TTh treatment remains a controversial topic, even after more than 70 years of clinical use, with a significant portion of the research literature providing evidence that TTh does improve sexual symptoms in men with ED. This may be due in part to various testosterone preparations possibly having differing modes of action [17–20]. Previous study have indicated that TTh treatment was ineffective in improving ED when there were high serum levels of estradiol [21]. Clinically, on-demand administration tadalafil was able to reduce serum estradiol levels significantly, but the testosterone/estradiol ratio also rose significantly regardless of whether total or free T rises [22]. Thus, some researchers recommend that clinicians consider starting PDE5-Is therapy during the first consultation for ED, without waiting for confirmation of a normal serum T leve[23]. At the same time, a qualitative systematic review concluded that TTh did not show consistent benefits for sexual function [24]. Another systematic review which included 17 RCTs, comprising of a total of 3165 men with hypogonadism indicated that erectile function did not differ significantly between individuals who received the TTh or those who received placebos[25].
Previous meta-analyses also reported that a positive effect of PDE5-Is was further improved with the co-administration of testosterone only in uncontrolled studies, but not in placebo-controlled studies[26]. Our analysis suggests that dual treatment with TTh and PDE5-Is significantly improves EFD when compared to the control group of TTh only. In patients who received dual treatment(TTh and PDE5-Is), there was a higher increase in EFD (4.88 point), but for TTh treatment only it was 2.04 point only. This supports the theory that TTh may facilitate the pharmacological effects of PDE5-Is[27]. The PDE5 gene is expressed less as males age, as well as in men with hypogonadism. Hence, TTh treatment may possibly be able to restore the expression of the PDE5 gene, through regulating its gene expression directly[28]. Accordingly, there was an observed mean increase of 2.3 point in EFD scores for patients with mild ED who were treated with TTh, but not for those with more severe ED. In our meta-analysis, only 2 of the selected articles considered the seriousness of ED. In Shabsigh et al.’s study, 69% of placebo gel control group had mild to moderate ED, while 81% in dual treatment group had mild to moderate ED.[14]. In Yassin et al.’s study, 74.3% of the TTh group had mild to moderate ED compared to 67.7% in the dual treatment group [16]. Hence, for men with milder ED, TTh alone may be a possible treatment option[29].
There was also a higher percentage of patients with improved response to treatment after 8–12 weeks for the group receiving treatment of TTh plus PDE5-Is, at 41.7%, compared to 33.0% for the group receiving the placebo plus PDE5-Is. In patients who received dual treatment(TTh and PDE5-Is), there was a higher increase in EFD (4.88 point) when compared with patients who underwent only PDE5-Is treatment (3.15 point), although when PDE5-Is treatment was used as the control group, the change of EFD did not reach statistical difference. This can be attributed to a number of factors. Firstly, ED patients treatment with PDE5-Is increased total T levels by 1.15–1.73 ng/ml[30, 31], significant erectile function improvements were seen only in samples with a lower testosterone threshold, and further increases in testosterone levels do not confer further benefits on erectile function if testosterone threshold has already been hit [32]. So it is unclear whether the additive benefit of TTh was negated by the potentially direct effect of PDE5-Is on serum T levels. Secondly, a meta-analysis of 14 RCTs found that when the testosterone threshold was less than 2.3 nmol/l, EFD increased by 2.95 after TTh, compared to only a 1.47 point increase in EFD when the total T threshold was less than 3.5 nmol/l [33]. Three selected articles described the classification of the total T levels at baseline. In Yassin et al.’s study, total T levels of < 2 ng/mL were observed in 20.6% of the TTh group, and in 17.6% of the dual treatment group [16], while in Shabsigh et al.’s study, total T levels of < 2 ng/mL were observed in 33% of the placebo gel group, compared to only 5% of the dual treatment group [14]. In addition, in Buvat et al.’s study, 28.1% of the sample were bounded by a total T of < 1.45 ng/ml [7]. Most of the included patients with a mild degree of androgen deficiency might possibly weakening the therapeutic effect of TTh, as TTh was more effective in patients with moderate to severe androgen deficiency. It must be noted that imbalances in total T distribution, as well as in ED grading can result in biases in the analyses. Moreover, as a lack of sexual activity also could have caused subclinical hypogonadism, TTh may benefit in ED patients restoring sexual activity and further increase their testosterone levels at a normal range[34].
Only two types of PDE5-Is (sildenafil, tadalafil) were used in the selected studies, and this may potentially result in a bias, even though previous meta-analyses indicate that there are no significant difference in the efficacy of PDE5-Is relative to each other[3]. A 10–20 mg dosage of tadalafil was associated with greater improvement in the mean proportion of successful sexual intercourse attempts (76.9%) compared to a dosage of 100mg sildenafil (72.2%). On the other hand, the mean change in EFD did not differ between groups[35, 36]. There was no significant dose-response effect when tadalafil was used [37]. The dose of sildenafil used varied among the included studies, where one particular study used 50–100 mg on demand [15] and the other used a dosage of 100 mg on demand [14]. There was only significant improvement in sexual intercourse success and erectile function in using a sildenafil dosage of 50mg when it was compared to a 25mg dose, but there was no difference in the improvements for both 100mf and 50mg doses[38].
In contrast with certain reviews that were published previously, we only included RCTs that enrolled initial PDE5-Is non-responders with hypogonadism. Our study also had several limitations. First, only 2 of the included articles described the classification of baseline T levels and the severity of ED, and the distribution of such participants across the various groups studied was also uneven. Second, the included studies used various cut-off values for the testosterone to determine hypogonadism. Third, the duration of treatment with TTh varied among the included studies and this difference in duration may have affected the outcomes. Therefore, further high-quality research studies need to be conducted to better elucidate the effects of the TTh treatment on patients with hypogonadism who are unresponsive to phosphodiesterase-5 inhibitors alone.