Underlying endothelial dysfunction (EnD) may present in the early stage of ED or psychogenic ED. We retrospectively evaluated 191 ED patients with effective nocturnal penile tumescence and rigidity (NPTR) recording, including detailed medical and psychosexual history, International Index of Erectile Function-5 and vascular parameter. All patients were allocated into psychogenic and organic groups according to the NPTR test. Brachial artery flow-mediated dilation (FMD) was used to diagnose EnD, and ED patients were classified into two groups: non-EnD (FMD10) and EnD (FMD<10). General and vascular parameters were compared between psychogenic and organic groups, and non-EnD and EnD groups with ED were compared in terms of NPTR parameters. In all, 48.7% and 51.3% patients were diagnosed as psychogenic and organic ED, respectively. 73.1% of the psychogenic patients had EnD and 39.8% organic patients had normal endothelial function. In all parameters, only the FMD value showed significant difference between psychogenic and organic ED groups (8.26±2.57 vs 9.16±2.76, P=0.020). No statistical difference was founded in NPTR parameters between non-EnD and EnD groups (P>0.05). In conclusion, NPTR cannot effectively identify the underlying vasculogenic ED from psychogenic ED. Psychogenic causes may cause or aggravate EnD in these ED patients with normal NPTR.
Nocturnal penile tumescence and rigidity (NPTR, or more simply, NPT) normally occurs in rapid eye movement sleep independently of sexual stimulation and results in sleep-related erections. The concept is that if a man with ED has normal nocturnal erectile activity, his problem is ‘psychogenic’,1 because the psychogenic factors of stress, anxiety, distress, depression and other relational problems are unable to affect sleep-related erections at night. NPTR monitoring was the first objective test to diagnose ED, and it had been considered to be a helpful test to diagnose ED and to distinguish psychogenic from organic ED.2 In 1970, Karacan et al.3 and Fisher et al.4 recognized its value in evaluating male impotency. Subsequently, the Rigiscan device (1985) was introduced as an economical home-monitoring device that allowed men to be assessed in their usual environment,5 and it has been considered to be one of the most reliable tests widely used to monitor NPTR. However, controversy remains about the diagnostic accuracy of the NPTR assessment, and the proposed normal criteria have been questioned by many investigators. Although there have been several published studies aimed at improving the diagnostic value of NPTR, there is still a lack of normative data that can be used to eliminate the questionable clinical value of different parameters.6
Recently, more consideration has been given to ED patients with normal NPTR, who also present with an abnormal endothelial state after vascular testing. The aim of the present study is to investigate the state of endothelial function in young ED patients with normal NPTR and to determine the role of NPTR parameters in differentiating underlying vasculogenic ED from psychogenic ED.
Patients and methods
We retrospectively scrutinized and enrolled consecutive ED patients who had undertaken an NPTR test by using the NX-IIIA Andrologic Disease Diagnosis System (Beijing Shining Sun Technology, Beijing, China). All patients were evaluated with a detailed medical and psychosexual history, the International Index of Erectile Function-5. In addition, physical examination, blood chemistry and endocrine assays were performed. Vascular and hemodynamic status targeted on the brachial artery and bilateral carotid were evaluated by using the Cardiovascular Ultrasound System (Vivid 7 Dimension, Probe, 5–12 MHz, GE, Milwaukee, WI, USA).
To obtain accurate monitoring parameters, patients were instructed by a physician before using the NPTR wave-form Holter recorder. Patients were asked to smoothly place the loop of NX-IIIA at the middle of penile shaft and correctly connect the sensor in the loop to the recorder tied on one thigh. In order to monitor the patients’ ‘natural’ nocturnal erections, NPTR was recorded at home for 1–3 nights with at least 8 h of sleep. The NX-IIIA device recorded several parameters, including total number of erections, tip rigidity during events, the cumulative and average duration of erectile events.
Vascular parameters including brachial artery and bilateral carotid diameter, blood flow velocity and intima–media thickness were recorded first. Brachial artery flow-mediated dilation (FMD) was used to assess vascular endothelial function, which was based on Celermajer's theory and its modified approaches in recent studies.7, 8, 9 Fifteen minutes rest in quiet conditions before the test was needed for every patient, and then brachial artery vasodilation was recorded by a high-frequency ultrasound probe. The probe was positioned ∼2–5 cm proximal to the elbow. All ultrasound images were obtained in longitudinal sections and the probe was maintained in the fixed position. The baseline parameters of brachial diameter and arterial blood flow velocity were obtained before reactive hyperemia, and then an arterial occlusion cuff was placed around the arm, and the cuff was inflated above 250 mm Hg for 5 min before deflating. The measurements of second arterial diameter and peak blood flow velocity were recorded again, and the greatest diameter and maximal velocity were used. FMD is expressed as the percentage change from the baseline diameter before cuff inflation to the greatest diameter after cuff deflation.7
Patients were excluded from the study if they had a clinically neurogenic pathology, noteworthy dysplasia, penile deformities, pelvic surgery or trauma of the perineal region. Patients with severe diseases such as unstable angina or any other evidence of recently diagnosed coronary artery disease, congestive heart failure and significant renal or hepatic dysfunction were excluded. Cardiovascular risk factors were defined as smoking or alcohol abuse for at least 3 months, hypertension, glycometabolic disorder, dyslipidemia, obvious atherosclerosis.
NX-IIIA criteria of ED were applied as described by the commercial form of NX-IIIA. All NPTR recording must include one effective erectile event, and no recording or no standard erectile events were excluded from the enrollment. In order to obtain the best accuracy, psychogenic ED diagnosed with NPTR was defined strictly. Only patients who met all the following criteria in the device examination could be considered to have a normal NPTR recording: (1) >three full erections during night.; (2) >70% of maximal tip rigidity; (3) >15 min of an average duration in erectile events; (4) >60 min of total duration in erectile events.
FMD expressed as the percentage change of diameter was detected by Vivid 7 Cardiovascular Ultrasound System. For the healthy populations, mean FMD varied from 0.20 to 19.2%, as the technical aspects of the measurements, the location and the duration of the occlusion.10 Generally, 7 to 10% of the baseline diameter were considered to be normal values of FMD in healthy people.11 Combined with our preliminary study,7 we set FMD=10 as a cutoff point. When FMD<10, ED was considered to be of endothelial dysfunction (EnD) origin, and when FMD10, ED was defined as of non-EnD origin.
After NPTR diagnostic examination, the patients were allocated into two groups as psychogenic (normal NPTR recording) and organic (abnormal NPTR recording) ED, and a comparison was made between the two groups in terms of vascular parameters. According to the value of FMD and the criteria defined, above, the patients with psychogenic ED were classified into two groups as non-EnD and EnD, and the two groups were compared in terms of NPTR parameters including total erection number, tip rigidity, average duration and total duration. Furthermore, a similar comparison was also made between psychogenic ED patients with non-EnD and EnD by using the NPTR parameters after excluding cardiovascular risk factors.
All analyses were conducted using SPSS 13.0. (SPSS, Chicago, IL, USA). Continuous variables were expressed as the mean±s.d. Independent samples t test, Mann–Whitney U-test, Pearson's χ2 test and correlation coefficient tests were used for statistical analysis.
In total, 191 ED patients with valid NPTR recording were enrolled in this study, and their age range was 18–57 (mean 31. 3±7.8). Based on NPTR data, 93 patients (48.7%) and 98 patients (51.3%) were diagnosed as having psychogenic (normal NPTR) and organic (abnormal NPTR) ED, respectively. The FMD test revealed non-EnD ED in 64 patients (33.5%) and EnD ED in 127 patients (66.5%). Of the 93 psychogenic ED patients, 68 (73.1%) had EnD and only 25 (26.9%) had normal endothelial function. In these patients with organic ED, 59(60.2%) had EnD and 39 (39.8%) had no EnD. (Table 1)
General data and vascular parameters of brachial artery and bilateral carotid are shown in Table 2 in patients with psychogenic and organic ED. Compared with organic ED, the FMD values in patients with psychogenic ED were decreased significantly (8.26±2.57 vs 9.16±2.76, P=0.020), whereas the other parameters were not significantly different between the two groups (P>0.05). Consequently, NPTR parameters in all ED patients with non-EnD origin were compared with the patients with EnD origin. No differences were observed between non-EnD and EnD ED with regard to these parameters (P>0.05; Table 3, G1 group). A comparison of NPTR parameters between non-EnD and EnD groups were made in psychogenic ED patients (before and after excluding cardiovascular risks). No significant difference was also found in the two groups with respect to the NPTR parameters (P>0.05; Table 3, G2 and G3 group).
Nowadays, many tests are available for the evaluation of men with ED.6 It is generally agreed that the first level of evaluation should consist of medical and psychosexual history, physical examination and appropriate laboratory tests. Further diagnostic testing can then be chosen according to the treatment requirement, and for this second level of assessment, NPTR is often the first choice. As an objective, noninvasive measure of erectile activity, NPTR has been considered a gold standard for differentiation between psychogenic and organic ED.12 However, the usefulness of classic NPTR measurement has been questioned, noting that NPTR testing mainly focuses on the differences between sexually induced erections and sleep erections. Although sexually induced erections are a combination of erotic and reflex erection activity, the mechanism initiating and maintaining sleep-related erections is unknown.13 Nevertheless, the difference between sleep and sexually induced erections is primarily neurological;14 both erections involve the same vascular and penile structural components.15
The basic mechanism of penile erection is the process of penile vasodilatation, congestion and tumescence. Therefore, the terminal target of risk factors that lead to ED is mostly the vascular and penile structure. The second level of assessment methods that have been used to evaluate the vascular and penile structure are penile color Doppler ultrasound and the more recent endothelial function detection. However, a normal hemodynamic response evaluated by color Doppler ultrasound is not invariably associated with normal penile rigidity and potency. The penile geometric and mechanical properties should not be overlooked during the evaluation of penile vascular system to avoid the patient being incorrectly diagnosed as having psychogenic impotence.16 Duplex ultrasound, the most common diagnostic test used to evaluate erectile function, was unreliable in psychogenic cases because of an excessive sympathetic stimulation that results in abnormal responses to pharmacological stimulation.17 Owing to anxiety, false-negative results of color Doppler ultrasound can also be seen in men with normal penile and vascular systems and result in misdiagnosis of psychogenic impotence.16
Normal NPT correlates well with normal Doppler parameters but does not exclude organic impotence.18 However, the more recent application of the FMD method used to test endothelial function may help us to detect a potential organic etiology of ED in the patient. FMD of the brachial artery is a widely accepted method to evaluate endothelial function as a tool to assess the presence of microvascular disease,9, 19, 20 and accumulated evidence demonstrates that impaired FMD was a sign of EnD in ED patients.21, 22, 23 Studies had shown that a positive correlation between the magnitude of FMD and the (International Index of Erectile Function) IIEF score was found in young psychogenic ED patients without cardiovascular risk factors and FMD can be an independent predictor of ED,7, 20 which suggested that EnD was associated with ED in young patients with no well-known causes. Thus the pathophysiologic changes caused by EnD may be one of the early potential factors causing ED.
In this study, 73.1% (68/93) psychogenic ED patients diagnosed with NPTR presented with EnD, and further statistical analysis showed that NPTR parameters cannot differentiate ED with EnD from ED without EnD in the patients with psychogenic origin (P>0.05). It is suggested that NPTR recording is recommended when a psychogenic etiology is suggested by the sexual history, and there are no neurovascular risk factors present.24, 25 A man with ED but no obvious risk factors, having a normal NPTR recording with three to five erectile events, lasting more than 10 min with tip rigidity more than 60–70%, can be safely diagnosed with a psychogenic etiology.18 However, after excluding cardiovascular risks, no statistical differences were found in NPTR parameters between non-EnD and EnD ED in the psychogenic group (P>0.05). Various studies undertaken in different decades revealed that NPTR has an important role in the differentiation of well-known organic impotence from psychogenic impotence but is insufficient in identifying the underlying cause of organic impotence.18, 25, 26 Hence, our result that the potential vascular lesion EnD presented in ED patients with normal NPTR support the conclusion in previous literature study.
As shown in Table 2, vascular parameters were compared in ED patients with psychogenic and organic origin. Except for FMD, no vascular parameters had statistical significance between the two groups (P>0.05). Surprisingly, the FMD value of patients with psychogenic origin was lower than that of patients with organic origin (8.26±2.57 vs 9.16±2.76, P=0.020), which seems to be inconsistent with the expectations. Retrospectively, our study cohort mainly focused on young ED patients (mean age 31.3±7.8) whose obvious clinical pathology and diagnosed cardiovascular disease were excluded, and only early EnD (mean FMD>8) was found in the patients. As shown in results, ED patients with EnD and non-EnD could not be identified by NPTR test. In other words, NPTR test lost the value on distinguishing organic and non-organic ED in the population with an early stage of pathological changes, which suggested that the two groups classified by NPTR parameters share the common potential vascular pathology. The highest value of NPTR test in the ED patients will be an indication whether the predominant cause of ED is a psychogenic factor or not. Compared with abnormal NPTR, normal NPTR suggests that psychogenic factor has more important role in the causes of ED. Endothelial function is an early sensitive marker that may be also affected by psychogenic factors, so under the condition of common potential vascular pathology, common potential etiological factors with obviously psychogenic factors, endothelial dysfunction in psychogenic group would suffer further aggravation. This is the reasonable explanation why the FMD value showed lower in the psychogenic ED patients.
Although no psychological scales were used to investigate the mental state, our data showed the existence of psychological causes indirectly through NPTR test. According to reports in literature, mental stress is one of the important risk factors contributing to the mechanisms underlying EnD, atherosclerosis, and coronary and cerebral artery diseases,27 and acute or chronic mental stress deteriorates endothelial function in humans and experimental animals. Stress-related hormones and mediators affect vascular actions possibly via downregulation of endothelial nitric oxide synthase expression, endothelial nitric oxide synthase inactivation, decreased nitric oxide (NO) actions and increased NO degradation, together with vasoconstriction counteracting against NO-induced vasodilatation.28 Our study also showed that psychological causes may be unfavourable factors affecting endothelial function in ED patients.
In conclusion, NPTR recording may identify the existence of psychogenic factors but cannot differentiate EnD consistent with underlying vasculogenic ED from psychogenic ED. Psychogenic causes may aggravate the existed EnD in ED patients with normal NPTR parameters. New methods need to be developed for clinical practice to detect the latent etiology and differentiate potential organic lesions from psychogenic disorders more exactly.
We thank Professor Yuan-yuan Zhang and Ching-Shwun Lin for the great efforts on revising the manuscript. This study was supported by the grant of National Natural Science Foundation of China (30872571, 81070488, Professor Deng received a grant from NSFC; 30901487, Professor Sun received a grant from NSFC), Guangdong Natural Science Fund (07001628, 10251008901000005, Professor Deng received a grant from GDNSFC; 8451008901000774, Professor Sun received a grant from GDNSFC; 10151008901000222, Dr Deng received a grant from GDNSFC); Guangdong Province Science and Technology Project (2011B031800115, Professor Deng received a grant from GDSTC; 2008B080703056, Professor Liu received a grant from GDSTC; 2009B030801178, Dr Deng received a grant from GDSTC) the grant of Research Fund for the Doctoral Program of Higher Education of China (20100171110060, Professor Deng received a grant from RFDP).