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Combined use of androgen and sildenafil for hypogonadal patients unresponsive to sildenafil alone

Abstract

To investigate the therapeutic effect of androgen on hypogonadal patients unresponsive to sildenafil alone. In total, 32 hypogonadal patients with erectile dysfunction (ED), initially had an inadequate response to sildenafil (100 mg). Oral testosterone undecanoate (Restandol®, 80 mg, bid or tid) alone was supplied for 2 months, and if patients could not achieve a satisfactory erection, combined use of testosterone and sildenafil was continued thereafter. Total testosterone (TT), free testosterone (FT), and the parameters of the International Index of Erectile Function (IIEF), International Prostate Symptom Score (IPSS), and uroflow rate (UFR) were assessed. Eleven patients (34.3%) achieved satisfactory erectile function after testosterone replacement only. Another 12 (37.5%) patients experienced satisfactory intercourse after combined therapy. Serum TT and FT levels significantly increased after the use of testosterone alone (415±163 vs 220±101 ng/dl, P<0.01; 10.4±4.6 vs 5.1±1.9 ng/dl; P<0.01, respectively) and the combined use of testosterone and sildenafil (498±178 vs 220±101 ng/dl, P<0.01; 11.7±4.6 vs 5.1±1.9 ng/dl, P<0.001, respectively); as did the IIEF score (14.8±6.8 vs 12.6±7.5, P<0.01, 17.5±5.2 vs 12.6±7.5, P<0.001, respectively). However, no statistical differences were demonstrated for IPSS or UFR. In conclusions, one-third of hypogonadal patients with ED who failed to respond to sildenafil, responded to testosterone alone, another third responded to sildenafil again after normalization of testosterone. So, in hypogonadal patients with ED, androgen supplementation is first-line therapy. If patients are unresponsive to androgen alone or sildenafil alone, combined use may improve erectile function and enhance the therapeutic effect of PDE-5 inhibitors.

Introduction

Sildenafil is well established as a very effective treatment of erectile dysfunction (ED); however, it is also known that 20–30% of patients are expected to report a failed response to sildenafil.1 Androgens are essential for the maintenance of the libido and have an important role in regulating erectile capacity in men.2 Animal and human studies have shown that the expression of the nitric oxide synthase (NOS) gene inside the penis depends on the presence of adequate androgen levels.3, 4 Testosterone also has a permissive role in erectile function, which is not exclusively NO-dependent and induces acute (nongenomic) vasorelaxation via K+ channel activation of vascular smooth muscle cells.5 Castration, besides leading to reduced NOS expression, also appeared to modify phosphodiesterase type-5 (PDE-5) gene expression in a rabbit model.6, 7 Recent evidence suggests that androgens may directly control the expression and activity of PDE-5 in the human corpus cavernosum. For patients with hypogonadism8 (total testosterone (TT) <10 nmol/l (290 ng/dl) and/or free testosterone (FT) <200 pmol/l (6.0 ng/dl)), androgen supplementation may improve the therapeutic response to PDE-5 inhibitors.9 This evidence indicates that testosterone is involved in the maintenance of sexual activity through different sites.10 Adequate blood testosterone concentrations are necessary for maintaining penile erection.10

Based on the observed correlation between low serum FT and impaired cavernous vasodilatation in men with ED, androgen replacement was hypothesized to be an effective concomitant therapy to sildenafil in hypogonadal men with ED who did not adequately respond to sildenafil alone.9, 10, 11 Some studies proposed that a threshold of serum testosterone levels below which erectile function is impaired and above which erectile function is maintained exists.8, 10 Therefore, we undertook this investigation on hypogonadal patients who were unresponsive to sildenafil to evaluate the clinical effects and the correlated parameters.

Materials and methods

Eligible subjects were screened from 84 patients. There were 32 males between 23 and 73 years of age (median, 51), who had had ED for 3 months or longer, and whose sexual partners had been consistent for 6 months or longer. The inclusion criteria were: an ED patient with hypogonadism, a normal electrocardiogram, no history of hematological disorders or prostate disease, no antiandrogen drug ingestion, and an inadequate response to 100 mg sildenafil (defined as a score of 2 or 3 on questions 3 and 4 of the International Index of Erectile Function (IIEF)) after having been administered at least four times. The exclusion criteria were: a history of prostate or breast cancer, a clinically significant or uncontrolled medical conditions, myocardial infarction within the past 2 weeks, hepatic disease (SGOT, SGPT>3 × of upper normal limit), a hematocrit>50%, psychiatric conditions (such as a manic depressive state, schizophrenia, sleep apnea, and drug abuse), and neurological disorders that can cause ED (Figure 1). Moreover, a complete urological workup including a detailed examination of the testes (size and consistency), and prostate (size, consistency, presence of nodules, and sensation) was given, and subjects with a prostate-specific antigen (PSA) level of >4.0 ng/ml and a concomitant urine peak flow rate of<12 ml/s were also excluded (visit 1). Hypogonadism was defined as low serum androgen levels, that is, serum TT values of <290 ng/dl (10 nmol/l) and/or serum FT values of <6.0 ng/dl (200 pmol/l) determined two times within 2 weeks.8

Figure 1
figure1

Flow chart of patients screening.

Serum concentrations of TT were measured by a radioimmunoassay (RIA) using a commercial kit (Elecsys®, Roche, Germany). The intra- and interassay coefficients of the TT assay were 2.36 and 3.76%, respectively, for the normal adult male range. Serum FT was measured by an RIA assay (DSL®, Webster, USA). The intra- and interassay precisions of FT were 5.03 and 8.30%, respectively. All subjects were asked to use sildenafil on demand (Viagra™, Pfizer, Australia) over the 1-month period of the study, have sexual activity at least once weekly, and record it in a personalized diary, which was returned to the physician at the end of the study (visit 2). The IIEF, International Prostate Symptom Score (IPSS), and urine flow rate (UFR) at the baseline and after 1 month of therapy were assessed. The patients were then directed to take oral testosterone undecanoate (Restandol®, Organon, The Netherlands) for 2 months with the dosage of two tablets two or three times daily depending on the serum level of testosterone (visit 3). Testosterone undecanoate is testosterone esterized in the 17β-position. After ingestion, it is absorbed from the gastrointestinal tract, transported in the portal vein, then to the thoracic duct, avoiding first pass through the liver and subsequent hepatic toxicity.12 If a patient was not clinically satisfied with his sexual function, then a full dose (100 mg) of sildenafil was combined with testosterone thereafter (visit 4). The parameters of IIEF, IPSS, and UFR were assessed at the end of the following month (visit 5).

Responders were defined as subjects with a response of 4 (most times) or 5 (almost always or always) to questions 3 and 4 of the IIEF (Table 1). Improvers were defined as subjects in whom the functional response increased by at least 1 category over the baseline for either question 3 or 4. Values are expressed as the mean±s.d. Differences in baseline characteristics of the two groups were investigated using the Mann–Whitney test. The Wilcoxon matched-paired signed-rank sum test was used to compare sequential data from patients within each treatment group. Within-group changes and between-treatment differences in serum TT and FT levels were evaluated using paired t-tests and ANOVA, respectively; P<0.05 was chosen as the limit for statistical significance.

Table 1 Demographic of hypogonadal patients (n=32)

Results

Clinical characteristics of the study population are summarized in Table 1. Most patients (25) had a history of ED for longer than 12 months. Among the 32 patients, some were associated with concurrent conditions, such as alcohol consumption (17), smoking (11), diabetes mellitus (4), hypertension (13), and hyperlipidemia (7).

Individually, there were 11 patients (34.3%) who achieved satisfactory improvement after testosterone replacement only, while the other 21 patients received the combination of testosterone and sildenafil. Twelve (37.5%) of these 21 patients experienced satisfactory sexual intercourse. However, there were nine patients who had failed to respond to the combined treatment by the end of the study.

Within-group analysis revealed that sildenafil treatment did not significantly change the TT or FT levels, compared to the baseline (Table 2); but the use of testosterone and subsequent combined use of testosterone and sildenafil led to significant increases in the TT (415±163 vs 220±101 ng/dl, P<0.01; 498±178 vs 220±101 ng/dl, P<0.01) and FT (10.4±4.0 vs 5.1±1.9 ng/dl, P<0.01; 11.7±4.6 vs 5.1±1.9 ng/dl, P<0.001, respectively) levels (Table 2). Though TT and FT values are numerically higher for the group of combined use of testosterone and sildenafil compared to the group of testosterone alone, there is no statistical significance. Within-group analysis among subgroups who responded to testosterone alone, who responded to combined use of testosterone and sildenafil, and who did not respond to either treatment revealed no significant change in TT and FT levels. Moreover, both testosterone alone and the combined use of testosterone and sildenafil significantly improved the score on the IIEF (14.8±6.8 vs 12.6±7.5, P<0.01; 17.5±5.2 vs 12.6±7.5, P<0.001, respectively) in those patients unresponsive to sildenafil (Table 3). Furthermore, the IIEF score of patients who responded to testosterone alone (n=11) was not significantly different from that of patients who responded to combined use of testosterone and sildenafil (n=12) (19.1±8.0 vs 20.4±7.6, P>0.05), but both were significantly different from that of patients who did not respond to either (n=9) (19.1±8.0 vs 13.2±8.2, P<0.001; 20.4±7.6 vs 13.2±8.2, P<0.001). Improvements were also found in achieving an erection (question 3) during testosterone treatment alone, the period of combined use, and maintaining an erection (question 4) during the period of combined use (Table 3). The IPSS and UFR were assessed throughout the entire study. However, no statistical differences were demonstrated in any of the groups compared to the baseline (Table 4).

Table 2 Total testosterone (TT) and free testosterone (FT) before and after treatment
Table 3 Changes in the international index of erectile function (IIEF) before and after treatment
Table 4 Changes in international prostate symptoms score (IPSS) and uroflow rate (UFR) before and after treatment

Discussion

For those hypogonadal patients unresponsive to sildenafil alone, this study demonstrated that 11 out of 32 patients (34.3%) achieved a significant result after testosterone alone, which suggests that the first-line therapy for this group of patients is testosterone instead of sildenafil. Guay et al.13 showed that 33% of hypogonadal ED patients who received testosterone for 3 months had an efficacious response. In patients with severe androgen deficiency, marginal increments in circulating androgen levels may restore sexual function.14 Vermeulen reported that testosterone supplementation has beneficial effects on erectile function, plasma lipid and insulin sensitivity.8 We also found that in 11 patients who had associated diabetes (2) and hyperlipidemia (3) responded to testosterone alone. Whether the patients present with specific cormorbid conditions (such as diabetes and hyperlipidemia) respond better, needs further investigation. Moreover, experimental studies had clearly demonstrated that androgens have important functions in the intrapenile mechanism, by modulating the synthesis and action of neurotransmitters that normally influence the contraction and relaxation states of the smooth muscle cells in the erectile tissues.4, 5, 6, 7

For those who were not responsive to sildenafil alone and testosterone alone, combined use of sildenafil and testosterone resulted in 12 of the remaining 21 patients regaining a satisfactory erection, which suggests androgen replacement normalized the hormonal milieu that is essential for the action of PDE-5 inhibitor. Shabsigh et al.9 also reported that androgens influence PDE-5's expression and activity in the corpus cavernosum, so androgen supplementation enhances the therapeutic effects of the PDE-5 inhibitor. However, these effect were only short-term results, long-term study should be continued. Moreover, a significant decrease in neuronal nitric oxide synthase (nNOS) mRNA was found in castrated rats, suggesting that testosterone acts at the genomic level to regulate the expression of the nNOS gene in neuronal and endothelial tissues.4 This study shows a rather impressive effect than the similar study, which was conducted by Shabsigh et al.,9 the difference was probably on the definition of hypogonadism and patients selection. In Shabsign's study, hypogonadism was defined as serum TT <400 ng/dl, while the present study defined as TT <290 ng/dl. Moreover, 41% of their testosterone group had mild hypogonadism (301–400 ng/dl), whereas this subset of patients was not enrolled in the present study. Bhasin et al.15 also demonstrated androgen supplementation contributed to debatable improvement in patients with low normal testosterone levels, but much beneficial effect in patients with overt hypogonadism.12, 16

In this short-term study, the effect of testosterone on prostate and voiding function was not observed in the change of IPSS and UFR (Table 4). Although there was a trend of increase of IPSS during testosterone treatment alone and the combined use period, the difference was not significant. No statistical significance was observed in this parameter and this was possibly due to time factor (short term) and sample size (small). Further long term and larger population studies are warranted.

It is known that testosterone and its metabolite, 5-α dihydrotestosterone, stimulate nNOS gene expression and increase the amount of NO produced by the corpus cavernosum and penile arteries during erection.17 Two other NOS isoforms, that is, endothelial and inducible NOS, have both been shown to be expressed in penile tissue of impotent men, and may significantly contribute to NO production in the penis during erection.18 Whether testosterone plays a key role in both central and peripheral modulation of erectile function remains to be established; it is possible that there are different brain and penile threshold values for testosterone in the maintenance of sexual function in humans.13, 19

Guay and colleagues found a 37% prevalence of hypogonadism among 521 impotent men treated with sildenafil,12 while others reported hypogonadism as a causative factor of ED ranging from 7 to 35%.2, 14 Since the prevalence is relatively high, and testosterone is necessary for penile erection, this study suggests that testosterone treatment maybe reasonably used as first-line therapy for this group of patients, instead of an initial trial of sildenafil. If patients do not achieve a satisfactory response, adjunctive use of testosterone with sildenafil may improve sexual activity.

It may be concluded that in patients with ED and hypogonadism, it is reasonable to use testosterone replacement as first-line therapy. If patients do not respond to testosterone alone, combined use of testosterone and sildenafil may be used thereafter. This study suggests that androgen may directly control the expression and activity of PDE-5 in the human corpus cavernosum, and the mechanism of enhancement of therapeutic efficacy of PDE-5 inhibitors warrants further investigation.

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Acknowledgements

We thank Dr Paul C Chang for reviewing of the manuscript.

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Correspondence to Ti-S Hwang.

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Hwang, TS., Chen, HE., Tsai, TF. et al. Combined use of androgen and sildenafil for hypogonadal patients unresponsive to sildenafil alone. Int J Impot Res 18, 400–404 (2006). https://doi.org/10.1038/sj.ijir.3901446

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Keywords

  • erectile dysfunction
  • hypogonadism
  • testosterone
  • free testosterone
  • sildenafil
  • phosphodiesterase type-5 inhibitor

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