Pharmacological treatment of LUTS in BPH:

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Pharmacological treatment of lower urinary tract symptoms in benign prostatic hyperplasia: consequences on sexual function and possible endocrine effects



ABSTRACT

Introduction: Benign prostate hyperplasia (BPH) is one of the most prevalent diseases in aging men. It may adversely affect quality-of-life due to the presence of low urinary tract symptoms (LUTS) and its effects on sexuality.

Areas covered: The impact of α1-blockers, 5α-reductase inhibitors (5-ARI), and phosphodiesterase 5 inhibitors (PDE-5i) on erectile and ejaculatory functions in men with BPH are covered. Endocrinological aspects have also been addressed, including the management of hypogonadism, which affects many patients with BPH, and the impact of the use of 5-ARI use on bone health.

Expert opinion: The adverse-event profile of α1-blockers depends on their affinity for the α1-adrenoceptors rather than selectivity. The probability of ejaculatory dysfunction is highest with silodosin than other nonselective drugs (tamsulosin, alfuzosin, doxazosin, and terazosin). Concerning the impact of finasteride and dutasteride on sexual desire, erectile function, and ejaculation, the vast majority of the studies have shown a low prevalence of treatment-related adverse events. Due to the benefits of erection, PDE5i represents the perfect class of drugs for the treatment of LUTS-BPH in patients with erectile dysfunction. Testosterone replacement therapy could be considered in some hypogonadal patients with BPH. Finally, current evidence supports the safety of 5-ARI on bone tissue.







8. Expert opinion

First-line therapy for BPH/LUTS syndrome is represented by α1-adrenoreceptor blockers. The adverse-event profile of these drugs depends on the affinity rather than selectivity for the α1Aadrenoceptor. Hence, the probability of ejaculatory dysfunctions is highest with silodosin than with other drugs with lower affinity for this receptor subtype (tamsulosin, alfuzosin, doxazosin, and terazosin). However, classifying these patients by age (older vs. younger) and sexual activity (present or not), the use of PDE5is should be considered even if this is more expensive especially when BPH/LUTS coexists with ED. Indeed, due to the benefits of erection, PDE5i represents the most advantageous class of drugs for the treatment of LUTS-BPH in patients with ED. Interestingly, the remarkable effects of daily PDE5is on body composition and endothelial function other than sexual improvements are reported [121] and suggest a pleiotropic beneficial effect of these drugs. LUTS-BPH often associates with metabolic syndrome, although the exact mechanism has not been clarified yet. Molecular studies address insulin as a role in prostatic hyperplasia and inflammation [122]. Also, insulin-resistance is a predictive factor of LUTS development, likely due to the close association between the hyperactivity of the autonomous nervous system (which involves the α-adrenergic pathway) and hyperinsulinemia [123]. Data coming out from the Third National Health and Nutrition Examination Survey (NHANES III), involving 2,372 patients, also reveal the association between hypertension and LUTS-BPH [124]. BMI has been demonstrated as a predictor of LUTS development, as confirmed by an analysis of 21,694 patients [125]. In addition, the second Nord-Trondelag Health Study, involving 21,694 patients, showed a higher risk for LUTS in patients with diabetes mellitus than in non-diabetic men [125], being the risk of BPH even fourfold higher in diabetic patients with high LDL cholesterol serum levels [126]. Taken together, these data strongly highlight the close association between LUTS-BPH with metabolic abnormalities and cardiovascular risk factors which has been ascribed by some authors to the male equivalent of polycystic ovarian syndrome (PCOS) occurring in these men [127–129]. In this view, the role of PDE-5i on metabolism and endothelial dysfunction deserves to be promoted and further addressed by focused studies.

According to guidelines, 5-ARI treatment (alone or in combination with α1-blockers) should be considered in older patients with prostate volume greater than 50 mL where a significant reduction of the prostate volume is expected after long-term use. Concerning the impact of finasteride and dutasteride on sexual desire, erectile function, and ejaculation, the vast majority of the studies have shown a low prevalence of treatment-related adverse events, being both almost well tolerated. However, they should be used cautiously because of their possible metabolic and reproductive adverse events, i.e. hypogonadism, that may be reverted by appropriate hormonal-specific treatments. Finally, few reported have been reported so far on the effects of these drugs on bone metabolism, the majority of these supporting the safety of 5-ARI on the bone tissue. This issue deserves to be further investigated in order to better assess the 5-ARIrelated adverse events.






The article highlights

● The probability of ejaculatory dysfunction is highest with silodosin than other non-selective drugs (tamsulosin, alfuzosin, doxazosin, and terazosin).

● Finasteride and dutasteride are well tolerated.

● Phosphodiesterase 5 inhibitors (PDE5i) are effective for the treatment of LUTS-BPH in patients with erectile dysfunction.

● Testosterone replacement therapy (TRT) can be considered in hypogonadal patients with non-obstructive BPH.

● 5α-reductase inhibitors (5-ARI) are not harmful to bone tissue.

● This box summarizes the key points contained in the article

 

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4. Impact of 5α-reductase inhibitors on sexual function

5-ARIs, mainly including finasteride and dutasteride, represent a class of drugs that competitively inhibit 5-alpha reductase isoenzymes (5-ARs). In humans, three types of 5-ARs have been described so far: type-1 is temporarily expressed in newborn skin and scalp and is permanently detectable in the skin after puberty onset; type-2 localizes predominately in fetal genital skin and male accessory glands including prostate [40]; type-3 is expressed both into androgen-dependent tissues (e.g. smooth muscle and prostate) and in the brain, heart, and other peripheral tissues [41].

In vitro experiments have shown a higher inhibitory activity of dutasteride on type 3 than type 2 5-ARs. By contrast, these isoenzymes are similarly sensitive to finasteride [41]. Several mechanisms have to be considered when the impact of 5-ARIs on sexual function is considered. First of all, dihydrotestosterone (DHT) more effectively than T enhances nitric oxide (NO) availability in the endothelium [42]. Thus, 5-ARIs can indirectly reduce the peripheral amount of NO concentration and, consequently, have a negative impact on erection. The reduction in DHT explains the reduced volume of ejaculate experienced by treated patients and, in addition, these drugs are able to prevent the conversion of progesterone and deoxycorticosterone into neurosteroids, the latter playing a role in regulating mood, anxiety, sleep, and sexual function [43,44]. Finally, finasteride can exert a central effect by crossing the blood-brain barrier and reducing the hormonal impregnation of the central nervous system [45,46].

 

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5. Benefits of PDE5i daily administration on sexual function

Four types of oral phosphodiesterase 5 (PDE5i) inhibitors have been developed for erectile dysfunction: sildenafil, tadalafil, avanafil, and vardenafil. For all PDE5is, men must take medications on demand prior to sexual activity [72,73]. Contrary to sildenafil, avanafil, and vardenafil, tadalafil is rapidly absorbed after oral administration and has a longer half-life (17.5 h). Steady-state plasma concentrations are reached after 5 days of administration once a day [74,75]. Therefore, its daily use has been proposed for the treatment of ED, at the dose of 2.5 and 5 mg, providing a therapeutic option of efficacy and continuous duration compared to the necessary dosage. ED/LUTS secondary to benign prostatic hyperplasia (BPH) can have a profound impact on the quality of life [76] and often occur in older males [77]. It is estimated that 70% of males with LUTS/BPH have simultaneous ED [78]. The association between ED and LUTS has previously been demonstrated in various large-scale community-based studies [79]. PDE5i have always been used for the treatment of ED, increasing the signaling of nitric oxide in the genitourinary tract tissues, which causes calcium-dependent vascular smooth muscle relaxation and increased blood flow. Recently it has been suggested that the same mechanism of action may be involved in the amelioration of BPH symptoms [80,81]. Currently, daily tadalafil is the only FDA approved PDE5i for the treatment of BPH. Patients suffering from LUTS/BPH and ED can derive maximum benefit from this treatment, although the real limit of this class of drugs is the high cost

The first-line treatment of medical management of LUTS secondary to BPH is α-1 blocker and 5-ARI. However, especially in young patients, the side effect on sexual function is of concern for both the patient and the doctor, who tends to reduce the use of 5-ARI whenever possible. Therefore, tamsulosin can be useful and safe for the treatment of LUTS secondary to BPH with or without ED. The daily dosage of tadalafil, with the same efficacy, can provide a spontaneous approach to sexual intercourse and better sexual satisfaction [82]. Additionally, daily administration may also have positive psychological and emotional impacts giving the patient more spontaneity, with add-on effects on cytostructural cavernous erectile tissue and metabolic parameters [83]. In fact, Mostafa and colleagues [84] reported on better cavernous architecture with significant morphometric increases in the percentage area of smooth muscles and elastic tissue and a significant decrease in fibrous tissue once tadalafil was chronically administered. The potential further advantage of using PDE5i in patients with ED and BPH is that with a single pill they have treated both bladder outlet obstruction and LUTS, therefore potentially improve compliance with medical care reducing the number of medications patients need to take. Therefore, PDE5-i can be perfect drugs for the treatment of LUTS secondary to benign prostatic hyperplasia associated or not associated with ED and also in young patients.

 

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Figure 1. Adverse effects of α-blockers and phosphodiesterase 5 inhibitors (PDE5is).

 

[madman]

Table 1. Effects of treatment with 5α-reductase inhibitors on sexual function in patients with benign prostate hyperplasia.