Single-dose Tadalafil Reduces Opening Urethral Pressure: A Randomized, Double-blind, Placebo-controlled, Crossover Trial in Healthy Women

The serendipitous discovery of the effect of the selective phosphodiesterase type 5 (PDE5) inhibitor sildenafil on male erectile dysfunction in the late 1990s led to extensive research on the physiological actions of the PDE isoenzymes and the potential therapeutic utility of various pharmacological PDE inhibitors [1]. The main findings that have led to additional therapeutic indications include the subjective improvements of lower urinary tract (LUT) symptoms due to benign prostatic hyperplasia and increased walking distance in patients with pulmonary arterial hypertension [2, 3].

Phosphodiesterases constitute a superfamily of hydrolytic enzymes that degrade the second messengers cAMP and cGMP. Intracellularly, cAMP and cGMP trigger signaling pathways leading to a range of processes, including smooth muscle relaxation. Nitric oxide (NO) is pivotal in these pathways, mediating cGMP synthesis. PDE inhibitors enhance the NO-dependent smooth muscle relaxation by inhibiting PDEs [4].

To date, the most pronounced effects of PDE inhibition have been demonstrated in the male urogenital tract and consequently, most research activities have focused on new therapeutic applications for male LUT dysfunctions. Despite the knowledge of widespread PDE enzyme distribution in female urogenital tissues [5], little is known about the physiological effects on the female urogenital system and the potential effects of PDE inhibitors in women.

Preclinical studies suggest an important role of the NO/cGMP pathways in the regulation of the female urethral sphincter tonus [6, 7]; however, the outcomes are inconclusive. Although in vitro experiments on isolated female urethral muscle strips have suggested a smooth muscle relaxant effect of PDE5 inhibitors [5], an experimental study in anesthetized female rats found that intra-urethral administration of the PDE (type 1, 5, 6, and 9) inhibitor zaprinast increased the tone of the striated urethral sphincter and thereby the baseline urethral pressure [8]. Further, sildenafil did not improve sphincter relaxation compared with placebo in women with urinary retention due to abnormal urethral sphincter activity (Fowler’s syndrome) [9].

Considering the dense vascular plexus surrounding the female urethra, which contributes to the maintenance of the urethral pressure during the storage phase [10], selective PDE5 inhibitors may potentially potentiate the relaxation of vascular smooth muscle cells thereby increasing the volume of the vascular plexus and, as a result, increase the urethral pressure. Alternatively, as previously suggested, PDE inhibitors may induce relaxation of both the urethral smooth muscle and the striated external urethral sphincter, thereby potentially reducing urethral pressure.

Urethral pressure reflectometry (UPR) has emerged as a sensitive and reliable technique for assessing physiological parameters of urethral function. Its improved reproducibility compared with conventional urethral pressure profilometry allows for a more accurate investigation of pharmacodynamic changes in urethral pressure with fewer subjects [11].

To further elucidate the effect of PDE5 inhibitors on the female urethra, we used UPR to evaluate the effect of tadalafil, a PDE5 inhibitor, on opening urethral pressure in the resting state of the pelvic floor and during voluntary squeeze in healthy women. Additionally, we examined the effect of tadalafil on non-invasive urinary flow rates.

After receiving approvals from the regional ethics committee (H-2100186) and the Danish Medicines Agency (EudraCT number 2020–005839-76), this trial, registered at www.​ClinicalTrials.​gov (ID NCT05095077), was conducted at the Zelo Phase 1 Unit, Copenhagen University Hospital Bispebjerg and Frederiksberg. The trial adhered to International Council for Harmonization Good Clinical Practice (GCP) guidelines and relevant legislation, and was overseen by the GCP Unit at Copenhagen University Hospital.

Among 24 healthy female participants, this trial found that a single oral dose of 40 mg of tadalafil caused a reduction in OUP compared with placebo. This reduction in urethral pressure, which was observed during both resting and squeezing conditions of the pelvic floor, suggests that tadalafil induces some relaxation of the female urethral musculature. These results support the findings from preclinical studies linking NO, cGMP, and PDE5 immunoreactivity in smooth and striated muscle cells from female urethral tissue to urethral smooth muscle relaxant actions of PDE5 inhibitors [5, 6]. Recently, the findings of PDE5 expression in the female urethra were confirmed and further expanded by Rahardjo et al. [18]. They found that all PDE isoenzymes examined in their Western blot experiments (PDE 1, −2, −4, −5, −10, and −11) were expressed in female urethral tissue specimens. As tadalafil has demonstrated an inhibitory effect of both PDE5 and, to some extent, of PDE11 [19], the combined inhibition of these enzymes may mediate relaxation of the female urethra. Further, it remains unclear whether the decrease in urethral pressure is a result of tadalafil-induced PDE inhibition affecting the striated external sphincter, solely due to the relaxation of smooth muscle (potentially including both urethral and vascular smooth muscle), or a combination of these factors. However, the expression of neuronal nitric oxide synthase in the external urethral sphincter suggests that the NO/cGMP pathways might play a role in the regulation of the striated urethral sphincter tonus [6].

We did not find any increases in urinary flow rates as a response to tadalafil, an expected consequence of urethral pressure reduction. There are several potential explanations for this inconsistency. Differences in urinary flow rates were explorative outcomes and, therefore, power calculations were not performed. Furthermore, the trial involved healthy, young women presumably entering the trial with an unrestricted urinary flow. This implies that any potential increase in urinary flow associated with a urethral pressure reduction may not be readily anticipated in this group of healthy volunteers. Finally, tadalafil may also induce relaxation of the detrusor smooth muscle. This relaxation could counterbalance the decreased urethral resistance caused by the reduction in urethral pressure [20].

With the caveat that a single-dose trial in healthy individuals should be interpreted with caution, the reduction in urethral pressure induced by tadalafil may have a clinical impact. For women with urinary retention the treatment goal is to ensure adequate bladder emptying [21]. As previously noted, the concept of augmenting the relaxation of the urethral sphincter through PDE5 inhibition to obtain improved bladder emptying is not novel. In the clinical crossover trial by Datta et al., which examined the effect of 50 mg of sildenafil twice daily for a duration of 4 weeks to women with Fowler’s syndrome, the study found no significant differences in urinary flow rates or symptom scores when compared with placebo [9]. However, it is important to note that the design of this trial differs from the current trial in several critical aspects. First, we used tadalafil, which may exert other pharmacodynamic effects on the female urethra owing to the higher activity against PDE11 compared with sildenafil [19]. As previously noted, PDE11 appears to be highly expressed in the female urethral tissue, supporting the notion that tadalafil could exert urethral sphincter relaxation via PDE11 inhibition. Second, because the trials involved different groups of participants, it is uncertain whether the decrease in urethral pressure caused by tadalafil in healthy women would have the same effect in individuals with urinary retention. Finally, the primary outcomes were different, precluding meaningful direct comparisons. Overall, tadalafil might have a different effect on the female urethra than sildenafil, and the potential clinical impact for women with urinary retention or related voiding dysfunctions is intriguing. Long-term clinical trials in these populations would be required to further evaluate the clinical potential. However, the magnitude of urethral pressure reduction obtained in the current trial was relatively small, suggesting that the efficacy may be limited.

Although the majority of AEs that emerged in this study were anticipated side effects to tadalafil, transient and mild in severity, the frequency of these tadalafil-related AEs was higher than that in longer-term studies involving male participants with erectile dysfunction [22] and premenopausal women with sexual dysfunction [23]. This increased frequency might be attributed to the study design, which involved a single high dose of the drug. In contrast, the referenced studies employed lower doses over an extended period, where the AE frequency generally appeared to decrease [22].

In addition to the restricted generalizability of the study results owing to the healthy study population, other limitations need to be considered. First, the urethral pressure measurements were specifically conducted during the storage phase. Consequently, we are unable to directly infer the impact of tadalafil on the female urethra during the voiding phase. Furthermore, the single-dose—and single-outcome measurement design—provided only a snapshot of the pharmacodynamic profile of tadalafil. If the maximal plasma concentration in some of the participants was reached substantially earlier or later than the anticipated 2 h according to the summary of product characteristics [12], the urethral pressure recordings may not have captured the maximum effect of tadalafil. Nevertheless, we do not expect that the direction of the effect would change, only the magnitude of the effect. Indeed, the trial design is based on our experience from previous single-dose UPR studies with healthy participants, demonstrating that the drugs under investigation exhibited their maximum effect on urethral pressure very close to the estimated t_max [14, 24]. Finally, we did not include sonographic evaluation of post-void residuals as part of our assessment of voiding function. Instead, we standardized the bladder volume by emptying the bladder, followed by the instillation of 300 ml (2 × 150 ml) of saline. The immediate recording of voided volume allowed us to estimate any potential post-void residuals. Although the participants typically voided more than the instilled volume, with only four exceptions (ranging from 261 to 297 ml), we cannot completely rule out minor post-void residuals due to the continuous diuresis occurring during the time lapse between bladder drainage and voiding. Nevertheless, given our crossover study design and clear instructions to the participants to maintain consistent fluid intake on both clinic visits, we anticipate that any such residuals would not significantly affect our results. In fact, our findings indicated no statistically significant differences in voided volume between the clinic visits (-11 ml [CI -41 to 18.0, p = 0.4]).

To our knowledge, this is the first randomized, placebo-controlled trial assessing the effect of tadalafil on urethral pressure in women. A single-dose (40 mg) tadalafil resulted in a placebo-corrected reduction in the opening urethral pressure in healthy women both during the resting state and during voluntary contraction of the pelvic floor. This finding suggests that PDE5 (and to some extent PDE11) inhibition might induce relaxation of the female urethra. The clinical implication of this reduction remains to be elucidated.