Published-Ahead-of-Print on August 21, 2008 by Journal of Andrology




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JANDROL/2008/005264                                                                                           2


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JANDROL/2008/005264                                                                                          3


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JANDROL/2008/005264                                                                                            4

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JANDROL/2008/005264                                                                                              5


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JANDROL/2008/005264                                                                                       6

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JANDROL/2008/005264                                                                                          7

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JANDROL/2008/005264                                                                                         8

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JANDROL/2008/005264                                                                                          9


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JANDROL/2008/005264                                                                                                10

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JANDROL/2008/005264                                                                                           11


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JANDROL/2008/005264                                                                                      12

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JANDROL/2008/005264                                                                                         13

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JANDROL/2008/005264                                                           14


Table 1. Patient Characteristics:

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JANDROL/2008/005264                                                                                     15



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JANDROL/2008/005264                                                                                        16



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JANDROL/2008/005264                                                                                   17



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JANDROL/2008/005264                                                                                       18


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JANDROL/2008/005264                                                                                     19


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Testosterone Improves Erectile Function in Hypogonadal ...
Testosterone Improves Erectile Function in Hypogonadal ...
Testosterone Improves Erectile Function in Hypogonadal ...
Testosterone Improves Erectile Function in Hypogonadal ...
Testosterone Improves Erectile Function in Hypogonadal ...
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  1. 1. Published-Ahead-of-Print on August 21, 2008 by Journal of Andrology 1 Testosterone Improves Erectile Function in Hypogonadal Patients with 2 Venous Leakage 3 4 Running Title: Androgens and erectile function 5 6 Dmitry Kurbatov1, Jury Kuznetsky², Abdulmaged Traish³ 7 1 8 Andrological and Urological Department, Endocrinological Research Centre, Moscow, Russia 9 ² Urological and Andrological Department, Medical Stomatological Institute, Moscow, Russia 10 ³ Departments of Biochemistry& Urology, Boston University School of Medicine, Boston, MA, USA 11 12 13 14 All correspondence should be addressed to: 15 Abdulmaged M. Traish, MBA, Ph.D. 16 Professor of Biochemistry & Urology 17 Director, 18 Laboratories for Sexual Medicine 19 Institute for Sexual Medicine 20 Boston University School of Medicine 21 Center for Advanced Biomedical Research 22 700 Albany Street, W607 23 Boston, MA 02118 24 617-638-4578 25 Fax 617-638-5412 26 27 28 This work is supported by Andrological and Urological Department, Endocrinological Research Centre, 29 Moscow, Russia; Urological and Andrological Department, Medical Stomatological Institute, Moscow, 30 Russia & Department of Urology, Boston University School of Medicine, Boston, MA, USA. Copyright 2008 by The American Society of Andrology
  2. 2. JANDROL/2008/005264 2 1 Abstract 2 Objectives: The goal of this study was to assess the therapeutic benefits of long-acting testosterone 3 therapy in hypogonadal patients with erectile dysfunction (ED). 4 Methods: We recruited 29 patients with ED ranging in age from 32 - 65 years (47±9.7) with low plasma 5 testosterone, who did not respond to phosphodiesterase type 5 (PDE-5) inhibitors therapy. To evaluate 6 penile arterial and venous blood flow, we employed Duplex Doppler Ultrasonography (DDU). For 7 confirmation of diagnosis of venous leakage, pharmaco-cavernosography (PCG) was carried out in 9 8 patients and Magnetic Resonance Imaging ( RI) with intracavernous contrast enhancement was carried М 9 out in 8 patients. All patients were treated with 1000 mg injectable testosterone undecanoate on day one, 10 followed by another injection after six weeks and every three months thereafter, in accordance with 11 NebidoTM therapy protocol. Plasma testosterone levels were determined in all patients at baseline and after 12 12 and 30 weeks of testosterone treatment. The International Index of Erectile Function (IIEF-5) was 13 administered at base line, and after 12 and 30 weeks of testosterone treatment. 14 Results: At base line total testosterone ranged from 7-11.8 nmol/l (200-345 ng/dl) in all patients. Twelve 15 and 30 weeks after testosterone treatment, the mean testosterone plasma levels were 18 and 21.5 nmol/l (520 16 and 625 ng/dl), respectively. After twelve and 30 weeks of testosterone treatment, 20 out of the 29 patients 17 demonstrated marked improvement in erectile function domain, as assessed by IIEF-5. This was also 18 associated with diminution of venous leakage. 19 Conclusions: We suggest that, in hypogonadal men with ED, testosterone therapy improves erectile function 20 in patients with ED and venous leakage. 21 22 Key Words: Testosterone, Veno-occlusive Function & Dysfunction, Erectile Function; Sexual 23 Function, MRI. 2
  3. 3. JANDROL/2008/005264 3 1 Introduction 2 Recent clinical observations in men with ED suggested that testosterone treatment alone improved erectile 3 function in patients who did not respond to other forms of therapy (Yassin et al, 2006 ;Hwang et al,.2006; 4 Shabsigh et al, 2008). In a series of case reports, Yassin et al (2006) employed pharmaco-cavernosmetry 5 and cavernosography and provided a “proof of concept” that treatment with testosterone probably remodels 6 human erectile tissue vascular bed and reverses or reduces venous leakage. Hwang et al (2006) investigated 7 the therapeutic effect of testosterone in hypogonadal patients who are unresponsive to sildenafil alone. 8 Eleven patients (34.3%) achieved satisfactory erectile function after testosterone replacement only. Another 9 12 (37.5%) patients experienced satisfactory intercourse after combined therapy. It was concluded that one- 10 third of hypogonadal patients with ED who failed to respond to sildenafil, responded to testosterone alone 11 and, androgen supplementation in hypogonadal patients with ED may be considered as first-line therapy. 12 Recent studies by Shabsigh et al (2008) have also suggested improvement of erectile function by 13 testosterone treatment in hypogonadal men with erectile dysfunction who are unresponsive to sildenafil 14 treatment alone. 15 Preclinical studies have suggested that androgens are important for maintaining the veno-occlusive function 16 (Traish et al 2006, 2007), and androgen deprivation results in venous leakage (Rogers et al 2003), it is 17 possible that androgen treatment in hypogondal men may reverse or attenuate venous leakage in men with 18 ED. Further, we have reported that MRI can be used to visualize venous leakage in men with ED (Kurbatov 19 et al 2008). Therefore, with the advent of new long-acting testosterone formulation for androgen therapy 20 and the available utility of MRI to visualize venous leakage, we have undertaken this study to investigate if 21 long-acting testosterone therapy improves erectile function in hypogonadal patients with venous leakage, 22 using MRI as tool to assess venous leakage before and after testosterone therapy. Here we report that 3
  4. 4. JANDROL/2008/005264 4 1 long-acting testosterone treatment improved erectile function in men with low testosterone as assessed by 2 IIEF and reduced venous leakage as assessed by PCG and MRI techniques. 3 4 Methods: 5 All patients recruited for the study were well-informed about the scope and extent of the study and the 6 diagnostic and treatment approaches. All patients singed an informed consent. This study was approved by 7 the Urological and Andrological Departments, Medical Stomatological Institute, Moscow, Russia. Twenty 8 nine men ranging in age from 32 - 65 years (47±9.7) who had ED for a period ranging from 1.5-5 years, and 9 had sexual partner for at least 6 months or longer were recruited. Patients complained from low libido, non- 10 rigid erection, premature ejaculation and rapid detumescence. None of these patients had previously 11 received testosterone replacement therapy. 12 13 All patients have been previously treated with PDE 5 inhibitors, with limited or no positive outcome as 14 assessed by insufficient penile rigidity for satisfactory sexual intercourse. Thirteen of the 29 patients did not 15 respond at all to any of the three available PDE 5 inhibitors therapy while 16 of the 29 patients had an 16 inadequate or very poor response to sildenafil (100 mg) or vardenafil (20 mg). The lack of response was 17 defined as a score of 2 or 3 on questions 3 and 4 of the International Index of Erectile Function (IIEF-5) 18 after having been administered the PDE 5 inhibitor, at least four times. Although all patients were educated 19 with regard to use of PDE 5 inhibitors, we speculated that the lack of response of these men to PDE5 20 inhibitors may be due to their hypogonadal status and/or venous leakage, as proposed in previous studies 21 (Shabsigh et al 2008; Yassin et al 2006; Rajfer et al., 1998). 22 23 4
  5. 5. JANDROL/2008/005264 5 1 Patients’ characteristics: 2 The patient characteristics are provided in Table 1. It should be noted that this study represents a series of 3 case studies. All 29 patients were hypogonadal based on testosterone plasma levels (<12 nmol/l or <300 4 ng/dl) and no history of hematological disorders or prostate disease. Seven patients had hypertension, two 5 had diabetes, three had LUTS/BPH, one had Peyronie’s disease and seven have history of alcohol abuse. 6 Twenty one are smokers. For evaluation of the safety of testosterone therapy on the prostate gland we 7 determined changes in PSA levels and assessed prostate size by ultrasound. These values are reported in 8 the tables 2-4 9 10 Assessment of venous leakage: We have recently described the use of Duplex Doppler Ultrasonography 11 (DDU), Pharmaco-Cavernosograyphy (PCG) and Magnetic Reasonance Imaging (MRI) to assess venous 12 leakage in patient with ED (Kurbatov et al 2008). After history and physical examination, all patients 13 underwent ultrasound of the prostate gland and Duplex Doppler Ultrasonography (DDU), using 14 conventional techniques to assess penile hemodynamics after inducing penile erection by administering 10 15 µg of PGE1 without re-dosing. Based on this information, venous leakage was suspected in 20 out of the 29 16 patients evaluated, while arterial insufficiency was absent in these cases - a peak systolic velocity (PSV) 17 was higher than 30cmsec and resistance index (RI) was higher than 0.8. When Valsalva test was 18 performed, patients had end diastolic velocities (EDV) 5 cm/sec, RI <0.8 and 30 to 50 % increase in vein ≥ 19 diameter and change of dorsal vein blood flow into the opposite direction. Arterial hemodynamic was not 20 changed in these patients. 21 22 To further document venous leakage, 7 patients were further evaluated with PCG and 8 patients were 23 evaluated with MRI and 2 patients were evaluated with both methods (PCG and MRI) at base line. A total 5
  6. 6. JANDROL/2008/005264 6 1 of 10 patients underwent MRI with intracavernous contrast enhancement as described previously (Kurbatov 2 et al., 2008). We introduced MRI with contrast enhancement in addition to the conventional PCG to 3 determine if this new approach improves the assessment of venous leakage visualization. Although Color 4 Doppler Ultra Sound is used for the diagnosis of veno-occlusive dysfunction in ED patients, this tool does 5 not permit visualization of venous leakage in patients with veno-occlusive ED. For this reason we used 6 conventional PCG and introduced MRI as a new diagnostic tool. 7 8 MRI technique is based on intracavernous injection of paramagnetic contrast agent that contains 9 gadolinium, after pharmacologically inducing erection while the patient is in the MRI machine. 10 Pharmacological penile erection was achieved by administering 20 mg of PGE 1. After having an erect 11 penis contrast agent was introduced into one of the corpora cavernosa within 1 minute. One to two minutes 12 later, imaging was commenced in the series. There was no time delay in obtaining films. 13 14 The advantages in employing MRI are that this method has no radiation and the sensitivity and specificity of 15 MRI exceeded that of dynamic infusion PCG (Kurbatov et al, 2008). Out of the 29 patients with ED 16 assessed by DDU, venous leakage was detected in 20 patients. Venous leakage was further confirmed by 17 either PCG or MRI in 17 patients, initially diagnosed having venous leakage with DDU. Based on this 18 clinical diagnosis, patients were divided into 2 subgroups depending on presence or absence of venous 19 leakage, as visualized by the above methods. Twenty patients with ED and venous leakage comprised the 20 first group (Group 1). Nine ED patients with arterial insufficiency (PSV< 30cmsec, RI <0.8) but no 21 documented venous leakage comprised the second group (Group 2). 22 6
  7. 7. JANDROL/2008/005264 7 1 Blood Hormone Levels at base line: Laboratory analyses for total testosterone, FSH, LH, prolactin and 2 SHBG were carried out in all 29 patients. Blood for testosterone measurements was always drawn in the 3 morning. Total testosterone levels were determined prior to testosterone treatment (baseline) to assess the 4 clinical diagnosis of hypogonadism. In all patients the ranges of testosterone levels at base line were 7-11.8 5 nmol/l or 200-345 ng/dl [normal range 12-35 nmol/l or 345-1010 ng/dl]. Based on these findings all 6 patients were considered potential candidates for treatment with testosterone. FSH levels were in the 7 normal range for most of the patients. LH values were normal for the majority of patients. Only two 8 patients had values of 9.5 and 24.3. Prolactin values were all in the normal range. The average SHBG 9 values were 48.8 ±3.7 and PSA values were 1.8±0.32. Glucose values in two patients with DM were: 22 10 mM (type 1) and 7. 4 mM (type 2). 11 12 Testosterone treatment: Testosterone undecanoate (Nebido; Bayer Schering Pharma, Germany) was 13 administered intramuscularly according to protocols published previously (Yassin et al 2006, Schubert et al, 14 2004; 2005). The patients received an injection (1000 mg) of the long acting testosterone preparation on day 15 1 with repeated administration at 6 weeks and every 12 weeks thereafter, following the recommendations in 16 the literature (Yassin et al 2006, Schubert et al, 2004; 2005). Duration of therapy was approximately 30 17 weeks for 20 patients and 18 weeks for 9 patients. After 3 injections (on weeks 20-21) we performed digital 18 rectal examination to assess the effects on the prostate and carried out ultrasound evaluation for the prostate 19 volume measurement. We further measured the levels of total testosterone. Plasma total testosterone levels 20 were measured over a period of time during the follow up (at 12 and 30 weeks) as indicated (Tables 2 & 3). 21 To evaluate the effects of this therapy on amelioration of venous leakage and restoration of erectile function, 22 5 patients underwent PCG and 4 patients underwent MRI with contrast enhancement. 23 7
  8. 8. JANDROL/2008/005264 8 1 Blood hormone levels subsequent to testosterone treatment: We have determined testosterone levels at 2 base-line (prior to testosterone treatment) in each patient. Blood samples were drawn for testosterone 3 measurements on week 18 and week 30 from commencing the first testosterone treatment. The average 4 total testosterone values after therapy were 19.8±0.6 nmol/l or 570 ng/dl ( <0.05). FSH, LH and prolactin р 5 levels remained in the normal range ( >0.05). Glucose levels did not change significantly. The mean PSA р 6 value was 2.1±0.6 ( >0.05). In two patients, however, the PSA values increased significantly (in one р 7 patient it went from 1.6 up to 2.6). Prostate biopsies were carried out and PIN was confirmed and treatment 8 with testosterone was halted for this patient. In a second patient, PSA went from 2.6 to 3.1. Treatment 9 continued because the patients did not wish to discontinue use of testosterone. His PSA levels are 10 monitored very closely every two months. 11 12 IIEF and AIMS assessment questionnaires: We administered in all patients the IIEF-5 and the Aging 13 Male Syndrome Scale (AMS) at baseline and after 12 and 30 weeks of therapy. AMS questionnaire was 14 expressed in points (weakly expressed attributes of 26-36 points, moderately expressed - up to 49 points and 15 strongly expressed - more than 50 points. The parameters of IIEF, AMS were assessed at 12 and 30 weeks 16 after treatment. Responders were defined as subjects with a good response to question 5 & 6 of the IIEF 17 Questionnaire (Table 3). Differences from the baseline characteristics were investigated using the 18 dispersion parametric or nonparametric tests for paired and unpaired samples. Results are expressed as mean 19 ±standard deviation and <0.05. р 20 8
  9. 9. JANDROL/2008/005264 9 1 Results 2 In all patients treated with the long-acting testosterone, the level of plasma total testosterone increased to 3 those levels found in normal men after twelve (18±0.25 nmol/l; [518 ng/dl]) and 30 weeks (21.5±2.3 nmol/l; 4 [620 ng/dl]) of therapy. Over all the total testosterone remained within the normal limits of physiological 5 levels. 6 7 Testosterone treatment significantly improved erectile function after 12 and 30 weeks of therapy. Seventeen 8 out of 20 patients from Group I and 7 out of 9 from Group II reported satisfactory sexual activity after 9 testosterone treatment alone. After testosterone therapy, we repeated DDU in 17 patients with documented 10 venous leakage. Assessment of penile hemodynamics (erectile function) with DDU suggested reduced or 11 absent venous leakage. The mean EDV was 3.1± 1.2 cm/sec and the mean RI was 0.87±0.05). No changes 12 in dorsal vein blood flow during Valsalva test were noted. While prior to treatment, evidence of venous 13 leakage was visualized by PCG (figure 1) or MRI (Figures 2-5). After testosterone therapy, imaging 14 showed a moderate or significant diminution of the intensity of venous leakage as assessed by PCG (Figure 15 1) and MRI techniques (Figures 2-5). Three patients, with severe venous leakage of mixed type and two 16 patients without venous leakage did not respond well to testosterone therapy alone and were unable to have 17 adequate erections for intromission. These patients were re-assigned to a combined therapy of testosterone 18 and PDE-5 – inhibitors. 19 20 We further noted a substantial improvement in libido, qualities of erectile function of the majority of 21 patients with or without veno-occlusive dysfunction after testosterone therapy (Tables 3 & 4). The domain 22 of sexual desire as assessed by IIEF-5 questionnaire was increased from 4.5±1.2 to 8.3±2.3 points. The 23 erectile function domain was increased from 9.4±1.8 to 25±0.4 points. It should be noted that 9 patients with 9
  10. 10. JANDROL/2008/005264 10 1 clinically demonstrated venous leakage, as assessed by PCG (in 5 patients) or MRI (in 4 patients) have 2 recovered fully their erectile function. A decrease in the intensity of documented venous leakage was 3 confirmed in most patients and examples are provided in Figures 1-5. Out of the 29 patients enrolled in this 4 study, only one patient (3.4 %) with severe venous leakage discontinued the treatment attributed to 5 dissatisfaction with conservative therapy and the patients opted to undergo surgical treatment for penile 6 prosthesis implantation. 7 8 We also noted a positive influence of testosterone therapy on overall well being of men in both groups 1 & 9 2: assessed by self reporting of increasing of physical activity, improvement of mood and vitality. None of 10 the patients stopped smoking during the study period. No Changes of the prostate sizes were noted 11 (Tables2-4). Similar results were obtained in patients of group 2 (n=9). The level of PSA in all but one 12 patient remained within the normal limits. The clinical symptoms of hypogonadism improved after 1 13 injection of testosterone in 2 patients and after 2 injections in all other patients. Interestingly, as the time 14 period expected for testosterone plasma levels to drop approached (i.e. at the end of 6, 10, 28-29 weeks 15 after injection), all patients noted that the therapeutic effect of testosterone was diminished, as determined 16 from the patient’s decreased penile rigidity during sex activity and detumescence becoming more quicker. 17 18 19 20 10
  11. 11. JANDROL/2008/005264 11 1 Discussion 2 In this study we investigated if long-acting testosterone therapy restores erectile function in hypogonadal 3 patient with venous leakage. We employed DDU, PCG and MRI as tools to determine venous leakage 4 before and after testosterone therapy. Our findings suggest that testosterone therapy improved erectile 5 function in hypogonadal patients with venous leakage. This study confirms and extends the observations 6 previously reported by Yassin et al, (2006) demonstrating that testosterone restored erectile function in 7 some patients with veno-occlusive dysfunction. These data support previous clinical findings reported by 8 others indicating a beneficial role of testosterone therapy in erectile dysfunction in hypogonadal men 9 (Aversa et al 2003; Yassin et al, 2006; Hwang et al, 2006; Shabsigh et al 2008; Foresta et al, 2004; Carani et 10 al, 1995; Suzuki et al, 2007; Zhang et al, 2006; Foresta et al, 2006; Zitzmann et al, 2006; Nieschlag 2006; 11 Lunenfeld, 2003; Wang et al, 2004; Steidle et al, 2003; Greco et al, 2006; Shabsigh et al 2008). While 12 many ED patients benefit from conventional PDE inhibitors therapy, those with venous leakage may not 13 respond adequately to this treatment and therefore would not benefit from PDE inhibitors treatment alone 14 (Yassin et al, 2006; Hwang et al 2006). The advent of new formulation of long-acting testosterone 15 derivative may provide a new form of therapy for erectile dysfunction, in hypogonadal patients with venous 16 leakage and ED. The work presented here represents a series of case studies and not a controlled clinical 17 trial and there fore suffers from some limitation. These include limited number of patients enrolled in this 18 case study, limited cases visualized for improvement in venous leakage by MRI due to cost. It is likely that 19 patients enrolled in this study are highly motivated, which may contribute to the observed improvement in 20 erectile function domain. 21 Based on the observations in this study, we suggest that improvement in erectile function subsequent to 22 testosterone therapy in hypogonadal patients with venous leakage is attributed to erectile tissue remodeling, 23 as documented by visualization with MRI before and after testosterone therapy. This new approach of 11
  12. 12. JANDROL/2008/005264 12 1 visualizing venous leakage with MRI may pave the way for new studies to explore this important concept in 2 androgen therapy for erectile function. 3 4 References: 5 Aversa A, Isidori AM, Spera G, Lenzi A, Fabbri A. Androgens improve cavernous vasodilation and 6 response to sildenafil in patients with erectile dysfunction. Clin Endocrinol (Oxf) 2003; 58:632-638. 7 8 Carani C, Granata AR, Bancroft J, Marrama P.. The effects of testosterone replacement on nocturnal penile 9 tumescence and rigidity and erectile response to visual erotic stimuli in hypogonadal men. 10 Psychoneuroendocrinology 1995; 20:743-753. 11 12 Foresta C, Caretta N, Rossato M, Garolla A, Ferlin A.. Role of androgens in erectile function. J Urol 2004; 13 171:2358-2362. 14 15 Foresta C, Caretta N, Lana A, De Toni L, Biagioli A, Ferlin A, Garolla A. Reduced number of circulating 16 endothelial progenitor cells in hypogonadal men. J Clin Endocrinol Metab 2006; 91:4599-4602. 17 18 Greco EA, Spera G, Aversa A. Combining testosterone and PDE5 inhibitors in erectile dysfunction: basic 19 rationale and clinical evidences. Eur Urol 2006;50:940-947. 20 21 Hwang TI, Chen HE, Tsai TF, Lin YC. Combined use of androgen and sildenafil for hypogonadal patients 22 unresponsive to sildenafil alone. Int J Impot Res. 2006;18:400-404. 23 Kurbatov DG, Kuznetsky YY, Kitaev SV, Brusensky VA. Magnetic resonance imaging as a potential tool 24 for objective visualization of venous leakage in patients with veno-occlusive erectile dysfunction. Int J 25 Impot Res 2008; 20: 192-198 26 27 Lunenfeld B. Androgen therapy in the aging male. World J Urol 2003;21:292-305. 28 29 Nieschlag E. Testosterone treatment comes of age: new options for hypogonadal men. Clin Endocrinol 30 (Oxf). 2006;65:275-281. 31 32 Rajfer J, Rosciszewski A, Mehringer M. Prevalence of corporeal venous leakage in impotent men. J Urol 33 1998; 140 :69-71. 34 35 Rogers RS, Graziottin TM, Lin CM, Kan YW, Lue T. Intracavernosal vascular endothelial growth factor 36 (VEGF) injection and adeno-assoicated virus-mediated VEGF gene therapy prevent and reverse venogenic 37 erectile dysfunction in rats. Int J Impot Res 2003;15:26-37. 38 39 Schubert M, Minnemann T, Hubler D, Rouskova D, Christoph A, Oettel M, Ernst M, Mellinger U, Krone 40 W, Jockenhovel F.. Intramuscular testosterone undecanoate: pharmacokinetic aspects of a novel testosterone 12
  13. 13. JANDROL/2008/005264 13 1 formulation during long-term treatment of men with hypogonadism. J Clin Endocrinol Metab 2 2004;89:5429–5434. 3 Schubert M, Jockenhovel F. Late-onset hypogonadism in the aging male (LOH): definition, diagnostic and 4 clinical aspects. J Endocrinol Invest. 2005;28:23-27. 5 6 Shabsigh R, Kaufman JM, Steidle C, Padma-Nathan H. Randomized study of testosterone gel as adjunctive 7 therapy to sildenafil in hypogonadal men with erectile dysfunction who do not respond to sildenafil alone. J 8 Urol. 2008;179 (5 Suppl):S97-S102. 9 10 Steidle C, Schwartz S, Jacoby K, Sebree T, Smith T, Bachand R. AA2500 testosterone gel normalizes 11 androgen levels in aging males with improvements in body composition and sexual function. J Clin 12 Endocrinol Metab 2003;88:2673-2681. 13 14 Suzuki N, Sato Y, Hisasue SI, Kato R, Suzuki K, Tsukamoto T. Effect of testosterone on intracavernous 15 pressure elicited with electrical stimulation of the medial preoptic area and cavernous nerve in male rats. J 16 Androl 2007; 28:218-222. 17 18 Traish AM, Guay AT. Are androgens critical for penile erections in humans? Examining the clinical and 19 preclinical evidence. J Sex Med 2006; 3:382-404. 20 21 Traish AM, Goldstein I, Kim NN. Testosterone and erectile function: from basic research to a new clinical 22 paradigm for managing men with androgen insufficiency and erectile dysfunction. Eur Urol. 2007;52 :54- 23 70. 24 25 Wang C, Cunningham G, Dobs A, Iranmanesh A, Matsumoto AM, Snyder PJ, Weber T, Berman N, Hull L, 26 Swerdloff RS. Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual 27 function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J Clin Endocrinol 28 Metab 2004;89:2085-2098. 29 30 Yassin AA, Saad F, Traish A. Testosterone undecanoate restores erectile function in a subset of patients 31 with venous leakage: a series of case reports. 32 J Sex Med. 2006;3:727-735. 33 34 Zhang XH, Filippi S, Morelli A, Vignozzi L, Luconi M, Donati S, Forti G, Maggi M. Testosterone restores 35 diabetes-induced erectile dysfunction and sildenafil responsiveness in two distinct animal models of 36 chemical diabetes. J Sex Med 2006; 3: 253-264. 37 38 Zitzmann M, Faber S, Nieschlag E. Association of specific symptoms and metabolic risks with serum 39 testosterone in older men. J Clin Endocrinol Metab 2006; 91: 4335-4343. 40 13
  14. 14. JANDROL/2008/005264 14 Table 1. Patient Characteristics: Patients characteristics, All Subjects Demography & Co- Total=29 morbidities Age range (yr) 32 – 65 Mean ± SD (47±9.7) age (yrs) ED severity Mild (7patients) (24,1%) Moderate 13 patients) (44,8%) Severe 9 patients) (31%) Mean IIEF EF domain 11 ± 0.2 At base-line ED etiology 29 organic Total serum testosterone ≤7nmol/l (≤200 ng/dl) in four patients (13.8%) =7-11.8 nmol/l (210-345 ng/dl) in 25 patients (86.2%) Mean AMS scores 48 ± 0.5 Smokers 21 Patients (72.4 %) Comorbidities Diabetes mellitus Type I 1 (3.4%) (%) Diabetes mellitus Type II 1 (3.4%) (%) Hypertension (%) 7 (24.1%) BPH (%) 3 (10.3%) Peyronie’s disease 1 (3.4%) Alcohol abuse 7 (24.1%) 14
  15. 15. JANDROL/2008/005264 15 Table 2: Follow up protocol for all 29 patient Number of Patients 29 29 29 Parameters Measured At Baseline After 18 weeks After 30 weeks from the from the first first injection injection Testosterone total (nmol/l) ng/dl 10.6±1.2 18±0.8 a 19.8±0.6 a [300 ng/dl] [518ng/dl] [570 ng/dl] IIEF (EF Domain) 11±0.2 22.5±1.6 a 27±0.4 b,c AMS 48±0.5 29±1.5 a 22±1.2 b,c V prostate ( m³) (mean of three с 34±3.4 34.2±5.3a 38.6±4.7* determinations) PSA (ng/ml) 1.8±0.32 2.0±0.5a 2.1±0.6* Hemoglobin (g/dl) 14.9±0,4 15.1±0.2a 17,2±0,8 (21 men) c,d a –Statistical differences are significant ( <0.05) for data after 12 weeks f the treatment р о b -Statistical differences are significant ( <0.05) for data after 30 weeks f the treatment р о c -Statistical differences are significant ( <0.05) for data after 12 and 30 weeks f the treatment. р о d- No changes were detected in 8 men * The changes are not statistically significant ( >0.05) for data after 12 and 30 weeks f the р о treatment. 15
  16. 16. JANDROL/2008/005264 16 Table 3. Comparison of several parameters in hypogonadal patients (Group 1; n=20) with ED and venous leakage before and after treatment by Testosterone undecanoate. Number of patients 20 20 20 Parameters Measured At Baseline After 18 weeks from the After 30 weeks from the first T-injection first T-injection Total Testosterone 9.8±3.1 nmol/l 18±0.25n mol/l (a) 21.5±2.3 nmol/l (b) [280 ng/dl] [518 ng/dl] [620 ng/dl] Libido 4.1±1.2 7.5±2.2 a 8.3±2.3 (b) IIEF Score Erectile Function (EF domain) 9.4±1.8 18.5±0.5 1 25±0.4 (b, c) IIEF -6 Score AMS (points) 48 ± 0,5 (40-55) 29 ±1.5 (20-37)(a) 22 ± 1.2 (b, c) V prostate ( m³) с 32.4±8.4 34.2±4.3* 33.1±5.7* PSA (ng/ml) 1.82±0.9 2.0±032* 2.1±0.28* (a)–Statistical differences are significant ( <0.05) for data after 12 weeks f the treatment р о (b)- Statistical differences are significant ( <0.05) for data after 30 weeks f the treatment р о (c )- Statistical differences are significant ( <0.05) for data after 12 and 30 weeks f the treatment р о * The changes are not statistically significant ( >0.05) for data after 12 and 30 weeks f the р о treatment. 16
  17. 17. JANDROL/2008/005264 17 Table 4 Comparison of several parameters in hypogonadal patients (Group 2; n=9) with ED but without venous leakage before and after treatment with Testosterone undecanoate. Number of patients 9 7 7 Parameters Measured At Baseline After 18 weeks from the first After 30 weeks from the T-injection first T-injection Total Testosterone 12.7±1.4(nmol/l) 16.3±0.25 nmol/l (a) 17.8±0.4 nmol/l (b) [365 ng/dl ] [470ng/dl] [513ng/dl] Libido 3.6±1.7 8.5±1.2 (a) 8.7±0.3 (b) IIEF (points) Erectile Function Domain 8.6±1.2 23.4±0.2 (a) 27±0.2 b IIEF-6 (points) AMS (points) 48±0.2 (40-55) 29±0.5 (20-37) (a) 22± 0.5 b(b,c) V prostate ( m³) с 37.2±4.4 39. 8±4.1* 41.2±3.1* PSA (ng/ml) 1.3±0.3 1.9±0.42* 2.1±0.2* a –Statistical differences are significant ( <0.05) for data after 12 weeks f the treatment р о b - Statistical differences are significant ( <0.05) for data after 30 weeks f the treatment р о c - Statistical differences are significant ( <0.05) for data after 12 and 30 weeks f the treatment р о * The changes are not statistically significant ( >0.05) for data after 12 and 30 weeks f the р о treatment. 17
  18. 18. JANDROL/2008/005264 18 Figure legends: Figure1. Assessment of the venous leakage by Pharmaco-cavernosmetry and Cavernosography (PCG) in a patient (Patient , 50y.o.) before and after testosterone treatment К Panel shows a mixed type pathologic venous drainage (PVD). Note venous leakage to the deep dorsal а vein, glans penis, veins of periprostatic plexus. Panel b shows PCG after 21 weeks of treatment with testosterone. Note that the PVD intensity decreased. Figure 2. Assessment of the venous leakage by MRI in a patient (Patient U., 34 y.o) before and after testosterone treatment. Upper Panel shows MRI with contrast enhancement before the treatment; note the mixed types of pathological venous drainage (PVD). Note, deep dorsal vein, glans penis, spongious body are visualized. Cavernous bodies are not filled completely with contrast due to leakage. Lower Panel shows MRI after 24 weeks of testosterone treatment; note the decrease in the intensity of venous leakage to the deep dorsal vein, glans penis. Note that the cavernous bodies became more contrasted. Figure 3: Assessment of the venous leakage by MRI in a patient (Patient B., 56y.o) before and after testosterone treatment. Left panel shows MRI with contrast enhancement before the treatment with testosterone; Note the mixed type PVD - visualized proximal part of deep dorsal vein, veins of periprostatic plexus, internal iliac veins. Right panel shows MRI after 30 weeks of testosterone treatment; note the decrease in the intensity of venous leakage to the deep dorsal vein, veins of periprostatic plexus, spongiosal body (the minimal trace of contrast medium in periprostatic veins is normal picture). The picture is darker for better visualization of leakage. Figure 4. Comparison of penile MRI before and after testosterone treatment in a 59 Y.O patient with distal type PVD, Left panel shows MRI with contrast enhancement before the treatment; Visualized deep dorsal vein, glans penis, spongious body. Cavernous bodies are not filled completely due to fast leakage; Right panel shows MRI after 35 weeks of testosterone treatment. Note the decrease in the intensity of venous leakage to the deep dorsal vein and spongiosal body. Note that the cavernous bodies became more contrasted. 18
  19. 19. JANDROL/2008/005264 19 Figure 5. Assessment of the venous leakage by MRI in a patient (Patient Z., 57 y.o) before and after testosterone treatment. Left panel shows MRI with contrast enhancement before the treatment with testosterone; Note the mixed type PVD - visualized deep dorsal vein, glans penis, veins of periprostatic plexus, internal iliacal veins. Right panel shows MRI after 40 weeks of testosterone treatment; note the absence of venous leakage to the deep dorsal vein, glans penis and veins of periprostatic plexus. The exhausting of the cavernous crura contrasting does not mean worse filling due to venous leakage. 19

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