International Journal of Impotence Research (2013) 25, 29–33 & 2013 Macmillan Publishers Limited All rights reserved 0955-9930/13 www.nature.com/ijir ORIGINAL ARTICLE Combination therapy of testosterone enanthate and tadalafil on PDE5 inhibitor non-reponders with severe and intermediate testosterone deficiency JW Kim1,MMOh1, MG Park2, JY Park3, JH Bae3, JJ Kim4 and DG Moon1 Several studies have suggested combination therapy with testosterone supplementation in patients not responding to PDE5 inhibitors. Considering the pathophysiological basis for testosterone supplementation, the present study aims to identify whether combination therapy allows persistence of treatment effect after testosterone discontinuation. Furthermore, we evaluated whether the degree of testosterone depletion affects treatment outcome from combination therapy. Hypogonadal patients (o350 ng dl À 1) with erectile dysfunction who previously did not respond to PDE5 inhibitors were treated with testosterone enanthate injections and daily tadalafil. Patients were stratified into two groups depending on the level of testosterone deficiency, with 250 ng dl À 1 as a reference point. Following testosterone supplementation (12 weeks) and combination therapy (12 weeks), patients with severe testosterone deficiency showed higher IIEF (International Index of Erectile Function) erectile function (EF) domain score (16.47±4.019 vs 12.36±4.051, P ¼ 0.001) and more patients responding satisfactorily to treatment by general assessment (57.9 vs 16.0%, P ¼ 0.009), despite reaching similar levels of serum total testosterone (602±169 ng dl À 1 vs 698±165 ng dl À 1, P ¼ 0.057). Testosterone supplementation was then discontinued and patients were maintained only on daily tadalafil (12 weeks). The severe depletion group maintained higher EF domain scores than baseline (13.06±3.38 vs 7.20±2.24, P ¼ 0.0004), despite testosterone levels returning to baseline. The results suggest that combination therapy was more beneficial to patients with severe testosterone depletion, possibly by improving underlying pathophysiology. International Journal of Impotence Research (2013) 25, 29–33; doi:10.1038/ijir.2012.32; published online 13 September 2012 Keywords: combination therapy; erectile dysfunction; tadalafil; testosterone enanthate INTRODUCTION MATERIALS AND METHODS Despite the success of PDE5 inhibitors in treating erectile Inclusion/exclusion criteria dysfunction, lower treatment rates have been observed for The study was conducted in accordance with the protocol approved by the diabetic (64%) and post prostatectomy patients (43%).1 Institutional Review Board of Korea University School of Medicine. To be Hypogonadism has been associated as a common etiological eligible for inclusion in the study, the men were older than 40 years and factor, and testosterone replacement in these patients have had a diagnosis of ED, suggestive by an International Index of Erectile demonstrated increased responsiveness to PDE5 inhibitors.2–4 Function (IIEF) erectile function (EF) domain score below 22, and at least 3 5 months treatment with any PDE5 inhibitor, which includes prescriptions of These studies have shown a general improvement of 34–100%. a PDE5 inhibitor equivalent to 100 mg sildenafil. Patients were also The question remains whether combination therapy allows primarily included for hypogonadism, as diagnosed by baseline testoster- fundamental recovery of erectile function. Furthermore, there is one levels of below 350 ng dl À 1. Men with Peyronie’s disease, penile a general lack of consensus in researchers as to what construes curvature or with a history of penile surgery other than circumcision were the state of hypogonadism. Interestingly, some studies have excluded, as were patients who received any form of testosterone presented that patients with more severe depletion of supplement in the past. Patients were required to discontinue any PDE5 testosterone showed better response to therapy, and conversely, inhibitors for 2 weeks before entering the study period. patients who reached higher testosterone levels during treatment 2 Study design lost treatment benefit. À 1 Our study proposed to investigate whether discontinuation Patients were divided into two groups, intermediate (o350 ng dl , X À 1 À 1 of testosterone supplementation allows persistent recovery of 250 ng dl ) and severe (o250 ng dl ) deficiency of testosterone based on baseline assessment. Both groups were given the same course of PDE5 inhibitor response, and as such, whether patients treatment and efficacy and persistence of efficacy following testosterone with severe or intermediate depletion of testosterone benefit discontinuation was observed. more from synergistic effects of testosterone repletion and PDE5 The total duration of the study was 36 weeks, divided into three phases inhibitors. of 12 weeks. Phase 1, termed the initiation period, consisted of outpatient 1Department of Urology, Korea University College of Medicine, Guro Hospital, Seoul, Korea; 2Department of Urology, Inje University College of Medicine, Seoul Paik Hospital, Seoul, Korea; 3Department of Urology, Korea University College of Medicine, Ansan Hospital, Ansan, Korea and 4Department of Urology, Korea University College of Medicine, Asam Hospital, Seoul, Korea. Correspondence: Professor DG Moon, Department of Urology, Korea University College of Medicine, Guro Hospital, Gurodong-gil 97, Guro-2-dong, Guro-gu, Seoul 152-703, Korea. E-mail: [email protected] Received 19 September 2011; revised 23 April 2012; accepted 7 August 2012; published online 13 September 2012 Tadalafil and testosterone combination therapy JW Kim et al 30 Figure 1. Patient flow chart and study design. visits every 4 weeks for intramuscular testosterone enanthate injection RESULTS only. This was followed by phase 2, termed the combination treatment Overall patient characteristics period, in which patients continued to receive intramuscular testosterone enanthate injections every 4 weeks, as well as daily tadalafil 5 mg. Phase 3, A total of 46 men (age range 41–75 years) comprised the study cohort. Twenty patients showed serum testosterone levels below termed the discontinuation period, consisted of patients receiving daily À 1 tadalafil 5 mg only, and discontinuing their testosterone supplementation 250 ng dl (severe group) and 26 patients showed testosterone À 1 (Figure 1). levels above 250 ng dl (intermediate group). Patients with one or more comorbidities comprised 91.3% (n ¼ 42). The most prevalent condition was diabetes, (n ¼ 18, 39.1%), followed by Assessments prostatic hyperplasia (n ¼ 16, 34.8%) and hypertension (n ¼ 10, Before treatment initiation, and at the termination of each 12-week phase, 21.7%). Although all 4 patients with no significant medical history baseline and treatment efficacy was assessed by the IIEF 15-item showed intermediate levels of testosterone deficiency, there was questionnaire, validated and translated into Korean. The primary efficacy no significant predominance of comorbidities between the two measure was assessed by the EF domain score. Secondary measures included the Sexual Encounter Profile Question 2 (SEP2: Were you able groups (Table 1). to insert your penis into your partner’s vagina?) and Question 3 (SEP3: Only 2 patients dropped out during combination therapy, and Did your erection last long enough for you to complete intercourse 10 more patients dropped out after testosterone was discon- with ejaculation?), and patient responses to the Global Assessment tinued, with only 73.9% (34 out of 46) completing the entire study Question (GAQ: Has the treatment you have been taking over the past duration. While a total of seven patients were lost during follow- study interval improved your erections?). Blood tests for total testosterone up for unknown reasons, five patients requested removal from and free testosterone was performed at initiation and at the end of phases study complaining of lack of treatment benefits. Overall patient 2 and 3. characteristics and characteristics by cohort divided by degree of testosterone deficiency is presented in Table 1 (Figure 1). Statistical methods Factors associated with treatment success were assessed at completion Effect of combination therapy (V3) of combination therapy and at completion of study. The initial variables examined at enrollment were compared between treatment success The initial EF domain scores showed no significant difference and failure groups. Statistical analyses were performed with P-values between the two groups (P ¼ 0.16). Effect of combination therapy o0.05 being considered significant. Statistical analyses were computed was estimated for patients who maintained treatment by the 24th with R (v 2.12.1. 2010-12-16, R Development Core Team 2010. Vienna, week (N ¼ 44). Both severe and intermediate groups showed Austria). improvement in EF domain scores. The severe group showed International Journal of Impotence Research (2013), 29 – 33 & 2013 Macmillan Publishers Limited Tadalafil and testosterone combination therapy JW Kim et al 31 Table 1. Comparison of initial patient characteristics and serum testosterone levels measured during study Total Severe Intermediate P Age (years) 56.26±7.57 56.90±8.51 55.80±6.90 0.62 Height (cm) 167.47±6.01 167.69±7.26 167.20±4.21 0.85 Weight (kg) 68.14±8.33 66.04±8.61 69.80±7.88 0.13 Waist (inch) 33.58±1.67 33.50±1.80 33.70±1.60 0.75 Testosterone (ng dl À 1) V1 (0 weeks) 260±54 208±30 299±28 o0.01 V3 (24 weeks) 656±171 602±169 698±165 0.06 V4 (36 weeks) 241±104 213±78 263±117 0.09 Diabetes