madman
Super Moderator
Abstract
Purpose Neuroactive steroids may have a role in regulating sexual function. This case-control study assessed whether dutasteride, a 5α-reductase inhibitor used for the treatment of patients with benign prostate hyperplasia (BPH), impacts the levels of neuroactive steroids, leading to erectile dysfunction (ED) and/or hypoactive sexual desire (HSD).
Methods Forty patients with BPH and moderate-to-severe lower urinary tract symptoms (LUTS), pre-scheduled for prostate transurethral resection or open prostatectomy were enrolled. Twenty of these patients with prostate volume ≤40 mL were treated with α-blockers (Group A) and the remaining 20, with prostate volume >40 mL, with dutasteride plus α-blockers (Group B) for at least 6 months before surgery. Serum sex steroids and gonadotropin levels were measured the day before surgery, and the neuroactive steroid levels were assessed in the cerebrospinal fluid (CSF) collected during spinal anesthesia, on the day of surgery.
Results Before surgery, the International Index of Erectile Function 5-item score was higher in Group A than in Group B (18.8 ± 4.8 vs. 15.1 ± 5.4, p < 0.01). Group A showed lower total testosterone (TT) (4.5 vs.6.4 ng/ml, p < 0.01) and 17β-estradiol (E2) (24.3 vs.30.7 pg/ml, p < 0.05) serum levels than Group B. CSF levels of TT (1446.6 vs. 19.9 pg/ml, p < 0.05) and dihydrotestosterone (7.9 vs. 1.4 pg/ml, p < 0.05) were higher and CSF E2 levels were lower (26.0 vs.36.0 pg/ml, p < 0.01) in Group A than Group B.
Conclusions A decrease of neuroactive steroids in the CSF of patients treated with dutasteride occurs. This may be one of the mechanisms by which dutasteride may cause ED and HSD.
Introduction
Benign prostatic hyperplasia (BPH) is a common urological disorder that affects about 20% of American men aged 30–79 years. Its prevalence increases proportionally with increasing age [1]. Its pharmacologic treatment involves the use of α–blockers (AB) and/or 5α-reductase inhibitors (5ARI) [2]. The combined treatment has shown greater efficacy in preventing the clinical progression compared to monotherapy, as showed by the amelioration of the international prostate symptom score (IPSS), uroflowmetry, the onset of acute urinary retention, urinary tract infections and/ or incontinence [3]. However, the medical treatment of BPH has some side effects. ABs often cause orthostatic hypotension and anejaculation. 5ARI can cause gynecomastia, erectile dysfunction (ED), a decrease in sexual desire, and ejaculatory dysfunction. These side effects may be more pronounced when combination therapy is prescribed [4].
A previously published study carried out in patients with androgenetic alopecia (AGA) has shown similar effects also with the use of finasteride [5]. In addition, two meta-analyses documented that the use of 5ARI significantly increases the prevalence of ED and hypoactive sexual desire (HSD) in patients with BPH [6, 7]
The mechanism(s) by which 5ARI causes sexual dysfunction is not well known. Hypothetically, one of the mechanisms involved may be the decreasing effect of dutasteride on neuroactive steroid levels in the central nervous system (CNS). In fact, the CNS is able to synthesize neuroactive steroids whose levels can, in turn, influence sexual desire [5]. 5ARI can hinder the effects of steroid metabolites involved in the regulation of sexual activity, within the CNS level [5]. In this regard, a recent study documented that an impairment of neuroactive steroid levels, associated with long-term sexual side effects as well as anxious/depressive symptoms, is still present in patients with AGA treated with finasteride even after the discontinuation of the treatment [5]. Therefore, this study aimed to evaluate the effects of dutasteride on CNS neuroactive steroid levels in patients with BPH and sexual dysfunction. To accomplish this, patients with BPH and sexual dysfunction were treated with ABs or ABs plus 5ARI before undergoing surgical treatment and the serum and CSF steroids were measured. A secondary aim was to analyze the correlation between the presence of ED and HSD in relationship to the treatment with 5ARI.
Discussion
Dutasteride and finasteride are drugs commonly used for the treatment of patients with BPH. Finasteride is also used to treat patients with AGA [8]. Both of these drugs share the same mechanism of action, which consists in the inhibition of the conversion of testosterone into DHT by blocking the 5AR enzyme. Dutasteride has been shown to decrease DHT production more efficiently than finasteride because it acts on both isoforms of the 5AR enzyme (types 1 and 2) [9]. Furthermore, some studies have shown that type 1 isoform is mainly expressed in the prostate tissue, while type 2 is found also in the liver and the skin [10]. The efficacy and safety of these drugs for the treatment of BPH are confirmed by literature data and clinical practice guidelines [4]. A recent study carried out on 40 patients with BPH treated with dutasteride investigated their neuropsychological features by using the following questionnaires: Mini-Mental State Examination (MMSE), Clock Drawing Test (CDT), Frontal Assessment Battery (FAB), Hamilton Anxiety Rating Scale (HAM-A), Beck Depression Inventory second edition (BDI-II), and Short Form-12 (SF-12). The authors found no significant changes in the scores of these questionnaires and concluded that dutasteride was safe on the mental profile [11]. However, some clinical studies and meta-analyses report an elevated chance of adverse effects on sexuality with their use [4, 6, 7].
*The adverse effects of 5ARI on the sexual sphere are mainly ascribed to their known antiandrogenic properties. However, the possible mechanisms of action by which 5ARI causes adverse effects on sexuality have not still clearly elucidated. In fact, while they decrease circulating DHT levels with a relative increase in serum TT, these drugs are often well tolerated by patients without particular negative effects on sexual function [16, 17]. Experimental evidence conducted on both animals and humans has also suggested that the onset of adverse sexual effects after treatment with 5ARI may be partly attributable to their central effect and, in particular, to the 5ARI ability to inhibit the levels of some CNS neurosteroids probably implicated in the regulation of sexual desire and erection [18, 19]. In fact, a study performed on a small number of patients treated with finasteride for AGA has shown a decrease in CSF levels of neurosteroids [5]. These neurosteroids, which are produced by both the testis and the CNS, are implicated not only in the regulation of sexual function but also in cognitive, behavioral, and reproductive aspects, and possibly also in neurodegenerative diseases [20–22]. Although other animal and human studies have just shown that an alteration of neurosteroid levels can alter the sexual sphere, the present study highlighted, for the first time, the central effects of dutasteride when administered to patients with BPH.
Conclusion
In this pilot study, the effects of dutasteride on CNS neuroactive steroid levels in patients with BPH and its impact on sexual dysfunction were evaluated. Patients treated with dutasteride plus ABs showed a significantly lower IIEF-5 questionnaire score than those treated only with ABs, suggesting a better sexual function in the latter group. Expectably, patients treated with dutasteride had significantly higher serum levels of TT and E2 than the others. Importantly, they also had significantly lower CSF TT and DHT levels, and significantly higher CSF E2 levels compared to patients treated only with ABs.
*In conclusion, the present study shows, for the first time, that the administration of dutasteride for almost 6 months to patients with BPH and sexual dysfunction is associated with altered CSF neuroactive steroid and serum sex hormone levels. This may explain the development of ED and HSD. Further randomized, controlled trials are needed to confirm these findings.
Purpose Neuroactive steroids may have a role in regulating sexual function. This case-control study assessed whether dutasteride, a 5α-reductase inhibitor used for the treatment of patients with benign prostate hyperplasia (BPH), impacts the levels of neuroactive steroids, leading to erectile dysfunction (ED) and/or hypoactive sexual desire (HSD).
Methods Forty patients with BPH and moderate-to-severe lower urinary tract symptoms (LUTS), pre-scheduled for prostate transurethral resection or open prostatectomy were enrolled. Twenty of these patients with prostate volume ≤40 mL were treated with α-blockers (Group A) and the remaining 20, with prostate volume >40 mL, with dutasteride plus α-blockers (Group B) for at least 6 months before surgery. Serum sex steroids and gonadotropin levels were measured the day before surgery, and the neuroactive steroid levels were assessed in the cerebrospinal fluid (CSF) collected during spinal anesthesia, on the day of surgery.
Results Before surgery, the International Index of Erectile Function 5-item score was higher in Group A than in Group B (18.8 ± 4.8 vs. 15.1 ± 5.4, p < 0.01). Group A showed lower total testosterone (TT) (4.5 vs.6.4 ng/ml, p < 0.01) and 17β-estradiol (E2) (24.3 vs.30.7 pg/ml, p < 0.05) serum levels than Group B. CSF levels of TT (1446.6 vs. 19.9 pg/ml, p < 0.05) and dihydrotestosterone (7.9 vs. 1.4 pg/ml, p < 0.05) were higher and CSF E2 levels were lower (26.0 vs.36.0 pg/ml, p < 0.01) in Group A than Group B.
Conclusions A decrease of neuroactive steroids in the CSF of patients treated with dutasteride occurs. This may be one of the mechanisms by which dutasteride may cause ED and HSD.
Introduction
Benign prostatic hyperplasia (BPH) is a common urological disorder that affects about 20% of American men aged 30–79 years. Its prevalence increases proportionally with increasing age [1]. Its pharmacologic treatment involves the use of α–blockers (AB) and/or 5α-reductase inhibitors (5ARI) [2]. The combined treatment has shown greater efficacy in preventing the clinical progression compared to monotherapy, as showed by the amelioration of the international prostate symptom score (IPSS), uroflowmetry, the onset of acute urinary retention, urinary tract infections and/ or incontinence [3]. However, the medical treatment of BPH has some side effects. ABs often cause orthostatic hypotension and anejaculation. 5ARI can cause gynecomastia, erectile dysfunction (ED), a decrease in sexual desire, and ejaculatory dysfunction. These side effects may be more pronounced when combination therapy is prescribed [4].
A previously published study carried out in patients with androgenetic alopecia (AGA) has shown similar effects also with the use of finasteride [5]. In addition, two meta-analyses documented that the use of 5ARI significantly increases the prevalence of ED and hypoactive sexual desire (HSD) in patients with BPH [6, 7]
The mechanism(s) by which 5ARI causes sexual dysfunction is not well known. Hypothetically, one of the mechanisms involved may be the decreasing effect of dutasteride on neuroactive steroid levels in the central nervous system (CNS). In fact, the CNS is able to synthesize neuroactive steroids whose levels can, in turn, influence sexual desire [5]. 5ARI can hinder the effects of steroid metabolites involved in the regulation of sexual activity, within the CNS level [5]. In this regard, a recent study documented that an impairment of neuroactive steroid levels, associated with long-term sexual side effects as well as anxious/depressive symptoms, is still present in patients with AGA treated with finasteride even after the discontinuation of the treatment [5]. Therefore, this study aimed to evaluate the effects of dutasteride on CNS neuroactive steroid levels in patients with BPH and sexual dysfunction. To accomplish this, patients with BPH and sexual dysfunction were treated with ABs or ABs plus 5ARI before undergoing surgical treatment and the serum and CSF steroids were measured. A secondary aim was to analyze the correlation between the presence of ED and HSD in relationship to the treatment with 5ARI.
Discussion
Dutasteride and finasteride are drugs commonly used for the treatment of patients with BPH. Finasteride is also used to treat patients with AGA [8]. Both of these drugs share the same mechanism of action, which consists in the inhibition of the conversion of testosterone into DHT by blocking the 5AR enzyme. Dutasteride has been shown to decrease DHT production more efficiently than finasteride because it acts on both isoforms of the 5AR enzyme (types 1 and 2) [9]. Furthermore, some studies have shown that type 1 isoform is mainly expressed in the prostate tissue, while type 2 is found also in the liver and the skin [10]. The efficacy and safety of these drugs for the treatment of BPH are confirmed by literature data and clinical practice guidelines [4]. A recent study carried out on 40 patients with BPH treated with dutasteride investigated their neuropsychological features by using the following questionnaires: Mini-Mental State Examination (MMSE), Clock Drawing Test (CDT), Frontal Assessment Battery (FAB), Hamilton Anxiety Rating Scale (HAM-A), Beck Depression Inventory second edition (BDI-II), and Short Form-12 (SF-12). The authors found no significant changes in the scores of these questionnaires and concluded that dutasteride was safe on the mental profile [11]. However, some clinical studies and meta-analyses report an elevated chance of adverse effects on sexuality with their use [4, 6, 7].
*The adverse effects of 5ARI on the sexual sphere are mainly ascribed to their known antiandrogenic properties. However, the possible mechanisms of action by which 5ARI causes adverse effects on sexuality have not still clearly elucidated. In fact, while they decrease circulating DHT levels with a relative increase in serum TT, these drugs are often well tolerated by patients without particular negative effects on sexual function [16, 17]. Experimental evidence conducted on both animals and humans has also suggested that the onset of adverse sexual effects after treatment with 5ARI may be partly attributable to their central effect and, in particular, to the 5ARI ability to inhibit the levels of some CNS neurosteroids probably implicated in the regulation of sexual desire and erection [18, 19]. In fact, a study performed on a small number of patients treated with finasteride for AGA has shown a decrease in CSF levels of neurosteroids [5]. These neurosteroids, which are produced by both the testis and the CNS, are implicated not only in the regulation of sexual function but also in cognitive, behavioral, and reproductive aspects, and possibly also in neurodegenerative diseases [20–22]. Although other animal and human studies have just shown that an alteration of neurosteroid levels can alter the sexual sphere, the present study highlighted, for the first time, the central effects of dutasteride when administered to patients with BPH.
Conclusion
In this pilot study, the effects of dutasteride on CNS neuroactive steroid levels in patients with BPH and its impact on sexual dysfunction were evaluated. Patients treated with dutasteride plus ABs showed a significantly lower IIEF-5 questionnaire score than those treated only with ABs, suggesting a better sexual function in the latter group. Expectably, patients treated with dutasteride had significantly higher serum levels of TT and E2 than the others. Importantly, they also had significantly lower CSF TT and DHT levels, and significantly higher CSF E2 levels compared to patients treated only with ABs.
*In conclusion, the present study shows, for the first time, that the administration of dutasteride for almost 6 months to patients with BPH and sexual dysfunction is associated with altered CSF neuroactive steroid and serum sex hormone levels. This may explain the development of ED and HSD. Further randomized, controlled trials are needed to confirm these findings.
