Spontaneous erectile function recovery among young men with erectile dysfunction taking tadalafil 5 mg once a day

Abstract

Introduction

Erectile dysfunction (ED) significantly affects young men, with 1 in 4 men under 40 years of age seeking medical help for ED.^1,2 Despite the common assumption that ED in this demographic is primarily psychogenic,^3,4 many young patients present with severe ED.¹ Lifestyle modifications are often the first step in treatment, followed by the use of phosphodiesterase type 5 (PDE5) inhibitors.⁵ Of all, tadalafil stands out due to its extended half-life of 17.5 hours, enabling a more flexible dosing schedule in comparison with other largely available PDE5 inhibitors.^6,7 Tadalafil can be taken on demand before sexual activity or once a day (OaD), regardless of planned sexual activity. The latter regimen provides a consistent effective profile, making it a valuable alternative for men preferring nonscheduled sexual intercourse.^8,9 This could be particularly beneficial for younger men with ED, helping them overcome emotional hurdles and re-establish a satisfactory sexual life.^2,10 However, factors that influence EF recovery in young men using OaD tadalafil remain poorly understood. Therefore, we aimed to explore the prevalence and the clinical factors associated with spontaneous medication-free EF recovery after discontinuing tadalafil 5 mg OaD in a cohort of young men seeking first medical help for ED.

Methods

Data from a cohort of 478 heterosexual sexually active men, consecutively seeking first medical help for ED at a tertiary referral center between 2018 and 2022 and prescribed with tadalafil either on-demand or OaD after several suggestions for lifestyle modifications, were analyzed. Of note, all included patients were PDE5 inhibitor naïve at the time of their first clinical assessment. Each patient underwent a detailed medical examination and history taking. Health-significant comorbidities were scored using the Charlson comorbidity index (CCI).¹¹ A thorough evaluation of sociodemographic characteristics was also conducted, including recreational activities such as smoking history, alcohol usage, and regular physical exercise (defined as a minimum of 2 h/wk). Smoking habits were measured in pack-years and subsequently divided into 2 categories: nonsmokers (those who never smoked) and ex-smokers/current smokers. Alcohol consumption was likewise divided into abstainers (those who did not consume alcohol) and drinkers (those who consumed any amount per week). Body mass index (BMI), defined as weight in kilograms divided by the square of height in meters, was recorded for each patient. All participants completed the International Index of Erectile Function (IIEF) at baseline. ED severity was scored using the Cappelleri’s criteria, with severe ED identified as an IIEF erectile function domain (IIEF-EF) score ≤11.¹² Furthermore, all patients compiled the Beck Depression Inventory (BDI), with clinical depression defined as a BDI score ≥17. All patients were investigated for either primary or secondary concomitant premature ejaculation, as defined according to the widely applied classification criteria suggested by the International Society for Sexual Medicine.¹³ Primary psychogenic ED was defined according to the criteria outlined by the current Sexual and Reproductive Health Guidelines of the European Association of Urology.⁵

Each patient had total testosterone levels measured via a direct chemiluminescence immunoassay; venous blood samples were drawn between 7 am and 11 am after an overnight fast. Moreover, glycated hemoglobin along with complete blood count was collected for each patient. As for study protocol, blood analyses were performed by the same laboratory. According to our internal protocol, dynamic penile color doppler ultrasound (CDDU) was performed in every patient at baseline. Specifically, CDDU measurements were taken after 20 minutes from intracavernosal injection of alprostadil 20 μg and self-sexual stimulation. Pathological CDDU was defined with an average peak systolic velocity <35 cm/s.^14,15 The average CDDU values between corpora cavernosa have been eventually considered. Patients with pathological veno-occlusive mechanism were excluded (n = 1). The follow-up protocol for our cohort was designed with an initial 3-month assessment. Specifically, all patients who were re-evaluated 3 months after the initial consultation were included in the study in order to assess their response to the treatment and any potential side effects. Following this, the follow-up intervals were extended to every 6 months. To ensure that we captured comprehensive data, phone calls were integrated into the follow-up to account for instances in which in-person visits were not possible. Once the treatment goal was achieved, the decision to discontinue the treatment regimen was made (by the treating physician). Thereafter, participants were asked to fulfill the IIEF after the treatment discontinuation by reporting the actual date of questionnaire completion. From that point forward, if a patient maintained his erectile function (EF) after stopping the treatment at the time of the subsequent follow-up (IIEF >22), they were then considered a responder. This ensured to accurate calculation of the median time from treatment discontinuation to IIEF completion (thus, EF recovery). If such outcome was achieved, follow-up data collection was discontinued (Supplementary Figure 1).

For the specific purpose of this study, we only considered those under 50 years of age, with a baseline normal CDDU and who were prescribed tadalafil 5 mg OaD (n = 125).

Data collection followed the principles outlined in the Declaration of Helsinki; all patients signed an informed consent agreeing to provide their own anonymous information for future studies. The study was approved by the Institutional Review Board (Authorization Protocol URI 001-2010, further amended in December 2015 by the Ethic Committee IRCCS Ospedale San Raffaele, Milan, Italy).

Statistical analysis

Statistical analysis consisted of several steps. First, descriptive statistics were used to compare clinical and sociodemographic characteristics between responders and nonresponders. Median and interquartile range (IQR) or frequency and proportion were reported for continuous or categorical variables, respectively. The Mann-Whitney and chi-square tests were used to compare the statistical significance of differences in the distribution of continuous or categorical variables among patients of the 2 groups, respectively. Second, Cox regression hazard models tested the association between patients' baseline characteristics and the risk of EF recovery. Last, Kaplan-Meier analyses estimated the probability of EF recovery over time.

Results

Of 125, 29 (23.2%) patients were lost at follow-up. Consequently, the ultimate analyses were carried out on a group of 96 young ED patients for whom follow-up data were accessible. Table 1 details the descriptive statistics of the whole cohort and responder and nonresponder groups. Median tadalafil length of intake was 3 (IQR, 2-11) months. The median time from treatment discontinuation to IIEF-EF assessment was 1 (IQR, 0.4-2) months. The overall median follow-up was 7 (IQR, 4.4-13) months. The reported treatment-emergent adverse events (TEAEs) during treatment were headache in 9 (9.4%), transient myalgia in 1 (1%), and nasal congestion in 1 (1%) patient, respectively. No patients discontinued treatment because of these TEAEs.

Of all, 82 (85.4%) men exhibited spontaneous medication-free EF recovery after OaD tadalafil discontinuation, while 14 (14.6%) patients were classified as nonresponders. Overall, 42 (43%), 57 (60%), and 70 (72%) patients achieved spontaneous medication-free EF recovery at 3, 6, and 12 months, respectively. Tadalafil nonresponders were older (P = .03), had higher BMI (P = .04), had and lower baseline IIEF-EF scores (P = .02) as compared with tadalafil responders. No difference was observed between responders and nonresponders in terms of baseline severe ED (IIEF-EF <11), BDI scores, rates of CCI ≥1, smoking, alcohol consumption, serum total testosterone and glycated hemoglobin levels, average peak systolic velocity at CDDU, rates of TEAEs, overall treatment duration, and rates of premature ejaculation (Table 1).

At multivariate Cox regression analysis, younger age (P = .01) was associated with spontaneous EF recovery, after adjusting for baseline severe EF, BMI, CCI ≥1, and smoking status (Table 2).

Table 3 shows the Kaplan-Meier estimates pertaining to EF recovery following tadalafil OaD discontinuation. More in detail, the estimates of EF recovery at the 3-, 6-, and 12-month follow-up intervals were 43%, 60%, and 72%, respectively. Figure 1 graphically displays the cumulative probability of EF recovery over time after discontinuation of tadalafil 5 mg OaD.

Figure 1

Kaplan-Meier showing the estimated probability of spontaneous erectile function (EF) recovery over time after tadalafil once a day (OaD) discontinuation (cumulative probability).

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Discussion

The rate of young men presenting for ED compliant is relevant and significantly growing. Of all, many young men depict criteria suggestive for severe ED, mostly primary psychogenic in nature. Current real-life findings showed that almost half of young ED patients taking tadalafil 5 mg OaD for 3 months achieved medication-free EF recovery after treatment discontinuation. Even more interestingly, the efficacy of this regimen appeared to further improve beyond this initial time frame. Moreover, the younger the patient, the greater the chance of effective treatment success, thus demonstrating that age per se eventually plays a significant role in determining the likelihood of success in achieving spontaneous EF recovery after having received tadalafil 5 mg OaD.

The study also revealed that nonresponders were not only older, but also had higher BMI, and reported lower baseline IIEF-EF scores compared with tadalafil responders. This information could be helpful for healthcare professionals in identifying which patients are likely to benefit the most from tadalafil 5 mg OaD with the specific goal of subsequent discontinuation and tailoring treatment plans accordingly.

The scientific literature extensively showed the role of tadalafil in restoring EF across various contexts and situations. In this context, Brock et al¹⁶ conducted a comprehensive meta-analysis aiming to compare the EF response to tadalafil in on-demand and OaD dosing regimens across various clinical subpopulations, using the IIEF questionnaire as a parameter to define treatment outcomes. Their analysis, inclusive of men with common associated conditions, treatments, and risk factors for ED, revealed the effectiveness of tadalafil in both dosing regimens and at different doses.¹⁶ Notably, the study did not conclusively favor on-demand over OaD tadalafil within specific ED patient populations. However, it is important to acknowledge that their comparison involved varied ED etiologies and tadalafil doses, and lacked a detailed analysis of EF improvement over time and, more importantly, after tadalafil discontinuation. Additionally, other studies have explored daily tadalafil for ED treatment, with generally positive outcomes. In this context, in one of the original randomized clinical trials, Porst et al¹⁷ aimed to evaluate the effectiveness and safety of OaD tadalafil, administered at 2.5 mg and 5 mg, in patients presenting varying degrees of ED severity alongside with comorbid conditions. Irrespective of the dosage, their findings indicated that tadalafil OaD regimen was well tolerated and resulted in significant EF improvements. Specifically, individuals with mild ED witnessed improvement rates of 54.3% and 74.8% for the respective doses. Similarly, patients with moderate ED experienced enhancements at rates of 51.3% and 63.1%, respectively, while those with severe ED reported improvement rates of 33.7% and 44.5% for the 2.5 mg and 5 mg doses, respectively.¹⁷ As such, we found similar results at long-term follow-up; in fact, 72% of men achieved spontaneous EF recovery after 12 months of treatment. Similar findings were also reported by Karabakan et al,¹⁸ who investigated the efficacy of tadalafil 5 mg OaD across different domains (ejaculation time, EF, and lower urinary tract symptoms) on 60 patients. The authors found a significant improvement on all domains explored with specific emphasis on EF improvement.¹⁸ Although this holds true, in contrast to prior studies, our analysis reports the results specifically examining the persistence of spontaneous medication-free EF recovery after tadalafil OaD discontinuation. Indeed, we found that almost 85% of relatively young men with primary psychogenic ED maintained spontaneous medication-free adequate EF after tadalafil 5 mg OaD deliberated discontinuation. Thereof, our focus on young men with normal CDDU parameters, while intentionally excluding those with organic ED, stands out as a relatively new investigation in the field of sexual medicine. Indeed, our findings suggest that tadalafil 5 mg OaD in the context of psychogenic ED may be used as a valuable and effective “temporary” therapeutic approach, thus allowing to stop the drug after a limited period of time while having recovered adequate and satisfactory EF. Theoretically, this regimen would aid in “breaking” psychological barriers associated with primarily psychogenic ED, offering an effective solution for the restoration of a normal, medication-free EF.

The study is not without limitations. First, it is important to note that it was limited to a relatively small cohort of heterosexual sexually active men, which may restrict the generalizability of the results. Second, far from preconceptions of noninclusion, we are aware that current findings could be not effectively expandable to the non-White European ethnic groups, as well as to a nonheterosexual or nonbinary population. Third, we lack data on very long-term follow-up, as these patients might have a relapse of their ED even after several months of their treatment discontinuation. As such, the median follow-up time after treatment discontinuation could only be calculated up to the point when patients have been lost to follow-up, but not from the time since when they potentially experienced ED relapse and eventually had resumed treatment (any). This could potentially impact the accuracy of our findings. Fourth, we do not have the overall median follow-up of the cohort because we ceased patient follow-up after assessing their EF upon medication discontinuation. Fifth, although we have clearly followed the European Association of Urology guidelines on this matter,⁵ distinguishing between primary psychogenic and organic ED is challenging due to their frequent overlap. To reduce confounding factors, we focused on a younger cohort (under 50 years of age) and those with normal CDDU parameters. Sixth, we neither gathered nor analyzed data concerning the potential influence of psychotherapy on our patient cohort, knowing that this omission could have introduced relevant bias into our results. Last, the relatively small cohort size prevented us from segregating the participants into distinct categories based on the severity of their ED. Likewise, due to the limited sample size, we faced a potential deficiency in statistical power, which could have affected the strength of our exploratory analysis. Hence, while our study offers valuable insights, these limitations need to be taken into consideration upon interpretation of current results. Nonetheless, this is the first study investigating the performance of tadalafil 5 mg OaD in a cohort of young men with ED after treatment discontinuation, showing its efficacy over the management workup of this type of patients in a real-life setting. Specifically, considering that nearly half of the patients achieved medication-free EF recovery after discontinuing the use of tadalafil 5 mg OaD at the 3-month mark, we suggest an average treatment duration of at least 3 months. However, this recommendation should be interpreted with caution due to the aforementioned limitations. To validate these preliminary findings, further research involving a larger and more heterogeneous cohort is necessary.

Conclusions

This study indicates that approximately half of young patients with psychogenic ED achieved medication-free EF recovery after discontinuing tadalafil 5 mg OaD over a period of 3 months of therapy. These insights are essential for healthcare providers to more accurately identify the patients who are most likely to benefit from a temporary course of tadalafil 5 mg OaD, ultimately enhancing sexual spontaneity and overall patient satisfaction.

Acknowledgments

The authors express their gratitude to Mrs. April Dawn Mann, Director of The Writing Center at the University of Miami, Florida, USA, for her assistance in revising the manuscript's English.

Author contributions

E.P. (Conceptualization [Equal], Data curation [Equal], Formal analysis [Equal], Methodology [Equal], Project administration [Equal], Writing – original draft [Equal]). C.C. (Data curation [Equal]). A.B. (Data curation [Equal]), F.B. (Data curation [Equal]), M.R. (Data curation [Equal]), F.N. (Data curation), F.C. (Data curation [Equal]), S.C. (Data curation), L.B. (Data curation), P.C. (Data curation), A.D.(Data curation), R.R. (Supervision [Equal], Writing – review & editing [Equal]), F.M. (Supervision), A.S. (Conceptualization [Equal], Project administration [Equal], Supervision, Writing – review & editing).

Funding

None declared.

Conflict of interest

None declared.

References