Sexual Dysfunctions Related to Drugs Used in the Management of Lower Urinary Tract Symptoms Due to Benign Prostatic Hyperplasia: A Narrative Review on α -Blockers and 5-Alpha Reductase Inhibitors

: This is a critical review of the current literature data about sexual dysfunction as a potential side effect related to drugs commonly used for the treatment of Benign Prostatic Hyperplasia and Lower Urinary Tract Symptoms. In this narrative review, we analyzed data from the literature related to the development of sexual dysfunctions during the treatment of BPH or LUTS. Both α -blockers and 5-alpha reductase inhibitors (5-ARIs) can induce erectile dysfunction, ejaculatory disorders and a reduction in sexual desire. The sexual side effect proﬁle of these drugs is different. Among the α -blockers, silodosin appears to have the highest incidence of ejaculatory disorders. Persistent sexual side effects after the discontinuation of ﬁnasteride have been recently reported; however, further studies are needed to clarify the true incidence and the signiﬁcance of this ﬁnding. However, most of the published studies are affected by a weak methodology and other important limitations, with only a few RCTs available. Therefore, it is desirable that future studies will include validated tools to assess and diagnose the sexual dysfunction induced by these medications, especially for ejaculation and sexual desire disorders.


α-Blocker
Both silodosin and tamsulosin induce ejaculatory disorders (up to 28.1%) [91] (Tables 3-5). The different sexual side effect profile of α-blockers may be related to the following several factors: (1) the chemical structure; (2) the binding affinity/selectivity for α1-adrenergic receptor subtypes; (3) binding to other receptor-mediated mechanisms; and (4) the different volume of distribution. Alfuzosin, doxazosin and terazosin show equal binding with the three subtypes of α1-adrenergic receptors, while tamsulosin and silodosin show a superselective binding with the α1-A receptor [4,14,43]. The most uroselective alpha-blocker is silodosin and has the most marked effect on ejaculation [23,113]. The sexual side effect profile of dutasteride appears to be similar to that of finasteride with regards to erectile dysfunction (ED), ejaculatory dysfunction (EjD) and decreased libido [72, 123,140]; both drugs appear to be associated with a higher risk of ED, EjD and reduced libido than a placebo [30, 131,233]. Recently, Corona et al. [125] found that 5-ARIs are associated with decreased libido and spontaneous nocturnal erection, while no relationship was found with ED or EjD. Table 3. Effects of α-blockers on erectile functions.

5-ARI
The sexual ADRs of 5-ARIs are comparable to placebos after a 2-year treatment [27,72,81,115]. Kaplan et al. [104] reported that a chronic treatment (5 years) with dutasteride induces a higher incidence of erectile dysfunction and gynecomastia than finasteride. Cases of persistent sexual dysfunction have been recently reported after the discontinuation of finasteride [32,60,97,99,100,129,131,134,141,147,149,166,170]. Irwig and Kolukula [99], using the Arizona Sexual Experience Scale (ASEX) validated questionnaire, interviewed 71 healthy male (21-46 years) finasteride-users, finding a high incidence of sexual dysfunction (Tables 6 and 7). In particular, 69-94% of those interviewed described "low libido" (94%), "erectile dysfunction" (92%), "decreased arousal" (92%) and "problem with orgasm" (69%). The same authors acknowledged the limitations of their study, stating that "the true incidence of these events is unknown as it is a post-hoc approach" and that, in previous randomized, placebo-controlled trials, the incidence of ADR on sexual function was 8% lower in the finasteride group and less than 3% in the control group. "Assuming the vast majority of these events have resolved, the incidence of persistent sexual side effects in patients receiving finasteride was less than 1%" [99]. Indeed, some methodological "biases", such as the following, could limit these results: (i) the study was conducted only through "standardized telephone or Skype interviews"; (ii) the study was conducted on a sample of patients recruited from a website for people complaining of sexual dysfunction; and (iii) the study was an observational survey (with no control groups) and involved only a small number of patients. The pathophysiological mechanisms responsible for 5-ARI-induced sexual dysfunction may be related to the decrease in dihydrotestosterone levels and possibly other neurosteroids, such as progesterone metabolites [32,47,133]. Psychological factors ("nocebo effect") have also been implicated as responsible for sexual dysfunction in patients treated with 5-ARIs [144]. However, to date, little is known about the exact mechanisms underlying the sexual dysfunctions related to 5-ARIs [61,71]. There is a cumulative risk of sexual ADRs with α-blockers vs. monotherapy or a placebo [40,65,85,92,112]: Gacci and co-authors [14] found that combination therapy with α-blockers and 5-ARIs resulted in a three-fold increased risk of ejaculation disorders vs. monotherapy. Table 6. 5-ARI: Effects on sexual function.

Finasteride
Dutasteride The

α-Blocker and PDE5i Combination
Several clinical studies seem to confirm that the combination of α-blockers and PDE5i is more effective in improving both LUTS and erectile dysfunction than treatment with α-blockers alone [28, 186,205,222,226]. The results from a combination treatment with αblockers and PDE5i in men with ED and BPH suggested a synergistic effect on both erectile dysfunction and LUTS [23,40,146,177,222].
PDE5i is used alone or as an add on to α-blockers, alfuzosin or tamsulosin, or finasteride [180,203,219]. Oelke et al. [206] reported a significant increase in Qmax ("maximum urinary flow rate", which is the urodynamic parameter for the evaluation of LUTS), even if other studies must be performed to validate this result [169]. The link between erectile dysfunction and LUTS is based on the following four hypotheses: (1) a decrease in or alteration of the endothelial nitroxide synthetase levels in the prostate and in the smooth muscle of the penis; (2) effects related to autonomic hyperactivity; (3) the increased activation of Rho-kinase; (4) pelvic atherosclerosis [33,38,112]. As recently reported, all these mechanisms could be countered by PDE5i [183]. Moreover, PDE5 inhibition has been shown to affect several pathogenic pathways contributing to LUTS, although the exact mechanism of action remains to be elucidated [222]. However, PDE5i use is well tolerated in patients with LUTS and/or BPH (Table 2).

Discussion
In the present review we found different and apparently conflicting epidemiological data on α-blockerand 5-ARI-induced sexual ADRs (Table 8). Several problems make it difficult to quantify and qualify α-blockerand 5-ARI-induced sexual dysfunction. These problems mainly concern the diagnostic criteria of ejaculatory disorders. None of the reviewed studies used the diagnostic criteria for sexual dysfunction proposed by ICD-10 (WHO, ICD) DSM-IV-TR (American Psychiatric Association, 2000 and DSM5 (American Psychiatric Association, 2013) [153,164,238]. Other proposed classifications, such as that of NIH (National Institutes of Health), are rarely used. There is no clear consensus on the classification of "non-premature ejaculatory dysfunction" [152]. There are no clear and shared diagnoses for delayed ejaculation [143]. Previously, Hartmann and Waldinger [138] wrote that "a big problem we should solve is finding consensus on the operational definitions of ejaculatory disorders". As far as we know, the classification of delayed ejaculatory dysfunction is still far from precise. Delayed ejaculation, inadequate ejaculation, inhibited ejaculation, idiopathic ejaculation, (primary) ejaculation and psychogenic ejaculation and psychogenic anejaculation have been used interchangeably to describe a delay or an absence of male orgasmic response [143]. Furthermore, some authors included orgasmic disorders in ejaculatory disorders [139], while others considered ejaculatory dysfunction as orgasm dysfunction [53] due to the lack of consensus on the diagnostic criteria of ejaculatory disorders. We think that it is also important to distinguish anejaculation from retrograde ejaculation. Jannini and Lenzi [139] argued that "it is important not to confuse the classification of anejaculation with that of retrograde ejaculation. In the latter case, orgasm is usually present, even if attenuated, while anejaculation always coincides with anorgasmia (even if the opposite is not true)". Hellstrom et al. [21] and Rosen and Seftel [150] defined "severe ejaculatory dysfunction as ejaculation with reduced sperm count or ejaculation loss". Retrograde ejaculation (or dry ejaculation) occurs when semen enters the bladder instead of emerging through the penis [152]. Despite this important difference, many studies do not distinguish between anejaculation and retrograde ejaculation. Tamsulosin is associated with a significantly lower risk of EjD than silodosin (OR: 0.09; p < 0.00001) [14] Alfuzosin, doxazosin and terazosin are associated with a lower risk of EjD compared to a placebo.
Both finasteride and dutasteride have a significantly higher risk of EjD than a placebo.
EjD is significantly more common with combination therapy than with α-blockers alone or 5 ARI alone [14]. The examination of the "post-ejaculate urine semen concentration" serves as a reliable indicator of retrograde ejaculation, but only a few studies considered these data [87,89,96]. Other methodological issues include the definition of reduced ejaculatory volume. Numerous physiological factors can cause a reduction in semen volume, e.g., a short period of sexual abstinence (<2 days) or frequent ejaculations before semen collection [167].
In many studies, the abstinence period before semen analysis was not specified. Another possible methodological "bias" is the absence of an objective measurement of semen volume leading to an underestimation of EjD [87]. A further methodological limitation depends on the lack of definition of the reduction in sperm volume. For example, the WHO indicated that the lower reference limit for semen volume is 1.5 mL, but none of the studies reviewed and reported in this study indicated a reference point for the definition of reduced ejaculate volume, except Hellstrom and Sikka [87], who defined a "decrease in ejaculate volume" as "a greater than 20% decrease from baseline". The Danish Prostatic Symptom Score (DAN-PSS) is a questionnaire used for the detection of ejaculatory disorders [137]. It includes 12 questions related to voiding problems and the perceived disturbance of each individual symptom and 3 questions related to sexuality (erection, volume of ejaculation, pain/discomfort during ejaculation). This questionnaire has been validated and used in numerous epidemiological surveys and clinical studies [130,135,137,158]. However, to the best of our knowledge, the DAN-PSS has only been validated for the evaluation of urinary symptoms and not for sexual function [171]. This could be a potential limitation of the studies using DAN-PSS, as it may have led to an overestimation (or underestimation) of ejaculatory disorders. Rosen and Fitzpatrick [5] reported that the DAN-PSS and ICS questionnaire evaluate only two ejaculatory dysfunctions, i.e., a reduced amount of semen and pain and discomfort during ejaculation. Rosen et al. [3] proposed the use of the MSHQ questionnaire, but few studies used it. As previously pointed out, among the RCTs examined on α-blockers and 5-ARIs, only two [82,85] of these used a specific and validated rating scale to measure sexual functioning. In studies that did not use a self-administered questionnaire or that did not directly ask the patient about sexual function, the identification of sexual dysfunction often relies on spontaneous disclosure by patients, but previous research has shown that patients rarely spontaneously report side effects concerning the sexual sphere [140]. Therefore, failure to use the rating scales compromises the true rate of sexual dysfunction. Most researchers used the term "libido," which does not indicate which stage (desire, arousal, orgasm) of the human sexual response is affected by sexual dysfunction. Indeed, the term "libido" does not discriminate between the various phases of the sexual response cycle [145]. In the literature, we have found the use of the following, apparently similar, expressions of sexual function, which, however, have probably been interpreted with different meanings: "loss of sexual desire", "Hypoactive Sexual Desire (HSD)", "Hypoactive Sexual Desire Disorder (HSDD)", "Low sexual desire", "reduced sexual desire (libido)", "loss of libido (sexual desire)", "reduced libido". Roehrborn et al. [40] distinguished between "altered (decreased) libido" and "loss of libido", but did not explain the difference between these. Skolarus and Wei, [46] described "erectile function" as defined in terms of (1) "Quality of erection", (2) "Libido/sexual desire" and (3) "Satisfaction". However, defining erectile function in terms of "libido/sexual desire" can be confusing and difficult for the patient to understand.

Conclusions
Few rigorous studies have been conducted using both control groups and validated questionnaires to evaluate the sexual side effects of α-blockers and 5-ARIs [53]. It is desirable that future studies include validated tools to assess and diagnose drug-induced sexual dysfunction, particularly for ejaculation and sexual desire disorder. Failure to use these assessment questionnaires reduces the possibility of detecting the exact incidence of sexual dysfunction and the likelihood of accurately diagnosing the specific type of sexual dysfunction involved, as well as hindering the objective monitoring of the improvement or worsening of symptoms during drug treatment. The MSHQ is a validated questionnaire for the assessment of sexual dysfunction, in particular for the assessment of strength, delay and pleasure in ejaculation [5,150]. Other specific rating scales, such as ASEX [142] or CSFQ [154], could also be used for patients with LUTS/BPH. Only a small amount of research has intentionally initiated the study of sexual dysfunction caused by α-blockers and 5-ARIs. Therefore, studies that specifically evaluate the sexual dysfunction induced by these drugs are needed. Further studies are needed to determine the pathophysiological mechanisms involved in the link between LUTS and sexual dysfunction (particularly ejaculation disorders) and the optimal management strategies for men with these concomitant conditions [5,21]. The sexual side effect profile of these drugs is different. Among the α-blockers, silodosin (followed by tamsulosin) shows the highest incidence of ejaculatory disorders. Alfuzosin has no deleterious effects on sexual function and is well tolerated when used in combination with a low dose of PD5i for the treatment of erectile dysfunction. Several authors have documented that the α-blocker/PD5i combination may act synergistically to improve both LUTS and sexual function [23,40,146,222]. With the exceptions of only silodosin and, to a lesser extent, tamsulosin, the effect of α-blockers on sexual function appears similar to a placebo. The sexual adverse event profile of dutasteride appears to be similar to that of finasteride. There have been recent reports of persistent sexual dysfunction after the discontinuation of finasteride treatment, but further studies are required to evaluate a causal relationship [49]. Further studies are also needed to evaluate the long-term role of a combination therapy of PD5i and α-blockers or 5-ARIs in LUTS/BPH treatment [184,222]. Several studies show that sexual dysfunction has a high prevalence in sexually active men with LUTS [4], which must be carefully evaluated and diagnosed before treating LUTS, as some treatments may further aggravate it. Despite this, Giona et al. [132] documented that there is a significant discrepancy in the attitude of urologists in advising patients with LUTS-related erectile dysfunction: in particular, a significant minority of urologists do not discuss either erectile dysfunction or ejaculatory disorders with patients before the treatment; moreover, they do not discuss an alternative treatment [132]. The tendency of urologists to not investigate the sex life of patients could negatively affect their quality of life to the extent that effective treatments are not proposed [58]. The importance of both sexological history and clinical evaluation is evident: this procedure is essential for the objective monitoring of the improvement or worsening of symptoms during drug treatment.

Patents
Male sexual dysfunction could be the result of inaccurate sexological history and clinical assessment in patients with urological diseases. In this sense, the evaluation of all drug-related side effects on male sexual function is essential to improve a patients' overall quality of life.