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Re: Treatment of Erectile Dysfunction in the Obese Type 2 Diabetic ZDF Rat With Adipose Tissue-Derived Stem Cells
EUROPEAN UROLOGY 59 (2011) 168–175
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Words of Wisdom Re: Identification of Late-Onset Hypogonadism in Middle-Aged and Elderly Men Wu FC, Tajar A, Beynon JM, et al., EMAS Study Group N Engl J Med 2010;363:123–35 Experts’ summary: In this prospective trial, Wu and coworkers analyzed a random population sample of 3369 men between 40 and 79 yr of age at eight European centers. Using questionnaires, data were collected on the subjects’ general, sexual, physical, and psychological health. In addition, levels of total testosterone were measured in morning blood samples, and free testosterone levels were calculated. Data were randomly split into separate training and validation sets for confirmatory analyses. From a broad variety of potential parameters, the authors identified the presence of three specific sexual symptoms (impaired morning erection, fewer sexual thoughts, increased erectile dysfunction) combined with low levels of total testosterone (<11 nmol/l) and free testosterone (<220 pmol/l) as diagnostic criteria for lateonset hypogonadism (LOH). Experts’ comments: The authors of this large-scale study have to be congratulated for their extensive work and the important findings that have been already reported [1]. In fact, LOH still remains a controversial concept. For instance, the clinical importance of decreased sexual thoughts seems debatable. Furthermore, erectile function did not always turn out to be independently associated with age and comorbidity for testosterone levels. This was also reported in another, earlier analysis from the same European
Re: Treatment of Erectile Dysfunction in the Obese Type 2 Diabetic ZDF Rat With Adipose Tissue-Derived Stem Cells Garcia MM, Fandel TM, Lin G, et al. J Sex Med 2010;7:89–98 Experts’ summary: Injection of autologous unmodified adipose tissue–derived stem cells (ADSC) into the penises of male fatty type 2 diabetic 0302-2838/$ – see back matter
Male Ageing Study database where erectile dysfunction was defined according to a validated questionnaire [1]. The following question regarding LOH seems to be the most important: Did the presented results prove LOH to be a distinctive clinical entity or did they just show a (weak) correlation between three single questions and testosterone levels? The difference between these two conclusions is based on the information of whether or not the participants suffered from these symptoms. Further studies investigating LOH should definitely consider obtaining and reporting information about the impact of LOH on health-related quality of life or the consequences on mental and physical health. Conflicts of interest: The authors have nothing to disclose.
Reference [1] Tajar A, Forti G, O’Neill TW, et al. Characteristics of secondary, primary, and compensated hypogonadism in aging men: evidence from the European Male Ageing Study. J Clin Endocrinol Metab 2010;95:1810–8. Anton Ponholzera,*, Stephan Madersbacherb a
Department of Urology and Andrology,
Hospital Saint John of God, Vienna, Austria b
Department of Urology and Andrology, Donauspital, SMZ-OST, Vienna, Austria *Corresponding author.
E-mail address: [email protected] (A. Ponholzer)
DOI: 10.1016/j.eururo.2010.10.011
ZDF rats with erectile dysfunction (ED) was investigated. Rats were divided into two groups, a sham control using phosphate buffered saline (PBS) vehicle only and a treatment group with penile injection of 1 106 ADSCPBS suspension. Three weeks after intervention both groups underwent in vivo cavernous nerve stimulation, and erectile responses were evaluated. Mean stimulation D intracranial pressure (ICP) and ICPto-blood-pressure ratio increased significantly in the ADSC
169
EUROPEAN UROLOGY 59 (2011) 168–175
group, whereas the control group achieved no obvious change. Bromodeoxyuridine-labeled ADSC were visualized within the corporal tissue of the treatment group, signifying survival after injection, although the authors did not report on the exact number of surviving cells. There was a marked increase in the number of diffused neuronal nitric oxide synthase–positive nerve fibers and RecA-positive endothelial cells in the ADSC treatment group. In addition, terminal deoxynucleotidyl transferase dUTP nick end labeling staining and caspase-3 messenger RNA expression to quantify apoptosis in the penile cavernous tissue was significantly higher in the control group versus treatment-group animals. These data demonstrate that penile injection of autologous ADSC can decrease the degree of nitrosative stress, inhibit apoptosis, increase the number of corporal body endothelial cells, and provide significant cavernous neurovascular protection, which in turn improves erectile function. Experts’ comments: ED is a consequence of a number of common medical conditions, with a high prevalence among diabetics (range: 35–90%) [1]. It is well accepted that phosphodiesterase type 5 inhibitors (sildenafil, tadalafil, vardenafil) are the first-line treatment option for men with ED. Second-line therapies include intracavernosal vasoactive injections and vacuum erection devices, and third-line treatment entails penile implants [2]. Although a spectrum of options are available for ED treatment, diabetic ED is multifactorial in etiology and is usually severe in degree and more resistant to medical treatment compared with nondiabetic ED. Unfortunately, there have been limited breakthroughs in treatment options for severe ED during the past decade. The authors were the first to propose the novel concept of autologous ADSC injection therapy in diabetes-induced ED and to undertake preliminary studies. New advances provided by such pioneering work will provide novel understanding and treatment options for diabetic men suffering with ED. According to the latest definition by Dr. CS Lin, ADSC exists as CD34+CD31 CD104b SMA cells in the capillaries and adventitia of larger vessels [3]. They have similar characteristics to mesenchymal stem cells and are capable of differentiating into cells and tissues of mesodermal origin, such as adipocytes, cartilage, bone, and skeletal muscle. The main advantage of ADSC is that it can be harvested easily from patients by a minimally invasive procedure (eg, liposuction) and easily cultured. Recent studies suggest
Re: Combination Therapy for Premature Ejaculation: Results of a Small-Scale Study Steggall MJ, Fowler CG, Pryce A Sex Rel Ther 2008;23:365–76 Expert’s summary: Premature ejaculation (PE) is often cited as the most common sexual complaint of men, and increasing scientific and clinical attention has been paid in the past decade. The rationale behind
that ADSC provides functional benefit in a wide range of neurologic conditions [4]. In addition, ADSCs have a potential role in accelerating wound healing, inducing antioxidant activities, preventing apoptosis, secreting growth factors, and inducing cross-mesoderm differentiation into epithelium under specific conditions. ADSC-based therapies are emerging as an innovative approach for the treatment of recalcitrant ED; accordingly, this approach has a sound theoretical foundation. Recently, this group reported its promising results using these concepts in bilateral cavernous nerve crush ED and in hyperlipidemia ED rat models. However, adoption of this novel therapy in human trials may be some time off. The actual mechanism of action and ostensible safety issues need delineation. Further issues include other unwanted side effects, the actual ADSC survival rate in cavernous tissues, and changes that occur in ADSC in the cavernous microenvironment. Although short-term results of this study are promising, it remains to be determined whether erectile function will be maintained over time. Further exploration of the pathophysiologic mechanisms and comprehensive outcome analyses are needed. Conflicts of interest: The authors have nothing to disclose.
References [1] Malavige LS, Levy JC. Erectile dysfunction in diabetes mellitus. J Sex Med 2009;6:1232–47. [2] Smith IA, McLeod N, Rashid P. Erectile dysfunction—when tablets don’t work. Aust Fam Physician 2010;39:301–5. [3] Lin CS, Xin ZC, Deng CH, et al. Defining adipose tissue-derived stem cells in tissue and in culture. Histol Histopathol 2010;25:807–15. [4] Zavan B, Vindigni V, Gardin C, et al. Neural potential of adipose stem cells. Discov Med 2010;10:37–43. Limin Maa,b, Wayne J.G. Hellstroma,* a
Tulane University School of Medicine, New Orleans, Louisiana, USA b
Affiliated hospital of Nantong University, Nantong, China
*Corresponding author. Tulane University School of Medicine, Department of Urology, 1430 Tulane Avenue, SL-42 New Orleans, LA 70112, USA. E-mail address: [email protected] (W.J.G. Hellstrom)
DOI: 10.1016/j.eururo.2010.10.012
the study by Steggall et al was the observation that the usual treatment approaches for PE are polarized into either the sole use of antidepressant medication or sex therapy. Premised on this analysis, a combination treatment was designed to test the hypotheses that an integrated therapy may (1) lead to an improvement in ejaculatory latency time and (2) facilitate the motivation for and adherence to subsequent behavioral treatment interventions. Participants were randomized either to paroxetine 20 mg daily or to a lidocaine-based spray (Premjact) for
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Words of Wisdom Re: Identification of Late-Onset Hypogonadism in Middle-Aged and Elderly Men Wu FC, Tajar A, Beynon JM, et al., EMAS Study Group N Engl J Med 2010;363:123–35 Experts’ summary: In this prospective trial, Wu and coworkers analyzed a random population sample of 3369 men between 40 and 79 yr of age at eight European centers. Using questionnaires, data were collected on the subjects’ general, sexual, physical, and psychological health. In addition, levels of total testosterone were measured in morning blood samples, and free testosterone levels were calculated. Data were randomly split into separate training and validation sets for confirmatory analyses. From a broad variety of potential parameters, the authors identified the presence of three specific sexual symptoms (impaired morning erection, fewer sexual thoughts, increased erectile dysfunction) combined with low levels of total testosterone (<11 nmol/l) and free testosterone (<220 pmol/l) as diagnostic criteria for lateonset hypogonadism (LOH). Experts’ comments: The authors of this large-scale study have to be congratulated for their extensive work and the important findings that have been already reported [1]. In fact, LOH still remains a controversial concept. For instance, the clinical importance of decreased sexual thoughts seems debatable. Furthermore, erectile function did not always turn out to be independently associated with age and comorbidity for testosterone levels. This was also reported in another, earlier analysis from the same European
Re: Treatment of Erectile Dysfunction in the Obese Type 2 Diabetic ZDF Rat With Adipose Tissue-Derived Stem Cells Garcia MM, Fandel TM, Lin G, et al. J Sex Med 2010;7:89–98 Experts’ summary: Injection of autologous unmodified adipose tissue–derived stem cells (ADSC) into the penises of male fatty type 2 diabetic 0302-2838/$ – see back matter
Male Ageing Study database where erectile dysfunction was defined according to a validated questionnaire [1]. The following question regarding LOH seems to be the most important: Did the presented results prove LOH to be a distinctive clinical entity or did they just show a (weak) correlation between three single questions and testosterone levels? The difference between these two conclusions is based on the information of whether or not the participants suffered from these symptoms. Further studies investigating LOH should definitely consider obtaining and reporting information about the impact of LOH on health-related quality of life or the consequences on mental and physical health. Conflicts of interest: The authors have nothing to disclose.
Reference [1] Tajar A, Forti G, O’Neill TW, et al. Characteristics of secondary, primary, and compensated hypogonadism in aging men: evidence from the European Male Ageing Study. J Clin Endocrinol Metab 2010;95:1810–8. Anton Ponholzera,*, Stephan Madersbacherb a
Department of Urology and Andrology,
Hospital Saint John of God, Vienna, Austria b
Department of Urology and Andrology, Donauspital, SMZ-OST, Vienna, Austria *Corresponding author.
E-mail address: [email protected] (A. Ponholzer)
DOI: 10.1016/j.eururo.2010.10.011
ZDF rats with erectile dysfunction (ED) was investigated. Rats were divided into two groups, a sham control using phosphate buffered saline (PBS) vehicle only and a treatment group with penile injection of 1 106 ADSCPBS suspension. Three weeks after intervention both groups underwent in vivo cavernous nerve stimulation, and erectile responses were evaluated. Mean stimulation D intracranial pressure (ICP) and ICPto-blood-pressure ratio increased significantly in the ADSC
169
EUROPEAN UROLOGY 59 (2011) 168–175
group, whereas the control group achieved no obvious change. Bromodeoxyuridine-labeled ADSC were visualized within the corporal tissue of the treatment group, signifying survival after injection, although the authors did not report on the exact number of surviving cells. There was a marked increase in the number of diffused neuronal nitric oxide synthase–positive nerve fibers and RecA-positive endothelial cells in the ADSC treatment group. In addition, terminal deoxynucleotidyl transferase dUTP nick end labeling staining and caspase-3 messenger RNA expression to quantify apoptosis in the penile cavernous tissue was significantly higher in the control group versus treatment-group animals. These data demonstrate that penile injection of autologous ADSC can decrease the degree of nitrosative stress, inhibit apoptosis, increase the number of corporal body endothelial cells, and provide significant cavernous neurovascular protection, which in turn improves erectile function. Experts’ comments: ED is a consequence of a number of common medical conditions, with a high prevalence among diabetics (range: 35–90%) [1]. It is well accepted that phosphodiesterase type 5 inhibitors (sildenafil, tadalafil, vardenafil) are the first-line treatment option for men with ED. Second-line therapies include intracavernosal vasoactive injections and vacuum erection devices, and third-line treatment entails penile implants [2]. Although a spectrum of options are available for ED treatment, diabetic ED is multifactorial in etiology and is usually severe in degree and more resistant to medical treatment compared with nondiabetic ED. Unfortunately, there have been limited breakthroughs in treatment options for severe ED during the past decade. The authors were the first to propose the novel concept of autologous ADSC injection therapy in diabetes-induced ED and to undertake preliminary studies. New advances provided by such pioneering work will provide novel understanding and treatment options for diabetic men suffering with ED. According to the latest definition by Dr. CS Lin, ADSC exists as CD34+CD31 CD104b SMA cells in the capillaries and adventitia of larger vessels [3]. They have similar characteristics to mesenchymal stem cells and are capable of differentiating into cells and tissues of mesodermal origin, such as adipocytes, cartilage, bone, and skeletal muscle. The main advantage of ADSC is that it can be harvested easily from patients by a minimally invasive procedure (eg, liposuction) and easily cultured. Recent studies suggest
Re: Combination Therapy for Premature Ejaculation: Results of a Small-Scale Study Steggall MJ, Fowler CG, Pryce A Sex Rel Ther 2008;23:365–76 Expert’s summary: Premature ejaculation (PE) is often cited as the most common sexual complaint of men, and increasing scientific and clinical attention has been paid in the past decade. The rationale behind
that ADSC provides functional benefit in a wide range of neurologic conditions [4]. In addition, ADSCs have a potential role in accelerating wound healing, inducing antioxidant activities, preventing apoptosis, secreting growth factors, and inducing cross-mesoderm differentiation into epithelium under specific conditions. ADSC-based therapies are emerging as an innovative approach for the treatment of recalcitrant ED; accordingly, this approach has a sound theoretical foundation. Recently, this group reported its promising results using these concepts in bilateral cavernous nerve crush ED and in hyperlipidemia ED rat models. However, adoption of this novel therapy in human trials may be some time off. The actual mechanism of action and ostensible safety issues need delineation. Further issues include other unwanted side effects, the actual ADSC survival rate in cavernous tissues, and changes that occur in ADSC in the cavernous microenvironment. Although short-term results of this study are promising, it remains to be determined whether erectile function will be maintained over time. Further exploration of the pathophysiologic mechanisms and comprehensive outcome analyses are needed. Conflicts of interest: The authors have nothing to disclose.
References [1] Malavige LS, Levy JC. Erectile dysfunction in diabetes mellitus. J Sex Med 2009;6:1232–47. [2] Smith IA, McLeod N, Rashid P. Erectile dysfunction—when tablets don’t work. Aust Fam Physician 2010;39:301–5. [3] Lin CS, Xin ZC, Deng CH, et al. Defining adipose tissue-derived stem cells in tissue and in culture. Histol Histopathol 2010;25:807–15. [4] Zavan B, Vindigni V, Gardin C, et al. Neural potential of adipose stem cells. Discov Med 2010;10:37–43. Limin Maa,b, Wayne J.G. Hellstroma,* a
Tulane University School of Medicine, New Orleans, Louisiana, USA b
Affiliated hospital of Nantong University, Nantong, China
*Corresponding author. Tulane University School of Medicine, Department of Urology, 1430 Tulane Avenue, SL-42 New Orleans, LA 70112, USA. E-mail address: [email protected] (W.J.G. Hellstrom)
DOI: 10.1016/j.eururo.2010.10.012
the study by Steggall et al was the observation that the usual treatment approaches for PE are polarized into either the sole use of antidepressant medication or sex therapy. Premised on this analysis, a combination treatment was designed to test the hypotheses that an integrated therapy may (1) lead to an improvement in ejaculatory latency time and (2) facilitate the motivation for and adherence to subsequent behavioral treatment interventions. Participants were randomized either to paroxetine 20 mg daily or to a lidocaine-based spray (Premjact) for