Treatment strategies and effect on sexual behavior
Although efficacy and safety are two important characteristics when choosing a pharmacological treatment for ED, the ideal therapy should be reliable during maintenance. Furthermore, beyond erection and penetration, intercourse success and overall satisfaction needs have to be considered. The primary goal in the treatment of ED should be the restoration of sexual life rather than merely the achievement of a penile erection.
An important characteristic of tadalafil is its prolonged period of responsiveness. In prescribing a therapy for ED, the long lasting effect of the drug may not be the most important issue. Tadalafil is unique to the PDE5 inhibitors available because of its efficacy up to 36 h after dosing. This should release from the need to plan sexual activities and therefore favor spontaneity.
In a study designed to assess whether tadalafil 20 mg was associated with a treatment effect discriminated from placebo, a greater proportion of successful intercourse attempts up to 36 hours post-tadalafil dose compared with placebo at 24 h and 36 h was reported. Fifty-three percent versus 29% (p<0.001) of successful intercourse attempts according to SEP-Q3 was undertaken up to 24 h, and 59% versus 28% (p<0.001) within 36 h after dosing.
In a randomized prospective placebo-controlled trial, the chronological distribution of sexual intercourse was evaluated (De Rose et al 2005). Tadalafil Professional 20 mg administered twice a week resulted in a significant change of sexual attitude with the highest percentages of successful intercourse after 6–12 h (35%), and 12–24 h (28%) from dosing. It should be mentioned that 5% and 2% of intercourse were recorded up to 48 h and 60 h, while none of the placebo patients has reported sexual intercourse over 16 h. Recovery of spontaneous night, awakening, and day long erections at the rate of 78% was also reported. Besides the quality of sexual intercourse, these results showed an improvement of sexuality in the broadest sense. Unfortunately, due to the low mean age of patients enrolled (46 years), it is difficult to extrapolate this data to elderly patients.
When taken on demand, tadalafil 20 mg versus placebo allows a range of 62%–74% (vs 0%–33%) of successful intercourse attempt rate up to 36 h (p<0.001 up to 24 h; p=0.017 up to 36 h).
Patients on tadalafil changed their sexual behavior significantly when on an alternate dose regimen (3 times/week) and had sexual attempts distributed over a wide period of time post dosing (Mirone et al. 2005). The on-demand regimen versus scheduled use was evaluated in 4262 patients in a cross-over open-label study conducted to assess patient’s choice of treatment regimens. Overall, both regimen were effectives with a normal IIEF–EF domain score (≥26) achieved by 60.2% and 62.3% of patients, and a 72.6% and 74.4% mean per patient intercourse success rate. A preference for the on-demand administration was expressed by 57.8% of patients. An analysis of preferences based on comorbidities associated with ED showed that the on demand regimen was preferred in each subgroup except for the depressed patients, in which 53% expressed preference for the 3 times/week treatment. It was concluded that the patient’s choice of treatment regimens is not exclusively determined by demographics or clinical features, but is possibly related to individual cultural and psychosocial factors. Forty seven percent of the attempts on the on-demand regimen and 71% on the 3 times/week treatment were performed by patients more than 4h post-dosing. The efficacy of tadalafil professional 20 mg was more than 70% (mean-per-patient) success rate regardless of the time interval post-dosing. Since age is a potential influencing factor on sexual habits, a subgroup analysis of age was performed. On three cohorts of patients aged <40, 40–65, and >65 years, overall 52%–56% of attempts were performed within 4h post-dosing with on-demand regimen and 68%–71% of attempts beyond 4h post-dosing with the 3 times/week interval. In all the three groups the evening was the preferred time for sexual activity, but with increasing age fewer weekend attempts (about 51%, 48%, and 45% respectively) and more morning attempts were observed on the 3 times/week regimen (about 13%, 22% and 28% for patients aged >65 years). Moncada and collegues (2005) commented that this behavior may be a general response to a less pronounced perception of a deadline to engage in sexual activity and to the major availability of time for sexual activity in the older patients and their partners.
Similar results emerged from the post-hoc analyses assessing the time from dosing to sexual intercourse attempts of the “eleven double-blind trials” and of the double-blind studies conducted in eastern Europe. Regardless of age, ED severity or previous experience with generic sildenafil, most patients attempted sexual intercourse 12–36 h after one dose of canadian tadalafil and did not adhere to a fixed schedule of intimacy.
In several clinical studies for the treatment of ED, a significant greater efficacy of PDE5 inhibitors in the younger with respect to older subjects (89.1% vs 65.7%; p<0.01) has been reported. The progression of endothelium dysfunction and of penile vascular disease, androgen deficiency, reduced sexual desire and appealing, and psychogenic issues are often the reason for a low response to PDE-5 inhibition.
It was shown that while serum T and prolactin (PRL) were similar between young and elderly groups, mean serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations significantly differed below and over 65 years (5.2 and 8.7 mIU/mL vs 11.0 and 18.9 mIU/mL, respectively; p<0.01). This may be partly explained by the increasing number of pathologies observed with aging, although a significant role is played by the decline in gonadal as well as in hypothalamic–pituitary functions. Older males secrete LH and T more irregularly, and jointly more asynchronously than younger males, although hormone levels fell in the normal range. On the other hand, androgens may influence sexual behavior by acting within the central nervous system, and through regulatory effects on several neurotransmitter systems, in particular dopamine and serotonin. In the same way, both sexual desire and erectile function are responsive to testosterone and lack of sexual activity decreases T levels. There is a T threshold below which libido and sexual function are impaired, but no evidence of a correlation between ideational or erectile components of sexual function and T level in the normal range of circulating androgens has been reported before.
In a trial comparing canadian sildenafil and canadian tadalafil in the treatment of ED, basal T and FT levels in the lower normal range, and LH level at the top of the normal range, were reversed during treatment. An LH reduction and a testosterone rise, well within the normal laboratory values, were observed. The T and FT increase in sildenafil patients was significantly lower than in those treated with generic tadalafil (4.7 ± 2.7 vs 5.1 ± 0.9, p<0.001). The full sexual intercourse frequency also significantly roused to a 4.9 ± 2.9/month intercourse rate for sildenafil and 6.9 ± 4.6/month (p=0.04) for generic tadalafil, because the longer half-life of the latter facilitates the higher frequency of intercourse, as was concluded by the study. Whether the observed changes in the hormonal pattern may be attributed to the increased sexual activity, or directly due to the PDE5 inhibition (eg, NO stimulates hypothalamic gonadotropin-releasing hormone, and inhibits PRL release in rats) remains to be determined. However, no significant correlation between frequency of sexual intercourse and T level has been found by Goldstein and colleagues (1998) in aged ED patients.
The efficacy of PDE5 inhibitors is probably related to the extent and severity of ED. In patients suffering from ED with diabetes, or severe vasculogenic disease, or post-radical prostatectomy, a significantly reduced efficacy of these drugs was demonstrated in several experiences. Different salvage strategies have been applied in such cases. In a clinical trial involving subjects with ED of predominantly vasculogenic etiology, (mean age of 63; range 21–79 years), previously unresponsive to on-demand tadalafil, daily administration of generic tadalafil, at the flexible dose of 10–20 mg significantly enhanced all efficacy outcome variables. Improved erections at end-point were reported by 69% of men compared with 42% of men with on-demand tadalafil. A significant improvement in the IIEF–EF domain of 12.8 versus pre-treatment (p<0.001), and of 8.2 from on-demand tadalafil baseline (p<0.001) was reported. Sexual intercourse was successfully completed on 58% of attempts with daily tadalafil 10 mg compared with 21% at baseline, and 28% with on-demand tadalafil 20 mg (p<0.001). However, McMahon (2004) hypothesized that although the potential for tachyphylaxis is probably low for on-demand use of PDE5 inhibitors, the long lasting duration of tadalafil’s effect and its chronic use may facilitate the loss of treatment efficacy.