Tuesday, July 15, 2008

Erectile Dysfunction: An Underdiagnosed Condition Associated With Multiple Risk Factors

sildenafil M. Shabbir; D. M. Mikhailidis; R. J. Morgan 

Erectile dysfunction (ED) is a common condition with a significant effect on the quality of life. The prevalence of ED rises with increasing age and other conditions (hypertension, diabetes, ischaemic heart disease, hypercholesterolaemia and depression). The MALES study is one of the largest epidemiological surveys to investigate the prevalence of ED. This study included 27 839 patients spanning eight countries. In addition to the MALES study, we review the emerging link between lower urinary tract symptoms (LUTS), benign prostatic hypertrophy (BPH) and ED, including the effect of BPH treatment on sexual function. Preliminary data from the MALES II study shows a significant cascade effect in the treatment seeking behaviour and treatment adherence of patients taking sildenafil for ED. We explore the possible reasons behind the discontinuation of oral phosphodiesterase inhibitors prescribed for the long-term treatment of ED.

Erectile dysfunction (ED) is defined as the inability to obtain and/or maintain penile erection sufficient for satisfactory sexual performance.[1] ED has a significant impact on the quality of life and it is a common problem (affecting more than 100 million men worldwide).[2]

This issue of Current Medical Research and Opinion includes the Men's Attitudes to Life Events and Sexuality (MALES) study which provides information regarding the prevalence of ED and related health matters.[3] This is one of the largest epidemiological studies in this field; it included 27839 patients spanning over eight countries. The study found an overall prevalence of self-reported ED of 16% in men aged 20-75 years. Differences were noted between the various countries, with the highest prevalence seen among men in the US (22%) and the lowest in Spain (10%). The study confirmed the increased prevalence of ED with both increasing age, and other co-morbid conditions (hypertension, diabetes, ischaemic heart disease, hypercholesterolaemia and depression) as noted in earlier studies.[4,5]

The MALES study[3] did not, however, address the relationship between ED and lower tract urinary symptoms (LUTS) or benign prostatic hypertrophy (BPH). Earlier reviews were sceptical about an association between these two common conditions and considered their relationship incidental to a similar age and gender distribution.[6] However, an emerging link between BPH and ED has been recognised in recent years. The MSAM-7 study investigated the association between LUTS and ED in 12815 men aged between 50 and 80 years. This large multinational survey assessed the correlation between the International Prostate Symptom Score (IPSS) and ED independent of age and other co-morbidities.[7] The prevalence of ED in men with no LUTS was 24.8%, compared to 43.3, 65.8 and 81.9% ED in men with mild, moderate and severe symptoms, respectively. Ejaculatory problems were reported by 25.3% of the men with no LUTS compared to 41.8, 61.4 and 76.0% with mild, moderate and severe symptoms, respectively. A similar association between LUTS and sexual dysfunction was also reported by others.[8-10]

An experimental model of bladder outflow obstruction (BOO) provided an insight into the potential pathophysiological link between BPH and ED.[11] There was an endothelin ETA/ET B receptor imbalance as well as adverse structural changes in the corpus cavernosum in a rabbit model of BOO. These effects may be responsible for the observed impaired nitric oxide (NO)-mediated cavernosal relaxation in this model.[11]

A common pathophysiological link between ED and BPH would mean that treating one condition could influence the other. For example, in a 1-year, prospective, open label study of 2829 men with BPH, alfuzosin (a α1-receptor antagonist) increased the perceived sexual function score by 191%, with the greatest improvements seen in men < 70 years with severe LUTS.[12] In a double blind, multicentre trial of 1475 men with BPH, doxazosin improved sexual function in the patients with ED.[13] Treatment of LUTS with tamsulosin for 6 months suggested improvements in libido, erection and overall sexual function in a study of 3000 men.[14] However, despite these improvements, ejaculation failure has been shown to occur more often in patients taking these drugs, particularly tamsulosin.[15] It remains unclear whether the beneficial effects seen with α1-receptor antagonists are due to a direct pharmacological effect or whether they are a consequence of improvements in urinary symptoms. In contrast to these drugs, the treatment of BPH with the 5-α-reductase inhibitor finasteride has a negative effect on sexual function. One study reported 33% ED in patients treated with finasteride for 6 months, none of whom had reported sexual dysfunction at baseline.[16] There is also evidence that sildenafil prescribed to treat ED can improve LUTS.[17] This effect was attributed to an effect on bladder muscle.[17] It follows that the treatment of patients with BPH and ED needs to be carefully considered since the choice of medication for one condition may influence the other.

The MALES II study[3] investigates the treatmentseeking behaviour of the subgroup of patients who reported ED (2912 men). These findings highlight some interesting information regarding the pattern of ED evaluation and treatment.[3] Currently there are numerous treatments for ED including vacuum-constriction devices, apomorphine, phosphodiesterase-5 (PDE5) inhibitors and transurethral or intracavernosal injection of vasoactive agents such as alprostadil (prostaglandin E1). More invasive surgical management includes implantation of penile prostheses, and venous or arterial surgery. The MALES II study focused on the use of sildenafil.[3]

The advent of sildenafil citrate (Viagra, Pfizer) revolutionised the treatment of ED. A selective PDE5 inhibitor, sildenafil was the first oral therapy with a combination of efficacy, tolerability and ease of use.[18,19] It is effective in the treatment of ED of organic, psychogenic and mixed aetiology[20] and is of benefit in cases where other medical treatments have failed.[21] Oral treatment with PDE5 inhibitors including sildenafil, and the newer vardenafil (Levitra, Bayer) and tadalafil (Cialis, Lilly), is now considered the first line treatment of choice.

It is interesting, therefore, that the MALES II study[3] highlights a discrepancy between the use of sildenafil and its efficacy and convenience. Only 58% of the 2912 men who self-reported ED actively sought attention for their condition. Only 41% of the men in this group discussed possible treatment with sildenafil, with only 25% of them filling their prescription for the drug. Only 16% of this group were still taking sildenafil at the time of the survey. This 'cascade effect' is larger than expected, taking into account the profile of the oral PDE5 inhibitors. While there are issues regarding the treatment-seeking behaviour and treatment adherence that future analyses of the MALES II data will reveal, there are some possible explanations for the discontinued use of sildenafil with time.

The adverse events associated with the use of sildenafil include headache, flushing, dyspepsia and visual disturbances.[20,21] However, discontinuation due to adverse events is low, ranging between 0 and 10%, suggesting that these side effects are generally well tolerated Another possibility for discontinuation is the potential development of tachyphylaxis with the continued use of sildenafil. El-Galley et al., performed a telephone survey of 151 patients within their first year of sildenafil use and they followed this up with another survey of the same group 2 years later.[23] In the first survey there was an overall improvement rate of 74%. In the follow-up survey (82 patients) only 43 of the respondents (52%) were still taking sildenafil. Of this group 16 (37%) had to increase their dose by 50 mg to achieve the same effect. Of the patients who were followed up for 2 years, 20% had some increase in the sildenafil dose necessary to achieve the same result and 17% had discontinued use due to a loss of efficacy. Another telephone survey involving 1074 patients taking sildenafil for 1-3 years reported similar findings.[24] They found that 28.5% of patients taking 50 mg of sildenafil had increased their dose to 100 mg. In the same series, an alarming 80.2% of patients had discontinued sildenafil in the last 3 months leading up to the survey, with 51.6% claiming a loss of efficacy as their primary reason. However, the pharmacological basis of developing tachyphylaxis with a drug that is taken intermittently is controversial.[25,26]

It remains to be seen whether treatment with the newer PDE5 inhibitors, vardenafil and tadalafil, will have the same discontinuation rates as sildenafil once more data exist on their long-term use. The PDE5 inhibitors have unique sets of pharmacological characteristics and their long-term efficacy may differ.[27]

It is also possible that the discontinued use of oral PDE5 inhibitors may not be due to a failure of the drug itself, but to the cost of treatment or a change in either the severity of the underlying condition or psychosocial need. Despite the increased prevalence of ED with increasing age, a concomitant decrease in sexual desire may explain why the elderly population has less of a need for treatment. However, it is also relevant to consider that in one study the response to sildenafil deteriorated with age and increasing degree of ED.[28] Nevertheless, PDE5 inhibitors are probably still the oral drugs of choice for the treatment of ED.[29] Thus, sildenafil, even at a 50 mg dose, was more effective than apomorphine 3 mg in men with arteriogenic ED.[29] It is also of interest that in the same study one out of five patients was not satisfied with the drug administered.[29] Therefore, other oral agents need to be evaluated.

Changes with time also affect the association between co-morbidities and ED. The systemic effects of conditions such as hypertension, ischaemic heart disease, hypercholesterolemia and diabetes are progressive, and their continued presence accentuates the pathophysiological processes known to cause ED. In addition to their effect in isolation, these co-morbidities may work in an additive or synergistic fashion to further reduce erectile function. Alterations (including treatment) to these underlying conditions may also influence the ability to treat ED.[30,31]

The effective management of ED remains an important goal to improving the quality of life. The emerging links between ED and increasing age, psychogenic conditions, systemic co-morbidities such as hypertension and diabetes, and localised conditions such as BPH/LUTS underline the multifactorial pathogenesis of ED. The selection of drugs to deal with these conditions may well influence the success of treating ED.[30,31] The introduction of safe and effective oral PDE5 inhibitors has radically altered the way we treat ED. However, careful monitoring of the efficacy of this treatment must be improved to prevent the large cascade effects and treatment failures highlighted in epidemiological studies.


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Reprint Address

Address for correspondence: Mr M. Shabbir, Research Registrar, Department of Urology, Royal Free Hospital, Pond Street, London NW3 2QG, UK
M. Shabbir,1 D. M. Mikhailidis2 and R. J. Morgan1

1Department of Urology, Royal Free and University College Medical School (Royal Free Campus), University College London, UK
2Department of Clinical Biochemistry, Royal Free and University College Medical School (Royal Free Campus), University College London, UK
Curr Med Res Opin.  2004;20(5):603-606.  ©2004 Librapharm Limited

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1 comment:

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