Testosterone Improves Erectile Function in Hypogonadal Patients with Venous Leakage (для специалистов)

Dmitry Kurbatov¹, Jury Kuznetsky², Abdulmaged Traish³

¹ Andrological and Urological Department, Endocrinological Research Centre, Moscow, Russia

² Urological and Andrological Department, Medical Stomatological Institute, Moscow, Russia

³ Departments of Biochemistry& Urology, Boston University School of Medicine, Boston, MA, USA

Abstract

The goal of this study was to assess the therapeutic benefits of testosterone in patients with erectile dysfunction (ED) and low plasma testosterone. Twenty nine patients ranging in age from 32 – 65 years (47±9.7) with low plasma testosterone and erectile dysfunction (ED), who did not respond to phosphodiesterase type 5 (PDE-5) inhibitors therapy due to suspected venous leakage, were recruited for this study.

Duplex Doppler Ultrasonography (DDU) was employed to evaluate penile arterial and venous blood flow. For confirmation of diagnosis of suspected venous leakage, pharmaco-cavernosography (PCG) was carried out in 9 patients and Magnetic Resonance Imaging (МRI) was carried out in 8 patients with intracavernous contrast enhancement. All patients were treated with 1000 mg injectable testosterone undecanoate on day one, followed by another injection after six weeks and every three months thereafter, in accordance with Nebido^TM therapy protocol. Plasma testosterone levels were determined in all patients at baseline and after 12 and 30 weeks of testosterone treatment. The International Index of Erectile Function (IIEF-5) and Aging Male Symptoms scale (AMS) were administered at base line, and after 12 and 30 weeks of testosterone treatment.

At base line total testosterone ranged from 7-11.8 nmol/l (200-345 ng/dl) in all patients. Twelve and 30 weeks after testosterone treatment, the mean testosterone plasma levels were 18 and 21.5 nmol/l (520 and 625 ng/dl), respectively. After twelve and 30 weeks of testosterone treatment, 20 out of the 29 patients demonstrated marked improvement in libido and the erectile function domain, as assessed by IIEF-5. There were no significant changes in prostate volume or prostatic specific antigen (PSA). Patients reported improvement in well being as assessed by the AMS scale. We suggest that testosterone treatment in men with low testosterone improves erectile function even in men with suspected venous leakage.

Key Words: Testosterone, Veno-occlusive Function & Dysfunction, Erectile Function; Sexual Function, MRI.

Introduction

It is well accepted that testosterone plays an important role in the physiology of erectile function in humans and animals (Simpson & Marshal, 1908; Tauber 1940; McCullagh & Renshaw 1934; Takahashi et al,. 1991; Palese et al, 2003; Mills et al, 1994; Suzuki et al, 2007; Bivalacqua et al, 1998; Muller et al, 1988; Traish et al, 1999, 2003, 2005, 2007; Traish & Kim 2005a,b; Traish & Guay 2006; Yassin et al, 2006 ;Hwang et al, 2006; Rogers 2003). More recently, testosterone has been recognized as having a role in ejaculation and spontaneous erections, as well as increased libido (Morales et al 2004 Rhoden &, Morgentaler 2004; Rhoden &, Morgentaler. 2003 Shabsigh, 2004, 2005 Shabsigh et al, 2006). Recent clinical observations suggested that testosterone alone improved erectile function in patients who did not respond to other forms of therapy (Yassin et al, 2006 ;Hwang et al,.2006). Androgen deprivation in the animal model produced dysfunctional veno-occlusive mechanism attributed to tissue remodeling and venous leakage (Traish et al, 1999; 2005; Traish & Kim 2005). In a series of case reports, Yassin et al (2006) employed pharmaco-cavernosmetry and cavernosography to assess tissue remodeling and provided a “proof of concept” that treatment with testosterone remodels human erectile tissue and reverses venous leakage, supporting the pre-clinical data reported in animal models. Hwang et al (2006) investigated the therapeutic effect of androgen on hypogonadal patients unresponsive to sildenafil alone. Eleven patients (34.3%) achieved satisfactory erectile function after testosterone replacement only. Another 12 (37.5%) patients experienced satisfactory intercourse after combined therapy. It was concluded that one-third of hypogonadal patients with ED who failed to respond to sildenafil, responded to testosterone alone and in hypogonadal patients with ED, androgen supplementation may be considered as first-line therapy.

We have undertaken this study to investigate if long acting testosterone therapy improves erectile function in patients with low plasma testosterone. To evaluate if patients with low testosterone may exhibit venous leakage, we have used several clinical methods including Duplex Doppler Ultrasonography (DDU), pharmaco-cavernosography (PCG) and Magnetic Resonance Imaging (MRI) to assess venous leakage. The utility and the availability of these diagnostic tools made it possible to evaluate the effect of testosterone treatment on reversibility of venous leakage in patients with erectile dysfunction and low testosterone. Here we report that testosterone treatment improved erectile function in men with low testosterone and suggest that the improvement is attributed to tissue remodeling and restoration of veno-occlusive function, as assessed by PCG and MRI.

Methods:

All patients recruited for the study were well informed about the scope and extent of the study and the diagnostic and treatment approaches. All patients singed an informed consent. This study was approved by the Urological and Andrological Departments, Medical Stomatological Institute, Moscow, Russia. Twenty 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 had sexual partner for at least 6 months or longer were recruited. Patients complained from low libido, non-rigid erection, premature ejaculation and rapid detumescence. No one man was administered previously testosterone replacement therapy.

All patients have been previously treated with PDE 5 inhibitors, with limited or no positive outcome as assessed by insufficient penile rigidity for satisfactory sexual intercourse. Thirteen patients did not respond at all to any of the three available PDE 5 inhibitors therapy. Sixteen patients had an inadequate or very poor response to Sildenafil (100mg) or Vardenafil (20 mg). The lack of response was defined as a score of 2 or 3 on questions 3 and 4 of the International Index of Erectile Function (IIEF-5) after having been administered the PDE 5 inhibitor, at least four times. We suppose patients were PDE5 failures due to venous leakage and hypogonadism, while all patients were educated about proper use of this therapy.

This study was not supported by any company or industry.

Patients’ characteristics:

The patient characteristics are provided in Table 1. It should be noted that this study represents a series of case studies. All 29 patients were hypogonadal based on testosterone plasma levels (<12 nmol/l or <300 ng/dl) and no history of hematological disorders or prostate disease. Seven patients had hypertension, two had diabetes, three had LUTS/BPH, one had Peyronie’s disease and seven have history of alcohol abuse. Twenty one are smokers but with no history of hematological disorders or prostate disease.

For the evaluation of the testosterone therapy safety and the influence on prostate gland we checked PSA levels and prostate size by ultrasound.

Assessment of venous leakage: After physical examination, all patients underwent ultrasound of the prostate gland and Duplex Doppler Ultrasonography (DDU), using conventional techniques to assess penile hemodynamics and inducing penile erection by administering 10 mg of PGE1 without re-dosing. Venous leakage was suspected in 20 out of the 29 patients evaluated, while arterial insufficiency was absent in these cases – a peak systolic velocity (PSV) was higher than 30cm\sec and resistance index (RI) was higher than 0,8. Patients had end diastolic velocities (EDV) ≥5 cm/sec, RI <0.8, 30 to 50 % increase in vein diameter and change of dorsal vein blood flow into the opposite direction when Valsalva test was performed. Arterial hemodynamic was not changed in these patients. At base-line 7 of these patients were further evaluated with PCG and 8 patients evaluated with MRI and 2 patients were evaluated with both methods, i.e. – PCG and MRI, to confirm the presence of venous leakage. Ten patients underwent MRI with intracavernous contrast enhancement as described previously (Kurbatov et al., 2008). We introduced MRI with contrast enhancement an addition or instead of the conventional PCG for the improvement the assessment of venous leakage visualization. It is well known that nowadays some authors perform only color Doppler US for the diagnosis of VOD related ED. But for the objective visualization of venous leakage in patients with veno-occlusive ED this method is not adequate. For this aim we used conventional PCG and introduced MRI as a new diagnostic tool. MRI technique is based on intracavernous injection of paramagnetic contrast agent that contains gadolinium, after pharmacologically inducing erection while the patient was in the MRI machine. Pharmacological penile erection was achieved by administering 20 mg of PGE 1. After having an erect penis contrast agent was introduced into one of the corpora cavernosa within 1 minute. One to two minutes later, imaging was started in the series. There was no any delay of time in obtaining films.

Important positive factors in using MRI are that this method has no radiation and the sensitivity and specificity of MRI exceeded that of dynamic infusion PCG (Kurbatov et al, 2008). Out of the 29 patients with ED venous leakage was confirmed in 20 patients as assessed by DDU. In 17 patients, who agreed and paid for the radiological investigation, venous leakage was further confirmed by either PCG or MRI. Based on these clinical diagnoses, patients were divided into 2 subgroups depending on presence or absence of venous leakage, as visualized by the above methods. Twenty patients with ED and venous leakage comprised the first group (Group 1).

Nine ED patients with arterial insufficiency (PSV< 30cm\sec, RI <0,8) but no documented venous leakage comprised the second group (Group 2).

Blood Hormone Levels at base line: Laboratory analyses for total testosterone, FSH, LH, prolactin and SHBG were carried out in all 29 patients. Total testosterone levels were determined always in the morning prior to treatment (baseline) to assess the clinical diagnosis of hypogonadism and is found in the range 7-11.8 nmol/l or 200-345 ng/dl [normal range 12-35 nmol/l or 345-1010 ng/dl]. Based on these findings all patients were considered potential candidates for treatment with testosterone. FSH levels were in the normal range for most of the patients. LH values were normal for the majority of patients. Only two patients had values of 9.5 and 24.3. Prolactin values were all in the normal range. The average SHBG values were 48.8 ±3.7 and PSA values were 1.8±0.32. Glucose values in two patients with DM were: 22 mM (type 1) and 7. 4 mM (type 2).

Testosterone treatment: Testosterone undecanoate (Nebido; Bayer Schering Pharma, Germany) was administered intramuscularly according to protocols published previously (Yassin et al 2006, Schubert et al, 2004; 2005). The patients received an injection (1000 mg) of the long acting testosterone preparation (testosterone undecanoate) with repeated administration after 6 weeks and every 12 weeks thereafter, following the recommendations in the literature ( Yassin et al 2006, Schubert et al, 2004; 2005). Duration of therapy was approximately 30 weeks for 20 patients and 18 weeks for 9 patients. After 2 and 3 injections (on weeks 12 and 20-21) we performed digital rectal examination to assess the effects on the prostates and carried out ultrasound evaluation for the prostate volume measurement. We further measured the levels of total testosterone. Plasma total testosterone levels were measured over a period of time during the follow up (at 12 and 30 weeks) as indicated (Tables 2 and 3). To evaluate the effects of this therapy on amelioration of venous leakage and restoration of erectile function, 5 patients underwent PCG and 4 patients underwent MRI with contrast enhancement.

Blood hormone levels subsequent to testosterone treatment: The average total testosterone values were 19.8±0.6 nmol/l or 570 ng/dl (р<0.05). FSH, LH and prolactin levels remained in the normal range (р>0.05). Glucose levels did not change significantly. The mean PSA value was 2.1±0.6 (р>0.05). In two patients, however, the PSA values increased significantly (in one patient it went from 1.6 up to 2.6). Prostate biopsies were carried out and PIN was confirmed and treatment with testosterone was halted for this patient. In a second patient, PSA went from 2.6 to 3.1. Treatment continued because the patients did not wish to discontinue use of testosterone. His PSA levels are monitored very closely every two months.

The IIEF-5 and the Aging Male Syndrome Scale (AMS) were administered at baseline and after 12 and 30 weeks of therapy were assessed. AMS questionnaire was expressed in points (weakly expressed attributes of 26-36 points, moderately expressed – up to 49 points and strongly expressed – more than 50 points. The parameters of IIEF, AMS were assessed at 12 and 30 weeks after treatment. Responders were defined as subjects with a good response to question 5 & 6 of the IIEF Questionnaire (Table 3).Differences from the baseline characteristics were investigated using the dispersion parametric or nonparametric tests for paired and unpaired samples. Results are expressed as mean ±standard deviation and р<0.05. To localize and confirm the site of venous leakage in these patients, we employed DDU, PCG and MRI as reported previously (Kurbatov et al, 2008).

Results

Long-acting Testosterone Treatment improves erectile function

The basal level of testosterone of all treated patients was increased to levels approximating those found in normal men after 12 week of treatment (18±0.25 nmol/l; or 518 ng/dl) and after 30 weeks of treatment 21.5±2.3 nmol/l; [620 ng/dl]. Total testosterone remained within the normal limits of physiological levels.

Testosterone treatment showed significant improvement in erectile function after 12 and 30 weeks of treatment. 17 patients out of 20 men from the Group 1 with venous leakage and 7 out of 9 from the Group 2 without venous leakage reported satisfactory sexual activity with testosterone treatment alone.

We repeated DDU after testosterone therapy in 17 patients out of 20 men with previously revealed venous leakage and who responded to the testosterone treatment alone. Assessment of penile hemodynamic (erectile function) with DDU suggested reduced or absence of venous leakage in all 17 men. The mean EDV was 3,1± 1.2 cm/sec and the mean RI was 0.87±0.05). No changes of dorsal vein blood flow during Valsalva test were noted. While prior to treatment, evidence of venous leakage was visualized by PCG (figure 1) or MRI (Figures 2-5). Images suggested a moderate or significant diminution of the intensity of venous leakage after androgen therapy assessed by PCG and MRI techniques (Figures 1-5).

The remaining 5 patients out of 29 with severe venous leakage of mixed type did not had adequate erections for intromission after testosterone treatment alone, and therefore these patients received a combined the therapy of testosterone and PDE-5 – inhibitor (vardenafil) of 10 mg before intercourse.

We also noted a positive influence of testosterone therapy on overall well being of men in both groups 1 & 2: assessed by self reporting of increasing of physical activity, improvement of mood and vitality. A substantial improvement in libido, qualities of erectile function of the majority of patients with or without VOD was noted (Table 3 and 4). None of the patients stopped smoking during the study period.

The basal level of testosterone of all treated patients was increased to levels approximating those found in normal men after 12 week of treatment (18±0.25 nmol/l; or 518 ng/dl) and throughout the treatment (at 30 week) – 21.5±2.3 nmol/l; or 620 ng/dl. Total testosterone remained within the normal limits of physiological levels.

The domain of sexual desire as assessed by IIEF-5 questionnaire was increased from 4.5±1.2 to 8.3±2.3 points. The erectile function domain was increased from 9.4±1.8 to 25±0.4 points. The level of PSA in all but one patient remained within the normal limits. No Changes of the prostate sizes were noted. Similar results were obtained in patients of group 2 (n=9). The clinical symptoms of hypogonadism improved after 1 injection of testosterone in 2 patients and after 2 injections in all other patients.

Interestingly, as the time period expected for testosterone plasma levels to drop approached (i.e. at the end of 6, 10, 28-29 weeks after injection), all patients noted that the therapeutic effect of testosterone was diminished, as determined from the patient’s decreased penile rigidity during sex activity and detumescence becoming more quicker.

It should be noted that 9 patients with clinically demonstrated venous leakage, as assessed by PCG (in 5 patients) or MRI (in 4 patients) have recovered fully their erectile function. A decrease in the intensity of documented venous leakage was confirmed in most patients and examples are provided in Figures 1-5.

Out of the 29 patients enrolled in this study, only one patient (3.4 %) with severe venous leakage discontinued the treatment attributed to dissatisfaction with conservative therapy and the patients opted to undergo surgical treatment for penile prosthesis implantation.

Discussion

Sufficient blood inflow into the cavernous arteries and the trapping mechanism of the veno-occlusive mechanism are two key components necessary for maintenance of high intracavernous pressure during an erection (Hatzichristou et al, 1995). Any pathology that contributes to this imbalance in the hemodynamic parameters would result in inadequate rigidity of the penis and development of ED. Most men with venous leakage did not respond to PDE 5 inhibitors, and are likely to suffer from veno-occlusive dysfunction (Rajfer et al, 1998). Several factors may contribute to veno-occlusive dysfunction, including vascular disease, endocrinological, structural and damage to the peripheral nervous system, aging and diabetes (Lue, 1992; Popken, 1999; Sasso et al, 1999). Although the role of androgens in management of erectile dysfunction has been previously dismissed, considerable evidence for basic science and clinical data is emerging to suggest that testosterone plays a role in human erectile function (Traish et al, 1999, 2003, 2005, 2007; Traish & Kim, 2005 a, b; Traish & Guay 2006; Yassin et al, 2006 ;Hwang et al, 2006; Rogers et al, 2003, Shabsigh; 2004 2005 Shabsigh et al, 2006). Studies from several laboratories have indicated that testosterone plays a role in maintaining the structural and functional elements of penile tissue and androgen deprivation produces specific pathophysiology related to alterations in the structure of the tunica albuginea and corpus cavernsosum smooth muscle cells and nerve fibers, thus culminating in ED (Traish et al 1999; 2005; “Rogers et al, 2003; Shen et al 2003; Giuliano et al 1993; Armagan et al 2006, 2007; Morelli et al 2004; Foresta et al 2006). Similarly, clinical studies in hypogonadal men have indicated that testosterone treatment improves sexual function and in particular erectile function (Aversa et al, 2003; Foresta et al, 2004; Carani et al, 1995; Zuzuki et al, 2006; Zhang et al, 2006; Foresta et al, 2006; Zitzmann et al, 2006; Nieschlag 2006; Lunenfeld, 2003; Wang et al, 2004; Steidle et al, 2003; Gredco et al, 2006). In this study we tested the hypothesis that testosterone therapy may restore erectile function in patient with venous leakage and veno-occlusive dysfunction, using DDU and MRI as tools to assess venous leakage before and after testosterone therapy. The findings suggest that testosterone improves erectile function in patients with suspected venous leakage.

Several pre-clinical and clinical studies have documented the role of testosterone in improving erectile function (Reviewed in Traish et al., 2007). Data from preclinical studies have documented that androgen deprivation alter tissues structure at multiple levels including loss of tunica elasticity (Shen et al, 2003), trabecular smooth muscle cell content (Traish et al, 1999; 2003), increased connective tissue deposition (Takahashi et al,. 1991; Traish et al, 1999), accumulation of adipocytes in the subtunical region of the corpus cavernosa (Traish et al, 2005), alterations in cavernosal and dorsal nerve structures ( Traish et al, 2007; Traish & Kim, 2005, Armagan et al, 2007), down regulation of nitric oxide synthase and phosphodiesterase type 5 (Armagan et al, 2006; Morelli et al, 2004). These alterations contribute to the venogenic erectile dysfunction. Testosterone treatment has been shown to restore all of these alterations and therefore it is believed that testosterone is critical for penile tissue remodeling in testosterone therapy. We believe the improvement in erectile function domain observed in this study and in previous studies (Yassin et al, 2006; Hwang et al, 2006) are attributed in major part to the remodeling of penile vascular tissue in response to testosterone treatment.

It should be noted that this series of case studies is not a controlled clinical trial and there fore suffers from some limitation. These include the limited number of patients enrolled in this case study, the limited visualization of the improvement of tissue function by MRI due to cost, and that the patients enrolled in this case study are all highly motivated, which may contribute to the observed improvement in erectile function domain. This study, however, has the preliminary results, that presents data showing that testosterone improves erectile function in patients with low testosterone and venous leakage and this is attributed to tissue remodeling with androgens, since upon re-visualization with MRI such changes are documented. We did not previously publish these reports. This approach paves the way for new studies to explore this important concept in androgen therapy for erectile function. We will extent the number of patients in the future randomized double blind placebo controlled study.

The importance of testosterone on sleep related erection has been very well documented previously. We will support our results with the Nocturnal Penile Tumescence (NPT) data in the further studies to show the effect of testosterone treatment on sleep related erections in men with veno-occlusive ED.

The findings presented here suggest that testosterone treatment improved erectile function in patients with low testosterone and suspected venous leakage. Indeed, while many patients benefit from PDE inhibitors therapy, those with venous leakage may not respond adequately and therefore would not benefit from PDE inhibitors treatment alone (Yassin et al, 2006; Hwang et al 2006). The advent of new formulation of long acting testosterone derivative may provide a new form of erectile dysfunction therapy in hypogonadal patients with ED. This study confirms and extends the observations previously reported by Yassin et al, (2006) in demonstrating that testosterone results in restoration of erectile function in patients with documented veno-occlusive dysfunction, as assessed by pharmaco-cavernosmetry and cavernosography. The data presented in this study provides additional evidence for a role of testosterone in restoring erectile function in hypogonadal patients with ED and venous leakage. These observations suggest that testosterone produces recovery in erectile function and reducing venous leakages. These data support previous preclinical as well as clinical findings reported by others (Yassin et al, 2006; Hwang et al, 2006; Traish et al, 1999; Traish et al, 2003; 2005; Rogers et al, 2003) and suggest a role for androgens therapy in erectile dysfunction.

Figure legends:

Figure1. Assessment of the venous leakage by Pharmaco-cavernosmetry and Cavernosography (PCG) in a patient (Patient К, 50y.o.) before and after testosterone treatment

Panel а shows a mixed type pathologic venous drainage (PVD). Note venous leakage to the deep dorsal 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 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. Cavernous bodies filled with contrast completely

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. Cavernous bodies are filled completely with contrast.

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.