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ORIGINAL RESEARCH—PEYRONIE’S DISEASE Systemic Vascular Endothelial Dysfunction in Peyronie’s Disease Vineet Agrawal, MRCSEd, MRCS (Eng.),* Elizabeth Ellins, BSc, AVS,† Ann Donald, AVS,† Suks Minhas, MD, FRCS (Urol.),* Julian Halcox, MD, MA, MRCP,† and David J. Ralph, BSc, MS, FRCS (Urol.)* *Institute of Urology, University College London, London, UK; †Vascular Physiology Unit, Institute of Child Health, University College London, London, UK DOI: 10.1111/j.1743-6109.2008.00947.x
ABSTRACT
Introduction. Many patients with Peyronie’s disease (PD) have one or more risk factors (RFs) for atherosclerosis and endothelial dysfunction. It is well recognized that such RFs commonly lead to the development of systemic vascular abnormalities. While not necessarily so, this may implicate vascular dysfunction in its pathogenesis. The cause of PD remains obscure despite intense research over the years and investigating the role of vascular dysfunction in the pathogenesis of PD is a novel approach worth undertaking. Aim. To test our hypothesis that PD is associated with systemic vascular changes even in the absence of RFs for atherosclerosis and endothelial dysfunction. Methods. Vascular function was assessed using high-resolution brachial artery ultrasound in 23 PD patients (aged 30–65 years) without RFs for endothelial dysfunction and atherosclerosis, and 23 age-matched healthy controls. Endothelium-dependent, flow-mediated brachial artery dilation was measured in response to increased shear stress (reactive hyperemia induced by 5 minutes of forearm ischemia). This response was contrasted with that of 400 mg sublingual glyceryl trinitrate, an endothelium-independent vasodilator. Anthropometric characteristics, blood pressure, fasting lipids, and glucose were also measured. Main Outcome Measure. Endothelium-dependent, flow-mediated brachial artery dilation and glyceryl trinitrateinduced endothelium-independent vasodilation. Results. Endothelium-dependent flow-mediated dilation (FMD) was impaired in PD patients compared to controls (5.62 ⫾ 0.58% vs. 7.46 ⫾ 0.56%, P = 0.03). In contrast, responses to glyceryl trinitrate were similar in PD patients and controls as were blood pressure, lipid, and glucose values. FMD remained impaired after multivariable adjustment for potential confounders. Conclusion. Patients with Peyronie’s disease have evidence of systemic vascular changes in the way of systemic conduit artery endothelial impairment even in the absence of RFs for atherosclerosis and endothelial dysfunction. These wider vascular abnormalities in PD are likely to be of clinical relevance and require further study. Agrawal V, Ellins E, Donald A, Minhas S, Halcox J, and Ralph DJ. Systemic vascular endothelial dysfunction in Peyronie’s disease. J Sex Med 2008;5:2688–2693. Key Words. Atherosclerosis; Endothelial Dysfunction; Etiology; Flow-Mediated Dilation; Penile Induration
Introduction
P
eyronie’s disease (PD) is a localized, benign, and acquired connective tissue disorder primarily affecting the tunica albuginea (TA) of the adult human penis. It is characterized by the pres-
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ence of a deformity (curvature, shortening, indentation, or hourglass) of the erect penis. This may develop with or without pain and palpable induration (fibrous plaques) in the penis [1]. The precise etiology of PD remains obscure despite its description more than 250 years ago [2]. © 2008 International Society for Sexual Medicine
Systemic Vascular Endothelial Dysfunction in Peyronie’s Disease Recent work has shown that risk factors (RFs) for atherosclerosis and endothelial dysfunction such as hypertension, dyslipidemia, diabetes mellitus, and smoking are commonly seen in patients with PD [3,4]. Although not proven, the link between these vascular risk factors and PD has been postulated to have a role in its pathogenesis by resulting in a hypoxic micro-environment in the penile corporal tissue and the TA leading to an exaggerated activation of the pro-fibrotic cytokine, transforming growth factor-beta 1 (TGF-b1) and the subsequent aggravation of a fibrotic cascade [5,6] as a result. It is well recognized that clinically apparent RFs commonly lead to the development of systemic vascular abnormalities. PD frequently also develops in the absence of classical RFs and it is unknown whether these patients have systemic vascular abnormalities even in the absence of such RFs. We therefore conducted a prospective casecontrol study comparing systemic vascular endothelial function using a well-validated, noninvasive ultrasound method [7,8] in subjects with PD free from RFs and a carefully matched healthy control group.
Patients and Methods
Patients Twenty-three subjects were recruited from consecutive PD patients attending a tertiary referral clinic between 2004 and 2005. All subjects gave written informed consent and the study was approved by the local ethics committee. Men with RFs for cardiovascular disorder (CVD) including hypertension, dyslipidemia, diabetes mellitus, smoking, peripheral vascular disease, cerebrovascular disease, and family history of premature heart disease were excluded, as were those with clinical evidence of CVD. Four patients recalled suffering penile trauma while three patients had Dupuytren’s contracture. Controls Twenty-three healthy male volunteers matched for age (+/-1 year) were included as controls. These men were part of another ongoing contemporary study in our vascular laboratory at the same time. All men were nonsmokers who had no history or clinical evidence of any CVD and who had undergone an identical assessment of cardiovascular RFs.
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RF Measurements A detailed medical history was carried out in all subjects. Blood pressure was measured twice in the sitting position after 5 minutes of rest with the Hawksley random-zero sphygmomanometer. Hypertension was defined as readings higher than 140/90 mm Hg on two separate occasions or the subject receiving antihypertensive medication. Diabetes mellitus and dyslipidemia were excluded in the recruited patients by measuring serum fasting glucose (values less than 5.6 mmol/L) and serum fasting lipid profile (total cholesterol less than 6.5 mmol/L) after a 12-hour overnight fast. Body mass index was calculated as weight/height [2]. Brachial Artery Vasomotor Function Brachial artery flow-mediated dilation (FMD) in this study was assessed using high-resolution ultrasound (Prosound SSD-5500, ALOKA, Keymed, UK) as previously reported [7]. Subjects were either fasted or had only had a low-fat meal and intake of caffeine was curtailed for at least 2 hours prior to the study. Subjects were rested in a supine position for 10 minutes (for blood pressure stabilization) in a temperature-controlled room (22– 26°C). The right brachial artery was imaged 5–10 cm above the antecubital fossa. FMD was induced by a 5-minute inflation of a blood pressure cuff on the forearm to 300 mm Hg followed by rapid deflation. Electrocardiograph (ECG)-gated images were acquired at 3-second intervals throughout the study and arterial diameter measured on each image using an automated edge detection system (Brachial Tools, Iowa City, IA, USA). Baseline brachial artery diameter was determined as the average of measurements made in the minute prior to cuff inflation. FMD was calculated as percentage change from baseline diameter. This response was contrasted with that to sublingual administration of 400 mg of nitroglycerine or Glyceryl Tri Nitrate (GTN), an endotheliumindependent, direct smooth muscle dilator in each participant. The response to GTN was calculated in the same manner as FMD. Blood flow velocity was monitored continuously using pulsed-wave Doppler and the blood flow was calculated at rest and at 5, 10, and 15 seconds after cuff deflation. The ratio of maximal change of flow relative to the baseline was calculated as reactive hyperemia (RH) and expressed as a percentage (RH %). Peak hyperemic blood flow was defined as the maximal blood flow during the first 15 seconds post-cuff deflation. J Sex Med 2008;5:2688–2693
2690 Table 1
Agrawal et al. Clinical features of study subjects at baseline
Mean age (years) Systolic pressure (mm Hg) Diastolic pressure (mm Hg) Heart rate (beats per minutes) Total cholesterol (mg/dL) Fasting glucose (mmol)
PD
Controls
P value
54.0 ⫾ 9.3 128.69 ⫾ 10.15 77.43 ⫾ 7.6 65 ⫾ 12 5.23 ⫾ 0.82 5.07 ⫾ 0.60
53.0 ⫾ 8.4 126.91 ⫾ 11.42 77.3 ⫾ 7.7 63 ⫾ 12 5.32 ⫾ 0.80 5.26 ⫾ 0.38
0.80 0.60 0.98 0.47 0.31 0.71
PD = Peyronie’s disease.
All studies were performed and analyzed by a single experienced operator.
Statistical Analysis Descriptive data are presented as means +/- standard error of mean or percentages when appropriate. Comparison between PD and controls were made using unpaired t test. Linear regression analysis was used to explore the relationship between PD status and FMD adjusting for potential confounders (baseline arterial diameter, magnitude of RH and RFs). Statistical significance was defined as a two-sided P value of less than 0.05.
lowing adjustment for baseline diameter and RH. Furthermore, age, RH%, and PD status (P = 0.05, 0.015, and 0.007, respectively) were independently associated with FMD following multiple linear regression analysis. Of note, the degree of FMD was not higher in Peyronie’s patients with history of trauma or Dupuytren’s contracture compared to Peyronie’s patients without such association. In contrast, endothelium-independent vasodilator responses to GTN were similar in PD and controls (18.60 ⫾ 1.24% and 19.71 ⫾ 1.14%, respectively, P = 0.71; Figure 2).
Discussion Results
There were no significant differences in age and systemic vascular diseases RFs between the two groups (Table 1). Resting brachial artery diameter (4.04 ⫾ 0.11 vs. 3.93 ⫾ 0.08 mm; P = 0.42) was similar in PD and controls, respectively. Resting brachial artery blood flow (25.9 ⫾ 2.9 and 15.3 ⫾ 1.56 mL/min; P = 0.003) and peak hyperemic blood flow (120.2 ⫾ 10.6 and 85.2 ⫾ 5.3 mL/min; P = 0.005) were higher in PD than controls, respectively; however, RH% change of blood flow from baseline (441 ⫾ 47.8% and 546 ⫾ 51.7%; P = 0.14) was similar in PD and controls, respectively (Table 2). FMD of the brachial artery was impaired in PD patients compared to controls (5.62 ⫾ 0.58% vs. 7.46 ⫾ 0.56%, P = 0.03; Figure 1). Of note, this relationship remained statistically significant folTable 2
Our study is the first to demonstrate impaired systemic vascular endothelial function in men with PD even in the absence of RFs for atherosclerosis. Preservation of endothelium-independent vasomotor function suggests that the vascular abnormality is localized to the endothelium and is not because of abnormal smooth muscle function. Our observations suggest the presence of a more widespread vascular abnormality in PD, which may have important implications for the long-term cardiovascular health in these patients. PD is not as rare as has previously been thought, with a recent study showing that it can affect up to 8.9% of adult males [9]. The penile plaque and curvature of PD are caused by a localized abnormal deposition of collagen in the TA. This process is thought to be multifactorial. Currently, the most widely accepted etiological theory attributes the histological findings and symptoms
Results in study subjects
Baseline artery diameter (mm) Reactive hyperemia (%) FMD (%) GTN-mediated dilatation (%)
PD
Controls
P value
4.04 ⫾ 0.11 441 ⫾ 47.8 5.62 ⫾ 0.58 18.60 ⫾ 1.24
3.93 ⫾ 0.08 546 ⫾ 51.7 7.46 ⫾ 0.56 19.71 ⫾ 1.14
0.42 0.14 0.03 0.71
PD = Peyronie’s disease; FMD = flow-mediated dilation; GTN = nitroglycerine or glyceryl tri nitrate.
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Systemic Vascular Endothelial Dysfunction in Peyronie’s Disease
12.50
10.00
7.50
FMD% 5.00
2.50
Figure 1 Box-whisker plot of FMD% in PD and control subjects. FMD = flow-mediated dilation; PD = Peyronie’s disease.
0.00
Control
of PD to the effects of penile trauma during penetrative sexual intercourse with abnormal posttraumatic wound healing [10,11]. A potential causal role for arterial disease in PD is not a new concept. In 1910, Horowitz described arteriosclerotic changes in penile blood vessels of PD patients and suggested that this was an etiological factor [12]. Janssen proposed that these changes arose from the adventitial sheath of the capillaries, possibly as a result of diabetic endothelial damage [13]. It has also been suggested that the aging of the vascular connective tissue makes it more sus-
PD
ceptible to repeated minor trauma [14,15]. Recent studies have shown that in addition to penile trauma and genetic predisposition to PD, RFs for systemic atherosclerosis and cardiovascular diseases including hypertension, diabetes mellitus, dyslipidaemia, and smoking are independently associated with an increased risk of PD [3–5]. Vascular dysfunction and weakening as a consequence of RF exposure could influence the development of PD by increasing susceptibility to vascular rupture during sexual intercourse and/or by causing a hypoxic micro-environment in penile
30.00
25.00
GTN-mediated dilatation (%) 20.00
15.00
Figure 2 Box-whisker plot of GTNmediated dilatation (%) in PD and control subjects. GTN = nitroglycerine or glyceryl tri nitrate; PD = Peyronie’s disease.
10.00
Control
PD
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2692 tissues that exacerbates fibrosis through increased activation of TGF-b1 [5]. Therefore, it is possible that PD characterized by local vascular changes and commonly associated with RFs for atherosclerosis may well reflect a more widespread systemic vascular abnormality. To address this issue, we studied systemic vascular endothelial function in men with PD without major RFs for systemic atherosclerosis (thus minimizing their potentially confounding effects on the systemic vasculature) and an appropriately agematched group of healthy men. We found significantly depressed endothelium-dependent brachial artery FMD in subjects with PD compared to controls. The endothelium-independent vasodilator responses to GTN were preserved localizing the vascular abnormality to the endothelium rather than an abnormal smooth muscle function. These changes are likely to be because of decreased bioavailability of endothelial nitric oxide (NO) and are consistent with a more widespread vascular dysfunction that cannot be explained by conventional RFs, which were absent in these men with PD. A large body of evidence is emerging that links erectile dysfunction to systemic arterial risk factors, clinical atherosclerotic disease, and adverse vascular prognosis [16–18]. Our study is the first to show a similar link between endothelial dysfunction and PD. Endothelial dysfunction, especially reduction in the bioavailability of endothelium-derived NO, is a key early event in atherogenesis typically appearing long before the formation of structural atherosclerotic disease. A large prospective population study of endothelial function and clinical outcome found that a difference in FMD of half a standard deviation was associated with an approximately 10% difference in developing a major cardiovascular event during follow-up after adjustment for risk factors [19]. Thus, a 2% lower FMD in PD patients (standard deviation 0.58%) is an important difference, suggesting that the presence of endothelial dysfunction distant from the penile vasculature may be clinically relevant for the future risk of developing systemic vascular disease in men with PD, which will require prospective evaluation. Importantly, this is further evidence that penile pathophysiology may be of clinical value as a cardiovascular risk barometer. In our study, the baseline brachial artery blood flow and maximal post-hyperemic flow was higher in PD patients, suggesting underlying differences in systemic microvasculature between PD and healthy controls. Whether this is because of strucJ Sex Med 2008;5:2688–2693
Agrawal et al. tural or functional differences requires further study or example with NO-antagonists such as NG-monomethyl-L-arginine. With regard to brachial artery endothelial function, however, RH% change of blood flow from baseline was similar in both the groups and the differences in FMD remained after adjustment for both absolute and percentage increase in blood flow. Thus, the magnitude of the vasodilator stimulus cannot account for differences in FMD between PD patients and controls. Our study is a small but adequately powered cross-sectional case-control study. As such, the question of reverse causality cannot be definitively answered. Also, larger-scale studies will be required to confirm our findings. Whether systemic dissemination of local cytokines that mediate penile changes in PD leads to systemic vascular abnormality or vice versa requires prospective evaluation in appropriately designed studies.
Conclusion
Our study is the first to demonstrate impaired systemic vascular endothelial function in men with PD even in the absence of RFs for atherosclerosis. Preservation of endothelium-independent vasomotor function localizes this vascular abnormality to the endothelium and is consistent with a more widespread vascular abnormality in these patients, which may have important implications for their long-term cardiovascular health and erectile function. Corresponding Author: Vineet Agrawal, MRCSEd, MRCS (Eng.), Institute of Urology, University College London, London NW1 2BU, UK. Tel: (44) 795 1237043; Fax: (44) 121 3542798; E-mail:
[email protected] Conflict of Interest: None declared.
Statement of Authorship
Category 1 (a) Conception and Design Vineet Agrawal; Elizabeth Ellins; Ann Donald; Suks Minhas; Julian Halcox; David J. Ralph (b) Acquisition of Data Vineet Agrawal; Elizabeth Ellins; Ann Donald; Suks Minhas; Julian Halcox; David J. Ralph (c) Analysis and Interpretation of Data Vineet Agrawal; Elizabeth Ellins; Ann Donald; Suks Minhas; Julian Halcox; David J. Ralph
Systemic Vascular Endothelial Dysfunction in Peyronie’s Disease
Category 2 (a) Drafting the Article Vineet Agrawal; Elizabeth Ellins; Ann Donald; Suks Minhas; Julian Halcox; David J. Ralph (b) Revising It for Intellectual Content Vineet Agrawal; Elizabeth Ellins; Ann Donald; Suks Minhas; Julian Halcox; David J. Ralph
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10
Category 3 (a) Final Approval of the Completed Article Vineet Agrawal; Elizabeth Ellins; Ann Donald; Suks Minhas; Julian Halcox; David J. Ralph
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