Salvage therapy trial for erectile dysfunction using phosphodiesterase type 5 inhibitors and vitamin E: Preliminary report

Abstract

We report our initial experience with salvage therapy for low responders to PDE-5 inhibitors by adding vitamin E. Of 89 patients with ED who visited our clinic between January 2004 to August 2006, 9 were unable to obtain a full response to a PDE-5 inhibitor and included in the present study. After providing informed consent, each was given 300 mg per day of α-tocophenol at least 1 month and completed IIEF-5 questionnaires to assess its efficacy while also taking a PDE-5 inhibitor. With α-tocophenol administration, the average IIEF-5 score increased from 13.8 ± 3.2 to 17.1 ± 3.6. Four of seven patients who completed the questionnaire each time showed improved IIEF-5 scores, with a maximum elevation of 9 points. Further, eight of the nine patients experienced favourable subjective changes, the majority being increased penile rigidity. The present clinical trial results are, to our knowledge, the first known to show the effects of vitamin E for enhancing the efficacy of a PDE-5 inhibitor.

Keywords:

• Erectile dysfunction
• oxidative stress
• PDE-5 inhibitor
• vitamin E
• salvage therapy

Introduction

Diabetes mellitus (DM), hypertension, and cigarette smoking are well known independent risk factors for erectile dysfunction (ED) [1]. For patients with DM, the most important clinical feature related to the genitourinary system is ED, which occurs in approximately 75% of those men [2],[3]. Although phosphodiesterase type 5 (PDE-5) inhibitors had made dramatic impact as treatment modalities for ED, with nearly 90% efficacy obtained in general populations, only slightly more than 50% of diabetic men have been reported to respond favourably to such treatment [4]. The reason why treatment for diabetic ED is relatively difficult can be mainly explained by oxidative stress-mediated neurovascular alterations, which induce impaired endothelial function and neuropathy in the corpus cavernosum. Therefore, ED and cardiovascular diseases share some fundamental causal factors and patho-mechanisms, including nitric oxide (NO)-mediated pathways [5].

NO is derived from vascular endothelial and neural sources, and mediates the early steps of the normal cascade of relaxation in the penile vasculature and cavernous smooth muscle through the cyclic guanosine monophosphate (GMP) system [6]. Consequently, NO plays a critical role in the mechanism of the efficacy of PDE-5 inhibitors, by maintaining cyclic GMP concentration through suppression of the function of PDE-5. On the other hand, NO is also a highly reactive free radical and interacts with superoxide anion to form peroxynitrite, which reduces the available NO concentration. Since this decreased availability of NO has been postulated to be the most important cause of ED [3],[5], adequate control of free radicals could enhance the effectiveness of PDE-5 inhibitors.

Vitamin E is a potent lipid-soluble oxygen free radical scavenger [7], whose delivery will theoretically increase the level of circulating NO, resulting in further relaxation of the penile vasculature and cavernous smooth muscle obtained by use of a PDE-5 inhibitor. De Young et al. first demonstrated that vitamin E enhanced the therapeutic effects of sildenafil, the most common PDE-5 inhibitor, in a diabetic animal model [8], and concluded that the interaction of oxygen free radical scavenger therapy with PDE-5 inhibitors might provide an enhanced erectile response for diabetic men with ED. In the present prospective study, we evaluated the efficacy of oral vitamin E (α-tocophenol) administration combined with a PDE-5 inhibitor in a group of ED patients, including diabetic men.

Patients and methods

From January 2004 to August 2006, 89 men came to our clinic with a complaint associated with ED. They were treated with an administration of 50 mg of sildenafil or 10 mg of vardenafil once on demand, as those doses are the upper limit allowed in Japan.

Although most of our patients obtained an excellent response with the criterion of achieving intra-vaginal ejaculation to their satisfaction, nine did not gain such a result. Each of those nine patients, who ranged in age from 46–74 (mean 61.6) years old, were enrolled in the present study of combined treatment with a PDE-5 inhibitor and vitamin E, after providing informed consent. Following an additional administration of 300 mg per day of α-tocophenol (Juvela®) for at least one month, the patients were asked to continue to take the same PDE-5 inhibitor in the same way as before, and also complete the International Index of Erectile Function (IIEF)- 5 questionnaire [9] before and after the addition of α-tocophenol administration. Any changes in subjective symptoms were noted in interviews, while the basal serum levels of luteinizing hormone (LH), follicular-stimulating hormone (FSH), and free testosterone were assessed from blood samples. Statistical analysis was not performed, because of the low number of subjects.

Results

Patient characteristics are shown in Table I. Six men received administrations of sildenafil and three vardenafil. The causes of ED in the subjects were DM in four, while disc herniation, hyperlipidemia, chronic hepatitis and unknown were the causes in the other five. The average serum free testosterone level in all subjects was 7.38 ± 2.45 pg/ml (mean ± SD). The study results are shown in Table II. The average IIEF-5 scores before and after α-tocophenol administration were 13.8 ± 3.2 and 17.1 ± 3.6, respectively. The score following the initial PDE-5 inhibitor administration increased by an average value of 8 points, however, none of the subjects attained greater than 21, the cut-off level for ED. Addition of α-tocophenol improved the IIEF-5 scores in five men, including one who gained 9 points. Three of the subjects did not obtain any improvement in IIEF-5 score, though they were satisfied with the subjective changes. Subjective changes first appeared several days after the addition of α-tocophenol, the majority of which were various levels of increased penile rigidity. No adverse effect owing to α-tocophenol was reported. Changes in IIEF-5 scores were evaluated from the results of three questionnaires completed by each patient, as shown in Figure 1.

Figure 1. Changes in scores of IIEF-5 questionnaires given 3 times; before treatment, after treatment with a PDE-5 inhibitor alone, and after combined treatment with α-tocophenol and a PDE-5 inhibitor.

Table I.  Patient characteristics.

				Serum hormones
Patient	Age (years)	PDE5-I	Risk factors	LH (mIU/ml)	FSH (mIU/ml)	free-T (pg/ml)
1	65	Sil	DM	3.2	7.2	5.0
2	71	Var	DM	10.2	13.0	7.2
3	59	Sil	Hyperlipidemia	4.4	10.2	7.6
4	46	Sil	DM	4.6	23.2	6.1
5	65	Var	Disc herniation	2.6	6.9	7.9
6	56	Sil	Unknown	2.5	8.6	5.2
7	55	Sil	Disc herniation	6.2	9.7	13.1
8	74	Var	DM	10.3	14.2	6.0
9	63	Sil	Chronic hepatitis	5.1	6.6	8.3

PDE5-I, PDE-5 inhibitor; Sil, Sildenafil; Var, Vardenafil; T, Testosterone.

Table II.  Study results.

	IIEF-5
Patient	I	II	III	Subjective change
1	11	11	20	excellent improvement on penile rigidity and erection-maintenance
2	2	8	12
3	5	15	22	increased penile rigidity
4	6	15	19	warming sensation
5	ND	12	19	increased penile rigidity
6	10	17	16	increased penile rigidity and frequency of morning erection
7	10	15	11	increased penile rigidity, warming sensation
8	5	17	17	warming sensation
9	9	ND	18	increased penile rigidity

I, IIEF-5 score determined before PDE-5 inhibitor administration; II, IIEF-5 score determined after.

PDE-5 inhibitor administration; III, IIEF-5 score after PDE-5 inhibitor and α-tocophenol.

administration; ND, not done.

Discussion

Diabetic vasculopathy is firmly associated with the oxidative stress-mediated etiology of ED, resulting in a reduced efficacy of PDE-5 inhibitors as compared with non-diabetic individuals with ED. As previously noted, an impaired availability of NO due to endothelial dysfunction caused by oxidative stress results in cavernosal dysfunction and is a key patho-mechanism of diabetic ED. In fact, this scenario may be the same in all types of vasculogenic ED, such as arteriogenic ED [10] and hypercholesterolemia [11]. Therefore, much attention has been paid to antioxidant therapy [12] and NO donating [11] as attractive new therapeutic strategies for ED.

In 2004, an important report was published by De Young et al. [8]. In that study, rats with streptozotocin-induced diabetes were tested for three weeks after being divided into four groups, in which group 1 received no treatment (control), group 2 vitamin E, group 3 sildenafil, and group 4 vitamin E and sildenafil. Intracavernosal pressure (ICP) during electrostimulation increased by the largest amount in group 4 and was statistically greater as compared with that in group 1. The authors concluded that vitamin E enhanced the therapeutic effect of the PDE-5 inhibitor, supporting the potential use for salvaging erectile function in sildenafil low responders.

In our andrological clinic, low responders to sildenafil at a dose of 50 mg or vardenafil at 10 mg are offered second line treatment options after re-education [13], including intracavernous injection, because the maximum doses of sildenafil and vardenafil in Japan are 50 mg and 10 mg, respectively. However, it is difficult to obtain the approval of patients for those treatments, outside of oral administration in this era of PDE-5 inhibitors. Therefore, we first began to prescribe α-tocophenol in February 2005 for a sildenafil low responder suffering from diabetic ED (present patient 2), based on the results of the previously mentioned study of De Young et al. The IIEF-5 score for that patient was increased by 4 points after α-tocophenol administration for a final score of 12. However, another patient with diabetes achieved a drastic improvement of 9 points and reached a final score of 20, along with desirable subjective changes (present patient 1). This difference in drug efficacy may be ascribed to the duration in which patients and their cavernous tissues are influenced in a diabetic condition. In the study of De Young et al., the diabetic rats used as an animal model of relatively early stage DM did not have extensive end organ damage. In their report, they commented that the outcome might not lend itself to direct human comparison, where diabetes is often detected and treated several months or years after onset.

In the present study, the addition of α-tocophenol led to increased scores in 57% of the patients who completed the questionnaire on all three occasions, (Figure 1). In contrast, even though a good final score was achieved by patient 1, as mentioned above, that subject saw no significant effect from the PDE-5 inhibitor alone in regard to the IIEF-5 score, whereas three patients responded to the PDE-5 inhibitor prior to vitamin E administration to a small or moderate degree, and showed a pattern similar to patient 3. These results seen in patient 1 are inconsistent with those of De Young et al., as those diabetic rats also responded to treatment with the PDE-5 inhibitor prior to being given vitamin E. A possible reason for this discrepancy may be inadequate usage of the PDE-5 inhibitor by the subject prior to re-education at the time of α-tocophenol addition. Another possibility could be that impairment of NO availability was so great that it diminished the function of the PDE-5 inhibitor in that patient.

In the present trial, non-diabetic ED and ED patients without an episode of diabetes reported by interview saw improved IIEF-5 scores with the addition of α-tocophenol. Since a placebo effect cannot be denied and the number of subjects is low, it is difficult to conclude that our results confirm the hypothesis that excessive levels of free radicals can fundamentally cause ED, the same as in male infertility [14], which is an important issue that remains to be clearly elucidated. In other words, if oxidative stress is the crucial factor from the standpoint of the pathophysiology of ED, vitamin E or other potent antioxidants should be routinely given to all ED patients. Nevertheless, our results indicate that salvage therapy using a PDE-5 inhibitor plus vitamin E has important therapeutic potential, which should be studied with a large population, including a randomized clinical trial.

Recently several meta-analyses reported that routine use of vitamin E provides no benefit in cardiovascular mortality [15],[16]. In spite of the outcome, we don't think that use of vitamin E should be strictly restricted for ED patients. Although oxidative stress plays a central role for both ED and cardiovasculopathy (atherosclerosis), it is presumed that population of clinical use for ED and prophylactic use for cardiovasculopathy is different. Moreover, our vitamin E dosage of 300 mg (200 IU) per day is not very high. Pre-treatment of a certain period of vitamin E before the administration of PDE-5 inhibitor other than routine use could be a choice.

To our knowledge, these are the first reported results of a clinical trial demonstrating the effectiveness of PDE-5 inhibitor administration combined with vitamin E for salvaging low responders to a PDE-5 inhibitor. This subject number is very small and only 10% of all patients because PDE-5 inhibitor was effective for most ED patients in our clinic without vitamin E. Additional studies should be performed to determine the optimal dose of vitamin E and duration of pre-treatment before taking a PDE-5 inhibitor, as well as to obtain significant parameters for the assessment of drug efficacy. We believe that the present results may provide a first step to establishment of a new antioxidant therapy in patients with difficult-to-treat ED.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.