Clinical value of penile sympathetic skin response to assess the efficacy of sertraline in the treatment of patients with sympathetic hyperexcitability in primary premature ejaculation

Abstract

Background

The pathogenesis of primary premature ejaculation (PPE) is complex, and the pathologic basis may be an overactive sympathetic nervous system.

Aim

To investigate sertraline efficacy in patients with sympathetic hyperexcitability in PPE and clarify the value of penile sympathetic skin response (PSSR) in assessing the efficacy of sertraline for PPE treatment.

Methods

Sixty-three patients with PPE were recruited in the outpatient clinic and asked to take 50 mg of oral sertraline daily for a 4-week treatment period. Changes in intravaginal ejaculation latency time (IELT), Premature Ejaculation Diagnostic Tool, International Index of Erectile Function (IIEF-5), and PSSR latency and wave amplitude were compared before and after treatment.

Outcomes

The principal aim was to determine the relationships among sertraline efficacy, IELT, and PSSR latency and amplitude.

Results

After sertraline treatment, patients with PPE demonstrated a significant decrease in Premature Ejaculation Diagnostic Tool scores (P < .001); a significant increase in IELT, PSSR latency, and wave amplitude (P < .001); and no significant change in International Index of Erectile Function scores (P > .05). Moreover, the latency changes of PSSR were positively correlated with the increment of IELT (r = 0.550, P < .001). In addition, there was some degree of improvement vs pretreatment, although IELT and PSSR latencies were significantly shorter after drug discontinuation when compared with posttreatment (both P < .001).

Clinical Implications

We aimed to find an objective test that accurately reflects the efficacy of treatment for sympathetic hyperexcitability in PPE.

Strengths and Limitations

The strengths include a well-powered study, use of validated instruments, and self-assessment of treatment benefit. The limitations include the single-center design, relatively short-term follow-up, and lack of more comprehensive monitoring between treatment and drug discontinuation.

Conclusion

These findings suggest that sertraline is effective for PPE treatment, that its efficacy can be partially maintained even after drug discontinuation, and that PSSR may be reliable for evaluating treatment success in patients with PPE.

Introduction

Premature ejaculation (PE) is one of the most common male sexual dysfunctions that seriously affect the quality of life and marital stability of patients and their partners.¹ The widely used evidence-based definition of PE developed by the International Society for Sexual Medicine (ISSM) in 2014 is as follows: (1) ejaculation that always occurs within 1 minute of vaginal penetration from the first sexual experience (primary premature ejaculation [PPE]) or a clinically significant shortening of the ejaculatory latency, usually to <3 minutes (secondary premature ejaculation); (2) failure to control ejaculation at all times; and (3) negative personal emotions and behaviors.² The etiology of PE is complex, and the pathogenesis is unclear. However, the prevailing view is that PPE may be associated with neurobiological imbalances or genetic variants, including central 5-hydroxytryptophan (5-HT) neurotransmitter disorders, sympathetic nervous system overactivity, penile hypersensitivity, and genetic susceptibility.^3,4 In addition, 5-hydroxytryptamine reuptake inhibitors (ie, selective serotonin reuptake inhibitors [SSRIs]), represented by sertraline, are the conventional treatment agents for PE and should be taken orally every day.^5,6 Moreover, some studies have demonstrated that sertraline exerts its effects mainly by reducing central sympathetic excitability.^7,8 In addition, its safety and efficacy have been confirmed by several clinical trials.^9,10 Penile sympathetic skin response (PSSR) objectively reflects sympathetic output of the thoracolumbar segment of the spinal cord and is a reliable means of detecting the excitability of the sympathetic nervous system in patients with PE.¹¹

The current clinical efficacy assessment of PE mainly relies on patient complaints and questionnaire scales, which are highly subjective. Intravaginal ejaculation latency time (IELT) has potential advantages as an objective test, but it may destroy sexual pleasure. Therefore, there is an urgent need to seek an accurate and effective test. Given the pathologic mechanism of PPE and the theoretical basis of PSSR, we hypothesized that PSSR could be used to predict the response to sertraline treatment in patients with PPE and sympathetic hyperexcitability. Therefore, this study aimed to investigate the exact efficacy of sertraline in patients with PPE and sympathetic hyperexcitability and clarify the clinical value of PSSR in assessing the efficacy of sertraline in the treatment of patients with PPE.

Methods

Participants

Sixty-three patients with PPE who presented to our male outpatient clinic between February and June 2022 were recruited for this study; however, 3 were lost to follow-up during treatment. These patients were all adult heterosexual men with stable sexual partners and regular sex lives, as well as normal sex hormone levels on outpatient screening, who self-reported that at the first sexual encounter, their IELT was <1 minute and initial PSSR latency was <1184.6 milliseconds (PSSR latency in healthy subjects is 1514.5 ± 168.3 milliseconds).¹² They denied having psychological and psychiatric disorders and had no comorbid erectile dysfunction or other underlying medical conditions. Patients who were taking medication or had recently taken medication affecting the sympathetic nervous system were excluded from this study. The study was approved by our ethics committee. All participants were fully informed of the study content and procedures and signed an informed consent form.

Procedure

Before the examination, the room environment was kept quiet, and the room temperature was appropriate (26 °C); the patient was asked to lie on his back on the examination bed and was informed of the examination procedure. The patient’s cooperation was obtained, and he was asked to relax for 1 to 2 minutes. The investigator then checked the instrument and started the examination.

The instrument used for PSSR was an electromyography/evoked potentials device (Nicolet EDX; Natus Medical Incorporated). The procedure was performed as follows: the penis was wiped with a 75% alcohol cotton ball; the anodic ring of the ring electrode was placed at the coronal sulcus of the penis; the cathode was placed 2 cm from the anode at the penis shaft; the grounded electrode was tied to the right wrist; the skin impedance was adjusted to <5 kΩ; and PSSR waveform was obtained through electrical stimulation of 1-millisecond duration and 20-mA intensity through the surface electrode of the right median nerve (Figure 1). Repeated stimulation was performed 3 times at irregular random intervals, each >30 seconds, and the latency and waveform amplitude were recorded. PSSR latency was measured as the first deflection point at the beginning of the baseline and the amplitude as the difference in position between the first peak and the next opposite trough (Figure 2).

Figure 1.

Application of sensors to the patient for the measurement of penile sympathetic skin response.

Figure 2.

A Penile sympathetic skin response in the same patient before (A), after the 4-weeks sertraline treatment (B) and after 4-weeks of discontinuation (C).

In this study, IELT, Premature Ejaculation Diagnostic Tool (PEDT), and International Index of Erectile Function (IIEF-5) were assessed at the patient’s initial visit with PSSR. During the subsequent 4 weeks of treatment, all patients were required to take 50 mg of sertraline (50 mg, Leyuan; Zhejiang Huahai Pharmaceutical Co, Ltd) orally every night and asked to have sexual intercourse at least once a week. After 4 weeks of treatment, IELT, PEDT, IIEF-5, and adverse drug reactions were reassessed, and PSSR was performed again. In addition, we tracked the changes in the indicators 4 weeks after the end of the treatment period for some of the patients.

Data analysis

Statistical analysis was performed with Statistical Analysis for Social Sciences 26.0 software (IBM). Measurements that conformed to a normal distribution were expressed as mean ± SD, and those that did not were expressed as median (IQR). A paired t-test was applied for comparison of the same patient before and after treatment and after discontinuation. Statistical significance was set at P < .05.

Results

A total of 63 patients with PPE who met the study criteria were recruited to our outpatient clinic, of whom 3 were lost to follow-up during treatment and 1 developed drowsiness, 1 nausea, and 2 diarrhea. However, none withdrew from the study due to mild side effects, resulting in 60 patients (95.2% of the original) completing the entire study and having their data analyzed. Table 1 shows the demographic and clinical characteristics of the included patients with PPE. Patients had a significantly longer IELT after 4 weeks of sertraline treatment as compared with pretreatment, a mean 5.6 ± 2.2 times higher than the initial ratio, and they also had a significantly improved ability to delay ejaculation (P < .05). Yet, patients’ PEDT scores were significantly lower after sertraline treatment than before (P < .05). Moreover, after treatment, PSSR latency was significantly higher while PSSR wave amplitude was lower (P < .05), and there was no difference in IIEF-5 scores vs before treatment (P > .05; Table 2). By correlation analysis, we observed a significant positive correlation between the change in PSSR latency and the increase in IELT before and after treatment (r = 0.550, P < .001; Figure 3). We further investigated what actually happened in some of these patients at 4 weeks after discontinuation of the drug: when compared with pretreatment, these patients still had an increase in IELT after drug discontinuation (P < .05), a slight decrease in PEDT score (P < .05), a mild increase in PSSR latency (P < .05), and no significant difference in PSSR wave amplitude and IIEF-5 score (P > .05; Table 3).

Table 1.

General information and clinical characteristics of patients with primary premature ejaculation (N = 60).^a

No. of patients	60
Age, y	28.9 ± 4.1
Height, cm	175.1 ± 6.0
Weight, kg	74.4 ± 8.6
Marital status
Married	26 (43.3)
Single	34 (56.7)
Testosterone, nmol/L	14.2 ± 1.7
Prolactin, mIU/L	153.9 ± 23.2
IELT, s	34.4 ± 9.5
PSSR
Latency, ms	931.3 ± 124.6
Amplitude, μV	25.8 (8.7-64.2)
Score
PEDT	14.5 (11-18)
IIEF-5	22.2 ± 1.0

Abbreviations: IELT, intravaginal ejaculation latency time; IIEF-5, International Index of Erectile Function; PEDT, Premature Ejaculation Diagnostic Tool; PSSR, penile sympathetic skin response.

^aData are presented as mean ± SD, No. (%), or median (IQR).

Table 2.

Statistical comparison of indicators before and after sertraline treatment (N = 60).^a

	Before treatment	After treatment	P value
IELT, s	34.4 ± 9.5	159.5 ± 45.0	<.001b
PSSR			<.001b
Latency, ms	931.3 ± 124.6	1365.9 ± 116.7	<.001c
Amplitude, μV	25.8 (8.7-64.2)	14.5 (4.6-36.6)
Score
PEDT	14.5 (11-18)	7.0 (4-11)	<.001c
IIEF-5	22.2 ± 1.0	22.3 ± 1.1	.263b

Abbreviations: IELT, intravaginal ejaculation latency time; IIEF-5, International Index of Erectile Function; PEDT, Premature Ejaculation Diagnostic Tool; PSSR, penile sympathetic skin response.

^aData are presented as mean ± SD or median (IQR).

^bPaired t-test.

^cWilcoxon test.

Figure 3.

Correlation analysis of the change in the value of PSSR latency with the increase in the value of IELT (significant positive correlation between the change in the value of PSSR latency and the increase in the value of IELT, r = 0.550, p < 0.001).

Table 3.

Statistical comparison of indicators before sertraline treatment and after discontinuation (n = 20).^a

	Before treatment	After discontinuation	P value
IELT, s	32.8 ± 7.7	77.4 ± 21.6	<.001b
PSSR
Latency, ms	910.9 ± 138.4	985.0 ± 110.6	<.001b
Amplitude, μV	23.3 (9.2-42.3)	20.6 (10.2-53.9)	.405c
Score
PEDT	14 (12-16)	11 (9-13)	<.001c
IIEF-5	22.3 ± 0.9	22.1 ± 1.0	.248b

Abbreviations: IELT, intravaginal ejaculation latency time; IIEF-5, International Index of Erectile Function; PEDT, Premature Ejaculation Diagnostic Tool; PSSR, penile sympathetic skin response.

^aData are presented as mean ± SD or median (IQR).

^bPaired t-test.

^cWilcoxon test.

Discussion

Ejaculation is a complex physiologic reflex that includes ejaculatory and seminal processes, mediated by autonomic and somatic motor nerves, respectively.¹³ Ejaculation is mainly mediated through the spinal ejaculation generator (at the L3-L4 level), of which lumbar spinothalamic cells are an important component. Lumbar spinothalamic cells reportedly coordinate activation of the autonomic and somatic spinal centers and integrate peripheral signals from the genital region upstream with central excitatory and inhibitory signals downstream.^14,15 The view that sympathetic overactivity is involved in the pathogenesis of PPE has recently become increasingly accepted, as an increase in sympathetic excitability or a decrease in central descending inhibition can lead to activation of the spinal ejaculatory center in response to a small amount of peripheral stimulation, thus causing a decrease in ejaculation. Zorba et al were the first to demonstrate a significant increase in sympathetic excitability in patients with PPE by measuring the heart rate variability between patients with PPE and controls.¹⁶ Furthermore, Xia et al compared the PSSR results of 53 patients with PPE with 46 healthy people and observed a significantly shorter PSSR latency and increased wave amplitude in patients with PPE vs the control population, suggesting that patients with PPE have higher excitatory sympathetic activity.¹² Interestingly, this idea is in line with the 5-HT hypothesis. Indeed, most neurons that project from the cerebral cortex to the lumbosacral medulla are 5-HTergic, and the release of 5-HT from the downstream brainstem pathway has an inhibitory effect on ejaculation. SSRIs, often used in clinical practice, act on this site to enhance the central downstream inhibitory effect and thus prolong ejaculation.

Sertraline is a long-acting SSRI with proven safety and efficacy in several clinical studies, mild side effects, and high patient compliance and tolerability, and it is routinely used in the treatment of PE. Previous studies clearly stated that 50 mg of sertraline treatment had few side effects and definitive efficacy and that ejaculatory control could be significantly improved after 4 weeks of treatment.¹⁰ Therefore, in this study, we asked patients with PPE to take 50 mg of oral sertraline daily for 4 weeks. Traditionally, sertraline treatment of PE is thought to prolong ejaculation mainly by blocking the reuptake of 5-HT by neurons via the 5-HT transporter and increasing the 5-HT concentration in the synaptic gap.¹⁷ We suggest that sertraline relieves sexual anxiety in patients with PPE and boosts confidence while improving ejaculation. Moreover, studies have shown that SSRIs can reduce sympathetic nerve activity in humans, and we speculate that sertraline may delay ejaculation by reducing sympathetic nervous system excitability. Our results showed that sertraline significantly improved symptoms and prolonged IELT in sympathetically aroused patients with PPE. Four weeks after sertraline discontinuation, patients’ IELT decreased as compared with posttreatment, although they all showed some improvement vs pretreatment, suggesting that the efficacy of sertraline could be partially maintained after discontinuation, albeit on a time-limited basis. During treatment follow-up, only 1 patient experienced drowsiness, and 3 patients experienced gastrointestinal discomfort, with all adverse effects resolving spontaneously at the end of the course of treatment.

The sympathetic skin response is a polysynaptic reflex with a latency that includes afferent and efferent conduction times and central processing time. This process involves the central sensory-motor cortex—specifically, the premotor area, hypothalamus, limbic system, basal ganglia, and reticular formation, whose efferent fibers are class C unmyelinated nerve fibers that mediate sweating activity. The sympathetic fibers that govern sweat gland activity in the vulva and those involved in ejaculatory activity are similar in their anatomic pathways; they both run from the lumbar spinal cord through the lumbar sympathetic ganglion to the postganglionic nerve fibers that innervate the vulvar region.^18,19 Thus, PSSR can effectively reflect the functional state of the sympathetic nervous system associated with ejaculation. However, the underlying mechanisms of PSSR abnormalities in patients with PPE are unclear. The central structures that process the sympathetic skin response are involved in the regulation of this reflex by releasing related neurotransmitters such as acetylcholine, norepinephrine, 5-HT, and dopamine. Dopamine is able to stimulate ejaculation, while 5-HT is able to inhibit it. A recent study demonstrated that 5-HT levels were significantly lower in patients with PPE vs control patients and were significantly associated with PSSR latency and wave amplitude.²⁰ We speculate that the abnormal PSSR parameters may indirectly reflect a functional imbalance between central excitatory and inhibitory neurotransmitters; that is, they may be associated with a decrease in sympathetic nervous system inhibitory neurotransmitters (eg, 5-HT). This is consistent with the pharmacologic mechanisms and actual clinical efficacy of sertraline in PE treatment. In this study, we examined sympathetic nervous system changes in patients with PPE before and after sertraline treatment and after discontinuation of the drug by PSSR. Xia et al first studied PSSR latency and wave amplitude in 61 patients with PPE in 2014. They divided the patients into 2 groups based on PSSR parameters and observed prolonged PSSR latency and reduced wave amplitude in all patients through 8 weeks of treatment. Moreover, the sympathetically excited group improved significantly more than the sympathetically normal group. It was proposed that PSSR could provide useful information on the response to treatment in patients with PPE.²¹ Similar conclusions were obtained by Kati and Ay, who studied the efficacy of dapoxetine in treating patients with PPE and abnormal PSSR.²² Similarly, in our study, all sympathetically excited patients with PPE treated with sertraline for 4 weeks had significantly longer PSSR latencies and lower wave amplitudes. After 4 weeks of drug discontinuation, the PSSR latencies of the patients whom we followed up were significantly shorter and even fell back to initial levels, with no significant difference in PSSR wave amplitude. By combining the changes in IELT of the patients before and after treatment and after discontinuation, we observed that PSSR was more sensitive than IELT to the determination of sertraline efficacy. These findings suggest that PSSR may be a reliable tool for assessing the efficacy of sertraline in the treatment of PPE and that its results may be useful for clinicians in managing the treatment process and prognosis of patients. Nevertheless, PSSR results can be influenced to some extent by the mental state of the patient and the subjective initiative of the examiner, which also deserve our attention.

In this study, we focused on patients with sympathetic excitability in PPE, and the selection of treatment drugs and tests was reasonable. In addition, to the best of our knowledge, only a few studies in the current literature have examined the regression of efficacy after sertraline discontinuation; thus, this should be further investigated.

We recognize some limitations associated with this study. First, the sample size was relatively small, which may have affected the statistical strength of the results. Hence, studies with larger samples are needed to obtain more accurate conclusions. Second, we observed that 21.7% of patients did not reach the reference value for PSSR latency at the end of treatment, although it was longer than that before treatment. Therefore, we believe that perhaps there are individual differences in medication and that the use of a treatment period ≥8 weeks is needed in further attempts. Finally, we consider that the 4-week discontinuation interval may be too long and that subsequent studies could be conducted at weeks 1, 2, 3, and 4 of discontinuation to clarify the specific sustained efficacy of sertraline. In conclusion, our study can help to understand better the pathologic mechanisms of PPE and the changes in sertraline treatment and postdiscontinuation.

Conclusion

Sertraline is a safe and effective drug for PPE treatment. It is likely that it reduces the excitability of the sympathetic nervous system, thus delaying ejaculation. In addition, PSSR may be a reliable tool to assess the efficacy of sertraline in the treatment of PPE, and its results may be useful for clinicians in managing the treatment process and prognosis of patients.

Funding

National Natural Science Foundation of China, Grant/Award Number: 8187141352 and National Natural Science Foundation of China, Grant/Award Number: 82274258.

Conflicts of interest: The authors have no conflicts of interest to declare regarding this study.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.