The value of 5-HT, leptin, and NE in the classification of premature ejaculation

Abstract

Background

While premature ejaculation (PE) can be divided into lifelong PE (LPE), acquired PE, natural variable PE (NPE), and subjective PE (SPE), there is no objective method to classify PE.

Aim

To determine the value of serum serotonin (5-HT), leptin, and norepinephrine (NE) levels in the classification of PE.

Methods

From July 2023 to July 2024, we recruited 150 participants and divided them into 4 groups: LPE (43 cases), NPE (32 cases), SPE (35 cases), and non-PE (40 cases) groups. All participants' baseline data, premature ejaculation diagnostic tool score, and intravaginal ejaculation latency time were investigated. In addition, all participants' serum 5-HT, leptin, and NE levels were measured.

Outcome

Serum 5-HT, NE, and leptin levels were compared among all groups.

Results

Serum 5-HT levels were lower and NE and leptin levels were higher in the LPE group compared to the SPE, NPE, and non-PE groups (P < .05). However, serum 5-HT, leptin, and NE levels were not significantly different among the non-PE, NPE, and SPE groups (P < .05). In addition, serum 5-HT <95.0 ng/mL, NE >543.0 ng/L, and leptin >19.8 ng/mL may be predictive indicators of LPE.

Clinical Significance

Based on serum 5-HT, NE, and leptin levels, LPE can be distinguished from SPE and NPE, which provides an objective basis for the treatment of PE.

Strengths and Limitations

There is no effective method to classify PE. The main limitation of this study is the limited sample size.

Conclusion

The serum 5-HT, leptin, and NE levels in PE patients may contribute to the classification of PE.

Introduction

Premature ejaculation (PE) is a prevalent type of male sexual dysfunction, and the prevalence of PE in man is approximately 20-30%.¹ In 2014, the International Society for Sexual Medicine (ISSM) divided PE into lifelong PE (LPE) and acquired PE (APE) based on previous clinical studies.² LPE and APE, as defined by the ISSM, are characterized by the following: patients with short intravaginal ejaculatory latency time (IELT); inability to delay all or almost all ejaculations; and negative consequences caused by PE. Some patients do not meet the diagnostic criteria for LPE or APE during the diagnosis of PE, but they still complain of rapid ejaculation. Therefore, Waldinger et al.³ proposed 2 new subtypes of PE: natural variable PE (NPE) and subjective PE (SPE).

While some epidemiological data suggest the validity of this categorization, differences in epidemiological data also indicate the requirement for a more objective classification.^4,5 Since there are significant differences in treatment for different types of PE, the classification of PE plays a key role in treating PE.⁶ The LPE, SPE, and NPE are more difficult to diagnose than APE, because they do not have the factors that contribute to causing rapid ejaculation. Therefore, finding an objective method for PE classification is very important.

There may be some association between increased sympathetic excitability and the development of PE through the current study.⁷ In addition, disturbed metabolism of several neurotransmitters, including serotonin (5-HT), dopamine, leptin, and norepinephrine (NE), may be associated with ejaculation regulation.^8-10 Therefore, some serum indicators including 5-HT, leptin, and NE are helpful in the diagnosis of LPE.¹¹ However, the clinical value of distinguishing LPE from SPE and NPE is greater than that of distinguishing LPE from normal subjects. To the best of our knowledge, there is no effective method to assist in the diagnosis of SPE and NPE. However, can these serum indicators be used to classify PE? Therefore, we will study serum 5-HT, NE, and leptin levels in LPE, SPE, and NPE patients in this research.

Materials and methods

Research subjects

From July 2023 to July 2024, we recruited patients with PE from the Andrology Clinic of First Affiliated Hospital of Anhui Medical University (Hefei, China). In addition, we recruited 40 normal people who visited this hospital for health examinations as the healthy control (HC) group. This single-center study has been approved by the Clinical Ethics Committee of the First Affiliated Hospital of Anhui Medical University (number: Quick-PJ2024-03-46) and complied with the Declaration of Helsinki. In addition, all participants had signed informed consent before the data collection.

The participants' inclusion criteria are as follows: (1) participants were between the ages of 18 and 60; (2) participants had a stable sexual partner for more than 6 months; (3) participants have not taken medications affecting sexual function, hormone metabolism, or mental health in the last 3 months; (4) participants had good cooperation and were able to complete the relevant questionnaire; (5) participants with genitourinary malformations, history of psychiatric disorders, erectile dysfunction (ED), testosterone deficiency, and prostatitis were excluded.

Data collection

We collected participants' age, smoking and drinking status, body mass index (BMI), marital status, educational level, and premature ejaculation diagnostic tool (PEDT) score.¹² In addition, the participants and their partners were instructed to record the IELT by stopwatch.¹³

After the 12-hour overnight fast, venous blood (5 mL) was drawn from all participants between 8 AM and 11 AM The blood samples were centrifuged at a rate of 3000 r/min for 10 min. The upper serum was extracted and stored at −80°C for further analysis. Serum 5-HT, NE, and leptin levels were measured by the enzyme-linked immunosorbent assay (ELISA) kit. All procedures comply with the manufacturer's instructions.

Statistical analysis

The Shapiro–Wilk test was used to test whether quantitative data conformed to the normal distribution. Normally and non-normally distributed data are expressed as mean ± standard deviation and median (interquartile range), respectively. Categorical variables were expressed as percentages. The one-way analysis of variance or chi-square test was used for statistical analysis and calculation of the P-value. Multiple comparisons of the data were conducted via the Bonferroni method. The diagnostic accuracy of serum indicators was assessed by the receiver operating characteristic (ROC) analysis. The ROC curve cutoffs were estimated using the maximum Youden index. P < .05 was considered statistically significant. All data analysis and graphics were performed using R software (version 4.4.1, Lucent Technologies Inc., Murray Hill, NJ), “ggplot2” (version 3.4.4), and “pROC” (version 1.18.5) packages.

Results

Subject characteristics

PE categorization criteria are primarily based on the patient's chief complaint and IELT. Figure 1 illustrates the criteria for categorizing PE patients.³ We enrolled 150 participants and divided them into 4 groups: LPE (43 cases), NPE (32 cases), SPE (35 cases), and HC (40 cases) groups.

Table 1 shows the demographic and clinical characteristics of participants included in the study. According to the results, no significant differences were observed in age (P = .103), BMI (P = .385), marital status (P = .792), education level (P = .775), smoking (P = .871), drinking (P = .780) among 4 groups. PEDT scores in the LPE group were higher than those in the HC, NPE, and SPE groups, while PEDT scores in the HC group were lower than those in the NPE and SPE groups (all P < .05).

Table 2 shows all participants' serum 5-HT, leptin, and NE levels. Serum 5-HT was lower and serum leptin and NE levels were higher in the LPE group compared to the non-PE, SPE, and NPE groups (P < .05). However, we did not find differences in serum 5-HT, leptin, and NE levels among the SPE, NPE, and HC groups (P > .05).

Diagnostic value of NE, leptin, and 5-HT among different types of PE

Since NPE and SPE may be mainly caused by psychological factors and their serum indices are not significantly different, we combined SPE and NPE into one group: psychogenic PE (PPE).³Table 3 and Figure 2 show the diagnostic value of NE, leptin, and 5-HT in different types of PE. The area under the ROC curve (AUC) of 5-HT, NE, and leptin was 0.91 (95% CI 0.86-0.96), 0.72 (95% CI 0.61-0.82), and 0.94 (95% CI 0.90-0.99), respectively. Based on ROC analysis, serum 5-HT <95.0 ng/mL, NE >543.0 ng/L, and leptin >19.8 ng/mL may be predictive indicators of LPE.

Discussion

Because different types of PE have different treatment regimens and effects on patients, Waldinger classified PE into 4 categories: LPE, APE, SPE, and NPE. SPE and NPE have less impact on patients than APE and LPE, so research on them is extremely limited. In the present study, we found that 5-HT, NE, and leptin levels did not differ significantly among SPE patients, NPE patients, and normal subjects, which may provide a theoretical basis for the current classification of PE. In addition, this study found that LPE patients had lower levels of 5-HT and higher levels of NE and leptin than those of SPE and NPE patients, which may help to identify LPE from SPE and NPE.

5-HT, an important neurotransmitter, is mainly distributed in brain tissue, peripheral blood, and digestive system tissues, and is mainly involved in physiological functions such as feeding, memory, and mental activity.¹⁴ Our study found that serum 5-HT levels were lower in LPE patients (75.3 ± 26.3 ng/mL) than in normal subjects (150.0 ± 33.2 ng/mL). Ejaculation is a complex neurophysiological reflex process, mainly regulated by the brain and the autonomic nervous system. In addition, some studies have found that disorders of 5-HT metabolism in the brain may lead to LPE.^7,15 The selective serotonin reuptake inhibitors (SSRIs) can increase 5-HT levels in the brain and reduce sympathetic excitability.¹⁶ Because the metabolism of 5-HT in the brain is similar to that in blood, the 5-HT level in blood can partially reflect the 5-HT level in the brain. In addition, the results of previous studies are consistent with the findings.¹⁷

NE, a neurotransmitter, is closely related to sympathetic system excitability. Our results showed that serum NE levels were higher in LPE patients than in normal controls. Hyperactivation of the sympathetic system is thought to be closely related to the development of LPE.⁷ NE causes ejaculation by promoting contraction of the vas deferens, prostate, and seminal vesicles.¹⁸ Xia et al.¹¹ found that serum NE levels can reflect the excitability of the sympathetic nervous system that regulates ejaculation in humans. Therefore, NE can be used as one of the diagnostic indicators of LPE.

Leptin, a hormone secreted by adipocytes, regulates feeding behavior and energy metabolism. Our study found that LPE patients had lower serum leptin levels than HC. Leptin accelerates the decomposition of 5-HT, which may reduce 5-HT levels in the brain.¹⁹ In addition, leptin can promote the release of catecholamines leading to increased excitability of the sympathetic system.²⁰ Previous studies have also found some differences in serum leptin and 5-HT between normal subjects and patients with LPE, which is consistent with our findings.²¹ In addition, serum leptin levels decreased from 32.94 ± 7.72 to 7.76 ± 2.22 ng/mL in LPE patients treated with sertraline, an SSRI.²¹

The IELT of SPE patients was in the normal range or longer. The lack of proper understanding of PE and certain psychological factors cause patients to subjectively recognize that their IELT is too short. Since patients with SPE do not have significant sexual dysfunction and their IELT is within the normal range. Thus, SPE may be due primarily to a lack of awareness of PE. In contrast to LPE, SPE may not experience so-called “rapid ejaculation”. NPE men only coincidentally and situationally experience early ejaculations. NPE may be mainly due to the patient's poor ejaculatory control and some psychological factors. Although current studies have hypothesized that SPE and NPE may not have abnormal neural pathways, these hypotheses lack some experimental basis. Since we did not find significant differences in serum 5-HT, leptin, and NE levels among SPE patients, NPE patients, and normal subjects, we hypothesized that SPE and NPE patients may not have abnormal neural pathways. The medications including SSRIs and local anesthetics may be more appropriate for LPE patients with abnormal neural pathways.²² Therefore, appropriate sexual education and guidance are more appropriate for SPE and NPE patients.

However, this study does have some limitations. Firstly, serum 5-HT, NE, and leptin levels do not accurately reflect the levels of these neurotransmitters in the nervous system that regulate ejaculation. In addition, the sample size of this study was small, and the study was single-center. Finally, whether 5-HT, leptin, and NE are helpful in the diagnosis of APE remains unstudied in this study.

Conclusion

Our results suggest that decreased 5-HT levels and increased NE and leptin levels are characteristic of LPE. There were no significant differences in leptin, NE, and 5-HT levels among SPE patients, NPE patients, and HC. This may imply that SPE and NPE patients do not have disturbances in neurotransmitter metabolism. More importantly, serum 5-HT <95.0 ng/mL, NE >543.0 ng/L, and leptin >19.8 ng/mL can distinguish LPE from SPE and NPE, which will promote standardization of PE diagnosis and treatment.

Author contributions

Conceptualization: X.Z.; Data curation: Z.C.; Formal analysis: Z.C.; Funding acquisition: X.Z.; Investigation: Z.C.; Methodology: Z.C.; Project administration: X.Z.; Resources: X.Z.; Software: Z.C.; Supervision: X.Z.; Validation: Z.C.; Writing—original draft: Z.C.; and Writing—review & editing: Z.C, X.Z.

Funding

This work was supported by the National Natural Science Foundation of China (82071637).

Conflicts of interest

The authors declare no conflict of interest.

Data availability

Data for this study are available from the corresponding author upon reasonable request.

References