J Sex Med 2005; 2: 432–437

432

Blackwell Science, LtdOxford, UKJSMJournal of Sexual Medicine1743-6095Journal of Sexual Medicine 2005 200523432437Original Article

Radiation-Induced Erectile DysfunctionMulhall et al.

ORIGINAL RESEARCH—ERECTILE DYSFUNCTION

The Hemodynamics of Erectile Dysfunction Following External Beam Radiation for Prostate Cancer

John Mulhall, MD,* Absaar Ahmed, BS,

†

Marilyn Parker, RN, BSN,

†

and Najeeb Mohideen, MD

‡

*Department of Urology, Weill Medical College of Cornell University, New York, NY;

†

Loyola University Medical Center, Stritch School of Medicine—Department of Urology;

‡

Loyola University Medical Center, Stritch School of Medicine—Department of Radiation Oncology, Chicago, IL, USA

Corresponding Author:

John P. Mulhall, Department of Urology, Weill Medical College of Cornell University, New YorkPresbyterian Hospital, 525 E 68TH Street, NY, NY 10021, USA. Tel: (212) 746-5693; Fax: (212) 746-0403; E-mail:jpm2005@med.cornell.edu

A B S T R A C T

Introduction.

Radiation to the pelvis is associated with erectile dysfunction (ED). The mechanismsinclude neural injury, vascular alterations, and corporal smooth structural changes. There existslittle data on the vascular assessment of men who present with ED following radiation therapy forprostate cancer. This study was conducted to evaluate the erectile hemodynamics in such a patientpopulation.

Methods.

Men who presented for the evaluation of ED following radiation therapy for prostatecancer underwent vascular evaluation in the form of dynamic infusion cavernosometry and caver-nosography (DICC). Established parameters were recorded to define arterial insufficiency andvenocclusive function including cavernosal artery occlusion pressure, flow-to-maintain, andpressure decay.

Results.

Sixteen men with a mean age of 61 years presenting with ED after radiation underwentDICC at a mean duration post radiation of 11 months. All of the patients in whom arterialhemodynamics were measurable had abnormal arterial parameters, and 85% had abnormal venoc-clusive parameters. Of the patients who could undergo cavernosography, 80% had venous leak,most commonly from the crura.

Conclusions.

Men presenting with ED following radiation therapy for prostate cancer are likely tohave significant alterations in erectile hemodynamics, often of a combined arterio-venogenic nature.In patients with venous leak the majority had venocclusive dysfunction with venous leak emanatingfrom the crura.

Key Words.

Erectile Dysfunction; Radiation Prostate Cancer

Introduction

adiation therapy to the pelvis is a well-recognized management strategy for prostate

cancer [1]. Prostate cancer is an increasing threatto men and represents a common cause of malig-nancy-related deaths in men in the United States

R

[2]. Therefore, an increasing number of men andtheir urologists are faced with decisions regardingthe appropriate course of patient management.The decision to opt for radiation therapy vs. oper-ative intervention, for some men, is often predi-cated upon the potential for the development ofpost-therapy erectile dysfunction (ED). Radiation

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therapy for prostate cancer is associated with anestimated incidence of post-therapy ED in the 20–80% range [3–5].

The putative mechanism of radiation-associated impotence is purported to be radiation-induced arterial injury with subsequent arterialocclusion and cavernosal artery insufficiency [6].More recent evidence has implicated structuralalterations in corporal smooth muscle and endot-helial dysfunction as potential contributors to thisproblem [7]. Prior retrospective and prospectiveanalyses of patients with pelvic radiation-associ-ated ED have been predominantly questionnaire-based or utilized vascular testing techniques whichhave now been supplanted by more sophisticatedinvestigations.

This investigation was undertaken to evaluateerectile hemodynamics, using dynamic infusioncavernosometry (DIC), to determine the contri-bution of vascular alterations in the genesis ofradiation-associated impotence and to define therelative contributions of arterial insufficiency andcorporovenocclusive dysfunction to this problem.

Methods

Study Population

Patients were enrolled in the study according toan institutional review board-approved protocol ifthey met the following criteria: (i) they had under-gone external beam radiation therapy for prostatecancer; (ii) they admitted to functional erectionsbefore the initiation of pelvic radiation therapy;(iii) they experienced the onset of ED followingthe completion of radiation therapy; and (iv) theyhad comprehensive evaluation for ED, includinga thorough history, physical examination, andhemodynamic investigation using DIC (conductedby J.P.M.). A comprehensive patient medicalrecord review was performed to define patient ageat the time of radiation therapy; mode of radiationdelivery; dose of radiation delivered; the intervalbetween radiation therapy and the onset of erectilecomplaints; and vascular risk factor status.

Radiation Therapy

Patients with prostate cancer were treated with amean dose of 72 Gy (68–74 Gy) using a two-phasefour-field approach. In the majority of patientssmall fields were used to treat the prostate and theseminal vesicles to a dose of 50–54 Gy with a boostto the prostate alone to the total dose over a 7–8-week period.

Dynamic Infusion Cavernosometry/Cavernosography (DICC)

Dynamic infusion cavernosometry/cavernosogra-phy (DICC) was performed in a state of maximumsmooth muscle relaxation using a redosing sched-ule [8]. The general technique of DICC has beenpreviously outlined in detail [9]. The vasoactiveagent solution utilized was a trimix (papaverine,phentolamine, prostaglandin E

1

) mixture eachdose of 1 mL containing 30 mg, 1 mg, 10 mcgs ofagent, respectively. The following cavernosomet-ric parameters were evaluated: (i) equilibriumpressure (P

Eq

), defined as that stable pressureachieved in the corporal bodies 10 minutes follow-ing the administration of intracavernosal vasoac-tive agents. Normal P

Eq

is defined as that valueequivalent to the mean arterial pressure; (ii) cav-ernosal artery occlusion pressure (CAOP), definedas the intracavernosal pressure at which (right andleft) cavernosal artery flow was occluded as evi-denced by loss of Doppler signal, a normal CAOPbeing one that was no more than 30 mm Hg lessthan the brachial artery systolic pressure; (iii) flow-to-maintain values (FTM), defined as the amountof saline required to maintain the intracorporalpressure at given pressures (30, 60, 90, 120,150 mm Hg); an FTM value of 3 mL/minute orless was considered normal; and (iv) pressure decay(PD) defined as the amount of pressure loss, overa 30-second period, from a starting pressure of150 mm Hg. Normal pressure decay was a valueless than a 45 mm Hg drop over 30 seconds.

Abnormal CAOP values indicated arterialinsufficiency. Corporovenocclusive dysfunction(CVOD) was deemed to exist when FTM valueswere greater than 3 mL/minute and/or pressuredecay values were greater than 45 mm Hg. Redos-ing was performed up to a maximum of three dosesof the vasoactive compound. Patients had repeatvasoactive agent administration when the venousparameters (FTM, pressure decay) were abnormal.Cavernosography was conducted by using a non-ionic contrast agent infused at an intracorporalpressure of 90 mm Hg with simultaneous fluoros-copy. Hard copies of the images were reviewed bya single urologist ( J.P.M.).

Results

Study Population

Sixteen patients met the inclusion criteria for thestudy. The mean age at the time of radiation ther-apy was 61.2

±

11 years (range 48–72 years). The

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mean interval between radiation therapy and thereported onset of ED was 8

±

5 months (range 1–12 months). The mean duration following radia-tion at which hemodynamic testing was performedwas 11

±

3 months. The vascular risk profile in ourstudy group was as follows: diabetes mellitus 12%,hypertension 25%, cigarette smoking history12%, and hyperlipidemia 18%. No patient admit-ted to a history of pelvic or perineal trauma(Table 1).

Hemodynamic Data

Equilibrium Pressure

All 16 patients demonstrated abnormal intraca-vernosal equilibrium pressures with a mean of24

±

12 mm Hg, indicating significant vascularpathology. The average mean arterial pressure was85

±

16 mm Hg.

Arterial Hemodynamics

Twelve of the 16 patients (75%) had CAOP deter-mination. The remaining four patients failed toobtain a sufficiently elevated intracorporal pres-sure (because of profound CVOD) to allow themeasurement of CAOP. All of the 12 patients whohad CAOP measurement demonstrated abnormalgradients between brachial artery and cavernosalartery systolic blood pressures. Mean CAOPswere 62

±

25 mm Hg on the right side and64

±

18 mm Hg mm Hg on the left side. Thesevalues represent mean arterial inflow gradients of60

±

18 mm Hg and 56

±

18 mm Hg on the right

and left sides, respectively, thus indicating signifi-cant bilateral arterial insufficiency.

Corporovenocclusive Function Assessment

The entire study group underwent FTM measure-ment. Fourteen patients (85%) had abnormalFTM values, with a mean for these patients of35

±

34 mL/minute. Only eight patients (50%)were able to develop an intracorporal pressure of150 mm Hg in order to undergo PD assessment.All of these patients demonstrated abnormal PDvalues, with a mean value of 60

±

24 mm Hg.Twelve patients (75%) had cavernosography per-formed on them, the remaining four having med-ical histories precluding the use of contrast agent.In these latter patients, the application of perinealpressure at an intracavernosal pressure of90 mm Hg was used to assess crural competency.Cavernosograms of 10 patients demonstratedpatent venous channels, eight demonstratedvenous leak from the crura, and four had purecrural venous leak. In those men who did not havecavernosography, perineal compression failed tonormalize either FTM or PD values in anypatient, ruling out isolated crural venous leakagein these men (Table 2).

Discussion

X-rays were discovered by Roentgen more than acentury ago [6]. Soon after this discovery, itbecame apparent that vascular damage resulted

Table 1

Summary of erectile hemodynamic findings

Patient

Arterial inflow gradients (normal

£

30 mm Hg) FTM(Normal

£

3 mL/min)PD (Normal

£

45 mm Hg) CGramRight Left

1 68 64 49 —

†

—

‡

2 42 44 11 78 —

‡

3 36 32 2 42 No leak4 90 82 24 —

†

Leak5 72 70 21 54 Leak6 —* —* 100 —

†

Leak7 48 42 16 78 Leak8 38 32 28 65 Leak9 —* —* 100 —

†

Leak10 —* —* 64 —

†

Leak11 68 70 25 71 —

‡

12 72 64 3 32 No leak13 —* —* 82 —

†

Leak14 74 66 22 —

†

—

‡

15 70 71 12 64 Leak16 38 31 17 —

†

Leak

Mean values 59.7

±

18 55.7

±

18 34.7

±

33.8 60.5

±

24

* Patients in whom a sufficient intracavernosal pressure (ICP) could not be generated in order to measure cavernosal artery occlusion pressures.

†

Patients who did not have pressure decay (PD) measured because an ICP of 150 mm Hg could not be attained.

‡

4 of 16 patients did not have cavernosography because of concerns about contrast allergy.FTM

=

flow-to-maintain value.

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from radiation exposure. In almost 100 years oftherapeutic radiology, radiation-induced vasculop-athy has been studied in animal models as well asclinical populations. From an anatomic perspec-tive, the prostate is situated close to the penis,located superior to the point at which the cruradiverge and attach to the ischiopubic rami. Fur-thermore, the distal internal pudendal arteries andtheir terminal branches, the common penile, dor-sal, and cavernosal arteries also have an intimaterelationship with the prostate, which is situated onthe opposite side of the urogenital diaphragm [10].These vascular structures (arteries and crura) aretherefore placed at risk for X-ray exposure duringradiation therapy for pelvic diseases, includingprostate cancer.

Pretherapy simulation using radiographicimaging and conformational delivery techniques(CRTs) have lowered the exposure of healthy tis-sues to damaging ionizing radiation [11]. How-ever, despite the use of CRTs, patients still havetheir crura exposed to a significant amount of theradiation dose [11,12]. While the predominanteffects of radiation on the vasculature occurs at themicrovascular (arteriolar) level, at higher doses(

>

20 Gy) large arterial damage may occur.A number of factors appear to be important in

the determination of the extent of the vascularalterations that occur following radiation exposure[6]. The dose of radiation that is received is aprime determinant of damage extent, e.g., dosesbelow 12 Gy (1,200 rads) result in little damage tolarger vessels [13]. Generally, doses in excess of20 Gy are required to induce large vessel (arterial)injury. Prostate cancer patients typically receive inexcess of 60 Gy (6,000 rads). In our population ofpatients the mean dose was 72 Gy, well in excessof the dose required for arterial injury. Further-

more, a recent study exploring the effects of low-dose (0.1–1 Gy or 10–100 rads) gamma radiationon endothelial cells demonstrated morphologicchanges resulting in endothelial cell retraction[14]. These structural alterations may lead toexposure of the basal lamina with subsequentinitiation of microthrombus formation and mayeventuate in luminal occlusion. Thus, lower radi-ation doses may also result in alterations at thecellular level [14,15].

A second important factor is the timing ofpatient assessment following radiation therapy. Itis recognized that the effect of radiation vasculardamage has a biphasic nature, namely acute andchronic. Acutely, arterial luminal occlusion resultsfrom microvessel rupture [16] and tends to occurfrom weeks to months post radiation exposure.The chronic changes have been presumed to bethe result of endarteritis obliterans, which presentslater, between months and years following thecompletion of therapy. The mean interval betweenradiation exposure and onset of erectile difficultiesin our study group was 6 months.

Another determinant of the degree of end-organ injury is the field size of radiation delivery.The wider the area exposed, the more significantthe damage. In smaller fields, peri-field collateral-ization is possible, circumventing the deleteriouseffects of arterial occlusion [13]. In more extensivefields, the area of vessel damage prevents a viablenetwork of collaterals developing, and the func-tional effect of the arterial damage is more pro-nounced. This may be the case in radiation forprostate cancer in general and is worsened by thefact that the penile-cavernosal arterial system is anend-artery system with limited potential forcollateralization.

The fourth factor that is of importance withregard to the effects of radiation on the vasculatureis the coexistence of any vascular risk factors [6].In the hypercholesterolemic rabbit model, syner-gism has been demonstrated between radiationand the elevated serum cholesterol. Other diseasessuch as diabetes, hypertension, and cigarettesmoking are also believed to augment the detri-mental effects of radiation on the vasculature [13].These findings are supported by clinical informa-tion from an analysis of a group of patients under-going radiation therapy for prostate cancer. In thatstudy a statistically significant higher incidence(

P

=

0.02) of cigarette smoking was found in menwho lost potency compared with those whoretained it [17]. In our study group 22% had atleast one vascular risk factor.

Table 2

Summary of cavernosography findings*

PatientCruralveins

Cavernosalveins

Dorsalvein

Spongiosalveins

Otherveins

4

+

—

+ +

—5

+ + + +

—6

+

—

+ +

—7

+

— — — —8 —

+

—

+

—9 —

+

—

+

—10

+

— — — —13

+ +

— —

+

15

+

— — — —16

+

— — — —

* In 10 of 12 men who had a cavernosogram that showed patent venouschannels.

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The literature cites a tremendously disparateincidence of radiation-associated impotence, withfigures ranging from 20% to 84% [3–5]. With fewexceptions, these studies have been either ques-tionnaire- or interview-based without any formalvascular evaluation. In contradistinction, a previ-ously published study assessed the penile vascularstatus of 23 men who had received radiation ther-apy for prostate cancer. Fifteen of the 23 patients(65%) had loss of erectile function following com-pletion of their radiation therapy [17]. The vascu-lar evaluation was performed by using the penilebrachial index (PBI), specifically during exercise(pelvic steal test). This earlier study demonstratedsignificantly reduced PBI values in all 15 men withpostradiation impotence, compared with thosemen who had preservation of erectile function(0.60 vs. 0.85). Most authorities would suggestthat the use of PBI is antiquated and has beensupplanted by the use of modern evaluation eitherin the form of DIC or of duplex Doppler ultra-sound of the penile vasculature. Thus, there existsa paucity of contemporary hemodynamic analysesinvestigating the etiology of radiation-associatedimpotence. Zelefsky and Eid used Doppler penileultrasound to study men with ED following radi-ation therapy for prostate cancer [18]. In theirpopulation, 63% had arteriogenic dysfunction,and 32% had venous leak.

All of the patients in our study group admittedto adequate erectile function before the initiationof radiation therapy and complained of the com-mencement of erectile problems temporallyrelated to their radiation exposure. The mean lagperiod between radiation therapy and onset of EDwas 6 months (range 1–12 months). Our dataindicate that a major factor in the genesis ofpostradiation erectile impairment is a hithertounder-reported dysfunction of the venocclusivemechanism, as 85% of our patients demonstratedvenous leak.

Wiedermann et al. reported decreased smoothmuscle response to nitroglycerin following radia-tion exposure, implying potentially defective nitricoxide (NO)-mediated smooth muscle relaxation,which would impact negatively upon penile erec-tion [19]. This finding is supported by Carrieret al., who examined the effect radiation therapyhad on the number of NO synthase (NOS) con-taining nerve fibers in the rat penis. They foundthat there was a marked reduction in such fibers,which were dose-dependent in degree [20].

One of the criticisms of such studies is theabsence of any vascular assessment before radia-

tion therapy and the absence of pretherapy docu-mentation of sexual function with a validated EDscale. However, in our study all patients had func-tional erections before receiving radiation, and themagnitude of the vascular changes documented onDIC, pertaining to both arterial insufficiency andvenocclusive dysfunction, were such that theirpresence before radiation would have precludednormal erectile function. The predominance ofcrural leak is not unexpected as the corporalsmooth muscle most exposed to radiation is thatwithin the proximal-most portion of the corporalbodies [12]. The degree of venocclusive dysfunc-tion in this analysis is unlikely to be explained bythe vascular comorbidity profile of the patientpopulation.

We have previously demonstrated that 35% ofthe total planning target volume dose of radiationis delivered to the proximal-most 2–3 cm of thecorporal body [12]. What the erectile hemody-namic profile of the patients would be if the timepostradiation therapy was longer is impossible topredict. However, it is unlikely that it would beany better than that of the patients in this studyand is likely to be worse, based on progression ofradiation-associated vasculopathy as well as pro-gression of vascular comorbidity-associated arte-rial and smooth muscle changes. These findingshave also driven us to explore more sophisticatedradiation therapy strategies to minimize dose tothe corporal tissues. We have shown that by usingintensity modulated radiotherapy we can reducethe dose to these structures almost by half [11].

Conclusions

We present a hemodynamic analysis using sophis-ticated vascular testing in patients complaining ofED following pelvic radiation therapy for prostatecancer. We have demonstrated a 100% incidenceof cavernosal artery insufficiency and a 90% inci-dence of corporovenocclusive dysfunction in the16 patients who developed ED after radiotherapy.In 50% of the cases with corporovenocclusivedysfunction, leak was from the crura alone. Thisinformation may help clinicians educate patientsregarding the mechanism of radiation-associatederectile function impairment.

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