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From the * Andrological and Urological Department,
Endocrinological Research Centre, Moscow, Russia; the
Urological and Andrological Department,
Medical Stomatological Institute, Moscow, Russia; and the
Departments of Biochemistry and Urology,
Boston University School of Medicine, Boston, Massachusetts.
| Correspondence to: Dr Abdulmaged M. Traish, Professor of Biochemistry and Urology, Director, Laboratories for Sexual Medicine, Institute for Sexual Medicine, Boston University School of Medicine, Center for Advanced Biomedical Research, 700 Albany St, W607, Boston, MA 02118 (e-mail: atraish{at}bu.edu). |
| Received for publication March 3, 2008; accepted for publication July 1, 2008. |
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Abstract |
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Key words: Veno-occlusive function and dysfunction, sexual function, MRI
Preclinical studies have suggested that androgens are important for maintaining the veno-occlusive function (Traish and Guay, 2006; Traish et al, 2007), and androgen deprivation results in venous leakage (Rogers et al, 2003); it is possible that androgen treatment in hypogonadal men may reverse or attenuate venous leakage in men with ED. Further, we have reported that magnetic resonance imaging (MRI) can be used to visualize venous leakage in men with ED (Kurbatov et al, 2008). Therefore, with the advent of a new long-acting testosterone formulation for androgen therapy and the available utility of MRI to visualize venous leakage, we have undertaken this study to investigate whether long-acting testosterone therapy improves erectile function in hypogonadal patients with venous leakage, using MRI as a tool to assess venous leakage before and after testosterone therapy. Here we report that long-acting testosterone treatment improved erectile function in men with low testosterone as assessed by the International Index of Erectile Function (IIEF-5) and reduced venous leakage as assessed by pharmacocavernosography (PCG) and MRI techniques.
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Methods |
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All patients had been previously treated with phosphodiesterase type 5 (PDE-5) inhibitors, with limited or no positive outcome as assessed by insufficient penile rigidity for satisfactory sexual intercourse. Thirteen of the 29 patients did not respond at all to any of the 3 available PDE-5 inhibitor therapies, and 16 of the 29 patients had an inadequate or very poor response to sildenafil (100 mg) or vardenafil (20 mg). The lack of response was defined as a score of 2 or 3 on questions 3 and 4 of the IIEF-5 after subjects had been administered the PDE-5 inhibitor at least 4 times. Although all patients were educated with regard to the use of PDE-5 inhibitors, we speculated that the lack of response of these men to PDE-5 inhibitors might be because of their hypogonadal status and/or venous leakage, as proposed in previous studies (Rajfer et al, 1998; Yassin et al, 2006; Shabsigh et al, 2008).
Patients' Characteristics
The patients' 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 had no history of hematological disorders or prostate disease.
Seven patients had hypertension, 2 had diabetes, 3 had lower urinary tract
symptoms/benign prostatic hyperplasia, 1 had Peyronie disease, and 7 had a
history of alcohol abuse. Twenty-one were smokers. For evaluation of the
safety of testosterone therapy on the prostate gland, we determined changes in
prostate-specific antigen (PSA) levels and assessed prostate volume by
ultrasound. These values are reported in Tables
2,
3,
4.
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Assessment of Venous Leakage
We have recently described the use of duplex Doppler ultrasonography (DDU),
PCG, and MRI to assess venous leakage in patients with ED
(Kurbatov et al, 2008). After
history and physical examination, all patients underwent ultrasound of the
prostate gland and DDU, using conventional techniques to assess penile
hemodynamics after inducing penile erection by administering 10 µg of
prostaglandin E1 (PGE1) without redosing. Based on this information, venous
leakage was suspected in 20 out of the 29 patients evaluated, whereas arterial
insufficiency was absent in these cases—peak systolic velocity (PSV) was
higher than 30 cm/sec and resistance index (RI) was higher than 0.8. When a
Valsalva test was performed, patients had end diastolic velocities (EDVs)
greater than or equal to 5 cm/sec, RI less than 0.8, and 30% to 50% increase
in vein diameter and change of dorsal vein blood flow into the opposite
direction. Arterial hemodynamics were not changed in these patients.
To further document venous leakage, 7 patients were further evaluated with PCG, 8 patients were evaluated with MRI, and 2 patients were evaluated with both methods (PCG and MRI) at baseline. A total of 10 patients underwent MRI with intracavernous contrast enhancement as described previously (Kurbatov et al, 2008). We introduced MRI with contrast enhancement in addition to the conventional PCG to determine whether this new approach improves the assessment of venous leakage visualization. Although color Doppler ultrasound is used for the diagnosis of veno-occlusive dysfunction in ED patients, this tool does not permit visualization of venous leakage in patients with veno-occlusive ED. For this reason we used conventional PCG and introduced MRI as a new diagnostic tool.
MRI technique is based on intracavernous injection of a paramagnetic contrast agent that contains gadolinium, after pharmacologically inducing erection while the patient is in the MRI machine. Pharmacological penile erection was achieved by administering 20 µg of PGE1. When the penis was erect, contrast agent was introduced into 1 of the corpora cavernosa within 1 minute. One to 2 minutes later, imaging was commenced in the series. There was no time delay in obtaining films.
The advantages in employing MRI are that this method uses no radiation and the sensitivity and specificity of MRI exceed those of dynamic-infusion PCG (Kurbatov et al, 2008). Out of the 29 patients with ED assessed by DDU, venous leakage was detected in 20 patients. Venous leakage was further confirmed by either PCG or MRI in 17 patients initially diagnosed as having venous leakage with DDU. Based on this clinical diagnosis, 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 <30 cm/sec, RI <0.8) but no documented venous leakage comprised the second group (group 2).
Blood Hormone Levels at Baseline
Laboratory analyses for total testosterone, follicle-stimulating hormone
(FSH), luteinizing hormone (LH), prolactin, and sex hormone binding globulin
(SHBG) were carried out in all 29 patients. Blood for testosterone
measurements was always drawn in the morning. Total testosterone levels were
determined prior to testosterone treatment (baseline) to assess the clinical
diagnosis of hypogonadism. In 25 out of 29 patients the ranges of testosterone
levels at baseline were 7–11.8 nmol/L or 200–345 ng/dL (normal
range, 12–35 nmol/L or 345–1010 ng/dL). In 4 patients, the levels
of testosterone were <7n µ. 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 2 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 2
patients with diabetes mellitus were 22 mM (type I) and 7. 4 mM (type II).
Testosterone Treatment
Testosterone undecanoate (Nebido; Bayer Schering Pharma, Germany) was
administered intramuscularly according to protocols published previously
(Schubert et al, 2004;
Schubert and Jockenhovel,
2005; Yassin et al,
2006). The patients received an injection (1000 mg) of the
long-acting testosterone preparation on day 1 with repeated administration at
6 weeks and every 12 weeks thereafter, following the recommendations in the
literature (Schubert et al,
2004; Schubert and
Jockenhovel, 2005; Yassin et
al, 2006). Duration of therapy was approximately 30 weeks for 20
patients and 18 weeks for 9 patients. After 3 injections (on weeks
20–21) we performed digital rectal examination to assess the effects on
the prostate and carried out ultrasound evaluation for 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
We determined testosterone levels at baseline (prior to testosterone
treatment) in each patient. Blood samples were drawn for testosterone
measurements on week 18 and week 30 from commencing the first testosterone
treatment. The average total testosterone values after therapy were 19.8
± 0.6 nmol/L or 570 ng/dL (P < .05). FSH, LH, and prolactin
levels remained in the normal range (P > .05). Glucose levels did
not change significantly. The mean PSA value was 2.1 ± 0.6 (P
> .05). In 2 patients, however, the PSA values increased significantly; in
1 patient the value went from 1.6 up to 2.6. Prostate biopsies were carried
out and prostate interepithelial neoplasia (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 patient did not wish to
discontinue use of testosterone. His PSA levels are monitored very closely
every 2 months.
IIEF and AMS Assessment Questionnaires
We administered to all patients the IIEF-5 and the Aging Male Syndrome
scale (AMS) at baseline and after 12 and 30 weeks of therapy. The AMS
questionnaire was expressed in points (weakly expressed attributes,
26–36 points; moderately expressed, up to 49 points; and strongly
expressed, more than 50 points). The parameters of the IIEF and AMS were
assessed at 12 and 30 weeks after treatment. Responders were defined as
subjects with a good response to questions 5 and 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 P < .05.
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Results |
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TopAbstractMethodsResultsDiscussionReferences |
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Testosterone treatment significantly improved erectile function after 18 and 30 weeks of therapy. Seventeen out of 20 patients from group 1 and 7 out of 9 from group 2 reported satisfactory sexual activity after testosterone treatment alone. After testosterone therapy, we repeated DDU in 17 patients with documented venous leakage. Assessment of penile hemodynamics (erectile function) with DDU suggested reduced or absent venous leakage. The mean EDV was 3.1 ± 1.2 cm/sec and the mean RI was 0.87 ± 0.05). No changes in dorsal vein blood flow during the Valsalva test were noted. Prior to treatment, evidence of venous leakage was visualized by PCG (Figure 1) or MRI (Figures 2, 3, 4, 5). After testosterone therapy, imaging showed a moderate or significant diminution of the intensity of venous leakage as assessed by PCG (Figure 1) and MRI techniques (Figures 2, 3, 4, 5). Three patients with severe venous leakage of mixed type and 2 patients without venous leakage did not respond well to testosterone therapy alone and were unable to have adequate erections for intromission. These patients were reassigned to a combined therapy of testosterone and PDE-5 inhibitors.
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We further noted a substantial improvement in libido and qualities of erectile function of the majority of patients with or without veno-occlusive dysfunction after testosterone therapy (Tables 3 and 4). The domain of sexual desire as assessed by the 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. It should be noted that 9 patients with clinically demonstrated venous leakage, as assessed by PCG (in 5 patients) or MRI (in 4 patients), fully recovered their erectile function. A decrease in the intensity of documented venous leakage was confirmed in most patients and examples are provided in Figures 1, 2, 3, 4, 5. Out of the 29 patients enrolled in this study, only 1 patient (3.4%) with severe venous leakage discontinued the treatment; this was attributed to dissatisfaction with conservative therapy, and the patient opted to undergo surgical treatment for penile prosthesis implantation.
We also noted a positive influence of testosterone therapy on overall well-being of men in both groups 1 and 2, assessed by self-reporting of increasing of physical activity and improvement of mood and vitality. None of the patients stopped smoking during the study period. No changes in prostate sizes were noted (Tables 2, 3, 4). Similar results were obtained for patients in group 2 (n = 9). The level of PSA in all but 1 patient remained within the normal limits. 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 (ie, at the end of 6, 10, and 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 quicker.
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Discussion |
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Based on the observations in this study, we suggest that improvement in erectile function subsequent to testosterone therapy in hypogonadal patients with venous leakage is attributed to erectile tissue remodeling, as documented by visualization with MRI before and after testosterone therapy. This new approach of visualizing venous leakage with MRI may pave the way for new studies to explore this important concept in androgen therapy for erectile function.
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Footnotes |
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