- Email: [email protected]
Can we clinically distinguish anejaculation from retrograde ejaculation in patients on α1A-blockers therapy for lower urinary tract symptoms?
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Can we clinically distinguish anejaculation from retrograde ejaculation in patients on α1A-blockers therapy for lower urinary tract symptoms? Carlo Pavone , Alberto Abrate , Pietro Li Muli , Calogero Guzzardo , Alessio Giuseppe Guarneri , Salvatore Dioguardi , Chiara Sanfilippo , Marco Vella , Vincenzo Serretta , Alchiede Simonato PII: DOI: Reference:
S0090-4295(20)30111-4 https://doi.org/10.1016/j.urology.2020.01.027 URL 21965
To appear in:
Urology
Received date: Revised date: Accepted date:
27 September 2019 20 January 2020 22 January 2020
Please cite this article as: Carlo Pavone , Alberto Abrate , Pietro Li Muli , Calogero Guzzardo , Alessio Giuseppe Guarneri , Salvatore Dioguardi , Chiara Sanfilippo , Marco Vella , Vincenzo Serretta , Alchiede Simonato , Can we clinically distinguish anejaculation from retrograde ejaculation in patients on α1A-blockers therapy for lower urinary tract symptoms?, Urology (2020), doi: https://doi.org/10.1016/j.urology.2020.01.027
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Inc.
Can we clinically distinguish anejaculation from retrograde ejaculation in patients on α1Ablockers therapy for lower urinary tract symptoms?
Carlo Pavone1*, Alberto Abrate1, Pietro Li Muli1, Calogero Guzzardo 1, Alessio Giuseppe Guarneri1, Salvatore Dioguardi1, Chiara Sanfilippo2, Marco Vella1, Vincenzo Serretta1, Alchiede Simonato1
1. Department of Surgical, Oncological and Oral Sciences, Section of Urology, University of Palermo, Palermo, Italy 2. Statistics, GSTU Foundation, Palermo, Italy
* Corresponding author: Prof. Carlo Pavone Department of Surgical, Oncological and Oral Sciences, Section of Urology, University of Palermo, via del Vespro 129, 90127 Palermo, Italy Phone: +39.091.655.2421
Email: [email protected]
RUNNING TITLE Anejaculation vs. retrograde ejaculation under α1A-blockers
KEYWORDS Alpha-blockers; Ejaculation; Lower urinary tract symptoms; Seminal vesicle volume; 1
Urine sperm count.
WORD COUNT: 2264
CONFLICTS OF INTERESTS None.
FUNDING None.
AKNOWLEDGEMENTS Special thanks to Lisa Marie Terzariol for the linguistic revision.
ABSTRACT Objective To investigate the physiopathology of ejaculatory disorders (EjD) and discriminate between retrograde ejaculation (REj) and anejaculation (AEj) induced by α1A-blockers, through the association between the mean post-orgasm seminal vesicle volume and the presence of sperm in mid-stream urine, in patients with moderate-to-severe lower urinary tract symptoms (LUTS) secondary to benign prostatic enlargement. Materials and Methods Therapy-naïve male patients with LUTS and without previous EjD were treated with α1A-blockers. Pre- and post-treatment EjD were investigated through question 4 of the 4-item Male Sexual 2
Function questionnaire (MSF-4 Q4) and the Male Sexual Health Questionnaire for Ejaculatory Dysfunction Short Form (MSHQ-EjD-SF). After 12 weeks, post-orgasm urine was collected for sperm count and seminal vesicle volume was calculated through trans rectal ultrasound. Results All 42 patients reported with EjD after treatment with α1A-blockers: MSF-4 Q4 and MSHQ-EjDSF Q4 scores were significantly higher (p < 0.001) and MSHQ-EjD-SF Q1-3 score was significantly lower (p < 0.001) than before. Post-orgasm seminal vesicle volume was significantly higher in patients with post-orgasm sperm-negative urine (AEj), and lower in patients with postorgasm sperm-positive urine (REj; p < 0.001). Conclusions We clearly demonstrated an association between the presence of sperm in the mid-stream urine and seminal vesicle volume after orgasm, strongly confirming and differentiating the hypothesis of a dual etiology for EjD (REj vs. AEj) secondary to α1A-blockers therapy for LUTS.
INTRODUCTION Male lower urinary tract symptoms (LUTS) are very common and likely to be increasing with population ageing. LUTS etiology is complex and often related to benign prostatic enlargement (BPE) causing bladder outflow obstruction. BPE has a prevalence ranging from 8% in the fourth decade to 90% in the ninth decade of life,1 depending also on the assessment method, the country and the age range studied.2 The International Prostate Symptoms Score (IPSS) is a useful tool to define the severity of LUTS and, in case of moderate-to-severe symptoms secondary to BPE, treatment with α1-blockers is recommended.3 According to the predominant distribution of α1Aadrenergic receptors in the urinary tract, α1-blockers relieve LUTS by reducing smooth muscle tone in the prostate and bladder neck. On the contrary, α1B- and α1D-adrenoceptors in blood vessels and the central nervous system are considered mediators of systemic side effects during treatment with 3
α1-blockers.4 In case of LUTS the use of α1A-blockers is favored by lower incidence of systemic side effects compared to nonselective α1-blockers. Tamsulosin and Silodosin are considered α1Aselective as they showed a 15- and 162-times higher selectivity for α1A receptors than α1B receptors, with a 20- and 280-times higher selectivity for prostate than for splenic tissue.5 This may reflect a mean reduction of 14.27 and 30.45 points of the bladder outlet obstruction index at the urodynamic studies, respectively.6 However significant improvements in total IPSS, storage, and voiding subscores for both tamsulosin and silodosin were reported over placebo, without any significant advantage in favor of one of them. 7 Ejaculatory disorders (EjD) are typical of α1Ablockers 5 and their prevalence secondary to α1-blockers therapy has been estimated to be up to the 82.6%,8 depending on the drug used and study duration. Unfortunately, a wide spectrum of conditions are usually defined as EjD and are not often investigated or reported with sufficient details in the available trials.9 The EjD induced by the α1-blockers are commonly described as absent ejaculate due to retrograde ejaculation (REj). However, in some cases the absence of sperm in post-ejaculatory urinalysis supports the diagnosis of anejaculation (AEj).10 In the end there is no clear evidence in literature of the physiopathology of EjD secondary to α1Ablockers and furthermore, to our knowledge, there are no published studies investigating the association between the presence of sperm in post-orgasm urine and the post-orgasm volume of the seminal vesicles. The evaluation of the post-orgasm seminal vesicle volume in addition to the postorgasm urinalysis could be helpful in clinical practice in order to distinguish AEj from REj, while verifying an adequate urine collection and excluding other possible causes of AEj. Thus the aim of this study was to investigate the physiopathology of EjD (REj vs. AEj) secondary to α1A-blockers therapy through the association between post-orgasm seminal vesicle volume and the presence of sperm in post-orgasm mid-stream urine.
4
MATERIALS AND METHODS Consecutive therapy-naïve (no chronic therapy) male patients with LUTS were recruited at our tertiary referral center from November 2017 to January 2019, after collection of written informed consent. The study received the approval of the local Ethical Board (resolution No. 3/2018). At first visit, LUTS were evaluated through the International Prostate Symptoms Score (IPSS) and the peak urinary flow rate (Qmax). Ejaculatory function was evaluated through question 4 (Q4) of the 4-item Male Sexual Function questionnaire (MSF-4) 11 and questions 1-3 (Q1-3) of the Male Sexual Health Questionnaire for Ejaculatory Dysfunction Short Form (MSHQ-EjD-SF).12 In particular the impact of EjD on the quality of life (QoL) of the patients was investigated through MSHQ-EjD-SF Q4. Inclusion criteria were: 50-80 years of age, no previous treatment with α1-blockers, pretreatment preserved ejaculation (MSF-4 Q4 ≤ 2), pre-treatment moderate-to-severe LUTS (IPSS ≥ 8), and pre-treatment Qmax < 15 ml/s. Conversely we excluded patients with mild LUTS (IPSS < 8), those already taking α1-blockers, and those with Qmax ≥ 15ml/s, previous ejaculatory dysfunctions (MSF-4 Q4 > 2), diagnosis of diabetes mellitus or other neurological dysfunctions, iatrogenic lesion of nerve fibers, and those already undergone bladder neck endoscopic surgery or transurethral resection of the prostate. Patients were then treated with α1A-blockers (tamsulosin 0.4 mg controlled-release capsule or silodosin 8 mg capsule) once daily after dinner for 12 weeks. Patients were randomly given tamsulosin or silodosin therapy based on prostate volume, Qmax and pre-treatment IPSS. At the second visit after 12 weeks, the questionnaires were re-submitted to those patients who were still on therapy, and Qmax was re-evaluated. Patients were also asked to ejaculate and collect the midstream urine for sperm count, after an abstinence period of at least three days since last ejaculation. Urine was considered sperm-positive or sperm-negative according to the presence or not of spermatozoa in the sediment. At the same time, a trans rectal ultrasound (TRUS) was performed by one of the authors (C.G.), blinded to the results of the sperm count in the urine, for the evaluation of the seminal vesicle volume after orgasm. We calculated the mean seminal vesicle volume as the 5
mean of the volumes of the right and left seminal vesicles, estimated according to the model of the prolate spheroid: 4/3ℼ x (1/2 antero-posterior diameter)² x 1/2 longitudinal diameter.13 Statistical analysis Patients were primarily stratified according to the presence of sperm in the post-orgasm urine and secondarily according to the type of α1A-blocker given. Mean values of the pre- and post-treatment continuous variables were compared using the Student t-tests. Nominal variables were compared through the Chi squared test. We also investigated the ability of the post-treatment post-orgasm volume of the seminal vesicles to predict retrograde ejaculation through the analysis of the area under the curve (AUC) of the receiver operating characteristic (ROC). A p value < 0.05 was considered as statistically significant.
6
RESULTS Overall, of the 62 patients recruited, 42 patients completed the study protocol and were included in the analyses. 14 (70%) and 6 (30%) of the other 20 patients stopped treatment and left the study for EjD and orthostatic hypotension, respectively, referring the complete remission of symptoms after stopping the drug. Table 1 summaries pre- and post-treatment variables of the patients included in the analyses stratified according to the presence of sperm in post-orgasm urine. 28 (66.7%) and 14 (33.3%) patients had post-orgasm sperm-negative and sperm-positive urine, respectively. Within the pretreatment variables, age and prostate volume were not statistically different. Only the IPSS was significantly different between the two groups (21.9 vs. 19.6, respectively; p = 0.035). Both groups got benefit from the therapy with α1A-blockers, as confirmed by a mean reduction of 8.6 points of the IPSS (p < 0.001) and a mean increase of 4.4 ml/s of the Qmax (p < 0.001). All the patients included in the study referred EjD secondary to α1A-blockers therapy. Overall MSF-4 Q4 scores were significantly higher (p < 0.001) and MSHQ-EjD-SF Q1-3 score was significantly lower (p < 0.001) after α1A-blockers therapy, confirming EjD. However posttreatment MSF-4 Q4 and MSHQ-EjD-SF Q1-3 scores did not differ between the two groups (p = 0.664 and p = 0.508, respectively). In terms of QoL, MSHQ-EjD-SF Q4 scores were significantly higher after α1A-blockers therapy (p < 0.001), without any significant differences between the two groups (p = 0.894), confirming that EjD (in any of its forms) had a negative impact on QoL. Interestingly, the post-orgasm seminal vesicle volume was significantly lower in patients with postorgasm sperm-positive urine, and significantly higher in patients with post-orgasm sperm-negative urine (p < 0.001). The mean seminal vesicle volume was predictive of REj with an AUC of 1.0 (p < 0.001). A post-orgasm seminal vesicle volume ≤ 1.9 cm3 was the best threshold to predict REj with a sensitivity of the 100% (95% CI 76.8 – 100.0) and a specificity of the 100% (95% CI 87.7 – 100.0).
7
Overall, 19 (45.2%) patients took tamsulosin and 23 (54.8%) patients took silodosin. No statistically significant differences were calculated between these two treatment in terms of pretreatment variables and post-treatment EjD (Supplementary 1), but only a slight benefit for silodosin in terms of post-treatment IPSS (11.3 ± 3.9 vs. 14.1 ± 3.2, p = 0.015).
8
DISCUSSION In the current study, we investigated the nature of the EjD in patients treated with α1A-blockers for LUTS. Interestingly we found an association between the post-orgasm seminal vesicle volume and the presence of sperm in urine, finally demonstrating the dual nature for EjD (REj vs. AEj). Although LUTS has at times been successfully treated with Serenoa Repens extracts,14 α1-blockers are considered the first choice in case of moderate-to-severe symptoms as they have been demonstrated to significantly improve both storage and voiding LUTS, quality of life, and urinary flow rates.6 On the other hand, common side effects include dizziness, fatigue, orthostatic hypotension, nasal congestion and EjD. In a recent meta-analysis, Gacci et al.9 confirmed that EjD was significantly more common with α-blockers than with placebo (p < 0.001), significantly more prevalent with tamsulosin (OR 8.57; P = 0.006) or silodosin (OR 32.5; P < 0.0001) than placebo, in comparison with a lower risk with doxazosin (OR0.80; P = 0.14) and terazosin (OR 1.78; P = 0.71). Interestingly tamsulosin was associated with a significantly lower risk of EjD than silodosin (p < 0.001). In our study we found EjD in the 90% of patients recruited and in all the patients included in the analyses, although without any significant differences between the two α1A-blockers used (Supplementary 1), confirming the fact that EjD is actually the most frequent and bothersome side effect of these drugs, affecting QoL (14 patients left the study for EjD). The etiopathogenetic role of α1-blockers in EjD is still not entirely clarified. It is still not clear whether α1-blockers induce REj (as reported in most studies) or AEj. In fact, REj caused by αblockers is thought to be secondary to the bladder neck relaxation. However a decreased contraction of the seminal vesicles has been also proposed as the cause of the EjD induced by α1-blockers, as suggested by the absence of sperm in post-ejaculatory urine in some studies.15, 16 Interestingly EjD seems to be more evident in case of treatment with α1A-blocker than nonselective α1-blocker. Accordingly, in a randomized trial, Hellstrom et al.17 showed a significantly decreased ejaculate volume (-2.4 ± 0.17 ml vs. +0.3 ± 0.18 ml, respectively; p < 0.001) and complete anejaculation in
9
35.4% of patients in the tamsulosin (α1A-blocker) group in comparison with the alfuzosin (nonselective α1-blocker) group. Few studies examined the pre- and post-ejaculatory seminal vesicle volume. Thus their size is not well standardized. In fact, the longitudinal diameter is normally considered > 25 mm, while the antero-posterior diameter is about 5-15 mm, with a calculated volume usually less than 7 cm3.13, 18, 19
However, it is clear that during ejaculation there is a physiological contraction of the seminal
vesicles, as demonstrated by a reduction in their diameter.20 For the first time we demonstrated an association between post-orgasm seminal vesicle volume and sperm count in the urine, confirming the hypothesis of a dual etiology for EjD induced by α1Ablockers. In fact, we reported REj in only 1/3 of the patients treated with α1A-blockers: the presence of sperm in the post-orgasm urine was associated with a lower volume of the seminal vesicles, indicating a physiological contraction of the seminal vesicles during ejaculation and relaxation of the bladder neck induced by the α1A-blockers. However, REj was not associated with a higher Qmax, thus excluding an higher grade of relaxation of the bladder neck in comparison with the other group. Conversely, we reported a higher post-orgasm volume of the seminal vesicles in the other 2/3 of patients, who were found with sperm-negative urine. This could be explained by the lack of physiological contraction given by the antagonistic action of the drug on the seminal vesicles, thus ending in a failed emission of sperm (AEj). It is also interesting that EjD affected the QoL of the patients, independently from its etiology, as shown by the comparable results of MSHQ-EjD-SF Q4 in the two groups. The main limitation of the current study is the small number of patients included, but it primarily depends on the difficulty in finding therapy-naïve patients. In consideration of the small number of patients included and of the variables taken into account, we did not performed a multivariate analysis. The lack of a control group and post-orgasm vesicle volume before treatment or preorgasm vesicle volume could limit the strength of our results, but only patients without previous EjD were included in this study, thus theoretically excluding serious artifacts. For the aims of the 10
study we used both tamsulosin and silodosin as part of the α1A-blockers pharmacological class, considering that EjD is a side effect typical of α1A-blockers and that tamsulosin and silodosin showed similar clinical efficacy. The secondary analyses, comparing the two drugs, is limited by the small subpopulation numbers. Although the therapy was well tolerated, we did not thoroughly investigate other side effects as that was beyond the aims of the current study. On the contrary, the main strength is that the TRUS was performed by only one author, blinded to the results of the sperm count in the urine.
11
CONCLUSIONS In the current study, we clearly demonstrated an association between the presence of sperm in the urine and seminal vesicle volume after orgasm in patients treated with α1A-blockers for LUTS. Our results strongly confirm the hypothesis of a dual etiology for EjD induced by α1A-blockers. This is an important notion to keep in mind in clinical practice, better investigating the symptoms of the patients and explaining to the patients the reasons of this common side effect: we should not speak only of REj, but on the contrary of AEj in the majority of cases.
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[2]
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Oelke M, Bachmann A, Descazeaud A, et al. EAU guidelines on the treatment and follow-
up of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. Eur Urol. 2013 Jul: 64:118-40 [4]
Barendrecht MM, Koopmans RP, de la Rosette JJ, et al. Treatment of lower urinary tract
symptoms suggestive of benign prostatic hyperplasia: the cardiovascular system. BJU Int. 2005 Jun: 95 Suppl 4:19-28 [5]
Roehrborn CG, Cruz F, Fusco F. alpha1-Blockers in Men with Lower Urinary Tract
Symptoms Suggestive of Benign Prostatic Obstruction: Is Silodosin Different? Adv Ther. 2017 Jan: 33:2110-21 [6]
Fusco F, Palmieri A, Ficarra V, et al. alpha1-Blockers Improve Benign Prostatic Obstruction
in Men with Lower Urinary Tract Symptoms: A Systematic Review and Meta-analysis of Urodynamic Studies. Eur Urol. 2016 Jun: 69:1091-101 [7]
Chapple CR, Montorsi F, Tammela TL, Wirth M, Koldewijn E, Fernandez Fernandez E.
Silodosin therapy for lower urinary tract symptoms in men with suspected benign prostatic 12
hyperplasia: results of an international, randomized, double-blind, placebo- and active-controlled clinical trial performed in Europe. Eur Urol. 2011 Mar: 59:342-52 [8]
Martin-Morales A, Meyer G, Ramirez E. [Prevalence of ejaculatory dysfunction secondary
to alpha-blocker therapy in patients with benign prostatic hyperplasia]. Actas Urol Esp. 2008 JulAug: 32:705-12 [9]
Gacci M, Ficarra V, Sebastianelli A, et al. Impact of medical treatments for male lower
urinary tract symptoms due to benign prostatic hyperplasia on ejaculatory function: a systematic review and meta-analysis. J Sex Med. 2014 Jun: 11:1554-66 [10]
Jiann BP. The office management of ejaculatory disorders. Transl Androl Urol. 2016 Aug:
5:526-40 [11]
Marquis P, Marrel A. Reproducibility and clinical and concurrent validity of the MSF-4: a
four-item male sexual function questionnaire for patients with benign prostatic hyperplasia. Value Health. 2001 Jul-Aug: 4:335-43 [12]
Rosen RC, Catania JA, Althof SE, et al. Development and validation of four-item version of
Male Sexual Health Questionnaire to assess ejaculatory dysfunction. Urology. 2007 May: 69:805-9 [13]
Lotti F, Corona G, Colpi GM, et al. Seminal vesicles ultrasound features in a cohort of
infertility patients. Hum Reprod. 2012 Apr: 27:974-82 [14]
Pavone C, Abbadessa D, Tarantino ML, et al. [Associating Serenoa repens, Urtica dioica
and Pinus pinaster. Safety and efficacy in the treatment of lower urinary tract symptoms. Prospective study on 320 patients]. Urologia. 2010 Jan-Mar: 77:43-51 [15]
Hisasue S, Furuya R, Itoh N, et al. Ejaculatory disorder caused by alpha-1 adrenoceptor
antagonists is not retrograde ejaculation but a loss of seminal emission. Int J Urol. 2006 Oct: 13:1311-6 [16]
Kobayashi K, Masumori N, Hisasue S, et al. Inhibition of Seminal emission is the main
cause of anejaculation induced by a new highly selective alpha1A-blocker in normal volunteers. J Sex Med. 2008 Sep: 5:2185-90 13
[17]
Hellstrom WJ, Sikka SC. Effects of acute treatment with tamsulosin versus alfuzosin on
ejaculatory function in normal volunteers. J Urol. 2006 Oct: 176:1529-33 [18]
Gofrit ON, Zorn KC, Taxy JB, et al. The dimensions and symmetry of the seminal vesicles.
J Robot Surg. 2009 Mar: 3:29-33 [19]
Lotti F, Maggi M. Ultrasound of the male genital tract in relation to male reproductive
health. Hum Reprod Update. 2015 Jan-Feb: 21:56-83 [20]
Revenig L, Leung A, Hsiao W. Ejaculatory physiology and pathophysiology: assessment
and treatment in male infertility. Transl Androl Urol. 2014 Mar: 3:41-9 Table 1. Patients’ characteristics and questionnaire scores. Variable Patients Age, yr Prostate volume, cm3 α1A-blocker Tamsulosin Silodosin Post-treatment postorgasm seminal vesicle volume, cm3 Qmax, ml/s Pre-treatment Post-treatment IPSS Pre-treatment Post-treatment Pre-treatment LUTS severity Moderate Severe Post-treatment LUTS severity Mild Moderate MSF-4 Q4 Pre-treatment Post-treatment MSHQEjD-SF Q1-3 Pre-treatment Post-treatment
42 65.1 ± 7.7 34.5 ± 8.1
Spermnegative urine 28 (66.7) 63.9 ± 7.3 33.1 ± 9.2
Spermpositive urine 14 (33.3) 67.6 ± 8.1 37.1 ± 4.9
19 (45.2) 23 (54.8)
13 (46.4) 15 (53.6)
6 (42.9) 8 (57.1)
0.913
2.5 ± 1.3
3.2 ± 1.1
1.3 ± 0.5
< 0.001
10.1 ± 2.1 14.5 ± 2.6
9.9 ± 2.3 14.2 ± 2.8
10.4 ± 1.5 14.9 ± 2.1
0.523 0.435
21.1 ± 3.5 12.5 ± 3.8
21.9 ± 3.1 13.7 ± 3.9
19.6 ± 3.6 10.1 ± 2.5
0.035 0.003
14 (33.3) 28 (66.7)
6 (21.4) 22 (78.6)
8 (57.1) 6 (42.9)
0.049
3 (7.1) 39 (92.9)
2 (7.1) 26 (92.9)
1 (7.1) 13 (92.9)
0.525
0.5 ± 0.6 4.3 ± 0.7
0.5 ± 0.6 4.2 ± 0.8
0.5 ± 0.6 4.4 ± 0.7
1.000 0.664
14.5 ± 0.6 5.3 ± 2.1
14.4 ± 0.7 5.1 ± 2.3
14.6 ± 0.5 5.6 ± 1.8
0.233 0.508
Total
p-value
0.139 0.238
14
MSHQEjD-SF Q4 Pre-treatment 0.5 ± 0.5 0.5 ± 0.5 0.4 ± 0.5 0.286 Post-treatment 4.2 ± 0.8 4.2 ± 0.8 4.2 ± 0.9 0.894 Continuous variables are expressed as mean ± SD; Nominal variables are expressed as No. (%). IPSS, International Prostate Symptoms Score; LUTS, lower urinary tract symptoms; MSF-4, 4-item Male Sexual Function questionnaire; MSHQEjD-SF, Male Sexual Health Questionnaire for Ejaculatory Dysfunction Short Form; Q, question; Qmax, peak urinary flow rate.
15
Can we clinically distinguish anejaculation from retrograde ejaculation in patients on α1A-blockers therapy for lower urinary tract symptoms? Carlo Pavone , Alberto Abrate , Pietro Li Muli , Calogero Guzzardo , Alessio Giuseppe Guarneri , Salvatore Dioguardi , Chiara Sanfilippo , Marco Vella , Vincenzo Serretta , Alchiede Simonato PII: DOI: Reference:
S0090-4295(20)30111-4 https://doi.org/10.1016/j.urology.2020.01.027 URL 21965
To appear in:
Urology
Received date: Revised date: Accepted date:
27 September 2019 20 January 2020 22 January 2020
Please cite this article as: Carlo Pavone , Alberto Abrate , Pietro Li Muli , Calogero Guzzardo , Alessio Giuseppe Guarneri , Salvatore Dioguardi , Chiara Sanfilippo , Marco Vella , Vincenzo Serretta , Alchiede Simonato , Can we clinically distinguish anejaculation from retrograde ejaculation in patients on α1A-blockers therapy for lower urinary tract symptoms?, Urology (2020), doi: https://doi.org/10.1016/j.urology.2020.01.027
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Inc.
Can we clinically distinguish anejaculation from retrograde ejaculation in patients on α1Ablockers therapy for lower urinary tract symptoms?
Carlo Pavone1*, Alberto Abrate1, Pietro Li Muli1, Calogero Guzzardo 1, Alessio Giuseppe Guarneri1, Salvatore Dioguardi1, Chiara Sanfilippo2, Marco Vella1, Vincenzo Serretta1, Alchiede Simonato1
1. Department of Surgical, Oncological and Oral Sciences, Section of Urology, University of Palermo, Palermo, Italy 2. Statistics, GSTU Foundation, Palermo, Italy
* Corresponding author: Prof. Carlo Pavone Department of Surgical, Oncological and Oral Sciences, Section of Urology, University of Palermo, via del Vespro 129, 90127 Palermo, Italy Phone: +39.091.655.2421
Email: [email protected]
RUNNING TITLE Anejaculation vs. retrograde ejaculation under α1A-blockers
KEYWORDS Alpha-blockers; Ejaculation; Lower urinary tract symptoms; Seminal vesicle volume; 1
Urine sperm count.
WORD COUNT: 2264
CONFLICTS OF INTERESTS None.
FUNDING None.
AKNOWLEDGEMENTS Special thanks to Lisa Marie Terzariol for the linguistic revision.
ABSTRACT Objective To investigate the physiopathology of ejaculatory disorders (EjD) and discriminate between retrograde ejaculation (REj) and anejaculation (AEj) induced by α1A-blockers, through the association between the mean post-orgasm seminal vesicle volume and the presence of sperm in mid-stream urine, in patients with moderate-to-severe lower urinary tract symptoms (LUTS) secondary to benign prostatic enlargement. Materials and Methods Therapy-naïve male patients with LUTS and without previous EjD were treated with α1A-blockers. Pre- and post-treatment EjD were investigated through question 4 of the 4-item Male Sexual 2
Function questionnaire (MSF-4 Q4) and the Male Sexual Health Questionnaire for Ejaculatory Dysfunction Short Form (MSHQ-EjD-SF). After 12 weeks, post-orgasm urine was collected for sperm count and seminal vesicle volume was calculated through trans rectal ultrasound. Results All 42 patients reported with EjD after treatment with α1A-blockers: MSF-4 Q4 and MSHQ-EjDSF Q4 scores were significantly higher (p < 0.001) and MSHQ-EjD-SF Q1-3 score was significantly lower (p < 0.001) than before. Post-orgasm seminal vesicle volume was significantly higher in patients with post-orgasm sperm-negative urine (AEj), and lower in patients with postorgasm sperm-positive urine (REj; p < 0.001). Conclusions We clearly demonstrated an association between the presence of sperm in the mid-stream urine and seminal vesicle volume after orgasm, strongly confirming and differentiating the hypothesis of a dual etiology for EjD (REj vs. AEj) secondary to α1A-blockers therapy for LUTS.
INTRODUCTION Male lower urinary tract symptoms (LUTS) are very common and likely to be increasing with population ageing. LUTS etiology is complex and often related to benign prostatic enlargement (BPE) causing bladder outflow obstruction. BPE has a prevalence ranging from 8% in the fourth decade to 90% in the ninth decade of life,1 depending also on the assessment method, the country and the age range studied.2 The International Prostate Symptoms Score (IPSS) is a useful tool to define the severity of LUTS and, in case of moderate-to-severe symptoms secondary to BPE, treatment with α1-blockers is recommended.3 According to the predominant distribution of α1Aadrenergic receptors in the urinary tract, α1-blockers relieve LUTS by reducing smooth muscle tone in the prostate and bladder neck. On the contrary, α1B- and α1D-adrenoceptors in blood vessels and the central nervous system are considered mediators of systemic side effects during treatment with 3
α1-blockers.4 In case of LUTS the use of α1A-blockers is favored by lower incidence of systemic side effects compared to nonselective α1-blockers. Tamsulosin and Silodosin are considered α1Aselective as they showed a 15- and 162-times higher selectivity for α1A receptors than α1B receptors, with a 20- and 280-times higher selectivity for prostate than for splenic tissue.5 This may reflect a mean reduction of 14.27 and 30.45 points of the bladder outlet obstruction index at the urodynamic studies, respectively.6 However significant improvements in total IPSS, storage, and voiding subscores for both tamsulosin and silodosin were reported over placebo, without any significant advantage in favor of one of them. 7 Ejaculatory disorders (EjD) are typical of α1Ablockers 5 and their prevalence secondary to α1-blockers therapy has been estimated to be up to the 82.6%,8 depending on the drug used and study duration. Unfortunately, a wide spectrum of conditions are usually defined as EjD and are not often investigated or reported with sufficient details in the available trials.9 The EjD induced by the α1-blockers are commonly described as absent ejaculate due to retrograde ejaculation (REj). However, in some cases the absence of sperm in post-ejaculatory urinalysis supports the diagnosis of anejaculation (AEj).10 In the end there is no clear evidence in literature of the physiopathology of EjD secondary to α1Ablockers and furthermore, to our knowledge, there are no published studies investigating the association between the presence of sperm in post-orgasm urine and the post-orgasm volume of the seminal vesicles. The evaluation of the post-orgasm seminal vesicle volume in addition to the postorgasm urinalysis could be helpful in clinical practice in order to distinguish AEj from REj, while verifying an adequate urine collection and excluding other possible causes of AEj. Thus the aim of this study was to investigate the physiopathology of EjD (REj vs. AEj) secondary to α1A-blockers therapy through the association between post-orgasm seminal vesicle volume and the presence of sperm in post-orgasm mid-stream urine.
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MATERIALS AND METHODS Consecutive therapy-naïve (no chronic therapy) male patients with LUTS were recruited at our tertiary referral center from November 2017 to January 2019, after collection of written informed consent. The study received the approval of the local Ethical Board (resolution No. 3/2018). At first visit, LUTS were evaluated through the International Prostate Symptoms Score (IPSS) and the peak urinary flow rate (Qmax). Ejaculatory function was evaluated through question 4 (Q4) of the 4-item Male Sexual Function questionnaire (MSF-4) 11 and questions 1-3 (Q1-3) of the Male Sexual Health Questionnaire for Ejaculatory Dysfunction Short Form (MSHQ-EjD-SF).12 In particular the impact of EjD on the quality of life (QoL) of the patients was investigated through MSHQ-EjD-SF Q4. Inclusion criteria were: 50-80 years of age, no previous treatment with α1-blockers, pretreatment preserved ejaculation (MSF-4 Q4 ≤ 2), pre-treatment moderate-to-severe LUTS (IPSS ≥ 8), and pre-treatment Qmax < 15 ml/s. Conversely we excluded patients with mild LUTS (IPSS < 8), those already taking α1-blockers, and those with Qmax ≥ 15ml/s, previous ejaculatory dysfunctions (MSF-4 Q4 > 2), diagnosis of diabetes mellitus or other neurological dysfunctions, iatrogenic lesion of nerve fibers, and those already undergone bladder neck endoscopic surgery or transurethral resection of the prostate. Patients were then treated with α1A-blockers (tamsulosin 0.4 mg controlled-release capsule or silodosin 8 mg capsule) once daily after dinner for 12 weeks. Patients were randomly given tamsulosin or silodosin therapy based on prostate volume, Qmax and pre-treatment IPSS. At the second visit after 12 weeks, the questionnaires were re-submitted to those patients who were still on therapy, and Qmax was re-evaluated. Patients were also asked to ejaculate and collect the midstream urine for sperm count, after an abstinence period of at least three days since last ejaculation. Urine was considered sperm-positive or sperm-negative according to the presence or not of spermatozoa in the sediment. At the same time, a trans rectal ultrasound (TRUS) was performed by one of the authors (C.G.), blinded to the results of the sperm count in the urine, for the evaluation of the seminal vesicle volume after orgasm. We calculated the mean seminal vesicle volume as the 5
mean of the volumes of the right and left seminal vesicles, estimated according to the model of the prolate spheroid: 4/3ℼ x (1/2 antero-posterior diameter)² x 1/2 longitudinal diameter.13 Statistical analysis Patients were primarily stratified according to the presence of sperm in the post-orgasm urine and secondarily according to the type of α1A-blocker given. Mean values of the pre- and post-treatment continuous variables were compared using the Student t-tests. Nominal variables were compared through the Chi squared test. We also investigated the ability of the post-treatment post-orgasm volume of the seminal vesicles to predict retrograde ejaculation through the analysis of the area under the curve (AUC) of the receiver operating characteristic (ROC). A p value < 0.05 was considered as statistically significant.
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RESULTS Overall, of the 62 patients recruited, 42 patients completed the study protocol and were included in the analyses. 14 (70%) and 6 (30%) of the other 20 patients stopped treatment and left the study for EjD and orthostatic hypotension, respectively, referring the complete remission of symptoms after stopping the drug. Table 1 summaries pre- and post-treatment variables of the patients included in the analyses stratified according to the presence of sperm in post-orgasm urine. 28 (66.7%) and 14 (33.3%) patients had post-orgasm sperm-negative and sperm-positive urine, respectively. Within the pretreatment variables, age and prostate volume were not statistically different. Only the IPSS was significantly different between the two groups (21.9 vs. 19.6, respectively; p = 0.035). Both groups got benefit from the therapy with α1A-blockers, as confirmed by a mean reduction of 8.6 points of the IPSS (p < 0.001) and a mean increase of 4.4 ml/s of the Qmax (p < 0.001). All the patients included in the study referred EjD secondary to α1A-blockers therapy. Overall MSF-4 Q4 scores were significantly higher (p < 0.001) and MSHQ-EjD-SF Q1-3 score was significantly lower (p < 0.001) after α1A-blockers therapy, confirming EjD. However posttreatment MSF-4 Q4 and MSHQ-EjD-SF Q1-3 scores did not differ between the two groups (p = 0.664 and p = 0.508, respectively). In terms of QoL, MSHQ-EjD-SF Q4 scores were significantly higher after α1A-blockers therapy (p < 0.001), without any significant differences between the two groups (p = 0.894), confirming that EjD (in any of its forms) had a negative impact on QoL. Interestingly, the post-orgasm seminal vesicle volume was significantly lower in patients with postorgasm sperm-positive urine, and significantly higher in patients with post-orgasm sperm-negative urine (p < 0.001). The mean seminal vesicle volume was predictive of REj with an AUC of 1.0 (p < 0.001). A post-orgasm seminal vesicle volume ≤ 1.9 cm3 was the best threshold to predict REj with a sensitivity of the 100% (95% CI 76.8 – 100.0) and a specificity of the 100% (95% CI 87.7 – 100.0).
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Overall, 19 (45.2%) patients took tamsulosin and 23 (54.8%) patients took silodosin. No statistically significant differences were calculated between these two treatment in terms of pretreatment variables and post-treatment EjD (Supplementary 1), but only a slight benefit for silodosin in terms of post-treatment IPSS (11.3 ± 3.9 vs. 14.1 ± 3.2, p = 0.015).
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DISCUSSION In the current study, we investigated the nature of the EjD in patients treated with α1A-blockers for LUTS. Interestingly we found an association between the post-orgasm seminal vesicle volume and the presence of sperm in urine, finally demonstrating the dual nature for EjD (REj vs. AEj). Although LUTS has at times been successfully treated with Serenoa Repens extracts,14 α1-blockers are considered the first choice in case of moderate-to-severe symptoms as they have been demonstrated to significantly improve both storage and voiding LUTS, quality of life, and urinary flow rates.6 On the other hand, common side effects include dizziness, fatigue, orthostatic hypotension, nasal congestion and EjD. In a recent meta-analysis, Gacci et al.9 confirmed that EjD was significantly more common with α-blockers than with placebo (p < 0.001), significantly more prevalent with tamsulosin (OR 8.57; P = 0.006) or silodosin (OR 32.5; P < 0.0001) than placebo, in comparison with a lower risk with doxazosin (OR0.80; P = 0.14) and terazosin (OR 1.78; P = 0.71). Interestingly tamsulosin was associated with a significantly lower risk of EjD than silodosin (p < 0.001). In our study we found EjD in the 90% of patients recruited and in all the patients included in the analyses, although without any significant differences between the two α1A-blockers used (Supplementary 1), confirming the fact that EjD is actually the most frequent and bothersome side effect of these drugs, affecting QoL (14 patients left the study for EjD). The etiopathogenetic role of α1-blockers in EjD is still not entirely clarified. It is still not clear whether α1-blockers induce REj (as reported in most studies) or AEj. In fact, REj caused by αblockers is thought to be secondary to the bladder neck relaxation. However a decreased contraction of the seminal vesicles has been also proposed as the cause of the EjD induced by α1-blockers, as suggested by the absence of sperm in post-ejaculatory urine in some studies.15, 16 Interestingly EjD seems to be more evident in case of treatment with α1A-blocker than nonselective α1-blocker. Accordingly, in a randomized trial, Hellstrom et al.17 showed a significantly decreased ejaculate volume (-2.4 ± 0.17 ml vs. +0.3 ± 0.18 ml, respectively; p < 0.001) and complete anejaculation in
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35.4% of patients in the tamsulosin (α1A-blocker) group in comparison with the alfuzosin (nonselective α1-blocker) group. Few studies examined the pre- and post-ejaculatory seminal vesicle volume. Thus their size is not well standardized. In fact, the longitudinal diameter is normally considered > 25 mm, while the antero-posterior diameter is about 5-15 mm, with a calculated volume usually less than 7 cm3.13, 18, 19
However, it is clear that during ejaculation there is a physiological contraction of the seminal
vesicles, as demonstrated by a reduction in their diameter.20 For the first time we demonstrated an association between post-orgasm seminal vesicle volume and sperm count in the urine, confirming the hypothesis of a dual etiology for EjD induced by α1Ablockers. In fact, we reported REj in only 1/3 of the patients treated with α1A-blockers: the presence of sperm in the post-orgasm urine was associated with a lower volume of the seminal vesicles, indicating a physiological contraction of the seminal vesicles during ejaculation and relaxation of the bladder neck induced by the α1A-blockers. However, REj was not associated with a higher Qmax, thus excluding an higher grade of relaxation of the bladder neck in comparison with the other group. Conversely, we reported a higher post-orgasm volume of the seminal vesicles in the other 2/3 of patients, who were found with sperm-negative urine. This could be explained by the lack of physiological contraction given by the antagonistic action of the drug on the seminal vesicles, thus ending in a failed emission of sperm (AEj). It is also interesting that EjD affected the QoL of the patients, independently from its etiology, as shown by the comparable results of MSHQ-EjD-SF Q4 in the two groups. The main limitation of the current study is the small number of patients included, but it primarily depends on the difficulty in finding therapy-naïve patients. In consideration of the small number of patients included and of the variables taken into account, we did not performed a multivariate analysis. The lack of a control group and post-orgasm vesicle volume before treatment or preorgasm vesicle volume could limit the strength of our results, but only patients without previous EjD were included in this study, thus theoretically excluding serious artifacts. For the aims of the 10
study we used both tamsulosin and silodosin as part of the α1A-blockers pharmacological class, considering that EjD is a side effect typical of α1A-blockers and that tamsulosin and silodosin showed similar clinical efficacy. The secondary analyses, comparing the two drugs, is limited by the small subpopulation numbers. Although the therapy was well tolerated, we did not thoroughly investigate other side effects as that was beyond the aims of the current study. On the contrary, the main strength is that the TRUS was performed by only one author, blinded to the results of the sperm count in the urine.
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CONCLUSIONS In the current study, we clearly demonstrated an association between the presence of sperm in the urine and seminal vesicle volume after orgasm in patients treated with α1A-blockers for LUTS. Our results strongly confirm the hypothesis of a dual etiology for EjD induced by α1A-blockers. This is an important notion to keep in mind in clinical practice, better investigating the symptoms of the patients and explaining to the patients the reasons of this common side effect: we should not speak only of REj, but on the contrary of AEj in the majority of cases.
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and treatment in male infertility. Transl Androl Urol. 2014 Mar: 3:41-9 Table 1. Patients’ characteristics and questionnaire scores. Variable Patients Age, yr Prostate volume, cm3 α1A-blocker Tamsulosin Silodosin Post-treatment postorgasm seminal vesicle volume, cm3 Qmax, ml/s Pre-treatment Post-treatment IPSS Pre-treatment Post-treatment Pre-treatment LUTS severity Moderate Severe Post-treatment LUTS severity Mild Moderate MSF-4 Q4 Pre-treatment Post-treatment MSHQEjD-SF Q1-3 Pre-treatment Post-treatment
42 65.1 ± 7.7 34.5 ± 8.1
Spermnegative urine 28 (66.7) 63.9 ± 7.3 33.1 ± 9.2
Spermpositive urine 14 (33.3) 67.6 ± 8.1 37.1 ± 4.9
19 (45.2) 23 (54.8)
13 (46.4) 15 (53.6)
6 (42.9) 8 (57.1)
0.913
2.5 ± 1.3
3.2 ± 1.1
1.3 ± 0.5
< 0.001
10.1 ± 2.1 14.5 ± 2.6
9.9 ± 2.3 14.2 ± 2.8
10.4 ± 1.5 14.9 ± 2.1
0.523 0.435
21.1 ± 3.5 12.5 ± 3.8
21.9 ± 3.1 13.7 ± 3.9
19.6 ± 3.6 10.1 ± 2.5
0.035 0.003
14 (33.3) 28 (66.7)
6 (21.4) 22 (78.6)
8 (57.1) 6 (42.9)
0.049
3 (7.1) 39 (92.9)
2 (7.1) 26 (92.9)
1 (7.1) 13 (92.9)
0.525
0.5 ± 0.6 4.3 ± 0.7
0.5 ± 0.6 4.2 ± 0.8
0.5 ± 0.6 4.4 ± 0.7
1.000 0.664
14.5 ± 0.6 5.3 ± 2.1
14.4 ± 0.7 5.1 ± 2.3
14.6 ± 0.5 5.6 ± 1.8
0.233 0.508
Total
p-value
0.139 0.238
14
MSHQEjD-SF Q4 Pre-treatment 0.5 ± 0.5 0.5 ± 0.5 0.4 ± 0.5 0.286 Post-treatment 4.2 ± 0.8 4.2 ± 0.8 4.2 ± 0.9 0.894 Continuous variables are expressed as mean ± SD; Nominal variables are expressed as No. (%). IPSS, International Prostate Symptoms Score; LUTS, lower urinary tract symptoms; MSF-4, 4-item Male Sexual Function questionnaire; MSHQEjD-SF, Male Sexual Health Questionnaire for Ejaculatory Dysfunction Short Form; Q, question; Qmax, peak urinary flow rate.
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