The past decade has witnessed significant medical progress as multiple invasive/non-invasive approaches have been developed for the management of ureteral stones, including conservative therapy, MET, external shock wave lithotripsy (ESWL), ureterorenoscopic lithotripsy (URS), percutaneous nephrolithotomy (PCNL), and Laparoscopic ureterolithotomy[13]. Among these, MET remains the mainstay of treatment for distal ureteral stones < 10 mm in size[5, 14]. It is widely believed that MET can increase the stone passage rate by 65%[14]. Many factors, including the stone location, size, number, type, ureteral spasm, mucosal inflammation and edema, and the ureteral anatomy, have been established to influence the expulsion of ureteral stones[15]. Importantly, routine medical expulsive therapy for ureteral stones can decrease edema and induce relaxation of the smooth muscle of the ureter, thereby allowing stone passage[14, 15].
As we all know, ureteral peristalsis is a myogenic process mediated by neurogenic factors. Biologically, the smooth muscle activity in the distal ureter and the ureterovesical junction is regulated by a combination of noradrenergic, cholinergic, and non-adrenergic non-cholinergic nerves[16]. Nitric oxide (NO) is a well-recognized non-adrenergic non-cholinergic inhibitory neurotransmitter that acts as an important gaseous regulator in different visceral organs and is important for smooth muscle relaxation. An increasing body of evidence suggests that the distal ureter is rich in nitrergic nerve fibers, which are responsible for the synthesis of NO that regulate the key transmitters involved in ureteral peristalsis, resistance to the urinary flow and regional blood flow[17–19].
Similarly, NO plays an important role in triggering and maintaining human sexual activity. Genital stimulation in males and females is a dynamic process, requiring the cooperation of a series of systems with the involvement of both nerves and vessels[20]. During that process, there will be elongation, thickening and rigid erection of penis in males while swelling of clitoris in females[21, 22]. It has been established that NO is the main neurotransmitter responsible for penile erection and clitoral congestion. Interestingly, the level of circulating NO increases following sexual stimulation until orgasm[18].
NO is usually either derived from the endothelium or released from nerve endings during sexual arousal and stimulation[23]. High NO concentrations are known to exert a positive effect on ureteral smooth muscle relaxation, altering the activities in the Ca2+ and K+ channels in smooth muscle cells by activating soluble guanylyl cyclase (sGC) and elevating the level of cyclic guanosine monophosphate (cGMP) in cells[18, 24]. Over the years, selective phosphodiesterase5 inhibitors (PDE5is) have been widely used to treat erectile dysfunction in males. Multiple PDE5is, such as Sildenafil, Vardenafil and Tadalafil, have been demonstrated to promote the expulsion of ureteral stones by increasing blood NO concentrations[25]. Hedlund et al.[18] found that sublingual administration of NO donors, such as isosorbide dinitrate, could reduce the ureteral smooth muscle tone. It was also found that NO could suppress the release of norepinephrine from the neuromuscular junctions[23]. These findings corroborate that either externally ingested or self-generated NO can reduce the peristaltic frequency, basal tone and decrease the incidence of spasms, providing a theoretical foothold for developing new method to enhance the expulsion of ureteral stones.
The above studies suggest that common PDE5is, such as tadalafil, can act on the NO/cGMP signaling pathway, resulting in smooth ureter muscle relaxation. In this regard, a meta-analysis by Bai et al.[26] showed that treatment with tadalafil alone or with tamsulosin in patients with distal ureteral stones resulted in a higher stone expulsion rate and shorter stone passage time. In addition, the use of tadalafil alone or in combination with tamsulosin could slightly reduce the need for analgesics. Recently, Jayant et al.[27] conducted an RCT to evaluate the potential role of tadalafil versus tamsulosin in ureteral stone expulsion. They found that tadalafil yielded a higher rate of ureteral stone excretion and better pain control, consistent with our findings.
In the present study, we sought to reveal whether sexual stimulation (3–4 times a week of sexual intercourse or masturbation) could promote the passage of distal ureteral stones. We found that the 2-week and 4-week expulsion rates in the intervention group were significantly higher than in the control group (75.5% vs. 43.5% and 85.2% vs. 57.2%, respectively). Additionally, the average expulsion time in the intervention group was 3.74 days less than in the control group, suggesting that sexual stimulation could reduce the time for stone expulsion. We also documented a decreased prevalence of renal colic attacks and analgesic use in patients that underwent sexual stimulation (on average 0.61-times lower than the control). The study by Turgut et al. [12] revealed a better stone expulsion rate after sexual intercourse 3–4 times a week than oral tamsulosin (0.4 mg) daily. Interestingly, Li et al. [10]reported that sexual intercourse at least 3 times a week in patients receiving ESWL could significantly reduce the formation of steinstrasse and enhance stone expulsion.
Alpha-blockers remain the most commonly used MET drugs in clinical practice and are associated with common side effects, including dizziness, headache, orthostatic hypotension, syncope, and abnormal ejaculation[28]. It has been shown that the incidence of side effects of different types of alpha-blockers is different. Tamsulosin is the most commonly used clinically, with a side effect prevalence of 20%[29]. Importantly, sexual intercourse or masturbation at a reasonable frequency can effectively promote the expulsion of stones, reduce side effects and even avoid potential damage to the human body caused by surgery, thereby reducing medical costs.
All studies included in our meta-analysis were from randomized, double-blind, placebo-controlled trials. We found that all these RCTs were of high quality according to The Cochrane Collaboration's tool for assessing risk of bias. Limitations of our study include the relatively small number of included studies and the small sample size. In addition, it remains unclear whether the subjects in both intervention and control groups strictly followed the specified measures. Furthermore, the effect of other involuntary types of erection, such as sleep-related erections, on the study results could not be controlled and excluded.