Defining the impact of vascular risk factors on erectile function recovery after radical prostatectomy

Authors


Correspondence: Patrick E. Teloken, GPO Box X2213, Perth, Western Australia, 6001.

e-mail: patrickteloken@gmail.com

Abstract

What's known on the subject? and What does the study add?

  • Erectile function recovery after radical prostatectomy is affected by surgical technique and patient factors. Age and preoperative erectile function are the 2 patient factors that have been consistently shown to impact postoperative erectile function.
  • The presence of vascular risk factors preoperatively seems to negatively impact erectile function recovery after radical prostatectomy independently from age, preoperative erectile function and surgical technique.

Objective

  • To examine whether vascular risk factors (VRFs) affect erectile function (EF) recovery after radical prostatectomy (RP).

Patients and Methods

  • From our prospective database we identified patients with clinically localised prostate cancer who had undergone RP and had preoperative information on EF and VRFs (hypertension, hypercholesterolaemia, diabetes mellitus, coronary artery disease [CAD], and cigarette smoking), surgeon-graded nerve-sparing status, and EF data collected between 24 and 30 months after RP.

Results

  • In all, 984 patients were included in the analyses. The frequency of the VRFs was as follows: hypertension (38%), hypercholesterolaemia (36%), diabetes mellitus (7%), CAD (5%), and cigarette smoking (37%).
  • On univariate analysis, EF between 24 and 30 months was associated with age (r = 0.37, P < 0.001), EF before RP (r = 0.41, P < 0.001), NSS (r = 0.35, P < 0.001), and VRFs (0–2 vs >3 VRFs; r = 0.15, P = 0.003).
  • On multivariable analysis all variables remained statistically significant, and accounted for 28% of the total variance in EF between 24 and 30 months after RP.

Conclusions

  • The presence of VRFs seems to adversely affect EF recovery after RP independently of other factors.
  • This observation might be useful for improving patient counselling before treatment and to support the development of new treatment strategies for erectile dysfunction after RP.
Abbreviations
CAD

coronary artery disease

ED

erectile dysfunction

EF(R)

erectile function (recovery)

IIEF

International Index of Erectile Function

NSS

nerve-sparing status

PDE-5

phosphodiesterase type 5

RP

radical prostatectomy

VRF

vascular risk factor

Introduction

Erectile dysfunction (ED) has long been recognised as a complication of radical prostatectomy (RP) [1]. The reported rates of long-term ED after RP vary between 14 and 90% of patients across studies [2], and such dramatic discrepancy may be explained not only by surgical technique but also by heterogeneity in patient populations studied, means of data acquisition and reporting, duration of follow-up, definitions of erectile function (EF) and use of postoperative rehabilitation schemes [3].

While the true incidence of long-term ED after RP may be contentious, it is widely accepted that ED is of concern to patients with prostate cancer, affecting decision-making about therapy [4]. Moreover, ED negatively affects health-related quality of life and treatment satisfaction in patients treated for prostate cancer [5]. Therefore, the identification of factors influencing EF recovery (EFR) after RP is also useful in an effort to improve patient counselling.

Various surgical and patient factors have been shown to affect the recovery of EF after RP [6]. On the surgical side, while different approaches and techniques have been proposed it is certain that the minimisation of injury to the cavernosal nerves through meticulous dissection, with avoidance of thermal damage and stretching, leads to improved postoperative EF outcomes [7]. Regarding patient characteristics, age and preoperative EF seem to be the most predictive factors of EF after RP [6].

Normal EF depends upon vascular health, more specifically, adequate endothelial function. Vascular risk factors (VRFs) and/or comorbidities have been robustly established to predispose patients to ED [8-10]. However, the effect of these in the recovery of sexual function in patients undergoing RP has not been adequately explored, with the exception of age, which has been repeatedly shown to influence the chances of EFR after RP [6, 11-14], and body mass index, which does not seem to influence it [11, 15].

On clinical grounds, a single study, using a non-validated assessment of EF, suggested that coronary artery disease (CAD), hypertension, diabetes and age, predicted EFR on univariate analysis, while only the latter two factors retained statistical significance upon multivariate analysis [16]. No study has evaluated whether the accumulation of VRFs impacts upon EFR after RP.

The purpose of the present study was to define the impact of VRFs on EFR after RP. We hypothesised that VRFs are an independent predictor of EFR after RP.

Patients and Methods

From an institutional prospectively fashioned database, we identified men with clinically localised prostate cancer who underwent RP between July 1998 and December 2008. Patients eligible for this analysis had data collected before RP for the following variables: age, EF, and VRFs. In addition, included patients had surgeon-graded nerve-sparing status (NSS) after RP, and 24-month EF data (recorded between 24 and 30 months after RP). The cohort of patients included in this analysis had not enrolled in a penile rehabilitation programme.

EF was measured both before and after RP with physician assessment on a 5-point scale where: 1 was fully rigid; 2, diminished, but capable of intercourse; 3, occasionally satisfactory for intercourse (≤50% of attempts); 4, tumescence, incapable of intercourse; and 5, no tumescence. While suboptimal, this single-question assessment of EF has been shown to correlate well with the International Index of Erectile Function (IIEF) [17]. NSS was graded intraoperatively by the surgeon, using a 4-point NSS score assigned to each nerve (total range of 2–8 for addition of both nerves) where: 1 was fully preserved; 2, partially preserved; 3, minimally preserved; and 4, resected. VRFs were assessed as the presence of the following comorbidities: hypertension, hypercholesterolaemia, diabetes mellitus, CAD, and cigarette smoking (current smoking or history of smoking). Although there are validated comorbidities scales (i.e. Charlson co-morbidity index), our main objective was to explore VRFs that have been consistently associated with EF. VRFs were tested both as a continuous variable (total number of VRFs) and as a dichotomised variable, at two thresholds, that is, both ≥2 and ≥3 VRFs.

Descriptive statistics were reported on demographic variables and percentages related to VRFs. Pearson product-moment correlations were used to assess the univariate relationship between the predictor variables (age, EF before RP, NSS, and VRFs) and 24-month EF. Multiple regression was used to test the multivariable relationships between the predictor variables and 24-month EF.

Results

We identified 984 patients with a mean (sd) age of 59.6 (7) years (Table 1). The frequency of VRFs was: hypertension 38%, hypercholesterolaemia 36%, diabetes mellitus 7%, CAD 5%, and cigarette smoking 37%. When computing a total VRF score, the following percentages were reported for total number of VRFs: 30%, no VRF; 32%, 1 VRF; 24%, 2 VRFs; 12%, 3 VRFs; 2%, 4 VRFs; <1% reported >4 VRFs. When dichotomising VRFs with a threshold of ≥2 VRFs, 62% (614 patients) reported 0–1 VRF and 38% (370) ≥2 VRFs. When dichotomising VRFs with a threshold of ≥3 VRFs, 86% (850 patients) reported 0–2 VRFs and 14% (134) reported ≥3 VRFs.

Table 1. The patients' characteristics
VariableValue
Number of patients934
Mean (sd) age, years59.6 (7)
Vascular comorbidity, %: 
Hypertension38
Cigarette smoking37
Hypercholesterolaemia36
Diabetes mellitus7
CAD5
≥2 VRFs38
≥3 VRFs14

Univariate analysis: The following are the correlations between 24-month EF and the following variables: age (r = 0.37, P < 0.01), EF before RP (r = 0.41, P < 0.001), NSS (r = 0.35, P < 0.001), and VRF status (0–2 vs ≥3 VRFs; r = 0.15, P = 0.003). We also ran correlations between 24-month EF and VRFs as a continuous variable dichotomised as 0–1 vs ≥2 VRFs. The correlations were similar in strength and significance to the dichotomised VRFs of 0–2 vs ≥3, and as such, are not reported.

Multivariable analysis: Multiple regression showed that age, EF before RP, NSS, and VRF status (0–2 vs ≥3 VRFs) were independently associated with 24-month EF (Table 2). This produced a significant model (F = 93.41, P < 0.001), which accounted for 28% of the total variance in 24-month EF. For VRF, we first entered VRF as a continuous variable, and then VRF as a dichotomous variable, 0–1 vs ≥2 VRFs. Neither of these variables were significant in the model. We then entered VRF defined as 0–2 vs ≥3 VRFs, which was a significant predictor. This stepwise variable selection has the potential to lead to model ‘overfitting’; however, as we had a large sample size and limited predictor variables, the subject to variable ratio remained very high and protects against overfitting.

Table 2. Multivariable analysis of factors predicting 24-month EF
VariableβtP
Baseline IIEF-EF0.258.29<0.001
Age0.237.89<0.001
NSS0.238.01<0.001
VRF group0.072.370.02

Discussion

When considering the different options for the management of prostate cancer, the effect of these on EF is of great importance for many men. Improving our ability to individually predict the chances of a man regaining erections after surgery has, thereby, the potential to greatly empower patients in this decision-making process. Moreover, understanding the factors that influence the recovery of EF might allow us to devise therapeutic strategies that could aid in achieving such a desirable outcome.

Relying upon a prospectively maintained database, we showed that the accumulation of vascular comorbidities decreases the chances of EF recovery after RP. Even after correcting for the factors known to influence return of erections namely, age, NSS, and EF before RP, the burden of vascular comorbidity remained statistically significant.

In a similar endeavour to ours, Marien et al. [16] reported data on 634 men who underwent open RP. At the 24-month assessment, 59% were ‘potent’, which was defined as engaging in sexual intercourse without the use of erectile aids (intracavernosal injections, intra-urethral suppositories, vacuum devices or penile prostheses). No validated EF assessment was used. Upon univariate analysis, age, CAD, hypertension, diabetes, EF before RP, frequency of intercourse, NSS and prior use of phosphodiesterase type 5 (PDE-5) inhibitors were predictive of potency, while dyslipidaemia, smoking history and body mass index were not. On multivariate analysis only diabetes, age and neurovascular bundle preservation remained independently associated with ‘potency’. The authors did not report any analysis on the effect of multiple vascular comorbidities.

Mulhall et al. [18] previously reported on 92 men who had participated in a penile rehabilitation programme after RP. In that study, multivariable analysis showed that an age of >60 years, NSS, more than one vascular comorbidity, commencement of rehabilitation >6 months after RP, no response to sildenafil at 12 months after RP, and requiring >50 U TriMix® to achieve a penetration rigidity erection, were all independently predictive of failure to regain natural erections.

A few mechanisms can be hypothesised as being responsible for this effect. Firstly, it could be postulated that the presence of vascular comorbidities would have resulted in ED regardless of RP after 24 months of follow-up. As shown by data from the placebo group of the Prostate Cancer Prevention Trial, after 5 years of follow-up 57% of men with a mean age of 61 years who did not have ED at study entry developed ED [19]. Of note, patients in the study had a particularly low prevalence of vascular comorbidities; only 17% were using anti-hypertensives, 7% currently smoked, 3% had diabetes and the mean cholesterol was 213 mg/dL. Thereby, one could speculate, in a population such as the present cohort, that the rate of incident ED, regardless of any effect from RP, could be even higher.

A second hypothesis is that in patients with vascular comorbidities, who most likely have worse baseline penile haemodynamics, injury to accessory pudendal vessels would be of significance, while it would not matter in healthy men. Accessory pudendal arteries seem to be identified much more commonly with the recent improvements in visualization during RP [20]. This hypothesis has to make allowance for the fact that the impact of their preservation or sacrifice is still contentious [21].

Finally, vascular comorbidity could interfere with nerve regeneration. In this regard, it has been shown in an experimental study that rats overexpressing the phosphoenolpyruvate carboxykinase, which serves as an experimental model of metabolic syndrome, have impaired nitrergic nerve regeneration [22].

Limitations of the present study include the use of a one-question assessment of EF (as opposed to the EF domain of the IIEF) and the traditional concerns about comorbidity data gathering, incorporating the failure to define the severity of comorbidities rather than just their presence. Also, while the present cohort of patients was not enrolled in a penile rehabilitation programme, data on PDE-5 inhibitor or intracavernosal therapy was not recorded. On the other hand, we describe a robust statistical analysis of a large sample of patients who were followed for >24 months after RP, using a previously published measure of EF [17] and NSS [23].

In conclusion, the presence of VRFs seems to adversely affect EFR after RP independently of other factors. This observation might be helpful in improving patient counselling before RP.

Conflict of Interest

None declared.

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