|Year : 2006 | Volume
| Issue : 3 | Page : 231-234
New insights into androgen treatment of erectile dysfunction
Department of Endocrinology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands
Endocrinology / VUmc, PO Box 7057, 1007 MB Amsterdam, The Netherlands
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Erectile response in mammals is centrally and peripherally regulated by androgens. Severe hypogonadism in men usually results in loss of libido and potency which can be restored by androgen administration. The original insights into the mechanisms of action of androgens on sexual function indicated that androgens particularly exert effects on libido and that sleep-related erections were androgen-sensitive but erections in response to erotic stimuli were relatively androgen-independent. There are a number of recent developments which shed new light on testosterone treatment of erectile dysfunction in aging men. There is growing insight that testosterone has profound effects on tissues of the penis involved in the mechanism of erection and that testosterone deficiency impairs the anatomical and physiological/biochemical substrate of erectile capacity, reversible upon androgen treatment. Several studies have indicated that the administration of PDE-5-inhibitors is not always sufficient to restore erectile potency in men and that administration of testosterone improves the therapeutical response to PDE-5-inhibitors considerably. There is increasing insight not to view erectile dysfunction (ED) as a single entity but as part of the aging process. Circulating levels of testosterone are closely related to manifestations of other etiological factors in ED, such as atherosclerotic disease and diabetes mellitus. The latter are correlated with lower-than-normal testosterone levels.
Keywords: Androgens, hypogonadsim, testosterone
|How to cite this article:|
Gooren L. New insights into androgen treatment of erectile dysfunction. Indian J Urol 2006;22:231-4
| Introduction|| |
This contribution will focus on the role of testosterone in erectile dysfunction (ED). Systematic observations became possible when testosterone became pharmaceutically available in the middle of the last century. The first studies pointed to a prominent role of testosterone in sexual interest while the effects of testosterone on erectile function were less apparent from these investigations In the view of many practitioners, treatment of ED with testosterone was not very efficacious. Then, in 1999 a class of new drugs, the phosphodiesterase Type 5 inhibitors (PDE-5 inhibitors) were introduced. The introduction of these highly efficacious and relatively safe compounds has had a profound impact on the diagnosis and treatment of ED. Once mainly the domain of the urologist attempting to define its precise etiology, ED is now largely treated by first-line physicians, usually without much of a diagnostic work-up, but with a degree of success. Despite the simplicity and safety of the present therapy of ED with PDE-5 inhibitors, approximately 50% of patients discontinue treatment. The reasons for discontinuation lie for a large part in an incomplete evaluation of the sexual problem. Hypogonadism, ejaculatory dysfunction, lower urinary tract symptoms, depression and last but not least, partner issues may all be components of the sexual dysfunction of the patient and should have been part of the diagnostic work-up of the patient.
Over the last years there is a renewed interest in the role testosterone in male (patho) physiology and more particular in a better definition of the place of testosterone in ED., Recent studies provide convincing evidence that there is powerful effect of testosterone on the anatomical and physiological substrate of penile erection. Furthermore, it has become clear that testosterone is not simply one of the many factors playing a role in erectile (dys) function. Circulating levels of testosterone are closely related to manifestations of other etiological factors in ED, such as atherosclerotic disease and diabetes mellitus. The latter are correlated with lower-than-normal testosterone levels. Therefore, the role of testosterone in erectile (dys) function is increasingly recognized.
Erectile potency is physiologically a complex interaction of vascular, neural, metabolic, endocrine and, last but not the least, psychological factors. Erectile difficulties often provide a window into the presence of pathology in these areas. Rather than a disease in itself, ED is, particularly in elderly men who have enjoyed normal sexual functions earlier in life, a manifestation of pathologies of the biological systems involved in erectile function. But the advent of successful treatment modalities of erectile difficulties, such as the PDE-5 inhibitors, have led to a concept of erectile failure as an entity in itself rather than an expression of the underlying pathology of its constituents. In other words, it has opened the door to view the diagnosing and treating of the underlying pathology of erectile failure a redundancy.
| Defining the role of testosterone|| |
When testosterone became pharmaceutically available, systemic studies were undertaken to define more precisely the role of testosterone in a man's sexual functioning. Most of the information has been collected from androgen withdrawal/replacement studies of hypogonadal men. Surprisingly, the findings strongly suggested that it was particularly sexual interest that was androgen-dependent. Further, the studies provided evidence that various types of erections showed a different relationship with circulating testosterone. In the first studies, spontaneous erections, particularly those that occur during sleep and probably fantasy-induced erections were thought to be exquisitely androgen-dependent, whereas erections in response to erotic (e.g., visual or tactile) stimuli were less so., Sexual complaints of patients relate to the latter type of erections, erections in the context of anticipated sexual activity. The original studies, however, monitored only penile circumference but not stiffness and later observations showed that androgens do affect penile responses to erotic stimuli with regard to the duration of response and maximal degree of rigidity, all significant aspects of androgen effects on sexual functioning. Nevertheless, these observations led to the belief that androgens had primarily effects on sexual interest or motivation. The influence on the penis was thought to be indirect, via the effects on libido, rather than direct on penile tissues. Consequently, it was assumed that androgens were therapeutically not very useful when men complained about erectile difficulties while their sexual appetite was not impaired, precisely their reason for medical consultation.
Another reason why testosterone was not regarded as a therapeutical option in men with ED was the finding that the blood level of testosterone critical for restoring sexual interest, though varying between individuals appeared to be 60 to 70% of the reference values for eugonadal men. It is of note that these observations were done in men across a wide range of ages. Therefore, it was assumed that in men with erectile dysfunction and low-normal or slightly lower-than-normal androgen levels, as is common in an elderly population, additional testosterone was likely to be of no help, which was in agreement with the clinical experience of many practitioners. When the PDE-5 inhibitors were introduced in 1998, patients who had earlier failed to respond to androgen or other types of treatment could now successfully be treated. The success of the PDE-5 inhibitors rendered androgens as treatment for erectile problems as something of the past, which seemed rational in view of the assumption that the primary effects of testosterone were on libido, in other words on the central nervous system and further that less-than-normal circulating levels of testosterone were sufficient to exert that function, which, however, is no longer tenable. Schiavi and Rehman, based on their vast clinical experience, hypothesized, however, that the threshold for the biological actions of testosterone might be higher in elderly men compared to young men. Their hypothesis was recently convincingly experimentally confirmed by Gray et al showing that in elderly men libido and erectile function respond only to higher levels of circulating testosterone than in younger men.
Over the last 15 years the age-related decline of circulating testosterone in men has received increasing attention, not only in relation to sexual functioning but in a wider context of male health.
Moreover, new research has presented convincing evidence, so far mainly in laboratory animals, that testosterone has profound effects on tissues of the penis involved in the mechanism of erection and that testosterone deficiency impairs the anatomical and physiological substrate of erectile capacity. The following will review recent findings and arrives at the conclusion that restoring plasma testosterone to normal is beneficial in the treatment of ED. It has been shown that the full therapeutical potential of PDE-5 inhibitors will only become manifest in a eugonadal state The above provides some alterations of the earlier beliefs that the effects of testosterone are primarily and predominantly exerted on the libidinous aspects of the male and not directly on the penis as well.
Animal experiments and, to a much more limited degree, human observations suggest that androgens are necessary to maintain the integrity of the anatomical structures of the penile erectile tissue and, further, that androgens are significant in the biochemical mechanisms subserving penile erection.
Studies of androgen effects on the anatomy and physiology/biochemistry of the penis
There is now ample evidence from animals studies that androgen deprivation produces changes in the histological properties of penile structures. In a rat model Shen et al demonstrated that androgen deprivation leads to loss of elastic fibers in the tunica albuginea and of smooth muscle fibers in the corpus cavernosum which were replaced by collagenous fibers in both structures. Singh et al found that the mesenchymal pluripotent cells follow a myogenic lineage or adipogenic lineage depending on the circulating levels of testosterone, confirmed by Traish et al .
Traish and coworkers demonstrated that even a 50% reduction in circulating testosterone reduced intracavernosal blood pressure which was not enhanced by administration of the PDE-5-inhibitor vardenafil. Nitric oxide synthase and arginase activities in the corpus cavernosum were not significantly affected by the reduction in circulating testosterone confirmed in human tissue by Morelli et al . Yassin and Saad could show that adequate testosterone treatment can restore venous leakage in the corpus cavernosum which is a frequent etiological factor in ED in elderly men.
Effects of testosterone therapy to elderly men with ED
While the effects of testosterone treatment in younger and middle-aged men on parameters of sexual functioning have been convincing, the effects in elderly men have been more problematic to demonstrate. These studies have been reviewed., The latter review concluded somewhat optimistically that testosterone therapy increased libido in seven of eight studies and improved erections in five of six studies. Also Yassin and coworkers could demonstrate the beneficial effects of normalization of testosterone levels in more than 50% of an aging population. The effects may not become apparent before three or more months of androgen administration.
Effects of testosterone administration to men who do not benefit from treatment with PDE-5 inhibitors
Park et al found recently that the success rate of treatment with sildenafil in a cohort of 162 men > 60 years was only 47%. It could further be established that among the risk factors predicting a poor response to sildenafil were smoking and hypogonadism (plasma testosterone < 3 ng/mL). In line with this, Aversa et al reported that the circulating levels of free testosterone, independently of age, positively correlated with the degree of relaxation of the corporal smooth muscle cells and the cavernous endothelial cells, giving support to the potential role of androgens in regulating smooth muscle function in the penis.
In a later well designed intervention study Aversa et al provided support for this mechanism of action of testosterone on the erectile tissues of the penis. They assessed the effects of androgen administration in 20 patients with arteriogenic ED (confirmed with dynamic color duplex ultrasound), not responding to treatment with sildenafil 100 mg. The patients' testosterone levels were in the lower quartile of the normal range. In this placebo-controlled study, treatment with transdermal testosterone raised plasma testosterone levels and led to an increase of arterial inflow into the cavernous tissue and to an improvement of ED thus enhancing the response to treatment with PDE-5 inhibitors. In line with the above Foresta et al have documented that normal plasma testosterone is required for erectile function. In severely hypogonadal men (plasma testosterone <2.0 ng/mL) the nocturnal penile tumescence, ultrasound measurement of arterial carvernous inflow and visually stimulated erection in response to sildenafil 50 mg or apomorphine 3 mg were minimal. The responses to these pharmacological stimuli normalized after six months of administration of testosterone patches evidencing the significant role of normal levels of testosterone for erectile function.
The notion that testosterone and PDE-5 inhibitors have synergistic effects on nocturnal erections was also confirmed in men in a laboratory setting by Rochira et al .
| Summary and conclusions|| |
Erectile response in mammals is centrally and peripherally regulated by androgens. Severe hypogonadism in men usually results in loss of libido and potency which can be restored by androgen administration.
The original insights into the mechanisms of action of androgens on sexual function indicated that androgens particularly exert effects on libido and that sleep-related erections were androgen-sensitive but erections in response to erotic stimuli were relatively androgen-independent.
There are a number of recent developments which shed new light on testosterone treatment of erectile dysfunction in aging men. There is growing insight that testosterone has profound effects on the tissues of the penis involved in the mechanism of erection and that testosterone deficiency impairs the anatomical and physiological / biochemical substrate of erectile capacity, reversible upon androgen treatment. Several studies have indicated that the administration of PDE-5 inhibitors is not always sufficient to restore erectile potency in men and that administration of testosterone improves the therapeutical response to PDE-5 inhibitors considerably.
| References|| |
|1.||Bancroft J, Wu FC. Changes in erectile responsiveness during androgen replacement therapy. Arch Sex Behav 1983;12:59-66. [PUBMED] |
|2.||Park K, Ku JH, Kim SW, Paick JS. Risk factors in predicting a poor response to sildenafil citrate in elderly men with erectile dysfunction. BJU Int 2005;95:366-70. [PUBMED] [FULLTEXT]|
|3.||Gooren LJ, Saad F. Recent insights into androgen action on the anatomical and physiological substrate of penile erection. Asian J Androl 2006;8:3-9. [PUBMED] [FULLTEXT]|
|4.||Shabsigh R. Testosterone therapy in erectile dysfunction. Aging Male 2004;7:312-8. [PUBMED] |
|5.||Shabsigh R, Perelman MA, Lockhart DC, Lue TF, Broderick GA. Health issues of men: Prevalence and correlates of erectile dysfunction. J Urol 2005;174:662-7. [PUBMED] |
|6.||Traish AM, Guay AT. Are androgens critical for penile erections in humans? Examining the clinical and preclinical evidence. J Sex Med 2006;3:382-407. [PUBMED] [FULLTEXT]|
|7.||Bancroft J. Hormones and human sexual behavior. J Sex Marital Ther 1984;10:3-21. [PUBMED] |
|8.||Granata AR, Rochira V, Lerchl A, Marrama P, Carani C. Relationship between sleep-related erections and testosterone levels in men. J Androl 1997;18:522-7. [PUBMED] |
|9.||Bhasin S, Woodhouse L, Casaburi R, Singh AB, Bhasin D, Berman N, et al . Testosterone dose-Response relationships in healthy young men. Am J Physiol Endocrinol Metab 2001;281:E1172-81. |
|10.||Gray PB, Singh AB, Woodhouse LJ, Storer TW, Casaburi R, Dzekov J, et al . Dose-dependent effects of testosterone on sexual function, mood and visuospatial cognition in older men. J Clin Endocrinol Metab 2005;90:3838-46. |
|11.||Schiavi RC, Rehman J. Sexuality and aging. Urol Clin North Am 1995;22:711-26. [PUBMED] |
|12.||Morelli A, Filippi S, Mancina R, Luconi M, Vignozzi L, Marini M, et al . Androgens regulate phosphodiesterase type 5 expression and functional activity in corpora cavernosa. Endocrinology 2004;145:2253-63. |
|13.||Yassin AA, Saad F. Dramatic improvement of penile venous leakage upon testosterone administration. A case report and review of literature. Andrologia 2006;38:34-7. [PUBMED] [FULLTEXT]|
|14.||Jain P, Rademaker AW, McVary KT. Testosterone supplementation for erectile dysfunction: Results of a meta-analysis. J Urol 2000;164:371-5. [PUBMED] |
|15.||Morley JE, Perry HM 3rd. Androgen treatment of male hypogonadism in older males. J Steroid Biochem Mol Biol 2003;85:367-73. [PUBMED] [FULLTEXT]|
|16.||Yassin AA, Saad F, Diede HE. Testosterone and erectile function in hypogonadal men unresponsive to tadalafil: Results from an open-label uncontrolled study. Andrologia 2006;38:61-8. [PUBMED] [FULLTEXT]|
|17.||Aversa A, Isidori AM, De Martino MU, Caprio M, Fabbrini E, Rocchietti-March M, et al . Androgens and penile erection: Evidence for a direct relationship between free testosterone and cavernous vasodilation in men with erectile dysfunction. Clin Endocrinol (Oxf) 2000;53:517-22. |
|18.||Aversa A, Isidori AM, Spera G, Lenzi A, Fabbri A. Androgens improve cavernous vasodilation and response to sildenafil in patients with erectile dysfunction. Clin Endocrinol (Oxf) 2003;58:632-8. [PUBMED] [FULLTEXT]|
|19.||Foresta C, Caretta N, Rossato M, Garolla A, Ferlin A. Role of androgens in erectile function. J Urol 2004;171:2358-62. [PUBMED] |
|20.||Rochira V, Balestrieri A, Madeo B, Granata AR, Carani C. Sildenafil improves sleep-related erections in hypogonadal men: Evidence from a randomized, placebo-controlled, crossover study of a synergic role for both testosterone and sildenafil on penile erections. J Androl 2006;27:165-75. [PUBMED] [FULLTEXT]|