The Efficacy of Sexual Intercourse or Masturbation For The Expulsion Of Distal Ureteral Stones In Men: A Systematic Review And Meta-analysis of Randomized-controlled Trials Yi Lu1, Wanyu Zhang2,3, Hao Su1, Chengquan Ma1, Hongjun Li1* Purpose: Several randomized-controlled trials (RCTs) were performed to compare the efficacy of sexual inter- course or masturbation with no sexual activity in treating distal ureteral stones, indicating conflicting results. The meta-analysis was conducted to assess the role of sexual intercourse or masturbation in the treatment of distal ureteral calculi. Materials and Methods: PubMed, Cochrane Library, EMBASE, Scopus, Clinicaltrail.gov, and Web of Science were searched by October 2021. Men who were instructed of no sexual intercourse or masturbation, and those who only received standard symptomatic treatment are comparators. Relative risk (RR), weighted mean difference (WMD), and their 95% confidence intervals (CIs) were calculated using random or fixed effects models. Results: Five RCTs including 500 subjects were analyzed in the study. Compared with controls, subjects in exper- imental group had significantly higher expulsion rate at 2nd and 4th week (95%CI: 1.334 to 2.638, RR: 1.876, I2 = 73.6%, P < .001; 95%CI: 1.148 to 1.752, RR: 1.418, I2 = 55.9%, P < .001), significantly decreased requirement for analgesic injections (95%CI: -1.071 to -.126, WMD: -.598, I2 = 90.3%, P = .013), and significantly shorter expulsion time (95%CI: -6.941 to -.436, WMD: -3.689, I2 = 83.7%, P = .026). Conclusion: Performing sexual intercourse or masturbation 3 or 4 times a week can be an alternative treatment option of distal ureteral calculi (0-10 mm in size). However, more clinical evidence with better designs aiming to solve raised concerns is warranted. Keywords: distal ureteral calculi; masturbation; meta-analysis; randomized-controlled trial; sexual intercourse INTRODUCTION Urolithiasis, a common and multifactorial disease affecting around 5-10% of people worldwide, is now increasing with an incidence of 1% per year.(1-3) Ureteral stones account for approximately one in the fifth of all urinary calculi, 70% of which are distal ureteral calculi.(4) Therapies for urolithiasis consists of invasive and non-invasive options including spontane- ous passage, conservative therapy, medical expulsive therapy (MET), extracorporeal shockwave lithotripsy (ESWL), etc.(5) The rate of spontaneous passage of dis- tal ureteral stones varies from 50% (5-10 mm in size) to 95% (2-4 mm in size), which depends on the size and location of the stone.(6-9) Therefore, MET is more preferred in the treatment of distal ureteral calculi with a size of 5-10 mm10. Currently, Tamsulosin is the most frequently used α-blockers in MET.(11-13) The MET is based on the wide distribution of α-re- ceptors in the distal ureter. Nitric oxygen (NO) plays a crucial role in erection as well as ureteral peristalsis. 1Department of Urology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China. 2National Clinical Research Center for Obstetric & Gynecologic Diseases, Beijing, China. 3Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. *Correspondence: The Department of Urology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Beijing 100730, China. Tel: +86 17731859375. E-mail: yplmailbox@126.com. Received December 2021 & Accepted May 2022 Anatomical and pharmacologic studies had indicated the distribution and the role of nitrergic fibers in the hu- man intravesical ureter.(14) During sexual intercourse or masturbation, NO is abundantly released in these nerve endings, causing ureteral muscle relaxation, providing a possible alternative option for the management of ureteral stones.(15) Studies have indicated the efficacy of sexual intercourse or masturbation in the treatment of distal ureteral calculi, while findings are controversial. (16-18) A previously published meta-analysis conducted by Xu et al. only included 3 RCTs and now new find- ings were available.(26) Therefore, we conducted the meta-analysis to make a summary of evidence to date. PATIENTS AND METHODS Data sources We made detailed inclusive criteria according to the well-established report guidelines before we searched the literatures.(19,20) In October 2021, all available evi- dence in PubMed, Web of Science, Cochrane library, Scopus, ClinicalTrail.gov website, and EMBASE was Urology Journal/Vol 19 No. 4/ July-August 2022/ pp. 246-252. [DOI: 10.22037/uj.v19i.7119] REVIEW systematically searched. No restrictions on language were made when searching for evidence. No observa- tional studies were found and only randomized con- trolled trials (RCTs) were included. References and ci- tations of related articles were also searched carefully. The search process was performed independently by 3 authors. The keywords for the search were “sexual behavior”, “masturbation”, “sexual intercourse”, and “distal ureteral stones”. Details about search meth- ods were summarized in Supplementary Table 1. The protocol of the study was registered in PROSPERO (CRD42021273390). Inclusion and exclusion criteria Studies that met the following criteria were included. (a) Population: men with distal ureteral stones; (b) In- terventions: sexual intercourse or masturbation alone, or combined with standard symptomatic treatment; (c) Comparators: men who were instructed of no sexual in- tercourse or masturbation, and only received standard symptomatic treatment; (d) Outcomes: providing suffi- cient data for analysis, including at least the expulsion rate of stone, number of analgesic injections, or mean expulsion time of stone; (e) Study design: only RCTs; (f) Article type: only original articles; (g) Studies with a sample size of more than 50 and follow-up duration of at least 2 weeks. Studies which failed to meet the inclusive criteria were excluded. Data collection Three authors screened retrieved literature inde- pendently. Information including the first author, pub- lication year, study design, regions, demographic and stone features, interventions and controls details, and outcomes were recorded from included studies. Miss- ing or unclear information was collected by contacting the article authors. When there is no reply from authors, corresponding information will be considered as “not available”. Risk of bias (RoB) assessment The Cochrane Collaboration’s tool for assessing the risk of bias in the trial was used to evaluate the RoB by 3 authors independently.(21) Disagreements in the assessment were solved by discussion among the 3 au- thors and communication with the article authors. Statistical analysis Weighted mean difference (WMD) and its 95% CI were used for continuous results by follow-up analysis and pooled relative risks (RRs) and their 95% confidence intervals (CIs) for dichotomous data that complies with normality assumption. Random effect model was applied when there was a significant heterogeneity (I2 > 50%), otherwise fixed effect model will be used.(22) Sensitivity analyses were conducted by excluding one study at each time. All statistical analyses were per- formed by using STATA 12.0 (Stata-Corp.) and R soft- ware (version 4.1.1). Two-tailed P < .05 was considered as statistically significant. RESULTS Literature selection Under the established search strategy, we found 36 Review 247 Sexual intercourse and distal ureteral stones-Lu et al. Table 1. Characteristic of included studies Abbreviation: RCT, Randomized Controlled Trial. Study Study Design Country Subjects Stone Features Interventio ns In The Experiment al Group Treatment In The Control Group Sample Size Total Follo w-up, Week s Main Outcomes Experi mental Group Control Group Doluoglu 2015 RCT Turkey Men aged over 18 with active partners Radiopaq ue distal ureteral stones ≤ 6 mm in size. Sexual intercourse at least 3-4 times a week and essential symptomatic treatment Standard symptomatic treatment alone and instruction of no sexual intercourse or masturbation 31 23 4 Expulsion rate at 2nd and 4th week, expulsion time, and need for analgesics Abdel- Kader 2017 RCT Egypt Married males aged 26- 55 Radiopaq ue distal ureteral stones 5– 10 mm in size. Sexual intercourse 3-4 times/week and symptomatic treatment Standard symptomatic treatment alone and instruction of no sexual intercourse or masturbation 28 28 4 Expulsion rate at 2nd and 4th week, expulsion time, need for analgesics, and frequency of colicky attacks Bayrakta r 2017 RCT Turkey Married males aged 26 to 55 Radiopaq ue distal ureteral stones or intramura l stones 5–10 mm in size. Sexual intercourse at least 3 times/week Standard symptomatic treatment alone 66 64 4 Expulsion rate at 2nd and 4th week, expulsion time, need for analgesics, and need for ureterorenoscop ic lithotripsy Li 2019 RCT China Men aged 21 to 50 who received shockwa ve lithotrips y for stones Radiopaq ue distal ureteral stones 7- 15 mm in size. Sexual intercourse 3-4 times/week and symptomatic treatment Standard symptomatic treatment alone 70 68 2 Stone free rate, time to stone expulsion, pain score at admission, number of hospital visits for pain and steinstrasse Turgut 2021 RCT Turkey Men aged over 18 having distal ureteral stones ≥ 5 mm and < 10 mm in size. Distal ureteral stones 5– 10 mm in size. Masturbatio n at least 3– 4 times a week and instruction to avoid sexual intercourse Standard symptomatic treatment alone and instruction to avoid sexual intercourse and masturbation 43 44 4 Rates of expulsion, need for analgesic, and ureterorenoscop ic lithotripsy Figure 1. PRISMA flow chart of the data search. Vol 19 No 4 July-August 2022 248 Figure 2. Risk of bias analysis (A): percentage; (B): traffic light. Sexual intercourse and distal ureteral stones-Lu et al. non-repeated records. After the screening and eligibility evaluation, 5 RCTs were included in the meta-analysis (shown in Figure 1).(16-18,23-25) Characteristics of included studies Five double-blinded RCTs published in recent 6 years were included in the analysis (shown in Table 1). All the follow-up durations were longer than 2 weeks. Among these studies, three were conducted in Turkey, one was in Egypt, and one in China. From the pooled results, no differences between experimental and con- trol group were observed in terms of age and stone size (95%CI: -1.576 to 1.460, WMD: -.063, I2 = .0%, P = .674; 95%CI: -.291 to .164, WMD: -.052, I2 = 11.7%, P = .542). The RoB analysis indicated that all studies had high qualities (shown in Figure 2 A and B). Expulsion rate and expulsion time of distal ureteral stones 500 individuals, including 238 in the sexual intercourse or masturbation group and 227 in the control group, were included. Compared with controls, individuals in sexual intercourse or masturbation groups had signifi- cantly higher expulsion rate at both 2nd and 4th week (95%CI: 1.334 to 2.638, RR: 1.876, I2 = 73.6%, P < .001; 95%CI: 1.148 to 1.752, RR: 1.418, I2 = 55.9%, P < .001) (shown in Figure 3 and Figure 4). Objects in the experimental group also had significantly shorter expulsion time than those in the control group (95%CI: Review 249 Figure 3. Pooled results of expulsion rate at 2nd week. RR: relative risk; CI: confidence interval. Figure 4. Pooled results of expulsion rate at 4th week. RR: relative risk; CI: confidence interval. Sexual intercourse and distal ureteral stones-Lu et al. -6.941 to -.436, WMD: -3.689, I2 = 83.7%, P = .026) (shown in Figure 5). Requirement for analgesic injections (per day) The number of analgesic injections was considered as a measurement for stone related pain in four studies. (16-18,23,25) The research performed by Li et al. was not included in the pooling because they used a quantified visual analog scale to evaluate pain.(24) The pooled re- sults demonstrated that controls had statistically more injections than subjects in experimental group (95%CI: -1.071 to -.126, WMD: -.598, I2 = 90.3%, P = .013) (shown in Figure 6). Subgroup analysis Details were summarized in Supplementary Table 2. Sensitivity analysis Studies were extracted subsequently in each analysis and no study could affect pooled results, indicating the results were reliable (Supplementary Figure 1 and Supplementary Figure 2). DISCUSSION A comprehensive meta-analysis containing 5 RCTs with 500 individuals was conducted to evaluate the ef- ficacy of sexual behavior, including sexual intercourse and masturbation in the expulsion of distal ureteral stones. Results indicated that compared with controls, sexual intercourse and masturbation can increase expul- sion rate, reduce expulsion time, and sexual intercourse can further lower the demand for analgesic injections. In the meta-regression analysis, no factors were found to significantly influence the pooled results. Results were robust. This study builds on a previous meta-anal- ysis that only investigated the role of sexual intercourse Figure 5. Pooled results of expulsion time. WMD: weighted mean difference; CI: confidence interval. Figure 6. Pooled results of requirement for analgesic injections. WMD: weighted mean difference; CI: confidence interval. Sexual intercourse and distal ureteral stones-Lu et al. Vol 19 No 4 July-August 2022 250 in the expulsion of distal ureteral stones and includes all available high-quality evidence to date.(26) Since 2015, a series of studies have reported the expul- sion role of sexual intercourse. Doluoglu et al. firstly demonstrated that men having at least 3 sexual inter- courses a week had significantly shorter median ex- pulsion time and higher expulsion rate than controls. (16) Subsequent two RCTs examined the efficacy of sex- ual intercourse in treating patients with larger ureteral stones in size (5-10 mm) and found consistent findings. (17,23) Li and his colleagues extended it further by inves- tigating the role of sexual intercourse after shockwave lithotripsy for men with 7-15 mm distal ureteral stones. (24) They indicated that having more than 3 sexual in- tercourse a week after shockwave lithotripsy can be a treatment choice for lower ureteral stones.(24) Former studies have some limitations such as only male sub- jects are included and only sexual intercourse were ex- amined. To fill the gap, Turgut et al. conducted a RCT investigating the role of masturbation in expulsion of distal ureteral stones in men.(18,25) However, the level of compliance in these studies is hard to measure and the loss to follow-up between groups is different in some studies. The underlying mechanisms lie in the role of nitric ox- ide (NO). NO is a non-adrenergic and non-cholinergic neurotransmitter which plays an inhibitory role in signal transmission.(27,28) Previous studies had shown that both exogenous and endogenous NO can cause relaxation of intravesical ureter in pigs.(29,30) The ureter is innervated by sympathetic nerves originating from T11-L1 and pa- ra-sympathetic nerves come from S2-4.(31) Erection can be induced by the stimulation of cavernous nerves and pelvic plexus, whereas detumescence can be caused by sympathetic system excitation.(32) NO is the main neu- rotransmitter that is helpful in erection, masturbation, and sexual intercourse.(32) When cavernous nerves were stimulated, they will activate nitrergic nerves which can release NO from its end, leading to penile smooth mus- cle relaxation and erection. Furthermore, the endothe- lium can also release NO. The hypothesis that erection and sexual intercourse induced NO release leads to ure- teric muscle relaxation may be supported by the follow- ing two points. Previous studies indicated that nitrergic nerve endings in the distal ureter can produce NO.(33,34) Moreover, many clinical trials reported that the stone expulsion rate of the sexual intercourse group is as high as the tamsulosin group.(16,23-25) Therefore, sexual inter- course or masturbation can reduce analgesic demand and increase stones passing through NO/ cGMP path- way during erection. Our findings may have some clinical and research im- plications. Firstly, performing sexual intercourse or masturbation 3 or 4 times a week can increase expul- sion rate of distal ureteral stones (diameter less than 10 mm) at 2nd or 4th week and reduce stone-related pain in men. This may be used for patient counselling and lifestyle modification. Secondly, more evidence is required for the role of masturbation in stone passage. Thirdly, given the fact that healthy men usually have morning or nocturnal erection, the confounding factor should be considered in further studies. Fourthly, how, when, and if the NO/cGMP pathway can be effectively used in treatment need further exploration. Moreover, a comparison of the efficacy of sexual intercourse and masturbation in the treatment of distal ureteral stones may help better understand the problem. The most notable strength of the meta-analysis is the origin of evidence. Only high quality randomized dou- ble-blind, placebo-controlled trails were included in the meta-analysis, making the final conclusions relative- ly reliable and solid. However, some limitations also should be mentioned. Firstly, the diverse stone sizes may influence the application of findings. While we pooled stone sizes data and found that the experimental group is comparable with the control group. We think that the findings in the study are applicable to distal ure- teral stones 0-10 mm in size. Secondly, there is still lack of long-term outcomes. Thirdly, the compliance of sub- jects to perform or not to perform masturbation or sex- ual intercourse are difficult to ascertain. Fourthly, due to the small number of included studies, the findings of the study should be treated tentatively until validated by more future studies. Last but not the least, sleep-re- lated erection is hard to control. Further studies should address these concerns. CONCLUSIONS Conducting sexual intercourse or masturbation 3 or 4 times a week can achieve better efficacy in the treat- ment of distal ureteral calculi and better pain controls compared with placebo. However, given the concerns mentioned above, more studies with better study de- signs are expected. ACKNOWLEDGEMENT This work was supported by the grants from Nation- al Natural Science Foundation of China (Grant No. 81871152 and Grant No.82171588) and the grant from National Population Health Science Data Sharing Ser- vice Platform Clinical Medical Science Data Center (NCMI-ABD02-201906). CONFLICT OF INTEREST The authors report no conflict of interest. REFERENCES 1. Türk C, Petřík A, Sarica K, et al. EAU Guidelines on Diagnosis and Conservative Management of Urolithiasis. Eur Urol. Mar 2016;69:468-74. 2. Pearle MS, Goldfarb DS, Assimos DG, et al. Medical management of kidney stones: AUA guideline. J Urol. 2014;192:316-24. 3. Moe OW, Pearle MS, Sakhaee K. Pharmacotherapy of urolithiasis: evidence from clinical trials. Kidney Int. 2011;79:385- 92. 4. Tzortzis V, Mamoulakis C, Rioja J, Gravas S, Michel MC, de la Rosette JJ. Medical expulsive therapy for distal ureteral stones. Drugs. 2009;69:677-92. 5. Türk C, Petřík A, Sarica K, et al. EAU Guidelines on Interventional Treatment for Urolithiasis. Eur Urol. 2016;69:475-82. 6. Yallappa S, Amer T, Jones P, et al. Natural History of Conservatively Managed Ureteral Stones: Analysis of 6600 Patients. J Endourol. 2018;32:371-79. 7. Loftus C, Nyame Y, Hinck B, et al. Medical Expulsive Therapy is Underused for the Review 251 Sexual intercourse and distal ureteral stones-Lu et al. Management of Renal Colic in the Emergency Setting. J Urol. 2016;195:987-91. 8. Sarier M, Duman I, Callioglu M, et al. Outcomes of Conservative Management of Asymptomatic Live Donor Kidney Stones. Urology. 2018;118:43-46. 9. Preminger GM, Tiselius H-G, Assimos DG, et al. 2007 Guideline for the management of ureteral calculi. Eur Urol. 2007;52:1610-31. 10. Ordon M, Andonian S, Blew B, Schuler T, Chew B, Pace KT. CUA Guideline: Management of ureteral calculi. Can Urol Assoc J. 2015;9:E837-51. 11. Hollingsworth JM, Rogers MA, Kaufman SR, et al. Medical therapy to facilitate urinary stone passage: a meta-analysis. Lancet. 30 2006;368:1171-9. 12. Lojanapiwat B, Kochakarn W, Suparatchatpan N, Lertwuttichaikul K. Effectiveness of low-dose and standard-dose tamsulosin in the treatment of distal ureteric stones: a randomized controlled study. The Journal of international medical research. 2008;36:529- 36. 13. Al-Ansari A, Al-Naimi A, Alobaidy A, Assadiq K, Azmi MD, Shokeir AA. Efficacy of tamsulosin in the management of lower ureteral stones: a randomized double-blind placebo-controlled study of 100 patients. Urology. 2010;75:4-7. 14. Smet PJ, Edyvane KA, Jonavicius J, Marshall VR. Colocalization of nitric oxide synthase with vasoactive intestinal peptide, neuropeptide Y, and tyrosine hydroxylase in nerves supplying the human ureter. J Urol. 1994;152:1292-6. 15. Fernandes VS, Hernández M. The Role of Nitric Oxide and Hydrogen Sulfide in Urinary Tract Function. Basic Clin Pharmacol Toxicol. 2016;119 Suppl 3:34-41. 16. Doluoglu OG, Demirbas A, Kilinc MF, et al. Can Sexual Intercourse Be an Alternative Therapy for Distal Ureteral Stones? A Prospective, Randomized, Controlled Study. Urology. 2015;86:19-24. 17. Abdel-Kader MS. Evaluation of the efficacy of sexual intercourse in expulsion of distal ureteric stones. Int Urol Nephrol. 2017;49:27- 30. 18. Turgut H. Evaluation of the efficacy of sexual intercourse on distal ureteral stones in women: a prospective, randomized, controlled study. International urology and nephrology. 2021;53:409-13. 19. Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. Jama. 19 2000;283:2008-12. 20. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. 21. Higgins JPT, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. 22. DerSimonian R, Kacker R. Random-effects model for meta-analysis of clinical trials: an update. Contemp Clin Trials. 2007;28:105-14. 23. Bayraktar Z, Albayrak S. Sexual intercourse as a new option in the medical expulsive therapy of distal ureteral stones in males: a prospective, randomized, controlled study. International urology and nephrology. 2017;49:1941-6. 24. Li W, Mao Y, Lu C, et al. Role of Sexual Intercourse after Shockwave Lithotripsy for Distal Ureteral Stones: A Randomized Controlled Trial. Urol J. 2020;17:134-8. 25. Turgut H, Sarıer M. Evaluation of the efficacy of masturbation on distal ureteral stones: a prospective, randomized, controlled study. Int Urol Nephrol. 2021;53:655-60. 26. Xu B, Yan H, Zhang X, Cui Y. Meta-analysis of the efficacy of sexual intercourse for distal ureteric stones. J Int Med Res. 2019;47:497- 504. 27. Bredt DS, Hwang PM, Snyder SH. Localization of nitric oxide synthase indicating a neural role for nitric oxide. Nature. 1990;347:768-70. 28. Bredt DS, Snyder SH. Nitric oxide, a novel neuronal messenger. Neuron. 1992;8:3-11. 29. Hernández M, Prieto D, Orensanz LM, Barahona MV, García-Sacristán A, Simonsen U. Nitric oxide is involved in the non- adrenergic, non-cholinergic inhibitory neurotransmission of the pig intravesical ureter. Neurosci Lett. 1995;186:33-6. 30. Stief C. A possible role of nitric oxide (NO) in the relaxation of renal pelvis and ureter. J Urol. 1993;149:492A. 31. Gosling JA, Dixon JS, Jen PY. The distribution of noradrenergic nerves in the human lower urinary tract. A review. Eur Urol. 1999;36 Suppl 1:23-30. 32. Lue TF. Erectile dysfunction. N Engl J Med. 2000;342:1802-13. 33. Yucel S, Baskin LS. Neuroanatomy of the ureterovesical junction: clinical implications. J Urol. 2003;170:945-8. 34. Iselin CE, Ny L, Larsson B, et al. The nitric oxide synthase/nitric oxide and heme oxygenase/carbon monoxide pathways in the human ureter. Eur Urol. 1998;33:214-21. Sexual intercourse and distal ureteral stones-Lu et al. Vol 19 No 4 July-August 2022 252