A Prospective, Multicenter Study on Efficacy of Long-Acting Testosterone Undecanoate, If Desired in Combination with Vardenafil, in Late Onset Hypogonadal Patients with Erectile Dysfunction

Sompol Permpongkosol, Krisada Ratana-Olarn, Anupan Tantiwong, Kavirach Tantiwongse, Apichat Kongkanand

Department of Surgery, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Bangkok, Thailand.
Department of Surgery, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
Department of Surgery, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Department of Urology, Bumrungrad International Hospital, Bangkok, Thailand.

DOI: 10.4236/oju.2013.33026                

Abstract

Introduction: There is substantial evidence suggesting the additive effect on erectile function (ED) of testosterone and phosphodiesterase (PDE)-5 inhibitors. But the combination of long-acting testosterone undecanoate (TU), in combination with the PDE5-I vardenafil men with with late-onset hypogonadal patients (LOH) with (ED) has not yet been studied. Aims: To evaluate the effects of TU i.m., and if desired, the PDE5i vardenafil (PDE-5I) in LOH patients with ED measured with the International Index of Erectile Function (IIEF-5). Methods: A prospective study was performed following four administrations of TU in week 0, 6, 18, 30. If no improvement of ED assessed with IIEF-5 or the Global Assessment Questionnaire (GAQ) in week 12, the PDE5 inhibitor vardenafil was added. The final evaluation was in week 46. Main Outcome Measures: Aging Male Symptom (AMS) score, IIEF-5 score, and International Prostate Symptoms Score (IPSS) at each visit were summarized as mean with standard deviation; while GAQ was summarized using frequency and percentage. Scores at each visit were also categorized into different levels of symptom severity. Results: AMS score decreased significantly at week 12, 30 and 46. IIEF-5 score increased but a significant change was found only at week 30 and 46. The GAQ assessment indicated erection and sexual intercourse already improved at the first assessment continuing thereafter. IPSS score decreased from baseline at week 46. Levels of total, free and bioavailable testosterone had increased significantly from baseline at all visits. Hematocrit, hemoglobin and prostate specific antigen increased significantly from baseline. Adverse events were rare with pain at injection site found in one patient. The two events were non-serious in type, mild in their intensity and recovered. Conclusions: Therapy with TU and, and if desired, combined with the PDE5 inhibitor vardenafil improved sexual activity in LOH patients with ED.

Keywords

Testosterone; Hypogonadanism; Erectile Dysfunction; Phosphodiesterase (PDE)-5 Inhibitors

1. Introduction

Conservative estimates suggest that approximately 12% of patients with ED may have subnormal levels of testosterone [1,2]. Hypogonadism on the basis of testicular disease (primary hypogonadism) or hypothalamo-pituitaty disease (secondary hypogonadism is rather easily diagnosed and patients usually receive testosterone replacement. However, decreased testosterone production also may occur with advancing age, the so-called late-onset hypogonadism (LOH) or androgen decline in the aging male [2-4]. Recent studies indicate that it is not age per se that determines the severity of LOH, but rather pathologies frequently occurring with advancing age such as obesity, the metabolic syndrome and other chronic medical disorders, such as diabetes type II [5]. It has been and is still debated whether this decline of testosterone is clinically relevant. The international consultation on sexual and erectile dysfunction recommended that adult onset hypogonadism be defined as clinical and biochemical syndrome [6,7] having both clinical signs of androgen deficiency and an objectively low serum testosterone. Testosterone plays a key role in the central and peripheral modulation of erectile function. New research in laboratory animals and in humans is shaping a better definition of the role of testosterone therapy in ED. It appears that testosterone (T) has effects not only on sexual desire, but also on the anatomical and physiological substrate of erection. Hypogonadism, when present, should be treated regardless of age because of the effects of testosterone on bone, muscle and metabolism. At least 30% - 35% of men with ED fail to respond to treatment with PDE-5 inhibitors. Several studies indicate synergistic effects of testosterone replacement therapy with a PDE-5 inhibitor [8]. Recently, Kim et al. suggested that combination therapy of TU and tadalafil in PDE5I non-responders with severe and intermediate testosterone deficiency was more beneficial to patients with severe testosterone depletion, possibly by improving underlying pathophysiology of the erectile mechanism [9]. Up to now, long-acting testosterone undecanoate (TU), in combination with vardenafil in men with LOH with ED has not yet been studied. Therefore, in this study the role of TU in the treatment of ED, was monitored and if desired vardenafil was added to evaluate how they benefit LOH patients with ED.

2. Aims

Primary objectives are to evaluate the response of a treatment with TU i.m. and, if desired by the patient combined with vardenafil in LOH patients with ED, using the International Index of Erectile Function (IIEF)-5 score. Secondary objectives were to determine the level of total and free testosterone in the patients under treatment and their impact on the Aging Male Symptom (AMS) and General Assessment Question (GAQ). Furthermore, potentially adverse events, such as changes of hemoglobin and biochemical blood parameters (lipid and glucose profile), prostate specific antigen (PSA) and of digital rectal examination were recorded.

3. Methods

The selection criteria for inclusion in the study were patients with ED with a duration over 3 months, age > 18 years, a stable sexual relationship, low or low normal serum testosterone level TT < 300 ng/dl, (<10.4 nmol/L) AMS scale with total score starting at 37 points. Subjects who previously took the oral androgen or a PDE-5 inhibitor should have discontinued their use for at least one month. The exclusion criteria were the well-known contra-indications to either testosterone or PDE-5 inhibitors, such as diagnosed or suspected carcinoma of the prostate or the male breast cancer, past or present liver tumors or acute or chronic hepatic diseases.

A total 30 patients with LOH with ED were entered into the study. The study was composed of 3 phases: screening phase, baseline, and 30-week treatment phase, and follow up. Upon entry of the subject in treatment phase of the study, each subject received TU i.m. (NEBIDO^®) 1000, on week 0, 6, 18, 30. If the patient did not report improvement of ED as assessed by the IIEF-5 or GAQ in week 12, treatment with vardenafil was added. Doses of vardenafil varied from 5 to 20 mg, from week 12 of the study onwards following the advice of the attending physician. The final evaluation was in week 46. The study did not require any changes in the existing concomitant treatment of the patient. The present protocol did not allow of dose of testosterone. There was no replacement of subjects who drop-out of the study.

4. Main Outcome Measures

Demographic and clinical characteristics of patients at baseline were summarized using descriptive statistics including frequency, percentage and mean with standard deviation. Main outcomes including AMS score, IIEF-5 score, and IPSS at each planned visit were summarized as mean with standard deviation; while GAQ was summarized using frequency and percentage. Each of AMS, IIEF-5 and IPSS scores at each visit was also categorized into different level of symptom severity based on well known defined criteria and presented as frequency and percentage. For continuous outcomes, difference between baseline value and each visit for each of outcomes was tested for statistical significance using paired t-test or Wilcoxon signed rank test as appropriate. For categorical outcomes, McNemar test or marginal homogeneity test was used as appropriate. Significance level (Type I error rate) was not adjusted for multiple comparisons.

5. Results

Thirty male patients were enrolled, but five patients dropped out and did not visit the center in violation of the protocol requirement. Therefore, data of 25 patients who received a complete set of 4 doses of TU injections were used for analysis. Table 1 demonstrates baseline patient demographics and clinical characteristics. We found that as many as 23 of 25 patients (92%) used vardenafil at least once during study periods after the second injection (week 12) when they had had 6 weeks treatment with TU.

Table 2 shows the effect of 1000 mg TU injection on the AMS and IIEF-5. Compared with baseline (44.40), the AMS score decreased significantly at week 12, 30 and 46 (p-value = 0.001, <0.001 and <0.001, respectively). Fifty-two percentages of patients were in moderate level at baseline, while more patients significantly

Conflicts of Interest

The authors declare no conflicts of interest.

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