Measurement of intracavernosal catecholamine during a prostaglandin E₁ test

Abstract

Background : Erectile dysfunction (ED) can be a cause of male infertility among young men. The prostaglandin E₁ (PGE₁) intracavernous injection test, an erectile function test, is known as an objective method of examining the penile vasculature system. However, some ED patients fail to sufficiently maintain an erection because of the stress load upon them during the test. Thus, we measured changes in catecholamine levels by stress loading when we performed dynamic infusion cavernosometry (DIC).

Methods : Among the 221 ED patients undergoing a PGE₁ test, 10 were selected as the subjects for the present study. These 10 patients were 25–56 years of age, with a mean of 32.8 years, whose maximal penile rigidity was normal, but in whom penile erection could not be maintained sufficiently in the PGE₁ test. Stress loading via vibratory sensory measurement during the PGE₁ test suppressed penile rigidity strongly. Catecholamine levels were measured by using blood samples obtained from the corpus cavernosum and the cubital vein when erection was suppressed by stress loading, pain caused by needle insertion, and also when erection recovered from the suppression. Dynamic infusion cavernosometry was performed after each blood sampling time, to check corporeal veno‐occlusive function and cavernosal arterial flow.

Results : Penile norepinephrine levels were 0.20 ± 0.06 ng/mL during a suppressed erection and 0.15 ± 0.03 ng/mL during an erection, showing a significantly higher level (Student’s t‐test, P = 0.0309) during suppressed erection. The results of the DIC measurement indicated a normal corporeal veno‐occlusive function and cavernosal artery in all cases.

Conclusion : The results of the present study revealed that corporeal veno‐occlusive function and cavernosal arterial flow are normal in men who have normal maximum penile rigidity, but cannot sufficiently maintain the erection in the PGE₁ test, suggesting the involvement of stress‐induced penile norepinephrine in the suppression of erection maintenance. (Reprod Med Biol 2002; 1: 11–15)

Introduction

ERECTILE DYSFUNCTION (ED) can be a cause of male infertility among young men. The technique of an intracavernosal injection of prostaglandin E₁ (PGE₁) has been used extensively worldwide in the diagnosis and treatment of ED since the experimental report by Hedlund and Andersson on the relaxing effect of PGE₁ on human penile tissue. ¹ Ishii et al. reported its use as treatment for erectile impotence. ² Because of its high level of reproducibility, the PGE₁ test has been highly regarded as a valuable diagnostic tool in the investigation of the penile vascular system. However, more recently, a number of factors that can affect the response to PGE₁ have been identified. Our research has shown that a maximal PGE₁‐induced erection can be achieved by simultaneous loading with a combination of audiovisual sexual stimulation (AVSS) and manual stimulation (MS), and that such an erection is suppressed by stress loading. ³ , ⁴ Moreover, we have found that this stress‐induced suppression can be prevented, to some extent, by injecting PGE₁ in combination with an α‐blocker. ³ , ⁵ Thus, we measured changes in the catecholamine levels by stress loading when we performed dynamic infusion cavernosometry (DIC) to determine the presence or absence of a penile vascular disorder (particularly a venous disorder).

Methods

SUBJECTS WERE SELECTED among 221 patients with erectile dysfunction (ED) who underwent a PGE₁ test at the Reproduction Center, Omori Hospital, Toho University School of Medicine during a 3‐year period from March 1994 to March 1997. They consisted of 10 cases in whom it was found that penile erection was good for a short period of time but could not be maintained sufficiently in the PGE₁ test, and it was also found that stress loading via a vibratory sensory measurement during the PGE₁ test suppressed penile rigidity strongly (Fig. 1). The age of the patients ranged from 25 to 56 years, with a mean age of 32.8 years. Maximum penile rigidity (R), measured in the initial PGE₁ test with a RigiScan™ (Timm Medical Technologies Inc., Eden Prairie, MN, USA), was 69.6 ± 8.3% at the tip and 70.3 ± 11.8% at the base, penile rigidity (r) at suppressed erection was 30.3 ± 10.2% at the tip and 31.7 ± 10.4% at the base, and the rigidity suppression rate [(R − r)/R] was 56.3 ± 15.3% at the tip and 53.9 ± 14.5% at the base (Fig. 2). Maximal penile tumescence (T) was 3.18 ± 0.39 cm at the tip and 3.26 ± 0.55 cm at the base, penile tumescence at a suppressed erection was 1.71 ± 0.60 cm at the tip and 2.30 ± 0.68 cm at the base, and the tumescence suppression rate [(T − t)/T] was 47.2 ± 19.7% at the tip and 29.8 ± 16.9% at the base. Accordingly, the values of maximal penile rigidity (R) and maximal penile tumescence (T) of these subjects were within the normal range.

Figure 1.

Prostaglandin E₁ (PGE₁)‐induced erection was suppressed by stress loading via vibratory sensory measurement. This is RigiScan data of the representative case of subjects. (a) Tip, (b) base, (i) rigidity (%), (ii) tumescence (cm). (□) Audiovisual sexual stimulation (AVSS) loading, () manual stimulation loading, () stress loading.

Figure 2.

Penile rigidity of the subjects (n = 10). Maximal penile rigidity is normal, but erection is strongly suppressed. (a) Tip, (b) base, (□) maximal rigidity (R), (▪) suppressed rigidity (r),() suppression rate (()/R).

Blood was withdrawn from the corpus cavernosum and cubital vein in the 10 patients who could not maintain an erection when DIC was performed to determine the presence or absence of penile vascular disorder (particularly venous disorder). The state of erection was evaluated through visual observation and palpation, without using a RigiScan™.

First, the patients received an intracavernosal injection of 20 µg PGE₁, and then AVSS and MS loads were applied simultaneously. After maximum erection was achieved, a 19 G winged needle was inserted into the corpus cavernosum and cubital vein, without anesthesia (neither marked bleeding nor ecchymosis occurred by the insertion of a 19 G winged needle). After confirming the suppression of penile rigidity by stress loading, pain induced by a needle insertion, blood was withdrawn from the corpus cavernosum and cubital vein, while the indwelling winged needle remained in situ. Furthermore, both AVSS and MS were simultaneously performed and blood was withdrawn, via a similar method used when the penis was in an erected state. The catecholamine assay was performed on the blood samples. Differences in catecholamine levels were analyzed by using a Student’s t‐test, and a P value of < 0.05 was considered to indicate statistical significance.

After completion of the blood sampling, DIC was performed, and the corporeal veno‐occlusive function and the cavernosal artery were checked (Fig. 3).

Figure 3.

Flowchart of the tests. DIC, dynamic infusion cavernosometry.

Results

A COMPLETE ERECTION could be produced temporarily in all of the 10 patients, but it was suppressed by stress loading, pain caused by the insertion of a 19 G winged needle. Erection was again achieved by using AVSS and MS, and DIC could be successively performed.

Penile norepinephrine levels were 0.20 ± 0.06 ng/mL during a suppressed erection and 0.15 ± 0.03 ng/mL during an erection, thus showing a significantly higher level (Student’s t‐test, P = 0.0309) during a suppressed erection. The cubital venous norepinephrine level during a suppressed erection was 0.25 ± 0.04 ng/mL, and did not differ significantly from the value of 0.22 ± 0.04 ng/mL during an erection. At erection, the norepinephrine level was 0.15 ± 0.03 ng/mL in the penis and 0.22 ± 0.04 ng/mL in the cubital vein, thus showing a significantly higher level (t‐test, P = 0.000367) in the cubital vein relative to the penis. At erection suppression, the norepinephrine level in the cubital vein was higher than in the penis, although the difference was not significant (t‐test, P = 0.0508; Fig. 4).

Figure 4.

Changes in noradrenaline (n = 10, normal value 0.15–0.57 mg/mL). Penile noradrenaline was significantly higher as assessed by a t‐test (P < 0.05) during a suppressed erection. A significant difference was not seen in the level of cubital vein noradrenaline at erection, relative to suppressed erection. The noradrenaline value at erection was significantly higher (t‐test, P < 0.001) in the cubital vein, relative to the penis; moreover, the noradrenaline value at suppressed erection was higher, although not significantly, in the cubital vein, relative to the penis.

The penile epinephrine level was 0.04 ± 0.02 ng/mL at erection suppression, which was not significantly different from the value of 0.03 ± 0.02 ng/mL at erection. Similarly, the epinephrine level in the cubital vein at erection suppression was 0.04 ± 0.02 ng/mL, which was not significantly different (t‐test, P = 0.46) from the value of 0.04 ± 0.02 ng/mL at erection (Table 1).

Table 1.

Changes in adrenaline and dopamine level

	Corpus cavernosal blood(ng/mL)	Cubital venous blood (ng/mL)
Changes in adrenaline
Suppressed erection	0.038 ± 0.020	0.042 ± 0.017
Maximum erection	0.033 ± 0.018	0.036 ± 0.018
Changes in dopamine
Suppressed erection	0.02	0.02
Maximum erection	0.02	0.02

All results were not significant.

The dopamine levels of both the penis and the cubital vein at erection suppression, and at erection, were 0.02 ng/mL or below, thus showing the absence of any significant differences (Table 1).

The results of DIC measurement were normal corporeal veno‐occlusive function and normal cavernosal artery in all cases (Table 2).

Table 2.

Dynamic infusion cavernosometry (DIC)

	Test value	Judgment
Flow to maintain erection Normal value >10 mL/min	0∼9 mL/min3.0 ± 2.25 mL/min	Corporeal veno‐occlusive functionAll cases normal
Cavernosal artery systolic occlusion pressure (CASOP) Normal value <100 mmHg	105∼130 mmHg113.3 ±  6.93 mmHg	Cavernosal arteryAll cases normal
Systolic blood pressure (BP)‐CASOP	15∼30 mmHg	Cavernosal artery
Normal value >35 mmHg	18.7 ± 7.01 mmHg	All cases nornal

n = 10.

Discussion

PROSTAGLANDIN E₁ IS used as a test of the penile vascular system. In order to evaluate penile rigidity and penile tumescence, tests such as color Doppler sonography, dynamic infusion cavernosometry and cavernosography (DICC), and pharmacoangiography are required. However, if the response to PGE₁ is suppressed by a factor other than penile vascular dysfunction, the test will give a false‐positive result.

Lee et al. applied visual sexual stimulation at the same time as the administration of an intracavernosal PGE₁ injection during color Doppler sonography in patients with anxiety, in order to overcome the problem of a sympathetic suppression of the vasoactive drug action. ⁶

Based on the premise that sympathetic stimulation suppresses erection, Katlowitz et al. ⁷ , ⁸ reported obtaining a potentiated response by applying audiovisual sexual stimulation after simultaneously administering PGE₁ with tri‐mix (a mixture of papaverine, phentolamine, and PGE₁).

As reported previously, we found that the erection response was suppressed by stress loading with the use of a vibratory sensory measurement, ⁹ which is used to examine peripheral nerve function in the PGE₁ test, and that the suppression of an erection response by stress loading could be prevented to some extent when 2.5 mg phentolamine was concomitantly administered with 20 µg PGE₁. In our previous study, ⁵ when maximum penile rigidity was achieved, and measured with the use of a RigScan™, it was induced by AVSS or by both AVSS and MS following an injection of 20 µg PGE₁ alone in 58 patients (mean age 43.2 years). Following the injection both 2.5 mg phentolamine and 20 µg PGE₁ in 56 patients (mean age 44.1 years), no difference in rigidity at the tip or base of the penis was detected between these two groups by the use of the Student’s t‐test (P > 0.05). However, the degree of erection suppression by stress loading was significantly smaller in the latter group at both the tip and base of penis on the t‐test, compared with the former group (P < 0.05 and P < 0.001, respectively; Fig. 5).

Figure 5.

Effect of phentolamine in preventing the suppression of prostaglandin (PG)E₁‐induced erection by stress loading. In the group given PGE₁ combined with phentolamine (•), stress loading‐induced suppression of the erection was significantly reduced. (•) PGE₁ 20 µg, n = 58, (s) PGE₁, 20 µg phentolamine, 2.5 mg, n = 56. (a) Tip, (b) base, (i) audiovisual sexual stimulation (AVSS) loading–first response period, (ii) stress‐loading–suppression period, (iii) simultaneous loading of AVSS and manual stimulation (MS) (second response period).

These findings prompted us, in the present comparative study, to assay catecholamine levels in blood collected from the penis and cubital vein during an erection and a suppressed erection. Although we selected 10 patients from 221 ED patients, based on the results of the stress‐loading test with vibratory sensory measurement, needle insertion without anesthesia was used as a means of stress loading in the present study because erectile suppression was identical between the two methods. Hence, we collected blood samples first from the patients in the suppressed erection state, and then applied AVSS and MS loading simultaneously to recover the erection and obtain blood samples in the erected state. Because the norepinephrine level of the penis during a suppressed erection was significantly higher (t‐test, P = 0.0309) than at erection, we deduced that erection suppression at stress loading occurs via the action of norepinephrine.

This notion is supported by the fact that a combined administration of phentolamine ameliorated this erection suppression to some extent. Furthermore, we found that the norepinephrine level was significantly higher (t‐test, P = 0.000367) in the cubital vein than in the penis, suggesting that norepinephrine secreted from a region other than the penis may participate in the suppression of an erection.

In our 10 ED patients, who failed to maintain an erection, DIC was performed to determine the presence or absence of penile vascular disorder (particularly venous disorder). Yanagi et al. diagnosed an artery disorder when the time to equilibrium was > 10 min, and a venous disorder when the corporeal pressure decay altered from 150 mmHg/30 s to > 2.6 mmHg/30 s. ¹⁰ We evaluated venous disorder by using cavernosal saline injection velocity flow to maintain an erection, and artery disorder by using cavernosal artery systolic occlusion pressure (CASOP). Systolic blood pressure (BP) minus CASOP (CASOP or BP minus CASOP) values were consistent with the results of arteriography, ¹¹ , ¹² and they were within the normal range in all subjects. These findings suggest that if the maximal penile rigidity is within the normal range, the corporeal veno‐occlusive function and the cavernosal artery may be normal even in patients whose erection is suppressed strongly.

In conclusion, venogenic or arteriogenic erectile dysfunction could be excluded from possible mechanisms of ED in patients who produced normal maximum penile rigidity, but failed to sufficiently maintain the erection in the PGE₁ test because the results of dynamic infusion cavernosometry (DIC) performed in the present study revealed that corporeal veno‐occlusive function and cavernosal arterial flow were normal in these patients. From penile catecholamine measurements, performed simultaneously with DIC, it was inferred that stress‐induced penile norepinephrine can also be involved in ED.