Abstract
Context
Erectile function is important for life satisfaction and often impaired in men with obstructive sleep apnea (OSA). Uncontrolled studies show that treating OSA with continuous positive airway pressure (CPAP) improves erectile function. Phosphodiesterase type 5 inhibitors (e.g., vardenafil) are the first-line therapy for erectile dysfunction (ED), but may worsen OSA.
Objective
To assess the effects of CPAP and vardenafil on ED.
Design
Sixty-one men with moderate-to-severe OSA and ED were randomized to 12 weeks of CPAP or sham CPAP, and 10 mg daily vardenafil or placebo in a two-by-two factorial design.
Main Outcome Measures
International Index of Erectile Function (primary end point), treatment and relationship satisfaction, sleep-related erections, sexual function, endothelial function, arterial stiffness, quality of life, and sleep-disordered breathing.
Results
CPAP increased the frequency of sleep-related erections, overall sexual satisfaction, and arterial stiffness but did not change erectile function or treatment or relationship satisfaction. Vardenafil did not alter erectile function, endothelial function, arterial stiffness, or sleep-disordered breathing, but did improve overall self-esteem and relationship satisfaction, other aspects of sexual function, and treatment satisfaction. Adherent CPAP improved erectile function, sexual desire, overall sexual, self-esteem, relationship, and treatment satisfaction, as well as sleepiness, and quality of life. Adherent vardenafil use did not consistently change nocturnal erection quality.
Conclusion
CPAP improves overall sexual satisfaction, sleep-related erections, and arterial stiffness. Low-dose daily vardenafil improves certain aspects of sexual function and did not worsen OSA. Adherent CPAP or vardenafil use further improves ED and quality of life.
This randomized controlled study investigating the effect of CPAP and a PDE-5 inhibitor on erectile function highlights the importance of identifying erectile dysfunction in patients with OSA.
The prevalence of erectile dysfunction (ED), the inability to attain or maintain penile erection sufficient for penetration, is present in ∼50% to 60% of men aged 40 to 70 years (1) and has been identified as an early warning sign for developing cardiovascular disease (2). Obstructive sleep apnea (OSA) is characterized by sleep fragmentation and intermittent blood oxygen desaturation from repetitive obstruction of the upper airway during sleep. An estimated 24% of men aged 30 to 60 years are affected by at least mild OSA, as defined by an apnea–hypopnea index (AHI) ≥5 (3). Furthermore, moderate to severe OSA is associated with an increased risk of cardiovascular disease and mortality (4) and sometimes occurs in the presence of hypogonadism, for which testosterone therapy may be considered (5, 6).
ED and OSA often coexist, with approximately half of men with one condition having the other (7–9). This association remains even after accounting for common risk factors such as obesity and increasing age and comorbidities such as diabetes, hypertension, depression, and cardiovascular disease (8), although one recent study in men aged 67 years or older did not concur (10). Possible mechanisms include a reduction of testosterone, interruption to sleep-related erections, or endothelial dysfunction (6, 9, 11–13). Previous research on the effect of continuous positive airway pressure (CPAP), the standard therapy for OSA, on ED are limited to studies that have been uncontrolled, inadequately controlled, or included study participants who did not have ED (14–19). A randomized sham-controlled study has not been previously reported and is needed because ED is a patient-reported outcome that is susceptible to the placebo effect. Furthermore, erectile and sexual function are greatly valued by many men, so compliance might be improved if CPAP could be unequivocally shown to improve ED. Although CPAP may increase testosterone in hypogonadal men with OSA, testosterone replacement therapy is usually still required, and in this circumstance, adherent CPAP to prevent worsening OSA is required (5, 20–22).
The first-line treatment of ED is phosphodiesterase type 5 (PDE-5) inhibitor, used on demand. However, the safety of PDE-5 inhibitors has been questioned in patients with OSA, with a small randomized controlled study in severe OSA reporting an increase in OSA severity with an on-demand dose of 50 mg sildenafil (23). Therefore, a lower daily dose could be an alternative treatment regimen in these patients, which requires further investigation. Vardenafil 10 mg daily has been successfully used to treat ED and is equivalent to on-demand therapy (24). In this randomized sham-controlled study, we assessed the effect of CPAP and a low daily dose of vardenafil given at night on sexual function in men with both OSA and ED, while also measuring sleep-related erections, endothelial function, arterial stiffness, hormone levels, quality of life, and sleep-disordered breathing, to investigate possible mechanisms underlying the two conditions. The nighttime dosing was to maximize effects on sleep, breathing, and nocturnal penile tumescence. We also evaluated the efficacy of CPAP and vardenafil on subjects who were adherent to each therapy because nonadherent therapy would not be expected to improve outcomes or unveil mechanisms.
Methods
Study design
The study was conducted at the Woolcock Institute of Medical Research (Sydney, New South Wales, Australia) and Monash Medical Centre Sleep Unit (Clayton, Victoria, Australia). This was a randomized controlled trial with a two-by-two factorial design allowing separate evaluation of the effects of CPAP vs sham CPAP and the PDE-5 inhibitor drug vardenafil vs placebo on erectile function in men with both OSA and ED. Men aged 18 to 65 years were included in the study if they had moderate to severe OSA [AHI ≥20 events/h and oxygen desaturation index ≥15 events/h (oxygen desaturation of ≥3%)], were CPAP naive, and had ED determined by a score <26 in the erectile function domain of the International Index of Erectile Function (IIEF) questionnaire. Full inclusion criteria are listed in the Supplemental Methods. We also prespecified definitions of adherence to CPAP as being usage ≥4 hours per night on average and, for vardenafil, ≥80% tablets taken over the duration of the 12-week study period.
This study protocol was approved by the Human Research Ethics Committee, Concord Repatriation General Hospital (Concord, New South Wales, Australia) and Monash Health Human Research Ethics Committee (Clayton, Victoria, Australia). All participants provided written informed consent. This was an investigator-initiated study, supported by the National Health and Medical Research Council, Australia (project grant 632833) and Bayer Pharma AG. Philips Respironics donated CPAP and sham CPAP equipment and Bayer Pharma AG donated vardenafil and matching placebo. Philips Respironics and Bayer Pharma AG were not involved in study conduct, data analyses, or manuscript preparation. All of the authors assure the accuracy and completeness of the data. The study is registered with the Australia New Zealand Clinical Trials Registry, (ACTRN12610000144011).
Randomization, allocation concealment, and blinding
Participants were randomized in a two-by-two factorial design to CPAP or sham, and vardenafil or placebo. Men were allocated on a 1:1:1:1 basis to CPAP + vardenafil, CPAP + placebo, sham + vardenafil, and sham + placebo. The randomization sequence was generated by computer program (the blockrand function in R) using random permuted blocks. Separate sequences were generated to achieve stratification by the two study centers. Printed cards allocating CPAP or sham were labeled sequentially by randomization number and placed in opaque, sealed envelopes by an individual independent of the study staff or investigators. CPAP machine preparation, download, and troubleshooting was performed by personnel separate to the study investigators and not involved in participant assessments. A trial pharmacist who was not otherwise involved with the study prepared the study medication (vardenafil or placebo) in identically appearing bottles labeled by randomization number using the generated allocation list. The participants and study investigators were blinded to treatment allocation (and adherence) for the duration of the trial.
OSA intervention
For participants allocated to receive real CPAP, the individual pressure requirement was determined via a minimum 3-night home autotitration using a Remstar Pro CPAP machine (Philips Respironics, Pittsburgh, PA). Participants then used the device at these settings at home for the remainder of the 12 weeks. Those participants allocated to receive sham CPAP completed the same procedure using a manufactured sham version of the Remstar Pro (Philips Respironics). Sham CPAP comprised an adapted machine and mask that ensured that the patient received subtherapeutic (<0.5 cm H2O) therapy but experienced all other facets of CPAP use. Compliance data were recorded by an internal clock within all real and sham CPAP machines and downloaded after the home titration and at each visit.
ED intervention
Participants received either 10 mg vardenafil hydrochloride trihydrate (Levitra; GlaxoSmithKline, Warren, NJ) or placebo (Bayer Schering, Berlin, Germany) for 12 weeks. Medication sufficient for a 4-week period was dispensed at baseline, week 4, and week 8 with any remaining tablets returned at the next visit. Participants were instructed to take one tablet daily 1 hour before attempting to fall asleep, regardless of their intention to attempt sexual activity. Returned tablets were counted to assess adherence with treatment.
End points
The prespecified primary end point was erectile function as measured by the IIEF questionnaire (25), which is a U.S. Food and Drug Administration–recognized patient-reported outcome. This was measured at 4, 8, and 12 weeks, with the measurement at 12 weeks being of primary interest. Objective secondary end points were sleep-related erection frequency using nocturnal penile tumescence monitoring (Rigiscan; Timm Medical Technologies, Chesterbrook, PA); endothelial function by brachial artery flow-mediated dilatation; peripheral arterial tonometry (EndoPAT; Itamar Medical Ltd, Caesarea, Israel); and arterial stiffness using peripheral arterial tonometry and pulse wave analysis (Sphymo-Cor; AtCor Medical, Sydney, New South Wales, Australia) (26). Other patient-reported secondary end points were measurements of sexual function and relationship quality using nonerectile domains of the IIEF and European Male Aging Study-Sexual Function Questionnaire (27) and Self-Esteem and Relationship Satisfaction (SERS) (28) questionnaires. General quality of life was assessed using Short-Form 36, mood using the Depression Anxiety Stress Scale (29), sleep-related quality of life by the Functional Outcome of Sleep Questionnaire (21), and sleepiness using the Epworth Sleepiness Scale (30). Treatment satisfaction was evaluated by the Erectile Dysfunction Index Treatment Satisfaction questionnaire (31). Luteinizing hormone, follicle-stimulating hormone, and total testosterone were measured as previously described (21).
Statistical analysis
A sample size of 50 was estimated to yield 80% power to detect either a 5.6-point improvement between interventions in the total IIEF score or a 2.3-point increase in the erectile function subscale of the IIEF with α set at 0.05, assuming standard deviations (SDs) of 6.8 and 2.8, respectively (15, 32). To allow for noncompletion, 61 subjects were recruited.
Statistical analysis was performed using SAS statistical package version 9.3 (SAS Institute, Cary, NC). The randomization code was broken only after all data were collected, then cleaned, and the database locked. Student t tests established any differences in groups at baseline. Data were analyzed using intention-to-treat principles and following established guidelines on factorial randomized controlled trials (33, 34). Briefly, mixed models were used with a repeated statement to account for outcomes with multiple observations within each subject under a compound symmetry covariance structure. Initially, the presence of noteworthy CPAP*drug*time and CPAP*drug interactions were excluded (Supplemental Table 1). Hence, subsequent analyses of the two interventions were performed separately with each model including treatment (either CPAP/sham or vardenafil/placebo), time (weeks 4, 8, and 12), and their interaction, with the difference between interventions at week 12 being of interest. General linear models were used to determine differences between treatments for outcome variables with a single observation. The baseline value of the outcome was included as a covariate in all models. Per-protocol analysis was then undertaken in the same manner to examine the influence of CPAP and vardenafil adherence on the effect of treatment. Preset criteria for adherent CPAP use (usage of at least 4 hours per night) and vardenafil use (at least 80% usage of medication) were used to define the per-protocol populations (35). Post hoc analyses of participants with severe ED (IIEF-ED score of 5 to 11) at baseline and those who improved four or more points on the IIEF-ED were also conducted. Data are presented as mean ± SD or between-group differences with 95% confidence intervals (CIs).
Results
Study participants
Between 1 May 2010 and 15 March 2013, 84 men were screened, and 61 men were randomized into the study. The flow of participants is shown in Supplemental Fig. 1. Six men withdrew from the study after randomization; therefore, 55 men completed both the CPAP and vardenafil studies. Baseline characteristics were similar between the treatment groups for both the intention-to-treat and per-protocol populations (Table 1).
Table 1.
Baseline Characteristics
| CPAP Arm | Vardenafil Arm | |||||||
|---|---|---|---|---|---|---|---|---|
| Intention-to-Treat Group | Per-Protocol Group | Intention-to-Treat Group | Per-Protocol Group | |||||
| CPAP (n = 31) | Sham CPAP (n = 30) | CPAP (n = 12) | Sham CPAP (n = 8) | Vardenafil (n = 30) | Placebo (n = 31) | Vardenafil (n = 21) | Placebo (n = 21) | |
| Age, y | 55.7 ± 7.7 | 52.6 ± 10.4 | 56.9 ± 6.7 | 54.9 ± 12.3 | 54.5 ± 9.5 | 53.8 ± 8.9 | 54.8 ± 9.2 | 55.7 ± 8.0 |
| Weight, kg | 101.0 ± 14.0 | 100.1 ± 18.0 | 99.7 ± 16.2 | 88.4 ± 16.6 | 100.7 ± 15.6 | 100.4 ± 16.5 | 101.0 ± 15.4 | 99.0 ± 16.6 |
| Body mass index, kg/m2a | 32.9 ± 4.2 | 32.7 ± 5.5 | 32.9 ± 4.4 | 29.7 ± 4.6 | 32.7 ± 4.6 | 32.9 ± 5.2 | 32.8 ± 4.5 | 32.5 ± 4.8 |
| Coexisting condition, n (%) | ||||||||
| Diabetes | 7 (23) | 4 (13) | 3 (25) | 1 (13) | 6 (20) | 5 (16) | 5 (24) | 4 (19) |
| Hypertension | 18 (58) | 14 (47) | 8 (67) | 2 (25) | 17 (57) | 15 (48) | 12 (57) | 12 (57) |
| Hyperlipidemia | 8 (26) | 8 (26) | 6 (50) | 3 (38) | 9 (30) | 7 (23) | 8 (38) | 6 (29) |
| Medication use, n (%) | ||||||||
| Statins | 6 (19) | 5 (17) | 5 (42) | 1 (13) | 7 (23) | 4 (13) | 6 (29) | 4 (19) |
| Antihypertensives | 15 (48) | 10 (33) | 8 (67) | 1 (13) | 13 (43) | 12 (39) | 9 (43) | 10 (48) |
| Medication for diabetes | 7 (23) | 4 (13) | 3 (25) | 1 (13) | 6 (20) | 5 (16) | 5 (24) | 4 (19) |
| Past smokers, n (%) | 25 (81) | 25 (83) | 9 (75) | 7 (88) | 25 (83) | 25 (81) | 17 (81) | 17 (81) |
| AHI, events/hb | 48.2 ± 26.9 | 44.0 ± 24.9 | 59.1 ± 28.5 | 37.8 ± 22.4 | 48.9 ± 26.8 | 43.4 ± 24.9 | 48.3 ± 20.1 | 44.1 ± 26.3 |
| Minimum SpO2, % | 77.3 ± 10.1 | 74.6 ± 11.2 | 77.1 ± 10.8 | 79.4 ± 13.1 | 74.8 ± 11.0 | 77.2 ± 10.3 | 73.6 ± 10.8 | 78.1 ± 9.1 |
| Oxygen desaturation index, events/h | 43.7 ± 30.9 | 44.5 ± 27.7 | 53.0 ± 36.4 | 41.7 ± 28.5 | 47.7 ± 30.6 | 40.9 ± 28.1 | 46.8 ± 23.8 | 41.1 ± 29.9 |
| Epworth sleepiness scale scorec | 10.3 ± 5.1 | 10.3 ± 4.4 | 8.8 ± 4.8 | 10.6 ± 3.9 | 10.4 ± 4.6 | 10.2 ± 5.0 | 12.0 ± 4.1 | 10.2 ± 4.6 |
| Testosterone, nmol/Ld | 10.2 ± 4.4 | 10.2 ± 2.9 | 10.5 ± 4.6 | 10.4 ± 4.1 | 9.6 ± 4.0 | 10.1 ± 4.1 | 10.8 ± 2.8 | 10.1 ± 4.4 |
| Luteinizing hormone, IU/Ld | 3.4 ± 1.9 | 4.1 ± 1.9 | 3.2 ± 1.6 | 3.7 ± 1.5 | 3.9 ± 2.0 | 3.7 ± 1.9 | 3.8 ± 2.2 | 3.9 ± 1.9 |
| Sex hormone-binding globulin, nmol/Ld | 30.1 ± 15.1 | 25.6 ± 10.3 | 33.0 ± 16.3 | 24.8 ± 10.0 | 27.0 ± 9.1 | 28.9 ± 16.3 | 27.8 ± 7.7 | 29.0 ± 16.3 |
| Calculated free T, pmol/Le | 216.0 ± 91.6 | 255.5 ± 138.3 | 211.4 ± 74.6 | 263.4 ± 188.3 | 251.4 ± 140.8 | 220.1 ± 89.5 | 251.6 ± 118.5 | 220.2 ± 99.5 |
| Relationship duration, y | 17.3 ± 13.5 | 17.2 ± 13.9 | 21.6 ± 12.3 | 21.6 ± 16.3 | 17.1 ± 14.0 | 17.4 ± 13.5 | 17.3 ± 13.3 | 18.1 ± 14.1 |
| Duration of ED, y | 6.0 ± 4.6 | 6.2 ± 5.5 | 5.1 ± 4.7 | 3.1 ± 2.4 | 6.0 ± 4.8 | 6.2 ± 5.4 | 5.3 ± 5.0 | 6.6 ± 6.1 |
| Sexual and erectile function, IIEF | ||||||||
| Overall scoref | 39.0 ± 14.9 | 30.0 ± 16.3 | 38.4 ± 15.0 | 25.4 ± 18.9 | 34.5 ± 16.2 | 34.6 ± 16.3 | 35.7 ± 17.3 | 31.0 ± 16.6 |
| Erectile function domaing | 14.3 ± 7.3 | 10.7 ± 7.4 | 14.3 ± 7.5 | 9.1 ± 8.1 | 12.7 ± 7.5 | 12.3 ± 7.7 | 13.3 ± 7.9 | 10.2 ± 7.2 |
| Severe EDh, n (%) | 12 (39) | 16 (53) | 5 (42) | 5 (63) | 13 (42) | 15 (50) | 8 (38) | 12 (57) |
Data are means ± SD unless otherwise indicated. There were no significant differences for any of the baseline characteristics (P > 0.05). Adherent CPAP group included participants who met prespecified adherence criteria of ≥4 h use per night.
Abbreviation: SpO2, arterial oxygen saturation.
The body mass index is the weight in kilograms divided by the square of the height in meters.
The AHI is the number of apnea and hypopnea episodes per hours of sleep time.
Scores on the Epworth sleepiness scale range from 0 to 24, with higher scores indicating more daytime sleepiness.
Hormone values are from a single morning sample.
Free testosterone was calculated by the Vermeulen equation.
Overall scores on the IIEF range from 6 to 75, with lower levels indicating lower sexual function, which includes sexual desire, erectile function and orgasmic function.
Scores on the Erectile Function domain range from 6 to 30, with lower scores indicating less erectile function and ED defined as being a score <26.
Severe ED defined as an IIEF-ED score 5 to 11 inclusive.
There was no difference in average CPAP use between the CPAP group (3.7 ± 2.5 hours/night) and the sham CPAP group (2.6 ± 2.2 hours/night; P = 0.09). The per-protocol population in the OSA intervention included 20 men (12 and 8 in the CPAP and sham CPAP groups, respectively) who met the prespecified adherence criteria. Treatment usage in the per-protocol population was 6.2 ± 0.9 hours/night for the CPAP group and 5.1 ± 1.2 hours/night for the sham CPAP group (P = 0.15). Similarly, medication adherence was not different between vardenafil (84.0%) and placebo (84.5%) (P = 0.92). The per-protocol population in the ED intervention was defined as taking ≥80% prescribed tablets, which was achieved by 42 men (21 in the vardenafil group and 21 in the placebo group; P = 0.99).
Compared with sham CPAP, CPAP effectively reduced the severity of OSA as measured by AHI in the intention-to-treat population [between-group difference of change from baseline: −41.6 events/h (95% CI −54.7 to −28.4); P < 0.001] and per-protocol population [−39.9 events/h (−65.9 to −14.0); P = 0.0006]. There were no changes in sleep duration or proportion of rapid eye movement (REM) sleep (all P > 0.28). Compared with placebo, vardenafil had no effect on AHI in either the intention-to-treat [between-group difference: 2.82 events/h (−11.3 to 17.0); P = 0.69] or per-protocol population analysis [5.5 events/h (−10.6 to 21.6); P = 0.49], nor were there any effects on any other sleep variable (data not shown).
Patient-reported erectile function (IIEF)
Compared with sham, CPAP did not improve erectile function as measured by the IIEF erectile function domain and the overall score, but did improve overall satisfaction in the intention-to-treat population (Table 2). There was no change in any other subjective measure of sexual function (Table 2 and Supplemental Table 2). In men who met the prespecified adherence criteria, adherent CPAP use improved the IIEF components of erectile function, sexual desire, as well as the overall score compared with sham CPAP (Table 2). Additional improvements were seen in self-esteem and sexual relationship satisfaction from the SERS and overall sexual function and distress due to sexual function from the European Male Aging Study-Sexual Function Questionnaire (Supplemental Table 2). Compared with placebo, vardenafil did not result in a statistically noteworthy improvement in either the erectile function domain or overall score of the IIEF (Table 3). Vardenafil reduced distress due to sexual functioning and improved the overall score in the SERS questionnaire. Adherence to vardenafil additionally improved confidence and self-esteem in relation to sexual function (Supplemental Table 3).
Table 2.
Effect of CPAP on Sexual Function
| Intention-to-Treat Group | Per-Protocol Group | |||||||
|---|---|---|---|---|---|---|---|---|
| CPAP (n = 29) | Sham CPAP (n = 26) | Difference (CPAP − Sham CPAP) [Mean (95% CI)] | P Value | CPAP (n = 12) | Sham CPAP (n = 8) | Difference (CPAP − Sham CPAP) [Mean (95% CI)] | P Value | |
| IIEF | ||||||||
| Overall score | ||||||||
| Baseline | 39.0 ± 14.9 | 30.0 ± 16.3 | 38.4 ± 15.0 | 25.4 ± 18.9 | ||||
| Week 12 | 43.3 ± 20 | 33.5 ± 20.1 | 4.3 (−4.6 to 13.2) | 0.34 | 48.6 ± 19.4 | 24.3 ± 17.3 | 14.6 (1.4–27.7) | 0.03 |
| Erectile function | ||||||||
| Baseline | 14.3 ± 7.3 | 10.7 ± 7.4 | 14.3 ± 7.5 | 9.1 ± 8.1 | ||||
| Week 12 | 16.3 ± 9.4 | 13.3 ± 9.4 | 0.9 (−3.3 to 5.1) | 0.68 | 18.7 ± 9.0 | 8.5 ± 8.3 | 6.1 (0.4–11.8) | 0.04 |
| Intercourse satisfaction | ||||||||
| Baseline | 6.8 ± 3.7 | 4.8 ± 4.0 | 7.0 ± 3.5 | 3.8 ± 4.2 | ||||
| Week 12 | 7.5 ± 4.9 | 5.1 ± 4.7 | 1.2 (−1.0 to 3.3) | 0.28 | 9.0 ± 4.3 | 3.6 ± 3.6 | 3.2 (−0.2 to 6.6) | 0.07 |
| Orgasmic function | ||||||||
| Baseline | 6.8 ± 2.9 | 4.6 ± 3.5 | 6.5 ± 2.9 | 3.5 ± 3.9 | ||||
| Week 12 | 6.8 ± 3.4 | 4.7 ± 3.7 | 0.9 (−0.8 to 2.7) | 0.29 | 7.6 ± 3.3 | 3.6 ± 3.7 | 1.9 (−0.7 to 4.5) | 0.14 |
| Overall satisfaction | ||||||||
| Baseline | 4.9 ± 2.3 | 3.8 ± 2.0 | 4.2 ± 2.1 | 3.8 ± 2.3 | ||||
| Week 12 | 6.2 ± 2.6 | 4.3 ± 2.5 | 1.3 (0.1–2.5) | 0.04 | 6.3 ± 2.7 | 3.4 ± 2.1 | 2.6 (0.8–4.4) | 0.01 |
| Sexual desire | ||||||||
| Baseline | 6.2 ± 1.6 | 6.1 ± 2.4 | 6.4 ± 1.2 | 5.3 ± 1.8 | ||||
| Week 12 | 6.6 ± 2.1 | 6.0 ± 2.4 | 0.5 (−0.4 to 1.4) | 0.28 | 7.1 ± 1.6 | 5.1 ± 2.0 | 1.7 (0.2–3.3) | 0.03 |
± values are raw means ± SD. Baseline values include all participants. The between-group differences are the mean differences at 12 weeks, adjusted for baseline values calculated using mixed-model analysis. Per-protocol group included participants who met prespecified adherence criteria of ≥4 h use per night.
Table 3.
Effect of Vardenafil on Sexual Function
| Intention-to-Treat Group | Per-Protocol Group | |||||||
|---|---|---|---|---|---|---|---|---|
| Vardenafil (n = 27) | Placebo (n = 28) | Difference (Vardenafil − Placebo) [Mean (95% CI)] | P Value | Vardenafil (n = 20) | Placebo (n = 21) | Difference (Vardenafil − Placebo) [Mean (95% CI)] | P Value | |
| IIEF | ||||||||
| Overall score | ||||||||
| Baseline | 34.5 ± 16.2 | 34.6 ± 16.3 | 35.7 ± 17.3 | 31.0 ± 16.6 | ||||
| Week 12 | 42.9 ± 22.0 | 34.3 ± 18.2 | 7.9 (−0.6 to 16.3) | 0.07 | 43.8 ± 22.6 | 35.0 ± 18.0 | 6.0 (−3.8 to 15.8) | 0.23 |
| Erectile function | ||||||||
| Baseline | 12.7 ± 7.5 | 12.3 ± 7.7 | 13.3 ± 7.9 | 10.2 ± 7.2 | ||||
| Week 12 | 17.1 ± 9.9 | 12.6 ± 8.6 | 3.7 (−0.3 to 7.6) | 0.07 | 17.8 ± 10.0 | 12.4 ± 8.5 | 3.3 (−1.3 to 7.9) | 0.15 |
| Intercourse satisfaction | ||||||||
| Baseline | 6.0 ± 3.8 | 5.7 ± 4.1 | 6.6 ± 3.9 | 4.9 ± 4.7 | ||||
| Week 12 | 7.5 ± 4.8 | 5.3 ± 4.8 | 1.7 (−0.3 to 3.8) | 0.10 | 7.3 ± 5.2 | 5.2 ± 5.1 | 1.0 (−1.4 to 3.4) | 0.42 |
| Orgasmic function | ||||||||
| Baseline | 5.7 ± 3.3 | 5.7 ± 3.5 | 5.9 ± 3.4 | 5.6 ± 3.9 | ||||
| Week 12 | 6.2 ± 3.7 | 5.4 ± 3.6 | 0.9 (−0.8 to 2.6) | 0.29 | 6.5 ± 4.0 | 5.9 ± 3.7 | 0.6 (−1.4 to 2.6) | 0.56 |
| Overall satisfaction | ||||||||
| Baseline | 4.2 ± 2.2 | 4.5 ± 2.2 | 4.0 ± 2.4 | 4.1 ± 1.7 | ||||
| Week 12 | 5.8 ± 3.2 | 4.8 ± 2.1 | 1.1 (−0.1 to 2.2) | 0.07 | 5.7 ± 3.0 | 5.0 ± 2.1 | 0.9 (−0.4 to 2.2) | 0.16 |
| Sexual desire | ||||||||
| Baseline | 5.9 ± 1.9 | 6.4 ± 2.1 | 5.9 ± 1.8 | 6.2 ± 2.4 | ||||
| Week 12 | 6.3 ± 2.1 | 6.3 ± 2.4 | 0.4 (−0.5 to 1.3) | 0.38 | 6.5 ± 2.1 | 6.7 ± 2.4 | 0.1 (−0.9 to 1.1) | 0.85 |
± values are raw means ± SD. Baseline values include all participants. The between-group differences are the mean differences at 12 weeks, adjusted for baseline values calculated using mixed-model analysis. Per-protocol group included participants who met prespecified adherence criteria of >4 h use per night.
Additionally, the linear effect of severity was assessed in the mixed model by the inclusion of a treatment*baseline severity interaction term. No impact of severity on the primary outcomes of IIEF and IIEF-ED at week 12 was observed between either CPAP and sham CPAP or vardenafil and placebo (all >0.16). Furthermore, there were no between-group differences in the subgroup of participants who had severe ED at baseline between CPAP and sham CPAP [IIEF: 4.85 (−9.33 to 19.02), P = 0.49; and IIEF-ED: −0.42 (−6.90 to 6.05), P = 0.90] or vardenafil and placebo [IIEF: 5.86 (−7.64 to 19.4), P = 0.39; and IIEF-ED: 2.80 (−3.27 to 8.86), P = 0.36]. We also found no differences in the number of people who reported a clinically important improvement (defined as an increase in ≥4.0 points) between CPAP and sham (14 vs 9; Fisher exact test, P = 0.41) or vardenafil and placebo (13 vs 10; P = 0.59).
Nocturnal penile tumescence
Nocturnal penile tumescence monitoring was successfully recorded on 28 men who agreed to undertake this procedure (CPAP: n = 15; sham CPAP: n = 13; vardenafil: n = 15; placebo, n = 13). CPAP increased the number of sleep-related erections compared with sham CPAP [between-group difference: 1.7 (95% CI 0.5 to 2.9); P = 0.007] in this group, but did not change any parameters of tumescence or rigidity (Table 4). Vardenafil did not significantly increase the number of sleep-related erections compared with placebo or any other measures of tumescence and rigidity (Table 4).
Table 4.
Effect of CPAP and Vardenafil on Nocturnal Penile Tumescence
| CPAP (n = 15) | Sham CPAP (n = 13) | Difference (CPAP − Sham CPAP) [Mean (95% CI)] | P Value | |
|---|---|---|---|---|
| Number of erections | ||||
| Baseline | 2.68 ± 1.92 | 2.47 ± 2.32 | ||
| Week 12 | 4.13 ± .03 | 2.38 ± 1.76 | 1.71 (0.51–2.92) | 0.007 |
| Tip RAU | ||||
| Baseline | 26.11 ± 27.78 | 21.72 ± 20.55 | ||
| Week 12 | 45.7 ± 45.2 | 47.0 ± 54.7 | −3.73 (−44.56 to 37.10) | 0.85 |
| Tip TAU | ||||
| Baseline | 19.53 ± 19.26 | 19.67 ± 20.13 | ||
| Week 12 | 33.6 ± 34.3 | 36.4 ± 47.0 | −8.50 (−41.97 to 24.98) | 0.60 |
| Base RAU | ||||
| Baseline | 33.53 ± 29.34 | 46.28 ± 62.67 | ||
| Week 12 | 68.2 ± 58.5 | 57.0 ± 58.6 | 1.07 (−41.78 to 43.93) | 0.96 |
| Base TAU | ||||
| Baseline | 27.74 ± 31.12 | 34.33 ± 42.82 | ||
| Week 12 | 41.6 ± 39.9 | 49.2 ± 67.8 | −20.94 (−66.43 to 24.55) | 0.35 |
| Vardenafil (n = 15) | Placebo (n = 13) | Difference (Vardenafil − Placebo) [Mean (95% CI)] | P Value | |
| Number of erections | ||||
| Baseline | 3.00 ± 2.09 | 2.24 ± 2.10 | ||
| Week 12 | 3.40 ± 2.10 | 3.23 ± 2.13 | −0.17 (−1.58 to 1.25) | 0.81 |
| Tip RAU | ||||
| Baseline | 25.18 ± 22.60 | 22.95 ± 26.19 | ||
| Week 12 | 58.87 ± 58.05 | 31.77 ± 31.85 | 32.61 (−5.71 to 70.93) | 0.09 |
| Tip TAU | ||||
| Baseline | 20.18 ± 17.84 | 19.10 ± 21.10 | ||
| Week 12 | 48.47 ± 48.57 | 19.23 ± 18.48 | 27.22 (−4.37 to 58.80) | 0.09 |
| Base RAU | ||||
| Baseline | 49.00 ± 63.74 | 31.85 ± 29.08 | ||
| Week 12 | 82.73 ± 66.79 | 40.23 ± 35.34 | 39.29 (−0.22 to 78.81) | 0.05 |
| Base TAU | ||||
| Baseline | 30.53 ± 31.33 | 31.30 ± 41.86 | ||
| Week 12 | 63.87 ± 65.29 | 23.54 ± 23.94 | 38.16 (−4.49 to 80.81) | 0.08 |
± values are raw mean ± SD. Baseline values include all available participants. The between-group differences are the mean differences at 12 weeks, adjusted for baseline values calculated using general linear models. Boldface denotes statistically significant difference.
Abbreviations: RAU, rigidity activity units; TAU, tumescence activity units.
Reproductive hormones
Baseline testosterone levels spanned the lower part of the normal young adult reference range (10.2 ± 3.7 nmol/L). Neither CPAP nor vardenafil increased testosterone, luteinizing hormone, follicle-stimulating hormone, prolactin, or sex hormone-binding globulin in either the intention-to-treat (all P > 0.22) or per-protocol populations (all P > 0.06).
Vascular function
CPAP significantly improved arterial stiffness measured using pulse wave analysis and peripheral arterial tonometry (both P < 0.05). In contrast, there was no change in either macrovascular or microvascular endothelial function, as measured by flow-mediated dilatation and peripheral arterial tonometry, respectively (Table 5). In the per-protocol population, similar results were observed in both the peripheral arterial tonometry measures; however, the effects on flow-mediated dilatation and pulse wave analysis were not reported due to insufficient numbers (Table 5).
Table 5.
Effect of CPAP on Vascular Function
| Intention-to-Treat Group | Per-Protocol Group | |||||||
|---|---|---|---|---|---|---|---|---|
| CPAP | Sham CPAP | Difference (CPAP − Sham CPAP) Mean (95% CI) | P Value | CPAP | Sham CPAP | Difference (CPAP − Sham CPAP) Mean (95% CI) | P Value | |
| Endothelial function | ||||||||
| Peripheral arterial tonometry | n = 24 | n = 21 | ||||||
| Reactive hyperemia index | n = 12 | n = 4 | ||||||
| Baseline | 2.0 ± 0.6 | 2.0 ± 0.6 | 2.0 ± 0.8 | 2.0 ± 0.8 | ||||
| Week 12 | 1.9 ± 0.5 | 2.1 ± 0.7 | −0.2 (−0.5 to 0.2) | 0.36 | 2.2 ± 0.6 | 2.1 ± 0.6 | 0.0 (−0.2 to 0.1) | 0.54 |
| Flow-mediated dilatation | n = 11 | n = 14 | ||||||
| Brachial diameter, mm | a | |||||||
| Baseline | 4.7 ± 0.5 | 4.1 ± 0.9 | ||||||
| Week 12 | 4.7 ± 0.6 | 4.3 ± 0.8 | −0.1 (−0.5 to 0.3) | 0.46 | ||||
| Dilatation, % | a | |||||||
| Baseline | 6.5 ± 3.5 | 7.0 ± 3.3 | ||||||
| Week 12 | 5.6 ± 2.6 | 7.3 ± 2.1 | −1.4 (−3.4 to 0.6) | 0.15 | ||||
| Arterial stiffness | ||||||||
| Peripheral arterial tonometry | n = 27 | n = 21 | n = 12 | n = 4 | ||||
| Augmentation index, at 75 bpm | ||||||||
| Baseline | 13.7 ± 14.7 | 12.0 ± 14.5 | 15.9 ± 16.4 | 6.9 ± 24.0 | ||||
| Week 12 | 7.3 ± 12.6 | 11.3 ± 15.1 | −6.0 (−10.6 to −1.4) | 0.01 | 5.8 ± 15.3 | 10.0 ± 30.9 | −14.9 (−26.8 to −2.9) | 0.02 |
| Pulse wave analysis | n = 23 | n = 17 | ||||||
| Augmentation index, at 75 bpm | ||||||||
| Baseline | 23.1 ± 7.1 | 21.6 ± 7.8 | a | |||||
| Week 12 | 18.7 ± 7.3 | 24.1 ± 8.6 | −6.4 (−9.3 to −3.6) | <0.0001 | ||||
| Time to reflection, ms | a | |||||||
| Baseline | 145.6 ± 10.5 | 148.3 ± 12.8 | ||||||
| Week 12 | 149.7 ± 13.0 | 148.2 ± 18.0 | 6.1 (0.3–12.0) | 0.04 | ||||
± values are raw means ± SD. Baseline values include all participants. The between-group differences are the mean differences at 12 weeks, adjusted for baseline values calculated using general linear models. Per-protocol group included participants who met prespecified adherence criteria of ≥4 h use per night.
Abbreviation: bpm, beats per minute.
Effects on flow-mediated dilatation and pulse wave analysis were not reported in per-protocol group because of insufficient numbers.
Vardenafil did not affect any measure of vascular function in either the intention-to-treat or per-protocol analyses (Table 6).
Table 6.
Effect of Vardenafil on Vascular Function
| Intention-to-Treat Group | Per-Protocol Group | |||||||
|---|---|---|---|---|---|---|---|---|
| Vardenafil | Placebo | Difference (Vardenafil − Placebo) [Mean (95% CI)] | P Value | Vardenafil | Placebo | Difference (Vardenafil − Placebo) [Mean (95% CI)] | P Value | |
| Endothelial function | ||||||||
| Peripheral arterial tonometry | n = 21 | n = 24 | ||||||
| Reactive hyperemia index | n = 18 | n = 18 | ||||||
| Baseline | 1.9 ± 0.5 | 2.1 ± 0.7 | 2.0 ± 0.6 | 2.2 ± 0.7 | ||||
| Week 12 | 2.1 ± 0.7 | 2.0 ± 0.5 | 0.2 (−0.1 to 0.5) | 0.20 | 2.1 ± 0.6 | 2.0 ± 0.5 | 0.1 (−0.2 to 0.4) | 0.48 |
| Flow-mediated dilatation | n = 11 | n = 14 | n = 10 | n = 11 | ||||
| Brachial diameter, mm | ||||||||
| Baseline | 4.4 ± 0.8 | 4.4 ± 0.8 | 4.3 ± 0.8 | 4.5 ± 0.9 | ||||
| Week 12 | 4.5 ± 1.0 | 4.5 ± 0.6 | −0.1 (−0.4 to 0.3) | 0.71 | 4.5 ± 1.0 | 4.7 ± 0.6 | −0.1 (−0.5 to 0.3) | 0.60 |
| Dilatation, % | ||||||||
| Baseline | 7.9 ± 3.7 | 5.7 ± 2.6 | 8.4 ± 3.5 | 5.1 ± 2.4 | ||||
| Week 12 | 6.5 ± 2.7 | 6.6 ± 2.3 | −0.8 (−2.9 to 1.3) | 0.45 | 6.4 ± 2.9 | 6.7 ± 2.6 | −1.4 (−4.0 to 1.2) | 0.28 |
| Arterial stiffness | ||||||||
| Peripheral arterial tonometry | n = 24 | n = 24 | n = 18 | n = 19 | ||||
| Augmentation index, at 75 bpm | ||||||||
| Baseline | 8.2 ± 13.8 | 17.8 ± 13.8 | 7.9 ± 11.9 | 20.9 ± 14.4 | ||||
| Week 12 | 4.6 ± 12.4 | 13.5 ± 13.9 | 1.1 (−4.6 to 6.8) | 0.69 | 6.4 ± 12.9 | 14.1 ± 15.5 | 3.0 (−3.2 to 9.2) | 0.33 |
| Pulse wave analysis | n = 21 | n = 19 | ||||||
| Augmentation index, at 75 bpm | n = 17 | n = 16 | ||||||
| Baseline | 22.2 ± 8.5 | 22.7 ± 6.2 | 23.0 ± 8.9 | 23.1± 6.5 | ||||
| Week 12 | 19.8 ± 8.9 | 22.1 ± 7.4 | −1.2 (−4.8 to 2.3) | 0.49 | 21.0 ± 8.7 | 21.8 ± 7.7 | −0.8 (−4.8 to 3.2) | 0.68 |
| Time to reflection, ms | ||||||||
| Baseline | 149.0 ± 14.1 | 144.4 ± 7.7 | 148.0 ± 15.7 | 143.7 ± 8.2 | ||||
| Week 12 | 151.5 ±15.2 | 146.2 ± 14.9 | 0.3 (−5.9 to 6.4) | 0.93 | 150.1 ± 16.0 | 146.7 ± 16.2 | −0.48 (−7.53 to 6.57) | 0.89 |
± values are raw means ± SD. Baseline values include all available participants. The between-group differences are the mean differences at 12 weeks, adjusted for baseline values calculated using general linear models. Per-protocol group included participants who met prespecified adherence criteria of at least ≥80% tablets taken over the duration of the 12-week study period.
Abbreviation: bpm, beats per minute.
Quality of life
In the intention-to-treat population, CPAP did not alter the overall score for Short-Form 36, Functional Outcome of Sleep Questionnaire, or the depression, anxiety, or stress domains of the Depression Anxiety Stress Scales compared with sham CPAP. In the per-protocol population, CPAP decreased sleepiness [between-group mean difference: −3.5 (95% CI −5.8 to −1.2); P = 0.004], stress [−5.8 (−11.0 to −0.5); P = 0.03], and depression [−5.8 (−11.0 to −0.7); P = 0.03]. There were no improvements seen in sleepiness, quality of life, or mood with 12 weeks of vardenafil compared with placebo in either analysis (data not shown).
Treatment satisfaction
At 12 weeks, there was no difference in treatment satisfaction between participants allocated to CPAP and sham CPAP [Erectile Dysfunction Index Treatment Satisfaction questionnaire score: 8.94 (95% CI −3.4 to 21.3); P = 0.15]. However, in the per-protocol population, satisfaction was greater with CPAP compared with sham [24.4 (6.5 to 42.3); P = 0.009]. Participants who received vardenafil reported greater treatment satisfaction compared with those who received placebo in both the intention-to-treat [23.2 (11.7 to 34.6); P = 0.0001] and per-protocol [23.1 (9.8 to 36.3); P = 0.0009] groups.
Discussion
This randomized sham-controlled study investigated the effect of CPAP and vardenafil on erectile function in men with both OSA and ED. Using a factorial two-by-two, randomized, controlled trial design, this study shows that CPAP improves sexual satisfaction, increases the number of sleep-related erections, and reduces arterial stiffness, but not patient-reported erectile function. However, erectile function improved in men who adhered to treatment, as did overall sexual function, sexual desire, treatment satisfaction, self-esteem and relationships, and sleepiness. Continuous lower-dose vardenafil did not alter erectile function and did not consistently improve sleep-related erectile tumescence and rigidity, but did increase treatment satisfaction as well as self-esteem and confidence in those adherent to medication. Vardenafil did not worsen sleep-disordered breathing.
In our study, overall, CPAP did not improve erectile function as measured by the gold standard patient-reported outcome, IIEF; however, there were improvements with objectively measured erectile function during sleep and subjective satisfaction with sexual function. Previous studies have shown an improvement in IIEF; however, design limitations include a lack of control group or adequate sham control (14, 15, 17, 18), which may have overestimated the treatment effect. Given the subjective nature of the outcome, sham controls are essential. Nocturnal erections have been proposed to have a role in maintaining erectile function (36–38), and hence improvements may precede any daytime effects on the latter. Our finding that the number of erections increased for the participants who undertook this monitoring may support this. The duration of REM sleep, the stage of sleep when nocturnal erections occur, did not change after treatment, which suggests REM duration is not a determining factor. Testosterone and gonadotropins also did not change, possibly due to no effects on REM.
Vardenafil increased the main outcome of IIEF-EF score by four points; however, this was not a statistically meaningful change. The change observed in this study is comparable to a previous randomized controlled trial using a once-daily regimen with the same drug and dose in comparison with on-demand dosing (24). In this study, on-demand and daily vardenafil dosing had comparable effects on IIEF-EF. A meta-analysis of vardenafil studies using on-demand doses between 5 and 20 mg reported increases in the IIEF-EF domain by a mean of 6.2 points (39). Other studies support the efficacy of continuous rather than on-demand dosing of vardenafil (40). Our own data showed nonsignificant increases in nocturnal tumescence and rigidity with vardenafil. Therefore, the lack of change observed in our current study suggests that men with OSA may be partly resistant to low-dose continuous PDE-5 inhibitor use because none of the studies using a once-daily dose formally defined or reported whether patients had or were treated for OSA. As the safety of PDE-5 inhibitor use in OSA has been called into question (41, 42), it is important to understand whether a lower daily dose is both efficacious and safe in this patient population. Parameters of sleep-disordered breathing were not worsened in this study. Furthermore, the increase in the IIEF-EF domain would be considered clinically relevant, albeit on the lower end of the spectrum (43). Nevertheless, our study supports the safety but cannot confirm the efficacy of a lower daily dose of vardenafil in patients with both OSA and ED. In clinical practice, the dose of a PDE-5 inhibitor would be maximized, if the clinical response were unsatisfactory.
We did not show a change in endothelial function measured by flow-mediated dilatation or peripheral arterial tonometry with either vardenafil or CPAP. The lack of an effect with CPAP thus does not support the proposed mechanistic link involving endothelial dysfunction between OSA and ED, which has been postulated by us and others (9). Positive effects of CPAP have been reported in randomized trials in populations not selected for ED; however, we might have expected enhanced effects from our population of patients with ED (9). Potentially, the smaller numbers for which these outcomes were available may have reduced statistical power. Considering other potential mechanisms for the improvement in ED, we found CPAP decreased arterial stiffness but did not increase serum testosterone. Improvements in arterial stiffness with CPAP were seen using two independent measurements in both the intention-to-treat and per-protocol group. The reduction in the augmentation index we found of 6.4% is similar to a previous randomized sham-controlled study that reported a decrease of 5.4% in men with OSA, but not assessed for ED (44).
A study limitation was that only ∼40% of participants met the prespecified adherence criteria (i.e., ≥4 h/night on average) to allow inclusion in the CPAP per-protocol analysis. Suboptimal adherence to CPAP may have limited the effect seen with treatment; however, this adherence rate is comparable to other sham-controlled studies and would be representative of real-world practice in a general OSA population (45). For this reason, a per-protocol analysis to unveil mechanisms was an important part of the statistical analysis plan. In fact, overall satisfaction and improved arterial stiffness were numerically greater in magnitude in those who were adherent to CPAP compared with the group unselected for adherence. These data provide evidence that 4 hours of CPAP use is sufficient to improve erectile function in men with OSA, also presenting with ED, supporting similar data for improving sleepiness and vascular function in men with OSA. In contrast, 75% of patients were adherent with medication, which most likely explains the lack of difference between the intention-to-treat and per-protocol analyses for the vardenafil study. Furthermore, we report unadjusted P values for our secondary end points, and therefore, the effect of multiple comparisons should be considered when interpreting these results. We also did not investigate any synergistic effects of CPAP and vardenafil treatment because the recruitment target to be adequately powered to detect an interaction between treatments would have made the trial impractical. A future trial will be required to address this issue. Despite this, we have undertaken this study to understand the individual effects of vardenafil and CPAP in men with OSA and ED.
This study demonstrates that CPAP improves sexual satisfaction, increases the number of sleep-related erections, and reduces arterial stiffness. Additionally, adherent CPAP use was associated with further improvements in erectile and sexual function, as well as quality of life. These data may convince some men who highly value erectile function to adhere to CPAP therapy. Using vardenafil for treatment of ED in this population does not worsen sleep-disordered breathing and may result in clinically important improvements in sexual function, but remains costly and does not seem to have the broad range of benefits that we unveiled for CPAP use. Alternative interventions addressing both OSA and ED, including weight loss, will need to be explored.
Supplementary Material
Acknowledgments
We thank Paul Williams (Royal Prince Alfred Hospital Endocrine Laboratory), Farid Saad (Bayer), Bill Hardy (Philips Respironics), and the physicians, sleep technicians, research assistants, and CPAP therapists at the Woolcock Institute of Medical Research, Royal Prince Alfred Hospital Sleep Disorders Unit, and Monash Medical Centre Sleep Unit. We also thank the men who participated in the study.
Financial Support: This work was supported by the National Health and Medical Research Council Australia (Project Grant 632833) and fellowships to K.L.M., C.M.H., R.R.G., and P.Y.L. (633166, 1104003, 202916, and 1025248, respectively). P.Y.L. is supported by the National Institutes of Health (Grants R01-HL-124211 and UL1-TR-001881). Philips Respironics supplied CPAP and sham CPAP machines. Trial medication, placebo, and financial support were provided by an investigator-initiated grant from Bayer Pharma AG.
Clinical Trial Information: ANZCTR.org.au no. ACTRN12610000144011 (registered 12 February 2010).
Author Contributions: K.L.M. performed data collection, with the assistance of G.S.H., K.K.W., B.J.Y., R.I.M., and S.O. K.L.M. and C.M.H. performed statistical analysis under the supervision of K.K.W. and P.Y.L. K.L.M. wrote the first draft, developed further with C.M.H. and K.K.W. K.K.W., B.J.Y., R.I.M., M.K.N., and P.Y.L. obtained funding. K.K.W., D.C., M.K.N., R.R.G., and P.Y.L. oversaw the study. P.Y.L. conceived the study, wrote the statistical analysis plan, is the principal investigator, and designed the study with input from M.K.N. All authors critically revised the article for important intellectual content and approved the final version.
Disclosure Summary: The authors have nothing to disclose.
Glossary
Abbreviations:
- AHI
apnea–hypopnea index
- CI
confidence interval
- CPAP
continuous positive airway pressure
- ED
erectile dysfunction
- IIEF
International Index of Erectile Function
- OSA
obstructive sleep apnea
- PDE-5
phosphodiesterase type 5
- REM
rapid eye movement
- SD
standard deviation
- SERS
Self-Esteem and Relationship Satisfaction
References
- 1. Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol. 1994;151(1):54–61. [DOI] [PubMed] [Google Scholar]
- 2. Dong JY, Zhang YH, Qin LQ. Erectile dysfunction and risk of cardiovascular disease: meta-analysis of prospective cohort studies. J Am Coll Cardiol. 2011;58(13):1378–1385. [DOI] [PubMed] [Google Scholar]
- 3. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med. 1993;328(17):1230–1235. [DOI] [PubMed] [Google Scholar]
- 4. Marshall NS, Wong KK, Liu PY, Cullen SR, Knuiman MW, Grunstein RR. Sleep apnea as an independent risk factor for all-cause mortality: the Busselton Health Study. Sleep. 2008;31(8):1079–1085. [PMC free article] [PubMed] [Google Scholar]
- 5. Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM; Task Force, Endocrine Society . Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(6):2536–2559. [DOI] [PubMed] [Google Scholar]
- 6. Luboshitzky R, Lavie L, Shen-Orr Z, Herer P. Altered luteinizing hormone and testosterone secretion in middle-aged obese men with obstructive sleep apnea. Obes Res. 2005;13(4):780–786. [DOI] [PubMed] [Google Scholar]
- 7. Hirshkowitz M, Karacan I, Arcasoy MO, Acik G, Narter EM, Williams RL. Prevalence of sleep apnea in men with erectile dysfunction. Urology. 1990;36(3):232–234. [DOI] [PubMed] [Google Scholar]
- 8. Budweiser S, Enderlein S, Jörres RA, Hitzl AP, Wieland WF, Pfeifer M, Arzt M. Sleep apnea is an independent correlate of erectile and sexual dysfunction. J Sex Med. 2009;6(11):3147–3157. [DOI] [PubMed] [Google Scholar]
- 9. Hoyos CM, Melehan KL, Phillips CL, Grunstein RR, Liu PY. To ED or not to ED--is erectile dysfunction in obstructive sleep apnea related to endothelial dysfunction? Sleep Med Rev. 2015;20:5–14. [DOI] [PubMed] [Google Scholar]
- 10. Bozorgmehri S, Fink HA, Parimi N, Canales B, Ensrud KE, Ancoli-Israel S, Canales M; MrOS Study . Association of Sleep Disordered Breathing with Erectile Dysfunction in Community Dwelling Older Men. J Urol. 2017;197(3 Pt 1):776–782. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Hoyos CM, Melehan KL, Liu PY, Grunstein RR, Phillips CL. Does obstructive sleep apnea cause endothelial dysfunction? A critical review of the literature. Sleep Med Rev. 2015;20:15–26. [DOI] [PubMed] [Google Scholar]
- 12. Barrett-Connor E, Dam TT, Stone K, Harrison SL, Redline S, Orwoll E; Osteoporotic Fractures in Men Study Group . The association of testosterone levels with overall sleep quality, sleep architecture, and sleep-disordered breathing. J Clin Endocrinol Metab. 2008;93(7):2602–2609. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Grunstein RR, Handelsman DJ, Lawrence SJ, Blackwell C, Caterson ID, Sullivan CE. Neuroendocrine dysfunction in sleep apnea: reversal by continuous positive airways pressure therapy. J Clin Endocrinol Metab. 1989;68(2):352–358. [DOI] [PubMed] [Google Scholar]
- 14. Margel D, Tal R, Livne PM, Pillar G. Predictors of erectile function improvement in obstructive sleep apnea patients with long-term CPAP treatment. Int J Impot Res. 2005;17(2):186–190. [DOI] [PubMed] [Google Scholar]
- 15. Karkoulias K, Perimenis P, Charokopos N, Efremidis G, Sampsonas F, Kaparianos A, Patouchas D, Tsiamita M, Spiropoulos K. Does CPAP therapy improve erectile dysfunction in patients with obstructive sleep apnea syndrome? Clin Ter. 2007;158(6):515–518. [PubMed] [Google Scholar]
- 16. Zhang XB, Lin QC, Zeng HQ, Jiang XT, Chen B, Chen X. Erectile dysfunction and sexual hormone levels in men with obstructive sleep apnea: efficacy of continuous positive airway pressure. Arch Sex Behav. 2016;45(1):235–240. [DOI] [PubMed] [Google Scholar]
- 17. Perimenis P, Karkoulias K, Konstantinopoulos A, Alchanatis M, Perimeni PP, Athanasopoulos A, Spyropoulos K. The impact of long-term conventional treatment for overlap syndrome (obstructive sleep apnea and chronic obstructive pulmonary disease) on concurrent erectile dysfunction. Respir Med. 2007;101(2):210–216. [DOI] [PubMed] [Google Scholar]
- 18. Budweiser S, Luigart R, Jörres RA, Kollert F, Kleemann Y, Wieland WF, Pfeifer M, Arzt M. Long-term changes of sexual function in men with obstructive sleep apnea after initiation of continuous positive airway pressure. J Sex Med. 2013;10(2):524–531. [DOI] [PubMed] [Google Scholar]
- 19. Petersen M, Kristensen E, Berg S, Midgren B. Sexual function in male patients with obstructive sleep apnoea after 1 year of CPAP treatment. Clin Respir J. 2013;7(2):214–219. [DOI] [PubMed] [Google Scholar]
- 20. Liu PY, Yee B, Wishart SM, Jimenez M, Jung DG, Grunstein RR, Handelsman DJ. The short-term effects of high-dose testosterone on sleep, breathing, and function in older men. J Clin Endocrinol Metab. 2003;88(8):3605–3613. [DOI] [PubMed] [Google Scholar]
- 21. Hoyos CM, Killick R, Yee BJ, Grunstein RR, Liu PY. Effects of testosterone therapy on sleep and breathing in obese men with severe obstructive sleep apnoea: a randomized placebo-controlled trial. Clin Endocrinol (Oxf). 2012;77(4):599–607. [DOI] [PubMed] [Google Scholar]
- 22. Killick R, Wang D, Hoyos CM, Yee BJ, Grunstein RR, Liu PY. The effects of testosterone on ventilatory responses in men with obstructive sleep apnea: a randomised, placebo-controlled trial. J Sleep Res. 2013;22(3):331–336. [DOI] [PubMed] [Google Scholar]
- 23. Roizenblatt S, Guilleminault C, Poyares D, Cintra F, Kauati A, Tufik S. A double-blind, placebo-controlled, crossover study of sildenafil in obstructive sleep apnea. Arch Intern Med. 2006;166(16):1763–1767. [DOI] [PubMed] [Google Scholar]
- 24. Zumbé J, Porst H, Sommer F, Grohmann W, Beneke M, Ulbrich E. Comparable efficacy of once-daily versus on-demand vardenafil in men with mild-to-moderate erectile dysfunction: findings of the RESTORE study. Eur Urol. 2008;54(1):204–210. [DOI] [PubMed] [Google Scholar]
- 25. Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, Mishra A. The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology. 1997;49(6):822–830. [DOI] [PubMed] [Google Scholar]
- 26. Phillips CL, Avolio A, Grunstein RR. Endothelial function and arterial stiffness in OSA using pulse wave analysis. Am J Respir Crit Care Med. 2009;179(10):968, author reply 969–970. [DOI] [PubMed] [Google Scholar]
- 27. O’Connor DB, Corona G, Forti G, Tajar A, Lee DM, Finn JD, Bartfai G, Boonen S, Casanueva FF, Giwercman A, Huhtaniemi IT, Kula K, O’Neill TW, Pendleton N, Punab M, Silman AJ, Vanderschueren D, Wu FC. Assessment of sexual health in aging men in Europe: development and validation of the European Male Ageing Study sexual function questionnaire. J Sex Med. 2008;5(6):1374–1385. [DOI] [PubMed] [Google Scholar]
- 28. Cappelleri JC, Althof SE, Siegel RL, Shpilsky A, Bell SS, Duttagupta S. Development and validation of the Self-Esteem And Relationship (SEAR) questionnaire in erectile dysfunction. Int J Impot Res. 2004;16(1):30–38. [DOI] [PubMed] [Google Scholar]
- 29. Henry JD, Crawford JR. The short-form version of the Depression Anxiety Stress Scales (DASS-21): construct validity and normative data in a large non-clinical sample. Br J Clin Psychol. 2005;44(Pt 2):227–239. [DOI] [PubMed] [Google Scholar]
- 30. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991;14(6):540–545. [DOI] [PubMed] [Google Scholar]
- 31. Althof SE, Corty EW, Levine SB, Levine F, Burnett AL, McVary K, Stecher V, Seftel AD. EDITS: development of questionnaires for evaluating satisfaction with treatments for erectile dysfunction. Urology. 1999;53(4):793–799. [DOI] [PubMed] [Google Scholar]
- 32. Perimenis P, Karkoulias K, Markou S, Gyftopoulos K, Athanasopoulos A, Barbalias G, Kiriazopoulou V, Spiropoulos K. Erectile dysfunction in men with obstructive sleep apnea syndrome: a randomized study of the efficacy of sildenafil and continuous positive airway pressure. Int J Impot Res. 2004;16(3):256–260. [DOI] [PubMed] [Google Scholar]
- 33. Montgomery AA, Peters TJ, Little P. Design, analysis and presentation of factorial randomised controlled trials. BMC Med Res Methodol. 2003;3(1):26. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34. McAlister FA, Straus SE, Sackett DL, Altman DG. Analysis and reporting of factorial trials: a systematic review. JAMA. 2003;289(19):2545–2553. [DOI] [PubMed] [Google Scholar]
- 35. Chasens ER, Drumheller OJ, Strollo PJ Jr. Success in blinding to group assignment with sham-CPAP. Biol Res Nurs. 2013;15(4):465–469. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36. Bogue DA. Setting priorities for quality control and edits. NLN Publ. 1976;(21-1637):123–125. [PubMed]
- 37. Koskimäki J, Shiri R, Tammela T, Häkkinen J, Hakama M, Auvinen A. Regular intercourse protects against erectile dysfunction: Tampere Aging Male Urologic Study. Am J Med. 2008;121(7):592–596. [DOI] [PubMed] [Google Scholar]
- 38. Mulhall JP. Penile rehabilitation following radical prostatectomy. Curr Opin Urol. 2008;18(6):613–620. [DOI] [PubMed] [Google Scholar]
- 39. Markou S, Perimenis P, Gyftopoulos K, Athanasopoulos A, Barbalias G. Vardenafil (Levitra) for erectile dysfunction: a systematic review and meta-analysis of clinical trial reports. Int J Impot Res. 2004;16(6):470–478. [DOI] [PubMed] [Google Scholar]
- 40. Santi D, Granata AR, Guidi A, Pignatti E, Trenti T, Roli L, Bozic R, Zaza S, Pacchioni C, Romano S, Nofer JR, Rochira V, Carani C, Simoni M. Six months of daily treatment with vardenafil improves parameters of endothelial inflammation and of hypogonadism in male patients with type 2 diabetes and erectile dysfunction: a randomized, double-blind, prospective trial. Eur J Endocrinol. 2016;174(4):513–522. [DOI] [PubMed] [Google Scholar]
- 41. Perimenis P, Giannitsas K. Safety of sildenafil in the treatment of erectile dysfunction in patients with obstructive sleep apnoea. Expert Opin Drug Saf. 2007;6(4):423–430. [DOI] [PubMed] [Google Scholar]
- 42. Aydin E, Hizal E, Onay O, Ozgen B, Turhan B, Zaimoglu M, Peskircioglu L, Budakoglu II. A double-blind, placebo-controlled, randomized clinical study of the effects of vardenafil on human nasal patency. Am J Rhinol. 2008;22(3):276–279. [DOI] [PubMed] [Google Scholar]
- 43. Rosen RC, Allen KR, Ni X, Araujo AB. Minimal clinically important differences in the erectile function domain of the International Index of Erectile Function scale. Eur Urol. 2011;60(5):1010–1016. [DOI] [PubMed] [Google Scholar]
- 44. Kohler M, Pepperell JC, Casadei B, Craig S, Crosthwaite N, Stradling JR, Davies RJ. CPAP and measures of cardiovascular risk in males with OSAS. Eur Respir J. 2008;32(6):1488–1496. [DOI] [PubMed] [Google Scholar]
- 45. Weaver TE, Grunstein RR. Adherence to continuous positive airway pressure therapy: the challenge to effective treatment. Proc Am Thorac Soc. 2008;5(2):173–178. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.