Combination Therapy of Testosterone Enanthate and Tadalafil on PDE5

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 18 (39.1%) 10 (50%) 8 (30.8%) 0.19 Hypertension 10 (21.7%) 5 (25.0%) 5 (19.2%) 0.45 Prostatic hyperplasia 16 (34.8%) 6 (30.0%) 10 (38.5%) 0.39

Figure 2. Patients with severe testosterone deficiency achieved higher treatment response estimated by IIEF (International Index of Erectile Function) erectile function (EF) domain score (V2, V3). These patients also maintained elevated response after discontinuation of Figure 3. Both groups achieved similar levels of serum testosterone testosterone supplementation (V4). **Po0.01, ***Po0.001. with testosterone supplementations (V3). After termination of testosterone enanthate injections, both groups showed return to increase of EF domain scores from 7.20± 2.24 to 15.35±4.07 at V2 pretreatment levels of serum testosterone (V4). **Po0.01, (Po0.0001) and 16.47±4.02 at V3 (P ¼ 0.0002), whereas the ***Po0.001. intermediate group showed increase from 8.31±2.45 to 15.35±0.91 at V2 (Po0.0001) and 12.36± 4.05 at V3 (P ¼ 0.0001). Persistent effects of combination therapy (V4) (Figure 2) Furthermore, the severe group showed higher EF domain Persistent effects of treatment was estimated for patients who score levels than the intermediate group (P ¼ 0.001). However, only maintained treatment until the 36th week (N ¼ 34). Effects were four patients in the severe group (21.1%) and one patient in the estimated by comparison with initial EF domain score values. The intermediate group (4.0%) achieved an EF domain score above 20, severe group showed a higher EF score maintained by the end of with no significant difference between groups (P ¼ 0.15). study with 13.06±3.38, compared with 9.53±3.11 for the Testosterone levels observed at this point was 602±169 ng dl À 1 intermediate group (P ¼ 0.0045). Furthermore, the EF domain and 698±165 ng dl À 1, respectively, for severe and intermediate scores for the intermediate group was not significantly different groups (P ¼ 0.057). Although no patient showed significant than the initial values (P ¼ 0.5879), whereas the scores for the supraphysiological levels of testosterone, two patients in the severe group was different from initial values (P ¼ 0.0004). However, severe group and one patient in the intermediate group showed no patient showed EF domain score values above 20. (Figure 2) serum testosterone level below 350 ng dl À 1 (Figure 3). Testosterone levels observed at this point was 212±78 ng dl À 1 Overall, 18 patients (34.1%) reported improvement based on for the severe group, and 263±117 ng dl À 1 for the intermediate GAQ, with 57.9% (11 out of 19) from the severe group and 16.0% group (P ¼ 0.102). While all patients in the severe group returned (4 out of 25) (P ¼ 0.009). Response to SEP2 and SEP3 questions also to testosterone levels below 350 ng dl À 1, 6 patients in the showed similar tendencies, with 13 patients (68.4%) from the intermediate group showed normal testosterone levels. However, severe group and 7 patients (28.0%) from the intermediate group when compared with their initial values, both groups showed no responding positive to the SEP2 question (P ¼ 0.014), and 12 significant change in testosterone levels (P ¼ 0.05 for severe patients (63.2%) from the severe group and 2 patients (8.0%) from group; P ¼ 0.33 for intermediate group) (Figure 3). the intermediate group responding positive to the SEP3 question Overall, four patients (11.8%) maintained based on GAQ; all (Po0.001) (Figure 4). patients were from the severe group (23.5%) (P ¼ 0.103).

& 2013 Macmillan Publishers Limited International Journal of Impotence Research (2013), 29 – 33 Tadalafil and testosterone combination therapy JW Kim et al 32 efficacious where hypogonadism was not primarily severe. Previous studies also suggested combination therapy to be effective only to proven hypogonadal patients.2–5,7,9 While both severe and intermediate levels of testosterone deficiency achieved significant increases in EF domain scores, patients who had severe testosterone deficiency achieved higher increase than patients who had intermediate deficiency, despite achieving similar levels of serum testosterone. These results implicate a different underlying pathophysiology of erectile dysfunction in these two patient groups. Testosterone deficiency alone is rarely the main or single cause of ED.10 Several studies have noted reciprocal effects between chronic disorders, such as diabetes, hypertension, obesity, metabolic syndrome and dyslipidemia.11–14 How severe these disorders affect erectile function cannot easily be stratified, although unresponsiveness of these patients have been attributed to progression to a more severe vascular disease, either by diabetic or untreated hypertension, leading to microvascular or macrovascular complications that deter erection, which may or may not present concomitant deficiency of testosterone.13,15 Significant pathology of the erectile tissue may be refractory to repletion of testosterone, especially if the deficiency is already not so marked. Various factors may be involved in the actual responsiveness to testosterone depending on the individuals.5,16 Studies have suggested that factors besides apparent serum testosterone levels, such as androgen receptor sensitivity, may not only vary among individuals but also significantly affect presentation of comorbidities, which may in turn affect erectile function.17,18 The persistent and higher response shown in the group with severe deficiency may represent patients in whom testosterone deficiency functions as the primary debilitating factor of erectile dysfunction. Conversely, the intermediate group may Figure 4. More patients with severe testosterone depletion reported paradoxically represent patients with other dysfunctional satisfactory treatment response (24 weeks). Only four patients from elements that could not be alleviated with testosterone the severe testosterone depletion group reported maintenance of treatment effects after discontinuation of testosterone supplemen- replacement, and may have more significant comorbidities, tation (36 weeks). GAQ, Global Assessment Question. **Po0.01. which deter treatment response. The current study also aimed to identify whether such differing benefits may eventually affect persistence of the restorative Similar tendencies were also observed with response to SEP2 effects possibly gleaned from testosterone supplementation in and SEP3 questions; five patients (29.4%) from the severe group these deficient patients. Previous studies have shown that and two patients (11.8%) from the intermediate group responded testosterone supplementation provides structural change of positive to the SEP2 question (P ¼ 0.398); three patients erectile tissue, leading to functional improvement evident by (17.6%) from the severe group and no patient from the decrease of venous leakage.6,7 It may be hypothesized that intermediate group responded positive to the SEP3 question supplementation of deficient testosterone may provide restorative (P ¼ 0.227) (Figure 4). properties to these tissues, which also may be evident even when testosterone is discontinued. Our results show that patients who were more severely deficient in testosterone maintained better DISCUSSION function after discontinuation of testosterone supplementation. The present study was an observational study of two cohort Although presence of actual structural regeneration of erectile groups treated for a prolonged period with testosterone and daily tissue is debatable, it is notable that the duration between tadalafil. The primary objective was to identify persistent termination of testosterone supplementation and measurement of treatment effects of testosterone replacement on erectile function. final outcome (12 weeks) was significantly longer than docu- Previous studies have shown that testosterone supplementation mented testosterone level decline to after intramuscular injection provides structural change of erectile tissue, leading to functional of testosterone enanthate.8 improvement evident by decrease of venous leakage.6,7 It may be Testosterone enanthate is an oil-based injectable steroid, hypothesized that supplementation of deficient testosterone may designed to slowly release testosterone from the injection site. provide restorative properties to these tissues, which may also be Once administered, serum concentrations have been shown to evident even when testosterone is discontinued. Our results show rise for several days and remain markedly elevated for 2 weeks, that patients who were more severely deficient in testosterone fully diminishing at 3 weeks. The decision behind the choice of maintained better function after discontinuation of testosterone selecting testosterone enanthate over testosterone gel, preferred supplementation. Although presence of actual structural in similar studies,2,3 was made to maintain an effective regimen for regeneration of erectile tissue has not been evaluated, it is long-term therapy, which required increased patient compliance notable that the duration between termination of testosterone by minimizing the number of interventions and clinical visits, but supplementation and measurement of final outcome (12 weeks) more importantly to avoid side effects from supraphysio- was significantly longer than documented testosterone level logical levels of testosterone. As evident by previous dosage decline to after intramuscular injection of testosterone enanthate.8 studies, testosterone enanthate maintains a relatively constant These outcomes were stratified between patients with severe serum level.19 While most dosing schedules dictate injection every and intermediate levels of hypogonadism, as theoretically 3 weeks, our patient group maintained slightly lower, but normal, testosterone replacement could be hypothesized to be less mean levels of testosterone during supplementation, with no

International Journal of Impotence Research (2013), 29 – 33 & 2013 Macmillan Publishers Limited Tadalafil and testosterone combination therapy JW Kim et al 33 patients showing supraphysiological levels and only three patients 2 Shabsigh R, Kaufman J, Steidle C, Padma-Nathan H. Randomized study of tes- À 1 failing to achieve 350 ng dl . No patients reported side effects or tosterone gel as adjunctive therapy to sildenafil in hypogonadal men with erectile complications from treatment. Furthermore, only two patients dysfunction who do not respond to sildenafil alone. J Urol 2004; 172: 658–663. were lost during treatment up to 24 weeks and all remaining 3 Greenstein A, Mabjeesh NJ, Sofer M, Kaver I, Matzkin H, Chen J. Does sildenafil patients showed good compliance to treatment. Thus, the combined with testosterone gel improve erectile dysfunction in hypogonadal protocol of injecting testosterone enanthate every 4 weeks men in whom testosterone supplement therapy alone failed? 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& 2013 Macmillan Publishers Limited International Journal of Impotence Research (2013), 29 – 33