence of macroprolactinemia.

Idiopathic hyperprolactinemia can be found in men with either normal or low serum testosterone (T) levels. The explanation for the differing effects on T of similar PRL levels has not been found. Macroprolactinemia, as a clinical entity, has been reported mostly in women. These macromolecules are biologically less active and/or are transported less easily across the capillary bed than the 22-kDa molecules. Therefore, women with elevated PRL levels retain normal menses and fertility. We studied six men, aged 28-53 yr (mean, 45 yr), in whom hyperprolactinemia was initially considered to be the cause of their erectile dysfunction. PRL levels ranged from 25-92 ng/mL (normal, 2-15 ng/mL), but T and gonadotropin levels were normal, suggesting that PRL was not disrupting gonadotropin and gonadal steroid function. The results of magnetic resonance imaging studies of the pituitary gland were normal. Separation by Sephadex G-100 column chromatography showed a predominance (85-90%) of big (60 kDa) and big big ( > 150 kDa) PRL, in contrast to the predominance of 22-kDa PRL in normal subjects. Nocturnal tumescence testing was normal, supporting the diagnosis of psychogenic impotence in these subjects, and potency returned after counseling. Hence, the biologically inactive macroprolactinemia did not cause any organic derangement in erectile function. It further obscured and delayed the appropriate diagnosis and treatment of these individuals.

Effect of raising endogenous testosterone levels in impotent men with secondary hypogonadism: double blind placebo-controlled trial with clomiphene citrate.

Secondary hypogonadism is not an infrequent abnormality in older patients presenting with the primary complaint of erectile dysfunction. Because of the role of testosterone in mediating sexual desire and erectile function in men, these patients are usually treated with exogenous testosterone, which, while elevating the circulating androgens, suppresses gonadotropins from the hypothalamic-pituitary axis. The response of this form of therapy, although extolled in the lay literature, has usually not been effective in restoring or even improving sexual function. This failure of response could be the result of suppression of gonadotropins or the lack of a cause and effect relationship between sexual function and circulating androgens in this group of patients. Further, because exogenous testosterone can potentially increase the risk of prostate disease, it is important to be sure of the benefit sought, i.e. an increase in sexual function. In an attempt to answer this question, we measured the hormone levels and studied the sexual function in 17 patients with erectile dysfunction who were found to have secondary hypogonadism. This double blind, placebo-controlled, cross-over study consisted of treatment with clomiphene citrate and a placebo for 2 months each. Similar to our previous observations, LH, FSH, and total and free testosterone levels showed a significant elevation in response to clomiphene citrate over the response to placebo. However, sexual function, as monitored by questionnaires and nocturnal penile tumescence and rigidity testing, did not improve except for some limited parameters in younger and healthier men. The results confirmed that there can be a functional secondary hypogonadism in men on an out-patient basis, but correlation of the hormonal status does not universally reverse the associated erectile dysfunction to normal, thus requiring closer scrutiny of claims of cause and effect relationships between hypogonadism and erectile dysfunction.