- Email: [email protected]
Testosterone Replacement Should be Given to Men with Erectile Dysfunction
Opposing Views
Testosterone Replacement Should be Given to Men with Erectile Dysfunction PRO AN erection is a complex process that requires intact vascular, structural, psychological and neurological function, as well as normal levels of sex hormones. Erectile dysfunction (ED) is defined as the inability to achieve or maintain an erection sufficient for satisfactory sexual performance. Currently, there are several treatments available for ED, such as oral phosphodiesterase type 5 inhibitors (PDE5is), intracavernosal injections, intraurethral suppositories and penile implants. However, before proceeding with any treatment, it is important to evaluate serum testosterone levels in men with ED as suggested by the AUA (American Urological Association) guidelines.1 Testosterone plays an important role in normal sexual function for libido and erections. In a well conducted dose ranging trial Finkelstein et al demonstrated that as testosterone levels decreased, particularly below 400 ng/dl, deficits in erectile function and libido increased.2 In another prospective randomized trial on the effect of testosterone supplementation in older men with testosterone levels less than 275 ng/dl those who received testosterone supplementation reported improvement in sexual function compared to those who did not receive supplementation.3 The detrimental effects of lower testosterone levels on erectile function and libido have been supported by multiinstitutional placebo controlled trials as well as a meta-analysis of 17 randomized, placebo controlled trials on the effects of testosterone replacement on improvement in erectile function.4,5 Therefore, there is obvious substantial level I evidence that normal testosterone level is critical for libido and erectile function. Several animal studies have proven that testosterone is necessary to preserve and maintain the structural integrity of the penis by stimulating smooth muscle growth and inhibiting apoptosis.6 Furthermore, testosterone can regulate nitric oxide (NO) and phosphodiesterase type 5 (PDE5) enzyme production, both of which are critical for erectile
0022-5347/17/1972-0284/0 THE JOURNAL OF UROLOGY® Ó 2017 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
284
j
www.jurology.com
AND
RESEARCH, INC.
function.7 Therefore, in men with low testosterone we can speculate that sufficient levels of PDE5 enzyme may not be present and could render PDE5i such as sildenafil ineffective. Clinically, the hypothesis that sufficient testosterone levels are needed so oral PDE5is have adequate PDE5 enzyme to work on was tested in at least 1 randomized controlled trial in which men with a testosterone level of less than 400 ng/dl who did not respond to sildenafil monotherapy did respond after treatment with exogenous testosterone.8 The finding that testosterone may be able to enhance the effect of PDE5i in previous nonresponders to this therapy suggests that testosterone therapy should be considered in men with low testosterone and mild ED (International Index of Erectile Function-EF 22 to 25). In men with mild ED testosterone therapy can convert PDE5i nonresponders to responders and conceivably can obviate the need for the use of PDE5i in select patients, the latter leading to patient savings given the significant cost of PDE5i. Testosterone therapy is unlikely to be helpful as a sole modality of treatment for men with moderate to severe ED. ED due to radical pelvic surgery or advanced diabetes and hypertension, eg caused by severe neurogenic or vascular damage, will unlikely improve with testosterone therapy alone. Men with severe ED are best treated with intracavernosal injections, vaccum erection devices or penile prostheses. Taken together, it is clear that testosterone therapy is critical for libido and erectile function. Testosterone therapy should not be used as the sole modality of treatment in men with moderate to severe ED. Nevertheless, men with mild erectile dysfunction or low libido combined with low serum testosterone may derive the most benefit from testosterone therapy. Raul I. Clavijo and Ranjith Ramasamy Department of Urology University of Miami Miller School of Medicine Miami, Florida
http://dx.doi.org/10.1016/j.juro.2016.11.074 Vol. 197, 284-286, February 2017 Printed in U.S.A.
OPPOSING VIEWS
CON THE issue of testosterone replacement therapy needs to be addressed at several levels, including definition of erectile dysfunction; multifactorial etiology/ pathophysiology of erectile dysfunction; testosterone physiology and pathophysiology as it relates to erectile function and age/other diseases; correlation between testosterone and symptoms and signs, especially erectile dysfunction; role of guidelines based on level of evidence; and finally FDA (U.S. Food and Drug Administration) approval based on the evidence alone, and their definition of indicated and off label use. In terms of this discussion, I do wish to be specific about what is being asked. The definitions of “erectile function or dysfunction” as opposed to “sexual dysfunction” are not synonymous. Erectile function/dysfunction is a subset of sexual function/dysfunction that includes sexual desire (libido), arousal, pleasure, ejaculation/ climax and satisfaction for the patient and partner. As such, erectile function/dysfunction is a physiological response to neurological, vascular, psychological and also endocrine factors. This last component is the purpose of this discussion. The multifactorial and intertwined nature of sexual function/dysfunction and erectile function/ dysfunction makes analysis of the issues and literature difficult to separate into pure physiology of erectile function. Endocrine factors, such as diabetes, thyroid dysfunction, other endocrine diseases and testosterone deficiency, play an important role in the overall issue but defining levels of hormone deficiency which titrate with sexual dysfunction or erectile dysfunction as independent variables is far from clear. On a broader note that is beyond the scope of this discussion, standardizing the testosterone assay is far from consistent around the world.9 The multifactorial nature of erectile dysfunction makes this neither a single hormone nor a single factor problem. Androgen receptors are present centrally and in the corpora cavernosa, and animal studies have shown androgen involvement in the nitric oxide pathway. The role in humans is less clear. However, the vascular and neurological changes that occur with age and diseases play a significant role. Eunuchs and Castratos, from fabled urology legend, who were castrated as young boys were still able to maintain erections, regardless of loss of libido, since many times orchiectomy was performed before puberty. At the other end of the spectrum, older men (usually) with metastatic prostate cancer on androgen deprivation therapy suffer desperately with loss of energy, muscle wasting, anemia and sexual dysfunction with loss of libido and associated ED (which many times were preexistent).
285
In 2010 the Endocrine Society developed some recommendations on the signs/symptoms and evaluation of testosterone deficiency but they were largely consensus based and the level of evidence to correlate with them was poor overall.10 This outcome was highlighted by Seftel et al who reviewed the evidence to support the Endocrine Society guidelines since their publication and found that only 17 level I evidence clinical trials had been published from 2010 to 2015.11 On the topic of correlation of testosterone deficiency and treatment of ED, they did not find a consistently beneficial role of testosterone therapy in hypogonadal men with ED that was refractory to PDE5i. The AUA is currently performing a detailed analysis of the evidence that exists on the overall topic of hypogonadism and hopefully will provide more robust guidelines. There are no good large-scale, randomized controlled trials on the treatment of hypogonadism and improvement in symptoms. There is no men’s health initiative trial equivalent to that for women, despite the fact that this was recommended as far back as the 1990s by the Institute of Medicine. However, there have been other surrogate studies that have tried to evaluate the issue and efforts to correct this gap continue. The EMAS (European Male Aging Study) showed that the only 2 symptoms that correlated with low testosterone levels were decreased libido and erectile dysfunction, with libido being the most specific, but distinguishing between libido and erectile function is difficult.12 The T-Trial, which is the first efficacy trial to be conducted, revealed erectile function improvement with a short course of testosterone treatment (1 year).3,4 However, the direct role testosterone therapy plays specifically on erectile function/ dysfunction remains unclear. The FDA approved testosterone for the treatment of specific causes of primary and secondary hypogonadism. There is no mention of associated symptoms and signs in the package inserts for any testosterone treatments. Idiopathic or age related (late onset hypogonadism) clinical symptomatic hypogonadism is not considered an indication for treatment. As such, treatment of clinical hypogonadism without a known disease remains “offlabel” use. To be specific, erectile dysfunction alone or sexual dysfunction alone, if not associated with one of the specified diseases, is technically not an indication for treatment. Therefore, until there is convincing evidence otherwise, the FDA requested that any misleading advertising to that effect be stopped in 2014. The overall issue of direct to patient marketing has resulted in some information and misinformation as it relates to patient perceptions about the role of testosterone for erectile dysfunction which cannot be ignored.
286
OPPOSING VIEWS
At a minimum, more research is needed and the issue leads to a point of entry to health evaluation for many men as well as a broader discussion of overall health, prevention and treatment. However, erectile dysfunction cannot be completely separated from sexual function/dysfunction or other multifactorial factors of overall men’s health to conclusively
say that testosterone treatment is indicated for erectile dysfunction alone. Ajay K. Nangia Department of Urology University of Kansas Health System Kansas City, Kansas
REFERENCES 1. Montague DK, Jarow JP, Broderick GA et al: Chapter 1: The management of erectile dysfunction: an AUA update. J Urol 2005; 174: 230.
5. Isidori AM, Giannetta E, Gianfrilli D et al: Effects of testosterone on sexual function in men: results of a meta-analysis. Clin Endocrinol (Oxf) 2005; 63: 381.
2. Finkelstein JS, Lee H, Burnett-Bowie SA et al: Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med 2013; 369: 1011.
6. Aversa A, Isidori AM, Greco EA et al: Hormonal supplementation and erectile dysfunction. Eur Urol; 45: 535 (Erratum. Eur Urol 2005; 47: 564).
3. Snyder PJ, Bhasin S, Cunningham GR et al: Effects of testosterone treatment in older men. N Engl J Med 2016; 374: 611. 4. Cunningham GR, Stephens-Shields AJ, Rosen RC et al: Testosterone treatment and sexual function in older men with low testosterone levels. J Clin Endocrinol Metab 2016; 101: 3096.
7. Morelli A, Filippi S, Zhang XH et al: Peripheral regulatory mechanisms in erection. Int J Androl, suppl., 2005; 28: 23. 8. Shabsigh R, Kaufman JM, Steidle C et al: Randomized study of testosterone gel as adjunctive therapy to sildenafil in hypogonadal men with erectile dysfunction who do not respond to sildenafil alone. J Urol, suppl., 2008; 179: S97.
9. Paduch D, Brannigan R, Fuchs E et al: The laboratory diagnosis of testosterone deficiency. Urology 2014; 83: 980. 10. Bhasin S, Cunningham G, Hayes F et al: Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocinol Metab 2010; 95: 2536. 11. Seftel AD, Kathrins M and Niederberger C: Critical update of the 2010 Endocrine Society clinical practice guidelines for male hypogonadism: a systematic analysis. Mayo Clin Proc 2015; 90: 1104. 12. Wu FC, Tajar A, Beynon JM et al: Identification of late-onset hypogonadism in middle-aged and elderly men. N Eng J Med 2010; 363: 123.
Testosterone Replacement Should be Given to Men with Erectile Dysfunction PRO AN erection is a complex process that requires intact vascular, structural, psychological and neurological function, as well as normal levels of sex hormones. Erectile dysfunction (ED) is defined as the inability to achieve or maintain an erection sufficient for satisfactory sexual performance. Currently, there are several treatments available for ED, such as oral phosphodiesterase type 5 inhibitors (PDE5is), intracavernosal injections, intraurethral suppositories and penile implants. However, before proceeding with any treatment, it is important to evaluate serum testosterone levels in men with ED as suggested by the AUA (American Urological Association) guidelines.1 Testosterone plays an important role in normal sexual function for libido and erections. In a well conducted dose ranging trial Finkelstein et al demonstrated that as testosterone levels decreased, particularly below 400 ng/dl, deficits in erectile function and libido increased.2 In another prospective randomized trial on the effect of testosterone supplementation in older men with testosterone levels less than 275 ng/dl those who received testosterone supplementation reported improvement in sexual function compared to those who did not receive supplementation.3 The detrimental effects of lower testosterone levels on erectile function and libido have been supported by multiinstitutional placebo controlled trials as well as a meta-analysis of 17 randomized, placebo controlled trials on the effects of testosterone replacement on improvement in erectile function.4,5 Therefore, there is obvious substantial level I evidence that normal testosterone level is critical for libido and erectile function. Several animal studies have proven that testosterone is necessary to preserve and maintain the structural integrity of the penis by stimulating smooth muscle growth and inhibiting apoptosis.6 Furthermore, testosterone can regulate nitric oxide (NO) and phosphodiesterase type 5 (PDE5) enzyme production, both of which are critical for erectile
0022-5347/17/1972-0284/0 THE JOURNAL OF UROLOGY® Ó 2017 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
284
j
www.jurology.com
AND
RESEARCH, INC.
function.7 Therefore, in men with low testosterone we can speculate that sufficient levels of PDE5 enzyme may not be present and could render PDE5i such as sildenafil ineffective. Clinically, the hypothesis that sufficient testosterone levels are needed so oral PDE5is have adequate PDE5 enzyme to work on was tested in at least 1 randomized controlled trial in which men with a testosterone level of less than 400 ng/dl who did not respond to sildenafil monotherapy did respond after treatment with exogenous testosterone.8 The finding that testosterone may be able to enhance the effect of PDE5i in previous nonresponders to this therapy suggests that testosterone therapy should be considered in men with low testosterone and mild ED (International Index of Erectile Function-EF 22 to 25). In men with mild ED testosterone therapy can convert PDE5i nonresponders to responders and conceivably can obviate the need for the use of PDE5i in select patients, the latter leading to patient savings given the significant cost of PDE5i. Testosterone therapy is unlikely to be helpful as a sole modality of treatment for men with moderate to severe ED. ED due to radical pelvic surgery or advanced diabetes and hypertension, eg caused by severe neurogenic or vascular damage, will unlikely improve with testosterone therapy alone. Men with severe ED are best treated with intracavernosal injections, vaccum erection devices or penile prostheses. Taken together, it is clear that testosterone therapy is critical for libido and erectile function. Testosterone therapy should not be used as the sole modality of treatment in men with moderate to severe ED. Nevertheless, men with mild erectile dysfunction or low libido combined with low serum testosterone may derive the most benefit from testosterone therapy. Raul I. Clavijo and Ranjith Ramasamy Department of Urology University of Miami Miller School of Medicine Miami, Florida
http://dx.doi.org/10.1016/j.juro.2016.11.074 Vol. 197, 284-286, February 2017 Printed in U.S.A.
OPPOSING VIEWS
CON THE issue of testosterone replacement therapy needs to be addressed at several levels, including definition of erectile dysfunction; multifactorial etiology/ pathophysiology of erectile dysfunction; testosterone physiology and pathophysiology as it relates to erectile function and age/other diseases; correlation between testosterone and symptoms and signs, especially erectile dysfunction; role of guidelines based on level of evidence; and finally FDA (U.S. Food and Drug Administration) approval based on the evidence alone, and their definition of indicated and off label use. In terms of this discussion, I do wish to be specific about what is being asked. The definitions of “erectile function or dysfunction” as opposed to “sexual dysfunction” are not synonymous. Erectile function/dysfunction is a subset of sexual function/dysfunction that includes sexual desire (libido), arousal, pleasure, ejaculation/ climax and satisfaction for the patient and partner. As such, erectile function/dysfunction is a physiological response to neurological, vascular, psychological and also endocrine factors. This last component is the purpose of this discussion. The multifactorial and intertwined nature of sexual function/dysfunction and erectile function/ dysfunction makes analysis of the issues and literature difficult to separate into pure physiology of erectile function. Endocrine factors, such as diabetes, thyroid dysfunction, other endocrine diseases and testosterone deficiency, play an important role in the overall issue but defining levels of hormone deficiency which titrate with sexual dysfunction or erectile dysfunction as independent variables is far from clear. On a broader note that is beyond the scope of this discussion, standardizing the testosterone assay is far from consistent around the world.9 The multifactorial nature of erectile dysfunction makes this neither a single hormone nor a single factor problem. Androgen receptors are present centrally and in the corpora cavernosa, and animal studies have shown androgen involvement in the nitric oxide pathway. The role in humans is less clear. However, the vascular and neurological changes that occur with age and diseases play a significant role. Eunuchs and Castratos, from fabled urology legend, who were castrated as young boys were still able to maintain erections, regardless of loss of libido, since many times orchiectomy was performed before puberty. At the other end of the spectrum, older men (usually) with metastatic prostate cancer on androgen deprivation therapy suffer desperately with loss of energy, muscle wasting, anemia and sexual dysfunction with loss of libido and associated ED (which many times were preexistent).
285
In 2010 the Endocrine Society developed some recommendations on the signs/symptoms and evaluation of testosterone deficiency but they were largely consensus based and the level of evidence to correlate with them was poor overall.10 This outcome was highlighted by Seftel et al who reviewed the evidence to support the Endocrine Society guidelines since their publication and found that only 17 level I evidence clinical trials had been published from 2010 to 2015.11 On the topic of correlation of testosterone deficiency and treatment of ED, they did not find a consistently beneficial role of testosterone therapy in hypogonadal men with ED that was refractory to PDE5i. The AUA is currently performing a detailed analysis of the evidence that exists on the overall topic of hypogonadism and hopefully will provide more robust guidelines. There are no good large-scale, randomized controlled trials on the treatment of hypogonadism and improvement in symptoms. There is no men’s health initiative trial equivalent to that for women, despite the fact that this was recommended as far back as the 1990s by the Institute of Medicine. However, there have been other surrogate studies that have tried to evaluate the issue and efforts to correct this gap continue. The EMAS (European Male Aging Study) showed that the only 2 symptoms that correlated with low testosterone levels were decreased libido and erectile dysfunction, with libido being the most specific, but distinguishing between libido and erectile function is difficult.12 The T-Trial, which is the first efficacy trial to be conducted, revealed erectile function improvement with a short course of testosterone treatment (1 year).3,4 However, the direct role testosterone therapy plays specifically on erectile function/ dysfunction remains unclear. The FDA approved testosterone for the treatment of specific causes of primary and secondary hypogonadism. There is no mention of associated symptoms and signs in the package inserts for any testosterone treatments. Idiopathic or age related (late onset hypogonadism) clinical symptomatic hypogonadism is not considered an indication for treatment. As such, treatment of clinical hypogonadism without a known disease remains “offlabel” use. To be specific, erectile dysfunction alone or sexual dysfunction alone, if not associated with one of the specified diseases, is technically not an indication for treatment. Therefore, until there is convincing evidence otherwise, the FDA requested that any misleading advertising to that effect be stopped in 2014. The overall issue of direct to patient marketing has resulted in some information and misinformation as it relates to patient perceptions about the role of testosterone for erectile dysfunction which cannot be ignored.
286
OPPOSING VIEWS
At a minimum, more research is needed and the issue leads to a point of entry to health evaluation for many men as well as a broader discussion of overall health, prevention and treatment. However, erectile dysfunction cannot be completely separated from sexual function/dysfunction or other multifactorial factors of overall men’s health to conclusively
say that testosterone treatment is indicated for erectile dysfunction alone. Ajay K. Nangia Department of Urology University of Kansas Health System Kansas City, Kansas
REFERENCES 1. Montague DK, Jarow JP, Broderick GA et al: Chapter 1: The management of erectile dysfunction: an AUA update. J Urol 2005; 174: 230.
5. Isidori AM, Giannetta E, Gianfrilli D et al: Effects of testosterone on sexual function in men: results of a meta-analysis. Clin Endocrinol (Oxf) 2005; 63: 381.
2. Finkelstein JS, Lee H, Burnett-Bowie SA et al: Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med 2013; 369: 1011.
6. Aversa A, Isidori AM, Greco EA et al: Hormonal supplementation and erectile dysfunction. Eur Urol; 45: 535 (Erratum. Eur Urol 2005; 47: 564).
3. Snyder PJ, Bhasin S, Cunningham GR et al: Effects of testosterone treatment in older men. N Engl J Med 2016; 374: 611. 4. Cunningham GR, Stephens-Shields AJ, Rosen RC et al: Testosterone treatment and sexual function in older men with low testosterone levels. J Clin Endocrinol Metab 2016; 101: 3096.
7. Morelli A, Filippi S, Zhang XH et al: Peripheral regulatory mechanisms in erection. Int J Androl, suppl., 2005; 28: 23. 8. Shabsigh R, Kaufman JM, Steidle C et al: Randomized study of testosterone gel as adjunctive therapy to sildenafil in hypogonadal men with erectile dysfunction who do not respond to sildenafil alone. J Urol, suppl., 2008; 179: S97.
9. Paduch D, Brannigan R, Fuchs E et al: The laboratory diagnosis of testosterone deficiency. Urology 2014; 83: 980. 10. Bhasin S, Cunningham G, Hayes F et al: Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocinol Metab 2010; 95: 2536. 11. Seftel AD, Kathrins M and Niederberger C: Critical update of the 2010 Endocrine Society clinical practice guidelines for male hypogonadism: a systematic analysis. Mayo Clin Proc 2015; 90: 1104. 12. Wu FC, Tajar A, Beynon JM et al: Identification of late-onset hypogonadism in middle-aged and elderly men. N Eng J Med 2010; 363: 123.