Effects of 12 weeks of tadalafil treatment on ejaculatory and orgasmic dysfunction and sexual satisfaction in patients with mild to severe erectile dysfunction: integrated analysis of 17 placebo-controlled studies†
Darius A. Paduch,
Consulting Research Services, Inc., Red Bank, NJ
Department of Urology and Reproductive Medicine, Weill Cornell Medical College, New York, NY
What's known on the subject? and What does the study add?
Disorders of ejaculation and orgasm are common, even in men with only mild erectile dysfunction (ED).
Treatment with the phosphodiesterase type-5 inhibitor tadalafil was associated with improvements in ejaculatory and orgasmic function. Patients with residual ejaculatory or orgasmic dysfunction experience reduced sexual satisfaction. These findings need to be corroborated in further clinical trials involving men without ED.
To compare effects of tadalafil on ejaculatory and orgasmic function in patients presenting with erectile dysfunction (ED).
To determine the effects of post-treatment ejaculatory dysfunction (EjD) and orgasmic dysfunction (OD) on measures of sexual satisfaction.
Patients and Methods
Data from 17 placebo-controlled 12-week trials of tadalafil (5, 10, 20 mg) as needed in patients with ED were integrated.
EjD and OD severities were defined by patient responses to the International Index of Erectile Function, question 9 (IIEF-Q9; ejaculation) and IIEF-Q10 (orgasm), respectively.
Satisfaction was evaluated using the intercourse and overall satisfaction domains of the IIEF and Sexual Encounter Profile question 5.
Analyses of covariance were performed to compare mean ejaculatory function and orgasmic function, and chi-squared tests evaluated differences in endpoint responses to IIEF-Q9 and IIEF-Q10.
A total of 3581 randomized subjects were studied.
Treatment with tadalafil 10 or 20 mg was associated with significant increases in ejaculatory and orgasmic function (vs placebo) across all baseline ED, EjD, and OD severity strata.
In the tadalafil group, 66% of subjects with severe EjD reported improved ejaculatory function compared with 36% in the placebo group (P < 0.001).
Similarly, 66% of the tadalafil-treated subjects (vs 35% for placebo; P < 0.001) with severe OD reported improvement.
Residual severe EjD and OD after treatment had negative impacts on sexual satisfaction.
Limitations of the analysis include its retrospective nature and the use of an instrument (IIEF) with as yet unknown performance in measuring treatment responses for EjD and OD.
Tadalafil treatment was associated with significant improvements in ejaculatory function, orgasmic function and sexual satisfaction.
Proportions of subjects reporting improved ejaculatory or orgasmic function were ≈ twofold higher with tadalafil than with placebo.
These findings warrant corroboration in prospective trials of patients with EjD or OD (without ED).
IIEF intercourse satisfaction and overall satisfaction domains
last observation carried forward
Sexual Encounter Profile
Disorders of ejaculation (ejaculatory dysfunction [EjD]) and orgasm (orgasmic dysfunction [OD]) are frequent and bothersome yet under-reported male sexual difficulties [1-8]. Conversely, sexual satisfaction is positively correlated with the likelihood of orgasm in both men and women [9, 10]. Ejaculation is defined as expulsion of semen from the urethra. Orgasm is a subjective sensation of intense pleasure which typically, but not always, is associated with ejaculation. EjD includes a range of disorders such as premature ejaculation (PE), delayed ejaculation (DE), decreased volume and force of ejaculation, as well as inability to ejaculate (anejaculation). Inability to achieve orgasm (anorgasmia), regardless of the presence of ejaculation, or decreased intensity of pleasure (hyporgasmia) constitute disorders of orgasm.
Delayed ejaculation (prevalence = 0−11%) [5, 7, 11-14] is often highly bothersome. In the Multinational Survey of the Aging Male (MSAM-7), 46% of respondents reported reduced semen volume, 5% reported anejaculation, and 7% reported pain/discomfort on ejaculation . In our previous study, we showed that 15.6% of men reported poor orgasmic sensation despite normal ejaculatory function . A frequent absence of orgasm can result in relationship discord secondary to decreased physical and emotional satisfaction in men and their sexual partners [9, 16, 17]. Like erectile dysfunction (ED), both EjD and OD are potential sources of psychological distress, embarrassment or even shame for the male patient.
Phosphodiesterase type-5 (PDE-5) inhibitors have been evaluated as potential treatments for EjD, particularly PE [18-24]. However, much less is known about the effects of PDE-5 inhibitors on other forms of EjD and OD. A small open-label study including 30 male patients with infertility and sexual dysfunction (both PE and DE) showed improved ejaculatory function with sildenafil treatment .
Our group recently reported findings from a retrospective, integrated analysis of baseline data among >12 000 male subjects in clinical trials enrolling patients with ED . The analysis showed that only 36% of subjects with ED reported normal orgasmic function and 42% reported normal ejaculatory function. Although OD and EjD were increasingly likely across advancing ED severity strata, both conditions were common complaints, even in men with mild ED. The objective of the current analysis was to investigate the effects of 12 weeks of tadalafil treatment (vs placebo) on EjD and OD as well as sexual satisfaction in patients enrolled in ED trials.
Internal study identifiers with available ClinicalTrials.gov registration numbers were Study H6D-MC-LVDI (ClinicalTrials.gov identifier NCT00547495) and H6D-MC-LVDY (ClinicalTrials.gov identifier NCT00547573) (http://www.clinicaltrials.gov).
Patients and Methods
Details concerning study designs and populations in these trials have been published elsewhere, including in previous pooled-data analyses . All 17 studies were double-blind and evaluated the clinical efficacy of tadalafil for ED at baseline and every 4 weeks; primary endpoints for all studies were based on efficacy data collected at the 12-week visit. These trials evaluated as-needed dosing of tadalafil 5, 10 and 20 mg. Subjects were instructed to attempt coitus at least four times each month for the duration of the clinical trial.
There is no validated instrument to measure diverse dimensions of EjD and OD. As a result, in this exploratory study we used subject-reported ability to ejaculate (‘how often you ejaculated’) through intravaginal intercourse (question 9 [Q9]) and subject-reported feeling of orgasm (‘how often you felt orgasm regardless of the presence or lack of ejaculation’) (Q10) of the International Index of Erectile Function (IIEF) questionnaire . The IIEF was administered at each study visit, and a Sexual Encounter Profile (SEP) diary was completed by subjects after each sexual attempt. Table 1 summarizes the ways in which responses were categorized for analysis purposes.
Table 1. Categorization of patient responses IIEF-Q9a and IIEF-Q10b.
How categorized (severity of EjD or OD)
aIIEF-Q9: ‘Over the past 4 weeks, when you had sexual stimulation or intercourse, how often did you ejaculate?’
bIIEF-Q10: ‘Over the past 4 weeks, when you had sexual stimulation or intercourse, how often did you have the feeling of orgasm with or without ejaculation?’
No intercourse attempts
Sometimes/about half the time
Sexual satisfaction was assessed using both the intercourse satisfaction and overall satisfaction domains of the IIEF (i.e.IIEF-IS and IIEF-OS, respectively) as well as SEP question 5 (SEP5: ‘Were you satisfied overall with this sexual experience?’).
Central endpoints comprised mean changes from baseline in scores on the IIEF-Q9, IIEF-Q10, mean IIEF-IS, IIEF-OS and SEP5, as well as distributions of responses to IIEF-Q9 and IIEF-Q10 after 12 weeks of treatment for subjects with severe EjD or OD at baseline. For these patients with severe EjD or OD, endpoint responses of 1 or 2 to IIEF-Q9 or IIEF-Q10 were operationally defined as ‘no improvement’, whereas ‘improvement’ was defined as an endpoint IIEF-Q9 or IIEF-Q10 response of 3, 4 or 5.
The study population included all patients who were randomized and started study medication. For patients who discontinued, endpoint data were derived using the last-observation-carried-forward (LOCF) imputation rule. If, for a particular analysis and study patient, no post-baseline data were collected, that patient was not included in the analysis. Subjects with IIEF-Q9 or IIEF-Q10 responses of ‘0’ (no sexual activity) were not included in the corresponding analyses.
Analyses of covariance (ancova) models with effects for study, baseline and treatment group were used to evaluate differences in mean changes. Chi-squared tests were conducted to evaluate differences in categorical responses. All statistical tests were two-sided at α = 0.05. All analyses performed to support this disclosure were of a post hoc nature and did not control for multiplicity.
A total of 3581 subjects were randomized, including 1512 (42%) with severe EjD and 1812 (51%) with severe OD. The distributions of baseline EjD and OD severity were balanced across treatment groups. The mean (sd) age of study subjects was 54.9 (11.3) years, and the mean (sd) body mass index was 26.8 (4.2) kg/m2. Approximately half the population were Caucasian (50.9%) and 39.3% were of Asian descent (Table 2).
Table 2. Baseline demographic and clinical characteristics of all randomized subjects receiving placebo (or tadalafil 5, 10 or 20 mg) as needed. Data are presented as n (%) unless noted otherwisea.
Tadalafil (N = 2579)
Placebo (N = 1002)
Total (N = 3581)
aSome percentages do not add to 100 because of rounding.
Treatment with tadalafil was associated with a significant increase in ejaculatory function (vs placebo), as measured using the IIEF-Q9 (Fig. 1). In patients with severe EjD at baseline, treatment with tadalafil was associated with a significant least-squares (LS) mean increase in IIEF-Q9, in a dose-related manner: 1.6, 1.9 and 2.0 for tadalafil 5, 10 and 20 mg, respectively. There was a significant improvement in IIEF-Q9 in patients with moderate baseline EjD taking tadalafil 20 mg. In patients with minimal or no EjD at baseline, tadalafil treatment was associated with a reduced worsening of EjD compared with placebo (Fig. 1).
Likewise, significant LS mean increases in orgasmic function (vs placebo) were associated with tadalafil treatment (Fig. 2). In patients with severe OD at baseline, treatment with tadalafil was associated with a significant increase in the mean IIEF-Q10 score, in a dose-related manner: 1.3, 1.8 and 2.0 for tadalafil 5, 10 and 20 mg, respectively. Significant (but non-dose-related) improvements in patients with moderate OD, andsignificantly reduced worsening of orgasmic function in patients with minimal or no OD were also observed in tadalafil-treated groups (Fig. 2).
Irrespective of baseline ED severity, subjects randomized to each dose of tadalafil experienced significant improvement in ejaculatory and orgasmic function from baseline to study completion (P < 0.05 for each tadalafil dose vs placebo, except for the 5 mg dose for orgasmic function in patients with severe ED at baseline; Table 3).
Table 3. Least-squares mean changes from baseline to study endpoint (week 12 or LOCF) in IIEF-Q9 and IIEF-Q10 by treatment group and baseline severity of ED.
Significantly higher proportions of subjects with severe baseline EjD or OD who received tadalafil experienced improvements compared with those on placebo: approximately two-thirds with active treatment compared with one-third with placebo (Table 4). In the tadalafil group, 66% of subjects with severe baseline EjD reported improvement, compared with 36% in the placebo group (P < 0.001). Corresponding data in subjects with severe baseline OD were 66% of tadalafil-treated subjects reporting improvement compared with 35% in the placebo group (P < 0.001).
Table 4. Distribution of 12-week responses to IIEF-Q9a and IIEF-Q10b in subjects with severe baseline EjD or OD by treatment group. Data are presented as n (%) unless noted otherwise.
Tadalafil treatment was associated with significant increases in both SEP and IIEF measures of sexual satisfaction (vs placebo) (Figs 3, 4; Table 5). For instance, treatment with tadalafil 20 mg was associated with an LS mean increase in per-patient percent ‘yes’ responses to SEP5 of 19.2% among patients with severe EjD at study completion, 28.6% among those with moderate EjD, and 57.6% among those with mild or no EjD (P < 0.001 vs placebo for each). Corresponding data for OD after tadalafil 20 mg were LS mean increases of 20.5% among patients with severe OD at study completion, 30.5% among those with moderate OD, and 59.6% among those with minimal or no OD (P < 0.001 vs placebo for each).
Table 5. Least-squares mean changes from baseline to study endpoint (week 12 or LOCF) in IIEF satisfaction variables by treatment group and endpoint EjD or OD.
As-needed treatment group
Tadalafil 5 mg
Tadalafil 10 mg
Tadalafil 20 mg
*IIEF-IS is the mean of responses to IIEF-Q6−8; scores range from 0 [worst] to 15 [best]; IIEF-OS is the mean of responses to IIEF-Q13−14; scores range from 2 [‘very dissatisfied'] to 10 [‘very satisfied']. †P < 0.05 vs placebo.
To determine the differential effect of EjD and OD on responses to measures of sexual satisfaction, we compared mean scores across EjD and OD severity categories after 12 weeks of tadalafil therapy. In general, patients with severe EjD or OD who were treated with tadalafil 20 mg had endpoint means that were ≈ 20% lower than those of subjects with moderate EjD or OD on both the IIEF-IS and IIEF-OS domains. Similarly, patients with moderate EjD or OD had endpoint means that were ≈ 20% lower than those of patients with mild/no EjD or OD. Taken together, these consistent findings suggest that each increased degree of EjD or OD severity was associated with a 20% decrease in sexual satisfaction as measured by the IIEF-IS and IIEF-OS domains.
A similar evaluation of SEP5 responses suggested, for tadalafil 20 mg treatment groups (Figs 5, 6), a decrease of ≈30–40% in per-patient sexual satisfaction for an increase from moderate to severe EjD or OD; a decrement of ≈50% in satisfaction rates for an increase from no/mild to moderate EjD or OD; and a decline of ≈65% in satisfaction rates for an increase from no/mild to severe EjD or OD. These results indicated that residual EjD and OD significantly impaired sexual satisfaction.
Tadalafil was well tolerated in the base studies. The most frequent treatment-emergent adverse events (e.g. headache, dyspepsia, back pain) have been reported in previous pooled-data analyses .
Ejaculatory and orgasmic dysfunction were common at baseline in more than 3000 patients enrolled in international clinical trials of tadalafil for ED. Treatment with tadalafil 10 or 20 mg as needed was associated with significant improvement in ejaculatory and orgasmic function (vs placebo) from baseline to 12 weeks, irrespective of baseline ED, EjD or OD severity. Subjects who continued to experience severe EjD or OD at study completion reported less marked improvements in sexual satisfaction than those whose ejaculatory and orgasmic function improved. For each degree of increasing EjD and OD severity (from minimal/no to moderate; and from moderate to severe) after 12 weeks of therapy with tadalafil 20 mg, there was about a 20% mean decrease in sexual satisfaction on the IIEF-IS and IIEF-OS domains and a ≈40% decline in sexual satisfaction on SEP5.
On the basis of our exploratory analysis, approximately two of three subjects with severe EjD or OD at baseline experienced improvements in ejaculatory and orgasmic function after tadalafil treatment, compared with about one of three in the placebo group. Similarly, ≈70% of per-patient responses to SEP5 were ‘yes’ among subjects who received tadalafil 20 mg treatment and had minimal or no EjD or OD at study completion, compared with about 30% on placebo. Our observed placebo effect suggests that there is a subjective dimension to self-reported improvements in ejaculatory and orgasmic function (as well as in erectile function) among patients with ED who participated in tadalafil clinical trials. However, it is unclear at this point if other factors, such as hypogonadism, contributed to the observed placebo effect.
Magnitudes of improvements in self-reported ejaculatory function (IIEF-Q9) and orgasmic function (IIEF-Q10) were numerically greater in subjects with more severe EjD or OD at baseline. The observed LS mean increases in IIEF-Q9 and IIEF-Q10 scores of 2.0 after tadalafil 20 mg treatment in subjects with severe EjD or OD at baseline were consistent with a potentially clinically meaningful categorical improvement in the average patient, from a score of 1 (‘almost never/never’) to 3 (‘sometimes/about half the time’), with regard to ejaculation or orgasm after sexual stimulation.
Patients with moderate dysfunction experienced significant, but smaller and not dose-related, improvements with tadalafil (vs placebo). On the other hand, patients with minimal or no baseline EjD or OD, who had the least severe symptoms and hence the least room for improvement (i.e. ‘ceiling effect’), experienced worsening ejaculatory and orgasmic function with placebo, which was significantly blunted by tadalafil treatment.
One limitation of the present study is our use of an instrument with unknown performance to measure responses to treatment for EjD and OD. There is a general paucity of office-based patient self-reported and other subjective measures of male sexual function apart from erectile function. The Male Sexual Health Questionnaire has specific questions about ejaculatory and orgasmic function; however, it has not been fully validated. Clearly, there is a need for validated instruments to measure ejaculatory and orgasmic function.
The promising, but preliminary and hypothesis-generating, findings of the present study suggest that tadalafil could help to meet patient needs beyond the ability to improve erections, such as ejaculation, orgasm and sexual satisfaction, as well as helping to achieve reproductive aims, where ejaculatory difficulties are not secondary to irreversible organic factors. That residual EjD or OD after treatment for ED was associated with decreased sexual satisfaction suggests that improving (or restoring) ejaculatory or orgasmic function could constitute an important patient-related outcome beyond improving erectile function.
Potential mechanisms by which tadalafil might improve ejaculatory and orgasmic function need to accommodate the multifactorial (‘psycho-neuro-endocrine’ ) physiology of these variables and the complex aetiology of EjD and OD. At a biopsychosocial level, the use of the long-acting PDE-5 inhibitor tadalafil might permit a relaxed encounter and a prolonged period of intimacy (and lengthier sexual encounter), promoting ejaculation and orgasm by increasing the capacity for, and amount of, sexual stimulation and also heightening the male patient's sensitivity to internal cues to reach ejaculation and orgasm. This mechanism would be consistent with Rowland and co-workers' concept of inhibited ejaculation resulting from an uncoupling of a reduced subjective and largely maintained genital reaction in sexual arousal . In addition, patients with EjD (mainly PE) and OD who have received PDE-5 inhibitors have reported a greater sense of control over their erections as well as their ejaculatory and orgasmic functions [18, 29, 30]. At a physiological level, the key target of PDE-5 inhibitors' activities – the cyclic guanosine monophosphate (cGMP) second messenger of nitric oxide – plays a role in contractility of the male genital tract and could modulate central processing of neural inputs that facilitate orgasm.
It has not been shown that tadalafil crosses the blood–brain barrier; however, oral administration of tadalafil in animals has effects on the central nervous system . Thus, it is possible that the observed effects of tadalafil on EjD and OD result from tadalafil's action on neuromuscular regulation of ejaculatory and orgasmic function.
Further studies of patients with EjD or OD (who may or may not have ED) are necessary to conclude reliably that tadalafil exerts favourable effects on ejaculatory and orgasmic function that transcend its effects on erectile function. The concept (or ‘construct’) of sexual satisfaction is highly subjective and, at the time of writing, has not been conclusively linked to more objective, observable outcome variables. Although all 17 studies analysed herein involved as-needed treatment with tadalafil (or placebo), trials assessing once-daily tadalafil generated similar findings (data not shown).
A limitation of the present analyses is that they might have underestimated the degrees of ejaculatory and orgasmic dysfunction compared with men who do not seek medical attention for EjD until after they have experienced ED.
Furthermore, some potentially beneficial effects of tadalafil could have been indirect, and the present analysis could not control for all covariates. For instance, the effects of tadalafil on orgasmic function could have been partly secondary to the agent's effects on ejaculatory function because attention to, and cerebral processing of, pleasurable contractions of the male genital tract during ejaculation contribute to the development of orgasm; the intensity of orgasm could also be potentiated by the robustness of the emission and ejaculatory processes. Our study focused on tadalafil; however, a class effect of PDE-5 inhibitors cannot be ruled out. Further research is needed to clarify the physiological mechanisms of male ejaculation and orgasm in general, and the potential effects of PDE-5 inhibitors on these mechanisms in particular.
In conclusion, difficulties with ejaculation and orgasm were associated with reduced sexual satisfaction in this exploratory, retrospective, pooled-data analysis of patients enrolled in double-blind clinical trials of tadalafil for treating ED. Treatment with tadalafil was associated with significant increases in ejaculatory and orgasmic function (vs placebo), irrespective of baseline ED severity, and also with significantly increased sexual satisfaction. Residual (post-treatment) EjD or OD was associated with a decrease in patients' sexual satisfaction. These findings warrant corroboration in further prospective, placebo-controlled clinical trials involving patients presenting with ejaculatory or orgasmic dysfunction (with or without ED).
Assistance with manuscript preparation was provided by Stephen W. Gutkin, Rete Biomedical Communications Corp. (Wyckoff, NJ, USA), with support from Eli Lilly.
Conflict of Interest
The base studies, as well as the present analysis and report, were supported by Eli Lilly and Company (Indianapolis, IN, USA). DAP and AB are paid investigators and/or consultants/advisors/speakers for the study sponsor. PKP and SDW are employees of, and minor shareholders in, Eli Lilly.