Peyronie’s Disease (PD) causes penile curvature and pain in acute phase. In two preclinical studies, tamoxifen and vardenafil (T&T) together showed to be effective in the acute phase. The aim of this study was to describe the clinical results of the off-label treatment of PD patients with T&T in combination with vacuum erection device (VED) in St Antonius hospital, urology outpatient clinic. Baseline descriptive Statistics, Fisher Exact and Chi-Square Test were used. 48 Men were included, mean age 53.0 years (SD 9.5), baseline curvature 46.7° (SD 18.8), median duration four months, 70.8% (n = 48) painful erections. Dorsal curvature is found in 27 (56.3%) men, mean stretched penile length 13.4 cm. Mean use of T&T was 13 weeks (1–52 weeks). Curvature improvement in 27.7% men, pain reduction in 48.5% men, sexual intercourse/coitus improvement in 34.2% men, erection improvement in 14.6% men. Adverse reactions of T&T in 39.6% (n = 19). This was the first study investigating the use of T&T in acute phase PD patients. 27.7% of patients reported improvement in curvature with T&T.
Introduction
Peyronie’s disease (PD) a collagen tissue disorder causing fibrotic tissue in the tunica albuginea in the corpora cavernosa in the penis, based on improper signalling of transforming growth factor β1 causing scarring of the tunica albuginea [1, 2].
PD is an invalidating illness with painful erections in the early stage of the disease in 35–45% of men and curvature of the erect penis, causing hindrance during sexual intercourse and leading to sexual disability with penetration. PD typically affects men between 40 and 70 years old with a prevalence of 1–13% [1‐4]. Caucasian men have a genetic predisposition of getting PD [1]. Research shows that 3–13% of men have spontaneous recovery in curvature of the penis [5‐8] PD also causes psychological distress tending to seek medical treatment [9].
Several medicines show some positive effect on the curvature or pain, but the evidence is weak. tamoxifen and tadalafil (T&T) are two of these medicines. Separately, they are tested on PD in the active phase, but without significant evidence of effectiveness [2].
Two studies have recently been published about the combination of tamoxifen and vardenafil in the acute phase on rodent models and PD tissue. The first study [10] was performed on a rodent model of PD and the first to demonstrate a synergetic activity between a phosphodiesterase type5inhibitor (PDE5i) and a selective oestrogen receptor modulator (SERM), discovered through a phenotypic screening approach. The second study [11] tested tamoxifen (SERM) and vardenafil (PDE5i) on human tissue derived from men who had a Nesbitt correction for PD. The transforming growth factor β1 (TGFβ1) grew on the tissue forming collagen. They tested the working mechanism of both drugs on the derived tissue in the laboratory. Their conclusion was that the timing of administration of the drugs affecting the myofibroblast transformation appears to be vital in the in vitro models of PD, where 36 hours of TGFβ1 growth is suggested as a point of no return.
In this study, tadalafil 5 mg was used instead of vardenafil 20 mg. Tadalafil 5 mg is a long acting drug, which creates a blood level of approximately 8 mg and is approved for daily use. Based on these two studies, men with PD in the acute phase were treated with T&T 5 mg.
The use of a Vacuum Erection Device (VED) is based on the findings of Raheem et al. [12, 13]. This study showed a reduction of curvature in 67% of patients with a reduction of 5–25 degrees. The VED was advised to use twice daily for a period of twelve weeks. The rationale is that the regular application of this therapy would mechanically stretch the penis and cause remodelling of the fibrous plaque leading to straightening. The VED is prescribed on regular basis for a few years already to patients with PD in our clinic.
In the evaluation of the literature in the ‘EAU guideline on male sexual reproductive health’ treatment of PD with tamoxifen shows contradictory evidence in the studies due to several methodological flaws. This makes it difficult to recommend it in a daily-life setting. In the guideline, the evaluation of the literature shows that PDE5inhibitors are suggested to be helpful in reducing collagen deposition and decreasing curvature, although they were small studies. VED therapy appears to decrease hypoxia-inducible factor 1α and TGFβ1, collagenase and apoptosis. Multimodal treatment is suggested a better outcome combining different oral drugs. There is no consensus on which drugs should be combined. A combination of drug therapy and VED is not described yet [2]. The aim of this study is to describe the clinical results of the off-label treatment of PD patients with T&T and with VED in St Antonius hospital, urology outpatient clinic.
Material and methods
Study design
This is a retrospective real world observational report of patients treated with tamoxifen 2 × 10 mg and tadalafil 1 × 5 mg off label and VED as usual treatment. Baseline measurement and post-treatment measurement were analysed.
Research question: What is the effect of T&T in combination with VED on the reduction of curvature in men with acute phase PD compared to spontaneous improvement of curvature as described in literature (3–13%)?
Patients were referred to the outpatient clinic with acute phase PD and curvature. After explanation of disease and treatment options in the acute phase and acquiring informed consent, patients were included. Acute phase of PD is defined as short term PD of ≤ 12 months and painful erections or instable curvature. Physical examination and a self-provided photograph were recorded in the electronic medical record. Collected baseline measurements were degrees of curvature, direction of curvature, plaque location and size based on physical examination, stretched penile length, painful erections, ED, time of curvature and time of complaints other than curvature (i.e. starting with pain). Patients were treated with T&T and VED at the same time. Results of treatment were evaluated after treatment. Maximum time of intervention was 12 months. After this period, PD is assumed to have stabilised, and medication is therefore less effective on the myofibroblasts.
Outcome measurements were self-reported reduction of curvature and penile pain, improvement of possibility to have coitus and change in ED. Duration of the use of T&T were registered. Reported side effects are described according to the WHO Adverse Reaction Terminology [14]. Comparison is made between men reporting improvement of curvature, non-responders and worsening of curvature from time of onset until ending of use of medication and use of VED.
Statistical analysis
Demographic characteristics are presented as means (±SD). Baseline and outcome measurements were reported with descriptive statistics. Chi-Square was used for analysis of outcome measures with ordinal data and more than two groups. Secondary outcomes and subgroup analysis were performed using appropriate non-parametric tests and one way ANOVA. SPSS 27 was used for analysis. A value of p < 0.05 was considered statistically significant.
Results
Baseline characteristics are shown in Tab. 1. In this study, 69 men were initially included after informed consent from 6‑3-2020 until 5‑10-2020. 17 men were excluded due to missing data, i.e. no photograph at baseline. Some patients having a telephone assessment due to COVID-19 pandemic and no possibility for physical examination. Another four men were excluded because of a duration of curvature of more than twelve months.
Table 1
Baseline characteristics
Baseline characteristics N = 48
Total
Age (y), mean (SD)
53.0 (9.5)
Penile curvature (°), mean (SD)
46.7° (18.8)
Duration of curvature (months) at first visit, median (min-max)
4 (0.5–12)
Duration of complaints at first visit (months), median (min-max)
5.5 (1–14)
Location of nodule n (%)
Dorsal, proximal
4 (8.3)
Dorsal mid penile
13 (27.1)
Dorsal distal
10 (20.8)
Ventral proximal
2 (4.2)
Ventral mid penile
1 (2.1)
Ventral distal
1 (2.1)
Others
8 (16.7)
Missing
9 (18.8)
Stretched penile length (cm) mean (SD) n = 39
13.4 (1.6)
Active phase (%)*
91.7%
Painful erections (%)
70.8%
ED n (%)
Grade 1 i.e. severe ED
0 (0)
Grade 2
8 (16.7)
Grade 3
21 (43.8)
Grade 4, i.e. no ED
19 (39.6)
*As defined by patient history taken all patients had curvature ≤ 12 months
Grade 1 = Enlarged penis but no erection; Grade 2 = Average erection, but penetration is not possible; Grade 3 = Erection with possibility of penetration; Grade 4 = Full erection
The mean age was 53 years (SD 9.5) and mean curvature was 46.7 degrees (SD 18.8). The median duration of curvature at first visit was four months (0.5–12). 23 patients started later than the first visit with the intervention. Painful erections were seen in 70.8% of men. Based on patient history. 91.7% were assessed in the acute phase, with twelve months or less having a curvature.
Primary outcomes
The primary outcome is the improvement of the curvature. Use of the drug treatment is divided into three groups: 0–5.5, 6–12 and > 12 weeks. The major improvement on curvature can be seen in eleven men that used the T&T the longest (> 12 weeks), see Fig. 1. A total of 27.7% noticed an improvement of curvature with T&T as shown in Fig. 1 compared to the literature where 3–13% of men noticed a spontaneous improvement, without any intervention. A total of 57.4% (p = 0.2) noticed no improvement of which 16 men had a duration of > 12 weeks of using T&T. The median duration of T&T use was 13 (1–52) weeks; in one patient the duration was not reported.
Fig. 1
Effect of the drug use on the change in curvature. Asterisks Chi-square for more than two groups
×
The VED is used concurrently with the medication. The improvement of the curvature after using the VED is seen in 13 (28.3%) men, of which seven used the VED consistently as shown in Fig. 2. A total of 26 men (56.5%) did not notice any improvement on curvature after using the VED, p = 0.1. The use of the VED is missing in two men, who are not included.
Fig. 2
VED effect on change in curvature. Asterisks: Chi-square for more than 2 groups
×
Secondary outcomes
For the secondary outcomes, 41 men were included, with 7 being excluded due to missing data on experienced improvement of coitus. Reduction of painful erections was shown in 58.5% of men. Experienced improvement in coitus was reported in 34.2% of men. Improvement of erections was reported in 14.6%. These are presented in Tab. 2 as percentages. Of the men (n = 15) with good erections (grade 4) only one (2.4%) showed additional improvement in curvature. Within the group with Grade 3 ED two (4.9%) showed improvement and in the Grade 2 ED three (7.3%) showed improvement of ED.
Table 2
Self-reported changes in coitus, painful erections and improvement of erections after treatment with medication and VED
N = 41
N
%
Experienced improvement in coitus
14
34.2
Reduction of painful erections
24
58.5
Improvement of erection
6
14.6
Difference between drug treatment and the VED
Improvement of coitus is seen in 31.7 and 33.7% after drug treatment and VED treatment (n = 41). The same percentage of men (12.2%) in both groups reported significant improvement of coitus after taking T&T and using the VED. All of them used the medication for > 12 weeks and three of them (7.3%) used the VED consistently.
A partial overlap is seen in men using the VED consistently and use of the T&T for ≥ 12 weeks. In the group using the medication for ≥ 12 weeks, the overlap is 67.7%, being the largest group. In the intermediate group (6–12 weeks), the overlap in consistently use of the VED was 55.5% and in the group with medication < 6 weeks the overlap was 28.6%. There is no relation between the groups or within the groups (p > 0.05).
Of the men having painful erections at the start of treatment (34/48), 22 (64.7%) showed reduction of pain after treatment of the men using the VED. Ten (21.7%) men mentioned improvement of pain after three months. Improvement of erection was mentioned by 13% of men after the medication, 63% mentioned no change and 23.9% mentioned deterioration of the erection (n = 46).
Medication prescribed for other disease and side effects of the medication
Medication for other conditions/disease (before referral) was prescribed to 28 (58.3%) patients, of which 12 (25%) had one other medication prescribed (n = 48). These medications had no relation with PD or interference with T&T.
Side effects and adverse reaction to T&T were seen in 19 (39.6%) men. The side effects are described according to WHO’s Adverse Reaction Terminology, see Tab. 3, including the type of side effect, reason to stop early or therapeutic failure [14]. From the nine patients who withdrew early from treatment, six of them stopped after 1–6 weeks and three after 6–12 weeks.
Table 3
Adverse reaction on tamoxifen/tadalafil
WHO’s adverse reaction Terminology
Number
Reason
Dose related
1
Stomach pain, hot flushes
Non-dose related
6
Gut, hot flushes, libido change, fatigue, sad feeling, nauseous, dizziness, pain (muscle, head, joints)
Dose related and time related
0
Time-related
0
Withdrawal
9
Nauseous, claudication, severe muscle pain, hair loss, anxiety, dizziness, medication too expensive (Tadalafil)
Unexpected failure of therapy
3
No change in curvature
Subgroup analysis
Improvement of curvature is not related to the baseline characteristics of painful erections, time of complaints and amount of curvature, p > 0.05 with Kruskal Wallis, as shown in Tab. 4.
Table 4
Improvement of curvature based on baseline characteristics
Improvement of curvature (yes/no)
P-value
Painful erectionsa (13/35)
0.205
Time of complaintsa (13–35)
0.407
Curvature in degreesa (13/35)
0.734
Time of taking medicationb (13/34)
0.112
Use of VEDb (13/33)
0.844
a Kruskal Wallis
b Mann Whitney test
Duration of the complaints at baseline does not significantly influence the improvement of the curvature, p = 0.053, n = 48 between groups (improvement, no improvement or worsening) with one way ANOVA.
Patients with improvement of curvature (n = 13) had a mean interval since onset of PD of 7.2 months (SD 4.0). Patients without improvement of curvature (n = 28) had a mean PD of 4.5 months (SD 2.7) and patients with worsening of curvature (n = 7) had a mean PD of 6.3 (SD 4.2) months, showing no significant difference (p > 0.05), see Tab. 5.
Table 5
Improvement of curvature in comparison with mean PD
Curvature (n)
Mean duration of curvature at first visit in months (SD)
Improvement (13)
7.2 (4.04)
No improvement (28)
4.5 (2.69)
Worsening (7)
6.3 (4.15)
Total
5.5 (3.46)
Consequent usage of the VED and medication for > 12 weeks showed a significant difference in patients with no painful erection (n = 32; mean rank 26.2) at baseline, p = 0.03 as shown in Tab. 6.
Table 6
Effect of consistent use of VED and medication for > 12 weeks on baseline characteristics
VED&medication > 12 wks (yes = 14/no = 32)
P-value
Painful erectionsa
0.030
Time of complaintsa
0.727
Curvature in degreesa
0.437
a Kruskal Wallis
Reduction of painful erections after treatment does not correlate with painful erections before treatment or duration of curvature before the start of treatment, p > 0.05, nor the place of the nodule at baseline.
There is no significant relation between painful erections and the change of curvature after treatment with the Kruskal Wallis, p > 0.05. The distribution of painful erection (n = 17), sensitive (n = 17) or no pain at all (n = 14) is equally distributed.
The Mann Witney test showed no significant difference between the active and chronic phase on the change of curvature, p > 0.05. Of the 48 patients, only four patients were assessed in the chronic phase by taking patient history.
The period of drug use showed no significant difference on improvement of curvature with the Pearson’s Chi-square, p > 0.05. Improvement of curvature was seen in 11/31 patients (35.5%) using the T&T for > 12 weeks.
Patients’ perceived improvement of the curvature after consistent use of the VED was 33.3% (7/21), p > 0.05.
The Spearmen’s rho correlation between the duration of complaints at baseline and the period of drug use has a low negative correlation, which is not significant, r = −0.075, p = 0.62, n = 47.
Discussion
This is the first real life retrospective observation of ad hoc off label treatment of T&T for PD in male patients, based on the results of the two preclinical studies with tamoxifen and vardenafil on a rodent model and in vitro tissue derived from PD patients [10, 11].
The current study showed better outcome with T&T and VED on reducing the curvature in PD patients compared to no treatment. The most interesting finding was experienced reduction of curvature of the penis in 27.7% patients after taking the T&T compared to spontaneous reduction of curvature in 3–13% in literature [5‐8]. After the use of the VED, 28.3% experienced improvement of curvature. Most of the men used both, so a distinction between both cannot be made.
The results of this study indicate that T&T with VED can have a positive effect on the improvement of the curvature. These results are based on self-reported outcomes on reduction of the curvature. Recent research from Megson et al. showed stabilising of the curvature in a retrospective study in 85% of patients (n = 102) receiving combination of tamoxifen 2 × 20 mg and tadalafil 1 × 5 mg compared to no treatment or vitamin E (n = 45) as presented during the ESSM congress 2022 [15].
The overall results did not show any significant improvement of curvature. Improvement of curvature does not seem correlated with the duration of curvature at baseline, which makes it difficult to select patients for this treatment based on history taken and physical examination, being the most common way of diagnosing PD and distinguish between the acute or chronic phase.
In our subgroup analysis, consistent use of VED and medication for > 12 weeks showed significant improvement in curvature, which suggests that this combination can be effective. Noticing an overlap between the groups. In the group with drug use > 12 weeks, 67.7% used the VED consistently, what makes it more difficult to subscribe the effect to one or the other treatment. Based on the preclinical research and the study on patients T&T stops progression of the plaque formation [10, 11]. Based on a study from Raheem et al. VED reduces curvature in 66% of patients [12]. Men with experienced reduction of curvature were more motivated to continue using T&T and VED for longer time.
Next to these results, improvement on performing coitus by 31.7% men and improvement of the erection by 20% of men are also reported. Reduction or relief of penile pain is also mentioned by 38.3% men of which most men report reduction after 12 weeks of treatment. Compared to the literature this reduction of penile pain is earlier than no treatment suggesting the acute phase ends earlier.
This study has several limitations. It is a retrospective observational report without a control group. Patients were included in the study based on referral to the outpatient clinic and motivated after being informed via PowerPoint presentation mentioning the two previous studies and off label treatment [10, 11]. The number of patients in this report was not sufficient to show significant differences in the subgroups.
The proportion of men with painful erections in acute phase of PD is rather high (70.8%) compared to the literature (20–70%). This can be related to the used definition of painful erections. In this report sensitivity during erection is interpreted as pain [2].
Due to the COVID-19 pandemic several patients were only consulted by phone or video consultation. Therefore, there are missing data on penile length and location of nodule, due to not being able to perform a physical examination. Some patients got lost to follow up, thus creating missing data in the reported outcomes.
The outcome measures were self-reported by the patients during the consultations. There were no validated PROM questionnaires used for the initial consultation or in the follow up. The results of the T&T and VED should be taken into account together, as both treatment modalities are used at the same time and have probably influenced each other in the outcome of the treatment.
In the pre-clinical studies on a rodent model and PD tissue after tamoxifen and vardenafil in different doses, the combination of medication showed significant difference in reducing scar tissue [10, 11].
The results of this study showed subjective improvement of the curvature in PD patients as well as subjective improvement of coitus and erection based on self-reported results. In previous research, non-significant measured reduction of curvature was reported after oral treatment with T&T separately [2, 16]. Chung et al. found a reduction of measured scarring with Doppler Ultrasound after treatment with tadalafil, but they did not report reduction in penile curvature [16].
This is the first report of with T&T off label treatment in patients with results based on self-reported outcome measurements, which is meaningful for clinical implications. It shows adherence to possible further research to the effects of T&T/vardenafil. New research should be set up as trial comparing T&T with VED using validated questionnaires and a sufficient power for finding significant difference. Another possible research is comparing T&T to pentoxifylline. These researches are focused on the acute phase of PD, which is difficult to distinguish from the chronic phase if no pain is present or curvature is present for some time. A good clinical imaging diagnostic that can assist in diagnosis of the acute phase would be very helpful. Unfortunately this is not available yet.
Conclusions
Drug treatment with T&T in combination with VED showed improvement of curvature in 27.7% of men with drug treatment and 28.3% with the VED. This is a better outcome than compared to spontaneous improvement of curvature as described in the literature. Anamnestic duration of the illness has no ‘predictive value’ for the effect of the T&T. No major side effects of T&T were found.
Further research including RCT with larger groups is needed. Development of a clinical imaging diagnostic to distinguish between acute and chronic phase is helpful in the choice of treatment.
Conflict of Interest
Payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing or educaional events: J.P. Geelhoed: Besins Healthcare; I.J. de Jong: Astra Zeneca, Bayer; J.J.H. Beck: MSD, Astellas, Sobi, Besins Healthcare, Health Investment.
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